Compounds containing fused bicyclic rings, pharmaceutical compositions, and uses thereof

Abstract

The present application belongs to the field of medicinal chemistry, and relates to a fused bicyclic compound, a pharmaceutical composition and use thereof, in particular to a compound shown in formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and use thereof in treating diseases.

Description

Compounds containing fused bicyclic rings, pharmaceutical compositions and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to Chinese invention patent applications No. 202311448787.3, No. 202410277416.1 and No. 202411481792.9 filed with the State Intellectual Property Office of the People's Republic of China on November 1, 2023, March 11, 2024 and October 23, 2024, and the entire contents of which are hereby incorporated herein in their entirety. Technical Field

[0003] The present application relates to a fused bicyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating diseases. Background Art

[0004] Poly(ADP-ribose) polymerases (PARPs) are cellular nuclear enzymes that catalyze ADP-ribosylation. The PARP family consists of 18 members and plays a crucial role in a wide range of cellular metabolic processes, including DNA damage repair, inflammation regulation, 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 homologous recombination repair (HR) defects caused by BRCA gene defects while sparing the survival of cells with normal BRCA gene function, a phenomenon known as cooperative lethality.

[0005] Since the approval of olaparib in 2014, several PARP inhibitors have been developed and have achieved widespread success. However, adverse reactions limit their ability to be used in combination with chemotherapy drugs. Therefore, PARP inhibitors with improved PARP1 selectivity may have better efficacy and lower toxicity.

[0006] Detailed Description of the Invention

[0007] In one aspect, the present application relates to a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] R is selected from

[0010] X 1 Selected from CR a 、CHR a , N or NR a ;

[0011] X 2 selected from CH or N;

[0012] X 3 selected from CH or N;

[0013] R 1 Selected from 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, wherein R 1 Optionally, one or more 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 group substitution;

[0014] R a Selected from H, halogen or C 1-6 alkyl;

[0015] or R a With R 1 Connected to form a 5-7 membered heterocycloalkyl, a 5-7 membered cycloalkenyl, a phenyl, a 5-7 membered heterocycloalkenyl or a 5-6 membered heteroaryl;

[0016] R 2 Selected from 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- , the R 2 Optionally, one or more selected from D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl), -N(C1-6 Alkyl)2, C 3-6 Substitution with a cycloalkyl group or a 3-8 membered heterocycloalkyl group;

[0017] R 3 、R 4 and R 5 Each independently selected from 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, the 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 optionally substituted by one or more 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 group substitution;

[0018] o, p and q are each independently selected from 0, 1 or 2;

[0019] L is selected from -NH- or -CH2-, said L is optionally replaced by one or more selected from 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 group substitution;

[0020] Ring A is selected from 3-8 membered heterocycloalkyl, wherein the ring A contains, in addition to the N atom connected to L, 1-3 heteroatoms independently selected from N, O or S, and the ring A is optionally substituted by one or more 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(C1-6 alkyl) or -C 1-4 Alkylene-N(C 1-6 Alkyl)2 group substitution;

[0021] Ring B is selected from an aromatic ring or a partially saturated ring;

[0022] Y 1 、Y 2 and Y 3 are each independently selected from C, CH, N, O or S.

[0023] 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,

[0024] in,

[0025] X 1 Selected from CR a or N;

[0026] X 2 selected from CH or N;

[0027] R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S, wherein R 1 Optionally, one or more 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 group substitution;

[0028] R a Selected from H, halogen or C 1-6 alkyl;

[0029] or R a With R 1 are connected to each other to form a 5-7 membered cycloalkenyl group or a 5-7 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from N, O or S;

[0030] R 2 Selected from 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 3-6Cycloalkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)(C 3-6 Cycloalkyl) or -N(C 3-6 Cycloalkyl) 2, said R 2 Optionally, one or more 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 group substitution;

[0031] R 3 、R 4 and R 5 Each independently selected from 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, the 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 optionally substituted by one or more 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 group substitution;

[0032] o, p and q are each independently selected from 0, 1 or 2;

[0033] L is selected from -NH- or -CH2-, said L is optionally replaced by one or more selected from 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 group substitution;

[0034] Ring A is selected from 3-8 membered heterocycloalkyl, wherein the ring A contains, in addition to the N atom connected to L, 1-3 heteroatoms independently selected from N, O or S, and the ring A is optionally substituted by one or more selected from D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)2 group substitution;

[0035] Ring B is selected from an aromatic ring or a partially saturated ring;

[0036] Y 1 、Y 2 and Y 3 are each independently selected from C, N, O or S.

[0037] 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,

[0038] in,

[0039] X 1 Selected from CR a or N;

[0040] X 2 selected from CH or N;

[0041] R 1 Selected from 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, wherein R 1 Optionally, one or more 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 group substitution;

[0042] R a Selected from H, halogen or C 1-6 alkyl;

[0043] or R a With R 1 Connected to form a 5-7 membered cycloalkenyl, phenyl, 5-7 membered heterocycloalkenyl or 5-6 membered heteroaryl;

[0044] R 2 Selected from 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(C3-6 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- , the R 2 Optionally, one or more 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 group substitution;

[0045] R 3 、R 4 and R 5 Each independently selected from 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, the 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 optionally substituted by one or more 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 group substitution;

[0046] o, p and q are each independently selected from 0, 1 or 2;

[0047] L is selected from -NH- or -CH2-, said L is optionally replaced by one or more selected from 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 group substitution;

[0048] Ring A is selected from 3-8 membered heterocycloalkyl, wherein the ring A contains, in addition to the N atom connected to L, 1-3 heteroatoms independently selected from N, O or S, and the ring A is optionally substituted by one or more selected from D, halogen, -OH, -C1-6 Alkyl, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)2 group substitution;

[0049] Ring B is selected from an aromatic ring or a partially saturated ring;

[0050] Y 1 、Y 2 and Y 3 are each independently selected from C, CH, N, O or S.

[0051] In some embodiments, the compound of formula (I) and the compound of formula (II) are not the following compounds:

[0052] In some embodiments, the X 1 Selected from CR a or N.

[0053] In other embodiments, the X 1 Selected from CHR a or NR a .

[0054] In other embodiments, the X 1 Selected from CHR a .

[0055] In some embodiments, the X 1 Selected from CR a , X 2 Selected from CH.

[0056] In some embodiments, the X 1 Selected from CH, X 2 Selected from N.

[0057] In some embodiments, the X 1 Selected from N, X 2 Selected from CH.

[0058] In some embodiments, the X 1 Selected from NR a , X 2 Selected from CH.

[0059] In some embodiments, the X 3 Selected from CH.

[0060] In yet other embodiments, R is selected from X 1 Selected from CR a or N, X 2 Selected from CH or N, X 3 is selected from CH or N.

[0061] In yet other embodiments, R is selected from X 1 Selected from CHR a or NR a , X 2 Selected from CH or N, X 3 is selected from CH or N.

[0062] In some embodiments, the X 1 Selected from CR a , X 2 Selected from CH, X 3 Selected from CH.

[0063] In some embodiments, the X 1 、X 2 and X 3 All are selected from CH.

[0064] In some embodiments, the X 1 Selected from CH, X 2 Selected from N, X 3 Selected from CH.

[0065] In some embodiments, the X 1 Selected from N, X 2 Selected from CH, X 3 Selected from CH.

[0066] In some embodiments, the X 1 Selected from CH, X 2 Selected from CH, X 3 Selected from N.

[0067] In some embodiments, the X 1 Selected from NR a , X 2 Selected from CH, X 3 Selected from CH.

[0068] In some embodiments, the R 1 Selected from 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, wherein R 1 Optionally, one or more selected from D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2 group substituted.

[0069] In some embodiments, the R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S, wherein R 1 Optionally, one or more 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 group substituted.

[0070] In some embodiments, the R 1 Selected from halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, the R 1 Optionally, one or more selected from 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 group substitution.

[0071] In some embodiments, the R 1 Selected from halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, the R 1 Optionally substituted with one or more groups selected from D or halogen.

[0072] In some embodiments, the R 1 Selected from halogen, C 1-3 Alkyl or C 3-6 Cycloalkyl, the R 1 Optionally substituted with one or more groups selected from halogen.

[0073] In some embodiments, the R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S, wherein R 1 Optionally, one or more selected from D, halogen, -OH, -OC 1-6 Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6alkyl) or -N(C 1-6 In some embodiments, R 1 Selected from halogen.

[0074] In some embodiments, the R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S, wherein R 1 Optionally, one or more selected from 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 Selected from halogen.

[0075] In some embodiments, the R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl or piperazinyl, wherein R 1 Optionally, one or more selected from 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.

[0076] In some embodiments, the R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl or tetrahydropyranyl, wherein R 1 Optionally, one or more selected from 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.

[0077] In some embodiments, the R 1 Selected from methyl, ethyl, propyl, The R 1 Optionally, one or more selected from 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 Selected from Cl.

[0078] In some embodiments, the R 1 Selected from Cl, methyl, ethyl, propyl, The R 1 Optionally substituted with one or more groups selected from D, F, Cl or Br.

[0079] In some embodiments, the R 1 Selected from Cl, methyl, ethyl, propyl, The R 1 Optionally substituted with one or more F.

[0080] In some embodiments, the R 1 Selected from chlorine, methyl, ethyl, propyl, trifluoromethyl,

[0081] In some embodiments, the R 1 Selected from methyl, ethyl, propyl,

[0082] In some embodiments, the R 1 Selected from chlorine, methyl, ethyl, trifluoromethyl or

[0083] In some embodiments, the R 1 Selected from ethyl or

[0084] In some further embodiments, the R 1 Selected from ethyl or trifluoromethyl.

[0085] In some embodiments, the R a Selected from H, F, Cl, Br or C 1-4 alkyl.

[0086] In some embodiments, the R a Selected from H, F, Cl or C 1-3 alkyl.

[0087] In some embodiments, the R a is selected from H, F, Cl, methyl, ethyl or propyl.

[0088] In other embodiments, the R a Selected from H or methyl.

[0089] In some embodiments, the R a Selected from H or F.

[0090] In some embodiments, the R a Selected from H.

[0091] In some embodiments, the R a With the R 1 They are connected to each other to form a 5-6 membered heterocycloalkyl, a 5-6 membered cycloalkenyl, a phenyl group, or a 5-6 membered heterocycloalkenyl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O or S.

[0092] In some embodiments, the R a With the R 1 They are connected to each other to form a 5-6 membered cycloalkenyl, a phenyl group, a 5-6 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from N, O or S, or a 5-6 membered heteroaryl group.

[0093] In some embodiments, the R a With the R 1 They are connected to each other to form a 5-6 membered cycloalkenyl or a 5-membered heterocycloalkenyl or a 5-membered heteroaryl containing one heteroatom independently selected from N or O.

[0094] In some embodiments, the R a With the R 1 They are connected to each other to form a 5-6 membered cycloalkenyl or a 5-6 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from N, O or S.

[0095] In some embodiments, the R a With the R 1 They are connected to each other to form a 5-6 membered cycloalkenyl or a 5-membered heterocycloalkenyl containing one heteroatom independently selected from N or O.

[0096] In other embodiments, the R a With the R 1 They are linked to each other to form a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O or S.

[0097] In other embodiments, the R a With the R 1They are linked to each other to form a 5-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, O or S.

[0098] In other embodiments, the R a With the R 1 They are connected to each other to form a 5-membered heteroaryl group containing 1-2 N atoms.

[0099] In some embodiments, the R a With the R 1 They are connected to each other to form cyclopentenyl, cyclohexenyl, dihydrofuranyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl or thiazolyl.

[0100] In some further embodiments, the R a With the R 1 They are connected to each other to form cyclopentenyl, cyclohexenyl, dihydrofuranyl, pyrrolyl, pyrazolyl or imidazolyl.

[0101] In some embodiments, the R a With the R 1 They are connected to each other to form cyclopentenyl, cyclohexenyl or dihydrofuranyl.

[0102] In other embodiments, the R is selected from

[0103] In other embodiments, the R is selected from

[0104] In other embodiments, the R is selected from

[0105] In some further embodiments, said R is selected from

[0106] In other embodiments, the R is selected from The R is 0, 1 or 2 R 3 replace.

[0107] In other embodiments, the R is selected from The R is 0, 1 or 2 R 3 replace.

[0108] In other embodiments, the R is selected from The R is 0, 1 or 2 R 3 replace.

[0109] In some embodiments, the R is selected from In some embodiments, the R is selected from

[0110] In some embodiments, the R is selected from And R a With R 1 They are linked to each other to form a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O or S.

[0111] In some embodiments, the R is selected from And R a With R 1 They are connected to each other to form a 5-membered heteroaryl group containing 1-2 N atoms.

[0112] In some embodiments, the R is selected from And R a With R 1 They are connected to each other to form pyrrolyl, pyrazolyl or imidazolyl.

[0113] In some embodiments, the R is selected from The R is 0, 1 or 2 R 3 replace.

[0114] In some further embodiments, said R is selected from And R a With R 1 They are connected to each other to form a 5-6 membered cycloalkenyl or a 5-membered heterocycloalkenyl or a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from N or O.

[0115] In some further embodiments, said R is selected from And R a With R 1 They are connected to each other to form a 5-6 membered cycloalkenyl or a 5-membered heterocycloalkenyl containing one heteroatom independently selected from N or O.

[0116] In some further embodiments, said R is selected from And R a With R 1 They are connected to each other to form cyclopentenyl, cyclohexenyl or dihydrofuranyl.

[0117] The compound of formula (II) of the present application, its stereoisomer or its pharmaceutically acceptable salt, wherein R is selected from When R 1 The adjacent ring nitrogen atoms can also be connected to each other to form a 5-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N or O.

[0118] In some further embodiments, said R is selected from When R 1The adjacent ring N atoms can also be connected to each other to form a 5-membered heteroaryl group containing 1-2 N heteroatoms.

[0119] In some further embodiments, said R is selected from When R 1 The adjacent ring nitrogen atoms can also be connected to each other to form a pyrrolyl, pyrazolyl or imidazolyl group.

[0120] In some embodiments, the R is selected from and R is replaced by 0, 1 or 2 R 3 replace.

[0121] In some embodiments, the R is selected from

[0122] In some embodiments, the R is selected from

[0123] In some embodiments, the R is selected from

[0124] In some further embodiments, said R is selected from

[0125] In other embodiments, the R 2 Selected from 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, said R 2 Optionally, one or more selected from 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 The cycloalkyl group or the 3-8 membered heterocycloalkyl group is substituted.

[0126] In some embodiments, the R 2 Selected from 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, said R 2 Optionally, one or more 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 In some embodiments, the R 2 Selected from -NH(3-6 membered heterocycloalkyl), said R 2 Optionally, one or more 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 In some embodiments, the R 2 Optionally, one or more selected from 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 The cycloalkyl group or the 3-6 membered heterocycloalkyl group is substituted.

[0127] In some embodiments, the R 2 Selected from 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(3-6 membered heterocycloalkyl) or -N(C 1-4 Alkyl) 2, said R 2 Optionally, one or more selected from D, halogen, -OH, -OC 1-6Alkyl, -SH, -SC 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 In some embodiments, the R 2 Optionally, one or more selected from 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 The cycloalkyl group or the 3-6 membered heterocycloalkyl group is substituted.

[0128] In some embodiments, the R 2 Selected from 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, said R 2 Optionally, one or more 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 In some embodiments, the R 2 Selected from -NH(3-6 membered heterocycloalkyl), said R 2 Optionally, one or more 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 In some embodiments, the R 2 Optionally, one or more selected from 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 The cycloalkyl group or the 3-6 membered heterocycloalkyl group is substituted.

[0129] In some embodiments, the R 2 Selected from -NH2, -NH(C 1-4 Alkyl), -NH(C 3-6 Cycloalkyl) or -N(C1-4 Alkyl) 2, said R 2 Optionally, one or more 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 In some embodiments, the R 2 Selected from -NH(3-6 membered heterocycloalkyl), said R 2 Optionally, one or more 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 In some embodiments, the R 2 Optionally, one or more selected from 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 The cycloalkyl group or the 3-6 membered heterocycloalkyl group is substituted.

[0130] In some embodiments, the R 2 Selected from -NH2, -NH(C 1-4 Alkyl), -NH(C 3-6 Cycloalkyl), or -N(C 1-4 Alkyl) 2, said R 2 Optionally, one or more 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 In some embodiments, the R 2 Selected from -NH(3-6 membered heterocycloalkyl), said R 2 Optionally, one or more 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 In some embodiments, the R 2 Selected from -NH(C 1-4 Alkyl), -NH(C 3-6cycloalkyl), or -NH(3-6 membered heterocycloalkyl), said R 2 Optionally substituted with one or more D.

