Fused imide compound and use thereof

Abstract

The present application belongs to the field of medicinal chemistry. Disclosed are a series of fused imide compounds and the use thereof. Specifically disclosed are a compound as shown in formula (I), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof.

Description

Fused imide compounds and uses thereof

[0001] Cross-reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202410904628.8, filed July 5, 2024, and Chinese Patent Application No. 202510883908.X, filed June 27, 2025, in the China National Intellectual Property Office, the contents of which are incorporated herein in their entirety. TECHNICAL FIELD

[0003] The present application relates to fused imide compounds, methods of making the same, pharmaceutical compositions containing the same, and uses thereof in the treatment of disease. BACKGROUND

[0004] Breast cancer (BC) is one of the most common malignancies in women worldwide. According to the status of tumor receptors, breast cancer can be further subdivided into three types: estrogen receptor positive (ER+), human epidermal growth factor receptor 2 positive (HER2+), and triple negative. About 80% of newly diagnosed breast cancer patients belong to ER+ breast cancer. Estrogen receptors ERa and ERb are members of the nuclear receptor family and are transcription factors that regulate gene expression and mediate the biological effects of estrogen. ERa and ERb are widely expressed in different tissues, and ERa is considered to be the main mediator of estrogen signal transduction in the female reproductive tract and breast.

[0005] Although the inhibition of estrogen synthesis by aromatase inhibitors and the inhibition of ER pathway signals by selective estrogen receptor modulators (SERMs) have shown considerable clinical benefits in the treatment of ER+ breast cancer, the development of intrinsic and acquired resistance to these drugs poses an obstacle to patients with advanced and metastatic breast cancer. Although there are multiple mechanisms of resistance to aromatase inhibitors and SERMs, in most drug-resistant cases, tumor growth and disease progression still depend on the signaling of ERa, and the ER protein remains the target for the treatment of ER+ breast cancer. + The main driver of metastatic breast cancer.

[0006] Selective estrogen receptor downregulators (SERDs) are small molecules that target ERa for proteasome-dependent degradation. Currently, fulvestrant is the only SERD approved for use in postmenopausal women with advanced ER+ breast cancer who have been treated with standard endocrine therapy. The clinical success of fulvestrant demonstrates that ER protein degradation is beneficial for ER+ breast cancer patients, especially those whose disease continues to progress after standard endocrine therapy. The possible mechanism of action of traditional SERDs such as fulvestrant is through inducing ER protein misfolding, ultimately leading to proteasome-dependent ERa protein degradation. SERD molecules can generally effectively induce degradation of ER protein in ER+ breast cancer cells, but they can only achieve partial degradation of ER protein. Therefore, new therapeutic drugs that can achieve more complete degradation of ER are likely to be more effective than traditional SERD molecules in the treatment of ER+ metastatic breast cancer.

[0007] The protein degradation targeting chimera (PROTAC) concept was first proposed in 2001 and is a technology that applies the ubiquitin-proteasome system to target specific proteins and induce their degradation in cells. PROTACs are a kind of hetero-bifunctional molecules, which are composed of three parts, respectively, a ligand that binds to the target protein, a ligand that binds to the E3 ubiquitin ligase, and a linker that connects the two ligands. Its mechanism of action is to make the target protein and the E3 ligase close enough by binding to the target protein, so that the E3 ligase can ubiquitinate and label the target protein, and then degrade the labeled protein through the proteasome.

[0008] ER ligand-based PROTAC molecules are expected to achieve more complete protein degradation than SERDs, which can maximize the degradation of ER protein and thus achieve better therapeutic effect on ER+ breast cancer. SUMMARY

[0009] The present application provides a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0010] wherein,

[0011] Ring A is selected from 5-10 membered cycloalkenyl or 5-10 membered heterocycloalkenyl;

[0012] Ring B is selected from phenyl;

[0013] each R 1 is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC

[0014] n is selected from 0, 1, 2, or 3;

[0015] L is selected from -LNK 1 -Cy 1 -LNK 2 -Cy 2 -LNK 3 -;

[0016] Cy 1 is selected from a single bond, or is optionally substituted with one or more R Cy1 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycloalkyl;

[0017] Cy 2 is selected from a single bond, or is optionally substituted with one or more R Cy2 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycloalkyl;

