Fused Bicyclic Compounds

Abstract

The present disclosure belongs to the field of medicinal chemistry and relates to fused bicyclic compounds, in particular to a compound represented by formula (II), its stereoisomers or pharmaceutically acceptable salts thereof, methods for preparing the same, pharmaceutical compositions containing the same and their use for treating diseases. [Formula 1] TIFF2025537520000181.tif35170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This disclosure claims the benefit of and priority to Chinese patent applications bearing application numbers 202211404183.4, 202310799109.5, and 202311448787.3, filed with the State Intellectual Property Office of the People's Republic of China on November 10, 2022, June 30, 2023, and November 1, 2023, the entire contents of which are hereby incorporated herein by reference in their entirety.

[0002] (Technical field) FIELD OF THE DISCLOSURE The present disclosure relates to fused bicyclic compounds, methods for their preparation, pharmaceutical compositions containing such compounds, and their use to treat disease. [Background technology]

[0003] Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that catalyzes the ribosylation of ADP. The PARP family consists of 18 members and plays important roles in a wide range of cellular metabolic processes, including DNA damage repair, inflammation control, transcriptional regulation, signal transduction, genome stability, cell cycle control, and mitosis. PARP1 is the most important PARP enzyme, accounting for 85%–90% of total PARP activity in cells and primarily involved in DNA damage repair. PARP inhibitors can selectively kill tumor cells with defective homologous recombination repair (HR) function due to BRCA gene defects without affecting the survival of normal cells with functional BRCA genes. This phenomenon is called synthetic lethality. Summary of the Invention [Problem to be solved by the invention]

[0004] Since the approval of olaparib in 2014, several PARP inhibitors have been developed and have achieved widespread success. However, the side effects of these drugs limit their use in combination with chemotherapy. Therefore, PARP inhibitors with improved PARP1 selectivity may have better efficacy and lower toxicity. [Means for solving the problem]

[0005] (Summary of the Invention) In one aspect, the present disclosure relates to a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0006] [ka]

[0007] During the ceremony, R is

[0008] [ka]

[0009] is selected from X 1 is CR a , CHR a , N or NR a is selected from X 2 is selected from CH or N, X 3 is selected from CH or N, R 1 is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, or S; 1 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C1-6 alkyl) or -N(C 1-6 alkyl)2, R a is H, halogen or C 1-6 alkyl, Or R a and R 1 are joined together to form a 5- to 7-membered heterocycloalkyl, a 5- to 7-membered cycloalkenyl, a phenyl, a 5- to 7-membered heterocycloalkenyl, or a 5- to 6-membered heteroaryl; R 2 is C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -SH, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -NH2, -NH(C 1-6 alkyl), -NH(C 3-6 -cycloalkyl), -NH(3-8 membered heterocycloalkyl), -N(C 1-6 alkyl)2, -N(C 1-6 Alkyl)(C 3-6 cycloalkyl) or -N(C 3-6 cycloalkyl)2, wherein R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 optionally substituted with one or more groups selected from cycloalkyl or 3- to 8-membered heterocycloalkyl; R 3 , R 4 and R 5 are each independently, C 1-6 Alkyl, D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, wherein C 1-6Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)2 is D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, o, p, and q are each independently selected from 0, 1, or 2; L is selected from -NH- or -CH2-, and said L is C 1-6 Alkyl, D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, Ring A is selected from 3- to 8-membered heterocycloalkyl, and said ring A may further contain 1 to 3 heteroatoms independently selected from N, O or S in addition to the N atom bonded to L, and said ring A is selected from D, halogen, —OH, —C 1-6 Alkyl, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -C 1-4 Alkylene-OC 1-6 Alkyl, -C 1-4 Alkylene-SC 1-6 Alkyl, -C 1-4 Alkylene-NH(C 1-6 alkyl) or -C 1-4 Alkylene-N(C 1-6 alkyl)2, Ring B is selected from an aromatic ring or a partially saturated ring; Y 1 , Y2 and Y 3 are each independently selected from C, CH, N, O, or S.

[0010] In some embodiments, the compound of formula (II) is selected from the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0011] [ka]

[0012] During the ceremony, X 1 is CR a or N, X 2 is selected from CH or N, R 1 is C 1-6 Alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, or S; 1 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, R a is H, halogen or C 1-6 alkyl, Or R a and R 1 are bonded to each other to form a 5- to 7-membered cycloalkenyl or a 5- to 7-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O, or S; R 2 is C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -SH, -SC 1-6 Alkyl, -SC 3-6Cycloalkyl, -NH2, -NH(C 1-6 alkyl), -NH(C 3-6 cycloalkyl), -N(C 1-6 alkyl)2, -N(C 1-6 Alkyl)(C 3-6 cycloalkyl) or -N(C 3-6 cycloalkyl)2, wherein R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, R 3 , R 4 and R 5 are each independently, C 1-6 Alkyl, D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, wherein C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)2 is D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, o, p, and q are each independently selected from 0, 1, or 2; L is selected from -NH- or -CH2-, and said L is C 1-6 Alkyl, D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6alkyl)2, Ring A is selected from 3- to 8-membered heterocycloalkyl, and said ring A may further contain 1 to 3 heteroatoms independently selected from N, O, or S in addition to the N atom bonded to L, and said ring A is selected from D, halogen, —OH, —OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, Ring B is selected from an aromatic ring or an incompletely saturated ring; Y 1 , Y 2 and Y 3 are each independently selected from C, N, O, or S.

[0013] In some embodiments, the compound of formula (II) is selected from the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, X 1 is CR a or N, X 2 is selected from CH or N, R 1 is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, or S; 1 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, Ra is H, halogen or C 1-6 alkyl, Or R a and R 1 are bonded to each other to form a 5- to 7-membered cycloalkenyl, phenyl, 5- to 7-membered heterocycloalkenyl, or 5- to 6-membered heteroaryl; R 2 is C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -SH, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -NH2, -NH(C 1-6 alkyl), -NH(C 3-6 -cycloalkyl), -NH(3-8 membered heterocycloalkyl), -N(C 1-6 alkyl)2, -N(C 1-6 Alkyl)(C 3-6 cycloalkyl) or -N(C 3-6 cycloalkyl)2, wherein R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, R 3 , R 4 and R 5 are each independently, C 1-6 Alkyl, D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, wherein C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)2 is D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, o, p, and q are each independently selected from 0, 1, or 2; L is selected from -NH- or -CH2-, and said L is C 1-6 Alkyl, D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, Ring A is selected from 3- to 8-membered heterocycloalkyl, and said ring A may further contain 1 to 3 heteroatoms independently selected from N, O or S in addition to the N atom bonded to L, and said ring A is selected from D, halogen, —OH, —C 1-6 Alkyl, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, Ring B is selected from an aromatic ring or an incompletely saturated ring; Y 1 , Y 2 and Y 3 are each independently selected from C, CH, N, O, or S.

[0014] In some embodiments, the X 1 is CR a or N.

[0015] In some other embodiments, the X 1 is CHR a or NR a is selected from.

[0016] In some other embodiments, the X 1is CHR a is selected from.

[0017] In some embodiments, the X 1 is CR a Selected from X 2 is selected from CH.

[0018] In some embodiments, the X 1 is selected from CH, and X 2 is selected from N.

[0019] In some embodiments, the X 1 is selected from N, and X 2 is selected from CH.

[0020] In some embodiments, the X 1 is NR a Selected from X 2 is selected from CH.

[0021] In some embodiments, the X 3 is selected from CH.

[0022] In some embodiments, the X 1 is CR a Selected from X 2 is selected from CH, and X 3 is selected from CH.

[0023] In some embodiments, the X 1 is selected from CH, and X 2 is selected from N, and X 3 is selected from CH.

[0024] In some embodiments, the X 1 is selected from N, and X 2 is selected from CH, and X 3 is selected from CH.

[0025] In some embodiments, the X 1 is selected from CH, and X 2 is selected from CH, and X 3 is selected from N.

[0026] In some embodiments, the X 1 is NR a Selected from X 2 is selected from CH, and X 3 is selected from CH.

[0027] In some embodiments, the R 1 is a halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, or S; 1 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2.

[0028] In some embodiments, the R 1 is C 1-4 Alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, or S; 1 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2.

[0029] In some embodiments, the R 1 is a halogen, C 1-4 Alkyl or C3-6 cycloalkyl, wherein R 1 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-3 Alkyl, -NH2, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl)2.

[0030] In some embodiments, the R 1 is a halogen, C 1-4 Alkyl or C 3-6 cycloalkyl, wherein R 1 is optionally substituted with one or more groups selected from D or halogen.

[0031] In some embodiments, the R 1 is a halogen, C 1-3 Alkyl or C 3-6 cycloalkyl, wherein R 1 may be substituted with one or more groups selected from halogen.

[0032] In some embodiments, the R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, or S; 1 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 In some embodiments, R 1 is selected from halogens.

[0033] In some embodiments, the R 1is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, or S; 1 are D, F, Cl, Br, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 In some embodiments, R 1 is selected from halogens.

[0034] In some embodiments, the R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, or piperazinyl; 1 are D, F, Cl, Br, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 In some embodiments, R 1 is selected from F, Cl, Br or I.

[0035] In some embodiments, the R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, or tetrahydropyranyl, and said R 1 are D, F, Cl, Br, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4In some embodiments, R 1 is selected from F, Cl, Br or I.

[0036] In some embodiments, the R 1 is methyl, ethyl, propyl,

[0037] [ka]

[0038] [ka]

[0039] wherein R is selected from 1 are D, F, Cl, Br, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 In some embodiments, R 1 is selected from Cl.

[0040] In some embodiments, the R 1 is Cl, methyl, ethyl, propyl,

[0041] [ka]

[0042] [ka]

[0043] wherein R is selected from 1 is optionally substituted with one or more groups selected from D, F, Cl or Br.

[0044] In some embodiments, the R 1 is Cl, methyl, ethyl, propyl,

[0045] [ka]

[0046] [ka]

[0047] wherein R is selected from 1 may be substituted with one or more F.

[0048] In some embodiments, the R 1 is chloro, methyl, ethyl, propyl, trifluoromethyl,

[0049] [ka]

[0050] [ka]

[0051] is selected from.

[0052] In some embodiments, the R 1 is methyl, ethyl, propyl,

[0053] [ka]

[0054] [ka]

[0055] is selected from.

[0056] In some embodiments, the R 1 is chloro, methyl, ethyl, trifluoromethyl or [ka] is selected from.

[0057] In some embodiments, the R 1 is ethyl or [ka] is selected from.

[0058] In some embodiments, the R a is H, F, Cl, Br or C 1-4 alkyl.

[0059] In some embodiments, the R a is H, F, Cl or C 1-3 alkyl.

[0060] In some embodiments, the R a is selected from H, F, Cl, methyl, ethyl or propyl.

[0061] In some other embodiments, the R a is selected from H or methyl.

[0062] In some embodiments, the R a is selected from H or F.

[0063] In some embodiments, the R a is selected from H.

[0064] In some embodiments, the R a and the R 1are bonded to each other to form a 5- to 6-membered heterocycloalkyl, a 5- to 6-membered cycloalkenyl, a phenyl, or a 5- to 6-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O, or S, or a 5- to 6-membered heteroaryl.

[0065] In some embodiments, the R a and the R 1 are bonded to each other to form a 5- to 6-membered cycloalkenyl, phenyl, or a 5- to 6-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O, or S, or a 5- to 6-membered heteroaryl.

[0066] In some embodiments, the R a and the R 1 are bonded to each other to form a 5- to 6-membered cycloalkenyl, or a 5-membered heterocycloalkenyl containing one heteroatom independently selected from N or O, or a 5-membered heteroaryl.

[0067] In some embodiments, the R a and the R 1 are bonded to each other to form a 5- to 6-membered cycloalkenyl or a 5- to 6-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O, or S.

[0068] In some embodiments, the R a and the R 1 are bonded to each other to form a 5- to 6-membered cycloalkenyl or a 5-membered heterocycloalkenyl containing one heteroatom independently selected from N or O.

[0069] In some other embodiments, the R a and the R 1 are bonded to each other to form a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O or S.

[0070] In some other embodiments, the R aand the R 1 are linked together to form a 5-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, or S.

[0071] In some other embodiments, the R a and the R 1 are linked together to form a 5-membered heteroaryl containing 1 to 2 N atoms.

[0072] In some embodiments, the R a and the R 1 are joined together to form cyclopentenyl, cyclohexenyl, dihydrofuranyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, or thiazolyl.

[0073] In some embodiments, the R a and the R 1 are linked to each other to form cyclopentenyl, cyclohexenyl, or dihydrofuranyl.

[0074] In some other embodiments, R is

[0075] [ka]

[0076] is selected from.

[0077] In some other embodiments, R is

[0078] [ka]

[0079] is selected from.

[0080] In some other embodiments, R is

[0081] [ka]

[0082] is selected from.

[0083] In some other embodiments, R is

[0084] [ka]

[0085] [ka]

[0086] [ka]

[0087] wherein R is selected from 0, 1 or 2 R 3 is replaced by .

[0088] In some other embodiments, R is

[0089] [ka]

[0090] wherein R is selected from 0, 1 or 2 R 3 is replaced by .

[0091] In some other embodiments, R is

[0092] [ka]

[0093] wherein R is selected from 0, 1 or 2 R 3 is replaced by .

[0094] In some embodiments, R is

[0095] [ka]

[0096] In some embodiments, R is selected from:

[0097] [ka]

[0098] is selected from.

[0099] In some embodiments, R is

[0100] [ka]

[0101] Selected from R a and R 1 are bonded to each other to form a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O or S.

[0102] In some embodiments, R is

[0103] [ka]

[0104] Selected from R a and R 1 are linked together to form a 5-membered heteroaryl containing 1 to 2 N atoms.

[0105] In some embodiments, R is

[0106] [ka]

[0107] Selected from R a and R 1 are linked together to form pyrrolyl, pyrazolyl, or imidazolyl.

[0108] In some embodiments, R is

[0109] [ka]

[0110] wherein R is selected from 0, 1 or 2 R 3 is replaced by .

[0111] In some embodiments, R is

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] and R is selected from 0, 1 or 2 R 3 is replaced by .

[0116] In some embodiments, R is

[0117] [ka]

[0118] [ka]

[0119] is selected from.

[0120] In some embodiments, R is

[0121] [ka]

[0122] [ka]

[0123] is selected from.

[0124] In some embodiments, R is

[0125] [ka]

[0126] is selected from.

[0127] In some other embodiments, the R 2 is C 1-4 Alkyl, -OH, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -SH, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -NH2, -NH(C 1-4 alkyl), -NH(C 3-6 -cycloalkyl), -NH(3-8 membered heterocycloalkyl), -N(C 1-4 alkyl)2, -N(C 1-4 Alkyl)(C 3-6 cycloalkyl) or -N(C 3-6 cycloalkyl)2, wherein R 2D, halogen, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)2, C 3-6 It may be substituted with one or more groups selected from cycloalkyl or 3- to 8-membered heterocycloalkyl.

[0128] In some embodiments, the R 2 is C 1-4 Alkyl, -OH, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -SH, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -NH2, -NH(C 1-4 alkyl), -NH(C 3-6 cycloalkyl), -N(C 1-4 alkyl)2, -N(C 1-4 Alkyl)(C 3-6 cycloalkyl) or -N(C 3-6 cycloalkyl)2, wherein R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 In some embodiments, the R 2 is selected from -NH(3- to 6-membered heterocycloalkyl), and said R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 In some embodiments, the R 2 D, halogen, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C1-4 alkyl) or -N(C 1-4 Alkyl)2, C 3-6 It may be substituted with one or more groups selected from cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0129] In some embodiments, the R 2 is C 1-4 Alkyl, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -NH(C 3-6 cycloalkyl), -NH(3- to 6-membered heterocycloalkyl) or -N(C 1-4 alkyl)2, wherein R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 In some embodiments, the R 2 D, halogen, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)2, C 3-6 It may be substituted with one or more groups selected from cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0130] In some embodiments, the R 2 is C 1-4 Alkyl, -OH, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -NH(C 3-6 cycloalkyl) or -N(C 1-4 alkyl)2, wherein R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 In some embodiments, the R 2 is selected from -NH(3- to 6-membered heterocycloalkyl), and said R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 In some embodiments, the R 2 D, halogen, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)2, C 3-6 It may be substituted with one or more groups selected from cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0131] In some embodiments, the R 2 -NH2, -NH(C 1-4 alkyl), -NH(C 3-6 cycloalkyl) or -N(C 1-4 alkyl)2, wherein R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 In some embodiments, the R 2 is selected from -NH(3- to 6-membered heterocycloalkyl), and said R 2 D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6In some embodiments, the R 2 D, halogen, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)2, C 3-6 It may be substituted with one or more groups selected from cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0132] In some embodiments, the R 2 -NH2, -NH(C 1-4 alkyl), -NH(C 3-6 cycloalkyl), or -N(C 1-4 alkyl)2, wherein R 2 are D, F, Cl, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 In some embodiments, the R 2 is selected from -NH(3- to 6-membered heterocycloalkyl), and said R 2 are D, F, Cl, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 In some embodiments, the R 2 is -NH(C 1-4 alkyl), -NH(C 3-6 -cycloalkyl), or -NH(3- to 6-membered heterocycloalkyl), wherein R 2 may be substituted with one or more D's.

[0133] In some embodiments, the R 2 is -NH(C1-4 alkyl), -NH(C 3-6 -cycloalkyl) or -NH(3- to 8-membered heterocycloalkyl), wherein R 2 D, halogen, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)2, C 3-6 It may be substituted with one or more groups selected from cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0134] In some embodiments, the R 2 is -NH(C 1-4 alkyl), -NH(C 3-6 -cycloalkyl) or -NH(3- to 6-membered heterocycloalkyl), wherein R 2 D, halogen, C 3-6 It may be substituted with one or more groups selected from cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0135] In some embodiments, the R 2 is -NH(C 1-4 alkyl), -NH(C 3-6 -cycloalkyl) or -NH(3- to 6-membered heterocycloalkyl), wherein R 2 is optionally substituted with one or more groups selected from D, F, Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, oxiranyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, or tetrahydrofuranyl.

[0136] In some embodiments, the R 2 are -NHCH3, -NHCH(CH3)2,

[0137] [ka]

[0138] In some embodiments, the R 2 are -NHCH3, -NHCH2CH3,

[0139] [ka]

[0140] [ka]

[0141] In some embodiments, the R 2 is -NHCH2CF3 or

[0142] [ka]

[0143] is selected from.

[0144] In some embodiments, the R 2 are -NHCH3, -NHCH(CH3)2,

[0145] [ka]

[0146] -NHCD3, -NHCH2CH3,

[0147] [ka]

[0148] is selected from.

[0149] In some embodiments, the R 2 are -NHCH3, -NHCH(CH3)2,

[0150] [ka]

[0151] -NHCD3, -NHCH2CH3, -NHCH2CF3,

[0152] [ka]

[0153] is selected from.

[0154] In some embodiments, the R 2 is -NHCH3,

[0155] [ka]

[0156] or —NHCH2CH3.

[0157] In some embodiments, the R 3 is C 1-4 Alkyl, D, F, Cl, Br, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 alkyl)2, wherein C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)2 is D, F, Cl, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 alkyl)2.

[0158] In some embodiments, the R 3 is C 1-3 Alkyl, D, F, Cl, -OH, -OC 1-3 Alkyl, -NH2, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl)2, wherein C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 The alkyl)2 may be substituted with one or more groups selected from D, F, Cl, -OH or -NH2.

[0159] In some embodiments, the R 3 is selected from methyl, ethyl, propyl, F or Cl, and said methyl, ethyl or propyl may be substituted with one or more groups selected from D, F, Cl, —OH or —NH 2 .

[0160] In some embodiments, the R 3 is selected from methyl, ethyl or halogen.

[0161] In some embodiments, the R 3 is selected from halogens.

[0162] In some embodiments, the R 3 is selected from F or Cl.

[0163] In some embodiments, the R 3 is selected from methyl, F or Cl.

[0164] In some embodiments, the R 4 is C 1-4 Alkyl, D, F, Cl, Br, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C1-4 alkyl)2, wherein C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)2 is D, F, Cl, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 alkyl)2.

[0165] In some embodiments, the R 4 is C 1-3 Alkyl, D, F, Cl, -OH, -OC 1-3 Alkyl, -NH2, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl)2, wherein C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 The alkyl)2 may be substituted with one or more groups selected from D, F, Cl, -OH or -NH2.