[0131] In some embodiments, the R 2 Selected from -NH(C 1-4 Alkyl), -NH(C 3-6 Cycloalkyl) or -NH (3-8 membered heterocycloalkyl), said R 2 Optionally, one or more selected from 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 The cycloalkyl group or the 3-6 membered heterocycloalkyl group is substituted.

[0132] In some embodiments, the R 2 Selected from -NH(C 1-4 Alkyl), -NH(C 3-6 Cycloalkyl) or -NH (3-6 membered heterocycloalkyl), said R 2 Optionally, one or more selected from D, halogen, C 3-6 The cycloalkyl group or the 3-6 membered heterocycloalkyl group is substituted.

[0133] In some embodiments, the R 2 Selected from -NH(C 1-4 Alkyl), -NH(C 3-6 Cycloalkyl) or -NH (3-6 membered heterocycloalkyl), said R 2 Optionally substituted with one or more selected from D, F, Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxirane, azetidinyl, oxetanyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0134] In some embodiments, the R 2 Selected from -NHCH3, -NHCH(CH3)2, -NHCD3, -NHCF3, -NH-O-CH3 or -NH-N(CH3)2. In some embodiments, the R 2 Selected from -NHCH3, -NHCH2CH 3、 In some embodiments, the R 2 Selected from -NHCH2CF3 or

[0135] In some embodiments, the R 2Selected from -NHCH3, -NHCH(CH3)2, -NHCD3, -NHCH2CH3,

[0136] In some embodiments, the R 2 Selected from -NHCH3, -NHCH(CH3)2, -NHCD3, -NHCH2CH3, -NHCH2CF3,

[0137] In some embodiments, the R 2 Selected from -NHCH3, Or -NHCH2CH3.

[0138] In some further embodiments, the R 2 Selected from -NHCH3.

[0139] In some embodiments, the R 3 Selected from 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, the 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 optionally replaced by one or more 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 alkyl)2 group substitution.

[0140] In some embodiments, the R 3 Selected from 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, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl)2 is optionally substituted with one or more groups selected from D, F, Cl, -OH or -NH2.

[0141] In some embodiments, the R 3 is selected from methyl, ethyl, propyl, F or Cl, wherein the methyl, ethyl or propyl group is optionally substituted by one or more groups selected from D, F, Cl, -OH or -NH2.

[0142] In some embodiments, the R 3 is selected from methyl, ethyl or halogen.

[0143] In some embodiments, the R 3 Selected from halogen.

[0144] In some embodiments, the R 3 Selected from F or Cl.

[0145] In some embodiments, the R 3 is selected from methyl, F or Cl.

[0146] In some embodiments, the R 4 Selected from 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, the 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 optionally replaced by one or more 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 alkyl)2 group substitution.

[0147] In some embodiments, the R 4 Selected from 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, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl)2 is optionally substituted with one or more groups selected from D, F, Cl, -OH or -NH2.

[0148] In some embodiments, the R 4 is selected from methyl, ethyl, propyl, F or Cl, wherein the methyl, ethyl or propyl group is optionally substituted by one or more groups selected from D, F, Cl, -OH or -NH2.

[0149] In some embodiments, the R 4 Selected from methyl, ethyl or propyl.

[0150] In some embodiments, the R 4 Selected from methyl.

[0151] In some embodiments, the R 5 Selected from 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, the 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 optionally replaced by one or more 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 alkyl)2 group substitution.

[0152] In some embodiments, the R 5 Selected from 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, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl)2 is optionally substituted with one or more groups selected from D, F, Cl, -OH or -NH2.

[0153] In some embodiments, the R 5 is selected from methyl, ethyl, propyl, F or Cl, wherein the methyl, ethyl or propyl group is optionally substituted by one or more groups selected from D, F, Cl, -OH or -NH2.

[0154] In some embodiments, o is selected from 0, 1 or 2.

[0155] In some embodiments, o is selected from 0 or 1.

[0156] In some embodiments, p is selected from 0, 1 or 2.

[0157] In some embodiments, p is selected from 0 or 1. In some embodiments, p is selected from 0. In some embodiments, p is selected from 1. In some embodiments, p is selected from 2.

[0158] In some embodiments, q is selected from 0, 1 or 2.

[0159] In some embodiments, q is selected from 0 or 1. In some embodiments, q is selected from 0.

[0160] In some embodiments, L is selected from -NH- or -CH2-, wherein L is optionally replaced by one or more selected from C 1-4 The alkyl group is substituted with D, F, Cl, -OH or -NH2.

[0161] In some embodiments, L is selected from -NH- or -CH2-, said L being optionally substituted with one or more groups selected from methyl, D or F.

[0162] In some embodiments, L is selected from -CH2-.

[0163] In some embodiments, ring A is selected from 3-6 membered heterocycloalkyl, wherein the ring A contains, in addition to the N atom connected to L, 1-3 heteroatoms independently selected from N, O or S, and the ring A is optionally substituted by one or more 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 group substituted; or, the ring A is optionally substituted by one or more selected from -C 1-6 Alternatively, the ring A is optionally substituted with one or more 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 1-4 alkyl)2 group substitution.

[0164] In some embodiments, ring A is selected from 3-6 membered heterocycloalkyl, wherein the ring A contains, in addition to the N atom connected to L, 1-3 heteroatoms independently selected from N or O, and the ring A is optionally substituted with one or more 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 Alkyl) 2 group substituted; or the ring A is optionally selected from one or more -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 group substitution.

[0165] In some embodiments, ring A is selected from 3-6 membered heterocycloalkyl, wherein the ring A contains, in addition to the N atom connected to L, 1-3 heteroatoms independently selected from N or O, and the ring A is optionally substituted by one or more selected from -OH or -C 1-4 or the ring A is optionally substituted with one or more 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 group substitution.

[0166] In some embodiments, ring A is selected from 3-6 membered heterocycloalkyl, wherein the ring A contains, in addition to the N atom connected to L, 1-3 heteroatoms independently selected from N or O, and the ring A is optionally substituted with one or more 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 Alkyl) 2 group substituted; or the ring A is optionally selected from one or more -C 1-3 Alkylene-OC 1-4 Alkyl groups are substituted.

[0167] In some embodiments, ring A is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, diazetidinyl, imidazolinyl, piperazinyl, oxazolinyl or morpholinyl, and the ring A is optionally substituted by one or more selected from D, F, Cl, -OH, -OC1-4 Alkyl, -SH, -SC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl) or -N(C 1-4 Alternatively, the ring A is optionally substituted with one or more -C 1-4 Alkyl group substituted; or the ring A is optionally selected from one or more -C 1-3 Alkylene-OC 1-4 Alkyl groups are substituted.

[0168] In some embodiments, ring A is selected from azetidinyl or tetrahydropyrrolyl, said ring A being optionally substituted with one or more selected from -OH, -C 1-4 Alkyl or -C 1-3 Alkylene-OC 1-4 Alkyl groups are substituted.

[0169] In some embodiments, ring A is selected from azetidinyl or tetrahydropyrrolyl, said ring A being optionally substituted by one or more selected from -OH or -C 1-4 Alkyl groups are substituted.

[0170] In some embodiments, Ring A is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, diazetidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, or morpholinyl.

[0171] In some embodiments, Ring A is selected from Among them, * indicates that the nitrogen atom with * is connected to L on one side and to the structural fragment on the other side. In some embodiments, ring A is selected from Among them, * indicates that the nitrogen atom with * is connected to L on one side and to the structural fragment on the other side. are connected.

[0172] In some embodiments, Ring A is selected from The ring A is optionally substituted by one or more selected from -OH or -C 1-4 Alternatively, the ring A is optionally substituted with one or more selected from -OH, -C 1-4 Alkyl or -C 1-3 Alkylene-OC 1-4 Alkyl groups are substituted.

[0173] In some embodiments, Ring A is selected from Here, * means the same as above.

[0174] In some embodiments, Ring A is selected from Here, * means the same as above.

[0175] In some embodiments, Ring A is selected from Here, * means the same as above.

[0176] In some embodiments, Ring A is selected from Here, * means the same as above.

[0177] In some embodiments, Ring A is selected from The * means the same as above.

[0178] In some embodiments, Ring B is selected from aromatic rings.

[0179] In some embodiments, Ring B is selected from aromatic rings containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0180] In some embodiments, Ring B is selected from a 5-membered aromatic heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0181] In some embodiments, Ring B is selected from a 5-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from N, O, or S.

[0182] In some embodiments, Ring B is selected from a 5-membered aromatic heterocycle, Y 1 、Y 2 and Y 3 are each independently selected from C, CH, N or S.

[0183] 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.

[0184] In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from

[0185] In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from

[0186] In some embodiments, Ring B is selected from

[0187] In some embodiments, the structural fragment Selected from

[0188] In some embodiments, the structural fragment Selected from

[0189] In some embodiments, the structural fragment Selected from

[0190] In some embodiments, the structural fragment Selected from described Selected from

[0191] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from

[0192] In some embodiments, Y 1 Select from N or S.

[0193] In some embodiments, Y 1 Selected from N.

[0194] In some embodiments, Y 2 Selected from C or N.

[0195] In some embodiments, Y 3 is selected from C, CH, N, O or S.

[0196] In some embodiments, Y 3 Selected from C, N, O or S.

[0197] In some embodiments, Y 3 Selected from CH or S.

[0198] In some embodiments, Y 1 、Y 2 and Y 3 One or two of them are selected from N, O or S.

[0199] In some embodiments, Y 1 、Y 2 and Y 3 At least two are selected from N, O or S.

[0200] In some embodiments, Y 1 and Y 2 Selected from N, Y 3 Selected from CH.

[0201] In some embodiments, Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from S.

[0202] In some embodiments, Y 1 Selected from S, Y 2 Selected from C, Y 3 Selected from CH.

[0203] In some embodiments, the compound of formula (I) or formula (II), its stereoisomer or pharmaceutically acceptable salt thereof of the present application is selected from the compound of formula (IB), its stereoisomer or pharmaceutically acceptable salt thereof,

[0204] Among them, 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 in this application;

[0205] Ring B is selected from aromatic rings containing 1-3 heteroatoms independently selected from N, O or S.

[0206] The present application also provides a compound of formula (IC), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0207] Among them, R 2 、R 3 、R 4 、R 5 、Y 2 、Y 3 , o, p and q are as defined in this application;

[0208] Ring B is selected from aromatic rings containing 1-3 heteroatoms independently selected from N, O or S;

[0209] X 4 Selected from C, is a double bond; or X 4 Selected from N, is a single bond;

[0210] X 2 selected from CH or N;

[0211] X 5 selected from CH2 or O;

[0212] n is selected from 1 or 2.

[0213] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula (ID), its stereoisomers or pharmaceutically acceptable salts thereof,

[0214] Among them, 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 in this application;

[0215] Ring B is selected from aromatic rings containing 1-3 heteroatoms independently selected from N, O or S.

[0216] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula (IIA), its stereoisomers or pharmaceutically acceptable salts thereof,

[0217] Among them, 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 in this application;

[0218] R b Selected from -OH, -C 1-6 Alkyl or -C 1-4 Alkylene-OC 1-6 alkyl;

[0219] t is selected from 0, 1 or 2;

[0220] Ring B is selected from aromatic rings containing 1-3 heteroatoms independently selected from N, O or S.

[0221] In some embodiments, the compound of formula (I) or formula (II), its stereoisomer or pharmaceutically acceptable salt thereof of the present application is selected from the compound of formula (IIB), its stereoisomer or pharmaceutically acceptable salt thereof,

[0222] Among them, R 1 、R 2 、R3 、R 4 、R 5 、X 1 、X 2 、Y 2 、Y 3 , o, p and q are as defined in this application;

[0223] R b 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;

[0224] t is selected from 1 or 2;

[0225] Ring B is selected from aromatic rings containing 1-3 heteroatoms independently selected from N, O or S.

[0226] In some embodiments, R b 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), -N(C 1-4 Alkyl)2, -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.

[0227] In some embodiments, R b Selected from -OH, -C 1-4 Alkyl, -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.

[0228] In some embodiments, R b Selected from -OH, -C 1-4 Alkyl or -C 1-3 Alkylene-OC 1-4 alkyl.

[0229] In some embodiments, R b Selected from -OH, methyl, ethyl, -CH2OCH3 or -CH2OCH2CH3.

[0230] In some embodiments, R b Selected from -OH, methyl or -CH2OCH3.

[0231] In some embodiments, R b Selected from methyl.

[0232] In some embodiments, t is selected from 1.

[0233] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula (IIB-1), its stereoisomers or pharmaceutically acceptable salts thereof,

[0234] Among them, 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 in this application;

[0235] Ring B is selected from aromatic rings containing 1-3 heteroatoms independently selected from N, O or S.

[0236] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula (IIB-2), its stereoisomers or pharmaceutically acceptable salts thereof,

[0237] Among them, 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 in this application;

[0238] Ring B is selected from aromatic rings containing 1-3 heteroatoms independently selected from N, O or S.

[0239] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula (IIB-3), its stereoisomers or pharmaceutically acceptable salts thereof,

[0240] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、X 1 、X 2 , o, p and q are defined as described in this application.

[0241] In some embodiments, the present application provides a solid oral pharmaceutical composition comprising the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, preferably excipients including but not limited to diluents.

[0242] In some embodiments, the present application provides a pharmaceutical composition comprising the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0243] In some embodiments, the present application provides a pharmaceutical composition comprising a compound of formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIB-1), formula (IIB-2), or formula (IIB-3) of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0244] In some embodiments, the present application encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0245] The heteroatoms in the heterocycloalkyl or heterocycloalkenyl groups are selected from nitrogen (NH or N), oxygen or sulfur (S), and the remaining ring atoms are 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.

[0246] In some embodiments, the compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0247] In some embodiments, the compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0248] On the other hand, the present application provides a pharmaceutical composition comprising the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0249] On the other hand, the present application provides a method for treating PARP1-related diseases in mammals, comprising administering a therapeutically effective amount of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0250] On the other hand, the present application provides the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating PARP1-related diseases.

[0251] On the other hand, the present application provides the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in treating diseases related to PARP1.

[0252] On the other hand, the present application provides the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof for treating diseases related to PARP1.

[0253] In some embodiments, the PARP1-related disease is selected from a tumor or a cancer. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, colon cancer, pancreatic cancer, or prostate cancer.

[0254] The compound of the present application has good inhibitory activity against PARP1 kinase and MDA-MB-436 cells, has high selectivity for PARP1 protein, and has good liver microsome stability and in vivo pharmacokinetic properties.

[0255] definition

[0256] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0257] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0258] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0259] As used herein, "one or more" refers to an integer between one and ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, or three. It will be understood by those skilled in the art that any group containing one or more substituents does not introduce any substitution or substitution pattern that is sterically impossible and / or cannot be synthesized.

[0260] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0261] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0262] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl or cyclohexadiene. For example, the three-ring structure in this application Substituted group R 3 Substitution, indicating R 3 It can be on any ring of the three rings.

[0263] It is understood that in this application, In, X 1 Selected from NR a , R a With R 1 When connected to form a ring, X 1 With C(R 1 ) According to the chemical bonding rules, it forms a single bond.

[0264] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0265] The term "hydroxy" refers to an -OH group.

[0266] The term "amino" refers to a -NH2 group.

[0267] The term "cyano" refers to a -CN group.

[0268] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-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.

[0269] The term "alkylene" refers to a group of the formula C n H 2n For example, the term "C 1-6 “Alkylene” refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (—CH2—), ethylene (—CH2CH2—), propylene (—CH2CH2CH2— or —CH2CH(CH3)—), butylene (—CH2CH2CH2CH2—, —CH2CH(CH3)CH2— or —CH2CH2CH(CH3)—), pentylene, hexylene, and the like.

[0270] The term "alkoxy" refers to an -O-alkyl group.

[0271] The term "alkylamino" refers to an -NH-alkyl group.

[0272] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 10-membered; preferably 3 to 6-membered. 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.

[0273] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring having at least one double bond and which can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 12-membered ring, a 4- to 10-membered ring, a 5- to 10-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, 3a, 4, 7, 7a-tetrahydro-1H-indene, etc.

[0274] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, 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 heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and cyclonitrilinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 4 or 6 ring atoms.

[0275] The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms are replaced by heteroatoms, for example, cycloalkenyl groups in which up to three carbon atoms, in one embodiment up to two carbon atoms, in another embodiment one carbon atom are each independently replaced by O, S, or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. The cyclic group may be present as a monocyclic, bridged, or spirocyclic ring and may be a 3- to 12-membered ring (e.g., a 5-membered, 6-membered, or 7-membered ring). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, dihydrofuranyl, tetrahydropyridyl, tetrahydroazepine, pyrrolidine ... Base or azaspirocyclooctene.