[0018] each R Cy1 and R Cy2 are each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC

[0019] LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 alkyl, C 1-6 alkyl, C 1-6 heteroalkylene;

[0020] LNK 2 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 alkyl, C 1-6 alkyl, C 1-6 heteroalkylene;

[0021] LNK 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3substituted with one or more groups selected from: C 1-6 alkylene or C 1-6 heteroalkylene;

[0022] each R LNK1 , R LNK2 , and R LNK3 is each independently selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0023] PTM is selected from:

[0024] represents a single or double bond;

[0025] X A , X B , X C is selected from C, CH, or N;

[0026] E A1 , E A2 , E B1 , E B2 , E B3 , E C1 , E C2 is each independently selected from -O- or -CR E1 R E2 -;

[0027] each R E1 and R E2 is each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0028] R A1 , R A2 , R A3 , RA4 R B1 R B2 R B3 R B4 R C1 R C2 R C3 and R C4 Each is independently selected from H, halogen, -OH, -NH2, -CN, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0029] Or, R A3 and R A4 Together they form an optional combination of one or more R A6 The following groups are substituted: phenyl or 5-6 membered heteroaryl;

[0030] Or, R B3 and R B4 Together they form an optional combination of one or more R B6 The following groups are substituted: phenyl or 5-6 membered heteroaryl;

[0031] Each R A6 and R B6 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0032] R A5 Selected from H or arbitrarily selected by one or more R A7 The following groups are substituted: C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 alkylene, 3-12 membered cycloalkyl, C 1-4 alkylene 3-12-membered cycloalkenyl, C 1-4alkylene 4-12 membered heterocyclyl, C 1-4 alkylene 6-10 membered aryl, or C 1-4 alkylene 5-10 membered heteroaryl;

[0033] each R A7 is each independently selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, -CN, or C A8 substituted alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, or di-C 1-6 alkylamino;

[0034] each R A8 is each independently selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, or -CN;

[0035] R B5 is selected from the group consisting of H or C B7 substituted alkyl, C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 alkylene 3-12 membered cycloalkyl, C 1-4 alkylene 3-12 membered cycloalkenyl, C 1-4 alkylene 4-12 membered heterocyclyl, C 1-4 alkylene 6-10 membered aryl, or C 1-4 alkylene 5-10 membered heteroaryl;

[0036] each R B7 is each independently selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, -CN, or C B8 substituted alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, or di-C 1-6 alkylamino;

[0037] each R B8 is each independently selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, or -CN;

[0038] R C5 is selected from the group consisting of H or C C7 substituted alkyl, C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 alkylene 3-12 membered cycloalkyl, C 1-4alkylene 3-12 membered cycloalkenyl, C 1-4 alkylene 4-12 membered heterocyclyl, C 1-4 alkylene 6-10 membered aryl, or C 1-4 alkylene 5-10 membered heteroaryl;

[0039] each R C7 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or C C8 substituted alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or di-C 1-6 alkylamino;

[0040] each R C8 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, or -CN;

[0041] ring D, ring E, and ring F are each independently selected from 6-10 membered aryl or 5-10 membered heteroaryl;

[0042] each R D , R E , and R F is each independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated di-C 1-6 alkylamino;

[0043] m, p, and q are each independently selected from 0, 1, 2, or 3;

[0044] the aforementioned C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated di-C 1-6 alkylamino optionally substituted with one or more groups independently selected from deuterium, oxo, halogen, -OH, -NH2, or -CN.

[0045] In some embodiments, the above heterocycloalkenyl, heterocycloalkyl, heteroaryl, heteroalkylene each contains 1, 2, or 3 heteroatoms and heteroatom groups independently selected from -NH-, -O-, -S-, N, -C(=O)O-, -C(=O)-, -C(=O)NH-, -C(=S)-, -S(=O)-, -S(=O)2-, -C(=NH)-, -S(=O)2NH-, -S(=O)NH-, and -NHC(=O)NH-.

[0046] In some embodiments, the L moiety is connected to ring A by a covalent bond.

[0047] In some embodiments, the L moiety is connected to ring B by a covalent bond.

[0048] In some embodiments, ring A is selected from 5-8 membered cycloalkenyl or 5-8 membered heterocycloalkenyl.

