Protein kinase inhibitors, their production methods and applications

Abstract

The present invention relates to compounds that modulate protein kinase activity, in particular compounds that inhibit PLK1 kinase activity. The present invention further provides pharmaceutical compositions containing said compounds and the use of said compounds and pharmaceutical compositions thereof in the manufacture of medicaments for the prevention or treatment of diseases caused by and / or associated with dysregulation of PLK1 kinase activity. [Formula 1] TIFF2024546115000197.tif18160

Description

[Technical field]

[0001] The present invention belongs to the field of pharmaceutical technology and relates to compounds and pharmaceutical compositions for preventing or treating diseases associated with dysregulation of protein kinase activity, as well as methods and applications thereof. In particular, the present invention provides compounds that can be used as protein kinase, particularly PLK1 kinase, inhibitors and their uses. [Background technology]

[0002] PLK1 is a serine / threonine kinase that is widely present in eukaryotic cells. PLK1 is involved in most processes of cell division, including biological processes such as cell division entry, nuclear membrane rupture, centriole duplication, chromosome perfect alignment, mitotic checkpoint initiation and cytokinesis.

[0003] In the G2 phase, PLK1 plays a key role in the activation of the cyclin B-CDK1 complex through at least two mechanisms. First, it activates CDC25C phosphatase, which in turn eliminates the inhibitory phosphorylation of CDK1, thereby activating CDK1. Second, PLK1 prevents further phosphorylation of CDK1 by inducing phosphorylation-dependent degradation of WEE1, allowing cells to enter the M phase. PLK1 is further involved in regulating the G2 and M DNA damage checkpoints.

[0004] Studies have shown that PLK1 is overexpressed in various tumor tissues, overexpression of wild-type PLK1 can cause multinucleation, and overactive PLK1 expression can allow cells to overcome the DNA damage-induced G2 block checkpoint. PLK1 is closely related to tumor development, and the expression level of PLK1 is associated with poor prognosis in clinical patients. Therefore, PLK1 inhibitors are expected to be an effective antitumor drug target.

[0005] Volasertib and Onvansertib are ATP-competitive PLK1 small molecule inhibitors that are currently undergoing rapid clinical development, and show clear antitumor effects in various preclinical models or clinical studies, whether used alone or in combination. Volasertib is an injection, and a high level of increased incidence of adverse events has been observed in clinical trials. Onvansertib is an oral formulation, and has shown low bioavailability in preclinical studies, with a small safety margin in clinical trials. Therefore, the field still needs compounds with high selectivity, high activity, and higher safety to meet clinical needs. Summary of the Invention

[0006] In one embodiment of the present invention, there is provided a compound according to formula (I), a pharma- ceutically acceptable salt or stereoisomer thereof, [ka] Where: X is independently selected from the divalent radicals piperidine, piperazine, 3,8-diazabicyclo[3.2.1]octane, -CH2-piperazine-, -NR-pyrrolidine-, -NR-azetidine-, or -NR-CH2-pyrrolidine-, and R is independently selected from H, D, and a C1-C6 alkyl group; Y is independently selected from the divalent radicals -C(R4)2-C(R4)2-, -CR4=CR4-, -C(R4)2-NR4-, -NR4-C(R4)2-, -CR4=N-, or -N=CR4-, each R4 being independently selected from H, D, or a C1-C6 alkyl group; Ring A is represented by the formula (A): [ka] is selected from the structures shown in X1 is independently selected from a C, N, O or S atom; X2 is independently selected from a C, N, O or S atom; R1 is independently selected from H, D, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C1-C6 haloalkoxy group; R2 is independently selected from H, D, and a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more halogen, OH, NH2, or CN groups; Each R3 is independently selected from H, D, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or -C(O)NHR5, where the C1-C6 alkyl group is optionally substituted with one or more halogens, OH, NH2, CN, or a C1-C6 alkoxy group; each R5 is independently selected from H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, HO-C1-C6 alkoxy group, OH, NH2, -NHC(O)NH2, or R6-S(O)2-; each R6 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group.

[0007] In some aspects of the invention, in the compound of formula (I), a pharma- ceutically acceptable salt, or stereoisomer thereof, X is independently [ka] wherein R is independently selected from H, D, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0008] In some aspects of the invention, in the compound of formula (I), its pharma- ceutically acceptable salt, or stereoisomer, Y is preferably independently selected from the divalent radicals -CH2-CH2-, -CH=CH-, -CH2-NH-, -NH-CH2-, -CH2-N(CH3)-, -N(CH3)-CH2-, -CH=N-, or -N=CH-, and more preferably -CH=CH-.

[0009] In some aspects of the invention, in the compound of formula (I), its pharma- ceutically acceptable salts or stereoisomers, R1 is independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoromethyl, 2,2-dichloroethyl ... Preferably, the group is selected from the group consisting of fluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy, n-pentyloxy, s-pentyloxy, hexyloxy, 2-ethylbutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0010] In some aspects of the invention, in the compound of formula (I), its pharma- ceutically acceptable salts, or stereoisomers, R2 is independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, The terminals of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl groups are optionally substituted with one or more F, Cl, Br, OH, NH, and CN groups.

[0011] In some aspects of the invention, in the compound of formula (I), a pharma- ceutically acceptable salt or stereoisomer thereof, ring A is a group represented by formula (A-1), formula (A-2), formula (A-3), formula (A-4) or formula (A-5): [ka] It is preferable that the structure is selected from the structures shown in R 3a is independently selected from H, D, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, where the C1-C6 alkyl group is optionally substituted with one or more halogen, OH, NH2, CN, a C1-C6 alkoxy group; R 3b is independently selected from -C(O)NHR5, wherein R5 is independently selected from H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, HO-C1-C6 alkoxy group, OH, NH2, -NHC(O)NH2, R6-S(O)2-, wherein R6 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group.

[0012] In some embodiments of the present invention, in the compounds of formula (I), pharma- ceutically acceptable salts or stereoisomers thereof, R 3a is preferably selected from H, D, a C1-C6 linear alkyl group, and a C3-C6 cycloalkyl group, and the end of the C1-C6 linear alkyl group is optionally substituted with one or more F, Cl, Br, OH, NH2, CN, a methoxy group, or an ethoxy group.

[0013] In some embodiments of the present invention, in the compounds of formula (I), pharma- ceutically acceptable salts or stereoisomers thereof, R 3a is particularly preferably selected from a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and the terminal of the methyl group, the ethyl group, the n-propyl group, the n-butyl group, the n-pentyl group, or the n-hexyl group is optionally substituted with one or more of F, Cl, Br, OH, NH2, CN, a methoxy group, or an ethoxy group.

[0014] In some embodiments of the present invention, in the compounds of formula (I), pharma- ceutically acceptable salts or stereoisomers thereof, R 3b is independently selected from -C(O)NHR5, wherein R5 is preferably selected from H, D, a C1-C6 straight chain alkyl group, a C1-C6 straight chain alkoxy group, HO-C1-C6 straight chain alkoxy group, OH, NH2, -NHC(O)NH2, R6-S(O)2-, and wherein R6 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group.

[0015] In some embodiments of the present invention, in the compounds of formula (I), pharma- ceutically acceptable salts or stereoisomers thereof, R 3bis independently selected from -C(O)NHR5, R5 is particularly preferably H, D, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, HO-methoxy, HO-ethoxy, HO-n-propoxy, HO-n-butoxy, HO-n-pentyloxy, HO-n-hexyloxy, OH, NH2, -NHC(O)NH2, R6-S(O)2-, R6 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl. , t-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 3,3,3-trifluoroethyl group, 3,3,3-trichloroethyl group, pentafluoroethyl group, pentachloroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.

[0016] In another embodiment of the present invention, there is provided a compound according to formula (II), a pharma- ceutically acceptable salt or stereoisomer thereof: [ka] Where: Y is independently selected from the divalent radicals -C(R4)2-C(R4)2-, -CR4=CR4-, -C(R4)2-NR4-, -NR4-C(R4)2-, -CR4=N-, or -N=CR4-, each R4 being independently selected from H, D, or a C1-C6 alkyl group; X1 is independently selected from a C, N, O or S atom; X2 is independently selected from a C, N, O or S atom; R1 is independently selected from H, D, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C1-C6 haloalkoxy group; R2 is independently selected from H, D, and a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more halogen, OH, NH2, or CN groups; R 3a is independently selected from H, D, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more halogen, OH, NH2, CN groups.

[0017] R 3b is independently selected from -C(O)NHR5; R5 is independently selected from H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, a HO-C1-C6 alkoxy group, OH, NH2, -NHC(O)NH2, and R6-S(O)2-, and R6 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group.

[0018] In some aspects of the invention, in the compound of formula (II), its pharma- ceutically acceptable salt, or stereoisomer, Y is preferably independently selected from the divalent radicals -CH2-CH2-, -CH=CH-, -CH2-NH-, -NH-CH2-, -CH2-N(CH3)-, -N(CH3)-CH2-, -CH=N-, or -N=CH-, and more preferably -CH=CH-.

[0019] In some aspects of the invention, in the compound of formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, R1 is independently selected from the group consisting of H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoromethyl, 3,3,3-trichloromethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl ... It is preferably selected from a fluoroethyl group, a 3,3,3-trichloroethyl group, a pentafluoroethyl group, a pentachloroethyl group, a methoxy group, an ethoxy group, a n-propoxy group, a isopropoxy group, a n-butoxy group, a s-butoxy group, a t-butoxy group, a n-pentyloxy group, a S-pentyloxy group, a hexyloxy group, a 2-ethylbutoxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2,2-difluoroethoxy group, a 2,2-dichloroethoxy group, a 3,3,3-trifluoroethoxy group, a 3,3,3-trichloroethoxy group, a pentafluoroethoxy group, and a pentachloroethoxy group.

[0020] In some aspects of the invention, in the compound of formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, R2 is independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, The terminals of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl groups are optionally substituted with one or more F, Cl, Br, OH, NH, and CN groups.

[0021] In some embodiments of the present invention, in the compound of formula (II), a pharma- ceutically acceptable salt or stereoisomer thereof, R 3a is preferably selected from H, D, a C1-C6 linear alkyl group, and a C3-C6 cycloalkyl group, the end of which is optionally substituted with one or more F, Cl, Br, OH, NH2, or CN groups.

[0022] In some embodiments of the present invention, in the compound of formula (II), a pharma- ceutically acceptable salt or stereoisomer thereof, R 3a is particularly preferably selected from a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, the terminal of which is optionally substituted with one or more F, Cl, Br, OH, NH2, or CN groups.

[0023] In some embodiments of the present invention, in the compound of formula (II), a pharma- ceutically acceptable salt or stereoisomer thereof, R 3b is independently selected from -C(O)NHR5, wherein R5 is preferably selected from H, D, a C1-C6 straight chain alkyl group, a C1-C6 straight chain alkoxy group, HO-C1-C6 straight chain alkoxy group, OH, NH2, -NHC(O)NH2, R6-S(O)2-, and wherein R6 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group.

[0024] In some embodiments of the present invention, in the compound of formula (II), a pharma- ceutically acceptable salt or stereoisomer thereof, R 3b is independently selected from -C(O)NHR5, R5 is particularly preferably H, D, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, HO-methoxy, HO-ethoxy, HO-n-propoxy, HO-n-butoxy, HO-n-pentyloxy, HO-n-hexyloxy, OH, NH2, -NHC(O)NH2, R6-S(O)2-, R6 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl. , t-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 3,3,3-trifluoroethyl group, 3,3,3-trichloroethyl group, pentafluoroethyl group, pentachloroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.

[0025] In another embodiment of the present invention, there is provided a compound of formula (IIa), (IIb), (IIc), (IId) or (IIe), a pharma- ceutically acceptable salt or stereoisomer thereof, [ka] Where: Y is independently selected from the divalent radicals -C(R4)2-C(R4)2-, -CR4=CR4-, -C(R4)2-NR4-, -NR4-C(R4)2-, -CR4=N-, or -N=CR4-, each R4 being independently selected from H, D, or a C1-C6 alkyl group; R1 is independently selected from H, D, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C1-C6 haloalkoxy group; R2 is independently selected from H, D, and a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more halogen, OH, NH2, or CN groups; R 3a is independently selected from H, D, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more halogen, OH, NH2, CN groups.

[0026] R 3b is independently selected from -C(O)NHR5; R5 is independently selected from H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, a HO-C1-C6 alkoxy group, OH, NH2, -NHC(O)NH2, and R6-S(O)2-, and R6 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group.

[0027] In some aspects of the invention, in the compound of formula (IIa), formula (IIb), formula (IIc), formula (IId) or formula (IIe), or a pharma- ceutically acceptable salt or stereoisomer thereof, Y is preferably independently selected from a divalent group selected from -CH2-CH2-, -CH=CH-, -CH2-NH-, -NH-CH2-, -CH2-N(CH3)-, -N(CH3)-CH2-, -CH=N- or -N=CH-, and more preferably -CH=CH-.

[0028] In some aspects of the invention, in the compound of formula (IIa), formula (IIb), formula (IIc), formula (IId) or formula (IIe), or a pharma- ceutically acceptable salt or stereoisomer thereof, R1 is independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloro ... Preferably, the group is selected from the group consisting of fluoroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy, n-pentyloxy, S-pentyloxy, hexyloxy, 2-ethylbutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0029] In some aspects of the invention, in the compound of formula (IIa), formula (IIb), formula (IIc), formula (IId) or formula (IIe), or a pharma- ceutically acceptable salt or stereoisomer thereof, R2 is independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl, 5,5-dimethylbutyl, 6,6-dimethylbutyl, 7,7-dimethylbutyl, 8,8-dimethylbutyl, 9,9-dimethylbutyl, 10,10-dimethylbutyl, 11,10-dimethylbutyl, 12,10-dimethylbutyl, 13,10-dimethylbutyl, 14,10-dimethylbutyl, 15,10-dimethylbutyl, 16,10-dimethylbutyl, 17,10-dimethylbutyl, 18,10-dimethylbutyl, 19 ...9,10-dimethylbutyl, 1 The terminals of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl groups are optionally substituted with one or more F, Cl, Br, OH, NH2, and CN groups.

[0030] In some embodiments of the present invention, the compounds of formula (IIa), (IIb), (IIc), (IId) or (IIe), pharma- ceutically acceptable salts or stereoisomers thereof, R 3a is preferably selected from H, D, a C1-C6 linear alkyl group, and a C3-C6 cycloalkyl group, the end of which is optionally substituted with one or more F, Cl, Br, OH, NH2, or CN groups.

[0031] In some embodiments of the present invention, the compounds of formula (IIa), (IIb), (IIc), (IId) or (IIe), pharma- ceutically acceptable salts or stereoisomers thereof, R 3ais particularly preferably selected from a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, the terminal of which is optionally substituted with one or more F, Cl, Br, OH, NH2, or CN groups.

[0032] In some embodiments of the present invention, the compounds of formula (IIa), (IIb), (IIc), (IId) or (IIe), pharma- ceutically acceptable salts or stereoisomers thereof, R 3b is independently selected from -C(O)NHR5, wherein R5 is preferably selected from H, D, a C1-C6 straight chain alkyl group, a C1-C6 straight chain alkoxy group, HO-C1-C6 straight chain alkoxy group, OH, NH2, -NHC(O)NH2, R6-S(O)2-, and wherein R6 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group.

[0033] In some embodiments of the present invention, the compounds of formula (IIa), (IIb), (IIc), (IId) or (IIe), pharma- ceutically acceptable salts or stereoisomers thereof, R 3bis independently selected from -C(O)NHR5, R5 is particularly preferably H, D, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, HO-methoxy, HO-ethoxy, HO-n-propoxy, HO-n-butoxy, HO-n-pentyloxy, HO-n-hexyloxy, OH, NH2, -NHC(O)NH2, R6-S(O)2-, R6 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl. , t-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 3,3,3-trifluoroethyl group, 3,3,3-trichloroethyl group, pentafluoroethyl group, pentachloroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.

[0034] In some embodiments of the present invention, in the compound of formula (IIa), a pharma- ceutically acceptable salt, or a stereoisomer thereof, Y is -CR4=CR4-, each R4 being independently selected from H, D, and a C1-C6 alkyl group, and preferably Y is -CH=CH-.

[0035] R1 is independently selected from H, D, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C1-C6 haloalkoxy group.

[0036] R2 is independently selected from H, D, and a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more halogen, OH, NH2, and CN groups.

[0037] R 3a is independently selected from H, D, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more halogen, OH, NH2, CN groups.

[0038] R 3b is independently selected from -C(O)NHR5, wherein R5 is independently selected from H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, HO-C1-C6 alkoxy group, OH, NH2, -NHC(O)NH2, R6-S(O)2-, wherein R6 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group.

[0039] In some aspects of the invention, in the compound of formula (IIa), or a pharma- ceutically acceptable salt or stereoisomer thereof, R1 is independently selected from the group consisting of H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoromethyl, 3,3,3-trichloromethyl ...chloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl, 3,3,3-trichloromethyl It is preferably selected from a fluoroethyl group, a 3,3,3-trichloroethyl group, a pentafluoroethyl group, a pentachloroethyl group, a methoxy group, an ethoxy group, a n-propoxy group, a isopropoxy group, a n-butoxy group, a s-butoxy group, a t-butoxy group, a n-pentyloxy group, a S-pentyloxy group, a hexyloxy group, a 2-ethylbutoxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2,2-difluoroethoxy group, a 2,2-dichloroethoxy group, a 3,3,3-trifluoroethoxy group, a 3,3,3-trichloroethoxy group, a pentafluoroethoxy group, and a pentachloroethoxy group.

