Toxin molecules suitable for antibody-drug conjugates

Abstract

Toxin molecules suitable for antibody-drug conjugates are provided, specifically, compounds as shown in the following formula (I), or pharmaceutically acceptable salts or hydrates thereof, which are used in the preparation of drugs for treating diseases associated with tumor cell proliferation: [Formula 1] JPEG2025526425000110.jpg38167

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of medicinal chemistry, and specifically, the present invention provides toxin molecules that have tumor cell growth inhibitory activity.

[0002] [Background technology] Antibody drug conjugates (ADCs) combine monoclonal antibodies or antibody fragments with biologically active cytotoxins via a stable chemical linker compound, making full use of the specificity of antibodies to bind to surface antigens on normal and tumor cells and the high efficiency of cytotoxic substances, while avoiding the disadvantages of the former (lower therapeutic efficacy) and the latter (excessive toxic side effects). This means that, compared with traditional chemotherapy drugs, antibody drug conjugates can bind more precisely to tumor cells and have less impact on normal cells.

[0003] Currently, various ADC drugs are in clinical use or clinical research, for example, Kadcyla is an ADC drug formed by trastuzumab and DM1 that targets Her2. At the same time, there are also patent reports on antibodies and ADC drugs that target B7H3.

[0004] There are several classes of specific cytotoxic small molecules used in antibody-drug conjugates, one of which is camptothecin derivatives, which have antitumor effects by inhibiting topoisomerase I. Although the application of the camptothecin derivative exatecan in antibody-drug conjugates (ADCs) has been reported in the literature, there is still a need in the art for further development of ADC drugs with better therapeutic efficacy.

[0005] DNA topoisomerase (Topo) is a type of essential enzyme widely present in living organisms and is involved in all important nuclear processes, including DNA replication, transcription, recombination, and repair. According to the various forms of temporary DNA strand breaks caused by topoisomerases, topoisomerases can be classified into two major categories: topoisomerase I and topoisomerase II. Topoisomerase I and topoisomerase II jointly catalyze supercoiled DNA unwinding during DNA replication. However, topoisomerase II is responsible for double-strand breaks, whereas topoisomerase I only causes single-strand breaks. Camptothecin and its analogs reversibly bind to the DNA topoisomerase I-DNA complex to form a camptothecin or its analog-DNA topoisomerase I-DNA ternary complex, which stalls progressive unwinding and ultimately leads to replication fork collision with the ternary complex, generating irreparable DNA breaks and causing cell death.

[0006] [Summary of the Invention] [Problem to be solved by the invention] It is an object of the present invention to provide toxin molecules suitable for antibody drug conjugates.

[0007] [Means for solving the problem] A first aspect of the present invention provides a compound as shown in formula (I) below, or a pharmaceutically acceptable salt or hydrate thereof:

[0008] [ka]

[0009] where n is 0 or 1, X is N or CR 0 is selected from the group consisting of R 0 is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a C1-C8 alkyl group, a C1-C8 alkoxy group, OH, NH2, N3, or NO2; R 1is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 haloalkyl group, a C1-C8 haloalkoxy group, N3, NO2, NH2, NH-OH, -NR'R'', -COOR', -CONR'R'', -NHR'''NR'R'', wherein R', R'' and R''' are each independently selected from a hydrogen atom, an alkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbonyl group and an aryloxycarbonyl group; R 2 , R 3 , R 4 , R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen atom, a hydroxy group, a cyano group, NH2, NO2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C1-C8 alkylthio group, a substituted or unsubstituted C1-C8 deuterated alkyl group, -(CH2) m Tri(C1-C4 alkyl)silyl group, -(CH2) m (C3-C8 cycloalkyl group), -(CH2) m (3- to 12-membered heterocyclic group), —(CH2) m N(R 7 )2, -(CH2) m S(CH2) p R 7 , -(CH2) m S(O)(CH2) p R 7 , -(CH2) m S(O)2(CH2) p R 7 , -(CH2) m NH(CH2) p R 7 , -(CH2) m NHC(O)(CH2) p R 7 , -(CH2) m OC(O)(CH2) p R 7 , -(CH2) m C(O)(CH2) p R 7, -CH=N(OtBu), wherein m and p are each independently 0, 1, 2, 3, or 4; Or, R 2 and R 3 together with the carbon atoms to which they are attached form a substituted or unsubstituted C5-C8 carbocyclic ring or a substituted or unsubstituted 5- to 12-membered heterocyclic ring group; Or, R 2 and R 3 together with the carbon atoms to which they are attached, are unsubstituted or one or more R a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R a and forming a structure selected from the group consisting of saturated or unsaturated 5- to 6-membered heterocycles substituted by Or, R 3 and R 4 or R 4 and R 5 together with the carbon atoms to which they are attached, are unsubstituted or one or more R a a saturated or unsaturated 5- to 12-membered carbocyclic ring, unsubstituted or substituted by one or more R a and forming a structure selected from the group consisting of saturated or unsaturated 5- to 12-membered heterocycles substituted by R a is a substituted or unsubstituted hydrogen atom, deuterium atom, halogen, nitrile group, nitro group, hydroxy group, amino group, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, allyl group, benzyl group, C6-C 12 Aryl group, C1-C6 alkoxy-C1-C6 alkyl group, C1-C6 alkoxy-carbonyl group, phenoxycarbonyl group, C2-C6 alkynyl-carbonyl group, C2-C6 alkenyl-carbonyl group, C3-C6 cycloalkyl-carbonyl group, C1-C6 alkyl-sulfonyl group, phenyl group, 5-7 membered heteroaryl group, C3-C8 cycloalkyl group, 3-12 membered heterocyclic group, -(CH2) m N(R 7 )2, -(CH2) mS(CH2) p R 7 , -(CH2) m S(O)(CH2) p R 7 ,- (CH2) m S(O)2(CH2) p R 7 , -(CH2) m NH(CH2) p R 7 , -(CH2) m NHC(O)(CH2) p R 7 , -(CH2) m OC(O)(CH2) p R 7 , -(CH2) m C(O)(CH2) p R 7 wherein m and p are each independently 0, 1, 2, 3 or 4, preferably 0, 1 or 2; Each R 7 are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 haloalkyl group, a C1-C8 deuterated alkyl group, a substituted or unsubstituted C1-C8 alkoxy group, a hydroxy group, an amino group, a cyano group, a nitro group, a mercapto group, a substituted or unsubstituted C1-C8 alkylene-OH, a substituted or unsubstituted C1-C8 alkylene-NH2, SO2Me, -OC(O) (a substituted or unsubstituted C1-C4 alkyl group), -C(O) (a substituted or unsubstituted C1-C4 alkyl group), a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5- to 7-membered heteroaryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, and a substituted or unsubstituted 3- to 12-membered heterocyclic group; Unless otherwise specified, any of the above groups is not a deuterium atom, a halogen, a nitrile group, a nitro group, a hydroxy group, an amino group, a C1-C6 alkyl-NH-, a (C1-C6 alkyl)2N-, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a haloC1-C6 alkyl group, a haloC2-C6 alkenyl group, a haloC2-C6 alkynyl group, a haloC1-C6 alkoxy group, an allyl group, a benzyl group, a C6-C 12 and the compound may be substituted by a substituent selected from the group consisting of an aryl group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkoxy-carbonyl group, a phenoxycarbonyl group, a C2-C6 alkynyl-carbonyl group, a C2-C6 alkenyl-carbonyl group, a C3-C6 cycloalkyl-carbonyl group, a C1-C6 alkyl-sulfonyl group, a phenyl group, a 5- to 7-membered heteroaryl group, a C3-C8 cycloalkyl group, and a 3- to 12-membered heterocyclic group, and the compound does not have a structure selected from the group consisting of:

[0010] [ka] JPEG2025526425000004.jpg158158JPEG2025526425000005.jpg158158JPEG2025526425000006.jpg207158

[0011] In another preferred embodiment, the compound of formula I has a structure as shown in formula II or formula III:

[0012] [ka]

[0013] [ka]

[0014] In another preferred embodiment, the compound of formula I has a structure as shown in formula IV or formula V:

[0015] [ka]

[0016] [ka]

[0017] In another preferred embodiment, the compound of formula I has a structure as shown in formula VI or VII:

[0018] [ka]

[0019] [ka]

[0020] In another preferred embodiment, the R 4 represents a hydrogen atom, a deuterium atom, a halogen atom, a hydroxy group, a cyano group, NH2, NO2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C1-C8 alkylthio group, a substituted or unsubstituted C1-C8 deuterated alkyl group, -(CH2) m (C3-C8 cycloalkyl group), -(CH2) m (3- to 12-membered heterocyclic group), —(CH2) m N(R 7 )2, -(CH2) m S(O)(CH2) p R 7 , -(CH2) m S(O)2(CH2) p R 7 , -(CH2) m NH(CH2) p R 7wherein m and p are each independently 0, 1, or 2; 7 is defined as above, R 5 is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, NH, OH, a substituted or unsubstituted C-C alkyl group, and a substituted or unsubstituted C-C alkoxy group; Or, R 4 and R 5 together with the carbon atoms to which they are attached, are unsubstituted or one or more R a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R a and forming a structure selected from the group consisting of saturated or unsaturated 5- to 6-membered heterocycles substituted by a The definition of is as described above.

[0021] In another preferred embodiment, R 4 is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a hydroxy group, an amino group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a deuterated C1-C3 alkyl group, a deuterated C1-C3 alkoxy group, a halogen-substituted C1-C3 alkyl group, a halogen-substituted C1-C3 alkoxy group, a C2-C4 alkynyl group, and a C3-C6 cycloalkyl group; In another preferred embodiment, R 5 is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a hydroxy group, an amino group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a deuterated C1-C3 alkyl group, a deuterated C1-C3 alkoxy group, a halogen-substituted C1-C3 alkyl group, and a halogen-substituted C1-C3 alkoxy group; In another preferred embodiment, R 4 is a methyl group, an ethyl group, a methoxy group, a deuterated methoxy group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, an ethynyl group, a cyclopropyl group, is selected from the group consisting of propyl groups, In another preferred embodiment, R 5 is selected from the group consisting of a methyl group, an ethyl group, a methoxy group, a deuterated methoxy group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group; In another preferred embodiment, R 4 and R 5 are bonded together to form a substituted or unsubstituted —OCH2O—, or a substituted or unsubstituted —O(CH2)2O—.

[0022] In another preferred embodiment, R 4 and R 5 are bonded together to form -OCH2O-, -OCF2O- or -O(CH2)2O-. In another preferred embodiment, the compound of formula I has the structure shown in formula VIII:

[0023] [ka]

[0024] wherein ring A is substituted or has one or more R a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R a a saturated or unsaturated 5- to 6-membered heterocycle substituted by a is defined as above, and R 1 , R 2 , R 3 , R 6 , the definition of X is as described above.

[0025] In another preferred embodiment, the compound of formula I has the structure shown in formula IX:

[0026] [ka]

[0027] In another preferred embodiment, the compound of formula I has a structure as shown in formulas X-XV:

[0028] [ka]

[0029] wherein ring A may be unsubstituted or optionally substituted, where the definitions of the substituents are as described above. In another preferred embodiment, R 2 and R 3 are each independently a hydrogen atom, a deuterium atom, a halogen atom, NH2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 deuterated alkyl group, -(CH2) m (C3-C6 cycloalkyl group), -(CH2) m (3- to 6-membered heterocyclic group), —(CH2) m N(R 7 )2, -(CH2) m OC(O)R 7 wherein m is 0, 1, 2, 3, or 4; and R 7 is defined as above, Or, R 2 and R 3 together with the carbon atoms to which they are attached, may be unsubstituted or may be one or more R a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R a and forming a structure selected from the group consisting of saturated or unsaturated 5- to 6-membered heterocycles substituted by a The definition of is as described above.

[0030] In another preferred embodiment, the compound of formula I has the structure shown in formula XVI:

[0031] [ka]

[0032] R 2 and R 3 together with the carbon atoms to which they are attached, may be unsubstituted or may be one or more R a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R a and forming a structure selected from the group consisting of saturated or unsaturated 5- to 6-membered heterocycles substituted by a The definition of is as described above.

