Pyrrolobenzodiazepine derivatives and their ligand-linker conjugates

Abstract

The present invention provides a novel pyrrolobenzodiazepine derivative compound with significantly reduced side effects such as toxicity, and a conjugate thereof with its ligand. It also provides a pharmaceutical composition for the prevention or treatment of proliferative disorders, containing the compound or its ligand conjugate as an active ingredient. Furthermore, the present invention provides a method for preventing or treating proliferative disorders by administering the compound or its ligand conjugate to an individual. [Solution] Specifically, for example, the following compound is shown. JPEG2026086866000188.jpg35136

Description

[Technical Field]

[0001] The present invention relates to pyrrolobenzodiazepine derivatives and their ligand-linker conjugates, pharmaceutically acceptable salts thereof, or solvates thereof. The present invention also relates to pharmaceutical compositions comprising the same for the prevention or treatment of proliferative disorders. [Background technology]

[0002] DNA refers to a high molecular weight compound with a double helix structure, consisting of two long chains of nucleotides that are intertwined. It is formed by the polymerization of nucleotides, which are divided into the unique nucleic acid bases cytosine (C), guanine (C), adenine (A), and thymine (T). Such DNA can form chromatin, and the condensed structure of chromatin restricts mechanical access to the DNA in cells, thus inhibiting essential processes such as transcription, replication, repair, and recombination.

[0003] Pyrrolobenzodiazepines (PBDs) are naturally occurring substances with antibiotic or antitumor properties, and refer to sequence-selective DNA alkylating compounds. Pyrrolobenzodiazepines exhibit biological activity by selectively binding to the 5'-purine-guanine-purine sequence in the minor groove of DNA, and by forming covalent bonds with the exocyclic amino groups of guanine bases 3 and 4. As a result, they are known to be more potent than systemic chemotherapeutic agents, inhibiting cancer cell division without disrupting the DNA helix, and thereby exerting anticancer effects without the common phenomenon of drug resistance. The first PBD, anthramycin, was discovered in 1965. Since then, many naturally occurring types of PBDs have been reported, and more than 10 synthetic routes to various analogues have been developed (Non-Patent Literature 1).

[0004] Other agents belonging to the discovered pyrrolobenzodiazepine antibiotic group include abbeymycin, chicamycin, DC-81, mazethramycin, neothramycin A, porothramycin, and prothracarcin, and analogues of pyrrolobenzodiazepines are being steadily studied.

[0005] Pyrrolobenzodiazepines are represented by the following general formula: [ka]

[0006] The aforementioned pyrrolobenzodiazepines differ in the number, type, and position of substituents on the aromatic rings A and C, as well as the degree of saturation of the C ring. The B ring contains an imine (N=C), a carbinolamine (NH-CH(OH)), or a carbinolamine methyl ether (NH-CH(OMe)) at the N10-C11 position, which is the electrophilic center responsible for DNA alkylation.

[0007] Recent studies have shown that pyrrolobenzodiazepines can bind to other monomers via the C8 position to form dimers, which can then be used as antibody-drug conjugates (ADCs). Examples include SG3249 (tesirine), which uses SG3199 as its payload, and SGD-1910 (talirine), which uses the endoexosaturated dimer SGD-1882 as its payload. In recent years, clinical trials of ADCT-301, ADCT-402, ADCT-601, and ADCT-602, which contain tesirine, have been conducted.

[0008] In this regard, examples include registered patents relating to pyrrolobenzodiazepine (MedImmune, Patent Document 1), registered patents relating to pyrrolobenzodiazepine and its conjugate (MedImmune, Patent Document 2), registered patents relating to pyrrolobenzodiazepine (Spirogen, Patent Document 3), registered patents relating to pyrrolobenzodiazepine-anti-CD22-antibody conjugate (ADC Therapeutics SA, Patent Document 4), published patents relating to pyrrolobenzodiazepine-antibody conjugate (ADC Therapeutics SA, Patent Document 5), published patents relating to pyrrolobenzodiazepine and its conjugate (Mersana Therapeutics, Patent Document 6), and published patents relating to pyrrolobenzodiazepine prodrugs (ENDOCYTE, Patent Document 7).

[0009] On the other hand, there is a paper (Non-Patent Literature 2) disclosing that using a monomeric pyrrolobenzodiazepine compound as a precursor resulted in less cytotoxicity and stability, and a description (Non-Patent Literature 3) of an antibody-drug conjugate having a form in which a pyrrolobenzodiazepine dimer is bound with a carbamate.

[0010] However, the aforementioned technology has limitations, including the problem of low yield during pyrrolobenzodiazepine synthesis making scaling up difficult, the problem of reduced stability in the blood after administration not being adequately addressed, and the problem that even if the drug has excellent efficacy, it cannot be clinically applied due to its corresponding toxicity.

[0011] DNA minor groove binders are compounds belonging to the lexitropsin family. The first compounds discovered were distamycin A and netropsin. Distamycin A was found to be an antibiotic isolated from a culture of Strptomyces disternallicus in 1962. Other examples include the anthracycline anticancer drugs actinomycin A and daunorubicin. These anticancer drugs inhibit DNA and RNA synthesis by intervening in GC base pair sites or by binding to DNA minor grooves and forming hydrogen bonds with base pairs. Although these agents are being studied for their anti-cancer effects, they share a common side effect: they are highly cardiotoxic and can cause life-threatening cardiac damage. Therefore, there is a need to develop drugs that are more selective and effective, while having very few side effects.

[0012] Therefore, the inventors of the present invention prepared novel compounds by attaching various substituents to the conventional pyrrolobenzodiazepine core structure, and confirmed that the synthesized compounds exhibited equivalent efficacy to conventionally known pyrrolobenzodiazepines while significantly reducing side effects such as toxicity, thus completing the present invention. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] Korean Registered Patent Publication No. 10-1960130 [Patent Document 2] Korean Registered Patent Publication No. 10-1891859 [Patent Document 3] Korean Registered Patent Publication No. 10-1059183 [Patent Document 4] Korean Registered Patent Publication No. 10-1995620

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

Non-Patent Document

[0014]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

[0015] The present invention aims to provide novel pyrrolobenzodiazepine derivative compounds and their ligand conjugates that exhibit comparable efficacy to conventional pyrrolobenzodiazepine compounds while significantly reducing side effects such as toxicity.

[0016] The present invention also aims to provide a pharmaceutical composition for preventing or treating a proliferative disease, which contains a conjugate of the compound or its ligand as an active ingredient.

[0017] Furthermore, the present invention aims to provide a method for preventing or treating a proliferative disease by administering to an individual a conjugate of the compound or its ligand.

Means for Solving the Problems

[0018] The present invention relates to a pyrrolobenzodiazepine derivative, a pharmaceutically acceptable salt or solvate thereof.

[0019] In the present invention, the pyrrolobenzodiazepine derivative is represented by the following chemical formula I, and a pharmaceutically acceptable salt or solvate thereof is provided.

[0020]

Chemical Formula

Chemical Formula

[0021] In one embodiment of the present invention, the linker may further include bond units formed by a 1,3-dipolar cycloaddition reaction, a hetero-Diels-Alder reaction, a nucleophilic substitution reaction, a non-aldol carbonyl reaction, an addition to a carbon-carbon multiple bond, an oxidation reaction, or a click reaction.

[0022] In one embodiment of the present invention, the binding unit is formed by a reaction between acetylene and an azide, or between an aldehyde or ketone group and a hydrazine or alkoxyamine.

[0023] In one embodiment of the present invention, the linker is [ka] It may further include at least one isoprenyl unit having the structure, where i is at least 2.

[0024] In one aspect of the present invention, at least one isoprenyl unit is a substrate of an isoprenoid transferase or a product of an isoprenoid transferase.

[0025] In one embodiment of the present invention, the isoprenyl unit of the linker is covalently bonded to the antibody by a thioether bond, the thioether bond contains a sulfur atom of the cysteine ​​of the antibody.

[0026] In one aspect of the present invention, the antibody comprises an amino acid motif recognized by an isoprenoid transferase, and the thioether bond comprises the sulfur atom of the cysteine ​​of the amino acid motif.

[0027] In one embodiment of the present invention, the dotted line may indicate the presence of a double bond between C2 and C3.

[0028] In one embodiment of the present invention, Q1 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 The group consisting of heteroaryls may be selected.

[0029] In one embodiment of the present invention, Q2, Q3, Q5, and Q7 may each be independently -H or -OH.

[0030] In one embodiment of the present invention, Q4 may be methoxy, ethoxy, or butoxy.

[0031] In one embodiment of the present invention, X is the linker I [ka] It may be joined to a part.

[0032] In one embodiment of the present invention, Y may be -O-.

[0033] In one embodiment of the present invention, Q6 is a substituted or unsubstituted saturated or unsaturated C 3-8 A hydrocarbon chain is also acceptable.

[0034] In one embodiment of the present invention, G is [ka] And, R c is a hydrogen or carboxyl protecting group, and each of the R d This may independently be a hydrogen or a hydroxyl protecting group.

[0035] In one specific embodiment of the present invention, the Rc is hydrogen, and each of the R d It may be hydrogen.

[0036] In one embodiment of the present invention, T is independently C 1-8 It may be alkyl, halogen, cyano, or nitro.

[0037] In one embodiment of the present invention, s may be 0.

[0038] In one embodiment of the present invention, W may be -C(=O)-, -C(=O)NR'-, or -C(=O)O-.

[0039] In one embodiment of the present invention, W may be -C(=O)NR'-, where C(=O) is bonded to a phenyl ring and NR' is bonded to L.

[0040] In one specific embodiment of the present invention, G is, [ka] W is -C(O)NR'-, where C(O) is bonded to a phenyl ring, NR' is bonded to L, and R c and R d It may be hydrogen.

[0041] In one embodiment of the present invention, the branching unit is C 2-8 Alkenyl, hydrophilic amino acid, -C(O)-, -C(O)NR v -, -C(O)O-, -(CH2) n1 -NHC(O)-(CH2) n2 -,-(CH2) n3 -C(O)NH-(CH2) n4 -,-(CH2) n1 -NHC(O)-(CH2) n2 -C(O)- and -(CH2) n3 -C(O)NH-(CH2) n4 Selected from the group consisting of -C(O)-, Here, the branching unit is C 2-8 If it is an alkenyl, the carbon atoms of the alkenyl may be substituted with at least one heteroatom selected from the group consisting of N, O, and S, and the alkenyl has at least one C 1-20 It may be further substituted with alkyl, Here, R v 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 5-20 It is Ariel, n1, n2, n3, and n4 may each be an independent integer between 0 and 5.

[0042] In one embodiment of the present invention, the connecting unit is -(CH2) t (V(CH2) u ) v -where t is an integer between 0 and 8, u is an integer between 0 and 12, v is an integer between 1 and 10, and V may be a single conjunction or -O-.

[0043] In one embodiment of the present invention, the connecting unit is -(CH2) t (V(CH2) u ) v -where t is an integer of 2, u is an integer of 2, v is an integer of 2, and V may be -O-.

[0044] In one embodiment of the present invention, the connecting unit is [ka] This includes, where L1 is a single bond or C 2-8 It is an alkenyl, R 11 is H or C 1-6 It is alkyl, and L2 is C 2-8 Alkenil may also be used.

[0045] In one embodiment of the present invention, the R z These are -O-NH2, -NH2, N3, -OCH3, -OCH2CH3, -O(CH2)2CH3, or [ka] That's fine.

[0046] In one embodiment of the present invention, at least one of B or B' may be -C(=O)-.

[0047] In one embodiment of the present invention, A1 and A2 may each be independently -C(=O)- or -NH-.

[0048] In one embodiment of the present invention, at least one of Z1, Z2, Z3, Z1', Z2', and Z3' may be N.

[0049] In one embodiment of the present invention, A-1 and A-2 are, [ka] Selected from, where the dotted line represents a double bond or a single bond, Z a is Z1 or Z1', Z b is Z2 or Z2', and Z c It is Z3 or Z3', Z1, Z2, Z3, Z1', Z2', and Z3' are the same as defined above. R1 or R1' is Z a It may be connected to it.

[0050] In one specific embodiment of the present invention, A-1 and A-2 are each independently, [ka] Here, the dotted line represents a double bond or a single bond, Z a is Z1 or Z1', Z bis Z2 or Z2', and Z c It is Z3 or Z3', Z1, Z2, Z3, Z 1' , Z 2' and Z 3' At least one of them is N or S, R1 or R1' is Z a It may be connected to it.

[0051] In one embodiment of the present invention, a1 and a2 may be integers of 1.

[0052] In one embodiment of the present invention, E1 is a bond, -NH-, or -C(=O)-, and e1 may be an integer from 1 to 5.

[0053] In one embodiment of the present invention, E2 is connected to C 1-5 Alkylene or -((CH2) p (CH2E 11 )) q -and, E2 is -((CH2) p (CH2E 11 )) q - In the case of E 11 The expression is O, and p is an integer from 1 to 3. q is an integer between 1 and 15, and e2 may be an integer between 1 and 5.

[0054] In one embodiment of the present invention, R1 and R1' are, independently, hydrogen and C 1-5 Alkyl, (CH2) m OH or (CH2) m It is NH2, and m can be an integer from 1 to 7.

[0055] In one embodiment of the present invention, F1 is -OH, -OCH3, -SH, -SCH3, [ka] And, F 11 and F 12These are, independently, C or N, F 21 F 22 and F 22' These are H and -(CH2) respectively, independently. r CH3, -(CH2) r OH, -(CH2) r NH2, -F 33 (CH2) r CH3, -F 33 (CH2) r OH, -F 33 (CH2) r Selected from NH2 or Linker II, F 33 It is selected from -C(=O)-, -NH-, or -C(=NH)-, F 21 ' is =CH2, =NH, =F 33 (CH2) r CH3, =F 33 (CH2) r OH, =F 33 (CH2) r Selected from NH2 or Linker II, F 33 ' is selected from =N-, =CH-, =C(OH)-, or =C(NH2)-, F 21 F 22 and F 22 At least one of them may be -CH3.

[0056] In one embodiment of the present invention, the present invention may further include the following general formula V.

[0057] [ka] ...(V) In the above formula, [ka] Each portion is independently bonded to a first linker or hydrogen, where the first linker is linker I or linker II. SL stands for the second linker, and the second linker is represented by the following equation VI: [ka] In the above formula, L' and R zz ' represents L and R of the aforementioned chemical formula IV, respectively. z It is the same as this.

[0058] In a specific embodiment of the present invention, the first linker includes at least one branching unit, wherein the branching unit is -C(O)-, -C(O)NR v -, -C(O)O-, -(CH2) n1 -NHC(O)-(CH2) n2 -,-(CH2) n3 -C(O)NH-(CH2) n4 -,-(CH2) n1 -NHC(O)-(CH2) n2 -C(O)-, -(CH2) n3 -C(O)NH-(CH2) n4 -C(O)-, -S(O)2NR v -,-P(O)R w NR v -, -S(O)NR v - and -PO2NR v - Selected from the group consisting of, The aforementioned R v and R w These are H and C, respectively, independently. 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 5-20 It is Ariel, n1, n2, n3, and n4 may each be an independent integer between 0 and 5.

[0059] In one embodiment of the present invention, L' includes at least one branching unit and a connecting unit, Here, the branching unit is C 2-8Selected from the group consisting of alkenyls, hydrophilic amino acids, -C(O)-, and -C(O)O-, The connecting unit is -(CH2) t (V(CH2) u ) v -and, Here, t is an integer between 0 and 5, u is an integer between 2, v is an integer between 1 and 10, and V is -O-. R zz ' may be -O-NH2, -NH2, N3, -OCH3, or -OCH2CH3.

[0060] In one specific embodiment of the present invention, the pyrrolobenzodiazepine derivative represented by the chemical formula I is [ka] JPEG2026086866000025.jpg121167JPEG2026086866000026.jpg120168 You may select from the group consisting of JPEG2026086866000027.jpg122170, JPEG2026086866000028.jpg120168, JPEG2026086866000029.jpg126169, and JPEG2026086866000030.jpg111168.

[0061] Furthermore, in one embodiment of the present invention, the pyrrolobenzodiazepine derivative represented by the chemical formula I is [ka] The image may be selected from the group consisting of JPEG2026086866000032.jpg82168.

[0062] Furthermore, in one embodiment of the present invention, a pyrrolobenzodiazepine derivative further comprising a linker containing the Tris structure is [ka] That's fine.

[0063] Furthermore, in the present invention, the pyrrolobenzodiazepine derivative is represented by the following chemical formula VII, and pharmaceutically acceptable salts or solvates thereof are provided.

[0064] [ka] In the above formula, P' is the same as P mentioned above, B' is B a '-B b '-B c 'and, Here, B a ' is -O-, -NH-, -S-, -C(=O)-, -S(=O)-, -(CH2) n (C=O)-, -(CH2) n '-, C 6-10 Arylene, 5-20 membered heteroarylene containing heteroatoms independently selected from N, O, and S, -((CH2) n 'B1) m 'B2-, where B1 and B2 are CH2, NH, O, or S respectively. B b ' is a combination, C 5-20 Alliren, C 5-20 A cycloalkylene is a 5-20 member heterocycloalkylene, 5-20 member heterocycloalkenylene, or 5-20 member heteroarylene in which at least one ring atom is a heteroatom independently selected from N, O, and S. B c ' represents bonds, -O-, -NH-, -S-, -C(=O)-, -S(=O)-, -CH2(C=O)-, -(CH2) n - or - (CH2CH2O) n '- and, Here, n' and m' are independent integers between 1 and 10. D' is the same as D mentioned above.

[0065] In one embodiment of the present invention, the B a ' is a bond, -(CH2)n' -or-(CH2) n' B2 is equal to O, and n' can be an integer from 1 to 10.

[0066] In one embodiment of the present invention, the B b ' is a combination [ka] And, Here, the dotted line represents a double bond or a single bond. B1', B2', and B3' may each be independently C, N, or S.

[0067] In one embodiment of the present invention, the B c ' represents a bond, -C(=O)-, -NH-, or -(CH2CH2O) n - where n may be an integer from 1 to 10. In one embodiment of the present invention, D' is the same as D, and a1+a2 may be an integer from 1 to 10, excluding 2.

[0068] In one specific embodiment of the present invention, the pyrrolobenzodiazepine derivative represented by chemical formula VII is, [ka] JPEG2026086866000037.jpg133169JPEG2026086866000038.jpg121168JPEG2026086866000039.jpg11 9169JPEG2026086866000040.jpg122169JPEG2026086866000041.jpg119170JPEG2026086866000042.j You may select from the group consisting of pg109168JPEG2026086866000043.jpg, 115170JPEG2026086866000044.jpg, 126170JPEG2026086866000045.jpg, 122168JPEG2026086866000046.jpg, 116169JPEG2026086866000047.jpg, 63165.

[0069] Furthermore, the present invention provides pyrrolobenzodiazepine derivative-ligand conjugates, pharmaceutically acceptable salts or solvates thereof, comprising the aforementioned pyrrolobenzodiazepine derivative.

[0070] In one embodiment of the present invention, the ligand may be an antibody.

[0071] In a specific embodiment of the present invention, the antibody may have at least one amino acid motif that is recognized by lanceferase.

[0072] Furthermore, in a specific embodiment of the present invention, the isoprenoid transferase may be FTase (farnesyl protein transferase) or GGTase (geranylgeranyl transferase).

[0073] Furthermore, in a specific embodiment of the present invention, the amino acid motif is CYYX, XXCC, XCXC, or CXX, where C may be cysteine, Y may be an aliphatic amino acid, and X may be an amino acid that determines the substrate specificity of the isoprenoid transferase.

[0074] Specifically, in each case, X independently represents glutamine, glutamic acid, serine, cysteine, methionine, alanine, or leucine, and the thioether bond contains the sulfur atom of the cysteine ​​amino acid motif.

[0075] In one specific embodiment of the present invention, the amino acid motif may be CYYX, where Y is independently alanine, isoleucine, leucine, methionine, or valine.

[0076] In one embodiment of the present invention, the protein is an antibody, and the antibody may contain the amino acid sequence GGGGGGGCVIM.

[0077] In one embodiment of the present invention, the protein having the amino acid motif is A-HC-(G) z CVIM, A-HC-(G) z CVLL, A-LC-(G) z CVIM and A-LC-(G) z Selected from the group consisting of CVLL, where A represents an antibody, HC represents a heavy chain, LC represents a light chain, G represents a glycine unit, and z may be an integer from 0 to 20.

[0078] Isoprenoid transferases may recognize substrates other than isosubstrates. An isosubstrate refers to a substrate analog that has a modified form of the substrate. Isoprenoid transferases alkylate a specific amino acid motif (e.g., the CAAX motif) at the C-terminus of a protein (see Non-Patent Documents 4-7). Functionalized proteins may be produced using isoprenoid transferases and isosubstrates by alkylation at the C-terminal cysteine(s).

[0079] For example, the cysteine ​​residue of the C-terminal CAAX motif may be reacted with an isosubstrate using an isoprenoid transferase. In certain cases, AAX may then be removed by a protease. The resulting cysteine ​​may then be enzymatically methylated at the C-terminus (see Non-Patent Literature 8).

[0080] The proteins of the present invention may be prepared by any molecular or cellular biological technique known in the art. For example, transient transfection methods are used. A genetic sequence encoding a specific amino acid motif recognized by isoprenoid transferase can be inserted using a known plasmid vector with standard PCR techniques so that a protein (fragment or analog thereof) having the specific amino acid motif at its C-terminus is expressed. In this way, a protein having at least one amino acid motif recognized by isoprenoid transferase is expressed.

[0081] In one embodiment 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 thereof may contain amino acid sites having an amino acid motif recognized by an isoprenoid transferase, and a person skilled in the art can immediately select a protein that selectively binds to a desired target (e.g., target cells of a subject).

[0082] In one embodiment of the present invention, the present invention may include a fragment of an antibody or antigen that specifically binds to a desired target.

[0083] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of proliferative disorders, comprising the pyrrolobenzodiazepine derivative-ligand complex, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0084] In one embodiment of the present invention, the proliferative disorder may be selected from the group consisting of neoplasms, tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders, and atherosclerosis.

[0085] In one specific aspect of the present invention, the cancer may be selected from the group consisting of lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and malignant melanoma.

[0086] Furthermore, the present invention may further include the pyrrolobenzodiazepine derivative-ligand conjugate, a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0087] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of proliferative disorders, comprising the pyrrolobenzodiazepine derivative-ligand conjugate, a pharmaceutically acceptable salt or solvate thereof, at least one therapeutic co-agent, and a pharmaceutically acceptable excipient.

[0088] Furthermore, the present invention provides a method for preventing or treating a proliferative disorder, comprising the step of administering the pyrrolobenzodiazepine derivative-ligand complex, a pharmaceutically acceptable salt or solvate thereof, to an individual. Herein, the method for preventing or treating a proliferative disorder may further comprise a pharmaceutically acceptable excipient and / or at least one therapeutic combination agent.

[0089] Furthermore, the present invention provides uses for the pyrrolobenzodiazepine derivative-ligand conjugate, its pharmaceutically acceptable salt, or solvate for use as a pharmaceutical composition for the prevention or treatment of proliferative disorders. Herein, the composition may further comprise a pharmaceutically acceptable excipient and / or at least one therapeutic adjuvant. [Effects of the Invention]

[0090] This invention relates to pyrrolobenzodiazepine derivative compounds, conjugates thereof with ligands, and their uses, which are more stable in plasma, stable in circulation, and exhibit excellent efficacy.

[0091] Furthermore, the ligand conjugate incorporates linker technology that maximizes drug efficacy by facilitating drug release within cancer cells. This allows the conjugate to reach target cells more stably and effectively exert its effects while significantly reducing toxicity. This offers significant clinical advantages in that it enables targeted treatment of proliferative diseases such as cancer, specific treatment, maximization of drug efficacy, and minimization of side effects. [Brief explanation of the drawing]

[0092] [Figure 1] This figure shows an example of the preparation of pyrrolobenzodiazepine derivatives. [Figure 2] This figure shows an example of the synthesis of an antibody-drug conjugate (ADC) using pyrrolobenzodiazepine derivatives. [Modes for carrying out the invention]

[0093] In the present invention, a pyrrolobenzodiazepine derivative is represented by the following chemical formula I, and a pharmaceutically acceptable salt or solvate thereof is provided. Furthermore, a pyrrolobenzodiazepine derivative-ligand conjugate containing the pyrrolobenzodiazepine derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof is also provided.

[0094] [Modes for carrying out the invention] The embodiments of the present invention will be described in detail below, with reference to them, so that those with ordinary skill in the art to which the present invention pertains can easily implement it. The embodiments of the present invention are provided to further fully explain the present invention to those with ordinary skill in the art, and the embodiments of the present invention may be modified in various other ways, and the scope of the present invention is not limited to the embodiments described below.

[0095] Unless otherwise defined in this invention, the scientific and technical terms used herein have the meanings generally understood by those skilled in the art. Furthermore, unless specifically required by the context, singular forms include plural forms, and plural forms include singular forms.

[0096] In the entirety of the specification of the present invention, when a part of the specification "includes" a certain component, unless otherwise specified, this does not mean that other components are excluded, but rather that other components may be included.

[0097] [Definition] In this specification, the following definitions apply:

[0098] In the present invention, “conjugates” means a cell-binding agent covalently bound to at least one molecule of a cytotoxic compound. Here, “cell-binding agent” is a molecule having affinity for a biological target, such as a ligand, protein, antibody, specifically a monoclonal antibody, protein or antibody fragment, peptide, oligonucleotide, or oligosaccharide, and the binding agent has the function of directing the biologically active compound to the biological target. In one aspect of the present invention, the conjugate may be designed to target tumor cells with a cell surface antigen. The antigen may be an overexpressed cell surface antigen in abnormal cell types, or it may be an expressed cell surface antigen. Specifically, the target antigen may be expressed only on proliferating cells (e.g., tumor cells). The target antigen is usually selected based on the different expression in proliferating and normal tissues. In the present invention, the ligand is bound to a linker.

[0099] In the present invention, "antibody" is an immunoglobulin molecule that specifically binds to a target, such as carbohydrates, polynucleotides, lipids, polypeptides, etc., via at least one antigen recognition site located in the variable region of the immunoglobulin molecule.

[0100] In the present invention, "antibody" includes, but is not limited to, intact polyclonal or monoclonal antibodies, as well as any antigen-binding portion (e.g., "antigen-binding fragment") or a single chain of an intact antibody having the ability to specifically bind to a given antigen, a fusion protein containing the antibody, and any other modified sequence of an immunoglobulin molecule including an antigen-recognition site, such as Fab, Fab', F(ab')2 Fd fragment, Fv fragment, single-domain antibody (dAb) fragment, isolated complementarity-determining region (CDR), single-chain (scFv) and single-domain antibodies (e.g., shark and camel antibodies), maxi-bodies, mini-bodies, intra-bodies, dia-bodies, tria-bodies, tetra-bodies, v-NAR and bis-scFv (see, for example, Non-Patent Document 9). Antibodies include antibodies of any classification, such as IgG, IgA or IgM (or their subcategories), and the antibody does not need to be of any particular classification. Immunoglobulins are assigned to different classifications based on the amino acid sequence of the invariant region of the antibody's heavy chain. There are five main classifications of immunoglobulins (IgA, IgD, IgE, IgG, and IgM), some of which are further classified into subcategories (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain (HC) invariant domains corresponding to different classifications of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional coordination of different classifications of immunoglobulins are well known. The antibodies of the present invention can be produced by techniques known in the relevant art, such as genetic engineering, phage display, synthesis, a combination of the above techniques, or other techniques known in the relevant art.

[0101] In this invention, "isolated antibody" means an antibody that substantially does not contain other antibodies having different antigen specificities and substantially does not contain other cellular material and / or chemical substances.

[0102] In this invention, "biological target" means an antigen located on the surface of a tumor, cancer cell, or extracellular matrix.

[0103] In the present invention, "substituted or unsubstituted" means a parent group that is substituted or unsubstituted, and "substituted" means a parent group having at least one substituent, and a substituent means a chemical part that is covalently bonded to or fused to the parent group.

[0104] In this invention, "halo" refers to fluorine, chlorine, bromine, iodine, and the like.

[0105] In this invention, "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, fully 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.

[0106] In this invention, "alkoxy" means -OR (where R is an alkyl group), and examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like.

[0107] In this invention, "aryl" refers to the monovalent portion obtained by removing a hydrogen atom from the aromatic ring atom of an aromatic compound having a ring atom.

[0108] In the present invention, "alkenyl" means an alkyl group having at least one carbon-carbon double bond. Examples of unsaturated alkenyl groups include ethenyl (vinyl, -CH=CH2), 1-profene (-CH=CHCH3), 2-profene, isoprofene, butenyl, pentenyl, and hexenyl.

[0109] In this invention, "alkynyl" means an alkyl group having at least one carbon-carbon triple bond, and examples of unsaturated alkynyl groups include ethynyl and 2-propynyl.

[0110] In this invention, "carboxy" means -C(=O)OH.

[0111] In this invention, "formyl" means -C(=O)H.