[0166] In some embodiments, the R 4 is selected from methyl, ethyl, propyl, F or Cl, and said methyl, ethyl or propyl may be substituted with one or more groups selected from D, F, Cl, —OH or —NH 2 .

[0167] In some embodiments, the R 5 is C 1-4 Alkyl, D, F, Cl, Br, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 alkyl)2, wherein C 1-4 Alkyl, -OC 1-4Alkyl, -SC 1-4 Alkyl, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)2 is D, F, Cl, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 alkyl)2.

[0168] In some embodiments, the R 5 is C 1-3 Alkyl, D, F, Cl, -OH, -OC 1-3 Alkyl, -NH2, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl)2, wherein C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 The alkyl)2 may be substituted with one or more groups selected from D, F, Cl, -OH or -NH2.

[0169] In some embodiments, the R 5 is selected from methyl, ethyl, propyl, F or Cl, and said methyl, ethyl or propyl may be substituted with one or more groups selected from D, F, Cl, —OH or —NH 2 .

[0170] In some embodiments, o is selected from 0, 1, or 2.

[0171] In some embodiments, o is selected from 0 or 1.

[0172] In some embodiments, p is selected from 0, 1, or 2.

[0173] In some embodiments, p is selected from 0 or 1. In some embodiments, p is selected from 0.

[0174] In some embodiments, q is selected from 0, 1, or 2.

[0175] In some embodiments, q is selected from 0 or 1. In some embodiments, q is selected from 0.

[0176] In some embodiments, L is selected from -NH- or -CH2-, and said L is C 1-4 It may be substituted with one or more groups selected from alkyl, D, F, Cl, -OH or -NH2.

[0177] In some embodiments, L is selected from -NH- or -CH2-, wherein said L is optionally substituted with one or more groups selected from methyl, D, or F.

[0178] In some embodiments, L is selected from -CH2-.

[0179] In some embodiments, ring A is selected from 3-6 membered heterocycloalkyl, and said ring A may further contain, in addition to the N atom bonded to L, 1-3 heteroatoms independently selected from N, O, or S, and said ring A may be selected from D, halogen, —OH, —OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 or the ring A may be substituted with one or more groups selected from -C 1-6 or the ring A may be substituted with one or more groups selected from -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-SC 1-4 Alkyl, -C 1-4 Alkylene-NH(C 1-4 alkyl) or -C 1-4 Alkylene-N(C 1-4alkyl)2.

[0180] In some embodiments, ring A is selected from 3-6 membered heterocycloalkyl, and said ring A may further contain, in addition to the N atom bonded to L, 1-3 heteroatoms independently selected from N or O, and said ring A is selected from D, F, Cl, —OH, —C 1-4 Alkyl, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 or the ring A may be substituted with one or more groups selected from -C 1-3 Alkylene-OC 1-4 Alkyl, -C 1-3 Alkylene-NH(C 1-4 alkyl) or -C 1-3 Alkylene-N(C 1-4 alkyl)2.

[0181] In some embodiments, ring A is selected from 3-6 membered heterocycloalkyl, and said ring A may further contain, in addition to the N atom bonded to L, 1-3 heteroatoms independently selected from N or O, and said ring A is selected from -OH or -C 1-4 or the ring A may be substituted with one or more groups selected from -C 1-3 Alkylene-OC 1-4 Alkyl, -C 1-3 Alkylene-NH(C 1-4 alkyl) or -C 1-3 Alkylene-N(C 1-4 alkyl)2.

[0182] In some embodiments, ring A is selected from 3-6 membered heterocycloalkyl, and said ring A may further contain, in addition to the N atom bonded to L, 1-3 heteroatoms independently selected from N or O, and said ring A is selected from D, F, Cl, —OH, —OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 or the ring A may be substituted with one or more groups selected from -C 1-3 Alkylene-OC 1-4 It may be substituted with one or more groups selected from alkyl.

[0183] In some embodiments, Ring A is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, diazetidinyl, imidazolinyl, piperazinyl, oxazolinyl, or morpholinyl, and said Ring A is selected from D, F, Cl, —OH, —OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 or the ring A may be substituted with one or more groups selected from -C 1-4 The ring A may be substituted with an alkyl group, or the ring A may be substituted with -C 1-3 Alkylene-OC 1-4 It may be substituted with one or more groups selected from alkyl.

[0184] In some embodiments, Ring A is selected from azetidinyl or tetrahydropyrrolyl, and said Ring A is selected from -OH, -C 1-4 Alkyl or -C 1-3 Alkylene-OC 1-4 It may be substituted with one or more groups selected from alkyl.

[0185] In some embodiments, ring A is selected from azetidinyl or tetrahydropyrrolyl, and said ring A is -OH or -C 1-4It may be substituted with one or more groups selected from alkyl.

[0186] In some embodiments, Ring A is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, diazetidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, or morpholinyl.

[0187] In some embodiments, ring A is

[0188] [ka]

[0189] [ka]

[0190] * is attached to L on the nitrogen atom side marked with * and to the structural fragment on the other side,

[0191] [ka]

[0192] In some embodiments, ring A is represented by

[0193] [ka]

[0194] * is attached to L on the nitrogen atom side marked with * and to the structural fragment on the other side,

[0195] [ka]

[0196] It represents that it is bonded to

[0197] In some embodiments, ring A is

[0198] [ka]

[0199] is selected from The ring A is —OH or —C 1-4 or the ring A may be substituted with one or more groups selected from -OH, -C 1-4 Alkyl or -C 1-3 Alkylene-OC 1-4 It may be substituted with one or more groups selected from alkyl.

[0200] In some embodiments, ring A is

[0201] [ka]

[0202] is selected from * has the same meaning as above.

[0203] In some embodiments, ring A is

[0204] [ka]

[0205] where * has the same meaning as above.

[0206] In some embodiments, ring A is

[0207] [ka]

[0208] where * has the same meaning as above.

[0209] In some embodiments, ring B is selected from aromatic rings.

[0210] In some embodiments, ring B is selected from an aromatic ring containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0211] In some embodiments, ring B is selected from a 5-membered heteroaromatic ring, wherein said 5-membered heteroaromatic ring contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0212] In some embodiments, ring B is selected from a 5-membered heteroaromatic ring, wherein said heteroaromatic ring contains 1 or 2 heteroatoms selected from N, O, or S.

[0213] In some embodiments, ring B is selected from a 5-membered aromatic heterocycle, and Y 1 , Y 2 and Y 3 are each independently selected from C, CH, N, or S.

[0214] In some embodiments, Ring B is selected from a pyrazole ring, a pyrrole ring, a thiazole ring, an oxazole ring, an isoxazole ring, a furan ring, an imidazole ring, or a thiophene ring. In some embodiments, Ring B is selected from a pyrazole ring, a thiazole ring, an imidazole ring, or a thiophene ring. In some embodiments, Ring B is selected from a pyrazole ring, a thiazole ring, or a thiophene ring.

[0215] In some embodiments, ring B is

[0216] [ka]

[0217] In some embodiments, ring B is selected from:

[0218] [ka]

[0219] is selected from.

[0220] In some embodiments, ring B is

[0221] [ka]

[0222] In some embodiments, ring B is selected from:

[0223] [ka]

[0224] is selected from.

[0225] In some embodiments, ring B is

[0226] [ka]

[0227] is selected from.

[0228] In some embodiments, the structural fragment:

[0229] [ka]

[0230] teeth,

[0231] [ka]

[0232] [ka]

[0233] is selected from.

[0234] In some embodiments, the structural fragment:

[0235] [ka] teeth,

[0236] [ka]

[0237] [ka]

[0238] is selected from.

[0239] In some embodiments, the structural fragment:

[0240] [ka]

[0241] teeth,

[0242] [ka]

[0243] [ka]

[0244] [ka]

[0245] In some embodiments, the structural fragment is selected from:

[0246] [ka]

[0247] teeth,

[0248] [ka]

[0249] is selected from.

[0250] In some embodiments, Y 1 is selected from N or S.

[0251] In some embodiments, Y 1 is selected from N.

[0252] In some embodiments, Y 2 is selected from C or N.

[0253] In some embodiments, Y 3 is selected from C, CH, N, O or S.

[0254] In some embodiments, Y 3 is selected from C, N, O or S.

[0255] In some embodiments, Y 3 is selected from CH or S.

[0256] In some embodiments, Y 1 , Y 2 and Y 3 One or two of are selected from N, O or S.

[0257] In some embodiments, Y 1 , Y 2 and Y 3 At least two of are selected from N, O or S.

[0258] In some embodiments, Y 1 and Y 2 is selected from N, Y 3 is selected from CH.

[0259] In some embodiments, Y 1 is selected from N, Y 2 is selected from C, and Y 3 is selected from S.

[0260] In some embodiments, Y 1 is selected from S and Y 2 is selected from C, and Y 3 is selected from CH.

[0261] In some embodiments, the compound of Formula (I) or Formula (II), its stereoisomer, or its pharmaceutically acceptable salt of the present disclosure is selected from the compound of Formula (IB), its stereoisomer, or its pharmaceutically acceptable salt.

[0262] [ka]

[0263] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , Y 2 , Y 3 , o, p, and q are as defined herein; Ring B is selected from aromatic rings containing 1 to 3 heteroatoms independently selected from N, O, or S.

[0264] In some embodiments, the compound of Formula (I) or Formula (II) of the present disclosure, its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of Formula (IC), its stereoisomer, or its pharmaceutically acceptable salt.

[0265] [ka]

[0266] In the formula, R 2 , R 3 , R 4 , R 5 , Y 2 , Y 3 , o, p, and q are as defined herein; Ring B is selected from aromatic rings containing 1 to 3 heteroatoms independently selected from N, O, or S; X 4 is selected from C,

[0267] [ka]

[0268] is a double bond, or X 4 is selected from N,

[0269] [ka]

[0270] is a single bond, X 2 is selected from CH or N, X 5 is selected from CH2 or O, n is selected from 1 or 2.

[0271] In some embodiments, the compound of Formula (I) or Formula (II), its stereoisomer, or its pharmaceutically acceptable salt of the present disclosure is selected from the compound of Formula (ID), its stereoisomer, or its pharmaceutically acceptable salt.

[0272] [ka]

[0273] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , Y 2 , Y 3 , o, p, and q are as defined herein; Ring B is selected from aromatic rings containing 1 to 3 heteroatoms independently selected from N, O, or S.

[0274] In some embodiments, the compound of Formula (I) or Formula (II) of the present disclosure, its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of Formula (IIA), its stereoisomer, or its pharmaceutically acceptable salt.

[0275] [ka]

[0276] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , Y 2 , Y 3 , o, p, and q are as defined herein; R b -OH, -C 1-6 Alkyl or -C 1-4 Alkylene-OC 1-6 alkyl, t is selected from 0, 1 or 2; Ring B is selected from aromatic rings containing 1 to 3 heteroatoms independently selected from N, O, or S.

[0277] In some embodiments, the present disclosure includes the above-defined variables and embodiments thereof, and any combination thereof.

[0278] The heteroatoms in the heterocycloalkyl or heterocycloalkenyl are selected from nitrogen (NH or N), oxygen, or sulfur (S), with the remaining ring atoms being selected from carbon. In some embodiments, the number of heteroatoms is selected from 1, 2, or 3. In some embodiments, the number of heteroatoms is selected from 1 or 2. In some embodiments, the number of heteroatoms is selected from 1.

[0279] In some embodiments, the compound of the present disclosure, its stereoisomer, or its pharmaceutically acceptable salt is selected from the following compounds, its stereoisomer, or its pharmaceutically acceptable salt:

[0280] [ka]

[0281] [ka]

[0282] [ka]

[0283] [ka]

[0284] In some embodiments, the compound of the present disclosure, its stereoisomer, or its pharmaceutically acceptable salt is selected from the following compounds, its stereoisomer, or its pharmaceutically acceptable salt:

[0285] [ka]

[0286] [ka]

[0287] [ka]

[0288] [ka]

[0289] [ka]

[0290] [ka]

[0291] In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0292] In another aspect, the present disclosure further provides a method for treating a PARP1-related disease in a mammal, comprising administering to a mammal (preferably a human) in need of said treatment a therapeutically effective amount of the above-described compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0293] In another aspect, the present disclosure provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for treating a PARP1-associated disease.

[0294] In another aspect, the present disclosure provides use of the above-mentioned compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating a PARP1-associated disease.

[0295] In another aspect, the present disclosure provides the above compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating a PARP1-associated disease.

[0296] In some embodiments, the PARP1-associated disease is selected from a tumor or cancer, hi some embodiments, the cancer is selected from breast cancer, ovarian cancer, colon cancer, pancreatic cancer, or prostate cancer.

[0297] The compounds of the present disclosure have excellent inhibitory activity against PARP1 kinase, MDA-MB-436 cells, high selectivity for PARP1 protein, and good liver microsome stability and in vivo pharmacokinetic properties.

[0298] definition Unless otherwise specified, the following terms used in this disclosure have the following meanings: Certain terms, if not specifically defined, should not be construed as vague or indefinite, but should be understood in their ordinary sense in the art. Trade names mentioned herein refer to the corresponding products or their active ingredients.

[0299] The term "substituted" means that any one or more hydrogen atoms on a specified atom may be replaced by a substituent, provided that the valence state of the specified atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =0), this means that two hydrogen atoms are replaced. Oxo substitution does not occur on aromatic groups.

[0300] The terms "may" or "optionally" mean that the events or circumstances described below may or may not occur, and the phrase encompasses both cases where such events or circumstances occur and cases where they do not occur. For example, ethyl "may" be substituted with a halogen means that ethyl can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), multiply substituted (e.g., CHFCH2F, CH2CHF2), or fully substituted (CF2CF3). One of ordinary skill in the art will understand that for any group containing one or more substituents, no substitutions or substitution patterns that are spatially impossible and / or cannot be synthesized are introduced.

[0301] As used herein, "one or more" refers to an integer between 1 and 10. For example, "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Alternatively, "one or more" refers to 1, 2, 3, 4, 5, or 6. Alternatively, "one or more" refers to 1, 2, or 3. Those skilled in the art will understand that for any group containing one or more substituents, no substitutions or substitution patterns that are spatially inexistent and / or cannot be synthesized are introduced.

[0302] C in this specification m-n means that the moiety has an integer number of carbon atoms in the specified range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0303] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition at each occurrence is independent. Thus, for example, when a group is substituted with two R, each R has an independent alternative.

[0304] If a bond of a substituent crosses two atoms on a ring, then such substituent can be bonded to any atom on the ring. For example, in the structural unit:

[0305] [ka]

[0306] means that the substituent can be substituted at any one position on the cyclohexyl or cyclohexadiene. For example, in the three-ring structure of the present disclosure,

[0307] [ka]

[0308] is the substituent R 3 The fact that it is replaced by R 3 can be present in any of the three rings.

[0309] In this disclosure,

[0310] [ka]

[0311] In X 1 is NR a Selected from R a and R 1 When they are bonded to each other to form a ring, X 1 and C(R 1 ) forms a single bond according to the rules of chemical bonding.

[0312] The term "halogen" or "elemental halogen" means fluorine, chlorine, bromine and iodine.

[0313] The term "hydroxyl" refers to an --OH group.

[0314] The term "amino" refers to the group --NH.sub.2.

[0315] The term "cyano" refers to the group --CN.

[0316] The term "alkyl" refers to a group having the general formula C n H 2n+1 The alkyl may be linear or branched. For example, the term "C alkyl" means an alkyl containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0317] The term "alkylene" refers to a group having the general formula C n H 2n For example, "C 1-6 The term "alkylene" means an alkylene containing from 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH- or -CHCH(CH)-), butylene (-CHCHCHCHCH-, -CHCH(CH)CH- or -CHCHCH(CH)-), pentylene, hexylene, and the like.

[0318] The term "alkoxy" means --O-alkyl.

[0319] The term "alkylamino" means -NH-alkyl.

[0320] The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the carbocyclic ring typically has 3 to 10 ring members, preferably 3 to 6 ring members. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0321] The term "heterocycloalkyl" refers to a fully saturated cyclic group that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocycle is typically a 3- to 8-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocycloalkyls include, but are not limited to, oxiranyl, thiiranyl, and aziranyl. Non-limiting examples of 4-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocycloalkyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-oxathianyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Monocyclic heterocycloalkyls having 4 or 6 ring atoms are preferred.

[0322] The term "heterocycloalkenyl" includes cycloalkenyl in which one or more carbon atoms are replaced with heteroatoms, specifically, for example, cycloalkenyl in which up to three carbon atoms, in one embodiment up to two carbon atoms, and in another embodiment one carbon atom, are each independently replaced with O, S, or N, provided that at least one carbon-carbon double bond of the cycloalkenyl is retained. Cycloalkenyl groups, which can exist as monocyclic, bridged, or spirocyclic rings, can be 3- to 12-membered rings (e.g., 5-, 6-, or 7-membered rings). Examples of heterocycloalkenyls include, but are not limited to, dihydropyrrolyl, dihydrofuranyl, tetrahydropyridyl, tetrahydroazetidinyl, or azaspirooctene.

[0323] The term "heterocyclyl" refers to a fully saturated, incompletely saturated, or aromatic ring that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocycle is typically a 3- to 10-membered, 5- to 8-membered, or 5- or 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from N, O, and S. Non-limiting examples of heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, furanyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, pyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3-azabicyclo[3.1.0]hexyl, and the like.

[0324] The term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. Unless otherwise specified, an aryl can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene. The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 5- to 8-membered ring, particularly a single 5- to 6-membered ring, or multiple fused rings containing 6 to 14, and particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

[0325] The term "fused" means that two or more carbocyclic or heterocyclic rings are joined so that they share two atoms to form a polycyclic compound, including fully saturated, incompletely saturated, and aromatic rings. Unless otherwise specified, the fused ring has 5 to 20 members, preferably 8 to 12 members, and more preferably 9 to 10 members. Non-limiting examples of fused heteroaryls include naphthalene, anthracene, phenanthrene,

[0326] [ka]

[0327] These include, but are not limited to:

[0328] As used herein, "cycloalkyl," "heterocycloalkyl," "cycloalkenyl," "heterocycloalkenyl," "aryl," and "heteroaryl" each independently represent oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, alkoxy halide, alkylamino, dialkylamino, alkylamino halide, dialkylamino halide, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH, -C(O)NH-alkyl, -C(O)N(alkyl), -NHC(O)-alkyl. and optionally substituted by one or more substituents selected from alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)-alkyl, -S(O)NH, -S(O)NH-alkyl, -S(O)N(alkyl), cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocycloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0329] The term "treatment" means administering a compound or formulation according to the present disclosure to improve or eliminate a disease or one or more symptoms associated with said disease, and includes: (i) To inhibit the disease or condition, i.e., to arrest its progression. (ii) Alleviating the disease or condition, i.e., reducing or eliminating the disease or condition.

[0330] The term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that (i) treats a specific disease, condition, or disorder described herein, (ii) reduces, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder described herein, or (iii) prevents or delays a specific disease, condition, or one or more disorders described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease and its severity, the method of administration, and the age of the mammal being treated, but can generally be determined by one of ordinary skill in the art based on their own knowledge and the present disclosure.

[0331] The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, with respect to a compound, material, composition and / or dosage form, 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.

[0332] Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.

[0333] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. Pharmaceutical compositions are intended to facilitate administration of the compounds of the present disclosure to a living organism.

[0334] The term "pharmaceutically acceptable additive" refers to an additive that is not significantly irritating to living organisms and does not impair the biological activity and properties of the active compound. Suitable additives are well known to those skilled in the art, and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0335] The terms "comprise" or "comprise" and their English variants, such as comprises or comprising, are to be understood in an open and non-exclusive sense, i.e., "including but not limited to."

[0336] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, where a proton can migrate between the two ring nitrogens. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0337] Unless otherwise specified, singular terms include plural terms and plural terms include the singular term. Unless otherwise specified, the words "one" or "one" mean "at least one" or "at least one."

[0338] The compounds of the present disclosure may exist in particular stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomer- or diastereomer-enriched mixtures, all of which are within the scope of the present disclosure. Substituents such as alkyl groups may also have additional asymmetric carbon atoms. All such isomers and mixtures thereof are within the scope of the present disclosure.

[0339] Solid wedge bonds unless otherwise noted

[0340] [ka]

[0341] and wedge-shaped dashed bond

[0342] [ka]

[0343] indicates the absolute configuration of the stereocenter, and a straight solid bond

[0344] [ka]

[0345] and straight dashed bond

[0346] [ka]

[0347] indicates the relative configuration of the stereocenters.