[0033] In another preferred embodiment, the compound of formula I has the structure shown in formula XVII: and

[0034] [ka]

[0035] In another preferred embodiment, the compound of formula I has the structure shown in formulas XVIII-X:

[0036] [ka]

[0037] Ring B can be unsubstituted or optionally substituted, where the definitions of the substituents are as set forth above. In another preferred embodiment, the ring B is substituted with a substituent as shown in the following formula: -Lx-R 11 where x is 1, 2, 3, 4, 5 or 6; Each L is independently CH2, O, S, NH, NHC(O), C(O), C(NH), S(O), S(O)2, C6-C 10 selected from the group consisting of an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 8-membered saturated or unsaturated carbocyclic ring, and a 4- to 10-membered saturated or unsaturated heterocyclic ring; R11 is selected from the group consisting of OH, SH, and NH2.

[0038] In another preferred example, ring B may be unsubstituted and is -Lx-R 11 and optionally substituted by where x is an integer between 0 and 10, Each L is independently CRwRx, O, S, NH, NRy, NHC(O), C(O), C(NH), S(O), S(O)2, C6-C 10 selected from the group consisting of an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 8-membered saturated or unsaturated carbocyclic ring, and a 3- to 10-membered saturated or unsaturated heterocyclic ring; R 11 is selected from the group consisting of a hydrogen atom, OH, SH, NH2, and NHRz.

[0039] The Rw, Rx, Ry, and Rz each independently represent a hydrogen atom, a deuterium atom, a halogen, a hydroxy group, NH, a substituted or unsubstituted C alkyl group, a C haloalkyl group, a C 10 Cycloalkyl groups are selected from the group consisting of alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups.

[0040] In another preferred embodiment, the R a represents a hydrogen atom, a deuterium atom, a halogen atom, a nitrile group, a nitro group, a hydroxy group, an amino group, a C1-C6 alkyl-NH-, a (C1-C6 alkyl)2N-, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a haloC1-C6 alkyl group, a haloC2-C6 alkenyl group, a haloC2-C6 alkynyl group, a haloC1-C6 alkoxy group, an allyl group, a benzyl group, a C6-C 12 Aryl group, C1-C6 alkoxy-C1-C6 alkyl group, C1-C6 alkoxy-carbonyl group, -(CH2) m N(R 7 )2, -(CH2) m NH(CH2) p R 7 , -(CH2)m NHC(O)(CH2) p R 7 wherein m and p are each independently 0, 1, 2, 3 or 4, preferably 0, 1 or 2.

[0041] In another preferred embodiment, R 1 and R 6 are each independently a hydrogen atom. In another preferred example, X is independently selected from N and CH.

[0042] In another preferred example, X is independently selected from CH. In another preferred embodiment, the R 4 and R 5 are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a hydroxy group, NH, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C1-C4 alkoxy group, and a cyclopropyl group; Or, R 4 and R 5 together with the carbon atoms to which they are attached, are unsubstituted or one or more R a forming a 5-6 membered oxa heterocycle substituted by a The definition of is as described above.

[0043] In another preferred embodiment, R 2 represents a hydrogen atom, a deuterium atom, a halogen atom, NH2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 deuterated alkyl group, -(CH2) m (C3-C6 cycloalkyl group), -(CH2) m (3- to 6-membered heterocyclic group), —(CH2) m N(R 7 )2, -(CH2) m OC(O)R 7 wherein m is 0, 1, 2, 3, or 4; R 3Each of the groups is a hydrogen atom, a deuterium atom, a halogen atom, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 deuterated alkyl group, -(CH2) m (C3-C6 cycloalkyl group), -(CH2) m (3- to 6-membered heterocyclic group), —(CH2) m N(R 7 )2, -(CH2) m OC(O)R 7 wherein m is 0, 1, 2, 3, or 4; Or, R 2 and R 3 together with the carbon atoms to which they are attached, are unsubstituted or one or more R a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R a and forming a structure selected from the group consisting of saturated or unsaturated 5- to 6-membered heterocycles substituted by R 4 is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a hydroxy group, a cyano group, NH, NO, a substituted or unsubstituted C-C alkyl group, and a substituted or unsubstituted C-C alkoxy group; R 5 is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and a substituted or unsubstituted C1-C8 alkyl group; Or, R 4 and R 5 are bonded to form -OCH2O- or -O(CH2)2O- unsubstituted or one or more R selected from the group a forming a structure substituted by R 7 is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, a substituted or unsubstituted C1-C8 alkyl group, a hydroxy group, an amino group, a cyano group, a nitro group, and a mercapto group; where R a The definition of is as described above.

[0044] In another preferred embodiment, the compound has a structure as shown in the following formula:

[0045] [ka] JPEG2025526425000020.jpg219158JPEG2025526425000021.jpg235159JPEG2025526425000022.jpg239158JPEG2025526 425000023.jpg224158JPEG2025526425000024.jpg239158JPEG2025526425000025.jpg241158JPEG2025526425000026.j pg229158JPEG2025526425000027.jpg222158JPEG2025526425000028.jpg222158JPEG2025526425000029.jpg222158JPE G2025526425000030.jpg227158JPEG2025526425000031.jpg228158JPEG2025526425000032.jpg224158JPEG2025526425 000033.jpg224159JPEG2025526425000034.jpg222158JPEG2025526425000035.jpg229158JPEG2025526425000036.jpg2 33158JPEG2025526425000037.jpg244167JPEG2025526425000038.jpg244167JPEG2025526425000039.jpg244167JPEG20 25526425000040.jpg246167JPEG2025526425000041.jpg222167JPEG2025526425000042.jpg231168JPEG2025526425000 043.jpg231168JPEG2025526425000044.jpg231168JPEG2025526425000045.jpg194168JPEG2025526425000046.jpg90168

[0046] A second aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I as defined in any one of the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0047] A third aspect of the present invention provides the use of a compound of formula I according to the first aspect of the present invention for use in the preparation of a pharmaceutical composition for the treatment of a disease associated with tumor cell proliferation.

[0048] In another preferred example, the disease is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, lung cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, pharyngeal cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma.

[0049] A fourth aspect of the present invention provides a use of a compound of formula I according to the first aspect of the present invention, characterized in that it is used as a toxin molecule to prepare coupled drugs including antibody drug conjugates, polypeptide drug conjugates, small molecule coupled drugs, polymer coupled drugs, lipid drug conjugates and protein drug conjugates.

[0050] A fifth aspect of the present invention provides an intermediate compound having the formula:

[0051] [ka]

[0052] Here, the definitions of each group are as described above. In another preferred embodiment, the compound has a structure according to formula II-b or III-b:

[0053] [ka]

[0054] In another preferred embodiment, the compound has the structure set forth in formula IV-b or Vb:

[0055] [ka]

[0056] A sixth aspect of the present invention provides a process for preparing a compound of formula I according to the first aspect of the present invention, said process comprising the steps of:

[0057] [ka]

[0058] The method comprises reacting a compound of formula Ia with a compound of formula Ib in an inert solvent to give a compound of formula I. [Effects of the invention] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE INVENTION

[0059] After extensive and intensive research, the present inventors have unexpectedly discovered a compound represented by formula I. The compound has unexpected activity in inhibiting tumor cell proliferation and is used for treating diseases associated with tumor cell proliferation. Based on the above, the present inventors have completed the present invention.

[0060] definition As used herein, the term "alkyl group" includes straight-chain or branched-chain alkyl groups. For example, a C1-C8 alkyl group refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, such as a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, etc.

[0061] As used herein, the term "alkenyl group" includes straight-chain and branched-chain alkenyl groups. For example, a C2-C6 alkenyl group refers to a straight-chain or branched-chain alkenyl group having from 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

[0062] As used herein, the term "alkynyl group" includes straight-chain and branched-chain alkynyl groups. For example, a C2-C6 alkynyl group refers to a straight-chain or branched-chain alkynyl group having from 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.

[0063] As used herein, "C3-C 10 The term "cycloalkyl group" refers to a cycloalkyl group having from 3 to 10 carbon atoms. It may be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may be bicyclic, such as bridged or spirocyclic.

[0064] As used herein, the term "C1-C8 alkylamino group" refers to an amino group substituted with a C1-C8 alkyl group, which may be mono- or di-substituted, such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, t-butylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di-t-butylamino group, and the like.

[0065] As used herein, the term "C1-C8 alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

[0066] As used herein, the term "3- to 10-membered heterocycloalkyl group having 1 to 3 heteroatoms selected from the group consisting of N, S, and O" refers to a saturated or partially saturated cyclic group having 3 to 10 atoms, of which 1 to 3 heteroatoms are selected from the group consisting of N, S, and O. It may be a monocyclic or bicyclic group in the form of a bridged ring or a spirocyclic ring. Specific examples include oxetane, azetidine, tetrahydro-2H-pyranyl group, piperidinyl group, tetrahydrofuranyl group, morpholinyl group, and pyrrolidinyl group.

[0067] As used herein, "C6-C 10 The term "aryl group" refers to an aryl group having 6 to 10 carbon atoms, such as a phenyl group or a naphthyl group or similar group.

[0068] As used herein, the term "5- to 10-membered heteroaryl group having 1 to 3 heteroatoms selected from the group consisting of N, S, and O" refers to a heteroaryl group having 5 to 10 atoms. "Aromatic" refers to a cyclic aromatic group in which 1 to 3 atoms are heteroatoms selected from the group consisting of N, S, and O. It may be a monocyclic or fused ring form. Specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.

[0069] Unless otherwise specified, the groups described in the present invention are "substituted or unsubstituted", and all groups in the present invention are substituted or unsubstituted, including halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C12 It may be substituted by a substituent selected from the group consisting of an aryl group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkoxy-carbonyl group, a phenoxycarbonyl group, a C2-C6 alkynyl-carbonyl group, a C2-C6 alkenyl-carbonyl group, a C3-C6 cycloalkyl-carbonyl group, a C1-C6 alkyl-sulfonyl group, and the like.

[0070] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halogenated" refers to substitution with an atom selected from F, Cl, Br, and I.

[0071] Unless otherwise specified, the structural formulae depicted in the present invention are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers), including asymmetric centers, such as the R and S configurations, and (Z) and (E) isomers of double bonds. Thus, all individual stereochemical isomers of the compounds of the present invention or mixtures of the enantiomers, diastereomers, or geometric (or conformational) isomers thereof are within the scope of the present invention.

[0072] As used herein, the term "tautomer" refers to structural isomers of different energies that can be interconverted across a low energy barrier. For example, proton tautomers (i.e., protonated) include interconversions via migration of a proton, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversions via recombination of some bond electrons.

[0073] As used herein, the term "hydrate" refers to a complex formed when a compound of the present invention is coordinated with water. The compounds of the present application can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining specific embodiments with other chemical synthetic methods, and equivalent substitution methods known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0074] The solvents used in this application are commercially available and the compounds are named artificially or by ChemDraw® software; for commercially available compounds, the supplier's catalog name is used.

[0075] Pharmaceutical compositions and methods of administration Since the compound of the present invention has excellent tumor cell proliferation inhibitory activity, the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for preventing diseases associated with tumor cell proliferation. and / or used for treatment (stabilization, relief or cure).

[0076] The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to clearly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 1 to 200 mg of the compound / agent of the present invention. Preferably, the "single agent" is one capsule or tablet.

[0077] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to be blended with each other without significantly reducing the efficacy of the compounds of the present invention and with each other. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0078] The administration route of the compound or pharmaceutical composition of the present invention is not particularly limited, and typical administration routes include (but are not limited to) oral and parenteral (intravenous, intramuscular, or subcutaneous).

[0079] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) a humectant, such as glycerin; or (d) agar, calcium carbonate, potato starch. It is mixed with ingredients such as disintegrating agents such as potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) retarders such as paraffin, (f) absorption accelerators such as quaternary amine compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffering agent.

[0080] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a specific part of the digestive tract. Examples of embedding materials that can be used include polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0081] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms contain an inert diluent conventionally used in the art, such as water or other solvents, and, for example, ethanol, isopropanol, carbonated Solubilizers and emulsifiers may be included such as ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor seed oil and sesame oil, or mixtures of these substances.

[0082] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents. In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0083] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0084] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents. When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable therapeutic agents, which may be used simultaneously, separately, or sequentially with the compounds of the present invention to prevent and / or treat diseases associated with tumor cell proliferation.

[0085] When a pharmaceutical composition is used, a safe and prevalent amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, and the dosage at the time of administration is the considered effective dose, and for a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 1 to 500 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0086] Hereinafter, the present invention will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are usually in accordance with conventional conditions or conditions suggested by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0087] Example 1

[0088] [ka]

[0089] Phase 1 1a (1.95 g, 7.40 mmol) and imidazole (2.52 g, 37.00 mmol) were sequentially placed in a three-necked flask (100 mL). After replacing the atmosphere with nitrogen, anhydrous N,N-dimethylformamide (30 mL) was added to the three-necked flask, the mixture was cooled to 0°C, and triethylchlorosilane (4.45 g, 29.60 mmol) and 4-dimethylaminopyridine (0.90 g, 7.40 mmol) were sequentially added. After the addition was completed, the mixture was stirred for 2 hours while maintaining the temperature at 0°C. The reaction mixture was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (25 mL × 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 to 100%) to give 1b-1 (0.90 g) and 1b-2 (1.50 g), total yield: 73%.