[0040] In some aspects of the invention, in the compound of formula (IIa), or a pharma- ceutically acceptable salt or stereoisomer thereof, R2 is independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl ... The terminals of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl groups are optionally substituted with one or more F, Cl, Br, OH, NH2, and CN groups.

[0041] In some embodiments of the present invention, in the compound of formula (IIa), a pharma- ceutically acceptable salt or stereoisomer thereof, R 3a is preferably selected from H, D, a C1-C6 linear alkyl group, and a C3-C6 cycloalkyl group, the end of which is optionally substituted with one or more F, Cl, Br, OH, NH2, or CN groups.

[0042] In some embodiments of the present invention, in the compound of formula (IIa), a pharma- ceutically acceptable salt or stereoisomer thereof, R 3a is preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups, the terminal of which is optionally substituted with one or more F, Cl, Br, OH, NH, or CN groups; R 3ais particularly preferably selected from a methyl group, an ethyl group, a cyclopropyl group, -CH2CH2F, -CH2CF3, and -CH2CH2OH.

[0043] In some embodiments of the present invention, in the compound of formula (IIa), a pharma- ceutically acceptable salt or stereoisomer thereof, R 3b is independently selected from -C(O)NHR5, wherein R5 is preferably selected from H, D, a C1-C6 straight chain alkyl group, a C1-C6 straight chain alkoxy group, HO-C1-C6 straight chain alkoxy group, OH, NH2, -NHC(O)NH2, R6-S(O)2-, and wherein R6 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group.

[0044] In some embodiments of the present invention, in the compound of formula (IIa), a pharma- ceutically acceptable salt or stereoisomer thereof, R 3bis independently selected from -C(O)NHR5, R5 is particularly preferably H, D, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, HO-methoxy, HO-ethoxy, HO-n-propoxy, HO-n-butoxy, HO-n-pentyloxy, HO-n-hexyloxy, OH, NH2, -NHC(O)NH2, R6-S(O)2-, R6 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl. , t-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 3,3,3-trifluoroethyl group, 3,3,3-trichloroethyl group, pentafluoroethyl group, pentachloroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.

[0045] In some aspects of the invention, the compound of formula (I) is [ka] [ka] [ka] is selected from.

[0046] The present invention further provides a pharmaceutical composition comprising any one of the above compounds or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. The pharmaceutical composition can be prepared in various pharma- ceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, or various sustained-release preparations. The pharmaceutical composition can be administered orally or parenterally (e.g., intravenously, subcutaneously, or topically). The dosage can be appropriately adjusted according to the age, sex, and disease type of the patient, and is generally about 1 to 200 mg per day. The present invention further provides a use of the above compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition in the manufacture of a medicament, the medicament being for preventing or treating a disease caused by dysregulation of protein kinase activity and / or a disease associated therewith, preferably for preventing or treating a disease caused by dysregulation of PLK1 kinase activity and / or a disease associated therewith. The disease is selected from cancer, cell proliferative disease, viral infection, autoimmune, and neurodegenerative disease.

[0047] Such cancers include cancers of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma), as well as leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and other types of cancers. hematopoietic tumors of the lymphoid system including acute and chronic myeloid leukemia, myelodysplastic syndromes and promyelocytic leukemia; tumors of stromal origin including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannoma; and other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma and Kaposi's sarcoma.

[0048] Said cell proliferative diseases are, for example, benign prostatic hyperplasia, familial adenomatous polyposis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis and restenosis.

[0049] Definitions and Explanations Unless otherwise indicated, the following terms and phrases used herein have the following meanings: A particular term or phrase should not be considered indefinite or uncertain, unless specifically defined, but should be interpreted according to its general meaning. Where trade names appear herein, it is intended to refer to the corresponding commercial product or its active ingredients.

[0050] "Pharmaceutically acceptable" as referred to in this invention refers to compounds, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0051] The term "pharmaceutical acceptable salt" as referred to in the present invention means that the salt of the compound of the present invention is prepared from the compound having a specific substituent and a relatively non-toxic acid and base discovered in the present invention.When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent.Examples of pharmaceutical acceptable acid addition salts include inorganic acid salts, organic acid salts, and further include salts of amino acids (such as arginine) and organic acids such as glucuronic acid.Some specific compounds of the present invention contain a basic functional group and can be converted into any acid addition salt.

[0052] Some compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers and single isomers are all included within the scope of the present invention.

[0053] The compounds of the present invention may have a particular geometric or stereoisomeric form. All such compounds are contemplated by the present invention to include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched from enantiomers or diastereomers, and all such mixtures are within the scope of the present invention. Substituents such as alkyl groups may have other asymmetric carbon atoms. All such isomers and mixtures thereof are within the scope of the present invention.

[0054] The pharma- ceutically acceptable salts of the present invention can be synthesized from parent compounds that contain an acid or base group by conventional chemical methods. In general, salts are prepared by reacting the free acid or free base forms of these compounds with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture of both.

[0055] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of an active agent of the present invention, does not interfere with the biological activity of the active agent, and has no toxic side effects to the host or patient; representative carriers include, but are not limited to, adhesives, fillers, lubricants, disintegrants, wetting agents, dispersants, solubility enhancers, suspension aids, and the like.

[0056] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those of skill in the art or by methods analogous to those described herein, using the appropriate isotopically labeled reagent in place of the otherwise non-labeled reagent used.

[0057] Unless otherwise indicated, the term "alkyl group" is intended to represent a straight or branched chain saturated hydrocarbon group, which may be singly (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methine). For example, C1-C6 represents 1 to 6 carbons, C 1-6 is selected from C1, C2, C3, C4, C5 and C6, and examples of the alkyl group include a methyl group (Me), an ethyl group (Et), a propyl group (e.g., n-propyl and isopropyl groups), a butyl group (e.g., n-butyl, isobutyl, s-butyl and t-butyl groups), a pentyl group (e.g., n-pentyl, isopentyl, neopentyl and 1-ethylpropyl groups), a hexyl group (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl groups), and the like.

[0058] Unless otherwise stated, the terms "halogenated element" or "halogen," by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0059] "Haloalkyl group" is intended to represent a straight or branched chain monohalo / polyhaloalkyl group. Exemplary haloalkyl groups include C 1-6 Haloalkyl groups include, for example, C1, C2, C3, C4, C5, and C6 haloalkyl groups. For example, examples of C1-C6 haloalkyl groups include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, and pentachloroethyl.

[0060] Unless otherwise indicated, the term "alkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms, including a cycloalkyl or haloalkyl group, linked through an oxygen bridge. Exemplary alkoxy groups include C1-6 Alkoxy groups include, for example, C1, C2, C3, C4, C5, C6 alkoxy groups, C3, C4, C5, C6 cycloalkoxy groups, and C1, C2, C3, C4, C5, C6 haloalkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy, n-pentyloxy, S-pentyloxy, hexyloxy, and 2-ethylbutoxy groups. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy groups.

[0061] Unless otherwise specified, cycloalkyl groups include any stable cyclic or polycyclic hydrocarbon group, any of which may be saturated at any of the carbon atoms, may be mono- or polysubstituted, and may be mono-, di- or polyvalent. Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0062] Compounds are named manually or with ChemDraw® software; commercially available compounds use the supplier catalog name. [Brief description of the drawings]

[0063] [Figure 1] 16 is a mouse in vivo pharmacodynamic study of Compound 1—Animal tumor growth curves. [Diagram 2] Mouse in vivo pharmacodynamic study of Compound 1 - Body weight during animal testing. [Diagram 3] 16 is a mouse in vivo pharmacodynamic study of compound 18—animal tumor growth curves. [Figure 4] Mouse in vivo pharmacodynamic study of compound 18 - Body weight during animal studies. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0064] The present invention will be further described below with reference to specific examples and test examples, but the scope of the present invention is not limited in any way.

[0065] In the examples below, the following reagent abbreviations have the following meanings. If not defined, they will have the meanings well known in the art.

[0066] [Table 1]

[0067] Example 1: Synthesis of Compound 1 Synthesis Route: [ka]

[0068] 1.1. Synthesis of intermediate 1-2 [ka]

[0069] Intermediate 1-1 (20.0 g, 78.1 mmol), bis(dibenzylideneacetone)palladium (0.715 g, 0.78 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (0.615 g, 1.56 mmol) were dissolved in tetrahydrofuran (32 mL), and N-methylpiperazine (12.5 g, 125 mmol) and lithium bistrimethylsilylamide (1.00 M, 187 mL) were added at 0 ° C. The reaction was carried out at 70 ° C. for 3 h. The reaction was quenched by adding water (200 mL) and extracted by adding dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / dichloromethane = 1% to 10%) to obtain intermediate 1-2 (15.5 g, yield 72.2%, brown solid). MS (ESI) m / z = 276.0 [M + H] + .

[0070] 1.2. Synthesis of intermediate 1-3 [ka]

[0071] Intermediate 1-2 (0.372 g, 1.35 mmol) was dissolved in 6N HCl (2 mL) and cyanamide (0.455 g, 10.8 mmol) was added. The reaction was carried out at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (C18, acetonitrile / water = 0% to 10%). Intermediate 1-3 (0.19 g, yield 45%, brown solid) was obtained. MS (ESI) m / z = 318.1 [M + H] + .

[0072] 1.3. Synthesis of intermediates 1-5 [ka]

[0073] Intermediate 1-4 (100g, 892mmol) was dissolved in toluene (1000mL) and ethanol (123g, 2680mmol), PTSA (15.4g, 89.2mmol) was added, and the mixture was reacted at 120°C for 12h. Water (1000mL x 2) was added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 50%) to obtain intermediate 1-5 (57.9g, yield 46.4%, oily product).

[0074] 1.4. Synthesis of intermediates 1-6 [ka]

[0075] Intermediate 1-5 (30.0 g, 214 mmol) was dissolved in tetrahydrofuran (450 mL), and LiHMDS (1 M, 256 mL) was added dropwise at -50.0 °C, and the mixture was stirred for 30 min. Diethyl oxalate (37.8 g, 258 mmol) was added, and the mixture was reacted at room temperature for 16 h. Saturated ammonium chloride (500 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added to extract the mixture. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% ~ 20%) to obtain intermediate 1-6 (25.0 g, yield 48.6%, oily product). MS (ESI) m / z = 241.1 [M + H] + .

[0076] 1.5. Synthesis of intermediate 1-7 [ka]

[0077] Intermediate 1-6 (25.0 g, 104 mmol) was dissolved in acetic acid (120 mL), hydroxyethylhydrazine (8.16 g, 107 mmol) was added, and the mixture was reacted at room temperature for 15 h. The mixture was quenched by adding water (500 mL), saturated Na2CO3 (800 mL) was added, and dichloromethane (800 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 5%) to obtain intermediate 1-7 (19.9 g, 76% yield, yellow solid). MS (ESI) m / z = 253.0 [M + H] + .

[0078] 1.6. Synthesis of intermediate 1-8 [ka]

[0079] Intermediate 1-7 (10.0 g, 39.6 mmol) was dissolved in DMF-DMA (100 mL) and reacted at 110 °C for 12 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in methyl tert-butyl ether and stirred for 3 h. Filtration and collection of the filter cake were dried to give intermediate 1-8 (6.0 g, crude). Used directly in the next step.

[0080] 1.7. Synthesis of intermediate 1-9 [ka]

[0081] Intermediate 1-8 (1.95 g, 6.34 mmol) and intermediate 1-3 (2.03 g, 6.41 mmol) were dissolved in DMF (20 mL) and reacted at 110°C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 5%) to obtain intermediate 1-9 (1.90 g, yield 53.3%, yellow solid). MS (ESI) m / z = 562.2 [M + H] + .

[0082] 1.8. Synthesis of intermediates 1-10 [ka]

[0083] Intermediate 1-9 (100 mg, 178 μmol) and DDQ (100 mg, 440 μmol) were dissolved in dioxane (20 mL) and reacted at 100° C. for 12 h. The reaction was quenched by adding saturated NaHCO3 (20 mL) and extracted by adding ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (C18 150*40 mm*10 μm, mobile phase: [water (TFA)-acetonitrile], B%: 25%-55%, 10 min). Intermediate 1-10 (10 mg, 10% yield, brown solid) was obtained. MS (ESI) m / z = 560.1 [M + H] + .

[0084] 1.9. Synthesis of Compound 1 [ka]

[0085] Intermediate 1-10 (160 mg, 285 μmol) was dissolved in NMP (6 mL) and NH3 / MeOH (50.0 mL) was added. The reaction was allowed to proceed for 48 h in a sealed container at 80.0°C. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 30*150 mm*7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 10% to 80%, 40 min). Compound 1 (56.7 mg, yield 37.5%, yellow solid) was obtained. MS (ESI) m / z = 531.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.56(s,1H),9.34(s,1H),7.89(d,J=8.6Hz,1H),7.67(d,J=8.8Hz,1H),7.33 - 7.20(m,2H),6.88 - 6.91(m,1H),4.91(t,J=4.9Hz,2H),4.65(d,J=5.3Hz,1H),4.41(q,J=7.1Hz,2H),3.70 - 3.54(m,3H),3.28 - 3.10(m,3H),3.10 - 3.09(m,1H),3.16 - 3.09(m,1H),2.34 - 2.19(m,3H),1.39(t,J=7.1Hz,3H),1.36 - 1.36(m,1H),1.31(t,J=7.1Hz,1H),1.26 - 1.12(m,1H).

[0086] Example 2: Synthesis of Compound 2 [ka]

[0087] 2.1 Synthesis of compound 2-2 [ka]

[0088] Intermediate 2-1 (5.00 g, 49.9 mmol) was dissolved in methanol (20 mL), concentrated sulfuric acid (0.33 mL) was added dropwise, and the mixture was reacted at 65° C. for 48 h under nitrogen gas protection. Potassium carbonate (2.00 g) was added and the mixture was stirred at room temperature for 0.5 h. The reaction solution was filtered, the filtrate was collected and concentrated under reduced pressure, and the residue was dissolved in water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 2-2 (5.48 g, crude) was obtained and used directly in the next step. MS (ESI) m / z=133.2 [M+H] + .

[0089] 2.2 Synthesis of intermediate 2-3 [ka]

[0090] Intermediate 2-2 (5.85 g, 44.3 mmol), TEMPO (0.35 g, 2.20 mmol) and KBr (0.53 g, 4.40 mmol) were dissolved in dichloromethane (60 mL), and NaClO (14.3 g, 23% aqueous solution) was added at -5°C, and the reaction was allowed to proceed at 0°C for 1 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain intermediate 2-3 (5.46 g, crude, oil). The product was used directly in the next step.

[0091] 2.3 Synthesis of intermediate 2-4 [ka]

[0092] Intermediate 2-3 (5.46 g, 42.0 mmol) and ethyl (triphenylphosphoranylidene)acetate (14.9 g, 42.8 mmol) were dissolved in toluene (50 mL) and reacted at 120°C for 12 h. The reaction was quenched by adding water (50 mL) and extracted by adding ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 15%) to obtain intermediate 2-4 (2.18 g, yield 21.7%, oily product). MS (ESI) m / z = 201.2 [M + H] + .

[0093] 2.4 Synthesis of intermediate 2-5 [ka]

[0094] Under nitrogen gas protection and at -78°C, 1M LiHMDS tetrahydrofuran solution (10.8mL, 10.8mmol) was added dropwise to 30mL of TosMIC (2.11g, 10.8mmol) tetrahydrofuran solution. Stirred at -78°C for 40min, added dropwise to tetrahydrofuran (30mL) solution of intermediate 2-4 (1.10g, 5.90mmol), stirred for 20min, and then warmed to room temperature for reaction. After detecting the completion of the reaction, quenched by adding water (100mL), and extracted by adding dichloromethane (100mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 30%) to obtain intermediate 2-5 (1.82g, yield 70.6%, oily substance). MS(ESI)m / z=240.0[M+H] + .

[0095] 2.5 Synthesis of intermediate 2-6 [ka]

[0096] Intermediate 2-5 (1.00 g, 4.20 mmol) was dissolved in dioxane (20 mL) and water (5 mL), lithium hydroxide (0.100 g, 0.420 mmol) was added, and the mixture was reacted at room temperature for 12 h. The pH was adjusted to acidic with 1N HCl, water (50 mL) was added, and ethyl acetate (50 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 2-6 (0.974 g, crude) was obtained and used directly in the next step. MS (ESI) m / z = 226.0 [M + H] + .

[0097] 2.6 Synthesis of intermediate 2-7 [ka]

[0098] Intermediate 2-6 (0.974 g, 4.32 mmol) was dissolved in trifluoroacetic acid (5 mL), TFAA (0.908 g, 4.32 mmol) was added, and the mixture was reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 32%) to obtain intermediate 2-7 (0.46 g, yield 50.8%, oily product). MS (ESI) m / z = 208.0 [M + H] + .

[0099] 2.7 Preparation of intermediate 2-8 [ka]

[0100] Intermediate 2-7 (0.44 g, 2.12 mmol) and (2-bromoethoxy)-t-butyldimethylsilane (0.61 g, 2.55 mmol) were dissolved in DMF (5 mL), K2CO3 (0.587 g, 4.24 mmol) was added, and the mixture was reacted at room temperature for 12 h. The mixture was quenched by adding water (50 mL) and extracted by adding ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 20%) to obtain intermediate 2-8 (0.64 g, yield 83.7%, oily product). MS (ESI) m / z = 366.2 [M + H] + .

[0101] 2.8 Synthesis of intermediate 2-9 [ka]

[0102] Intermediate 2-8 (0.5 g, 1.37 mmol) was dissolved in DMF (5 mL), t-butoxybis(dimethylamino)methane (953 mg, 5.47 mmol) was added, and the reaction was carried out under microwave at 150° C. for 4 h. The temperature was lowered to room temperature, water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 2-9 (0.6 g, crude) was obtained and used directly in the next step.