[0112] In this invention, "aryl" refers to the monovalent portion obtained by removing a hydrogen atom from the aromatic ring atom of an aromatic compound. For example, "C 5-7 "Aryl" refers to a compound that has 5 to 7 ring atoms, and means the monovalent part obtained by removing a hydrogen atom from the aromatic ring atom of an aromatic compound. 5-10 The term "aryl" refers to a monovalent part of an aromatic compound that has 5 to 10 ring atoms, obtained by removing a hydrogen atom from the aromatic ring atom. Here, the prefix (C 5-7 , C 5-10 (etc.) indicates the number of ring atoms, or the range of ring atoms, whether they are carbon atoms or heteroatoms. For example, "C 5-6"Aryl" refers to an aryl group having five or six ring atoms. Here, the ring atoms may all be carbon atoms, as in the "carboaryl group." Examples of carboaryl groups include, but are not limited to, those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene, and pyrene. Examples of aryl groups containing a fusion ring in which at least one is an aromatic ring include, but are not limited to, those derived from indan, indene, isoindene, tetralin, acenaphthene, fluorene, phenalene, acephenanthrene, and aceanthrene. Alternatively, the ring atoms may include one or more heteroatoms, as in the "heteroaryl group."

[0113] In this invention, "heteroaryl" means an aryl containing at least one heteroatom, and examples include pyridine, pyrimidine, benzothiophene, furyl, dioxalanyl, pyrrolyl, oxazolyl, pyridyl, pyridadinyl, pyrimidinyl, and more specifically, C9 having two fusion rings derived from benzofuran, isobenzofuran, indole, isoindole, indidine, indoline, isoindoline, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzoisoxazole, benzodioxol, benzofuran, benzotriazole, benzothiofuran, benzothiazole, benzothiadiazole, chromene, isochromene, chroman, isochroman, benzodioxane, quinoline, isoquinoline, quinoridine, benzoxazine, benzodiazine, pyridopyrimidine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine. 10 , C having two fusion rings derived from benzodiazepines 11 C, which has three fusion rings derived from carbazole, dibenzofuran, dibenzothiophene, carboline, perimidine, and pyridoindole. 13C, which has three fusion rings derived from acridine, xanthene, thioxanthene, oxanthrene, phenoxathiin, phenazine, phenoxazine, phenothiazine, thianthrene, phenanthridine, and phenanthroline. 14 These are some examples.

[0114] In this invention, "cycloalkyl" refers to an alkyl group that is a cyclyl group, and means the monovalent portion obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound. Examples of cycloalkyl groups include, but are not limited to, those derived from saturated monocyclic hydrocarbon compounds (cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane), unsaturated monocyclic hydrocarbon compounds (cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene, methylcyclohexene), and saturated heterocyclic hydrocarbon compounds (norcalane, norpinane, norbornane).

[0115] In this invention, "heterocyclyl" refers to the monovalent portion obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound. Heterocyclic compounds are not limited to single bonds in their cyclic structure, but include double or triple bonds. They also include compounds having at least two fused rings.

[0116] In this specification, prefixes (e.g., C 1-12 , C 3-8 "C" (etc.) indicates the number of ring atoms or the range of ring atoms, whether they are carbon atoms or heteroatoms. For example, "C" in the present invention 3-6 A "heterocyclyl" refers to a heterocyclyl group that has 3 to 6 ring atoms.

[0117] Examples of monocyclic heterocyclyl groups include N1 (aziridine, azetidine, pyrrolidine, pyrroline, 2H- or 3H-pyrrole, piperidine, dihydropyridine, tetrahydropyridine, azepine), N2 (imidazolidine, pyrazolidine, imidazoline, pyrazoline, piperazine), O1 (oxiran, oxetane, oxolane, oxol, oxane, dihydropyran, pyrane, oxepin), O2 (dioxolane, dioxane, dioxepane), O3 (trioxane), and N1O1 (tetrahydropyridine). Examples include, but are not limited to, those derived from dioxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, oxazine), S1 (thiran, thiethane, thiolan, thian, thiepan), N1S1 (thiazoline, thiazolidinedione, thiomorpholine), N2O1 (oxadiazine), O1S1 (oxathiol, oxatian), and N1O1S1 (oxathian).

[0118] In this invention, the "pharmaceutically acceptable salt" is an acid addition salt formed from a pharmaceutically acceptable free acid, and the free acid can be an organic acid or an inorganic acid.

[0119] The aforementioned organic acids include, but are not limited to, 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. The aforementioned inorganic acids also include, but are not limited to, hydrochloric acid, bromate, sulfuric acid, and phosphoric acid. For example, if a compound is an anion, or has a functional group that becomes an anion (e.g., -COOH becomes -COO-), a salt can be formed with a suitable cation. An example of a suitable inorganic cation is Na. + , K + Alkali metal cations such as Ca 2+ Mg 2+Alkaline earth metal cations such as Al 3+ Other cations include, but are not limited to, those listed above. A suitable example of an organic cation is the ammonium ion (i.e., NH4). + ) and substituted ammonium ions (e.g., NH3R + NH2R2 + NHR3 + NR4 + These are some examples, but are not limited to them.

[0120] Some suitable examples of substituted ammonium ions include ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from amino acids such as lysine and arginine. A typical example of a quaternary ammonium ion is N(CH3) 4+ These are some examples.

[0121] If the compound is a cation, or has a functional group that becomes a cation (for example, -NH2 is -NH3) + (This can be achieved by forming a salt with a suitable anion.) Examples of suitable inorganic anions include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrite, phosphoric acid, and phosphorous acid.

[0122] Suitable organic anions include, but are not limited to, those derived from organic acids such as 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 polymer organic anions include, but are not limited to, those derived from polymer acids such as tannic acid and carboxymethylcellulose.

[0123] In the present invention, "solvate" refers to a molecular complex of the compound according to the present invention and solvent molecules. Examples of solvates include, but are not limited to, the compound according to the present invention bonded to water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or a mixture thereof.

[0124] It may be convenient, and even preferable, to prepare, purify, and / or handle solvates corresponding to the active compound. In this invention, "solvate" is used in the usual sense, meaning 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 is simply called a hydrate, such as a monohydrate, dihydrate, or trihydrate.

[0125] The pharmaceutical composition of the present invention may contain pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include macromolecules that are normally metabolized gradually, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, amino acid polymers, amino acid copolymers, and lipid aggregates. These pharmaceutically acceptable excipients can be appropriately selected and used by those skilled in the art.

[0126] The compositions containing pharmaceutically acceptable excipients are available in various oral or parenteral dosage forms. When formulated, they are typically prepared using fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and other diluents or excipients.

[0127] Oral solid dosage forms include tablets, pills, powders, granules, and capsules. These solid dosage forms are prepared by mixing at least one compound with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, or gelatin. In addition to the usual excipients, lubricants such as magnesium stearate and talc are also used.

[0128] Oral liquid formulations include suspensions, oral solutions, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives are also used.

[0129] Parenteral administration formulations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized agents, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, tween 61, cocoa butter, lauric acid butter, and glycerol gelatin.

[0130] The pharmaceutical composition may be in any dosage form selected from the group consisting of injections, tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, lyophilized agents, and suppositories.

[0131] For intravenous, cutaneous, or subcutaneous injection, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free, has an appropriate pH, isotonicity, and stability. Those skilled in the art can prepare a suitable solution using an isotonic vehicle such as sodium chloride aqueous solution, Ringer's solution, or lactated Ringer's solution, and may include preservatives, stabilizers, buffers, antioxidants, or other additives as needed. The solid form suitable for injection may be in the form of an emulsion or a polypeptide encapsulated in liposomes.

[0132] In this invention, "effective dose" or "therapeutic effective dose" means the amount (dosage, duration of administration, and means) required to achieve the desired therapeutic outcome. The effective dose is the minimum amount of the active agent necessary to provide a therapeutic benefit to the target body, and is below the toxic dose. For example, the dose is in the range of about 100 ng to about 100 mg / kg for a patient, and is typically in the range of about 1 μg / kg to about 10 mg / kg. When the active compound is a salt, ester, amide, or precursor drug (prodrug), the dose is calculated in terms of the parent compound, so the actual weight used increases proportionally. The pyrrolobenzodiazepine derivative compounds according to this invention are 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 dosage form, but are not limited to these. The active ingredient may be administered in such a way that peak plasma concentrations of the active compound are obtained at approximately 0.05 μM to 100 μM, 1 μM to 50 μM, or 5 μM to 30 μM. For example, it may be administered by intravenous injection of a solution containing 0.1 w / v% to 5 w / v% of the active ingredient in saline solution.

[0133] The concentration of the active compound in a pharmaceutical composition is determined by the drug's absorption, inactivation, and excretion rates, as well as other factors known to those skilled in the art. The dosage may vary depending on the severity of the symptoms / disease. Furthermore, the dosage and therapy for a particular patient are adjusted based on the professional judgment of the caregiver, taking into account the patient's symptoms / disease severity, needs, age, and responsiveness to the drug. The range of concentrations presented in this invention is merely an example, and the embodiments of the claimed composition are not limited to these. Moreover, the active ingredient may be administered in a single dose, or in smaller doses divided into several doses.

[0134] In this invention, "proliferative disorder" means unintentional, undesirable, excessive, or abnormal uncontrolled cell proliferation, such as neonatal or hyperplastic growth, in vitro or in vivo. Examples of proliferative disorders include neoplasms, tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders, and atherosclerosis, and include, but are not limited to, benign, premalignant, or malignant cell proliferation. The cancers mentioned include, but are not limited to, lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, or malignant melanoma.

[0135] In this invention, "therapeutic agent" refers to an agent 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.

[0136] The pyrrolobenzodiazepine derivatives and their precursors, and pyrrolobenzodiazepine derivative-ligand conjugates according to the present invention are synthesized by the following process.

[0137] However, the following examples and experimental examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples and experimental examples. [Examples]

[0138] Preparation of compound 7 JPEG2026086866000048.jpg73161

[0139] Preparation of Compound 1 4-bromobutyric acid (10.0 g, 59.9 mmol) and allyl alcohol (40.7 mL, 598.7 mmol) were dissolved in toluene (240 mL), then p-toluenesulfonic acid (1.1 g, 6.0 mmol) was added, and the mixture was stirred under a nitrogen atmosphere with heating and reflux for 17 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with 0.1 N sodium hydroxide aqueous solution (200 mL). The washed organic layer was washed with saline solution (200 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 1 (11.5 g, 92%). 1 H-NMR (400MHz, CDCl3) δ 5.93(m,1H),5.30(d,1H),5.26(d,1H),4.59(d,2H),3.47(t,2H),2.54(t,2H),2.19(q,2H).

[0140] Preparation of Compound 3 Compound 2 (36 g, 62.1 mmol, prepared by the method described in Patent Document 8) was dissolved in N,N-dimethylformamide / distilled water (300 mL / 6 mL), then sodium acetate (6.1 g, 74.6 mmol) was added, and the reaction solution was stirred at room temperature under a nitrogen atmosphere. After 3 hours, distilled water (500 mL) was added, and the mixture was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were sequentially washed with distilled water (200 mL) and saline solution (200 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated and purified by column chromatography to obtain compound 3 (26 g, 99%). 1H-NMR(400MHz,CDCl3)δ 7.77-7.76(m,1H),6.81-6.76(m,1H),6.05-6.01(m,1H),5.10-4.83(m,2H),4.58-4.54(m,1H), 3.99(s,3H),3.89-3.56(m,3H),3.34-3.26(m,1H),2.81-2.67(m,2H),0.89(s,9H),0.09(s,6H).

[0141] Preparation of Compound 4 Compound 3 (9.1 g, 21.7 mmol) and Compound 1 (6.8 g, 32.6 mmol) were dissolved in N,N-dimethylformamide (50 mL), then potassium carbonate (6.0 g, 43.5 mmol) and sodium iodide (1.6 g, 10.8 mmol) were added, and the mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate (300 mL) and then washed with distilled water (2 × 100 mL). The washed organic layer was washed with saline solution (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 4 (11.0 g, 92%). 1 H-NMR(400MHz,CDCl3)δ 7.69(s,1H),6.73(s,1H),5.93(m,1H),5.30(d,1H),5.26(d,1H),4.98(s,1H),4.83(s,1H),4.59(d,2H),4.58(brs,1H),4.13(t,2 H),3.89(s,4H),3.75(brs,1H),3.71(s,1H),3.31-3.27(m,1H),2.73(m,2H),2.57(t,2H),2.20(q,2H),0.91(s,9H),0.09(s,6H).

[0142] Preparation of compound 5 Compound 4 (11.0 g, 20.0 mmol) was dissolved in ethyl acetate (80 mL) and ethanol (120 mL). Zinc dust (26.1 g, 400.2 mmol) was then added at 0°C, followed by the addition of formic acid (15.1 mL, 400.2 mmol). The mixture was stirred at room temperature for 2.5 hours, then diluted with ethyl acetate (30 mL), filtered through Celite, and ethyl acetate (70 mL) was added. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution (2 × 100 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated and purified by column chromatography to obtain compound 5 (9.9 g, 95%). 1 H-NMR(400MHz,CDCl3)δ 6.74(s,1H),6.25(s,1H),5.92(m,1H),5.30(d,1H),5.24(d,1H),4.97(s,1H),4.90(s,1H),4.59(d,2H),4.33(brs,1H),4.18( m,1H),4.09(m,1H),4.03(t,2H),3.76(s,3H),3.61(brs,1H),2.68(m,2H),2.57(t,2H),2.16(q,2H),0.87(s,9H),0.09(s,6H).

[0143] Preparation of compound 7 Compound 5 (9.9 g, 19.1 mmol) was dissolved in dry tetrahydrofuran (250 mL), and then triphosgene (2.0 g, 6.8 mmol) and triethylamine (10.7 mL, 76.3 mmol) were added at 0°C. Compound 6 (16.4 g, 21.0 mmol; compound 6 was prepared by the method described in Patent Document 9) was dissolved in dry tetrahydrofuran (50 mL) and added. The mixture was stirred at room temperature for 17 hours, then the reaction mixture was diluted with ethyl acetate (200 mL), washed with distilled water (150 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 7 (14.4 g, 60%). 1H-NMR(400MHz,CDCl3)δ 8.95(brs,1H),8.02(s,1H),7.83(s,1H),7.72(s,1H),7.49(d,1H),7.43(t,1H),7.03(d,1H),6.67(s,1H),5.9 1(m,1H),5.40-5.22(m,6H),5.12(s,2H),5.00(s,1H),4.97(s,1H),4.59(d,2H),4.19(d,2H),3.98(t,2H),3.86(m,2H),3.80(s,1H),3. 77(s,3H),3.70-3.65(m,12H),3.53(m,1H),2.68(m,2H),2.56(t,2H),2.15(q,2H),2.05(s,9H),1.46(s,9H),0.87(s,9H),0.09(s,6H). EI-MSm / z:[M+H] + 1275.8. [Examples]

[0144] Preparation of compound 10 JPEG2026086866000049.jpg86160

[0145] Preparation of compound 8 Compound 7 (14.4 g, 11.3 mmol) was dissolved in tetrahydrofuran / distilled water (50 mL / 50 mL), acetic acid (50 mL) was added at 0°C, and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (50 mL), and then saturated sodium bicarbonate solution (2 × 100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 8 (12.6 g, 96%). 1H-NMR(400MHz,CDCl3)δ 8.37(s,1H),8.03(s,1H),7.74(s,1H),7.72(s,1H),7.51(t,1H),7.43(d,1H),7.02(d,1H), 6.81(s,1H),5.92(m,1H),5.40-5.22(m,6H),5.13(s,2H),5.00(s,1H),4.91(s,1H),4.60(d ,2H),4.19(d,1H),4.16(s,1H),4.11(m,3H),3.98(t,2H),3.78(s,3H),3.73-3.65(m,12H), 3.53(m,1H),2.76(m,1H),2.57(t,2H),2.50(m,1H),2.17(q,2H),2.05(s,9H),1.46(s,9H). EI-MSm / z:[M+H] + 1161.6.

[0146] Preparation of compound 9 Compound 8 (12.6 g, 10.9 mmol) was dissolved in dichloromethane (200 mL), then Dess-Martin periodinane (5.6 g, 13.1 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction solution was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate aqueous solution (150 mL) and sodium thiosulfate aqueous solution (100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 9 (6.6 g, 52%). 1H-NMR(400MHz,CDCl3)δ 7.97(s,1H),7.80(s,1H),7.45(s,1H),7.23(d,1H),7.19(s,1H),7.00(d,1H),6.61( s,3H),5.92(m,1H),5.58(d,1H),5.41-5.22(m,8H),5.13(s,2H),4.83(d,1H),4.59(d ,2H),4.27(m,2H),4.11(m,2H),3.96(m,2H),3.88(s,3H),3.74-3.65(m,15H),3.52( m,1H),2.90(m,1H),2.70(d,1H),2.57(t,2H),2.13(q,2H),2.05(s,9H),1.46(s,9H). EI-MSm / z:[M+H] + 1159.6.

[0147] Preparation of compound 10 Compound 9 (600 mg, 0.52 mmol) was dissolved in N,N-dimethylformamide (10 mL), then tetrakis(triphenylphosphine)palladium (0) (238 mg, 0.21 mmol) and pyrrolidine (0.05 mL, 0.57 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL) and distilled water (50 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain compound 10 (570 mg, 98%) as a yellow solid. EI-MS m / z:[M+H] + 1119.6,[M / 2+H] + 510.3. [Examples]

[0148] Preparation of compound 14 [ka]

[0149] Preparation of compound 11 1-Methylpyrrole (20.0 g, 246.5 mmol) was dissolved in tetrahydrofuran (100 mL), and then trichloroacetyl chloride (27.5 ml, 246.5 mmol) dissolved in tetrahydrofuran (100 mL) was gradually added using a dropping funnel at 0°C under a nitrogen atmosphere. The reaction solution was heated to room temperature and stirred for 3 hours. The reaction solution was concentrated, diluted with ethyl acetate (100 mL), and then washed with distilled water (100 mL). The combined organic layers were dried over anhydrous sodium sulfate to obtain compound 11 (55.7 g, 99%). 1 H-NMR (400MHz, CDCl3) δ 7.51-7.49 (m, 1H), 6.96 (s, 1H), 6.23-6.21 (m, 1H), 3.97 (s, 3H).

[0150] Preparation of compound 12 Compound 11 (15.8 g, 69.7 mmol) was dissolved in acetic anhydride (170 mL), and then copper(II) nitrate hydrate (17 g, 73.2 mmol) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 2 hours. Saturated sodium bicarbonate aqueous solution (200 mL) was slowly added to the reaction solution. The aqueous layer was extracted with ethyl acetate (200 mL) and then washed with distilled water (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, and then filtered and concentrated. Recrystallization was performed with dichloromethane / hexane (50 mL / 50 mL), and the remaining filtrate was purified by column chromatography to obtain compound 12 (0.8 g, 72%) as a white solid. 1 H-NMR (400MHz, CDCl3) δ 7.94 (d, J = 1.6 Hz, 1H), 7.75 (s, 1H), 4.05 (s, 1H).

[0151] Preparation of compound 13 Compound 12 (45.7 g, 168.4 mmol) was diluted with methanol (300 mL), and then sodium methoxide (1.8 g, 33.6 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 neutralized with 6N hydrochloric acid aqueous solution, then concentrated under reduced pressure, and after adding distilled water (200 mL), it was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, and then filtered and concentrated. Acetone (50 mL) was added, and the resulting white solid was filtered to obtain compound 13 (29.6 g, 95%). 1 H NMR (400MHz, CDCl3) δ 7.59(d,J=1.6Hz,1H),7.41(d,J=1.6Hz,1H),3.99(s,3H),3.86(s,3H).

[0152] Preparation of compound 14 Compound 13 (15.1 g, 81.9 mmol) was diluted with methanol (200 mL), and then sodium hydroxide (9.8 g, 245.9 mmol) dissolved in distilled water (200 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 12 hours. The reaction solution was adjusted to pH ~2 by adding 6N hydrochloric acid aqueous solution, then concentrated under reduced pressure, and after adding distilled water (200 mL), it was extracted with ethyl acetate (2 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, then filtered and concentrated. Recrystallization was performed using ethyl acetate / hexane (50 mL / 50 mL) to obtain compound 14 (13.4 g, 96%). 1 H NMR (400MHz, DMSO-d6) δ 13.14 (brs, 1H), 8.23 ​​(d, J = 1.6 Hz, 1H), 7.25 (d, J = 2 Hz, 1H), 3.91 (s, 3H). [Examples]

[0153] Preparation of compound 18 [ka]

[0154] Preparation of compound 15 Compound 13 (7.5 g, 40.8 mmol) was dissolved in methanol (200 mL) and ethyl acetate (200 mL), and then palladium / charcoal (10% w / w, 1.5 g) was added at 0°C under a nitrogen atmosphere. Sodium borohydride (4.6 g, 122.5 mmol) dissolved in distilled water (100 mL) was gradually added using a dropping funnel, and then the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite, then diluted with ethyl acetate (100 mL), and washed with distilled water (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, then filtered and concentrated, and purified by column chromatography to obtain compound 15 (6.2 g, 99%). 1 H-NMR (400MHz, CDCl3) δ 6.45(d,J=2.4Hz,1H),6.36(d,J=2Hz,1H),3.81(s,3H),3.77(s,3H).

[0155] Preparation of compound 16 Compound 14 (4.8 g, 28.2 mmol) was dissolved in N,N-dimethylformamide (70 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 16.8 g, 42.3 mmol) and N,N'-diisopropylethylamine (14.7 mL, 84.6 mmol) were sequentially added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 30 minutes. Compound 15 (6.2 g, 40.8 mmol) dissolved in N,N-dimethylformamide (70 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and then diluted with dichloromethane (100 mL). The resulting solid was filtered to obtain compound 16 (8.5 g, 99%). 1 H-NMR(400MHz,DMSO-d6)δ 10.25(s,1H),8.19(s,1H),7.55(d,J=1.6Hz,1H),7.45(s,1H),6.88(d,J=1.6Hz,1H),3.94(s,3H),3.84(s,3H),3.74(s,3H).

[0156] Preparation of compound 17 Compound 16 (6.0 g, 19.58 mmol) was dissolved in methanol (60 mL) and N,N-dimethylformamide (60 mL), and then palladium / charcoal (10% w / w, 1.0 g) and di-t-butyl dicarbonate (13.5 mL, 58.7 mmol) were added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction solution was filtered through Celite and then concentrated. It was diluted with ethyl acetate (200 mL), washed with distilled water (150 mL), and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the solution was purified by column chromatography to obtain compound 17 (5.7 g, 78%). 1 H-NMR (400MHz, CDCl3) δ 7.41(s,2H),6.82(s,1H),6.72(s,1H),6.56(s,1H),6.20(s,1H),3.90(s,6H),3.81(s,3H),1.50(s,9H).

[0157] Preparation of compound 18 Compound 17 (651 mg, 1.73 mmol) was mixed with 1,4-dioxane (15 mL), and then sodium hydroxide (345 mg, 8.64 mmol) dissolved in distilled water (5 mL) was added at 0°C under a nitrogen atmosphere. The solution was heated to 70°C and stirred for 5 hours. The 1,4-dioxane was concentrated, then the pH was adjusted to approximately 2 with 6N hydrochloric acid aqueous solution, then diluted with ethyl acetate (50 mL), washed with distilled water (50 mL), and dried over anhydrous sodium. After filtration, the solution was concentrated to obtain compound 18 (630 mg, 98%). 1 H-NMR (400MHz, CDCl3) δ 7.64(s,1H),7.49(s,1H),6.90(s,1H),6.78(s,1H),6.73(s,1H),6.24(s,1H),3.90(s,6H),1.44(s,9H). [Examples]

[0158] Preparation of compound 20 [ka]

[0159] Preparation of compound 19 Compound 18 (1.3 g, 3.72 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then 3-(dimethylamino)-1-propylamine (0.56 mL, 4.46 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 2.2 g, 5.58 mmol), and N,N'-diisopropylethylamine (2.0 mL, 11.16 mmol) were sequentially added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with ethyl acetate (150 mL), then washed with saturated ammonium chloride aqueous solution (100 mL), saturated sodium bicarbonate solution (100 mL), and distilled water (100 mL), and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and purified by column chromatography to obtain compound 19 (1.2 g, 72%). 1 H-NMR(400MHz,CDCl3)δ 7.64(s,1H),7.57(s,1H),7.20(s,1H),6.80(s,1H),6.62(s,1H),6.44(s,1H),6.31(s,1H),3. 90(s,6H),3.48-3.43(m,2H),2.56-2.53(m,2H),2.38(s,6H),1.81-1.76(m,2H),1.49(s,9H).

[0160] Preparation of compound 20 Compound 19 (300 mg, 0.67 mmol) was dissolved in dichloromethane (4 mL), and then hydrochloric acid (4 M 1,4-dioxane solution, 2 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 20 (278 mg). EI-MS m / z:[M+H] + 347.53, 1 / 2 [M+H] + 174.32. [Examples]

[0161] Preparation of compound 23 [ka]

[0162] Preparation of compound 21 Compound 10 (144 mg, 0.128 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then, under a nitrogen atmosphere at 0°C, compound 20 (70 mg, 0.167 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 77 mg, 0.193 mmol), and N,N'-diisopropylethylamine (0.11 mL, 0.645 mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (50 mL) was added to the reaction solution, and then the mixture was washed with saturated ammonium chloride aqueous solution (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and distilled water (50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography to obtain compound 21 (163 mg, 87%). EI-MS m / z:[M+H] + 1448.25, 1 / 2 [M+H] + 724.57.

[0163] Preparation of compound 22 Compound 21 (163 mg, 0.126 mmol) was dissolved in methanol / tetrahydrofuran (2 mL / 2 mL), and then a solution of lithium hydroxide (14 mg, 0.337 mmol) dissolved in distilled water (2 mL) was slowly added at -40°C under a nitrogen atmosphere. The reaction was stirred for 2 hours while gradually raising the temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, and freeze-dried to obtain compound 22 (150 mg, crude). EI-MS m / z:[M+H] + 1308.03,[M / 2+H] + 664.60.

[0164] Preparation of compound 23 Compound 22 (150 mg, 0.1 mmol) was diluted with dichloromethane (16 mL), and then trifluoroacetic acid (4 mL) was added at 0°C under a nitrogen atmosphere, 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 23 as a white solid (12 mg). EI-MS m / z:[M+H] + 1207.93,[M / 2+H] + 604.59. [Examples]

[0165] Preparation of compound 26 [ka]

[0166] Preparation of compound 24 Compound 16 (5.46 g, 17.8 mmol) was mixed with 1,4-dioxane (100 mL), and then sodium hydroxide (3.56 g, 89.1 mmol) dissolved in distilled water (40 mL) was added at 0°C under a nitrogen atmosphere. The solution was heated to 80°C and stirred for 6 hours. The 1,4-dioxane was concentrated, then the pH was adjusted to approximately 2 with 6N hydrochloric acid aqueous solution, then diluted with ethyl acetate (150 mL), washed with distilled water (100 mL), and dried over anhydrous sodium. After filtration, the solution was concentrated to obtain compound 24 (4.63 g, 89%). 1 H-NMR (400MHz, DMSO-d6) δ 8.19 (s, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 6.83 (s, 1H), 3.95 (s, 3H), 3.83 (s, 3H).

[0167] Preparation of compound 25 Compound 24 (217 mg, 0.74 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then 3-amino-1-propanol (0.07 mL, 0.97 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 443 mg, 1.12 mmol), and N,N'-diisopropylethylamine (0.26 mL, 1.49 mmol) were sequentially added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution (100 mL) and distilled water (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained compound was dissolved in N,N-dimethylformamide / dichloromethane (5 mL / 10 mL), and imidazole (101.3 mg, 1.49 mmol) and t-butyldimethylsilyl chloride (168 mg, 1.12 mmol) were added at 0°C. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 17 hours, then concentrated, diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL) and distilled water (50 mL), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 25 (310 mg, 90%). 1 H-NMR(400MHz,DMSO-d6)δ 10.22(s,1H),8.17(s,1H),8.01(t,1H),7.57(s,1H),7.19(s,1H),6.82(s,1H),3.95(s, 3H), 3.80 (s, 3H), 3.63 (t, 2H), 3.21 (q, 2H), 1.72-1.65 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H).

[0168] Preparation of compound 26 Compound 25 (158 mg, 0.34 mmol) was dissolved in methanol (5 mL), and then palladium / charcoal (10% w / w, 80 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through Celite and then concentrated to obtain compound 26 (142 mg, 96%). 1H-NMR(400MHz,DMSO-d6)δ 9.55(s,1H),7.93(t,1H),7.13(s,1H),6.79(s,1H),6.35(s,1H),6.25(s,1H),3.77(s,3 H),3.71(s,3H),3.63(t,2H),3.21(q,2H),1.71-1.65(m,2H),0.87(s,9H),0.03(s,6H). [Examples]

[0169] Preparation of compound 29 [ka]

[0170] Preparation of compound 27 Compound 10 (crude 146 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then 1-hydroxybenzotriazole (27 mg, 0.20 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol) were added sequentially under a nitrogen atmosphere at 0°C. Compound 26 (114 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (1 mL) and added. The mixture was stirred at room temperature for 5 hours, the reaction solution was diluted with ethyl acetate (50 mL), and then washed in the order of saturated ammonium chloride aqueous solution (50 mL), saturated sodium bicarbonate solution (50 mL), and distilled water (50 mL), before drying over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 27 (85 mg, 42%). EI-MS m / z:[M+H] + 1534.88,1 / 2[M+H] + 768.49,1 / 2[M-BOC+H] + 718.36.