[0090] 1b-1: MS-ESI calculated value [M+H] + 378, actual value 378. 1b-2: MS-ESI calculated value [M+H] + 492, observed value 378 (removing one TES molecule).

[0091] Phase 2 1b-2 (1.10 g, 2.20 mmol) and Lawesson's reagent (1.80 g, 4.40 mmol) were sequentially placed in a three-necked flask (100 mL). After purging with nitrogen gas, anhydrous toluene (30 mL) was added to the three-necked flask, and the mixture was heated to 90 °C and stirred for 5-6 hours. The reaction mixture was diluted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give 1c (620 mg) in a 51% yield.

[0092] MS-ESI calculated value [M+H] + 394, actual value 394. Phase 3 Compound 1c (540 mg, 1.37 mmol) was dissolved in tetrahydrofuran (20 mL) and triethylamine trifluoride (552 mg, 3.43 mmol) was added in an ice bath. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give 1 (210 mg) in a 55% yield.

[0093] MS-ESI calculated value [M+H] + 280, actual measured value 280. 1H NMR(500MHz,CDCl3)δ 7.56(s,1H),6.12(d,J=17.5Hz,1H),5.25(d,J=17.5Hz,1H),4.71-4.52(m,2H),3.09-3.03(m,2H),1.80(q,J=7.0Hz,2H),0.96(t,J=7.0Hz,3H).

[0094] Example 2

[0095] [ka]

[0096] Phase 1 Under a nitrogen atmosphere, a 1.0 M solution of boron oxychloride in n-heptane (94 mL, 94.00 mmol) was added to a dried three-necked flask (500 mL), and anhydrous 1,2-dichloroethane (150 mL) was added. The mixture was cooled to 0°C, and 2a (9.00 g, 72.00 mmol) was added in batches. After stirring for 10 minutes while maintaining the temperature at 0°C, chloroacetonitrile (7.05 g, 94.00 mmol) and aluminum chloride (13.43 g, 101.00 mmol) were added. After the addition was completed, the mixture was slowly heated to 80°C and refluxed. The reaction mixture was cooled to 0°C, and ice water (50 mL) and an aqueous solution of hydrochloric acid (1N, 100 mL) were slowly added in that order. The mixture was then stirred for 30 minutes while maintaining the temperature at 0°C, and the layers were separated. The aqueous phase was separated into a mixture of dichloromethane and methanol (V ジクロロメタン :V メタノール = 4:1, 200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 to 100%) to give crude product 2b (5.5 g), which was used directly in the next step.

[0097] MS-ESI calculated value [M+H] + 202, actual value 202. Phase 2 Under a nitrogen atmosphere, the crude product 2b (700 mg) from the previous step was dissolved in anhydrous dichloromethane (5 mL), and benzylamine (3 mL) was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was directly concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 2c (390 mg) in a 41% yield.

[0098] MS-ESI calculated value [M+H] + 273, actual value 273. Phase 3 Compound 2c (390 mg, 1.43 mmol) and 10% wet palladium on carbon (90 mg) were added sequentially to a single-neck flask (100 mL), followed by anhydrous tetrahydrofuran (10 mL). After purging with hydrogen gas using a hydrogen balloon, the mixture was stirred at room temperature under a hydrogen atmosphere for 20 hours. The reaction mixture was filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure to give crude product 2d (290 mg).

[0099] MS-ESI calculated value [M+H] + 183, measured value 183. Phase 4 The crude product 2d (290 mg) from the previous step was dissolved in a tetrahydrofuran / water mixed solvent (V テトラヒドロフラン :V 水 The mixture was dissolved in 1:1 ethanol (10 mL), 9-fluorenylmethyl chloroformate (410 mg, 1.59 mmol) and potassium carbonate (439 mg, 3.18 mmol) were added, and the mixture was stirred at 0 °C for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 to 100%) to give compound 2e (390 mg), a two-step yield of 67%.

[0100] MS-ESI calculated value [M+H] + 405, actual value 405. Stage 5 To a Schlenk reaction tube (100 mL), 2e (240 mg, 0.59 mmol), 1 (165 mg, 0.59 mmol), and p-toluenesulfonic acid (60 mg, 0.35 mmol) were sequentially added, followed by anhydrous toluene (6 mL). The mixture was heated to 110 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 2f (120 mg) in a 31% yield.

[0101] MS-ESI calculated value [M+H] + 648, actual value 648. Stage 6 2f (120 mg, 0.19 mmol) was dissolved in anhydrous tetrahydrofuran (2.5 mL), diethylamine (135 mg, 1.85 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%). Compound 2 (30 mg) was obtained in a yield of 38%.

[0102] MS-ESI calculated value [M+H] + 426, actual value 426. 1 H NMR(400MHz,DMSO-d6)δ 8.30(d,J=8.4Hz,1H),7.91(d,J=10.8Hz,1H),7.80(s,1H),6.69(s,1H),5.93(d,J=16.4Hz,1H),5.7 1(s,2H),5.51(d,J=16.8Hz,1H),4.41(s,2H),2.51(s,3H),1.96-1.85(m,2H),0.86(t,J=7.2Hz,3H).

[0103] Example 3

[0104] [ka]

[0105] Phase 1 A single-neck flask (25 mL) was charged with 2 (18 mg, 0.04 mmol) and glycolic acid (6 mg, 0.08 mmol), followed by N,N-dimethylformamide (1.5 mL). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (16 mg, 0.12 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (15 mg, 0.04 mmol) were added sequentially. The reaction mixture was stirred for 30 min at 0 °C. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative thin-layer chromatography (methanol:dichloromethane) to give compound 3 (4.4 mg) in a 21% yield.

[0106] MS-ESI calculated value [M+H] + 484, actual value 484. 1 H NMR(400MHz,DMSO-d6)δ 8.80(t,J=6.0Hz,1H),8.50(d,J=8.0Hz,1H),7.94(d,J=10.8Hz,1H),7.80(s,1H),6.68(s,1H),5.93(d,J=16.8Hz,1H),5.7 8(s,2H),5.52(d,J=16.4Hz,1H),4.89(d,J=6.0Hz,2H),3.86(s,2H),2.51(s,3H),1.95-1.83(m,2H),0.86(t,J=7.2Hz,3H).

[0107] Example 4

[0108] [ka]

[0109] Phase 1 Under a nitrogen atmosphere, a 1.0 M solution of boron oxychloride in n-heptane (12.8 mL, 12.80 mmol) was added to a dried three-neck flask (100 mL), and anhydrous 1,2-dichloroethane (50 mL) was added. The mixture was cooled to 0 °C, and 2a (2.00 g, 16.00 mmol) was added in batches. After stirring for 10 minutes while maintaining the temperature at 0 °C, 5-bromopentanenitrile (3.63 g, 22.40 mmol) and aluminum chloride (3.38 g, 22.40 mmol) were added. After the addition was complete, the mixture was slowly heated to 80 °C and refluxed for 30 hours. The reaction mixture was cooled to 0 °C, and ice water (50 mL) and an aqueous solution of hydrochloric acid (1 N, 60 mL) were slowly added in sequence. The mixture was stirred for 30 minutes while maintaining the temperature at 0 °C. The aqueous phase was separated and the aqueous phase was separated with a dichloromethane / methanol mixed solvent (V). ジクロロメタン :V メタノール The mixture was extracted with ethyl acetate (Et 2 O = 4:1, 200 mL), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 to 100%) to give crude product 4a (3.1 g), which was used directly in the next step.

[0110] MS-ESI calculated value [M+H] + 288,290, measured value 288,290. Phase 2 4a (495 mg), 1 (320 mg, 1.15 mmol), and p-toluenesulfonic acid (198 mg, 1.15 mmol) were sequentially added to a Schlenk reaction tube (100 mL), and anhydrous toluene (6 mL) was added. The mixture was heated to 110°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography. The crude product 4b (200 mg) was obtained by filtration (ethyl acetate:petroleum ether = 0 to 100%).

[0111] MS-ESI calculated value [M+H] + 531,533, actual value 531,533. Phase 3 4b (90 mg) was dissolved in hexamethylphosphoric triamide (0.9 mL) and water (0.1 mL), and the mixture was heated to 101° C. and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (25 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by preparative HPLC to obtain compound 4 (12 mg) in a 15% yield.

[0112] MS-ESI calculated value [M+H] + 469, actual value 469. 1 H NMR(400MHz,DMSO-d6)δ 8.26(d,J=8.0Hz,1H),7.90(d,J=10.8Hz,1H),7.79(s,1H),5.92(d,J=16.4Hz,1H),5.78(s,2H),5.50(s,2H),5.49(d,J=16 .4Hz,1H),3.29-3.20(m,2H),2.51(s,3H),1.94-1.82(m,2H),1.82-1.70(m,2H),1.67-1.56(m,2H),0.86(t,J=7.2Hz,3H).

[0113] Example 5

[0114] [ka]

[0115] Phase 1 5a (2.50 g, 17.00 mmol) was dissolved in anhydrous dichloromethane (25 mL) and cooled to 0° C. Triethylamine (2.60 g, 20.00 mmol) and acetyl chloride (1.40 g, 18.00 mmol) were added sequentially, and the mixture was stirred for 1 hour while maintaining the temperature at 0° C. The reaction mixture was diluted with dichloromethane (100 mL), and the organic phase was washed with saturated brine (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was slurried with methyl t-butyl ether (50 mL) and purified to give compound 5b (2.80 g), yield: 87%.

[0116] MS-ESI calculated value [M+H] + 190, actual measured value 190. Phase 2 At -20°C, 5b (2.00 g, 10.60 mmol) was slowly added in batches to concentrated sulfuric acid (35 mL), and after stirring to dissolve, potassium nitrate (1.07 g, 10.58 mmol) was added in batches. The mixture was stirred for 1 hour while maintaining the temperature at -20°C. The reaction mixture was slowly added dropwise to ice water (100 mL), the aqueous phase was extracted with dichloromethane (500 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The distillate was collected, and the residue was slurried and purified with methyl t-butyl ether (25 mL) to give the first batch of compound 5c (1.00 g). The mother liquor was concentrated and then slurried with methyl t-butyl ether (15 mL) to give the second batch of compound 5c (1.20 g), with a total yield of 89%.

[0117] MS-ESI calculated value [M+H] + 235, actual value 235. Phase 3 5c (2.10 g, 8.97 mmol) was dissolved in acetone (60 mL), and aqueous magnesium sulfate (1.51 g, 12.56 mmol, 1.5 M) was added. The mixture was cooled to 0 °C, and potassium permanganate (5.95 g, 37.68 mmol) was added in batches. After the addition was complete, the mixture was stirred for 1.5 h while maintaining the temperature at 0 °C. The reaction was filtered to remove insoluble solids. The filter cake was washed with dichloromethane (200 mL). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 5d (400 mg) in 18% yield.

[0118] MS-ESI calculated value [M+H] + 249, actual value 249. 1H NMR(400MHz,DMSO-d6)δ 12.28(s,1H),8.64(d,J=9.2Hz,1H),8.19(d,J=9.6Hz,1H),3.12(t,J=6.0Hz,2H),2.75(t,J=6.4Hz,2H),2.21(s,3H),2.06-1.95(m,2H).

[0119] Phase 4 5d (400 mg, 1.61 mmol) was dissolved in aqueous hydrochloric acid (6 N, 6 mL), heated to 80 °C, and stirred for 2.5 h. The reaction mixture was diluted with water (25 mL), and sodium bicarbonate was slowly added to adjust the pH to approximately 9. The aqueous phase was extracted with dichloromethane (100 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude product 5e (350 mg).

[0120] MS-ESI calculated value [M+H] + 207, measured value 207. Stage 5 The crude product 5e (350 mg) from the previous step was dissolved in anhydrous dichloromethane (25 mL), and pyridine (254 mg, 3.22 mmol) and trifluoroacetic anhydride (676 mg, 3.22 mmol) were added sequentially in an ice bath. The mixture was stirred for 0.5 h while maintaining the temperature at 0 °C. The reaction mixture was diluted with dichloromethane (50 mL). The organic phase was washed with saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 5f (410 mg). The yield for the two steps was 84%.