[0049] In some embodiments, ring A is selected from 5-7 membered cycloalkenyl or 5-7 membered heterocycloalkenyl.

[0050] In some embodiments, ring A is selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydrooxazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydroazepinyl, or tetrahydroazepinyl. In some embodiments, ring A is selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, dihydropyrrolyl, tetrahydropyridinyl, or tetrahydroazepinyl. In some embodiments, ring A is selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, dihydropyrrolyl, tetrahydropyridinyl, or tetrahydroazepinyl.

[0051] In some embodiments, ring A is selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, dihydropyrrolyl, tetrahydropyridinyl, or tetrahydroazepinyl.

[0052] In some embodiments, R 1 is substituted at a substitution site on ring A and / or ring B.

[0053] In some embodiments, R 1 is substituted at a substitution site on ring A.

[0054] In some embodiments, R 1 is substituted at a substitution site on ring B.

[0055] In some embodiments, each R 1 is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C​1-4 alkylamino, or halodialkylamino. 1-4 alkylamino.

[0056] In some embodiments, each R 1 is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, dialkylamino. 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3 alkylamino, or halodialkylamino. 1-3 alkylamino.

[0057] In some embodiments, each R 1 is independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0058] In some embodiments, each R 1 is independently selected from deuterium, -F, -Cl, or methyl.

[0059] In some embodiments, n is selected from 0, 1, or 2.

[0060] In some embodiments, n is selected from 0 or 1.

[0061] In some embodiments, n is selected from 1 or 2.

[0062] In some embodiments, structural unit is selected from

[0063] In some embodiments, structural unit is selected from

[0064] In some embodiments, structural unit is selected from

[0065] In some embodiments, structural unit is selected from Each R 1 Independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino or halogenated diC 1-3 Alkylamino.

[0066] In some implementation schemes, structural units Selected from Each R 1 It is independently selected from halogens.

[0067] In some implementation schemes, structural units Selected from

[0068] In some implementation schemes, structural units Selected from

[0069] In some implementation schemes, structural units Selected from

[0070] In some implementation schemes, structural units Selected from

[0071] In some embodiments, the 3-12 membered cycloalkyl group includes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered cycloalkyl groups.

[0072] In some embodiments, the 4-12 membered heterocyclic alkyl group includes 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered heterocyclic alkyl groups.

[0073] In some implementations, Cy 1 Selected from a single key, or optionally by one or more R keys Cy1 The following groups are substituted: 3-10 membered cycloalkyl or 4-12 membered heterocycloalkyl.

[0074] In some embodiments, Cy is selected from a single bond, or a group optionally substituted with one or more R 1 substituted with one or more R Cy1 substituted with one or more R

[0075] In some embodiments, Cy is selected from a single bond, or a group optionally substituted with one or more R 1 substituted with one or more R Cy1 substituted with one or more R

[0076] In some embodiments, Cy is selected from a single bond, or a group optionally substituted with one or more R 1 substituted with one or more R Cy1 substituted with one or more R

[0077] In some embodiments, Cy is selected from a single bond, or a group optionally substituted with one or more R 1 substituted with one or more R Cy1 substituted with one or more R

[0078] In some embodiments, Cy is selected from a single bond, or a group optionally substituted with one or more R 1 substituted with one or more R Cy1 substituted with one or more R

[0079] In some embodiments, Cy is selected from a single bond, or a group optionally substituted with one or more R 1 substituted with one or more R Cy1 substituted with one or more R

[0080] In some embodiments, Cy is selected from a single bond, or a group optionally substituted with one or more R 1 substituted with one or more R Cy1 substituted with one or more R “*” represents the attachment to LNK 1 .

[0081] In some embodiments, Cy is selected from the following groups optionally substituted as set forth below: 1 selected from the following groups optionally substituted as set forth below: Cy1 substituted as set forth below: “*” represents the attachment to LNK 1 .

[0082] In some embodiments, Cy is selected from the following groups optionally substituted as set forth below: 1 selected from the following groups optionally substituted as set forth below: Cy1 substituted as set forth below:

[0083] In some embodiments, Cy is selected from the following groups optionally substituted as set forth below: 1 selected from the following groups optionally substituted as set forth below: Cy1 substituted as set forth below: “*” represents the attachment to LNK 1 .

