GSPT1 degrader compound, pharmaceutical composition containing same, and use thereof

Abstract

Provided in the present invention is a new GSPT1 protein modulator. The new GSPT1 modulator of the present invention has a high affinity and can degrade GSPT1, and therefore has the potential for preventing and treating GSPT1-associated diseases, disorders, or conditions.

Description

GSPT1 degrading compounds, pharmaceutical compositions containing them, and their uses Technical Field

[0001] This disclosure relates to a compound having the ability to regulate or degrade GSPT1, pharmaceutical compositions comprising the compound, and uses thereof. Background Technology

[0002] The MYC gene is an important proto-oncogene, acting as a transcription factor to regulate the expression of downstream target genes, thereby regulating various biological processes such as cell proliferation, differentiation, metabolism, and apoptosis. Approximately 15% of genes in the human genome are transcribed and regulated by MYC. More than 70% of tumors exhibit MYC mutations or altered expression levels, and at least one-third of cancer deaths are attributable to MYC activation. However, MYC proteins are difficult to target due to their disordered structure and nuclear localization, making them a recognized challenging drug target; currently, no drugs targeting MYC have been approved for marketing. Therefore, there is a significant unmet clinical need for the treatment of MYC-driven tumors.

[0003] GSPT1 encodes eukaryotic peptide chain releasing factor 3 (eRF3), a translation termination factor that mediates protein translation and mRNA degradation, thereby regulating downstream gene expression. GSPT1 participates in various biological processes, including regulating cell proliferation, migration, cell cycle, and apoptosis. Recent studies have shown that GSPT1 is closely associated with the development and progression of various common malignancies, particularly MYC-driven tumors. GSPT1 high expression and MYC high expression tumor types highly overlap, and their expression levels are positively correlated in most tumors. In vitro and in vivo studies have shown that GSPT1 degradation affects protein synthesis and interferes with the expression of MYC and its downstream target genes. Furthermore, in several MYC-overexpressing PDX models, GSPT1 degradation significantly inhibited tumor growth, suggesting that GSPT1 degradation has a potential therapeutic effect on MYC-driven tumors. Summary of the Invention

[0004] This disclosure provides novel GSPT1 protein modulators. These novel GSPT1 modulators have high affinity and are capable of degrading GSPT1, thus possessing the potential to prevent and treat diseases, disorders, or conditions related to GSPT1.

[0005] In a first aspect, this disclosure provides compounds of formula (I) as defined below, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or prodrugs thereof:

[0006] in,

[0007] Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-11 membered carbon rings, and 4-11 membered heterocycles;

[0008] M is selected from CH or N.

[0009] X is selected from: halogen, -NR 3a R4, -NR 3a COR4, -OR3, -C 1-4 Alkyl-OR3; optionally selected from halogen, hydroxyl, CN, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 C substituents of alkyl)2 1-6 Alkyl groups; and optionally selected from C 1-4 Alkyl, halogen, hydroxyl, CN, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 5-6 membered heterocyclic groups substituted with alkyl groups;

[0010] W is selected from single bond, -NR 1a -、-CR a R b -and-O-;

[0011] L0 is selected from single bond, -NR 1a -、-CR a R b -and-O-;

[0012] L1 is selected from -NR 1a -、-CR a R b -, -O- and 3-6-membered heterocyclic rings;

[0013] L2 is selected from single bond, -NR 1a -、-CR a R b -and-O-;

[0014] R a and R b Each is independently selected from hydrogen, amino, halogen, oxo, cyano, and C. 1～3 alkyl and cyclopropyl, wherein the C 1～3 The alkyl or cyclopropyl groups are optionally substituted with halogens 1 to 3 times;

[0015] R 1a R 2a R 2b and R 3a Each is independently selected from H and C. 1～3 alkyl and cyclopropyl, wherein the C 1～3 The alkyl or cyclopropyl groups are optionally substituted with halogens 1 to 3 times;

[0016] Each R1 is independently selected from halogen, hydroxyl, -NR 2a R2b , cyano, C 1～6 Alkyl, C 1～6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group and C 1～6 Halogenated alkyl groups;

[0017] Each R2 is independently selected from halogen, hydroxyl, -NR 2a R 2b , cyano, oxo, C 1～6 Alkyl, C 2～6 alkenyl, C 2～6 alkynyl group, C 1～6 Alkyl group, -SO2NR 2a R 2b -SONR 2a R 2b -C(O)R 2a The C mentioned therein 1～6 Alkyl, C 2～6 alkenyl, C 2～6 alkynyl or C 1～6 The alkoxy group is optionally substituted by a halogen or a hydroxyl group 1 to 3 times;

[0018] R3 is selected from C 1～6 Alkyl groups and 5-6 membered heterocyclic groups, wherein the C 1～6 Alkyl or 5-6 membered heterocyclic groups are optionally surrounded by halogen, hydroxyl, CN, C 1～4 Alkoxy, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 Alkyl)2-substituted 1 to 3 times;

[0019] R4 is selected from R x Optional substitution of C 1 to 3 times 1～6 Alkyl groups, and R5, -(CR a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl and C 2～6 Alkyne group, wherein R5, -(CR a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl or C 2～6 The alkynyl group is optionally replaced by R x Replace 1 to 3 times;

[0020] R5 is selected from 3- to 10-membered carbon rings, 4- to 10-membered heterocycles, 6- to 10-membered aromatic rings, and 5- to 10-membered aromatic heterocycles, wherein the 3- to 10-membered carbon rings, 4- to 10-membered heterocycles, 6- to 10-membered aromatic rings, and 5- to 10-membered aromatic heterocycles are selected from monocyclic, fused, fused, and spirocyclic rings, and optionally R5 is selected from monocyclic, fused, fused, and spirocyclic rings. x Replace 1 to 3 times;

[0021] n is selected from 0, 1, 2, or 3;

[0022] m is selected from 0, 1, 2, or 3;

[0023] p is selected from 1, 2, or 3;

[0024] q is selected from 0, 1, or 2;

[0025] Dashed lines in ring B Indicates whether ring B exists or not;

[0026] When ring B is present, ring B and ring C together form an 8-12 fused heterocycle, in which:

[0027] When the heteroatom in the fused heterocycle is only N, the fused heterocycle is as well as

[0028] When ring B and ring C are formed together At that time, structural unit for Where end a and Partially connected, with end b connected to ring A; and X is -OR3 or -NR. 3a R4;

[0029] When ring B and ring C are formed together When X is -OR3 or -NR3R4;

[0030] When ring B is absent, ring C is a benzene ring, and X is selected from -NR. 3a R4;

[0031] R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, oxo, CN, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1～6 Alkyl, C 1～6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, and 6-10 membered aryl, wherein the C 1～6 Alkyl, C 1～6Alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally selected from halogen, cyano, hydroxyl, -NH2, -NH(C) under the condition that the valence allows. 1-4 alkyl) and -N(C) 1-4 Alkyl)2, C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Halogenated alkyl groups and C 1～3 The substituents of the haloalkoxy group are substituted 1 to 3 times.

[0032] In some embodiments, the compound of formula (I) is not

[0033] In some implementations, when ring B and ring C are formed together When the compound of formula (I) has the structure of formula (I'):

[0034] In some embodiments, ring A is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzopyranyl, dihydrobenzothiophenyl, dihydrobenzopyrroleyl, dihydrofuranopyridyl, dihydrothiophenopyridyl, dihydropyranopyridyl, dihydrothiophenopyridyl, dihydrothiophenopyridyl, and dihydropyrroleopyridyl.

[0035] In some implementations, ring A is selected from...

[0036] In some implementations, ring A is selected from...

[0037] In some implementations, X is selected from: halogen, -NR 3a R4, -NR 3a COR4, -OR3, -C 1-4 Alkyl-OR3, 5-6 membered heterocyclic alkyl; and optionally selected from halogen, hydroxyl, CN, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 C substituents of alkyl)2 1-4 alkyl.

[0038] In some implementations, X is selected from: F, Cl, Br, -NR 3a R4, -NR 3a COR4, -OR3, -C 1-4Alkyl-OR3, 5-6 membered heterocyclic alkyl; and optionally selected from F, Cl, Br, hydroxyl, CN, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 C substituents of alkyl)2 1-4 alkyl.

[0039] In some implementations, X is selected from: F, Cl, -NR 3a R4, -NR 3a COR4, -OR3, -C 1-4 Alkyl-OR3, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, oxazolyl, thiazolyl, piperidinyl, piperazine, hexahydropyrimidinyl, and morpholinyl; and optionally selected from hydroxyl, -NH2, -NH(C 1-4 alkyl) and -N(C) 1-4 C substituents of alkyl)2 1-4 alkyl.

[0040] In some implementation schemes, R 3a Selected from H and C 1～3 Alkyl group. In some embodiments, R 3a For H.

[0041] In some implementations, R3 is selected from C 1～4 Alkyl and 5-6 membered heterocyclic alkyl, wherein the C 1～4 Alkyl or 5-6 membered heterocyclic alkyl groups optionally surrounded by F, Cl, hydroxyl, CN, C 1～4 Alkoxy, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 Alkyl)2-substituted 1 to 3 times.

[0042] In some embodiments, R3 is selected from: methyl, ethyl, propyl, or butyl, optionally substituted 1 to 3 times with F, Cl, hydroxyl, CN, methoxy, ethoxy, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, or -N(CH2CH3)2; and tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, oxazolyl, thiazolyl, piperidinyl, piperazine, hexahydropyrimidinyl, and morpholinyl.

[0043] In some embodiments, R3 is selected from: methyl, ethyl, propyl, or butyl, optionally substituted 1 to 3 times with F, Cl, hydroxyl, CN, methoxy, ethoxy, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, or -N(CH2CH3)2; and pyrrolidinyl, piperidinyl, piperazineyl, and morpholinyl.

[0044] In some embodiments, the R3 is selected from -CN, -CH3, -CF3, -CH2CH3, -CH(CH3)CH3, -CClF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2, -CH(CH2F)(CHF2), -CH2CH2OH, -CH2CH2NHCH3, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

[0045] In some embodiments, R3 is selected from -CF3, -CF2Cl, -CH2CH2OCF3, -CH2CH2OH, -CH2CH2NHCH3 and piperidinyl.

[0046] In some implementations, R4 is selected from: the R x Optional substitution of C 1 to 3 times 1～4 Alkyl group; R5, and -CH2-R5, wherein the R5 is optionally replaced by R x Replace 1 to 3 times.

[0047] In some implementations, R4 is selected from: the R x Optional substitution of methyl, ethyl, and isopropyl groups 1 to 3 times; R5, and -CH2-R5, wherein the R5 is optionally replaced by R x Replace 1 to 3 times.

[0048] In some embodiments, R5 is selected from 3- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, and phenyl, wherein the 3- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, and phenyl are optionally replaced by R x Replace 1 to 3 times.

[0049] In some embodiments, R5 is selected from 3- to 6-membered cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocycloalkyl are optionally replaced by R x Replace 1 to 3 times.

[0050] In some implementations, R5 is optionally R x It can be replaced by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, oxazolyl, thiazolyl, piperidinyl, piperazine, hexahydropyrimidinyl, or morpholinyl once or three times.

[0051] In some implementations, R5 is optionally R xIt can replace cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl or tetrahydrothiophenyl 1 to 3 times.

[0052] In some implementations, R5 is cyclohexyl or

[0053] In some implementations, the -CH2-R5 is selected from...

[0054] In some implementation schemes, R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, CN, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl) 2, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein the 3-7 membered cycloalkyl, 4-7 membered heterocycloyl, 6-10 membered aryl and 5-10 membered heteroaryl are optionally selected from halogen, cyano, hydroxyl, -NH2, -NH(C) under the condition that the valence allows. 1-4 alkyl) and -N(C) 1-4 The alkyl group is substituted 1 to 3 times.

[0055] In some implementation schemes, R x Each time it appears, it is independently selected from F, Cl, hydroxyl, CN, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, and phenyl, wherein the 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, and phenyl are optionally substituted 1 to 3 times by substituents selected from F, Cl, cyano, hydroxyl, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -N(CH2CH3)2, subject to valence allowance.

[0056] In some implementation schemes, R x Each time it appears, it is independently selected from: F, Cl, hydroxyl, CN, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2; and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, oxazolyl, thiazolyl, piperidinyl, piperazine, hexahydropyrimidinyl, morpholinyl, and phenyl.

[0057] In some implementation schemes, R xEach time it appears, it is independently selected from: F, Cl, hydroxyl, CN, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2; and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, and phenyl, each optionally substituted 1 to 3 times by a substituent selected from F, Cl, cyano, hydroxyl, and -NH2.

[0058] In some implementation schemes, R x Each time it appears, it is independently selected from: F, Cl, hydroxyl, CN, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2; and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl and phenyl, each optionally substituted 1 to 3 times by a substituent selected from F, Cl and hydroxyl.

[0059] In some embodiments, R4 is selected from: methyl, ethyl, -CH2CH3, -CH2OH, -CF3, -CH2CF3,

[0060] In some implementations, X is selected from: F, Cl, methyl, ethyl, propyl,

[0061] For the ring B and ring C together form Compounds of formula (I) or of formula (I'), in some embodiments, where X is -OR3 and R3 is C 1～4 Alkoxy substitution 1 to 3 times C 1～6 Alkyl, and the structural unit for (where end a and When the parts are partially connected, and end b is connected to ring A, then n is not 0 and / or M is not CH.

[0062] In some implementation schemes, Part of

[0063] In a preferred embodiment, Part of:

[0064] In a preferred embodiment, Part of

[0065] In a preferred embodiment, Part of

[0066] In some implementation schemes, R 1a R 2a R 2b and R 3a Each is independently selected from H, methyl, and ethyl, preferably H or methyl.

[0067] In some implementations, each R2 is independently selected from F, Cl, Br, -OH, -CN, =O, C 1～4 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group and C 1～4 Alkoxy, wherein the C 1～4 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group and C 1～4 The alkoxy group may be optionally substituted by F, Cl, Br or hydroxyl group 1 to 3 times.

[0068] In some embodiments, each R2 is independently selected from -F, -Cl, -Br, -OH, -CN, =O, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F, vinyl, allyl, prop-1-ynyl, and propyne.

[0069] In some embodiments, each R2 is independently selected from -F, -Cl, -OH, -CN, -CH3, -CH2CH3, -OCH3, vinyl, allyl, prop-1-ynyl, and propyne.

[0070] In some implementations, m is 0, 1, or 2.

[0071] In some implementation schemes, R a and R b Selected independently from hydrogen and C 1-2 Alkyl groups and halogens. In some embodiments, R a and R b Each of the following is independently selected from hydrogen, methyl, F, and Cl.

[0072] In some implementations, W is selected from single bonds, -CH2-, -CF2-, -NH-, and -O-.

[0073] In some embodiments, the L0 is selected from single bond, -CH2-, -NH- and -O-, preferably single bond or -NH-.

[0074] In some implementations, L1 is selected from -NR1a -、-CR a R b -, -O- and 4-6 membered heterocyclic alkyl groups. In some embodiments, the L1 is selected from -CH2-, -NH-, -N(CH3)-, -CF2-, -CHF-, -C(CH3)2-, -CH(CH3)-, -O-, aziridine, tetrahydrofuranyl and piperidinyl.

[0075] In some embodiments, L1 is selected from -CH2-, -NH-, -N(CH3)-, -CF2-, -CHF-, -C(CH3)2-, -CH(CH3)-, -O-,

[0076] In some embodiments, the L2 is selected from single bond, -CH2-, -NH-, -N(CH3)-, -CH(CH3)-, preferably single bond or -NH-.

[0077] In some implementation schemes, the structural unit Selected from Where end a and Partially connected, while end b is connected to ring A.

[0078] In some implementation schemes, the structural unit Selected from and Where end a and Partially connected, while end b is connected to ring A.

[0079] In some implementations, the Not for Where end a and Partially connected, while end b is connected to ring A.

[0080] In some embodiments of compounds according to formula (I'), the structural unit Selected from Preferred

[0081] In some implementations, each R1 is independently selected from halogen, hydroxyl, cyano, -NH2, C 1～4 Alkyl, C 1～4 Alkoxy and C 1～4 Halogenated alkyl groups.

[0082] In some implementations, each R1 is independently selected from -F, -Cl, -Br, -OH, -CN, -NH2, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F, -OCH2CH3, and -CH2CHF2.

[0083] In some implementations, each R1 is independently selected from -F, -Cl, -CN, -CH3, -CF3, and -OCH3.

[0084] In some implementations, q is 0, 1, or 2.

[0085] In some implementations, ring B exists, and Partially selected from:

[0086] In some implementations, when ring B is present, and the Part of When the compound of formula (I) is the compound of formula (I'), then the compound of formula (I) is the compound of formula (I').

[0087] In some implementations, ring B exists, and Partially selected from:

[0088] In some implementations, ring B does not exist, and Part of

[0089] In some implementations, M is CH. In some implementations, M is N.

[0090] In some implementations, q is 0. In some implementations, q is 1. In some implementations, q is 2.

[0091] In some implementation schemes, Partially selected from: In some implementation schemes, Partially selected from:

[0092] In some embodiments, this disclosure provides compounds of formula (I) or (I') as described above, which are compounds of formula (I-1):

[0093] In some embodiments, in the compound of formula (I') or the compound of formula (I-1), ring A is selected from... In some implementation schemes, Part of Preferred As mentioned above.

[0094] In some embodiments, in the compound of formula (I') or the compound of formula (I-1), X is selected from halogens, -NR 3a R4, -NR 3a COR4, -OR3, unsubstituted 5-6 membered heterocyclic groups, or -C 1-4 Alkyl-OR3. In some embodiments, X is selected from halogens, -NR 3a R4, -OR3, or methyl. In some embodiments, X is selected from halogens, -NR... 3a R4, -OR3, or methyl. In a preferred embodiment, X is selected as -NHR4, and R4 is selected as methyl, ethyl, and isopropyl, selectively substituted 1 to 3 times with F, Cl, hydroxyl, CN, or -NH2, preferably -CF3, -CH2CF3, or...

[0095] In some implementation schemes, Part of

[0096] In some embodiments, in the compound of formula (I') or the compound of formula (I-1), the structural unit Selected from Where end a and Partially connected, with end b connected to ring A. In some embodiments, the structural unit... Selected from In a preferred embodiment, the structural unit for

[0097] In some embodiments, in the compounds of formula (I') or formula (I-1), R4 is selected from -CH3, -CH2CH3, -CH2CF3, -CH(CH3)CF3, -CH2OH, -CH2CH2NHCH3, In some implementations, R4 is selected from -CH2CF3,

[0098] In some embodiments, the compound of formula (I-1) is a compound of formula (I-1-1):

[0099] In a preferred embodiment, in the compound of formula (I-1-1), Part of As stated above;

[0100] In a more preferred embodiment, in the compound of formula (I-1-1), X is -NHR4;

[0101] The structural unit for as well as

[0102] The R4 is -CH2CF3.

[0103] In some embodiments, this disclosure provides compounds of formula (I) as described above, wherein the compounds of formula (I) are compounds of formula (I-2):

[0104] In some embodiments, in the compounds of formula (I-2), ring A is selected from 6- to 10-membered aromatic rings and 5- to 10-membered aromatic heterocycles. In some embodiments, ring A is... In some implementation schemes, Part of As mentioned above.

[0105] In some embodiments, in the compounds of formula (I-2), preferably, X is a halogen or -NR. 3a R4 or -OR3. In some implementations, R3 is -CF3 or -CF2Cl. In some implementations, R... 3a For H. In some implementations, R4 is selected from -CH2CF3,

[0106] In some embodiments, in compounds of formula (I-2), the structural unit for

[0107] In some embodiments, n is 2 in the compound of formula (I-2).

[0108] In some embodiments, the compound of formula (I-2) is a compound of formula (I-2-1):

[0109] In some embodiments, in compounds of formula (I-2) or (I-2-1), R1 is a halogen, preferably F or Cl, more preferably F.

[0110] In some embodiments, this disclosure provides compounds of formula (I) as described above, wherein the compounds of formula (I) are compounds of formula (I-3):

[0111] In some embodiments, X is -OR3 in the compound of formula (I-3). In some embodiments, X is...

[0112] In some embodiments, in the compound of formula (I-3), ring A is In some implementation schemes, Part of As mentioned above.

[0113] In some embodiments, in compounds of formula (I-3), the structural unit for

[0114] In some embodiments, this disclosure provides compounds of formula (I) as described above, wherein the compounds of formula (I) are compounds of formula (I-4):

[0115] In some embodiments, in the compounds of formula (I-4), Part of As described above. In some implementations, X is selected from -NR. 3a R4 or -OR3. In some implementations, R 3a For H. In some implementations, R4 is selected from -CH2CF3, In some implementations, R3 is selected from -C 1-4 Alkyl-C 1～4 Alkoxy groups, preferably -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3.

[0116] In some embodiments, in compounds of formula (I-4), the structural unit for

[0117] In some embodiments, this disclosure provides compounds of formula (I) as described above, wherein the compounds of formula (I) are compounds of formulas (I-5):

[0118] In some embodiments, in the compound of formula (I-5), Part of As described above. In some implementations, X is -NR. 3a R4 or -OR3. In some implementations, R3 is -CF3 or -CF2Cl. In some implementations, R... 3a For H. In some implementations, R4 is -CH2CF3.

[0119] In some embodiments, in compounds of formula (I-5), the structural unit for

[0120] In a second aspect, this disclosure provides compounds of formula (I) as defined below, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or prodrugs thereof:

[0121] in,

[0122] Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-11 membered carbon rings, and 4-11 membered heterocycles;

[0123] M is selected from CH or N.

[0124] X is selected from halogens, NR3R4, NR3COR4, OR3, 5-6 membered heterocyclic groups, or C. 1-4 OR3;

[0125] W is selected from single bond, -NR a -、-CR a R b -、-O-;

[0126] L0 is selected from single bond, -NR a -、-CR a R b -、-O-;

[0127] L1 is selected from -NR a -、-CR a R b -、-O-、3-6-membered heterocyclic rings;

[0128] L2 is selected from single bond, -NR a -、-CR a R b -、-O-;

[0129] R a and R bEach is independently selected from hydrogen, amino, halogen, oxo, cyano, and C. 1～3 alkyl, cyclopropyl, wherein the C 1～3 Alkyl, cyclopropyl, and optionally substituted with halogens 1 to 3 times;

[0130] R1 is independently selected from halogens, hydroxyl groups, and NR. a R b , cyano, C 1～6 Alkyl, C 1～6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1～6 Halogenated alkyl groups;

[0131] R2 is independently selected from halogens, hydroxyl groups, and NR. a R b , cyano, oxo, C 1～6 Alkyl, C 1～6 Alkoxy, SO2NR a R b SONR a R b C(O)R a The C mentioned therein 1～6 Alkyl, C 1～6 The alkoxy group may optionally be replaced by a halogen or a hydroxyl group 1 to 3 times;

[0132] R3 is selected from hydrogen, C 1～6 Alkyl, C 1～6 alkoxy, 5-6 membered heterocyclic group, wherein the C 1～6 Alkyl, C 1～6 The alkoxy group and the 5-6 membered heterocyclic group may optionally be substituted 1 to 3 times with halogen, hydroxyl, or alkylamino groups;

[0133] R4 is selected from R x Optional substitution of C 1 to 3 times 1～6 Alkyl groups and R5, -(CR) a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl, C 2～6 Alkyne group, namely R5, -(CR a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl, C 2～6 The alkynyl group can be optionally replaced by R x Replace 1 to 3 times;

[0134] R5 is selected from 3-10 membered carbon rings, 4-10 membered heterocyclic rings, 6-10 membered aromatic rings, and 5-10 membered aromatic heterocyclic rings. The R5 ring can be a monocyclic, fused, fused, or spirocyclic ring. The R5 ring can optionally be replaced by R... x Replace 1 to 3 times;

[0135] n is selected from 0, 1, 2, or 3;

[0136] m is selected from 0, 1, 2, or 3;

[0137] p is selected from 1, 2, or 3;

[0138] q is selected from 0, 1, or 2;

[0139] The dashed line indicates whether ring B exists or not;

[0140] When ring B is present, ring B and ring C together form an 8-12 member fused heterocycle, in which...

[0141] When the heteroatom in the fused heterocycle is selected only from N, ring B and ring C together form

[0142] When ring B and ring C are When X is OR3 or NR3R4;

[0143] When ring B is absent, ring C is a benzene ring, and X is selected from NR3R4;

[0144] R x Independently selected from hydrogen, halogen, hydroxyl, oxo, CN, C 1～6 Alkyl, C 1～6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, 6-10 membered aryl, wherein R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be derived from halogens, cyano groups, hydroxyl groups, or C-terminal groups, provided that the valence allows. 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl, C 1～3 The alkyl halide is substituted 1 to 3 times.

[0145] In some embodiments, the compound of formula (I) is not

[0146] In some implementations, when ring B and ring C are formed together When the compound of formula (I) has the structure of formula (I'):

[0147] In some embodiments, X is selected from halogens, NR3R4, OR3, or methyl; R3 is selected from hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the C 1～6 Alkyl, C 1～6 The alkoxy group can optionally be substituted by a halogen 1 to 3 times.

[0148] In some embodiments, ring A is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, and ring A may optionally be substituted by R2 m times.

[0149] In some implementations, ring A is selected from... The ring A can be optionally replaced by R2 m times.

[0150] In some implementations, ring A is selected from... The ring A can be optionally replaced by R2 m times.

[0151] In some implementations, W is selected from -CH2-, -NH-, and -O-.

[0152] In some implementations, L0 is selected from single bonds, -CH2-, -NH-, -O-, with single bonds being preferred.

[0153] In some embodiments, L1 is selected from -CH2-, -NH-, -N(CH3)-, -CF2-, -CHF-, -C(CH3)2-, -CH(CH3)-, -O-,

[0154] In some implementations, the L2 is selected from -CH2-, -NH-, -N(CH3)-, and -CH(CH3)-.

[0155] In some implementation schemes, the structural unit Selected from Among them, end a and Connected, end b is connected to ring A.

[0156] In some embodiments, the R3 is selected from -H, -CN, -CH3, -CF3, -CH2CH3, -CH(CH3)CH3, -CClF2, -CH2CH2OCH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2, -CH(CH2F)(CHF2).

[0157] In some embodiments, R4 is selected from R5, -CH2-R5, and R4 may optionally be replaced by R x Replace 1 to 3 times.

[0158] In some embodiments, the -CH2-R5 is selected from -CH2CF3,

[0159] In some implementations, R5 is selected from -CF3,

[0160] In some embodiments, the R4 is selected from -CH3, -CH2CH3, -CH2CF3, -CH(CH3)CF3, -CH2OH, -CH2CH2NHCH3,

[0161] In some embodiments, the R4 is selected from -CH2CF3,

[0162] In some implementations, R1 is independently selected from -F, -Cl, -Br, -OH, -CN, -NH2, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F, -OCH2CH3, and -CH2CHF2.

[0163] In some implementations, R2 is independently selected from -F, -Cl, -Br, -OH, -CN, =O, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, and -CH2CH2F.

[0164] In some embodiments, this disclosure provides compounds of formula (I) as described above, wherein the compounds of formula (I) are compounds of formula (I-1):

[0165] The rest of the definitions are the same as before.

[0166] In a further preferred embodiment, in the compound of formula (I-1), X is selected from halogens, NR3R4, NR3COR4, OR3, 5-6 membered heterocyclic groups, or C 1-4 OR3;

[0167] Preferably, ring A is selected from...

[0168] The structural unit Selected from

[0169] The R4 is selected from -CH3, -CH2CH3, -CH2CF3, -CH(CH3)CF3, -CH2OH, -CH2CH2NHCH3,

[0170] In a further preferred embodiment, in the compound of formula (I-1), X is selected from halogens, NR3R4, OR3, or methyl.

[0171] Preferably, ring A is selected from... More

[0172] The structural unit Selected from Preferred

[0173] The R4 is selected from -CH2CF3, Preferred -CH2CF3.

[0174] In a further preferred embodiment, this disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-1-1):

[0175] The rest of the definitions are the same as before.

[0176] In some embodiments, this disclosure provides compounds of formula (I) as described above, wherein the compounds of formula (I) are compounds of formula (I-2):

[0177] in,

[0178] Ring A is selected from 6- to 10-membered aromatic rings and 5- to 10-membered aromatic heterocycles, and the rest are defined as above.

[0179] In a further preferred embodiment, in the compound of formula (I-2), ring A is selected from 6- to 10-membered aromatic rings and 5- to 10-membered aromatic heterocycles.

[0180] The rest of the definitions are the same as before;

[0181] Preferably, X is selected from NR3R4;

[0182] More preferably, the ring A is selected from...

[0183] The structural unit Selected from

[0184] The R4 is selected from -CH2CF3,

[0185] In some embodiments, this disclosure provides compounds of formula (I) as described above, wherein the compounds of formula (I) are compounds of formula (I-3):

[0186] The rest of the definitions are the same as before.

[0187] In a further preferred embodiment, in the compound of formula (I-3), X is selected from OR3;

[0188] More preferably, the ring A is selected from...

[0189] The structural unit Selected from

[0190] The R4 is selected from -CH2CF3,

[0191] In some embodiments, this disclosure provides compounds of formula (I) as described above, wherein the compounds of formula (I) are compounds of formula (I-4):

[0192] The rest of the definitions are the same as before.

[0193] In a further preferred embodiment, in the compounds of formula (I-4), X is selected from NR3R4 or OR3;

[0194] More preferably, the ring A is selected from...

[0195] The structural unit Selected from

[0196] The R4 is selected from -CH2CF3.

[0197] In some embodiments, this disclosure provides compounds of formula (I) as described above, wherein the compounds of formula (I) are compounds of formulas (I-5):

[0198] The rest of the definitions are the same as before.

[0199] In a further preferred embodiment, in the compounds of formula (I-5), X is selected from NR3R4 or OR3;

[0200] More preferably, the ring A is selected from...

[0201] The structural unit Selected from

[0202] The R4 is selected from -CH2CF3.

[0203] The embodiments described above according to the first aspect and the embodiments described above according to the second aspect may overlap in scope. One or more embodiments described above according to the first aspect have the same scope as one or more embodiments described above according to the second aspect.

[0204] This disclosure covers compounds obtained by any combination of the various embodiments. The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds are selected from:

[0205] definition

[0206] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0207] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps (i.e., these terms also cover the terms “consistently made up of” and “comprises of”).

[0208] As used in this article, the term "alkane" refers to a straight-chain or branched saturated aliphatic hydrocarbon.

[0209] As used herein, the term "alkyl" refers to a straight-chain or branched monovalent saturated aliphatic hydrocarbon, which can be considered as a group obtained by losing one hydrogen atom from an alkane. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-8 "Alkyl" refers to a straight-chain or branched group with 1 to 8 carbon atoms, including "C". 1-6 Alkyl", C 2-6 Alkyl", C 2-5 Alkyl", C 1-4"alkyl" and "C" 1-2 Alkyl group. "C" 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. The alkyl group is optionally substituted with one or more (such as one to three) suitable substituents such as halogens (in which case the group is called "haloalkyl", for example CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C" 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0210] As used herein, the term "alkylene" refers to a straight-chain or branched divalent saturated aliphatic hydrocarbon. In some embodiments, the alkylene has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0211] As used herein, the term "alkenyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2-8 carbon atoms ("C..."). 2-8 Alkenyl), for example, 2-6 carbon atoms ("C") 2-6 Alkenyl group or 2-4 carbon atoms ("C") 2-4 The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side) form, pure Z (iso-side) form, or any mixture thereof.

[0212] As used herein, the term "alkynyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, 6, 7, or 8 carbon atoms ("C"). 2-8 The alkynyl group (e.g., ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc.) may optionally be substituted by one or more (e.g., 1 to 3) identical or different substituents.

[0213] As used in this article, the term "fusion" means that two or more ring structures share two adjacent atoms with each other.

[0214] As used herein, the terms “cycloalkyl” and “cycloalkylene” refer to saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl), or bicyclic, such as… The cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3 to 8, such as 3 to 7, 3 to 6, 4 to 6, or 5 to 6. The cycloalkyl and cycloalkylene groups are optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., methyl or halogen), such as methyl-substituted cyclopropyl.

[0215] As used herein, the terms “heterocyclic,” “heterocyclic,” and “hemiecyclic” refer to a saturated (i.e., “hemiecyclic alkyl” and “hemiecyclic alkyl”) or partially unsaturated (e.g., having one or more double bonds within the ring, i.e., “hemiecyclic alkenyl” and “hemiecyclic alkenyl”) monovalent monocyclic or bicyclic fused cyclic structure having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(=O), S(=O)2, and NR’, wherein R’ is a hydrogen atom or C 1-6 Alkyl or halogenated -C 1-6 Alkyl group. The heterocyclic group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom (if present). In particular, a 3-10 membered heterocyclic group is a group having 3-10 (e.g., 3-8, 3-7, 3-6, 4-6, or 5-6) carbon atoms and heteroatoms in the ring. The heterocyclic group is optionally substituented by one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, OH, NH2, oxo (=O), C). 1-6 Alkyl, C 1-6 (Halogenated alkyl) substitution. Examples that can be listed include, but are not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolyl, pyrrolidone, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazine, morpholinyl, dithianyl, thiomorpholinyl, piperazine, trithianyl, azetidinyl, dihydropyrrolyl, dihydroimidazolyl, and azetidinyl.

[0216] As used herein, the term "aryl" refers to a fully carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C 6-14"Aryl" refers to an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituented with one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0217] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from N, O, S, and S(O)₂. One or more ring carbon atoms in the heteroaryl group may be replaced by C(O). Heteroaryl groups may be benzofused.

[0218] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0219] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0220] If a group is described as “optionally substituted” or “optionally substituted”, then the group may be: (1) unsubstituted or (2) substituted. If the carbon of the group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0221] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0222] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0223] When a substituent is shown to be a bond that passes through the ring and connects two atoms (“floating bond”), such a substituent may be bonded to any cyclic atom in the substituted ring, unless otherwise stated. In cases where a substituted hydrogen atom is shown to be carried by a substituted ring member, the substituted hydrogen atom is substantially substituted (i.e., not present) when the floating bond is bonded to that substituted ring member.

[0224] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium (D, ...). 2 H), tritium (T), 3 H); carbon isotopes (e.g., ... 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6. In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

[0225] The term "stereoisomer" refers to isomers formed due to at least one asymmetric center, having the same chemical composition but different spatial arrangements of atoms or groups. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can occur. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0226] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0227] "Enantiomers" refer to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0228] The term "chirality" refers to molecules that have mirror pairs that are not overlapping, while the term "chirality" refers to molecules that can overlap on their mirror pairs.

[0229] The compounds of the present invention can be prepared in racemic form, or a single enantiomer can be prepared by enantioselective synthesis or by resolution.

[0230] As used herein, the terms “cis-trans isomers” or “geometric isomers” arise from the fact that the single bonds of double or cyclic carbon atoms cannot rotate freely. The compounds presented herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers and their corresponding mixtures.

[0231] Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0232] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the various derivative forms of the compounds described above.

[0233] As used in this article, waveform lines This represents the connection point between a substituent and another group.

[0234] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components constituting the formulation and / or the mammals treated with it.

[0235] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0236] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0237] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0238] When the number of a substituent is 0, it means that the substituent does not exist. For example, -A-(R)0 means that the structure is actually -A.

[0239] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0240] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0241] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond to any atom on that ring, for example, a structural unit. This indicates that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridyl group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0242] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0243] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line express.

[0244] The term "halogenated alkyl" in this disclosure refers to an alkyl group that has been substituted with one or more halogens.

[0245] The term "aryl" in this disclosure refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably a 6- to 10-membered ring, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo3- to 8-membered cycloalkyl and benzo3- to 8-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1-3 heterocyclic atoms independently selected from N, O, and S; or may further comprise a three-membered nitrogen-containing fused ring containing a benzene ring.

[0246] The term "heteroaryl" or "heteroaryl ring" in this disclosure refers to a heteroaryl system having 5 to 14 ring atoms, having 1 to 4 heterocyclic atoms independently selected from N, O, and S. The heteroaryl group may be optionally substituted or unsubstituted.

[0247] Unless otherwise specified, the terms "5-6-membered heteroaryl" and "5-6-membered heteroaryl" in this disclosure are used interchangeably. The term "5-6-membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). 5-6-membered heteroaryl groups can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-6-membered heteroaryl groups include both 5-membered and 6-membered heteroaryl groups.

[0248] The term "3- to 6-membered heterocyclic group" in this disclosure refers to a non-aromatic cyclic group having 3 to 6 ring atoms, comprising one or more heterocyclic atoms independently selected from N, O, and S, and may be fully saturated (i.e., 3- to 8-membered heterocyclic alkyl) or partially unsaturated. The heterocycle may be a 3- to 6-membered monocyclic, bicyclic, or spirocyclic ring.

[0249] The compounds disclosed herein 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 synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0250] The compounds described in this disclosure are named according to their chemical structural formulas. If the name of a compound representing the same compound differs from its chemical structural formula, the chemical structural formula shall prevail.