[0121] MS-ESI calculated value [M+H] + 303, actual value 303. 1H NMR(400MHz, CDCl3)δ 13.64(s,1H),8.76(d,J=9.2Hz,1H),8.14(d,J=9.6Hz,1H),3.27(t,J=6.0Hz,2H),2.82(t,J=6.4Hz,2H),2.21-2.11(m,2H).

[0122] Stage 6 5f (410 mg, 1.36 mmol) was dissolved in a mixed solvent of methanol (50 mL), water (4 mL), and formic acid (4 mL), and the solution was stirred under ice bath with zinc powder (1.74 g, 27.20 mmHg). ol) is added in batches, and the mixture is stirred for 0.5 hours while maintaining the temperature at 0°C. The reaction mixture is filtered to remove insoluble matter, and the filter cake is washed successively with ethyl acetate (200 mL) and water (50 mL). The filtrate is adjusted to pH 8-9 by slow addition of sodium bicarbonate, and the layers are separated. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give 5g (330 mg) of crude product.

[0123] MS-ESI calculated value [M+H] + 273, actual value 273. Stage 7 The crude product 5g (330 mg) from the previous step was dissolved in anhydrous dichloromethane (25 mL). Triethylamine (260 mg, 2.57 mmol) and acetyl chloride (200 mg, 2.57 mmol) were added sequentially in an ice bath, and the mixture was stirred for 1 hour while maintaining the temperature at 0 °C. The reaction mixture was diluted with dichloromethane (50 mL). The organic phase was washed with saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give compound 5h (310 mg). The yield for the two steps was 72%.

[0124] MS-ESI calculated value [M+H] + 315, actual value 315. Stage 8 5h (310 mg, 0.99 mmol) was dissolved in a mixed solvent of methanol (22 mL) and water (1.5 mL), potassium carbonate (550 mg, 3.99 mmol) was added, and the mixture was heated to 50 °C and stirred for 1 hour. The reaction mixture was diluted with dichloromethane (100 mL) and water (25 mL), and the layers were separated. The aqueous phase was then dissolved in a mixed solvent of dichloromethane / methanol (V ジクロロメタン :V メタノール The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give compound 5i (205 mg), yield: 95%.

[0125] MS-ESI calculated value [M+H] + 219, actual value 219. Stage 9 5i (200 mg, 0.92 mmol), 1 (257 mg, 0.92 mmol), and p-toluenesulfonic acid (158 mg, 0.92 mmol) were sequentially added to a Schlenk reaction tube (100 mL), and anhydrous toluene (10 mL) was added. The mixture was heated to 110 °C and stirred for 6 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give crude product 5j (170 mg), which was used directly in the next step.

[0126] MS-ESI calculated value [M+H] + 462, actual value 462. Stage 10 The crude product 5j (170 mg) from the previous step was dissolved in a 6N aqueous solution of hydrochloric acid (2 mL), and the mixture was heated to 80°C and stirred for 4 hours. The reaction mixture was then diluted with a dichloromethane / methanol mixed solvent (V ジクロロメタン :V メタノール The mixture was diluted with a mixture of dichloromethane and methanol (V = 10:1, 100 mL) and water (20 mL), and the pH was adjusted to about 9 by slowly adding sodium bicarbonate. ジクロロメタン :V メタノールThe organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give compound 5 (100 mg). The yield for the two steps was 26%.

[0127] MS-ESI calculated value [M+H] + 420, actual value 420. 1 H NMR(400MHz,DMSO-d6)δ 7.76(d,J=8.8Hz,1H),7.67(s,1H),7.32(d,J=9.2Hz,1H),6.62(s,1H),5.91(d,J=16.4Hz,1H),5.72(s,2H),5.49(d,J=16.8Hz, 1H),5.42(s,2H),3.09(t,J=5.6Hz,2H),2.76(t,J=6.0Hz,2H),2.07-1.98(m,2H),1.88(q,J=7.2Hz,2H),0.86(t,J=7.2Hz,3H).

[0128] Example 6

[0129] [ka]

[0130] Phase 1 6a (20.00 g, 159.80 mmol) was dissolved in a dichloromethane / methanol mixture (V ジクロロメタン :V メタノール Liquid bromine (63.84 g, 399.50 mmol) was dissolved in a dichloromethane / methanol mixed solvent (V = 1:1, 350 mL) and cooled to 0 °C. ジクロロメタン :V メタノールAfter dissolving in a 1:1 distillate (50 mL) and adding it dropwise to the above solution, the mixture is stirred and reacted for 4 hours while maintaining the temperature at 25°C after the addition is complete. The reaction mixture is concentrated under reduced pressure to obtain a residue, which is then diluted with an aqueous sodium thiosulfate solution (1 M, 350 mL) and ethyl acetate (350 mL). The mixture is stirred for 10 minutes, and then an aqueous sodium carbonate solution (1 M, 50 mL) is added and the layers are separated. The organic phase is washed successively with an aqueous sodium thiosulfate solution (1 M, 230 mL x 1) and saturated brine (230 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a residue. The product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0-100%) to give compound 6b (40 g), yield: 89%.

[0131] 1 H NMR (400MHz, CDCl3) δ 7.16 (d, J = 8.4 Hz, 1H), 4.40 (br s, 2H), 2.27 (d, J = 2.4Hz, 3H).

[0132] Phase 2 p-Toluenesulfonic acid (1.83 g, 10.63 mmol) was dissolved in anhydrous acetonitrile (15 mL), stirred to dissolve, and cooled to 0°C. 6b (1.00 g, 3.53 mmol) was added, and a solution of potassium iodide (1.47 g, 8.86 mmol) and sodium nitrite (480 mg, 7.10 mmol) in water (2 mL) was added dropwise to the reaction mixture. The mixture was stirred for 10 minutes while maintaining the temperature at 0°C, then returned to room temperature and stirred for another 1 hour. The reaction mixture was added to water (8 mL), and the pH of the aqueous phase was adjusted to approximately 9 with saturated aqueous sodium bicarbonate. 2.5 mL of 2M aqueous sodium thiosulfate was added. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 6c (500 mg) in a 36% yield.

[0133] Phase 3 Under a nitrogen atmosphere, 6c (9.00 g, 22.85 mmol) was dissolved in anhydrous toluene (54 mL), cooled to -30 °C, and isopropyl magnesium chloride tetrahydrofuran solution (2.82 g, 27.42 mmol, 2 M) was added dropwise. After the addition was complete, the mixture was stirred for 1.5 hours while maintaining the temperature at -30 °C. N,N-dimethylformamide (5.51 g, 75.42 mmol) was added dropwise. After the addition was complete, the mixture was returned to 20 °C and stirred for 2 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (150 mL). The aqueous phase was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 6d (4.2 g) in 62% yield.

[0134] 1 H NMR (400MHz, CDCl3) δ 10.20 (s, 1H), 7.38 (d, J = 8.8 Hz, 1 H), 2.35 (d, J = 2.4 Hz, 3 H).

[0135] Phase 4 6d (4.20 g, 14.19 mmol) was dissolved in anhydrous 1,2-dichloroethane (35 mL), ethylene glycol (4.43 g, 71.45 mmol), triethyl orthoformate (2.31 g, 5.61 mmol), and p-toluenesulfonic acid (244.40 mg, 1.42 mmol) were added, and the mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was washed with saturated aqueous sodium carbonate (80 mL) and saturated aqueous ammonium chloride (80 mL), successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 6e (3.9 g) in 81% yield.

[0136] 1H NMR(400MHz, CDCl3)δ 7.33(d,J=8.8Hz,1H),6.43(s,1H),4.36-4.30(m,2H),4.11-4.04(m,2H),2.32(d,J=1.2Hz,3H).

[0137] Stage 5 Under nitrogen gas protection, 6e (1.5 g, 4.41 mmol), benzophenone imine (880 mg, 4.85 mmol), palladium acetate (99 mg, 0.44 mmol), palladium t-butoxide (255 mg, 0.44 mmol), and sodium t-butoxide (850 mg, 8.82 mmol) were dissolved in anhydrous toluene (15 mL). The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 6f (300 mg) in a 15% yield.

[0138] 1 H NMR(400MHz,CDCl3)δ 7.76(d,J=7.2Hz,2H),7.52-7.44(m,1H),7.44-7.36(m,2H),7.34-7.27(m,3H),7.26-7.21(m,2H) ,6.47(s,1H),5.91(d,J=10.4Hz,2H),4.10-4.04(m,2H),3.96-3.90(m,2H),2.21(d,J=2.0Hz,3H).

[0139] Stage 6 Under nitrogen gas protection, (but-3-en-1-yloxy)(t-butyl)dimethylsilane (30 mg, 0.16 mmol) was dissolved in anhydrous toluene (1 mL) and cooled to 0 °C. 9-Borabicyclo[3.3.1]nonane (24 mg, 0.19 mmol) was added. The mixture was heated to 80 °C and stirred for 20 min. After that, the mixture was cooled to 0 °C. A solution of sodium hydroxide (13 mg, 0.32 mmol) in water (1 mL) was added dropwise. The mixture was stirred for 10 min while maintaining the temperature at 0 °C. 6f (57 mg, 0.13 mmol), tetrabutylammonium iodide (3 mg, 0.008 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (3 mg, 0.003 mmol) were added. After the addition was complete, the mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative thin layer chromatography to give compound 6g (40 mg), yield: 56%.

[0140] Stage 7 6g (120 mg, 0.22 mmol) was dissolved in absolute ethanol (4 mL), and compound 1 (62 mg, 0.22 mmol) and concentrated hydrochloric acid (52.56 mg, 1.44 mmol, 12 N) were added. The mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was concentrated to give a residue, which was purified by preparative thin-layer chromatography to give 6 (7 mg), yield: 7%.

[0141] MS-ESI calculated value [M+H] + 469, actual value 469. 1 H NMR(500MHz,DMSO-d6)δ 8.98(s,1H),7.80(d,J=10.5Hz,1H),7.79(s,1H),5.92(d,J=16.5Hz,1H),5.50(d,J=16.5Hz,1H),5.497(s, 2H),3.19-3.12(m,2H),2.43(d,J=2.0Hz,3H),1.92-1.84(m,2H),1.68-1.55(m,4H),0.86(t,J=7.0Hz,3H).

[0142] Example 7

[0143] [ka]

[0144] Phase 1 7a (11.00 g, 67.00 mmol) was dissolved in trifluoroacetic acid (165 mL), sodium nitrite (13.78 g, 199.72 mmol) was added in batches, and the mixture was stirred for 12 hours while maintaining the temperature at 25 °C. The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL × 3), and the combined organic phases were washed with saturated aqueous sodium bicarbonate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 7b (7.20 g) in 51% yield.

[0145] MS-ESI calculated value [M+H] + 210, actual value 210. Phase 2 7b (7.20 g, 34.42 mmol) was dissolved in a tetrahydrofuran / water mixture (V テトラヒドロフラン :V 水 The mixture was dissolved in 35 mL of palladium-carbon (700 mg, 6.58 mmol, 10% w / w) and stirred for 12 hours under a hydrogen atmosphere at room temperature. The reaction mixture was filtered to remove insoluble matter, and the filter cake was extracted with dichloromethane. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was then extracted with anhydrous sodium sulfate. The mixture was dried over silica gel, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 7c (5.60 g), yield: 91%.

[0146] MS-ESI calculated value [M+H] + 180, actual measured value 180. 1H NMR (400MHz, DMSO-d6) δ 7.16 (s, 1H), 6.30 (s, 1H), 5.92 (s, 2H), 2.38 (s, 3H).

[0147] Phase 3 7c (5.50 g, 30.70 mmol) was dissolved in dichloromethane (110 mL). The mixture was cooled to 0 °C, and N,N-diisopropylethylamine (5.95 g, 46.04 mmol) and acetyl chloride (3.61 g, 46.04 mmol) were added dropwise. After the addition was complete, the mixture was stirred for 1 h at room temperature. The reaction was quenched with methanol (5 mL). The reaction was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 7d (6.60 g) in 96% yield.

[0148] MS-ESI calculated value [M+H] + 222, actual value 222. 1 H NMR (400MHz, CDCl3) δ 12.06 (br s, 1H), 8.35 (s, 1H), 7.24 (s, 1H), 6.01 (s, 2H), 2.55 (s, 3H), 2.19 (s, 3H).