[0171] Preparation of compound 28 Compound 27 (85 mg, 0.05 mmol) was dissolved in methanol / tetrahydrofuran (1.0 mL / 1.0 mL), and then a solution of lithium hydroxide (7 mg, 0.16 mmol) dissolved in distilled water (1.0 mL) was slowly added at -40°C under a nitrogen atmosphere. The reaction was stirred for 5 hours while gradually raising the temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, purified by HPLC, and freeze-dried to obtain compound 28 (18 mg). EI-MS m / z:[M-TBS+H] + 1280.82,1 / 2[M-BOC+H] + 591.04.

[0172] Preparation of compound 29 Compound 28 (18 mg) was diluted with dichloromethane (1.5 mL), and then trifluoroacetic acid (0.5 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 29 as a pale yellow solid (6.1 mg). EI-MS m / z:[M+H] + 1180.59,[M / 2+H] + 591.88. [Examples]

[0173] Preparation of compound 34 [ka]

[0174] Preparation of compound 30 Ethylenediamine (6 mL, 90 mmol) was dissolved in dichloromethane (90 mL), and then benzyl chloroformate (1.5 g, 9 mmol) dissolved in dichloromethane (25 mL) was slowly added at 0°C under a nitrogen atmosphere, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (100 mL) and washed with saline solution (100 mL). The organic layer was dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain compound 30 (1.75 g, 99%). 1H NMR(400MHz, CDCl3)δ 7.32-7.28(m,5H),5.07(s,2H),3.21(t,J=6.4Hz,2H),2.73(t,J=2Hz,2H).

[0175] Preparation of compound 31 Compound 30 (880 mg, 4.5 mmol) was dissolved in dichloromethane (15 mL), and then N,N'-Di-Boc-1H-pyrazole-1-carboxamidine (1.68 g, 5.4 mmol) and triethylamine (0.8 mL, 5.4 mmol) were sequentially added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and purified by column chromatography to obtain compound 31 (1.96 g, 99%). 1 H-NMR(400MHz,CDCl3)δ 11.43(s,1H),8.53(s,1H),7.35-7.29(m,5H),5.09(s,1H),3.62-3.54(m,2H),3.40-3.36(m,2H),1.48(s,9H),1.44(s,9H).

[0176] Preparation of compound 32 Compound 31 (1.9 g, 4.3 mmol) was dissolved in ethyl acetate (40 mL), and then palladium / charcoal (10% w / w, 190 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through Celite, concentrated, and purified by column chromatography to obtain compound 32 (0.92 g, 67%). 1 H-NMR (400MHz, CDCl3) δ 11.51 (s, 1H), 8.66 (s, 1H), 3.51-3.46 (m, 2H), 2.91-2.88 (m, 2H), 1.50 (s, 18H).

[0177] Preparation of compound 33 Compound 24 (150 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then, under a nitrogen atmosphere at 0°C, compound 32 (186 mg, 0.62 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 305 mg, 0.77 mmol), and N,N'-diisopropylethylamine (0.18 mL, 1.02 mmol) were sequentially added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 33 (174 mg, 59%). 1 H-NMR(400MHz,CDCl3)δ 11.55(s,1H),8.69(s,1H),7.59(s,1H),7.50(s,1H),7.22(s,1H),7.12(s,1H),6.46(s,1H) ,4.02(s,3H),3.92(s,3H),3.74-3.62(m,2H),3.56-3.52(m,2H),1.53(s,9H),1.50(s,9H).

[0178] Preparation of compound 34 Compound 33 (174 mg, 0.3 mmol) was dissolved in methanol (5 mL), and then palladium / charcoal (10% w / w, 70 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through Celite and then concentrated to obtain compound 34 (158 mg, 96%). EI-MS m / z:[M+H] + 547.30. [Examples]

[0179] Preparation of compound 35 [ka] Compound 35 was prepared from compound 10 and compound 34 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1207.44,[M / 2+H] + 604.50. [Examples]

[0180] Preparation of compound 37 [ka]

[0181] Preparation of compound 36 Compound 18 (200 mg, 0.55 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then NH2-PEG6-OH (232 mg, 0.83 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 328 mg, 0.83 mmol), and N,N'-diisopropylethylamine (0.3 mL, 1.66 mmol) were added sequentially under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (50 mL), then washed with saturated ammonium chloride aqueous solution (50 mL), saturated sodium bicarbonate solution (50 mL), and distilled water (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and then purified by column chromatography to obtain compound 36 (255 mg, 74%). 1 H-NMR (400MHz, CDCl3) δ 8.35(s,1H),7.36(s,1H),6.95(s,1H),6.88(s,1H),6.65(s,3H),3.91(s,6H),3.72-3.54(m,24H),1.49(s,9H).

[0182] Preparation of compound 37 Compound 36 (139 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL), and then hydrochloric acid dissolved in 1,4-dioxane (4 M 1,4-dioxane solution, 1 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 37 (124 mg). EI-MS m / z:[M+H] + 526.33, 1 / 2 [M+H] + 282.37. [Examples]

[0183] Preparation of compound 38 [ka]

[0184] Compound 38 was prepared from compound 10 and compound 37 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1386.33,[M / 2+H] + 694.09. [Examples]

[0185] Preparation of compound 40 [ka]

[0186] Preparation of compound 39 Compound 18 (100 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then, under a nitrogen atmosphere at 0°C, compound NH2-PEG12-OH (238 mg, 0.4 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 164 mg, 0.4 mmol), and N,N'-diisopropylethylamine (0.14 mL, 0.8 mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain compound 39 (245 mg, crude). 1 H-NMR (400MHz, CDCl3) δ 8.47(s,1H),7.33(s,1H),6.66(s,2H),3.99(s,3H),3.89(s,3H),3.75-3.42(m,48H),1.49(s,9H). EI-MS m / z:[M+Na] + 912.42,[M+H] + 890.45,1 / 2[M-BOC+H] + 395.99.

[0187] Preparation of compound 40 Compound 39 (245 mg, 0.27 mmol) was diluted with dichloromethane (8 mL), and then hydrochloric acid (4 M 1,4-dioxane solution, 2 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 40 (213 mg). EI-MS m / z: [M + Na] + 813.47,[M / 2+H] + 395.94. [Examples]

[0188] Preparation of compound 41 [ka]

[0189] Compound 41 was prepared from compound 10 and compound 40 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1651.57,[M / 2+H] + 826.17. [Examples]

[0190] Preparation of compound 44 [ka]

[0191] Preparation of compound 42 3-(methylamino)propylamine (20.0 g, 228.02 mmol) was dissolved in tetrahydrofuran (300 mL), and then di-t-butyl dicarbonate (9.8 g, 44.9 mmol) dissolved in tetrahydrofuran (200 mL) was slowly added using a dropping funnel at 0°C under a nitrogen atmosphere. The reaction solution was heated to room temperature and stirred for 5 hours. The reaction solution was concentrated, diluted with dichloromethane (200 mL), washed with distilled water (100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 42 (5.1 g, 60%). 1H-NMR (400MHz, CDCl3) δ 3.29 (s, 2H), 2.83 (s, 3H), 2.70-2.67 (m, 2H), 1.68-1.61 (m, 2H), 1.43 (s, 9H).

[0192] Preparation of compound 43 Compound 24 (400 mg, 1.36 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 778 mg, 2.05 mmol) and N,N'-diisopropylethylamine (0.47 mL, 2.73 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred for 3 minutes. Compound 42 (309 mg, 1.64 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then added to the reaction solution at 0°C. The temperature was gradually increased, and the mixture was stirred at room temperature for 16 hours. Saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The extracted solution was washed with saturated sodium bicarbonate solution (15 mL) and distilled water (15 mL), and then dried over anhydrous sodium sulfate. After filtration, the compound was concentrated and then purified by column chromatography to obtain compound 43 (582 mg, 92%). 1 H-NMR(400MHz,CDCl3)δ 7.69(brs,1H),7.59(s,1H),7.36(brs,1H),7.29(brs,1H),7.19(s,1H),6.58(brs,1H) ),4.02(s,3H),3.93(s,3H),3.37(m,4H),2.85(s,3H),1.71(m,2H),1.49(s,9H),EI-MS m / z:[M+H] + 463.39.

[0193] Preparation of compound 44 Compound 43 (160 mg, 0.34 mmol) was dissolved in methanol (5 mL), and then palladium / charcoal (10% w / w, 80 mg) was added at room temperature. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through Celite and then concentrated to obtain compound 44 (140 mg). 1H-NMR(400MHz,CDCl3)δ 7.36(brs,1H),7.30(brs,1H),6.53(s,1H),6.33(s,1H),6.19(s,1H),3.92(s,3 H),3.86(s,3H),3.37-3.32(m,4H),2.84(s,3H),1.71(m,2H),1.48(s,9H),EI-MS m / z:[M+H] + 433.41.

Example

[0194] Production of Compound 45

change

[0195] Compound 10, compound 44, and compound 23 were synthesized by the same method, and compound 45 was produced. 1 H-NMR(400MHz,Methanol-d4)δ 7.76(brs,1H),7.30(m,2H),7.14(s,3H),6.87(s,1H),6.79(s,1H),6.76(brs,1H),5 .57(d,J=8.8Hz,1H),5.23-5.18(m,3H),5.11(d,J=7.6Hz,1H),4.25-4.21(m,1H),4.1 5(m,2H),4.08-4.03(m,3H),3.88-3.80(m,12H),3.69-3.52(m,13H),3.41(t,J=6Hz, 2H),3.03(t,J=7.2Hz,2H),2.94(m,1H),2.50(m,2H),2.11(m,2H),1.93(m,2H),EI-MS m / z:[M+H] + 1193.44, [M / 2+H] + 597.49.

Example

[0196] Production of Compound 51

change

[0197] Preparation of compound 46 1-Methylimidazole (5 g, 95.9 mmol) was dissolved in dichloromethane (40 mL), and then trichloroacetyl chloride (6.79 ml, 95.9 mmol) dissolved in dichloromethane (40 mL) was slowly added over 1 hour using a dropping funnel at 0°C under a nitrogen atmosphere. The reaction solution was heated to room temperature and stirred for 6 hours. Triethylamine (13.3 mL, 95.9 mmol) was added at room temperature, and the reaction solution was stirred for 30 minutes. The reaction solution was concentrated and recrystallized with chloroform and hexane to obtain compound 46 (12.6 g, 96%). 1 H-NMR (400MHz, CDCl3) δ 7.35 (s, 1H), 7.16 (s, 1H), 4.06 (s, 3H).

[0198] Preparation of compound 47 At -10°C under a nitrogen atmosphere, 110 mL of acetic anhydride was mixed with 8 mL of nitric acid (193.9 mmol) and 0.35 mL of sulfuric acid (6.6 mmol), followed by the addition of compound 46 (12.6 g, 55.3 mmol). The mixture was stirred at 0°C for 3 hours, after which the reaction solution was diluted with 200 mL of chloroform, and then 200 mL of saturated sodium bicarbonate aqueous solution was slowly added. The aqueous layer was extracted with 100 mL of chloroform, and the combined organic layers were dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated, and methanol (200 mL) was added and stirred at room temperature for 2 hours. The methanol was concentrated and diluted with 100 mL of dichloromethane, and the resulting solid was filtered to obtain compound 47 (6.3 g, 61%). 1 H-NMR (400MHz, CDCl3) δ 7.84 (s, 1H), 4.12 (s, 3H), 3.98 (s, 3H).

[0199] Preparation of compound 48 Methanol (300 mL) was added to compound 47 (6.3 g, 34.1 mmol), followed by di-t-butyl dicarbonate (20 mL, 102.4 mmol), and then palladium / charcoal (10% w / w, 630 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was further stirred under a nitrogen atmosphere for 12 hours. The reaction solution was filtered through Celite, concentrated, and purified by column chromatography to obtain compound 48 (7.9 g, 91%). 1 H-NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 7.32 (s, 1H), 3.88 (s, 3H), 3.78 (s, 3H), 1.46 (s, 9H).

[0200] Preparation of compound 49 Compound 48 (300 mg, 1.17 mmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (1 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, then diluted with dichloromethane (30 mL), and washed with saturated sodium bicarbonate aqueous solution (30 mL). The aqueous layer was extracted with dichloromethane (30 mL), and then the combined organic layers were dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to obtain compound 49 (160 mg). 1 H-NMR (400MHz, CDCl3) δ 6.37 (s, 1H), 3.92 (s, 3H). 3.90(s,3H),3.56(brs,2H) EI-MS m / z:[M+H] + 156.17.

[0201] Preparation of compound 50 Compound 14 (300 mg, 1.76 mmol) was dissolved in thionyl chloride (3 mL), then heated at 70°C for 1 hour, and the reaction solution was concentrated under reduced pressure. Dichloromethane (4 mL) and N,N'-diisopropylethylamine (0.92 mL, 5.29 mmol) were added at -50°C under a nitrogen atmosphere, and then compound 49 (329 mg, 2.12 mmol) was diluted with dichloromethane (4 mL) and added to the reaction solution. The mixture was heated to room temperature and then stirred for 18 hours. Saturated ammonium chloride aqueous solution (15 mL) was added to the reaction solution, then extracted with ethyl acetate (20 mL x 3), and washed with saturated sodium bicarbonate aqueous solution (20 mL), distilled water (20 mL), and sodium chloride aqueous solution (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain compound 50 (140 mg, 25%). 1 H-NMR(400MHz,CDCl3)δ 8.27(brs,1H),7.61(s,1H),7.53(s,1H),7.13(d,J=1.6Hz,1H),4.11(s,6H),3.95(s,3H),EI-MS m / z:[M+H] + 308.20.

[0202] Preparation of compound 51 Compound 50 (140 mg, 0.45 mmol) was dissolved in methanol (2.5 mL), and then a solution of lithium hydroxide (25.8 mg, 0.61 mmol) dissolved in distilled water (2.5 mL) was slowly added at room temperature under a nitrogen atmosphere. The mixture was heated to 70°C and stirred for 1 hour. The reaction solution was acidified with 1N hydrochloric acid aqueous solution (pH ~ 4), and then concentrated under reduced pressure to obtain compound 51 (133 mg). 1 H-NMR(400MHz,DMSO-d6)δ 11.11(s,1H),8.19(s,1H),7.80(d,J=2Hz,1H),7.64(s,1H),3.96(s,3H),3.93(s,3H),EI-MS m / z:[M+H] + 294.09. [Examples]

[0203] Preparation of compound 53 [ka]

[0204] Preparation of compound 52 Compound 51 (133 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 258 mg, 0.68 mmol) and N,N'-diisopropylethylamine (0.16 mL, 0.91 mmol) were added at 0°C under a nitrogen atmosphere. N,N'-dimethyl-1,3-propanediamine (0.11 mL, 0.91 mmol) was added to the reaction solution, and then the temperature was raised to room temperature and stirred for 17 hours. Saturated ammonium aqueous solution (15 mL) was added to the reaction solution, and then the solution was extracted with ethyl acetate (20 mL x 3), and washed in the following order with saturated sodium bicarbonate aqueous solution (20 mL), distilled water (20 mL), and sodium chloride aqueous solution (20 mL). The compound was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain compound 52 (70 mg, 40%). 1 H-NMR(400MHz,DMSO-d6)δ 10.78(s,1H),8.19(s,1H),8.02(t,J=6.4Hz,1H),7.75(d,J=0.8Hz,1H),7.51(s,1H) ,3.95(s,3H),3.93(s,3H),3.25(m,2H),2.24(m,2H),2.21(m,6H),1.62(m,2H),EI-MS m / z:[M+H] + 378.30.

[0205] Preparation of compound 53 Compound 52 (70 mg, 0.18 mmol) was dissolved in methanol (3 mL), and then palladium / charcoal (10% w / w, 35 mg) was added at room temperature. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through Celite, and then concentrated under reduced pressure to obtain compound 53 (58 mg). EI-MS m / z:[M+H] + 348.34,[M / 2+H] + 174.75. [Examples]

[0206] Preparation of compound 54 [ka]

[0207] Compound 54 was prepared from compound 10 and compound 53 using the same method as in the synthesis of compound 23. 1 H-NMR(400MHz,Methanol-d4)δ 7.76(brs,1H),7.40(brs,1H),7.29-7.26(m,2H),7.15(m,2H),6.79(m,2H),5.58(d,J=1 0Hz,1H),5.25(d,J=12Hz,1H),5.17-5.12(m,4H),4.24-4.15(m,4H),4.11(d,J=9.2Hz,2 H),4.09-3.99(m,6H),3.87-3.80(m,11H),3.69-3.55(m,17H),3.46(t,J=6.4Hz,2H),3. 21(m,3H),2.92(m,10H),2.67-2.62(m,2H),2.52(m,2H),2.12(m,2H),2.00(m,2H),EI-MS m / z:[M+H] + 1208.43,[M / 2+H] + 605.08. [Examples]

[0208] Preparation of compound 56 [ka]

[0209] Preparation of compound 55 Compound 51 (156 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 303 mg, 0.79 mmol) and N,N'-diisopropylethylamine (0.28 mL, 1.59 mmol) were added at 0°C under a nitrogen atmosphere. 3-amino-1-propanol (0.12 mL, 1.59 mmol) was added to the reaction solution, and then the temperature was raised to room temperature and stirred for 18 hours. Saturated ammonium chloride aqueous solution (15 mL) was added to the reaction solution, and it was extracted with chloroform (20 mL x 3), followed by washing with saturated sodium bicarbonate aqueous solution (20 mL), distilled water (20 mL), and sodium chloride aqueous solution (20 mL). The compound was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain compound 55 (115 mg, 61%). 1 H-NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.17(s,1H),7.92(t,J=6Hz,1H),7.74(d,J=1.2Hz,1H),7.50(s,1H),4 .54(brs,1H),3.93(s,3H),3.92(s,3H),3.46(m,2H),3.27(m,2H),1.62(m,2H),EI-MS m / z:[M+H] + 351.26.

[0210] Preparation of compound 56 Compound 55 (115 mg, 0.32 mmol) was dissolved in methanol (5 mL), and then palladium / charcoal (10% w / w, 50 mg) was added at room temperature. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction solution was filtered through Celite and then concentrated under reduced pressure to obtain compound 56 (100 mg). 1H-NMR(400MHz,DMSO-d6)δ 9.92(s,1H),7.91(t,J=6Hz,1H),7.42(s,1H),6.47(d,J=1.6Hz,1H),6.28(d,J=2Hz,1H),4.52( brs,1H),3.90(s,3H),3.78(brs,2H),3.71(s,3H),3.44(m,2H),3.27(m,2H),1.66(m,2H),EI-MS m / z:[M+H] + 321.29.

Example

[0211] Production of Compound 57

change

[0212] Compound 10, compound 56, and compound 23 were synthesized by the same method, and compound 57 was produced. 1 H-NMR(400MHz,Methanol-d4)δ 7.76(brs,1H),7.38(s,1H),7.29-7.26(m,2H),7.16(d,J=10Hz,2H),6.81(brs,1H ),6.75(brs,1H),5.58(m,1H),5.27(d,J=11.6Hz,1H),5.15(m,3H),4.24-4.09(m, 4H),4.09(s,1H),4.00(m,4H),3.87-3.79(m,9H),3.68-3.55(m,14H),3.44(t,J=6 .8Hz,2H),2.98(m,1H),2.63(m,1H),2.50(m,2H),2.11(m,2H),1.80(m,2H),EI-MS m / z:[M+H] + 1181.44, [M / 2+H] + 591.51.

Example

[0213] Production of Compound 60

change

[0214] Preparation of compound 58 To compound 48 (7.9 g, 31.2 mmol), tetrahydrofuran (150 mL) was added, followed by the addition of sodium hydroxide (12.5 g, 312 mmol) dissolved in distilled water (150 mL) at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 12 hours. The reaction solvent was concentrated, then acidified with 6N hydrochloric acid aqueous solution (pH ~2), and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, then filtered and concentrated. Acetone (100 mL) was added, followed by stirring. The resulting solid was filtered to obtain compound 58 (5.6 g, 74%). 1 H-NMR (400MHz, CDCl3) δ 9.63 (s, 1H), 7.25 (s, 1H), 3.86 (s, 3H), 1.46 (s, 9H).

[0215] Preparation of compound 59 Compound 58 (686 mg, 2.84 mmol) and Compound 15 (570 mg, 3.69 mmol) were dissolved in N,N-dimethylformamide (9 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 1.61 g, 4.26 mmol) and N,N'-diisopropylethylamine (0.99 mL, 5.68 mmol) were slowly added at 0°C under a nitrogen atmosphere. The reaction temperature was raised to room temperature and then stirred for 3 hours. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated sodium bicarbonate solution (10 mL) and distilled water (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and purified by column chromatography to obtain Compound 59 (1.0 g, 93%). 1 H-NMR(400MHz,CDCl3)δ 8.77(brs,1H),7.41(d,J=1.6Hz,1H),7.14(brs,1H),6.90(brs,1H),6.78(brs,1H),4.04(s,3H),3.91(s,3H),3.81(s,3H),1.51(s,9H),EI-MS m / z:[M+H] + 378.16.

[0216] Preparation of compound 60 Compound 59 (260 mg, 0.68 mmol) was dissolved in dichloromethane (4.8 mL), and then hydrochloric acid (4 M in 1,4-dioxane, 2.4 mL, 9.63 mmol) was slowly added at 0°C under a nitrogen atmosphere. The mixture was heated to room temperature and stirred for 24 hours, after which the reaction solution was based with saturated sodium carbonate aqueous solution (pH ~12). This solution was extracted with dichloromethane (20 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and then purified by column chromatography to obtain compound 60 (70 mg, 36%). 1 H-NMR(400MHz,CDCl3)δ 8.11(s,1H),7.40(d,J=1.6Hz,1H),6.78(d,J=2Hz,1H),6.31(s,1H),3.99(s,3H),3.90(s,3H),3.80(s,3H),EI-MS m / z:[M+H] + 278.23. [Examples]

[0217] Preparation of compound 61 [ka]

[0218] Compound 61 was prepared from compound 10 and compound 60 using the same method as in the synthesis of compound 23. 1 H-NMR(400MHz,DMSO-d6)δ 10.22(brs,1H),10.07(brs,1H),8.28(brs,1H),7.74(brs,1H),7.50(s,1H),7.45(s,1H),7.37(m,1H),7.23(m,1H),7.04(s,1H),6.98(s, 1H),6.71(brs,1H),5.35(m,1H),5.19-5.13(m,4H),4.84(m,1H),4.10-3.73(m,18H),3.62(brs,3H),3.54-3.51(m,6H),2.00(m,1H),EI-MS m / z:[M+H] + 1138.36,[M / 2+H] +569.85. [Examples]

[0219] Preparation of compound 64 [ka]

[0220] Preparation of compound 62 Compound 59 (200 mg, 0.52 mmol) was dissolved in methanol (3 mL), and then a solution of lithium hydroxide (63.5 mg, 1.58 mmol) dissolved in distilled water (3 mL) was slowly added at room temperature under a nitrogen atmosphere. The mixture was then heated to 80°C and stirred for 1 hour. The reaction solution was diluted with ethyl acetate (20 mL), then acidified with 1N hydrochloric acid aqueous solution (pH ~ 4), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 62 (166 mg). 1 H-NMR(400MHz,DMSO-d6)δ 10.06(brs,1H),9.34(br s,1H),7.43(s,1H),7.20(br s,1H),6.91(br s,1H),3.92(s,3H),3.82(s,3H),1.45(s,9H),EI-MS m / z:[M+H] + 364.28.

[0221] Preparation of compound 63 Compound 62 (166 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 259 mg, 0.68 mmol) and N,N'-diisopropylethylamine (0.16 mL, 0.91 mmol) were added at 0°C under a nitrogen atmosphere. N,N'-dimethyl-1,3-propanediamine (0.11 mL, 0.91 mmol) was added to the reaction solution, and then the temperature was raised to room temperature and stirred for 18 hours. Saturated ammonium aqueous solution (15 mL) was added to the reaction solution, and then extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed in the following order with saturated sodium bicarbonate aqueous solution (20 mL), distilled water (20 mL), and sodium chloride aqueous solution (20 mL). The compound was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain compound 63 (188 mg, 92%). 1 H-NMR(400MHz,CDCl3)δ 8.72(s,1H),7.73(br s,1H),7.19(d,J=1.2Hz,1H),7.13(br s,1H),6.85(br s,1H),6.43(d,J=1.6Hz,1H),4.04(s,3H),3.92(s,3H),3.46(m,2H),2.46(t,J=5.6Hz,2H),1.71(m,2H),EI-MS m / z:[M+H] + 448.27,[M / 2+H] + 224.93.

[0222] Preparation of compound 64 Compound 63 (188 mg, 0.42 mmol) was diluted with dichloromethane (3.2 mL), and then trifluoroacetic acid (1.6 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 3 hours. The reaction solution was concentrated under a nitrogen gas atmosphere to obtain compound 64 (145 mg). 1H-NMR(400MHz,DMSO-d6)δ 10.32(s,1H),9.29(br s,1H),8.18(t,J=5.2Hz,1H),7.23(s,2H),7.03(s,1H),3.96(s,3H),3.81(s,3H),3.24(m,2H),3.06(m,2H),2.79(m,6H),1.83(m,2H),EI-MS m / z:[M+H] + 348.34, [M / 2+H] + 174.75.

Example

[0223] Production of Compound 65

change

[0224] Compound 10, compound 64, and compound 23 were synthesized by the same method, and compound 65 was produced. 1 H-NMR(400MHz,Methanol-d4)δ 7.77(br s,1H),7.40(s,1H),7.35-7.28(m,2H),7.24(s,1H),7.14(s,1H),6.92(s,1H),6.70(s,1H),5 .56(d,J=9.6Hz,1H),5.30(d,J=9.6Hz,1H),5.17(m,3H),4.80(d,J=11.6Hz,1H),4.25-4.01( m,6H),4.03-3.95(m,5H),3.89(s,3H),3.83(s,3H),3.74(m,2H),3.67-3.54(m,14H),3.41(t ,J=6Hz,2H),3.16(t,J=7.6Hz,2H),2.66(m,1H),2.53(m,2H),2.11(m,2H),1.99(m,2H),EI-MS m / z:[M+H] + 1208.51, [M / 2+H] + 605.05.

Example

[0225] Production of Compound 67

change

[0226] Preparation of compound 66 Compound 62 (240 mg, 0.66 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 376 mg, 0.99 mmol) and N,N'-diisopropylethylamine (0.34 mL, 1.98 mmol) were added at 0°C under a nitrogen atmosphere. 3-amino-1-propanol (0.15 mL, 1.98 mmol) was added to the reaction solution, and then the temperature was raised to room temperature and stirred for 18 hours. Saturated ammonium chloride aqueous solution (15 mL) was added to the reaction solution, and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed in the following order with saturated sodium bicarbonate aqueous solution (20 mL), distilled water (20 mL), and sodium chloride aqueous solution (20 mL). The compound was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain compound 66 (242 mg, 87%). 1 H-NMR(400MHz,CDCl3)δ 8.80(br s,1H),7.14(br s,2H),7.06(br s,1H),6.56(s,1H),6.27(br s,1H),4.03(s,3H),3.89(s,3H),3.69(m,2H),3.53(m,2H),3.26(br s,1H),1.51(s,9H),EI-MS m / z:[M+H] + 421.33.

[0227] Preparation of compound 67 Compound 66 (100 mg, 0.23 mmol) was diluted with dichloromethane (1 mL), then trifluoroacetic acid (1 mL) and distilled water (0.2 mL) were added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 1 hour. The reaction solution was based with sodium carbonate (pH ~8) and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 67 (46 mg). 1H-NMR(400MHz,DMSO-d6)δ 9.90(s,1H),7.95(t,J=5.6Hz,1H),7.16(s,1H),6.90(s,1H),6.37(s,1H),4.47(m,1H),4.38(br s,2H),3.83(s,3H),3.76(s,3H),3.36(m,2H),3.21(m,2H),1.60(m,2H),EI-MS m / z:[M+H] + 321.30,[M / 2+H] + 159.08. [Examples]

[0228] Preparation of compound 68 [ka]

[0229] Compound 68 was prepared from compound 10 and compound 67 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1181.37,[M / 2+H] + 591.49. [Examples]

[0230] Preparation of compound 75 [ka]

[0231] Preparation of compound 69 Ethyl 2-aminothiazole-4-carboxylate (1.0 g, 5.81 mmol) was dissolved in dichloromethane (7 mL), and then 4-dimethylaminopyridine (14.0 mg, 0.12 mmol) and di-t-butyl dicarbonate (1.76 mL, 7.55 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 mL), washed with distilled water (50 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. The combined organic layer was dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain compound 69 (1.7 g, crude). EI-MS m / z: [M+H] + 273.21.2,[M+H] + 545.17.

[0232] Preparation of compound 70 Compound 69 (1.7 g, 5.81 mmol) was dissolved in tetrahydrofuran (6 mL) and methanol (6 mL). Then, under a nitrogen atmosphere, a solution of lithium hydroxide (697 mg, 17.3 mmol) dissolved in distilled water (1 mL) was added, and the mixture was stirred for 3 hours. The organic solvent was concentrated under reduced pressure, then diluted with distilled water (50 mL), and the pH was adjusted to approximately 4 with 6N hydrochloric acid aqueous solution. The resulting solid was then filtered to obtain compound 70 (1.4 g, 99%). 1 H-NMR (400MHz, DMSO-d6) δ 12.80 (br s, 1H), 11.70 (s, 1H), 7.91 (s, 1H), 1.48 (s, 9H).