[0103] 2.9 Synthesis of intermediate 2-10 [ka]

[0104] Intermediate 2-9 (0.45 g, 1.07 mmol) and 1-3 (0.34 g, 1.07 mmol) were dissolved in DMF (10 mL). The reaction was allowed to proceed at 120° C. for 12 h. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / dichloromethane=0%-6%) to obtain intermediate 2-10 (0.30 g, 42.1% yield, brown solid). MS(ESI)m / z=675.4[M+H] + .

[0105] 2.10 Synthesis of intermediate 2-11 [ka]

[0106] Intermediate 2-10 (0.289 g, 0.428 mmol) and LiOH (0.103 g, 4.28 mmol) were dissolved in methanol (7 mL) and water (3 mL). The mixture was reacted at 50°C for 24 h. The pH of the reaction solution was adjusted to acidic with dilute hydrochloric acid and concentrated under reduced pressure. The residue was subjected to column chromatography (C18, acetonitrile / water = 0% to 20%) to obtain intermediate 2-11 (0.16 g, yield 72.7%, pink solid). MS (ESI) m / z = 533.1 [M + H] + .

[0107] 2.11 Synthesis of compound 2 [ka]

[0108] Intermediate 2-11 (0.30 g, 0.563 mmol), ammonium chloride (0.302 g, 5.63 mmol), HOBt (0.0989 g, 0.732 mmol) and DIEA (0.291 g, 2.25 mmol) were dissolved in dichloromethane (10 mL) and EDCI (0.14 g, 0.732 mmol) was added. The reaction was carried out at 50° C. for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to column chromatography (C18, acetonitrile / water (0.1% FA) = 38%) to obtain compound 2 (0.10 g, yield 34.2%, yellow solid). MS (ESI) m / z = 532.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.52(s,1H),8.11(s,1H),7.52(s,1H),7.36 - 7.14(m,3H),6.94 - 6.66(m,2H),4.68(t,J=4.8Hz,1H),4.32(t,J=4.8Hz,2H),3.42 - 3.37(m,2H),3.17 - 3.09(m,4H),2.99 - 2.92(m,2H),2.73 - 2.66(m,2H),2.46 - 2.41(m,4H),2.22(s,3H).

[0109] Example 3: Synthesis of Compound 3 [ka]

[0110] 3.1 Synthesis of intermediate 3-1 [ka]

[0111] Intermediate 1-6 (20 g, 83.2 mmol) was dissolved in acetic acid (100 mL), methylhydrazine (6.2 g, 53.8 mmol) was added at 0°C, and the mixture was reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (500 mL) and adjusted to pH = 7-8 with saturated NaHCO3. Dichloromethane (100 mL x 3) was added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane 100%) to obtain intermediate 3-1 (13.0 g, yield 70.3%, gray-white solid). MS (ESI) m / z = 223.2 [M + H] + .

[0112] 3.2 Synthesis of intermediate 3-2 [ka]

[0113] Intermediate 3-1 (1 g, 4.50 mmol) was dissolved in DMF (5 mL), t-butoxybis(dimethylamino)methane (1.83 g, 9.00 mmol) was added, and the mixture was reacted at 80° C. for 4 h. The reaction solution was concentrated under reduced pressure to give intermediate 3-2 (1.2 g, crude), which was used directly in the next step.

[0114] 3.3 Synthesis of intermediate 3-3 [ka]

[0115] Intermediate 3-2 (5 g, 18.0 mmol) was dissolved in DMF (50 mL), and 2-methyl-2-thiopseudourea sulfate (3.01 g, 10.8 mmol) and potassium acetate (1.77 g, 18.0 mmol) were added, and the mixture was reacted at 95° C. for 4 h. The mixture was quenched by adding water (200 mL), and a solid precipitated. The solid was collected by filtration. The solid was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) ​​to obtain intermediate 3-3 (2.76 g, 50.5% yield, yellow solid). MS (ESI) m / z=305.1 [M+H] + .

[0116] 3.4 Synthesis of intermediate 3-4 [ka]

[0117] Intermediate 3-3 (1.32 g, 4.34 mmol) was dissolved in chlorobenzene (50 mL) and DDQ (1.97 g, 8.67 mmol) was added. The reaction was carried out at 135°C for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) to obtain intermediate 3-4 (0.76 g, yield 57.8%, brown solid). MS (ESI) m / z = 302.9 [M + H] + .

[0118] 3.5 Synthesis of intermediate 3-5 [ka]

[0119] Intermediate 3-4 (0.86 g, 2.84 mmol) was dissolved in DMF (30 mL), potassium peroxymonosulfonate (5.25 g, 8.53 mmol) was added, and the reaction was carried out at room temperature for 16 h. The reaction was quenched by adding ice water, and a solid precipitated and filtered. The filter cake was dissolved in tetrahydrofuran (30 mL), and the solution was concentrated under reduced pressure. This operation was repeated three times. Intermediate 3-5 (0.80 g, crude, white solid) was obtained and used directly in the next step. MS (ESI) m / z = 335.1 [M + H] +.

[0120] 3.6 Synthesis of intermediate 3-6 [ka]

[0121] Intermediate 1-2 (0.284 g, 1.03 mmol) was dissolved in tetrahydrofuran (10 mL), LiHMDS (1 M, 1.55 mL) was added, and the mixture was reacted at −78° C. for 0.5 h with stirring. Intermediate 3-5 (0.23 g, 0.688 mmol) was added and reacted at room temperature for 12 h. The mixture was quenched by adding water (100 mL), extracted by adding dichloromethane (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to column chromatography (C18 150 * 40 mm * 10 μm; mobile phase: [H2O (NH3H2O ​​+ NH4HCO3) -ACN], B%: 50% ~ 90%, 10 min) to obtain intermediate 3-6 (0.11 g, yield 20.5%, yellow solid). MS (ESI) m / z = 530.3 [M + H] + .

[0122] 3.7 Synthesis of compound 3 [ka]

[0123] Compound 3-6 (40 mg, 75.5 umol) was dissolved in DMF (10 mL) and ammonia in methanol (75 mL) was added. The reaction was allowed to proceed for 48 hours in a sealed container at 135°C. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (C18 75*30 mm*3 μm, mobile phase: [H2O(NH4HCO3)-ACN], B%: 30%-90%, 28 min). Compound 3 (3.9 mg, yield 10.4%, white solid) was obtained. MS (ESI) m / z = 501.1 [M+H] + . 1H NMR(400MHz,CD3OD)δ 9.03 - 9.09(m,1 H). 7.98 - 8.08(m,2 H)7.49 - 7.54(m,1 H)7.19 - 7.27(m,1 H)6.76 - 6.82(m,1 H)4.71 - 4.75(m,3 H)4.53 - 4.57(m,4 H)4.30(br,1 H)3.29(br,4 H)2.59 - 2.70(m,4 H)2.31 - 2.40(m,3 H).

[0124] Example 4: Synthesis of Compound 4 [ka]

[0125] 4.1 Synthesis of intermediate 4-1 [ka]

[0126] Intermediate 1-6 (10.0 g, 41.6 mmol) was dissolved in acetic acid, 2-cyanoethylhydrazine (4.25 g, 50.0 mmol) was added, and the mixture was reacted at 25°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain intermediate 4-1 (5.4 g, yield 49.6%, white solid). MS (ESI) m / z = 261.9 [M + H] + .

[0127] 4.2 Synthesis of intermediate 4-2 [ka]

[0128] Intermediate 4-1 (0.50 g, 1.91 mmol) was dissolved in DMF (10 mL), and t-butoxybis(dimethylamino)methane (0.95 g, 3.83 mmol) was added and reacted at 110° C. for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methyl tert-butyl ether (50 mL) and stirred at 25° C. for 0.5 h, and a solid precipitated. The mixture was filtered with suction, and the filter cake was dried to obtain intermediate 4-2 (1.2 g, crude product). It was used directly in the next step.

[0129] 4.3 Synthesis of intermediate 4-3 [ka]

[0130] Intermediate 4-2 (1.2 g, 1.91 mmol) was dissolved in DMF (10 mL), and intermediate 1-3 (0.90 g, 2.84 mmol) was added, and the mixture was reacted at 110°C for 6 h. The mixture was quenched by adding water (200 mL), extracted by adding ethyl acetate (200 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol:dichloromethane = 0-10%). Intermediate 4-3 (0.47 g, yield 43.5%, brown solid) was obtained. MS (ESI) m / z = 571.3 [M + H] + .

[0131] 4.4 Synthesis of compound 4 [ka]

[0132] Intermediate 4-3 (0.10 g, 0.175 mmol) was dissolved in methanol (5 mL), and ammonia water (2 mL) was added and reacted under sealed conditions at 85 ° C for 48 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and washed with water (50 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (C18 75 * 30 mm * 3 μm, mobile phase: [H2O (0.05% NH3H2O ​​10 mM NH4HCO3)-ACN], B%: 29% ~ 59%, 11 min). Compound 4 (0.02 g, yield 20.6%, white solid) was obtained. MS (ESI) m / z = 542.3 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.03 - 9.06(m,1 H). 9.00 - 9.07(m,1 H). 8.33 - 8.38(m,1 H). 7.43 - 7.50(m,1 H). 7.33 - 7.38(m,1 H). 7.18 - 7.28(m,2 H). 6.75 - 6.83(m,1 H). 4.72 - 4.81(m,2 H). 3.11 - 3.18(m,4 H). 2.94 - 3.02(m,2 H). 2.91(t,J=6.40Hz,2 H)2.76 - 2.83(m,2 H). 2.29(br,2 H). 2.25 - 2.39(m,1 H). 2.17 - 2.24(m,3 H).

[0133] Example 5: Synthesis of Compound 5 [ka]

[0134] 5.1 Synthesis of intermediate 5-2 [ka]

[0135] Intermediate 5-1 (30.0 g, 141 mmol) was dissolved in acetonitrile (500 mL), and CAN (38.8 g, 70.7 mmol) and iodine (21.5 g, 84.8 mmol) were added, and the mixture was reacted at 80 ° C for 16 h. The reaction was quenched by adding saturated sodium thiosulfate solution (500 mL), and ethyl acetate (300 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0 ~ 30%) to obtain intermediate 5-2 (37.4 g, yield 78.3%, yellow solid). MS (ESI) m / z = 339.0 [M + H] + .

[0136] 5.2 Synthesis of intermediate 5-3 [ka]

[0137] Intermediate 5-2 (40.0 g, 118 mmol) was dissolved in acetonitrile (400 mL), K2CO3 (24.5 g, 177 mmol) and (2-bromoethoxy)-t-butyldimethylsilane (34.0 g, 142 mmol) were added, and the mixture was reacted at 80°C for 16 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0 to 20%). Intermediate 5-3 (54.4 g, yield 92.9%, white solid) was obtained. MS (ESI) m / z = 497.1 [M + H] + .

[0138] 5.3 Synthesis of intermediate 5-4 [ka]

[0139] Intermediate 5-3 (50.0 g, 101 mmol), tert-butyl 3-aminopropanoate hydrochloride (27.5 g, 151 mmol), cesium carbonate (131 g, 403 mmol) and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (2.91 g, 5.04 mmol) were dissolved in dioxane (500 mL), and Pd2(dba)3 (4.61 g, 5.04 mmol) was added under nitrogen gas protection, and the reaction was carried out for 16 h under nitrogen gas protection at 110 ° C. The reaction was quenched by adding saturated ammonium chloride solution (500 mL), and ethyl acetate (500 mL × 3) was added for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:petroleum ether = 0 to 20%) to obtain intermediate 5-4 (38.9 g, yield 75.0%, oil). MS (ESI) m / z = 514.3 [M + H] + .

[0140] 5.4 Synthesis of intermediate 5-5 [ka]

[0141] Intermediate 5-4 (24.0 g, 46.7 mmol) was dissolved in tetrahydrofuran (300 mL), potassium tert-butoxide (10.5 g, 93.4 mmol) was added, and the mixture was stirred at -20 ° C for 2 h. Saturated ammonium chloride solution (300 mL) was added to quench the reaction, and ethyl acetate (300 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0 ~ 30%) to obtain intermediate 5-5 (8.9 g, yield 40.6%, yellow solid). MS (ESI) m / z = 468.2 [M + H] + .

[0142] 5.5 Synthesis of intermediate 5-6 [ka]

[0143] Intermediate 5-5 (5.00 g, 10.7 mmol) was dissolved in acetic acid (50 mL), and formaldehyde solution (2.60 g, 32.1 mmol) and NaBH3CN (1.34 g, 21.4 mmol) were added at 0°C. The reaction was allowed to proceed at room temperature for 2 h. The reaction was quenched by adding saturated Na2CO3 solution (10 mL), and ethyl acetate (10 mL x 2) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 30%) to obtain intermediate 5-6 (3.50 g, yield 68.0%, yellow solid). MS (ESI) m / z = 482.3 [M + H] + .

[0144] 5.6 Synthesis of intermediates 5-7 [ka]

[0145] Intermediate 5-6 (1.00 g, 2.08 mmol) was dissolved in ethanol (5 mL) and hydrochloric acid (3 M, 15.0 mL). The reaction was allowed to proceed at 60°C for 16 h. Saturated sodium carbonate solution (50 mL) was added to quench the reaction, and ethyl acetate (50 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain intermediate 5-7 (0.35 g, yield 63.1%, white solid). MS (ESI) m / z = 268.1 [M + H] + .

[0146] 5.7 Synthesis of intermediate 5-8 [ka]

[0147] Intermediate 5-7 (0.30 g, 1.12 mmol) was dissolved in DMF (3 mL) and t-butoxybis(dimethylamino)methane (0.456 g, 2.24 mmol) was added. The reaction was carried out at 60° C. for 16 h. The reaction solution was concentrated under reduced pressure to give intermediate 5-8 (0.25 g, crude product). It was used directly in the next step.

[0148] 5.8 Synthesis of intermediate 5-9 [ka]

[0149] Intermediate 5-8 (0.10g, 0.31mmol), intermediate 1-3 (0.13g, 0.31mmol) and sodium ethoxide (0.025g, 0.37mmol) were dissolved in ethanol (10mL). The reaction was carried out at 120℃ under microwave for 1.5h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (C18 150*40mm*10μm, mobile phase: [H2O(10mM NH4HCO3)-ACN], B%: 20%~50%, 8min) to obtain intermediate 5-9 (0.0034g, yield 1.88%). MS(ESI)m / z=577.2[M+H] + .

[0150] 5.9 Synthesis of Compound 5 [ka]

[0151] Intermediate 5-9 (5.00 mg, 8.67 μmol) was dissolved in tetrahydrofuran (1 mL), NH4Cl (1.45 mg, 27.1 μmol) was added, and LiHMDS (1M, 54.2 μL) was added at 0°C. The reaction was allowed to proceed at room temperature for 16 h. Water (2 mL) was added to quench the reaction, ethyl acetate (5 mL * 3) was added to extract, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to column chromatography (C18 150 * 40 mm * 10 μm, mobile phase: [H2O (10 mM NH4HCO3)-ACN], B%: 20% ~ 50%, 8 min) to obtain compound 5 (1.61 mg, yield 32.4%). MS (ESI) m / z = 548.1 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.88(s,1H),8.24(s,1H),7.42(br s,1H),7.14 - 7.32(m,3H),6.75 - 5.77(m,1H),4.64(br,1H),4.52(br,2H),4.09(s,2H),3.64(br,2H),3.31(br,3H),3.10 - 3.17(m,4H),2.94(s,3H),2.43(br,4H).

[0152] Example 6: Synthesis of Compound 6 [ka]

[0153] 6.1 Synthesis of intermediate 6-2 [ka]

[0154] Intermediate 6-1 (8.0 g, 40.1 mmol) was dissolved in toluene (100 mL), morpholine (5.8 g, 66.4 mmol), p-toluenesulfonic acid (0.034 g, 0.2 mmol) and benzaldehyde (4.0 mL, 40.0 mmol) were added, and the mixture was reacted at 110°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 25%) to obtain intermediate 6-2 (2.9 g, yield 25%, yellow solid). MS (ESI) m / z = 288.2 [M + H] + .

[0155] 6.2 Synthesis of intermediate 6-3 [ka]

[0156] Intermediate 6-2 (2.87 g, 10 mmol) was dissolved in tetrahydrofuran (50 mL), and LiHMDS (1 M, 12 mL) was added dropwise at -50.0°C, followed by stirring for 30 min. Diethyl oxalate (1.75 g, 12 mmol) was added and reacted at room temperature for 16 h. Saturated ammonium chloride (50 mL) was added to quench the reaction, and ethyl acetate (50 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 20%) to obtain intermediate 6-3 (2.8 g, yield 73.7%, oily product). MS (ESI) m / z = 388.2 [M + H] + .

[0157] 6.3 Synthesis of intermediate 6-4 [ka]

[0158] Intermediate 6-3 (2.85 g, 7.36 mmol) was dissolved in acetic acid (10 mL), hydroxyethylhydrazine (0.57 g, 7.57 mmol) was added, and the reaction was carried out at room temperature for 15 h. Water (50 mL) was added to quench the reaction, saturated Na2CO3 (60 mL) was added, and dichloromethane (50 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 50%) to obtain intermediate 6-4 (1.59 g, yield 50.7%, yellow solid). MS (ESI) m / z = 428.2 [M + H] + .

[0159] 6.4 Synthesis of intermediate 6-5 [ka]

[0160] Intermediate 6-4 (1.58 g, 3.70 mmol) was dissolved in tetrahydrofuran (16 mL) and water (16 mL), and NaIO4 (1.58 g, 7.40 mmol) and K2OsO4.2H2O (0.11 g, 0.37 mmol) were added. The reaction was allowed to proceed at room temperature for 5 h. The reaction was quenched by adding water (50 mL), and ethyl acetate (50 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 30%) to obtain intermediate 6-5 (0.313 g, 24% yield, yellow solid). MS (ESI) m / z = 354.2 [M + H] + .