[0149] Phase 4 7d (6.60 g, 29.84 mmol) was dissolved in glacial acetic acid (105 mL). The mixture was cooled to 0 °C, and liquid bromine (4.77 g, 29.84 mmol) and hydrobromic acid acetic acid (12 M, 4.83 g, 59.68 mmol) were added dropwise. After the addition was complete, the mixture was stirred for 1 hour while maintaining the temperature at room temperature. The reaction mixture was poured into ice water (100 mL), and the solid precipitated. The filter cake was filtered. The filter cake was dissolved in dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 7e (7.00 g) in 78% yield.

[0150] MS-ESI calculated value [M+H]+ 300,302, measured value 300,302. Stage 5 7e (5.90 g, 19.67 mmol) was dissolved in absolute ethanol (60 mL), concentrated hydrochloric acid (12 M, 5.0 mL, 60.00 mmol) was added, and the mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give crude product 7f (4.56 g).

[0151] MS-ESI calculated value [M+H] + 214,216, measured value 214,216. Stage 6 7f (4.0 g, 18.70 mmol) was dissolved in anhydrous dichloromethane (40 mL), benzylamine (10 mL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 7g (2.5 g), with a two-step yield of 47%.

[0152] MS-ESI calculated value [M+H] + 285, actual value 285. Stage 7 7g (2.0 g, 7.04 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and wet palladium on carbon (200 mg, 10% w / w) was added. The mixture was stirred for 20 hours under a hydrogen atmosphere at 50° C. The reaction mixture was filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure to give crude product 7h (1.3 g).

[0153] MS-ESI calculated value [M+H] + 195, actual value 195. Stage 8 The crude product 7h (1.3 g) from the previous step was dissolved in a tetrahydrofuran / water mixed solvent (V テトラヒドロフラン :V 水The mixture was dissolved in a 2:1 ethanol solution (24 mL), potassium carbonate (1.85 g, 13.40 mmol) and 9-fluorenylmethyl chloroformate (1.38 g, 5.36 mmol), and the mixture was stirred for 1 hour while maintaining the temperature at 0°C. The mixture was diluted with water (20 mL) and ethyl acetate (100 mL), and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride (250 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 to 100%) to give compound 7i (820 mg), a two-step yield of 28%.

[0154] MS-ESI calculated value [M+H] + 417, measured value 417. Stage 9 7i (200 mg, 0.48 mmol), 1 (107 mg, 0.38 mmol), and p-toluenesulfonic acid (34 mg, 0.20 mmol) were sequentially added to a Schlenk reaction tube (100 mL), and anhydrous toluene (10 mL) was added. The mixture was heated to 110 °C and stirred for 6 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give crude product 7j (200 mg), which was used directly in the next step.

[0155] MS-ESI calculated value [M+H] + 660, actual measured value 660. Stage 10 7j (200 mg, 0.30 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), piperidine (255 mg, 3.00 mmol) was added, and the mixture was stirred at room temperature for 3.5 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 7 (80 mg) in a 61% yield.

[0156] MS-ESI calculated value [M+H] + 438, actual value 438. 1 H NMR(500MHz,DMSO-d6)δ 7.72(s,1H),7.66(s,1H),7.51(s,1H),6.29(d,J=2.0Hz,2H),5.91(d,J=16.5Hz,1 H),5.48(d,J=16.5Hz,1H),4.28(s,2H),1.92-1.84(m,2H),0.86(t,J=7.0Hz,3H).

[0157] Example 8

[0158] [ka]

[0159] Phase 1 7 (30 mg, 0.07 mmol) and hydroxyacetic acid (10.6 mg, 0.14 mmol) were sequentially added to a single-neck flask (25 mL), followed by anhydrous dichloromethane (1.0 mL). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (18 mg, 0.14 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24 mg, 0.06 mmol) were sequentially added to the reaction mixture. The reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 8 (12 mg) in 35% yield.

[0160] MS-ESI calculated value [M+H] + 496, actual value 496. Example 9

[0161] [ka]

[0162] Phase 1 To a single-neck flask (25 mL) were added 7 (65 mg, 0.15 mmol) and Nt-butyloxycarbonyl-glycine (52 mg, 0.30 mmol), followed by anhydrous dichloromethane (2 mL). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (39 mg, 0.38 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (54 mg, 0.14 mmol) were added sequentially. The reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 9a (80 mg) in 90% yield.

[0163] MS-ESI calculated value [M+H] + 595, actual value 595. Phase 2 9a (60 mg, 0.10 mmol) was dissolved in anhydrous dichloromethane (4 mL), trifluoroacetic acid (0.4 mL) was added in an ice bath, and the reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 9 (15 mg) in a 30% yield.

[0164] MS-ESI calculated value [M+H] + 495, actual value 495. 1 H NMR(500MHz,DMSO-d6)δ 7.74(s,2H),7.58(s,1H),6.32(d,J=2.0Hz,2H),5.92(d,J=16.5Hz,1H),5.73(s,2H),5. 50(d,J=16.5Hz,1H),4.85(s,2H),3.56(s,2H),1.92-1.84(m,2H),0.85(t,J=7.0Hz,3H).

[0165] Example 10

[0166] [ka]

[0167] Phase 1 7b (500 mg, 2.39 mmol) was dissolved in ethanol (2 mL), and paraformaldehyde (1.08 g, 35.64 mmol) and isopropylamine (3.43 g, 35.89 mmol) were added. The mixture was stirred at 100 °C for 72 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL), the pH of the aqueous phase was adjusted to 7 with saturated aqueous sodium bicarbonate, and the aqueous phase was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give compound 10a (80 mg) in 12% yield.

[0168] MS-ESI calculated value [M+H] + 281, actual value 281. 1 H NMR (400MHz, CDCl3) δ 7.73(s,1H),7.29(s,1H),6.30(s,2H),3.40-3.20(m,5H),1.24(d,J=6.8Hz,6H).

[0169] Phase 2 10a (80 mg, 0.29 mmol) was dissolved in a tetrahydrofuran / water mixture (V テトラヒドロフラン :V 水The mixture was dissolved in 2 mL of ethyl acetate (3:1, 2 mL), and fluorenylmethoxycarbonyl chloride (74 mg, 0.29 mmol) and sodium bicarbonate (24 mg, 0.29 mmol) were added sequentially. The mixture was stirred for 12 hours while maintaining the temperature at 25 °C. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL). The aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 to 100%) to give compound 10b (70 mg) in a 78% yield.

[0170] MS-ESI calculated value [M+H] + 503, actual value 503. Phase 3 10b (540 mg, 1.07 mmol) was dissolved in ethanol (10 mL), wet palladium on carbon (10% w / w, 54 mg) was added, and the reaction mixture was heated to 40 °C and stirred for 4 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 10c (360 mg) in a 71% yield.

[0171] MS-ESI calculated value [M+H] + 473, actual value 473. Phase 4 10c (150 mg, 0.32 mmol) was dissolved in anhydrous toluene (4 mL), 1 (89 mg, 0.32 mmol) and p-toluenesulfonic acid (28 mg, 0.16 mmol) were added, and the mixture was heated to 120 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 10d (70 mg) in a 31% yield.

[0172] MS-ESI calculated value [M+H] + 716, measured value 716. Stage 5 10d (80 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL), piperidine (19 mg, 0.22 mmol) was added, and the mixture was heated to 40° C. and stirred for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative thin-layer chromatography to give compound 10 (30 mg), yield: 55%.

[0173] MS-ESI calculated value [M+H] + 494, actual value 494. 1 H NMR(400MHz,DMSO-d6)δ 7.71(s,1H),7.63(s,1H),7.49(s,1H),6.28(s,2H),5.91(d,J=16.4Hz,1H),5.47(d,J=16.8Hz,1H),5.45-5.40(m,1H),3 .36-3.28(m,2H),3.19-3.10(m,1H),3.09-3.00(m,2H),1.93-1.82(m,2H),1.14(d,J=6.4Hz,6H),0.85(t,J=7.2Hz,3H). Example 11

[0174] [ka]

[0175] Phase 1 11a (2.5 g, 215.14 mmol) was dissolved in ethanol (30 mL), and paraformaldehyde (6.82 g, 227.11 mmol) and isopropylamine (21.70 g, 227.06 mmol) were added. The mixture was stirred at 100 °C for 72 h. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (30 mL). The aqueous phase was adjusted to pH 7 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 11b (2.20 g) in 61% yield.

[0176] MS-ESI calculated value [M+H] + 237, actual value 237. Phase 2 11b (2.20 g, 9.65 mmol) was dissolved in a tetrahydrofuran / water mixture (V テトラヒドロフラン :V 水 The mixture was dissolved in 13 mL of ethyl acetate (3:1), fluorenylmethoxycarbonyl chloride (3.75 g, 14.50 mmol), and sodium bicarbonate (1.26 g, 14.50 mmol). The mixture was stirred for 12 hours at 25°C. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (30 mL). The aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 11c (345 mg) in 8% yield.

[0177] MS-ESI calculated value [M+H] + 459, actual value 459. Phase 3 11c (345 mg, 0.72 mmol) was dissolved in ethanol (10 mL), wet palladium on carbon (10% w / w, 35 mg) was added, and the mixture was heated to 40 °C and stirred for 4 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 11d (220 mg) in a 71% yield.

[0178] MS-ESI calculated value [M+H] + 429, actual value 429. Phase 4 11d (100 mg, 0.23 mmol) was dissolved in anhydrous toluene (4 mL), and 1 (66 mg, 0.24 mmol) and p-toluenesulfonic acid (20 mg, 0.12 mmol) were added. After the addition was complete, the mixture was heated to 120 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give compound 11e (100 mg) in a 64% yield.

[0179] MS-ESI calculated value [M+H] + 672, actual value 672. Stage 5 11e (80 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL), piperidine (21 mg, 0.25 mmol) was added, and the mixture was heated to 40° C. and stirred for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by thin-layer chromatography to give compound 11 (6 mg), yield: 11%.

[0180] MS-ESI calculated value [M+H] + 450, actual measured value 450. Example 12

[0181] [ka]

[0182] Phase 1 12a (5.00 g, 22.00 mmol) was dissolved in dichloromethane (450 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.55 g, 33.00 mmol), N,N-diisopropylethylamine (5.69 g, 44.00 mmol), and N-methyl-N-methoxyamine hydrochloride (1.41 g, 33.00 mmol) were added. The mixture was stirred for 12 hours while maintaining the temperature at 25°C. The reaction mixture was diluted with dichloromethane (200 mL), and aqueous hydrochloric acid (1N, 50 mL) was added. The layers were separated, and the organic phase was washed successively with saturated aqueous sodium bicarbonate (50 mL × 1) and saturated brine (50 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0~100%) to give compound 12b (5.30 g), yield: 89%.

[0183] Phase 2 4-Bromo-1,2-methylenedioxybenzene (9.37 g, 46.61 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to -65°C. n-Butyllithium (1.6 M n-hexane solution, 29 mL) was added dropwise, and the mixture was stirred for 0.5 hours while maintaining the temperature at -65°C. 12b (5.04 g, 18.64 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) and added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred for 3 hours while maintaining the temperature at -65°C. The mixture was quenched with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with saturated brine (500 mL x 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was removed. The solution was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0-100%) to obtain compound 12c (4.00 g), yield: 45%.

[0184] 1H NMR (400MHz, CDCl3) δ 7.63(d,J=8.0Hz,1H),7.44(s,1H),6.82(d,J=8.4Hz,1H),6.03(s,2H),2.50(s,6H),1.46(s,9H).

[0185] Phase 3 12c (3.00 g, 9.05 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0 °C. Trifluoroacetic acid (27.61 g, 242.15 mmol) was added, and the mixture was warmed to 25 °C and stirred for 3 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (40 mL). The mixture was cooled to 0 °C, and N,N-diisopropylethylamine (7.42 g, 57.41 mmol) and trifluoroacetic anhydride (3.85 g, 18.33 mmol) were added dropwise. After the addition was complete, the mixture was warmed to 25 °C and stirred for 4 h. The mixture was quenched with water (200 mL), extracted with ethyl acetate (200 mL × 3), and the organic phase was washed with saturated brine (200 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0~100%) to obtain compound 12d (2.50 g), yield: 84%.

[0186] Phase 4 12d (2.50 g, 7.64 mmol) was dissolved in acetic anhydride (5.8 mL), cooled to 0 °C, and copper nitrate (860 mg, 4.59 mmol) was added in batches. After the addition was complete, the mixture was stirred for 3 h while maintaining the temperature at 0 °C. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 12e (900 mg) in 75% yield.