[0276] The term "heterocyclyl" refers to a ring that is fully saturated, partially saturated or aromatic and that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 10-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from N, O, and S, or a 5 to 8-membered ring, or a 5 or 6-membered ring. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, furanyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, pyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and the like.

[0277] 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 indicated, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene. In some embodiments of the present application, the "aryl" or "aromatic ring" may be fused with a cycloalkyl, cycloalkenyl, or heterocyclic group to form a fused polycyclic ring system.

[0278] The term "heteroaryl" or "aromatic heterocycle" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have a single 5- to 8-membered ring, in particular a single 5- to 6-membered ring, or multiple fused rings containing 6 to 14, in particular 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

[0279] The term "fused" refers to two or more carbocyclic or heterocyclic rings joined with two atoms in common to form a polycyclic compound, including fully saturated, partially saturated and aromatic rings. Unless otherwise indicated, the fused ring is 5 to 20 members, preferably 8 to 12 members, and more preferably 9 to 10 members. Non-limiting examples of fused heteroaryl groups include, but are not limited to, naphthalene, anthracene, phenanthrene, wait.

[0280] The "cycloalkyl", "heterocycloalkyl", "cycloalkenyl", "heterocycloalkenyl", "aryl", "heteroaryl" described herein are each independently optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0281] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0282] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0283] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0284] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats a specific disease, condition, or disorder described herein, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0285] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0286] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, etc. can be mentioned. When the compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic ammonium or magnesium salts or similar salts. When the compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acids, aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Certain specific compounds of the present application contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0287] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0288] The term "pharmaceutically acceptable excipient" refers to excipients that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. Suitable excipients 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, and the like. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, and flavoring agents.

[0289] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0290] The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0291] Unless specifically stated otherwise, singular terms encompass plural terms and plural terms encompass the singular term. Unless specifically stated otherwise, the word "a" or "an" means "at least one" or "at least one."

[0292] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are within the scope of the present invention.

[0293] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter.

[0294] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereoisomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., to form carbamates from amines).

[0295] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application 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 Cl et al.

[0296] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0297] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution can be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium. Exemplary deuterated compounds are shown below, but are not limited thereto.

[0298] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated 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, etc.

[0299] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0300] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0301] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0302] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.01 to 200 mg / kg body weight per day in single or divided doses.

[0303] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0304] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0305] An important consideration in synthetic route planning in this field is the selection of a suitable protecting group for a reactive functional group (such as the amino group in this application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this application are incorporated herein in their entirety. DETAILED DESCRIPTION

[0306] For the sake of clarity, the present application is further illustrated by examples, but the examples are not intended to limit the scope of the present application. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application. All reagents used in this application are commercially available and can be used without further purification.

[0307] The compounds of the present application can be prepared by those skilled in the art of organic synthesis with reference to the routes or methods of the following examples, and the obtained compounds can be characterized by known instruments or methods, including but not limited to mass spectrometry, nuclear magnetic resonance, etc.

[0308] This application uses the following abbreviations:

[0309] Boc represents tert-butyloxycarbonyl; THF represents tetrahydrofuran; IBX represents 2-iodoxybenzoic acid; TFA represents trifluoroacetic acid; mCPBA represents m-chloroperbenzoic acid; RuPhosPdG3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II); DIBAL-H represents diisobutylaluminum hydride; DIPEA represents N,N-diisopropylethylamine; and PdCl2(dppf) represents 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride.

[0310] Example 1: Preparation of Compound 1

[0311] Step A: Preparation of compound 1-1

[0312] To a 100mL single-necked flask, add tert-butyl pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-carboxylate (1g), dichloromethane (40mL), sodium carbonate (1.25g), and p-nitrophenyl chloroformate (1g) in sequence. React at room temperature for 4 hours. Dilute the reaction mixture with 500mL of water and 200mL of dichloromethane, shake well, and separate the two phases. The organic and aqueous phases are retained. The aqueous phase is extracted twice with dichloromethane (100mL x 2). The organic phases are combined and washed with water (10mL x 2). The retained organic phase is dried, spin-dried, and then oven-dried. 1.75g ​​of compound 1-1 is obtained.

[0313] Step B: Preparation of compound 1-2

[0314] To a 100 mL single-necked flask, compound 1-1 (1.3 g), dichloromethane (40 mL), triethylamine (0.9 g), and methylamine hydrochloride (0.27 g) were added sequentially and allowed to react at room temperature for 4 h. The reaction solution was concentrated until no fractions were distilled off. 30 mL of purified water was added sequentially to slurry the solution, and the filter cake was retained. After slurrying three times, the filter cake was collected and dried to yield 800 mg of compound 1-2.

[0315] MS (ESI, [M+H] + )m / z:267.12.

[0316] Step C: Preparation of Compound 1-3

[0317] To a 100 mL single-necked flask, add compound 1-2 (250 mg), dichloromethane (10 mL), and trifluoroacetic acid (3 mL) in sequence. After the additions are complete, replace the atmosphere with nitrogen and allow the reaction to proceed at room temperature. After the reaction is complete, remove the excess acid and solvent under reduced pressure to yield compound 1-3.

[0318] MS (ESI, [M+H] + )m / z:167.12.

[0319] Step D: Preparation of Compound 1-4

[0320] To a 100 mL three-necked flask, m-bromoaniline (4 g), dichloromethane (50 mL), and triethylamine (4.7 g) were added sequentially. Under nitrogen, n-butyryl chloride (2.6 g) was slowly added dropwise in an ice-salt bath. After addition, the mixture was stirred at room temperature for 1 h. 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 yield 2.6 g of compound 1-4.

[0321] MS (ESI, [MH] - )m / z:240.0.

[0322] Step E: Preparation of Compound 1-5

[0323] Take a 100mL single-necked bottle, add phosphorus oxychloride (30g) to the bottle, place the reaction system in an ice-salt bath under nitrogen protection, then slowly add N,N-dimethylformamide (2.5g) dropwise to the bottle. After the addition is complete, control the temperature and stir for 2 hours. Take compound 1-4 (5.5g) and slowly add it to the bottle in batches. After the addition, slowly return the temperature to room temperature and raise the temperature to 65°C, and react for 12 hours under controlled temperature. After the reaction is complete, pour the reaction solution into 100mL of ice water, add ammonia water to adjust the pH to neutral, extract three times with ethyl acetate (100mL), and collect the organic phase. The organic phase is concentrated and purified by column chromatography to obtain 1.8g of compound 1-5.

[0324] MS (ESI, [M+H] + )m / z:269.93.

[0325] Step F: Preparation of Compound 1-6

[0326] To a 250 mL single-necked flask, compound 1-5 (4.75 g), 1,4-dioxane (40 mL), and 3 M aqueous hydrochloric acid (80 mL) were added sequentially. The temperature was raised to 100°C and the reaction was controlled for 6 h. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure and dried to obtain 4 g of compound 1-6.

[0327] MS (ESI, [M+H] + )m / z:252.10.

[0328] Step G: Preparation of Compound 1-7

[0329] In a 100mL three-necked flask, dissolve compound 1-6 (650mg) in tetrahydrofuran (20mL) under nitrogen. Cool the reaction system to -78°C and slowly add 2.5M n-butyllithium (2.3mL) dropwise to the reaction system, controlling the temperature not to exceed -70°C. Reaction at -78°C for 1 hour. Add N,N-dimethylformamide (0.94g) dropwise to the flask, controlling the temperature not to exceed -70°C during the addition process, and react at -78°C for 2 hours. Once the reaction is complete, quench the reaction by adding saturated aqueous ammonium chloride. Extract three times with ethyl acetate (100mL) and collect the organic phase. Concentrate the organic phase and purify by column chromatography to yield 130mg of compound 1-7.

[0330] MS (ESI, [M+H] + )m / z:202.10.

[0331] Step H: Preparation of Compound 1-8

[0332] Referring to the method of Step C of Example 1, compound 1-8 was prepared by reacting 1-Boc-3-iodoazetidine with trifluoroacetic acid.

[0333] MS (ESI, [M+H] + )m / z:184.00.

[0334] Step I: Preparation of Compound 1-9

[0335] To a 50 mL single-necked bottle, add compound 1-7 (800 mg), toluene (20 mL), compound 1-8 (500 mg), tetraisopropyl titanate (706 mg), and triethylamine (503 mg). Heat to 60°C. Then, slowly add sodium triacetoxyborohydride (1.5 g) in batches. Maintain the reaction temperature at 60°C for 10 h. Extraction, concentration, and column chromatography purification yield 300 mg of compound 1-9.

[0336] MS (ESI, [M+H] + )m / z:369.07.

[0337] Step J: Preparation of Compound 1

[0338] Compound 1-3 (100 mg), acetonitrile (20 mL), triethylamine (150 mg), and compound 1-9 (150 mg) were added to a 100 mL single-necked bottle in sequence and reacted at 60°C for 18 h. 10 mg of compound 1 was obtained by purification by column chromatography.

[0339] 1H 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).

[0340] HRMS (ESI, [M+H] + )m / z:407.2195.

[0341] Example 2: Preparation of Compound 2

[0342] Step A: Preparation of compound 2-1

[0343] Add cyclopropylethanol (4 g), acetonitrile (60 mL), and 2-iodoacylbenzoic acid (39.0 g) to a 250 mL single-necked bottle. After the addition, replace with nitrogen and heat to 80°C in an oil bath for reflux reaction. After the reaction is complete, filter and concentrate to obtain compound 2-1.

[0344] MS(EI,[M] + )m / z:84.10.

[0345] Step B: Preparation of compound 2-2

[0346] To a 250 mL three-necked flask, add compound 2-1 (3.91 g), 2-amino-4-bromobenzaldehyde (9.30 g), potassium hydroxide (7.82 g), and ethanol (90 mL) in sequence. After nitrogen purge, heat the mixture to 95°C in an oil bath. After the reaction is complete, pour 300 mL of saturated ammonium chloride solution into the reaction mixture and extract with ethyl acetate. The organic phase is collected, dried, concentrated, and purified by column chromatography to yield compound 2-2.

[0347] MS (ESI, [M+H] + )m / z:248.08.

[0348] Step C: Preparation of Compound 2-3

[0349] To a 500mL single-necked flask, add compound 2-2 (8.1g), m-chloroperbenzoic acid (16.9g), and 150mL of ethyl acetate. After nitrogen purge, heat in an oil bath to 70°C. After completion of the reaction, extract, concentrate, and purify by column chromatography to obtain compound 2-3.

[0350] MS (ESI, [M+H] + )m / z:264.02.

[0351] Step D: Preparation of Compound 2-4

[0352] To a 250 mL single-necked flask, add compound 2-3 (6.1 g), 1,2-dichloroethane (150 mL), and phosphorus oxychloride (6.46 mL) in sequence. After nitrogen purge, heat the mixture to 65°C in an oil bath. After completion of the reaction, pour the reaction mixture into 300 mL of ice water and adjust the pH to neutral with sodium carbonate. Extraction, concentration, and column chromatography purification yield compound 2-4.

[0353] MS (ESI, [M+H] + )m / z:282.03.

[0354] Step E: Preparation of Compound 2-5

[0355] Take a 250 mL single-necked bottle and add compound 2-4 (2.56 g), methanol (150 mL), and sodium methoxide (16.31 g) in sequence. After the addition, replace with nitrogen for protection, place in an oil bath and heat to 65 ° C for reaction. After the reaction is completed, extract, concentrate, and purify by column chromatography to obtain compound 2-5.

[0356] MS (ESI, [M+H] + )m / z:278.03.

[0357] Step F: Preparation of Compound 2-6

[0358] To a 250 mL three-necked flask, add compound 2-5 (2.3 g), methanesulfonic acid (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). After the addition, replace the mixture with nitrogen and heat to 80°C in an oil bath. After the reaction is complete, concentrate the mixture and purify it by column chromatography to obtain compound 2-6.

[0359] MS (ESI, [M+H] + )m / z:230.03.

[0360] Step G: Preparation of compound 2-7

[0361] To a 100 mL single-necked flask, add compound 2-6 (1.3 g), 1,4-dioxane (30 mL), and a 2M hydrochloric acid solution in 1,4-dioxane (27.4 mL) in sequence. After addition, heat the mixture to 80°C in an oil bath. After completion of the reaction, adjust the pH to 10 with saturated sodium carbonate solution. Compound 2-7 is then obtained by extraction, concentration, and column chromatography.

[0362] MS (ESI, [M+H] + )m / z:216.17.

[0363] Step H: Preparation of Compound 2-8

[0364] In a 250 mL single-necked bottle, compound 2-7 (1.15 g), acetonitrile (150 mL), and 2-iodoacylbenzoic acid (3 g) were added in sequence. After nitrogen replacement, the mixture was placed in an oil bath and heated to 80°C for reaction. After the reaction was complete, the mixture was filtered, concentrated, and purified by column chromatography to obtain compound 2-8.

[0365] MS (ESI, [M+H] + )m / z:214.22.

[0366] Step I: Preparation of Compound 2-9

[0367] To a 100 mL single-necked flask, add 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) in sequence. After the addition, replace the atmosphere with nitrogen and allow the reaction to proceed at room temperature. After completion of the reaction, extract, concentrate, and purify by column chromatography to yield compound 2-9.

[0368] MS (ESI, [M+H] + )m / z:322.26.

[0369] Step J: Preparation of Compound 2-10

[0370] Referring to the method of step C of Example 1, compound 2-9 was reacted with trifluoroacetic acid to prepare compound 2-10.

[0371] MS (ESI, [M+H] + )m / z:222.21.

[0372] Step K: Preparation of Compound 2

[0373] Referring to the method of step I of Example 1, compound 2-8 was reacted with compound 2-10 to prepare compound 2.

[0374] 1 H 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).

[0375] HRMS (ESI, [M+H] + )m / z:419.2197.

[0376] Example 3: Preparation of Compound 3

[0377] Step A: Preparation of compound 3-1

[0378] To a 250 mL single-necked flask, add 2,6-difluoronitrobenzene (15 g), concentrated sulfuric acid (100 mL), and N-bromosuccinimide (17.62 g) in sequence. Under nitrogen, stir the mixture at 80°C overnight. After the reaction is complete, pour the reaction mixture into ice water and extract three times with ethyl acetate (200 mL). The organic phase is dried and purified by column chromatography to yield 17.63 g of compound 3-1.

[0379] Step B: Preparation of compound 3-2

[0380] To a 250 mL single-necked flask, compound 3-1 (17.63 g), N,N-dimethylformamide (150 mL), and DL-2-aminobutyric acid methyl ester hydrochloride (12.52 g) were added sequentially. The reaction system was transferred to an ice-salt bath, and N,N-diisopropylethylamine (28.7 g) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed by concentration, and 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.

[0381] MS (ESI, [MH] - )m / z:333.07.

[0382] Step C: Preparation of compound 3-3

[0383] To a 500 mL single-necked flask, compound 3-2 (12 g), methanol (150 mL), iron powder (10 g), and acetic acid (10.75 g) were added in sequence. The reaction system was transferred to 70°C and stirred for 1 h. After the reaction was completed, the reaction solution was filtered, concentrated, washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried, and purified by column chromatography to obtain 9 g of compound 3-3.

[0384] MS (ESI, [MH] - )m / z:271.06.

[0385] Step D: Preparation of compound 3-4

[0386] To a 500 mL single-necked flask, compound 3-3 (8.73 g), dichloromethane (250 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (9.43 g) were added sequentially. The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was concentrated and removed. 300 mL of saturated sodium bicarbonate solution was added to the crude product, and the mixture was stirred at room temperature overnight. The filter cake was collected by filtration and dried to yield 8 g of compound 3-4.

[0387] MS (ESI, [MH] - )m / z:269.06.

[0388] Step E: Preparation of Compound 3-5

[0389] Referring to the method of step F of Example 2, compound 3-4 was reacted with (tributyltin)methanol to prepare compound 3-5.

[0390] MS (ESI, [M+H] + )m / z:223.18.

[0391] Step F: Preparation of Compound 3-6

[0392] Referring to the method of step H of Example 2, compound 3-5 was reacted with 2-iodoacylbenzoic acid to prepare compound 3-6.

[0393] MS (ESI, [MH] - )m / z:219.15.

[0394] Step G: Preparation of compound 3

[0395] Referring to the method of step I of Example 1, compound 3-6 was reacted with compound 2-10 to prepare compound 3.

[0396] 1H 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).

[0397] HRMS (ESI, [M+H] + )m / z:426.2056.