[0161] 6.5 Synthesis of intermediate 6-6 [ka]

[0162] Intermediate 6-5 (0.313 g, 0.89 mmol) was dissolved in DMF-DMA (10 mL) and reacted at 110° C. for 12 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in methyl tert-butyl ether and stirred for 3 h. Filtration and collection of the filter cake gave intermediate 6-6 (0.36 g, crude), which was used directly in the next step.

[0163] 6.6 Synthesis of intermediates 6-7 [ka]

[0164] Intermediate 6-6 (0.16 g, 0.40 mmol) and intermediate 1-3 (0.14 g, 0.44 mmol) were dissolved in DMF (5 mL) and reacted at 110°C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 100%) to obtain intermediate 6-7 (0.14 g, yield 53.3%, yellow solid). MS (ESI) m / z = 663.2 [M + H] + .

[0165] 6.7 Synthesis of intermediates 6-8 [ka]

[0166] Intermediate 6-7 (0.14 g, 0.21 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to give intermediate 6-8 (0.12 g, crude product). The product was used directly in the next step.

[0167] 6.8 Synthesis of Compound 6 [ka]

[0168] Intermediate 6-8 (0.12 g, 0.21 mmol) was dissolved in NMP (6 mL) and NH3 / MeOH (5 mL) was added. The reaction was allowed to proceed for 48 h in a sealed container at 80.0°C. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 30*150 mm*7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 10%-80%, 40 min). Compound 6 (0.045 g, 40% yield, yellow solid) was obtained. MS (ESI) m / z = 532.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.66(s,1H),9.35(d,J=1.7Hz,2H),7.97(s,1H),7.68(s,1H),7.27 - 7.30(m,2H),6.87 - 6.90(m,1H),4.88 - 4.90(m,2H),4.65 - 4.67(m,1H),3.77(d,J=5.5Hz,2H),3.17 - 3.20(m,4H),2.45 - 2.47(m,4H),2.23(s,3H).

[0169] Example 7: Synthesis of Compound 7 [ka]

[0170] 7.1 Synthesis of intermediate 7-2 [ka]

[0171] K2CO3 (206g, 1.50mol) was dissolved in DMF (450mL), and intermediate 7-1 (55.9g, 0.50mol) was added and reacted at room temperature with stirring for 10min. CS2 (56.9g, 0.75mol) was added and reacted at room temperature with stirring for 10min. Ethyl bromoacetate (83.3g, 0.50mol) in DMF (500mL) was added dropwise at 0℃ and reacted at 0℃ for 1h. Finally, iodomethane (77.8g, 0.55mol) in DMF (200mL) was added dropwise at 0℃ and reacted at 0℃ for 0.5h. The reaction solution was filtered, the filtrate was put into water (5L), and ethyl acetate (1L×5) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 7-2 (720g, crude, oily) was obtained. Used directly in the next step.

[0172] 7.2 Synthesis of intermediate 7-3 [ka]

[0173] Intermediate 7-2 (53.5 g, 197 mmol) was dissolved in ethanol (650 mL) and water (650 mL), potassium monopersulfate (401 g, 2.39 mol) was added, and the mixture was reacted at 60°C for 16 h. Water (1.1 L) was added, the mixture was stirred at 50-60°C for 0.5 h, and the mixture was cooled to 15°C. A solid was precipitated, filtered, and the filter cake was dried. The filter cake was subjected to silica gel column chromatography (ethyl acetate:petroleum ether = 0-40%) to obtain intermediate 7-3 (6.5 g, yield 11%, orange solid). MS (ESI) m / z = 303.0 [M + H] + .

[0174] 7.3 Synthesis of intermediate 7-4 [ka]

[0175] Intermediate 7-3 (9.00 g, 29.8 mmol) was dissolved in tetrahydrofuran (90 mL) and ethyl magnesium bromide (1.00 M, 32.7 mL) was added at 0°C. The reaction was allowed to proceed at 35°C for 16 h. Saturated ammonium chloride (100 mL) was added to quench the reaction, and ethyl acetate (100 mL x 3) was added to extract the reaction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 10%) to obtain intermediate 7-4 (1.47 g, yield 19.5%, white solid). MS (ESI) m / z = 253.1 [M + H] + .

[0176] 7.4 Synthesis of intermediate 7-5 [ka]

[0177] Intermediate 7-4 (0.50 g, 1.98 mmol) was dissolved in DMF-DMA (4.49 g, 37.6 mmol, 5.00 mL) and reacted at 100° C. for 16 h. The reaction solution was concentrated under reduced pressure to give intermediate 7-5 (0.75 g, crude product), which was used directly in the next step.

[0178] 7.5 Synthesis of intermediate 7-6 [ka]

[0179] Intermediate 7-5 (0.37 g, 1.20 mmol) and intermediate 1-3 (0.34 g, 1.08 mmol) were dissolved in DMF (5 mL) and reacted at 110 °C for 4 h. The reaction was quenched by adding water (80 mL) and extracted by adding ethyl acetate (80 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol:dichloromethane = 0% to 7%) to obtain intermediate 7-6 (0.23 g, yield 34.8%, brown solid). MS (ESI) m / z = 562.2 [M + H] + .

[0180] 7.6 Compound 7 Synthesis [ka]

[0181] Intermediate 7-6 (100 mg, 178 μmol) was dissolved in NMP (2 mL) and NH3 / MeOH (4.0 mL) was added. The reaction was carried out at 15 Psi and 100.0°C for 32 h. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 75*30 mm*3 μm, mobile phase: [H2O(NH3H2O+NH4HCO3)-ACN], B%: 40.0%~58.0%, 14.0 min). Compound 7 (11.6 mg, yield 95.0%, white solid) was obtained. MS (ESI) m / z = 533.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.64(s,1H),8.32(s,1H),7.39(br,2H),7.26 - 7.13(m,2H),6.83 - 6.74(m,1H),3.20 - 3.03(m,8H),2.70(br,2H),2.48 - 2.38(m,5H),2.21(s,3H),1.04(t,J=7.3Hz,3H).

[0182] Example 8: Synthesis of Compound 8 [ka]

[0183] 8.1 Synthesis of intermediate 8-1 [ka]

[0184] Compound 1-9 (550 mg, 0.766 mmol) was dissolved in ethanol (5 mL) and LiOH.H2O (2 M, 1.53 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 5 h. Water (10 mL) was added to quench the reaction, and ethyl acetate (20 mL) was added for extraction. The aqueous phase was collected and adjusted to pH=3-4, and a solid precipitated. Filtration and drying of the filter cake gave intermediate 8-1 (290 mg, crude). It was used directly in the next step. MS(ESI)m / z=534.3[M+H] + .

[0185] 8.2 Synthesis of compound 8 [ka]

[0186] Intermediate 8-1 (53.1 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), and trifluoromethanesulfonamide (89.4 mg, 0.60 mmol), EDCI (76.8 mg, 0.40 mmol) and DMAP (48.8 mg, 0.40 mmol) were added. The mixture was stirred at room temperature for 16 h. Dichloromethane (10 mL) was added for dilution, water (20.0 mL * 3) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to column chromatography (C18 150 * 30 mm * 5 μm, mobile phase: [H2O(NH4HCO3)-ACN], B%: 10% to 60%, 12 min) to obtain compound 8 (21.7 mg, yield 32.6%, white solid). MS(ESI)m / z=665.3[M+H] + . 1 H NMR(400MHz DMSO-d6)δ 8.82(s,1H),8.29(s,1H),7.23 - 7.21(m,2H),6.80 - 6.78(m,1H),4.60(m,3H),3.57(s,2H),3.19(s,4H),2.98 - 2.94(m,2H),2.78 - 2.74(m,2H),2.67 - 2.65(m,4H),2.36 - 2.33(m,3H).

[0187] Example 9: Synthesis of Compound 9 [ka]

[0188] Compound 9 (13 mg, 38.5% yield, white solid) was prepared from intermediate 8-1 and cyclopropanesulfonamide using a method similar to that described in Example 8. MS (ESI) m / z=637.2 [M+H] + . 1 H NMR(400MHz DMSO-d6)δ 10.99(br,1H),8.99(s,1H),8.36(s,1H),7.28 - 7.25(m,2H),6.85 - 6.82(m,1H),4.66(m,3H),3.68 - 3.66(m,2H),3.33 - 3.29(m,4H),3.07 - 3.03(m,1H),3.00 - 2.92(m,6H),2.84 - 2.80(m,2H),2.55 - 2.50(m,3H),1.10 - 1.00(m,4H).

[0189] Example 10: Synthesis of Compound 10 [ka]

[0190] Na (40.9 mg, 1.78 mmol) was dissolved in methanol (1.8 mL), HONH2.HCl (37.1 mg, 0.534 mmol) was added, and the mixture was stirred at room temperature for 1 h under nitrogen gas protection. Intermediate 1-9 (100 mg, 0.178 mmol) was added, and the mixture was reacted at 65 ° C for 0.5 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (C18 150 * 40 mm * 10 μm, mobile phase: [H2O (TFA) -ACN], B%: 10.0% ~ 50.0%, 10 min) to obtain compound 10 (12.0 mg, yield 11.3%, trifluoroacetate, white solid). MS (ESI) m / z = 549.1 [M + H] + . 1H NMR(400MHz DMSO-d6)δ 10.89(s,1H),9.86 - 9.65(m,1H),9.00(s,1H),8.34(s,1H),7.35 - 7.26(m,2H),6.85 - 6.90(m,1H),4.62(br,2H),3.84(br,2H),3.64(br,3H),3.20 - 3.10(m,2H),2.94(br,4H),2.86(s,3H),2.83 - 2.77(m,2H),2.55(t,J=5.5Hz,2H).

[0191] Example 11: Synthesis of Compound 11 [ka]

[0192] 11.1 Synthesis of intermediate 11-2 [ka]

[0193] Intermediate 11-1 (10.0 g, 61.3 mmol) was dissolved in acetonitrile (20 mL), and triethylamine (7.43 g, 73.4 mmol) and 2-bromoethanol (9.18 g, 73.4 mmol) were added under ice bath conditions. The reaction was carried out at 80° C. for 8 h. The mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 11-2 (4.5 g, crude) was obtained. It was used directly in the next step. MS (ESI) m / z=207.9 [M+H] + .

[0194] 11.2 Synthesis of intermediate 11-3 [ka]

[0195] Intermediate 11-2 (2.00 g, 9.65 mmol) was dissolved in dichloromethane (40 mL) and N2H4 .H2O (1.02 g, 19.3 mmol, 987 μL) was added. The reaction was allowed to proceed at room temperature for 12 h. HCl / dioxane (2 mL, 4 M) was added and stirred at room temperature, resulting in the precipitation of a solid. Filtration and drying of the filter cake gave intermediate 11-3 (0.69 g, crude). Used directly in the next step.

[0196] 11.3 Synthesis of intermediate 11-4 [ka]

[0197] Intermediate 11-3 (2.32 g, 8.43 mmol) was dissolved in dichloromethane (40 mL), and DMAP (79.2 mg, 0.648 mmol), imidazole (1.10 g, 16.2 mmol) and t-butylchlorodiphenylsilane (1.78 g, 6.48 mmol) were added. The reaction was carried out at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain intermediate 11-4 (0.23 g, yield 11.3%, oily product). MS (ESI) m / z = 316.0 [M + H] + .

[0198] 11.4 Synthesis of intermediate 11-5 [ka]

[0199] Intermediate 3-2 (800 mg, 2.88 mmol) was dissolved in DMF (20 mL), and intermediate 1-3 (915 mg, 2.88 mmol) was added, and the mixture was reacted at 110°C for 16 h. The mixture was quenched by adding water (50 mL), extracted by adding ethyl acetate (50 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol:dichloromethane = 0-10%). Intermediate 11-5 (738 mg, yield 48.1%, pale yellow solid) was obtained. MS (ESI) m / z = 532.2 [M + H] + .

[0200] 11.5 Synthesis of intermediate 11-6 [ka]

[0201] Compound 11-5 (660 mg, 1.24 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and an aqueous solution (5 mL) of LiOH.H2O (140 mg, 3.35 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 16 h. Water (10 mL) was added to quench the reaction, and ethyl acetate (20 mL) was added for extraction. The aqueous phase was collected and adjusted to pH=3-4 with dilute hydrochloric acid, resulting in the precipitation of a solid. Filtration and drying of the filter cake gave intermediate 11-6 (531 mg, crude). It was used directly in the next step. MS(ESI)m / z=504.1[M+H] + .

[0202] 11.6 Synthesis of intermediate 11-7 [ka]

[0203] Intermediate 11-6 (125 mg, 397 μmol) was dissolved in DMF (10 mL), CDI (32.2 mg, 199 μmol) was added, and the mixture was stirred at 50° C. for 2 h. Intermediate 11-4 (50 mg, 99.3 μmol) was added, and the mixture was reacted at 50° C. for 46 h. The reaction solution was poured into water (100 mL), and a solid precipitated. The mixture was filtered, and the filter cake was collected and subjected to silica gel column chromatography (ethyl acetate:petroleum ether=30%). Intermediate 11-7 (2.77 g, yield 55.5%, yellow solid) was obtained. MS (ESI) m / z=801.3 [M+H] + .

[0204] 11.7 Synthesis of Compound 11 [ka]

[0205] Intermediate 11-7 (100 mg, 125 μmol) was dissolved in dichloromethane (10 mL) and . 3HF (20.1 mg, 125 μmol) was added. The reaction was allowed to proceed at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (C18 30*150 mm*7 μm, mobile phase: [H2O(NH4HCO3)-MeOH], B%: 30% to 80%, 40 min) to obtain compound 11 (33.0 mg, yield 46.0%, white solid). MS (ESI) m / z = 563.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.90 - 8.98(m,1H),8.34 - 8.37(m,1H),7.25 - 7.32(m,1H),7.14 - 7.23(m,1H),6.76(dd,J=9.2,2.8Hz,1H),4.16(s,3H),3.86(s,2H),3.57(s,3H),3.08 - 3.22(m,4H),2.90 - 2.99(m,2H),2.76 - 2.86(m,3H),2.42 - 2.47(m,4H),2.21(s,3H).

[0206] Example 12: Synthesis of Compound 12 [ka]

[0207] Using a method similar to that described in Example 11, intermediate 11-6 was reacted with semicarbazide to prepare compound 12. MS (ESI) m / z=561.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 8.30(s,1H),7.67(s,1H),7.24(d,J=8.8Hz,1H),6.78 - 6.81(m,1H),4.28(s,3H),3.37 - 3.35(m,4H),3.13 - 3.05(m,6H),2.88(t,J=7.6Hz,2H),2.68(s,3H).

[0208] Example 13: Synthesis of Compound 13 [ka]

[0209] Intermediate 1-9 (20 mg, 0.036 mmol) was dissolved in methanol (1 mL) and N2H4-H2O (54.6 mg, 1.07 mmol, 53 μL) was added. The reaction was carried out at 70.0 °C for 36 h. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionation liquid (C18 75 * 30 mm * 3 μm; mobile phase: [H2O (NH3H2O ​​+ NH4HCO3) -ACN], B%: 21% ~ 41%, 10 min). Compound 13 (6.0 mg, yield 30.5%, white solid) was obtained. MS (ESI) m / z = 548.3 [M + H] + . 1 H NMR(400MHz,CD3OD)δ 8.28 - 8.32(m,1 H),7.46 - 7.54(m,1 H),7.20 - 7.24(m,1 H),6.80 - 6.84(m,1 H),4.77(t,J=5.6Hz,3 H),4.56 - 4.62(m,2 H),4.51 - 4.63(m,3 H),3.75 - 3.85(m,2 H),3.21 - 3.27(m,4 H), 2.98 - 3.11(m,2 H),2.85 - 2.92(m,2 H),2.59 - 2.66(m,4 H),2.34 - 2.39(m,3H).

[0210] Example 14: Synthesis of Compound 17 [ka] 14.1 Synthesis of intermediate 17-1 [ka]

[0211] Intermediate 1-9 (200 mg, 0.36 mmol) was dissolved in dichloromethane (20 mL) and DAST (293 mg, 1.82 mmol) was added dropwise at -78 °C. The reaction was allowed to proceed at room temperature for 12 h. The reaction solution was cooled to room temperature, water (70 mL) was added to quench the reaction, and dichloromethane (50 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative elution (C18 30 * 150 mm * 5 μm, mobile phase: [water (NH4HCO3) - acetonitrile], B%: 45% ~ 82%, 12 min) to obtain intermediate 17-1 (170 mg, yield 84.8%, brown solid). MS (ESI) m / z = 564.2 [M + H] + .

[0212] 14.2 Synthesis of compound 17 [ka]

[0213] Na (40.9 mg, 1.78 mmol) was dissolved in methanol (1.8 mL), HONH2.HCl (37.1 mg, 0.534 mmol) was added, and the mixture was stirred at room temperature for 1 h under nitrogen gas protection. Intermediate 17-1 (100 mg, 0.178 mmol) was added, and the mixture was reacted at 65 ° C for 0.5 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (C18 150 * 40 mm * 10 μm, mobile phase: [H2O (TFA) -ACN], B%: 10.0% ~ 50.0%, 10 min) to obtain compound 17 (11.1 mg, yield 11.3%, trifluoroacetate, white solid). MS (ESI) m / z = 551.2 [M + H] + . 1H NMR(400MHz DMSO-d6)δ 10.90(s,1 H),9.52 - 9.82(m,1 H),9.10(s,1 H),8.36(s,1 H),7.23 - 7.36(m,2 H),6.88(dd,J=9.01,2.75Hz,1 H),4.78 - 4.94(m,2 H),4.65(t,J=4.63Hz,1 H),4.53(t,J=4.44Hz,1 H),3.84(d,J=13.01Hz,2 H),3.07 - 3.26(m,3 H),2.93 - 3.01(m,4 H),2.78 - 2.92(m,6 H).