[0233] Preparation of compound 71 Compound 70 (700 mg, 2.87 mmol) was dissolved in dichloromethane (20 mL), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (668 mg, 4.30 mmol) and 1-hydroxybenzotriazole (581 mg, 4.30 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. Triethylamine (0.59 mL, 4.30 mmol) and 3-amino-1-propanol (0.65 mL, 8.60 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. The reaction solution was washed with saturated sodium bicarbonate aqueous solution (20 mL) and saline solution (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, then filtered and concentrated, and purified by column chromatography to obtain compound 71 (520 mg, 60%). 1 H-NMR(400MHz,DMSO-d6)δ 11.59(s,1H),7.75(t,J=6Hz,1H),7.69(s,1H),4.52(s,1H),3.45(s,2H),3.30(s,2H),1.64(m,2H),1.48(s,9H).

[0234] Preparation of compound 72 Compound 71 (260.0 mg, 0.86 mmol) was diluted with dichloromethane (12 mL), then trifluoroacetic acid (3 mL) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. Distilled water (10 mL) was added to the reaction solution, and the pH was adjusted to approximately 11 with 2N sodium hydroxide aqueous solution, after which it was extracted with dichloromethane (10 mL x 5). The combined organic layer was dried over anhydrous sodium sulfate, then filtered and concentrated to obtain compound 72 (170 mg, 98%). EI-MS m / z:[M+H] + 202.19.

[0235] Preparation of compound 73 Compound 72 (490 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (6 mL), and then imidazole (250 mg, 3.66 mmol) and t-butyldimethylsilyl chloride (440 mg, 2.93 mmol) were added under a nitrogen atmosphere at 0°C, followed by stirring at room temperature for 2 hours. Ethyl acetate (20 mL) was added to the reaction solution, and then it was washed with an aqueous sodium hydroxide solution (20 mL) with a pH of approximately 11. The organic layer was dried over anhydrous sodium sulfate, then filtered and concentrated, and purified by column chromatography to obtain compound 73 (430 mg, 80%). 1 H-NMR(400MHz,CDCl3)δ 7.42(s,1H),7.33(s,1H),4.91(s,2H),3.75(t,J=5.6Hz,2H),3.50(q,J=6.4Hz,2H),1.80(m,2H),0.91(s,9H),0.08(s,6H).

[0236] Preparation of compound 74 Compound 73 (210.0 mg, 1.24 mmol) was dissolved in thionyl chloride (6 mL) and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, redissolved in dichloromethane, and then concentrated under reduced pressure several times. The resulting compound was dissolved in N,N-dimethylformamide (2 mL), and then N,N'-diisopropylethylamine (1.0 mL, 6.20 mmol) and compound 14 (430 mg, 1.36 mmol) were added sequentially under a nitrogen atmosphere at 0°C, followed by heating at 100°C for 3 hours. Ethyl acetate (20 mL) was added to the reaction solution, and then washed with distilled water (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, then filtered and concentrated, and purified by column chromatography to obtain compound 74 (130 mg, 23%). 1 H-NMR(400MHz,CDCl3)δ 9.05(s,1H)7.79(s,1H),7.70(s,1H),7.55(s,1H),7.36(s,1H),4.09(s,3H) ,3.79(t,J=5.6Hz,2H),3.57(m,2H),1.83(m,2H),0.95(s,9H),0.13(s,6H).

[0237] Preparation of compound 75 Compound 74 (130 mg, 0.27 mmol) was dissolved in methanol (3 mL) and ethyl acetate (3 mL), and then palladium / charcoal (10% w / w, 60 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction solution was filtered through Celite and then concentrated to obtain compound 75 (115 mg, 97%). EI-MS m / z:[M+H] + 438.37. [Examples]

[0238] Preparation of compound 76 [ka]

[0239] Compound 76 was prepared from compound 10 and compound 75 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1184.49,[M / 2+H] + 592.85. [Examples]

[0240] Preparation of compound 84 [ka]

[0241] Preparation of compound 77 Compound 13 (5.5 g, 29.8 mmol) was dissolved in methanol (100 mL) and ethyl acetate (100 mL), and then palladium / charcoal (10% w / w, 1.1 g) was added at 0°C under a nitrogen atmosphere. Sodium borohydride (NaBH4, 3.4 g, 89.6 mmol) was added to distilled water (100 mL), and then this solution was slowly added to the reaction solution using a dropping funnel, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through Celite, then diluted with dichloromethane (100 mL), washed with distilled water (100 mL), and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and diluted with dichloromethane (450 mL). To this solution, di-t-butyl dicarbonate (9.4 g, 43.1 mmol) dissolved in dichloromethane (300 mL) was added. The reaction solution was heated under reflux and stirred for 18 hours. The reaction solution was washed with distilled water (300 mL) and then dried over anhydrous sodium sulfate. After filtration, it was concentrated and purified by column chromatography to obtain compound 77 (6.0 g, 80%). 1 H-NMR (400MHz, CDCl3) δ 7.08 (s, 1H), δ 6.60 (s, 1H), δ 6.21 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 1.49 (s, 9H).

[0242] Preparation of compound 78 Compound 77 (3.7 g, 14.51 mmol) was diluted with 1,4-dioxane (30 mL), and then sodium hydroxide (1.1 g, 29.0 mmol) dissolved in distilled water (15 mL) was added at 0°C under a nitrogen atmosphere. The solution was stirred for 3 hours while being heated to 70°C. The reaction solvent was concentrated, then adjusted to pH ~2 with 6N hydrochloric acid aqueous solution, then diluted with ethyl acetate (100 mL), washed with distilled water (50 mL), and dried over anhydrous sodium. After filtration, the solution was concentrated to obtain compound 78 (3.4 g, 97%). 1 H-NMR (400 MHz, CDCl3) δ 7.18 (s, 1H), δ 6.72 (s, 1H), δ 6.28 (s, 1H), 3.86 (s, 3H), 1.50 (s, 9H).

[0243] Preparation of compound 79 2-chloro-5-nitrobenzaldehyde (3.7 g, 19.9 mmol) was dissolved in N,N-dimethylformamide (40 mL), and then methyl mercaptoacetate (1.82 mL, 19.9 mmol) and potassium carbonate (3.3 g, 24 mmol) were added. The mixture was stirred at room temperature for 18 hours. Distilled water (50 mL) was added to the reaction solution, and the resulting solid was filtered to obtain compound 79 (4.65 g, 95%). 1 H-NMR (400MHz, DMSO-d6) δ 9.00 (d, J = 1.6 Hz, 1H), 8.45 (s, 1H), 8.38-8.30 (m, 2H), 3.93 (s, 3H).

[0244] Preparation of compound 80 Compound 79 (1.6 g, 6.74 mmol) was dissolved in methanol (50 mL), and then palladium / charcoal (10% w / w, 312 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction solution was filtered through Celite and then concentrated to obtain compound 80 (1.23 g, 81%). 1 H-NMR(400MHz,DMSO-d6)δ 7.92(s,1H),7.65(d,J=8.8Hz,1H),7.04(s,1H),6.88(d,J=8.8Hz,1H),5.28(s,2H),3.84(s,3H).

[0245] Preparation of compound 81 Compound 78 (564 mg, 2.35 mmol) and compound 80 (444 mg, 2.14 mmol) were dissolved in N,N-dimethylformamide (20 mL). Then, under a nitrogen atmosphere at 0°C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (821 mg, 4.28 mmol) and 4-dimethylaminopyridine (645 mg, 5.35 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (30 mL) was added to the reaction solution, and then the mixture was washed in the following order: saturated ammonium chloride aqueous solution (30 mL), saturated sodium bicarbonate aqueous solution (30 mL), and distilled water (30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization with diethyl ether and hexane yielded compound 81 (770 mg, 84%). 1 H-NMR(400MHz,DMSO-d6)δ 9.99(s,1H),9.15(s,1H),8.96(d,J=1.6Hz,1H),8.18(s,1H),7.98-7.96(m,1H), 7.80-7.78(m,1H),6.98(d,J=7.6Hz,2H),3.88(s,3H),3.81(s,3H),1.46(s,9H). EI-MS m / z:[M+H] + 430.1.

[0246] Preparation of compound 82 Compound 81 (270 mg, 0.627 mmol) was dissolved in methanol (10 mL), and then a solution of sodium hydroxide (250 mg, 6.26 mmol) dissolved in distilled water (10 mL) was slowly added under a nitrogen atmosphere. The mixture was stirred under reflux for 4 hours. The reaction solution was adjusted to pH ~3 with 1N hydrochloric acid aqueous solution, then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 82 (227 mg, 87%). 1 H-NMR(400MHz,DMSO-d6)δ 9.96(s,1H),9.14(s,1H),8.45(s,1H),8.06(s,1H),7.95-7.93(m,1H),7.77-7.75(m,1H),6.98(d,J=7.6Hz,2H),3.83(s,3H),1.46(s,9H).

[0247] Preparation of compound 83 Compound 82 (227 mg, 0.54 mmol) and 3-(dimethylamino)-1-propylamine (0.75 mL, 0.59 mmol) were dissolved in N,N-dimethylformamide (10 mL). Then, under a nitrogen atmosphere at 0°C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (209 mg, 1.09 mmol) and 4-dimethylaminopyridine (167 mg, 1.36 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction solution, followed by washing with saturated ammonium chloride aqueous solution (10 mL), saturated sodium bicarbonate aqueous solution (10 mL), and distilled water (10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 83 (280 mg). EI-MS m / z:[M+H] + 500.23.

[0248] Preparation of compound 84 Compound 83 (170 mg, 0.34 mmol) was dissolved in dichloromethane (2 mL), hydrochloric acid (4 M 1,4-dioxane solution, 2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 84 (160 mg). EI-MS m / z:[M+H] + 400.3. [Examples]

[0249] Preparation of compound 85 [ka]

[0250] Compound 85 was prepared from compound 10 and compound 84 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1260.41,[M / 2+H] + 631.1. [Examples]

[0251] Preparation of compound 87 [ka]

[0252] Preparation of compound 86 Compound 82 (253 mg, 0.609 mmol) and 3-amino-1-propanol (0.07 mL, 0.913 mmol) were dissolved in N,N-dimethylformamide (5 mL). Then, under a nitrogen atmosphere at 0°C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (233 mg, 1.21 mmol) and 4-dimethylaminopyridine (186 mg, 1.52 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction solution, and then the mixture was washed in the following order: saturated ammonium chloride aqueous solution (10 mL), saturated sodium bicarbonate aqueous solution (10 mL), and distilled water (10 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. After dilution with dichloromethane (10 mL) and diethyl ether (20 mL), the resulting solid was filtered to obtain compound 86 (123 mg, 43%). 1 H-NMR(400MHz,DMSO-d6)δ 9.92(s,1H),9.14(s,1H),8.68(t,J=5.6Hz,1H),8.32(s,1H),7.98-7.89(m,2H),7.75-7.73(m,1H),6.96(s, 1H),4.49(t,J=5.2Hz,1H)3.82(s,3H),3.60-3.45(m,2H),3.35-3.30(m,2H),1.73-1.66(m,2H),1.46(s,9H).

[0253] Preparation of compound 87 Compound 86 (123 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), hydrochloric acid (4 M 1,4-dioxane solution, 2 mL) was added, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the mixture was washed with ethyl acetate (10 mL) and aqueous sodium carbonate solution (10 mL), and concentrated to dryness with anhydrous sodium sulfate to obtain compound 87 (97 mg). 1H-NMR(400MHz,DMSO-d6)δ 9.92(s,1H),9.14(s,1H),8.79(br,2H),8.68(t,J=5.6Hz,1H),8.32(s,1H),7.98-7.89(m,2H),7.75-7.73(m,1H),6 .96(s,1H),4.49(t,J=5.2Hz,1H)3.82(s,3H),3.60-3.45(m,2H),3.35-3.30(m,2H),1.73-1.66(m,2H),1.46(s,9H). [Examples]

[0254] Preparation of compound 88 [ka]

[0255] Compound 88 was prepared from compound 10 and compound 87 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1234.41,[M / 2+H] + 617.56. [Examples]

[0256] Preparation of compound 93 [ka]

[0257] Preparation of compound 89 Compound 14 (300 mg, 1.72 mmol) was mixed with thionyl chloride (2 mL) and stirred under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, dried, and then dissolved in dichloromethane (8 mL). This solution was then added to a solution of 3-(dimethylamino)-1-propylamine (466 mg, 5.29 mmol) and triethylamine (0.74 mL, 5.29 mmol) dissolved in dichloromethane (5 mL) under a nitrogen atmosphere at -50°C. The reaction temperature was gradually increased to 0°C while stirring for 2 hours. The reaction solution was diluted with dichloromethane (30 mL), washed with distilled water (20 mL), and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated to obtain compound 89 (396 mg, 94%). 1 H-NMR (400MHz, DMSO-d6) δ 8.40(t,1H),8.11(d,1H),7.40(d,1H),3.90(s,3H),3.20(m,2H),2.23(t,2H),1.61(m,2H).

[0258] Preparation of compound 90 Compound 89 (150 mg, 0.59 mmol) was dissolved in methanol (6 mL), and then palladium / charcoal (10% w / w, 80 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through Celite and then concentrated to obtain compound 90 (132 mg, 100%).

[0259] Preparation of compound 91 Methanol (5.5 mL) was added to compound 79 (300 mg, 1.26 mmol), and then 1 M sodium hydroxide aqueous solution (5 mL) was added under a nitrogen atmosphere at 0°C. The mixture was heated under reflux for 3 hours. The methanol was concentrated, and then the pH was adjusted to approximately 2 with 1 N hydrochloric acid aqueous solution. The resulting solid was then filtered to obtain compound 91 (248 mg, 88%). 1 H-NMR (400MHz, DMSO-d6) δ 8.98 (d, J=1.6Hz, 1H), 8.35-8.28 (m, 3H).

[0260] Preparation of compound 92 To compound 91 (166 mg, 0.744 mmol), thionyl chloride (3 mL) was added, and the mixture was stirred at 70°C for 1 hour and then concentrated under reduced pressure. Dichloromethane (5 mL) was added to dissolve the mixture, and then triethylamine (0.3 mL, 2.23 mmol) and compound 90 (217 mg, 0.967 mmol) were added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and then purified by column chromatography to obtain compound 92 (189 mg, 60%). 1 H-NMR(400MHz,DMSO-d6)δ 10.57(s,1H),8.96(d,J=1.6Hz,1H),8.41(s,1H),8.35-8.32(m,1H),8.28-8.25(m,1H),8.16(t,J=5.6Hz,1H),7.28(s, 1H),6.88(s,1H),3.83(s,3H),3.22-3.18(m,2H),2.32-2.26(m,2H),2.16(s,6H),1.66-1.59(m,2H),1.24-1.21(m,1H). EI-MS m / z:[M+H] + 430.2.

[0261] Preparation of compound 93 Compound 92 (110 mg, 0.25 mmol) was dissolved in methanol (20 mL), then palladium / charcoal (10% w / w, 110 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction solution was filtered through Celite, and then concentrated under reduced pressure to obtain compound 93 (102 mg, 99%). EI-MS m / z:[M+H] + 400.2. [Examples]

[0262] Preparation of compound 94 [ka]

[0263] Compound 94 was prepared from compound 10 and compound 93 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1260.61,[M / 2+H] +630.90. [Examples]

[0264] Preparation of compound 99 [ka]

[0265] Preparation of compound 95 To compound 14 (600 mg, 3.526 mmol), thionyl chloride (10 mL) was added, and the mixture was stirred at 70°C for 1 hour and then concentrated under reduced pressure. Dichloromethane (15 mL) was added and dissolved, and then triethylamine (1.47 mL, 10.58 mmol) and 3-amino-1-propanol (0.8 mL, 10.6 mmol) were added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. Dichloromethane (200 mL) was added to the reaction solution, and then washed with saturated sodium bicarbonate aqueous solution (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 95 (527 mg, crude). 1 H-NMR(400MHz,CDCl3)δ 7.55(s,1H),7.08(s,1H),6.72(br,1H),3.99(s,3H),3.78-3.75(m,2H),3.59-3.54(m,2H),3.03-2.98(m,1H),1.88-1.78(m,2H).

[0266] Preparation of compound 96 Compound 95 (527 mg, 2.32 mmol) was dissolved in dichloromethane (30 mL), and t-butyldimethylsilyl chloride (524 mg, 3.48 mmol) and imidazole (315 mg, 4.64 mmol) were added at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain compound 96 (660 mg, 83%). 1H-NMR(400MHz,CDCl3)δ 7.53(s,1H),7.07(s,1H),6.88(br,1H),3.98(s,3H),3.84-3.81(m,2H),3.54-3.50(m,2H),1.84-1.20(m,2H),0.91(s,9H),0.10(s,6H).

[0267] Preparation of compound 97 Compound 96 (400 mg, 1.17 mmol) was dissolved in methanol (30 mL), then palladium / charcoal (10% w / w, 200 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction solution was filtered through Celite, and then concentrated under reduced pressure to obtain compound 97 (293 mg, 76%). 1 H-NMR(400MHz,CDCl3)δ 7.53(s,1H),7.07(s,1H),6.88(br,1H),6.66(br,2H),3.98(s,3H),3.84-3 .81(m,2H),3.54-3.50(m,2H),1.84-1.20(m,2H),0.91(s,9H),0.10(s,6H).

[0268] Preparation of compound 98 Compound 91 (100 mg, 0.446 mmol) and Compound 97 (145 mg, 0.490 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (171 mg, 0.892 mmol) and 4-dimethylaminopyridine (136 mg, 1.11 mmol) were added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction solution, and then the mixture was washed in the following order: saturated ammonium chloride aqueous solution (10 mL), saturated sodium bicarbonate aqueous solution (10 mL), and distilled water (10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain Compound 98 (117 mg, 51%). 1H-NMR(400MHz,DMSO-d6)δ 10.85(2,1H),8.96(s,1H),8.41(s,1H),8.35-8.31(m,1H),8.28-8.25(m,1H),8.05(t,J=5.2Hz,1H),7.28(s,1H) ),6.89(s,1H),3.82(s,3H),3.67-3.62(m,2H),3.24-3.21(m,2H),1.73-1.68(m,2H),0.87(s,9H),0.06(s,6H).

[0269] Preparation of compound 99 Compound 98 (117 mg, 0.226 mmol) was dissolved in methanol (20 mL), then palladium / charcoal (10% w / w, 100 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through Celite and then concentrated under reduced pressure to obtain compound 99 (110 mg, crude). EI-MS m / z:[M+H] + 487.33. [Examples]

[0270] Preparation of compound 100 [ka]

[0271] Compound 100 was prepared from compound 10 and compound 99 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1234.41,[M / 2+H] + 617.60. [Examples]

[0272] Preparation of compound 109 [ka]

[0273] Preparation of compound 101 3-amino-1-propanol (1.5 g, 20.0 mmol) was dissolved in dichloromethane (30 mL), and t-butyldimethylsilyl chloride (3.15 g, 21.0 mmol) and imidazole (2.72 g, 40.0 mmol) were added at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound 101 (3.65 g, 96%). 1 H-NMR (400MHz, CDCl3) δ 3.71-3.67(m,2H),2.81-2.78(m,2H),2.06(br,2H),1.69-1.62(m,2H),0.88(s,9H),0.04(s,6H).

[0274] Preparation of compound 102 3-(methylamino)-1-propanol (1.2 g, 13.4 mmol) was dissolved in dichloromethane (15 mL), and then di-t-butyl dicarbonate (3.2 g, 14.74 mmol) dissolved in dichloromethane (5 mL) was slowly added at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour, and then 0.1 N hydrochloric acid aqueous solution (10 mL) was added at 0°C. The organic layer was washed with distilled water (10 mL) and saline solution (10 mL), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 102 (2.0 g, 78%). 1 H-NMR (400MHz, CDCl3) δ 3.54-3.48 (m, 2H), 3.42-3.39 (m, 2H), 2.83 (s, 3H), 1.78-1.68 (m, 2H), 1.46 (s, 9H).

[0275] Preparation of compound 103 Compound 102 (1 g, 5.28 mmol) was dissolved in dichloromethane (16 mL), and then triphenylphosphine (2.12 g, 8.08 mmol) was added. Carbon tetrabromide (2.6 g, 8.08 mmol) dissolved in dichloromethane (10 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 30 minutes. After concentration under reduced pressure, the mixture was purified by column chromatography to obtain compound 103 (0.6 g, 45%). 1H-NMR (400MHz, CDCl3) δ 3.41-3.33 (m, 4H), 2.87 (s, 3H), 2.10-2.06 (m, 2H), 1.46 (s, 9H). JPEG2026086866000086.jpg55160

[0276] Preparation of compound 104 Ethyl 4-nitro-1H-pyrrole-2-carboxylic acid (292 mg, 1.56 mmol) was dissolved in acetone (20 mL), compound 103 (0.6 g, 2.38 mmol) and potassium carbonate (493 mg, 3.57 mmol) were added, and the mixture was stirred at 60°C under a nitrogen atmosphere for 12 hours. The mixture was concentrated under reduced pressure, extracted with dichloromethane (20 mL) and distilled water (20 mL), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated and purified by column chromatography to obtain compound 104 (0.53 g, 98%). 1 H-NMR(400MHz,CDCl3)δ 7.74(br s,1H),7.52(s,1H),4.37-4.28(m,4H),3.42(s,2H),2.86(s,3H),2.06-1.99(m,2H),1.46(s,9H),1.38-1.30(t,J=7.2Hz,3H).

[0277] Preparation of compound 105 Compound 104 (0.53 g, 1.55 mmol) was dissolved in ethanol (10 mL), and 10 mL of 1 N sodium hydroxide aqueous solution was added under a nitrogen atmosphere. The mixture was stirred at 60°C for 2 hours. The ethanol was concentrated, and then the pH was adjusted to approximately 5 with 1 N hydrochloric acid aqueous solution. After extraction with ethyl acetate (20 mL), the organic layer was dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to obtain compound 105 (493 mg, 96%). 1 H-NMR (400MHz, CDCl3) δ 7.80 (br s, 1H), 7.55 (s, 1H), 4.39-4.35 (m, 2H), 3.32 (s, 2H), 2.87 (s, 3H), 2.17-2.03 (m, 2H), 1.46 (s, 9H).

[0278] Preparation of compound 106 Compound 105 (350 mg, 1.07 mmol) and Compound 101 (303 mg, 1.6 mmol) were dissolved in N,N-dimethylformamide (10 mL). Then, under a nitrogen atmosphere at 0°C, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 637 mg, 1.60 mmol) and N,N'-diisopropylethylamine (0.55 mL, 3.20 mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with ethyl acetate (20 mL), then washed with distilled water (20 mL) and saline solution (20 mL), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 106 (290 mg, 54%). 1 H-NMR(400MHz,CDCl3)δ 7.65(br s,1H),7.01(s,1H),6.89(br s,1H),4.37-4.30(m,2H),3.83-3.81(m,2H),3.53-3.49(m,2H),3.28-3.26(m,2H),2.8 4(s,3H),2.07-2.00(m,2H),1.83-1.78(m,2H),1.45(s,9H),0.90(s,9H),0.10(s,6H).

[0279] Preparation of compound 107 Compound 106 (290 mg, 0.58 mmol) was dissolved in methanol (30 mL), and then palladium / charcoal (10% w / w, 100 mg) was added under a hydrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through Celite, and then concentrated under reduced pressure to obtain compound 107 (250 mg, 92%). 1 H-NMR(400MHz,CDCl3)δ 6.99(br s,1H),6.83(br s,1H),6.61(br s,2H),4.28-4.24(m,2H),3.71-3.70(m,2H),3.45-3.40(m,2H),3.23-3.19(m,2H),2.8 4(s,3H),1.97-1.94(m,2H),1.81-1.75(m,2H),1.45(s,9H),0.88(s,9H),0.11(s,6H).

[0280] Preparation of compound 108 Compound 14 (76 mg, 0.44 mmol) and Compound 107 (250 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (10 mL), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (171 mg, 0.88 mmol) and 4-dimethylaminopyridine (136 mg, 1.11 mmol) were added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction solution, and then the mixture was washed with saturated ammonium chloride aqueous solution (10 mL), saturated sodium bicarbonate aqueous solution (10 mL), and distilled water (10 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and then purified by column chromatography to obtain Compound 108 (197 mg, 72%). 1 H-NMR(400MHz,CDCl3)δ 7.60(s,1H),7.19(br s,2H),6.54(br s,1H),6.37(br s,1H),4.29(s,2H),4.03(s,3H),3.78-3.75(m,2H),3.50-3.46(m,2H),3.26(s,2H),2. 84(s,3H),2.04-1.99(m,2H),1.82-1.76(m,2H),1.45(s,9H),0.98(s,9H),0.08(s,6H). EI-MS m / z:[M+H] + 621.80.

[0281] Preparation of compound 109 Compound 108 (197 mg, 0.317 mmol) was dissolved in methanol (20 mL), and then palladium / charcoal (10% w / w, 80 mg) was added under a hydrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through Celite and then concentrated under reduced pressure to obtain compound 109 (185 mg, 99%). 1H-NMR(400MHz,CDCl3)δ 7.29(br s,1H),7.19(br s,1H),6.54(br s,1H),6.33(br s,2H),6.15(s,1H),4.30-4.26(m,2H),3.88(s,3H),3.77-3.74(m,2H),3.48-3.44(m,2H),3.29( s, 2H), 2.84 (s, 3H), 2.05-1.98 (m, 2H), 1.79-1.76 (m, 2H), 1.40 (s, 9H), 0.90 (s, 9H), 0.08 (s, 6H). [Examples]

[0282] Preparation of compound 110 [ka]

[0283] Compound 110 was prepared from compound 10 and compound 109 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1238.03,[M / 2+H] + 619.81. [Examples]

[0284] Preparation of compound 117 [ka]

[0285] Preparation of compound 111 3-bromo-1-propanol (1.0 g, 7.19 mmol) was dissolved in dichloromethane (20 mL), and t-butyldimethylsilyl chloride (1.08 g, 7.19 mmol) and imidazole (0.49 g, 7.19 mmol) were added at 0°C. The mixture was then stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound 111 (1.47 g, 81%). 1H-NMR (400MHz, CDCl3) δ 3.72(t,J=5.6Hz,2H),3.51(t,J=5.62Hz,2H),2.06-2.00(m,2H),0.89(s,9H),0.06(s,6H).

[0286] Preparation of compound 112 Ethyl 4-nitro-1H-pyrrole-2-carboxylic acid (500 mg, 2.71 mmol) was dissolved in acetone (30 mL), compound 111 (1.03 g, 4.07 mmol) and potassium carbonate (1.12 g, 8.14 mmol) were added, and the mixture was stirred at 60°C under a nitrogen atmosphere for 12 hours. The mixture was concentrated under reduced pressure, diluted with dichloromethane (20 mL), and then washed with distilled water (20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography to obtain compound 112 (894 mg, 92%). 1 H-NMR(400MHz,CDCl3)δ 7.67(s,1H),7.45(s,1H),4.50-4.47(m,2H),4.35-4.29(m,2H),3.59-3.5 6(m,2H),2.02-1.96(m,2H),1.38-1.36(m,2H),0.93(s,9H),0.07(s,6H).

[0287] Preparation of compound 113 Compound 112 (890 mg, 2.49 mmol) was dissolved in ethanol (20 mL), and 10 mL of 1 M sodium hydroxide aqueous solution was added under a nitrogen atmosphere. The mixture was stirred at 60°C for 2 hours. The ethanol was concentrated, then the pH was adjusted to approximately 2 with 1 N hydrochloric acid aqueous solution. After extraction with ethyl acetate (20 mL), the organic layer was concentrated to dryness with anhydrous sodium sulfate to obtain compound 113 (724 mg, 88%). 1 H-NMR (400MHz, CDCl3) δ 7.70 (br s, 1H), 7.55 (s, 1H), 4.48 (br s, 2H), 3.56 (s, 2H), 1.99 (s, 2H), 0.91 (s, 9H), 0.10 (s, 6H).

[0288] Preparation of compound 114 Compound 113 (548 mg, 1.66 mmol) and Compound 101 (537 mg, 2.83 mmol) were dissolved in N,N-dimethylformamide (20 mL). Then, under a nitrogen atmosphere at 0°C, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 999 mg, 2.50 mmol) and N,N'-diisopropylethylamine (0.58 mL, 3.30 mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (20 mL) was added, followed by washing with distilled water (20 mL) and saline solution (20 mL). The organic layer was then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain Compound 114 (556 mg, 67%). 1 H-NMR(400MHz,CDCl3)δ 7.60(s,1H),7.01(s,1H),6.87(br s,1H),4.49-4.45(m,2H),3.83-3.81(m,2H),3.56-3.49(m,4H),2.01-1 .98(m,2H),1.81-1.76(m,2H),0.91(s,18H),0.10(s,6H),0.05(s,6H).

[0289] Preparation of compound 115 Compound 114 (300 mg, 0.60 mmol) was dissolved in methanol (30 mL), and then palladium / charcoal (10% w / w, 100 mg) was added under a hydrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through Celite, and then concentrated under reduced pressure to obtain compound 115 (276 mg, 98%). 1 H-NMR(400MHz,CDCl3)δ 6.35(s,1H),6.27(br s,1H),6.05(s,1H),4.30-4.27(m,2H),3.77-3.74(m,2H),3.58-3.56(m ,2H),3.46-3.43(m,2H),1.96-1.89(m,2H),1.80-1.76(m,2H),1.72(br s, 2H), 0.91 (s, 18H), 0.08 (s, 6H), 0.05 (s, 6H). EI-MS m / z:[M+H] + 470.5.