[0251] Pharmaceutical Compositions and Uses

[0252] The compounds of formula (I) described in this disclosure, or their pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, and prodrugs, are GSPT1 protein modulators that can degrade GSPT1 activity. Therefore, the compounds of this invention can be used to prevent or treat GSPT1-related diseases or conditions.

[0253] This disclosure provides pharmaceutical compositions comprising a compound of formula (I) as described in this disclosure or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug, and a pharmaceutically acceptable carrier.

[0254] In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional therapeutically active agents.

[0255] In some implementations, the GSPT1-related disease or condition is a tumor (e.g., cancer), including solid tumors and hematologic malignancies.

[0256] This disclosure also provides the use of compounds of Formula I as described above, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, and prodrugs thereof, in the preparation of medicaments for the treatment and / or prevention of cancer / tumor-related diseases or conditions. The cancer / tumor-related diseases or conditions include GSPT1-mediated diseases or conditions and related diseases or conditions.

[0257] The compound of formula (I) provided in this disclosure is a GSPT1 modulator and can be used to treat one or more diseases or conditions associated with GSPT1 activity. In some embodiments, this disclosure provides a method for treating GSPT1-mediated diseases or conditions, comprising the step of administering a compound of this disclosure or a pharmaceutically acceptable salt or composition thereof to a subject in need.

[0258] The term “GSPT1-mediated” refers to any disease or condition that is known to be caused by GSPT1 or its mutants.

[0259] The compound of formula (I) provided in this disclosure has the following characteristics:

[0260] 1. To prepare drugs for treating diseases related to GSPT1 activity or expression levels;

[0261] 2. Preparation of GSPT1 protein regulators or degraders;

[0262] 3. Therapeutic or non-therapeutic degradation or inhibition of GSPT1, either in vivo or in vitro;

[0263] 4. Inhibits tumor cell proliferation in vitro without therapeutic effect;

[0264] 5. Treatment of diseases related to GSPT1 activity or expression levels.

[0265] The term "cancer inhibition" or "tumor cell proliferation inhibition" as used in this disclosure refers to inhibiting the growth, division, maturation, or survival of cancer cells, and / or causing the death of cancer cells through cytotoxicity, nutrient depletion, or induction of apoptosis, individually or collectively with other cancer cells.

[0266] Examples of cancer cells or tissues to which the proliferation of a compound of formula (I) described in this disclosure is inhibited, or which are pharmaceutically acceptable salts or compositions thereof, and to which the methods described in this disclosure are applicable, include, but are not limited to: breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, vagina, thyroid, parathyroid, pituitary, thymus, conjunctiva, spleen, head and neck, trachea, gallbladder, rectum, salivary glands, adrenal glands, pharynx, esophagus, lymph nodes, muscles, stomach, and heart.

[0267] This disclosure also provides a treatment for a disease or condition comprising administering to a patient in need a therapeutically effective amount of a compound of formula I as described above and a pharmaceutically acceptable salt thereof, wherein the disease or condition is a GSPT1 receptor-mediated disease or condition and related diseases or conditions.

[0268] In some implementations, the GSPT1-mediated diseases or conditions are selected from melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, liposarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell tumor, and Wilms' tumor. Example

[0269] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0270] The structures of the compounds disclosed herein can be confirmed using conventional methods well known to those skilled in the art. If this disclosure pertains to the absolute configuration of a compound, that absolute configuration can be confirmed using techniques in the art. For example, single-crystal X-ray diffraction (SXRD) can be used, in which diffraction intensity data of the grown single crystal is collected using a Bruker D8 venture diffractometer with CuKα radiation as the light source and a φ / ω scan mode. After collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure using the direct method (Shelxs 97).

[0271] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names.

[0272] The structure of the reference compound selected in this disclosure is as follows: (Hereinafter referred to as Ref1). The chemical formula of Ref1 is [2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-3-oxo-1H-isoindol-5-yl]methyl-N-[2-fluoro-5-(trifluoromethoxy)phenyl]carbamate, CAS No. 2803881-11-8. It was first disclosed in patent applications WO2022152821A1 and WO2022152822A1, and was prepared by the preparation method described in the above patents.

[0273] Preparation Example

[0274] intermediate preparation example

[0275] Intermediate 1 and its preparation method:

[0276] Step 1: Intermediate 1-0 (5 g, 15.68 mmol), methyl 2-(azacyclobutane-3-yl)acetate triacetate (2.43 g, 18.82 mmol), tris(dibenzylacetone)palladium (1.44 g, 1.57 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (900 mg, 1.57 mmol), and cesium carbonate (15.3 g, 47.04 mmol) were dissolved in ultra-dry dioxane (100 mL). The reaction was carried out at 90 °C for 2 hours under nitrogen protection. After the reaction was complete, saturated brine and ethyl acetate were added for extraction. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to obtain intermediate 1-1 (1.8 g, 35.87%).

[0277] LCMS[M+H] + m / z:calcd 320.0, found 320.0.

[0278] Step 2: Intermediate 1-1 (1.8 g, 5.64 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (2.82 g, 6.77 mmol), Pd(dtbpf)Cl2 (182.1 mg, 0.28 mmol), and cesium fluoride (1.71 g, 11.28 mmol) were dissolved in N,N-dimethylformamide (50 mL) and water (5 mL). The reaction was carried out at 80 °C for 2 hours under nitrogen protection. After the reaction was completed, saturated brine was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give intermediate 1-2 (1.2 g, 40.1%).

[0279] LCMS[M+H] + m / z:calcd 531.2, found 531.2.

[0280] 1 HNMR (400MHz, CDCl3) δ7.52–7.18(m,11H),6.44(d,J=8.1Hz,1H),5.98(d,J=9.3Hz,2H),5.34(d,J=25.4 Hz,4H),4.14–4.02(m,2H),3.70(s,3H),3.57(dd,J=7.4,5.5Hz,2H),3.09(s,1H),2.71(d,J=7.8Hz,2H).

[0281] Step 3: Intermediate 1-2 (1.2 g, 2.26 mmol), palladium hydroxide / carbon (100 mg), and palladium / carbon (100 mg) were dissolved in dioxane (20 ml) and reacted at 40 °C for 2 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain intermediate 1-3 (760 mg, 95.5%).

[0282] LCMS[M+H] + m / z:calcd 353.2, found 353.2.

[0283] 1HNMR(400MHz,DMSO-d6)δ10.86(s,1H),6.10(d,J=11.1Hz,2H),3.98(dd,J=14.0,6.3Hz,2H),3.60(s,3H),3.57(s,1 H),3.50(t,J=6.5Hz,2H),3.02–2.90(m,1H),2.72(d,J=7.7Hz,2H),2.49(dd,J=7.5,5.8Hz,2H),2.13–1.88(m,2H).

[0284] Step 4: Intermediates 1-3 (760 mg, 2.16 mmol) and trimethyltin hydroxide (1.95 g, 10.8 mmol) were dissolved in 1,2-dichloroethane (20 mL) and reacted at 80 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain intermediate 1 (700 mg, 95.9%).

[0285] LCMS[M+H] + m / z:calcd 339.2, found 339.2.

[0286] Int-2 and its preparation method:

[0287] (1) INT-2-0 (40 g, 175 mmol), NBS (31.1 g, 175 mmol), and AIBN (1.44 g, 8.75 mmol) were dissolved in 500 mL of CCl4, and the reaction mixture was stirred at 85 °C for 2 hours. The reaction mixture was filtered through a silica gel pad, and the organic filtrate was concentrated to obtain crude INT-2-1 (53.6 g).

[0288] (2) INT-2-1 (53.6 g, 138.5 mmol) and DIEA (19.7 g, 152.4 mmol) were dissolved in 500 mL of ACN, and diethyl phosphite (19.1 g, 138.5 mmol) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0 / 100~5 / 95) to give INT-2-2 (43.2 g, 81%). ¹H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 8.3, 2.2 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 4.99 (s, 2H), 3.93–3.87 (m, 3H).

[0289] (3) INT-2-2 (43.2 g, 140 mmol) and SM2 (28 g, 168 mmol) were dissolved in 500 mL of DMF, and DIEA (54.6 g, 420 mmol) was added under nitrogen protection. The reaction mixture was stirred at 120 °C for 2 hours. The reaction mixture was cooled to room temperature and stirred at 25 °C for 30 min with hydrochloric acid (1 M) / ethyl acetate (1200 mL / 800 mL). The mixture was filtered, the filter cake was washed with ethyl acetate, and dried under reduced pressure to obtain INT-2-3 (32 g, 71%). 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.90–7.76(m,2H),7.60(d,J=8.1Hz,1H),5.12(dd,J=13.3,5.1Hz,1H), 4.39(dd,J=52.5,17.7Hz,2H),2.91(m,1H),2.60(d,J=17.6Hz,1H),2.39(dd,J=13.0,4.4Hz,1H),2.02(m,1H).

[0290] (4) INT-2-3 (8 g, 24.844 mmol) was dissolved in 80 mL of anhydrous Dioxane, and 3-aminopiperidine-2,6-dione (8.6 mg, 27.129 mmol) and Xphos-Pd-G3 (2.1 g, 2.482 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (DCM / MeOH = 5-10%) to give Int-2 (5 g). LCMS[M+H]+m / z:275.0,1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),7.68(s,1H),7.58-7.54(m,2H),5.34(t,J=10.0Hz,1H),5.07(dd,J=13.2Hz,5.2Hz,1H),4.60(d,J =5.6Hz,2H),4.43(d,J=17.2Hz,1H),4.30(d,J=17.2Hz,1H),2.96-2.87(m,1H),2.86-2.58(m,1H),2.45-2.34(m,1H),2.04-1.98(m,1H).

[0291] Example 1: Synthesis of Compound 1

[0292] Step 1: Compound 1-0 (3.6 g, 25.352 mmol) and pyridinium tribromide (9 g, 28.213 mmol) were dissolved in acetic acid (50 mL). The reaction was carried out at 40 °C under nitrogen protection for 12 hours. After the reaction temperature dropped to room temperature, the reaction solution was poured into water, resulting in the precipitation of a solid. After stirring for 1 hour, the solid was filtered off. The obtained solid was washed three times with water and dried under vacuum to obtain compound 1-1 (4.6 g, 83%).

[0293] 1 H NMR (400MHz, CDCl3) δ7.39 (s, 1H), 2.70 (s, 3H).

[0294] Step 2: Compound 1-1 (0.5 g, 2.27 mmol) was dissolved in 5.5 mL of a mixed solvent of dichloromethane and N,N-dimethylformamide. Oxaloyl chloride was added dropwise under nitrogen protection at 0 °C. The reaction was stirred at room temperature for 4 hours. The dichloromethane was removed by concentration, and the resulting mixture was dissolved again in dichloromethane. Potassium tert-butoxide (0.76 g, 6.77 mmol) was added under nitrogen protection at 0 °C. The reaction was stirred at 25 °C for 30 min and then quenched in a small amount of water. Extraction was performed using ethyl acetate (10 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (PE:EtOAc = 15:1) to give compound 1-2 (0.2 g, 32%).

[0295] 1 H NMR (400MHz, DMSO-d6) δ7.28 (d, J = 4.4Hz, 1H), 2.59 (s, 3H), 1.50 (s, 9H).

[0296] Step 3: Compounds 1-2 (200 mg, 0.72 mmol), N-succinimide bromide (129 mg, 0.72 mmol), and azobisisobutyronitrile (6 mg, 0.04 mmol) were dissolved in 15 mL of carbon tetrachloride. The reaction mixture was stirred at 85 °C for 2 hours. The reaction mixture was filtered through a silica gel pad and concentrated under vacuum to obtain a crude product. The crude product (150 mg, 0.35 mmol), N,N-diisopropylethylamine (0.07 mL, 0.38 mmol), and diethyl phosphite (50 mg, 0.35 mmol) were dissolved in 5 mL of acetonitrile. Diethyl phosphite was slowly added dropwise at 0 °C for 2 hours. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was extracted with ethyl acetate (8 mL * 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0 / 100–5 / 95) to obtain compounds 1-3 (110 mg, 43%).

[0297] 1H NMR (400MHz, DMSO-d6) δ7.39(s,1H),5.14(s,2H),1.54(s,9H).

[0298] Step 4: Compounds 1-3 (800 mg, 2.44 mmol) were dissolved in 15 mL of N,N-dimethylformamide. 3-Aminopiperidin-2,6-dione (483 mg, 2.93 mmol) and triethylamine (0.75 mL, 5.37 mmol) were added at 0 °C. The reaction was continued at 80 °C with stirring for 16 h. The reaction solution was then quenched in water and extracted with ethyl acetate (15 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (PE:EtOAc = 8:1) to give compounds 1-4 (550 mg, 61%).

[0299] 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),7.30(s,1H),4.35-4.18(m,2H),3.48(d, J=3.4Hz,2H),2.62-2.52(m,2H),2.08-2.00(m,1H),1.79(s,1H),1.50(s,9H).

[0300] Step 5: Dissolve compound 1-4 (550 mg) in 5 mL of dichloromethane. Add 5 mL of trifluoroacetic acid under nitrogen protection at 0 °C. After reacting at 25 °C for 1 hour, evaporate to dryness to obtain compound 1-5 (400 mg, 85%), which can be used directly in the next step.

[0301] LCMS[M+H]+m / z:calcd 347.0, found 347.0.

[0302] Step 6: Under a nitrogen atmosphere, compounds 1-5 (300 mg, 0.87 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (495 mg, 1.29 mmol) were dissolved in N,N-dimethylformamide (8 mL). At 0 °C, N,N-diisopropylethylamine (498 mg, 2.61 mmol) was added, and the reaction was continued for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate (10 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give compounds 1-6 (160 mg, 42%).

[0303] LCMS[M+H]+m / z:329.0.

[0304] Step 7: Compounds 1-6 (160 mg, 0.49 mmol), tributyltin methanol (219 mg, 0.68 mmol), and Xphos-Pd-G3 (41 mg, 0.049 mmol) were dissolved in 8 mL of 1,4-dioxane. The reaction was stirred at 100 °C under nitrogen protection for 16 hours. The reaction solution was then directly evaporated to dryness and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give compounds 1-7 (25 mg, 18%).

[0305] LCMS[M+H]+m / z:281.0.

[0306] Step 8: Compounds 1-7 (25.0 mg, 0.09 mol) and 2-fluoro-5-trifluoromethoxybenzoic acid (29 mg, 0.11 mol) were dissolved in 3 mL of dimethyl sulfoxide. Under nitrogen protection at 0 °C, diphenyl azidophosphate (0.03 mL, 0.11 mmol) and triethylamine (0.04 mL, 0.27 mmol) were added. The reaction was carried out at 90 °C for 1 hour, quenched with saturated ammonium chloride, and the organic phase was washed three times with saturated sodium bicarbonate and extracted three times with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reversed-phase column chromatography (H₂O / ACN = 40%) to give compound 1 (2.06 mg, 5%).

[0307] LCMS[M+H]+m / z:502.1.

[0308] 1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),9.90(s,1H),7.83-7.74(m,1H),7.41–7.35(m,2H),7.18 -7.13(m,1H),5.38(s,2H),5.00(dd,J=13.6,5.2Hz,1H),4.52(d,J=18.4Hz,1H),4.39(d,J =18.0Hz,1H),2.91-2.84(m,1H),2.60-2.54(m,1H),2.40-2.28(m,1H),2.04-1.94(m,1H).

[0309] Example 2: Synthesis of Compound 2

[0310] Step 1: Compound 2-0 (1.5 g, 6.79 mmol) was dissolved in 25 mL of dichloromethane. N,N-dimethylformamide (0.3 mL) and oxaloyl chloride (1.71 g, 13.54 mmol) were added dropwise to the reaction solution at 0 °C. The reaction solution was stirred at 25 °C for 4 hours under nitrogen protection. After low-temperature concentration, the reaction solution was dissolved in dichloromethane, and potassium tert-butoxide (2.28 g, 20.36 mmol) was added in portions at 0 °C. The reaction solution was stirred at 20 °C for 0.5 hours. After the reaction was complete, the reaction solution was concentrated at low temperature, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the target compound 2-1 (1.16 g, 61.7%).

[0311] 1 H NMR (400MHz, CDCl3) δ6.85(s,1H),2.47(s,3H),1.55(s,9H).

[0312] Step 2: Compound 2-1 (1.16 g, 4.19 mmol) was dissolved in 12 mL of carbon tetrachloride, followed by the addition of N-bromosuccinimide (820.0 mg, 4.61 mmol) and azobisisobutyronitrile (34.0 mg, 0.21 mmol). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was directly evaporated to dryness, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the target compound 2-2 (930 mg, 62.4%).

[0313] 1 H NMR (400MHz, CDCl3) δ7.12(s,1H),4.80(s,2H),1.57(s,9H).

[0314] Step 3: Compound 2-2 (0.93 g, 2.61 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by the addition of 3-aminopiperidine-2,6-dione (431 mg, 2.61 mmol) and triethylamine (530 mg, 5.22 mmol). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was extracted with water (50 mL) and ethyl acetate (50 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH = 25 / 1) to obtain the target compound 2-3 (500 mg, 47.6%).

[0315] 1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),7.39(s,1H),4.12–4.00(m,2H),3.32(s,1H),3. 30–3.28(m,1H),2.51–2.50(m,2H),2.14–2.07(m,1H),1.77–1.68(m,1H),1.51(s,9H).

[0316] Step 4: Compound 2-3 (500 mg, 1.24 mmol) and trifluoroacetic acid (5 mL) were dissolved in 10 mL of dichloromethane solution. The reaction solution was reacted overnight at 25 °C under nitrogen balloon protection. After the reaction was completed, the reaction solution was concentrated at low temperature, and the residue was dissolved in dichloromethane (50 mL) and rotary evaporated five times. After concentration, the crude target compound 2-4 (600 mg) was obtained.

[0317] LCMS[M+H]+m / z:calcd 347.0; found 347.0.

[0318] Step 5: Compound 2-4 (550.1 mg, 1.59 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (904.0 mg, 2.38 mmol), and N,N-diisopropylethylamine (615.0 mg, 4.76 mmol) were added to 8 mL of N,N-dimethylformamide. The reaction mixture was stirred at 25 °C for 3 hours under nitrogen protection. After the reaction was completed, the reaction mixture was extracted with water (50 mL) and ethyl acetate (50 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the target compound 2-5 (170.1 mg, 32.5%).

[0319] LCMS[MH] - m / z:329.0.

[0320] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.48(s,1H),5.02–4.97(m,1H),4.43–4.26(m,2H),2.94–2.80(m,2H),2.41–2.30(m,1H),2.03–1.97(m,1H).

[0321] Step 6: Compound 2-5 (150 mg, 0.46 mmol), (tributyltin)methanol (161.1 mg, 0.50 mmol), and XPhos-Pd-G3 (40.0 mg, 0.05 mmol) were added to 2 mL of anhydrous 1,4-dioxane. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain the target compound 2-6 (40 mg, 31.0%).

[0322] LCMS[MH] - m / z:281.0.

[0323] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),7.08(s,1H),5.76(t,J=5.7Hz,1H),5.01–4.97(m,1H),4.72(d,J=5 .4Hz,2H),4.36–4.18(m,2H),2.93–2.84(m,1H),2.40–2.29(m,1H),2.01–1.98(m,1H),0.91–0.86(m,1H).

[0324] Step 7: Compounds 2-6 (40 mg, 0.25 mmol), 2-fluoro-5-(trifluoromethoxy)benzoic acid (38 mg, 0.17 mmol), triethylamine (42 mg, 0.42 mmol), and diphenyl azidophosphate (47 mg, 0.17 mmol) were dissolved in 2 mL of dimethyl sulfoxide and reacted at 90 °C for one hour. The reaction solution was purified by Pre-HPLC to obtain compound 2 (1.51 mg, 2.2%).

[0325] LCMS[M+H] + m / z:502.1.

[0326] 1H NMR(400MHz, DMSO-d6)δ7.78(s,1H),7.41–7.36(m,2H),7.16(d,J=8.8Hz,1H),5.43(s,2H),5.03–4.98(m ,1H),4.42–4.24(m,2H),2.93–2.84(m,1H),2.64(d,J=26.6Hz,1H),2.42–2.31(m,1H),2.03–1.97(m,1H).

[0327] Example 3: Synthesis of Compound 3

[0328] Step 1: Dissolve SM2-0 (450 mg, 1.931 mmol) in anhydrous toluene, and add 4,4-difluorocyclohexane-1-amine hydrochloride (300 mg, 2.223 mmol), cesium carbonate (880 mg, 2.707 mmol), BINAP (100 mg, 0.161 mmol), and palladium acetate (22 mg, 0.097 mmol). The reaction solution is purged twice with nitrogen, and the temperature is raised to 120 °C for 12 hours. After the reaction is complete, water and ethyl acetate are added to extract the product. The organic phase is dried and concentrated, and the residue is purified by column chromatography (PE / EA = 4:1) to obtain compound SM2-1 (300 mg, 54.1%).

[0329] LCMS[M+H]+m / z:calcd 288.1, found 288.0.

[0330] Step 2: Dissolve SM2-1 (150 mg, 0.520 mmol) in a tetrahydrofuran / methanol (4 / 1) mixture, and slowly add 3 mL of 2.0 M lithium hydroxide solution. React at room temperature for 12 hours. After the reaction is complete, remove the solvent by vacuum evaporation, adjust the pH to 4-5 with an appropriate amount of dilute hydrochloric acid, extract with ethyl acetate, and dry the organic phase to obtain SM2 (140 mg, 100%), which can be used directly in the next step.

[0331] LCMS[M+H]+m / z:calcd 274.1,found 274.0.

[0332] Step 3: Compound 3-0 (5.0 g, 23.474 mmol) and SM1 (9.81 g, 28.169 mmol) were dissolved in 40 mL of anhydrous toluene. Under nitrogen protection, the reaction mixture was stirred at 130 °C for 18 hours. The reaction solution was concentrated under reduced pressure. Methyl tert-butyl ether (70 mL) was added to the residue, and the mixture was filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (EA / PE = 0-10%) to give compound 3-1 (4.1 g).

[0333] 1H NMR (400MHz, CDCl3) δ7.65 (d, J = 1.6Hz, 1H), 7.60 (s, 1H), 7.44-7.36 (m, 2H), 3.73 (s, 3H), 3.69 (s, 2H).

[0334] Step 4: Compound 3-1 (2 g, 7.46 mmol) was dissolved in 20 mL of anhydrous DMF. Acrylamide (636.5 mg, 8.95 mmol) and potassium tert-butoxide (1 g, 8.95 mmol) were added under nitrogen protection and in an ice bath. The mixture was heated to room temperature and reacted for 0.5 h. After the reaction was complete, the mixture was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate (40 mL * 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, filtered, and evaporated to dryness again. The residue was purified by silica gel column chromatography (EA / PE = 0-90%) to obtain compound 3-2 (800 mg, 35%).

[0335] 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.95(s,1H),7.90(d,J=1.4Hz,1H),7.57(d,J=8.4Hz,1H),7.43(dd,J=8.4,1.6Hz,1H),4.16(dd,J =12.2,4.8Hz,1H),2.77(dd,J=12.5,5.5Hz,1H),2.59(dt,J=17.2,3.7Hz,1H),2.32(dd,J=12.8,4.3Hz,1H),2.12(td,J=8.4,4.3Hz,1H).

[0336] Step 5: Compound 3-2 (300 mg, 0.98 mmol) was dissolved in 6 mL of anhydrous Dioxane, and Bu3SnCH2OH (439.3 mg, 1.37 mmol) and XPhos-Pd-G3 (82.7 mg, 0.1 mmol) were added. The mixture was heated to 100 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, filtered, evaporated to dryness again, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to give compound 3-3 (120 mg, 47%).

[0337] 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),7.85(s,1H),7.52(d,J=8.0Hz,1H),7.49(s,1H),7.19(d,J=8. 0Hz,1H),5.25(t,J=5.8Hz,1H),4.60(d,J=5.7Hz,2H),4.12(dd,J=11.9,4.9Hz,1H),2.74(ddd,J=17 .4,12.1,5.3Hz,1H),2.57(dt,J=17.2,3.9Hz,1H),2.32(qd,J=12.3,4.4Hz,1H),2.12(dt,J=13.2,4 .4Hz,1H),1.69–1.51(m,1H),1.31(dd,J=14.7,7.4Hz,1H),1.21–1.03(m,1H),0.87(t,J=7.3Hz,1H).

[0338] Step 6: Compound 3-3 (120 mg, 0.46 mmol) was dissolved in 5 mL of DMSO, and SM2 (151.8 mg, 0.55 mmol), TEA (140.7 mg, 1.39 mmol), and DPPA (153 mg, 0.55 mmol) were added. The mixture was heated to 90 °C for 1 hour under nitrogen protection. After cooling to room temperature, the mixture was purified by reversed-phase column chromatography (H2O / ACN = 95 / 5–60 / 40) to give compound 3 (26.0 mg, 10.6%).

[0339] LCMS[M+H] + m / z:530.3.

[0340] 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),9.26(s,1H),7.93(s,1H),7.64(s,1H),7.60(d, J=8.0Hz,1H),7.30(d,J=8.1Hz,1H),7.06–6.92(m,2H),6.42(s,1H),5.24(s,2H),4.1 5(dd,J=12.0,4.9Hz,1H),3.37(s,1H),2.81–2.57(m,4H),2.33(td,J=12.6,8.6Hz,1H ), 2.09 (ddd, J = 27.6, 13.9, 7.1Hz, 3H), 1.90 (d, J = 12.4Hz, 3H), 1.47 (d, J = 11.0Hz, 2H).

[0341] Example 4: Synthesis of Compound 4

[0342] Step 1: Compound 4-0 (1.3 g, 4.85 mmol), Zn(CN)2 (683 mg, 5.82 mmol), Pd2(dba)3 (228 mg, 0.24 mmol), and XPhos (234 mg, 0.49 mmol) were dissolved in 15 mL of DMF. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL * 3). The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the target compound 4-1 (950 mg, 83.6%).

[0343] LCMS[M+MeCN] + m / z:257.0.

[0344] Step 2: Compound 4-1 (900 mg, 4.185 mmol) was dissolved in 8 mL of DMF. After vacuuming and purging with nitrogen, the solution was cooled to 0 °C. SM2 (360 mg, 5.02 mmol) and potassium tert-butoxide (702 mg, 6.3 mmol) were added, and the reaction was continued at low temperature for 0.5 hours. After the reaction was completed, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL * 3). The organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 5-100 / 8) to obtain compound 4-2 (450 mg, 42.4%).

[0345] LCMS[M+H] + m / z:255.0.

[0346] Step 3: Compound 4-2 (200 mg, 0.78 mmol) was dissolved in 30 mL of methanol, followed by the addition of 10% palladium / carbon (200 mg) and concentrated hydrochloric acid (0.57 mL). The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was then evaporated to dryness to obtain compound 4-3 (70 mg, 34.8%).

[0347] 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.59(s,2H),7.95(s,1H),7.84–7.70(m,1H),7.62(d,J=7.9Hz,1H) ,7.36(d,J=8.0Hz,1H),4.13(dd,J=14.4,4.8Hz,3H),2.76(m,1H),2.58(m,1H),2.34(m,1H),2.11(m,1H).

[0348] Step 4: Dissolve N1-(4,4-difluorocyclohexyl)-4-fluorobenzene-1,3-diamine (150 mg, 0.614 mmol) in anhydrous DCM (5 mL), add sodium carbonate solution (105 mg dissolved in 5 mL water), triphosgene (75 mg, 0.382 mmol), and after the reaction is complete (tested by TLC), add water (10 mL) and dichloromethane (10 mL). * 3) Extract the intermediate isocyanate, dry and concentrate the organic phase, dissolve the residue in dichloromethane (5 mL), add triethylamine (0.13 mL), compound 4-3 (70 mg, 0.271 mmol), stir at room temperature for one hour, and after the reaction is complete, add water (10 mL) and dichloromethane (10 mL). * 3) Extract the product, combine the organic phases and dry them with anhydrous sodium sulfate, then evaporate to dryness. The residue was purified by reversed-phase column chromatography (ACN / H2O = 40 / 60) to give compound 4 (1.98 mg, 0.67%).

[0349] LCMS[M+H] + m / z:529.2.

[0350] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.14(d,J=2.1Hz,1H),7.87(s,1H),7.54(d,J=8.0Hz,1H),7.5 2–7.41(m,2H),7.20(d,J=7.2Hz,1H),7.07(t,J=5.7Hz,1H),6.91–6.74(m,1H),6.14–6.05(m,1H),5 .39(d,J=8.2Hz,1H),4.40(d,J=5.6Hz,2H),4.21–4.03(m,1H),2.82–2.65(m,2H),2.63–2.53(m,2H) ,2.39–2.23(m,1H),2.11–2.00(m,3H),1.90(d,J=12.4Hz,4H),1.46(d,J=10.6Hz,3H),1.24(s,2H).

[0351] Example 5: Synthesis of Compound 5

[0352] Step 1: Dissolve NaH (60% in mineral oil) (2.8 g, 69.9 mmol) in 40 mL of toluene. Add a toluene solution (40 mL) of compound 5-0 (5 g, 23.3 mmol) at 0 °C. After stirring for 0.5 hours, add diethyl carbonate (13.8 g, 116.5 mmol). Stir the reaction mixture at 110 °C for 16 hours. Cool the reaction mixture to room temperature, quench with ice water, adjust the pH to 3-5 with 2 M hydrochloric acid, precipitate a solid, filter, collect the solid, and dry under vacuum to give compound 5-1 (3.7 g, 66%).

[0353] 1H NMR (400MHz, DMSO-d6) δ12.73(s,1H),7.74(d,J=8.4Hz,1H),7.70(d,J=1.6Hz,1H),7.54(dd,J=8.4,1.7Hz,1H),5.61(s,1H).

[0354] Step 2: Dissolve 10 g (29.2 mmol) of 20% sodium ethoxide in 40 mL of ethanol, add 40 mL of an ethanol solution containing 2.03 g (29.2 mmol) of NH₂OH·HCl and 3.5 g (14.6 mmol) of compound 5-1, and stir the reaction mixture at 80 °C for 4 hours. Cool the reaction mixture to room temperature, pour it into saturated sodium bicarbonate, wash with dichloromethane, acidify the aqueous phase with 2 M dilute hydrochloric acid, precipitate a solid, and filter. Collect the solid, dry it under vacuum to give compound 5-2 (2.48 g, 67%).

[0355] 1H NMR (400MHz, DMSO-d6) δ12.95(s,1H),8.12(d,J=1.4Hz,1H),7.82(d,J=8.4Hz,1H),7.60(dd,J=8.4,1.5Hz,1H),4.12(s,2H).

[0356] Step 3: Compound 5-2 (1.7 g, 6.7 mmol) was dissolved in ethanol (60 mL), and 5 drops of concentrated sulfuric acid were added dropwise. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5-3 (1.7 g, 90%).

[0357] 1H NMR (400MHz, DMSO-d6) δ8.13 (s, 1H), 7.82 (d, J = 8.4Hz, 1H), 7.60 (dd, J = 8.4, 1.3Hz, 1H), 4.23 (s, 2H), 4.15 (q, J = 7.1Hz, 2H), 1.19 (t, J = 7.1Hz, 3H).

[0358] Step 4: Compound 5-3 (1.0 g, 3.53 mmol) was dissolved in 15 mL of DMF. Acrylamide (301.4 mg, 4.24 mmol) and sodium tert-butoxide (407.5 mg, 4.24 mmol) were added under nitrogen protection and in an ice bath. The mixture was heated to room temperature and reacted for 0.5 hours. After the reaction was complete, the mixture was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to give compound 5-4 (260 mg, 24%).

[0359] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.15(d,J=1.1Hz,1H),7.85(d,J=8.5Hz,1H),7.59(dd,J=8.5 ,1.5Hz,1H),4.63(dd,J=12.1,4.9Hz,1H),2.82–2.71(m,1H),2.67–2.52(m,2H),2.25–2.16(m,1H).

[0360] Step 5: Compound 5-4 (260 mg, 0.84 mmol) was dissolved in 6 mL of Dioxane, and Bu3SnCH2OH (379.5 mg, 1.18 mmol) and XPhos-Pd-G3 (71.45 mg, 0.08 mmol) were added. The mixture was heated to 100 °C for 16 hours under nitrogen protection. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to give compound 5-5 (100 mg, 46%).

[0361] 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),7.78(d,J=8.2Hz,1H),7.65(s,1H),7.33(d,J=8.2Hz,1H),5.47(t,J=5.7Hz, 1H),4.67(d,J=5.7Hz,2H),4.58(dd,J=11.9,5.0Hz,1H),2.83–2.72(m,1H),2.65–2.51(m,2H),2.25–2.15(m,1H).

[0362] Step 6: Compound 5-5 (100 mg, 0.38 mmol) was dissolved in 5 mL of anhydrous DMSO, and SM2 (126 mg, 0.46 mmol), TEA (117 mg, 1.15 mmol), and DPPA (127 mg, 0.46 mmol) were added. After reacting at 90 °C for 1 hour under nitrogen protection, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (H2O / ACN = 1 / 1) to obtain compound 5 (28.09 mg, 13.8%).

[0363] LCMS[M+H] + m / z:531.2.

[0364] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.29(s,1H),7.87(d,J=8.2Hz,1H),7.80(s,1H),7.43 (d,J=8.3Hz,1H),6.93(dd,J=10.6,8.9Hz,2H),6.33(dt,J=8.7,3.3Hz,1H),5.50(d,J=8.2Hz ,1H),5.31(s,2H),4.61(dd,J=12.0,4.9Hz,1H),3.34(s,1H),2.83–2.73(m,1H),2.69–2.54( m,2H),2.25–2.17(m,1H),2.09–2.00(m,2H),1.90(d,J=14.0Hz,4H),1.45(d,J=11.0Hz,2H).

[0365] Example 6: Synthesis of Compound 6

[0366] Step 1: Compound 6-0 (5 g, 0.029 mol), m-fluorobenzaldehyde (4.3 g, 0.035 mol), and triethylsilane (11.4 g, 0.017 mol) were dissolved in acetonitrile (50 mL). Trifluoroacetic acid (16.82 g, 0.145 mol) was added under nitrogen protection, and the reaction was stirred at 80 °C for 3 hours. After removing acetonitrile by vacuum concentration, the mixture was washed three times with saturated NaCl and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (PE:EtOAc = 5:1) to give compound 6-1 (6.5 g, 76.8%).

[0367] LCMS[M+H]+m / z:265.0.

[0368] Step 2: Dissolve compound 6-1 (2g, 0.730mmol) in 20mL of THF, add 10% Pd / C (200mg), and purge three times to ensure the reaction is carried out under H2 atmosphere. Stir overnight at 25°C. Filter Pd / C through diatomaceous earth to remove the residue, and evaporate to dryness to obtain compound 6-2 (1.77g, 100%).

[0369] 1 H NMR (400MHz, DMSO-d6) δ7.37(t,J=7.6Hz,1H),7.27(d,J=7.8Hz,1H),7.20–7.11(m,2H),6.66(dd,J= 11.3,8.7Hz,1H),6.01(dd,J=7.9,2.7Hz,1H),5.81–5.70(m,2H),4.80(s,2H),4.20(d,J=5.8Hz,2H).

[0370] Step 3: Compound 6-2 (28 mg, 0.12 mmol) and intermediate 1 (40 mg, 0.12 mmol) were dissolved in 10 mL of Py. EDCI (37 mg, 0.15 mmol) was added at 0 °C under nitrogen protection. The reaction mixture was stirred at 25 °C for 14 h. The reaction mixture was quenched with water, extracted three times with ethyl acetate (5 mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration, rotary evaporation, and purification by column chromatography (H2O:ACN = 1.5:1) yielded compound 6 (10.62 mg, 16%).

[0371] LCMS[M+H] + m / z:555.2.

[0372] 1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.52(s,1H),7.46 -7.08(m,5H),7.04-6.70(m,1H),6.27(d,J=8.6Hz,1H),6.14(dd,J=18.7,8.6Hz,3H),4.24(d,J=6.1H z,2H),4.00(m,3H),3.55(t,J=6.1Hz,2H),3.01(d,J=6.4Hz,1H),2.88-2.64(m,3H),2.33(s,1H),2.17 -1.71(m,2H),1.23(s,1H).

[0373] Example 7: Synthesis of Compound 7

[0374] Step 1: Compound 7-0 (5 g, 0.029 mol), 4,4-difluorocyclohexanone (4.3 g, 0.035 mol), and triethylsilane (11.4 g, 0.017 mol) were dissolved in acetonitrile (50 mL). Trifluoroacetic acid (16.82 g, 0.145 mol) was added under nitrogen protection, and the reaction was stirred at 80 °C for 3 hours. After removing acetonitrile by vacuum concentration, the mixture was washed three times with saturated NaCl and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (PE:EtOAc = 5:1) to give product compound 7-1 (6.5 g, 76.8%).