[0348] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other common techniques. If a single enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, and the resulting mixture of diastereomers can be separated and the auxiliary cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the pure enantiomer can be recovered by forming a diastereomeric salt with an appropriate optically active acid or base, followed by resolution of the diastereomers by conventional methods well known in the art. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography using chiral stationary phases, optionally followed by chemical derivatization (e.g., formation of carbamates from amines).

[0349] The present disclosure further includes isotopically labeled compounds of the present disclosure that are the same as those described herein, except that one or more atoms are replaced with an atom having an atomic mass or mass number different from that typically found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 It is Cl.

[0350] Some isotopically labeled versions of the compounds of the present disclosure (e.g., 3 H and 14 C) can be used to assay the distribution of compounds and / or substrates in tissues. 3 H) isotopes and carbon-14 (i.e. 14 C) Isotopes are particularly preferred because they are easy to prepare and detect. 15 O. 13 N, 11 C. 18 Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to measure substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared following procedures similar to those disclosed in the following embodiments and / or examples by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0351] Additionally, heavier isotopes (e.g., deuterium (i.e. 2Substitution with H) may confer certain therapeutic benefits (e.g., increased in vivo half-life and reduced dosage needs) resulting from greater metabolic stability and therefore may be preferred in some cases. Deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium. Exemplary deuterated compounds are shown below, but are not limited to:

[0352] Pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be prepared into solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols.

[0353] Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0354] The pharmaceutical compositions of the present disclosure can be manufactured by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, and lyophilizing methods which are well known in the art.

[0355] In all administration methods of the compound of general formula I described herein, the daily dose is 0.01 to 200 mg / kg body weight, and is administered in the form of a single dose or divided doses. The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments exemplified below, embodiments formed in combination with other chemical synthetic methods, and equivalent alternative embodiments known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0356] The chemical reactions in specific embodiments of the present disclosure are carried out in suitable solvents, which must be suitable for the chemical transformations of the present disclosure and the necessary reagents and materials. In some cases, those skilled in the art may need to modify or select synthetic steps or reaction schemes based on existing embodiments to obtain compounds of the present disclosure.

[0357] An important consideration in designing a synthetic route in the art is the selection of a suitable protecting group for a reactive functional group (e.g., an amino group in the present disclosure). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed.), Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this disclosure are incorporated herein in their entirety. DETAILED DESCRIPTION OF THE INVENTION

[0358] Furthermore, the present disclosure will be clearly explained with reference to examples, but the examples are not intended to limit the scope of the present disclosure. It will be apparent to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0359] The compounds of the present disclosure can be prepared by those skilled in the art of organic synthesis by referring to the routes or methods in the following examples, and the resulting compounds can be characterized by known instruments or methods, including but not limited to mass spectrometry, NMR, etc.

[0360] The following abbreviations are used in this disclosure:

[0361] Boc represents tert-butoxycarbonyl, THF represents tetrahydrofuran, IBX represents 2-iodoxybenzoic acid, TFA represents trifluoroacetic acid, mCPBA represents m-chloroperoxybenzoic acid, RuPhosPdG3 represents (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, DIBAL-H represents diisobutylaluminum hydride, DIPEA represents N,N-diisopropylethylamine, and PdCl2(dppf) represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0362] Example 1: Preparation of Compound 1

[0363] [ka]

[0364] Step A: Preparation of Compound 1-1 The following compounds were added sequentially to a 100 mL single-neck flask: pyrrolo[3,4-C]pyrazole-5(2H,4H,6H)-carboxylic acid tert-butyl ester (1 g), dichloromethane (40 mL), sodium carbonate (1.25 g), and p-nitrophenyl chloroformate (1 g), and the mixture was allowed to react at room temperature for 4 hours. The reaction mixture was diluted with 500 mL of water and 200 mL of dichloromethane, shaken vigorously, and separated. The organic and aqueous phases were separated, and the aqueous phase was extracted twice with dichloromethane (100 mL each). The organic phases were combined, washed with water (10 mL each), and the remaining organic phase was dried, followed by rotary drying and heat drying. 1.75 g of compound 1-1 was obtained.

[0365] Step B: Preparation of Compound 1-2 Compound 1-1 (1.3 g), dichloromethane (40 mL), triethylamine (0.9 g), and methylamine hydrochloride (0.27 g) were added sequentially to a 100 mL single-neck flask and reacted at room temperature for 4 hours. The reaction mixture was concentrated until the distillate stopped evaporating, and then 30 mL of purified water was added and triturated to leave a filter cake. After trituration three times, the filter cake was collected and dried under heat. 800 mg of compound 1-2 was obtained.

[0366] MS (ESI, [M+H] + ) m / z: 267.12. Step C: Preparation of Compounds 1-3 Compound 1-2 (250 mg), dichloromethane (10 mL), and trifluoroacetic acid (3 mL) were sequentially added to a 100 mL single-neck flask. After the addition, the mixture was reacted at room temperature under nitrogen purging. After the reaction was completed, excess acid and the solvent were removed under reduced pressure to obtain compound 1-3.

[0367] MS (ESI, [M+H] + ) m / z: 167.12. Step D: Preparation of Compounds 1-4 To a 100 mL three-neck flask, m-bromoaniline (4 g), dichloromethane (50 mL), and triethylamine (4.7 g) were sequentially added. Under nitrogen protection, n-butyryl chloride (2.6 g) was slowly added dropwise to the mixture in an ice-salt bath. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, 30 mL of water was added to the reaction system, and the mixture was extracted three times with dichloromethane (60 mL). The organic phases were combined, dried, concentrated, and purified by column chromatography to obtain 2.6 g of compound 1-4.

[0368] MS(ESI, [MH] - ) m / z: 240.0. Step E: Preparation of Compounds 1-5 A 100 mL single-neck flask was prepared, and phosphorus oxychloride (30 g) was weighed and added to the flask. Under nitrogen protection, the reaction system was placed in an ice-salt bath. N,N-dimethylformamide (2.5 g) was then weighed and slowly added dropwise to the flask. After the dropwise addition, the mixture was stirred for 2 hours while controlling the temperature. Compound 1-4 (5.5 g) was slowly added to the flask in batches. After the addition, the mixture was slowly returned to room temperature, then the temperature was raised to 65 °C, and the reaction was continued for 12 hours while controlling the temperature. Upon completion of the reaction, the reaction solution was poured into 100 mL of ice water, and the pH was adjusted to neutral with the addition of aqueous ammonia. The mixture was extracted three times with ethyl acetate (100 mL), and the organic phase was collected. The organic phase was concentrated and purified by column chromatography to obtain 1.8 g of compound 1-5.

[0369] MS (ESI, [M+H] + ) m / z: 269.93. Step F: Preparation of Compounds 1-6 Compound 1-5 (4.75 g), 1,4-dioxane (40 mL), and 3 M aqueous hydrochloric acid (80 mL) were added sequentially to a 250 mL single-neck flask, and the temperature was raised to 100° C. The reaction was carried out for 6 hours while controlling the temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and dried by heating to obtain 4 g of compound 1-6.

[0370] MS (ESI, [M+H] + ) m / z: 252.10. Step G: Preparation of Compounds 1-7 A 100 mL three-neck flask was prepared, and compound 1-6 (650 mg) was dissolved in tetrahydrofuran (20 mL). Under nitrogen gas protection, the temperature of the reaction system was lowered to -78 °C. 2.5 M n-butyllithium (2.3 mL) was weighed and slowly added dropwise to the reaction system, controlling the temperature so that it did not exceed -70 °C. The reaction was allowed to proceed at -78 °C for 1 hour. N,N-dimethylformamide (0.94 g) was weighed and added dropwise to the flask. The temperature during the addition was controlled so that it did not exceed -70 °C, and the reaction was allowed to proceed at -78 °C for 2 hours. Upon completion of the reaction, the reaction system was quenched by adding saturated aqueous ammonium chloride solution. The reaction was extracted three times with ethyl acetate (100 mL), and the organic phase was collected. The organic phase was concentrated and purified by column chromatography to obtain 130 mg of compound 1-7.

[0371] MS (ESI, [M+H] + ) m / z: 202.10. Step H: Preparation of Compounds 1-8 Following the procedure of Step C of Example 1, compound 1-8 was prepared by reacting 1-Boc-3-iodoazetidine with trifluoroacetic acid.

[0372] MS (ESI, [M+H] + ) m / z: 184.00. Step I: Preparation of Compounds 1-9 A 50 mL single-neck flask was prepared, and compound 1-7 (800 mg), toluene (20 mL), compound 1-8 (500 mg), tetraisopropyl titanate (706 mg), and triethylamine (503 mg) were sequentially added to the flask. The temperature was raised to 60°C. Sodium triacetoxyborohydride (1.5 g) was then weighed and slowly added to the flask in batches. The temperature was controlled at 60°C and the reaction was carried out for 10 hours. After extraction, concentration, and purification by column chromatography, 300 mg of compound 1-9 was obtained.

[0373] MS (ESI, [M+H] + ) m / z: 369.07. Step J: Preparation of Compound 1 Compound 1-3 (100 mg), acetonitrile (20 mL), triethylamine (150 mg), and compound 1-9 (150 mg) were sequentially added to a 100 mL single-neck flask and reacted at 60° C. for 18 hours. Purification by column chromatography was carried out to obtain 10 mg of compound 1.

[0374] 1 H NMR(500MHz,DMSO-d6)δ11.65(s,1H),8.29(q,J=4.4Hz,1H),7.94(s,1H),7.6 7(s,1H),7.53(d,J=8.0Hz,1H),7.22(s,1H),7.09-7.01(m,1H),3.69(s,2H),3 .65(d,J=6.7Hz,4H),3.57(p,J=6.2Hz,1H),3.39(t,J=7.0Hz,2H),3.06(t,J=6 .8Hz,2H),2.77(d,J=4.7Hz,3H),2.47(d,J=7.4Hz,2H),1.15(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 407.2195. Example 2: Preparation of Compound 2

[0375] [ka]

[0376] Step A: Preparation of Compound 2-1 A 250 mL single-neck flask was prepared, and cyclopropylethanol (4 g) and 2-iodoxybenzoic acid (39.0 g) were added. After the addition, the flask was placed in an oil bath under nitrogen protection and heated to 80°C to cause a reflux reaction. After the reaction was completed, the mixture was filtered and concentrated to obtain compound 2-1.

[0377] MS(EI,[M] + ) m / z: 84.10. Step B: Preparation of Compound 2-2 A 250 mL three-neck flask was prepared and compound 2-1 (3.91 g), 2-amino-4-bromobenzaldehyde (9.30 g), potassium hydroxide (7.82 g), and ethanol (90 mL) were added sequentially. After the addition, the flask was placed in an oil bath under nitrogen protection and heated to 95 °C to react. After the reaction was completed, 300 mL of saturated aqueous ammonium chloride solution was poured into the reaction solution, followed by extraction with EA. The organic phase was collected, dried, concentrated, and purified by column chromatography to obtain compound 2-2.

[0378] MS (ESI, [M+H] + ) m / z: 248.08. Step C: Preparation of Compound 2-3 A 500 mL single-neck flask was prepared, and compound 2-2 (8.1 g), m-chloroperoxybenzoic acid (16.9 g), and 150 mL of ethyl acetate were added sequentially. After the addition, the flask was placed in an oil bath under nitrogen protection and heated to 70 °C to react. After the reaction was completed, extraction, concentration, and purification by column chromatography were performed to obtain compound 2-3.

[0379] MS (ESI, [M+H] + ) m / z: 264.02. Step D: Preparation of Compounds 2-4 A 250 mL single-neck flask was prepared, and compound 2-3 (6.1 g), 1,2-dichloroethane (150 mL), and phosphorus oxychloride (6.46 mL) were added sequentially. After the addition, the flask was placed in an oil bath under nitrogen purging protection and heated to 65°C to react. After the reaction was completed, the reaction solution was poured into 300 mL of ice water, and sodium carbonate was added to adjust the pH to neutral. Compound 2-4 was then obtained by extraction, concentration, and purification by column chromatography.

[0380] MS (ESI, [M+H] + ) m / z: 282.03. Step E: Preparation of Compounds 2-5 A 250 mL single-neck flask was prepared, and compound 2-4 (2.56 g), methanol (150 mL), and sodium methoxide (16.31 g) were added in that order. After the addition, the flask was placed in an oil bath under nitrogen protection and heated to 65°C to cause a reaction. After the reaction was completed, extraction, concentration, and purification by column chromatography were carried out to obtain compound 2-5.

[0381] MS (ESI, [M+H] + ) m / z: 278.03. Step F: Preparation of Compounds 2-6 A 250 mL three-neck flask was prepared, and compound 2-5 (2.3 g), methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium(II) (0.692 g), 1,4-dioxane (60 mL), and (tributyltin)methanol (5.31 g) were sequentially added. After the addition, the flask was placed in an oil bath under nitrogen protection and heated to 80 °C to react. After the reaction was completed, the mixture was concentrated and purified by column chromatography to obtain compound 2-6.

[0382] MS (ESI, [M+H] + ) m / z: 230.03. Step G: Preparation of Compounds 2-7 A 100 mL single-neck flask was prepared, and compound 2-6 (1.3 g), 1,4-dioxane (30 mL), and 2 M hydrochloric acid (27.4 mL) were added sequentially. After the addition, the flask was placed in an oil bath and heated to 80°C to react. After the reaction was completed, the pH was adjusted to 10 with saturated aqueous sodium carbonate, followed by extraction, concentration, and purification by column chromatography to obtain compound 2-7.

[0383] MS (ESI, [M+H] + ) m / z: 216.17. Step H: Preparation of Compounds 2-8 A 250 mL single-neck flask was prepared, and compound 2-7 (1.15 g), acetonitrile (150 mL), and 2-iodoxybenzoic acid (3 g) were added sequentially. After the addition, the flask was placed in an oil bath under nitrogen protection and heated to 80°C to react. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography to obtain compound 2-8.

[0384] MS (ESI, [M+H] + ) m / z: 214.22. Step I: Preparation of Compounds 2-9 A 100 mL single-neck flask was prepared, and compound 1-3 (2.3 g), dichloromethane (50 mL), triethylamine (6 mL), 1-Boc-3-azetidinone (2.98 g), and sodium triacetoxyborohydride (5.53 g) were added sequentially. After addition, the mixture was reacted at room temperature under nitrogen protection. After completion of the reaction, extraction, concentration, and purification by column chromatography were performed to obtain compound 2-9.

[0385] MS (ESI, [M+H] + ) m / z: 322.26. Step J: Preparation of Compound 2-10 Following the method of Step C of Example 1, compound 2-10 was prepared by reacting compound 2-9 with trifluoroacetic acid.

[0386] MS (ESI, [M+H] + ) m / z: 222.21. Step K: Preparation of Compound 2 Compound 2 was prepared by reacting Compound 2-8 with Compound 2-10 according to the method of Step I in Example 1.

[0387] 1H NMR(500MHz,DMSO-d6)δ11.67(s,1H),8.34-8.24(m,1H),7.94(s,1H),7.47(d,J=8 .0Hz,1H),7.39(s,1H),7.21(s,1H),7.03(d,J=8.0Hz,1H),3.69(s,2H),3.66(s,2 H),3.63(s,2H),3.57(p,J=6.2Hz,1H),3.38(t,J=6.9Hz,2H),3.06(t,J=6.7Hz,2H ),2.78(d,J=4.7Hz,3H),2.12-2.05(m,1H),0.93-0.88(m,2H),0.74-0.70(m,2H). HRMS (ESI, [M+H] + ) m / z: 419.2197. Example 3: Preparation of Compound 3

[0388] [ka]

[0389] Step A: Preparation of Compound 3-1 The following compounds were sequentially added to a 250 mL single-neck flask: 2,6-difluoronitrobenzene (15 g), concentrated sulfuric acid (100 mL), and N-bromosuccinimide (17.62 g). Under nitrogen protection, the mixture was stirred overnight at 80°C. After completion of the reaction, the reaction solution was poured into ice water and extracted three times with ethyl acetate (200 mL). The organic phase was dried and purified by column chromatography to obtain 17.63 g of compound 3-1.

[0390] Step B: Preparation of Compound 3-2 Compound 3-1 (17.63 g), N,N-dimethylformamide (150 mL), and DL-2-amino-n-butyric acid methyl ester hydrochloride (12.52 g) were sequentially added to a 250 mL single-neck flask. The reaction system was transferred to an ice-salt bath, and N,N-diisopropylethylamine (28.7 g) was slowly added dropwise. After the addition, the mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated to remove the solvent. The crude product was redissolved in ethyl acetate, washed with saturated brine, dried, and purified by column chromatography to obtain 13 g of compound 3-2.

[0391] MS(ESI, [MH] - ) m / z: 333.07. Step C: Preparation of Compound 3-3 Compound 3-2 (12 g), methanol (150 mL), iron powder (10 g), and acetic acid (10.75 g) were sequentially added to a 500 mL single-neck flask. The reaction system was heated to 70 °C and stirred for 1 hour. After the reaction was completed, the reaction solution was filtered, concentrated, washed with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried, and purified by column chromatography to obtain 9 g of compound 3-3.

[0392] MS(ESI, [MH] - ) m / z: 271.06. Step D: Preparation of Compound 3-4 Compound 3-3 (8.73 g), dichloromethane (250 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (9.43 g) were sequentially added to a 500 mL single-neck flask. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to remove the solvent. 300 mL of saturated aqueous sodium bicarbonate solution was added to the crude product and stirred overnight at room temperature. The mixture was filtered, and the filter cake was collected and dried by heating to obtain 8 g of compound 3-4.

[0393] MS(ESI, [MH] - ) m / z: 269.06. Step E: Preparation of Compounds 3-5 Referring to Step F of Example 2, compound 3-5 was prepared by reacting compound 3-4 with (tributyltin)methanol.

[0394] MS (ESI, [M+H] + ) m / z: 223.18. Step F: Preparation of Compounds 3-6 Referring to Step H of Example 2, compound 3-6 was prepared by reacting compound 3-5 with 2-iodoxybenzoic acid.

[0395] MS(ESI, [MH] - ) m / z: 219.15. Step G: Preparation of Compound 3 Compound 3 was prepared by reacting compound 3-6 with compound 2-10 according to the method of Step I in Example 1.

[0396] 1 H NMR(500MHz,DMSO-d6)δ12.40(s,1H),8.37-8.22(m,1H),8.06-7.38(m,2H),7.24(t,J=7.1Hz,1H),3.97(s,1H),3.72(s,2H),3.68(d,J=6.8H) z,2H),3.65(s,1H),3.61-3.54(m,1H),3.43-3.39(m,2H),3.14-3.06( m,2H),2.86-2.80(m,2H),2.78(d,J=4.6Hz,3H),1.21(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 426.2056. Example 4: Preparation of Compound 4

[0397] [ka]

[0398] Step A: Preparation of Compound 4-1 Referring to Step B of Example 1, compound 1-1 was reacted with cyclopropylamine to prepare compound 4-1.

[0399] MS (ESI, [M+H-Boc] + ) m / z:=193.12. Step B: Preparation of Compound 4-2 Referring to the method of Step C of Example 1, compound 4-1 was reacted with trifluoroacetic acid to prepare compound 4-2.

[0400] MS (ESI, [M+H] + ) m / z: 193.20. Step C: Preparation of Compound 4-3 Referring to Step I of Example 2, compound 4-3 was prepared by reacting compound 4-2 with tert-butyl 3-oxoazetidine-1-carboxylate.

[0401] MS (ESI, [M+H] + ) m / z: 348.28. Step D: Preparation of Compound 4-4 Following the method of Step C of Example 1, compound 4-3 was reacted with trifluoroacetic acid to prepare compound 4-4.

[0402] MS (ESI, [M+H] + ) m / z: 248.27. Step E: Preparation of Compound 4 Compound 4 was prepared by reacting compound 1-7 with compound 4-4 according to the method of Step I in Example 1.

[0403] 1 H NMR(500MHz,DMSO-d6)δ11.65(s,1H),8.39(d,J=3.6Hz,1H),7.94(s,1H),7.67(s ,1H),7.53(d,J=8.0Hz,1H),7.22(s,1H),7.05(d,J=7.9Hz,1H),3.75-3.60(m,6H) ,3.57(p,J=6.0Hz,1H),3.40(t,J=6.2Hz,2H),3.17-2.98(m,2H),2.78-2.70(m,1H ),2.50-2.45(m,2H),1.36-1.22(m,2H),1.16(t,J=7.4Hz,3H),0.66-0.64(m,2H). HRMS (ESI, [M+H] + ) m / z: 433.2348. Example 5: Preparation of Compound 5

[0404] [ka]

[0405] Step A: Preparation of Compound 5-1 Referring to Step A of Example 2, compound 5-1 was prepared by reacting 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one with 2-iodoxybenzoic acid.