[0290] Preparation of compound 116 Compound 14 (83 mg, 0.48 mmol) and Compound 115 (276 mg, 0.58 mmol) were dissolved in N,N-dimethylformamide (10 mL). Then, under a nitrogen atmosphere at 0°C, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 350 mg, 0.73 mmol) and N,N'-diisopropylethylamine (0.20 mL, 0.97 mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain Compound 116 (208 mg, 57%). 1 H-NMR(400MHz,CDCl3)δ 7.71(s,1H),7.60(s,1H),7.20(br s,1H),6.55(s,1H),6.36(br s,1H),4.40-4.36(m,2H),4.02(s,3H),3.77-3.74(m,2H),3.61-3.58(m,2H),3.49-3.4 5(m,2H),2.07-1.94(m,2H),1.82-1.80(m,2H),0.91(s,18H),0.08(s,6H),0.05(s,6H). EI-MS m / z:[M+H] + 622.7.

[0291] Preparation of compound 117 Compound 116 (100 mg, 0.16 mmol) was dissolved in methanol (20 mL), and then palladium / charcoal (10% w / w, 30 mg) was added under a hydrogen atmosphere. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through Celite and then concentrated under reduced pressure to obtain compound 117 (88 mg, 93%). EI-MS m / z:[M+H] + 592.5. [Examples]

[0292] Preparation of compound 118 [ka]

[0293] Compound 118 was prepared from compound 10 and compound 117 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1224.9,[M / 2+H] + 623.08. [Examples]

[0294] Preparation of compound 124 [ka]

[0295] Preparation of compound 120 Compound 5 (1.84 g, 3.6 mmol) was dissolved in dichloromethane (10 mL), and then triphosgene (767 mg, 2.59 mmol) and N,N'-diisopropylethylamine (1.69 mL, 9.72 mmol) were added at 0°C and the mixture was stirred for 10 minutes. Dibutyltin dilaurate (227 mg, 0.36 mmol) and N,N'-diisopropylethylamine (1.25 mL, 7.2 mmol) were added to the reaction solution and the mixture was stirred for 5 minutes. A solution of Compound 119 (16.4 g, 21.0 mmol, Compound 119 was prepared by the method described in Patent Document 9) dissolved in dichloromethane (5 mL) was added, and then the temperature was gradually increased and the mixture was stirred at room temperature for 1.5 hours before the reaction solution was concentrated under reduced pressure. A saturated ammonium chloride aqueous solution (15 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3), washing with distilled water (50 mL) and sodium chloride aqueous solution (50 mL), and then drying over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 120 (2.84 g, 72%). 1H-NMR(400MHz,CDCl3)δ 8.93(br s,1H),8.04(d,J=2.4Hz,1H),7.83(br s,1H),7.52-7.44(m,2H),7.05(d,J=8.8Hz,1H),6.81(s,1H),5.93(m,1H),5.41-5.22(m,7H),5.13(s,2H),4.97(br s,1H),4.89(br s,1H),4.59(d,J=5.6Hz,2H),4.18(d,J=8.4Hz,2H),4.12(m,3H),3.80(s,3H),3.73(s,3H),3.69(m,1H),3.62-3. 53(m,4H),3.41(s,3H),2.66(m,2H),2.58(t,J=7.6Hz,2H),2.19(m,2H),2.05-2.04(m,9H),0.87(s,9H),0.02(br s,6H),EI-MS m / z:[M+H] + 1087.49,[M / 2+H] + 544.13.

[0296] Preparation of compound 121 Compound 120 (2.84 g, 2.6 mmol) was dissolved in tetrahydrofuran / distilled water (4 mL / 4 mL), acetic acid (8 mL) was added at 0°C, and the mixture was stirred at room temperature for 15 hours. After concentration under reduced pressure, saturated sodium bicarbonate aqueous solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The extracted solution was washed with distilled water (30 mL) and sodium chloride aqueous solution (30 mL), and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the solution was purified by column chromatography to obtain compound 121 (2.34 g, 92%). 1H-NMR(400MHz,CDCl3)δ 8.37(br s,1H),8.06(s,1H),7.74(br s,1H),7.52(m,1H),7.44(dd,J=8.8Hz,2Hz,1H),7.05(d,J=8.4Hz,1H),6.81(s,1H),5.93(m,1H),5.42-5.22(m,7H),5.14(br s,2H),5.00(br s,1H),4.91(br s,1H),4.59(m,3H),4.18(d,J=8.4Hz,2H),4.13-4.04(m,5H),3.83(s,3H),3.72-3.67(m,6H),3.62-3.53( EI-MS m / z:[M+H] + 972.48,[M / 2+H] + 486.99.

[0297] Preparation of compound 122 Compound 121 (2.34 g, 2.4 mmol) was dissolved in dichloromethane (24 mL), then Dess-Martin periodinane (1.23 g, 2.9 mmol) was added at 0°C, the mixture was heated to room temperature, and stirred under a nitrogen atmosphere for 1 hour. The reaction solution was diluted with saturated sodium thiosulfate aqueous solution / saturated sodium bicarbonate aqueous solution (v / v=1 / 1, 30 mL) and stirred for 10 minutes. The mixture was extracted with dichloromethane (30 mL x 3), and then washed with distilled water (30 mL) and saline solution (30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography to obtain compound 122 (1.75 g, 75%). 1H-NMR(400MHz,CDCl3)δ 7.99(br s,1H),7.50(br s,1H),7.23-7.19(m,2H),7.01(d,J=7.2Hz,1H),6.60(s,1H),5.92(m,1H),5.59(m,1H),5.43- 5.22(m,7H),5.14(m,2H),4.89(d,J=11.6Hz,1H),4.59(d,J=5.6Hz,2H),4.30-4.23(m,2H),4. 15-4.09(m,2H),3.95(m,1H),3.88(s,3H),3.72-3.69(m,4H),3.63-3.52(m,5H),3.41(s,3H), 2.89(m,1H),2.70(d,J=12Hz,1H),2.56(t,J=7.2Hz,2H),2.10(m,2H),2.05-2.04(m,9H),EI-MS m / z:[M+H] + 970.46,[M / 2+H] + 485.97.

[0298] Preparation of compound 123 Compound 122 (250 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2.5 mL), and then tetrakis(triphenylphosphine)palladium (0) (119 mg, 0.10 mmol) and pyrrolidine (0.02 mL, 0.28 mmol) were slowly added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction solution was acidified with 1N hydrochloric acid aqueous solution (pH ~ 4), then extracted with dichloromethane (20 mL x 3), and washed with sodium chloride aqueous solution (20 mL). After drying over anhydrous sodium sulfate, the solution was filtered and concentrated under reduced pressure to obtain compound 123 (239 mg). EI-MS m / z: [M + H] + 930.40,[M / 2+H] + 466.13.

[0299] Preparation of compound 124 Compound 123 (239 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 146 mg, 0.38 mmol) and N,N'-diisopropylethylamine (0.09 mL, 0.51 mmol) were added at 0°C under a nitrogen atmosphere. A solution of Compound 44 (133 mg, 0.30 mmol) dissolved in N,N-dimethylformamide (1 mL) was added to the reaction solution and stirred at room temperature for 1 hour. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, and then extracted with ethyl acetate (20 mL x 3), washed with saturated sodium bicarbonate aqueous solution (10 mL) and distilled water (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the compound was concentrated and then purified by column chromatography to obtain compound 124 (267 mg, 77%). EI-MS m / z:[M+H] + 1344.69,[M / 2+H] + 673.20. [Examples]

[0300] Preparation of compound 129 [ka]

[0301] Preparation of compound 125 Compound 124 (170 mg, 0.12 mmol) was diluted with dichloromethane (1.6 mL), and then trifluoroacetic acid (0.4 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 1 hour. The reaction solution was concentrated under a nitrogen gas atmosphere to obtain compound 125 (156 mg). EI-MS m / z:[M+H] + 1244.67,[M / 2+H] + 623.13.

[0302] Preparation of compound 127 Compound 125 (156 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then N,N'-diisopropylethylamine (0.06 mL, 0.37 mmol) was added at 0°C under a nitrogen atmosphere. Compound 126 (123 mg, 0.13 mmol, compound 126 was prepared by the method described in Patent Document 10), 1-hydroxy-7-azabenzotriazole (3.4 mg, 0.38 mmol), and N,N'-diisopropylethylamine (0.04 mL, 0.19 mmol) were added sequentially, the temperature was gradually increased, and the mixture was stirred at room temperature for 17 hours. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL x 3), washed with distilled water (10 mL) and sodium chloride aqueous solution (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the compound was concentrated and then purified by column chromatography to obtain compound 127 (143 mg, 56%). EI-MS m / z:[M+H] + 2001.40,[M / 2+H] + 1001.52.

[0303] Preparation of compound 128 Compound 127 (142 mg, 0.07 mmol) was dissolved in methanol / tetrahydrofuran (2 mL / 2 mL), and then a solution of lithium hydroxide (18 mg, 0.42 mmol) dissolved in distilled water (3 mL) was slowly added at -40°C under a nitrogen atmosphere. The reaction was stirred for 4 hours while gradually raising the temperature to 0°C. The reaction solution was acidified with acetic acid (pH ~ 4), then concentrated under reduced pressure, purified by HPLC, and then freeze-dried to obtain compound 128 (70.4 mg, 57%). EI-MS m / z: [M + H] + 1721.15,[M / 2+H] + 861.25.

[0304] Preparation of compound 129 Compound 128 (70.4 mg, 0.04 mmol) was diluted with dichloromethane (1.6 mL), and then trifluoroacetic acid (0.4 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 1 hour. The reaction solution was concentrated under a nitrogen gas atmosphere, then purified by HPLC, and lyophilized to obtain compound 129 (53.8 mg, 81%). EI-MS m / z:[M+H] + 1621.35,[M / 2+H] + 811.21. [Examples]

[0305] Preparation of compound 134 [ka]

[0306] Preparation of compound 130 m-Tolyethyl acetate (3 g, 16.83 mmol) was dissolved in carbon tetrachloride (20 mL), and then N-bromosuccinimide (NBS, 3.6 g, 20.19 mL) and 2,2'-azobis(isobutyronitrile) (AIBN, 111 mg, 0.67 mmol) were added, and the mixture was stirred under reflux for 18 hours. After cooling to room temperature, the resulting solid was filtered, washed with hexane (20 mL), and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 130 (2.63 g, 60%). 1 H-NMR (400MHz, CDCl3) δ 7.35-7.28(m,3H),7.24-7.20(m,1H),4.49(s,2H),4.16(q,2H),3.61(s,2H),1.26(t,3H).

[0307] Preparation of compound 131 Compound 3 (3.5 g, 8.28 mmol) and Compound 130 (2.4 g, 9.33 mmol) were dissolved in N,N-dimethylformamide (20 mL), then potassium carbonate (1.72 g, 12.42 mmol) and sodium iodide (0.25 g, 1.65 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction solution was diluted with ethyl acetate (100 mL) and then washed with distilled water (2 × 60 mL). The washed organic layer was washed with saline solution (60 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 131 (4.7 g, 94%). 1 H-NMR(400MHz,CDCl3)(rotamers)δ 7.67(s,1H),7.32-7.24(m,3H),7.19(m,1H),6.68(s,1H),5.10(s,2H),5.01(d,1H),4.89(s,1H),4.75(s,1H),4.10-4.01(m,2H),3.87(s ,3H),3.79(m,1H),3.70-3.60(m,2H),3.55(s,2H),2.76-2.58(m,2H) ,1.16(t,3H),0.80(s,6H),0.70(s,3H),-0.09(s,4H),-0.21(d,2H).

[0308] Preparation of compound 132 Compound 131 (4.7 g, 7.85 mmol) was dissolved in 1,4-dioxane (20 mL), and then 1 N sodium hydroxide aqueous solution (9.4 mL) was added at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction solvent was concentrated under reduced pressure, then the pH was adjusted to ~3 with 1 N hydrochloric acid aqueous solution, and after extraction with dichloromethane (3 × 40 mL), the combined organic layer was dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to obtain compound 132 (4.56 g, 100%). 1H-NMR(400MHz,CDCl3)(rotamers)δ 7.73(s,1H),7.37-7.34(m,2H),7.25(t,1H),7.18(s,1H),6.75(s,1H),5.22 9s, 2H), 5.09(d, 1H), 4.99(s, 1H), 4.84 9s, 1H), 4.59(m, 1H), 3.89(s, 4H), 3.75(s, 2H), 3.71(s, 8H), 3.58(s, 3H) ,2.82-2.64(m,2H),0.89(s,6H),0.79(s,3H),0.09(s,4H),-0.11(d,3H).

[0309] Preparation of compound 133 Compound 132 (4.56 g, 7.85 mmol) was dissolved in N,N-dimethylformamide (40 mL), and then potassium carbonate (1.63 g, 11.77 mmol) and allyl bromide (0.81 mL, 9.42 mmol) were added at 0°C, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate (70 mL), and then washed with saturated ammonium chloride aqueous solution (50 mL) and distilled water (2 × 60 mL). The washed organic layer was washed with saline solution (60 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 133 (4.36 g, 91%). 1 H-NMR(400MHz,CDCl3)(rotamers)δ 7.76(s,1H),7.39-7.36(m,3H),7.28(t,1H),6.77(s,1H),5.95-5.86 (m,1H),5.30-5.19(m,5H),5.09(m,1H),4.99(s,1H),4.84(s,1H),4. 60(d,3H),4.03-3.95(m,4H),3.93-3.85(m,1H),3.81-3.72(m,2H),3 .68(s,3H),3.32(m,1H),2.84-2.65(m,2H),0.90(s,9H),0.09(s,6H).

[0310] Preparation of compound 134 Compound 133 (4.36 g, 7.13 mmol) was dissolved in ethyl acetate (30 mL) and ethanol (60 mL). Zinc dust (14 g, 214 mmol) was then added at 0°C, followed by the addition of formic acid (5.38 mL, 143 mmol). The mixture was stirred at room temperature for 4 hours, then diluted with ethyl acetate (30 mL), filtered through Celite, and ethyl acetate (70 mL) was added. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution (2 × 100 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated and purified by column chromatography to obtain compound 134 (2.52 g, 61%). 1 H-NMR(400MHz,CDCl3)δ 7.38-7.30(m,3H),7.24(s,1H),6.77(s,1H),6.26(s,1H),5.95-5.85(m,1H),5.30-5.10(m,2H),5.10(s,2H),5.10-4.85(m,2H), 4.59(d,2H),4.40-4.18(m,3H),4.20-4.05(m,2H),3.80(s,3H),3.66(s,2H),3.61(m,1H),2.68(m,2H),0.87(s,9H),0.02(s,6H). EI-MS m / z:[M+H] + 581.42. [Examples]

[0311] Preparation of compound 138 [ka]

[0312] Preparation of compound 135 Compound 134 (2.4 g, 4.13 mmol) was dissolved in dry tetrahydrofuran (40 mL), and then triphosgene (0.44 g, 1.48 mmol) and triethylamine (2.32 mL, 16.5 mmol) were added at -10°C. Compound 6 (3.32 g, 4.54 mmol) was dissolved in dry tetrahydrofuran (20 mL) and added. The mixture was stirred at room temperature for 17 hours, then the reaction mixture was diluted with ethyl acetate (100 mL), washed with distilled water (50 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 135 (4.2 g, 76%). EI-MS m / z:[M+H] + 1337.94.

[0313] Preparation of compound 136 Compound 135 (4.21 g, 3.14 mmol) was dissolved in tetrahydrofuran / distilled water (20 mL / 20 mL), acetic acid (20 mL) was added at 0°C, and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (50 mL) and saturated sodium bicarbonate solution (2 × 70 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 136 (3.5 g, 91%). EI-MS m / z:[M+H] + 1223.61.

[0314] Preparation of compound 137 Compound 136 (3.5 g, 2.68 mmol) was dissolved in dichloromethane (140 mL), then Dess-Matin periodinane (1.33 g, 3.14 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction solution was diluted with dichloromethane (200 mL), washed with distilled water (80 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 137 (2.03 g, 58%). 1H-NMR(400MHz,CDCl3)δ 7.97(s,1H),7.80(s,1H),7.45(s,1H),7.23(d,1H),7.19(s,1H),7.00(d,1H),6.61( s,1H),5.92(m,1H),5.58(d,1H),5.41-5.22(m,8H),5.13(s,2H),4.83(d,1H),4.59( d,2H),4.27(m,2H),4.11(m,2H),3.96(m,2H),3.88(s,3H),3.74-3.65(m,15H),3.52 (m,1H),2.90(m,1H),2.70(d,1H),2.57(t,2H),2.13(q,2H)2.05(s,9H),1.46(s,9H). EI-MS m / z:[M+H] + 1121.65.

[0315] Preparation of compound 138 Compound 137 (350 mg, 0.286 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then tetrakis(triphenylphosphine)palladium (0) (132 mg, 0.114 mmol) and pyrrolidine (0.026 mL, 0.314 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The solvent was concentrated under reduced pressure, and then purified by column chromatography to obtain compound 138 (279 mg, 83%). EI-MS m / z:[M+H] + 1181.52. [Examples]

[0316] Preparation of compound 139 [ka]

[0317] Compound 139 was prepared from compound 138 and compound 26 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1228.7. [Examples]

[0318] Preparation of compound 147 [ka]

[0319] Preparation of compound 140 2-chloroethanol (5.0 g, 62.1 mmol) and sodium azide (5.6 g, 86.9 mmol) were dissolved in N,N-dimethylformamide (15 mL), and the mixture was stirred at 100°C under a nitrogen atmosphere for 18 hours. The reaction solution was cooled to room temperature, and then 4-toluenesulfonyl chloride (13.0 g, 68.3 mmol) and triethylamine (13.0 mL, 93.1 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with diethyl ether (200 mL), washed with distilled water (150 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 140 (8.8 g, 58%). 1 H-NMR (400MHz, CDCl3) δ 7.82(d,2H),7.37(d,2H),4.16(t,2H),3.48(t,2H),2.46(s,3H).

[0320] Preparation of compound 142 Compound 141 (2.26 g, 4.73 mmol; compound 141 was prepared by the method described in Patent Document 8) and compound 140 (1.7 g, 7.10 mmol) were dissolved in N,N-dimethylformamide (30 mL), then potassium carbonate (1.3 g, 9.46 mmol) was added, and the mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The reaction solution was diluted with ethyl acetate (200 mL), and then washed with distilled water (2 × 100 mL) and saline solution (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 142 (2.3 g, 89%). 1H-NMR(400MHz,CDCl3)(rotamers)δ 7.86(s,1H),6.84(s,1H),5.98-5.91(m,1H),5.35(d,1H),5.24(d,1H),4.99(br s,1H),4.92(br s,1H),4.25(t,2H),4.17(br s,1H),3.82(s,3H),3.66(t,2H),2.70(br s,2H),0.91(s,9H),0.09(s,6H).

[0321] Preparation of compound 143 Compound 142 (2.3 g, 4.21 mmol) was dissolved in 1,2-dichloroethane (50 mL), and then trimethyltin hydroxide (7.6 g, 42.1 mmol) was added. The mixture was heated under a nitrogen atmosphere under reflux and stirred for 18 hours. The reaction solution was diluted with dichloromethane (200 mL), washed with 0.01 N potassium bisulfate aqueous solution (100 mL) and saline solution (100 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 143 (1.7 g, 88%). EI-MS m / z:[M+H] + 462.25.

[0322] Preparation of compound 144 Compound 143 (1.7 g, 3.69 mmol) was dissolved in dry tetrahydrofuran (40 mL), and then triphosgene (393 mg, 1.33 mmol) and triethylamine (2.1 mL, 14.8 mmol) were added at 0°C. A solution of compound 6 (3.2 g, 4.43 mmol) dissolved in dry tetrahydrofuran (20 mL) was added. The mixture was stirred at room temperature for 2 hours, then the reaction mixture was diluted with ethyl acetate (200 mL), washed with distilled water (100 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 144 (3.5 g, 78%). EI-MS m / z:[M+H] + 1218.70,1 / 2[M-BOC+H] + 559.82.

[0323] Preparation of compound 145 Compound 144 (3.5 g, 2.87 mmol) was dissolved in tetrahydrofuran / distilled water (10 mL / 10 mL), acetic acid (10 mL) was added at 0°C, and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (50 mL) and saturated sodium bicarbonate solution (2 × 100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 145 (2.9 g, 92%). EI-MS m / z:[M+H] + 1104.53,1 / 2[M-BOC+H] + 502.74.

[0324] Preparation of compound 146 Compound 145 (2.9 g, 2.63 mmol) was dissolved in dichloromethane (60 mL), then Dess-Martin periodinane (1.3 g, 3.15 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. The reaction solution was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate aqueous solution (150 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 146 (1.37 g, 47%). EI-MS m / z:[M+H] + 1102.45,1 / 2[M+H] + 501.98.

[0325] Preparation of compound 147 Compound 146 (150 mg, 0.14 mmol) and propiolic acid (0.01 mL, 0.16 mmol) were dissolved in ethanol (4 mL) and distilled water (2 mL). Then, copper sulfate pentahydrate (14 mg, 0.05 mmol) and sodium L-ascorbate (22 mg, 0.11 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction solution was diluted with dichloromethane (50 mL), washed with distilled water (50 mL), and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the mixture was purified by column chromatography to obtain compound 147 (154 mg, 96%). EI-MS m / z:[M+H]+ 1172.26. [Examples]

[0326] Preparation of compound 148 [ka]

[0327] Compound 148 was prepared from compound 147 and compound 26 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1233.49,[M / 2+H] + 617.29. [Examples]

[0328] Preparation of compound 151 [ka]

[0329] Preparation of compound 149 Propiolic acid (4 ml, 64.52 mmol) was dissolved in N,N-dimethylformamide (25 mL), then sodium bicarbonate (10.9 g, 129.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Allyl bromide (8.4 mL, 96.8 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with diethyl ether (25 mL), washed with distilled water (50 × 3 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 149 (6.9 g, 97%). 1 H-NMR (400MHz, CDCl3) δ 5.98-5.41 (m, 1H), 5.39 (dd, 1H), 5.31 (dd, 1H), 4.69 (d, 2H), 2.89 (s, 1H).

[0330] Preparation of compound 150 Compound 149 (800 mg, 7.26 mmol) and 3-azido-1-propanol (734 mg, 7.26 mmol) were dissolved in t-butyl alcohol / distilled water (8 mL / 2 mL) at 0°C under a nitrogen atmosphere. Then, a solution of copper sulfate pentahydrate (180 mg, 0.72 mmol) and sodium L-ascorbate (718 mg, 3.62 mmol) dissolved in distilled water (1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The reaction product was filtered through Celite and then concentrated under reduced pressure. The filtered solution was extracted with dichloromethane (20 mL x 3), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by column chromatography to obtain compound 150 (720 mg, 46%). 1 H-NMR(400MHz,CDCl3)δ 8.15(s,1H),6.09-5.99(m,1H),5.44(dd,J=17.2Hz,1.6Hz,1H),5.31(dd,J=10.8Hz,1.2Hz,1H) ,4.86(d,J=6Hz,2H),4.61(t,J=6.8Hz,2H),3.67(q,J=4.8Hz,2H),2.17(quin,2H),1.91(t,1H).

[0331] Preparation of compound 151 Compound 150 (265 mg, 1.25 mmol) was dissolved in dichloromethane (10 mL), and then methanesulfonyl chloride (0.11 mL, 1.38 mmol) and triethylamine (0.34 mL, 2.51 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at 0°C for 2 hours. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, and it was extracted with dichloromethane (20 mL x 2). The mixture was washed with distilled water (10 mL) and saline solution (10 mL), and then dried over anhydrous sodium sulfate. Compound 151 obtained after filtration and concentration was used in the next reaction without further purification. 1H-NMR(400MHz,CDCl3)δ 8.18(s,1H),6.09-5.99(m,1H),5.42(dd,J=17.2Hz,1.2Hz,1H),5.31(dd,J=10.8Hz,1.2Hz,1 H),4.86(d,J=6Hz,2H),4.61(t,J=7.2Hz,2H),4.25(t,J=6Hz,2H),3.02(s,3H),2.43(m,2H). [Examples]

[0332] Preparation of compound 157 [ka]

[0333] Preparation of compound 152 Compound 3 (528 mg, 1.25 mmol) and Compound 151 (361 mg, 1.25 mmol) were dissolved in N,N-dimethylformamide (12 mL), and then cesium carbonate (488 mg, 1.49 mmol) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at 60°C for 2 hours. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, and then extracted with ethyl acetate (40 mL). The mixture was washed with distilled water (10 mL x 2) and saline solution (10 mL), and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and then purified by column chromatography to obtain Compound 152 (455 mg, 60%). 1 H-NMR(400MHz,CDCl3)(rotamers)δ 8.25(s,1H),7.69(d,2H),6.81(d,1H),6.09-6.00(m,1H),5.45(d,1H),5.32(d,1H),5.11-5.00(m,1H),4.87(d,2H) ,4.71(t,2H),4.61(t,1H),4.16-4.15(m,2H),3.97(s,3H),3.79-3.71(m,2H),2.79-2.69(m,2H),2.58-2.52(m,2H). EI-MS m / z:[M+H] + 616.4.

[0334] Preparation of compound 153 Compound 152 (455 mg, 0.73 mmol) was dissolved in ethyl acetate (6 mL), and then zinc dust (1.5 g, 22.2 mmol) and a formic acid solution (0.56 mL, 14.8 mmol) diluted with ethanol (6 mL) were sequentially added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through Celite and then concentrated under reduced pressure. The filtrate was based with saturated sodium bicarbonate aqueous solution (pH ~8), extracted with ethyl acetate, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the solution was purified by column chromatography to obtain compound 153 (406 mg, 94%). 1 H-NMR(400MHz,CDCl3)(rotamers)δ 8.26(s,1H),6.76(s,1H),6.21(s,1H),6.07-5.98(m,1H),5.41(dd,J=17.2Hz,1.6Hz,1H),5.29(dd,J=10.4Hz,1.6Hz,1H),4.98(bs,1H),4.91(b s, 1H), 4.86 (d, J=6Hz, 2H), 4.59 (t, 2H), 4.26-4.19 (m, 2H), 3.96 (t, 2H) ,3.79(s,3H),2.71(m,2H),2.48-2.42(m,2H),0.87(s,9H),0.03(s,6H). EI-MS m / z:[M+H] + 587.5.

[0335] Preparation of compound 154 Compound 153 (406 mg, 0.69 mmol) was dissolved in dichloromethane (12 mL), and then triphosgene (74 mg, 0.25 mmol) and triethylamine (0.29 mL, 2.07 mmol) were added at 0°C and the mixture was stirred for 10 minutes. A solution of compound 6 (607 mg, 0.83 mmol) and triethylamine (0.19 mL, 1.38 mmol) dissolved in dichloromethane (8 mL) was added to the reaction solution, and the temperature was gradually increased and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with dichloromethane (20 mL), distilled water (20 mL) was added, and then the mixture was extracted. The aqueous solution layer was extracted with dichloromethane (20 mL x 2), and then the combined organic layers were washed with saline solution (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 154 (780 mg, 84%). 1 H-NMR(400MHz,CDCl3)δ 8.46(s,1H),8.04-8.03(m,1H),7.84(s,1H),7.51-7.42(m,2H),7.04-7.02(m,1H),6.82(s,1H) ,6.07-6.01(m,1H),5.44-5.25(m,6H),5.12(s,2H),4.98(m,1H),4.87-4.86(m,3H),4.59(t,J=6 .8Hz,2H),4.20-4.11(m,5H),4.01-3.97(m,3H),3.83(s,3H),3.74-3.53(m,18H),2.69(m,2H), 2.47(m,2H),2.05-2.03(m,9H),1.85-1.83(m,2H),1.47-1.46(m,9H),0.87(s,9H),0.03(s,6H). EI-MS m / z:[M+H] + 1343.3.

[0336] Preparation of compound 155 Compound 154 (780 mg, 0.58 mmol) was dissolved in tetrahydrofuran / distilled water (3 mL / 3 mL), acetic acid (6 mL) was added at 0°C, and the mixture was stirred at room temperature for 15 hours. After concentration under reduced pressure, the reaction solution was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The extracted solution was dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure, and purified by column chromatography to obtain compound 155 (460 mg, 63%). EI-MS m / z:[M+H] + 1229.1.

[0337] Preparation of compound 156 Compound 155 (460 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL), then Dess-Martin periodinane (190 mg, 0.45 mmol) was added at 0°C, the temperature was raised to room temperature, and the mixture was stirred under a nitrogen atmosphere for 3 hours. The reaction solution was diluted with saturated sodium thiosulfate aqueous solution / saturated sodium bicarbonate aqueous solution (v / v=1 / 1, 30 mL) and stirred for 10 minutes. The mixture was extracted with dichloromethane (20 mL x 3), and then washed with distilled water (20 mL) and sodium chloride aqueous solution (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 156 (340 mg, 72%). EI-MS m / z:[M+H] + 1226.9.