[0375] Step 2: Dissolve compound 7-1 (2g, 0.730mmol) in 20mL of THF, add 10% Pd / C (200mg), and purge three times to ensure the reaction is carried out under H2 atmosphere. Stir overnight at 25°C. Filter Pd / C through diatomaceous earth to remove the residue, and evaporate to dryness to obtain product compound 7-2 (1.77g, 100%).

[0376] Step 3: Compound 7-2 (50 mg, 0.204 mmol) was dissolved in anhydrous pyridine (3 mL), and intermediate 1 (125 mg, 0.251 mmol) and EDCI (55 mg, 0.286 mmol) were added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, water (10 mL) and ethyl acetate (15 mL * 3) were added to extract the product. The organic phase was dried and concentrated. The residue was purified by reversed-phase column chromatography (ACN / H2O = 1 / 1) to give compound 7 (47.05 mg, 40.86%).

[0377] LCMS[M+H] + m / z:565.3.

[0378] 1 H NMR (400MHz, DMSO-d6) δ10.85 (s, 1H), 9.52 (s, 1H), 7.18 (d, J = 4.1Hz, 1H), 6.99–6.76(m,1H),6.37–6.25(m,1H),6.12(d,J=11.1Hz,2H),5.49(d,J=8. 1Hz,1H),4.12–3.93(m,3H),3.56(t,J=6.3Hz,2H),3.34(d,J=4.0Hz,1H),3 .14–2.94(m,1H),2.87–2.65(m,3H),2.23–1.79(m,8H),1.56–1.34(m,2H).

[0379] Example 8: Synthesis of Compound 8

[0380] Step 1: Compound 8-0 (1.39 g, 10.0 mmol) was dissolved in dichloromethane, and triethylamine (2 mL), di-tert-butyl dicarbonate (2.40 g, 11.0 mmol), and 4-dimethylaminopyridine (122.0 mg, 1.0 mmol) were added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the concentrated reaction solution was purified by silica gel column chromatography (PE / EA = 5 / 1) to give the product compound 8-1 (1.25 g, 52.3%).

[0381] LCMS[M-tBu] + m / z:184.0.

[0382] Step 2: Compound 8-1 (1.2 g, 5.017 mmol) was dissolved in N,N-dimethylformamide (24 mL), and 2,2,2-trifluoroethyltrifluoromethanesulfonate (3.49 g, 15.051 mmol) and potassium carbonate (2.077 g, 15.051 mmol) were added. The mixture was reacted at 50 °C for 5 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 8:2) to give compound 8-2 (1.297 g, 80.1%).

[0383] LCMS[M-tBu] + m / z:266.0.

[0384] Step 3: Compound 8-2 (1.297 g, 4.03 mmol) was dissolved in tetrahydrofuran (12 mL), and 10% palladium / carbon was added. The mixture was purged three times under a hydrogen atmosphere and reacted overnight at room temperature. The palladium / carbon was removed by filtration through diatomaceous earth. The filtrate was evaporated to dryness to give product compound 8-3 (1.1 g, 93.2%).

[0385] LCMS[M+H] + m / z:292.0.

[0386] Step 4: Compound 8-3 (1.1 g, 3.767 mmol) was dissolved in 10 mL of hydrochloric acid / 1,4-dioxane solution and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure to give compound 8-4 (719.0 mg, 100%).

[0387] LCMS[M+H] + m / z:192.0.

[0388] Step 5: Compound 8-4 (30 mg, 0.157 mmol) and intermediate 1 (44 mg, 0.130 mmol) were dissolved in pyridine (6 mL). The gas was purged three times to ensure the reaction was carried out under nitrogen protection. EDCI (32.5 mg, 0.169 mmol) was added at 0 °C. After reacting for 2 hours, the reaction solution was poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography (H2O:ACN = 3:2) to obtain compound 8 (6.3 mg, 9.5%).

[0389] LCMS[M+H] + m / z:512.2.

[0390] 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),7.86(d,J=5.7Hz,1H),7.10(t,J=6.6H z,1H),7.04(s,1H),6.69(dd,J=5.7,1.6Hz,1H),6.12(d,J=11.1Hz,2H),4.21 -3.92(m,5H),3.55(t,J=6.3Hz,2H),3.10 -2.96(m,1H),2.86-2.63(m,3H),2.03(dd,J=33.0,20.3Hz,2H),1.26(d,J=23.4Hz,1H).

[0391] Example 9: Synthesis of Compound 9

[0392] Step 1: Compound 9-0 (10.0 g, 55.802 mmol) was dissolved in 90 mL of fuming nitric acid, and 24 mL of concentrated sulfuric acid was added. The mixture was stirred at 45°C for 15 hours. After the reaction was complete, the reaction solution was added dropwise to ice water (100 mL), extracted with ethyl acetate (50 mL * 3), and the organic phases were combined and washed with saturated sodium bicarbonate aqueous solution. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness to obtain compound 9-1 (4.6 g, 37.1%).

[0393] 1 H NMR (400MHz, CDCl3) δ8.93 (d, J = 6.1 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H).

[0394] Step 2: Compound 9-1 (4.6 g, 20.534 mmol) was dissolved in acetic acid (10 mL), and iron powder (16.0 g, 285.714 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was filtered, and water (50 mL) and ethyl acetate (50 mL * 3) were added to the filtrate for extraction. The organic phases were combined and washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 9-2 (2.1 g, 56.7%).

[0395] LCMS[M+H]+m / z:195.0.

[0396] Step 3: Compound 9-2 (2.1 g, 12.370 mmol) was dissolved in dichloromethane, and triethylamine (4 mL), di-tert-butyl dicarbonate (8.2 g, 37.614 mmol), and 4-dimethylaminopyridine (150 mg, 1.228 mmol) were added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the concentrated reaction solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 9-3 (3.1 g, 73.8%).

[0397] 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=9.9Hz,1H),8.06(d,J=6.4Hz,1H),3.90(s,3H),1.39(s,18H).

[0398] Step 4: Compound 9-3 (3.1 g, 8.373 mmol) was dissolved in dichloromethane, and triethylamine (6 mL) and copper trifluoromethanesulfonate (300 mg, 0.831 mg) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) and ethyl acetate (20 mL * 3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, and then evaporated to dryness to give compound 9-4 (1.9 g, 82.6%).

[0399] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.99(d,J=10.2Hz,1H),7.93(d,J=6.4Hz,1H),3.89(s,3H),1.48(s,9H).

[0400] Step 5: Compound 9-4 (1.9 g, 6.432 mmol) was dissolved in dimethyl sulfoxide, and potassium carbonate (2.7 g, 19.565 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (7.49 g, 32.284 mmol) were added. The mixture was stirred at 60 °C for 3 hours. After the reaction was complete, water (30 mL) and ethyl acetate (30 mL * 3) were added for extraction. The organic phases were combined and washed with saturated sodium chloride aqueous solution (20 mL * 3), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 9-5 (700 mg, 29.1%).

[0401] 1 H NMR (400MHz, DMSO-d6) δ8.15(t,J=7.8Hz,1H),4.88–4.34(m,1H),3.89(d,J=6.2Hz,2H),1.52–1.30(m,5H).

[0402] Step 6: Dissolve compound 9-5 (700 mg, 1.861 mmol) in dioxane hydrochloride (10 mL) and stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution to obtain compound 9-6 (510 mg, 100%).

[0403] LCMS[M+H]+m / z:277.0.

[0404] Step 7: Compound 9-6 (510 mg, 2.653 mmol) was dissolved in tetrahydrofuran / methanol = 4 / 1 (10 mL), and 2M lithium hydroxide aqueous solution (4 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was adjusted to a weak acidity with dilute hydrochloric acid, and water (10 mL) and ethyl acetate (10 mL * 3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain compound 9-7 (480 mg, 100%).

[0405] LCMS[M+H]+m / z:263.0.

[0406] Step 8: Compound 9-7 (480 mg, 1.832 mmol) was dissolved in tert-butanol (10 mL), and triethylamine (0.77 mL) and diphenyl azidophosphate (75 mg, 0.272 mmol) were added. The mixture was stirred at 90 °C for 2 hours. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL * 3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was then evaporated to dryness and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 9-8 (440 mg, 72.1%).

[0407] LCMS[M+H]+m / z:334.2.

[0408] Step 9: Compound 9-8 (440 mg, 1.321 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and water (5 mL) and ethyl acetate (5 mL * 3) were added for extraction. The organic phases were combined and washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain compound 9-9 (210 mg, 68.4%).

[0409] Step 10: Intermediate 1 (70.0 mg, 0.206 mmol), 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (57 mg, 0.206 mmol), and N,N-diisopropylethylamine (67.1 mg, 0.516 mmol) were dissolved in 5 mL of N-methylpyrrolidone, followed by the addition of compound 9-9 (40.1 mg, 0.172 mmol). The reaction was carried out overnight at room temperature under nitrogen protection. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL * 3) were added for extraction. The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was subjected to reversed-phase column chromatography (water:acetonitrile = 39%) to give target compound 9 (8.64 mg, 9.09%).

[0410] LCMS[M+H] + m / z:calcd.:554.3.

[0411] 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.98(s,1H),7.84(d,J=6.8Hz,1H),7.57(d,J=10.0Hz,1H),6.56(t,J=6.8Hz,1H),6.11(d,J=11.2Hz ,2H),4.09–3.85(m,5H),3.72–3.43(m,3H),3.09–2.95(m,1H),2.91– 2.81(m,2H),2.82–2.65(m,1H),2.15–2.00(m,1H),1.98–1.89(m,1H).

[0412] Example 10: Synthesis of Compound 10

[0413] Step 1: Compound 10-0 (600 mg, 1.980 mmol) was dissolved in 20 mL of tetrahydrofuran. Under nitrogen protection at 0 °C, lithium tert-butoxide (0.19 mL, 2.178 mmol), N,N-dimethylpropenylurea (0.12 mL, 0.990 mmol), and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.12 mL, 5.940 mmol) were added. After reacting at 30 °C for 6 h, the mixture was washed three times with saturated sodium bicarbonate solution (8 mL) and extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 12:1) to give compound 10-1 (450 mg, 59.1%).

[0414] LCMS [M-55] + m / z:330.0.

[0415] Step 2: Under nitrogen protection, compound 10-1 (450 mg, 1.168 mmol) was dissolved in hydrochloric acid / dioxane (8 mL) solution and reacted at 25 °C for 2 hours. The reaction solution was then evaporated to dryness to obtain compound 10-2 (320 mg, 97.0%), which was used directly in the next step.

[0416] LCMS[M+H]+m / z:286.0.

[0417] Step 3: Compound 10⁻² (320 mg, 1.123 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and methanol (1 mL). 5 mL of an aqueous lithium hydroxide solution (2 M) was added under nitrogen protection at 0 °C. The reaction was carried out at 25 °C for 1 hour. The reaction mixture was adjusted to a weakly acidic state using an aqueous hydrochloric acid solution (6 M), and extracted three times with ethyl acetate (8 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain compound 10⁻³ (300 mg, 98.7%), which was used directly in the next step.

[0418] LCMS[M+H]+m / z:272.0.

[0419] Step 4: Compound 10⁻³ (450 mg, 1.660 mol), diphenyl azide phosphate (685 mg, 2.491 mmol), and triethylamine (503 mg, 4.981 mmol) were dissolved in tert-butanol (15 mL) and stirred at 90 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched in water (10 mL), extracted three times with ethyl acetate (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1) to give the product compound 10⁻⁴ (250 mg, 44.0%).

[0420] LCMS[M+H] + m / z:343.0.

[0421] Step 5: Under nitrogen protection, compound 10⁻⁴ (250 mg, 0.731 mmol) was dissolved in hydrochloric acid / dioxane (6 mL) solution. The reaction was carried out at 25 °C for 2 hours. The reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography (PE:EA = 9:1) to give compound 10⁻⁵ (80 mg, 45.2%), which was used directly in the next step.

[0422] LCMS[M+H] + m / z:243.0.

[0423] Step 6: Compound 10-5 (40 mg, 0.165 mmol) and compound 8-3 (84 mg, 0.248 mmol) were dissolved in 8 mL of 1-methyl-2-pyrrolidone. Under nitrogen protection at 0 °C, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (92 mg, 0.330 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.496 mmol) were added. After reacting at 90 °C for 1 hour, the reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate (8 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography (H₂O:ACN = 3:2) to give compound 10 (10.75 mg, 11.6%).

[0424] LCMS[M+H]+m / z:563.1.

[0425] 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.73(s,1H),7.54(d,J=7.0Hz,1H),7.33(d,J=10.2Hz,1H),6.12(d,J=11.1Hz,2H), 5.86(t,J=6.7Hz,1H),4.08-3.78(m,5H),3.55(t,J=6.3Hz,2H),3.11-2.96(m,1H),2.86-2.70(m,3H),2.13-1.86(m,3H).

[0426] Example 11: Synthesis of Compound 11

[0427] Step 1: Compound 11-0 (4.7 g, 27.6 mmol) and 4,4-difluorocyclohexane-1-one (4.46 g, 33.1 mmol) were dissolved in acetonitrile (30 mL). Triethylsilane (22.0 mL, 138.1 mmol) and trifluoroacetic acid (10.6 mL, 138.1 mmol) were added under nitrogen protection. The reaction mixture was stirred at 80 °C for 2 hours. The reaction solution was then quenched in a saturated ammonium chloride aqueous solution (15 mL), extracted with ethyl acetate (35 mL x 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 11-1 (7.8 g, 98.1%).

[0428] LCMS[M+H] + m / z:289.

[0429] Step 2: Compound 11-1 (1.5 g, 5.20 mmol) was dissolved in a mixed solvent of tetrahydrofuran (12 mL) and methanol (3 mL). Under nitrogen protection at 0 °C, 10 mL of an aqueous lithium hydroxide solution (2 M) was added. After reacting at 25 °C for 1 hour, the reaction solution was adjusted to weakly acidic with an aqueous hydrochloric acid solution (6 M), extracted three times with ethyl acetate (8 mL), and the organic phase was dried over anhydrous sodium sulfate. The dried phase yielded compound 11-2 (1.1 g, 78.6%), which was used directly in the next step.

[0430] LCMS[M+H] + m / z:275.0.

[0431] Step 3: Compound 11-2 (1.0 g, 3.65 mmol), diphenyl azide phosphate (1.15 mL, 5.48 mmol), and triethylamine (1.52 mL, 10.95 mmol) were dissolved in tert-butanol (20 mL). After reacting at 90 °C under nitrogen protection for 1 hour, the reaction solution was quenched in a saturated ammonium chloride aqueous solution (20 mL), extracted three times with ethyl acetate (15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give compound 11-3 (700 mg, 56.0%).

[0432] LCMS[M+H] + m / z:346.0.

[0433] Step 4: Under nitrogen protection, compound 11-3 (700 mg, 2.03 mmol) was dissolved in hydrochloric acid / 1,4-dioxane solution (15 mL). After reacting at 25 °C for 16 hours, the reaction solution was evaporated to dryness. The residue was dissolved in ethyl acetate (20 mL) and washed three times with saturated sodium bicarbonate aqueous solution (10 mL) until the aqueous phase was weakly alkaline. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give product compound 11-4 (450 mg, 90.5%).

[0434] LCMS[M+H] + m / z:246.2.

[0435] Step 5: Compound 11-4 (200 mg, 0.82 mmol) was dissolved in a mixed solvent of dichloromethane (10 mL) and water (5 mL). Sodium carbonate (138 mg, 1.31 mmol) was added, and the mixture was stirred at room temperature for 5 min. Then, triphosgene (97 mg, 0.33 mmol) was added at 0 °C. After continuing the reaction at 25 °C for 1 hour, the reaction solution was slowly poured into a saturated ammonium chloride aqueous solution (15 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting residue, compound 11-5, was used directly in the next step.

[0436] Step 6: Compound 11-5 (100 mg, 0.37 mmol) and compound 4-3 (109 mg, 0.37 mmol) were dissolved in dichloromethane (10 mL), and triethylamine (111 mg, 1.11 mmol) was added at 0 °C. After stirring for 1 hour, the mixture was quenched with saturated ammonium chloride aqueous solution (15 mL), extracted three times with ethyl acetate (8 mL * 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was subjected to Prep-HPLC to prepare compound 11 (20.13 mg, 4.6%).

[0437] LCMS[M+H] + m / z:530.5.

[0438] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.03(d,J=3.2Hz,1H),7.84(s,1H),7.46(d,J= 8.0Hz,1H),7.37(s,1H),7.12(d,J=8.0Hz,1H),6.54(d,J=7.0Hz,1H),6.32-6.27(m,3 H),4.25(d,J=6.0Hz,3H),4.10(dd,J=12.0,4.8Hz,1H),2.78-2.66(m,1H),2.59-2.5 3(m,1H),2.39-2.21(m,1H),2.17-2.04(m,1H),2.05-1.70(m,6H),1.58-1.42(m,2H).

[0439] Example 12: Synthesis of Compound 12

[0440] Step 1: Compound 12-0 (10.0 g, 6.41 mmol) and tetrahydro-pyran-4-one (7.7 g, 7.69 mmol) were dissolved in 100.0 mL of acetonitrile, followed by the addition of triethylsilane (37 g, 32.05 mmol) and trifluoroacetic acid (36.5 g, 32.05 mmol). The mixture was heated to 80 °C under nitrogen protection and stirred for 3 hours. After the reaction was complete, the trifluoroacetic acid was removed by concentration. 100.0 mL of saturated sodium bicarbonate solution was slowly added to the residue, followed by extraction three times with ethyl acetate (120.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to give compound 12-1 (10.0 g, 66.6%).

[0441] LCMS[M+H]+m / z:241.0.

[0442] Step 2: Dissolve compound 12-1 (1.0 g, 4.16 mmol) in 10.0 mL of a mixed solvent of ethyl acetate and ethanol, add 10% palladium / carbon (100.0 mg), and purge the gas three times to ensure the reaction is carried out under a hydrogen atmosphere. Stir the reaction overnight at 25 °C. Filter off the palladium on carbon with diatomaceous earth, and evaporate the filtrate to dryness to obtain compound 12-2 (200.0 mg, 22.8%).

[0443] LCMS[M+H] + m / z:211.0.

[0444] Step 3: Compound 12-2 (70 mg, 0.33 mmol) and intermediate 1 (112.6 mg, 0.33 mmol) were dissolved in 10.0 mL of pyridine solution. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (83.2 mg, 0.396 mmol) was added at 0 °C under nitrogen protection. The reaction mixture was stirred at 25 °C for 14 h. The reaction mixture was quenched with water, extracted three times with ethyl acetate (10.0 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the residue was purified by reversed-phase column chromatography (water:acetonitrile = 1.5:531.4) to give compound 12.

[0445] 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.53(s,1H),7.15(d,J=4.1Hz,1H),7.02–6.81(m, 1H),6.32(d,J=8.6Hz,1H),6.12(d,J=11.2Hz,2H),5.42(d,J=8.2Hz,1H),4.10–3.93(m, 3H),3.91–3.80(m,2H),3.59-3.50(m,3H),3.33-3.21(m,3H),3.07–2.98(m,1H),2.80-2 .74(m,3H),2.14–1.99(m,1H),1.99–1.91(m,1H),1.88-1.80(m,2H),1.40–1.27(m,2H).

[0446] Example 13: Synthesis of Compound 13

[0447] Step 1: Compound 13-0 (10.0 g, 64.1 mmol) was dissolved in 300 mL of dichloromethane, and 10 mL of triethylamine was added. At 0 °C, 16.1 g of a trifluoroacetic anhydride solution in dichloromethane (30 mL) was added to the above solution, and the reaction was carried out at room temperature for 16 hours. The reaction solution was washed three times with water (300 mL × 3), and once with saturated NaHCO3 (300 mL). The organic phase was concentrated and purified by column chromatography (ethyl acetate / petroleum ether: 0 / 100~40 / 100). The concentrated fraction yielded compound 13-1 (16.1 g, 99.7%).

[0448] Step 2: Compound 13-1 (500 mg, 1.98 mmol) was added to a 5 mL THF solution, followed by 200 mL of 1.0 M THF solution (BH3). The mixture was purged three times with nitrogen and heated to 80 °C for 16 h. The reaction was quenched with water and the product was extracted with ethyl acetate. The product was purified by column chromatography (ethyl acetate / petroleum ether = 0 / 100–30 / 100) to obtain compound 13-2 (300 mg, 72.7%).

[0449] 1H NMR (400MHz, DMSO-d6) δ7.38(m,2H),7.14(m,1H),6.83-6.66(m,1H),4.05(m,2H).

[0450] Step 3: Compound 13-2 (300 mg 1.26 mmol) was added to EtOH (6 mL) solution, followed by NH4Cl (400 mg in 2 mL water) and zinc powder (245.7 mg 3.78 mmol). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the mixture was filtered. The filter cake was washed twice with ethanol, and the ethanol was removed by rotary evaporation. Water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 30 / 100) to obtain compound 13-3 (80 mg, 30.5%).

[0451] 1H NMR (400MHz, DMSO-d6) δ6.80–6.59(m,1H),6.11(dd,J=7.9,2.8Hz,1H),5.90-5.74(m,2H),4.87(s,2H),3.73(m,2H).

[0452] Step 4: Compound 13-3 (200 mg, 0.961 mmol) was dissolved in dichloromethane (6 mL), sodium carbonate (160 mg, 1.509 mmol), triphosgene (75 mg, 0.382 mmol), and water (2 mL) were added. The mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, 2 mL of water and 3 x 5 mL of dichloromethane were added to extract the product. The organic phase was dried and concentrated to obtain crude compound 13-4 (120 mg).

[0453] Step 5: Dissolve compound 13-4 (120 mg, 0.576 mmol) in dichloromethane (5 mL), add compound 4-3 (130 mg, 0.512 mmol) and triethylamine (0.2 mL), and stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution, and purify the residue by reversed-phase column chromatography (water / acetonitrile = 1 / 1) to obtain compound 13 (15.0 mg, 5.9%).

[0454] LCMS[M+H]+m / z:493.4.

[0455] 1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.20(s,1H),7.87(s,1H),7.63–7.57(m,1H),7.55 (d,J=8.0Hz,1H),7.49(s,1H),7.20(d,J=8.0Hz,1H),7.09(s,1H),6.96–6.88(m,1H),6.2 4(d,J=8.6Hz,1H),6.09(t,J=6.8Hz,1H),4.40(d,J=4.0Hz,2H),4.19–4.07(m,1H),3.88– 3.69(m,2H),2.77–2.65(m,1H),2.62-2.53(m,1H),2.37-2.28(m,1H),2.18-2.08(m,1H).

[0456] Example 14: Synthesis of Compound 14

[0457] Step 1: Dissolve compound 14-0 (5 g, 23.14 mmol) in 50 mL of acetic anhydride. After reacting at 150 °C for 3 hours under nitrogen protection, remove the solvent from the reaction solution under reduced pressure. The residue obtained is compound 14-1 (5.5 g, 99.1%).

[0458] 1 H NMR (400MHz, CDCl3) δ8.30 (d, J = 2.4Hz, 1H), 7.87 (dd, J = 8.6, 2.4Hz, 1H), 7.42 (d, J = 8.6Hz, 1H), 2.46 (s, 3H).

[0459] Step 2: Compound 14-1 (1.5 g, 6.23 mmol) and 3-aminopiperidin-2,6-dione (0.8 g, 6.23 mmol) were placed in a microwave tube and pyridine (12 mL) was added to dissolve them. After reacting at 140 °C for 1.5 hours, the pyridine was removed under reduced pressure, and acetonitrile (30 mL) was added to dissolve it. Impurities were removed by filtration. The filtrate was evaporated to dryness, and the residue was then slurried with ethyl acetate (10 mL * 2). The solid obtained by filtration was the product compound 14-2 (430 mg, 19.6%).

[0460] LCMS[M+H] + m / z: 350.0; 352.0.

[0461] Step 3: Compound 14-2 (200 mg, 0.573 mmol), (tributyltin)methanol (221 mg, 0.687 mmol), and Xphos-Pd-G3 (48 mg, 0.057 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction was carried out under nitrogen protection at 80 °C for 8 hours, followed by quenching with water (15 mL). The mixture was extracted with ethyl acetate (8 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 16:1) to give product compound 14-3 (100 mg, 52.9%).

[0462] LCMS[M+H] + m / z:302.0.

[0463] Step 4: Compound 14-3 (100 mg, 0.332 mmol) and (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (89 mg, 0.399 mmol) were dissolved in 10 mL of dimethyl sulfoxide. Under nitrogen protection at 0 °C, diphenyl azidophosphate (0.08 mL, 0.399 mmol) and triethylamine (0.14 mL, 0.997 mmol) were added. After reacting at 90 °C for 1 hour, the reaction was quenched with saturated sodium bicarbonate aqueous solution (15 mL), extracted with ethyl acetate (8 mL * 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was subjected to Prep-HPLC to prepare product compound 14 (25.44 mg, 14.5%).

[0464] LCMS[M+H] + m / z:523.3.

[0465] 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),9.92(s,1H),8.10(d,J=1.8Hz,1H),7.89-7.79(m,2H),7.65(d,J=8.3Hz,1H),7.38 (dd,J=10.4,9.2Hz,1H),7.15-7.11(m,1H),5.34-5.23(m,3H),2.88-2.80(m,1H),2.73-2.55(m,5H),2.24-2.07(m,1H).

[0466] Example 15 Preparation of Compound 15

[0467] Step 1: Dissolve compound 15-0 (300 mg, 1.282 mmol) in anhydrous dimethyl sulfoxide (10 mL), add triethylamine (0.3 mL) and diphenyl azidophosphate (0.22 mL), stir at room temperature for 1 hour, add water (2 mL), heat to 90 °C and stir for 30 minutes. After the reaction is complete, cool to room temperature, purify the reaction solution by reversed-phase column chromatography (water / acetonitrile = 1 / 1) to obtain compound 15-1, extract the product with dichloromethane (10 mL * 3), and concentrate to 5 mL for direct use in the next step.

[0468] LCMS[M+H]+m / z:calcd 239.0; found 239.0.

[0469] Step 2: To compound 15-1 (5 mL), pyridine (0.15 mL), 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)acetic acid (50 mg, 0.147 mmol), and phosphorus oxychloride (0.1 mL) were added under ice bath conditions, and the mixture was reacted at room temperature for 30 minutes. After the reaction was complete, the reaction solution was added dropwise to saturated sodium bicarbonate ice water, and dichloromethane (5 mL * 3) was added to extract the product. The combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated, and the residue was purified by reversed-phase column chromatography (water / acetonitrile = 1 / 1) to give compound 15 (15 mg).

[0470] LCMS[M+H]+m / z:calcd 532.1; found 532.3.

[0471] 1 H NMR (400MHz, DMSO-d6) δ10.85 (s, 1H), 10.06 (s, 1H), 8.11 (d, J = 3.3Hz, 1H) ,7.64–7.29(m,1H),7.29–7.03(m,1H),6.12(d,J=11.1Hz,2H),4.09–3.96 (m,3H),3.56(t,J=6.2Hz,2H),3.09–3.01(m,1H),2.84(d,J=7.6Hz,2H),2 .80–2.72(m,1H),2.50-2.46(m,1H),2.15–2.02(m,1H),2.00–1.88(m,1H).

[0472] Example 16 Preparation of Compound 16

[0473] Step 1: Intermediate 1 (3 g, 20.84 mmol), diphenyl azidophosphate (3.49 g, 12.67 mmol), and triethylamine (2.56 g, 25.33 mmol) were added to 40 mL of dimethyl sulfoxide. After stirring at room temperature for 1 hour, water (182.6 mg, 10.13 mmol) was added, and the mixture was heated to 90 °C and stirred for 3 hours. After the reaction was complete, the reaction solution was diluted with water (40 mL), extracted with ethyl acetate (20 mL * 3), the organic phase was collected, washed with saturated sodium chloride, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 12 / 1) to obtain the target compound 16-1 (800.1 mg, 29.0%).

[0474] LCMS[M-56] + m / z:calcd 271.0, found 271.1.

[0475] Step 2: Compound 16-2 (800 mg, 2.45 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate (20 mL * 3). The organic phase was collected, washed with saturated sodium chloride, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the target compound 16-3 (340 mg, 61.3%).

[0476] LCMS[M+H] + m / z:calcd 227.1, found 227.0.

[0477] Step 3: Compound 16-3 (90 mg, 0.39 mmol), 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)acetic acid (134.6 mg, 0.39 mmol), and pyridine (155.4 mg, 1.99 mmol) were dissolved in 5 mL of N,N-dimethylformamide. After cooling to 0 °C, phosphorus oxychloride (61.0 mg, 0.39 mmol) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction mixture was slowly added dropwise to ice-cold saturated sodium bicarbonate aqueous solution, and then extracted with water (10 mL) and ethyl acetate (10 mL * 3). The organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by reverse column chromatography to obtain target compound 16 (17.83 mg, 8.2%).

[0478] LCMS[M+H] + m / z:calcd 547.4, found 547.4.

[0479] 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.62(s,1H),7.36(t,J=8.4Hz,1H),7.19(t,J=10.8Hz,1H),6.12(d,J=11.2Hz,2H),6.02(d,J=7.2Hz ,1H),4.05–3.96(m,3H),3.90–3.79(m,2H),3.59–3.52(m,2H),3.08– 2.97(m,1H),2.83–2.71(m,3H),2.46-2.46(m,1H)2.14–1.89(m,2H).

[0480] Example 17: Synthesis of Compound 17

[0481] Step 1: 17-1 (1.3 g, 4.85 mmol), Zn(CN)2 (683 mg, 5.82 mmol), Pd2(dba)3 (228 mg, 0.24 mmol), and XPhos (234 mg, 0.49 mmol) were dissolved in 15 mL of DMF. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 12 hours. After the reaction was complete, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL * 3). The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the target compound 17-2 (950 mg, 83.6%).

[0482] LCMS[M+MeCN]+m / z:calcd.:257.2,found:257.0.

[0483] Step 2: Dissolve 17-2 (900 mg, 4.185 mmol) in 8 mL of DMF, evacuate and purge with nitrogen, then cool to 0 °C. Add SM2 (360 mg, 5.02 mmol) and potassium tert-butoxide (702 mg, 6.3 mmol), and continue the reaction at low temperature for 0.5 hours. After the reaction is complete, extract the reaction mixture with water (10 mL) and ethyl acetate (10 mL * 3). Collect the organic phase and wash with saturated sodium chloride. Dry the mixture with anhydrous sodium sulfate, evaporate to dryness, and purify the residue by silica gel column chromatography (DCM / MeOH = 100 / 5-100 / 8) to obtain the target compound 17-3 (450 mg, 42.4%).

[0484] LCMS[M+H]+m / z:calcd.:255.1,found:255.0.

[0485] Step 3: Dissolve 17-3 (200 mg, 0.78 mmol) in 30 mL of methanol, then add 10% palladium / carbon (200 mg) and concentrated hydrochloric acid (0.57 mL). Stir the reaction solution overnight at room temperature under a hydrogen atmosphere. After the reaction is complete, filter the reaction solution with diatomaceous earth and wash with methanol. Then, evaporate the filtrate to dryness to obtain the target compound 17-4 (70 mg, 34.8%).

[0486] 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.59(s,2H),7.95(s,1H),7.84–7.70(m,1H),7.62(d,J=7.9Hz,1H) ,7.36(d,J=8.0Hz,1H),4.13(dd,J=14.4,4.8Hz,3H),2.76(m,1H),2.58(m,1H),2.34(m,1H),2.11(m,1H).

[0487] Step 4: Compound 17-4 (120 mg, 0.46 mmol) and 5-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)-2,4-difluorobenzoic acid (150 mg, 0.42 mmol) were dissolved in toluene (8 mL). Diphenyl azidophosphate (0.11 mL, 0.51 mmol) and triethylamine (0.12 mL, 0.84 mmol) were added under nitrogen protection at 0 °C. After reacting at 90 °C for 1 hour, the reaction was quenched with saturated sodium bicarbonate aqueous solution (15 mL), extracted with ethyl acetate (8 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain product 17-5 (260 mg, 91.5%).

[0488] LCMS [M-55] + m / z:calcd 555.2, found 555.2.

[0489] Step 5: Compound 17-5 (260 mg) was dissolved in 10 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. After reacting at 25 °C for 1 hour, the reaction solution was evaporated to dryness. The residue was washed with saturated sodium bicarbonate aqueous solution (5 mL * 3), extracted with ethyl acetate (8 mL * 3), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by reversed-phase column chromatography (pure water: acetonitrile = 3:2) to give compound 17 (18.98 mg, 8.7%).

[0490] LCMS[M+H] + m / z:calcd 511.1,found 511.3.

[0491] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.21(s,1H),7.87(s,1H),7.71(t,J=8.9H z,1H),7.54(d,J=8.0Hz,1H),7.48(s,1H),7.20-7.11(m,2H),7.03(t,J=5.7Hz, 1H),5.94(t,J=6.3Hz,1H),4.40(d,J=5.7Hz,2H),4.13(dd,J=11.9,4.9Hz,1H), 3.85-3.76(m,2H),2.78-2.66(m,1H),2.60-2.54(m,1H),2.37-2.26(m,1H),2.14 -2.07(m, 1H).

[0492] Example 18 Preparation of Compound 18

[0493] Step 1: Compound 18-1 (7.0 g, 41.034 mmol) was dissolved in concentrated sulfuric acid (50.0 mL), and then N-iodosuccinimide (10.16 g, 45.137 mmol) was added in portions. The reaction mixture was allowed to react overnight at room temperature. The reaction mixture was then slowly poured into an ice-cold saturated sodium bicarbonate solution for neutralization, and then extracted three times with ethyl acetate (100.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give compound 18-2 (11 g, 90.4%).

[0494] 1 H NMR (400MHz, DMSO-d6) δ8.25(d,J=1.6Hz,1H),7.89(d,J=1.2Hz,1H),2.56(s,3H).

[0495] Step 2: Compound 18-2 (11.0 g, 37.101 mmol), methyl iodoformate (7.9 g, 55.652 mmol), and potassium carbonate (15.4 g, 111.303 mmol) were placed in N,N-dimethylformamide (60.0 mL), and the reaction mixture was reacted overnight at room temperature. Water (300.0 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (100.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give compound 18-3 (11.8 g, 100.0%).

[0496] 1H NMR (400MHz, DMSO-d6) δ8.27(d,J=1.6Hz,1H),7.91(d,J=1.6Hz,1H),3.86(s,3H),2.58(s,3H).

[0497] Step 3: Compound 18-3 (2.0 g, 6.441 mmol), tert-butyl carbamate (1.13 g, 9.661 mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (307 mg, 0.644 mmol), cesium carbonate (6.3 g, 19.322 mmol), and tris(dibenzylacetone)palladium (590 mg, 0.644 mmol) were placed in dioxane (30.0 mL), and the reaction mixture was reacted overnight at 100 °C. The reaction mixture was extracted three times with ethyl acetate (10.0 mL), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give compound 18-4 (700.0 mg, 36.2%).

[0498] LCMS[M+H-56] + m / z:calcd 244.1;found 244.0.

[0499] Step 4: Compound 18-4 (376 mg, 1.254 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (582 mg, 2.508 mmol), lithium tert-butoxide (110 mg, 1.379 mmol), and N,N-dimethylpropenylurea (80 mg, 0.627 mmol) were placed in tetrahydrofuran (10.0 mL), and the reaction mixture was reacted overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give crude product 18-5 (250.1 mg).

[0500] LCMS[M+H-56] + m / z:calcd 326.1; found 326.0.

[0501] Step 5: Compound 18-5 (1.2 g) was dissolved in ethyl acetate solution of hydrochloric acid (10.0 mL), and the reaction solution was reacted at room temperature for two hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound 18-6 (850.2 mg).

[0502] LCMS[M+H] + m / z:calcd 282.0; found 282.0.

[0503] Step 6: Compound 18-6 (850 mg, 3.025 mmol) and lithium hydroxide (635 mg, 15.125 mmol) were dissolved in methanol and water (1 / 1, 20.0 mL), and the reaction mixture was reacted overnight at room temperature. The reaction mixture was adjusted to acidity and extracted three times with ethyl acetate (10.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give compound 18-7 (680 mg, 84.0%).

[0504] LCMS[M+H] + m / z:calcd 268.0; found 268.0.

[0505] Step 7: Compound 18-7 (300.0 mg, 1.13 mmol) was dissolved in 5 mL of dimethyl sulfoxide, followed by the addition of diphenyl azidophosphate (465.2 mg, 1.69 mmol) and triethylamine (340.5 mg, 3.37 mmol). The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection, then 0.5 mL of water was added, and the temperature was raised to 90 °C, and the reaction was continued for 30 minutes. After the reaction was completed, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL * 3), the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 3) to obtain the target compound 18-8 (50.2 mg, 12.6%).

[0506] LCMS [M-55] + m / z:calcd 239.0, found 239.0.