[0084] In some embodiments, Cy is selected from the following groups optionally substituted as set forth below: 1 selected from the following groups optionally substituted as set forth below: Cy1 substituted as set forth below: “*” represents the attachment to LNK 1 .

[0085] In some embodiments, Cy is selected from the following groups optionally substituted as set forth below: 1 selected from the following groups optionally substituted as set forth below: Cy1 substituted as set forth below:

[0086] In some embodiments, each R is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C Cy1 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated di-C 1-4 alkylamino.

[0087] In some embodiments, each R is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C Cy1 alkyl, C 1-3 alkyl, C 1-3alkyl, haloC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkyl, haloC

[0088] each R Cy1 is each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0089] each R Cy1 is each independently selected from deuterium, -F, -Cl, or methyl.

[0090] each R Cy1 is each independently selected from -F.

[0091] Cy 1 is selected from a single bond,

[0092] Cy 1 is selected from

[0093] Cy 1 is selected from a single bond,

[0094] Cy 2 is selected from a single bond, or a group optionally substituted with one or more R Cy2 is a 3-10 membered cycloalkyl or 4-12 membered heterocycloalkyl.

[0095] Cy 2 is selected from a single bond, or a group optionally substituted with one or more R Cy2 is a 3-6 membered cycloalkyl or 4-11 membered heterocycloalkyl.

[0096] Cy 2 is selected from a single bond, or a group optionally substituted with one or more RCy2 The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, azirspironyl, diazirspironyl, azirspirodealkyl, diazirspirodealkyl, azirspiroundecyl, or diazirspiroundecyl.

[0097] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups are substituted:

[0098] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups are substituted:

[0099] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups are substituted:

[0100] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups are substituted: "*" represents LNK 2 connect.

[0101] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups are substituted: "*" represents LNK 2 connect.

[0102] In some implementations, Cy 2 Selected from one or more R Cy2 The following groups are substituted:

[0103] In some implementations, Cy 2 Selected from one or more R Cy2 The following groups are substituted: " " represents the attachment to LNK 2 attached.

[0104] In some embodiments, Cy is selected from the group consisting of: 2 optionally substituted by one or more R Cy2 substituents: " " represents the attachment to LNK 2 attached.

[0105] In some embodiments, Cy is selected from the group consisting of: 2 optionally substituted by one or more R Cy2 substituents:

[0106] In some embodiments, each R Cy2 is each independently selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.

[0107] In some embodiments, each R Cy2 is each independently selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3 alkylamino, or halogenated diC 1-3 alkylamino.

[0108] In some embodiments, each R Cy2 is each independently selected from the group consisting of deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0109] In some implementations, each R Cy2 Each is independently selected from deuterium, -F, -Cl, or methyl.

[0110] In some implementations, each R Cy2 Each is selected independently from -F.

[0111] In some implementations, Cy 2 Selected from single bonds,

[0112] In some implementations, Cy 2 Selected from

[0113] In some implementations, Cy 2 Selected from single bonds,

[0114] In some implementations, Cy 2 Selected from single bonds,

[0115] In some implementations, Cy 2 Selected from

[0116] In some implementation schemes, LNK 1 Connected to the PTM terminal.

[0117] In some implementation schemes, LNK 3 Connected to the PTM terminal.

[0118] In some implementation schemes, LNK 1 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK1 The following groups are substituted: C 1-4 Alkylene or C 1-4 Heteroalkylene.

[0119] In some implementation schemes, LNK 1 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK1 The following groups are substituted: C 1-3 Alkylene or C 1-3 Heteroalkylene.

[0120] In some implementation schemes, LNK 1 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK1-CH2-, -CH2CH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, or -CH2CH2NH-.

[0121] In some embodiments, LNK 1 is selected from a single bond, -O-, or is optionally substituted with one or more R LNK1 -CH2-, or -CH2CH2-.

[0122] In some embodiments, each R LNK1 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylamino, or halo diC 1-4 alkylamino.

[0123] In some embodiments, each R LNK1 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino.

[0124] In some embodiments, each R LNK1 is each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0125] In some embodiments, each R LNK1Each is independently selected from deuterium, oxo, -F, -Cl, or methyl.

[0126] In some implementation schemes, LNK 1 Selected from single bond, -O-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, or -C(O)CH2-.