[0406] MS (ESI, [M+H] + ) m / z: 203.17. Step B: Preparation of Compound 5 Compound 5 was prepared by reacting compound 5-1 with compound 4-4 according to the method of Step I in Example 1.

[0407] 1 H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.40(d,J=3.8Hz,1H),8.35(d,J=1.6 Hz,1H),7.95(s,1H),7.73(s,1H),7.56(s,1H),3.72-3.65(m,6H),3.58(p,J =6.3Hz,1H),3.40(t,J=6.9Hz,2H),3.09(t,J=6.7Hz,2H),2.74(tq,J=8.1, 4.2Hz,1H),2.56-2.52(m,2H),1.18(t,J=7.4Hz,3H),0.65(t,J=4.8Hz,4H). HRMS (ESI, [M+H] + ) m / z: 434.2292. Example 6: Preparation of Compound 6

[0408] [ka]

[0409] Step A: Preparation of Compound 6-1 Referring to Step B of Example 1, compound 1-1 was reacted with isopropylamine to prepare compound 6-1.

[0410] MS (ESI, [M+H-Boc] + ) m / z: 195.22. Step B: Preparation of Compound 6-2 Referring to the method of Step C of Example 1, compound 6-2 was prepared by reacting compound 6-1 with trifluoroacetic acid.

[0411] MS (ESI, [M+H] + ) m / z: 195.21. Step C: Preparation of Compound 6-3 Referring to Step I of Example 2, compound 6-3 was prepared by reacting compound 6-2 with tert-butyl 3-oxoazetidine-1-carboxylate.

[0412] MS (ESI, [M+H] + ) m / z: 350.23. Step D: Preparation of Compound 6-4 Following the method of Step C of Example 1, compound 6-3 was reacted with trifluoroacetic acid to prepare compound 6-4.

[0413] MS (ESI, [M+H] + ) m / z: 250.25. Step E: Preparation of Compound 6 Compound 6 was prepared by reacting compound 5-1 with compound 6-4 according to the method of Step I in Example 1.

[0414] 1H NMR(500MHz,DMSO-d6)δ11.84(s,1H),8.35(d,J=1.5Hz,1H),8.08(d,J=8.4Hz,1H),7.94(s,1H),7.73(s,1H),7.56(s,1H),3.96(dq,J=13. 3,6.6Hz,1H),3.76-3.64(m,6H),3.58(p,J=6.3Hz,1H),3.41(t,J=6.8Hz,2H),3.10(t,J=6.5Hz,2H),2.58-2.52(m,2H),1.21-1.14(m,9H). HRMS (ESI, [M+H] + ) m / z: 436.2460. Example 7: Preparation of Compound 7

[0415] [ka]

[0416] Step A: Preparation of Compound 7-1 To a 1 L single-neck flask, 2-chloro-3-oxosuccinic acid diethyl ester (50.31 g), ethanol (500 mL), and thiourea (17.20 g) were added sequentially. Under nitrogen protection, the mixture was heated to 90 °C and stirred at reflux overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to remove excess ethanol. 200 mL of water was added to the residue, and the mixture was triturated for 1 hour. After filtration, the filter cake was collected and dried under vacuum at 50 °C to obtain 46.7 g of compound 7-1.

[0417] MS (ESI, [M+H] + ) m / z: 245.11. Step B: Preparation of Compound 7-2 Copper bromide (74.4 g), acetonitrile (200 mL), and tert-butyl nitrite (25.8 g) were added sequentially to a 500 mL three-neck flask. The mixture was placed in an ice-salt bath to cool to -5 °C. A solution of compound 7-1 in acetonitrile (60 mL) was slowly added dropwise to the reaction system, controlling the temperature below 0 °C. After the addition, the mixture was stirred at 0 °C for 1 hour. Upon completion of the reaction, the reaction solution was poured into 200 mL of water and extracted with ethyl acetate (300 mL * 3). The organic phase was collected, dried, concentrated, and purified by column chromatography to obtain 51 g of compound 7-2.

[0418] MS (ESI, [M+H] + ) m / z: 307.80. Step C: Preparation of Compound 7-3 Compound 7-2 (31 g) and toluene (100 mL) were sequentially added to a 500 mL three-neck flask. Under nitrogen protection, the mixture was transferred to a low-temperature environment at -78 °C and stirred. A 1.5 M solution of diisobutylaluminum hydride in toluene (201 mL) was slowly added dropwise, and the internal temperature was controlled at -70 °C or below. After the addition, the reaction system was stirred at -78 °C for 3 hours. Upon completion of the reaction, the reaction system was quenched by adding 40 mL of aqueous ammonium chloride solution, filtered through diatomaceous earth to remove insoluble matter, and the filtrate was concentrated, mixed with silica gel, and purified by column chromatography to obtain 16 g of compound 7-3.

[0419] Step D: Preparation of Compound 7-4 Compound 7-3 (0.5 g), anhydrous tetrahydrofuran (20 mL), triphenylphosphine (1.288 g), and carbon tetrabromide (1.628 g) were sequentially added to a 50 mL single-neck flask. The mixture was stirred at room temperature for 1 hour under nitrogen protection. Upon completion of the reaction, 10 mL of water was added to the reaction mixture. The mixture was extracted three times with dichloromethane (50 mL). The organic phase was collected, dried, filtered, concentrated, mixed with silica gel, and purified by column chromatography to give 0.4 g of compound 7-4.

[0420] Step E: Preparation of Compound 7-5 Compound 7-4 (0.1 g), ethanol (10 mL), tert-butyl 3-aminoazetidine-1-carboxylate (68.9 mg), and N,N-diisopropylethylamine (0.11 g) were sequentially added to a 50 mL single-neck flask. The mixture was stirred at 60 °C for 3 h under nitrogen protection. Upon completion of the reaction, 10 mL of water was added to the reaction mixture, which was then extracted three times with ethyl acetate (50 mL). The organic phase was collected, dried, filtered, concentrated, mixed with silica gel, and purified by column chromatography to give 30 mg of compound 7-5.

[0421] MS (ESI, [M+HC(CH3)3] + ) m / z: 304.01. Step F: Preparation of Compound 7-6 Compound 7-5 (0.24 g), methanol (50 mL), triethylamine (0.3 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (60 mg), and 1,3-bis(diphenylphosphino)propane (60 mg) were sequentially added to a 250 mL autoclave. After the addition was complete, the autoclave was sealed and carbon monoxide was passed through it, purging the atmosphere three times. The pressure was then adjusted to 1.5 MPa, the internal temperature was set to 100 °C, and the reaction was allowed to proceed with stirring for 4 hours. Upon completion of the reaction, the reaction mixture was filtered through diatomaceous earth. 1 g of silica gel was added to the filtrate, which was then directly purified by column chromatography to yield 0.1 g of compound 7-6.

[0422] MS (ESI, [M+H] + ) m / z: 340.14. Step G: Preparation of Compound 7-7 Compound 7-6 (0.11 g) and 30% methylamine solution in ethanol (3 mL) were added sequentially to a 15 mL microwave tube. After the addition, the reaction system was sealed and stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction solution was concentrated directly. 20 mL of ethyl acetate and 10 mL of water were added to the crude product. The organic phase was extracted, collected, dried, filtered, concentrated, mixed with silica gel, and purified by column chromatography to give 65 mg of compound 7-7.

[0423] MS (ESI, [M+HC(CH3)3] + ) m / z: 283.15. Step H: Preparation of Compounds 7-8 Following the method of Step C of Example 1, compound 7-7 was reacted with trifluoroacetic acid to prepare compound 7-8.

[0424] MS (ESI, [M+H] + ) m / z: 239.20. Step I: Preparation of Compound 7 Compound 7 was prepared by reacting compound 5-1 with compound 7-8 according to the method of Step I in Example 1.

[0425] 1 H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.75(q,J=4.5Hz,1H),8.35(d,J=1.7Hz,1H),7.73(s,1H),7.56(s,1H),4.02(t,J=3.0Hz,2H),3.88(t,J=3. 0Hz,2H),3.71(s,2H),3.67-3.60(m,1H),3.41(t,J=7.0Hz,2H),3.10(t, J=6.7Hz,2H),2.77(d,J=4.8Hz,2H),2.54(s,3H),1.17(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 425.1757 Example 8: Preparation of Compound 8

[0426] [ka]

[0427] Step A: Preparation of Compound 8 Compound 8 was prepared by reacting Compound 3-6 with Compound 7-8 according to the method of Step I in Example 1.

[0428] 1H NMR(500MHz,DMSO-d6)δ12.40(s,1H),8.74(q,J=4.5Hz,1H),7.52(d,J=8.3 Hz,1H),7.28-7.21(m,1H),4.01(t,J=3.0Hz,2H),3.87(t,J=3.0Hz,2H),3.7 3(s,2H),3.61(dd,J=12.5,6.2Hz,1H),3.42(t,J=6.9Hz,2H),3.12(t,J=6.7 Hz,2H),2.81(q,J=7.4Hz,2H),2.77(d,J=4.8Hz,3H),1.21(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 443.1660. Example 9: Preparation of Compound 9

[0429] [ka]

[0430] Step A: Preparation of Compound 9 Compound 9 was prepared by reacting Compound 1-7 with Compound 6-4 according to the method of Step I in Example 1.

[0431] 1 H NMR(500MHz,DMSO-d6)δ11.64(s,1H),8.06(d,J=8.4Hz,1H),7.94(s,1H),7. 67(s,1H),7.53(d,J=8.0Hz,1H),7.22(s,1H),7.05(d,J=8.0Hz,1H),4.00-3 .92(m,1H),3.69(s,2H),3.66(d,J=4.6Hz,4H),3.57(p,J=6.2Hz,1H),3.40( t,J=6.8Hz,2H),3.07(t,J=6.5Hz,2H),2.50-2.46(m,2H),1.19-1.14(m,9H). HRMS (ESI, [M+H] + ) m / z: 435.2504. Example 10: Preparation of Compound 10

[0432] [ka]

[0433] Step A: Preparation of Compound 10 Compound 10 was prepared by reacting compound 5-1 with compound 2-10 according to the method of Step I in Example 1.

[0434] 1 H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.35(d,J=1.8Hz,1H),8.28(q,J=4.6H z,1H),7.94(s,1H),7.73(d,J=1.4Hz,1H),7.56(d,J=1.8Hz,1H),3.70(d,J= 1.6Hz,4H),3.66(s,2H),3.58(p,J=6.3Hz,1H),3.44-3.37(m,2H),3.09(dd, J=7.4,5.9Hz,2H),2.77(d,J=4.6Hz,3H),2.54(m,2H),1.17(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 408.2143. Example 11: Preparation of Compound 11

[0435] [ka]

[0436] Step A: Preparation of Compound 11 Compound 11 was prepared by reacting compound 2-8 with compound 4-4 according to the method of Step I in Example 1.

[0437] 1H NMR(500MHz,DMSO-d6)δ11.66(s,1H),8.39(d,J=3.9Hz,1H),7.94(s,1H),7.47(d, J=8.0Hz,1H),7.39(s,1H),7.20(s,1H),7.03(d,J=8.0Hz,1H),3.68-3.62(m,6H),3 .56(p,J=6.2Hz,1H),3.38(t,J=6.8Hz,2H),3.05(t,J=6.6Hz,2H),2.78-2.71(m,1 H),2.11-2.05(m,1H),0.92-0.88(m,2H),0.73-0.70(m,2H),0.66(d,J=6.9Hz,4H). HRMS (ESI, [M+H] + ) m / z: 445.2348. Example 12: Preparation of Compound 12

[0438] [ka]

[0439] Step A: Preparation of Compound 12-1 Referring to Step B of Example 1, compound 12-1 was prepared by reacting compound 1-1 with ethylamine.

[0440] MS (ESI, [M+H] + ) m / z: 281.12. Step B: Preparation of Compound 12-2 Following the method of Step C of Example 1, compound 12-1 was reacted with trifluoroacetic acid to prepare compound 12-2.

[0441] MS (ESI, [M+H] + ) m / z: 181.12. Step C: Preparation of Compound 12-3 Referring to Step I of Example 2, compound 12-3 was prepared by reacting compound 12-2 with tert-butyl 3-oxoazetidine-1-carboxylate.

[0442] MS (ESI, [M+H] +) m / z: 336.25. Step D: Preparation of Compound 12-4 Following the method of Step C of Example 1, compound 12-3 was reacted with trifluoroacetic acid to prepare compound 12-4.

[0443] MS (ESI, [M+H] + ) m / z: 236.24. Step E: Preparation of Compound 12 Compound 12 was prepared by reacting compound 5-1 with compound 12-4 according to the method of Step I in Example 1.

[0444] 1 H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.35(d,J=7.9Hz,2H),7.94(s,1H),7.74(s,1H),7.58(s,1H),3.71(d,J=5.1Hz,4H),3.67( m,3H),3.27-3.23(m,2H),3.10(t,J=6.6Hz,2H),2.55(t,J=7.4Hz,2H),1.88(s,2H),1.18(t,J=7.5Hz,3H),1.11(t,J=7.1Hz,3H). HRMS (ESI, [M+H] + ) m / z: 422.2300. Example 13: Preparation of Compound 13

[0445] [ka]

[0446] Step A: Preparation of Compound 13-1 Following the method of Step E of Example 2, compound 13-1 was prepared by reacting compound 1-5 with sodium methoxide.

[0447] Step B: Preparation of Compound 13-2 In a 100 mL three-neck flask, compound 13-1 (650 mg) was dissolved in anhydrous tetrahydrofuran (20 mL). Under nitrogen protection, the temperature of the reaction system was lowered to -78 °C, and 2.5 M n-butyllithium (2.3 mL) was slowly added dropwise to the reaction system, controlling the temperature so that it did not exceed -70 °C. The reaction was carried out at -78 °C for 1 hour. N,N-dimethylformamide (0.94 g) was slowly added dropwise to the reaction system, controlling the temperature so that it did not exceed -70 °C during the addition, and the reaction was carried out at -78 °C for 2 hours. Upon completion of the reaction, the reaction system was quenched by adding saturated aqueous ammonium chloride solution. The reaction was extracted three times with ethyl acetate (100 mL), and the organic phase was collected. The organic phase was concentrated and purified by column chromatography to obtain compound 13-2.

[0448] MS (ESI, [M+H] + ) m / z: 216.09. Step C: Preparation of Compound 13-1 Referring to the method of Step I in Example 1, compound 13-2 was reacted with compound 12-4 to prepare compound 13-1.

[0449] MS (ESI, [M+H] + ) m / z: 435.37. Step D: Preparation of Compound 13 Compound 13-1 (80 mg) and 4 M hydrogen chloride in dioxane (4.60 mL) were added sequentially to a 25 mL one-neck flask, and the mixture was placed in an oil bath at 60 °C under nitrogen protection and reacted overnight. Upon completion of the reaction, the pH was adjusted to 8 using saturated aqueous sodium bicarbonate, extracted three times with ethyl acetate (20 mL), and the organic phase was collected, dried, filtered, concentrated, mixed with silica gel, and purified by column chromatography to give 45 mg of compound 13.

[0450] 1H NMR(500MHz,DMSO-d6)δ11.72(s,1H),8.37(t,J=5.5Hz,1H),7.95(s,1H),7. 69(s,1H),7.57(d,J=7.9Hz,1H),7.26(s,1H),7.12(d,J=7.1Hz,1H),3.85(s ,2H),3.73(s,2H),3.69(s,2H),3.62(d,J=40.6Hz,3H),3.25(dd,J=13.3,6. 7Hz,4H),2.48(d,J=7.3Hz,2H),1.16(t,J=7.4Hz,3H),1.11(t,J=7.1Hz,3H). HRMS (ESI, [M+H] + ) m / z: 421.2346. Example 14: Preparation of Compound 14

[0451] [ka]

[0452] Step A: Preparation of Compound 14-1 Referring to Step B of Example 1, compound 14-1 was prepared by reacting compound 1-1 with deuterated methylamine hydrochloride.

[0453] MS (ESI, [M+H-Boc] + ) m / z: 170.16. Step B: Preparation of Compound 14-2 Following the method of Step C of Example 1, compound 14-1 was reacted with trifluoroacetic acid to prepare compound 14-2.

[0454] MS (ESI, [M+H] + ) m / z: 170.15. Step C: Preparation of Compound 14-3 Referring to Step I of Example 2, compound 14-3 was prepared by reacting compound 14-2 with tert-butyl 3-oxoazetidine-1-carboxylate.

[0455] MS (ESI, [M+H] +) m / z: 325.21. Step D: Preparation of Compound 14-4 Following the method of Step C of Example 1, compound 14-3 was reacted with trifluoroacetic acid to prepare compound 14-4.

[0456] MS (ESI, [M+H] + ) m / z: 225.22. Step E: Preparation of Compound 14 Compound 14 was prepared by reacting compound 1-7 with compound 14-4 according to the method of Step I in Example 1.

[0457] 1 H NMR(500MHz,DMSO-d6)δ11.64(s,1H),8.25(s,1H),7.94(s,1H),7.67(s,1H),7.53(d,J=8.0Hz,1H),7.22(s,1H),7.05(d,J=8.0Hz,1H),3 .70(s,2H),3.68-3.62(m,4H),3.61-3.53(m,1H),3.39(t,J=6.8Hz,2H),3.06(t,J=6.6Hz,2H),2.49-2.45(m,2H),1.16(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 410.2387. Example 15: Preparation of Compound 15

[0458] [ka]

[0459] Step A: Preparation of Compound 15-1 Methyl 2-oxocyclopentane-1-carboxylate (7 g) and anhydrous tetrahydrofuran (100 mL) were added sequentially to a 250 mL three-neck flask. Under nitrogen protection, the reaction system was transferred to an ice-salt bath. Sodium hydride (2.95 g) was added in batches and stirred in the ice-salt bath for 10 minutes. Trifluoromethanesulfonic anhydride (16.67 g) was then slowly added dropwise. After the addition, the reaction system was transferred to room temperature and stirred for 4 hours. Upon completion of the reaction, the reaction was quenched by slowly adding ice water dropwise. The mixture was extracted three times with dichloromethane (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 15-1.

[0460] Step B: Preparation of Compound 15-2 A 100 mL single-neck flask was prepared and charged with compound 15-1 (520 mg), 1,4-dioxane (20 mL), [2-amino-4-(methoxycarbonyl)phenyl]boronic acid (370 mg), potassium carbonate (656 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg), and water (1 mL). The atmosphere was purged with nitrogen three times, and the reaction system was placed in an oil bath and heated to 100 °C. The reaction was allowed to proceed overnight while controlling the temperature. After completion of the reaction, silica gel was added directly to the reaction solution, mixed, and purified by column chromatography to obtain compound 15-2.

[0461] MS (ESI, [M+H] + ) m / z: 244.18. Step C: Preparation of Compound 15-3 Compound 15-2 (280 mg) and anhydrous tetrahydrofuran (10 mL) were sequentially added to a 50 mL single-neck flask. Under nitrogen protection, the reaction system was transferred to an ice-salt bath, and a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (0.9 mL) was slowly added dropwise. The reaction was allowed to proceed for 30 minutes while maintaining the temperature. After completion of the reaction, water was added to quench the reaction, silica gel was added, the mixture was mixed, and the mixture was purified by column chromatography to obtain compound 15-3.

[0462] MS (ESI, [M+H] +) m / z: 216.17. Step D: Preparation of Compound 15-4 Referring to Step H of Example 2, compound 15-4 was prepared by reacting compound 15-3 with 2-iodoxybenzoic acid.

[0463] MS (ESI, [M+H] + ) m / z: 214.21. Step E: Preparation of Compound 15 Compound 15 was prepared by reacting compound 15-4 with compound 2-10 according to the method of Step I in Example 1.