[0507] Step 8: Compound 18-8 (50.2 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), and sodium carbonate (35.6 mg, 0.33 mmol) was dissolved in water (1 mL). The mixture was stirred for 5 minutes under nitrogen protection, and triphosgene (24.9 mg, 0.084 mmol) was added. Stirring was continued for another 30 minutes. After the reaction was complete, the reaction solution was extracted with water (10 mL) and dichloromethane (10 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 18-9, which was then directly used for the next reaction.

[0508] Step 9: Dissolve 18-9 (crude product) and 17-4 (54.2 mg, 0.21 mmol) in dichloromethane (4 mL) and N,N-dimethylformamide (2 mL), then add triethylamine (63.6 mg, 0.63 mmol). The reaction mixture is stirred at room temperature for 30 minutes under nitrogen protection. After the reaction is complete, the reaction mixture is extracted with water (10 mL) and dichloromethane (10 mL * 3). The organic phase is collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue is purified by reversed-phase column chromatography (water / acetonitrile = 41%) to obtain the target compound 18 (4.68 mg, 4.3%).

[0509] LCMS[M+H] + m / z:calcd 523.1, found 523.3.

[0510] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.52(s,1H),7.86(s,1H),7.53(d,J=8.0 Hz,1H),7.47(s,1H),7.19(d,J=8.4Hz,1H),7.06(s,1H),6.76–6.58(m,2H),5. 75(t,J=6.4Hz,1H),4.38(d,J=5.6Hz,2H),4.16–4.08(m,1H),3.90–3.83(m,2H ),2.78–2.68(m,1H),2.60–2.53(m,1H),2.40–2.26(m,1H),2.17–2.00(m,4H).

[0511] Example 19: Synthesis of Compound 19

[0512] Step 1: Dissolve 19-1 (10.0 g, 55.802 mmol) in 90 mL of fuming nitric acid, add 24 mL of concentrated sulfuric acid, and stir at 45 °C for 15 hours. After the reaction is complete, add the reaction solution dropwise to ice water (100 mL), extract with ethyl acetate (50 mL * 3), combine the organic phases, wash with saturated sodium bicarbonate aqueous solution, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain 19-2 (4.6 g, 37.1%).

[0513] 1 H NMR (400MHz, CDCl3) δ8.93 (d, J = 6.1 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H).

[0514] Step 2: Dissolve 19-2 (4.6 g, 20.534 mmol) in acetic acid (10 mL), add iron powder (16.0 g, 285.714 mmol), and stir the reaction solution at room temperature for 12 hours under nitrogen protection. After the reaction is complete, filter the reaction solution, add water (50 mL) and ethyl acetate (50 mL * 3) to the filtrate for extraction, combine the organic phases and wash with saturated sodium bicarbonate aqueous solution, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain 19-3 (2.1 g, 56.7%).

[0515] LCMS[M+H]+m / z:calcd 195.2; found 195.0.

[0516] Step 3: Dissolve 19-3 (2.1 g, 12.370 mmol) in dichloromethane, add triethylamine (4 mL), di-tert-butyl dicarbonate (8.2 g, 37.614 mmol), and 4-dimethylaminopyridine (150 mg, 1.228 mmol), and stir at room temperature for 12 hours. After the reaction is complete, concentrate the reaction solution and purify it by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 19-4 (3.1 g, 73.8%).

[0517] 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=9.9Hz,1H),8.06(d,J=6.4Hz,1H),3.90(s,3H),1.39(s,18H).

[0518] Step 4: Dissolve 19-4 (3.1 g, 8.373 mmol) in dichloromethane, add triethylamine (6 mL) and copper trifluoromethanesulfonate (300 mg, 0.831 mg), and stir at room temperature for 1 hour. After the reaction is complete, extract with water (20 mL) and ethyl acetate (20 mL * 3), combine the organic phases and dry them with anhydrous sodium sulfate, then evaporate to dryness to obtain 19-5 (1.9 g, 82.6%).

[0519] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.99(d,J=10.2Hz,1H),7.93(d,J=6.4Hz,1H),3.89(s,3H),1.48(s,9H).

[0520] Step 5: Dissolve 19-5 (1.9 g, 6.432 mmol) in dimethyl sulfoxide, add potassium carbonate (2.7 g, 19.565 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (7.49 g, 32.284 mmol), and stir at 60 °C for 3 hours. After the reaction is complete, extract with water (30 mL) and ethyl acetate (30 mL * 3), combine the organic phases and wash with saturated sodium chloride aqueous solution (20 mL * 3), dry to anhydrous sodium sulfate, evaporate to dryness, and purify the residue by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 19-6 (700 mg, 29.1%).

[0521] 1 H NMR (400MHz, DMSO-d6) δ8.15(t,J=7.8Hz,1H),4.88–4.34(m,1H),3.89(d,J=6.2Hz,2H),1.52–1.30(m,5H).

[0522] Step 6: Dissolve 19-6 (700 mg, 1.861 mmol) in dioxane hydrochloride (10 mL) and stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution to obtain 19-7 (510 mg, 100%).

[0523] LCMS[M+H]+m / z:calcd 277.1; found 277.0.

[0524] Step 7: Dissolve 19-7 (510 mg, 2.653 mmol) in tetrahydrofuran / methanol = 4 / 1 (10 mL), add 2M lithium hydroxide aqueous solution (4 mL), and stir at room temperature for 2 hours. After the reaction is complete, adjust the pH to weak acidity with dilute hydrochloric acid, add water (10 mL) and ethyl acetate (10 mL * 3), extract, combine the organic phases and dry them with anhydrous sodium sulfate, then evaporate to dryness to obtain 19-8 (480 mg, 100%).

[0525] LCMS[M+H]+m / z:calcd 263.0; found 263.

[0526] Step 8: Dissolve 19-8 (480 mg, 1.832 mmol) in tert-butanol (10 mL), add triethylamine (0.77 mL) and diphenyl azidophosphate (75 mg, 0.272 mmol), and stir at 90 °C for 2 hours. After the reaction is complete, extract with water (10 mL) and ethyl acetate (10 mL * 3), combine the organic phases and dry them with anhydrous sodium sulfate. Reduce the concentration by rotary evaporation and purify by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 19-9 (440 mg, 72.1%).

[0527] LCMS[M+H]+m / z:calcd 334.1; found 334.2.

[0528] Step 9: Dissolve 19-9 (440 mg, 1.321 mmol) in trifluoroacetic acid (3 mL) and stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution, extract with water (5 mL) and ethyl acetate (5 mL * 3), combine the organic phases and wash with saturated sodium bicarbonate aqueous solution, dry to anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography to obtain 19-10 (210 mg, 68.4%).

[0529] LCMS[M+H]+m / z:calcd 234.1; found 234.0.

[0530] Step 10: Compound 19-10 (120 mg, 0.515 mmol) was dissolved in 10 mL of a mixed solvent of dichloromethane and water. Sodium carbonate (87 mg, 0.824 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Then, triphosgene (76 mg, 0.258 mmol) was added at 0 °C, and the reaction was continued at 25 °C for 1 hour. The reaction solution was slowly poured into a saturated ammonium chloride aqueous solution (10 mL), extracted with dichloromethane (8 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting residue 19-11 was used directly in the next step.

[0531] Step 11: 19-11 (100 mg, 0.386 mmol) and 3-(6-(aminomethyl)benzofuran-3-yl)piperidin-2,6-dione (100 mg, 0.386 mmol) were dissolved in a mixed solvent of dichloromethane (10 mL) and N,N-dimethylformamide (1 mL). Triethylamine (117 mg, 1.158 mmol) was added at 0 °C. After reacting for 1 hour, the reaction was quenched with saturated ammonium chloride aqueous solution (10 mL), and extracted three times with ethyl acetate (8 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reversed-phase column chromatography (water / acetonitrile = 45%) to obtain target compound 19 (17.07 mg, 6.4%).

[0532] LCMS[M+H] + m / z:calcd 518.1, found 518.3.

[0533] 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.74(d,J=2.6Hz,1H),7.96(d,J=6.8Hz,1H) ,7.88(s,1H),7.55-7.49(m,3H),7.34(t,J=5.6Hz,1H),7.20(d,J=7.8Hz,1H),6.45 (t,J=6.4Hz,1H),4.43(d,J=5.6Hz,2H),4.13(dd,J=13.2,5.2Hz,1H),4.02-3.81( m,2H),2.81-2.65(m,1H),2.59-2.53(m,1H),2.37-2.25(m,1H),2.16-2.04(m,1H).

[0534] Example 20: Synthesis of Compound 20

[0535] Step 1: Add 1.2 g of zinc powder to 8 mL of N,N-dimethylacetamide. Heat the reaction mixture to 65 °C under argon protection. Add trimethylchlorosilane (0.24 g, 2.28 mmol) and dibromoethane (0.196 mL, 2.28 mmol). Continue stirring for 40 minutes. Then, add compound 20-1 (4.0 g, 14.12 mmol) in portions and stir for 30 minutes each time. After the reaction is complete, cool the reaction mixture to room temperature. The reaction mixture can be used directly in the next step.

[0536] Step 2: INT-2-3 (540.0 mg, 1.68 mmol) was dissolved in N,N-dimethylacetamide (6 mL), followed by the addition of 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (128.4 mg, 0.175 mmol) and cuprous iodide (35.0 mg, 0.184 mmol). Under nitrogen protection, 10 mL of the reaction solution obtained in Step 1 was rapidly added, and the mixture was then heated to 85 °C and stirred overnight. After the reaction was complete, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95:5) to obtain the target compound 20-3 (200 mg, 29.8%).

[0537] LCMS [M-55] + m / z:calcd 344.2, found 344.2.

[0538] Step 3: Compound 20-3 (200.0 mg, 0.50 mmol) was dissolved in 3 mL of dichloromethane, followed by the addition of 1 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was directly evaporated to dryness. The residue was purified by reversed-phase column chromatography (water / acetonitrile = 18%) to obtain the target compound 20-4 (120 mg, 80.0%).

[0539] LCMS[M+H] + m / z:calcd 300.1, found 300.0.

[0540] Step 4: Dissolve 4,6-difluoro-N1-(2,2,2-trifluoroethyl)benzene-1,3-diamine (130.0 mg, 0.58 mmol) in dichloromethane (4 mL), and dissolve sodium carbonate (98.0 mg, 0.92 mmol) in water (1 mL). Mix the two solutions and stir for 5 minutes under nitrogen protection. Add triphosgene (69.0 mg, 0.23 mmol), and continue stirring for 30 minutes. After the reaction is complete, extract the reaction solution with water (10 mL) and dichloromethane (10 mL * 3). Collect the organic phase, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain compound 20-5, which can be directly used for the next reaction.

[0541] Step 5: Compound 20-4 (120.0 mg, 0.40 mmol) and compound 20-5 (crude product) were dissolved in dichloromethane (4 mL) and N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (121.2 mg, 1.20 mmol). The reaction mixture was stirred at room temperature for 30 minutes under nitrogen protection. After the reaction was completed, the reaction mixture was extracted with water (10 mL) and dichloromethane (10 mL * 3). The organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by reversed-phase column chromatography (water / acetonitrile = 45%) to obtain target compound 20 (33.70 mg, 15.3%).

[0542] LCMS[M+H] + m / z:calcd 552.2, found 552.4.

[0543] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.14(s,1H),7.75(s,1H),7.69–7.58(m,2H),7.18–7.09(m,2H),5.97(t,J=6.0Hz,1H),5.21–5.07 (m,1H),4.45–4.38(m,4H),3.95(s,3H),3.90–3.83(m,2H),3.00–2.84(m,1H),2.64-2.58(m,1H),2.46–2.37(m,1H),2.09–1.98(m,1H).

[0544] Example 21: Synthesis of Compound 21

[0545] Step 1: Compound 21-0 (1 g, 3.716 mmol) and potassium tert-butoxide (500 mg, 4.459 mmol) were placed in 20 mL of dimethylformamide and stirred. Acrylamide (317 mg, 4.459 mmol) was slowly added under nitrogen protection at 0 °C. The reaction mixture was brought to room temperature and reacted for half an hour. The reaction was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (10.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30%) to obtain compound 21-1 (450 mg, 39.3%).

[0546] LCMS[M+H] + m / z:calcd 308.0,310.0; found 308.0,310.0.

[0547] Step 2: Compound 21-1 (540 mg, 1.753 mmol), cuprous iodide (42 mg, 0.221 mmol), and bis(diphenylphosphine)ferrocene palladium dichloride (132 mg, 0.162 mmol) were dried at high temperature and placed in dimethylacetamide (6.0 mL). Under nitrogen protection, a dimethylacetamide solution (10.0 mL) of (1-(tert-butoxycarbonyl)azacyclobutane-3-yl)zinc(II) iodide was added. The reaction mixture was reacted overnight at 85 °C. The reaction mixture was extracted three times with ethyl acetate (10.0 mL), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 7%) to obtain crude product 21-2 (800.1 mg).

[0548] LCMS[Mt-Bu+H] + m / z:calcd 329.2; found 329.0.

[0549] Step 3: The crude product 21-2 (800.1 mg) was dissolved in a mixed solution of trifluoroacetic acid and dichloromethane (1 / 3, 12.0 mL), and the reaction solution was reacted at room temperature for one hour. The reaction solution was evaporated to dryness, and the residue was purified by reversed-phase column chromatography (acetonitrile / water = 0%) to give compound 21-3 (200.2 mg, two-step yield 40.0%).

[0550] LCMS[M+H] + m / z:calcd 285.1; found 285.0.

[0551] Step 3: Dissolve 4,6-difluoro-N1-(2,2,2-trifluoroethyl)benzene-1,3-diamine (50 mg, 0.221 mmol) and sodium carbonate (38 mg, 0.354 mmol) in a mixture of water and dichloromethane (1 / 3, 12.0 mL). Add triphosgene (26 mg, 0.088 mmol) and react the solution at room temperature for one hour. Extract the reaction solution three times with dichloromethane (5.0 mL), evaporate to dryness, dissolve in tetrahydrofuran (2.0 mL), and then add to a suspension of compound 21-3 (50 mg, 0.176 mmol) and triethylamine (53 mg, 0.528 mmol) in tetrahydrofuran (5.0 mL). Continue the reaction for half an hour. After the reaction is complete, evaporate to dryness, and purify the residue by reversed-phase column chromatography (acetonitrile / water = 40%) to obtain compound 21 (25 mg, 26.5%).

[0552] LCMS[M+H] + m / z:calcd 537.2; found 537.0.

[0553] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.12(s,1H),7.89(s,1H),7.60–7.57(m,2H),7.27(d,J =8.8Hz,1H),7.16(d,J=11.2Hz,1H),7.12–7.08(m,1H),5.98(d,J=6.0Hz,1H),4.37(d,J=7.2 Hz,2H),4.14(dd,J=12.0,4.8Hz,1H),3.98(d,J=5.6Hz,2H),3.95–3.92(m,1H),3.85(dd,J=1 6.4,9.2Hz,2H),2.79–2.70(m,1H),2.61–2.55(m,1H),2.37–2.29(m,1H),2.15–2.09(m,1H).

[0554] Example 22: Synthesis of Compound 22

[0555] Step 1: Compound 22-1 (200.0 mg, 0.96 mmol) was dissolved in dichloromethane (8.0 mL), and sodium carbonate (162.5 mg, 1.52 mmol) was dissolved in water (2.0 mL). The mixture was stirred for 5 minutes under nitrogen protection, and triphosgene (113.8 mg, 0.38 mmol) was added. Stirring was continued for another 30 minutes. After the reaction was complete, the reaction solution was extracted with water (10.0 mL) and dichloromethane (10.0 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 22-2, which was then directly used for the next reaction.

[0556] Step 2: 3-(6-(azacyclobutan-3-yl)benzofuran-3-yl)piperidine-2,6-dione (240.0 mg, 0.80 mmol) and compound 22-2 (crude product) were dissolved in dichloromethane (6.0 mL) and N,N-dimethylformamide (2.0 mL), followed by the addition of triethylamine (242.2 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 30 minutes under nitrogen protection. After the reaction was complete, the reaction mixture was extracted with water (10.0 mL) and dichloromethane (10.0 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by reversed-phase column chromatography (water / acetonitrile = 45%) to obtain the target compound 22 (5.02 mg, 1.0%).

[0557] LCMS[M+H] + m / z:calcd 519.2, found 519.3.

[0558] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.02(s,1H),7.89(s,1H),7.59-7.57(m,2H),7.28(d,J=9 .2Hz,1H),7.06(dd,J=6.8,2.8Hz,1H),6.97–6.91(m,1H),6.42-6.39(m,1H),6.13(t,J=6.8Hz, 1H),4.40(t,J=7.8Hz,2H),4.14(dd,J=12.4,4.8Hz,1H),4.02–3.93(m,3H),3.86–3.77(m,2H), 2.79–2.68(m,1H),2.61–2.55(m,1H),2.35-2.30(m,1H),2.16–2.08(m,1H),2.04-1.98(m,1H).

[0559] Example 23: Synthesis of Compound 23

[0560] Step 1: Compound 23-1 (5.0 g, 27.296 mmol) and di-tert-butyl dicarbonate (11.9 g, 54.591 mmol) were dissolved in ethanol (100.0 mL), and the reaction mixture was reacted overnight at room temperature. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give compound 23-2 (7.5 g, 97.0%).

[0561] LCMS [M-55] + m / z:calcd 228.1; found 228.0.

[0562] Step 2: Compound 23-2 (4.0 g, 14.119 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (6.55 g, 28.239 mmol), lithium tert-butoxide (1.24 g, 15.531 mmol), and N,N-dimethylpropenylurea (900 mg, 7.060 mmol) were placed in tetrahydrofuran (60.0 mL), and the reaction mixture was reacted overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give crude product 23-3 (3.6 g, 69.8%).

[0563] LCMS [M-55] + m / z:calcd 310.1;found 310.0.

[0564] Step 3: Compound 23-3 (3.6 g, 9.854 mmol) was dissolved in a dioxane solution (30.0 mL) of hydrochloric acid, and the reaction was carried out at room temperature for two hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 23-4 (2.5 g, 95.7%).

[0565] LCMS[M+H] + m / z:calcd 266.1; found 266.0.

[0566] Step 4: Compound 23-4 (2.5 g, 9.426 mmol) and lithium hydroxide (2.4 g, 56.559 mmol) were dissolved in methanol and water (1 / 1, 40.0 mL), and the reaction mixture was reacted at room temperature for three hours. The reaction mixture was adjusted to acidity and extracted three times with ethyl acetate (20.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give compound 23-5 (2.25 g, 95.0%).

[0567] LCMS[M+H] +m / z:calcd 252.1; found 252.0.

[0568] Step 5: Compound 23-5 (2.0 g, 7.962 mmol), diphenyl azidophosphate (3.28 g, 11.944 mmol), and triethylamine (2.41 g, 23.887 mmol) were dissolved in anhydrous tert-butanol (40.0 mL). The reaction mixture was reacted at 90 °C for three hours. The reaction mixture was extracted three times with ethyl acetate (10.0 mL), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 23-6 (1.3 g, 50.7%).

[0569] LCMS [M-55] + m / z:calcd 267.1; found 267.0.

[0570] Step 6: Compound 23-6 (1.3 g, 4.034 mmol) was dissolved in a dioxane solution (15.0 mL) of hydrochloric acid, and the reaction was carried out at room temperature for two hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give compound 23-7 (640 mg, 71.4%).

[0571] LCMS[M+H] + m / z:calcd 223.1; found 223.0.

[0572] Step 7: Compound 23-7 (90 mg, 0.405 mmol), triphosgene (60 mg, 0.203 mmol), and triethylamine (205 mg, 2.205 mmol) were dissolved in tetrahydrofuran (15.0 mL). The reaction mixture was reacted at room temperature for half an hour, and then 3-(6-(aminomethyl)benzofuran-3-yl)piperidin-2,6-dione (104 mg, 0.405 mmol) was added, and the reaction was continued for another half hour. The reaction mixture was concentrated, and the residue was purified by reversed-phase column chromatography (acetonitrile / water = 35%) to give compound 23 (70 mg, 34.1%).

[0573] LCMS[M+H] + m / z:calcd 507.2; found 507.3.

[0574] 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.14(s,1H),7.87(s,1H),7.56(dd,J=12.0,7.6Hz, 2H),7.48(s,1H),7.19(d,J=8.0Hz,1H),7.02(t,J=5.6Hz,1H),6.86(d,J=11.6Hz,1H),5.2 9(t,J=6.8Hz,1H),4.40(d,J=5.6Hz,2H),4.13(dd,J=12.0,4.8Hz,1H),3.84–3.75(m,2H) ,2.79–2.70(m,1H),2.59–2.54(m,1H),2.37–2.27(m,1H),2.13–2.09(m,1H),2.04(s,3H).

[0575] Example 24: Synthesis of Compound 24

[0576] Step 1: Compound 24-1 (25.0 g, 135.579 mmol) and triethylamine (26.6 g, 263.158 mmol) were dissolved in ultra-dry dichloromethane (500.0 mL). Acetyl chloride (15.3 g, 194.764 mmol) was added in portions at 0 °C, and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was quenched with ice water and extracted three times with ethyl acetate (100.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give compound 24-2 (30.1 g, 95.8%), which was used directly in the next step.

[0577] Step 2: Compound 24-2 (30.0 g, 0.129 mol) was dissolved in 250 mL of dichloromethane, and aluminum trichloride (51.7 g, 0.388 mol) was added in portions at 0 °C. After reacting at 0 °C for 10 minutes, the solvent was removed under reduced pressure. The resulting residue was reacted at 140 °C for 3 hours, and then slowly cooled to room temperature. Crushed ice was added to the reaction solution, and 10% hydrochloric acid aqueous solution (150 mL) was slowly added at 0 °C. The mixture was extracted with ethyl acetate (50 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 9:1) to give compound 24-3 (25.0 g, 83.3%).

[0578] 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),7.65(dd,J=8.8,1.6Hz,1H),7.26(dd,J=8.8,6.0Hz,1H),2.65(s,3H).

[0579] Step 3: Compound 24-3 (17.0 g, 0.073 mol) was dissolved in a mixed solvent of ethyl acetate (100 mL) and chloroform (100 mL), and copper bromide (32.3 g, 0.146 mol) was added in portions. After reacting for 16 hours under nitrogen protection at 90 °C, the copper bromide was filtered through diatomaceous earth. Triethylamine (14.8 g, 0.146 mol) was added to the filtrate, and the reaction was continued at 25 °C for 2 hours. The reaction solution was then quenched in a saturated ammonium chloride aqueous solution (150 mL), extracted with ethyl acetate (70 mL * 3), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 33:1) to give product 24-4 (8.5 g, 50.6%).

[0580] 1 H NMR(400MHz,DMSO-d6)δ7.45-7.43(m,2H),4.95(s,2H).

[0581] Step 4: Dissolve 24-4 (8.5 g, 0.037 mol) and ethoxyformylmethylenetriphenylphosphine (15.4 g, 0.044 mol) in toluene (120 mL). After reacting at 130 °C for 18 hours, quench the reaction mixture in water (80 mL), extract three times with ethyl acetate (30 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain product 24-5 (5.7 g, 51.4%).

[0582] 1 H NMR (400MHz, DMSO-d6) δ8.05 (s, 1H), 7.53-7.50 (m, 1H), 7.41 (d, J = 8.4Hz, 1H), 4.11 (q, J = 7.2Hz, 2H), 3.82 (s, 2H), 1.19 (t, J = 7.2Hz, 3H).

[0583] Step 5: Dissolve 24-5 (4.1 g, 13.67 mmol), potassium N-aminomethyltrifluoroborate (3.9 g, 16.40 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (0.9 g, 1.36 mmol), and cesium carbonate (13.35 g, 40.99 mmol) in a mixed solvent of toluene (50 mL) and water (5 mL). After reacting at 150 °C under nitrogen protection for 16 hours, the reaction solution was quenched in water (30 mL), extracted three times with ethyl acetate (20 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give product 24-6 (3.0 g, 62.5%).

[0584] 1 H NMR(400MHz, DMSO-d6)δ7.98(s,1H),7.44(t,J=5.6Hz,1H),7.37(d,J=8.0Hz,1H),7.25-7.16(m,1 H), 4.27 (d, J = 5.7Hz, 2H), 4.11 (q, J = 7.1Hz, 2H), 3.79 (s, 2H), 1.38 (s, 9H), 1.19 (t, J = 7.1Hz, 3H).

[0585] Step 6: Compound 24-6 (3.5 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (40 mL). Acrylamide (897 mg, 13.0 mmol) and potassium tert-butoxide (1.42 g, 13.0 mmol) were added under nitrogen protection at 0 °C. After reacting for 20 minutes, the reaction solution was quenched in saturated sodium chloride (40 mL), extracted with ethyl acetate (15 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane:methanol = 25:1) to give product 24-7 (3.2 g, 80.8%).

[0586] Step 7: Dissolve compound 24-7 (1.5 g) in 15 mL of dichloromethane and add 5 mL of trifluoroacetic acid. After reacting at 25 °C for 1 hour, evaporate the reaction solution to dryness to obtain compound 24-8 (1 g, 90.9%), which can be used directly in the next step.

[0587] LCMS[M-16] + m / z:calcd 260.0,found 260.0.

[0588] Step 8: Phenyl (2-fluoro-5-((2,2,2-trifluoroethyl)amino)phenyl)carbamate (200 mg, 0.610 mmol) and compound 24-8 (140 mg, 0.508 mmol) were dissolved in N,N-dimethylformamide (15 mL). Sodium hydride (73 mg, 1.830 mmol) was added under nitrogen protection at 0 °C. After reacting at 0 °C for 30 min, the reaction was quenched with saturated sodium chloride aqueous solution (15 mL), extracted with ethyl acetate (8 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography (pure water:acetonitrile = 3:2) to give compound 24 (44.10 mg, 14.2%).

[0589] LCMS[M+H]+m / z:calcd 511.1,found 511.2.

[0590] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.19(d,J=2.4Hz,1H),7.99(s,1H),7.57(dd,J=7.0,2.8Hz ,1H),7.39(d,J=8.1Hz,1H),7.30-7.17(m,1H),7.12(t,J=5.9Hz,1H),6.91(dd,J=11.2,8.8Hz,1 H),6.29-6.18(m,1H),6.09(t,J=6.8Hz,1H),4.45(d,J=5.6Hz,2H),4.16(dd,J=12.0,4.8Hz,1H) ,3.86-3.68(m,2H),2.79-2.70(m,1H),2.64-2.54(m,1H),2.36-2.27(m,1H),2.14-2.08(m,1H).

[0591] Example 25: Synthesis of Compound 25

[0592] Step 1: Compound 25-1 (31.0 g, 162.304 mmol) and triethylamine (24.6 g, 243.455 mmol) were dissolved in ultradry dichloromethane (500.0 mL). Acetyl chloride (15.3 g, 194.764 mmol) was added in portions at 0 °C. After the addition was complete, the reaction mixture was allowed to react overnight at room temperature. The reaction solution was quenched with ice water and extracted three times with ethyl acetate (100.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give compound 25-2 (37.8 g, 99.9%).

[0593] 1 H NMR (400MHz, DMSO-d6) δ7.52–7.46(m,1H),7.34(dd,J=2.8,1.6Hz,1H),7.19(dt,J=9.6,2.0Hz,1H),2.27(s,3H).

[0594] Step 2: Compound 25-2 (36.1 g, 154.480 mmol) was dissolved in dichloromethane (400.0 mL), and then aluminum trichloride (61.8 g, 463.440 mmol) was added in portions. After stirring at room temperature for one hour, the mixture was concentrated. The concentrated solid was reacted at 140 °C for three hours. Ice water was slowly added, and after returning to room temperature, the mixture was extracted three times with ethyl acetate (100.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%) to give product 25-3 (28 g, 77.8%).

[0595] 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),7.10(dd,J=10.0,1.6Hz,1H),7.01(t,J=1.6Hz,1H),2.54(d,J=3.6Hz,3H).

[0596] Step 3: Compound 25-3 (26 g, 111.569 mmol) and copper bromide (49.84 g, 223.138 mmol) were placed in a mixture of ethyl acetate and chloroform (1 / 1) (400.0 mL), and the reaction mixture was reacted overnight at 80 °C. After the reaction mixture was cooled to room temperature, it was filtered, and triethylamine (22.54 g, 223.138 mmol) was added to the filtrate, followed by stirring at room temperature for four hours. After completion, the mixture was extracted three times with ethyl acetate (100.0 mL), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5%) to give compound 25-4 (8 g, 31.0%).

[0597] 1 H NMR (400MHz, DMSO-d6) δ7.50 (s, 1H), 7.28 (dd, J = 8.8, 1.2Hz, 1H), 4.85 (s, 2H).

[0598] Step 4: Compound 25-4 (8 g, 34.629 mmol) and ethyl 2-(triphenyl-5-phosphorimide) (13.3 g, 38.092 mmol) were dissolved in toluene (80.0 mL), and the reaction mixture was reacted overnight at 120 °C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5%) to give compound 25-5 (9 g, 86.3%).

[0599] 1 H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.80 (d, J = 1.2Hz, 1H), 7.37 (dd, J = 9.6, 1.2Hz, 1H), 4.11 (d, J = 7.2Hz, 2H), 3.83 (s, 2H), 1.18 (t, J = 7.2Hz, 3H).

[0600] Step 5: Compound 25-5 (2.0 g, 6.642 mmol), potassium N-aminomethyltrifluoroborate (4.7 g, 19.926 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (444 mg, 0.664 mmol), and cesium carbonate (6.5 g, 19.926 mmol) were placed in a 5 / 1 mixture of toluene and water (30.0 mL). The reaction mixture was reacted overnight at 105 °C. The reaction mixture was extracted three times with ethyl acetate (20.0 mL), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 25-6 (2.1 g, 89.0%).

[0601] 1 H NMR (400MHz, DMSO-d6) δ7.87(s,1H),7.48(t,J=6.0Hz,1H),7.28(s,1H),6.93(d,J=10.8Hz,1H) ,4.21(d,J=6.0Hz,2H),4.11(q,J=7.2Hz,2H),3.81(s,2H),1.39(s,9H),1.18(t,J=7.2Hz,3H).

[0602] Step 6: Compound 25-6 (2.1 g, 5.977 mmol) and potassium tert-butoxide (805 mg, 7.172 mmol) were placed in N,N-dimethylformamide (30.0 mL). Acrylamide (510 mg, 7.172 mmol) was added to the reaction solution in portions at 0 °C. After the addition was complete, the reaction was carried out at room temperature for one hour. The reaction solution was quenched in saturated ammonium chloride and extracted three times with ethyl acetate (30.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by reversed-phase column chromatography (acetonitrile / water = 35%) to give compound 25-7 (1.0 g, 44.5%).

[0603] LCMS[M+H-56] + m / z:calcd 321.0; found 321.0.

[0604] Step 7: Compound 25-7 (500.0 mg, 1.328 mmol) was dissolved in dichloromethane (12.0 mL) and trifluoroacetic acid (3.0 mL). The reaction solution was reacted at room temperature for two hours, then concentrated and lyophilized to obtain trifluoroacetate of compound 25-8 (600 mg, 100%).

[0605] 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.34(s,3H),8.01(s,1H),7.60(s,1H),7.22(d,J=11.2Hz,1H),4.20–4. 17(m,1H),4.16(d,J=4.4Hz,2H),2.87–2.74(m,1H),2.65–2.55(m,1H),2.25–2.14(m,1H),2.12–2.02(m,1H).

[0606] Step 8: Dissolve 4-fluoro-N1-(2,2,2-trifluoroethyl)benzene-1,3-diamine (83 mg, 0.401 mmol) and triethylamine (242 mg, 2.403 mmol) in tetrahydrofuran (15.0 mL). Slowly add triphosgene (60 mg, 0.201 mmol) at 0 °C. After stirring at room temperature for 30 minutes, add the trifluoroacetate of compound 25-8 (125 mg, 0.320 mmol). Continue the reaction at room temperature for half an hour. Concentrate the reaction solution, and purify the residue by reversed-phase column chromatography (acetonitrile / water = 41%) to obtain compound 25 (50.0 mg, 30.6%).

[0607] LCMS[M+H] + m / z:calcd 511.1; found 511.0.

[0608] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.25(d,J=2.0Hz,1H),7.92(s,1H),7.57(dd,J=7 .2,2.8Hz,1H),7.38(s,1H),7.14(t,J=5.6Hz,1H),7.01(d,J=11.2Hz,1H),6.96-6.91(m ,1H),6.28-6.24(m,1H),6.09(t,J=6.8Hz,1H),4.40(d,J=5.6Hz,2H),4.14(dd,J=12.8, 5.2Hz,1H),3.83–3.73(m,2H),2.85–2.71(m,1H),2.61–2.54(m,1H),2.22-2.06(m,2H).

[0609] Example 26: Synthesis of Compound 26

[0610] Step 1: Compound 26-0 (170.0 mg, 0.791 mmol), phenyl chloroformate (111.1 mg, 0.712 mmol), and pyridine (187.0 mg, 2.373 mmol) were dissolved in acetonitrile (5.0 mL). The reaction mixture was reacted at room temperature for three hours. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (5.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give crude compound 26-1 (210.0 mg, 79.5%).

[0611] LCMS[M+H] + m / z:calcd.:336.1,found:336.0.

[0612] Step 2: Compound 26-1 (100.0 mg, 0.299 mmol) and compound 24-8 (116.6 mg, 0.449 mmol) were dissolved in N,N-dimethylformamide (10.0 mL), and sodium / hydrogen (14.3 mg, 0.359 mmol, 60% in mineral oil) was added at 0 °C. The reaction mixture was reacted at 0 °C for half an hour. Ice water (10.0 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by reversed-phase column chromatography (acetonitrile / water = 48%) to give compound 26 (16.32 mg, 25.3%).

[0613] LCMS[M+Na] + m / z:calcd.:518.1,found:517.9.

[0614] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.66(s,1H),7.99(s,1H),7.38(d,J=8.4Hz,1 H),7.24(t,J=6.4Hz,1H),7.15(s,1H),6.98(t,J=5.6Hz,1H),6.76(s,1H),4.43(d, J=2.4Hz,2H),4.20-4.12(m,1H),4.06-4.01(m,2H),3.70-3.65(m,2H),3.30–3.28( m,3H),2.75-2.65(m,1H),2.63-2.58(m,1H),2.35-2.30(m,1H),2.15-2.08(m,4H).

[0615] Example 27: Synthesis of Compound 27

[0616] Step 1: Compound 27-1 (10.0 g, 46.29 mmol) was added to 100 mL of acetic anhydride, and then the temperature was raised to 150 °C and stirred for two hours under controlled temperature. After the reaction was completed, the acetic anhydride was removed by rotary evaporation to obtain compound 27-2 (8 g, 71.99%).

[0617] 1 H NMR (400MHz, DMSO-d6) δ8.18–8.11(m,2H),8.08–8.00(m,2H),7.54–7.47(m,2H).

[0618] Step 2: Compound 27-2 (5.0 g, 20.83 mmol), 3-amino-2,6-piperidinedione (3.20 g, 24.99 mmol), and 40 mL of pyridine were added to a 100 mL sealed container. The reaction mixture was stirred at 140 °C for 4 hours. After the reaction was completed, most of the pyridine was removed by rotary evaporation. The reaction mixture was then slowly added to an ice-cold aqueous solution of ammonium chloride, extracted with ethyl acetate (30 mL * 3), and the organic phase was collected and washed with saturated sodium chloride. The mixture was then evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 1) to obtain compound 27-3 (1.6 g, 21.94%).

[0619] LCMS[M+H] + m / z:calcd 350.2; 352.0, found 350.2; 352.0.

[0620] Step 3: Compound 27-3 (500.0 mg, 1.43 mmol), zinc cyanide (201.2 mg, 1.71 mmol), tris(dibenzylacetone)palladium (130.8 mg, 0.14 mmol), and cesium carbonate (1.40 g, 4.28 mmol) were dissolved in 8 mL of N,N-dimethylformamide. After purging with nitrogen three times, the reaction mixture was stirred at 80 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by reverse preparation (water / acetonitrile = 0-30%) to obtain the target compound 27-4 (245 mg, 57.91%).

[0621] LCMS[M+H] + m / z:calcd 297.1, found 297.0.

[0622] Step 4: Compound 27-4 (245.0 mg, 0.83 mmol) was dissolved in 5 mL of methanol, then 10% palladium / carbon (120 mg) was added, followed by one drop of hydrochloric acid. After three hydrogen purgings, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the palladium on carbon was removed by filtration, the filtrate was concentrated to remove methanol, and the residue was purified by reversed-phase column chromatography (water / acetonitrile = 0-19%) to obtain the target compound 27-5 (47.1 mg, 18.95%).

[0623] LCMS[M+H] + m / z:calcd 301.1, found 301.1.