[0187] MS-ESI calculated value [M+H] + 373, actual value 373. 1H NMR (400MHz, CDCl3) δ 7.60 (s, 1H), 6.66 (br s, 1H), 6.64 (s, 1H), 6.21 (s, 2H), 2.43 (s, 6H).

[0188] Stage 5 12e (400 mg, 1.07 mmol) was dissolved in ethanol (10 mL), and wet palladium-carbon (10% w / w, 40 mg) was added. The mixture was heated to 40 °C and stirred for 4 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 12f (220 mg) in a 60% yield.

[0189] MS-ESI calculated value [M+H] + 343, actual value 343. Stage 6 12f (100 mg, 0.29 mmol) was dissolved in anhydrous toluene (4 mL), and 1 (82 mg, 0.32 mmol) and p-toluenesulfonic acid (26 mg, 0.15 mmol) were added. After the addition was complete, the mixture was heated to 120 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 12g (80 mg) in a 47% yield.

[0190] Stage 7 12g (80 mg, 0.14 mmol) was dissolved in methanol (4 mL), hydrochloric acid (1.6 mL, 4 M) was added, and the mixture was heated to 65 °C and stirred for 4 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to obtain compound 12 (14 mg) in a 21% yield.

[0191] MS-ESI calculated value [M+H] + 490, actual value 490. 1H NMR(400MHz,DMSO-d6)δ 7.74(s,1H),7.64(s,1H),7.58(s,1H),6.32(s,2H),5.92(d,J=16.4Hz,1H),5.61(s ,2H),5.50(d,J=16.4Hz,1H),2.81(s,6H),1.93-1.84(m,2H),0.84(t,J=7.2Hz,3H).

[0192] Example 13

[0193] [ka]

[0194] Phase 1 13a (15 g, 73.90 mmol) was added batchwise to a mixture of concentrated sulfuric acid (45 mL) and concentrated nitric acid (12 mL) under ice bath conditions. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction mixture was poured into ice water (1 L) and a yellow solid was precipitated. The solid was filtered and dried to give compound 13b (22 g).

[0195] Phase 2 13b (750 mg, 3.02 mmol), t-butyl carbamate (424 mg, 3.62 mmol), Pd(dba) (138 mg, 0.15 mmol), XPhos (288 mg, 0.60 mmol), and cesium carbonate (1.96 g, 6.04 mmol) were sequentially added to a Schlenk reaction tube. After purging with nitrogen three times, anhydrous toluene (8 mL) was added. The reaction mixture was sealed and placed in an oil bath at 90 °C and stirred overnight. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed sequentially with water (25 mL × 1) and brine (25 mL × 2), dried, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 13c (550 mg) in 64% yield.

[0196] 1H NMR(400MHz,DMSO-d6)δ 10.44(s,1H),8.75(d,J=6.0Hz,1H),7.92(d,J=8.4Hz,1H),7.05(s,1H),1.55(s,9H).

[0197] Phase 3 13c (500 mg, 1.76 mmol) and ammonium chloride (156 mg, 2.94 mmol) were dissolved in a mixture of ethanol (8 mL) and water (2 mL). Iron powder (394 mg, 7.04 mmol) was added in batches, and the reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with water (25 mL × 1) and brine (25 mL × 1), dried, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 13d (310 mg) in 69% yield.

[0198] MS-ESI calculated value [M+H] + 255, actual measured value 255. Phase 4 13d (250 mg, 0.98 mmol), 1 (167 mg, 0.60 mmol), and p-toluenesulfonic acid (26 mg, 0.15 mmol) were sequentially added to a Schlenk reaction tube (100 mL), followed by anhydrous toluene (3 mL). The mixture was heated to 110 °C and stirred for 2 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give crude product 13e (180 mg), which was used directly in the next step.

[0199] MS-ESI calculated value [M+H] + 498, actual value 498. Stage 5 13e (45 mg, 0.09 mmol) was dissolved in anhydrous dichloromethane (1 mL), trifluoroacetic acid (0.3 mL) was added in an ice bath, and the reaction mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 9 (20 mg) in a 30% yield.

[0200] MS-ESI calculated value [M+H] + 398, actual value 398. 1 H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),7.80(d,J=12.4Hz,1H),7.70(s,1H),7.16(d,J=9.6Hz,1H),5.90(d,J=16. 4Hz, 1H), 5.46 (d, J = 16.4Hz, 1H), 5.43 (s, 2H), 1.93-1.80 (m, 2H), 0.85 (t, J = 7.2Hz, 3H).

[0201] Example 14

[0202] [ka]

[0203] Phase 1 7 (20 mg, 0.05 mmol) and 2-cyclopropyl-2-hydroxyacetic acid (12 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), followed by anhydrous dichloromethane (1.0 mL). The reaction mixture was cooled to 0 °C, and triethylamine (10 mg, 0.10 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were sequentially added to the reaction mixture. The reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 14 (12 mg) in 49% yield.

[0204] MS-ESI calculated value [M+H] + 536, actual value 536. 1 H NMR(400MHz,DMSO-d6)δ 8.66(t,J=5.6Hz,1H),7.87(s,1H),7.74(s,1H),7.54(s,1H),6.30(s,2H),5.92(d,J=16.4Hz,1H),5.74(s,2H),5.49(d,J=16.4Hz,1H),4. 75(d,J=5.2Hz,2H),3.56-3.51(m,1H),1.94-1.83(m,2H),1.07-0.97(m,1H),0.85(t,J=7.2Hz,3H),0.39-0.29(m,2H),0.28-0.18(m,2H).

[0205] Example 15

[0206] [ka]

[0207] Phase 1 7 (20 mg, 0.05 mmol) and lactic acid (9 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), followed by anhydrous dichloromethane (1.0 mL). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.05 mmol) were sequentially added to the reaction mixture. The reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 15 (10 mg) in a 43% yield.

[0208] MS-ESI calculated value [M+H] + 510, actual value 510. 1H NMR(400MHz,DMSO-d6)δ 8.74(t,J=5.2Hz,1H),7.89(s,1H),7.76(s,1H),7.57(s,1H),6.32(s,2H),5.94(d,J=16.8Hz,1H),5.74(s,2H) ),5.51(d,J=16.4Hz,1H),4.77(d,J=5.6Hz,2H),4.05-3.96(m,1H),1.94-1.82(m,2H),0.88(t,J=7.2Hz,3H). Example 16

[0209] [ka]

[0210] Phase 1 7 (20 mg, 0.05 mmol) and 3-hydroxycyclobutanecarboxylic acid (12 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (17 mg, 0.13 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 16 (15 mg) in 61% yield.

[0211] MS-ESI calculated value [M+H] + 536, actual value 536. 1H NMR(400MHz,DMSO-d6)δ 7.72(s,1H),7.69(s,1H),7.52(s,1H),6.29(s,2H),5.91(d,J=16.4Hz,1H),5.58(s,2H),5.48(d,J=16.8Hz,1H),4. 77-4.69(m,2H),3.97-3.82(m,1H),2.45-2.35(m,1H),2.30-2.22(m,2H),2.00-1.82(m,4H),0.85(t,J=7.2Hz,3H).

[0212] Example 17

[0213] [ka]

[0214] Phase 1 7 (20 mg, 0.05 mmol) and 4-hydroxycyclohexanecarboxylic acid (14 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (17 mg, 0.13 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 17 (9 mg) in 35% yield.

[0215] MS-ESI calculated value [M+H] + 564, actual value 564. 1H NMR (400 MHz, DMSO-d6) δ 8.60(s,1H),7.73(s,1H),7.71(s,1H),7.54(s,1H),6.30(s,2H),5.92(d,J= 16.8Hz,1H),5.67-5.57(m,2H),5.48(d,J=16.4Hz,1H),4.79-4.70(m,2H),3. 35-3.22(m,1H),2.12-2.00(m,1H),1.92-1.84(m,2H),1.84-1.77(m,2H),1. 77-1.67(m,2H),1.42-1.32(m,2H),1.15-1.02(m,2H),0.85(t,J=7.2Hz,3H).

[0216] Example 18

[0217] [ka]

[0218] Phase 1 7 (20 mg, 0.05 mmol) and (R)-3-hydroxybutyric acid (10 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give compound 18 (17 mg) in 71% yield.

[0219] MS-ESI calculated value [M+H] + 524, actual value 524. 1H NMR(400MHz,DMSO-d6)δ 7.730(s,1H),7.726(s,1H),7.53(s,1H),6.29(d,J=2.0Hz,2H),5.92(d,J=16.4Hz,1H),5.64(s,2H),5.49(d,J=16.4Hz,1H),4.81-4 .65(m,2H),4.00-3.89(m,1H),2.29-2.20(m,1H),2.17-2.09(m,1H),1.94-1.82(m,2H),0.99(d,J=6.4Hz,3H),0.85(t,J=7.2Hz,3H).

[0220] Example 19

[0221] [ka]

[0222] Phase 1 7 (20 mg, 0.05 mmol) and (S)-3-hydroxybutyric acid (10 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 19 (15 mg) in 63% yield.

[0223] MS-ESI calculated value [M+H] + 524, actual value 524. 1H NMR(400MHz,DMSO-d6)δ 8.66(t,J=5.6Hz,1H),7.73(s,2H),7.54(s,1H),6.30(s,2H),5.92(d,J=16.4Hz,1H),5.68-5.62(m,2H),5.49(d,J=16.4Hz,1H),4.77- 4.71(m,2H),4.00-3.89(m,1H),2.28-2.21(m,1H),2.17-2.10(m,1H),1.93-1.84(m,2H),1.00(d,J=6.4Hz,3H),0.85(t,J=7.2Hz,3H).

[0224] Example 20

[0225] [ka]

[0226] Phase 1 2 (20 mg, 0.05 mmol) and 3-hydroxycyclobutanecarboxylic acid (12 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 20 (15 mg) in 61% yield.

[0227] MS-ESI calculated value [M+H] + 524, actual value 524. 1H NMR(400MHz,DMSO-d6)δ 8.30(d,J=8.0Hz,1H),7.89(d,J=10.8Hz,1H),7.79(s,1H),5.91(d,J=16.4Hz,1H),5.61(s,2H),5.49(d,J=16.8Hz,1H),4.89-4.81(m ,2H),3.98-3.85(m,1H),2.46-2.38(m,1H),2.45-2.35(m,2H),1.98-1.82(m,4H),0.85(t,J=7.2Hz,3H).

[0228] Example 21

[0229] [ka]

[0230] Phase 1 2 (20 mg, 0.05 mmol) and 4-hydroxycyclohexanecarboxylic acid (14 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 20 (22 mg) in 89% yield.

[0231] MS-ESI calculated value [M+H] + 552, actual value 552. 1H NMR(400MHz,DMSO-d6)δ 8.30(d,J=8.0Hz,1H),7.91(d,J=10.4Hz,1H),7.79(s,1H),5.92(d,J=16.8Hz,1H),5.66-5.60(m,2H),5.49(d,J=16.4Hz,1H),3.36 -3.25(m,1H),2.14-2.04(m,1H),1.92-1.85(m,2H),1.85-1.68(m,4H),1.55-1.35(m,2H),1.16-1.02(m,2H),0.86(t,J=7.2Hz,3H).

[0232] Example 22

[0233] [ka]

[0234] Phase 1 2 (25 mg, 0.06 mmol) and lactic acid (11 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), followed by anhydrous dichloromethane (1.0 mL). The reaction mixture was cooled to 0 °C, and triethylamine (23 mg, 0.18 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were sequentially added to the reaction mixture. The reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give compound 22 (28 mg) in 96% yield.

[0235] MS-ESI calculated value [M+H] + 498, actual value 498. 1H NMR(400MHz,DMSO-d6)δ 8.74(t,J=6.0Hz,1H),8.42(d,J=8.0Hz,1H),7.92(d,J=10.8Hz,1H),7.79(s,1H) ,5.92(d,J=16.4Hz,1H),5.78-5.68(m,2H),5.50(d,J=16.4Hz,1H),5.00-4.76(m ,2H),4.06-3.95(m,1H),1.94-1.82(m,2H),0.86(t,J=7.2Hz,3H).

[0236] Example 23

[0237] [ka]

[0238] Phase 1 To a single-neck flask (25 mL) were added 2 (25 mg, 0.06 mmol) and 2-cyclopropyl-2-hydroxyacetic acid (14 mg, 0.12 mmol), followed by anhydrous dichloromethane (1.0 mL). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (23 mg, 0.18 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol) were added sequentially. The reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 23 (28 mg) in 91% yield.