[0398] Example 4: Preparation of Compound 4

[0399] Step A: Preparation of compound 4-1

[0400] Referring to the method of step B of Example 1, compound 1-1 was reacted with cyclopropylamine to prepare compound 4-1.

[0401] MS (ESI, [M+H-Boc] + )m / z:=193.12.

[0402] Step B: Preparation of compound 4-2

[0403] Referring to the method of step C of Example 1, compound 4-1 was reacted with trifluoroacetic acid to prepare compound 4-2.

[0404] MS (ESI, [M+H] + )m / z:193.20.

[0405] Step C: Preparation of compound 4-3

[0406] Referring to the method of step I of Example 2, compound 4-2 was reacted with tert-butyl 3-oxoazetidine-1-carboxylate to prepare compound 4-3.

[0407] MS (ESI, [M+H] + )m / z:348.28.

[0408] Step D: Preparation of compound 4-4

[0409] Referring to the method of step C of Example 1, compound 4-3 was reacted with trifluoroacetic acid to prepare compound 4-4.

[0410] MS (ESI, [M+H] + )m / z:248.27.

[0411] Step E: Preparation of compound 4

[0412] Referring to the method of step I of Example 1, compound 1-7 was reacted with compound 4-4 to prepare compound 4.

[0413] 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).

[0414] HRMS (ESI, [M+H] + )m / z:433.2348.

[0415] Example 5: Preparation of Compound 5

[0416] Step A: Preparation of compound 5-1

[0417] Referring to the method of step A of Example 2, 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one was reacted with 2-iodoacylbenzoic acid to prepare compound 5-1.

[0418] MS (ESI, [M+H] + )m / z:203.17.

[0419] Step B: Preparation of compound 5

[0420] Referring to the method of step I of Example 1, compound 5-1 was reacted with compound 4-4 to prepare compound 5.

[0421] 1H 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).

[0422] HRMS (ESI, [M+H] + )m / z:434.2292.

[0423] Example 6: Preparation of Compound 6

[0424] Step A: Preparation of compound 6-1

[0425] Referring to the method of step B of Example 1, compound 1-1 was reacted with isopropylamine to prepare compound 6-1.

[0426] MS (ESI, [M+H-Boc] + )m / z:195.22.

[0427] Step B: Preparation of compound 6-2

[0428] Referring to the method of step C of Example 1, compound 6-1 was reacted with trifluoroacetic acid to prepare compound 6-2.

[0429] MS (ESI, [M+H] + )m / z:195.21.

[0430] Step C: Preparation of compound 6-3

[0431] Referring to the method of step 1 of Example 2, compound 6-2 was reacted with tert-butyl 3-oxoazetidine-1-carboxylate to prepare compound 6-3.

[0432] MS (ESI, [M+H] + )m / z:350.23.

[0433] Step D: Preparation of compound 6-4

[0434] Referring to the method of step C of Example 1, compound 6-3 was reacted with trifluoroacetic acid to prepare compound 6-4.

[0435] MS (ESI, [M+H] + )m / z:250.25.

[0436] Step E: Preparation of compound 6

[0437] Referring to the method of step I of Example 1, compound 5-1 was reacted with compound 6-4 to prepare compound 6.

[0438] 1 H 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).

[0439] HRMS (ESI, [M+H] + )m / z:436.2460.

[0440] Example 7: Preparation of Compound 7

[0441] Step A: Preparation of compound 7-1

[0442] To a 1L single-necked flask, diethyl 2-chloro-3-oxosuccinate (50.31 g), ethanol (500 mL), and thiourea (17.20 g) were added sequentially. Under nitrogen, the mixture was heated to 90°C and refluxed with stirring overnight. After the reaction was complete, 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 blended for 1 hour. The filter cake was collected by filtration and dried under vacuum at 50°C to yield 46.7 g of compound 7-1.

[0443] MS (ESI, [M+H] + )m / z:245.11.

[0444] Step B: Preparation of compound 7-2

[0445] To a 500mL three-necked flask, add copper bromide (74.4g), acetonitrile (200mL), and tert-butyl nitrite (25.8g) in sequence. Place the mixture in an ice-salt bath and cool to -5°C. Slowly add a solution of compound 7-1 in acetonitrile (60mL) dropwise to the reaction system, controlling the temperature below 0°C. After addition, stir the mixture at 0°C for 1h. After the reaction is complete, pour the reaction solution into 200mL of water and extract with ethyl acetate (300mL*3). Collect the organic phase, dry, concentrate, and purify by column chromatography to obtain 51g of compound 7-2.

[0446] MS (ESI, [M+H] + )m / z:307.80.

[0447] Step C: Preparation of compound 7-3

[0448] To a 500mL three-necked flask, compound 7-2 (31g) and toluene (100mL) were added in sequence. Under nitrogen protection, the mixture was transferred to -78°C and stirred. 1.5M diisobutylaluminum hydride toluene solution (201mL) was slowly added dropwise, and the internal temperature was controlled below -70°C. After the addition, the reaction system was stirred at -78°C for 3h. After the reaction was complete, 40mL of ammonium chloride aqueous solution was added to the reaction system to quench the reaction, and the insoluble matter was filtered off with diatomaceous earth. The filtrate was concentrated, sanded, and purified by column chromatography to obtain 16g of compound 7-3.

[0449] Step D: Preparation of compound 7-4

[0450] To a 50 mL single-necked flask, compound 7-3 (0.5 g), anhydrous tetrahydrofuran (20 mL), triphenylphosphine (1.288 g), and carbon tetrabromide (1.628 g) were added in sequence. Under nitrogen, the mixture was stirred at room temperature for 1 h. Upon completion of the reaction, 10 mL of water was added to the reaction solution. Extraction was performed three times with dichloromethane (50 mL). The organic phase was collected, dried, filtered, concentrated, and purified by column chromatography to yield 0.4 g of compound 7-4.

[0451] Step E: Preparation of compound 7-5

[0452] To a 50 mL single-necked flask, 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 added in sequence. Under nitrogen, the mixture was stirred at 60°C for 3 h. Upon completion of the reaction, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phase was collected, dried, filtered, concentrated, and purified by column chromatography to yield 30 mg of compound 7-5.

[0453] MS (ESI, [M+HC(CH3)3] + )m / z:304.01.

[0454] Step F: Preparation of compound 7-6

[0455] To a 250 mL autoclave, compound 7-5 (0.24 g), methanol (50 mL), triethylamine (0.3 g), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (60 mg), and 1,3-bis(diphenylphosphino)propane (60 mg) were added in sequence. After the additions were complete, the autoclave was sealed and carbon monoxide was introduced three times. After the pressure was adjusted to 1.5 MPa, the internal temperature was set at 100°C, and the reaction was stirred for 4 hours. After the reaction was complete, the reaction solution was filtered through celite, and 1 g of silica gel was added to the filtrate for direct column chromatography to obtain 0.1 g of compound 7-6.

[0456] MS (ESI, [M+H] + )m / z:340.14.

[0457] Step G: Preparation of compound 7-7

[0458] To a 15 mL microwave tube, compound 7-6 (0.11 g) and a 30% methylamine solution in ethanol (3 mL) were added sequentially. The reaction system was sealed and stirred at room temperature for 3 h. Upon completion, the reaction solution was concentrated, and 20 mL of ethyl acetate and 10 mL of water were added to the crude product. The organic phase was extracted and collected. The organic phase was dried, filtered, concentrated, and purified by column chromatography to yield 65 mg of compound 7-7.

[0459] MS (ESI, [M+HC(CH3)3] + )m / z:283.15.

[0460] Step H: Preparation of Compound 7-8

[0461] Referring to the method of step C of Example 1, compound 7-7 was reacted with trifluoroacetic acid to prepare compound 7-8.

[0462] MS (ESI, [M+H] + )m / z:239.20.

[0463] Step I: Preparation of compound 7

[0464] Referring to the method of step I of Example 1, compound 5-1 was reacted with compound 7-8 to prepare compound 7.

[0465] 1H 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).

[0466] HRMS (ESI, [M+H] + )m / z:425.1757

[0467] Example 8: Preparation of Compound 8

[0468] Step A: Preparation of compound 8

[0469] Referring to the method of step I of Example 1, compound 3-6 was reacted with compound 7-8 to prepare compound 8.

[0470] 1 H 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).

[0471] HRMS (ESI, [M+H] + )m / z:443.1660.

[0472] Example 9: Preparation of Compound 9

[0473] Step A: Preparation of compound 9

[0474] Referring to the method of step I of Example 1, compound 1-7 was reacted with compound 6-4 to prepare compound 9.

[0475] 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).

[0476] HRMS (ESI, [M+H] + )m / z:435.2504.

[0477] Example 10: Preparation of Compound 10

[0478] Step A: Preparation of compound 10

[0479] Referring to the method of step I of Example 1, compound 5-1 was reacted with compound 2-10 to prepare compound 10.

[0480] 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).

[0481] HRMS (ESI, [M+H] + )m / z:408.2143.

[0482] Example 11: Preparation of Compound 11

[0483] Step A: Preparation of compound 11

[0484] Referring to the method of step 1 of Example 1, compound 2-8 was reacted with compound 4-4 to prepare compound 11.

[0485] 1 H 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).

[0486] HRMS (ESI, [M+H] + )m / z:445.2348.

[0487] Example 12: Preparation of Compound 12

[0488] Step A: Preparation of compound 12-1

[0489] Referring to the method of step B of Example 1, compound 1-1 was reacted with ethylamine to prepare compound 12-1.

[0490] MS (ESI, [M+H] + )m / z:281.12.

[0491] Step B: Preparation of compound 12-2

[0492] Referring to the method of step C of Example 1, compound 12-1 was reacted with trifluoroacetic acid to prepare compound 12-2.

[0493] MS (ESI, [M+H] + )m / z:181.12.

[0494] Step C: Preparation of compound 12-3

[0495] Referring to the method of step I of Example 2, compound 12-2 was reacted with tert-butyl 3-oxoazetidine-1-carboxylate to prepare compound 12-3.

[0496] MS (ESI, [M+H] + )m / z:336.25.

[0497] Step D: Preparation of compound 12-4

[0498] Referring to the method of step C of Example 1, compound 12-3 was reacted with trifluoroacetic acid to prepare compound 12-4.

[0499] MS (ESI, [M+H] + )m / z:236.24.

[0500] Step E: Preparation of compound 12

[0501] Referring to the method of step I of Example 1, compound 5-1 was reacted with compound 12-4 to prepare compound 12.

[0502] 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).

[0503] HRMS (ESI, [M+H] + )m / z:422.2300.

[0504] Example 13: Preparation of Compound 13

[0505] Step A: Preparation of compound 13-1

[0506] Referring to the method of Example 2, Step E, compound 1-5 was reacted with sodium methoxide to prepare compound 13-1.

[0507] Step B: Preparation of compound 13-2

[0508] In a 100mL three-necked flask, dissolve compound 13-1 (650mg) in anhydrous tetrahydrofuran (20mL) under nitrogen. Cool the reaction system to -78°C and slowly add 2.5M n-butyllithium (2.3mL) dropwise to the reaction system, controlling the temperature not to exceed -70°C. Reaction at -78°C for 1 hour. Slowly add N,N-dimethylformamide (0.94g) dropwise to the reaction system, controlling the temperature not to exceed -70°C during the addition process, and react at -78°C for 2 hours. Once the reaction is complete, quench the reaction by adding saturated aqueous ammonium chloride. Extract three times with ethyl acetate (100mL), and collect the organic phase. The organic phase is concentrated and purified by column chromatography to obtain compound 13-2.

[0509] MS (ESI, [M+H] + )m / z:216.09.

[0510] Step C: Preparation of compound 13-1

[0511] Referring to the method of step I of Example 1, compound 13-2 was reacted with compound 12-4 to prepare compound 13-1.

[0512] MS (ESI, [M+H] + )m / z:435.37.

[0513] Step D: Preparation of compound 13

[0514] To a 25 mL single-necked bottle, compound 13-1 (80 mg) and a 4 M solution of hydrogen chloride in dioxane (4.60 mL) were added sequentially. Under nitrogen, the mixture was placed in a 60°C oil bath and reacted overnight. After the reaction was complete, the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (20 mL). The organic phase was collected, dried, filtered, concentrated, and purified by column chromatography to yield 45 mg of compound 13.

[0515] 1 H 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).

[0516] HRMS (ESI, [M+H] + )m / z:421.2346.

[0517] Example 14: Preparation of Compound 14

[0518] Step A: Preparation of compound 14-1

[0519] Referring to the method of step B of Example 1, compound 1-1 was reacted with deuterated methylamine hydrochloride to prepare compound 14-1.

[0520] MS (ESI, [M+H-Boc] + )m / z:170.16.

[0521] Step B: Preparation of compound 14-2

[0522] Referring to the method of step C of Example 1, compound 14-1 was reacted with trifluoroacetic acid to prepare compound 14-2.

[0523] MS (ESI, [M+H] + )m / z:170.15.

[0524] Step C: Preparation of compound 14-3

[0525] Referring to the method of step I of Example 2, compound 14-2 was reacted with tert-butyl 3-oxoazetidine-1-carboxylate to prepare compound 14-3.

[0526] MS (ESI, [M+H] + )m / z:325.21.

[0527] Step D: Preparation of compound 14-4

[0528] Referring to the method of step C of Example 1, compound 14-3 was reacted with trifluoroacetic acid to prepare compound 14-4.

[0529] MS (ESI, [M+H] + )m / z:225.22.

[0530] Step E: Preparation of compound 14

[0531] Referring to the method of step I of Example 1, compound 1-7 was reacted with compound 14-4 to prepare compound 14.

[0532] 1H 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).

[0533] HRMS (ESI, [M+H] + )m / z:410.2387.

[0534] Example 15: Preparation of Compound 15

[0535] Step A: Preparation of compound 15-1

[0536] Take a 250mL three-necked flask and add methyl 2-oxocyclopentane-1-carboxylate (7g) and anhydrous tetrahydrofuran (100mL) in sequence. Under nitrogen protection, transfer the reaction system to an ice-salt bath. Add sodium hydroxide (2.95g) in batches, stir in an ice-salt bath for 10min, slowly add trifluoromethanesulfonic anhydride (16.67g) dropwise, and after addition, transfer the reaction system to room temperature and stir for 4h. After the reaction is complete, slowly add ice water dropwise to quench the reaction, add dichloromethane (100mL) and extract three times, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and column chromatography to obtain compound 15-1.

[0537] Step B: Preparation of compound 15-2

[0538] To a 100 mL single-necked flask, add 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)diphenylferric palladium chloride (140 mg), and water (1 mL). Nitrogen was purged three times, and the reaction system was heated to 100°C in an oil bath and allowed to react overnight. After completion of the reaction, silica gel was added directly to the reaction solution and purified by column chromatography to yield compound 15-2.

[0539] MS (ESI, [M+H] + )m / z:244.18.

[0540] Step C: Preparation of compound 15-3

[0541] To a 50 mL single-necked flask, add compound 15-2 (280 mg) and anhydrous tetrahydrofuran (10 mL) sequentially. Under nitrogen, transfer the reaction system to an ice-salt bath and slowly add 2.5 M lithium aluminum hydride solution in tetrahydrofuran (0.9 mL) dropwise. Incubate for 0.5 h. After completion, quench the reaction with water, add silica gel, and purify by column chromatography to yield compound 15-3.

[0542] MS (ESI, [M+H] + )m / z:216.17.

[0543] Step D: Preparation of compound 15-4

[0544] Referring to the method of step H of Example 2, compound 15-3 was reacted with 2-iodoacylbenzoic acid to prepare compound 15-4.

[0545] MS (ESI, [M+H] + )m / z:214.21.

[0546] Step E: Preparation of compound 15

[0547] Referring to the method of step I of Example 1, compound 15-4 was reacted with compound 2-10 to prepare compound 15.

[0548] 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).

[0549] HRMS (ESI, [M+H] + )m / z:419.2197.

[0550] Example 16: Preparation of Compound 16

[0551] Step A: Preparation of compound 16-1

[0552] To a 250 mL single-necked 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 added sequentially. Under nitrogen, the mixture was refluxed and stirred in a 90°C oil bath overnight. After the reaction, the product was extracted, concentrated, and purified by column chromatography to yield 10 g of compound 16-1.

[0553] 1 H NMR (500MHz, DMSO-d6) δ8.22–8.09 (m, 2H), 4.73 (d, J = 1.6Hz, 2H).