[0624] Step 5: Dissolve 3-chloro-p-toluidine (44.3 mg, 0.31 mmol) in 6 mL of dichloromethane, add 2 mL of an aqueous solution of sodium carbonate (46.4 mg, 0.44 mmol), cool the reaction solution to 0 °C, add triphosgene (55.7 mg, 0.18 mmol), stir at 0 °C for 30 minutes, then add 8 mL of water to dilute the reaction solution. Collect the organic phase by separation and dry it with anhydrous sodium sulfate. Filter to remove inorganic salts to obtain filtrate 1. Add compound 27-5 (47 mg, 0.15 mmol) and N,N-diisopropylethylamine (60.7 mg, 0.47 mmol) to 3 mL of N,N-dimethylformamide, add mixture 1 to the system, and stir at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL * 3), the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by reversed-phase column chromatography (water / acetonitrile = 38%) to obtain target compound 27 (11.28 mg, 15.40%).

[0625] LCMS[M+H] + m / z:calcd 468.2, found 468.2.

[0626] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.79(s,1H),7.94(s,1H),7.75(d,J=8.4Hz,1H),7.65(d,J=1.6Hz,1H),7.59(d,J=8.4Hz,1H),7.22–7.0 9(m,2H),6.86(t,J=5.6Hz,1H),5.26(dd,J=11.2,5.6Hz,1H),4.40(d,J=5.6Hz,2H),2.89–2.79(m,1H),2.71–2.59(m,5H),2.25–2.14(m,4H).

[0627] Example 28: Synthesis of Compound 28

[0628] Step 1: Compound 28-1 (150.0 mg, 0.64 mmol) was dissolved in dichloromethane (4 mL), and sodium carbonate (109.2 mg, 1.03 mmol) was dissolved in water (1 mL). The mixture was stirred for 5 minutes under nitrogen protection, and then di(trichloromethyl) carbonate (76.0 mg, 0.26 mmol) was added. Stirring was continued for another 30 minutes. After the reaction was complete, the reaction solution was extracted with water (10 mL) and dichloromethane (10 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 28-2, which was then directly used for the next reaction.

[0629] Step 2: Compound 28-2 (100.0 mg, 0.28 mmol) and 3-(6-(aminomethyl)benzofuran-3-yl)piperidin-2,6-dione (86.7 mg, 0.34 mmol) were added to 10 mL of N,N-dimethylformamide. The reaction solution was cooled to 0 °C under nitrogen protection, and 60% sodium hydride (16.8 mg, 0.42 mmol) was added. The mixture was stirred for another 30 minutes. After the reaction was complete, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by reversed-phase column chromatography (water / acetonitrile = 45%) to obtain the target compound 28 (16.52 mg, 11.5%).

[0630] LCMS[M+H] + m / z:calcd 518.1, found 518.2.

[0631] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.84(s,1H),8.34(d,J=6.8Hz,1H),7.8 8(s,1H),7.55(d,J=8.0Hz,1H),7.50(s,1H),7.44(d,J=11.6Hz,1H),7.28(t,J =5.6Hz,1H),7.21(d,J=7.6Hz,1H),4.43(d,J=5.6Hz,2H),4.15–4.11(m,1H),2 .78–2.70(m,1H),2.63–2.55(m,1H),2.37–2.28(m,1H),2.07(d,J=3.2Hz,4H).

[0632] Example 29: Synthesis of Compound 29

[0633] Step 1: Dissolve intermediate 1 (120 mg, 0.355 mmol) in dichloromethane (5.0 mL). Add pyridine (0.15 mL), compound 28-2 (100 mg, 0.429 mmol), and phosphorus oxychloride (0.1 mL) sequentially under ice bath conditions. React at room temperature for 30 minutes. After the reaction is complete, slowly add the reaction solution dropwise to ice-cold saturated sodium bicarbonate aqueous solution (20.0 mL). Add dichloromethane (10.0 mL * 3) to extract the product. Combine the organic phases and dry with anhydrous sodium sulfate. Concentrate the filtrate. Purify the residue by reversed-phase column chromatography (water / acetonitrile = 1 / 1) to obtain compound 29 (11.1 mg, 5.6%).

[0634] LCMS[M+H]+m / z:calcd 554.1; found 554.4.

[0635] 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),10.15(s,1H),8.24(d,J=7.2Hz,1H),7.52(d,J=11.2Hz,1H),6.12(d,J=11.2Hz,2H),4. 05–3.97(m,3H),3.57–3.54(m,2H),3.11–2.94(m,1H),2.86–2.74(m,3H),2.48–2.45(m,1H),2.09(s,3H),2.06–1.89(m,1H).

[0636] Example 30: Synthesis of Compound 30

[0637] Step 1: Compound 30-1 (3.0 g, 15.228 mmol) was dissolved in a toluene / water mixture of 10 / 1 (50.0 mL). Potassium N-aminomethyltrifluoroborate (4.4 g, 18.565 mmol), cesium carbonate (14.8 g, 45.538 mmol), and chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (1.1 g, 1.646 mmol) were added. The mixture was heated to 105 °C and stirred for 12 hours. After the reaction was complete, the reaction solution was poured into water (50.0 mL), and ethyl acetate (50.0 mL * 3) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound 30-2 (3.5 g, 83.3%).

[0638] LCMS [M-55] + m / z:calcd 192.1, found 192.0.

[0639] Step 2: Compound 30-2 (3.5 g, 14.171 mmol) was dissolved in anhydrous dichloromethane (40.0 mL), and then liquid bromine (1.0 mL) was added. The reaction was carried out at room temperature for 15 minutes. After the reaction was complete, the mixture was quenched with a saturated aqueous solution of sodium thiosulfate (50 mL), extracted with dichloromethane (50.0 mL * 3), the organic phases were combined and dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain crude compound 30-3. This crude compound was dissolved in anhydrous tetrahydrofuran (40.0 mL), and a methanol solution of potassium hydroxide (720 mg, 12.857 mmol) (8.0 mL) was added. The reaction was carried out at room temperature for 30 minutes. After the reaction was complete, the reaction solution was poured into water (30.0 mL), extracted with ethyl acetate (30.0 mL * 3), the organic phases were combined and dried with anhydrous sodium sulfate, the filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound 30-4 (2.2 g, 56.4%).

[0640] 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.55–7.44(m,3H),7.28(d,J=8.4Hz,1H),4.26(d,J=6.0Hz,2H),1.40(s,9H).

[0641] Step 3: Compound 30-4 (540.0 mg, 1.656 mmol) was dissolved in anhydrous dioxane (10.0 mL), and 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (510.0 mg, 2.179 mmol), cuprous iodide (160.0 mg, 0.842 mmol), levo-trans-1,2-cyclohexanediamine (100.0 mg, 0.877 mmol) and potassium phosphate (700.0 mg, 3.301 mmol) were added. The reaction mixture was stirred overnight at 120 °C under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature and poured into water (10.0 mL). The solution was extracted with ethyl acetate (10.0 mL * 3), the organic phases were combined, and the mixture was washed with saturated sodium chloride solution (10 mL * 3). The mixture was dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the target compound 30-5 (550.0 mg, 66.8%).

[0642] LCMS [M-55] + m / z:calcd 424.2, found 424.0.

[0643] Step 4: Compound 30-5 (550.0 mg, 1.428 mmol) was dissolved in trifluoromethanesulfonic acid (3.0 mL), stirred at 40 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated by vacuum evaporation. The residue was purified by reversed-phase column chromatography (acetonitrile / water = 1 / 5) to obtain target compound 30-6 (50.0 mg, 18.5%).

[0644] LCMS[M-16] + m / z:calcd 243.1, found 243.0.

[0645] Step 5: Compound 30-6 (50.0 mg, 0.193 mmol) and phenyl (2-fluoro-5-((2,2,2-trifluoroethyl)amino)phenyl)carbamate (65.0 mg, 0.198 mmol) were dissolved in anhydrous N,N-dimethylformamide (10.0 mL). Sodium hydroxide (11.0 mg, 0.289 mmol) was added under ice bath conditions, and the mixture was stirred for 30 minutes. After the reaction was complete, the reaction solution was added dropwise to ice water (10.0 mL), and ethyl acetate (10.0 mL * 3) was added to extract the product. The combined organic phases were washed with saturated sodium chloride aqueous solution (10.0 mL * 3) and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by reversed-phase column chromatography (water / acetonitrile = 1 / 1) to give compound 30 (5.13 mg, 5.3%).

[0646] LCMS[M+H]+m / z:calcd 494.1; found 494.2.

[0647] 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.22(s,1H),8.09(s,1H),7.63–7.54(m,2H),7.50(s,1H),7.23(d,J=8.2Hz,1H),7.16–7.06 (m,1H),6.99–6.84(m,1H),6.30–6.21(m,1H),6.08(s,1H),4.42(d,J=5.6Hz,2H),3.93–3.72(m,4H),2.87–2.69(t,J=6.8Hz,2H).

[0648] Example 31: Synthesis of Compound 31

[0649] Step 1: Compound 31-1 (25.0 g, 145.704 mmol) was dissolved in a mixed solution of n-heptane (125.0 mL) and sulfuric acid (125.0 mL). The solution was heated to 50 °C, and bromosuccinimide (34.0 g, 191.011 mmol) was added in portions. The mixture was stirred for 2 hours. After the reaction was complete, the reaction solution was added dropwise to ice water (100.0 mL), and ethyl acetate (100.0 mL * 3) was added for extraction. The organic phase was collected and dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the target compound 31-2 (11.3 g, 31.3%).

[0650] 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=2.2Hz,1H),8.29(d,J=2.2Hz,1H),2.55(s,3H).

[0651] Step 2: Compound 31-2 (1.7 g, 6.827 mmol) was dissolved in N,N-dimethylformamide (20.0 mL), followed by the addition of (E)-benzaldehyde oxime (905.0 mg, 7.510 mmol), di-tert-butyl-(2,4,6-triisopropyl-3,6-dimethoxyphenylbi-2-yl)phosphine (396.1 mg, 0.819 mmol), allyl palladium(II) chloride dimer (124.2 mmol, 0.341 mmol), and cesium carbonate (3.3 g, 10.241 mmol). The reaction mixture was heated to 90 °C and stirred for 8 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and then poured into 0.5M dilute hydrochloric acid (150.0 mL). The solution was extracted with ethyl acetate (50.0 mL * 3), and the organic phases were combined. The mixture was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the target compound 31-3 (400.0 mg, 31.3%).

[0652] LCMS[M-1] + m / z:calcd 186.0, found 186.0.

[0653] Step 3: Compound 31-3 (400.0 mg, 2.139 mmol) was dissolved in N,N-dimethylformamide (8.0 mL), and then 2-bromoethyl methyl ether (358.2 mg, 2.567 mmol), potassium iodide (35.2 mg, 0.214 mmol), and potassium carbonate (593.5 mg, 4.278 mmol) were added. The reaction mixture was stirred overnight at 50 °C under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into water (10.0 mL). The mixture was extracted with ethyl acetate (10.0 mL * 3), and the organic phases were combined and washed three times with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the target compound 31-4 (350.0 mg, 66.8%).

[0654] LCMS[M+H] + m / z:calcd 246.0, found 246.0.

[0655] Step 4: Compound 31-4 (350.0 mg, 1.428 mmol) was dissolved in ethanol (8.0 mL), and then water (2.0 mL), iron powder (400.5 mg, 7.143 mmol), and ammonium chloride (451.6 mg, 8.571 mmol) were added. The reaction solution was stirred overnight at 70 °C under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (10.0 mL), and extracted with ethyl acetate (10.0 mL * 3). The organic phases were combined and washed three times with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound 31-5 (280.0 mg, 91.2%).

[0656] Step 5: Compound 31-5 (170.0 mg, 0.791 mmol), phenyl chloroformate (111.1 mg, 0.712 mmol), and pyridine (187.0 mg, 2.373 mmol) were dissolved in acetonitrile (5.0 mL). The reaction mixture was reacted at room temperature for three hours. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give crude compound 31-6 (210.0 mg, 79.5%).

[0657] LCMS[M+H] + m / z:calcd.:336.1,found:336.0.

[0658] Step 6: Dissolve starting material 31-6 (120 mg, 0.359 mmol) and compound 30-6 (120 mg, 0.463 mmol) in anhydrous N,N-dimethylformamide (10.0 mL). Add sodium hydroxide (20 mg, 0.525 mmol) under ice bath conditions and stir for 30 minutes. After the reaction is complete, add the reaction solution dropwise to ice water (10.0 mL), add ethyl acetate (10.0 mL * 3) to extract the product, combine the organic phases, wash with saturated sodium chloride and dry with anhydrous sodium sulfate, concentrate the filtrate, and purify the residue by reversed-phase column chromatography (water / acetonitrile = 1 / 1) to obtain compound 31 (27.41 mg, 21.6%).

[0659] LCMS[M+H]+m / z:calcd 501.1; found 501.3.

[0660] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.69(s,1H),8.09(s,1H),7.56(d,J= 8.1Hz,1H),7.49(s,1H),7.29–7.20(m,1H),7.20–7.15(m,1H),7.04–6.95( m,1H),6.83–6.68(m,1H),4.40(d,J=5.8Hz,2H),4.09–3.99(m,2H),3.89–3 .79(m,2H),3.72–3.63(m,2H),3.30(s,3H),2.83–2.74(m,2H),2.11(s,3H).

[0661] Example 32: Synthesis of Compound 32

[0662] Step 1: Add sodium hydroxide (7.55 g, 188.80 mmol) to 100 mL of ultra-dry toluene. After cooling to 0 °C, slowly add a toluene solution (300 mL) of compound 32-1 (14.5 g, 67.43 mmol). Stir for 30 minutes while maintaining the temperature. Then add diethyl carbonate (15.93 g, 134.85 mmol). Heat to 115 °C and reflux for 12 hours. After the reaction is complete, add the reaction solution to 1000 mL of water and extract with ethyl acetate (300 mL * 3). Collect the aqueous phase, adjust the pH to 3 with hydrochloric acid (2 M), filter the mixture, collect the filter cake, wash the filter cake with petroleum ether (500 mL), and dry the filter cake to obtain compound 32-2 (11.3 g, 68.5%).

[0663] LCMS[M+H] +m / z:calcd 240.9,242.9; found 241.0; 243.0.

[0664] Step 2: Dissolve sodium ethoxide (6.38 g, 93.76 mmol) in 80 mL of ethanol. After cooling to 0 °C, add an ethanol solution (120 mL) of hydroxylamine hydrochloride (6.52 g, 93.76 mmol). Finally, add compound 32-2 (11.3 g, 46.88 mmol) to the mixture. Stir the reaction mixture at 80 °C for 4 hours. After the reaction is complete, remove most of the ethanol by rotary evaporation. Slowly add the residue to an ice-cold aqueous solution of sodium chloride. Adjust the pH to 3 with dilute hydrochloric acid (2 M). Filter, collect the filter cake, and dry the filter cake to obtain compound 32-3 (8.6 g, 71.64%).

[0665] LCMS[M+H] + m / z:calcd 256.0,258.0; found 256.0,258.0.

[0666] Step 3: Compound 32-3 (8.6 g, 33.59 mmol) was dissolved in 80 mL of N,N-dimethylformamide, followed by the addition of potassium carbonate (13.93 g, 100.76 mmol) and methyl iodide (5.72 g, 40.30 mmol). The reaction mixture was stirred at 30 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was extracted with water (100 mL) and ethyl acetate (60 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by normal phase (petroleum ether / ethyl acetate = 0-27%) to obtain the target compound 32-4 (6.5 g, 71.7%).

[0667] LCMS[M+H] + m / z:calcd 270.0,272.0;found 270.0,272.0.

[0668] Step 4: Compound 32-4 (3 g, 11.11 mmol), potassium salt of ((trifluoro-L4-boryl)methyl)carbamate (3.16 g, 13.33 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (742.71 mg, 1.11 mmol), and cesium carbonate (10.86 g, 33.32 mmol) were dissolved in 50 mL of toluene. The mixture was purged with nitrogen three times, and the reaction solution was stirred at 105 °C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (40 mL * 3). The organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by reverse-phase (water / acetonitrile = 0-19%) to obtain the target compound 32-5 (816 mg, 23.0%).

[0669] LCMS[M+H] + m / z:calcd 301.1, found 301.1.

[0670] 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=8.0Hz,1H),7.53(s,1H),7.29(d,J=8.0Hz,1H),4.20(s,1H),3.67(s,1H).

[0671] Step 5: Compound 32-5 (816 mg, 2.55 mmol) was dissolved in 20 mL of ultra-dry tetrahydrofuran. After cooling to 0 °C, acrylamide (235.37 mg, 3.31 mmol) and potassium tert-butoxide (428.75 mg, 3.82 mmol) were added. After stirring at 0 °C for 1 hour, the reaction solution was added dropwise to 20 mL of ice-cold dilute hydrochloric acid aqueous solution. Ethyl acetate (30 mL * 3) was added for extraction. The organic phase was collected and dried over anhydrous sodium sulfate. The residue was purified by reversed-phase column chromatography (water / acetonitrile = 13%) to obtain the target compound 32-6 (417.0 mg, 45.6%).

[0672] LCMS[M+Na] + m / z:calcd 382.2, found 382.2.

[0673] Step 6: Dissolve compound 32-6 (417 mg, 1.16 mmol) in 5 mL of dichloromethane, add 2 mL of trifluoroacetic acid, stir at 25 °C for 2 hours, evaporate the reaction solution to dryness, and purify the residue by reversed-phase column chromatography (water / acetonitrile = 3%) to obtain target compound 32-7 (168 mg, 55.9%).

[0674] LCMS[M+H] +m / z:calcd 260.1, found 260.1.

[0675] Step 7: At 0°C, compound 32-7 (128.0 mg, 0.493 mmol) and phenyl (2-fluoro-5-((2,2,2-trifluoroethyl)amino)carbamate (161.7 mg, 0.493 mmol) were dissolved in 15 mL of N,N-dimethylformamide. 60% sodium hydroxide (23.7 mmol, 0.592 mmol) was added, and the reaction was continued at 0°C for 1 hour. The reaction solution was then added dropwise to 20 mL of icy dilute hydrochloric acid and extracted with ethyl acetate (15 mL * 3). The organic phase was concentrated, and the residue was purified by reversed-phase column chromatography (water / acetonitrile = 39%) to obtain target compound 32 (9.5 mg, 3.90%).

[0676] LCMS[M+H] + m / z:calcd 494.1, found 494.2.

[0677] 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.28(d,J=2.4Hz,1H),7.81(d,J=8.4Hz,1H),7.63(s,1H),7. 57(dd,J=7.2,2.8Hz,1H),7.34(d,J=8.4Hz,1H),7.19(t,J=5.6Hz,1H),6.93(dd,J=11.2,8.8Hz,1H) ,6.26(dd,J=8.0,4.4Hz,1H),6.09(t,J=7.2Hz,1H),4.59(dd,J=12.0,4.8Hz,1H),4.48(d,J=5.6Hz, 2H),3.86–3.72(m,2H),2.84–2.73(m,1H),2.69–2.60(m,1H),2.48–2.42(m,1H),2.25–2.16(m,1H).

[0678] Example 33: Synthesis of compound 33-1

[0679] Step 1: Compound 33-1 (10 g, 59.12 mmol), 2,2-difluorocyclopropane-1-carboxylic acid (7.22 g, 59.12 mmol), and pyridine (23.38 g, 295.59 mmol) were added to 200 mL of dichloromethane. After cooling to 0 °C, phosphorus oxychloride (9.06 g, 59.13 mmol) was slowly added dropwise to the system. The mixture was stirred at 0 °C for two hours. After the reaction was complete, the reaction solution was slowly added dropwise to an ice-cold sodium bicarbonate aqueous solution (300 mL), and extracted with dichloromethane (50 mL * 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound 33-2 (5.12 g, 31.70%).

[0680] LCMS[M+H] + m / z:calcd 274.2, found 274.0.

[0681] Step 2: Compound 33-2 (4.0 g, 14.652 mmol) was dissolved in 40.0 mL of boranetetrahydrofuran solution. The reaction mixture was stirred overnight at 80 °C under nitrogen protection. After the reaction was completed, the reaction mixture was slowly added dropwise to ice water (100.0 mL), and extracted with ethyl acetate (50.0 mL * 3). The organic phases were collected, combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the target compound 33-3 (1.4 g, 36.8%).

[0682] LCMS[M+H] + m / z:calcd:260.1,found:260.0.

[0683] Step 3: Chiral resolution of compound 33-3 (700 mg, 2.692 mmol) was performed on CHIRALPAK IE-3 (IE30CE-XB011) with ACN / MeOH = 85 / 15 (V / V), yielding compound 33-3-P1 (400.0 mg) and compound 33-3-P2 (100.0 mg).

[0684] Step 4: Compound 33-3-P1 (400 mg, 1.56 mmol) was dissolved in a mixture of tetrahydrofuran (8.0 mL) and methanol (2.0 mL), followed by the addition of 2N lithium hydroxide aqueous solution (4.0 mL). The reaction mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was complete, 10.0 mL of 3N dilute hydrochloric acid aqueous solution was added to adjust the pH to weakly acidic. The mixture was then extracted with ethyl acetate (15.0 mL * 3), and the organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the target compound 33-4-1 (350.0 mg, 93.1%).

[0685] Step 5: Compound 33-4-1 (200.0 mg, 0.80 mmol) was dissolved in 5.0 mL of anhydrous toluene, followed by the addition of 21-3 (233.1 mg, 0.92 mmol), diphenyl azidophosphate (671.02 mg, 2.4 mmol), and triethylamine (247.34 mg, 2.4 mmol). The reaction mixture was stirred at 90 °C for one hour under nitrogen protection. After the reaction was complete, the reaction mixture was extracted with water (20.0 mL) and ethyl acetate (20.0 mL * 3), the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the target compound 33-P1 (25.52 mg, 6.12%).

[0686] LCMS[M+H] + m / z:calcd:501.2,found:501.3.

[0687] 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.17(s,1H),7.87(s,1H),7.57-7.52(m,1H),7.55-7.47(m,3 H),7.21-7.19(m,1H),7.08-7.06(m,1H),6.91-6.86(m,1H),6.13(m,1H),5.69-5.59(m,1H),4.40( d,J=6.0Hz,2H),4.12(dd,J=12.0,4.8Hz,1H),3.06-3.03(m,2H),2.74-2.64(m,1H),2.59-2.58(m, 1H),2.32-2.22(m,1H),2.21-2.19(m,1H),2.10-2.05(m,1H),1.33-1.31(m,1H),1.25-1.22(m,1H).

[0688] Example 34: Synthesis of compound 33-P2

[0689] Step 1: Compound 33-3-P2 (100 mg, 0.39 mmol) was dissolved in a mixed solvent of 4.0 mL tetrahydrofuran and 1.0 mL methanol, followed by the addition of 4.0 mL of 2N lithium hydroxide aqueous solution. The reaction mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was complete, 10.0 mL of 3N dilute hydrochloric acid aqueous solution was added to adjust the pH to weakly acidic. Subsequently, the mixture was extracted with water (20 mL) and ethyl acetate (20 mL * 3), and the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the target compound 33-4-P2 (60.0 mg, 63.43%).

[0690] LCMS[M+H] + m / z:calcd:246.1,found:246.0.

[0691] Step 2: Compound 33-4-P2 (60.0 mg, 0.24 mmol) was dissolved in 5.0 mL of anhydrous toluene, followed by the addition of 21-3 (69.50 mg, 0.27 mmol), diphenyl azidophosphate (80.88 mg, 0.29 mmol), and triethylamine (74.34 mg, 0.73 mmol). The reaction mixture was stirred at 90 °C for two hours under nitrogen protection. After the reaction was complete, the reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the target compound 33-P2 (15.0 mg, 12.25%).

[0692] LCMS[M+H] + m / z:calcd:501.2,found:501.3.

[0693] 1 H NMR (400MHz, DMSO-d6) δ10.89 (s, 1H), 8.17-8.16 (d, J = 2.4Hz, 1H), 7.87 (s, 1H), 7.55-7.47 (m, 3H), 7.21-7.19(m,1H),7.08-7.06(m,1H),6.91-6.86(m,1H),6.13-6.11(m,1H),5.69-5.59(m,1H),4.40 (d,J=6.0Hz,2H),4.12(dd,J=12.0,4.8Hz,1H),3.06-3.03(m,2H),2.74-2.64(m,1H),2.59-2.58(m, 1H),2.32-2.22(m,1H),2.21-2.19(m,1H),2.10-2.05(m,1H),1.33-1.31(m,1H),1.25-1.22(m,1H).

[0694] Example 35: Synthesis of Compound 34

[0695] Step 1: Dissolve 33-2 (1.3 g, 4.467 mmol) in boranetetrahydrofuran solution (44.6 mL) and stir at 80 °C for 8 hours. After the reaction is complete, quench the reaction solution in ice water (100.0 mL), extract with ethyl acetate (30.0 mL * 3), combine the organic phases and dry over anhydrous sodium sulfate. Filter the filtrate and purify the residue by silica gel column chromatography (PE / EA = 3 / 1) to give compound 34-1 (1.0 g, 81.3%).

[0696] LCMS[M+H]+m / z:calcd 278.1; found 278.0.

[0697] Step 2: Compound 34-1 (1.0 g, 3.610 mmol) was dissolved in a tetrahydrofuran / methanol mixture of 4 / 1 (20.0 mL), and 2M lithium hydroxide aqueous solution (10.0 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to weakly acidic with dilute hydrochloric acid, and the mixture was extracted with water (10.0 mL) and ethyl acetate (10.0 mL * 3). The organic phases were combined and dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain compound 34-2 (900 mg, 94.7%).

[0698] LCMS[M+H]+m / z:calcd 264.1; found 264.0.

[0699] Step 3: Dissolve starting material 34-2 (200 mg, 0.763 mmol) in anhydrous dimethyl sulfoxide (10.0 mL), add triethylamine (0.31 mL), diphenyl azidophosphate (250 mg, 0.909 mmol), and 21-3 (250 mg, 0.923 mmol), and react at 90 °C for 1 hour. After the reaction is complete, extract the product with water (10.0 mL) and ethyl acetate (20.0 mL * 3). Combine the organic phases and wash with saturated sodium chloride aqueous solution (10.0 mL * 3), dry with anhydrous sodium sulfate and concentrate. The residue is subjected to reversed-phase column chromatography to obtain compound 34 (34.55 mg, 8.5%).

[0700] LCMS[M+H]+m / z:calcd 519.2; found 519.2.

[0701] 1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.19(s,1H),7.87(s,1H),7.62–7.53(m,2H),7.50–7.4 6(m,1H),7.22–7.17(m,1H),7.15–7.06(m,1H),7.06–6.98(m,1H),5.51–5.40(m,1H),4.40(d ,J=5.8Hz,2H),4.21–4.06(m,1H),3.23–3.14(m,1H),3.14–2.98(m,1H),2.82–2.66(m,1H),2 .64–2.55(m,1H),2.37–2.24(m,1H),2.15–1.94(m,2H),1.64–1.49(m,1H),1.42–1.21(m,1H).

[0702] Example 36: Synthesis of Compound 35

[0703] Step 1: Compound 35-1 (15.0 g, 0.067 mol) was dissolved in sulfuric acid (200 mL). Under nitrogen protection, potassium nitrate (13.0 g, 0.271 mol) was added. After reacting at 25 °C for 16 hours, the reaction solution was slowly poured into ice water (250 mL), and extracted three times with ethyl acetate (200 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give product 35-2 (15.0 g, 86.5%).

[0704] 1 H NMR (400MHz, DMSO-d6) δ8.41 (d, J = 6.6 Hz, 1H), 8.25 (d, J = 9.9 Hz, 1H), 3.89 (d, 3H).

[0705] Step 2: Compound 35-2 (15.0 g, 0.046 mol) and ammonium chloride (15.0 g, 0.276 mol) were dissolved in a mixed solvent of ethanol (50 mL) and water (5 mL). Under nitrogen protection, iron powder (13.0 g, 0.230 mol) was added. After reacting at 70 °C for 16 hours, the iron powder was filtered through diatomaceous earth, and the ethanol was removed from the filtrate under reduced pressure. The residue was washed three times (40 mL * 3) with saturated sodium chloride aqueous solution, extracted three times with ethyl acetate (50 mL * 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to give product 35-3 (10.0 g, 73.5%).

[0706] LCMS[M+H]+ m / z:calcd 296.0, found 296.0.

[0707] Step 3: Compound 35-3 (10.0 g, 33.89 mmol) and 4-dimethylaminopyridine (417 mg, 3.39 mmol) were dissolved in 50 mL of dichloromethane. Under nitrogen protection, di-tert-butyl dicarbonate (11.1 g, 50.85 mmol) and triethylamine (10.3 g, 101.69 mmol) were added. After reacting at 25 °C for 16 hours, the reaction solution was quenched in water (70 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give product 35-4 (4.4 g, 33.1%).

[0708] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),7.92(d,J=12.0Hz,1H),7.77(d,J=8.0Hz,1H),3.85(s,3H),1.46(s,9H).

[0709] Step 4: Compound 35-4 (4.4 g, 11.14 mmol) was dissolved in N,N-dimethylformamide (30 mL), and sodium hydride (668 mg, 16.71 mmol) was added under nitrogen protection at 0 °C. After reacting at 0 °C for 30 min, 2,2,2-trifluoroethyltrifluoromethanesulfonate (5.17 g, 22.28 mol) was added. After reacting for another hour, the reaction solution was quenched in ice water, washed with saturated sodium chloride aqueous solution (30 mL * 3), extracted with ethyl acetate (30 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give product 35-5 (4.3 g, 82.8%).

[0710] LCMS[M+H-55] + m / z:calcd 422.0, found 421.8.

[0711] Step 5: Compound 35-5 (4.3 g, 9.01 mmol), palladium dichloride bis(triphenylphosphine) (633 mg, 0.901 mmol), cuprous iodide (172 mg, 0.901 mmol), and tetrabutylammonium fluoride (3.5 g, 13.52 mmol) were dissolved in N,N-dimethylformamide (35 mL). Under nitrogen protection, triethylamine (6.23 mL, 45.07 mmol) and 1-(trimethylsilyl)propyne (1.5 g, 13.52 mmol) were added. After reacting at 25 °C for 16 hours, the reaction solution was quenched in saturated sodium chloride (50 mL) and extracted with ethyl acetate (30 mL * 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 12:1) to give product 35-6 (2.8 g, 80.0%).

[0712] LCMS[M+H-55] + m / z:calcd 334.0, found 334.0.

[0713] Step 6: Under nitrogen protection, compound 35-6 (1 g, 2.56 mmol) was dissolved in hydrochloric acid / 1,4-dioxane solution (10 mL). After reacting at 25 °C for 2 hours, the reaction solution was evaporated to dryness. The residue was dissolved in ethyl acetate (25 mL) and washed with saturated sodium bicarbonate aqueous solution (15 mL * 3) until the aqueous phase was weakly alkaline. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give product 35-7 (520 mg, 70.1%).

[0714] LCMS[M+H] + m / z:calcd 290.0, found 290.1.

[0715] Step 7: Compound 35-7 (520 mg, 1.80 mmol) was dissolved in a mixed solvent of tetrahydrofuran (8 mL) and methanol (2 mL). Under nitrogen protection at 0 °C, 5 mL of an aqueous lithium hydroxide solution (2 M) was added. After reacting at 25 °C for 1 hour, the reaction solution was adjusted to weakly acidic using an aqueous hydrochloric acid solution (6 M), extracted with ethyl acetate (15 mL * 3), and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give product 35-8 (490 mg, 99.0%), which was used directly in the next step.

[0716] LCMS[M+H] + m / z:calcd 276.0, found 276.0.

[0717] Step 8: Compound 35-8 (100 mg, 0.36 mmol) and 5-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)-2,4-difluorobenzoic acid (112 mg, 0.44 mmol) were dissolved in toluene (10 mL). Diphenyl azidophosphate (0.09 mL, 0.44 mmol) and triethylamine (0.15 mL, 1.09 mmol) were added under nitrogen protection at 0 °C. After reacting at 90 °C for 1 hour, the reaction was quenched with saturated sodium bicarbonate aqueous solution (25 mL), extracted with ethyl acetate (10 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was subjected to Prep-HPLC to prepare product 35 (38.20 mg, 19.8%).

[0718] LCMS[M+H] + m / z:calcd 531.1, found 531.4.

[0719] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.38(d,J=2.4Hz,1H),7.87(s,1H),7.74(d,J=7 .2Hz,1H),7.55(d,J=8.0Hz,1H),7.49(s,1H),7.21-7.14(m,2H),7.01(d,J=11.6Hz,1H ),5.61(t,J=6.8Hz,1H),4.41(d,J=5.6Hz,2H),4.12(dd,J=11.6,4.4Hz,1H),3.92-3. 84(m,2H),2.75-2.66(m,1H),2.60-2.53(m,1H),2.35-2.29(m,1H),2.13-2.06(m,4H).

[0720] Example 37: Synthesis of Compound 36

[0721] Step 1: DD217-255-8 (100 mg, 0.405 mmol), triphosgene (60 mg, 0.203 mmol), and triethylamine (205 mg, 2.025 mmol) were dissolved in tetrahydrofuran (15.0 mL). The reaction solution was reacted at room temperature for half an hour, and then 3-(6-(aminomethyl)benzofuran-3-yl)piperidin-2,6-dione (104 mg, 0.405 mmol) was added, and the reaction was continued for another half hour. The reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (acetonitrile / water = 42%) to give compound 36 (50.1 mg, 23.5%).

[0722] LCMS[M+H] +m / z:calcd 527.1; found 527.2.

[0723] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.38(d,J=2.4Hz,1H),7.87(s,1H),7.85(d,J=7.8Hz, 1H),7.55(d,J=8.0Hz,1H),7.49(s,1H),7.26(d,J=10.8Hz,1H),7.22–7.17(m,1H),7.14(t, J=5.6Hz,1H),5.77(t,J=6.8Hz,1H),4.41(d,J=5.6Hz,2H),4.13(dd,J=12.0,4.8Hz,1H),3. 93–3.81(m,2H),2.79–2.70(m,1H),2.60–2.54(m,1H),2.34–2.28(m,1H),2.13–2.09(m,1H).

[0724] Example 38: Synthesis of Compound 37

[0725] Step 1: Compound 37-1 (900 mg, 2.68 mmol), 2-aminomethyloxetane hydrochloride (210.48 mg, 2.42 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (243.34 mg, 0.268 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (125.26 mg, 0.268 mmol), and cesium carbonate (1.75 g, 5.37 mmol) were added to 15 mL of ultra-dry toluene, and then the temperature was raised to 90 °C and the reaction was continued for twelve hours. After the reaction was completed, the reaction solution was added dropwise to 50 mL of water, extracted with ethyl acetate (30 mL * 3), the organic phase was concentrated, and the target compound 37-2 (260 mg, 37.7%) was obtained by normal phase purification (petroleum ether: ethyl acetate = 8:1).

[0726] LCMS[M+H] + m / z:calcd 258.1,found 258.0.

[0727] Step 2: Compound 37-2 (260 mg, 1.01 mmol) was dissolved in 6 mL of tetrahydrofuran, and then 5.0 mL of lithium hydroxide aqueous solution (2 M) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to weakly acidic with dilute hydrochloric acid, and water (10.0 mL) and ethyl acetate (10.0 mL * 3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain compound 37-3 (120 mg, 48.8%).

[0728] LCMS[M+H] + m / z:calcd 244.1, found 244.0.

[0729] Step 3: Compound 37-3 (120 mg, 0.49 mmol), 3-(6-(aminomethyl)benzofuran-3-yl)piperidin-2,6-dione (152.92 mg, 0.59 mmol), diphenyl azidophosphate (203.68 mg, 0.74 mmol), and triethylamine (74.89 mg, 0.74 mmol) were dissolved in 8 mL of ultra-dry toluene. After purging with nitrogen three times, the reaction solution was stirred at 90 °C for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by Prep-HPLC (water / acetonitrile = 0-43%) to obtain the target compound 37 (7.57 mg, 3.1%).

[0730] LCMS[M+H] + m / z:calcd 499.2, found 499.3.

[0731] 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),8.28(s,1H),7.81(d,J=8.4Hz,1H),7.63(s,1H),7.57(dd,J=7.2, 2.8Hz,1H),7.34(d,J=8.0Hz,1H),7.20(t,J=5.6Hz,1H),6.93(dd,J=11.2,8.8Hz,1H),6.27–6.23(m,1H) ,6.09(t,J=6.8Hz,1H),4.59(dd,J=12.0,4.8Hz,1H),4.48(d,J=5.6Hz,2H),3.83–3.72(m,2H),3.36-3.3 1(m,1H),3.30-3.25(m,2H),2.83–2.72(m,1H),2.65–2.56(m,3H),2.48–2.42(m,1H),2.25–2.15(m,1H).