[0464] 1 H NMR(500MHz,DMSO-d6)δ11.50(s,1H),8.27(d,J=4.8Hz,1H),7.93(s,1H),7.67(s,1H),7.32(d,J=8.1Hz,1H),7.17(dd,J=8.1,6.3Hz,1H),3 .79-3.61(m,6H),3.56(q,J=6.3Hz,1H),3.40(t,J=6.9Hz,4H),3.09(q,J=7.0,6.4Hz,3H),2.77(d,J=4.8Hz,4H),2.11(p,J=8.5,8.0Hz,2H). HRMS (ESI, [M+H] + ) m / z: 419.2197. Example 16: Preparation of Compound 16

[0465] [ka]

[0466] Step A: Preparation of Compound 16-1 To a 250 mL single-neck flask, 4-bromo-2-fluoro-6-nitrotoluene (10 g), carbon tetrachloride (100 mL), N-bromosuccinimide (9.13 g), and dibenzoyl peroxide (1.04 g) were sequentially added. Under nitrogen protection, the mixture was stirred overnight at reflux in an oil bath at 90 °C. After the reaction was completed, extraction, concentration, and purification by column chromatography were performed to obtain 10 g of compound 16-1.

[0467] 1 H NMR(500MHz,DMSO-d6)δ8.22-8.09(m,2H),4.73(d,J=1.6Hz,2H). Step B: Preparation of Compound 16-2 Compound 16-1 (1 g), acetonitrile (15 mL), 4A molecular sieves (2.5 g), and N-methylmorpholine oxide (0.75 g) were sequentially added to a 25 mL single-neck flask. The mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, extraction, concentration, and purification by column chromatography were performed to obtain 0.64 g of compound 16-2.

[0468] 1 H NMR(500MHz,DMSO-d6)δ10.13(s,1H),8.29-8.27(m,1H),8.25(dd,J=9.5,1.7Hz,1H). Step C: Preparation of Compound 16-3 Anhydrous tetrahydrofuran (10 mL) and sodium hydride (0.25 g, 60% by mass) were added sequentially to a 100 mL three-neck flask. After no gas evolution occurred, the flask was protected with nitrogen. The reaction system was transferred to an ice-salt bath and the temperature was lowered to 0-5°C. Ethyl 2-(diethoxyphosphoryl)butyrate (0.98 g) was slowly added dropwise using a disposable syringe, and the temperature was controlled at 0-5°C. After the addition was complete, the reaction system was transferred to 0-5°C and stirred for 30 minutes. The reaction system became slightly cloudy, so it was transferred to 40°C and stirred for 5 minutes, resulting in a clear brown liquid. The reaction system was transferred to -78°C, and a tetrahydrofuran solution (5 mL) of compound 16-2 (0.64 g) was slowly added dropwise. After the addition was complete, the reaction system was stirred at -78°C for 1 hour. Upon completion of the reaction, the reaction was quenched by adding 20 mL of saturated aqueous ammonium chloride solution to the reaction system. The reaction mixture was extracted, concentrated, and purified by column chromatography to obtain 0.6 g of compound 16-3.

[0469] 1H NMR(500MHz,DMSO-d6)δ8.29-8.21(m,1H),8.18(dd,J=8.8,1.8Hz,1H),7.34(s,1H),4. 24(q,J=7.1Hz,2H),2.09(q,J=7.4Hz,2H),1.28(t,J=7.1Hz,3H),0.88(t,J=7.4Hz,3H). MS (ESI, [M+H] + ) m / z: 345.96. Step D: Preparation of Compound 16-4 Compound 16-3 (0.6 g), ethanol (6 mL), acetic acid (5 mL), and iron powder (0.3 g) were sequentially added to a 50 mL single-neck flask. The mixture was stirred at 80 °C for 1 hour under nitrogen protection. After the reaction was completed, the mixture was filtered, concentrated, washed with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried, and purified by column chromatography to obtain 0.16 g of compound 16-4.

[0470] 1 H NMR(500MHz,DMSO-d6)δ7.00(s,1H),6.71(d,J=0.7Hz,1H),6.61(dd,J=9.3,1.7Hz,1H),5.63(s ,2H),4.21(q,J=7.1Hz,2H),2.14(q,J=7.3Hz,2H),1.28(t,J=7.1Hz,3H),0.93(t,J=7.4Hz,3H). Step E: Preparation of Compound 16-5 Compound 16-4 (0.2 g), ethanol (2 mL), and acetic acid (2 mL) were added sequentially to a 15 mL microwave tube. The reaction mixture was transferred to a photocatalytic synthesizer and stirred at room temperature for 24 hours at a wavelength of 450 nM. Upon completion of the reaction, the target compound precipitated from the reaction mixture. The precipitate was filtered and dried by heating to obtain 0.07 g of compound 16-5.

[0471] 1 H NMR(500MHz,DMSO-d6)δ12.03(s,1H),7.71(s,1H),7.29(s,2H),2.51-2.20(m,2H),1.16(s,3H). Step F: Preparation of Compound 16-6 Referring to Step F of Example 2, compound 16-6 was prepared by reacting compound 16-5 with (tributyltin)methanol.

[0472] MS (ESI, [M+H] + ) m / z: 222.33. Step G: Preparation of Compound 16-7 Referring to Example 2, Step A, compound 16-7 was prepared by reacting compound 16-6 with 2-iodoxybenzoic acid.

[0473] MS (ESI, [M+H] + ) m / z: 220.16. Step H: Preparation of Compound 16 Compound 16 was prepared by reacting compound 16-7 with compound 2-10 according to the method of Step I in Example 1.

[0474] 1 H NMR(500MHz,DMSO-d6)δ11.90(s,1H),8.28(d,J=4.6Hz,1H),7.95(s,1H),7.72(s,1H),7.08(s,1H),6.91(d,J=10.7Hz,1H),3. 79-3.64(m,6H),3.64-3.55(m,1H),3.45(s,2H),3.14(s,2H),2.78(d,J=4.6Hz,3H),2.57-2.51(m,2H),1.16(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 425.2090. Example 17: Preparation of Compound 17

[0475] [ka]

[0476] Step A: Preparation of Compound 17-1 Referring to Step B of Example 1, compound 17-1 was prepared by reacting compound 1-1 with (R)-3-aminotetrahydrofuran.

[0477] MS (ESI, [M+H] + ) m / z: 323.15. Step B: Preparation of Compound 17-2 Following the method of Step C of Example 1, compound 17-1 was reacted with trifluoroacetic acid to prepare compound 17-2.

[0478] MS (ESI, [M+H] + ) m / z: 223.19. Step C: Preparation of Compound 17-3 Referring to Step I of Example 2, compound 17-3 was prepared by reacting compound 17-2 with tert-butyl 3-oxoazetidine-1-carboxylate.

[0479] MS (ESI, [M+H] + ) m / z: 378.30. Step D: Preparation of Compound 17-4 Following the method of Step C of Example 1, compound 17-3 was reacted with trifluoroacetic acid to prepare compound 17-4.

[0480] MS (ESI, [M+H] + ) m / z: 278.19. Step E: Preparation of Compound 17 Compound 17 was prepared by reacting compound 1-7 with compound 17-4 according to the method of Step E of Example 1.

[0481] 1 H NMR(500MHz,DMSO-d6)δ11.63(s,1H),8.34(d,J=6.2Hz,1H),7.95(s,1H),7.67(s,1H),7.53(d,J=7.6Hz,1H),7.23(s,1H),7.06(d,J=7.5Hz,1H),4. 35(s,1H),3.89-3.79(m,2H),3.78-3.63(m,7H),3.63-3.55(m,2H),3.41( s,2H),3.09(s,2H),2.48(s,2H),2.18-1.95(m,2H),1.16(t,J=6.9Hz,3H). HRMS (ESI, [M+H] + ) m / z: 463.2462. Example 18: Preparation of Compound 18

[0482] [ka]

[0483] Step A: Preparation of Compound 18-1 Methyl 2-fluoro-4-methylbenzoate (18 g) and concentrated sulfuric acid (200 mL) were added to a 500 mL three-neck flask. After the addition, the mixture was placed in an ice bath to lower the temperature to 0°C and stirred. Potassium nitrate (16.24 g) was then slowly added in batches, maintaining the internal temperature of the reaction mixture below 10°C. After completion of the reaction, the reaction mixture was poured into 1 L of ice water and extracted with an appropriate amount of EA. The organic phase was washed with saturated aqueous sodium chloride, concentrated, and purified by column chromatography to obtain compound 18-1.

[0484] Step B: Preparation of Compound 18-2 Following the method of Step D in Example 16, compound 18-1 was reacted with iron powder to obtain compound 18-2.

[0485] MS(ESI, [MH] - ) m / z: 182.12. Step C: Preparation of Compound 18-3 Referring to the method of Step D in Example 1, compound 18-2 was reacted with n-butyryl chloride to give compound 18-3.

[0486] MS(ESI, [MH] - ) m / z: 252.21. Step D: Preparation of Compound 18-4 Compound 18-3 (23 g), dichloromethane (250 mL), triethylamine (32 mL), di-tert-butyl dicarbonate (25.8 g), and 4-dimethylaminopyridine (555 mg) were added to a 500 mL three-neck flask and allowed to react at room temperature. After completion of the reaction, the reaction mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, concentrated, and purified by column chromatography to give compound 18-4.

[0487] MS (ESI, [M-Boc+H] + ) m / z: 254.25. Step E: Preparation of Compound 18-5 Compound 18-4 (29.3 g), dichloroethane (500 mL), N-bromosuccinimide (14.6 g), and azobisisobutyronitrile (1.17 g) were added to a 1 L three-neck flask, and the mixture was heated to 80°C under nitrogen protection. After completion of the reaction, the reaction mixture was washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give compound 18-5.

[0488] MS (ESI, [M-Boc+H] + ) m / z: 332.04. Step F: Preparation of Compound 18-6 Referring to the method of Step B of Example 16, compound 18-5 was reacted with N-methylmorpholine oxide to give compound 18-6.

[0489] MS (ESI, [M-Boc+H] + ) m / z: 268.15. Step G: Preparation of Compound 18-7 Following the method of Step C of Example 1, compound 18-7 was prepared by reacting compound 18-6 with trifluoroacetic acid.

[0490] MS(ESI, [MH] - ) m / z: 266.12. Step H: Preparation of Compound 18-8 Compound 18-7 (4.4 g), N,N-dimethylformamide (120 mL), and potassium carbonate (11.4 g) were added to a 250 mL three-neck flask. After the addition, the mixture was heated to 60 °C under nitrogen protection to allow the reaction to proceed. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. An appropriate amount of saturated aqueous sodium chloride and ethyl acetate were added to the residue, stirred for a while, and then separated. The organic phase was concentrated and purified by column chromatography to obtain compound 18-8.

[0491] MS (ESI, [M+H] + ) m / z: 250.18. Step I: Preparation of compound 18-9 Following the method of Step C of Example 15, compound 18-9 was prepared by reacting compound 18-8 with a solution of lithium aluminum hydride in tetrahydrofuran.

[0492] MS(ESI, [MH] - ) m / z: 220.19. Step J: Preparation of Compound 18-10 Referring to Step A of Example 2, compound 18-10 was prepared by reacting compound 18-9 with 2-iodoxybenzoic acid.

[0493] MS(ESI, [MH] - ) m / z: 218.18. Step K: Preparation of Compound 18 Compound 18 was prepared by reacting compound 18-10 with compound 2-10 according to the method of Step I in Example 1.

[0494] 1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),8.28(q,J=4.7Hz,1H),7.95(s,1H),7.67(s,1H),7.43(d,J=10.2Hz,1H),7.33(d,J=6.3Hz,1H),3.73-3.71(m ,2H),3.70-3.66(m,4H),3.63-3.54(m,2H),3.47-3.41(m,2H),3.17-3.0 9(m,2H),2.78(d,J=4.7Hz,3H),2.49-2.45(m,1H),1.15(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 425.2095. Example 19: Preparation of Compound 19

[0495] [ka]

[0496] Step A: Preparation of Compound 19-1 Referring to the method of Step I in Example 1, compound 13-2 was reacted with compound 7-8 to prepare compound 19-1.

[0497] MS (ESI, [M+H] + ) m / z: 438.48. Step B: Preparation of Compound 19 Following the method of Step D of Example 13, compound 19 was prepared by reacting compound 19-1 with a 4 M solution of hydrogen chloride in dioxane.

[0498] 1H NMR(500MHz,DMSO-d6)δ11.67(s,1H),8.75(d,J=4.6Hz,1H),7.68(s,1H),7.54(d,J=8.0Hz,1H),7.24(s,1H),7.07(d,J=7.9Hz,1H),4.03(s,2 H),3.89(s,2H),3.72(s,2H),3.69-3.59(m,1H),3.46(s,2H),3.15(s,2 H),2.78(d,J=4.6Hz,3H),2.47(d,J=7.3Hz,2H),1.16(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 424.1802. Example 20: Preparation of Compound 20

[0499] [ka]

[0500] Step A: Preparation of Compound 20 Compound 20 was prepared by reacting compound 16-7 with compound 4-4 according to the method of Step I in Example 1.

[0501] 1 H NMR(500MHz,DMSO-d6)δ11.91(s,1H),8.39(d,J=3.6Hz,1H),7.95(s,1H),7.73(s,1H),7.09(s,1H),6.93(d,J=10.7Hz,1H),3.70(t,J=13.3 Hz,6H),3.61(d,J=5.7Hz,1H),3.48(s,2H),3.19(s,2H),2.79-2.70(m,1H),2.56-2.51(m,2H),1.16(t,J=7.4Hz,3H),0.66(d,J=7.1Hz,4H). HRMS (ESI, [M+H] + ) m / z: 451.2260. Example 21: Preparation of Compound 21

[0502] [ka]

[0503] Step A: Preparation of Compound 21 Compound 21 was prepared by reacting compound 16-7 with compound 7-8 according to the method of Step I in Example 1.

[0504] 1 H NMR(500MHz,DMSO-d6)δ11.89(s,1H),8.74(d,J=4.7Hz,1H),7.73(s,1H),7.07(s,1H),6.91(d,J=10.8Hz,1H),4.03(d,J=2.9Hz,2H),3 .89(d,J=2.9Hz,2H),3.73-3.60(m,3H),3.43(s,2H),3.11(s,2H),2.77(d,J=4.8Hz,3H),2.53(d,J=7.3Hz,2H),1.16(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 442.1707. Example 22: Preparation of Compound 22

[0505] [ka]

[0506] Step A: Preparation of Compound 22-1 2-Amino-4-bromobenzaldehyde (5 g), ethanol (100 mL), propionaldehyde (2.9 g), and potassium hydroxide (5.61 g) were added to a 250 mL single-neck flask, and the mixture was heated to 90 °C to react. After the reaction was completed, the ethanol was removed by evaporation under reduced pressure, and the remaining solid was washed with saturated aqueous ammonium chloride and then extracted with ethyl acetate. The mixture was then concentrated and purified by column chromatography to obtain compound 22-1.

[0507] MS (ESI, [M+H] + ) m / z: 222.04. Step B: Preparation of Compound 22-2 Following the method of Step C of Example 2, compound 22-2 was prepared by reacting compound 22-1 with m-chloroperoxybenzoic acid.

[0508] MS (ESI, [M+H] + ) m / z: 238.06. Step C: Preparation of Compound 22-3 Following the method of Step D of Example 2, compound 22-2 was reacted with phosphorus oxychloride to prepare compound 22-3.

[0509] MS (ESI, [M+H] + ) m / z: 255.97. Step D: Preparation of Compound 22-4 Following the method of Step E of Example 2, compound 22-3 was reacted with sodium methoxide to prepare compound 22-4.

[0510] MS (ESI, [M+H] + ) m / z: 252.08. Step E: Preparation of Compound 22-5 Referring to Step F of Example 2, compound 22-5 was prepared by reacting compound 22-4 with (tributyltin)methanol.

[0511] MS (ESI, [M+H] + ) m / z: 204.15. Step F: Preparation of Compound 22-6 Following the method of Step G in Example 2, compound 22-4 was reacted with hydrochloric acid to prepare compound 22-6.

[0512] MS (ESI, [M+H] + ) m / z: 190.15. Step G: Preparation of Compound 22-7 Referring to Example 2, Step A, compound 22-7 was prepared by reacting compound 22-6 with 2-iodoxybenzoic acid.

[0513] MS(ESI, [MH] - ) m / z: 186.11. Step H: Preparation of Compound 22 Compound 22 was prepared by reacting compound 22-7 with compound 2-10 according to the method of Step I in Example 1.

[0514] 1 H NMR(500MHz,Chloroform-d)δ8.90(s,1H),7.88(s,1H),7.58(s,1H),7.43(d,J=8.1Hz,1H),7.11(d,J=7.7Hz,1H),7.06(s,1H), 6.92(d,J=4.3Hz,1H),3.73(s,6H),3.64-3.61(m,1H),3.56-3.52(m,2H),3.21-3.08(m,2H),3.00(d,J=4.9Hz,3H),2.25(s,3H). HRMS (ESI, [M+H] + ) m / z: 393.2029. Example 23: Preparation of Compound 23

[0515] [ka]

[0516] Step A: Preparation of Compound 23 Compound 22-7 was reacted with compound 4-4 to prepare compound 23, following the procedure of Step I in Example 1.

[0517] 1 H NMR(500MHz,Chloroform-d)δ10.86(s,1H),7.88(s,1H),7.60(s,1H),7.45(d,J=8.0Hz,1H),7.32(s,1H),7.19(d,J=7.9Hz,1H),7 .07(s,1H),3.90(s,2H),3.72(d,J=3.4Hz,7H),3.32(s,2H),2.84-2.78(m,1H),2.27(s,3H),0.87-0.83(m,2H),0.69-0.65(m,2H). HRMS (ESI, [M+H] + ) m / z: 419.2199. Example 24: Preparation of Compound 24

[0518] [ka]

[0519] Step A: Preparation of Compound 24-1 To a 100 mL single-neck flask were sequentially added 2-amino-4-bromobenzaldehyde (1 g), dichloromethane (10 mL), 3,3,3-trifluoropropionic acid (0.83 g), N,N-diisopropylethylamine (1.3 g), and 1-propylphosphoric acid anhydride (4.1 g). The mixture was stirred at room temperature for 30 minutes under nitrogen protection. Upon completion of the reaction, the reaction mixture was quenched by adding 10 mL of water. The mixture was extracted three times with dichloromethane (50 mL). The organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, mixed with silica gel, and purified by column chromatography to give 1.2 g of compound 24-1.

[0520] MS(ESI, [MH] - ) m / z: 308.06. Step B: Preparation of Compound 24-2 Compound 24-1 (0.9 g), N,N-dimethylformamide (10 mL), and potassium carbonate (1.2 g) were sequentially added to a 100 mL single-neck flask. Under nitrogen protection, the mixture was stirred in a 60 °C oil bath for 2 hours. Upon completion of the reaction, insoluble materials were removed by filtration, and the filtrate was directly concentrated to remove the solvent. The crude product was redissolved in 50 mL of ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, mixed with silica gel, and purified by column chromatography to obtain 0.6 g of compound 24-2.

[0521] MS (ESI, [M+H] + ) m / z: 292.03. Step C: Preparation of Compound 24-3 Referring to Step F of Example 2, compound 24-3 was prepared by reacting compound 24-2 with (tributyltin)methanol.

[0522] MS (ESI, [M+H] + ) m / z: 244.29. Step D: Preparation of Compound 24-4 Referring to Step A of Example 2, compound 24-4 was prepared by reacting compound 24-3 with 2-iodoxybenzoic acid.

[0523] MS(ESI, [MH] - ) m / z: 240.14. Step E: Preparation of Compound 24 Compound 24 was prepared by reacting compound 24-4 with compound 2-10 according to the method of Step I in Example 1.

[0524] 1 H NMR(500MHz,DMSO-d6)δ12.25(s,1H),8.51(s,1H),8.28(d,J=4.6Hz,1H),7.95(s,1H),7.79(d,J=8.1Hz,1H),7.32(s,1H),7.19( d,J=8.1Hz,1H),3.72(d,J=5.1Hz,4H),3.68(s,2H),3.64-3.56(m,1H),3.43(t,J=6.3Hz,2H),3.12(s,2H),2.78(d,J=4.6Hz,3H) HRMS (ESI, [M+H] + ) m / z: 447.1757. Example 25: Preparation of Compound 25

[0525] [ka]

[0526] Step A: Preparation of Compound 25-1 Referring to the method of Example 16, Step A, compound 25-1 was prepared by reacting 3-chloro-5-bromo-2-methylnitrobenzene with N-bromosuccinimide.

[0527] Step B: Preparation of Compound 25-2 Following the method of Step B of Example 16, compound 25-2 was prepared by reacting compound 25-1 with N-methylmorpholine oxide.