[0338] Preparation of compound 157 Compound 156 (340 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (3.5 mL), and then tetrakis(triphenylphosphine)palladium (0) (128 mg, 0.11 mmol) and pyrrolidine (0.04 mL, 0.54 mmol) were added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride (10 mL) was added to the reaction solution, and then the mixture was extracted with ethyl acetate (20 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated under reduced pressure to obtain compound 157 (165 mg), which was used in the next reaction without further purification. EI-MS m / z:[M+H] +1187.1. [Examples]

[0339] Preparation of compound 158 [ka]

[0340] Compound 158 was prepared from compound 157 and compound 20 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1375.3. [Examples]

[0341] Preparation of compound 161 [ka]

[0342] Preparation of compound 159 4-Chloro-1-butanol (3 g, 27.6 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then sodium azide (3.58 g, 55.2 mmol) was added under a nitrogen atmosphere at 0°C. The mixture was heated to 70°C and stirred for 17 hours. The reaction solution was diluted with diethyl ether (30 mL), washed with distilled water (50 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. Compound 159 (2.21 g, 69%) was obtained by filtration and concentration under reduced pressure. 1 H-NMR (400MHz, CDCl3) δ 3.70 (m, 2H), 3.33 (t, J=6.4Hz, 2H), 1.73-1.64 (m, 4H).

[0343] Preparation of compound 160 Compound 149 (1 g, 9.1 mmol) and Compound 159 (1.04 g, 9.1 mmol) were dissolved in tertiary butyl alcohol / distilled water (12 mL / 3 mL) at 0°C under a nitrogen atmosphere, and then stirred. Copper sulfate pentahydrate (227 mg, 0.91 mmol) and sodium L-ascorbate (901 mg, 4.55 mmol) were dissolved in distilled water (3 mL), and then added to the reaction solution, which was stirred at room temperature for 17 hours. The reaction product was filtered through Celite and then concentrated under reduced pressure. The filtered solution was extracted with dichloromethane (20 mL x 3), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 160 (997 mg, 48%) was obtained by purification by column chromatography. 1 H-NMR(400MHz,CDCl3)δ 8.11(s,1H),6.09-5.99(m,1H),5.42(dd,J=17.2Hz,1.6Hz,1H),5.31(dd,J=10.8Hz,1.2Hz,1H),4.86 (d,J=6Hz,2H),4.49(t,J=7.2Hz,2H),3.71(q,J=4.8Hz,2H),2.07(m,2H),1.60(m,2H),1.35(br,1H). EI-MS m / z:[M+H] + 226.20,[M / 2+H] + 113.82.

[0344] Preparation of compound 161 Compound 160 (450 mg, 1.99 mmol) was dissolved in dichloromethane (10 mL), and then methanesulfonyl chloride (251 mg, 0.17 mL) and triethylamine (404 mg, 3.99 mmol) were sequentially added at 0°C under a nitrogen atmosphere, and the mixture was stirred at 0°C for 1 hour. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, and then extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with distilled water (10 mL) and saline solution (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to obtain compound 161 (606 mg). 1H-NMR(400MHz,CDCl3)δ 8.11(s,1H),6.09-5.99(m,1H),5.42(dd,J=17.2Hz,1.2Hz,1H),5.31(dd,J=10.8Hz,1.2Hz,1H),4. 86(d,J=6Hz,2H),4.49(t,J=7.2Hz,2H),4.27(t,J=6Hz,2H),3.02(s,3H),2.12(m,2H),1.81(m,2H). [Examples]

[0345] Preparation of compound 162 [ka]

[0346] Compound 162 was prepared from compound 3 and compound 161 using the same method as the synthesis of compound 157. EI-MS m / z:[M+H] + 1200.91. [Examples]

[0347] Preparation of compound 163 [ka]

[0348] Compound 163 was prepared from compound 158 and compound 20 using the same method as in the synthesis of compound 23. 1H-NMR(400MHz,Methanol-d4)δ 8.53(s,1H),7.75(s,1H),7.35(m,1H),7.29-7.27(m,2H),7.18-7.15(m,2H),7.01(s,1H),6 .90(s,1H),6.73(s,1H),5.57(d,J=7.2Hz,1H),5.28-5.24(m,1H),5.17-5.11(m,3H),4.57( m,2H),4.23-4.06(m,6H),3.92-3.89(m,11H),3.78(m,3H),3.67-3.54(m,15H),3.39(t,J=6 .4Hz,2H),3.17(t,J=7.6Hz,2H),2.91(s,8H),2.10(m,2H),2.02-1.97(m,3H),1.75(m,2H). EI-MS m / z:[M+H] + 1289.09,[M / 2+H] + 645.13. [Examples]

[0349] Preparation of compound 166 [ka]

[0350] Preparation of compound 164 1-Chloro-5-hydroxypentane (1 g, 8.15 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then sodium azide (2.1 g, 32.6 mmol) was added under a nitrogen atmosphere at 0°C. The mixture was heated to 80°C and stirred for 15 hours. The reaction solution was diluted with diethyl ether (30 mL), washed with distilled water (50 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. Compound 164 (980 mg, 93%) was obtained by filtration and concentration under reduced pressure. 1 H-NMR (400MHz, CDCl3) δ 3.66(t,J=6Hz,2H),3.29(t,J=6.8Hz,2H),1.68-1.53(m,4H),1.54-1.42(m,2H).

[0351] Preparation of compound 165 Compound 149 (919 mg, 8.34 mmol) and Compound 164 (980 mg, 7.58 mmol) were dissolved in tertiary butyl alcohol / distilled water (16 mL / 4 mL) at 0°C under a nitrogen atmosphere, and then stirred. Copper sulfate pentahydrate (189 mg, 0.75 mmol) and sodium L-ascorbate (751 mg, 3.79 mmol) were dissolved in distilled water (1 mL), and then added to the reaction solution, which was stirred at room temperature for 5 hours. The reaction product was filtered through Celite and then concentrated under reduced pressure. The filtered solution was extracted with dichloromethane (20 mL x 3), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 165 (920 mg, 50%) was obtained by purification by column chromatography. 1 H-NMR(400MHz,CDCl3)δ 8.09(s,1H),6.09-5.99(m,1H),5.42(dd,J=17.2Hz,1.6Hz,1H),5.31(dd,J=10.8Hz,1.2Hz,1H),4.86 (d,J=6Hz,2H),4.43(t,J=7.2Hz,2H),3.65(bs,2H),1.98(quin,2H),1.61(quin,2H),1.41(quin,2H).

[0352] Preparation of compound 166 Compound 165 (920 mg, 3.84 mmol) was dissolved in dichloromethane (40 mL), and then methanesulfonyl chloride (0.32 mL, 4.22 mmol) and triethylamine (1.07 mL, 7.68 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at 0°C for 2 hours. A saturated aqueous solution of ammonium chloride (40 mL) was added to the reaction solution, and it was extracted with dichloromethane (20 mL x 2). The mixture was washed with distilled water (10 mL) and saline solution (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and used in the next reaction without purification. 1H-NMR(400MHz,CDCl3)δ 8.11(s,1H),6.09-5.99(m,1H),5.42(dd,J=17.2Hz,1.2Hz,1H),5.31(dd,J=10.8Hz,1.2Hz,1H),4.86(d,J=6Hz,2H),4.44( t,J=7.2Hz,2H),4.22(t,J=6Hz,2H),3.01(s,3H),2.01(quin,J=7.6Hz,2H),1.81(quin,J=7.6Hz,2H),1.512-1.452(m,2H). [Examples]

[0353] Preparation of compound 167 [ka]

[0354] Compound 167 was prepared from compound 3 and compound 166 using the same method as the synthesis of compound 157. EI-MS m / z:[M+H] + 1215.2. [Examples]

[0355] Preparation of compound 168 [ka]

[0356] Compound 168 was prepared from compound 167 and compound 20 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1303.4,[M+Na] + 652.1 [Examples]

[0357] Preparation of compound 171 [ka]

[0358] Preparation of compound 169 1-Bromo-7-hydroxyheptane (1 g, 5.12 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then sodium azide (666 mg, 10.2 mmol) was added under a nitrogen atmosphere at 0°C. The mixture was heated to 80°C and stirred for 15 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with distilled water (50 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. Compound 169 (800 mg, 99%) was obtained by filtration and concentration under reduced pressure. 1 H-NMR (400MHz, CDCl3) δ 3.64(t,J=6Hz,2H),3.26(t,J=6.8Hz,2H),1.61-1.54(m,4H),1.42-1.36(m,6H).

[0359] Preparation of compound 170 Compound 149 (564 mg, 5.12 mmol) and Compound 169 (800 mg, 5.12 mmol) were dissolved in tertiary butyl alcohol / distilled water (8 mL / 2 mL) at 0°C under a nitrogen atmosphere, and then stirred. Copper sulfate pentahydrate (127 mg, 0.51 mmol) and sodium L-ascorbate (507 mg, 2.5 mmol) were dissolved in distilled water (1 mL), and then added to the reaction solution, which was stirred at room temperature for 5 hours. The reaction product was filtered through Celite and then concentrated under reduced pressure. The filtered solution was extracted with dichloromethane (20 mL x 3), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 170 (566 mg, 41%) was obtained by purification by column chromatography. 1 H-NMR(400MHz,CDCl3)δ 8.09(s,1H),6.09-5.99(m,1H),5.42(dd,J=17.2Hz,1.6Hz,1H),5.31(dd,J=10.8Hz,1.2Hz,1H),4.86(d ,J=6Hz,2H),4.41(t,J=7.2Hz,2H),3.63(bs,2H),1.98(quin,2H),1.61-1.54(m,4H),1.42-1.36(m,6H).

[0360] Preparation of compound 171 Compound 170 (566 mg, 2.11 mmol) was dissolved in dichloromethane (20 mL), and then methanesulfonyl chloride (0.19 mL, 2.54 mol) and triethylamine (0.59 mL, 4.23 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at 0°C for 2 hours. Saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, and it was extracted with dichloromethane (20 mL x 2). The mixture was washed with distilled water (10 mL) and saline solution (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and used in the next reaction without purification. 1 H-NMR(400MHz,CDCl3)δ 8.09(s,1H),6.09-5.99(m,1H),5.42(dd,J=17.2Hz,1.6Hz,1H),5.31(dd,J=10.8Hz,1.2Hz,1H),4.86(d,J=6Hz ,2H),4.41(t,J=7.2Hz,2H),3.63(bs,2H),3.01(s,3H),1.98(quin,2H),1.61-1.54(m,4H),1.42-1.36(m,6H). [Examples]

[0361] Preparation of compound 172 [ka]

[0362] Compound 172 was prepared from compound 3 and compound 171 using the same method as the synthesis of compound 157. EI-MS m / z:[M+H] + 1243.2. [Examples]

[0363] Preparation of compound 173 [ka]

[0364] Compound 173 was prepared from compound 167 and compound 26 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1467.8. [Examples]

[0365] Preparation of compound 175 [ka]

[0366] Preparation of compound 174 4-Pyrazolecarboxylic acid (500 mg, 4.46 mmol) was dissolved in N,N-dimethylformamide (5 mL) and dichloromethane (5 mL). Then, allyl alcohol (0.37 mL, 5.35 mmol), 4-dimethylaminopyridine (54 mg, 0.45 mmol), and 1,3-diisopropylcarbodiimide (0.83 mL, 5.35 mmol) were added, and the mixture was stirred at room temperature for 17 hours. After heating to 60 °C, the mixture was stirred for a further 3 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (2 × 100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 174 (328 mg, 48%). 1 H-NMR (400MHz, CDCl3) δ 8.07 (s, 1H), 6.04-5.96 (m, 1H), 5.38 (d, 1H), 5.27 (d, 1H), 4.76 (d, 2H).

[0367] Preparation of compound 175 Compound 174 (328 mg, 2.16 mmol) and 1,4-diiodobutane (0.71 mL, 5.39 mmol) were dissolved in N,N-dimethylformamide (20 mL), and then cesium carbonate (913 mg, 2.80 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (2 × 100 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 175 (535 mg, 74%). 1H-NMR(400MHz,CDCl3)δ 7.93(s,1H),7.90(s,1H),6.03-5.96(m,1H),5.37(d,1H),5.27(d,1H),4. 74(d,2H),4.16(t,2H),3.18(t,2H),2.05-1.98(m,2H),1.84-1.79(m,2H). [Examples]

[0368] Preparation of compound 176 [ka] Compound 176 was prepared from Compound 3 and Compound 175 using the same method as the synthesis of Compound 157. EI-MS m / z:[M+H] + 1200.21. [Examples]

[0369] Preparation of compound 177 [ka]

[0370] Compound 177 was prepared from compound 176 and compound 20 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1288.24,1 / 2[M+H] + 644.73. [Examples]

[0371] Preparation of compound 181 [ka]

[0372] Preparation of compound 179 3-(2-(3-methoxy-3-oxopropoxy)ethoxy)propanoic acid (200 mg, 0.85 mmol) was dissolved in dichloromethane (4 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 440 mg, 1.11 mmol), N,N'-diisopropylethylamine (0.22 mL, 1.28 mmol), and compound 178 (259 mg, 0.94 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 5 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and it was extracted with dichloromethane (20 mL x 3), then washed with distilled water (10 mL) and saline solution (10 mL), and dried over anhydrous sodium sulfate. After filtration, the compound was concentrated and then purified by column chromatography to obtain compound 179 (391 mg, 93%). 1 H-NMR(400MHz,CDCl3)δ 7.68(d,1H),7.44-7.24(m,7H),6.53(t,1H),5.14(d,1H),4.15(q,2H),3.79-3.44(m,9H),3.42-3.30( m,1H),3.28-3.14(m,2H),2.59(t,2H),2.56-2.46(m,1H),2.33(t,2H),2.02-1.92(m,2H),1.25(t,3H).

[0373] Preparation of compound 180 Compound 179 (391 mg, 0.79 mmol) was dissolved in methanol / tetrahydrofuran (5 mL / 5 mL), and then a solution of lithium hydroxide (50 mg, 1.19 mmol) dissolved in distilled water (5 mL) was slowly added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 2 hours. The pH was adjusted to approximately 4 with 0.1 N hydrochloric acid aqueous solution, and then extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to obtain compound 180 (380 mg, 100%). 1H-NMR(400MHz,CDCl3)δ 7.66(d,1H),7.46-7.22(m,7H),6.83(t,1H),5.15(d,1H),3.79-3.44(m,9H),3.42-3.3 2(m,1H),3.28-3.12(m,2H),2.56(t,2H),2.51(t,1H),2.42-2.32(m,2H),2.12(t,1H).

[0374] Preparation of compound 181 Compound 180 (200 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), and then N-hydroxysuccinimide (50 mg, 0.43 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodimamide (84 mg, 0.43 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction was terminated with distilled water (10 mL), extracted with dichloromethane (10 mL x 2), washed with distilled water (10 mL) and saline solution (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated, and compound 181 (220 mg, crude) was used in the next reaction without purification. EI-MS m / z:[M+H] + 562.5. [Examples]

[0375] Preparation of compound 186 [ka]

[0376] Preparation of compound 183 Compound 5 (500 mg, 0.96 mmol) was dissolved in dry dichloromethane (20 mL), and then triphosgene (206 mg, 0.69 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.60 mmol) were added at 0°C. Compound 182 (679 mg, 1.06 mmol; compound 182 was prepared by the method described in Patent Document 9) was dissolved in dry dichloromethane (3 mL) and added. The mixture was stirred at room temperature for 17 hours, then the reaction solution was diluted with dichloromethane (30 mL), washed with distilled water (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 183 (1.14 g, 79%). EI-MS m / z:[M+H] + 1185.8.

[0377] Preparation of compound 184 Compound 183 (899 mg, 0.76 mmol) was dissolved in tetrahydrofuran / distilled water (5 mL / 5 mL), acetic acid (5 mL) was added at 0°C, and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate (10 mL), washed sequentially with distilled water (5 mL) and saturated sodium bicarbonate solution (2 × 10 mL), and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the solution was purified by column chromatography to obtain compound 184 (812 mg, 86%). EI-MS m / z:[M+H] + 1071.7.

[0378] Preparation of compound 185 Compound 184 (700 mg, 0.65 mmol) was dissolved in dichloromethane (60 mL), then Dess-Martin periodinane (333 mg, 0.78 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction solution was diluted with dichloromethane (40 mL), washed with saturated sodium bicarbonate aqueous solution (150 mL) and sodium thiosulfate aqueous solution (100 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 185 (460 mg, 66%). EI-MS m / z:[M+H] +1069.9.

[0379] Preparation of compound 186 Compound 185 (450 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (10 mL), then tetrakis(triphenylphosphine)palladium (0) (97 mg, 0.08 mmol) and pyrrolidine (0.04 mL, 0.51 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL) and distilled water (50 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain compound 186 (354 mg, 82%). EI-MS m / z:[M+H] + 1029.7. [Examples]

[0380] Preparation of compound 190 [ka]

[0381] Preparation of compound 187 Compound 186 (354 mg, 0.35 mmol) and Compound 26 (164 mg, 0.38 mmol) were dissolved in N,N-dimethylformamide (8 mL). Then, under a nitrogen atmosphere at 0°C, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU 196 mg, 0.52 mmol) and N,N'-diisopropylethylamine (0.09 mL, 0.52 mmol) were sequentially added, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of ammonium chloride (10 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL). After washing with distilled water (10 × 2 mL) and saline solution (10 mL), the mixture was dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and then purified by column chromatography to obtain Compound 187 (497 mg, 70%). EI-MS m / z:[M+H] + 1145.4

[0382] Preparation of compound 188 Compound 187 (325 mg, 0.24 mmol) was dissolved in methanol (4 mL), and then a solution of sodium hydroxide (41 mg, 0.97 mmol) dissolved in distilled water (4 mL) was slowly added at -40°C under a nitrogen atmosphere. The reaction was stirred for 2 hours while gradually raising the temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, and freeze-dried to obtain compound 188 (297 mg). EI-MS m / z:[M+H] + 1305.1.

[0383] Preparation of compound 189 Compound 188 (297 mg, 0.11 mmol) was diluted with dichloromethane (5 mL), and then trifluoroacetic acid (1 mL) was added at 0°C under a nitrogen atmosphere and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 189 as a white solid (51 mg, 41%). EI-MS m / z:[M / 2+H] + 1090.9,[M / 2+H] + 546.1.

[0384] Preparation of compound 190 Compound 189 (51 mg, 0.047 mmol) and compound 181 (29 mg, 0.052 mmol) were dissolved in N,N-dimethylformamide (2.7 mL), and then N,N-diisopropylethylamine (0.02 mL, 0.12 mmol) was sequentially added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 190 as a white solid (38 mg, 52%). EI-MS m / z:[M / 2+H] + 769.4 [Examples]

[0385] Preparation of compound 192 [ka]

[0386] Preparation of compound 191 3-Hydroxybenzoic acid (2.0 g, 14.5 mmol) was dissolved in distilled water (15 mL), then potassium hydroxide (893 mg, 15.9 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes to concentrate the reaction solution. The concentrated reaction product was diluted with N,N-dimethylformamide (30 mL), then allyl bromide (1.4 mL, 15.9 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The reaction solution was diluted with ethyl acetate (300 mL), then washed with distilled water (2 × 100 mL) and saline solution (100 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 191 (2.5 g, 96%). 1 H-NMR(400MHz,CDCl3)δ 7.65(d,1H),7.57(s,1H),7.32(t,1H),7.07-7.05(m,1H),6.06-5.98(m,1H),5.41(d,1H),5.36(s,1H),5.29(d,1H),4.82(d,2H).

[0387] Preparation of compound 192 Compound 191 (2.5 g, 14.0 mmol) and 1,5-diiodopentane (6.5 mL, 43.5 mmol) were dissolved in acetone (100 mL), then potassium carbonate (2.2 g, 15.95 mmol) was added, and the mixture was heated under a nitrogen atmosphere under reflux and stirred for 18 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 192 (3.8 g, 70%). 1 H-NMR(400MHz,CDCl3)δ 7.65(d,1H),7.56(s,1H),7.34(t,1H),7.10-7.08(m,1H),6.09-5.99(m,1H),5.41(d,1H),5.29(d, 1H),4.82(d,2H),4.01(t,2H),3.22(t,2H),1.94-1.87(m,2H),1.86-1.79(m,2H),1.64-1.5(m,2H). [Examples]

[0388] Preparation of compound 193 [ka]

[0389] Compound 193 was prepared from compound 3 and compound 192 using the same method as the synthesis of compound 157. EI-MS m / z:[M+H] + 1240.09,[M / 2+H] + 570.48. [Examples]

[0390] Preparation of compound 194 [ka]

[0391] Compound 194 was prepared from compound 193 and compound 20 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1328.38,[M / 2+H] + 664.82. [Examples]

[0392] Preparation of compound 200 [ka]

[0393] Preparation of compound 195 5-hydroxypyridine-3-carboxylic acid (500 mg, 3.6 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then allyl alcohol (0.3 mL, 4.31 mmol), 4-dimethylaminopyridine (44 mg, 0.36 mmol), and 1,3-diisopropylcarbodiimide (0.67 mL, 4.31 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (2 × 100 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 195 (347 mg, 54%). 1H-NMR (400MHz, CDCl3) δ 8.81(s,1H),8.45(s,1H),7.83(s,1H),6.06-5.98(m,1H),5.42(d,1H),5.32(d,1H),4.85(d,2H).

[0394] Preparation of compound 196 1,5-Pentanediol (2.0 g, 19.2 mmol) was dissolved in dichloromethane (3 mL), and then 4-toluenesulfonyl chloride (4.4 g, 23.04 mmol), 4-dimethylaminopyridine (234 mg, 1.92 mmol), and triethylamine (8.0 mL, 57.6 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane (100 mL), washed with distilled water (2 × 100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 196 (2.6 g, 52%). 1 H-NMR(400MHz,CDCl3)δ 7.79(d,2H),7.35(d,2H),4.03(t,2H),3.60(t,2H),2.45(s,3H),1.72-1.65(m,2H),1.54-1.48(m,2H),1.42-1.38(m,2H). JPEG2026086866000119.jpg49160

[0395] Preparation of compound 197 Compound 3 (1.78 g, 4.19 mmol) and Compound 196 (1.3 g, 5.03 mmol) were dissolved in N,N-dimethylformamide (40 mL), then cesium carbonate (1.78 g, 5.45 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (2 × 100 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 197 (1.42 g, 67%). 1H-NMR(400MHz,CDCl3)(rotamers)δ 7.71(s,1H),6.75(s,1H),4.98(br s,1H),4.83(br s,1H),4.59(br s,1H),4.11(t,2H),3.95(s,3H),3.73-3.69(m,4H),2.82-2.67(m,2H),1.94-1.91(m,2H),1.69-1.56(m,4H),0.91(s,9H),0.09(s,6H).

[0396] Preparation of compound 198 Compound 197 (1.1 g, 2.61 mmol) and compound 195 (342 mg, 1.90 mmol) were dissolved in tetrahydrofuran (25 mL). Then, diethyl azodicarboxylate (40% toluene solution, 1.4 mL, 2.85 mmol) and triphenylphosphine (750 mg, 2.85 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 198 (915 mg). EI-MS m / z:[M+H] + 671.85,[M / 2+H] + 336.07.

[0397] Preparation of compound 199 Compound 198 (915 mg) was dissolved in ethyl acetate (10 mL) and ethanol (20 mL). Zinc dust (2.2 g, 33.5 mmol) was then added at 0°C, followed by the addition of formic acid (1.3 mL, 33.48 mmol). The mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate (30 mL), filtered through Celite, and ethyl acetate (70 mL) was added. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution (2 × 100 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated and purified by column chromatography to obtain compound 199 (582 mg). EI-MS m / z:[M+H] + 640.74,[M / 2+H] + 320.99.

[0398] Preparation of compound 200 Compound 199 (582 mg) was dissolved in dry tetrahydrofuran (10 mL), and then triphosgene (61.4 mg, 0.24 mmol) and triethylamine (0.4 mL, 2.69 mmol) were added at 0°C. Compound 6 (589 mg, 0.81 mmol) was dissolved in dry tetrahydrofuran (5 mL) and added. The mixture was stirred at room temperature for 4 hours, then the reaction mixture was diluted with ethyl acetate (100 mL), washed with distilled water (50 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 200 (330 mg, 35%). EI-MS m / z:[M+H] + 1397.36,1 / 2[M-BOC+H] + 649.30. [Examples]

[0399] Preparation of compound 203 [ka]

[0400] Preparation of compound 201 Compound 200 (330 mg, 0.24 mmol) was dissolved in tetrahydrofuran / distilled water (2 mL / 2 mL), acetic acid (6 mL) was added at 0°C, and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (50 mL) and saturated sodium bicarbonate solution (2 × 100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 201 (254 mg, 84%). EI-MS m / z:[M+H] + 1283.09,1 / 2[M-BOC+H] + 592.09.

[0401] Preparation of compound 202 Compound 201 (254 mg, 0.20 mmol) was dissolved in dichloromethane (8 mL), then Dess-Martin periodinane (100 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 22 hours. The reaction solution was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate aqueous solution (50 mL), and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the mixture was purified by column chromatography to obtain compound 202 (139 mg, 55%). EI-MS m / z:[M+H] + 1281.20,1 / 2[M-BOC+H] + 591.08.

[0402] Preparation of compound 203 Compound 202 (139 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (3 mL), then tetrakis(triphenylphosphine)palladium (0) (50 mg, 0.04 mmol) and pyrrolidine (0.01 mL, 0.13 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The solution was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL) and distilled water (50 mL), and then dried over anhydrous sodium sulfate. Compound 203 (144 mg) was obtained by filtration and vacuum concentration. EI-MS m / z:[M+H] + 1241.18,1 / 2[M-BOC+H] + 571.21. [Examples]

[0403] Preparation of compound 204 [ka] Compound 204 was prepared from compound 203 and compound 20 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1329.71,[M / 2+H] + 665.39. [Examples]

[0404] Preparation of compound 209 [ka]

[0405] Preparation of compound 206 Compound 205 (500 mg, 0.97 mmol, prepared by the method described in Patent Document 9) and bis(4-nitrophenyl) carbonate (356 mg, 1.17 mmol) were dissolved in N,N-dimethylformamide (10 mL). Then, N,N-diisopropylethylamine (0.25 mL, 1.46 mmol) was added at 0°C, and the mixture was stirred at room temperature under a nitrogen atmosphere for 15 hours. Ethyl acetate (30 mL) was added to the reaction solution, and then extracted with distilled water (30 × 3 mL). The combined organic layer was washed with saline solution (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 206 (528 mg, 79%). EI-MS m / z: [M + H] + 687.5.

[0406] Preparation of compound 207 Compound 125 (687 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then N,N'-diisopropylethylamine (0.26 mL, 1.51 mmol) was added at 0°C under a nitrogen atmosphere. Compound 206 (451 mg, 0.66 mmol), 1-hydroxy-7-azabenzotriazole (30 mg, 0.22 mmol), and then N,N-diisopropylethylamine (0.26 mL, 1.51 mmol) were added sequentially, the temperature was gradually increased, and the mixture was stirred at room temperature for 17 hours. Saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, and then extracted with ethyl acetate (40 mL). The mixture was washed with distilled water (20 × 3 mL) and saline solution (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and then purified by column chromatography to obtain compound 207 (629 mg, 70%). EI-MS m / z:[M+H] + August 1792. JPEG2026086866000123.jpg95160

[0407] Preparation of compound 209 Compound 207 (273 mg, 0.15 mmol) and Compound 208 (50 mg, 0.069 mmol; Compound 208 was prepared by the method described in Patent Document 11) were dissolved in tertiary butyl alcohol / distilled water (2.3 mL / 0.8 mL) at 0°C under a nitrogen atmosphere and then stirred. Copper sulfate pentahydrate (3.46 mg, 0.013 mmol) and sodium L-ascorbate (13.7 mg, 0.069 mmol) were dissolved in distilled water (1 mL) and then added to the reaction solution. Subsequently, 3,3',3''-(4,4',4''-(nitrotris(methylene))tris(1H-1,2,3-triazole-4,1-diyl))tris(propan-1-ol) (THPTA, 12 mg, 0.027 mmol) were added and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was passed through Celite to filter out inorganic substances, and then concentrated under reduced pressure. The filtered solution was extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography was used to purify compound 209 (210 mg, 69%). EI-MS m / z: [M / 3 + H] + 1435.4. [Examples]

[0408] Preparation of compound 211 [ka]

[0409] Preparation of compound 210 Compound 209 (210 mg, 0.05 mmol) was dissolved in methanol / tetrahydrofuran (1 mL / 1 mL), and then a solution of lithium hydroxide (8.2 mg, 0.19 mmol) dissolved in distilled water (1 mL) was slowly added under a nitrogen atmosphere at -40°C. The reaction was stirred for 2 hours while gradually raising the temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, and freeze-dried to obtain compound 210 (220 mg). EI-MS m / z:[M / 2+H]+ 1872.6,[M / 3+H] + 1248.6.