[0732] Example 39: Synthesis of Compound 38

[0733] Step 1: 3-(6-(aminomethyl)-4-fluorobenzofuran-3-yl)piperidine-2,6-dione (150 mg, 0.38 mmol) was dissolved in 10 mL of anhydrous toluene. Then, diphenyl azidophosphate (155 mg, 0.56 mmol), triethylamine (115 mg, 1.38 mmol), and 2,4-difluoro-5-((2,2,2-trifluoroethyl)amino)benzoic acid (115 mg, 0.46 mmol) were added. The mixture was heated to 90 °C under nitrogen protection and reacted for 1 hour. After the reaction was complete, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL * 3). The organic phase was collected, washed with saturated sodium chloride, and evaporated to dryness. The residue was purified by reversed-phase column chromatography (water / acetonitrile = 41%) to obtain the target compound 38 (66.28 mg, 33.8%).

[0734] LCMS[M+Na] + m / z:calcd 529.1,found 529.2.

[0735] 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.43(s,1H),7.93(s,1H),7.66(t,J=8. 8Hz,1H),7.45–7.35(m,2H),7.13(t,J=11.2Hz,1H),7.01(d,J=11.2Hz,1H),5. 93(t,J=5.6Hz,1H),4.40(d,J=5.6Hz,2H),4.18–4.10(m,1H),3.88–3.73(m,2H ),2.83–2.74(m,1H),2.62–2.55(m,1H),2.28–2.14(m,1H),2.12–2.04(m,1H).

[0736] Example 40: Synthesis of Compound 39

[0737] Step 1: 25-5 (4.0 g, 13.288 mmol) and potassium tert-butoxide (1.79 g, 15.948 mmol) were placed in 100.0 mL of dimethylformamide and stirred. Acrylamide (1.1 g, 15.948 mmol) was slowly added under nitrogen protection at 0 °C. The reaction mixture was brought to room temperature and reacted for one hour. The reaction was quenched with saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate (10.0 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give compound 39-1 (4.3 g, 99.3%).

[0738] LCMS[M+H] + m / z:calcd 326.0,328.0; found 326.0,328.0.

[0739] Step 2: 39-1 (1.1 g, 3.374 mmol), cuprous iodide (84.0 mg, 0.442 mmol), and bis(diphenylphosphine)ferrocene palladium dichloride (264.1 mg, 0.324 mmol) were dried at high temperature and placed in dimethylacetamide (6.0 mL). Under nitrogen protection, a dimethylacetamide solution (25.0 mL) of (1-(tert-butoxycarbonyl)azacyclobutane-3-yl)zinc(II) iodide was added. The reaction mixture was reacted overnight at 85 °C. The reaction mixture was extracted three times with ethyl acetate (30.0 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 4%) to obtain crude product 39-2 (2.0 g).

[0740] LCMS[Mt-Bu+H] + m / z:calcd 347.2; found 347.0.

[0741] Step 3: The crude product 39-2 (2.0 g) was dissolved in a mixed solution of trifluoroacetic acid and dichloromethane (1:3, 20.0 mL), and the reaction solution was reacted overnight at room temperature. The reaction solution was evaporated to dryness, and the residue was purified by reversed-phase column chromatography (acetonitrile / water = 5%) to give compound 39-3 (1.2 g, 83.5%).

[0742] LCMS[M+H] + m / z:calcd 303.1; found 303.0.

[0743] Step 4: 39-3 (100.0 mg, 0.301 mmol) and phenyl(2-fluoro-5-((2,2,2-trifluoroethyl)amino)carbamate (138.0 mg, 0.331 mmol) were placed in dimethylformamide (10.0 mL). Sodium / hydrogen (15.0 mg, 0.391 mmol) was added at 0 °C, and the reaction mixture was stirred for 40 minutes. The reaction mixture was then added to ice water and extracted three times with ethyl acetate (20.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by reversed-phase column chromatography (acetonitrile / water = 43%) to give compound 39 (40.0 mg, 24.8%).

[0744] LCMS[M+H] + m / z:calcd 537.1; found 537.3.

[0745] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.01(s,1H),7.95(s,1H),7.50(s,1H),7.13(d,J =11.2Hz,1H),7.09–7.01(m,1H),6.94(t,J=9.6Hz,1H),6.45–6.36(m,1H),6.13(t,J=6. 8Hz,1H),4.38(t,J=7.6Hz,2H),4.15(dd,J=12.4,4.8Hz,1H),4.00–3.94(m,3H),3.87–3 .78(m,2H),2.84–2.75(m,1H),2.59-2.52(m,1H),2.25–2.16(m,1H),2.10–2.07(m,1H).

[0746] Example 41: Synthesis of Compound 40

[0747] Step 1: DD217-236-4 (500.0 mg, 1.498 mmol), N-chlorosuccinimide (337.0 mg, 1.798 mmol), and triethylenediamine (44.0 mg, 0.392 mmol) were dissolved in chloroform (20.0 mL) and reacted overnight at 70 °C. The reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography to give compound 40-1 (170.0 mg, 28.9%).

[0748] LCMS[M+Na] + m / z:calcd 415.1; found 415.0.

[0749] Step 2: Dissolve 40-1 (170.0 mg, 0.433 mmol) in dichloromethane (5.0 mL) and trifluoroacetic acid (1.0 mL). React the reaction solution at room temperature for two hours. After the reaction is complete, evaporate the solvent and freeze-dry to obtain trifluoroacetate of compound 40-2 (160.0 mg, 91.0%).

[0750] LCMS[M-16] + m / z:calcd 276.1; found 276.0.

[0751] Step 3: 4-Fluoro-N1-(2,2,2-trifluoroethyl)benzene-1,3-diamine (104.0 mg, 0.50 mmol) and triethylamine (303.0 mg, 3.0 mmol) were dissolved in tetrahydrofuran (20.0 mL). Triphosgene (75.0 mg, 0.251 mmol) was slowly added at 0 °C. After restoring to room temperature and stirring for 30 minutes, 40-2 trifluoroacetate (160.0 mg, 0.394 mmol) was added. The reaction mixture was allowed to react for another 30 minutes at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase column chromatography (acetonitrile / water = 41%) to give compound 40 (30.0 mg, 14.7%).

[0752] LCMS[M+H] + m / z:calcd 527.1; found 527.2.

[0753] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.21(d,J=2.4Hz,1H),7.58(dd,J=7.2,2.8Hz,1H),7.5 3–7.46(m,2H),7.23(d,J=8.0Hz,1H),7.10(t,J=6.0Hz,1H),6.92(dd,J=11.2,8.8Hz,1H),6. 26–6.22(m,1H),6.09(t,J=6.8Hz,1H),4.39(d,J=6.0Hz,2H),4.14(dd,J=13.2,5.2Hz,1H),3 .83–3.73(m,2H),2.88–2.77(m,1H),2.56-2.50(m,1H),2.46–2.33(m,1H),2.01–1.98(m,1H).

[0754] Example 42: Synthesis of Compound 43

[0755] Step 1: Under nitrogen protection and at 0°C, 60% sodium hydroxide (8.3 g, 208.62 mmol, 60% in mineral oil) was added to a solution of compound 43-1 (10.0 g, 57.95 mmol) in N,N-dimethylformamide (40.0 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with ice water (50.0 mL) and ethyl acetate (50.0 mL * 3). The organic phase was collected, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give the target compound 43-2 (3.5 g, 20.74%).

[0756] 1 H NMR (400MHz, DMSO-d6) δ13.30 (s, 1H), 11.16 (s, 1H), 7.45 (d, J = 1.6Hz, 1H), 7.33 (s, 1H).

[0757] Step 2: 43-2 (3.5 g, 11.73 mmol) was added to 40.0 mL of methanol, followed by 4.0 mL of concentrated sulfuric acid. The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, methanol was removed by rotary evaporation, and the mixture was extracted with water (50.0 mL) and ethyl acetate (50.0 mL * 3). The organic phase was collected, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target compound 43-3 (3.6 g, 98.24%).

[0758] 1H NMR (400MHz, DMSO-d6) δ11.42 (s, 1H), 7.42 (s, 2H), 7.34 (d, J = 1.6Hz, 2H), 3.83 (s, 5H).

[0759] Step 3: 43-3 (3.6 g, 11.52 mmol) was added to 50.0 mL of acetone, followed by potassium carbonate (3.2 g, 23.04 mmol). After stirring at room temperature for 30 minutes, 1,2-dibromoethane (10.8 g, 57.60 mmol) was added, and the mixture was heated to 40 °C and stirred overnight. After the reaction was complete, water (50.0 mL) and ethyl acetate (50.0 mL * 3) were added for extraction. The organic phase was collected, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give the target compound 43-4 (1.25 g, 25.87%).

[0760] 1 H NMR400 MHz, DMSO-d6)δ7.66(s,1H),7.33(s,1H),4.50(t,J=5.2Hz,2H),3.87(s,3H),3.86–3.83(m,2H).

[0761] Step 4: Under nitrogen protection, 43-4 (1.3 g, 11.52 mmol) was added to 30.0 mL of tetrahydrofuran. After cooling to -78 °C, n-butyllithium (4.61 mL, 2.5 M) was slowly added dropwise. The mixture was stirred at -78 °C for 1 hour. After the reaction was complete, the reaction solution was slowly poured into 60.0 mL of ice water to quench it. Ethyl acetate (50.0 mL * 3) was added for extraction, and the organic phase was collected. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to give the target compound 43-5 (186.0 mg, 29.35%).

[0762] 1 H NMR (400MHz, CDCl3) δ7.56(s,1H),7.30(s,1H),4.67(t,J=8.8Hz,2H),3.90(s,3H),3.29(t,J=8.8Hz,2H).

[0763] Step 5: Add 43-5 (186.0 mg, 0.87 mmol) to 6.0 mL of tetrahydrofuran and 2.0 mL of water, then add lithium hydroxide monohydrate (146.8 mg, 3.5 mmol), and stir at room temperature for 3 hours. After the reaction is complete, adjust the pH to weakly acidic using 1 M dilute hydrochloric acid, extract with ethyl acetate (10.0 x 3 mL), dry to anhydrous sodium sulfate, and evaporate to dryness to obtain 43-6 (116.0 mg, 66.77%).

[0764] 1 H NMR (400MHz, DMSO-d6) δ7.41(s,1H),7.18(s,1H),4.66(t,J=8.8Hz,2H),3.27(t,J=8.8Hz,2H).

[0765] Step 6: 43-6 (90.0 mg, 0.45 mmol), 3-(6-(aminomethyl)benzofuran-3-yl)piperidin-2,6-dione (140.5 mg, 0.54 mmol), triethylamine (68.8 mg, 0.68 mmol), and diphenyl azidophosphate (187.1 mg, 0.68 mmol) were added to 10.0 mL of anhydrous toluene. After purging with nitrogen three times, the mixture was stirred at 90 °C for half an hour. After the reaction was complete, the reaction solution was extracted with water (20 mL) and ethyl acetate (10 mL * 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by reversed-phase column chromatography (water / acetonitrile = 41%) to obtain the target compound 43 (24.54 mg, 11.67%).

[0766] LCMS[M+H] + m / z:calcd 454.1, found 454.2.

[0767] 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.69(s,1H),7.86(s,1H),7.53(d,J=8.0Hz,1H),7 .47(s,1H),7.19(d,J=8.0Hz,1H),7.02(d,J=1.6Hz,1H),6.81(d,J=1.6Hz,1H),6.72(s,1 H),4.55(t,J=8.4Hz,2H),4.38(d,J=6.0Hz,2H),4.12(dd,J=11.6,4.8Hz,1H),3.11(t,J =8.4Hz,2H),2.79–2.68(m,1H),2.61–2.56(m,1H),2.37–2.25(m,1H),2.17–2.04(m,1H).

[0768] Example 43: Synthesis of Compound 44

[0769] Step 1: 3-Chloro-5-(2-methoxyethoxy)-4-methylaniline (95.0 mg, 0.442 mmol), triphosgene (65.0 mg, 0.221 mmol), and triethylamine (268.0 mg, 2.652 mmol) were dissolved in tetrahydrofuran (15.0 mL). The reaction solution was reacted at room temperature for half an hour, and then compound 25-8 (122.0 mg, 0.442 mmol) was added, and the reaction was continued for another half hour. The reaction solution was concentrated, and the residue was purified by normal-phase column chromatography (methanol / dichloromethane = 3%) to give compound 44 (90.0 mg, 42.3%).

[0770] LCMS[M+H] + m / z:calcd 518.1; found 518.3.

[0771] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.73(s,1H),7.92(s,1H),7.37(s,1H),7.18( d,J=2.0Hz,1H),7.04–6.96(m,2H),6.80(t,J=5.6Hz,1H),4.38(d,J=5.6Hz,2H),4. 13(dd,J=12.4,5.2Hz,1H),4.06–4.00(m,2H),3.70–3.63(m,2H),3.31(s,3H),2.84 –2.73(m,1H),2.62–2.54(m,1H),2.23–2.15(m,1H),2.11(s,3H),2.08–2.05(m,1H).

[0772] Example 44: Synthesis of Compound 45

[0773] Step 1: Compounds 21-3 (200.0 mg, 0.70 mmol) and 26-1 (283.0 mg, 0.84 mmol) were dissolved in 20 mL of anhydrous N,N-dimethylformamide. The mixture was cooled to 0 °C under nitrogen protection, and then 60% sodium hydroxide (42.0 mg, 1.04 mmol, 60% in mineral oil) was added. The mixture was stirred for another 30 minutes. After the reaction was complete, the reaction mixture was added dropwise to ice water (20.0 mL), extracted with ethyl acetate (20.0 mL * 3), and the organic phase was collected and washed with saturated sodium chloride. The mixture was then evaporated to dryness, and the residue was purified by reversed-phase column chromatography (water / acetonitrile = 42%) to obtain the target compound 45 (48.54 mg, 13.1%).

[0774] LCMS[M+H] + m / z:calcd 526.2, found 526.4.

[0775] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.58(s,1H),7.89(s,1H),7.68–7.50(m, 2H),7.35(d,J=1.6Hz,1H),7.29(d,J=7.6Hz,1H),7.17(s,1H),4.40(t,J=7.6H z,2H),4.09–4.16(m,1H),4.05–3.93(m,5H),3.68(t,J=4.8Hz,2H),3.32(s,3H ),2.79–2.65(m,1H),2.61–2.54(m,1H),2.41–2.26(m,1H),2.14–2.07(m,4H).

[0776] Example 45: Synthesis of Compound 46

[0777] Step 1: Compound 21-3 (100.0 mg, 0.331 mmol) and phenyl (3-chloro-5-(2-methoxyethoxy)-4-methylphenyl)carbamate (110.0 mg, 0.332 mmol) were dissolved in anhydrous N,N-dimethylformamide (10.0 mL). Sodium hydroxide (20.0 mg, 0.496 mmol) was added under ice bath conditions, and the mixture was stirred for 30 minutes. After the reaction was complete, the reaction solution was added dropwise to ice water (10.0 mL), and ethyl acetate (10.0 mL * 3) was added to extract the product. The combined organic phases were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by reversed-phase column chromatography (water / acetonitrile = 1 / 1) to give compound 46 (26.09 mg, 14.6%).

[0778] LCMS[M+H]+m / z:calcd 544.2; found 544.4.

[0779] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.58(s,1H),7.95(s,1H),7.52(s,1H),7.34(s,1H),7.22–7.07(m,2H),4.41-4.35(m,2H) ,4.17-4.13(m,1H),4.01-3.95(m,5H),3.73-3.65(m,2H),3.35(s,3H),2.86–2.71(m,1H),2.68–2.56(m,1H),2.34–1.97(m,5H).

[0780] Example 46: Synthesis of Compound 47

[0781] Step 1: Dissolve 47-1 (6.5 g, 14.171 mmol) in anhydrous acetonitrile (60.0 mL), and add N-iodosuccinimide (7.8 g, 34.667 mmol) in portions. React at room temperature for 12 hours. After the reaction is complete, filter the reaction solution and wash the filter cake with acetonitrile (30.0 mL). Combine the organic phases and concentrate to obtain 47-2 (4.7 g, 44.3%).

[0782] LCMS[M+H] + m / z:calcd 322.9,324.9,found 322.8,324.8.

[0783] Step 2: Dissolve 47-2 (1.9 g, 5.882 mmol) in anhydrous dioxane (30.0 mL), add 3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.8 g, 6.818 mmol), cuprous iodide (560.0 mg, 2.947 mmol), levo-trans-1,2-cyclohexanediamine (340.0 mg, 0.982 mmol) and potassium phosphate (2.5 g, 11.792 mmol), and stir the reaction mixture overnight at 70 °C under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature and poured into water (30.0 mL). The solution was extracted with ethyl acetate (30.0 mL * 3), the organic phases were combined, and the mixture was washed with saturated sodium chloride solution (30.0 mL * 3). The mixture was dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the target compound 47-3 (760.0 mg, 25.9%).

[0784] LCMS[M+H]+ m / z:calcd 459.1,461.1, found 459.0,461.0.

[0785] Step 3: Dissolve 47-3 (380.0 mg, 0.827 mmol) in anhydrous dioxane (3.0 mL), add (tributyltin)methanol (320 mg, 0.996 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (70.0 mg, 0.082 mmol), 10 The mixture was stirred at 0℃ for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and poured into water (10.0 mL). The mixture was extracted with ethyl acetate (10.0 mL * 3). The organic phases were combined and washed with saturated sodium chloride solution (10.0 mL * 3). The mixture was dried over anhydrous sodium sulfate and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the target compound 47-4 (250.0 mg, 80.6%).

[0786] LCMS[M+H] + m / z:calcd 411.1, found 411.0.

[0787] Step 4: Dissolve starting material 47-4 (200.0 mg, 0.487 mmol) and phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (250.0 mg, 0.793 mmol) in anhydrous N,N-dimethylformamide (10.0 mL). Add sodium hydride (30.0 mg, 0.750 mmol) under ice bath conditions and stir for 30 minutes. After the reaction is complete, add the reaction solution dropwise to ice water (10.0 mL), add ethyl acetate (10.0 mL * 3) to extract the product, combine the organic phases, wash with saturated sodium chloride aqueous solution (10.0 mL * 3) and dry with anhydrous sodium sulfate. Concentrate the filtrate, and purify the residue by column chromatography (dichloromethane / methanol = 10 / 1) to obtain 47-5 (250.0 mg, 75.7%).

[0788] LCMS[M+H] + m / z:calcd 632.2; found 632.1.

[0789] Step 5: Dissolve raw material 47-5 (250.0 mg, 0.487 mmol) in a trifluoroacetic acid / trifluoromethanesulfonic acid (1 / 2) mixed solution (9.0 mL) and stir at room temperature for 30 minutes. After the reaction is complete, add the reaction solution dropwise to saturated sodium bicarbonate ice water (20.0 mL), add ethyl acetate (10.0 mL * 3) to extract the product, combine the organic phases and dry with anhydrous sodium sulfate, concentrate the filtrate, and slurry the residue with a dichloromethane / methanol (10 / 1) mixed solution (10.0 mL), and wash the filter cake several times with acetonitrile to obtain compound 47 (60.0 mg, 31.5%).

[0790] LCMS[M+H]+m / z:calcd 482.1; found 482.1.

[0791] 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),9.88(s,1H),8.81(s,1H),8.07(s,1H),7.84(s,1H),7.63(d,J=9.2Hz,1H),7.39( t,J=9.6Hz,1H),7.30(d,J=9.6Hz,1H),7.14(d,J=8.8Hz,1H),5.23(s,2H),3.79(t,J=6.4Hz,2H),2.78(t,J=6.4Hz,2H).

[0792] Example 47: Synthesis of Compound 48

[0793] Step 1: Dissolve 47-3 (380.0 mg, 0.827 mmol) in a toluene / water mixture of 10 / 1 (10.0 mL), add potassium N-aminomethyltrifluoroborate (240.0 mg, 1.012 mmol), cesium carbonate (800.0 mg, 2.461 mmol), and chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (55.0 mg, 0.0748 mmol), and heat to 105 °C with stirring for 12 hours. After the reaction is complete, pour the reaction solution into water (10.0 mL), add ethyl acetate (10.0 mL * 3) for extraction, combine the organic phases and dry with anhydrous sodium sulfate, evaporate the filtrate to dryness, and purify the residue by silica gel column chromatography (PE / EA = 10 / 1) to obtain the target compound 48-1 (200.0 mg, 47.6%).

[0794] LCMS[M+H] + m / z:calcd 510.2, found 510.2.

[0795] Step 2: Dissolve 48-1 (200.0 mg, 0.392 mmol) in anhydrous dichloromethane (10.0 mL), add trifluoroacetic acid (1.0 mL), and react at room temperature for 30 minutes. After the reaction is complete, remove the solvent by rotary evaporation to obtain the target compound 48-2 (160.0 mg, 100%).

[0796] LCMS[M+H] + m / z:calcd 410.2, found 410.0.

[0797] Step 3: Dissolve 48-0 (200.0 mg, 0.961 mmol) in dichloromethane (6.0 mL), add sodium carbonate (160.0 mg, 1.509 mmol), triphosgene (75.0 mg, 0.382 mmol), and water (2.0 mL), and stir at room temperature for 0.5 hours. After the reaction is complete, add water (5.0 mL) and dichloromethane (5.0 mL * 3) to extract the product, dry and concentrate the organic phase to obtain crude 48-3 (120.0 mg). Dissolve 48-3 (120.0 mg) in dichloromethane (5.0 mL), add 48-2 (160.0 mg, 0.391 mmol), and triethylamine (0.2 mL), and stir at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 48-4 (120.0 mg, 48.6%).

[0798] LCMS[M+H] + m / z:calcd 644.2, found 644.2.

[0799] Step 4: Dissolve raw material 48-4 (120.0 mg, 0.186 mmol) in a trifluoroacetic acid / trifluoromethanesulfonic acid (1 / 2) mixed solution (9.0 mL) and stir at room temperature for 30 minutes. After the reaction is complete, add the reaction solution dropwise to ice-cold saturated sodium bicarbonate solution (20.0 mL), add ethyl acetate (10.0 mL * 3) to extract the product, combine the organic phases and dry with anhydrous sodium sulfate, concentrate the filtrate, and slurry the residue with a dichloromethane / methanol (10 / 1) mixed solution (40.0 mL), and wash the filter cake several times with acetonitrile to obtain compound 48 (72.4 mg 79.1%).

[0800] LCMS[M+H] + m / z:calcd 494.2, found 494.3.

[0801] 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.53(s,1H),8.24(d,J=2.0Hz,1H),8.01(s,1H),7.62–7.50(m,2H),7.21(d,J=9.2Hz,1H),7.17– 7.03(m,1H),7.03–6.79(m,1H),6.34–6.18(m,1H),6.18–6.03(m,1H),4.33(d,J=5.6Hz,2H),3.91–3.69(m,4H),2.78(t,J=7.6Hz,2H).

[0802] Example 48: Synthesis of Compound 49

[0803] Step 1: Dissolve 21-3 (60.0 mg, 0.21 mmol) and 49-1 (86.7 mg, 0.25 mmol) in N,N-dimethylformamide (15.0 mL). Under nitrogen protection at 0 °C, add sodium hydride (12.7 mg, 0.32 mmol, 60% in mineral oil). After reacting for 30 minutes, quench the reaction mixture in ice water, extract with ethyl acetate (15.0 mL * 3), wash with saturated sodium chloride aqueous solution (10.0 mL * 3), dry the organic phase with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by reversed-phase column chromatography (acetonitrile:water = 3:2) to obtain the target compound 49 (35.12 mg, 31.2%).

[0804] LCMS[M+H] + m / z:calcd 533.2, found 533.3.

[0805] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.00(s,1H),7.89(s,1H),7.68-7.51(m,2H),7.28(dd,J=8.0,1.2Hz,1H),6.97 (d,J=6.8Hz,1H),6.88(d,J=11.2Hz,1H),5.33(t,J=6.8Hz,1H),4.41-4.34(m,2H),4.13(dd,J=12.0,4.8Hz,1H),4.01 -3.90(m,3H),3.89-3.77(m,2H),2.80-2.69(m,1H),2.62-2.53(m,1H),2.39-2.27(m,1H),2.17-2.01(m,4H).

[0806] Example 49: Synthesis of Compound 50

[0807] Step 1: Dissolve 50-0 (200.0 mg, 0.83 mmol) in 10 mL of acetonitrile, add pyridine (196.0 mg, 2.49 mmol), and cool the reaction solution to 0 °C under nitrogen protection. Then add phenyl chloroformate (141.0 mg, 0.91 mmol) and continue stirring for 30 minutes. After the reaction is complete, extract the reaction solution with water (10.0 mL) and ethyl acetate (10.0 mL * 3), collect the organic phase, wash with saturated sodium chloride, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the target compound 50-1 (210.00 mg, 66.8%).

[0808] LCMS[M+H] + m / z:calcd 363.0, found 363.0.

[0809] Step 2: Dissolve 21-3 (100.0 mg, 0.35 mmol) in 10.0 mL of N,N-dimethylformamide, add 50-1 (153.0 mg, 0.42 mmol), and cool the reaction solution to 0 °C under nitrogen protection. Then add 60% NaH (21.0 mg, 0.53 mmol, 60% in mineral oil) and continue stirring for 30 minutes. After the reaction is complete, extract the reaction solution with water (20.0 mL) and ethyl acetate (20.0 mL * 3), collect the organic phase and wash with saturated sodium chloride, evaporate to dryness, and purify the residue by reversed-phase column chromatography (water / acetonitrile = 43%) to obtain the target compound 50 (70.10 mg, 36.3%).

[0810] LCMS[M+H] + m / z:calcd 553.1, found 553.4.

[0811] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.19(s,1H),7.89(s,1H),7.58(d,J=8.4Hz,2H),7.43–7.18(m,3H),5.80(t,J=6.8Hz,1H),4.4 1(t,J=7.6Hz,2H),4.18–4.10(m,1H),4.05–3.77(m,5H),2.82–2.67(m,1H),2.64–2.55(m,1H),2.36–2.29(m,1H),2.19–1.99(m,1H).

[0812] Example 50: Synthesis of Compound 51

[0813] Step 1: 51-1 (500.0 mg, 2.211 mmol), pyridine (524.0 mg, 6.633 mmol), and phenyl chloroformate (690.0 mg, 4.422 mmol) were dissolved in acetonitrile (20.0 mL) and reacted at room temperature for two hours. The reaction solution was concentrated, and the residue was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 5%) to obtain compound 51-2 (660.0 mg, 86.3%).

[0814] LCMS[M+H] + m / z:calcd 347.1; found 347.0.

[0815] Step 2: Compound 39-3 (183.0 mg, 0.401 mmol) and 51-2 (153.0 mg, 0.441 mmol) were placed in dimethylformamide (20.0 mL), and sodium hydroxide (24 mg, 0.601 mmol, 60% in mineral oil) was added at 0 °C, and the reaction was continued for 40 minutes. The reaction solution was quenched with ice water, extracted three times with ethyl acetate (20.0 mL), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated, and the residue was purified by normal-phase column chromatography (methanol / dichloromethane = 3%) to give compound 51 (70.0 mg, 31.6%).

[0816] LCMS[M+H] + m / z:calcd 555.1; found 555.3.

[0817] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.12(s,1H),7.95(s,1H),7.50(d,J =0.8Hz,1H),7.18–7.09(m,3H),5.98(dd,J=6.8,4.8Hz,1H),4.39-4.35(m, 2H),4.15(dd,J=12.4,5.2Hz,1H),3.99–3.92(m,3H),3.90–3.80(m,2H),2 .85–2.74(m,1H),2.63–2.55(m,1H),2.26–2.15(m,1H),2.12–2.04(m,1H).

[0818] Example 51: Synthesis of Compound 52

[0819] Step 1: Dissolve 3-(6-bromobenzofuran-3-yl)piperidine-2,6-dione (600.0 mg, 1.94 mmol) in a mixed solvent of 10.0 mL of 1,4-dioxane and 1.0 mL of water, then add tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (858.2 mg, 2.91 mmol), 1,1'-bis(diphenyl phosphonium)dichloroferrocene palladium (70.9 mg, 0.097 mmol), and cesium fluoride (590.0 mg, 3.88 mmol). The reaction solution is heated to 90 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was extracted with ethyl acetate (20.0 mL * 3) and water (20.0 mL), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain product 52-1 (400.0 mg, 52.1%).

[0820] LCMS[M-55]m / z:calcd 341.2, found 341.0.

[0821] Step 2: Dissolve 52-2 (400.0 mg, 1.01 mmol) in 40.0 mL of methanol, then add palladium on carbon (50.0 mg). The reaction solution is reacted at room temperature under a hydrogen atmosphere for 3 hours. After the reaction is complete, the reaction solution is filtered directly, the filter cake is washed several times with methanol, the filtrate is collected, and evaporated to dryness to obtain product 52-3 (80.0 mg, 20.0%).

[0822] LCMS[M+H] + m / z:calcd 343.2, found 343.0.

[0823] Step 3: Dissolve 52-3 (80.0 mg, 0.20 mmol) in 5.0 mL of dichloromethane, then add trifluoroacetic acid (1.0 mL), and stir the reaction solution at room temperature for 3 hours. After the reaction is complete, evaporate the reaction solution directly to dryness to obtain product 52-4 (55.0 mg, 91.7%).

[0824] LCMS[M+H] + m / z:calcd 299.0, found 299.0.

[0825] Step 4: Dissolve 52-4 (55.0 mg, 0.18 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (70.0 mg, 0.21 mmol) in 10.0 mL of N,N-dimethylformamide. Under nitrogen protection, add sodium hydride (14.0 mg, 0.21 mmol) at 0 °C. Continue the reaction for 10 minutes, then quench the reaction mixture by slowly adding it dropwise to ice water. Extract with ethyl acetate (10.0 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and the residue is subjected to reversed-phase column chromatography (water / acetonitrile = 43%) to give 53 (28.59 mg, 25.6%).

[0826] LCMS[M+H]+m / z:calcd 551.2; found 551.4.

[0827] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.87(s,1H),7.81(s,1H),7.59–7.51(m,2H ),7.23(d,J=8.4Hz,1H),7.14(d,J=8.0Hz,1H),7.08–6.97(m,1H),5.96(t,J=5.6 Hz,1H),4.13(dd,J=11.8,4.8Hz,1H),3.88(dd,J=7.2,2.8Hz,3H),3.68–3.38(m, 4H),2.84–2.67(m,1H),2.64–2.54(m,1H),2.39–2.25(m,2H),2.19–1.97(m,2H).

[0828] Example 52: Synthesis of Compound 53

[0829] Step 1: Dissolve DD217-INT (0.3 g, 0.974 mmol) in dimethylacetamide (10.0 mL), add (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (7.8 mL), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (70 mg, 0.095 mmol), and cuprous iodide (18 mg, 0.095 mmol). Heat to 80 °C and stir for 3 hours. After the reaction is complete, cool the reaction solution to room temperature, pour the reaction solution into water (10.0 mL), extract with ethyl acetate (10.0 mL * 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL * 3), dry with anhydrous sodium sulfate, evaporate the filtrate to dryness, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the crude target compound 53-1 (500.0 mg).

[0830] LCMS [M-55] + m / z:calcd 357.2, found 357.0.

[0831] Step 2: Dissolve 53-1 (500.0 mg, 1.213 mmol) in dichloromethane (10.0 mL), add trifluoroacetic acid (4.0 mL), stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution by vacuum evaporation. The residue is purified by reversed-phase column chromatography (acetonitrile / water = 1 / 5) to obtain the target compound 53-2 (250 mg).

[0832] LCMS[M+1] + m / z:calcd 313.1, found 313.2.

[0833] Step 3: Dissolve starting material 53-2 (50.0 mg, 0.159 mmol) and phenyl (2,4-difluoro-5-(2,2,2-trifluoroethyl)amino)carbamate (65.0 mg, 0.187 mmol) in anhydrous N,N-dimethylformamide (10.0 mL). Add sodium hydroxide (10.0 mg, 0.239 mmol) under ice bath conditions and stir for 30 minutes. After the reaction is complete, add the reaction solution dropwise to ice water (10.0 mL), add ethyl acetate (10.0 mL * 3) to extract the product, combine the organic phases and wash with saturated sodium chloride aqueous solution (10.0 mL * 3), dry with anhydrous sodium sulfate, concentrate the filtrate, and purify the residue by reversed-phase column chromatography (water / acetonitrile = 1 / 1) to obtain 53 (27.0 mg, 30%).

[0834] LCMS[M+H]+m / z:calcd 565.2; found 565.4.

[0835] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.17(s,1H),7.85(s,1H),7.50(d,J=8.0Hz,1H),7.46( s,1H),7.21–7.06(m,2H),7.01–6.84(m,1H),6.01–5.82(m,1H),4.23(d,J=12.8Hz,2H),4.11( dd,J=12.0,4.8Hz,1H),3.99–3.73(m,2H),2.98–2.80(m,3H),2.78–2.67(m,1H),2.57(dd,J= 13.2,4.2Hz,1H),2.39–2.27(m,1H),2.17–2.05(m,1H),1.91–1.78(m,2H),1.73–1.51(m,2H).

[0836] Example 53: Synthesis of Compound 54

[0837] Step 1: Dissolve 54-0 (1.00 g, 5.33 mmol) in 10.0 mL of N,N-dimethylformamide, then add N-BOC-iodoethylamine (1.73 g, 6.40 mmol), potassium carbonate (2.21 g, 15.99 mmol), and potassium iodide (88.50 mg, 0.533 mmol). The reaction mixture was incubated at 40 °C for 4 hours under nitrogen protection. After the reaction was complete, the reaction mixture was quenched in water (20 mL), extracted with ethyl acetate (20.0 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain product 54-1 (1.5 g, 85.07%).

[0838] LCMS[M+Na] + m / z:calcd 353.1, found 353.0.

[0839] Step 2: Dissolve 54-1 (1.50 g, 4.53 mmol) in 15.0 mL of tetrahydrofuran. Under nitrogen protection at 0 °C, add sodium hydride (1.09 g, 27.21 mmol) in portions. After stirring for 30 minutes, add iodomethane (0.85 mL, 13.60 mmol) and continue the reaction for 2 hours. After the reaction is complete, quench the reaction solution slowly in ice water (50 mL). Extract with ethyl acetate (50.0 mL * 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness. Purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to obtain product 54-2 (1.15 g, 73.55%).

[0840] LCMS[M+Na] + m / z:calcd 367.1, found 367.0.

[0841] Step 3: Dissolve 54-2 (1.15 g, 3.34 mmol) in 10.0 mL of a mixture of ethanol and water (4:1), then add ammonium chloride (1.78 g, 33.35 mmol) and iron powder (931.31 mg, 16.68 mmol). The reaction was stirred at room temperature under nitrogen protection for 2 hours. After the reaction was complete, the iron powder was removed from the reaction solution using a vacuum filter funnel. The filtrate was extracted with ethyl acetate (10.0 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude product 54-3 (0.79 g, 75.24%).

[0842] LCMS [M-55] +m / z:calcd 259.1,found 259.1.

[0843] Step 4: Dissolve 54-3 (0.79 g, 2.51 mmol) in 5.0 mL of acetonitrile, then add pyridine (0.20 mL, 2.51 mmol) and phenyl chloroformate (0.28 mL, 2.26 mmol). The reaction is carried out under nitrogen protection at room temperature for 12 hours. The reaction solution is quenched in water (20.0 mL), extracted with ethyl acetate (20.0 mL * 3), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give product 54-4 (0.72 g, 65.97%).

[0844] LCMS[M-100+H] + m / z:calcd 335.1, found 335.2.

[0845] Step 5: Dissolve 54-4 (0.72 g, 1.66 mmol) in 5.0 mL of N,N-dimethylformamide, add 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (0.56 g, 1.99 mmol), and add sodium hydride (0.079 g, 1.99 mmol) in portions under nitrogen protection at 0 °C, continuing stirring for 30 minutes. After the reaction is complete, quench the reaction solution by slowly adding it dropwise to ice water (30.0 mL), extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry to anhydrous sodium sulfate, filter, and evaporate to dryness. The residue is 54-5 (0.77 g, 74.40%).

[0846] LCMS[M-100+H]+m / z:calcd 525.2; found 525.2.

[0847] Step 6: Dissolve 54-5 (0.77 g, 1.23 mmol) in 5.0 mL of dichloromethane and add 2.0 mL of trifluoroacetic acid. After reacting at 25 °C for 16 hours, the reaction solution was evaporated to dryness, and the residue was purified by reversed-phase column chromatography (pure water: acetonitrile = 3:1) to give 54 (255.0 mg, 39.43%).

[0848] LCMS[M+H] + m / z:calcd 525.1, found 525.4.

[0849] 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.62-8.58(m,3H),7.89(s,1H),7.60-7.57(m,2H),7.33-7.26(m,3H),4.42-4.38(m,2H),4.17-4.1 1(m,3H),4.01-3.98(m,3H),3.39-3.31(m,2H),2.75-2.68(m,4H),2.60-2.55(m,1H),2.51-2.49(m,1H),2.31(s,3H),2.18-2.12(m,1H).