[0528] Step C: Preparation of Compound 25-3 Following the method of Step C of Example 16, compound 25-3 was prepared by reacting compound 25-2 with ethyl 2-(diethoxyphosphoryl)butyrate.

[0529] MS (ESI, [M+H] + ) m / z: 362.14. Step D: Preparation of Compound 25-4 Following the method of Step D of Example 16, compound 25-3 was reacted with iron powder to prepare compound 25-4.

[0530] Step E: Preparation of Compound 25-5 Referring to the method of Step E of Example 16, compound 25-4 was reacted in a photocatalytic synthesis apparatus to prepare compound 25-5.

[0531] MS (ESI, [M+H] + ) m / z: 286.01 Step F: Preparation of Compound 25-6 Referring to Step F of Example 2, compound 25-6 was prepared by reacting compound 25-5 with (tributyltin)methanol.

[0532] MS (ESI, [M+H] + ) m / z: 238.17. Step G: Preparation of Compound 25-7 Referring to Example 2, Step A, compound 25-7 was prepared by reacting compound 25-6 with 2-iodoxybenzoic acid.

[0533] MS(ESI, [MH] - ) m / z: 234.12. Step H: Preparation of Compound 25 Compound 25 was prepared by reacting compound 25-7 with compound 2-10 according to the method of Step I in Example 1.

[0534] 1 H NMR(500MHz,DMSO-d6)δ11.93(s,1H),8.28(q,J=4.6Hz,1H),7.94(s,1H),7.83(s,1H),7.25-7.18(m,2H),3.70(s,2H),3.66(d,J=9.0 Hz,4H),3.59(p,J=6.3Hz,1H),3.43-3.40(m,2H),3.11-3.06(m,2H),2.78(d,J=4.6Hz,3H),2.57-2.52(m,2H),1.17(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 441.1801 Example 26: Preparation of Compound 26

[0535] [ka]

[0536] Step A: Preparation of Compound 26-1 Following the method of Step C of Example 2, compound 26-1 was prepared by reacting 7-bromo-3-chloroquinoline with m-chloroperoxybenzoic acid.

[0537] MS (ESI, [M+H] + ) m / z: 258.16. Step B: Preparation of Compound 26-2 Following the method of Step D of Example 2, compound 26-2 was prepared by reacting compound 26-1 with phosphorus oxychloride.

[0538] MS (ESI, [M+H] + ) m / z: 276.07. Step C: Preparation of Compound 26-3 Compound 26-2 (0.4 g) and concentrated hydrochloric acid (5 mL) were added sequentially to a 15 mL microwave tube. The reaction system was transferred to a microwave reactor, heated to 100 °C at 150 W, and reacted for 2 hours. Upon completion of the reaction, the pH was adjusted to alkaline using saturated aqueous sodium bicarbonate solution, and then extracted three times with ethyl acetate (50 mL). The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, mixed with silica gel, and purified by column chromatography to give 0.35 g of compound 26-3.

[0539] MS(ESI, [MH] - ) m / z: 255.96. Step D: Preparation of Compound 26-4 Referring to Step F of Example 2, compound 26-4 was prepared by reacting compound 26-3 with (tributyltin)methanol.

[0540] MS (ESI, [M+H] + ) m / z: 210.15. Step E: Preparation of Compound 26-5 Referring to Example 2, Step A, compound 26-5 was prepared by reacting compound 26-4 with 2-iodoxybenzoic acid.

[0541] MS(ESI, [MH] - ) m / z: 206.10. Step F: Preparation of Compound 26 Compound 26 was prepared by reacting compound 26-5 with compound 2-10 according to the method of Step I in Example 1.

[0542] 1H NMR(500MHz,DMSO-d6)δ12.22(s,1H),8.27(d,J=5.7Hz,2H),7.94(s,1H),7.60(d,J=8.1Hz,1H),7.29(s,1H),7.14(d,J=8.0Hz,1 H),3.70(s,2H),3.67(d,J=3.9Hz,4H),3.58(p,J=6.1Hz,1H),3.40(t,J=6.9Hz,2H),3.08(t,J=6.7Hz,2H),2.78(d,J=4.6Hz,3H). HRMS (ESI, [M+H] + ) m / z: 413.1490. Example 27: Preparation of Compound 27

[0543] [ka]

[0544] Step A: Preparation of Compound 27 Compound 27 was prepared by reacting compound 26-5 with compound 7-8 according to the method of Step I in Example 1.

[0545] 1 H NMR(500MHz,DMSO-d6)δ12.25(s,1H),8.75(d,J=4.8Hz,1H),8.27(s,1H),7.61(d,J=8.1Hz,1H),7.29(s,1H),7.15(d,J=8.1Hz,1H),4.07 -3.98(m,2H),3.89(d,J=2.8Hz,2H),3.74(d,J=16.4Hz,2H),3.68-3.61(m,1H),3.45(t,J=6.6Hz,2H),3.13(s,2H),2.78(d,J=4.8Hz,3H). HRMS (ESI, [M+H] + ) m / z: 430.1103. Example 28: Preparation of Compound 28

[0546] [ka]

[0547] Step A: Preparation of Compound 28 Compound 28 was prepared by reacting compound 24-4 with compound 7-8 according to the method of Step I in Example 1.

[0548] 1 H NMR(500MHz,DMSO-d6)δ12.26(s,1H),8.74(d,J=4.7Hz,1H),8.52(s,1H),7.80(d,J=8.1Hz,1H),7.32(s,1H),7.20(d,J =8.1Hz,1H),4.04(s,2H),3.90(s,2H),3.75(s,2H),3.69-3.61(m,1H),3.45(s,2H),3.14(s,2H),2.78(d,J=4.7Hz,3H). HRMS (ESI, [M+H] + ) m / z: 464.1379. Example 29: Preparation of Compound 29

[0549] [ka]

[0550] Step A: Preparation of Compound 29-1 A 100 mL three-neck flask was prepared and charged with 3-bromo-2-fluoroaniline (1 g), sodium iodide (0.079 g), and 4 M sulfuric acid (25 mL). After the addition, the mixture was heated to 110 °C under nitrogen protection, and then 2-ethylacrylaldehyde (0.531 g) was added dropwise to the reaction system. After the reaction was completed, the mixture was neutralized with saturated aqueous sodium carbonate, extracted, concentrated, and purified by column chromatography to obtain compound 29-1.

[0551] MS (ESI, [M+H] + ) m / z: 254.24. Step B: Preparation of Compound 29-2 Following the method of Step C of Example 2, compound 29-2 was prepared by reacting compound 29-1 with m-chloroperoxybenzoic acid.

[0552] MS (ESI, [M+H] + ) m / z: 270.23. Step C: Preparation of Compound 29-3 Following the method of Step D of Example 2, compound 29-3 was prepared by reacting compound 29-2 with phosphorus oxychloride.

[0553] MS (ESI, [M+H] + ) m / z: 288.16. Step D: Preparation of Compound 29-4 Following the method of Step E of Example 2, compound 29-4 was prepared by reacting compound 29-3 with sodium methoxide.

[0554] MS (ESI, [M+H] + ) m / z: 284.22. Step E: Preparation of Compound 29-5 Referring to Step F of Example 2, compound 29-5 was prepared by reacting compound 29-4 with (tributyltin)methanol.

[0555] MS (ESI, [M+H] + ) m / z: 236.36. Step F: Preparation of Compound 29-6 Following the method of Step G of Example 2, compound 29-5 was reacted with hydrochloric acid to prepare compound 29-6.

[0556] MS (ESI, [M+H] + ) m / z: 222.18. Step G: Preparation of Compound 29-7 Referring to Example 2, Step A, compound 29-7 was prepared by reacting compound 29-6 with 2-iodoxybenzoic acid.

[0557] MS(ESI, [MH] - ) m / z: 218.17. Step H: Preparation of Compound 29 Compound 29 was prepared by reacting compound 29-7 with compound 2-10 according to the method of Step I in Example 1.

[0558] 1 H NMR(500MHz,DMSO-d6)δ11.69(s,1H),8.28(d,J=4.6Hz,1H),7.93(s,1H), 7.73(s,1H),7.40(d,J=8.0Hz,1H),7.13(t,J=7.1Hz,1H),3.70(s,2H),3.6 8(s,2H),3.65(s,2H),3.55(p,J=6.2Hz,1H),3.40(t,J=6.7Hz,2H),3.10( t,J=6.5Hz,2H),2.77(d,J=4.6Hz,3H),2.48(s,2H),1.17(t,J=7.4Hz,3H). HRMS(ESI,[M+H] + )m / z:425.2099. Example 30: Preparation of compound 30

[0559]

change

[0560] ステップA: Preparation of compound 30 The method used in Example 1 was based on the reference method, the compound 29-7 and the compound 7-8, and the reaction compound 30 were prepared.

[0561] 1 H NMR(500MHz,DMSO-d6)δ11.70(s,1H),8.75(d,J=4.7Hz,1H),7.73(s,1H),7.40(d,J=8.1Hz,1H),7.21-7.05(m,1H),4.01(s,2H),3.86(s,2H),3 .71(s,2H),3.61(p,J=6.2Hz,1H),3.40(t,J=6.9Hz,2H),3.10(t,J=6.6 Hz,2H),2.77(d,J=4.7Hz,3H),2.50-2.48(m,2H),1.17(t,J=7.4Hz,3H). HRMS(ESI,[M+H] + )m / z:442.1709. Example 31: Preparation of Compound 31

[0562] [ka]

[0563] Step A: Preparation of Compound 31 Compound 31 was prepared by reacting Compound 2-8 with Compound 7-8 according to the method of Step I in Example 1.

[0564] 1 H NMR(500MHz,DMSO-d6)δ11.67(s,1H),8.75(d,J=4.7Hz,1H),7.47(d,J=8.0Hz ,1H),7.39(s,1H),7.21(s,1H),7.03(d,J=8.0Hz,1H),4.02(s,2H),3.88(s,2 H),3.63(d,J=8.2Hz,3H),3.39(t,J=6.8Hz,2H),3.06(t,J=6.5Hz,2H),2.78( d,J=4.7Hz,3H),2.15-2.01(m,1H),0.99-0.84(m,2H),0.72(q,J=5.5Hz,2H). HRMS (ESI, [M+H] + ) m / z: 436.1808. Example 32: Preparation of Compound 32

[0565] [ka]

[0566] Step A: Preparation of Compound 32-1 Referring to Step I of Example 2, compound 32-1 was prepared by reacting compound 1-3 with tert-butyl 3-oxopyrrolidine-1-carboxylate.

[0567] MS (ESI, [M+H] + ) m / z: 336.29. Step B: Preparation of Compound 32-2 Following the method of Step C of Example 1, compound 32-1 was reacted with trifluoroacetic acid to prepare compound 32-2.

[0568] MS (ESI, [M+H] + ) m / z: 236.29. Step C: Preparation of Compound 32 Compound 32 was prepared by reacting compound 1-7 with compound 32-2 using the method described in Step I of Example 1. Compound 32 was separated using an ASA CHIRALPAK IG chromatography column (30 x 250 mm, S-10 μm). The mobile phase A was ethanol-dichloromethane (2:1, V / V), the mobile phase B was n-hexane, the elution gradient was mobile phase A:mobile phase B = 75:25 (V / V), the flow rate was 40 mL / min, and the detection wavelength was 254 nM. Compounds 32-a and 32-b were prepared using the method described in Step I of Example 1. The peak times were 13.28 min (compound 32-a) and 19.50 min (compound 32-b), respectively.

[0569] Compound 32-a: 1 H NMR(500MHz,DMSO-d6)δ11.65(s,1H),8.26(q,J=4.6Hz,1H),7.92(s,1H),7.68(s,1H),7.54(d,J=8.0Hz,1H),7.25(d,J=1.6Hz,1H),7.10(dd,J=8.1, 1.6Hz,1H),3.74-3.55(m,6H),2.84-2.69(m,4H),2.65-2.52(m,4H),2.49 -2.41(m,2H),2.04-1.92(m,1H),1.82-1.72(m,1H),1.16(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 421.2353. Compound 32-b: 1H NMR(500MHz,DMSO-d6)δ11.65(s,1H),8.26(q,J=4.6Hz,1H),7.91(s,1H),7.68(s,1 H),7.54(d,J=8.0Hz,1H),7.25(s,1H),7.10(dd,J=8.1,1.5Hz,1H),3.69(p,J=7.3Hz ,4H),3.60(dd,J=16.0,12.7Hz,2H),2.77(d,J=4.7Hz,4H),2.65-2.50(m,4H),2.49- 2.41(m,2H),2.03-1.93(m,1H),1.78(tt,J=13.5,5.9Hz,1H),1.15(t,J=7.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 421.2349. Example 33: Preparation of Compound 33

[0570] [ka]

[0571] Step A: Preparation of Compound 33-1 A 100 mL single-neck flask was prepared, and methyl 3-methylthiophene-2-carboxylate (2 g), chloroform (20 mL), N-bromosuccinimide (2.165 g), and a catalytic amount of benzoyl peroxide were added, followed by refluxing overnight at 70 °C. Upon completion of the reaction, the solvent was removed by rotary evaporation, and the mixture was diluted with ethyl acetate (100 mL), washed with water, dried, and purified by column chromatography to obtain compound 33-1.

[0572] Step B: Preparation of Compound 33-2 Compound 33-1 (2.2 g) and ammonia in methanol were added to a 100 mL single-neck flask and stirred at room temperature for 2 hours. The reaction mixture was then dried by rotary evaporation, mixed with silica gel, and purified by column chromatography to give compound 33-2.

[0573] MS (ESI, [M+H] + ) m / z: 172.08. Step C: Preparation of Compound 33-3 A 100 mL single-neck flask was prepared, and compound 33-2 (0.5 g), ethanol (5 mL), methanol (5.00 mL), and potassium carbonate (0.444 g) were added and reacted overnight at reflux at 90° C. After reaction completion, the reaction solution was rotary evaporated, diluted with ethyl acetate (50 mL), washed with water, dried, and rotary evaporated to obtain compound 33-3.

[0574] MS (ESI, [M+H] + ) m / z: 140.01. Step D: Preparation of Compound 33-4 Following the method of Step D of Example 18, compound 33-4 was prepared by reacting compound 33-3 with di-tert-butyl dicarbonate.

[0575] MS (ESI, [M+H] + ) m / z: 240.01. Step E: Preparation of Compound 33-5 A 100 mL three-neck flask was prepared, compound 33-4 (0.3 g) and tetrahydrofuran (15 mL) were added, and borane dimethyl sulfide (0.5 g) was added dropwise under nitrogen protection and ice bath conditions. After the dropwise addition, the mixture was placed in an oil bath at 40 °C and stirred overnight. After completion of the reaction, a small amount of methanol was added to quench the reaction, and the mixture was concentrated to remove the solvent. 50 mL of ethyl acetate was added to redissolve the product, washed with water, dried, and purified by column chromatography to obtain compound 33-5.

[0576] MS (ESI, [M+H] + ) m / z: 226.08. Step F: Preparation of Compound 33-6 Compound 33-5 (120 mg), chloroform (5 mL), and a catalytic amount of acetic acid were added to a 100 mL single-neck flask. Liquid bromine (85 mg) was added dropwise in an ice bath and the mixture was stirred overnight at room temperature. 5 mL of ethyl ether was added directly to the reaction mixture, followed by filtration. The filter cake was washed with ethyl ether and the resulting filter cake was compound 33-6.

[0577] MS (ESI, [M+H] +) m / z: 204.03. Step G: Preparation of Compound 33-7 Following the method of Step D of Example 18, compound 33-7 was prepared by reacting compound 33-6 with di-tert-butyl dicarbonate.

[0578] MS (ESI, [M+H] + ) m / z: 304.03. Step H: Preparation of Compound 33-8 Following the method of Step F of Example 7, compound 33-7 was reacted with carbon monoxide to prepare compound 33-8.

[0579] MS (ESI, [M+H] + ) m / z: 284.41. Step I: Preparation of compound 33-9 Following the method of Step G of Example 7, compound 33-9 was prepared by reacting compound 33-8 with a solution of methylamine in ethanol.

[0580] MS (ESI, [M+H] + ) m / z: 283.22. Step J: Preparation of Compound 33-10 Following the method of Step C of Example 1, compound 33-10 was prepared by reacting compound 33-9 with trifluoroacetic acid.

[0581] MS (ESI, [M+H] + ) m / z: 183.22. Step K: Preparation of Compound 33-11 Referring to Step I of Example 2, compound 33-11 was prepared by reacting compound 33-10 with 1-Boc-3-azetidinone.

[0582] MS (ESI, [M+H] + ) m / z: 338.23. Step L: Preparation of Compound 33-12 Following the method of Step C of Example 1, compound 33-12 was prepared by reacting compound 33-11 with trifluoroacetic acid.

[0583] MS (ESI, [M+H] + ) m / z: 238.23. Step M: Preparation of Compound 33 Compound 33 was prepared by reacting compound 24-4 with compound 33-12 according to the method of Step I in Example 1. 1 H NMR(500MHz,DMSO-d6)δ12.24(s,1H),8.51(s,1H),8.33(d,J=4.6Hz,1H),7.79(d,J=8.1Hz,1H),7.47(s,1H),7.32(s,1H),7.18(d,J=8.1 Hz,1H),3.93(s,2H),3.78(d,J=2.7Hz,2H),3.71(s,2H),3.60(s,1H),3.41(t,J=7.0Hz,2H),3.08(t,J=6.7Hz,2H),2.74(d,J=4.5Hz,3H). HRMS (ESI, [M+H] + ) m / z: 463.1409. Example 34: Preparation of Compound 34

[0584] [ka]

[0585] Step A: Preparation of Compound 34-1 Methyl 3-amino-4-bromobenzoate (1 g), acetonitrile (20 mL), cesium carbonate (2.83 g), and bis(triphenylphosphine)palladium(II) chloride (3.05 ml) were sequentially added to a 100 mL single-neck flask. Under nitrogen protection, the mixture was heated to 80 °C, and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (1.1 g) dissolved in 10 mL of acetonitrile was slowly added dropwise to the reaction mixture, over approximately 0.5 h. After the addition, the reaction mixture was stirred overnight at 100 °C. After completion of the reaction, the reaction mixture was mixed directly with silica gel and purified by column chromatography to obtain 0.6 g of compound 34-1.

[0586] MS (ESI, [M+H] + ) m / z: 243.22. Step B: Preparation of Compound 34-2 Following the method of Step C of Example 15, compound 34-1 was reacted with a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran to prepare compound 34-2.

[0587] MS (ESI, [M+H] + ) m / z: 215.24. Step C: Preparation of Compound 34-3 Referring to Step H of Example 2, compound 34-3 was prepared by reacting compound 34-2 with 2-iodoxybenzoic acid.

[0588] MS(ESI, [MH] - ) m / z: 211.19. Step D: Preparation of Compound 34 Compound 34 was prepared by reacting compound 34-3 with compound 2-10 according to the method of Step I in Example 1.

[0589] 1 H NMR(500MHz,DMSO-d6)δ11.43(s,1H),8.28(d,J=4.7Hz,1H),7.94(s,1H),7.84(d,J=8. 0Hz,1H),7.57(dd,J=3.0,1.4Hz,1H),7.20(s,1H),7.11(d,J=8.1Hz,1H),6.96(dd,J=3 .5,1.3Hz,1H),6.66(t,J=3.3Hz,1H),3.70(s,2H),3.67(s,2H),3.64(s,2H),3.59(dd, J=12.7,6.4Hz,1H),3.40(t,J=6.9Hz,2H),3.08(t,J=6.3Hz,2H),2.78(d,J=4.7Hz,3H). HRMS (ESI, [M+H] + ) m / z: 418.1990. Example 35: Preparation of Compound 35

[0590] [ka]

[0591] Step A: Preparation of Compounds 35-a and 35-b Referring to Step I of Example 2, compound 1-3 was reacted with tert-butyl (R)-2-methyl-3-oxoazetidin-1-methyl to prepare compound 35-1. Compound 35-1 was separated using an ASA Pre-packed Regis IA chromatography column (30*250 mm, 10 μm). Mobile phase A was ethanol, mobile phase B was n-hexane, the elution gradient was mobile phase A:mobile phase B = 35:65 (V / V), the flow rate was 40 mL / min, and the detection wavelength was 254 nm. Compounds 35-a and 35-b were prepared. The peak times were 7.58 min (compound 35-a) and 12.08 min (compound 35-b), respectively.