[0214] Example 15: Synthesis of Compound 18 [ka]

[0215] Compound 1 (50 mg, 94.2 μmol) was dissolved in dichloromethane (5 mL), and DAST (77.5 mg, 481 μmol) was added dropwise at -78°C. The reaction was allowed to proceed at room temperature for 16 h. The reaction solution was cooled to room temperature, and water (20 mL) was added to quench the reaction, followed by addition of dichloromethane (10 mL x 3) for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative elution (C18 30*150 mm*5 μm, mobile phase: [water (NH4HCO3)-acetonitrile], B%: 27%~73%, 12 min) to obtain compound 18 (5 mg, 10% yield, brown solid). MS (ESI) m / z = 533.2 [M+H] + . 1 H NMR:(400MHz MeOD)δ 9.21(s,1H),8.07(d,J=8.0Hz,1H),7.57 - 7.49(m,2H),7.32 - 7.30(d,J=8.0Hz,1H),6.93 - 6.91(m,1H),5.30 - 5.21(m,2H),4.80 - 4.66(m,2H),3.37(m,4H),2.96(m,4H),2.60(s,3H).

[0216] Example 16: Synthesis of Compound 19 [ka]

[0217] 16.1 Synthesis of intermediate 19-1 [ka]

[0218] Intermediate 1-10 (100 mg, 0.178 mmol) was dissolved in methanol (2 mL) and an aqueous solution of lithium hydroxide (1 M, 890 μL) was added. The reaction was carried out at room temperature for 6 h. At 0 ° C, the pH was adjusted to 5-7 using hydrochloric acid, the solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 150 * 30 mm * 5 μm, mobile phase: [water (TFA)-acetonitrile], B%: 10%-50%, 10 min) to obtain intermediate 19-1 (37 mg, yield 39%, brown solid). MS (ESI) m / z = 532.3 [M + H] + .

[0219] 16.2 Synthesis of Compound 19 [ka]

[0220] Intermediate 19-1 (37.0 mg, 69.6 μmol), HATU (29.1 mg, 76.6 μmol) and DIEA (36.0 mg, 278 μmol) were dissolved in DMF (2 mL) and hydroxylamine hydrochloride (9.68 mg, 139 μmol) was added. The reaction was allowed to proceed at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 150*30 mm*5 μm, mobile phase: [water (TFA)-acetonitrile], B%: 5% to 45%, 10 min), to obtain compound 19 (17 mg, yield 37%, brown solid, trifluoroacetate salt). MS (ESI) m / z = 547.2 [M + H] + . 1H NMR(DMSO-d6)δ 10.89(s,1H),9.86 - 9.65(m,1H),9.00(s,1H),8.34(s,1H),7.35 - 7.26(m,2H),6.86(dd,J=2.9,9.0Hz,1H),4.62(br t,J=5.3Hz,2H),3.84(br d,J=12.5Hz,2H),3.64(br t,J=5.4Hz,3H),3.20 - 3.10(m,2H),2.94(br t,J=7.8Hz,4H),2.86(s,3H),2.83 - 2.77(m,2H),2.55(t,J=5.5Hz,2H).

[0221] Example 17: Synthesis of Compound 20 [ka]

[0222] 17.1 Synthesis of intermediate 20-1 [ka]

[0223] Intermediate 1-1 (10 g, 39.1 mmol) was dissolved in acetic anhydride (9.97 g, 97.6 mmol) and reacted at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / dichloromethane = 0% to 10%) to obtain intermediate 20-1 (10.5 g, yield 89.3%, white solid). MS (ESI) m / z = 297.9 [M + H] + .

[0224] 17.2 Synthesis of intermediate 20-3 [ka]

[0225] Intermediate 20-2 (2.50 g, 19.2 mmol) was dissolved in dichloromethane (50 mL), and TBDPSCl (6.33 g, 23.0 mmol), DMAP (0.23 g, 1.92 mmol) and imidazole (1.96 g, 28.8 mmol) were added. The reaction was carried out at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / dichloromethane = 0% to 10%) to obtain intermediate 20-3 (6.5 g, yield 91%, yellow solid). MS (ESI) m / z = 369.1 [M + H] + .

[0226] 17.3 Synthesis of intermediate 20-4 [ka]

[0227] Intermediate 20-3 (3.56 g, 9.66 mmol) was dissolved in tetrahydrofuran (50 mL), LiHMDS (1 M, 18 mL) was added at 0 ° C, and the mixture was stirred at 0 ° C for 1 h. DavePhos (0.317 g, 0.805 mmol), Pd2(dba)3 (368.68 mg, 0.403 mmol) and intermediate 20-1 (2.4 g, 8.05 mmol) were added. The mixture was reacted at 80 ° C for 12 h. The reaction solution was cooled to room temperature, water (100 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% ~ 10%) to obtain intermediate 20-4 (2.2 g, yield 46.3%, yellow oil). MS(ESI)m / z=586.8[M+H] + .

[0228] 17.4 Synthesis of intermediate 20-5 [ka]

[0229] Intermediate 20-4 (2.4 g, 4.10 mmol) was dissolved in ethanol (20 mL) and hydrochloric acid (12 M, 112 mL) was added. The reaction was carried out at 80° C. for 12 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Intermediate 20-5 (1.8 g, crude) was obtained. It was used directly in the next step. MS (ESI) m / z=306.1 [M+H] + .

[0230] 17.5 Synthesis of intermediate 20-6 [ka]

[0231] Intermediate 20-5 (1.8 g, 5.90 mmol) was dissolved in hydrochloric acid (12 M, 107 mL) and water (107 mL), and cyanamide (3.72 g, 88.44 mmol) was added. The reaction was carried out at 65° C. for 48 h. The reaction solution was cooled to room temperature, and sodium hydroxide solution (1 M) was added to adjust the pH to 13, and ethyl acetate (100 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 20-6 (1.2 g, crude product) was obtained. It was used directly in the next step. MS (ESI) m / z=348.1 [M+H] + .

[0232] 17.6 Synthesis of intermediate 20-7 [ka]

[0233] Intermediate 20-6 (1.2 g, 3.45 mmol) and intermediate 3-2 (0.80 g, 2.88 mmol) were dissolved in DMF (10 mL) and reacted at 110 °C for 16 h. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / dichloromethane = 0% to 10%) to obtain intermediate 20-7 (0.21 g, yield 13.2%, yellow oil). MS (ESI) m / z = 562.2 [M + H]+ .

[0234] 17.7 Synthesis of Compound 20 [ka]

[0235] Intermediate 20-7 (150 mg, 267 μmol) was dissolved in ammonia in methanol (75 mL). The mixture was sealed at 85°C and reacted for 48 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (C18 75*30 mm*3 μm, mobile phase: [H2O(NH4HCO3)-ACN], B%: 27%-62%, 12 min). Compound 20 (21 mg, yield 15%, yellow solid) was obtained. MS (ESI) m / z = 533.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.86 - 8.94(m,1 H)8.31 - 8.39(m,1 H)7.45(br s,1 H)7.17 - 7.31(m,3 H)6.71 - 6.77(m,1 H)4.37 - 4.47(m,1 H)4.10 - 4.18(m,3 H)3.50 - 3.56(m,2 H)3.08 - 3.16(m,4 H)2.91 - 3.00(m,2 H)2.77 - 2.82(m,2 H)2.51 - 2.56(m,4 H)2.37 - 2.45(m,2 H).

[0236] Example 18: Synthesis of Compound 21 [ka]

[0237] 18.1 Synthesis of intermediate 21-1 [ka]

[0238] Intermediate 2-10 (100 mg, 148 μmol) and DDQ (168 mg, 741 μmol) were dissolved in dioxane (20 mL) and reacted at 100 °C for 12 h. The reaction was quenched by adding saturated NaHCO3 (20 mL) and extracted by adding ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (Waters Torus 2-PIC 150 * 19 mm * 5 μm, mobile phase: [heptane-ethanol (0.1% NH3H2O)], B%: 0% ~ 20%, 15 min). Intermediate 21-1 (28 mg, yield 28.5%, yellow solid) was obtained. MS (ESI) m / z = 673.3 [M + H] + .

[0239] 18.2 Synthesis of intermediate 21-2 [ka]

[0240] Intermediate 21-1 (40.0 mg, 59.4 μmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and an aqueous solution (2 mL) of lithium hydroxide hydrate (24.9 mg, 594 μmol) was added. The mixture was reacted at room temperature for 24 h and then at 50° C. for 24 h. The reaction solution was concentrated under reduced pressure, and the residue was triturated with petroleum ether, filtered, and the filter cake was collected and dried. Intermediate 21-2 (35 mg, crude) was obtained. MS (ESI) m / z=531.2 [M+H] + .

[0241] 18.3 Synthesis of compound 21 [ka]

[0242] Intermediate 21-2 (31.0 mg, 58.4 μmol), HATU (44.4 mg, 117 μmol) and DIEA (75.5 mg, 584 μmol) were dissolved in DMF (2 mL) and ammonium chloride (31.2 mg, 584 μmol) was added. The reaction was allowed to proceed at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 150*30 mm*5 μm, mobile phase: [water (NH4HCO3)-acetonitrile], B%: 27%-62%, 14 min), to obtain compound 21 (10 mg, yield 32%, white solid). MS (ESI) m / z = 530.2 [M+H] + . 1 H NMR(DMSO-d6)δ 9.18(s,1H),9.13(s,1H),8.16(d,J=8.4Hz,1H),8.06(s,1H),7.50 - 7.48(m,2H),7.26(d,J=8.8Hz,1H),7.17(d,J=2.8Hz,1H),6.87 - 6.84(m,2H),4.66(t,J=5.2Hz,1H),4.60 - 4.58(m,2H),3.42 - 3.41(m,2H),3.19 - 3.17(m,4H),2.50 - 2.48(m,4H),2.25(s,3H).

[0243] Example 19: Synthesis of Compound 22 [ka]

[0244] 19.1 Synthesis of intermediate 22-1 [ka]

[0245] Intermediate 2-7 (0.44 g, 2.12 mmol) was dissolved in DMF (5 mL), K2CO3 (0.67 g, 4.83 mmol) and iodomethane (0.68 g, 4.83 mmol) were added, and the reaction was carried out at room temperature for 4 h. The reaction was quenched by adding water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 22-1 (0.57 g, crude) was obtained. It was used directly in the next step. MS (ESI) m / z = 222.2 [M + H] + .

[0246] 19.2 Synthesis of intermediate 22-2 [ka]

[0247] Intermediate 22-1 (0.13 g, 0.588 mmol) was dissolved in DMF (5 mL), N,N-dimethylformamide dimethyl acetal (1.02 g, 8.58 mmol) was added, and the mixture was reacted at 145° C. for 6 h under microwave. The temperature was lowered to room temperature, water (50 mL) was added to quench, and ethyl acetate (50 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 22-2 (0.11 g, crude) was obtained and used directly in the next step.

[0248] 19.3 Synthesis of intermediate 22-3 [ka]

[0249] Intermediate 22-2 (0.11 g, 0.398 mmol) and intermediate 1-3 (0.19 g, 0.597 mmol) were dissolved in DMF (5 mL). The reaction was allowed to proceed at 110° C. for 16 h. The reaction was quenched by adding water (50 mL) and extracted by adding ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / dichloromethane=0%-8%) to obtain intermediate 22-3 (0.046 g, 21.6% yield, brown solid). MS(ESI)m / z=531.2[M+H] + .

[0250] 19.4 Synthesis of intermediate 22-4 [ka]

[0251] Intermediate 22-3 (60 mg, 113 μmol) and DDQ (128 mg, 565 μmol) were dissolved in dioxane (12 mL) and reacted at 100 °C for 2 h. Saturated NaHCO3 (20 mL) was added to quench, and ethyl acetate (20 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (C18 150 * 19 mm * 5 μm, mobile phase: [heptane-ethanol (0.1% NH3H2O)], B%: 0% ~ 20%, 15 min). Intermediate 22-4 (22 mg, yield 36.6%, yellow solid) was obtained. MS (ESI) m / z = 529.2 [M + H] + .

[0252] 19.5 Synthesis of intermediate 22-5 [ka]

[0253] Intermediate 22-4 (30.0 mg, 56.7 μmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and an aqueous solution (2 mL) of lithium hydroxide hydrate (23.8 mg, 567 μmol) was added. The reaction was allowed to proceed at room temperature for 24 h and then at 50° C. for 24 h. The reaction solution was concentrated under reduced pressure to give intermediate 22-5 (30 mg, crude). It was used directly in the next step. MS (ESI) m / z=501.2 [M+H] + .

[0254] 19.6 Synthesis of compound 22 [ka]

[0255] Intermediate 22-5 (28.0 mg, 55.9 μmol), HATU (31.9 mg, 83.9 μmol) and DIEA (72.3 mg, 559 μmol) were dissolved in DMF (2 mL) and ammonium chloride (29.9 mg, 559 μmol) was added. The reaction was allowed to proceed at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified with a preparative liquid (C18 150*30 mm*5 μm, mobile phase: [water (TFA)-acetonitrile], B%: 20%-55%, 25 min), to obtain compound 22 (5.00 mg, yield 14.6%, trifluoroacetate salt, yellow solid). MS (ESI) m / z = 500.2 [M + H] + . 1 H NMR(400MHz CD3OD)δ 9.32(s,1H),8.32(d,J=8.8Hz,1H),8.13(d,J=5.2Hz,1H),7.65(d,J=8.8Hz,1H),7.59(d,J=3.2Hz,1H),7.40(d,J=9.2Hz,1H),7.08 - 7.05(m,1H),4.24(s,3H),3.93(d,J=13.2Hz,2H),3.64(d,J=11.6Hz,2H),3.35 - 3.25(m,2H),3.24 - 3.17(m,2H),2.99(s,3H).

[0256] Example 20: Synthesis of Compound 23 [ka]

[0257] 20.1 Synthesis of intermediate 23-1 [ka]

[0258] Intermediate 1-1 (2.0 g, 7.81 mmol) was dissolved in tetrahydrofuran (50 mL), and KHMDS (1.0 M tetrahydrofuran solution, 15.6 mL, 15.6 mmol) was added at 0°C under nitrogen gas protection, and the mixture was reacted at 0°C for 0.5 h. Then, Boc2O (1.7 g, 7.81 mol) was added at 0°C under nitrogen gas protection, and the mixture was reacted at room temperature for 2 h. The mixture was quenched by adding water (20 mL), and extracted by adding ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 10% to 20%) to obtain intermediate 23-1 (2.2 g, yield 79%, yellow oil). MS (ESI) m / z = 356.0 [M + H] + .

[0259] 20.2 Synthesis of intermediate 23-2 [ka]

[0260] Intermediate 23-1 (2.2 g, 6.18 mmol), Cs2CO3 (9.07 g, 27.8 mmol), Pd2(dba)3 (286.2 mg, 0.6 mmol) and X-Phos (274.5 mg, 0.3 mmol) were dissolved in dioxane (100 mL) and 8-methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (1.23 g, 6.18 mmol) was added under nitrogen gas protection. The reaction was carried out at 100 °C overnight. The reaction was quenched by adding water (200 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether=30%-50%) to obtain intermediate 23-2 (1.87 g, 75% yield, white solid). MS(ESI)m / z=402.1[M+H] + .

[0261] 20.3 Synthesis of intermediate 23-3 [ka]

[0262] Intermediate 23-2 (1.87 g, 4.66 mmol) was dissolved in hydrochloric acid / dioxane (20 mL) and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / dichloromethane = 5% to 10%) to obtain intermediate 23-3 (0.73 g, yield 51.7%, yellow solid). MS (ESI) m / z = 301.8 [M + H] + .

[0263] 20.4 Synthesis of intermediate 23-4 [ka]

[0264] Intermediate 23-3 (500 mg, 1.66 mmol), cyanamide (175 mg, 4.17 mmol) and TMSCl (254 mg, 3.54 mmol) were dissolved in acetonitrile (15 mL). The reaction was carried out at 140°C under microwave conditions for 1.5 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / dichloromethane = 5% to 10%) to obtain intermediate 23-4 (530 mg, yield 94%, yellow solid). MS (ESI) m / z = 344.0 [M + H] + .

[0265] 20.5 Synthesis of intermediate 23-5 [ka]

[0266] Intermediate 1-8 (475 mg, 1.56 mmol) and intermediate 23-4 (530 mg, 1.56 mmol) were dissolved in DMF (10 mL) and reacted at 110 °C for 16 h. Ethyl acetate (100 mL) was added to dilute, and water (50 mL × 3) was added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / dichloromethane = 10% ~ 13%) to obtain intermediate 23-5 (240 mg, yield 26.2%, white solid). MS (ESI) m / z = 588.0 [M + H] + .

[0267] 20.6 Synthesis of compound 23 [ka]

[0268] Intermediate 23-5 (200 mg, 0.340 mmol) was dissolved in NH3 / MeOH (10.0 mL). The reaction was carried out at 110°C under microwave for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by fractionation (C18 30*150 mm*7 μm, mobile phase: [water-acetonitrile], B%: 5%-30%, 40 min). Compound 23 (56.7 mg, yield 37.5%, yellow solid) was obtained. MS (ESI) m / z = 559.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.82(s,1H),8.32(s,1H),7.43(s,1H),7.24(s,1H),7.17(dd,J=1.2Hz,9.2Hz,1H),7.06(d,J=2.8Hz,1H),6.49(dd,J=3.2Hz,9.2Hz,1H),4.62 - 4.58(m,3H),3.61(d,J=5.2Hz,2H),3.31(s,2H),3.19(s,2H),2.97(t,J=7.6Hz,2H),2.85 - 2.77(m,4H),2.22(s,3H),1.95 - 1.93(m,2H),1.61(d,J=7.6Hz,2H).