[0850] Example 54: Synthesis of Compound 55

[0851] Step 1: Dissolve 55-0 (20.0 g, 116.959 mmol) in sulfuric acid (200.0 mL), and slowly add iodosuccinimide (32.0 g, 142.222 mmol). The reaction is carried out under nitrogen protection at 60 °C for 1 hour. After the reaction is complete, the reaction solution is quenched in ice water (500.0 mL), the precipitated solid is filtered off, and the filter cake is dissolved with ethyl acetate (200.0 mL). Water (300.0 mL) is added to extract the product. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product 55-1 (15.0 g, 44.1%).

[0852] 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=2.4Hz,1H),8.28(d,J=2.4Hz,1H),2.61(s,3H).

[0853] Step 2: Dissolve 55-1 (10.0 g, 33.67 mmol), cuprous iodide (1.28 g, 6.73 mmol), L-proline (1.55 g, 13.47 mmol), cesium carbonate (43.9 g, 134.69 mmol), and diethyl malonate (6.47 g, 40.40 mmol) in tetrahydrofuran (100.0 mL). The reaction was carried out under nitrogen protection at 50 °C for 16 hours. The reaction solution was then quenched by slowly adding dropwise to a saturated sodium chloride aqueous solution (150.0 mL). Extraction was performed with ethyl acetate (50.0 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 12:1) to obtain product 55-2 (3.0 g, 27.3%).

[0854] LCMS[M+Na] +m / z:calcd 330.1, found 330.0.

[0855] Step 3: 55-2 (3.0 g, 9.12 mmol) and lithium chloride (1.16 g, 27.36 mmol) were dissolved in a mixed solvent of dimethyl sulfoxide (20.0 mL) and water (10.0 mL). The reaction was carried out under nitrogen protection at 100 °C for 16 hours. The mixture was washed with saturated sodium chloride aqueous solution (15.0 mL * 3), washed with water (20.0 mL * 3), and extracted with ethyl acetate (40.0 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give product 55-3 (1.5 g, 65.2%).

[0856] LCMS[M+Na] + m / z:calcd 280.1,found 280.0.

[0857] Step 4: Dissolve 55-3 (1.5 g, 5.83 mmol) in a mixed solvent of tetrahydrofuran (16 mL) and methanol (4 mL). Under nitrogen protection at 0 °C, add 8 mL of an aqueous lithium hydroxide solution (2 M). After reacting at 25 °C for 2 hours, adjust the reaction solution to weakly acidic using an aqueous hydrochloric acid solution (6 M), extract with ethyl acetate (30 mL x 3), dry the organic phase with anhydrous sodium sulfate, and evaporate to dryness to obtain product 55-4 (900 mg, 67.7%), which is used directly in the next step.

[0858] LCMS[M+H] + m / z:calcd 230.0, found 230.0.

[0859] Step 5: Dissolve 55-4 (900 mg, 3.93 mmol) in tetrahydrofuran (30.0 mL). Add borane dimethyl sulfide complex (20.0 mL, 39.30 mmol) at 0 °C. After reacting at 75 °C for 16 hours under nitrogen protection, quench the reaction solution dropwise with methanol, then evaporate the solution to dryness. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain product 55-5 (600 mg, 67.8%).

[0860] 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=2.4Hz,1H),8.06(d,J=2.4Hz,1H),4.75(t,J =5.2Hz,1H),3.65(dd,J=12.0,6.4Hz,2H),2.93(t,J=6.4Hz,2H),2.43(s,3H).

[0861] Step 6: Dissolve 55-5 (600 mg, 2.79 mmol), tetrabutylammonium hydrogen sulfate (758 mg, 2.23 mmol), and tert-butyl bromoacetate (4.3 g, 22.32 mmol) in toluene (15.0 mL). Under nitrogen protection at 0 °C, add dropwise 5M sodium hydroxide aqueous solution (11.2 g, 279.07 mol). After reacting for 16 hours, quench the reaction mixture by slowly adding water (30.0 mL). Extract with ethyl acetate (30.0 mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain product 55-6 (550 mg, 59.9%).

[0862] LCMS[M+Na] + m / z:calcd 352.1, found 352.0.

[0863] Step 7: Dissolve 55-6 (550 mg, 1.67 mmol) in dichloromethane (20.0 mL), followed by the addition of trifluoroacetic acid (6.0 mL). After reacting at room temperature for 1 hour, the reaction solution was evaporated to dryness, and the residue was slurried using ethyl acetate / petroleum ether = 1 / 20 to obtain product 55-7 (450 mg, 98.7%).

[0864] LCMS[M+18] + m / z:calcd 291.0, found 291.0.

[0865] Step 8: Dissolve 55-7 (500 mg, 1.83 mmol) and methylamine hydrochloride (247 mg, 3.66 mmol) in 20.0 mL of N,N-dimethylformamide. Under nitrogen protection, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.04 g, 2.75 mmol) and triethylamine (370 mg, 3.66 mmol) at 0 °C. After reacting at room temperature for 30 minutes, quench the reaction mixture in a saturated sodium chloride aqueous solution (40.0 mL), extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain product 55-8 (400 mg, 76.3%).

[0866] LCMS[M+H] + m / z:calcd 287.1, found 287.0.

[0867] Step 9: Dissolve 55-8 (400 mg, 1.40 mmol) in tetrahydrofuran (20.0 mL). Add borane dimethyl sulfide complex (7.0 mL, 14.0 mmol) at 0 °C. After reacting at 75 °C for 16 hours under nitrogen protection, quench the reaction mixture dropwise with methanol, and then evaporate the mixture to dryness to obtain crude product 55-9 (400 mg), which can be used directly in the next step.

[0868] LCMS[M+H] + m / z:calcd 273.1, found 273.0.

[0869] Step 10: 55-9 (400 mg, 1.47 mmol) was dissolved in 20.0 mL of tetrahydrofuran. Under nitrogen protection, di-tert-butyl dicarbonate (642 mg, 2.94 mmol), triethylamine (446 mg, 4.41 mmol), and 4-dimethylaminopyridine (8.9 mg, 0.07 mmol) were added. After reacting at 50 °C for 16 hours, the reaction solution was washed with saturated ammonium chloride aqueous solution (20.0 mL * 3) and extracted with ethyl acetate (20.0 mL * 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give the mixed product 55-10 (180 mg, 34.6%).

[0870] LCMS[M-100] + m / z:calcd 273.1, found 273.1.

[0871] Step 11: Dissolve 55-10 (180 mg, 0.48 mmol) in a mixture of ethanol (12.0 mL) and water (3.0 mL), then add ammonium chloride (259 mg, 4.84 mmol) and iron powder (135 mg, 2.42 mmol). After stirring at 70 °C under nitrogen protection for 5 hours, filter the iron powder through diatomaceous earth. Dry the filtrate under reduced pressure and extract with ethyl acetate (20.0 mL x 3), washing with water (15.0 mL x 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain crude product 55-11 (120 mg, 72.7%), which is used directly in the next step.

[0872] LCMS[M+Na] + m / z:calcd 365.2, found 365.0.

[0873] Step 12: Dissolve 55-11 (120 mg, 0.35 mmol) in 15.0 mL of acetonitrile. Under nitrogen protection, add pyridine (83 mg, 1.05 mmol) and phenyl chloroformate (49 mg, 0.32 mmol) dropwise at 0 °C. After continuing the reaction for 5 min, quench the reaction solution in ice water, extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 12:1) to obtain product 55-12 (130 mg, 80.2%).

[0874] LCMS[M+Na] + m / z:calcd 485.2, found 485.2.

[0875] Step 13: Dissolve 55-12 (130 mg, 0.28 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (96 mg, 0.28 mmol) in 20.0 mL of N,N-dimethylformamide. Add sodium hydride (17 mg, 0.42 mmol) under nitrogen protection at 0 °C. Continue the reaction for 10 minutes, then quench the reaction mixture by slowly adding it dropwise to ice water. Extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain product 55-13 (100 mg, 54.6%).

[0876] LCMS[M-100+H]+m / z:calcd 553.3; found 553.0.

[0877] Step 14: Dissolve 55-13 (100 mg, 0.15 mmol) in 10 mL of dichloromethane and add 3 mL of trifluoroacetic acid. After reacting at 25 °C for 1 hour, evaporate the reaction solution to dryness. The residue was then processed by Prep-HPLC to obtain 55 (38.67 mg, 45.6%).

[0878] LCMS[M+H] + m / z:calcd 553.2, found 553.3.

[0879] 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.55(s,1H),7.89(s,1H),7.63-7.54(m,3H),7.31-7. 25(m,2H),4.39(t,J=7.6Hz,2H),4.13(dd,J=12.0,4.8Hz,1H),4.03-3.87(m,3H),3.54(dd,J =14.8,7.6Hz,2H),3.45(t,J=5.6Hz,2H),2.84-2.76(m,2H),2.77-2.69(m,1H),2.61(t,J=5. 3Hz,3H),2.58-2.54(m,1H),2.40-2.30(m,1H),2.27(s,3H),2.24(s,3H),2.18-2.05(m,1H).

[0880] Example 55: Synthesis of Compound 56

[0881] Step 1: 56-0 (1.0 g, 5.76 mmol) was dissolved in N,N-dimethylformamide (18.0 mL), followed by the addition of N-Boc-iodoethylamine (1.56 g, 5.76 mmol), potassium carbonate (1.19 g, 8.64 mmol), and potassium iodide (95.6 mg, 0.576 mmol). The reaction was carried out under nitrogen protection at 50 °C for 16 hours. The reaction solution was then quenched in a saturated sodium chloride aqueous solution (50 mL), extracted with ethyl acetate (40.0 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain product 56-1 (1.1 g, 61.1%).

[0882] LCMS[M+Na] + m / z:calcd 339.0, found 338.8.

[0883] Step 2: Dissolve 56-1 (1.2 g, 3.79 mmol) in tetrahydrofuran (30.0 mL). Under nitrogen protection, add sodium hydride (0.911 g, 22.78 mmol) in portions at 0 °C. After stirring for 30 minutes, add iodomethane (0.7 mL, 11.39 mmol). Continue the reaction for 2 hours, then quench the reaction mixture by slowly adding it dropwise to ice water (50.0 mL). Extract with ethyl acetate (50.0 mL * 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness. Purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to obtain product 56-2 (1.1 g, 88.0%).

[0884] LCMS[M+Na] + m / z:calcd 353.0, found 353.0.

[0885] Step 3: Dissolve 56-2 (500.0 mg, 1.52 mmol) in a mixture of ethanol (8.0 mL) and water (2.0 mL), then add ammonium chloride (811.0 mg, 15.15 mmol) and iron powder (424.0 mg, 7.58 mmol). Stir the reaction mixture at room temperature under nitrogen protection for 3 hours. Remove the iron powder from the reaction mixture using a vacuum funnel. Extract the filtrate with ethyl acetate (10.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain crude product 56-3 (400.0 mg, 88.1%), which is used directly in the next step.

[0886] LCMS[M+Na] + m / z:calcd 323.0, found 323.0.

[0887] Step 4: Dissolve 56-3 (400.0 mg, 1.33 mmol) in 10.0 mL of acetonitrile. Under nitrogen protection, add pyridine (421.0 mg, 5.33 mmol) and phenyl chloroformate (187.0 mg, 1.20 mmol) dropwise at 0 °C. After continuing the reaction for 5 minutes, quench the reaction mixture in ice water, extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 12:1) to obtain product 56-4 (500.0 mg, 89.3%).

[0888] LCMS[M+Na] + m / z:calcd 443.1, found 443.0.

[0889] Step 5: Dissolve 56-4 (500.0 mg, 1.19 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (407.0 mg, 1.19 mmol) in 20.0 mL of N,N-dimethylformamide. Under nitrogen protection, add sodium hydride (71.0 mg, 1.78 mmol) at 0 °C. After continuing the reaction for 10 minutes, quench the reaction solution by slowly adding it dropwise to ice water. Extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry to anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 12:1) to obtain product 56-5 (700.0 mg, 96.4%).

[0890] LCMS[M-100+H]+m / z:calcd 511.2; found 511.0.

[0891] Step 6: Dissolve 56-5 (250.0 mg, 0.410 mmol) in 10.0 mL of dichloromethane and add 2.0 mL of trifluoroacetic acid. After reacting at 25 °C for 1 hour, the reaction solution was evaporated to dryness. The residue was washed with saturated sodium bicarbonate aqueous solution (15.0 mL * 3), extracted with ethyl acetate (20.0 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by reversed-phase column chromatography (pure water containing 0.1% formic acid: acetonitrile = 3:1) to give 56 (36.0 mg, 17.2%).

[0892] LCMS[M+H] + m / z:calcd 511.2, found 511.4.

[0893] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.64(s,1H),8.30(s,1H),7.89(s,1H),7.64- 7.56(m,2H),7.45(d,J=2.0Hz,1H),7.27(dd,J=12.4,8.4Hz,2H),7.16(dd,J=8.4,2 .0Hz,1H),4.41(t,J=8.0Hz,2H),4.21-3.92(m,6H),2.95-2.90(m,2H),2.82-2.68( m,1H),2.57-2.54(m,1H),2.39-3.31(m,3H),2.36-2.25(m,1H),2.14-2.08(m,1H).

[0894] Example 56: Synthesis of Compound 57

[0895] Step 1: Dissolve 57-0 (6.0 g, 27.82 mmol) in tetrahydrofuran (40.0 mL). Add borane dimethyl sulfide complex (139.1 mL, 278.2 mmol) at 0 °C. After reacting at 75 °C for 16 hours under nitrogen protection, quench the reaction solution dropwise with methanol, then evaporate the solution to dryness. Wash the residue with saturated sodium chloride aqueous solution (50.0 mL * 3), extract with ethyl acetate (40.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to obtain product 57-1 (5.3 g, 94.8%).

[0896] 1H NMR (400MHz, DMSO-d6) δ8.24 (d, J=2.8Hz, 1H), 8.09 (dd, J=8.8, 2.8Hz, 1H), 7.72 (d, J= 8.8Hz, 1H), 4.82 (t, J = 5.2Hz, 1H), 3.69 (dd, J = 12.0, 6.4Hz, 2H), 2.97 (t, J = 6.4Hz, 2H).

[0897] Step 2: Dissolve 57-1 (6.3 g, 31.34 mmol), tetrabutylammonium hydrogen sulfate (8.5 g, 25.07 mmol), and tert-butyl bromoacetate (48.9 g, 250.75 mmol) in toluene (50.0 mL). Under nitrogen protection, add 5M sodium hydroxide aqueous solution (125.3 g, 3.13 mol) dropwise at 0 °C. After reacting for 16 hours, quench the reaction mixture by slowly adding water (80.0 mL). Extract with ethyl acetate (50.0 mL * 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain product 57-2 (6.0 g, 60.8%).

[0898] LCMS[M+Na] + m / z:calcd 338.1, found 338.0.

[0899] Step 3: Dissolve 57-2 (6.0 g, 19.04 mmol) in dichloromethane (30.0 mL), followed by the addition of trifluoroacetic acid (10.0 mL). After reacting at room temperature for 16 hours, the reaction solution was evaporated to dryness, and the residue was slurried using ethyl acetate / petroleum ether = 1 / 20 to obtain product 57-3 (4.8 g, 97.9%).

[0900] LCMS[M+Na] + m / z:calcd 282.0, found 282.0.

[0901] Step 4: Dissolve 57-3 (4.8 g, 18.53 mmol) and methylamine hydrochloride (2.5 g, 37.06 mmol) in 40.0 mL of N,N-dimethylformamide. Under nitrogen protection, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (10.8 g, 27.79 mmol) and triethylamine (3.74 g, 37.06 mmol) at 0 °C. After reacting at room temperature for 5 hours, quench the reaction mixture in a saturated sodium chloride aqueous solution (60.0 mL), extract with ethyl acetate (30.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain product 57-4 (5.0 g, 99.2%).

[0902] LCMS[M+Na] + m / z:calcd 295.1, found 295.0.

[0903] Step 5: Dissolve 57-4 (2.5 g, 9.19 mmol) in tetrahydrofuran (20.0 mL). Add borane dimethyl sulfide complex (46.0 mL, 91.91 mmol) at 0 °C. After reacting at 75 °C for 16 hours under nitrogen protection, quench the reaction mixture dropwise with methanol, then evaporate the mixture to dryness. Wash the residue with saturated sodium chloride aqueous solution (30.0 mL * 3), wash with saturated sodium bicarbonate aqueous solution until weakly alkaline, extract with ethyl acetate (40.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain crude product 57-5 (2.2 g), which can be used directly in the next step.

[0904] LCMS[M+H] + m / z:calcd 259.1, found 259.0.

[0905] Step 6: Dissolve 57-5 (2.2 g, 8.53 mmol) in 30.0 mL of tetrahydrofuran. Under nitrogen protection, add di-tert-butyl dicarbonate (3.7 g, 17.05 mmol), triethylamine (2.58 g, 25.58 mmol), and 4-dimethylaminopyridine (0.05 g, 0.43 mmol). After reacting at 25 °C for 16 hours, the reaction solution is washed with saturated ammonium chloride aqueous solution (40.0 mL * 3) and extracted with ethyl acetate (50.0 mL * 3). The organic phase is dried over anhydrous sodium sulfate, evaporated to dryness, and the residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give the mixed product 57-6 (900 mg, 30.0%).

[0906] LCMS[M+Na] +m / z:calcd 381.1, found 381.2.

[0907] Step 7: Dissolve 57-6 (900 mg, 2.51 mmol) in a mixture of ethanol (24.0 mL) and water (6.0 mL), then add ammonium chloride (1.34 g, 19.55 mmol) and iron powder (704 mg, 12.57 mmol). After stirring at 70 °C under nitrogen protection for 16 hours, filter the iron powder through diatomaceous earth. The filtrate is evaporated to dryness and extracted with ethyl acetate (20.0 mL x 3), followed by washing with water (15.0 mL x 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain crude product 57-7 (700 mg, 84.9%), which is used directly in the next step.

[0908] LCMS[M+Na] + m / z:calcd 351.2, found 351.2.

[0909] Step 8: Dissolve 57-7 (700 mg, 2.13 mmol) in 15.0 mL of acetonitrile. Under nitrogen protection, add pyridine (506 mg, 6.40 mmol) and phenyl chloroformate (299 mg, 1.92 mmol) dropwise at 0 °C. After continuing the reaction for 5 min, quench the reaction solution in ice water, extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 12:1) to obtain product 57-8 (800 mg, 83.7%).

[0910] LCMS[M+Na] + m / z:calcd 471.2, found 471.2.

[0911] Step 9: Dissolve 57-8 (400 mg, 0.893 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (305 mg, 0.89 mmol) in 20.0 mL of N,N-dimethylformamide. Add sodium hydride (54 mg, 1.34 mmol) under nitrogen protection at 0 °C. Continue the reaction for 10 minutes, then quench the reaction mixture by slowly adding it dropwise to ice water. Extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 12:1) to obtain product 57-9 (420 mg, 73.8%).

[0912] LCMS[M-100+H]+m / z:calcd 539.2; found 539.0.

[0913] Step 11: Dissolve 57-9 (190 mg, 0.298 mmol) in 10 mL of dichloromethane and add 3 mL of trifluoroacetic acid. After reacting at 25 °C for 1 hour, evaporate the reaction solution to dryness. The residue was then processed by Prep-HPLC to obtain 57 (65.31 mg, 40.6%).

[0914] LCMS[M+H] + m / z:calcd 539.2, found 539.4.

[0915] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.64(s,1H),8.35(s,2H),7.89(s,1H),7.6 7-7.56(m,3H),7.46-7.22(m,3H),4.41(t,J=7.6Hz,2H),4.13(dd,J=12.0,4.8Hz ,1H),4.03-3.93(m,3H),3.68-3.64(m,5H),3.14-3.08(s,2H),2.93(t,J=6.8Hz, 2H),2.78-2.70(m,1H),2.59-2.54(m,3H),2.34-2.29(m,1H),2.14-2.08(m,1H).

[0916] Example 57: Synthesis of Compound 58

[0917] Step 1: Dissolve 58-0 (1.0 g, 5.75 mmol) in 10.0 mL of dichloromethane. Under nitrogen protection, add sodium cyanoborohydride (904.0 mg, 14.4 mmol), then cool to 0 °C, add trifluoroacetic acid (729.0 mg, 9.22 mmol) and trifluoroacetone (1.6 g, 14.4 mmol), and allow to return to room temperature. React overnight. After the reaction is complete, extract the reaction solution with ethyl acetate (20.0 mL * 3) and water (20.0 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain product 58-1 (1.4 g, 90.3%).

[0918] LCMS[M+H] + m / z:calcd 271.0, found 270.8.

[0919] Step 2: Dissolve 58-1 (1.4 g, 5.19 mmol) in 25.0 mL of methanol, add palladium on carbon (140.0 mg), and then stir overnight at room temperature under a hydrogen atmosphere. After the reaction is complete, filter the reaction solution directly, wash the filter cake with methanol, and evaporate the filtrate to dryness to obtain product 58-2 (1.05 g, 84.7%).

[0920] LCMS[M+H] + m / z:calcd 241.1, found 241.0.

[0921] Step 3: Dissolve 58-2 (600.0 mg, 2.52 mmol) in 10.0 mL of acetonitrile. Under nitrogen protection, add pyridine (597.0 mg, 7.56 mmol) and phenyl chloroformate (390.0 mg, 2.52 mmol) dropwise at 0 °C. After reacting for 30 min, quench the reaction mixture in ice water, extract with ethyl acetate (10.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product 58-3 (710.0 mg, 78.3%).

[0922] LCMS[M+H] + m / z:calcd 361.1, found 361.0.

[0923] Step 4: 58-3 (150.0 mg, 0.42 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (194.4 mg, 0.51 mmol) were dissolved in 15.0 mL of N,N-dimethylformamide. Sodium hydride (20.4 mg, 0.51 mmol) was added under nitrogen protection at 0 °C. After reacting for 10 minutes, the reaction solution was slowly quenched dropwise in ice water. The mixture was extracted with ethyl acetate (20.0 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was analyzed by Prep-HPLC to obtain 58 (94.22 mg, 40.7%).

[0924] LCMS[M+H]+m / z:calcd 551.2; found 551.3.

[0925] 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.12(s,1H),7.89(s,1H),7.58(d,J=4.8Hz,2 H),7.27(d,J=8.4Hz,1H),7.18–7.09(m,2H),5.57(d,J=8.8Hz,1H),4.40-4.35(m,2H ),4.28–4.18(m,1H),4.14(dd,J=12.0,4.8Hz,1H),3.99-3.92(m,3H),2.78–2.71(m, 1H),2.64–2.54(m,1H),2.36–2.31(m,1H),2.18–2.04(m,1H),1.34(d,J=6.4Hz,3H).

[0926] Example 58: Synthesis of Compound 59

[0927] Step 1: Dissolve 59-0 (20.0 g, 116.959 mmol) in sulfuric acid (200.0 mL), add N-iodosuccinimide (32.0 g, 142.223 mmol), and stir for 12 hours. After the reaction is complete, quench the reaction solution in ice water, filter to obtain a solid, dissolve the solid in ethyl acetate, wash with sodium bicarbonate aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter, evaporate the filtrate to dryness, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound 59-1 (15.0 g, 44.1%).

[0928] LCMS[M+41] + m / z:calcd 338.0, found 338.4.

[0929] Step 2: Dissolve 59-1 (1.0 g, 3.367 mmol) in anhydrous toluene (10.0 mL), add tert-butyl(2-aminoethyl)(methyl)carbamate (710.0 mg, 4.081 mmol), palladium acetate (75.0 mg, 0.334 mmol), and cesium carbonate (3.3 g, 10.101 mmol), stir at 130 °C under a nitrogen atmosphere for 12 hours. After the reaction is complete, cool to room temperature, add water (20.0 mL) and ethyl acetate (20.0 mL * 3) to extract the product, combine the organic phases, wash with saturated sodium chloride aqueous solution (20.0 mL * 3) and dry with anhydrous sodium sulfate, concentrate the filtrate, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 59-2 (320 mg 27.8%).

[0930] LCMS [M-55] +m / z:calcd 288.1, found 288.0.

[0931] Step 3: Dissolve raw material 59-2 (400.0 mg, 1.167 mmol) in ethanol / water (4 / 1) (15.0 mL), add ammonium chloride (600.0 mg, 11.321 mmol), iron powder (530.0 mg, 9.464 mmol), and 50 0 Stirred at C for 12 hours. After the reaction was complete, the reaction solution was filtered, and water (10.0 mL) and ethyl acetate (10.0 mL * 3) were added to the filtrate to extract the product. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 59-3 (300.0 mg 83.3%).

[0932] LCMS[M+H]+m / z:calcd 314.2; found 314.2.

[0933] Step 4: Dissolve 59-3 (300.0 mg, 0.958 mmol) in anhydrous acetonitrile (10.0 mL), add pyridine (0.3 mL) and phenyl chloroformate (150 mg, 0.958 mmol) under ice bath conditions, and stir for 20 minutes. After the reaction is complete, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound 59-4 (230.0 mg, 56.1%).

[0934] LCMS[M-Boc]+m / z:calcd 334.2; found 334.2.

[0935] Step 5: Dissolve starting material 59-4 (230.0 mg, 0.531 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (150.0 mg, 0.531 mmol) in anhydrous N,N-dimethylformamide (10.0 mL). Add sodium hydroxide (10.0 mg, 0.796 mmol) under ice bath conditions and stir for 30 minutes. After the reaction is complete, add the reaction solution dropwise to ice water (10.0 mL), add ethyl acetate (10.0 mL * 3) to extract the product, combine the organic phases and wash with saturated sodium chloride aqueous solution (10.0 mL * 3). Dry the organic phase with anhydrous sodium sulfate, concentrate the filtrate, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 59-5 (300.0 mg, 90.9%).

[0936] LCMS[M-Boc]+m / z:calcd 524.2; found 524.0.

[0937] Step 6: Dissolve the raw material 59-5 (300.0 mg, 0.481 mmol) in dichloromethane (10.0 mL), add trifluoroacetic acid (3.0 mL), and stir for 30 minutes. After the reaction is complete, concentrate the reaction solution, and purify the residue by reversed-phase column chromatography (acetonitrile / water = 1 / 1) to obtain 59 (236.0 mg, 94.9%).

[0938] LCMS[M+1]+m / z:calcd 524.2; found 524.4.

[0939] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.40(s,1H),8.36(s,1H),7.89(s,1H),7.58(d,J= 8.8Hz,2H),7.37–7.22(m,1H),7.10–6.94(m,1H),6.85–6.76(m,1H),5.28-5.23(m,1H), 4.46–4.33(m,2H),4.14(dd,J=12.0,4.9Hz,1H),4.04–3.89(m,3H),3.33(s,3H),3.25–3 .10(m,2H),2.81–2.68(m,1H),2.66–2.58(m,3H),2.37–2.29(m,1H),2.22–2.09(m,4H).

[0940] Example 59: Synthesis of Compound 60

[0941] Step 1: Dissolve 60-0 (600.0 mg, 3.07 mmol) in 20.0 mL of acetonitrile. Under nitrogen protection, add pyridine (729.0 mg, 9.22 mmol) and phenyl chloroformate (432.0 mg, 2.77 mmol) dropwise at 0 °C. After reacting for 5 min, quench the reaction mixture in ice water, extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product 60-1 (600.0 mg, 61.9%).

[0942] LCMS[M+H] + m / z:calcd 316.0, found 315.9.

[0943] Step 2: 60-1 (200.0 mg, 0.635 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (217.0 mg, 0.635 mmol) were dissolved in 20.0 mL of N,N-dimethylformamide. Sodium hydride (38.0 mg, 0.952 mmol) was added under nitrogen protection at 0 °C. After continuing the reaction for 10 minutes, the reaction solution was slowly quenched dropwise in ice water. The mixture was extracted with ethyl acetate (20.0 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was subjected to Prep-HPLC to prepare 60 (82.28 mg, 25.6%).

[0944] LCMS[M+H]+m / z:calcd 506.1; found 506.2.

[0945] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.47(s,1H),7.99-7.80(m,2H),7.66 -7.53(m,2H),7.47-7.20(m,2H),7.16-7.00(m,1H),4.45(t,J=8.4Hz,2H),4.14(dd,J=12.0,4.8Hz,1H),4.09 -4.01(m,2H),4.00-3.92(m,1H),2.79-2.69(m,1H),2.64-2.53(m,1H),2.39-2.26(m,1H),2.18-2.05(m,1H).

[0946] Example 60: Synthesis of Compound 61

[0947] Step 1: Dissolve 61-0 (1.0 g, 4.27 mmol) in 20.0 mL of acetonitrile. Under nitrogen protection, add pyridine (1.01 g, 12.81 mmol) and phenyl chloroformate (666.0 mg, 4.27 mmol) dropwise at 0 °C. After reacting for 5 min, quench the reaction mixture in ice water, extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product 61-1 (1.25 g, 83.3%).

[0948] LCMS[M+H] + m / z:calcd 354.1, found 354.0.

[0949] Step 2: 61-1 (150.0 mg, 0.42 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (192.0 mg, 0.51 mmol) were dissolved in 20.0 mL of N,N-dimethylformamide. Sodium hydride (19.0 mg, 0.51 mmol) was added under nitrogen protection at 0 °C. After continuing the reaction for 10 minutes, the reaction solution was slowly quenched dropwise in ice water. The mixture was extracted with ethyl acetate (10.0 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was analyzed by Prep-HPLC to obtain 61 (94.18 mg, 79.7%).

[0950] LCMS[M+H]+m / z:calcd 544.1; found 544.4.

[0951] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.57(s,1H),8.00(d,J=6.4Hz,1H),7.89(s,1H),7.64–7.54(m,2H),7.46(d,J=11.2Hz,1H),7.29(dd,J=8.4,1 .2Hz,1H),4.45(t,J=8.4Hz,2H),4.16–4.11(m,1H),4.09–3.91(m,3H),2. 82–2.67(m,1H),2.61–2.57(m,1H),2.37–2.30(m,1H),2.15–2.03(m,4H).

[0952] Example 61: Synthesis of Compound 62

[0953] Step 1: Dissolve 62-0 (7.0 g, 38.57 mmol) and 1,3-dichloro-5,5-dimethylhydantoin (7.0 g, 46.28 mmol) in sulfuric acid (30 mL). After reacting at 80 °C for 16 hours, slowly pour the reaction solution into ice water, and a solid precipitates out. The solid obtained after filtration is 62-1 (5.3 g, 63.8%).

[0954] Step 2: Dissolve 62-1 (1.5 g, 6.96 mmol) and methylamine hydrochloride (939 mg, 13.91 mmol) in 20.0 mL of N,N-dimethylformamide. Under nitrogen protection, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.97 g, 10.43 mmol) and triethylamine (1.40 g, 13.91 mmol) at 0 °C. After reacting at room temperature for 1 hour, quench the reaction mixture in a saturated sodium chloride aqueous solution (40.0 mL), extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain product 62-2 (1.2 g, 75.5%).

[0955] LCMS[M+H] + m / z:calcd 229.0, found 229.0.

[0956] Step 3: Dissolve 62-2 (600 mg, 2.63 mmol) in tetrahydrofuran (30.0 mL). Add borane dimethyl sulfide complex (13.0 mL, 26.32 mmol) at 0 °C. After reacting at 75 °C for 16 hours under nitrogen protection, quench the reaction with methanol by slow dropwise addition, then evaporate the reaction solution to dryness. The crude product 62-3 (800 mg) is used directly in the next step.

[0957] Step 4: Dissolve 62-3 (800 mg, 3.74 mmol) in 20.0 mL of tetrahydrofuran. Under nitrogen protection, add di-tert-butyl dicarbonate (1.63 g, 7.48 mmol), triethylamine (1.13 g, 11.21 mmol), and 4-dimethylaminopyridine (22.83 mg, 0.187 mmol). After reacting at 50 °C for 16 hours, the reaction solution is washed with saturated ammonium chloride aqueous solution (40.0 mL * 3) and extracted with ethyl acetate (20.0 mL * 3). The organic phase is dried over anhydrous sodium sulfate, evaporated to dryness, and the residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain the mixed product 62-4 (400 mg, 48.4%).

[0958] LCMS [M-55] + m / z:calcd 259.0, found 259.0.

[0959] Step 5: Dissolve 62-4 (400 mg, 1.27 mmol) in a mixture of ethanol (24.0 mL) and water (6.0 mL), then add ammonium chloride (681 mg, 12.74 mmol) and iron powder (357 mg, 6.37 mmol). After stirring at 70 °C under nitrogen protection for 5 hours, filter the iron powder through diatomaceous earth. Dry the filtrate under reduced pressure and extract with ethyl acetate (20.0 mL x 3), washing with water (15.0 mL x 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain crude product 62-5 (350 mg, 96.9%), which is used directly in the next step.

[0960] LCMS [M-55] + m / z:calcd 229.0, found 229.0.

[0961] Step 6: Dissolve 62-5 (350 mg, 1.23 mmol) in 20.0 mL of acetonitrile. Under nitrogen protection, add pyridine (292 mg, 3.70 mmol) and phenyl chloroformate (173 mg, 1.11 mmol) dropwise at 0 °C. After continuing the reaction for 5 minutes, quench the reaction mixture in ice water, extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product 62-6 (380 mg, 76.3%).

[0962] LCMS[M+Na] + m / z:calcd 427.2, found 427.0.

[0963] Step 7: Dissolve 62-6 (380 mg, 0.94 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (322 mg, 0.94 mmol) in 20.0 mL of N,N-dimethylformamide. Add sodium hydride (56 mg, 1.41 mmol) under nitrogen protection at 0 °C. Continue the reaction for 10 minutes, then quench the reaction mixture by slowly adding it dropwise to ice water. Extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 12:1) to obtain product 62-7 (400 mg, 71.6%).

[0964] LCMS[M-100+H]+m / z:calcd 495.2; found 495.0.

[0965] Step 8: Dissolve 62-7 (400 mg, 0.673 mmol) in 20 mL of dichloromethane and add 5 mL of trifluoroacetic acid. After reacting at 25 °C for 1 hour, the reaction solution was evaporated to dryness, and the residue was used to prepare 62 (214.18 mg, 64.4%) by Prep-HPLC.

[0966] LCMS[M+H] + m / z:calcd 495.2, found 539.4.

[0967] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.81-8.42(m,2H),7.89(s,1H),7.69-7.56(m,4H),7.27(dd,J=8.4,1.2Hz,1H),4.41(t,J =7.6Hz,2H),4.19-4.06(m,3H),4.05-3.91(m,3H),2.80-2.69(m,1H),2.65-2.53(m,4H),2.41-2.25(m,4H),2.19-2.05(m,1H).

[0968] Example 62: Synthesis of Compound 63

[0969] Step 1: Dissolve 63-0 (557.0 mg, 1.88 mmol) in 10.0 mL of N,N-diethylacetamide, then add cuprous iodide (35.7 mg, 0.19 mmol) and 1,1'-bis(diphenyl ether)dichloroferrocene palladium (137.0 mg, 0.19 mmol). Under argon protection, rapidly add (15 mL, 7.52 mmol) zinc(II) iodide. Then, heat to 85 °C and react for 6 hours. After the reaction is complete, extract the reaction solution with ethyl acetate (20.0 mL * 3) and water (20.0 mL). Combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain product 63-1 (300.0 mg, 45.1%).

[0970] LCMS[M-55]m / z:calcd 299.1, found 299.0.

[0971] Step 2: Dissolve 63-1 (300.0 mg, 0.85 mmol) in 5.0 mL of ethanol, add iron powder (240.0 mg, 4.25 mmol), then dissolve ammonium chloride (449.4 mg, 8.5 mmol) in 1.0 mL of water, add the above reaction solution, and heat to 70 °C for 3 hours. After the reaction is complete, filter the reaction solution, extract the filtrate with ethyl acetate (10.0 mL * 3) and water (10.0 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain product 63-2 (250.0 mg, 90.9%).

[0972] LCMS [M-55] + m / z:calcd 269.2, found 269.1.

[0973] Step 3: Dissolve 63-2 (250.0 mg, 0.77 mmol) in 5.0 mL of acetonitrile, then cool to 0 °C, add phenyl chloroformate (120.0 mg, 0.77 mmol) and pyridine (185.0 mg, 2.31 mmol), and continue stirring for 0.5 hours. After the reaction is complete, extract the reaction solution with ethyl acetate (10.0 mL * 3) and water (10.0 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain product 63-3 (320.0 mg, 90.9%).

[0974] LCMS[M-100+H] + m / z:calcd 345.2, found 345.2.

[0975] Step 4: Dissolve 63-3 (150.0 mg, 0.44 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (148.0 mg, 0.52 mmol) in 10.0 mL of N,N-dimethylformamide. Add sodium hydride (26.0 mg, 0.66 mmol) under nitrogen protection at 0 °C. Continue the reaction for 10 minutes, then quench the reaction mixture by slowly adding it dropwise to ice water. Extract with ethyl acetate (10.0 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and precipitate the residue by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 63-4 (75.0 mg, 26.9%).