[0554] Step B: Preparation of compound 16-2

[0555] To a 25 mL single-necked flask, compound 16-1 (1 g), acetonitrile (15 mL), 4A molecular sieves (2.5 g), and N-methylmorpholine oxide (0.75 g) were added sequentially. Under nitrogen, the mixture was stirred at room temperature for 2 h. After the reaction, the mixture was extracted, concentrated, and purified by column chromatography to yield 0.64 g of compound 16-2.

[0556] 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).

[0557] Step C: Preparation of compound 16-3

[0558] To a 100 mL three-necked flask, add anhydrous tetrahydrofuran (10 mL) and sodium hydroxide (0.25 g, 60% by weight) sequentially. Once gas production ceases, place under nitrogen protection. Transfer the reaction system to an ice-salt bath and cool to 0-5°C. Slowly add ethyl 2-(diethoxyphosphoryl)butyrate (0.98 g) dropwise via a disposable syringe, maintaining the temperature at 0-5°C. Stir the reaction system at 0-5°C for 30 min. The reaction system becomes slightly turbid. Transfer the reaction system to 40°C and stir for 5 min, until the solution turns brown and clear. Transfer the reaction system to -78°C and slowly add a solution of compound 16-2 (0.64 g) in tetrahydrofuran (5 mL) dropwise until the addition is complete. Stir the reaction system at -78°C for 1 h. Upon completion, quench the reaction by adding 20 mL of saturated aqueous ammonium chloride. The reaction system was then extracted, concentrated, and purified by column chromatography to obtain 0.6 g of compound 16-3.

[0559] 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).

[0560] MS (ESI, [M+H] + )m / z:345.96.

[0561] Step D: Preparation of compound 16-4

[0562] To a 50 mL single-necked flask, compound 16-3 (0.6 g), ethanol (6 mL), acetic acid (5 mL), and iron powder (0.3 g) were added sequentially. Under nitrogen, the mixture was stirred at 80°C for 1 h. After completion of the reaction, the mixture was filtered, concentrated, washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried, and purified by column chromatography to obtain 0.16 g of compound 16-4.

[0563] 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).

[0564] Step E: Preparation of compound 16-5

[0565] To a 15 mL microwave tube, compound 16-4 (0.2 g), ethanol (2 mL), and acetic acid (2 mL) were added sequentially. The reaction system was transferred to a photocatalytic synthesizer and stirred at room temperature for 24 h at a wavelength of 450 nM. Upon completion of the reaction, the target compound precipitated in the reaction system. Filter and dry the mixture to obtain 0.07 g of compound 16-5.

[0566] 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).

[0567] Step F: Preparation of compound 16-6

[0568] Referring to the method of step F of Example 2, compound 16-5 was reacted with (tributyltin)methanol to prepare compound 16-6.

[0569] MS (ESI, [M+H] + )m / z:222.33.

[0570] Step G: Preparation of compound 16-7

[0571] Referring to the method of Example 2, Step A, compound 16-6 was reacted with 2-iodoacylbenzoic acid to prepare compound 16-7.

[0572] MS (ESI, [M+H] + )m / z:220.16.

[0573] Step H: Preparation of compound 16

[0574] Referring to the method of step I of Example 1, compound 16-7 was reacted with compound 2-10 to prepare compound 16.

[0575] 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).

[0576] HRMS (ESI, [M+H] + )m / z:425.2090.

[0577] Example 17: Preparation of Compound 17

[0578] Step A: Preparation of compound 17-1

[0579] Referring to the method of step B of Example 1, compound 1-1 was reacted with (R)-3-aminotetrahydrofuran to prepare compound 17-1.

[0580] MS (ESI, [M+H] + )m / z:323.15.

[0581] Step B: Preparation of compound 17-2

[0582] Referring to the method of step C of Example 1, compound 17-1 was reacted with trifluoroacetic acid to prepare compound 17-2.

[0583] MS (ESI, [M+H] + )m / z:223.19.

[0584] Step C: Preparation of compound 17-3

[0585] Referring to the method of step 1 of Example 2, compound 17-2 was reacted with tert-butyl 3-oxoazetidine-1-carboxylate to prepare compound 17-3.

[0586] MS (ESI, [M+H] + )m / z:378.30.

[0587] Step D: Preparation of compound 17-4

[0588] Referring to the method of step C of Example 1, compound 17-3 was reacted with trifluoroacetic acid to prepare compound 17-4.

[0589] MS (ESI, [M+H] + )m / z:278.19.

[0590] Step E: Preparation of compound 17

[0591] Referring to the method of Example 1, Step E, compound 1-7 was reacted with compound 17-4 to prepare compound 17.

[0592] 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).

[0593] HRMS (ESI, [M+H] + )m / z:463.2462.

[0594] Example 18: Preparation of Compound 18

[0595] Step A: Preparation of compound 18-1

[0596] To a 500ml three-necked flask, add methyl 2-fluoro-4-methylbenzoate (18g) and concentrated sulfuric acid (200mL). After addition, cool the mixture to 0°C in an ice bath with stirring. Then, slowly add potassium nitrate (16.24g) in batches, maintaining the reaction temperature below 10°C. After completion of the reaction, pour the reaction mixture into 1L of ice water and extract with an appropriate amount of EA. The organic phase is washed with saturated sodium chloride solution, concentrated, and purified by column chromatography to yield compound 18-1.

[0597] Step B: Preparation of compound 18-2

[0598] Referring to the method of step D of Example 16, compound 18-1 was reacted with iron powder to obtain compound 18-2.

[0599] MS (ESI, [MH] - )m / z:182.12.

[0600] Step C: Preparation of compound 18-3

[0601] Referring to the method of Example 1 Step D, compound 18-2 was reacted with n-butyryl chloride to obtain compound 18-3.

[0602] MS (ESI, [MH] - )m / z:252.21.

[0603] Step D: Preparation of compound 18-4

[0604] To a 500 mL three-necked flask, add compound 18-3 (23 g), dichloromethane (250 mL), triethylamine (32 mL), di-tert-butyl dicarbonate (25.8 g), and 4-dimethylaminopyridine (555 mg). Allow to react at room temperature. After completion of the reaction, the reaction solution was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, concentrated, and purified by column chromatography to obtain compound 18-4.

[0605] MS (ESI, [M-Boc+H] + )m / z:254.25.

[0606] Step E: Preparation of compound 18-5

[0607] 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-necked flask. After the addition, the atmosphere was replaced with nitrogen and heated to 80°C for reaction. After the reaction, the reaction solution was washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain compound 18-5.

[0608] MS (ESI, [M-Boc+H] + )m / z:332.04.

[0609] Step F: Preparation of compound 18-6

[0610] Referring to the method of Example 16 Step B, compound 18-5 was reacted with N-methylmorpholine oxide to give compound 18-6.

[0611] MS (ESI, [M-Boc+H] + )m / z:268.15.

[0612] Step G: Preparation of compound 18-7

[0613] Referring to the method of step C of Example 1, compound 18-6 was reacted with trifluoroacetic acid to prepare compound 18-7.

[0614] MS (ESI, [MH] - )m / z:266.12.

[0615] Step H: Preparation of compound 18-8

[0616] Add compound 18-7 (4.4 g), N,N-dimethylformamide (120 mL), and potassium carbonate (11.4 g) to a 250 mL three-necked flask. After addition, replace with nitrogen and heat to 60°C. After completion of the reaction, evaporate the solvent under reduced pressure. Add an appropriate amount of saturated sodium chloride solution and ethyl acetate to the residue, stir for a while, and then separate the layers. The organic phase is concentrated and purified by column chromatography to yield compound 18-8.

[0617] MS (ESI, [M+H] + )m / z:250.18.

[0618] Step I: Preparation of compound 18-9

[0619] Referring to the method of step C of Example 15, compound 18-8 was reacted with a tetrahydrofuran solution of lithium aluminum hydride to prepare compound 18-9.

[0620] MS (ESI, [MH] - )m / z:220.19.

[0621] Step J: Preparation of compound 18-10

[0622] Referring to the method of Example 2, Step A, compound 18-9 was reacted with 2-iodoacylbenzoic acid to prepare compound 18-10.

[0623] MS (ESI, [MH] -)m / z:218.18.

[0624] Step K: Preparation of Compound 18

[0625] Referring to the method of step I of Example 1, compound 18-10 was reacted with compound 2-10 to prepare compound 18.

[0626] 1 H 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).

[0627] HRMS (ESI, [M+H] + )m / z:425.2095.

[0628] Example 19: Preparation of Compound 19

[0629] Step A: Preparation of compound 19-1

[0630] Referring to the method of step I of Example 1, compound 13-2 was reacted with compound 7-8 to prepare compound 19-1.

[0631] MS (ESI, [M+H] + )m / z:438.48.

[0632] Step B: Preparation of compound 19

[0633] Referring to the method of Step D of Example 13, Compound 19-1 was reacted with a 4M solution of hydrogen chloride in dioxane to prepare Compound 19.

[0634] 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).

[0635] HRMS (ESI, [M+H] + )m / z:424.1802.

[0636] Example 20: Preparation of Compound 20

[0637] Step A: Preparation of compound 20

[0638] Referring to the method of step I of Example 1, compound 16-7 was reacted with compound 4-4 to prepare compound 20.

[0639] 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).

[0640] HRMS (ESI, [M+H] + )m / z:451.2260.

[0641] Example 21: Preparation of Compound 21

[0642] Step A: Preparation of compound 21

[0643] Referring to the method of step I of Example 1, compound 16-7 was reacted with compound 7-8 to prepare compound 21.

[0644] 1H 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).

[0645] HRMS (ESI, [M+H] + )m / z:442.1707.

[0646] Example 22: Preparation of Compound 22

[0647] Step A: Preparation of compound 22-1

[0648] To a 250 mL single-necked flask, add 2-amino-4-bromobenzaldehyde (5 g), ethanol (100 mL), propionaldehyde (2.9 g), and potassium hydroxide (5.61 g). Heat to 90°C and allow to react. After the reaction is complete, remove the ethanol under reduced pressure. The remaining solid is washed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The mixture is then concentrated and purified by column chromatography to yield compound 22-1.

[0649] MS (ESI, [M+H] + )m / z:222.04.

[0650] Step B: Preparation of compound 22-2

[0651] Referring to the method of step C of Example 2, compound 22-1 was reacted with m-chloroperbenzoic acid to prepare compound 22-2.

[0652] MS (ESI, [M+H] + )m / z:238.06.

[0653] Step C: Preparation of compound 22-3

[0654] Referring to the method of step D of Example 2, compound 22-2 was reacted with phosphorus oxychloride to prepare compound 22-3.

[0655] MS (ESI, [M+H] + )m / z:255.97.

[0656] Step D: Preparation of compound 22-4

[0657] Referring to the method of Example 2, Step E, compound 22-3 was reacted with sodium methoxide to prepare compound 22-4.

[0658] MS (ESI, [M+H] + )m / z:252.08.

[0659] Step E: Preparation of compound 22-5

[0660] Referring to the method of step F of Example 2, compound 22-4 was reacted with (tributyltin)methanol to prepare compound 22-5.

[0661] MS (ESI, [M+H] + )m / z:204.15.

[0662] Step F: Preparation of compound 22-6

[0663] Referring to the method of step G of Example 2, compound 22-5 was reacted with hydrochloric acid to prepare compound 22-6.

[0664] MS (ESI, [M+H] + )m / z:190.15.

[0665] Step G: Preparation of compound 22-7

[0666] Referring to the method of Example 2, Step A, compound 22-6 was reacted with 2-iodoacylbenzoic acid to prepare compound 22-7.

[0667] MS (ESI, [MH] - )m / z:186.11.

[0668] Step H: Preparation of compound 22

[0669] Referring to the method of step I of Example 1, compound 22-7 was reacted with compound 2-10 to prepare compound 22.

[0670] 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).

[0671] HRMS (ESI, [M+H] + )m / z:393.2029.

[0672] Example 23: Preparation of Compound 23

[0673] Step A: Preparation of compound 23

[0674] Referring to the method of step I of Example 1, compound 22-7 was reacted with compound 4-4 to prepare compound 23.

[0675] 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).

[0676] HRMS (ESI, [M+H] + )m / z:419.2199.

[0677] Example 24: Preparation of Compound 24

[0678] Step A: Preparation of compound 24-1

[0679] To a 100 mL single-necked flask, 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 anhydride (4.1 g) were added sequentially. Under nitrogen, the mixture was stirred at room temperature for 30 min. Upon completion, 10 mL of water was added to quench the reaction mixture. The mixture was then extracted three times with dichloromethane (50 mL). The organic phase was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, sanded, and purified by column chromatography to yield 1.2 g of compound 24-1.

[0680] MS (ESI, [MH] - )m / z:308.06.

[0681] Step B: Preparation of compound 24-2

[0682] To a 100 mL single-necked flask, compound 24-1 (0.9 g), N,N-dimethylformamide (10 mL), and potassium carbonate (1.2 g) were added sequentially. Under nitrogen, the mixture was stirred in a 60°C oil bath for 2 h. Upon completion of the reaction, insoluble matter was removed by filtration, and the filtrate was directly concentrated to remove the solvent. The crude product was re-dissolved in 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, sanded, and purified by column chromatography to yield 0.6 g of compound 24-2.

[0683] MS (ESI, [M+H] + )m / z:292.03.

[0684] Step C: Preparation of compound 24-3

[0685] Referring to the method of step F of Example 2, compound 24-2 was reacted with (tributyltin)methanol to prepare compound 24-3.

[0686] MS (ESI, [M+H] + )m / z:244.29.

[0687] Step D: Preparation of compound 24-4

[0688] Referring to the method of Example 2, Step A, compound 24-3 was reacted with 2-iodoacylbenzoic acid to prepare compound 24-4.

[0689] MS (ESI, [MH] - )m / z:240.14.

[0690] Step E: Preparation of compound 24

[0691] Referring to the method of step I of Example 1, compound 24-4 was reacted with compound 2-10 to prepare compound 24.

[0692] 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).

[0693] HRMS (ESI, [M+H] +)m / z:447.1757.

[0694] Example 25: Preparation of Compound 25

[0695] Step A: Preparation of compound 25-1

[0696] Referring to the method of step A of Example 16, 3-chloro-5-bromo-2-methylnitrobenzene was reacted with N-bromosuccinimide to prepare compound 25-1.

[0697] Step B: Preparation of compound 25-2

[0698] Referring to the method of step B of Example 16, compound 25-1 was reacted with N-methylmorpholine oxide to prepare compound 25-2.

[0699] Step C: Preparation of compound 25-3

[0700] Referring to the method of step C of Example 16, compound 25-2 was reacted with ethyl 2-(diethoxyphosphoryl)butyrate to prepare compound 25-3.

[0701] MS (ESI, [M+H] + )m / z:362.14.

[0702] Step D: Preparation of compound 25-4

[0703] Referring to the method of step D of Example 16, compound 25-3 was reacted with iron powder to prepare compound 25-4.

[0704] Step E: Preparation of compound 25-5

[0705] Referring to the method of step E of Example 16, compound 25-4 was reacted in a photocatalytic synthesizer to prepare compound 25-5.

[0706] MS (ESI, [M+H] + )m / z:286.01

[0707] Step F: Preparation of compound 25-6

[0708] Referring to the method of Step F of Example 2, compound 25-5 was reacted with (tributyltin)methanol to prepare compound 25-6.

[0709] MS (ESI, [M+H] + )m / z:238.17.

[0710] Step G: Preparation of compound 25-7

[0711] Referring to the method of Example 2, Step A, compound 25-6 was reacted with 2-iodoacylbenzoic acid to prepare compound 25-7.

[0712] MS (ESI, [MH] - )m / z:234.12.

[0713] Step H: Preparation of compound 25

[0714] Referring to the method of step I of Example 1, compound 25-7 was reacted with compound 2-10 to prepare compound 25.

[0715] 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).

[0716] HRMS (ESI, [M+H] + )m / z:441.1801

[0717] Example 26: Preparation of Compound 26

[0718] Step A: Preparation of compound 26-1

[0719] Referring to the method of step C of Example 2, 7-bromo-3-chloroquinoline was reacted with m-chloroperbenzoic acid to prepare compound 26-1.

[0720] MS (ESI, [M+H] + )m / z:258.16.

[0721] Step B: Preparation of compound 26-2

[0722] Referring to the method of step D of Example 2, compound 26-1 was reacted with phosphorus oxychloride to prepare compound 26-2.

[0723] MS (ESI, [M+H] + )m / z:276.07.

[0724] Step C: Preparation of compound 26-3

[0725] To a 15 mL microwave tube, compound 26-2 (0.4 g) and concentrated hydrochloric acid (5 mL) were added sequentially. The reaction system was transferred to a microwave reactor and heated to 100°C at 150 W for 2 h. Upon completion, the pH was adjusted to alkaline using saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, sanded, and purified by column chromatography to obtain 0.35 g of compound 26-3.