[0592] Compound 35-a: MS (ESI, [M+H] + ) m / z: 336.40. Compound 35-b: MS (ESI, [M+H] + ) m / z: 336.01. Step B: Preparation of Compound 35-2 Following the method of Step C of Example 1, compound 35-2 was prepared by reacting compound 35-b with trifluoroacetic acid.

[0593] MS (ESI, [M+H] + ) m / z: 236.33. Step C: Preparation of Compound 35 Compound 35 was prepared by reacting compound 24-4 with compound 35-2 according to the method of Step I in Example 1.

[0594] 1H NMR(500MHz,DMSO-d6)δ12.23(s,1H),8.51(s,1H),8.26(d,J=4.7Hz,1H),7 .95(s,1H),7.79(d,J=8.1Hz,1H),7.35(s,1H),7.19(dd,J=8.1,1.0Hz,1H) ,3.81(dd,J=14.1,11.5Hz,5H),3.60-3.53(m,2H),3.47(s,1H),3.36(dd,J =7.9,2.9Hz,1H),3.03(s,1H),2.78(d,J=4.7Hz,3H),1.12(d,J=6.5Hz,3H). HRMS (ESI, [M+H] + ) m / z: 461.1908. Example 36: Preparation of Compound 36

[0595] [ka]

[0596] Step A: Preparation of Compounds 36-a and 36-b Referring to Step I of Example 2, compound 1-3 was reacted with tert-butyl (S)-2-methyl-3-oxoazetidine-1-carboxylate to prepare compound 36-1. Compound 36-1 was separated on a (R,R)-Whelk-O1 column (20*250 mm, S-5 μm). Mobile phase A was ethanol-dichloromethane (1:1, V / V) and mobile phase B was n-hexane. The elution gradient was mobile phase A:mobile phase B = 30:70 (V / V), the flow rate was 25 mL / min, and the detection wavelength was 254 nm. Compounds 36-a and 36-b were prepared. The peak times were 10.3 min (compound 36-a) and 11.7 min (compound 36-b), respectively.

[0597] Compound 36-a: MS (ESI, [M+H] + ) m / z: 336.01. Compound 36-b: MS (ESI, [M+H] + ) m / z: 336.01. Step B: Preparation of Compound 36-2 Following the method of Step C of Example 1, compound 36-2 was prepared by reacting compound 36-a with trifluoroacetic acid.

[0598] MS (ESI, [M+H] + ) m / z: 236.34. Step C: Preparation of Compound 36 Compound 36 was prepared by reacting compound 24-4 with compound 36-2 according to the method of Step I in Example 1.

[0599] 1 H NMR(500MHz,DMSO-d6)δ12.08(s,1H),8.51(s,1H),8.30-8.18(m,J=4.3Hz,1H),7.95 (s,1H),7.79(d,J=8.1Hz,1H),7.36(s,1H),7.19(d,J=8.1Hz,1H),3.84(s,1H),3.81( s,2H),3.79(s,2H),3.60-3.52(m,2H),3.51-3.42(m,J=12.8,6.4Hz,1H),3.36(d,J= 2.9Hz,1H),3.07-2.99(m,J=7.4Hz,1H),2.79(d,J=4.6Hz,3H),1.12(d,J=6.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 461.1915. Example 37: Preparation of Compound 37

[0600] [ka]

[0601] Step A: Preparation of Compound 37-1 Referring to Step I of Example 2, compound 37-1 was prepared by reacting compound 1-3 with tert-butyl 2-(methoxymethyl)-3-oxoazetidine-1-carboxylate.

[0602] MS (ESI, [M+H] + ) m / z: 366.37. Step B: Preparation of Compound 37-2 Following the method of Step C of Example 1, compound 37-1 was reacted with trifluoroacetic acid to prepare compound 37-2.

[0603] MS (ESI, [M+H] + ) m / z: 266.35. Step C: Preparation of Compound 37 Compound 37 was prepared by reacting compound 24-4 with compound 37-2 according to the method of Step I in Example 1.

[0604] 1 H NMR(500MHz,DMSO-d6)δ12.24(s,1H),8.51(s,1H),8.33-8.20(m,J=4.5Hz,1H),7.95(s, 1H),7.79(d,J=8.0Hz,1H),7.33(s,1H),7.18(d,J=8.0Hz,1H),3.93(d,J=14.4Hz,1H),3 .84-3.75(m,J=17.7,8.0Hz,4H),3.68-3.55(m,3H),3.50(d,J=5.6Hz,1H),3.40-3.35(m ,1H),3.21(s,3H),3.13-3.05(m,1H),3.05-2.97(m,J=7.4Hz,1H),2.78(d,J=4.7Hz,3H). HRMS (ESI, [M+H] + )m / z:491.32017. Example 38: Preparation of Compound 38

[0605] [ka]

[0606] Step A: Preparation of Compound 38-1 Following the method of Step C of Example 1, compound 38-1 was prepared by reacting compound 36-b with trifluoroacetic acid.

[0607] MS (ESI, [M+H] + ) m / z: 236.34. Step B: Preparation of Compound 38 Compound 38 was prepared by reacting compound 24-4 with compound 38-1 according to the method of Step I in Example 1.

[0608] 1 H NMR(500MHz,DMSO-d6)δ12.23(s,1H),8.52(s,1H),8.30-8.21(m,J=4.5Hz,1H),7.94(s,1H),7.79 (d,J=8.1Hz,1H),7.34(s,1H),7.27-7.13(m,J=8.1,1.0Hz,1H),3.87(d,J=14.0Hz,1H),3.69-3.62 (m,J=5.7Hz,3H),3.62-3.53(m,2H),3.48-3.41(m,J=6.4Hz,1H),3.22-3.14(m,J=6.0Hz,1H),3.1 3-3.05(m,J=6.7Hz,1H),2.78(d,J=4.7Hz,3H),2.76-2.71(m,J=6.9Hz,1H),1.13(d,J=6.0Hz,3H). HRMS (ESI, [M+H] + ) m / z: 461.1913. Example 39: Preparation of Compound 39

[0609] [ka]

[0610] Step A: Preparation of Compound 39 Compound 39 was prepared by reacting compound 1-7 with compound 38-1 according to the method of Step I in Example 1.

[0611] 1H NMR(500MHz,DMSO-d6)δ11.65(s,1H),8.27(q,J=4.6Hz,1H),7.95(s,1H),7.69(s,1H),7.55(d,J=8.0Hz,1H),7.25(s,1H),7.10(d,J=7 .9Hz,1H),3.83(s,1H),3.74-3.40(m,6H),3.11(s,2H),2.78(d,J=4.7Hz,4H),1.25(dd,J=12.0,3.9Hz,2H),1.16(h,J=6.4,5.9Hz,6H). HRMS (ESI, [M+H] + ) m / z: 421.2350 Example 40: Preparation of Compound 40

[0612] [ka]

[0613] Step A: Preparation of Compound 40 Compound 40 was prepared by reacting compound 2-8 with compound 35-2 according to the method of Step I in Example 1. 1 H NMR(500MHz,DMSO-d6)δ11.66(s,1H),8.26(q,J=4.3Hz,1H),7.93(d,J=10.7Hz,1H),7.47(d,J=8.0H z,1H),7.39(s,1H),7.24(s,1H),7.04(d,J=8.0Hz,1H),3.77(s,5H),3.54(td,J=6.7,3.0Hz,1H),3.4 8(d,J=13.8Hz,1H),3.45-3.41(m,1H),3.31(dd,J=7.7,2.8Hz,1H),3.00(t,J=7.4Hz,1H),2.79(d,J= 4.7Hz,3H),2.08(dq,J=8.5,5.4Hz,1H),1.09(d,J=6.5Hz,3H),0.95-0.85(m,2H),0.77-0.67(m,2H). HRMS (ESI, [M+H] + ) m / z: 433.2356. Example 41: Preparation of Compound 41

[0614] [ka]

[0615] Step A: Preparation of Compound 41 Compound 41 was prepared by reacting compound 1-7 with compound 36-2 according to the method of Step I in Example 1.

[0616] 1 H NMR(500MHz,DMSO-d6)δ11.65(s,1H),8.27(q,J=4.6Hz,1H),7.94(s,1H),7.68(s,1H),7.53(d,J=8.0Hz,1H),7.26(s,1H),7.07(d,J= 8.0Hz,1H),3.88-3.68(m,5H),3.63-3.35(m,5H),3.02(s,1H),2.79(d,J=4.7Hz,3H),1.25(dd,J=12.5,3.9Hz,1H),1.21-1.04(m,6H). HRMS (ESI, [M+H] + ) m / z: 421.2342. Example 42: Preparation of Compound 42

[0617] [ka]

[0618] Step A: Preparation of Compound 42 Compound 42 was prepared by reacting compound 2-8 with compound 36-2 according to the method of Step I in Example 1.

[0619] 1H NMR(500MHz,DMSO-d6)δ11.66(s,1H),8.30-8.21(m,J=4.4Hz,1H),7.94(s,1H),7.47(d,J=8.0Hz,1H),7.38(s ,1H),7.23(s,1H),7.08-7.00(m,J=8.0,1.1Hz,1H),3.85-3.71(m,J=19.0,13.9Hz,5H),3.58-3.52(m,J=6.8, 3.0Hz,1H),3.48(d,J=13.8Hz,1H),3.45-3.38(m,J=13.0,6.5Hz,1H),3.31-3.28(m,1H),3.03-2.97(m,J=7.4 Hz,1H),2.78(d,J=4.7Hz,3H),2.12-2.03(m,1H),1.10(d,J=6.5Hz,3H),0.94-0.87(m,2H),0.75-0.66(m,2H). HRMS (ESI, [M+H] + ) m / z: 433.2361. Example 43: Preparation of Compound 43

[0620] [ka]

[0621] Step A: Preparation of Compound 43 Compound 43 was prepared by reacting compound 2-8 with compound 38-1 according to the method of Step I in Example 1.

[0622] 1H NMR(500MHz,DMSO-d6)δ11.64(s,1H),8.31-8.22(m,J=4.4Hz,1H),7.93(s,1H),7.47(d,J=8.0Hz,1H),7.39(s,1 H),7.22(s,1H),7.10-6.99(m,J=8.0,0.9Hz,1H),3.79(d,J=13.4Hz,1H),3.67-3.55(m,4H),3.49(d,J=13.4Hz,1 H),3.43-3.36(m,J=6.3Hz,1H),3.17-3.10(m,J=6.0Hz,1H),3.10-3.03(m,J=13.4,6.7Hz,1H),2.77(d,J=4.7Hz, 3H),2.74-2.68(m,J=6.9Hz,1H),2.12-2.02(m,1H),1.10(d,J=6.0Hz,3H),0.94-0.86(m,2H),0.76-0.68(m,2H). HRMS (ESI, [M+H] + ) m / z: 433.2355. Example 44: Preparation of Compound 44

[0623] [ka]

[0624] Step A: Preparation of Compound 44 Compound 44 was prepared by reacting compound 1-7 with compound 35-2 according to the method of Step I in Example 1.

[0625] 1 H NMR(500MHz,DMSO-d6)δ11.67(s,1H),8.26(q,J=4.7Hz,1H),7.94(s,1H),7.68(s,1H),7.54(d,J=8.0Hz,1H),7.27(s,1H),7.0 9(s,1H),3.96-3.71(m,5H),3.57(s,3H),3.03(s,2H),2.78(d,J=4.7Hz,3H),2.47(d,J=7.4Hz,2H),1.15(q,J=8.6,8.0Hz,6H). HRMS (ESI, [M+H] + ) m / z: 421.2354. Example 45: Preparation of Compound 45

[0626] [ka]

[0627] Step A: Preparation of Compound 45-1 Referring to the method of Example 3, Step B, compound 45-1 was prepared by reacting methyl 4-fluoro-3-nitrobenzoate with DL-2-amino-n-butyric acid methyl ester hydrochloride.

[0628] MS(ESI, [MH] - ) m / z: 295.20. Step B: Preparation of Compound 45-2 Compound 45-2 was prepared by reacting compound 45-1 with iron powder according to the method of Step C in Example 3.

[0629] MS(ESI, [MH] - ) m / z: 233.18. Step C: Preparation of Compound 45-3 Following the method of Step D of Example 3, compound 45-3 was prepared by reacting compound 45-2 with 2,3-dichloro-5,6-dicyanobenzoquinone.

[0630] MS(ESI, [MH] - ) m / z: 231.18. Step D: Preparation of Compound 45-4 Following the method of Example 15, Step C, compound 45-4 was prepared by reacting compound 45-3 with a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran.

[0631] MS(ESI, [MH] - ) m / z: 203.15. Step E: Preparation of Compound 45-5 Referring to Example 2, Step H, compound 45-5 was prepared by reacting compound 45-4 with 2-iodoxybenzoic acid.

[0632] MS(ESI, [MH] - ) m / z: 201.17. Step F: Preparation of Compound 45 Compound 45 was prepared by reacting compound 45-5 with compound 36-2 according to the method of Step I in Example 1.

[0633] 1 H NMR(500MHz,DMSO-d6)δ12.23(s,1H),8.27(q,J=4.6Hz,1H),7.95(s,1H),7.65(d,J=8.2Hz,1H),7.26(d,J=1.7Hz,1H),7.19(dd,J=8.2,1.8Hz,1H), 3.88-3.70(m,5H),3.62-3.52(m,2H),3.46(p,J=6.5Hz,1H),3.03(t,J=7. 4Hz,1H),2.87-2.72(m,6H),1.22(t,J=7.4Hz,3H),1.12(d,J=6.4Hz,3H). HRMS (ESI, [M+H] + ) m / z: 422.2303. Example 46: Preparation of Compound 46

[0634] [ka]

[0635] Step A: Preparation of Compound 46 Compound 46 was prepared by reacting compound 16-7 with compound 38-1 according to the method of Step I in Example 1.

[0636] 1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),8.26(d,J=4.7Hz,1H),7.93(s,1H),7.73(s,1H),7. 09(s,1H),6.92(d,J=10.8Hz,1H),3.80(d,J=13.8Hz,1H),3.61(dd,J=24.5,9.7Hz,4H),3. 50(d,J=13.8Hz,1H),3.43(t,J=6.4Hz,1H),3.20-3.12(m,1H),3.08(dd,J=13.4,6.7Hz,1 H),2.78(d,J=4.6Hz,3H),2.74(t,J=6.9Hz,1H),2.53(d,J=7.6Hz,2H),1.20-1.08(m,6H). HRMS (ESI, [M+H] + ) m / z: 439.2263. Example 47: Preparation of Compound 47

[0637] [ka]

[0638] Step A: Preparation of Compound 47 Compound 47 was prepared by reacting compound 5-1 with compound 36-2 according to the method of Step I in Example 1.

[0639] 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),8.35(s,1H),8.31-8.15(m,1H),7.94(s,1H),7.73(s,1H),7.59(s,1H),3.89-3.70(m,5H),3.61-3 .51(m,2H),3.50-3.43(m,1H),3.04(t,J=6.7Hz,1H),2.88-2.69(m,3H),2.60-2.51(m,3H),1.18(t,J=7.1Hz,3H),1.11(d,J=5.7Hz,3H). HRMS (ESI, [M+H] + ) m / z: 422.2301. Example 48: Preparation of Compound 48

[0640] [ka]

[0641] Step A: Preparation of Compound 48-1 Methyl 4-formyl-3-nitrobenzoate (4.5 g) and methanol (100 ml) were added sequentially to a 250 ml three-neck flask. After the addition, the atmosphere was purged with nitrogen for protection. A solution of ammonia in methanol (7 M; 45 ml) and glyoxal (22 ml) were then added to the system via syringe. The reaction was allowed to proceed overnight at room temperature. After completion of the reaction, excess solvent was removed by evaporation under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound 48-1.

[0642] MS (ESI, [M+H] + ) m / z: 248.24. Step B: Preparation of Compound 48-2 A 100 mL single-neck flask was prepared and compound 48-1 (900 mg), ethyl acetate (40 mL), and stannic chloride dihydrate (4.1 g) were added. After addition, the flask was placed in an oil bath under nitrogen purging and heated to 80 °C for 4 hours. After completion of the reaction, the reaction solution was diluted with 100 mL of purified water, and then saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was further purified by silica gel column chromatography to obtain compound 48-2.

[0643] MS (ESI, [M+H] + ) m / z: 218.21. Step C: Preparation of Compound 48-3 A 50 ml two-neck flask was prepared, and compound 48-2 (565 mg) and 1,4-dioxane (20 ml) were added sequentially. After the addition, the atmosphere was replaced with nitrogen for protection. Then, triphosgene (810 mg) was added to the reaction system under a nitrogen atmosphere. After the addition, the reaction system was heated to 80 °C in an oil bath and reacted for approximately 12 hours. After the reaction was completed, the reaction solution was quenched by adding 5 ml of methanol. The mixture was then concentrated and purified by column chromatography to obtain compound 48-3.

[0644] MS (ESI, [M+H] + ) m / z: 244.26. Step D: Preparation of Compound 48-4 Following the method of Example 15, Step C, compound 48-3 was reacted with 2.5 M lithium aluminum hydride in tetrahydrofuran to prepare compound 48-4.

[0645] MS (ESI, [M+H] + ) m / z: 216.19. Step E: Preparation of Compound 48-5 A 50 ml single-neck flask was prepared, and compound 48-4 (250 mg), dichloromethane (20 ml), and N,N-dimethylformamide (0.05 ml) were added sequentially. After the addition, the reaction system was placed in an ice bath, cooled to 0 °C, and stirred. Dichlorosulfoxide (0.22 ml) was then slowly added dropwise to the reaction system. After the addition, the reaction system was brought to room temperature and allowed to react overnight. After the reaction was completed, the solvent and dichlorosulfoxide were removed by evaporation under reduced pressure to obtain compound 48-5, which was used directly as a crude product in the next step.

[0646] MS (ESI, [M+H] + ) m / z: 234.17. Step F: Preparation of Compound 48 A 50 ml single-neck flask was prepared, and compound 36-2 (104 mg), acetonitrile (10 ml), triethylamine (0.25 ml), anhydrous potassium carbonate (103 mg), potassium iodide (10 mg), and compound 48-5 (70 mg) were added in that order. After the addition, the atmosphere was replaced with nitrogen, and the system was placed in an oil bath, heated to 80°C, and reacted for 2 hours. After completion of the reaction, the mixture was concentrated and purified by column chromatography to obtain compound 48.

[0647] 1 H NMR(500MHz,DMSO-d6)δ11.92(s,1H),8.38-8.20(m,1H),8.05(d,J=7.9Hz ,1H),7.95(s,1H),7.86(s,1H),7.43(s,1H),7.36(s,1H),7.24(d,J=7.8H z,1H),3.87-3.75(m,5H),3.60-3.52(m,2H),3.51-3.44(m,1H),3.35-3.3 4(m,1H),3.08-3.00(m,1H),2.79(d,J=4.2Hz,3H),1.13(d,J=6.1Hz,3H). HRMS (ESI, [M+H] + ) m / z: 433.2102. Example 49: Preparation of Compound 49

[0648] [ka]

[0649] Step A: Preparation of Compound 49 Compound 49 was prepared by reacting compound 48-5 with compound 38-1 according to the method of Step F of Example 48.

[0650] 1H NMR(500MHz,DMSO-d6)δ11.91(s,1H),8.27(q,J=4.6Hz,1H),8.06(d,J=8.0Hz,1H),7.9 4(s,1H),7.86(d,J=1.6Hz,1H),7.43(d,J=1.6Hz,1H),7.34(s,1H),7.26(dd,J=8.1,1. 5Hz,1H),3.85(d,J=13.6Hz,1H),3.69-3.62(m,3H),3.62-3.52(m,2H),3.44(t,J=6.4H) z,1H),3.22-3.14(m,1H),3.13-3.05(m,1H),2.84-2.70(m,4H),1.14(d,J=6.0Hz,3H). HRMS (ESI, [M+H] + ) m / z: 433.2109. Test Example 1 In vitro cell proliferation inhibitory activity 1.1 Measurement of MDA-MB-436 cell proliferation inhibitory activity MDA-MB-436 cells in good growth condition were harvested and collected in a centrifuge tube. The cells were then cultured in complete medium (DMEM high glucose + 10% FBS + 1x insulin-transferrin-selenium (ITS-G) + 16 μg / mL reduced glutathione) at a cell density of 2 x 10 4 The solution was adjusted to a concentration of 100 μL / well and inoculated into a 96-well plate (100 μL / well). After overnight incubation in a cell culture incubator, compounds were added using a nanoliter pipettor to final concentrations of 400 nM to 0.02 nM. Duplicate wells were also set up, including control wells. After 168 hours of incubation in the cell culture incubator, detection reagent CCK-8 (manufacturer: Beijing Dojindo Chemical Co., Ltd., 10 μL / well) was added. After 1.5 hours of incubation in the cell culture incubator, absorbance values ​​at 450 nm were detected using a PerkinElmer Envision plate reader. A four-parameter analysis was performed, and a dose-response curve was fitted to determine the IC. 50 was calculated, where A is the IC 50 ≦50 nM, and the results are shown in Table 1.