[0976] LCMS[M-100+H] + m / z:calcd 535.3; found 535.2.

[0977] Step 5: Dissolve 63-4 (75.0 mg, 0.12 mmol) in 10.0 mL of dichloromethane, add 2.0 mL of trifluoroacetic acid, and stir at room temperature for 4 hours. After the reaction is complete, evaporate the reaction solution to dryness, and the residue is subjected to reversed-phase column chromatography (acetonitrile:water = 27%) to obtain 63 (32.0 mg, 49.8%).

[0978] LCMS[M+H] + m / z:calcd 535.2; found 535.3.

[0979] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.62(s,1H),7.89(s,1H),7.62–7.54(m,3H),7.45(d,J =1.6Hz,1H),7.28(dd,J=8.4,1.6Hz,1H),4.40(t,J=7.2Hz,2H),4.14(dd,J=12.0,4.8Hz,1H) ,4.05–3.92(m,3H),3.42–3.37(m,2H),3.12–3.08(m,3H),2.78–2.71(m,1H),2.60–2.54(m,1 H),2.40–2.31(m,1H),2.29(s,3H),2.18–2.05(m,1H),1.96–1.81(m,2H),1.75–1.70(m,2H).

[0980] Example 63: Synthesis of Compound 64

[0981] Step 1: Dissolve 64-0 (300.0 mg, 1.351 mmol) in anhydrous acetonitrile (10.0 mL), add pyridine (0.45 mL) and phenyl chloroformate (250.0 mg, 1.621 mmol) under ice bath conditions, and stir for 20 minutes. After the reaction is complete, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the target compound 64-1 (350 mg, 75.7%).

[0982] LCMS [M-55] + m / z:calcd 287.2, found 287.0.

[0983] Step 2: Dissolve 64-1 (350.0 mg, 1.023 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (290.0 mg, 1.023 mmol) in anhydrous N,N-dimethylformamide (20.0 mL). Under ice bath conditions, slowly add sodium hydride (60.0 mg, 1.535 mmol) and stir for 0.5 hours. After the reaction is complete, add the reaction solution dropwise to ice water (20.0 mL). Add ethyl acetate (20.0 mL * 3) to extract the product. Combine the organic phases and wash with saturated sodium chloride aqueous solution (20.0 mL * 3). Dry the organic phase with anhydrous sodium sulfate. Concentrate the filtrate and purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 64-2 (200.0 mg, 37.1%).

[0984] LCMS [M-55] + m / z:calcd 477.2, found 477.2.

[0985] Step 3: Dissolve 64-2 (200.0 mg, 0.375 mmol) in anhydrous dichloromethane (10.0 mL), add trifluoroacetic acid (3.0 mL), stir for 30 minutes, concentrate the reaction solution, and purify the residue by reverse-phase column chromatography (acetonitrile / water = 1 / 1) to obtain 64 (160.7 mg 98.7%).

[0986] LCMS[M+1]+m / z:calcd 433.2; found 433.2.

[0987] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.33–8.30(s,1H),7.89(s,1H),7.68–7.50(m,2H),7.2 8(d,J=9.2Hz,1H),6.92(t,J=8.0Hz,1H),6.78(d,J=2.0Hz,1H),6.72(d,J=8.0Hz,1H),6.30–5 .95(m,1H),5.66–5.31(m,1H),4.37(t,J=7.6Hz,2H),4.20–4.04(m,1H),4.04–3.77(m,3H),2 .79–2.69(m,1H),2.67–2.59(m,3H),2.60–2.53(m,1H),2.42–2.28(m,1H),2.18–1.99(m,1H).

[0988] Example 64: Synthesis of Compound 65

[0989] Step 1: Dissolve 65-0 (3.0 g, 10.1 mmol) in a mixed solvent of 30.0 mL of 1,4-dioxane and 5.0 mL of water. Then add potassium hydroxide (1.7 g, 30.3 mmol), tris(dibenzylacetone)dipalladium (460.0 mg, 0.5 mmol), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (214.2 mg, 0.5 mmol). The reaction solution is heated to 85 °C under nitrogen protection and reacted for 16 hours. After the reaction is complete, the reaction solution is extracted with ethyl acetate (30.0 mL * 3) and water (30.0 mL). Combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product 65-1 (400.0 mg, 21.1%).

[0990] LCMS[MH] - m / z:calcd 186.0, found 186.0.

[0991] Step 2: Dissolve 65-1 (400.0 mg, 2.2 mmol) in 5.0 mL of N,N-dimethylformamide, add tert-butyl-(2-iodoethoxy)dimethylsilane (944.0 mg, 3.2 mmol), potassium carbonate (944.0 mg, 3.2 mmol), and potassium iodide (944.0 mg, 3.2 mmol), then heat to 120 °C and react overnight. After the reaction is complete, cool the reaction solution to room temperature, extract with ethyl acetate (10.0 mL * 3) and water (10.0 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain product 65-2 (300.0 mg, 39.5%).

[0992] 1 H NMR(400MHz,DMSO-d6)δ7.84(d,J=2.0Hz,1H),7.71(d,J=2.4Hz,1H),4.25–4.1 4(m,2H),3.92(dd,J=15.6,12.0Hz,2H),2.25(s,3H),0.79(s,9H),0.00(s,6H).

[0993] Step 3: Dissolve 65-2 (300.0 mg, 0.87 mmol) in 5.0 mL of ethanol, add iron powder (243.6 mg, 4.35 mmol), then dissolve ammonium chloride (469.8 mg, 8.7 mmol) in 1.0 mL of water, add the above reaction solution, heat to 70 °C, and continue stirring for 5 hours. After the reaction is complete, filter the reaction solution, extract the filtrate with ethyl acetate (10.0 mL * 3) and water (10.0 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain product 65-3 (260.0 mg, 94.9%).

[0994] LCMS[M+H] + m / z:calcd 316.1, found 316.0.

[0995] Step 4: Dissolve 65-3 (260.0 mg, 0.83 mmol) in 5.0 mL of acetonitrile, then cool to 0 °C, add phenyl chloroformate (128.7 mg, 0.83 mmol) and pyridine (197.1 mg, 2.49 mmol), and continue stirring for 0.5 hours. After the reaction is complete, extract the reaction solution with ethyl acetate (10.0 mL * 3) and water (10.0 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain product 65-4 (300.0 mg, 90.9%).

[0996] LCMS[M-100+H] + m / z:calcd 345.2, found 345.2.

[0997] Step 5: Dissolve 65-4 (200.0 mg, 0.46 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (109.0 mg, 0.38 mmol) in 10.0 mL of N,N-dimethylformamide. Add sodium hydride (22.8 mg, 0.57 mmol) under nitrogen protection at 0 °C. After continuing the reaction for 10 minutes, quench the reaction mixture by slowly adding it dropwise to ice water. Extract with ethyl acetate (10.0 mL * 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain crude 65-5, which can be used directly in the next step.

[0998] Step 6: Dissolve 65-5 in 10.0 mL of tetrahydrofuran, add 0.2 mL of tetrabutylammonium fluoride, and stir overnight at room temperature. After the reaction is complete, extract with ethyl acetate (10.0 mL * 3) and saturated brine (10.0 mL), combine the organic phases, dry to anhydrous sodium sulfate, filter, evaporate to dryness, and the residue is subjected to reversed-phase column chromatography (acetonitrile:water = 32%) to give 65 (70.31 mg, 36.1%).

[0999] LCMS[M+H] + m / z:calcd 512.1; found 512.2.

[1000] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.56(s,1H),7.89(s,1H),7.64–7.55(m,2 H),7.35(d,J=1.6Hz,1H),7.32–7.26(m,1H),7.16(d,J=1.6Hz,1H),4.85(s,1H) ,4.40(t,J=7.2Hz,2H),4.17–4.10(m,1H),4.02–3.93(m,5H),3.74(t,J=4.8Hz, 2H),2.75-2.71(m,1H),2.66–2.54(m,1H),2.39–2.31(m,1H),2.19–2.04(m,4H).

[1001] Example 65: Synthesis of Compound 66

[1002] Step 1: Dissolve 66-0 (1.0 g, 4.926 mmol) in thionyl chloride (5.0 mL), and add a small amount of dimethylformamide dropwise. Heat to 80 °C and stir for 40 minutes. After the reaction is complete, concentrate the reaction solution, dissolve the residue in dichloromethane (10.0 mL), cool to -40 °C, add triethylamine (2.1 mL) and methylamine hydrochloride (340.0 mg, 4.926 mmol), stir for 1 hour, heat to 0 °C, stir for 10 minutes, after the reaction is complete, return to room temperature, add water (20.0 mL) and dichloromethane (20.0 mL * 3) to extract the product, combine the organic phases, wash with saturated sodium chloride aqueous solution (20.0 mL * 3) and dry with anhydrous sodium sulfate, concentrate the filtrate, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 66-1 (600.0 mg 56.6%).

[1003] LCMS[M+1] + m / z:calcd 217.0, found 217.0.

[1004] Step 2: Dissolve 66-1 (600.0 mg, 2.778 mmol) in anhydrous tetrahydrofuran (10.0 mL), and slowly add borane dimethyl sulfide (1 M) (14.0 mL) under ice bath conditions. Heat to 70 °C and stir for 3 hours. After the reaction is complete, add the reaction solution dropwise to methanol (20.0 mL) under ice bath conditions. After complete quenching, concentrate the reaction solution to obtain crude 66-2 (600.0 mg), which can be used directly in the next step.

[1005] LCMS[M+1] + m / z:calcd 203.1, found 203.0.

[1006] Step 3: Dissolve 66-2 (520.0 mg, 2.574 mmol) in tetrahydrofuran (5.0 mL), then add di-tert-butyl dicarbonate (1.5 mL), triethylamine (1.1 mL), and 4-dimethylaminopyridine (15.0 mg) sequentially. Stir at room temperature for 4 hours. After the reaction is complete, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 66-3 (300.0 mg, 38.6%).

[1007] 1 H NMR (400MHz, DMSO-d6) δ8.21–7.96(m,1H),7.75(t,J=10.4Hz,1H),4.47(s,2H),2.83(s,3H),1.52–1.32(m,9H).

[1008] Step 4: Dissolve 66-3 (300.0 mg, 0.991 mmol) in anhydrous ethanol (10.0 mL), add palladium on carbon (30.0 mg) and palladium hydroxide (30.0 mg), and stir for 12 hours. After the reaction is complete, filter and concentrate the filtrate to obtain 66-4 (270.0 mg, 100%).

[1009] LCMS[M-55]+m / z:calcd 217.1; found 217.0.

[1010] Step 5: Dissolve 66-4 (270.0 mg, 0.992 mmol) in acetonitrile (5.0 mL), add pyridine (0.33 mL) and phenyl chloroformate (0.13 mL) under ice bath conditions, and stir for 20 minutes. After the reaction is complete, extract the product by adding water (10.0 mL) and ethyl acetate (10.0 mL * 3). Combine the organic phases and dry them over anhydrous sodium sulfate. Concentrate the filtrate, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 66-5 (230.0 mg, 59.1%).

[1011] LCMS[M-55]+m / z:calcd 337.2; found 337.0.

[1012] Step 6: Dissolve 66-5 (200.0 mg, 0.510 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (145.0 mg, 0.510 mmol) in anhydrous dimethylformamide (10.0 mL). Under ice bath conditions, slowly add sodium hydride (30.0 mg, 0.751 mmol) and stir for 0.5 hours. After the reaction is complete, add the reaction solution dropwise to ice water (10.0 mL). Add ethyl acetate (10.0 mL * 3) to extract the product. Combine the organic phases, wash with saturated sodium chloride aqueous solution (20.0 mL * 3), and dry with anhydrous sodium sulfate. Concentrate the filtrate, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 66-6 (200.0 mg, 67.5%).

[1013] LCMS [M-55] + m / z:calcd 527.2, found 527.2.

[1014] Step 7: Dissolve 66-6 (200.0 mg, 0.343 mmol) in anhydrous dichloromethane (10.0 mL), add trifluoroacetic acid (3.0 mL), stir for 30 minutes, concentrate the reaction solution, and purify the residue by reversed-phase column chromatography (acetonitrile / water = 1 / 1) to obtain 66 (21.75 mg, 13.3%).

[1015] LCMS[M+1]+m / z:calcd 483.2; found 483.3.

[1016] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.77(s,1H),8.42(s,1H),8.02–7. 76(m,2H),7.66–7.52(m,2H),7.52–7.33(m,1H),7.27(d,J=8.2Hz,1H),4. 44(d,J=7.6Hz,2H),4.26–4.09(m,3H),4.09–3.93(m,3H),2.82–2.69(m,1 H),2.60(s,3H),2.58–2.54(m,1H),2.42–2.25(m,1H),2.20–2.03(m,1H).

[1017] Example 66: Synthesis of Compound 67

[1018] Step 1: Dissolve 67-0 (5.0 g, 24.88 mmol) in tetrahydrofuran (50 mL). Under nitrogen protection at 0 °C, add sodium hydride (2.0 g, 83.33 mmol), stir for 30 minutes, then add allyl bromo (6.0 g, 49.59 mmol). Continue the reaction for 2 hours, then add a saturated aqueous solution of ammonium chloride dropwise to the reaction system until the pH of the reaction solution reaches 8. Extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain product 67-1 (2.5 g, 41.7%).

[1019] 1H NMR(400MHz,DMSO-d6)δ5.98–5.82(m,1H),5.30–5.18(m,1H),5.15–5.09(m,1H),4.0 4–3.93(m,2H),3.52–3.07(m,5H),1.80(s,1H),1.68–1.56(m,1H),1.44–1.24(m,11H)

[1020] Step 2: Dissolve 67-1 (1 g, 4.15 mmol) and 9-boronbicyclo[3.3.1]nonane (10 mL) in 20.0 mL of tetrahydrofuran. After stirring at 80 °C under nitrogen protection for 2 hours, the reaction solution was allowed to cool naturally and then used directly in the next step.

[1021] Step 3: Add 20.0 mL of N,N-dimethylformamide, 10 mL of water, 3-bromo-4-chloroaniline (1.32 g, 7.03 mmol), potassium phosphate (1.7 g, 10.41 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (470 mg, 0.06 mmol) to the reaction solution obtained in Step 2. After reacting at 90 °C for 30 hours under nitrogen protection, filter the solids from the reaction solution with diatomaceous earth. After evaporating the filtrate to dryness, extract with ethyl acetate (20.0 mL * 3), and wash with water (15.0 mL * 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain product 67-3 (600 mg, 40.3%).

[1022] LCMS[M+H] + m / z:calcd 369.2, found 369.2.

[1023] Step 4: Dissolve 67-3 (300 mg, 0.81 mmol) in 10.0 mL of dichloromethane, and add diisopropylethylamine (210 mg, 3.26 mmol). Under nitrogen protection, add phenyl chloroformate (153 mg, 1.17 mmol) dropwise at 0 °C. After continuing the reaction for 30 minutes, quench the reaction solution in ice water, extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product 67-4 (300 mg, 75.6%).

[1024] LCMS[M+H] + m / z:calcd 488.2, found 489.2.

[1025] Step 5: Dissolve 67-4 (300 mg, 0.62 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (210 mg, 0.62 mmol) in 10.0 mL of N,N-dimethylformamide. Add sodium hydride (22 mg, 0.93 mmol) under nitrogen protection at 0 °C. Continue the reaction for 10 minutes, then quench the reaction mixture by slowly adding it dropwise to ice water. Extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 12:1) to obtain product 67-5 (300 mg, 71.9%).

[1026] LCMS[M+H] + m / z:calcd 679.3, found 679.2.

[1027] Step 6: Dissolve 67-5 (150 mg, 0.221 mmol) in 10 mL of dichloromethane and add 3 mL of trifluoroacetic acid. After reacting at 25 °C for 1 hour, the reaction solution was evaporated to dryness, and the residue was used to prepare 67 (61.5 mg, 48.1%) by Prep-HPLC.

[1028] LCMS[M+H] + m / z:calcd 579.2, found 579.5.

[1029] 11H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.68–8.51(m,2H),8.45–8.25(s,1H),7.90(s,1H) ,7.65–7.56(m,3H),7.37–7.24(m,3H),4.45–4.34(m,2H),4.20–4.10(m,1H),4.03–3.93( m,3H),3.68-3.58(m,1H),3.55-3.32(m,2H),3.21-3.12(m,1H),3.08-2.85(m,3H),2.80- 2.65(m,3H),2.63-2.58(m,1H),2.37–2.28(m,1H),2.16–2.06(m,1H),1.85–1.59(m,6H).

[1030] Example 67: Synthesis of Compound 68

[1031] Step 1: Dissolve 68-0 (1.0 g, 7.24 mmol) in 20 mL of tetrahydrofuran. Under nitrogen protection, add di-tert-butyl dicarbonate (5.0 g, 26.08 mmol) and triethylamine (6.5 g, 72.46 mmol). After reacting at 50 °C for 18 hours, the reaction solution is washed with saturated ammonium chloride aqueous solution (30 mL x 3) and extracted with ethyl acetate (30 mL x 3). The organic phase is dried over anhydrous sodium sulfate, evaporated to dryness, and the residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain the mixed product 68-1 (1.0 g, 58.0%).

[1032] Step 2: Dissolve 68-1 (1.0 g, 3.90 mmol) in N,N-dimethylformamide (20 mL), and add sodium hydride (390 mg, 9.76 mmol) under nitrogen protection at 0 °C. After reacting at 0 °C for 30 minutes, add iodoethane (1.39 g, 9.76 mmol). Continue the reaction for 1 hour, then slowly quench the reaction mixture in ice water. Wash with saturated sodium chloride aqueous solution (30 mL * 3), extract with ethyl acetate (30 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain product 68-2 (900 mg, 81.8%).

[1033] 1H NMR (400MHz, DMSO-d6) δ8.10 (t, J=2.1Hz, 1H), 8.05 (ddd, J=8.1, 2.2, 0.9Hz, 1H), 7.73 (ddd, J=8.0 ,2.0,0.9Hz,1H),7.64(t,J=8.1Hz,1H),3.71(q,J=7.1Hz,2H),1.41(s,9H),1.09(t,J=7.1Hz,3H).

[1034] Step 3: Dissolve 68-2 (1.0 g, 3.52 mmol) in a mixed solution of ethanol (24.0 mL) and water (8.0 mL), then add ammonium chloride (1.9 g, 35.21 mmol) and iron powder (986 mg, 17.60 mmol). After stirring at 70 °C under nitrogen protection for 5 hours, filter the iron powder through diatomaceous earth. The filtrate is evaporated to dryness and extracted with ethyl acetate (30.0 mL x 3), followed by washing with water (20.0 mL x 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain crude product 68-3 (700 mg, 78.3%), which is used directly in the next step.

[1035] 1H NMR(400MHz,DMSO-d6)δ6.95(t,J=8.2Hz,1H),6.40(dd,J=4.5,2.3Hz,2H),6.34–6.24(m, 1H),5.08(s,2H),3.50(q,J=7.0Hz,2H),1.45(s,1H),1.36(s,9H),1.03(t,J=7.0Hz,3H).

[1036] Step 4: Dissolve 68-3 (300 mg, 1.18 mmol) in 25.0 mL of acetonitrile. Under nitrogen protection, add pyridine (280 mg, 3.54 mmol) and phenyl chloroformate (166 mg, 1.06 mmol) dropwise at 0 °C. After continuing the reaction for 5 minutes, quench the reaction mixture in ice water, extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 12:1) to obtain product 68-4 (350 mg, 79.4%).

[1037] LCMS[M+18] + m / z:calcd 374.0,found 374.2.

[1038] Step 5: Dissolve 68-4 (150 mg, 0.40 mmol) and 3-(6-(azatidine-3-yl)benzofuran-3-yl)piperidin-2,6-dione (137 mg, 0.40 mmol) in 20.0 mL of N,N-dimethylformamide. Add sodium hydride (24 mg, 0.60 mmol) under nitrogen protection at 0 °C. Continue the reaction for 10 minutes, then quench the reaction mixture by slowly adding it dropwise to ice water. Extract with ethyl acetate (20.0 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain product 68-5 (150 mg, 66.4%).

[1039] LCMS [M-55] + m / z:calcd 491.2.2; found 491.1.

[1040] Step 6: Dissolve 68-5 (120 mg, 0.26 mmol) in 10 mL of dichloromethane and add 3 mL of trifluoroacetic acid. After reacting at 25 °C for 1 hour, evaporate the reaction solution to dryness. The residue was then analyzed by Prep-HPLC to obtain 68 (6.3 mg, 6.%).

[1041] LCMS[M+H] + m / z:calcd 477.2, found 477.3.

[1042] 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.22(s,1H),7.89(s,1H),7.64-7.52(m,2H),7.34-7 .25(m,1H),6.97-6.88(m,1H),6.81(s,1H),6.73-6.67(m,1H),6.21-6.13(m,1H),5.45-5. 35m,1H),4.45-4.32(m,2H),4.18-4.10(m,1H),4.01–3.89(m,3H),3.05–2.94(m,2H),2.80 -2.70(m,1H),2.65–2.56(m,1H),2.38-2.27(m,1H),2.19–2.03(m,1H),1.20-1.10(m,3H).

[1043] Example 68: Synthesis of Compound 69

[1044] Step 1: Dissolve 69-0 (1.0 g, 6.40 mmol) in 20 mL of tetrahydrofuran. Under nitrogen protection, add di-tert-butyl dicarbonate (5.0 g, 23.05 mmol) and triethylamine (6.5 g, 64.05 mmol). After reacting at 50 °C for 18 hours, the reaction solution is washed with saturated ammonium chloride aqueous solution (30 mL x 3) and extracted with ethyl acetate (30 mL x 3). The organic phase is dried over anhydrous sodium sulfate, evaporated to dryness, and the residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain the mixed product 69-1 (1.0 g, 60.9%).

[1045] 1 H NMR (400MHz, DMSO-d6) δ9.86(s,1H),8.35(dd,J=6.4,2.4Hz,1H),7.83-7.62(m,1H),7.49(dd,J=11.2,9.2Hz,1H),1.48(s,9H).

[1046] Step 2: Dissolve 69-1 (1.0 g, 3.90 mmol) in N,N-dimethylformamide (20 mL), and add sodium hydride (390 mg, 9.76 mmol) under nitrogen protection at 0 °C. After reacting at 0 °C for 30 minutes, add iodoethane (1.39 g, 9.76 mmol). Continue the reaction for 1 hour, then slowly quench the reaction mixture in ice water. Wash with saturated sodium chloride aqueous solution (30 mL * 3), extract with ethyl acetate (30 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain product 69-2 (900 mg, 81.8%).

[1047] 1 H NMR(400MHz,DMSO-d6)δ8.02(dd,J=6.8,2.8Hz,1H),7.77-7.65(m,1H),7.57( dd,J=11.2,9.2Hz,1H),3.66(q,J=7.2Hz,2H),1.40(s,9H),1.11-1.01(m,3H).

[1048] Step 3: Dissolve 69-2 (1.0 g, 3.52 mmol) in a mixed solution of ethanol (24.0 mL) and water (8.0 mL), then add ammonium chloride (1.9 g, 35.21 mmol) and iron powder (986 mg, 17.60 mmol). After stirring at 70 °C under nitrogen protection for 5 hours, filter the iron ...

Claims

1. Compounds of formula (I): Or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, prodrugs, in: Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-11 membered carbon rings, and 4-11 membered heterocycles; M is selected from CH or N. X is selected from: halogen, -NR 3a R4, -NR 3a COR4, -OR3, -C 1-4 Alkyl-OR3; optionally selected from halogen, hydroxyl, CN, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 C substituents of alkyl)2 1-6 Alkyl groups; and optionally selected from C 1-4 Alkyl, halogen, hydroxyl, CN, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 5-6 membered heterocyclic groups substituted with alkyl groups; W is selected from single bond, -NR 1a -、-CR a R b -and-O-; L0 is selected from single bond, -NR 1a -、-CR a R b -and-O-; L1 is selected from -NR 1a -、-CR a R b -, -O- and 3-6-membered heterocyclic rings; L2 is selected from single bond, -NR 1a -、-CR a R b -and-O-; R a and R b Each is independently selected from hydrogen, amino, halogen, oxo, cyano, and C. 1～3 alkyl and cyclopropyl, wherein the C 1～3 The alkyl or cyclopropyl groups are optionally substituted with halogens 1 to 3 times; R 1a R 2a R 2b and R 3a Each is independently selected from H and C. 1～3 alkyl and cyclopropyl, wherein the C 1～3 The alkyl or cyclopropyl groups are optionally substituted with halogens 1 to 3 times; Each R1 is independently selected from halogen, hydroxyl, -NR 2a R 2b , cyano, C 1～6 Alkyl, C 1～6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group and C 1～6 Halogenated alkyl groups; Each R2 is independently selected from halogen, hydroxyl, -NR 2a R 2b , cyano, oxo, C 1～6 Alkyl, C 2～6 alkenyl, C 2～6 alkynyl group, C 1～6 Alkyl group, -SO2NR 2a R 2b -SONR 2a R 2b -C(O)R 2a The C mentioned therein 1～6 Alkyl, C 2～6 alkenyl, C 2～6 alkynyl or C 1～6 The alkoxy group is optionally substituted by a halogen or a hydroxyl group 1 to 3 times; R3 is selected from C 1～6 Alkyl groups and 5-6 membered heterocyclic groups, wherein the C 1～6 Alkyl or 5-6 membered heterocyclic groups are optionally surrounded by halogen, hydroxyl, CN, C 1～4 Alkoxy, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 Alkyl)2-substituted 1 to 3 times; R4 is selected from R x Optional substitution of C 1 to 3 times 1～6 Alkyl groups, and R5, -(CR a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl and C 2～6 Alkyne group, wherein R5, -(CR a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl or C 2～6 The alkynyl group is optionally replaced by R x Replace 1 to 3 times; R5 is selected from 3- to 10-membered carbon rings, 4- to 10-membered heterocycles, 6- to 10-membered aromatic rings, and 5- to 10-membered aromatic heterocycles, wherein the 3- to 10-membered carbon rings, 4- to 10-membered heterocycles, 6- to 10-membered aromatic rings, and 5- to 10-membered aromatic heterocycles are selected from monocyclic, fused, fused, and spirocyclic rings, and optionally R5 is selected from monocyclic, fused, fused, and spirocyclic rings. x Replace 1 to 3 times; n is selected from 0, 1, 2, or 3; m is selected from 0, 1, 2, or 3; p is selected from 1, 2, or 3; q is selected from 0, 1, or 2; Dashed lines in ring B Indicates whether ring B exists or not; When ring B is present, ring B and ring C together form an 8-12 fused heterocycle, in which: When the heteroatom in the fused heterocycle is only N, the fused heterocycle is as well as When ring B and ring C are formed together At that time, structural unit for Where end a and Partially connected, with end b connected to ring A; and X is -OR3 or -NR. 3a R4; When ring B and ring C are formed together When X is -OR3 or -NR3R4; When ring B is absent, ring C is a benzene ring, and X is selected from -NR. 3a R4; R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, oxo, CN, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1～6 Alkyl, C 1～6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, and 6-10 membered aryl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally selected from halogen, cyano, hydroxyl, -NH2, -NH(C) under the condition that the valence allows. 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Halogenated alkyl and C 1～3 The substituents of the haloalkoxy group are substituted 1 to 3 times; Wherein, the compound of formula (I) is not 2. Compounds of formula (I): Or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, prodrugs, in: Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-11 membered carbon rings, and 4-11 membered heterocycles; M is selected from CH or N. X is selected from halogens, NR3R4, NR3COR4, OR3, 5-6 membered heterocyclic groups, or C. 1-4 OR3; W is selected from single bond, -NR a -、-CR a R b -、-O-; L0 is selected from single bond, -NR a -、-CR a R b -、-O-; L1 is selected from -NR a -、-CR a R b -、-O-、3-6-membered heterocyclic rings; L2 is selected from single bond, -NR a -、-CR a R b -、-O-; R a and R b Each is independently selected from hydrogen, amino, halogen, oxo, cyano, and C. 1～3 alkyl, cyclopropyl, wherein the C 1～3 Alkyl, cyclopropyl, and optionally substituted with halogens 1 to 3 times; R1 is independently selected from halogens, hydroxyl groups, and NR. a R b , cyano, C 1～6 Alkyl, C 1～6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1～6 Halogenated alkyl groups; R2 is independently selected from halogens, hydroxyl groups, and NR. a R b , cyano, oxo, C 1～6 Alkyl, C 1～6 Alkoxy, SO2NR a R b SONR a R b C(O)R a The C mentioned therein 1～6 Alkyl, C 1～6 The alkoxy group may optionally be replaced by a halogen or a hydroxyl group 1 to 3 times; R3 is selected from hydrogen, C 1～6 Alkyl, C 1～6 alkoxy, 5-6 membered heterocyclic group, wherein the C 1～6 Alkyl, C 1～6 The alkoxy group and the 5-6 membered heterocyclic group may optionally be substituted 1 to 3 times with halogen, hydroxyl, or alkylamino groups; R4 is selected from R x Optional substitution of C 1 to 3 times 1～6 Alkyl groups and R5, -(CR) a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl, C 2～6 Alkyne group, namely R5, -(CR a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl, C 2～6 The alkynyl group can be optionally replaced by R x Replace 1 to 3 times; R5 is selected from 3-10 membered carbon rings, 4-10 membered heterocyclic rings, 6-10 membered aromatic rings, and 5-10 membered aromatic heterocyclic rings. The R5 ring can be a monocyclic, fused, fused, or spirocyclic ring. The R5 ring can optionally be replaced by R... x Replace 1 to 3 times; n is selected from 0, 1, 2, or 3; m is selected from 0, 1, 2, or 3; p is selected from 1, 2, or 3; q is selected from 0, 1, or 2; The dashed line indicates whether ring B exists or not; When ring B is present, ring B and ring C together form an 8-12 member fused heterocycle, in which... When the heteroatom in the fused heterocycle is selected only from N, ring B and ring C together form When ring B and ring C are When X is OR3 or NR3R4; When ring B is absent, ring C is a benzene ring, and X is selected from NR3R4; R x Independently selected from hydrogen, halogen, hydroxyl, oxo, CN, C 1～6 Alkyl, C 1～6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, 6-10 membered aryl, wherein R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be derived from halogens, cyano groups, hydroxyl groups, or C-terminal groups, provided that the valence allows. 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl, C 1～3 The alkyl group is substituted 1 to 3 times; Wherein, the compound of formula (I) is not 3. The compound according to claim 2, characterized in that: Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-11 membered carbon rings, and 4-11 membered heterocycles; M is selected from CH or N. X is selected from halogens, NR3R4, OR3, or methyl groups; W is selected from single bond, -NR a -、-CR a R b -、-O-; L0 is selected from single bond, -NR a -、-CR a R b -、-O-; L1 is selected from -NR a -、-CR a R b -、-O-、3-6-membered heterocyclic rings; L2 is selected from single bond, -NR a -、-CR a R b -、-O-; R a and R b Each is independently selected from hydrogen, amino, halogen, oxo, cyano, and C. 1～3 alkyl, cyclopropyl, wherein the C 1～3 Alkyl, cyclopropyl, and optionally substituted with halogens 1 to 3 times; R1 is independently selected from halogens, hydroxyl groups, and NR. a R b , cyano, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Halogenated alkyl groups; R2 is independently selected from halogens, hydroxyl groups, and NR. a R b , cyano, oxo, C 1～6 Alkyl, C 1～6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SO2NR a R b SONR a R b C(O)R a The C mentioned therein 1～6 Alkyl, C 1～6 The alkoxy group may optionally be replaced by a halogen or a hydroxyl group 1 to 3 times; R3 is selected from hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the C 1～6 Alkyl, C 1～6 The alkoxy group can optionally be substituted by a halogen 1 to 3 times; R4 is selected from R x Optional substitution of C 1 to 3 times 1～6 Alkyl groups and R5, -(CR) a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl, C 2～6 Alkyne group, namely R5, -(CR a R b ) p -R5、-C(O)-R5、C 1～6 Alkoxy, C 2～6 alkenyl, C 2～6 The alkynyl group can be optionally replaced by R x Replace 1 to 3 times; R5 is selected from 3-10 membered carbon rings, 4-10 membered heterocyclic rings, 6-10 membered aromatic rings, and 5-10 membered aromatic heterocyclic rings. The R5 ring can be a monocyclic, fused, fused, or spirocyclic ring. The R5 ring can optionally be replaced by R... x Replace 1 to 3 times; n is selected from 0, 1, 2, or 3; m is selected from 0, 1, 2, or 3; p is selected from 1, 2, or 3; q is selected from 0, 1, or 2; The dashed line indicates whether ring B exists or not; When ring B is present, ring B and ring C together form an 8-12 membered fused heterocycle. When the heteroatom in the fused heterocycle is selected only from nitrogen, ring B and ring C are... When ring B and ring C are When X is OR3 or NR3R4; When ring B is absent, ring C is a benzene ring, and X is selected from NR3R4; R x Independently selected from hydrogen, halogen, hydroxyl, oxo, CN, C 1～6 Alkyl, C 1～6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, 6-10 membered aryl, wherein R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be derived from halogens, cyano groups, hydroxyl groups, or C-terminal groups, provided that the valence allows. 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl, C 1～3 The alkyl halide is substituted 1 to 3 times.

4. The compound according to any one of claims 1-3, characterized in that, The compound represented by Formula I satisfies any of the following conditions: (1) The W is selected from -CH2-, -NH-, and -O-; (2) The L0 is selected from single bond, -CH2-, -NH-, -O-, with single bond being preferred; (3) The L1 is selected from -CH2-, -NH-, -N(CH3)-, -CF2-, -CHF-, -C(CH3)2-, -CH(CH3)-, -O-, (4) The L2 is selected from -CH2-, -NH-, -N(CH3)-, -CH(CH3)-; and (5) When ring B and ring C are formed together When the compound of formula (I) has the following structure:

5. The compound according to any one of claims 1-4, characterized in that, The compound represented by Formula I satisfies any of the following conditions: (1) The ring A is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, and pyridazine ring, preferably the ring A is selected from... Further preferably, ring A is selected from... (2) M is CH; (3) The structural unit Selected from Where end a and Partially connected, while end b is connected to ring A; (4) R3 is selected from -H, -CN, -CH3, -CF3, -CH2CH3, -CH(CH3)CH3, -CClF2, -CH2CH2OCH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2, -CH(CH2F)(CHF2); (5) R1 is independently selected from -F, -Cl, -Br, -OH, -CN, -NH2, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F, -OCH2CH3, -CH2CHF2; (6) R2 is independently selected from -F, -Cl, -Br, -OH, -CN, =O, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F; and (7) Not for Where end a and Partially connected, while end b is connected to ring A.

6. The compound according to any one of claims 1-5, characterized in that, The R4 is selected from R5 and -CH2-R5; preferably, the -CH2-R5 is selected from -CH2CF3, And / or, R5 is selected from -CF3, The R4 is selected from -CH2CF3, 7. The compound of formula (I) according to claim 2 or 3, wherein the compound of formula (I) comprises the following: (1) Compounds of formula (I-1): The rest of the definitions are the same as before; Preferably, X is selected from halogens, NR3R4, OR3, or methyl. More preferably, the ring A is selected from... The structural unit Selected from The R4 is selected from -CH2CF3, (2) Compounds of formula (I-2): in, Ring A is selected from 6-10 membered aromatic rings and 5-10 membered aromatic heterocycles, and the other definitions are the same as above; Preferably, X is selected from NR3R4; More preferably, the ring A is selected from... The structural unit Selected from The R4 is selected from -CH2CF3, (3) Compounds of formula (I-3): The rest of the definitions are the same as before; Preferably, X is selected from OR3; More preferably, the ring A is selected from... The structural unit Selected from The R4 is selected from -CH2CF3, (4) Compounds of formula (I-4): The rest of the definitions are the same as before; Preferably, X is selected from NR3R4 or OR3; More preferably, the ring A is selected from... The structural unit Selected from The R4 is selected from -CH2CF3; (5) Compounds of formula (I-5): The rest of the definitions are the same as before; Preferably, X is selected from NR3R4 or OR3; More preferably, the ring A is selected from... The structural unit Selected from The R4 is selected from -CH2CF3.

8. The compound of formula (I) according to any one of claims 1-3, wherein the compound of formula (I) is a compound of formula (I-1-1):

9. The compound according to claim 1, wherein the compound is selected from:

10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug, and a pharmaceutically acceptable carrier, optionally comprising one or more additional therapeutic agents.

11. Use of the compound of any one of claims 1 to 9, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug in the preparation of a medicament as a protein degrading agent.

12. Use of any compound of claims 1 to 9, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug in the preparation of a medicament for the prevention and / or treatment of GSPT1-mediated diseases or conditions and related diseases or conditions.

13. The use according to claim 12, wherein the GSPT1-mediated disease or condition is selected from: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, liposarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell tumor, Wilms' tumor.

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