[0726] MS (ESI, [MH] - )m / z:255.96.

[0727] Step D: Preparation of compound 26-4

[0728] Referring to the method of step F of Example 2, compound 26-3 was reacted with (tributyltin)methanol to prepare compound 26-4.

[0729] MS (ESI, [M+H] + )m / z:210.15.

[0730] Step E: Preparation of compound 26-5

[0731] Referring to the method of Example 2, Step A, compound 26-4 was reacted with 2-iodoacylbenzoic acid to prepare compound 26-5.

[0732] MS (ESI, [MH] - )m / z:206.10.

[0733] Step F: Preparation of compound 26

[0734] Referring to the method of step I of Example 1, compound 26-5 was reacted with compound 2-10 to prepare compound 26.

[0735] 1 H 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).

[0736] HRMS (ESI, [M+H] + )m / z:413.1490.

[0737] Example 27: Preparation of Compound 27

[0738] Step A: Preparation of compound 27

[0739] Referring to the method of step I of Example 1, compound 26-5 was reacted with compound 7-8 to prepare compound 27.

[0740] 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).

[0741] HRMS (ESI, [M+H] + )m / z:430.1103.

[0742] Example 28: Preparation of Compound 28

[0743] Step A: Preparation of compound 28

[0744] Referring to the method of step I of Example 1, compound 24-4 was reacted with compound 7-8 to prepare compound 28.

[0745] 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).

[0746] HRMS (ESI, [M+H] + )m / z:464.1379.

[0747] Example 29: Preparation of Compound 29

[0748] Step A: Preparation of compound 29-1

[0749] To a 100mL three-necked flask, add 3-bromo-2-fluoroaniline (1g), sodium iodide (0.079g), and 4M aqueous sulfuric acid (25mL). After the addition, replace the atmosphere with nitrogen and heat to 110°C. Then, add 2-ethylacrolein (0.531g) dropwise to the reaction system. After completion of the reaction, neutralize with saturated aqueous sodium carbonate, extract, concentrate, and purify by column chromatography to obtain compound 29-1.

[0750] MS (ESI, [M+H] + )m / z:254.24.

[0751] Step B: Preparation of compound 29-2

[0752] Referring to the method of step C of Example 2, compound 29-1 was reacted with m-chloroperbenzoic acid to prepare compound 29-2.

[0753] MS (ESI, [M+H] + )m / z:270.23.

[0754] Step C: Preparation of compound 29-3

[0755] Referring to the method of step D of Example 2, compound 29-2 was reacted with phosphorus oxychloride to prepare compound 29-3.

[0756] MS (ESI, [M+H] + )m / z:288.16.

[0757] Step D: Preparation of compound 29-4

[0758] Referring to the method of Example 2, Step E, compound 29-3 was reacted with sodium methoxide to prepare compound 29-4.

[0759] MS (ESI, [M+H] + )m / z:284.22.

[0760] Step E: Preparation of compound 29-5

[0761] Referring to the method of Step F of Example 2, compound 29-4 was reacted with (tributyltin)methanol to prepare compound 29-5.

[0762] MS (ESI, [M+H] + )m / z:236.36.

[0763] Step F: Preparation of compound 29-6

[0764] Referring to the method of step G of Example 2, compound 29-5 was reacted with hydrochloric acid to prepare compound 29-6.

[0765] MS (ESI, [M+H] + )m / z:222.18.

[0766] Step G: Preparation of compound 29-7

[0767] Referring to the method of Example 2, Step A, compound 29-6 was reacted with 2-iodoacylbenzoic acid to prepare compound 29-7.

[0768] MS (ESI, [MH] - )m / z:218.17.

[0769] Step H: Preparation of compound 29

[0770] Referring to the method of step I of Example 1, compound 29-7 was reacted with compound 2-10 to prepare compound 29.

[0771] 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).

[0772] HRMS (ESI, [M+H] + )m / z:425.2099.

[0773] Example 30: Preparation of Compound 30

[0774] Step A: Preparation of compound 30

[0775] Referring to the method of step I of Example 1, compound 29-7 was reacted with compound 7-8 to prepare compound 30.

[0776] 1H 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).

[0777] HRMS (ESI, [M+H] + )m / z:442.1709.

[0778] Example 31: Preparation of Compound 31

[0779] Step A: Preparation of compound 31

[0780] Referring to the method of step I of Example 1, compound 2-8 was reacted with compound 7-8 to prepare compound 31.

[0781] 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).

[0782] HRMS (ESI, [M+H] + )m / z:436.1808.

[0783] Example 32: Preparation of Compound 32

[0784] Step A: Preparation of compound 32-1

[0785] Referring to the method of step I of Example 2, compound 1-3 was reacted with tert-butyl 3-oxopyrrolidine-1-carboxylate to prepare compound 32-1.

[0786] MS (ESI, [M+H] + )m / z:336.29.

[0787] Step B: Preparation of compound 32-2

[0788] Referring to the method of step C of Example 1, compound 32-1 was reacted with trifluoroacetic acid to prepare compound 32-2.

[0789] MS (ESI, [M+H] + )m / z:236.29.

[0790] Step C: Preparation of compound 32

[0791] Following the method of Step I in Example 1, compound 1-7 was reacted with compound 32-2 to prepare compound 32. Compound 32 was separated on a CHIRALPAK IG column (30*250 mm, S-10 μm) with mobile phase A consisting of ethanol-dichloromethane (2:1, V / V) and mobile phase B consisting of n-hexane. The elution gradient was mobile phase A:mobile phase B = 75:25 (V / V) at a flow rate of 40 mL / min and detection at a wavelength of 254 nM to obtain compounds 32-a and 32-b. The peak elution times were 13.28 min (compound 32-a) and 19.50 min (compound 32-b), respectively.

[0792] Compound 32-a:

[0793] 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).

[0794] HRMS (ESI, [M+H] + )m / z:421.2353.

[0795] Compound 32-b:

[0796] 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).

[0797] HRMS (ESI, [M+H] + )m / z:421.2349.

[0798] Example 33: Preparation of Compound 33

[0799] Step A: Preparation of compound 33-1

[0800] To a 100 mL single-necked flask, add methyl 3-methylthiophene-2-carboxylate (2 g), chloroform (20 mL), N-bromosuccinimide (2.165 g), and a catalytic amount of benzoyl peroxide. Reflux at 70°C overnight. Once the reaction is complete, the solvent is dried, and the mixture is diluted with ethyl acetate (100 mL). The mixture is washed with water and dried. Purify by column chromatography to obtain compound 33-1.

[0801] Step B: Preparation of compound 33-2

[0802] In a 100 mL single-necked bottle, compound 33-1 (2.2 g) and ammonia in methanol were added and stirred at room temperature for 2 h. The reaction solution was directly spin-dried and sanded, and then purified by column chromatography to obtain compound 33-2.

[0803] MS (ESI, [M+H] + )m / z:172.08.

[0804] Step C: Preparation of compound 33-3

[0805] In a 100 mL single-necked flask, compound 33-2 (0.5 g), ethanol (5 mL), methanol (5.00 mL), and potassium carbonate (0.444 g) were added and refluxed at 90°C overnight. After the reaction, the reaction solution was dried by spin-drying, diluted with ethyl acetate (50 mL), washed with water, and dried, and then spin-dried to obtain compound 33-3.

[0806] MS (ESI, [M+H] + )m / z:140.01.

[0807] Step D: Preparation of compound 33-4

[0808] Referring to the method of step D of Example 18, compound 33-3 was reacted with di-tert-butyl dicarbonate to prepare compound 33-4.

[0809] MS (ESI, [M+H] + )m / z:240.01.

[0810] Step E: Preparation of compound 33-5

[0811] Compound 33-4 (0.3 g) and tetrahydrofuran (15 mL) were added to a 100 mL three-necked flask. Under nitrogen, borane dimethyl sulfide (0.5 g) was added dropwise under an ice bath. After addition, the mixture was stirred overnight in a 40°C oil bath. After completion of the reaction, a small amount of methanol was added to quench the reaction, the solvent was removed by concentration, and the mixture was redissolved in 50 mL of ethyl acetate. The mixture was washed with water and dried. After purification by column chromatography, compound 33-5 was obtained.

[0812] MS (ESI, [M+H] + )m / z:226.08.

[0813] Step F: Preparation of compound 33-6

[0814] To a 100 mL single-necked bottle, add compound 33-5 (120 mg), chloroform (5 mL), and a catalytic amount of acetic acid. Add bromine (85 mg) dropwise under ice-cooling and stir at room temperature overnight. Add 5 mL of ether directly to the reaction mixture, filter, and wash the filter cake with ether to obtain compound 33-6.

[0815] MS (ESI, [M+H] + )m / z:204.03.

[0816] Step G: Preparation of compound 33-7

[0817] Referring to the method of Step D of Example 18, compound 33-6 was reacted with di-tert-butyl dicarbonate to prepare compound 33-7.

[0818] MS (ESI, [M+H] + )m / z:304.03.

[0819] Step H: Preparation of compound 33-8

[0820] Referring to the method of Example 7 Step F, compound 33-7 was reacted with carbon monoxide to prepare compound 33-8.

[0821] MS (ESI, [M+H] + )m / z:284.41.

[0822] Step I: Preparation of compound 33-9

[0823] Referring to the method of step G of Example 7, compound 33-8 was reacted with methylamine ethanol solution to prepare compound 33-9.

[0824] MS (ESI, [M+H] + )m / z:283.22.

[0825] Step J: Preparation of compound 33-10

[0826] Referring to the method of step C of Example 1, compound 33-9 was reacted with trifluoroacetic acid to prepare compound 33-10.

[0827] MS (ESI, [M+H] + )m / z:183.22.

[0828] Step K: Preparation of compound 33-11

[0829] Referring to the method of step I of Example 2, compound 33-10 was reacted with 1-Boc-3-azetidinone to prepare compound 33-11.

[0830] MS (ESI, [M+H] + )m / z:338.23.

[0831] Step L: Preparation of compound 33-12

[0832] Referring to the method of step C of Example 1, compound 33-11 was reacted with trifluoroacetic acid to prepare compound 33-12.

[0833] MS (ESI, [M+H] + )m / z:238.23.

[0834] Step M: Preparation of compound 33

[0835] Referring to the method of step I of Example 1, compound 24-4 was reacted with compound 33-12 to prepare compound 33.

[0836] 1H 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).

[0837] HRMS (ESI, [M+H] + )m / z:463.1409.

[0838] Example 34: Preparation of Compound 34

[0839] Step A: Preparation of compound 34-1

[0840] To a 100mL single-necked flask, add methyl 3-amino-4-bromobenzoate (1g), acetonitrile (20mL), cesium carbonate (2.83g), and bis(triphenylphosphine)palladium(II) dichloride (3.05g) in sequence. Under nitrogen, heat the mixture to 80°C. Dissolve (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (1.1g) in 10mL of acetonitrile and slowly add it dropwise to the reaction system over approximately 0.5h. Stir the reaction system at 100°C overnight. After the reaction is complete, sand the reaction solution and purify it by column chromatography to obtain 0.6g of compound 34-1.

[0841] MS (ESI, [M+H] + )m / z:243.22.

[0842] Step B: Preparation of compound 34-2

[0843] Referring to the method of step C of Example 15, compound 34-1 was reacted with 2.5 M lithium aluminum hydride tetrahydrofuran solution to prepare compound 34-2.

[0844] MS (ESI, [M+H] + )m / z:215.24.

[0845] Step C: Preparation of compound 34-3

[0846] Referring to the method of step H of Example 2, compound 34-2 was reacted with 2-iodoacylbenzoic acid to prepare compound 34-3.

[0847] MS (ESI, [MH] - )m / z:211.19.

[0848] Step D: Preparation of compound 34

[0849] Referring to the method of step I of Example 1, compound 34-3 was reacted with compound 2-10 to prepare compound 34.

[0850] 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).

[0851] HRMS (ESI, [M+H] + )m / z:418.1990.

[0852] Example 35: Preparation of Compound 35

[0853] Step A: Preparation of compounds 35-a and 35-b

[0854] Following the procedure of Example 2, Step I, compound 1-3 was reacted with tert-butyl (R)-2-methyl-3-oxoazetidine-1-carboxylate to prepare compound 35-1. Compound 35-1 was separated on an Ansa Pre-packed Regis IA (30*250 mm, 10 μm) column with ethanol as mobile phase A and n-hexane as mobile phase B. The elution gradient was 35:65 (V / V) at a flow rate of 40 mL / min and detection at a wavelength of 254 nm to yield compounds 35-a and 35-b. The peak elution times were 7.58 min (compound 35-a) and 12.08 min (compound 35-b), respectively.

[0855] Compound 35-a:

[0856] MS (ESI, [M+H] +)m / z:336.40.

[0857] Compound 35-b:

[0858] MS (ESI, [M+H] + )m / z:336.01.

[0859] Step B: Preparation of compound 35-2

[0860] Referring to the method of step C of Example 1, compound 35-b was reacted with trifluoroacetic acid to prepare compound 35-2.

[0861] MS (ESI, [M+H] + )m / z:236.33.

[0862] Step C: Preparation of compound 35

[0863] Referring to the method of step I of Example 1, compound 24-4 was reacted with compound 35-2 to prepare compound 35.

[0864] 1 H 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).

[0865] HRMS (ESI, [M+H] + )m / z:461.1908.

[0866] Example 36: Preparation of Compound 36

[0867] Step A: Preparation of compounds 36-a and 36-b

[0868] Following the procedure of Step 1 in 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) with mobile phase A consisting of ethanol-dichloromethane (1:1, V / V) and mobile phase B consisting of n-hexane. The elution gradient was 30:70 (V / V) at a flow rate of 25 mL / min and detection at a wavelength of 254 nm to obtain Compounds 36-a and 36-b. The peak elution times were 10.3 min (Compound 36-a) and 11.7 min (Compound 36-b), respectively.

[0869] Compound 36-a:

[0870] MS (ESI, [M+H] + )m / z:336.01.

[0871] Compound 36-b:

[0872] MS (ESI, [M+H] + )m / z:336.01.

[0873] Step B: Preparation of compound 36-2

[0874] Referring to the method of step C of Example 1, compound 36-a was reacted with trifluoroacetic acid to prepare compound 36-2.

[0875] MS (ESI, [M+H] + )m / z:236.34.

[0876] Step C: Preparation of compound 36

[0877] Referring to the method of step I of Example 1, compound 24-4 was reacted with compound 36-2 to prepare compound 36.

[0878] 1H 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).

[0879] HRMS (ESI, [M+H] + )m / z:461.1915.

[0880] Example 37: Preparation of Compound 37

[0881] Step A: Preparation of compound 37-1

[0882] Referring to the method of step I of Example 2, compound 1-3 was reacted with tert-butyl 2-(methoxymethyl)-3-oxoazetidine-1-carboxylate to prepare compound 37-1.

[0883] MS (ESI, [M+H] + )m / z:366.37.

[0884] Step B: Preparation of compound 37-2

[0885] Referring to the method of step C of Example 1, compound 37-1 was reacted with trifluoroacetic acid to prepare compound 37-2.

[0886] MS (ESI, [M+H] + )m / z:266.35.

[0887] Step C: Preparation of compound 37

[0888] Referring to the method of step I of Example 1, compound 24-4 was reacted with compound 37-2 to prepare compound 37.

[0889] 1H 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).

[0890] HRMS (ESI, [M+H] + )m / z:491.32017.

[0891] Example 38: Preparation of Compound 38

[0892] Step A: Preparation of compound 38-1

[0893] Referring to the method of step C of Example 1, compound 36-b was reacted with trifluoroacetic acid to prepare compound 38-1.

[0894] MS (ESI, [M+H] + )m / z:236.34.

[0895] Step B: Preparation of compound 38

[0896] Referring to the method of step I of Example 1, compound 24-4 was reacted with compound 38-1 to prepare compound 38.

[0897] 1H 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).

[0898] HRMS (ESI, [M+H] + )m / z:461.1913.

[0899] Example 39: Preparation of Compound 39

[0900] Step A: Preparation of compound 39

[0901] Referring to the method of step I of Example 1, compound 1-7 was reacted with compound 38-1 to prepare compound 39.

[0902] 1 H 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).

[0903] HRMS (ESI, [M+H] + )m / z:.421.2350

[0904] Example 40: Preparation of Compound 40

[0905] Step A: Preparation of compound 40

[0906] Referring to the method of step I of Example 1, compound 2-8 was reacted with compound 35-2 to prepare compound 40.

[0907] 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).