[0651] [Table 1]

[0652] Test Example 2 PARP protein inhibitory activity 2.1 Measurement of PARP1 protein activity A chemiluminescence assay kit (BPS, product number 80551) was used. 50 μl of 1x histones was added to a 96-well plate and incubated overnight at 4°C. 200 μl of PBST buffer (containing 0.05% Tween-20) was added to each well, washed three times, and the liquid in the well plate was removed. 200 μl of blocking buffer 3 was added and blocked for 60-90 minutes at room temperature. The blocking solution was discarded, and the well plate was washed three times with PBST buffer and the liquid in the well plate was removed. 25 μL of master mix (2.5 μL 10x PARP buffer + 2.5 μL 10x assay mixture containing biotinylated substrate + 5 μL activated DNA (5x) + 15 μL water) and 5 μL of 1x PARP buffer were added to each well, and the compound was sprayed onto the compound group using a nanoliter pipettor. The blank control group received 20 μL of 1x PARP buffer, while the other wells received 20 μL of PARP1 enzyme (2.4 ng / ml) to initiate the reaction and were incubated at room temperature for 1 hour. 50 μL of streptavidin-HRP (diluted 1:50 in blocking buffer 3) was added to each well and incubated at room temperature for 30 minutes. The well plate was washed three times with PBST to remove any liquid. Before use, 50 μL of ELISA ECL Substrate A and 50 μL of ELISA ECL Substrate B were mixed on ice and added to each well in 100 μL aliquots. Absorbance was detected using a PerkinElmer Envision Luminescence plate reader. A four-parameter analysis was performed, and a dose-response curve was fitted to determine the IC. 50 was calculated, where +++ is the IC 50 ≤1 nM, ++ denotes IC 50 ≦10 nM, and the results are shown in Table 2.

[0653] [Table 2]

[0654] The compounds of the present disclosure have high PARP1 protein kinase inhibitory activity.

[0655] Test Example 3 PARP protein trap activity 3.1 Measurement of PARP1 protein Trap activity PARPtrap (商標) A detection kit (BPS, product number 80584-2) was used, and the experiment was divided into a blank group, a control group, a low FP control group, a high FP control group, and a compound group. (商標) A mixture consisting of assay buffer, 25 nM fluorescent labeled DNA, and water was prepared. The mixture or 5× PARPtrap was added according to the group settings. (商標) Assay buffer, 1x PARP trap (商標) Assay buffer, 1x PARP trap (商標) PARP1 (0.5 ng / μl) and compounds prepared in assay buffer were added to a 384-well plate and incubated at room temperature for 60 minutes. After that, 10× NAD+ or water was added to each well according to the group configuration, and the mixture was incubated at room temperature for 60 minutes.

[0656] The degree of polarization (FP) was detected using a PerkinElmer Envision FP-480 / 530 plate reader, and mP was calculated. mP = 1000 * (SG * P) / (S + G * P), where S represents the fluorescence intensity in perpendicular light, P represents the fluorescence intensity in parallel light, and G represents a correction coefficient. Four-parameter analysis was performed to fit the dose-response curve, and the EC 50 was calculated.

[0657] 3.2 Measurement of PARP2 protein Trap activity PARPtrap (商標) A detection kit (BPS, product number 78296-2) was used, and the experiment was divided into a blank group, a control group, a low FP control group, a high FP control group, and a compound group. (商標)Add DTT to the assay buffer to make a final concentration of 5x PARPtrap containing 10 mM DTT. (商標) Prepare assay buffer 2, then 5x PARPtrap (商標) A mixture consisting of assay buffer 2, 12.5 nM fluorescent labeled DNA, and water was prepared. The mixture or 5× PARPtrap was used according to the group settings. (商標) Assay buffer 2, 1x PARPtrap (商標) Assay buffer 2, 1x PARPtrap (商標) PARP2 (3.75 ng / μl) and compounds prepared in assay buffer 2 were added to a 384-well plate and incubated at room temperature for 60 minutes. After that, 10× NAD+ or water was added to each well and incubated at room temperature for 60 minutes.

[0658] The degree of polarization (FP) was detected using a PerkinElmer Envision FP-480 / 530 plate reader, and mP was calculated. mP = 1000 * (SG * P) / (S + G * P), where S represents the fluorescence intensity in perpendicular light, P represents the fluorescence intensity in parallel light, and G represents a correction coefficient. Four-parameter analysis was performed to fit the dose-response curve, and the EC 50 was calculated.

[0659] Test Example 4 In vitro pharmacokinetics 4.1 Liver microsome stability test The incubated liver microsome sample was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / ml), test compound, and NADPH + MgCl2 solution and incubating at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / ml), and test compound. The sample was added to an acetonitrile solution containing an internal standard, and the supernatant was prepared by protein precipitation. The supernatant was then diluted and used for LC / MS / MS analysis.

[0660] The compounds of the present disclosure have good liver microsomal stability.

[0661] Test Example 5 In vivo pharmacokinetics 5.1 Pharmacokinetics in mice ICR mice weighing 20 to 25 g were acclimated for 3 to 5 days, then randomly divided into groups of 9 mice each, and a test compound solution was administered intragastrically at a dose of 1 mg / kg.

[0662] Blood was collected at 0 minutes, 5 minutes, 0.25 minutes, 0.5 hours, 2 hours, 6 hours, 10 hours and 24 hours and blood was collected via the orbit to prepare plasma samples for testing.

[0663] 20 μL of the test plasma sample and the standard curve sample were aspirated and added to an acetonitrile solution containing an internal standard substance, and the supernatant was obtained by protein precipitation, diluted, and used for LC / MS / MS measurement.

[0664] 5.2 Pharmacokinetics in rats SD rats weighing 180 to 220 g were acclimated for 3 to 5 days, then randomly divided into groups of 3 rats, and a test compound solution was administered intragastrically at a dose of 0.5 mg / kg.

[0665] Blood samples were collected at 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h, and plasma samples were prepared for testing by orbital collection.

[0666] 50 μL of the test plasma sample and the standard curve sample were aspirated and added to an acetonitrile solution containing an internal standard substance, and the supernatant was obtained by protein precipitation, diluted, and used for LC / MS / MS measurement.

[0667] Compounds of the present disclosure may have, for example, a long half-life (T 1 / 2 ), high in vivo exposure (AUC), and high bioavailability (F%), among other favorable in vivo pharmacokinetic properties.

[0668] Test Example 6 PARP1 / 2-Tracer activity measurement experiment Compounds were tested for PARP1 / 2-Tracer enzyme activity inhibition using the FP method. First, 100 nL of inhibitor in DMSO was transferred to a 384-well reaction plate (Corning 4514) using an Echo 655 to a final concentration of 1%. 5 μL of PARP1 / 2 (BPS, Cat# 80501 / 80502) enzyme solution was added to each well, centrifuged at 1000 RPM for 1 minute at room temperature, and incubated for 10 minutes. Next, 5 μL of Tracer (ICE, Cat# 001315-009) solution was added to each well, centrifuged at 1000 RPM for 1 minute at room temperature, and incubated for 60 minutes. PARP1 / 2 and Tracer were prepared in 50 mM Tris (pH 8.0), 10 mM MgCl2, 150 mM NaCl, and 0.001% Triox-100 buffer at final concentrations of 5 / 10 nM and 2.5 nM, respectively. Finally, the FP signal was read by BMG (PHERAstar FSX) and the IC was analyzed using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fitting were obtained and the results are shown in Table 3.

[0669] [Table 3]

[0670] The compounds of the present disclosure have high selectivity for the PARP1 protein.

Claims

1. A compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, R is 【Chemistry 2】 is selected from X １ is CR ａ , CHR ａ , N or NR ａ is selected from X ２ is selected from CH or N; X ３ is selected from CH or N; R １ is a halogen, C １－６ Alkyl, C １－６ Alkoxy, C ３－８ cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S; １ is D, halogen, -OH, -OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from R ａ is H, halogen or C １－６ alkyl, Or, R ａ and R １ are joined together to form a 5- to 7-membered heterocycloalkyl, a 5- to 7-membered cycloalkenyl, a phenyl, a 5- to 7-membered heterocycloalkenyl, or a 5- to 6-membered heteroaryl; R ２ is C １－６ Alkyl, —OH, —OC １－６ Alkyl, —OC ３－６ Cycloalkyl, —SH, —SC １－６ Alkyl, -SC ３－６ Cycloalkyl, —NH ２ , —NH(C １－６ alkyl), -NH(C ３－６ cycloalkyl), —NH(3- to 8-membered heterocycloalkyl), —N(C １－６ alkyl) ２ , -N(C １－６ alkyl) (C ３－６ cycloalkyl) or —N(C ３－６ cycloalkyl) ２ wherein R ２ is D, halogen, -OH, -OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , C ３－６ optionally substituted with one or more groups selected from cycloalkyl or 3- to 8-membered heterocycloalkyl; R ３ , R ４ and R ５ are each independently １－６ Alkyl, D, halogen, —OH, —OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and C is selected from １－６ Alkyl, —OC １－６ Alkyl, -SC １－６ Alkyl, —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ is D, halogen, -OH, -OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from o, p, and q are each independently selected from 0, 1, or 2; L is —NH— or —CH ２ -, wherein L is selected from C １－６ Alkyl, D, halogen, —OH, —OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from Ring A is selected from 3- to 8-membered heterocycloalkyl, and said ring A may further contain, in addition to the N atom bonded to L, 1 to 3 heteroatoms independently selected from N, O, or S, and said ring A is selected from D, halogen, —OH, —C １－６ Alkyl, —OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , -C １－４ Alkylene-OC １－６ Alkyl, —C １－４ Alkylene-SC １－６ Alkyl, —C １－４ Alkylene-NH(C １－６ alkyl) or -C １－４ Alkylene-N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from Ring B is selected from an aromatic ring or an incompletely saturated ring; Y １ , Y ２ and Y ３ are each independently selected from C, CH, N, O, or S.

2. The compound of claim 1, its stereoisomer or its pharmaceutically acceptable salt, wherein the compound represented by formula (II) is selected from the compound represented by formula (I), its stereoisomer or its pharmaceutically acceptable salt. 【Transformation 3】 (In the formula, X １ is CR ａ or N, X ２ is selected from CH or N; R １ is a halogen, C １－６ Alkyl, C １－６ Alkoxy, C ３－８ cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S; １ is D, halogen, -OH, -OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from R ａ is H, halogen or C １－６ alkyl, Or, R ａ and R １ are joined together to form a 5- to 7-membered cycloalkenyl, phenyl, 5- to 7-membered heterocycloalkenyl, or 5- to 6-membered heteroaryl; R ２ is C １－６ Alkyl, —OH, —OC １－６ Alkyl, —OC ３－６ Cycloalkyl, —SH, —SC １－６ Alkyl, -SC ３－６ Cycloalkyl, —NH ２ , —NH(C １－６ alkyl), -NH(C ３－６ cycloalkyl), —NH(3- to 8-membered heterocycloalkyl), —N(C １－６ alkyl) ２ , -N(C １－６ alkyl) (C ３－６ cycloalkyl) or —N(C ３－６ cycloalkyl) ２ wherein R ２ is D, halogen, -OH, -OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from R ３ , R ４ and R ５ are each independently １－６ Alkyl, D, halogen, —OH, —OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and C is selected from １－６ Alkyl, —OC １－６ Alkyl, -SC １－６ Alkyl, —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ is D, halogen, -OH, -OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from o, p, and q are each independently selected from 0, 1, or 2; L is —NH— or —CH ２ -, wherein L is selected from C １－６ Alkyl, D, halogen, —OH, —OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from Ring A is selected from 3- to 8-membered heterocycloalkyl, and said ring A may further contain, in addition to the N atom bonded to L, 1 to 3 heteroatoms independently selected from N, O, or S, and said ring A is selected from D, halogen, —OH, —C １－６ Alkyl, —OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from Ring B is selected from an aromatic ring or an incompletely saturated ring; Y １ , Y ２ and Y ３ are each independently selected from C, CH, N, O, or S.

3. X １ is CR ａ or N, or X １ is CHR ａ or NR ａ is selected from Optionally, X １ is CR ａ is selected from X ２ is selected from CH, or X １ is selected from CH; X ２ is selected from N, or X １ is selected from N, and X ２ is selected from CH, or X １ is NR ａ is selected from X ２ is selected from CH, Optionally, X １ is CR ａ is selected from X ２ is selected from CH; X ３ is selected from CH, or X １ is selected from CH; X ２ is selected from N, and X ３ is selected from CH, or X １ is selected from N, and X ２ is selected from CH; X ３ is selected from CH, or X １ is selected from CH; X ２ is selected from CH; X ３ is selected from N, or X １ is NR ａ is selected from X ２ is selected from CH; X ３ is selected from CH, its stereoisomers or pharmaceutically acceptable salts thereof according to claim 1 or 2.

4. R １ is a halogen, C １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl or 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, or S; １ is D, halogen, -OH, -OC １－６ Alkyl, -SH, -SC １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ and optionally substituted with one or more groups selected from Or, R １ is a halogen, C １－４ Alkyl or C ３－６ cycloalkyl, wherein R １ is optionally substituted with one or more groups selected from D or halogen; Or, R １ is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, or piperazinyl; １ is D, F, Cl, Br, -OH, -OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ and optionally substituted with one or more groups selected from Or, R １ is chloro, methyl, ethyl, propyl, trifluoromethyl, 【Chemistry 4】 【Transformation 5】 is selected from Or, R １ is chloro, methyl, ethyl, trifluoromethyl or 【Transformation 6】 The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from the following:

5. R ａ is selected from H, F, Cl, methyl, ethyl or propyl, or R ａ is selected from H or methyl, or R ａ is selected from H or F, Optionally, R ａ and the R １ are joined together to form a 5- to 6-membered heterocycloalkyl, a 5- to 6-membered cycloalkenyl, a phenyl, or a 5- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, or S, or R ａ and the R １ are joined together to form a 5- to 6-membered cycloalkenyl or a 5- to 6-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O, or S, or R ａ and the R １ are joined together to form a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, or S, or R ａ and the R １ are joined together to form cyclopentenyl, cyclohexenyl, dihydrofuranyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl or thiazolyl, or R ａ and the R １ The compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt thereof, wherein: are bonded to each other to form cyclopentenyl, cyclohexenyl or dihydrofuranyl.

6. R is 【Transformation 7】 is selected from Or, R is 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 and R is selected from 0, 1 or 2 R ３ is replaced by Or, R is 【Chemistry 11】 【Chemistry 12】 The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

7. R ２ is C １－４ Alkyl, —OH, —OC １－４ Alkyl, —OC ３－６ Cycloalkyl, —SH, —SC １－４ Alkyl, -SC ３－６ Cycloalkyl, —NH ２ , —NH(C １－４ alkyl), -NH(C ３－６ cycloalkyl), —NH(3- to 8-membered heterocycloalkyl), —N(C １－４ alkyl) ２ , -N(C １－４ alkyl) (C ３－６ cycloalkyl) or —N(C ３－６ cycloalkyl) ２ wherein R ２ is D, halogen, -OH, -OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ , C ３－６ optionally substituted with one or more groups selected from cycloalkyl or 3- to 8-membered heterocycloalkyl; Or, R ２ is -NH(C １－４ alkyl), -NH(C ３－６ -cycloalkyl) or -NH(3- to 8-membered heterocycloalkyl), ２ is D, halogen, -OH, -OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ , C ３－６ optionally substituted with one or more groups selected from cycloalkyl or 3- to 6-membered heterocycloalkyl; Or, R ２ is -NHCH ３ , -NHCH(CH ３ ) ２ , 【Chemistry 13】 -NHCD ３ 、-NXCH ２ CH ３ 、-NXCH ２ CF ３ 、 【Chemistry 14】 【Chemistry 15】 is selected from Or, R ２ is -NHCH ３ , 【Chemistry 16】 or -NHCH ２ CH ３ The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

8. R ３ is C １－４ Alkyl, D, F, Cl, Br, —OH, —OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ and C is selected from １－４ Alkyl, —OC １－４ Alkyl, -SC １－４ Alkyl, —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ is D, F, Cl, -OH, -OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ or may be substituted with one or more groups selected from R ３ is selected from methyl, ethyl, propyl, F or Cl, and said methyl, ethyl or propyl is selected from D, F, Cl, —OH or —NH ２ or may be substituted with one or more groups selected from R ３ is selected from methyl, F or Cl; Optionally, R ４ is C １－４ Alkyl, D, F, Cl, Br, —OH, —OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ and C is selected from １－４ Alkyl, —OC １－４ Alkyl, -SC １－４ Alkyl, —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ is D, F, Cl, -OH, -OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ or may be substituted with one or more groups selected from R ４ is selected from methyl, ethyl, propyl, F or Cl, and said methyl, ethyl or propyl is selected from D, F, Cl, —OH or —NH ２ and optionally substituted with one or more groups selected from Optionally, R ５ is C １－４ Alkyl, D, F, Cl, Br, —OH, —OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ and C is selected from １－４ Alkyl, —OC １－４ Alkyl, -SC １－４ Alkyl, —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ is D, F, Cl, -OH, -OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ or may be substituted with one or more groups selected from R ５ is selected from methyl, ethyl, propyl, F or Cl, and said methyl, ethyl or propyl is selected from D, F, Cl, —OH or —NH ２ The compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, optionally substituted with one or more groups selected from:

9. o is selected from 0, 1 or 2; Or, o is selected from 0 or 1; Optionally, p is selected from 0 or 1, or p is selected from 0; 9. The compound, its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein optionally q is selected from 0 or 1, or q is selected from 0.

10. L is —NH— or —CH ２ -, wherein L is optionally substituted with one or more groups selected from methyl, D, or F. Or L is -CH ２ The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

11. Ring A is selected from 3- to 6-membered heterocycloalkyl, and said ring A may further contain, in addition to the N atom bonded to L, 1 to 3 heteroatoms independently selected from N or O, and said ring A is selected from D, F, Cl, —OH, —C １－４ Alkyl, —OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ or said ring A may be substituted with one or more groups selected from -C １－３ Alkylene-OC １－４ Alkyl, —C １－３ Alkylene-NH(C １－４ alkyl) or -C １－３ Alkylene-N(C １－４ alkyl) ２ and optionally substituted with one or more groups selected from Or, Ring A is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, diazetidinyl, imidazolinyl, piperazinyl, oxazolinyl, or morpholinyl, wherein said Ring A is selected from D, F, Cl, —OH, —OC １－４ Alkyl, -SH, -SC １－４ Alkyl, —NH ２ , —NH(C １－４ alkyl) or -N(C １－４ alkyl) ２ or the ring A may be substituted with one or more groups selected from one or more -C １－４ may be substituted with alkyl, Or, the ring A is -C １－３ Alkylene-OC １－４ alkyl, Or, ring A is 【Chemistry 17】 wherein ring A is selected from -OH or -C １－４ or the ring A may be substituted with one or more groups selected from -OH, -C １－４ Alkyl or -C １－３ Alkylene-OC １－４ alkyl, Or, ring A is [Chemistry 18] * is attached to L on the nitrogen atom side marked with * and is attached to the structural fragment 【Chemistry 19】 The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein

12. Ring B is selected from an aromatic ring containing 1, 2 or 3 heteroatoms selected from N, O or S, or Ring B is selected from a 5-membered aromatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; or ring B is selected from a pyrazole ring, a pyrrole ring, a thiazole ring, an oxazole ring, an isoxazole ring, a furan ring, an imidazole ring, or a thiophene ring; Or, ring B is 【Chemistry 20】 Or ring B is selected from 【Chemistry 21】 【Chemistry 22】 The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

13. The following compound, its stereoisomer or pharmaceutically acceptable salt thereof: 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, for the manufacture of a medicament for treating a PARP1-associated disease, wherein optionally the PARP1-associated disease is selected from tumors or cancers, and optionally the cancer is selected from breast cancer, ovarian cancer, colon cancer, pancreatic cancer or prostate cancer.

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