[0269] Example 21: Synthesis of Compound 24 [ka]

[0270] 21.1 Synthesis of intermediate 24-2 [ka]

[0271] Intermediate 24-1 (7.0 g, 31.8 mmol), trifluoroethanol (31.8 g, 318 mmol) and cesium carbonate (25.9 g, 79.5 mmol) were reacted at 70° C. for 4 h. The reaction solution was filtered, and the filtrate was dissolved in ethyl acetate (200 mL) and washed with water (200 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 24-2 (7.8 g, 80% yield, yellow oil) was obtained. MS (ESI) m / z = 299.9 [M + H] + .

[0272] 21.2 Synthesis of intermediate 24-3 [ka]

[0273] Intermediate 24-2 (5.1 g, 17.0 mmol) was dissolved in ethanol / acetic acid (200 mL / 200 mL), iron powder (9.49 g, 170 mmol) was added, and the mixture was reacted at 80° C. for 2 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL), and washed with saturated sodium bicarbonate (200 mL) and water (200 mL), respectively. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 24-3 (3.2 g, 68.5% yield, yellow solid) was obtained. MS (ESI) m / z = 270.0 [M + H] + .

[0274] 21.3 Synthesis of intermediate 24-4 [ka]

[0275] Intermediate 24-3 (3.0 g, 11.1 mmol), K3PO4 (4.71 g, 22.2 mmol), BFMO (0.29 g, 0.6 mmol), CuI (0.21 g, 1.1 mmol), BFMO (0.28 g, 1.1 mmol) and N-methylpiperazine (3.34 g, 33.3 mmol) were dissolved in ethanol (50 mL). The mixture was reacted at 100 °C for 24 h under nitrogen gas protection. The reaction solution was cooled to room temperature, dissolved in dichloromethane (50 mL), filtered, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 10% ~ 50%) to obtain intermediate 24-4 (1.2 g, yield 36.9%, white solid). MS(ESI)m / z=290.2[M+H] + .

[0276] 21.4 Synthesis of intermediate 24-5 [ka]

[0277] Intermediate 24-4 (1.1 g, 3.8 mmol), cyanamide (0.32 g, 7.6 mmol) and TMSCl (0.62 g, 5.7 mmol) were dissolved in acetonitrile (15 mL). The reaction was carried out at 140 °C under microwave for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (C18, ACN / H2O = 3 / 97 to 25 / 75) to obtain intermediate 24-5 (1.0 g, yield 78.9%, yellow solid). MS (ESI) m / z = 332.0 [M + H] + .

[0278] 21.5 Synthesis of intermediate 24-6 [ka]

[0279] Intermediate 1-8 (1.06 g, 3.44 mmol) and intermediate 24-5 (0.95 g, 2.86 mmol) were dissolved in DMF (60 mL) and reacted at 110 ° C for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (C18, ACN / H2O = 5 / 95 ~ 80 / 20) to obtain intermediate 24-6 (0.40 g, yield 24.5%, yellow solid). MS (ESI) m / z = 576.0 [M + H] + .

[0280] 21.6 Synthesis of compound 24 [ka]

[0281] Intermediate 24-6 (300 mg, 0.52 mmol) was dissolved in NH3 / MeOH (10.0 mL). The mixture was sealed at 120°C and reacted for 17 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by fractionation (C18 30*150 mm*7 μm, mobile phase: [water-acetonitrile], B%: 5%-30%, 40 min). Compound 24 (105 mg, yield 36%, yellow solid) was obtained. MS (ESI) m / z = 547.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.37(s,1H),8.18(s,1H),7.50-7.47(m,2H),7.27(s,1H),7.06(d,J=8.8Hz,1H),6.66(d,J=8.8,2.8Hz,1H),4.70-4.63(m ,5H),3.72-3.70(m,2H),3.06-3.04(m,4H),2.97(t,J=7.6Hz,2H),2.79(t,J=7.6Hz,2H),2.50-2.44(m,4H),2.22(s,3H).

[0282] Example 22: Synthesis of Compound 25 [ka]

[0283] 22.1 Synthesis of intermediate 25-1 [ka]

[0284] Intermediate 17-1 (160 mg, 0.280 mmol) and DDQ (319 mg, 1.41 mmol) were dissolved in dioxane (20 mL) and reacted at 100 °C for 2 h. Saturated NaHCO3 (20 mL) was added to quench, and ethyl acetate (20 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (C18 150 * 40 mm * 10 μm, mobile phase: [water (NH4HCO3)-ACN-acetonitrile], B%: 45% ~ 85%, 10 min). Intermediate 25-1 (57 mg, yield 35.7%, brown solid) was obtained. MS (ESI) m / z = 562.2 [M + H] + .

[0285] 22.2 Synthesis of intermediate 25-2 [ka]

[0286] Intermediate 25-1 (45.0 mg, 82.2 μmol) was dissolved in methanol (2 mL) and an aqueous solution of lithium hydroxide (1 M, 411 μL) was added. The reaction was carried out at room temperature for 6 h. At 0°C, the pH was adjusted to 5-7 using hydrochloric acid, the solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 150*30 mm*5 μm, mobile phase: [water (TFA)-acetonitrile], B%: 10%-50%, 10 min), and intermediate 25-2 (14.8 mg, yield 30.1%, brown solid) was obtained. MS (ESI) m / z = 534.2 [M + H] + .

[0287] 22.3 Synthesis of compound 25 [ka]

[0288] Intermediate 25-2 (20.9 mg, 39.3 μmol), HATU (16.4 mg, 43.2 μmol) and DIEA (10.2 mg, 78.67 μmol) were dissolved in DMF (2 mL) and hydroxylamine hydrochloride (10.2 mg, 78.67 μmol) was added. The reaction was allowed to proceed for 2 h at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 150*30 mm*5 μm, mobile phase: [water (TFA)-acetonitrile], B%: 20%-50%, 25 min), to obtain compound 25 (2.5 mg, yield 9.6%, brown solid). MS (ESI) m / z = 549.2 [M + H] + . 1 H NMR(400MHz,MeOD)δ 9.22(s,1 H),8.05(d,J=8.76Hz,1 H),7.53 - 7.61(m,2 H),7.36(d,J=8.88Hz,1 H),6.97(dd,J=9.07,2.81Hz,1 H),5.21 - 5.31(m,2 H),4.81(d,J=4.88Hz,1 H),4.69(t,J=4.88Hz,1 H),3.93(d,J=13.51Hz,2 H),3.64(d,J=12.01Hz,2 H),3.26 - 3.30(m,2 H),3.05 - 3.17(m,2 H),2.99(s,3 H).

[0289] Example 23: Synthesis of Compound 16 [ka]

[0290] Compound 20 (149 mg, 0.28 mmol) and DDQ (319 mg, 1.41 mmol) were dissolved in dioxane (20 mL) and reacted at 100°C for 2 h. The reaction was quenched by adding saturated NaHCO3 (20 mL) and extracted by adding ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (C18 150 * 40 mm * 10 μm, mobile phase: [water (NH4HCO3)-ACN-acetonitrile], B%: 45% ~ 85%, 10 min). Compound 16 (14.8 mg, yield 10%, brown solid) was obtained. MS (ESI) m / z = 531.2 [M + H] + .

[0291] Example 24: Synthesis of Compound 26 [ka]

[0292] 24.1 Synthesis of intermediate 26-1 [ka]

[0293] Compound 2-bromoethyl ethyl ether (1.00 g, 6.54 mmol) and tert-butyl 2-(propan-2-ylidene)hydrazine carboxylate (1.13 g, 6.54 mmol) were dissolved in acetonitrile (40 mL), and NaH (324 mg, 13.5 mmol) was added. The reaction was carried out at 80° C. for 12 h, and the completion of the reaction was detected. The reaction was quenched by adding water, and ethyl acetate (40 mL×3) was added for extraction, dried over anhydrous sodium sulfate, filtered, and the organic phase was collected and concentrated under reduced pressure. The residue was dissolved in ethyl acetate hydrochloride (4 M, 10 mL) and reacted at room temperature overnight. The reaction solution was concentrated, and the residue was dissolved in ethanol (20 mL), and concentrated hydrochloric acid (5 mL) was added and stirred overnight. The reaction solution was concentrated under reduced pressure to obtain intermediate 26-1 (0.95 g, crude). It was used directly in the next step.

[0294] 24.2 Synthesis of intermediate 26-2 [ka]

[0295] Intermediate 1-6 (850 mg, 3.54 mmol) was dissolved in acetic acid (10 mL), compound 26-1 (737 mg, 7.08 mmol) was added, and the mixture was reacted at room temperature for 15 h. The mixture was quenched by adding water (20 mL), saturated Na2CO3 (100 mL) was added, and dichloromethane (80 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 5%) to obtain intermediate 26-2 (473 mg, yield 47.8%, yellow solid). MS (ESI) m / z = 281.2 [M + H] + .

[0296] 24.3 Synthesis of intermediate 26-3 [ka]

[0297] Intermediate 26-2 (600 mg, 2.14 mmol) was dissolved in DMF-DMA (10 mL) and reacted at 110° C. for 12 h. The reaction solution was concentrated under reduced pressure to give intermediate 26-3 (650 mg, crude), which was used directly in the next step.

[0298] 24.4 Synthesis of intermediate 26-4 [ka]

[0299] Intermediate 26-3 (600 mg, 1.79 mmol) and intermediate 1-3 (851 mg, 2.68 mmol) were dissolved in DMF (20 mL) and reacted at 110 ° C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 5%) to obtain intermediate 26-4 (228 mg, yield 21.6%, yellow solid). MS (ESI) m / z = 590.3 [M + H] +.

[0300] 24.5 Synthesis of intermediate 26-5 [ka]

[0301] Intermediate 26-4 (44.0 mg, 74.6 μmol) and DDQ (88.0 mg, 387 μmol) were dissolved in dioxane (20 mL) and reacted at 100 °C for 12 h. Saturated NaHCO3 (20 mL) was added to quench, and ethyl acetate (20 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (C18 150 * 40 mm * 10 μm, mobile phase: [water (TFA)-acetonitrile], B%: 44% ~ 84%, 30 min). Intermediate 26-5 (16 mg, yield 36.5%, brown solid) was obtained. MS (ESI) m / z = 588.4 [M + H] + .

[0302] 24.6 Synthesis of Compound 26 [ka]

[0303] Intermediate 26-5 (16 mg, 27.2 μmol) was dissolved in NMP (6 mL) and NH3 / MeOH (50.0 mL) was added. The reaction was allowed to proceed for 48 h under sealed conditions at 80.0°C. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 30*150 mm*7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 10% to 80%, 40 min). Compound 26 (56.7 mg, yield 37.5%, yellow solid) was obtained. MS (ESI) m / z = 531.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.59(s,1 H),9.38(s,1 H),8.05 - 8.07(d,J=8.00Hz,1 H),7.82(s,1 H),7.63 - 7.66(d,J=12.0Hz,1 H),7.53(s,1 H),7.28 - 7.36(m,2 H),6.93 - 6.95(m,1 H),5.03 - 5.06(t,J=8.00Hz,2 H),3.67 - 3.70(t,J=8.00Hz,2 H),3.17 - 3.25(m,6 H),2.56 - 2.57(m,3 H),2.28(s,3 H), 1.28 - 1.37(m,1 H), 0.88 - 0.91(m,3 H).

[0304] Example 25: Synthesis of Compound 27 [ka]

[0305] 25.1 Synthesis of intermediate 27-1 [ka]

[0306] Intermediate 1-6 (200 mg, 832 μmol) was dissolved in acetic acid (10 mL), and compound cyclopropylhydrazine (71.9 mg, 998 μmol) was added and reacted at room temperature for 15 h. Water (20 mL) was added to quench the reaction, saturated Na2CO3 (100 mL) was added, and dichloromethane (80 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 10%) to obtain intermediate 27-1 (90 mg, yield 43.6%, yellow solid). MS (ESI) m / z = 249.1 [M + H] + .

[0307] 25.2 Synthesis of intermediate 27-2 [ka]

[0308] Intermediate 27-1 (500 mg, 2.01 mmol) was dissolved in DMF-DMA (10 mL) and reacted at 110° C. for 12 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in methyl tert-butyl ether and stirred for 3 h. Filtration and collection of the filter cake gave intermediate 27-2 (500 mg, crude), which was used directly in the next step.

[0309] 25.3 Synthesis of intermediate 27-3 [ka]

[0310] Intermediate 27-2 (500 mg, 1.65 mmol) and intermediate 1-3 (630 mg, 1.98 mmol) were dissolved in DMF (20 mL) and reacted at 110°C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 5%) to obtain intermediate 27-3 (100 mg, yield 10.9%, yellow solid). MS (ESI) m / z = 558.2 [M + H] + .

[0311] 25.4 Synthesis of intermediate 27-4 [ka]

[0312] Intermediate 27-3 (50.0 mg, 89.7 μmol) and DDQ (101 mg, 444 μmol) were dissolved in dioxane (20 mL) and reacted at 100° C. for 12 h. The reaction was quenched by adding saturated NaHCO3 (20 mL) and extracted by adding ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (C18 150*40 mm*10 μm, mobile phase: [water (TFA)-acetonitrile], B%: 51%~81%, 10 min). Intermediate 27-4 (30 mg, yield 20.1%, brown solid) was obtained. MS (ESI) m / z = 556.3 [M + H] + .

[0313] 25.5 Synthesis of compound 27 [ka]

[0314] Intermediate 27-4 (30.0 mg, 54.0 μmol) was dissolved in NMP (6 mL) and NH3 / MeOH (50.0 mL) was added. The reaction was allowed to proceed for 48 h in a sealed container at 80.0°C. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 30*150 mm*7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 40%-80%, 14 min). Compound 27 (17.0 mg, yield 59.8%, yellow solid) was obtained. MS (ESI) m / z = 527.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.50(s,1H),9.32(s,1H),7.96(d,J=8.40Hz,1H),7.72(s,1H,) 7.58(d,J=8.40Hz,1H),7.44(s,1H),7.29(d,J=2.80Hz,2H),6.83(dd,J=9.20,2.88Hz,1H),4.83 - 4.92(m,1H),3.33(s,13H),3.08 - 3.17(m,4H),2.39 - 2.47(m,5H),2.21(s,3H),1.28 - 1.33(m,2H),1.23(br s,1H),0.82 - 0.89(m,1H),0.81 - 0.90(m,1H).

[0315] Example 26: Synthesis of Compound 28 [ka]

[0316] 26.1 Synthesis of intermediate 28-1 [ka]

[0317] Intermediate 1-6 (2.00 g, 8.32 mmol) was dissolved in acetic acid (20 mL), and compound trifluoroethylhydrazine (1.14 g, 9.99 mmol) was added and reacted at room temperature for 15 h. Water (20 mL) was added to quench the reaction, saturated Na2CO3 (200 mL) was added, and dichloromethane (80 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 10%) to obtain intermediate 28-1 (1.18 g, yield 49.1%, yellow solid). MS (ESI) m / z = 291.0 [M + H] + .

[0318] 26.2 Synthesis of intermediate 28-2 [ka]

[0319] Intermediate 28-1 (1.23 g, 4.24 mmol) was dissolved in DMF-DMA (30 mL) and reacted at 110° C. for 12 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in methyl tert-butyl ether and stirred for 3 h. Filtration and collection of the filter cake gave intermediate 28-2 (1.4 g, crude). Used directly in the next step.

[0320] 26.3 Synthesis of intermediate 28-3 [ka]

[0321] Intermediate 28-2 (1.23 g, 3.56 mmol) and intermediate 1-3 (1.36 g, 4.28 mmol) were dissolved in DMF (50 mL) and reacted at 110 ° C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 5%) to obtain intermediate 28-3 (0.476 g, yield 22.3%, yellow solid). MS (ESI) m / z = 600.6 [M + H] + .

[0322] 26.4 Synthesis of intermediate 28-4 [ka]

[0323] Intermediate 28-3 (0.61 g, 1.02 mmol) and DDQ (1.14 g, 5.04 mmol) were dissolved in dioxane (20 mL) and reacted at 100 °C for 12 h. Saturated NaHCO3 (20 mL) was added to quench, and ethyl acetate (20 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (C18 150 * 40 mm * 10 μm, mobile phase: [water (TFA)-acetonitrile], B%: 50% ~ 90%, 35 min). Intermediate 28-4 (0.078 g, yield 12.8%, brown solid) was obtained. MS (ESI) m / z = 598.2 [M + H] + .

[0324] 26.5 Synthesis of Compound 28 [ka]

[0325] Intermediate 28-4 (50.0 mg, 83.7 μmol) was dissolved in NMP (6 mL) and NH3 / MeOH (50.0 mL) was added. The reaction was allowed to proceed for 48 h under sealed conditions at 80.0°C. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 30*150 mm*7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 32%-72%, 36 min). Compound 28 (9.0 mg, yield 18.9%, yellow solid) was obtained. MS (ESI) m / z = 569.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.66(s,1H),9.36(s,1H),8.00(d,J=8.74Hz,1H),7.55 - 7.84(m,3H),7.25(d,J=9.00Hz,1H),6.90(dd,J=9.14,2.88Hz,1H),5.80(d,J=8.50Hz,2H),3.12 - 3.20(m,4H),2.40 - 2.46(m,4H),2.21(s,3H).