[0908] HRMS (ESI, [M+H] + )m / z:433.2356.

[0909] Example 41: Preparation of Compound 41

[0910] Step A: Preparation of compound 41

[0911] Referring to the method of step I of Example 1, compound 1-7 was reacted with compound 36-2 to prepare compound 41.

[0912] 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).

[0913] HRMS (ESI, [M+H] + )m / z:421.2342.

[0914] Example 42: Preparation of Compound 42

[0915] Step A: Preparation of compound 42

[0916] Referring to the method of step I of Example 1, compound 2-8 was reacted with compound 36-2 to prepare compound 42.

[0917] 1 H 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=7.4Hz,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).

[0918] HRMS (ESI, [M+H] + )m / z:433.2361.

[0919] Example 43: Preparation of Compound 43

[0920] Step A: Preparation of compound 43

[0921] Referring to the method of step I of Example 1, compound 2-8 was reacted with compound 38-1 to prepare compound 43.

[0922] 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).

[0923] HRMS (ESI, [M+H] + )m / z:433.2355.

[0924] Example 44: Preparation of Compound 44

[0925] Step A: Preparation of compound 44

[0926] Referring to the method of step I of Example 1, compound 1-7 was reacted with compound 35-2 to prepare compound 44.

[0927] 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).

[0928] HRMS (ESI, [M+H] + )m / z:421.2354.

[0929] Example 45: Preparation of Compound 45

[0930] Step A: Preparation of compound 45-1

[0931] Referring to the method of step B of Example 3, methyl 4-fluoro-3-nitrobenzoate was reacted with methyl DL-2-amino-n-butyrate hydrochloride to prepare compound 45-1.

[0932] MS (ESI, [MH] - )m / z:295.20.

[0933] Step B: Preparation of compound 45-2

[0934] Referring to the method of step C of Example 3, compound 45-1 was reacted with iron powder to prepare compound 45-2.

[0935] MS (ESI, [MH] - )m / z:233.18.

[0936] Step C: Preparation of compound 45-3

[0937] Referring to the method of step D of Example 3, compound 45-2 was reacted with 2,3-dichloro-5,6-dicyanobenzoquinone to prepare compound 45-3.

[0938] MS (ESI, [MH] - )m / z:231.18.

[0939] Step D: Preparation of compound 45-4

[0940] Referring to the method of step C of Example 15, compound 45-3 was reacted with 2.5 M lithium aluminum hydride tetrahydrofuran solution to prepare compound 45-4.

[0941] MS (ESI, [MH] - )m / z:203.15.

[0942] Step E: Preparation of compound 45-5

[0943] Referring to the method of step H of Example 2, compound 45-4 was reacted with 2-iodoacylbenzoic acid to prepare compound 45-5.

[0944] MS (ESI, [MH] - )m / z:201.17.

[0945] Step F: Preparation of compound 45

[0946] Referring to the method of Step I of Example 1, compound 45-5 was reacted with compound 36-2 to prepare compound 45.

[0947] 1H 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).

[0948] HRMS (ESI, [M+H] + )m / z:422.2303.

[0949] Example 46: Preparation of Compound 46

[0950] Step A: Preparation of compound 46

[0951] Referring to the method of step I of Example 1, compound 16-7 was reacted with compound 38-1 to prepare compound 46.

[0952] 1 H 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,1H ),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)..

[0953] HRMS (ESI, [M+H] + )m / z:439.2263.

[0954] Example 47: Preparation of Compound 47

[0955] Step A: Preparation of compound 47

[0956] Referring to the method of step I of Example 1, compound 5-1 was reacted with compound 36-2 to prepare compound 47.

[0957] 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).

[0958] HRMS (ESI, [M+H] + )m / z:422.2301.

[0959] Example 48: Preparation of Compound 48

[0960] Step A: Preparation of compound 48-1

[0961] To a 250ml three-necked flask, add methyl 4-formyl-3-nitrobenzoate (4.5g) and methanol (100ml) in sequence. After addition, replace the atmosphere with nitrogen. A 7M methanolic ammonia solution (45ml) and glyoxal (22ml) were then added via syringe. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the excess solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography to yield compound 48-1.

[0962] MS (ESI, [M+H] + )m / z:248.24.

[0963] Step B: Preparation of compound 48-2

[0964] To a 100ml single-necked flask, add compound 48-1 (900mg), ethyl acetate (40ml), and stannous chloride dihydrate (4.1g). After the addition is complete, heat the mixture to 80°C in an oil bath under nitrogen protection for 4 hours. After the reaction is complete, dilute the mixture with 100ml of purified water, then adjust the pH to 8 with saturated sodium bicarbonate solution. Extract the aqueous phase with ethyl acetate, combine the organic phases, and dry over anhydrous sodium sulfate. Concentrate the organic phase to obtain the crude product, which is further purified by silica gel column chromatography to yield compound 48-2.

[0965] MS (ESI, [M+H] +)m / z:218.21.

[0966] Step C: Preparation of compound 48-3

[0967] To a 50ml two-necked flask, add compound 48-2 (565mg) and 1,4-dioxane (20ml) sequentially. After addition, replace the system with nitrogen. Triphosgene (810mg) is then added to the reaction system under a nitrogen atmosphere. Heat to 80°C in an oil bath and react for approximately 12 hours. After completion of the reaction, quench the reaction mixture with 5ml of methanol. The mixture is then concentrated and purified by column chromatography to yield compound 48-3.

[0968] MS (ESI, [M+H] + )m / z:244.26.

[0969] Step D: Preparation of compound 48-4

[0970] Referring to the method of step C of Example 15, compound 48-3 was reacted with 2.5 M lithium aluminum hydride tetrahydrofuran solution to prepare compound 48-4.

[0971] MS (ESI, [M+H] + )m / z:216.19.

[0972] Step E: Preparation of compound 48-5

[0973] To a 50ml single-necked flask, add compound 48-4 (250mg), dichloromethane (20ml), and N,N-dimethylformamide (0.05ml) in sequence. After the addition, cool the reaction system to 0°C in an ice bath and stir. Then, slowly add thionyl chloride (0.22ml) dropwise to the reaction system. After the addition, bring the reaction system to room temperature and react overnight. After the reaction is complete, evaporate the solvent and thionyl chloride under reduced pressure to obtain crude compound 48-5, which is used directly in the next reaction.

[0974] MS (ESI, [M+H] + )m / z:234.17.

[0975] Step F: Preparation of compound 48

[0976] To a 50ml single-necked flask, compound 36-2 (104mg), acetonitrile (10ml), triethylamine (0.25ml), anhydrous potassium carbonate (103mg), potassium iodide (10mg), and compound 48-5 (70mg) were added sequentially. After the addition, the atmosphere was replaced with nitrogen and the system was heated to 80°C in an oil bath for 2h. After completion of the reaction, the residue was concentrated and purified by column chromatography to obtain compound 48.

[0977] 1H 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).

[0978] HRMS (ESI, [M+H] + )m / z:433.2102.

[0979] Example 49: Preparation of Compound 49

[0980] Step A: Preparation of compound 49

[0981] Referring to the method of Step F of Example 48, compound 48-5 was reacted with compound 38-1 to prepare compound 49.

[0982] 1 H 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).

[0983] HRMS (ESI, [M+H] + )m / z:433.2109.

[0984] Example 50: Preparation of Compound 50

[0985] Step A: Preparation of compound 50-1

[0986] Referring to the method of Example 24, step A, 2'-amino-4'-bromoacetophenone was reacted with 3,3,3-trifluoropropionic acid to prepare compound 50-1.

[0987] MS (ESI, [MH] - )m / z:322.07.

[0988] Step B: Preparation of compound 50-2

[0989] Referring to the method of Example 24 Step B, compound 50-1 was reacted with potassium carbonate to prepare compound 50-2.

[0990] MS (ESI, [MH] - )m / z:304.02.

[0991] Step C: Preparation of compound 50-3

[0992] Referring to the method of Step F of Example 2, compound 50-2 was reacted with (tributyltin)methanol to prepare compound 50-3.

[0993] MS (ESI, [M+H] + )m / z:258.22.

[0994] Step D: Preparation of compound 50-4

[0995] Referring to the method of Example 2, Step A, compound 50-3 was reacted with 2-iodoacylbenzoic acid to prepare compound 50-4.

[0996] MS (ESI, [MH] - )m / z:254.14.

[0997] Step E: Preparation of compound 50

[0998] Referring to the method of Step I of Example 1, compound 50-4 was reacted with compound 2-10 to prepare compound 50.

[0999] 1 H NMR (500MHz, DMSO-d6) δ12.04(s,1H),8.27(q,J=4.3Hz,1H),8.06–7.81(m,2H),7.28(s,1H),7.18(d,J=8.5Hz,1H),3.71(d,J=4. 9Hz, 4H), 3.67 (s, 2H), 3.63–3.55 (m, 1H), 3.41 (t, J = 7.0Hz, 2H), 3.10 (t, J = 6.7Hz, 2H), 2.78 (d, J = 4.7Hz, 3H), 2.66–2.61 (m, 3H).

[1000] HRMS (ESI, [M+H] + )m / z:461.1917.

[1001] Example 51: Preparation of Compound 51

[1002] Referring to the method of step I of Example 1, compound 3-6 was reacted with compound 36-2 to prepare compound 51.

[1003] 1 H NMR(500MHz,DMSO-d6)δ12.39(s,1H),8.26(d,J=4.7Hz,1H),7.93(s,1H),7.52(d,J=8 .3Hz,1H),7.25(t,J=7.7Hz,1H),3.84–3.70(m,5H),3.61(d,J=13.5Hz,1H),3.53(td, J=6.7,2.8Hz,1H),3.47(dd,J=12.7,6.3Hz,1H),3.33(s,1H),3.07(t,J=7.4Hz,1H),2 .85–2.79(m,2H),2.78(t,J=4.3Hz,3H),1.21(t,J=7.4Hz,3H),1.10(d,J=6.4Hz,3H).

[1004] HRMS (ESI, [M+H] + )m / z:440.2217.

[1005] Example 52: Preparation of Compound 52

[1006] Referring to the method of step I of Example 1, compound 34-3 was reacted with compound 36-2 to prepare compound 52.

[1007] 1H NMR (500MHz, DMSO-d6) δ11.42(s,1H),8.26(d,J=4.6Hz,1H),7.94(s,1H),7.84(d,J=8.0H z,1H),7.57(d,J=1.4Hz,1H),7.23(s,1H),7.12(d,J=8.0Hz,1H),6.95(d,J=2.2Hz,1H),6 .66(t,J=3.2Hz,1H),3.87–3.70(m,5H),3.60–3.51(m,1H),3.51–3.45(m,1H),3.43(dd,J =12.7,6.4Hz,1H),3.33(s,1H),3.02(t,J=7.4Hz,1H),2.79(s,3H),1.11(d,J=6.4Hz,3H).

[1008] HRMS (ESI, [M+H] + )m / z:432.2150.

[1009] Example 53: Preparation of Compound 53

[1010] Referring to the method of step I of Example 1, compound 18-10 was reacted with compound 36-2 to prepare compound 53.

[1011] 1 H NMR (500MHz, DMSO-d6) δ11.71(s,1H),8.27(s,1H),7.96(s,1H),7.68(s,1H),7.40(dd,J=29.8,8.1Hz,2H),3.80(t,J=16.4Hz,5H) ,3.64–3.45(m,3H),3.41(d,J=7.8Hz,1H),3.04(t,J=7.4Hz,1H),2.86–2.73(m,3H),2.48(d,J=7.7Hz,2H),1.16(q,J=7.1Hz,6H).

[1012] HRMS (ESI, [M+H] + )m / z:439.2251.

[1013] Example 54: Preparation of Compound 54

[1014] Referring to the method of Step I of Example 1, compound 50-4 was reacted with compound 36-2 to prepare compound 54.

[1015] 1H NMR(500MHz,DMSO-d6)δ12.04(s,1H),8.26(d,J=4.6Hz,1H),8.10–7.86(m ,2H),7.32(s,1H),7.19(d,J=8.4Hz,1H),3.87–3.75(m,5H),3.54(d,J=14. 7Hz,2H),3.47(dd,J=12.7,6.3Hz,1H),3.38–3.33(m,1H),3.03(t,J=7.3H z,1H),2.79(d,J=4.5Hz,3H),2.64(d,J=2.0Hz,3H),1.12(d,J=6.4Hz,3H).

[1016] HRMS (ESI, [M+H] + )m / z:475.2073.

[1017] Example 55: Preparation of Compound 55

[1018] Step A: Preparation of compound 55-1

[1019] To a 1000mL three-necked flask, add 2-amino-4-bromo-3-fluorobenzoic acid (20g) and anhydrous tetrahydrofuran (300mL) sequentially. Under nitrogen, transfer the reaction system to -78°C and slowly add 2.5M lithium aluminum hydride solution in tetrahydrofuran (52.7mL) dropwise. Incubate for 4 hours. After completion, quench the reaction with water, add silica gel, and purify by column chromatography to obtain compound 55-1.

[1020] Step B: Preparation of compound 55-2

[1021] Referring to the method of Example 2, Step A, compound 55-1 was reacted with 2-iodoacylbenzoic acid to prepare compound 55-2.

[1022] 1 H NMR (500MHz, DMSO-d6) δ9.87(d,J=2.0Hz,1H),7.40(dd,J=8.5,1.3Hz,1H),7.23(s,2H),6.93(dd,J=8.5,5.9Hz,1H).

[1023] Step C: Preparation of compound 55-3

[1024] To a 100 mL three-necked flask, compound 55-2 (3.6 g), 3,3,3-trifluoropropionic acid (3.76 g), and 1-propylphosphoric anhydride (13.74 g) were added sequentially. Under nitrogen, N,N-diisopropylethylamine (9.48 g) was slowly added dropwise via a constant pressure dropping funnel. After the addition was complete, the mixture was stirred in a 100°C oil bath for 2 h. After completion of the reaction, the mixture was quenched with water, extracted, dried, sanded, and purified by column chromatography to yield compound 55-3.

[1025] MS (ESI, [MH] - )m / z:307.97.

[1026] Step D: Preparation of compound 55-4

[1027] Referring to the method of Step F of Example 2, compound 55-3 was reacted with (tributyltin)methanol to prepare compound 55-4.

[1028] MS (ESI, [MH] - )m / z:260.11.

[1029] Step E: Preparation of compound 55-5

[1030] Referring to the method of Example 2, Step A, compound 55-4 was reacted with 2-iodoacylbenzoic acid to prepare compound 55-5.

[1031] MS (ESI, [MH] - )m / z:258.00.

[1032] Step F: Preparation of compound 55

[1033] Referring to the method of Step I of Example 1, compound 55-5 was reacted with compound 36-2 to prepare compound 55.

[1034] 1 H NMR(500MHz,DMSO-d6)δ12.34(s,1H),8.58(s,1H),8.26(d,J=4.6Hz,1H),7.9 3(s,1H),7.66(d,J=8.1Hz,1H),7.37–7.12(m,1H),3.90–3.70(m,5H),3.64(d ,J=13.8Hz,1H),3.54(td,J=6.7,2.8Hz,1H),3.52–3.44(m,1H),3.34(d,J=2. 7Hz, 1H), 3.08 (t, J = 7.4Hz, 1H), 2.78 (d, J = 4.6Hz, 3H), 1.11 (d, J = 6.3Hz, 3H).

[1035] HRMS (ESI, [M+H] + )m / z:479.1829.

[1036] Example 56: Preparation of Compound 56

[1037] Step A: Preparation of compound 56-1

[1038] Referring to the method of Example 24, step A, ethyl 5-amino-6-methylnicotinate was reacted with 2-cyclopropylacetic acid to prepare compound 56-1.

[1039] MS (ESI, [M+H] + )m / z:263.30.

[1040] Step B: Preparation of compound 56-2

[1041] To a 50 mL single-necked flask, compound 56-1 (5.43 g), anhydrous dioxane (50 mL), and selenium oxide (3.45 g) were added sequentially. Under nitrogen, the mixture was incubated at 80°C for 3 hours. Upon completion of the reaction, water (10 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried, concentrated, and purified by column chromatography to yield compound 56-2.

[1042] MS (ESI, [M+H] + )m / z:277.23.

[1043] Step C: Preparation of compound 56-3

[1044] To a 50 mL single-necked flask, compound 56-2 (2.5 g), anhydrous N,N-dimethylformamide (80 mL), and cesium carbonate (8.84 g) were added sequentially. Under nitrogen, the mixture was incubated at 60°C for 1 hour. After the reaction was complete, the filtrate was collected by filtration and ethyl acetate (50 mL) was added. The mixture was washed once with saturated aqueous ammonium chloride (30 mL) and once with saturated aqueous sodium chloride (30 mL). The organic phase was dried, concentrated, and purified by column chromatography to obtain compound 56-3.