[0410] Preparation of compound 211 Compound 210 (220 mg, 0.05 mmol) was diluted with dichloromethane (4 mL), and then trifluoroacetic acid (1 mL) was added at 0°C under a nitrogen atmosphere, 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 211 as a white solid (45 mg, 21%). EI-MS m / z:[M / 2+H] + 1822.4,[M / 3+H] + 1215.4. [Examples]

[0411] Preparation of compound 214 [ka]

[0412] Preparation of compound 213 300 mg, 1.72 mmol of compound 14 was mixed with 2 mL of thionyl chloride and stirred under reflux for 30 minutes. The solvent was concentrated under reduced pressure to obtain compound 212. 3-(dimethylamino)-1-propylamine (466 mg, 5.29 mmol) was dissolved in dichloromethane (5 mL), and then triethylamine (0.74 mL, 5.29 mmol) was added under a nitrogen atmosphere at -50°C. The prepared compound 212 was dissolved in dichloromethane (8 mL) and added, and the reaction was stirred for 2 hours while gradually raising the reaction temperature to 0°C. The reaction solution was diluted with dichloromethane (30 mL), washed with distilled water (20 mL), and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated to obtain compound 213 (396 mg, 94%). 1 H-NMR (400MHz, DMSO-d6) δ 8.40(t,1H),8.11(d,1H),7.40(d,1H),3.90(s,3H),3.20(m,2H),2.23(t,2H),1.61(m,2H).

[0413] Preparation of compound 214 Compound 213 (150 mg, 0.59 mmol) was dissolved in methanol (6 mL), and then palladium / charcoal (10% w / w, 80 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through Celite and then concentrated to obtain compound 214 (132 mg, 100%). [Examples]

[0414] Preparation of compound 215 [ka]

[0415] Compound 215 was prepared from compound 10 and compound 214 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1085.68,[M / 2+H] + 543.46. [Examples]

[0416] Preparation of compound 217 [ka]

[0417] Preparation of compound 216 3-chloropropanol (3.0 g, 31.7 mmol) and sodium azide (3.1 g, 47.6 mmol) were dissolved in N,N-dimethylformamide (15 mL), and the mixture was stirred at 100°C under a nitrogen atmosphere for 18 hours. The reaction solution was cooled to room temperature, and then 4-toluenesulfonyl chloride (6.6 g, 34.9 mmol) and triethylamine (6.7 mL, 47.6 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with diethyl ether (200 mL), washed with distilled water (150 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 216 (1.9 g, 23%). 1H-NMR (400MHz, CDCl3) δ 7.80(d,2H),7.36(d,2H),4.11(t,2H),3.38(t,2H),2.45(s,3H),1.92-1.86(m,2H).

[0418] Preparation of compound 217 Compound 217 was prepared from compound 141 and compound 216 using the same method as the synthesis of compound 146. EI-MS m / z:[M+H] + 1116.42. [Examples]

[0419] Preparation of compound 223 [ka]

[0420] Preparation of compound 218 4-Methoxy-4-oxobutanoic acid (2.0 g, 15.13 mmol) was dissolved in tetrahydrofuran (30 mL), and then boranedimethyl sulfide (1.0 M, 19.6 mL, 19.6 mmol) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 48 hours. Distilled water and calcium carbonate were slowly added to the reaction solution, and the mixture was then filtered through Celite and concentrated. The concentrated compound was dissolved in dichloromethane (30 mL), and then t-butylchlorodiphenylsilane (TBDPS-Cl, 4.3 mL, 16.65 mmol), 4-dimethylaminopyridine (184 mg, 1.51 mmol), and triethylamine (4.2 mL, 30.27 mmol) were sequentially dissolved, and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with dichloromethane (200 mL), washed with saturated ammonium chloride aqueous solution (150 mL), and then dried over anhydrous sodium sulfate. The compound was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 218 (2.3 g, 42%). 1 H-NMR (400MHz, CDCl3) δ 7.65-7.63(m,4H),7.42-7.35(m,6H),3.68(t,2H),3.65(s,3H),2.46(t,2H),1.92-1.84(m,2H),1.04(s,9H).

[0421] Preparation of compound 219 Compound 218 (500 mg, 1.40 mmol) was dissolved in 1,2-dichloroethane (10 mL), and then trimethyltin hydroxide (1.2 g, 7.01 mmol) was added. The reaction solution was heated under a nitrogen atmosphere under reflux and stirred for 8 hours. The reaction solution was diluted with dichloromethane (100 mL), washed with 0.01 N potassium bisulfate aqueous solution (50 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. Compound 219 (451 mg, 94%) was obtained by filtration and concentration under reduced pressure. 1 H-NMR (400MHz, CDCl3) δ 7.66-7.64(m,4H),7.44-7.38(m,6H),3.70(t,2H),2.52(t,2H),1.92-1.89(m,2H),1.07(s,9H). JPEG2026086866000129.jpg100160

[0422] Preparation of compound 220 Compound 217 (472 mg, 0.42 mmol) was dissolved in ethyl acetate (4 mL) and ethanol (4 mL). Zinc dust (1.1 g, 16.91 mmol) was then added at 0°C, followed by the addition of acetic acid (1.0 mL, 16.91 mmol). The mixture was stirred at room temperature for 5 hours, diluted with ethyl acetate (30 mL), filtered through Celite, and then ethyl acetate (70 mL) was added. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution (2 × 100 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to obtain compound 220 (423 mg, 92%). EI-MS m / z:[M+H] + 1090.85,1 / 2[M-BOC+H] + 496.13.

[0423] Preparation of compound 221 Compound 220 (423 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then, under a nitrogen atmosphere at 0°C, compound 24 (185 mg, 0.50 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 252 mg, 0.63 mmol), and diisopropylethylamine (0.2 mL, 1.26 mmol) were sequentially added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated and then purified by column chromatography to obtain compound 221 (321 mg, 56%). EI-MS m / z:[M+H] + 1364.84,1 / 2[M-BOC+H] + 633.20.

[0424] Preparation of compound 222 Compound 221 (321 mg, 0.24 mmol) was dissolved in ethyl acetate (4 mL) and ethanol (4 mL). Zinc dust (615 mg, 9.41 mmol) was then added at 0°C, followed by the addition of acetic acid (0.5 mL, 9.41 mmol). The mixture was stirred at room temperature for 5 hours, diluted with ethyl acetate (30 mL), filtered through Celite, and then ethyl acetate (70 mL) was added. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution (2 × 100 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to obtain compound 222 (266 mg, 85%). EI-MS m / z:[M+H] + 1334.92,[M / 2+H] + 668.29,1 / 2[M-BOC+H] + 618.19.

[0425] Preparation of compound 223 Compound 222 (266 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then, under a nitrogen atmosphere at 0°C, compound 219 (75 mg, 0.22 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 96 mg, 0.24 mmol), and diisopropylethylamine (0.06 mL, 0.33 mmol) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated and then purified by column chromatography to obtain compound 223 (122 mg, 66%). EI-MS m / z:[M+H] + 1660.02,[M / 2+H] + 830.52,1 / 2[M-BOC+H] + 780.43. [Examples]

[0426] Preparation of compound 225 [ka]

[0427] Preparation of compound 224 Compound 223 (122 mg, 0.07 mmol) was dissolved in methanol / tetrahydrofuran (1.0 mL / 1.0 mL), and then a solution of lithium hydroxide (9.2 mg, 0.22 mmol) dissolved in distilled water (2.0 mL) was slowly added under a nitrogen atmosphere at -40°C. The reaction was stirred for 4 hours while gradually raising the temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, purified by HPLC, and freeze-dried to obtain compound 224 (22 mg). EI-MS m / z:[M+H] + 1519.97,[M / 2+H] + 760.30,1 / 2[M-BOC+H] + 710.32.

[0428] Preparation of compound 225 Compound 224 (22 mg) was diluted with dichloromethane (1.5 mL), and then trifluoroacetic acid (0.5 mL) was added at 0°C under a nitrogen atmosphere, 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 225 (4.5 mg). EI-MS m / z:[M+H] + 1182.18,[M / 2+H] + 591.16. [Examples]

[0429] Preparation of compound 230 [ka]

[0430] Preparation of compound 226 Compound 16 (4.6 g, 15.0 mmol) was dissolved in methanol (70 mL) and N,N-dimethylformamide (70 mL), and then palladium / charcoal (10% w / w, 0.9 g) was added at 0°C under a nitrogen atmosphere. Sodium borohydride (1.7 g, 45.0 mmol) dissolved in distilled water (35 mL) was gradually added using a dropping funnel, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite, then diluted with ethyl acetate (100 mL), and washed with distilled water (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, then filtered and concentrated, and purified by column chromatography to obtain compound 226 (4.08 g, 99%). 1 H-NMR(400MHz,DMSO-d6)δ 9.59(s,1H),7.42(d,J=1.6Hz,1H),6.85(d,J=1.6Hz,1H),6.33(d,J=2Hz,1H),6.26(d,J=2Hz,1H),3.82(s,3H),3.73(s,3H),3.72(s,3H).

[0431] Preparation of compound 227 Compound 14 (2.3 g, 13.5 mmol) was dissolved in N,N-dimethylformamide (40 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 8.0 g, 20.2 mmol) and diisopropylethylamine (7.0 mL, 40.5 mmol) were sequentially added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. Compound 226 (4.1 g, 14.8 mmol) dissolved in N,N-dimethylformamide (20 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and then chloroform (50 mL) was added to produce a solid, which was filtered to obtain compound 227 (5.65 g, 99%). 1 H-NMR(400MHz,DMSO-d6)δ 10.28(s,1H),9.97(s,1H),8.18(d,J=1.6Hz,1H),7.58(d,J=2Hz,1H),7.46(d,J=1.6Hz,1H),7.26(d,J=1 .6Hz,1H),7.05(d,J=1.6Hz,1H),6.90(d,J=2Hz,1H),3.96(s,3H),3.85(s,3H),3.83(s,3H),3.73(s,3H).

[0432] Preparation of compound 228 Methanol (120 mL) was added to compound 227 (3.7 g, 8.6 mmol), and then sodium hydroxide (1.72 g, 43.1 mmol) dissolved in distilled water (90 mL) was added at 0°C under a nitrogen atmosphere. The reaction solution was heated to 90°C and stirred for 12 hours. The methanol was concentrated, and then the pH was adjusted to approximately 2 with 6N hydrochloric acid aqueous solution. The resulting solid was then filtered to obtain compound 228 (3.5 g, 99%). 1 H-NMR(400MHz,DMSO-d6)δ 12.15(bs,1H),10.30(s,1H),9.95(s,1H),8.18(d,J=1.2Hz,1H),7.59(d,J=2Hz,1H),7.42(d,J=1.6Hz,1H) ,7.26(d,J=1.6Hz,1H),7.05(d,J=1.2Hz,1H),6.85(d,J=1.6Hz,1H),3.96(s,3H),3.85(s,3H),3.82(s,3H).

[0433] Preparation of compound 229 Compound 228 (500 mg, 1.2 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then 3-(dimethylamino)-1-propylamine (0.18 mL, 1.4 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 623 mg, 1.5 mmol), and diisopropylethylamine (0.63 mL, 3.6 mmol) were added sequentially at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and then dichloromethane (20 mL) was added, followed by stirring. The resulting solid was filtered to obtain compound 229 (600 mg, 99%). 1 H-NMR(400MHz,DMSO-d6)δ 10.31(s,1H),9.96(s,1H),8.19(s,1H),7.60(s,1H),7.27(s,1H),7.19(s,1H),7.04(s,1H),6.90(s, 1H),3.96(s,3H),3.85(s,3H),3.81(s,3H),3.25-3.22(m,2H),2.68-2.64(m,2H),1.77-1.76(m,2H).

[0434] Preparation of compound 230 Compound 229 (300 mg, 0.6 mmol) was dissolved in methanol (30 mL), and then palladium / charcoal (10% w / w, 240 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 5 hours. The reaction solution was filtered through Celite and then concentrated to obtain compound 230 (275 mg, 98%). EI-MS m / z:[M+H] + 469.20. [Examples]

[0435] Preparation of compound 231 [ka]

[0436] Compound 231 was prepared from compound 10 and compound 230 using the same method as the synthesis of compound 23. EI-MS m / z:[M+H] + 1330.07,[M / 2+H] + 665.5. [Examples]

[0437] Preparation of compound 234 [ka]

[0438] Preparation of compound 232 Compound 228 (980 mg, 2.36 mmol) and 3-amino-1-propanol (0.26 mL, 3.54 mmol) were dissolved in N,N-dimethylformamide (12 mL). Then, under a nitrogen atmosphere at 0°C, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 1.4 g, 3.54 mmol) and diisopropylethylamine (0.82 mL, 4.72 mmol) were sequentially added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate (100 mL) and washed with distilled water (60 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 232 (3.93 g). EI-MS m / z:[M+H] + 1491.80,1 / 2[M+H] + 746.41.

[0439] Preparation of compound 233 Compound 232 (3.93 g, 2.36 mmol) was dissolved in dichloromethane (200 mL) and N,N-dimethylformamide (10 mL). Then, under a nitrogen atmosphere at 0°C, imidazole (321 mg, 4.72 mmol) and t-butyldimethylsilyl chloride (534 mg, 3.54 mmol) were added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, then diluted with ethyl acetate (80 mL), washed sequentially with saturated ammonium chloride aqueous solution (50 mL) and distilled water (50 mL), and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the solution was purified by column chromatography to obtain compound 233 (1.01 g, 74%). 1 H-NMR(400MHz,DMSO-d6)δ 10.30(s,1H),9.96(s,1H),8.02(s,1H),7.99(t,1H),7.60(d,1H),7.28(d,1H),7.19(d,1H),7.03(d,1H),6.84( d,1H),3.96(s,3H),3.86(s,3H),3.79(s,3H),3.63(t,2H),3.22(m,2H),1.69(m,2H),0.87(s,9H),0.04(s,6H).

[0440] Preparation of compound 234 Compound 233 (750 mg, 1.28 mmol) was dissolved in methanol (20 mL) and ethyl acetate (10 mL), and then palladium / charcoal (10% w / w, 440 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through Celite and then concentrated to obtain compound 234 (704 mg, 99%). 1 H-NMR(400MHz,DMSO-d6)δ 9.88(s,1H),9.63(s,1H),7.96(t,1H),7.21(d,1H),7.17(d,1H),7.00(d,1H),6.84(d,1H),6.39(d,1H),6.28( d,1H),3.83(s,3H),3.79(s,3H),3.74(s,3H),3.63(t,2H),3.22(m,2H),1.69(m,2H),0.87(s,9H),0.04(s,6H) EI-MS m / z:[M+H] + 556.30. [Examples]

[0441] Preparation of compound 235 [ka]

[0442] Compound 235 was prepared from compound 10 and compound 234 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1303.22,[M / 2+H] + 652.07. [Examples]

[0443] Preparation of compound 239 [ka]

[0444] Preparation of compound 236 Compound 5 (2.49 g, 4.8 mmol) was dissolved in dichloromethane (25 mL), and then pyridine (0.85 mL, 10.56 mmol) and allyl chloroformate (0.56 mL, 5.28 mmol) were sequentially added at -78 °C under a nitrogen atmosphere, and the mixture was heated to room temperature and stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure, washed with distilled water (20 mL) and saline solution (20 mL), and then dried over anhydrous sodium sulfate. Compound 236 (2.86 g) was obtained by filtration and concentration under reduced pressure. 1 H-NMR(400MHz,CDCl3)δ 7.82(s,1H),6.81(s,1H),5.94(m,1H),5.36-5.32(m,2H),5.27(m,2H),4.98(brs,1H),4.90(brs,1H),4.64-4.59(m,5H),4.2 0(m.2H),4.12(t,J=6.4Hz,2H),3.81(s,3H),2.69(m,2H),2.57(t,J=7.6Hz,2H),2.19(m,2H),0.87(s,9H),0.03(s,6H),EI-MS m / z:[M+H] + 603.54.

[0445] Preparation of compound 237 Compound 236 (2.86 g, 4.7 mmol) was dissolved in tetrahydrofuran / distilled water (5 mL / 5 mL), acetic acid (15 mL) was added at 0°C, and the mixture was stirred at room temperature for 17 hours. Another acetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 6 hours to terminate the reaction. After concentration under reduced pressure, the reaction solution was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium bicarbonate aqueous solution (50 mL), distilled water (30 mL), and then saline solution (30 mL), and then dried over anhydrous sodium sulfate. After filtration, the solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 237 (1.96 g, 85%). 1 H-NMR(400 MHz, CDCl3)δ 8.50(brs,1H),7.75(brs,1H),6.82(s,1H),5.96(m,1H),5.37-5.30(m,2H),5.26-5.22(m,2H),5.02( brs,1H),4.94(brs,1H),4.64-4.59(m,5H),4.18(m,2H),4.12(t,J=6.4Hz,2H),3.83(s,3H),3.70(br s,1H),2.79(m,1H),2.57(t,J=7.2Hz,2H),2.47(m,2H),2.19(m,2H),EI-MS m / z:[M+H] + 490.39.

[0446] Preparation of compound 238 Compound 237 (1.95 g, 4 mmol) was dissolved in dichloromethane (40 mL), then Dess-Martin periodinane (2.03 g, 4.8 mmol) was added at 0°C, the temperature was raised to room temperature, and the mixture was stirred under a nitrogen atmosphere for 2 hours. The reaction solution was diluted with saturated sodium thiosulfate aqueous solution / saturated sodium bicarbonate aqueous solution (20 mL / 20 mL) and stirred for 10 minutes. The mixture was extracted with dichloromethane (30 mL x 3), then washed with saturated sodium thiosulfate aqueous solution / saturated sodium bicarbonate aqueous solution (15 mL / 15 mL), distilled water (20 mL), and saline solution (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 238 (899 mg, 46%). 1 H-NMR(400MHz,CDCl3)δ 7.21(s,1H),6.86(brs,1H),5.94(m,1H),5.80(m,1H),5.56(m,1H),5.32(m,1H),5.30 (m,1H),5.13(m,4H),4.67(dd,J=13.2Hz,5.2Hz,1H),4.66(d,J=5.6Hz,2H),4.45(m,1 H),4.32(d,J=15.6Hz,1H),4.15(d,J=15.6Hz,1H),4.09(m,2H),3.90(s,3H),3.63(m, 1H),3.48(m,1H),2.91(m,1H),2.71(m,1H),2.57(t,J=7.2Hz,2H),2.17(m,2H),EI-MS m / z:[M+H] + 487.39.

[0447] Preparation of compound 239 Compound 238 (100 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3 mL), and then a solution of lithium hydroxide (17.2 mg, 0.41 mmol) dissolved in distilled water (3 mL) was slowly added at 0°C under a nitrogen atmosphere. The reaction was stirred for 6 hours while maintaining the reaction temperature at 0°C. The reaction solution was washed with dichloromethane (5 mL), and then the aqueous layer was acidified with 1N hydrochloric acid aqueous solution (pH ~ 4). The solution was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 239 (91.5 mg). 1H-NMR(400MHz,CDCl3)δ 7.22(s,1H),6.75(brs,1H),5.77(m,1H),5.58(d,J=10Hz,1H),5.14(m,4H),4.66(dd,J=13.2Hz,5.2Hz,1H),4.43(m,1H),4.32(d,J EI-MS m / z:[M+H] + 447.24. [Examples]

[0448] Preparation of compound 242 [ka]

[0449] Preparation of compound 240 Compound 239 (141 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then, under a nitrogen atmosphere at 0°C, compound 26 (150 mg, 0.35 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 163 mg, 0.41 mmol), and diisopropylethylamine (0.11 mL, 0.63 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL), then washed with saturated ammonium chloride aqueous solution (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and distilled water (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and then purified by column chromatography to obtain compound 240 (178 mg, 66%). EI-MS m / z:[M+H] + 862.44, [M-TBS+H] + 748.36,[M / 2+H] + 423.04,1 / 2 [M-TBS+H] + 374.92.

[0450] Preparation of compound 241 Compound 240 (178 mg, 0.20 mmol) was dissolved in tetrahydrofuran (5 mL), and then tetra-n-butylammonium fluoride (1.0 M tetrahydrofuran solution, 1.2 mL, 1.2 mmol) was slowly added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. The mixture was washed with saturated ammonium chloride aqueous solution (50 mL) and distilled water (50 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 241 (115 mg, 74%). EI-MS m / z:[M+H] + 748.42,[M / 2+H] + 374.96.

[0451] Preparation of compound 242 Compound 241 (115 mg, 0.15 mmol) was dissolved in dichloromethane (4 mL), and then tetrakis(triphenylphosphine)palladium (0) (8.8 mg, 0.01 mmol) and pyrrolidine (0.05 mL, 0.62 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 hours. The mixture was concentrated under reduced pressure, and then purified by column chromatography to obtain compound 242 (74 mg, 75%). EI-MS m / z:[M+H] + 646.18. [Examples]

[0452] Preparation of compound 244 [ka]

[0453] Preparation of compound 243 Compound 239 (155 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then, under a nitrogen atmosphere at 0°C, compound 37 (200 mg, 0.38 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 179 mg, 0.45 mmol), and diisopropylethylamine (0.18 mL, 1.04 mmol) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (50 mL), and then washed in the following order: saturated ammonium chloride aqueous solution (50 mL), saturated sodium bicarbonate solution (50 mL), and distilled water (50 mL), before being dried over anhydrous sodium sulfate. After filtration, the solution was concentrated and then purified by column chromatography to obtain compound 243 (281 mg, 85%). EI-MS m / z:[M+H] + 954.54,[M / 2+H] + 478.04.

[0454] Preparation of compound 244 Compound 243 (281 mg, 0.15 mmol) was dissolved in dichloromethane (6 mL), then tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.01 mmol) and pyrrolidine (0.1 mL, 1.18 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was concentrated under reduced pressure, and then purified by column chromatography to obtain compound 244 (28 mg). EI-MS m / z:[M+H] + 852.57,[M / 2+H] + 427.06. [Examples]

[0455] Preparation of compound 245 [ka]

[0456] Compound 245 was prepared from compound 239 and compound 40 using the same method as the synthesis of compound 244. EI-MS m / z:[M+OH] + 1138.69,[M+H]+ 1116.70,[M / 2+H] + 559.15. [Examples]

[0457] Preparation of compound 248 [ka]

[0458] Preparation of compound 246 Compound 239 (137 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (2.5 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 175 mg, 0.46 mmol) and diisopropylethylamine (0.1 mL, 0.61 mmol) were slowly added at 0°C under a nitrogen atmosphere. A solution of Compound 44 (160 mg, 0.36 mmol) dissolved in N,N-dimethylformamide (1 mL) was added to the reaction solution and stirred at room temperature for 1.5 hours. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, and then extracted with ethyl acetate (20 mL x 3), washed with saturated sodium bicarbonate solution (10 mL) and distilled water (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the compound was concentrated and then purified by column chromatography to obtain compound 246 (210 mg, 79%). 1H-NMR(400MHz,CDCl3)δ 8.89(br s,0.5H),8.02(m,0.5H),7.73(br s,0.5H),7.32-7.27(m,1H),7.25-7.22(m,2H),7.05(br s,1H),6.81(m,1.5H),6.66(br s,0.5H),6.39(br s,0.5H),5.97(br,0.5H),5.75(br s,0.5H),5.57(m,1H),5.37(m,0.5H),5.13(m,3H),4.67(m,1H),4.43(m,1H),4.30(m,1H),4.13(m,2H),3.92-3.90(m,7) EI-MS m / z:[M+H] + 861.49

[0459] Preparation of compound 247 Compound 246 (140 mg, 0.16 mmol) was diluted with dichloromethane (1.6 mL), and then trifluoroacetic acid (0.4 mL) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 1 hour. The reaction solution was concentrated under a nitrogen gas atmosphere to obtain compound 247 (123 mg). EI-MS m / z:[M+H] + 761.56,[M / 2+H] + 381.5

[0460] Preparation of compound 248 Compound 247 (123 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL), and then tetrakis(triphenylphosphine)palladium (0) (3.5 mg, 0.003 mmol) and pyrrolidine (0.06 mL, 0.81 mmol) were slowly added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under a nitrogen atmosphere, then purified by HPLC, and freeze-dried to obtain compound 248 (20.3 mg, 38%). EI-MS m / z:[M+H] + 659.55, [M / 2+H] + 330.45 [Examples]

[0461] Preparation of compound 250 [ka]

[0462] Preparation of compound 249 Compound 239 (215 mg, 0.439 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then compound 230 (180 mg, 0.337 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 189 mg, 0.498 mmol), and diisopropylethylamine (0.29 mL, 1.68 mmol) were sequentially added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (50 mL) was added to the reaction solution, and then the mixture was washed with saturated ammonium chloride aqueous solution (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and distilled water (50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography to obtain compound 249 (233 mg, 77%). EI-MS m / z:[M+H] + 897.59, 1 / 2 [M+H] + 440.35.

[0463] Preparation of compound 250 Compound 249 (233 mg, 0.126 mmol) was dissolved in dichloromethane (3 mL), and tetrakis(triphenylphosphine)palladium (0) (6.0 mg, 0.005 mmol) and pyrrolidine (0.021 mL, 1.298 mmol) were added under a nitrogen atmosphere. The mixture was then stirred at room temperature for 3 hours. The reaction solution was concentrated, purified by HPLC, and freeze-dried to obtain compound 250 as a white solid (24 mg). EI-MS m / z:[M+H] + 795.50, [M / 2+H] + 398.34. [Examples]

[0464] Preparation of compound 251 [ka]

[0465] Compound 251 was prepared from compounds 239 and 234 using the same method as in the synthesis of compound 242. 1 H-NMR(400MHz,DMSO-d6)δ 9.87(m,3H),7.94(t,J=5.6Hz,1H),7.20(m,2H),7.15(s,2H),7.03(m,1H),6.84(dd,J= 11.2Hz,1.2Hz,2H),6.57(s,0.5H),6.34(s,1H),6.10(s,0.5H),5.08(m,1H),4.94(m,1H) ),4.50-4.44(m,2H),4.24-4.18(m,1H),4.13-4.11(m,2H),4.03-3.95(m,2H),3.86-3.7 7(m,10H),3.70-3.65(m,4H),3.45(m,2H),2.42(m,2H),2.05(m,2H),1.61(m,2H),EI-MS m / z:[M+H] + 768.32,[M / 2+H] + 384.97. [Examples]

[0466] Preparation of compound 255 [ka]

[0467] Preparation of compound 253 Compound 252 (1.0 g, 2.36 mmol; compound 252 was prepared by the method described in Patent Document 8) and compound 1 (735 mg, 3.54 mmol) were dissolved in N,N-dimethylformamide (20 mL), then potassium carbonate (654 mg, 4.73 mmol) and sodium iodide (177 mg, 1.18 mmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 2 hours. The reaction solution was diluted with ethyl acetate (300 mL), then washed with distilled water (2 × 100 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 253 (1.12 g, 86%). 1 H-NMR(400MHz,CDCl3)δ 7.70(s,1H),6.78(s,1H),5.91-5.88(m,1H),5.53(s,1H),5.33(d,1H),5.25(d,1H),4.65(br s,1H),4.61(d,2H),4.15(t,2H),3.93(s,3H),2.82-2.75(m,1H),2.61- 2.57 (m, 3H), 2.23-2.20 (m, 2H), 1.62 (s, 3H), 0.90 (s, 9H), 0.10 (s, 6H).

[0468] Preparation of compound 254 Compound 253 (2.4 g, 20.0 mmol) was dissolved in ethyl acetate (20 mL) and ethanol (20 mL). Zinc dust (5.7 g, 87.4 mmol) was then added at 0°C, followed by the addition of formic acid (3.3 mL, 87.4 mmol). The mixture was stirred at room temperature for 2.0 hours, then diluted with ethyl acetate (30 mL), filtered through Celite, and ethyl acetate (70 mL) was added. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution (2 × 100 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound 254 (2.2 g, 97%). EI-MS m / z:[M+H] + 519.38.

[0469] Preparation of compound 255 Compound 254 (2.2 g, 4.24 mmol) was dissolved in dry tetrahydrofuran (50 mL), and then triphosgene (452 ​​mg, 1.53 mmol) and triethylamine (2.4 mL, 16.9 mmol) were added at 0°C, followed by the addition of compound 6 (3.4 g, 4.66 mmol). The mixture was stirred at room temperature for 3 hours, then the reaction mixture was diluted with ethyl acetate (200 mL), washed with distilled water (150 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 255 (3.2 g, 60%). EI-MS m / z:[M+H] + 1275.53,[M / 2+H] + 638.53. [Examples]

[0470] Preparation of compound 258 [ka]

[0471] Preparation of compound 256 Compound 255 (3.2 g, 2.51 mmol) was dissolved in tetrahydrofuran / distilled water (10 mL / 10 mL), acetic acid (10 mL) was added at 0°C, and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (50 mL) and saturated sodium bicarbonate aqueous solution (2 × 100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 256 (2.6 g, 89%). EI-MS m / z:[M+H] + 1161.45,[(M-BOC) / 2+H] + 531.47.

[0472] Preparation of compound 257 Compound 256 (2.0 g, 1.72 mmol) was dissolved in dichloromethane (50 mL), then Dess-Matin periodinane (876 mg, 2.0 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction solution was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate aqueous solution (150 mL) and sodium thiosulfate aqueous solution (100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 257 (1.4 g, 71%). EI-MS m / z:[M+H] + 1159.40,[(M-BOC) / 2+H] + 530.46.