[0326] Example 27: Synthesis of Compound 29 [ka]

[0327] 27.1 Synthesis of intermediate 29-1 [ka]

[0328] Intermediate 1-6 (1.60 g, 6.66 mmol) was dissolved in acetic acid (20 mL), and compound ethylhydrazine (0.44 g, 7.33 mmol) was added and reacted at room temperature for 15 h. Water (20 mL) was added to quench the reaction, saturated Na2CO3 (200 mL) was added, and dichloromethane (80 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 10%) to obtain intermediate 29-1 (0.74 g, yield 47.1%, yellow solid). MS (ESI) m / z = 237.1 [M + H]+ .

[0329] 27.2 Synthesis of intermediate 29-2 [ka]

[0330] Intermediate 29-1 (1.00 g, 3.81 mmol) was dissolved in DMF-DMA (30 mL) and reacted at 110° C. for 12 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in methyl tert-butyl ether and stirred for 3 h. Filtration and collection of the filter cake gave intermediate 29-2 (1.0 g, crude), which was used directly in the next step.

[0331] 27.3 Synthesis of intermediate 29-3 [ka]

[0332] Intermediate 29-2 (1.00 g, 3.43 mmol) and intermediate 1-3 (1.09 g, 3.43 mmol) were dissolved in DMF (50 mL) and reacted at 110°C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / dichloromethane = 0% to 10%) to obtain intermediate 29-3 (0.70 g, yield 37.4%, yellow solid). MS (ESI) m / z = 546.2 [M + H] + .

[0333] 27.4 Synthesis of intermediate 29-4 [ka]

[0334] Intermediate 29-3 (0.70 g, 1.28 mmol) and DDQ (1.02 g, 4.49 mmol) were dissolved in dioxane (20 mL) and reacted at 100 °C for 12 h. Saturated NaHCO3 (20 mL) was added to quench, and ethyl acetate (20 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (C18 150 * 40 mm * 10 μm, mobile phase: [water (TFA)-acetonitrile], B%: 45% ~ 85%, 10 min). Intermediate 29-4 (0.3 g, yield 43%, yellow solid) was obtained. MS (ESI) m / z = 544.3 [M + H] + .

[0335] 27.5 Synthesis of Compound 29 [ka]

[0336] Intermediate 29-4 (300 mg, 552 μmol) was dissolved in NMP (6 mL) and NH3 / MeOH (50.0 mL) was added. The reaction was allowed to proceed for 48 h under sealed conditions at 80.0°C. The reaction solution was concentrated under reduced pressure, and the residue was purified using a fractionation column (C18 30*150 mm*7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 32%-72%, 35 min). Compound 29 (72 mg, yield 25.3%, yellow solid) was obtained. MS (ESI) m / z = 515.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.52(br s,1 H),9.31(s,1 H),7.98(d,J=8.80Hz,1 H),7.76(s,1 H),7.57(d,J=8.80Hz,1 H),7.45(s,1 H),7.27(d,J=8.00Hz,1 H),7.21(d,J=2.80Hz,1 H),6.88(dd,J=9.20,2.80Hz,1 H),4.82(q,J=7.20Hz,2 H),3.08 - 3.25(m,4 H),2.42 - 2.43(m,4 H),2.21(s,3 H),1.23(t,J=7.20Hz,3H).

[0337] Example 28: Synthesis of Compound 30 [ka]

[0338] 28.1 Synthesis of intermediate 30-1 [ka]

[0339] 2-Aminooxyethanol (1.00 g, 12.9 mmol) was dissolved in dichloromethane (20 mL), DMAP (0.158 g, 1.30 mmol), imidazole (1.32 g, 19.5 mmol) and TBDPSCl (4.28 g, 15.6 mmol) were added, and the mixture was reacted at room temperature for 12 h. The mixture was quenched by adding water (50 mL) and extracted by adding ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 15%) to obtain intermediate 30-1 (1.59 g, yield 39%, oily product). MS (ESI) m / z = 316.1 [M + H] + .

[0340] 28.2 Synthesis of intermediate 30-2 [ka]

[0341] Compound 25-2 (50.0 mg, 93.7 μmol) was dissolved in DMF (3.00 mL) and HATU (39.2 mg, 103 μmol) was added. The mixture was stirred at room temperature for 10 min, and DIEA (24.2 mg, 187 μmol) and intermediate 30-1 (59.1 mg, 187 μmol) were added. The reaction was allowed to proceed at room temperature for 1 h. The mixture was quenched by adding water (50 mL) and extracted by adding ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 30-2 (60.0 mg, crude) was obtained. The mixture was used directly in the next step. MS (ESI) m / z = 831.5 [M + H] + .

[0342] 28.3 Synthesis of compound 30 [ka]

[0343] Intermediate 30-2 (50.0 mg, 60.2 μmol) was dissolved in DCM (5 mL), triethylamine trihydrofluoride (19.4 mg, 120 μmol) was added, and the mixture was reacted at room temperature for 5 h. The mixture was quenched by adding water (50 mL), and extracted by adding ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid (C18 30 * 150 mm * 7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 13% ~ 60%, 14 min). Compound 30 (60 mg, yield 76.0%, yellow solid) was obtained. MS (ESI) m / z = 593.0 [M + H] + . 1H NMR(400MHz,DMSO-d6)δ 9.59(s,1H)9.34(s,1H)7.93(d,J=8.80Hz,1H)7.63(d,J=8.80Hz,1H)7.26 - 7.35(m,1H)7.19(d,J=2.80Hz,1H)6.89(dd,J=9.20,8.80Hz,1H)5.06 - 5.22(m,2H)4.69 - 4.81(m,2H)4.61(s,1H)3.95(t,J=4.80Hz,2H)3.62(m,J=4.80Hz,2H)3.14 - 3.22(m,4H)2.40 - 2.45(m,4H) 2.21(s,3H).

[0344] Example 29: Synthesis of Compound 31 [ka]

[0345] 29.1 Synthesis of intermediate 31-1 [ka]

[0346] Compound 19-1 (50.0 mg, 94.1 μmol) was dissolved in DMF (3.00 mL) and HATU (39.4 mg, 103 μmol) was added. Stirred at room temperature for 10 min, and DIEA (24.3 mg, 188 μmol) and intermediate 30-1 (59.4 mg, 188 μmol) were added. The reaction was allowed to proceed at room temperature for 12 h. The reaction was quenched by adding water (50 mL) and extracted by adding ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 31-1 (60.0 mg, crude) was obtained. It was used directly in the next step. MS (ESI) m / z = 829.5 [M + H] + .

[0347] 29.2 Synthesis of compound 31 [ka]

[0348] Intermediate 31-1 (50.0 mg, 60.3 μmol) was dissolved in DCM (5 mL), triethylamine trihydrofluoride (48.6 mg, 301 μmol) was added, and the mixture was reacted at room temperature for 5 h. The mixture was quenched by adding water (50 mL), and extracted by adding ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid separation (C18 30 * 150 mm * 7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 25% ~ 85%, 14 min). Compound 31 (22.0 mg, yield 30.6%, yellow solid) was obtained. MS (ESI) m / z = 591.3 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.50(s,1H)9.32(s,1H)7.90 - 8.00(m,1H)7.61(d,J=8.40Hz,1H)7.19 - 7.31(m,2H)6.88(dd,J=9.07,3.20Hz,1H)4.88(m,2H)4.76 - 4.84(m,1H)4.57 - 4.63(m,1H)3.88 - 3.96(m,2H)3.55 - 3.72(m,5H)3.15 - 3.21(m,4H)2.42 - 2.46(m,4H)2.18 - 2.22(m,1H)2.22(s,3H).

[0349] Example 30: Synthesis of Compound 32 [ka]

[0350] 30.1 Synthesis of intermediate 32-1 [ka]

[0351] Intermediate 28-4 (50.0 mg, 83.7 μmol) was dissolved in methanol (5 mL) and an aqueous solution of lithium hydroxide (1.00 M, 418 μL) was added. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction solution was adjusted to acidic with hydrochloric acid, concentrated under reduced pressure, and the residue was purified with a fractionating liquid (C18 30*150 mm*7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 20% to 50%, 10 min). Intermediate 32-1 (40.0 mg, yield 83.8%, yellow solid) was obtained. MS (ESI) m / z = 570.1 [M + H] + .

[0352] 30.2 Synthesis of compound 32 [ka]

[0353] Intermediate 32-1 (40.0 mg, 70.2 μmol), HATU (29.4 mg, 77.1 μmol), DIEA (18.2 mg, 140 μmol), and NH2OH (9.76 mg, 140 μmol) were dissolved in DMF (2 mL) and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified with a fractionation liquid (C18 30 * 150 mm * 7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 10% to 50%, 12 min). Compound 32 (5.0 mg, yield 12.2%, brown solid) was obtained. MS (ESI) m / z = 585.3 [M + H] + .

[0354] Example 31: Synthesis of Compound 33 [ka]

[0355] 31.1 Synthesis of intermediate 33-1 [ka]

[0356] Compound 1-1 (13.0 g, 50.8 mmol) was dissolved in water (130 mL), and concentrated hydrochloric acid (12 mL) and cyanamide (10.6 g, 254 mmol) were added. The reaction was carried out at 60° C. for 16 h. The pH was adjusted to 14 with 40% sodium hydroxide solution, and ethyl acetate (150 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Intermediate 33-1 (10.9 g, 72.2% yield, brown solid) was obtained. MS (ESI) m / z=297.9 [M+H] + .

[0357] 31.2 Synthesis of intermediate 33-2 [ka]

[0358] Intermediate 33-1 (5.00 g, 16.8 mmol) was dissolved in DMF (50 mL) and intermediate 1-8 (5.16 g, 16.8 mmol) was added. The reaction was allowed to proceed at 110° C. for 16 h. Water (200 mL) was added to quench the reaction, and ethyl acetate (100 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether=0%-100%) to obtain intermediate 33-2 (2.96 g, 32.5% yield, yellow solid). MS(ESI)m / z=542.3[M+H] + .

[0359] 31.3 Synthesis of intermediate 33-3 [ka]

[0360] Intermediate 33-2 (2.55 g, 4.70 mmol) and DDQ (2.35 g, 10.34 mmol) were dissolved in dioxane (60 mL) and reacted at 100 °C for 9 h. Filtration was performed, and the filtrate was collected and concentrated under reduced pressure to give intermediate 33-3 (2 g, crude). It was used directly in the next step. MS (ESI) m / z = 540.0 [M + H] + .

[0361] 31.4 Synthesis of intermediate 33-4 [ka]

[0362] Intermediate 33-3 (1.20 g, 1.49 mmol, purity 67%), piperazine-1-carboxylic acid tert-butyl acetate (1.39 g, 7.44 mmol) were dissolved in dioxane (6 mL), and XPhos (354 mg, 744 μmol), KOtBu (334 mg, 2.98 mmol) and Pd2(dba)3 (341 mg, 372 μmol) were added. The reaction was carried out at 75 °C for 20 h. The reaction was quenched by adding water (100 mL), and extraction was carried out by adding ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (C18 30*150mm*7μm, mobile phase: [water (NH3H2O+NH4HCO3)-acetonitrile], B%: 30%~70%, 20min). Intermediate 33-4 (0.12g, 12.5% ​​yield, brown solid) was obtained. MS(ESI)m / z=646.2[M+H] + .

[0363] 31.5 Synthesis of intermediate 33-5 [ka]

[0364] Intermediate 33-4 (90.0 mg, 139 μmol) was dissolved in NH3 / MeOH (10 mL, 7 M) and reacted at 80 °C for 48 h. The temperature was lowered to room temperature, and the reaction solution was concentrated under reduced pressure to give intermediate 33-5 (100 mg, crude). It was used directly in the next step. MS (ESI) m / z = 617.4 [M + H] + .

[0365] 31.6 Synthesis of compound 33 [ka]

[0366] Intermediate 33-5 (90.0 mg, 124 μmol, 85% purity) was dissolved in dichloromethane (5 mL), TFA (212 mg, 1.86 mmol) was added, and the mixture was reacted at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by fractionation (C18 30*150 mm*7 μm, mobile phase: [water (TFA)-acetonitrile], B%: 4%-44%, 36 min). The product produced and freeze-dried was dissolved in water and acetonitrile (volume ratio 1:1), and the solid precipitated, filtered by suction, and dried. Compound 33 (30.3 mg, yield 57.2%, yellow solid) was obtained. MS (ESI) m / z = 517.4 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.44(s,1 H),9.31(s,1 H),8.00(d,J=8.8Hz,1 H),7.74(br s,1 H),7.58(d,J=8.8Hz,1 H),7.44(br s,1 H),7.19 - 7.30(m,2 H),6.85(dd,J=9.2,2.8Hz,1 H),4.89(t,J=4.8Hz,2 H),4.59(br s,1 H),3.64 - 3.73(m,2 H),3.00 - 3.15(m,4 H),2.76 - 2.90(m,4 H).

[0367] Test Example 1. PLK1 kinase inhibitory activity 1. Test material: PLK1 kinase (Carnabio #05-157) Detection solution PerkinElmer #TRF0218-M Detection equipment: PerkinElemer EnVision 2. Test method: a. Using an Echo machine, compounds to be tested were diluted 1:3 in a 384-well plate with the highest concentration being 1 μM for a total of 10 concentration points, with parallel wells tested for each concentration.

[0368] b. 5 μL / well of PLK1 kinase and peptide substrate mix was added to the assay plates (including controls). Each assay plate contained GSK461364 as a positive control and DMSO solvent as a negative control.

[0369] c. Centrifuge the test plate at 1000 rpm for approximately 15 seconds and incubate at 23°C for 15 minutes. d. Add 5 μL / well of ATP solution to start the reaction. e. Centrifuge the test plate at a rotation speed of 1000 rpm for about 15 seconds, seal the test plate with a film, and incubate at 23° C. for a certain period of time; f. Add detection solution to all wells of the assay plate; g. Centrifuge at 1000 rpm for approximately 15 seconds, seal the assay plate with film, and incubate at 23° C. for 60 minutes.

[0370] h. The test plates were read on an EnVision. The test results were analyzed using XLFIT5 software.

[0371] 3. Test results: Inhibitory activity IC of the compounds of the present invention against PLK1 kinase 50 and I max (%) is as shown in Table 1. I max is the maximum effect of the compound at the test concentration (S / B 8.52, Z factor 0.94).

[0372] [Table 2]

[0373] Conclusion: Most of the compounds of the present invention have inhibitory IC 50 The levels of 1-2 nM were comparable to those of the control drug onvansertib. Compounds 3, 7, 17, 18, 21, 27-30, and 32 showed increased kinase activity compared to the control drug.

[0374] Test Example 2. HCT116 cell proliferation inhibitory activity 1. Test materials: Cell line: HCT116 cells Cell culture medium: RPMI1640 + 10% FBS (GBICO) Cell culture plate: 96-well plate (Shanghai Jing'an Biotechnology Co., Ltd.) Detection kit: ATPlite 1step Luminescence (PerkinElmer) Detection equipment: BioTek multifunctional microplate reader

[0375] 2. Test method: HCT116 cells in logarithmic growth phase were seeded into a white 96-well plate with a clear bottom at a density of 720 cells per well, and cultured overnight in an incubator at 37℃ and 5% CO2. The next day, the test compounds were added to the cells, and the test compounds were diluted in a 3-fold gradient of 9 percent, with duplicate parallel wells for each concentration. Blank medium was used as the negative control, and Onvansertib at the same concentration was used as the positive control. After adding the drugs, the cells were cultured for 72h in an incubator at 37℃ and 5% CO2. Then, the cells were added with an equal volume of ATPlite 1step Luminescence reagent to the cell solution, incubated at room temperature in the dark for 3min, and shaken in a micro shaker at 500r for 2min. The luminescence intensity was detected by a plate reader, and the cell inhibition rate was calculated.

[0376] Cell inhibition rate (%) = [100-(Lum 試験対象試料 -Lum 培養液 ) / (Lum 陰性対照 -Lum 培養液 )×100]%.

[0377] Data were processed with GraphPad Prism 7.0 to obtain cell inhibition rate curves and IC 50 was calculated.

[0378] 3. Test results: The half inhibitory concentration IC of the compounds of the present invention on HCT116 cell proliferation 50 is as shown in Table 2.

[0379] [Table 3]

[0380] Conclusion: The half inhibitory concentration of compound 1 of the present invention against HCT116 cells is 51nM, the half inhibitory concentration of compound 10 against HCT116 cells is 49nM, which is equivalent to the control Onvansertib. The half inhibitory concentration of compound 2 against HCT116 cells is 27nM, the half inhibitory concentration of compound 24 against HCT116 cells is 32nM, and the half inhibitory concentration of compound 18 against HCT116 cells is 5nM, which is enhanced compared to the control drug Onvansertib.

[0381] Test Example 3. Evaluation of permeability of test substances and transporter substrates 1. Test materials: In this experiment, Caco-2 cells were inoculated into Transwell-96 well plates at a seeding density of 1 × 10 5 cells / cm 2 The cells were cultured in a carbon dioxide incubator for 21 to 28 days before use in the transport experiment, during which the medium was changed once every 4 to 5 days.

[0382] 2. Test method: In this study, Hank's balanced salt buffer (pH 7.40±0.05) containing 10 mM HEPES was used as the transport buffer. The medium in the culture plate was removed, and the cells were rinsed twice with pre-warmed transport buffer (approximately 75 μL and 40 mL of transport buffer were used each time for each top well and bottom end receiving plate, respectively). The dosing and receiving solutions were added to the corresponding well positions of the cell plate, respectively (75 and 250 μL of sample were added to each top and substrate end well, respectively), and the bidirectional transport experiment was started (from the top to the substrate end (AB) and from the substrate end to the top (BA)).