[1045] MS (ESI, [M+H] + )m / z:259.25.

[1046] Step D: Preparation of compound 56-4

[1047] Referring to the method of step C of Example 15, compound 56-3 was reacted with a tetrahydrofuran solution of lithium aluminum hydride to prepare compound 56-4.

[1048] MS (ESI, [MH]- )m / z:215.15.

[1049] Step E: Preparation of compound 56-5

[1050] Referring to the method of Example 2, Step A, compound 56-4 was reacted with 2-iodoacylbenzoic acid to prepare compound 56-5.

[1051] MS (ESI, [M+H] + )m / z:215.02.

[1052] Step F: Preparation of compound 56

[1053] Referring to the method of step I of Example 1, compound 56-5 was reacted with compound 36-2 to prepare compound 56.

[1054] 1 H NMR(500MHz,DMSO-d6)δ11.84(s,1H),8.33(d,J=1.8Hz,1H),8.26(q,J=4.6Hz,1H),7.94 (s,1H),7.57(d,J=1.9Hz,1H),7.40(s,1H),3.96–3.67(m,5H),3.64–3.50(m,2H),3.49– 3.42(m,1H),3.31–3.28(m,1H),3.03(t,J=7.4Hz,1H),2.78(d,J=4.6Hz,3H),2.13(tt,J =8.4,5.3Hz,1H),1.11(d,J=6.4Hz,3H),0.96(dt,J=8.4,3.0Hz,2H),0.87–0.75(m,2H).

[1055] HRMS (ESI, [M+H] + )m / z:434.2313.

[1056] Test Example 1 In vitro cell proliferation inhibitory activity

[1057] 1.1 MDA-MB-436 cell proliferation inhibitory activity assay

[1058] MDA-MB-436 cells in good growth condition were collected into centrifuge tubes and the cell density was adjusted to 2×10 cells in complete medium (DMEM high glucose + 10% FBS + 1× insulin-transferrin-selenium (ITS-G) + 16 μg / mL reduced glutathione). 4The cells were incubated in a 96-well plate (100 μL / well) at 400 nM / mL. After overnight culture in a cell culture incubator, the compound was added using a pipette to a final concentration of 400 nM-0.02 nM, with two replicates. A control was also set up. After 168 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 1.5 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC. 50 , where A represents IC 50 ≤50nM, the results are shown in Table 1:

[1059] Table 1 Results of DA-MB-436 cell proliferation inhibitory activity of compounds

[1060] Test Example 2 PARP protein inhibitory activity

[1061] 2.1 PARP1 protein activity assay

[1062] A chemiluminescence assay kit (BPS, Cat. No. 80551) was used. 50 μL of 1× histone was added to a 96-well plate and incubated overnight at 4°C. Each well was washed three times with 200 μL of PBST buffer (containing 0.05% Tween-20). The plate was then removed and 200 μL of blocking buffer 3 was added. The plate was blocked for 60-90 min at room temperature. The blocking buffer was discarded and the plate was washed three times with PBST buffer. The plate was then removed. 25 μL of the master mix (2.5 μL of 10× PARP buffer, 2.5 μL of 10× assay mix containing biotinylated substrate, 5 μL of activated DNA (5×), and 15 μL of water) and 5 μL of 1× PARP buffer were added to each well. Compounds were then sprayed into the wells using a nanoliter pipette. A blank control was treated with 20 μL of 1× PARP buffer, and 20 μL of PARP1 enzyme (2.4 ng / mL) was added to the remaining wells. The reaction was initiated and incubated at room temperature for 1 hour. Add 50 μl of streptavidin-HRP (diluted 1:50 in blocking buffer 3) to each well and incubate at room temperature for 30 min. Wash three times with PBST to remove any liquid from the wells. Immediately before use, mix 50 μl of ELISA ECL substrate A and 50 μl of ELISA ECL substrate B on ice and add 100 μl to each well. Absorbance was measured using a PerkinElmer Envision microplate reader (LUMINESCENCE). Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 , where +++ represents IC 50 ≤1nM, ++ represents IC 50 ≤10nM, the results are shown in Table 2.

[1063] Table 2 PARP1 kinase inhibitory activity results of the compounds

[1064] The compound of the present application has high PARP1 protein kinase inhibitory activity.

[1065] Test Example 3 In vitro pharmacokinetics

[1066] 3.1 In vitro liver microsome stability test

[1067] Liver microsomal incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl2 solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. The sample was added to acetonitrile containing an internal standard for protein precipitation, and the supernatant was prepared and diluted for LC / MS / MS analysis.

[1068] The compound of the present application has good liver microsome stability, and the remaining percentage (T=60 min) in human liver microsomes reaches more than 95%.

[1069] Test Example 4 In vivo pharmacokinetics

[1070] 4.1 Pharmacokinetics in mice

[1071] ICR mice weighing 24-27 g were randomly divided into intravenous injection group (n=6) and oral gavage group (n=3) after acclimation for 3-5 days. The Example solution was injected intravenously at a dose of 0.1 mg / kg and gavage was performed at a dose of 0.1 mg / kg, respectively.

[1072] Blood was collected from the eye socket at 0, 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 2, 4, 8, and 24 h after intravenous injection, and plasma samples were prepared. Blood was collected from the eye socket at 0, 0.25 (15 min), 2, 8, and 24 h after oral gavage, and plasma samples were prepared.

[1073] 30 μL of the plasma sample to be tested and the standard sample were aspirated and added to an acetonitrile solution containing the internal standard for protein precipitation. The resulting supernatant was diluted and used for LC / MS / MS analysis. The relevant pharmacokinetic parameters were calculated using a non-compartmental model, and the results are shown in Table 3.

[1074] Table 3 Pharmacokinetic results of compounds in mice

[1075] 4.2 Pharmacokinetics in rats

[1076] SD rats weighing 200-240 g were randomly divided into groups of 3 after acclimation for 3-5 days, and the Example solution was administered intravenously at a dose of 0.1 mg / kg or orally at a dose of 0.5 mg / kg.

[1077] Blood was collected from the eye socket at 0, 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, and 24 h after intravenous injection to prepare plasma samples. Blood was collected from the eye socket at 0, 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, and 24 h after oral gavage to prepare plasma samples.

[1078] 30 μL of the plasma sample to be tested and the standard curve were aspirated and added to an acetonitrile solution containing the internal standard for protein precipitation. The resulting supernatant was diluted and used for LC / MS / MS analysis. The relevant pharmacokinetic parameters were calculated using a non-compartmental model, and the results are shown in Table 4.

[1079] Table 4 Pharmacokinetic results of compounds in rats

[1080] The compounds of the present invention have good pharmacokinetic properties in vivo, such as a long half-life (T 1 / 2 ), higher in vivo exposure (AUC), higher maximum plasma concentration (C max ), higher bioavailability (F%), etc.

[1081] Experimental Example 5 PARP1 / 2-Tracer Activity Test

[1082] Compounds were tested for inhibition of PARP1 / 2-Tracer enzyme activity using the FP method. First, 100 nL of inhibitor (final concentration: 1% DMSO) was transferred to a 384-well plate (Corning 4514) using an Echo655. Then, 5 μL of PARP1 / 2 (BPS, Cat#80501 / 80502) enzyme solution was added to each well, followed by centrifugation at 1000 RPM for 1 minute at room temperature and a 10-minute reaction. Then, 5 μL of Tracer (ICE, Cat#001315-009) solution was added to each well, followed by centrifugation at 1000 RPM for 1 minute at room temperature and a 60-minute reaction. 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 to 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 obtained using GraphPad Prism software. 50The results of the nonlinear regression curve fitting are shown in Table 5.

[1083] Table 5 Selective activity of compounds against PARP1 / 2 protein

[1084] The compounds of the present application have high selectivity for PARP1 protein.

[1085] Experimental Example 6: Experiment on distribution in rat brain

[1086] SD rats weighing 230-250 g were randomly divided into groups of 9 after acclimation for 3-5 days and orally administered with the example solution at a dose of 2 mg / kg. Blood was collected from the eye sockets at 0.5, 3, and 8 hours to prepare plasma samples. Tissue samples were collected at 0.5, 3, and 8 hours after sacrifice by exsanguination. Brain tissue was removed and homogenized with ice-cold 50% acetonitrile in water at a ratio of 1:3 (w / v) to prepare brain homogenate samples. 30 μL of the plasma and brain homogenate samples, along with the corresponding standard curves, were aspirated and protein precipitated with acetonitrile containing the internal standard to obtain the supernatant, which was diluted and used for LC / MS / MS analysis.

[1087] Table 6 Distribution of compounds in rat brain (AUC (0-8h))

[1088] The results showed that the compound of the present application had a higher brain-blood ratio distribution.

[1089] Test Example 7 In vivo efficacy experiment in mice

[1090] 7.1 Pharmacodynamic Evaluation of MDA-MB-436 in a Subcutaneous Xenograft Model of BRCA1m Human Breast Cancer in Nude Mice

[1091] MDA-MB-436BRCA1m human breast cancer cells were subcutaneously inoculated in the right axilla of SPF female nude mice, with a total of 5 × 10 6 When the average tumor volume reaches 150mm 3 When about 30 seconds, divide the animals into groups.

[1092] The day of grouping was designated Day 0. The compound of the present invention was administered once by gavage on Day 0, followed by daily dosing at a dose of 4 mg / kg in a vehicle ratio of DMSO:PEG400 = 10:90 (v / v). Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. Tumors were removed, weighed, and photographed at the end of the experiment.

[1093] The detection indicators and calculation formulas are as follows:

[1094] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[1095] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[1096] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[1097] Tumor inhibition rate, (1-T / C) (%) = (1-T RTV / C RTV )×100%.

[1098] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[1099] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[1100] The results showed that the tumor inhibition rate of compound 55 was as high as 97% 22 days after administration, showing good in vivo therapeutic effect.

Claims

1. A compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, R is selected from X 1 Selected from CR a , CHR a , N or NR a ; X 2 is selected from CH or N; X 3 is selected from CH or N; R 1 Selected from 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, wherein R 1 Optionally, one or more 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 group substitution; R a Selected from H, halogen or C 1-6 alkyl; or R a With R 1 Connected to each other to form a 5-7 membered heterocycloalkyl, a 5-7 membered cycloalkenyl, a phenyl, a 5-7 membered heterocycloalkenyl or a 5-6 membered heteroaryl; R 2 Selected from 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, said R 2 Optionally, one or more selected from 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 Substitution with a cycloalkyl or 3-8 membered heterocycloalkyl group; R 3 , R 4 and R 5 Each independently selected from 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, the 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 optionally substituted by one or more 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 group substitution; o, p and q are each independently selected from 0, 1 or 2; L is selected from -NH- or -CH2-, wherein L is optionally substituted by one or more selected from 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 group substitution; Ring A is selected from 3-8 membered heterocycloalkyl, wherein the ring A contains, in addition to the N atom connected to L, 1-3 heteroatoms independently selected from N, O or S, and the ring A is optionally substituted by one or more 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 group substitution; Ring B is selected from an aromatic ring or a partially saturated ring; Y 1 , Y 2 and Y 3 are each independently selected from C, CH, N, O or S.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein X 1 Selected from CR a or N; or, X 1 Selected from CHR a or NR a ; Optionally, X 1 Selected from CH, X 2 Selected from N; or, X 1 Select from N, X 2 Selected from CH; Optionally, X 3 Selected from CH; Optionally, X 1 Selected from CH, X 2 Select from N, X 3 is selected from CH; or, X 1 Select from N, X 2 Selected from CH, X 3 Selected from CH; or X 1 Select from N, X 2 Selected from CH, X 3 is selected from CH; or, X 1 , X 2 and X 3 All selected from CH; Optionally, R a is selected from H, F, Cl, methyl, ethyl or propyl; or, R a is selected from H or methyl; or, R a Selected from H or F; Optionally, R a With the R 1 are connected to each other to form a 5-6 membered heterocycloalkyl, a 5-6 membered cycloalkenyl, a phenyl, or a 5-6 membered heterocycloalkenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O or S; or, R a With the R 1 They are connected to each other to form cyclopentenyl, cyclohexenyl, dihydrofuranyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl or thiazolyl.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 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, wherein R 1 Optionally, one or more 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 group substitution; Or, R 1 Selected from halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, the R 1 is optionally substituted by 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, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl or piperazinyl, wherein R 1 Optionally, one or more selected from 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 group substitution; Or, R 1 Selected from chlorine, methyl, ethyl, propyl, trifluoromethyl, 4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is selected from Alternatively, R is selected from and R is replaced by 0, 1, or 2 R 3 replace; Alternatively, R is selected from Optionally, R 3 Selected from 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, the 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 optionally replaced by one or more 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 alkyl)2; or, R 3 is selected from methyl, ethyl, propyl, F or Cl, wherein the methyl, ethyl or propyl is optionally substituted by one or more groups selected from D, F, Cl, -OH or -NH2; or, R 3 is selected from methyl, F or Cl.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 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, said R 2 Optionally, one or more selected from 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 Substitution with a cycloalkyl or 3-8 membered heterocycloalkyl group; Or, R 2 Selected from -NH(C 1-4 Alkyl), -NH(C 3-6 Cycloalkyl) or -NH(3-8 membered heterocycloalkyl), said R 2 Optionally, one or more selected from 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 Substitution with a cycloalkyl or 3-6 membered heterocycloalkyl group; Or, R 2 Selected from -NHCH3, -NHCH(CH3)2, <h2 style=";text-align:left;direction:ltr">-NHCD3, -NHCH2CH3, -NHCH2CF3,<h2 style=";text-align:left;direction:ltr"> 6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from 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, the 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 optionally replaced by one or more 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 alkyl)2; or, R 4 is selected from methyl, ethyl, propyl, F or Cl, wherein the methyl, ethyl or propyl is optionally substituted by one or more groups selected from D, F, Cl, -OH or -NH2; Optionally, R 5 Selected from 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, the 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 optionally replaced by one or more 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 alkyl)2; or, R 5 is selected from methyl, ethyl, propyl, F or Cl, wherein the methyl, ethyl or propyl is optionally substituted by one or more groups selected from D, F, Cl, -OH or -NH2.

7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein 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 2; Optionally, q is selected from 0 or 1; or, q is selected from 0.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is selected from -NH- or -CH2-, and the L is optionally substituted with one or more groups selected from methyl, D or F; Alternatively, L is selected from -CH2-.

9. The compound according to any one of claims 1 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from a 3-6 membered heterocycloalkyl group, and in addition to the N atom connected to L, the ring A optionally contains 1-3 heteroatoms independently selected from N or O, and the ring A is optionally substituted by one or more 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 is optionally substituted by one or more 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 group substitution; Alternatively, ring A is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, diazetidinyl, imidazolinyl, piperazinyl, oxazolinyl or morpholinyl, and the ring A is optionally substituted by one or more 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 alkyl)2; or, the ring A is optionally substituted with one or more -C 1-4 Alkyl group substitution; Or the ring A is optionally selected from one or more of -C 1-3 Alkylene-OC 1-4 Alkyl radical substitution; Alternatively, ring A is selected from The ring A is optionally substituted by one or more selected from -OH or -C 1-4 Alternatively, the ring A is optionally substituted with one or more selected from -OH, -C 1-4 Alkyl or -C 1-3 Alkylene-OC 1-4 Alkyl radical substitution; Alternatively, ring A is selected from in, * indicates that the nitrogen atom with an * is connected to L on one side and to the structural fragment on the other side. are connected.

10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a 5-membered aromatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; Alternatively, 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; Alternatively, ring B is selected from Alternatively, ring B is selected from 11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 and Y 3 At least 2 of them are selected from N, O or S; or, Y 1 and Y 2 Selected from N, Y 3 Selected from CH; or, Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from S; Or, Y 1 Selected from S, Y 2 Selected from C, Y 3 Selected from CH.

12. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II) is selected from the compound of formula (IIA), the compound of formula (IIB), the compound of formula (IIB-1), the compound of formula (IIB-2), or the compound of formula (IIB-3), its stereoisomer or pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , Y 2 , Y 3 , o, p and q are defined as in any one of claims 1-11; t is selected from 0, 1 or 2.

13. The following compound, its stereoisomer or its pharmaceutically acceptable salt:

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

15. Use of the compound according to any one of claims 1 to 13, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a disease associated with PARP1; optionally, the disease associated with PARP1 is selected from a tumor or a cancer; optionally, the cancer is selected from breast cancer, ovarian cancer, colon cancer, pancreatic cancer or prostate cancer.

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