[0473] Preparation of compound 258 Compound 257 (200 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (2 mL), then tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.05 mmol) and sodium 2-ethylhexanoate (91 mg, 0.61 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL) and distilled water (50 mL), and then dried over anhydrous sodium sulfate. Compound 258 (196 mg) was obtained by filtration and concentration under reduced pressure. EI-MS m / z:[M+H] + 1119.37,[M / 2+H] + 510.44. [Examples]

[0474] Preparation of compound 259 [ka]

[0475] Compound 259 was prepared from compound 258 and compound 26 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1180.48,[M / 2+H] + 591.67. [Examples]

[0476] Preparation of compound 264 [ka]

[0477] Preparation of compound 261 Compound 260 (4.6 g, 6.45 mmol; compound 260 was prepared by the method described in Non-Patent Document 10) was dissolved in ethanol / toluene / distilled water (10 mL / 20 mL / 10 mL), and then 4-methoxyphenylboronic acid (1.27 g, 8.39 mmol), sodium carbonate (2.0 g, 19.36 mmol), and tetrakis(triphenylphosphine)palladium (0) (745 mg, 0.65 mmol) were added at room temperature under a nitrogen atmosphere. The reaction solution was stirred at 85 °C for 1 hour, then diluted with ethyl acetate (100 mL), and the organic layer was washed with saline solution (100 mL) and distilled water (100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained compound was dissolved in N,N-dimethylformamide / distilled water (50 mL / 1.0 mL), sodium acetate (688 mg, 8.38 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction solution was diluted with ethyl acetate (200 mL), washed with distilled water (2 × 100 mL), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 261 (2.75 g, 83%). 1 H-NMR(400MHz,CDCl3)δ 7.81(s,1H),7.14(d,2H),6.85(s,1H),6.80(d,2H),6.15(s,1H),6.05(br s,1H),4.79(br s,1H),4.00(s,3H),3.78(s,3H),3.18(br,1H),3.02-2.98(m,1H),0.90(s,9H),0.10(s,6H).

[0478] Preparation of compound 262 Compound 261 (3.7 g, 7.19 mmol) and Compound 1 (2.2 g, 10.78 mmol) were dissolved in acetone / N,N-dimethylformamide (40 mL / 10 mL), then potassium carbonate (2.0 mg, 14.4 mmol) and sodium iodide (538 mg, 3.59 mmol) were added, and the mixture was stirred for 19 hours under reflux and heating under a nitrogen atmosphere. The reaction solution was concentrated, then diluted with ethyl acetate (300 mL), washed with distilled water (2 × 100 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 262 (4.2 g, 91%). 1 H-NMR(400MHz,CDCl3)δ 7.73(s,1H),7.13(d,2H),6.82(s,1H),6.80(d,2H),6.13(s,1H),5.97-5.90(m,1H),5.33(d,1H),5.25(d,1H),4.79(brs,1H),4.62(d, 2H),4.18(t,2H),3.95(s,3H),3.78(s,3H),3.18(br,1H),3.02-2.98(m,1H),2.61(t,2H),2.27-2.20(m,2H),0.90(s,9H),0.10(s,6H).

[0479] Preparation of compound 263 Compound 262 (2.0 g, 3.12 mmol) was dissolved in ethyl acetate (20 mL) and ethanol (30 mL). Zinc dust (5.1 g, 78.0 mmol) was then added at 0°C, followed by the addition of formic acid (2.9 mL, 78.03 mmol). The mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate (30 mL), filtered through Celite, and ethyl acetate (70 mL) was added. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution (2 × 100 mL) and saline solution (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound 263 (1.9 g, 96%). EI-MS m / z:[M+H] + 612.83.

[0480] Preparation of compound 264 Compound 263 (1.9 g, 3.08 mmol) was dissolved in dry tetrahydrofuran (20 mL), and then triphosgene (328 mg, 1.11 mmol) and triethylamine (1.7 mL, 12.33 mmol) were added at 0°C, followed by the addition of compound 6 (2.5 g, 3.39 mmol). The mixture was stirred at room temperature for 17 hours, then the reaction mixture was diluted with ethyl acetate (200 mL), washed with distilled water (150 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 264 (2.9 g, 70%). EI-MS m / z:[M+H] + 1368.79,[(M-BOC) / 2+H] + 634.80. [Examples]

[0481] Preparation of compound 267 [ka]

[0482] Preparation of compound 265 Compound 264 (2.9 g, 2.15 mmol) was dissolved in tetrahydrofuran / distilled water (5 mL / 5 mL), acetic acid (5 mL) was added at 0 °C, and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (50 mL) and saturated sodium bicarbonate aqueous solution (2 × 100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 265 (2.2 g, 81%). EI-MS m / z: [M + H] + 1254.45,[(M-BOC) / 2+H] + 577.73.

[0483] Preparation of compound 266 Compound 265 (507 mg, 0.40 mmol) was dissolved in dichloromethane (8 mL), then Dess-Martin periodinane (206 mg, 0.49 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The reaction solution was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate aqueous solution (150 mL) and sodium thiosulfate aqueous solution (100 mL), and then dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 266 (483 mg, 48%). EI-MS m / z:[M+H] + 1252.34,[(M-BOC) / 2+H] + 576.42.

[0484] Preparation of compound 267 Compound 266 (300 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (6 mL), then tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.01 mmol) and pyrrolidine (0.04 mL, 0.48 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL) and distilled water (50 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain compound 267 (232 mg, 80%). EI-MS m / z:[M+H] + 1211.80,[(M-BOC) / 2+H] + 556.42. [Examples]

[0485] Preparation of compound 268 [ka]

[0486] Compound 268 was prepared from compound 267 and compound 26 using the same method as the synthesis of compound 29. EI-MS m / z:[M+H] + 1272.65,[M / 2+H]+ 637.12. [Examples]

[0487] Fabrication of ADC Example 97-1 Method for fabricating an ADC ADCs were fabricated through the following two steps. The isoprenoids LCB14-0511, 0512, and 0606, which were used in common, were fabricated by the method described in Patent Document 12. The structural formulas of LCB14-0511, 0512, and 0606 are as follows.

[0488] [ka]

[0489] Step 1: Preparation of prenylated antibodies The antibody prenylation reaction in this invention was performed using a reaction mixture containing 24 μM antibody, 200 nM FTase, and a buffer containing 0.144 mM or 0.250 mM isoprenoid (LCB14-0511, 0512, or 0606) [50 mM Tris-HCl (pH 7.4), 5 mM magnesium chloride (MgCl2), 10 μM zinc chloride (ZnCl2), and 0.250 mM dithiothreitol (DTT)]. After the reaction was complete, the prenylated antibody was desalted using a G25 Sepharose column (AKTA purifier, GE healthcare) equilibrated with PBS buffer.

[0490] Step 2: Drug-conjugation response For ADCs using the oxime-binding reaction, a reaction mixture was prepared by mixing 100 mM sodium acetate (NaOAc) buffer (pH 5.2), 10% dimethyl sulfoxide (DMSO), 24 μM prenylated antibody, and 240 μM linker-drug, and gently agitated at 30°C. After 2 or 24 hours of reaction, excess low molecular weight compounds were removed using a G25 Sepharose column, and the protein fraction was collected and concentrated.

[0491] For ADCs using a copper-free click binding reaction, a reaction mixture was prepared by mixing PBS buffer (pH 7.4), 1% dimethyl sulfoxide (DMSO), 10 μM prenylated antibody, and 100 μM linker-drug. The mixture was reacted at 25°C for 6 hours, after which excess low molecular weight compounds were removed using a G25 Sepharose column, and the protein fraction was collected and concentrated.

[0492] ADCs using a copper-based click-joint reaction were prepared by mixing 20 μM prenylated antibody, 200 μM linker-drug, 10% dimethyl sulfoxide (DMSO), 1 mM copper sulfate pentahydrate, 2 mM (BimC4A)3 (Sigma-Aldrich), 10 mM sodium ascorbate, and 10 mM aminoguanidine hydrochloride. The mixture was reacted at 25°C for 3 hours, followed by treatment with 20 mM EDTA and reaction for 30 minutes. After the reaction, excess low molecular weight compounds were removed using a G25 Sepharose column, and the protein fraction was collected and concentrated.

[0493] Example 97-2 Preparation of ADC using antibody HER2 ADCs were prepared using the linker-drug and antibody HER2 prepared in the examples, including Examples 23 and 29. The antibody HER2 was prenylated by the first step of the method disclosed in Example 97-1, and then ADCs were prepared using the oxime bonding reaction and copper-free click bonding reaction or copper-based click bonding reaction in the second step of the method disclosed in Example 97-1. The compounds used and the ADCs prepared are shown in Table 1 below (Table 1. ADC Preparation List).

[0494] [Table 1] JPEG2026086866000150.jpg211111 [Examples]

[0495] In vitro cytotoxicity evaluation The cell proliferation inhibitory activity of ADCs prepared in Example 91 against cancer cells was measured. Commercially available cancer cell lines (SK-BR3, JIMT-1, MDA-MB-468 cell lines) were used for this purpose. Each cancer cell line was inoculated into 96-well plates at a rate of 1500-5000 cells per well, cultured for 24 hours, and then treated with serially diluted ADC samples. After 144 hours, the number of viable cells was quantified by SRB assay. The results of cytotoxicity against cancer cells are shown in Table 2 (Table 2. Comparison of cytotoxicity of ADC samples in cancer cell lines expressing antigens).

[0496] [Table 2] JPEG2026086866000152.jpg197139*ND: Undetermined (Not determined).

[0497] In cancer cell lines overexpressing the antigen, ADC1-7, 10, 14, 17-19, 27, and 30 were confirmed to exhibit cytotoxicity equivalent to or superior to that of Comparative Example 1 or Comparative Example 2. In particular, ADC2 showed superior cytotoxicity compared to Comparative Example 1 and similar cytotoxicity to that of Comparative Example 2.

[0498] Cytotoxicity was evaluated in the MDA-MB-468 cell line, which does not express the antigen, by treatment with high concentrations of ADC (Table 3. Comparison of cytotoxicity of ADC samples in cancer cell lines that do not express the antigen).

[0499] [Table 3]

[0500] In the MDA-MB-468 cancer cell line, which does not express the antigen, ADC2 showed cytotoxicity results that were more than four times weaker than those of Comparative Example 2.

[0501] From the results described above, it was shown that ADC2 according to the present invention has similar efficacy in antigen-expressing cell lines as the comparative example, and weak toxicity in antigen-non-expressing cells, thus offering advantages such as a much wider therapeutic window. [Examples]

[0502] Preliminary toxicity assessment in rats The ADCs prepared in Example 91 were administered intravenously as a single dose to 8-week-old SD rats, and changes in body weight and mortality were observed for 70 days. Based on the mortality rate for each ADC and dose, the lethal dose and maximum tolerable dose (MTD) were summarized as follows (Table 4. Comparison of toxicity of ADC samples in SD rats).

[0503] [Table 4] (*NA: Not available (MTD cannot be confirmed as all deaths occurred at the experimental dose)

[0504] In rat toxicity tests, the lethal dose of ADC2 according to the present invention was confirmed to be significantly higher than that of Comparative Examples 1 and 2.

[0505] From these results, it can be seen that ADC2 according to the present invention exhibits relatively low toxicity and excellent safety, as the lethal dose in SD rats is significantly higher than that of Comparative Examples 1 and 2. [Industrial applicability]

[0506] This invention is applicable to the pharmaceutical and medical industries related to the treatment of diseases, including the treatment of proliferative disorders.

Claims

1. Pyrrolobenzodiazepine derivative-ligand conjugates, pharmaceutically acceptable salts thereof, or solvates thereof, The pyrrolobenzodiazepine derivative is a pyrrolobenzodiazepine derivative-ligand conjugate represented by the following chemical formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof. [Case 1] P-(B) ａ -(B') ｂ -D ・・・(I) In the above formula, P is represented by the following chemical formula II, where P is bonded to linker I. 【Chemistry 2-1】 ... (II) In the above formula, The dotted line indicates the arbitrary presence of a double bond between C2 and C3. Q １ is selected from the group consisting of 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 is selected from the group consisting of halo and dihalo, Here, R ｍ' R ｍ CO ２ R ｍ COR ｍ , CHO, CO ２ Selected from the group consisting of H and halo, Here, R ｍ C is either substituted or non-substituted. 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 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, If substitution occurs here, 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 of a cycloalkyl, 3-7 membered heterocyclyl, 3-7 membered heterocycloalkyl, or 5-7 membered heteroaryl molecule 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 at least one selected from the group consisting of cycloalkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocycloalkyl, and 5- to 7-membered heteroaryl, Q ２ Q ３ Q ５ , and Q ７ These are -H and -R, respectively, independently. ｍ -OH, -OR ｍ -SH, -SR ｍ , -NH ２ , - NHR ｍ , -NR ｍ R ｍ' , -NO ２ Selected from the group consisting of and halos, Here, R ｍ and R ｍ' This is as defined above, Q ４ is -H, -R ｍ , -OH, -OR ｍ , -SH, -SR ｍ , -NH ２ , -NHR ｍ , -NR ｍ R ｍ' , -NO ２ , 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 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 , -NR ｏ , -NR ｎ , -NR ｏ , -NR ｎ , -NR ｏ R ｏ' , -NR ｎ , -NR ｏ , -NR ｎ , -NR 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 the group consisting of, Here, if substitution occurs, at least one hydrogen atom 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 ５－１０ Aryl, 5-7 member 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 R ｑ' , -NR ｐ S(=O)R ｑ , -NR ｐ S (=O) ２ R ｑ , -NR ｐ S(=O)NR ｑ R ｑ' , -NR ｐ S (=O) ２ NR ｑ R ｑ' , -C(=O)R ｐ , -C (=O) OR ｐ or -C(=O)NR ｐ R ｐ Replaced by, Here, R ｎ , R ｎ' , R ｏ , Ｒｏ' , R ｐ , R ｐ' , R ｑ and R ｑ' These are, independently, hydrogen and C 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, X' is the part that is coupled to Linker I. Y' is selected from the group consisting of -O-, -S-, and -NH-, Q ６ C is either absent, substituted or unsubstituted, saturated or unsaturated. ３－１２ It is a hydrocarbon chain, B and B' are independent of each other, bonded as -O-, -NH-, -S-, -C(=O)-, -S(=O)-, -O-(CH ２ ) ｎ -, - (CH ２ ) ｎ -, - (CH ２ ) ｎ (C=O)-,-(CH ２ ) ｎ (C=O)NH-, or -(CH ２ CH ２ O) ｎ - and Here, n is an independent integer between 1 and 10, a and b are each independent integers of 0 or 1. D is represented by the following chemical formula III: 【Transformation 3】 ... (III) Here, 【Chemistry 4】 This refers to the site that binds to P, B, or B'. A １ and A ２ These are, independently, bond, -NH-, -O-, -C(=O)-, -C(=O)NH-, or -NHC(=O)-, A-1 and A-2 are each independently selected from 5-20 member heterocycloalkylenes, 5-20 member heterocycloalkenylenes, or 5-20 member heteroarylenes, where one ring atom is a heteroatom independently selected from N. Z １ Z ２ Z ３ Z １ ', Z ２ 'and Z ３ ' is either C or N, independently of each other. A-1 and A-2 are, 【change】 or 【change】 Selected from, Here, the dotted line represents a double bond or a single bond. Z ａ is, Z １ or Z １ 'and, Z ｂ is, Z ２ or Z ２ 'and, Z ｃ is, Z ３ or Z ３ 'and, Z １ Z ２ Z ３ Z １ ', Z ２ 'and Z ３ ' is the same as the definition above, R １ or R １ ' is Z ａ It is connected to, R １ and R １ Each of these independently contains a heteroatom in which at least one atom is independently selected from N, O, and S, C １－１０ Heteroalkyl, C １－１０ Alkyl, -(CH ２ ) ｍ OH, - (CH ２ ) ｍ NH ２ ,-(CH ２ ) ｍ NHCH ３ , hydrogen, halo or -C(=O)OH, m is an integer between 0 and 10. B １ and B ２ These are, independently, -NH-, -O-, -C(=O)-, or -S-, a １ and a ２ These are each an independent integer of 1, E １ is -NH- or -C(=O)-, and e １ These are integers from 1 to 5, E ２ C ２－５ Alkylene or -((CH ２ ) ｐ (CH ２ E １１ )) ｑ - and E ２ But ((CH ２ ) ｐ (CH ２ E １１ )) ｑ - If E １１ It is O, p is an integer from 1 to 3, q ​​is an integer from 1 to 15, and e ２ These are integers from 1 to 5, F １ These are hydrogen, -OH, -OCH ３ , -SH, -SCH ３ , 【Transformation 5】 And, Here, F １１ F １２ F １３ F １４ F １５ F １６ F １７ and F １８ These are, independently, C, N, O, or S. The dotted line indicates a double bond or a single bond. F ２１ F ２２ and F ２２' These are independently -H and -NH ２ ien-CH ３ ,-(CH ２ ) ｒ CH ３ ,-(CH ２ ) ｒ OH, - (CH ２ ) ｒ NH ２ , -F ３３ (CH ２ ) ｒ CH ３ , -F ３３ (CH ２ ) ｒ OH, -F ３３ (CH ２ ) ｒ NH ２ Alternatively, it is selected from Linker II, F ３３ These are -O-, -S-, and -CH ２ -, -C(=O)-, -NH-, -C(NH ２ ) - or -C (=NH) - are selected, F ２１ ' is, = CH ２ ,=NH,=F ３３ '(CH ２ ) ｒ CH ３ , = F ３３ '(CH ２ ) ｒ OH or = F ３３ '(CH ２ ) ｒ NH ２ Selected from, F ３３ ' is =N-, =CH-, =C(OH)- or =C(NH ２ ) - is selected from, and r is an integer from 0 to 10. Here, Linker I and Linker II are represented by the following chemical formula IV and are selected independently. 【Transformation 6】 ... (IV) In the above formula, G stands for glucuronic acid or 【Transformation 7】 And, The aforementioned R ｃ is a hydrogen or carboxyl protecting group, Each of the aforementioned R ｄ These are independently hydrogen or hydroxyl protecting groups, R ａ and R ｂ These are, independently, hydrogen and C １－８ Alkyl or C ３－８ It is a cycloalkyl, W is -C(=O)-, -C(=O)NR'-, -C(=O)O-, -S(=O) ２ NR'-, -P(=O)R''NR'-, -S(=O)NR'- or -P(=O) ２ It is NR'-, and the C, S, or P is directly bonded to the phenyl ring. Here, R' and R'' are independently hydrogen and C. １－８ Alkyl, C ３－８ Member cycloalkyl, C １－８ Alkoxy, C １－８ Alkylthio, mono-, or di-C １－８ Alkylamino, 3-20 membered heteroaryl or C ６－２０ It is a compound of the aryl group, T is independent of C １－８ They are alkyl, halogen, cyano, or nitro, s is an integer between 0 and 3. L is at least one unit selected from the group consisting of connection units and branching units, or a combination thereof. Here, the connecting unit is W and R ｚ Connect them, or connect W and the branching unit, or connect branching units to each other, where the branching unit connects the connecting unit and W, or connects the connecting unit to another connecting unit, The connecting unit is 【Transformation 8】 - (CH ２ CH ２ V) ｔ -, - (CH ２ ) ｔ (V(CH ２ ) ｕ ) ｖ - or a combination thereof, Here, L １ is a single bond or C ２－３０ It is an alkenyl, R １１ is H or C １－１０ It is alkyl, L ２ C ２－３０ It is alkenyl, Here, t is an integer between 0 and 10, u is an integer between 0 and 12, v is an integer between 1 and 20, and V is a single bond, -O-, or -S-. The branching unit is C ２－１００ Alkenyl, hydrophilic amino acid, -C(=O)-, -C(=O)NR ｖ -, -C(=O)O-, -(CH ２ ) ｎ１ -NHC(=O)-(CH ２ ) ｎ２ -, - (CH ２ ) ｎ３ -C(=O)NH-(CH ２ ) ｎ４ -, - (CH ２ ) ｎ１ -NHC(=O)-(CH ２ ) ｎ２ -C(=O)-, -(CH ２ ) ｎ３ -C(=O)NH-(CH ２ ) ｎ４ -C(=O)-, -S(=O) ２ NR ｖ -, -P(=O)R ｗ NR ｖ -, -S(=O)NR ｖ - and -P (=O) ２ NR ｖ - Selected from the group consisting of, Here, the branching unit is C ２－１００ If it is an alkenyl, the carbon atoms of the alkenyl may be substituted with a heteroatom selected from the group consisting of at least one N, O, and S, and the alkenyl has at least one C １－２０ It may be further substituted with alkyl, Here, R ｖ and R ｗ These are H and C, respectively, independently. 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 ５－２０ It is Ariel, n1, n2, n3, and n4 are each independent integers between 0 and 10. R ｚ is, -O-NH ２ , -NH ２ , N ３ , substitution or non-substitution of C １－１２ Alkyl, C １－１２ Alkinyl, C １－３ Alkoxy, substituted or unsubstituted 3- to 20-membered heteroaryls, 3- to 20-membered heterocyclyls, substituted or unsubstituted C ５－２０ Ariel, 【Chemistry 9】 , or a site that binds to a ligand, Here, R ｚ ' is N or C, Here, the substituent selected from the group consisting of the Rz of linker I and the Rz of linker II is the ligand-binding site. In this case, if substitution occurs, at least one hydrogen atom is independently OH, =O, halo, or C. １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenyl, oxy, 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 It is replaced with a heteroaryl compound.

2. The pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, wherein the ligand is an antibody, a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. The antibody comprises at least one amino acid motif recognized by an isoprenoid transferase, the pyrrolobenzodiazepine derivative-ligand conjugate according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. The pyrrolobenzodiazepine derivative-ligand conjugate according to claim 3, wherein the isoprenoid transferase is FTase (farnesyl protein transferase) or GGTase (geranylgeranyl transferase), a pharmaceutically acceptable salt thereof, or a solvate thereof.

5. The aforementioned amino acid motif is CYYX, XXCC, XCXC, or CXX, The pyrrolobenzodiazepine derivative-ligand conjugate according to claim 3, wherein C is cysteine, Y is an aliphatic amino acid, and X is an amino acid that determines the substrate specificity of the isoprenoid transferase, a pharmaceutically acceptable salt thereof or a solvate thereof.

6. The aforementioned Q １ C is either substituted or non-substituted. １－６ Alkyl, substituted, or unsubstituted C ２－６ Alkenyl, substituted or unsubstituted C ５－７ Aryl and substituted or unsubstituted C ５－６ Selected from the group consisting of heteroaryls, The aforementioned Q ２ Q ３ Q ５ and Q ７ These are, independently, -H or -OH, The aforementioned Q ４ is methoxy, ethoxy or butoxy, or The aforementioned Q ６ This refers to substituted or unsubstituted, saturated or unsaturated C ３－８ A pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, which is a hydrocarbon chain, a pharmaceutically acceptable salt thereof, or a solvate thereof.

7. The aforementioned G is, 【Chemistry 10】 And, The aforementioned R ｃ is a hydrogen or carboxyl protecting group, Each of the aforementioned R ｄ The pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, wherein is independently a hydrogen or hydroxyl protecting group, a pharmaceutically acceptable salt thereof, or a solvate thereof.

8. The aforementioned R ｃ is hydrogen, and each of the R ｄ The pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, wherein is hydrogen, or W is -C(=O)NR'-, where C(=O) is bonded to a phenyl ring and NR' is bonded to L, a pharmaceutically acceptable salt thereof or a solvate thereof.

9. The aforementioned branching unit is C ２－８ Alkenyl, hydrophilic amino acid, -C(O)-, -C(O)NR ｖ -, -C(O)O-, -(CH ２ ) ｎ１ -NHC(=O)-(CH ２ ) ｎ２ -, - (CH ２ ) ｎ３ -C(O)NH-(CH ２ ) ｎ４ -, - (CH ２ ) ｎ１ -NHC(O)-(CH ２ ) ｎ２ -C(O)- and -(CH ２ ) ｎ３ -C(O)NH-(CH ２ ) ｎ４ Selected from the group consisting of -C(O)-, Here, the branching unit is C ２－８ If it is an alkenyl, the carbon atoms of the alkenyl may be substituted with a heteroatom selected from the group consisting of at least one N, O, and S, and the alkenyl has at least one C １－２０ It may be further substituted with alkyl, Here, R ｖ 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 ５－２０ It is Ariel, n1, n2, n3, and n4 are each independently integers from 0 to 5, or The aforementioned connecting unit is -(CH ２ ) ｔ (V(CH ２ ) ｕ ) ｖ A pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, wherein t is an integer from 0 to 8, u is an integer from 0 to 12, v is an integer from 1 to 10, and V is a single bond or -O-, a pharmaceutically acceptable salt thereof or a solvate thereof.

10. The aforementioned connecting unit is -(CH ２ ) ｔ (V(CH ２ ) ｕ ) ｖ A pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, wherein t is an integer of 2, u is an integer of 2, v is an integer of 2, and V is -O-, a pharmaceutically acceptable salt thereof or a solvate thereof.

11. The aforementioned connecting unit is 【Chemistry 12】 This includes, where L １ is a single bond or C ２－８ It is an alkenyl, R １１ is H or C １－６ It is alkyl, L ２ C ２－８ A pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, wherein the derivative is an alkenyl, a pharmaceutically acceptable salt thereof, or a solvate thereof.

12. The aforementioned R ｚ is, -O-NH ２ , -NH ２ , N ３ , -OCH ３ , -OCH ２ CH ３ , -O(CH ２ ) ２ CH ３ or 【Chemistry 13】 or a site that binds to a ligand, Hereinafter, the substituent selected from the group consisting of Rz of linker I and Rz of linker II is a ligand-binding site, the pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

13. The aforementioned R １ and R １ ' are, independently, hydrogen and C １－５ Alkyl, (CH ２ ) ｍ OH or (CH ２ ) ｍ NH ２ The pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, wherein m is an integer from 1 to 7, a pharmaceutically acceptable salt thereof, or a solvate thereof.

14. Said F １ is -OH, -OCH ３ , -SH, -SCH ３ , 【Chemistry 16】 And, F １１ and F １２ These are, independently, C or N, F ２１ F ２２ and F ２２ ' are H, -(CH ２ ) ｒ CH ３ ,-(CH ２ ) ｒ OH, - (CH ２ ) ｒ NH ２ , -F ３３ (CH ２ ) ｒ CH ３ , -F ３３ (CH ２ ) ｒ OH, -F ３３ (CH ２ ) ｒ NH ２ Alternatively, it is selected from Linker II, F ３３ This is selected from -C(=O)-, -NH-, or -C(=NH)-, F ２１ ' is, = CH ２ ,=NH,=F ３３ '(CH ２ ) ｒ CH ３ , = F ３３ '(CH ２ ) ｒ OH, = F ３３ '(CH ２ ) ｒ NH ２ Alternatively, it is selected from Linker II, F ３３ ' is =N-, =CH-, =C(OH)- or =C(NH ２ ) - Selected from, F ２１ F ２２ and F ２２ ' at least one of which is -CH ３ The pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

15. The pyrrolobenzodiazepine derivative further comprises the following general formula V, the pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. 【Chemistry 17】 ... (V) In the above formula, 【change】 Each portion is independently bonded to a first linker or hydrogen, where the first linker is linker I or linker II. 【change】 When each part is independently linked to linker I or linker II, 【change】 Each part is independently coupled to Rz. SL stands for the second linker, and the second linker is represented by the following formula VI. [C18] L'-R ｚｚ '・・・(VI) In the above formula, L' and R ｚｚ ' represents L and R of the aforementioned chemical formula IV, respectively. ｚ It is the same as this.

16. The first linker includes at least one branch unit, where the branch unit is -C(O)-, -C(O)NR ｖ -, -C(O)O-, -(CH ２ ) ｎ１ -NHC(O)-(CH ２ ) ｎ２ -, - (CH ２ ) ｎ３ -C(O)NH-(CH ２ ) ｎ４ -, - (CH ２ ) ｎ１ -NHC(O)-(CH ２ ) ｎ２ -C(O)-,-(CH ２ ) ｎ３ -C(O)NH-(CH ２ ) ｎ４ -C(O)-, -S(O) ２ NR ｖ -, -P(O)R ｗ NR ｖ -, -S(O)NR ｖ - and -PO ２ NR ｖ - Selected from the group consisting of R ｖ and R ｗ These are H and C, respectively, independently. 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 ５－２０ It is an array where n1, n2, n3, and n4 are each independently integers from 0 to 5, or L' includes at least one branching unit and a connecting unit, where the branching unit is C ２－８ The linking unit is selected from the group consisting of alkenyls, hydrophilic amino acids, -C(O)- and -C(O)O-, and the linking unit is -(CH ２ ) ｔ (V(CH ２ ) ｕ ) ｖ - where t is an integer from 0 to 5, u is an integer of 2, v is an integer from 1 to 10, V is -O-, and Rzz' is -O-NH ２ , -NH ２ , N ３ , -OCH ３ , or -OCH ２ CH ３ The pyrrolobenzodiazepine derivative-ligand conjugate according to claim 15, a pharmaceutically acceptable salt thereof, or a solvate thereof.

17. The pyrrolobenzodiazepine derivative represented by the aforementioned chemical formula I is 【Chemistry 19】 【change】 【change】 【change】 【change】 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 , and 【change】 A pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, which is one selected from the group consisting of the following, a pharmaceutically acceptable salt thereof, or a solvate thereof.

18. The aforementioned pyrrolobenzodiazepine derivative is 【Chemistry 21】 The pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

19. One or more linkers selected from the group consisting of linker I and linker II are: It further comprises at least one isoprenyl unit having the structure, Herein, i is at least 2, the pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

20. A pharmaceutical composition comprising a pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

21. A pharmaceutical composition comprising a pyrrolobenzodiazepine derivative-ligand conjugate according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the treatment of proliferative disorders.

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