[0239] MS-ESI calculated value [M+H] + 524, actual value 524. 1H NMR(400MHz,DMSO-d6)δ 8.69(t,J=5.6Hz,1H),8.43(d,J=7.6Hz,1H),7.92(d,J=10.8Hz,1H),7.80(s,1H) ,5.92(d,J=16.4Hz,1H),5.78-5.70(m,2H),5.50(d,J=16.4Hz,1H),5.00-4.79(m ,2H),3.57-3.52(m,1H),1.94-1.82(m,2H),1.09-0.97(m,1H),0.86(t,J=6.8Hz,3H),0.38-0.28(m,2H),0.28-0.18(m,2H). Example 24

[0240] [ka]

[0241] Phase 1 2 (20 mg, 0.05 mmol) and (S)-3-hydroxybutyric acid (10 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (19 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 24 (18 mg) in 75% yield.

[0242] MS-ESI calculated value [M+H] + 512, measured value 512. 1H NMR(400MHz,DMSO-d6)δ 8.32(d,J=8.4Hz,1H),7.91(d,J=10.4Hz,1H),7.79(s,1H),5.92(d,J=16.8Hz,1H),5.66(s,2H),5.50(d, J=16.4Hz,1H),4.91-4.76(m,2H),4.00-3.90(m,1H),2.31-2.22(m,1H),2.20-2.10(m,1H),1.93-1.84(m. 2H), 0.99(d,J=6.4Hz,3H),0.85(d,J=7.2Hz,3H).

[0243] Example 25

[0244] [ka]

[0245] Phase 1 2 (25 mg, 0.06 mmol) and (R)-3-hydroxybutyric acid (13 mg, 0.12 mmol) were sequentially added to a single-neck flask (25 mL), followed by anhydrous dichloromethane (1.0 mL). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (23 mg, 0.18 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were sequentially added to the reaction mixture. The reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 25 (18 mg) in 60% yield.

[0246] MS-ESI calculated value [M+H] + 512, measured value 512. 1H NMR(400MHz,DMSO-d6)δ 8.30(d,J=8.4Hz,1H),7.89(d,J=10.8Hz,1H),7.78(s,1H),5.91(d,J=16.4Hz,1H),5.72-5.56(m,2H),5.49( d,J=16.8Hz,1H),4.92-4.76(m,2H),4.00-3.90(m,1H),2.30-2.22(m,1H),2.20-2.10(m,1H),1.94-1.82(m. 2H), 0.99(d,J=6.4Hz,3H),0.85(d,J=7.2Hz,3H). Example 26

[0247] [ka]

[0248] Phase 1 26a (30 mg, 0.06 mmol) and (S)-3-hydroxybutyric acid (10 mg, 0.12 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were sequentially added to the reaction mixture. The reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 26 (22 mg) in 67% yield.

[0249] MS-ESI calculated value [M+H] + 538, actual value 538. 1H NMR (400 MHz, DMSO-d6) δ 8.52(d,J=8.8Hz,1H),7.793(d,J=10.8Hz,1H),7.789(s,1H),5.90(d,J=1 6.4Hz,1H),5.63-5.54(m,1H),5.52-5.54(m,2H),5.41-5.32(m,1H),4.15 -4.04(m,1H),3.28-3.03(m,2H),2.39(s,3H),2.38-2.25(m,2H),2.22-2. 07(m,2H),1.93-1.84(m,2H),1.12(d,J=6.4Hz,3H),0.85(t,J=7.2Hz,3H).

[0250] Example 27

[0251] [ka]

[0252] Phase 1 26a (45 mg, 0.09 mmol) and (R)-3-hydroxybutyric acid (19 mg, 0.18 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (30 mg, 0.23 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give compound 27 (45 mg) in 91% yield.

[0253] MS-ESI calculated value [M+H] + 538, actual value 538. 1H NMR (400 MHz, DMSO-d6) δ 8.50(d,J=8.4Hz,1H),7.80-7.72(m,2H),5.90(d,J=16.4Hz,1H),5.62-5.5 3(m,1H),5.52-5.43(m,2H),5.35(d,J=20.0Hz,1H),4.12-4.00(m,1H),3.2 7-3.05(m,2H),2.44-2.39(m,1H),2.38(s,3H),2.28-2.21(m,1H),2.20-2. 08(m,2H),1.93-1.83(m,2H),1.10(d,J=6.0Hz,3H),0.85(t,J=7.2Hz,3H).

[0254] Example 28

[0255] [ka]

[0256] Phase 1 26a (25 mg, 0.05 mmol) and 3-hydroxycyclobutanecarboxylic acid (12 mg, 0.10 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (17 mg, 0.13 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 28 (26 mg) in 92% yield.

[0257] MS-ESI calculated value [M+H] + 550, actual value 550. 1H NMR(400MHz,DMSO-d6)δ 7.81-7.75(m,2H),5.90(d,J=16.4Hz,1H),5.60-5.53(m,1H),5.48(d,J=16.8Hz,1H),5.41(d,J=20.0Hz,1H),5.30(d,J=20 .0Hz,1H),4.00-3.89(m,1H),3.30-3.05(m,2H),2.38(s,3H),2.25-2.00(m,4H),1.94-1.83(m,2H),0.85(t,J=7.2Hz,3H).

[0258] Example 29

[0259] [ka]

[0260] Phase 1 26a (30 mg, 0.06 mmol) and cis-3-hydroxycyclobutanecarboxylic acid (14 mg, 0.12 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0 to 100%) to give compound 29 (33 mg) in 99% yield.

[0261] MS-ESI calculated value [M+H] + 550, actual value 550. 1H NMR(400MHz,DMSO-d6)δ 8.49(d,J=8.8Hz,1H),7.78(s,1H),7.77(d,J=10.4Hz,1H),5.90(d,J=1 6.4Hz,1H),5.61-5.52(m,1H),5.48(d,J=16.8Hz,1H),5.40(d,J=20.0H z,1H),5.28(d,J=20.0Hz,1H),4.01-3.89(m,1H),3.30-3.05(m,2H),2. 38(s,3H),2.25-2.00(m,4H),1.94-1.82(m,2H),0.85(t,J=7.2Hz,3H).

[0262] Example 30

[0263] [ka]

[0264] Phase 1 26a (30 mg, 0.06 mmol) and trans-3-hydroxycyclobutanecarboxylic acid (14 mg, 0.12 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 30 (22 mg) in 65% yield.

[0265] MS-ESI calculated value [M+H] + 550, actual value 550. 1H NMR(400MHz,DMSO-d6)δ 8.46(d,J=8.8Hz,1H),7.79(d,J=10.4Hz,1H),7.78(s,1H),5.90(d,J=16.4Hz,1H),5.62-5.53(m,1H),5.47(d,J=16.4Hz,1H),5.44-5.27( m,2H),4.42-4.32(m,1H),3.28-3.06(m,2H),3.00-2.90(m,1H),2.38(s,3H),2.25-1.98(m,4H),1.94-1.82(m,2H),0.85(t,J=7.2Hz,3H).

[0266] Example 31

[0267] [ka]

[0268] Phase 1 A 25 mL single-neck flask was charged with 26a (30 mg, 0.06 mmol) and 3-hydroxycyclobutanecarboxylic acid (17 mg, 0.12 mmol), followed by anhydrous dichloromethane (1.0 mL). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were added sequentially. The reaction mixture was stirred for 30 min at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 31 (32 mg) in 90% yield.

[0269] MS-ESI calculated value [M+H] + 578, actual value 578. 1H NMR(400MHz,DMSO-d6)δ 7.78(s,1H),7.75(d,J=11.2Hz,1H),5.89(d,J=16.8Hz,1H),5.60-5.51 (m,1H),5.50-5.37(m,2H),5.34-5.20(m,1H),3.40-3.32(m,1H),3.28- 3.05(m,2H),2.37(s,3H),2.21-2.11(m,2H),2.10-2.00(m,1H),1.94-1 .62(m,6H),1.60-1.35(m,2H),1.19-1.04(m,2H),0.85(t,J=7.2Hz,3H). Example 32

[0270] [ka]

[0271] Phase 1 26a (30 mg, 0.06 mmol) and trans-4-hydroxycyclohexanecarboxylic acid (17 mg, 0.12 mmol) were sequentially added to a single-neck flask (25 mL), and anhydrous dichloromethane (1.0 mL) was added. The reaction mixture was cooled to 0 °C. N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were sequentially added to the reaction mixture, and the reaction mixture was stirred for 30 min while maintaining the temperature at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 32 (25 mg) in 70% yield.

[0272] MS-ESI calculated value [M+H] + 578, actual value 578. 1H NMR (400 MHz, DMSO-d6) δ 8.46(d,J=8.4Hz,1H),7.80-7.73(m,2H),5.90(d,J=16.8Hz,1H),5.59-5.51 (m,1H),5.47(d,J=16.4Hz,1H),5.43(d,J=19.6Hz,1H),5.27(d,J=19.6Hz,1 H),3.27-3.05(m,2H),2.38(s,3H),2.22-2.11(m,2H),2.10-2.00(m,2H),1. 94-1.77(m,6H),1.58-1.42(m,2H),1.18-1.05(m,2H),0.85(t,J=7.2Hz,3H).

[0273] Example 33

[0274] [ka]

[0275] Phase 1 A 25 mL single-neck flask was charged with 26a (30 mg, 0.06 mmol) and cis-4-hydroxycyclohexanecarboxylic acid (17 mg, 0.12 mmol), followed by anhydrous dichloromethane (1.0 mL). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were added sequentially. The reaction mixture was stirred for 30 min at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to give compound 33 (25 mg, 79% yield).

[0276] MS-ESI calculated value [M+H] + 578, actual value 578. 1H NMR (400 MHz, DMSO-d6) δ 8.41(d,J=8.8Hz,1H),7.78(s,1H),7.77(d,J=10.8Hz,1H),5.90(d,J=16.4H z,1H),5.61-5.52(m,1H),5.47(d,J=16.4Hz,1H),5.44(d,J=20.0Hz,1H),5. 32(d,J=20.0Hz,1H),3.28-3.05(m,2H),2.38(s,3H),2.30-2.03(m,4H),1.9 5-1.80(m,4H),1.73-1.63(m,2H),1.56-1.34(m,4H),0.85(t,J=7.2Hz,3H).

[0277] Biological Activity Tests Cell proliferation inhibition experiment Logarithmic growth phase KPL-4 tumor cells were harvested, resuspended in fresh RPMI 1640 medium, counted, and the cell suspension was diluted to 2 x 10 4 The cell suspension is inoculated into a 96-well cell culture plate at 100 μL / well and cultured overnight in a carbon dioxide incubator (37°C, 5% CO2). The next day, one of the 96-well plates containing the inoculated cells is removed and equilibrated to room temperature. Then, 100 μL of CellTiter-Glo reagent (Promega, USA), which has been pre-equilibrated to room temperature and mixed, is added to each well of the test plate. After incubation in the dark for 30 minutes, the luminescence value is read using a microplate reader ( Another parallel plate was prepared, and different concentrations of the test compound or DMSO (final concentration 0.5%) was added to the corresponding wells of the test plate. After culturing for 72 hours in a carbon dioxide incubator, the test plate was equilibrated to room temperature and the cell activity was detected using CellTiter-Glo reagent, which was recorded as the G value.

[0278] DXd was used as a positive control compound and has the following structure:

[0279] [ka]

[0280] The cell proliferation rate is calculated according to the following formula: Cell proliferation rate (%) = (mean G3 value of test compound wells - mean G0 value) / (mean G3 value of DMSO control wells - mean G0 value) x 100. Graphpad Prism software is used to fit the inhibition curves and calculate GI50 values (see the following table).

[0281] [Table 1]

[0282] [Table 2] JPEG2025526425000087.jpg113167

[0283] The results show that the compounds of the present invention exhibit higher tumor cell growth inhibition activity in the above tumor cell growth inhibition experiments, and their activity is significantly superior to that of DXd. Because the compounds of the present invention have excellent tumor cell growth inhibition activity, they can be used as tumor therapeutic agents or toxin molecules for preparing antibody-drug conjugates for treating tumors.