[0383] The test concentration of the test substance was 5.00μM, and two parallel wells were prepared for each dose concentration. The test concentration of digoxin was 10.0μM, and it was administered bidirectionally, and the test concentrations of nadolol and metoprolol were both 2.00μM, and it was administered unidirectionally (AB direction), and two parallel wells were prepared for each of the three control compounds. After the samples were added, the cell plates were incubated at 37±1℃, 5% CO2, and saturated humidity for 120 minutes.

[0384] The initial dosing solution was the TO sample, which was taken after sample addition and mixed with transport buffer and stop solution in a given ratio. After 120 min of incubation, the final samples were collected from the dosing end and the receiving end, and similarly mixed with transport buffer and stop solution in a given ratio.

[0385] All samples were shaken in a vortex form and then centrifuged at 3220 × g and 20 °C for 20 min, and an appropriate volume of the supernatant was transferred to a sample analysis plate, and after sealing the plate, the samples were stored at 2–8 °C if not analyzed immediately and analyzed by LC MS / MS method.

[0386] The integrity of the Caco-2 cell layer was tested using the Lucifer Yellow Rejection Assay.

[0387] 3. Data Analysis: The apparent permeability coefficient (P app The flow rate (cm / s), efflux ratio (ER), and solution recovery rate (%Solution Recovery) were calculated.

number

number

number

[0388] V Ris the volume of the receiving end solution (0.075 mL on side A and 0.25 mL on side B), and Area is the relative surface area of ​​the cell monolayer (0.0804 cm 2 ), Time is the incubation time (7200 s), C0 is the starting concentration (nM) of the test sample at the administration end or the peak area ratio of the control compound, and V D is the volume of the dosing end (side A is 0.075 mL and side B is 0.25 mL), and C D and C R are the ratio of the peak areas of the dosing end and receiving end test samples (nM) or the control compound, respectively; Lucifer Yellow transmittance (%Lucifer Yellow) is calculated using the following formula:

number

[0389] 4. Classification criteria: [Table 4]

[0390] 5. Test Results: The results of the permeability of the compounds of the present invention in Caco-2 cells are shown in Table 5.

[0391] [Table 5] Conclusion: The compounds of the present invention are low or moderately permeable in Caco-2 cells.

[0392] Test Example 4. Evaluation of metabolic stability in liver microsomes 1. Reagents:

[0393] [Table 6]

[0394] 2. Equipment [Table 7]

[0395] 3. Test Method a. Preparation of phosphate buffer solution: Phosphate buffer powder was dissolved in 100 mL of pure water to prepare a phosphate buffer solution with a pH of 7.4 and a concentration of 100 mM, which was then stored in a refrigerator at 4° C.

[0396] b. All samples and controls Testosterone was dissolved in DMSO to a stock solution of 10 mM. The 10 mM stock solution was diluted to 100 μM with acetonitrile to prepare a working solution and then left on standby.

[0397] c. Preparation of liver microsome working solution: Stock solutions of mouse, rat and human liver microsomes (concentration: 20 mg / mL) were taken and diluted with 100 mM phosphate buffer solution to 0.56 mg / mL to prepare liver microsome working solutions.

[0398] d. Preparation of solutions: Weigh out an appropriate amount of MgCl2 and prepare a 60 mM MgCl2 solution with 100 mM phosphate buffer solution. Weigh out an appropriate amount of NADPH and prepare a 20 mM NADPH solution with 100 mM phosphate buffer solution, and add an equal volume of 60 mM MgCl2 solution to prepare an NADPH working solution containing 10 mM NADPH and 30 mM MgCl2. An acetonitrile solution containing 20 ng / mL tolbutamide was prepared as a stop solution.

[0399] e. Liver microsome incubation: 2 μL of each compound and positive drug testosterone working solution was added to 178 μL of liver microsome working solution (0.56 mg / mL), mixed gently, and pre-incubated for 10 minutes in a shaking thermostatic water bath at 37° C. Next, 20 μL of NADPH working solution was added, and the mixture was placed in a shaking thermostatic water bath at 37° C., timing was started, and the mixture was incubated for 5, 10, 20, 30, and 60 minutes.

[0400] f. Stopping the reaction: After the corresponding incubation time was completed, 400μL of stop solution was added to stop the reaction, and the sample was immediately shaken for 1 minute. Centrifuged at 10℃ and 13500rpm for 10 minutes. After centrifugation, the supernatant was taken and diluted with water as required for each compound, and then subjected to LC-MS analysis. For the 0 minute sample, stop solution was added and mixed uniformly with liver microsomes, and then NADPH working solution was added. For the negative control sample, 20μL of 30mM MgCl2 solution was added instead of NADPH working solution.

[0401] 4. Data Analysis: The following formula is used to calculate T 1 / 2 and C.L. int(mic) was calculated.

[0402] C t= C0*e -k e ·t C t= In the case of 1 / 2C0, T 1 / 2 =ln2 / k e =0.693 / k e CL int(mic)= 0.693 / T 1 / 2 / Liver microsomal protein concentration at incubation (mg / mL) CL int(liver) =CL int(mic) *Liver microsomal protein (mg) / Liver weight (g)*Liver weight to body weight ratio Liver microsomal protein (mg) / liver weight (g): The value is 45 in both animal and human species.

[0403] Liver weight to body weight ratio: The parameters in mice, rats and humans are 88, 40 and 20 g / kg, respectively.

[0404] 5. Test Results: The metabolic stability results of the compounds of the present invention in mouse, rat and human liver microsomes are shown in Table 6.

[0405] [Table 8]

[0406] Test Example 5. In vivo pharmacodynamics study of compound 1 in mice 1. Test materials: Balb / C nude mice, SPF grade, male, weighing 18-20 g, were purchased from Jiangsu Jisui Yaokang Biotechnology Co., Ltd.

[0407] HCT116 cells, purchased from ATCC.

[0408] Matrigel Matrix, catalog number 354248, is purchased from Becton, Dickinson and Company.

[0409] Kolliphor® HS 15, catalog number 42966, is purchased from Sigma-Aldrich.

[0410] 2. Test method: a. Tumor-bearing mouse model creation: HCT116 cells in logarithmic growth phase were harvested and cultured, and the cells were harvested and counted, and 1 × 10 6 Balb / C nude mice were subcutaneously inoculated with the antibody at 100 / mouse. The tumor volume and body weight of the mice were measured periodically. Seven days after inoculation, the tumor volume was 150 mm 3 The mice were randomly divided into groups and given the corresponding drug treatments.

[0411] b. Animal grouping and administration: All mice were randomly grouped into a negative control group (sham group, 20% Solutol HS15), an onvansertib single administration group (ONV-20mg / kg group), and a compound 1 single administration group (T1-20mg / kg group). The mice were intragastrically administered once daily for 21 consecutive days, and the tumor volume and body weight of the mice were measured periodically.

[0412] 3. Data processing: All data were organized using EXCEL, and One-way ANOVA analysis and plotting were performed using GraphPad Prism 8.0 software. p<0.05 was considered statistically significant.

number

number

[0413] 4. Test results: As shown in Figure 1, when mice were treated with the drug for 11 days, the tumor inhibition rate of the T1-20mg / kg group reached 82.0% (p<0.0001) and the tumor inhibition rate of the ONV-20mg / kg group reached 54.9% (p<0.05) compared with the sham group. After 16 consecutive days of treatment, the tumor inhibition rate of the T1-20mg / kg group reached 86.5% (p<0.001) and the tumor inhibition rate of the ONV-20mg / kg group reached 39.6% (p<0.05) compared with the sham group, and the data of both T1-20mg / kg and ONV-20mg / kg groups were significantly different (p<0.01). After 21 consecutive days of administration, compared with the sham group, the tumor inhibition rate of the T1-20 mg / kg group reached 88.3% (p<0.0001), and the tumor inhibition rate of the ONV-20 mg / kg group reached 37.0% (p<0.05), and there was a significant difference between the data of the T1-20 mg / kg and ONV-20 mg / kg groups (p<0.01).

[0414] As shown in FIG. 2, there were no significant differences in body weight between animals in each group at each measurement during the study.

[0415] 5. Study conclusion: Compound 1 of the present invention has a significant inhibitory effect on the volume increase of colorectal tumors, and its efficacy at the same dose is superior to that of the control drug onvansertib.

[0416] Test Example 6. In vivo pharmacodynamics study of compound 18 in mice 1. Experimental materials: Same as in Test Example 5.

[0417] 2. Experimental Method: a. Preparation of tumor-bearing mouse model: same as in Test Example 5.

[0418] b. Animal grouping and administration: All mice were randomly grouped into 7 mice in the negative control group (control group, 20% Solutol HS15), 7 mice in the onvansertib alone group (onv-60mg / kg group), and 7 mice in the compound 18 alone group (T18-10mg / kg group). The mice were intragastrically administered once a day for 7 consecutive days, and the tumor volume and body weight of the mice were measured periodically.

[0419] 3. Data processing: Same as in Test Example 5.

[0420] 4. Test results: As shown in Figure 3, when mice were treated with the drug for 7 days, compared with the control group, the T18-10 mg / kg group was able to significantly inhibit the growth of mouse tumors, with the inhibition rate reaching 70.9% (p<0.001), and the tumor inhibition rate of the onv-60 mg / kg group was 62.7% (p<0.01).

[0421] As shown in Figure 4, after 5 consecutive days of administration, the mice in the T18-10 mg / kg group lost 7.6% of their body weight compared to before administration, and the mice in the onv-60 mg / kg group lost 8.4% (p<0.05) of their body weight compared to before administration. After 7 consecutive days of administration, the mice in the T18-10 mg / kg group lost 16.1% (p<0.01) of their body weight compared to before administration, and the mice in the onv-60 mg / kg group lost 19.5% (p<0.001) of their body weight compared to before administration.

[0422] 5. Study conclusion: Compound 18 of the present invention has a significant inhibitory effect on the increase of mouse tumor volume when administered at a dose of 10mg / kg for 7 consecutive days.To achieve the same efficacy, the required dose of compound 18 is about 1 / 6 of that of the control drug onvansertib, and the effect on animal body weight is smaller than that of the control drug.

Claims

1. A compound of formula (I), a pharma- ceutically acceptable salt or stereoisomer thereof, 【Chemistry 1】 X is independently selected from piperidine, piperazine, 3,8-diazabicyclo[3.2.1]octane, -CH ２ -piperazine-, -NR-pyrrolidine-, -NR-azetidine-, or -NR-CH ２ -pyrrolidine-, wherein R is independently selected from H, D, C １ -C ６ alkyl groups, Y is independently -CR ４ =CR ４ -, -CR ４ =N- or -N=CR ４ -, and each R ４ are each independently H, D, C １ -C ６ alkyl groups, Ring A is represented by the formula (A): 【Chemistry 2】 is selected from the structures shown in X １ are independently selected from a C, N, O or S atom; X ２ are independently selected from a C, N, O or S atom; R １ are independently H, D, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ haloalkoxy groups; R ２ are independently H, D, C １ -C ６ alkyl group, wherein said C １ -C ６ The alkyl group may optionally contain one or more halogens, OH, NH ２ , substituted with a CN group, Each R ３ are each independently H, D, C １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl group, —C(O)NHR ５ wherein said C １ -C ６ The alkyl group may optionally contain one or more halogens, OH, NH ２ , C.N., C. １ -C ６ is substituted with an alkoxy group, ５ are independently H, D, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, HO-C １ -C ６ Alkoxy groups, OH, NH ２ , -NHC(O)NH ２ , R ６ -S (O) ２ -, wherein R ６ is independently １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ３ -C ６ A compound, a pharma- ceutically acceptable salt, or stereoisomer thereof, selected from: a cycloalkyl group.

2. A compound of formula (II), a pharma- ceutically acceptable salt or stereoisomer thereof, 【Chemistry 3】 Where: Y is independently -CR ４ =CR ４ -, -CR ４ =N- or -N=CR ４ -, and each R ４ are each independently H, D, C １ -C ６ alkyl groups, X １ are independently selected from a C, N, O or S atom; X ２ are independently selected from a C, N, O or S atom; R １ are independently H, D, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ haloalkoxy groups; R ２ are independently H, D, C １ -C ６ alkyl group, wherein said C １ -C ６ The alkyl group may optionally contain one or more halogens, OH, NH ２ , substituted with a CN group, R ３ａ are independently H, D, C １ -C ６ Alkyl group, C ３ -C ６ cycloalkyl groups, wherein said C １ -C ６ The alkyl group may optionally contain one or more halogens, OH, NH ２ , C.N., C. １ -C ６ substituted with an alkoxy group, R ３ｂ are independently -C(O)NHR ５ is selected from The R ５ are independently H, D, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, HO-C １ -C ６ Alkoxy groups, OH, NH ２ , -NHC(O)NH ２ , R ６ -S (O) ２ -, wherein R ６ is independently １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ３ -C ６ A compound, a pharma- ceutically acceptable salt, or stereoisomer thereof, selected from: a cycloalkyl group.

3. A compound of formula (IIa), (IIb), (IIc), (IId) or (IIe), or a pharma- ceutically acceptable salt or stereoisomer thereof, 【Chemistry 4】 Where: Y is independently -CR ４ =CR ４ -, -CR ４ =N- or -N=CR ４ -, and each R ４ are each independently H, D, C １ -C ６ alkyl groups, R １ are independently H, D, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ haloalkoxy groups; R ２ are independently H, D, C １ -C ６ alkyl group, wherein said C １ -C ６ The alkyl group may optionally contain one or more halogens, OH, NH ２ , substituted with a CN group, R ３ａ are independently H, D, C １ -C ６ Alkyl group, C ３ -C ６ cycloalkyl groups, wherein said C １ -C ６ The alkyl group may optionally contain one or more halogens, OH, NH ２ , C.N., C. １ -C ６ substituted with an alkoxy group, R ３ｂ are independently -C(O)NHR ５ is selected from The R ５ are independently H, D, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, HO-C １ -C ６ Alkoxy groups, OH, NH ２ , -NHC(O)NH ２ , R ６ -S (O) ２ -, wherein R ６ is independently １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ３ -C ６ A compound, a pharma- ceutically acceptable salt, or stereoisomer thereof, selected from: a cycloalkyl group.

4. X is independently 【Chemistry 5】 wherein R is independently selected from H, D, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group; Ring A is represented by formula (A-1), formula (A-2), formula (A-3), formula (A-4) or formula (A-5): 【Chemistry 6】 It is preferable that the structure is selected from the structures shown in R ３ａ are independently H, D, C １ -C ６ Alkyl group, C ３ -C ６ cycloalkyl groups, wherein said C １ -C ６ The alkyl group may optionally contain one or more halogens, OH, NH ２ , C.N., C. １ -C ６ substituted with an alkoxy group, R ３ｂ are independently -C(O)NHR ５ wherein R ５ are independently H, D, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, HO-C １ -C ６ Alkoxy groups, OH, NH ２ , -NHC(O)NH ２ , R ６ -S (O) ２ -, wherein R ６ is independently １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ３ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the cycloalkyl group is selected from the group consisting of cycloalkyl groups.

5. Y is independently -CH ２ -CH ２ -, -CH=CH-, -CH ２ -NH-, -NH-CH ２ --, --CH ２ -N(CH ３ ) -, -N(CH ３ )-CH ２ The compound according to any one of claims 2 to 4, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the divalent radical -, -CH=N- or -N=CH- is preferably selected from the group consisting of -, -CH=N- or -N=CH-.

6. R １ are independently H, D, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a 1-ethylpropyl group, an n-hexyl group, an isohexyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 3,3,3-trifluoroethyl group, a 3,3,3-trichloroethyl group, a pentafluoroethyl group, or a pentachloroethyl group.

5. The compound according to claim 2, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the aryl group is preferably selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy, n-pentyloxy, S-pentyloxy, hexyloxy, 2-ethylbutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

7. R ２ are preferably independently selected from H, D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, and 2-ethylbutyl group, and the terminal of the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, and 2-ethylbutyl group may optionally be terminated with one or more of F, Cl, Br, OH, NH ２ 5. The compound according to claim 2, substituted with a CN group, or a pharma- ceutically acceptable salt or stereoisomer thereof.

8. R ３ａ is preferably selected from a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and the terminal of the methyl group, the ethyl group, the n-propyl group, the n-butyl group, the n-pentyl group, or the n-hexyl group may optionally be terminated with one or more of F, Cl, Br, OH, NH ２ 5. The compound according to claim 2, substituted with CN, a methoxy group, or an ethoxy group, or a pharma- ceutically acceptable salt or stereoisomer thereof.

9. R ３ｂ are independently -C(O)NHR ５ wherein R ５ is particularly preferably H, D, a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, a n-hexyl group, a methoxy group, an ethoxy group, a n-propoxy group, a n-butoxy group, a n-pentyloxy group, a n-hexyloxy group, a HO-methoxy group, a HO-ethoxy group, a HO-n-propoxy group, a HO-n-butoxy group, a HO-n-pentyloxy group, a HO-n-hexyloxy group, OH, or NH. ２ , -NHC(O)NH ２ , R ６ -S (O) ２ -, and R ６ are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

10. The following compound, a pharma- ceutically acceptable salt or stereoisomer thereof: 【Chemistry 7】 【change】 【change】 A compound, a pharma- ceutically acceptable salt or stereoisomer thereof, selected from:

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable carrier.

12. Use of a compound according to any one of claims 1 to 10, a pharma- ceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for preventing or treating a disease caused by dysregulation of protein kinase activity and / or a disease associated therewith.

13. Use of a compound according to any one of claims 1 to 10, a pharma- ceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for preventing or treating a disease caused by dysregulation of PLK1 kinase activity and / or a disease associated therewith.

14. The application according to claim 12 or 13, wherein the diseases include cancer, cell proliferative diseases, viral infections, autoimmune and neurodegenerative diseases.

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