[0284] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A compound as shown in formula (I) below, or a pharmaceutically acceptable salt or hydrate thereof: 【Chemical 1】 where n is 0 or 1, X is N or CR ０ is selected from the group consisting of R ０ represents a hydrogen atom, a deuterium atom, a halogen, or C １ -C ８ Alkyl group, C １ -C ８ Alkoxy groups, OH, NH ２ , N ３ Or NO ２ is selected from the group consisting of R １ represents a hydrogen atom, a deuterium atom, a halogen, or C １ -C ８ Alkyl group, C １ -C ８ Alkoxy group, C １ -C ８ Haloalkyl group, C １ -C ８ Haloalkoxy group, N ３ , NO ２ , N.H. ２ , NH—OH, —NR′R″, —COOR′, —CONR′R″, —NHR′″NR′R″, wherein R′, R″ and R′″ are each independently selected from hydrogen, alkyl groups, aryl groups, arylalkyl groups, acyl groups, alkoxycarbonyl groups and aryloxycarbonyl groups; R ２ , R ３ , R ４ , R ５ and R ６ are each independently a hydrogen atom, a deuterium atom, a halogen, a hydroxy group, a cyano group, or NH ２ , NO ２ , substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted C １ -C ８ Alkoxy group, substituted or unsubstituted C １ -C ８ alkylthio group, substituted or unsubstituted C １ -C ８ Deuterated alkyl groups, -(CH ２ ) ｍ Bird (C １ -C ４ alkyl)silyl group, -(CH ２ ) ｍ (C ３ -C ８ cycloalkyl group), -(CH ２ ) ｍ (3- to 12-membered heterocyclic group), —(CH ２ ) ｍ N (R ７ ) ２ , -(CH ２ ) ｍ S (CH ２ ) ｐ R ７ , -(CH ２ ) ｍ S(O)(CH ２ ) ｐ R ７ , -(CH ２ ) ｍ S (O) ２ (CH ２ ) ｐ R ７ , -(CH ２ ) ｍ NH (CH ２ ) ｐ R ７ , -(CH ２ ) ｍ NHC(O)(CH ２ ) ｐ R ７ , -(CH ２ ) ｍ OC(O)(CH ２ ) ｐ R ７ , -(CH ２ ) ｍ C(O)(CH ２ ) ｐ R ７ , —CH═N(OtBu), wherein m and p are each independently 0, 1, 2, 3, or 4; Or, R ２ and R ３ together with the carbon atom to which they are attached, form a substituted or unsubstituted C ５ -C ８ forming a carbocyclic ring or a substituted or unsubstituted 5- to 12-membered heterocyclic ring; Or, R ２ and R ３ together with the carbon atom to which they are attached, are unsubstituted or one or more R ａ a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R ａ and forming a structure selected from the group consisting of saturated or unsaturated 5- to 6-membered heterocycles substituted by Or, R ３ and R ４ or R ４ and R ５ together with the carbon atom to which they are attached, are unsubstituted or one or more R ａ a saturated or unsaturated 5- to 12-membered carbocyclic ring, unsubstituted or substituted by one or more R ａ and forming a structure selected from the group consisting of saturated or unsaturated 5- to 12-membered heterocycles substituted by R ａ represents a substituted or unsubstituted hydrogen atom, a deuterium atom, a halogen atom, a nitrile group, a nitro group, a hydroxy group, an amino group, C １ -C ６ Alkyl-NH-, (C １ -C ６ alkyl) ２ N-, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, allyl group, benzyl group, C ６ -C １２ Aryl group, C １ -C ６ Alkoxy-C １ -C ６ Alkyl group, C １ -C ６ Alkoxy-carbonyl group, phenoxycarbonyl group, C ２ -C ６ Alkynyl-carbonyl group, C ２ -C ６ Alkenyl-carbonyl group, C ３ -C ６ cycloalkyl -carbonyl group, C １ -C ６ Alkyl-sulfonyl group, phenyl group, 5- to 7-membered heteroaryl group, C ３ -C ８ a cycloalkyl group, a 3- to 12-membered heterocyclic group, —(CH ２ ) ｍ N (R ７ ) ２ , -(CH ２ ) ｍ S (CH ２ ) ｐ R ７ , -(CH ２ ) ｍ S(O)(CH ２ ) ｐ R ７ , -(CH ２ ) ｍ S (O) ２ (CH ２ ) ｐ R ７ , -(CH ２ ) ｍ NH (CH ２ ) ｐ R ７ , -(CH ２ ) ｍ NHC(O)(CH ２ ) ｐ R ７ , -(CH ２ ) ｍ OC(O)(CH ２ ) ｐ R ７ , -(CH ２ ) ｍ C(O)(CH ２ ) ｐ R ７ wherein m and p are each independently 0, 1, 2, 3, or 4, preferably 0, 1, or 2; Each R ７ are each independently a hydrogen atom, a deuterium atom, a halogen atom, a substituted or unsubstituted C １ -C ８ Alkyl group, C １ -C ８ Haloalkyl group, C １ -C ８ Deuterated alkyl groups, substituted or unsubstituted C １ -C ８ an alkoxy group, a hydroxy group, an amino group, a cyano group, a nitro group, a mercapto group, a substituted or unsubstituted C １ -C ８ Alkylene-OH, substituted or unsubstituted C １ -C ８ Alkylene-NH ２ , S.O. ２ Me, —OC(O) (substituted or unsubstituted C １ -C ４ alkyl group), —C(O)(substituted or unsubstituted C １ -C ４ alkyl group), a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5- to 7-membered heteroaryl group, a substituted or unsubstituted C ３ -C ８ selected from the group consisting of cycloalkyl groups, substituted or unsubstituted 3- to 12-membered heterocyclic groups; Unless otherwise specified, any of the above groups is a deuterium atom, a halogen atom, a nitrile group, a nitro group, a hydroxy group, an amino group, a C １ -C ６ Alkyl-NH-, (C １ -C ６ alkyl) ２ N-, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, halo C １ -C ６ Alkyl group, halo C ２ -C ６ Alkenyl group, halo C ２ -C ６ Alkynyl group, halo C １ -C ６ Alkoxy group, allyl group, benzyl group, C ６ -C １２ Aryl group, C １ -C ６ Alkoxy-C １ -C ６ Alkyl group, C １ -C ６ Alkoxy-carbonyl group, phenoxycarbonyl group, C ２ -C ６ Alkynyl-carbonyl group, C ２ -C ６ Alkenyl-carbonyl group, C ３ -C ６ Cycloalkyl-carbonyl group, C １ -C ６ Alkyl-sulfonyl group, phenyl group, 5- to 7-membered heteroaryl group, C ３ -C ８ may be substituted by a substituent selected from the group consisting of a cycloalkyl group, a 3- to 12-membered heterocyclic group, and the compound does not have a structure selected from the group consisting of: 【Chemistry 2】 【change】 【change】 【change】

2. The compound of formula I is characterized in that it has a structure as shown in formula II or formula III below:

10. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof. 【Chemistry 3】 【Chemistry 4】

3. The compound of formula I is characterized in that it has a structure as shown in formula IV or formula V:

3. The compound according to claim 1, or a pharmaceutically acceptable salt or hydrate thereof. 【Chemistry 5】 【Chemistry 6】

4. The compound of formula I is characterized in that it has a structure as shown in formula VI or formula VII: A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or hydrate thereof. 【Chemistry 7】 【Chemistry 8】

5. The R ４ represents a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a cyano group, NH ２ , NO ２ , substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted C １ -C ８ Alkoxy group, substituted or unsubstituted C １ -C ８ alkylthio group, substituted or unsubstituted C １ -C ８ Deuterated alkyl groups, -(CH ２ ) ｍ (C ３ -C ８ cycloalkyl group), -(CH ２ ) ｍ (3- to 12-membered heterocyclic group), —(CH ２ ) ｍ N (R ７ ) ２ , -(CH ２ ) ｍ S(O)(CH ２ ) ｐ R ７ , -(CH ２ ) ｍ S (O) ２ (CH ２ ) ｐ R ７ , -(CH ２ ) ｍ NH (CH ２ ) ｐ R ７ wherein m and p are each independently 0, 1, or 2; ７ is defined as above, R ５ represents a hydrogen atom, a deuterium atom, a halogen, NH ２ , OH, substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted C １ -C ８ alkoxy groups; Or, R ４ and R ５ together with the carbon atom to which they are attached, are unsubstituted or one or more R ａ a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R ａ and forming a structure selected from the group consisting of saturated or unsaturated 5- to 6-membered heterocycles substituted by ａ The definition of is as described above.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or hydrate thereof.

6. R ２ and R ３ are each independently a hydrogen atom, a deuterium atom, a halogen, or NH ２ , substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted C １ -C ８ Deuterated alkyl groups, -(CH ２ ) ｍ (C ３ -C ６ cycloalkyl group), -(CH ２ ) ｍ (3- to 6-membered heterocyclic group), —(CH ２ ) ｍ N (R ７ ) ２ , -(CH ２ ) ｍ O.C.(O.)R. ７ where m is 0, 1, 2, 3, or 4; ７ is defined as above, Or, R ２ and R ３ together with the carbon atom to which they are attached, are unsubstituted or one or more R ａ a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R ａ and forming a structure selected from the group consisting of saturated or unsaturated 5- to 6-membered heterocycles substituted by ａ The definition of is as described above.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or hydrate thereof.

7. R １ and R ６ are each independently a hydrogen atom.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or hydrate thereof.

8. The R ４ and R ５ are each independently a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, or NH ２ , substituted or unsubstituted C １ -C ４ alkyl group, substituted or unsubstituted C １ -C ４ selected from the group consisting of alkoxy groups and cyclopropyl groups; Or, R ４ and R ５ together with the carbon atom to which they are attached, are unsubstituted or one or more R ａ and forming an oxa 5-6 membered heterocycle substituted by ａ The definition of is as described above.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or hydrate thereof.

9. R ２ is a deuterium atom, a halogen, NH ２ , substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted C １ -C ８ Deuterated alkyl groups, -(CH ２ ) ｍ (C ３ -C ６ cycloalkyl group), -(CH ２ ) ｍ (3- to 6-membered heterocyclic group), —(CH ２ ) ｍ N (R ７ ) ２ , -(CH ２ ) ｍ O.C.(O.)R. ７ wherein m is 0, 1, 2, 3, or 4; R ３ represents a hydrogen atom, a deuterium atom, a halogen atom, a substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted C １ -C ８ Deuterated alkyl groups, -(CH ２ ) ｍ (C ３ -C ６ cycloalkyl group), -(CH ２ ) ｍ (3- to 6-membered heterocyclic group), —(CH ２ ) ｍ N (R ７ ) ２ , -(CH ２ ) ｍ O.C.(O.)R. ７ wherein m is 0, 1, 2, 3, or 4; Or, R ２ and R ３ together with the carbon atom to which they are attached, are unsubstituted or one or more R ａ a saturated or unsaturated 5- to 6-membered carbocyclic ring, unsubstituted or substituted by one or more R ａ and forming a structure selected from the group consisting of saturated or unsaturated 5- to 6-membered heterocycles substituted by R ４ represents a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a cyano group, NH ２ , NO ２ , substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted C １ -C ８ alkoxy groups; R ５ represents a hydrogen atom, a deuterium atom, a halogen atom, a substituted or unsubstituted C １ -C ８ alkyl groups, Or, R ４ and R ５ is bonded to form -OCH ２ O- or -O(CH ２ ) ２ O—, or one or more R ａ forming a structure substituted by R ７ represents a hydrogen atom, a deuterium atom, a halogen atom, a substituted or unsubstituted C １ -C ８ selected from the group consisting of alkyl groups, hydroxy groups, amino groups, cyano groups, nitro groups, and mercapto groups; Here, R ａ The definition of is as described above.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or hydrate thereof.

10. The compound is characterized in that it has a structure as shown in the following formula:

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or hydrate thereof. 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

11. 1. A pharmaceutical composition comprising:

11. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

12. Use of a compound of formula I according to any one of claims 1 to 10, Use of a compound of formula I according to any of the preceding claims 1 to 10, characterized in that it is used for the preparation of a pharmaceutical composition for the treatment of diseases associated with tumor cell proliferation.

13. and preparing an antibody-drug conjugate by using the compound as a toxin in the antibody-drug conjugate. Use of a compound of formula I according to any one of claims 1 to 10.

14. A compound as shown in formula II-b or III-b below: 【Chemistry 10】 wherein the definitions of each group are as set forth in claim 1.

15. The compound is characterized in that it has a structure according to the following formula IV-b or V-b:

15. The compound of claim 14. 【Chemistry 11】

16. A process for preparing a compound of formula I according to any one of claims 1 to 10, comprising the steps of: The method comprises: 【Chemistry 12】 A process for preparing a compound of formula I according to any one of claims 1 to 10, comprising reacting a compound of formula Ia with a compound of formula Ib in an inert solvent to obtain a compound of formula I.

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