[0127] In some implementation schemes, LNK 1 Selected from single bonds or -O-.

[0128] In some implementation schemes, LNK 2 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK2 The following groups are substituted: C 1-4 Alkylene or C 1-4 Heteroalkylene.

[0129] In some implementation schemes, LNK 2 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK2 The following groups are substituted: C 1-3 Alkylene or C 1-3 Heteroalkylene.

[0130] In some implementation schemes, LNK 2 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK2 The following groups may be substituted: -CH2-, -CH2CH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, or -CH2CH2NH-.

[0131] In some implementation schemes, LNK 2 Selected from single keys, -O-, or optionally by one or more R keys. LNK2 The following groups are substituted: -CH2- or -CH2CH2-.

[0132] In some implementations, each R LNK2 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C1-4 alkylamino, or halodialkylamino. 1-4 alkylamino.

[0133] In some embodiments, each R LNK2 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, dialkylamino. 1-3 alkylamino, deuteroalkylamino. 1-3 alkyl, halogenalkyl. 1-3 alkyl, halogenalkyl. 1-3 alkoxy, halogenalkoxy. 1-3 alkylamino, or halodialkylamino. 1-3 alkylamino.

[0134] In some embodiments, each R LNK2 is each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0135] In some embodiments, each R LNK2 is each independently selected from deuterium, oxo, -F, -Cl, or methyl.

[0136] In some embodiments, each R LNK2 is each independently selected from oxo or methyl.

[0137] In some embodiments, each R LNK2 is each independently selected from oxo.

[0138] In some embodiments, LNK 2 is selected from a single bond, -O-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, -CH(CH3)C(O)-, -C(O)CH2-, or -C(O)CH(CH3)-.

[0139] In some embodiments, LNK 2 is selected from

[0140] In some embodiments, LNK 2 is selected from a single bond, -O-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, or -C(O)CH2-.

[0141] In some implementation schemes, LNK 2 Selected from single bond, -CH2-, -CH2CH2-, -CH2C(O)-, or -C(O)CH2-.

[0142] In some implementation schemes, LNK 3 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK3 The following groups are substituted: C 1-4 Alkylene or C 1-4 Heteroalkylene.

[0143] In some implementation schemes, LNK 3 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK3 The following groups are substituted: C 1-3 Alkylene or C 1-3 Heteroalkylene.

[0144] In some implementation schemes, LNK 3 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK3 The following groups may be substituted: -CH2-, -CH2CH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, or -CH2CH2NH-.

[0145] In some implementation schemes, LNK 3 Selected from single keys, -O-, or optionally by one or more R keys. LNK3 The following groups are substituted: -CH2- or -CH2CH2-.

[0146] In some implementations, each R LNK3 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino.

[0147] In some implementations, each R LNK3each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino. 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino.

[0148] In some embodiments, each R LNK3 each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0149] In some embodiments, each R LNK3 each independently selected from deuterium, oxo, -F, -Cl, or methyl.

[0150] In some embodiments, each R LNK3 each independently selected from oxo.

[0151] In some embodiments, LNK 3 is selected from a single bond, -O-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, or -C(O)CH2-.

[0152] In some embodiments, LNK 3 is selected from a single bond, -CH2-, or -C(O)-.

[0153] In some embodiments, LNK 3 is selected from a single bond or -CH2-.

[0154] In some embodiments, L is selected from -Cy 1 -, -Cy 1 -Cy 2 -, -Cy 1 -LNK 2 -, -Cy 1 -Cy 2 -LNK 3 -, -Cy 1 -LNK 2 -Cy 2 -LNK3 -, -Cy 1 -LNK 2 -Cy 2 -, or -LNK 1 -Cy 1 -LNK 2 -.

[0155] In some embodiments, L is selected from -Cy 1 -, -Cy 1 -Cy 2 -, -Cy 1 -LNK 2 -, -Cy 1 -Cy 2 -LNK 3 -, or -Cy 1 -LNK 2 -Cy 2 -.

[0156] In some embodiments, L is selected from

[0157] said L is optionally substituted with one or more halogens, and “*” represents attachment to the PTM.

[0158] In some embodiments, L is selected from said L is optionally substituted with one or more halogens, and “*” represents attachment to the PTM.

[0159] In some embodiments, L is selected from said L is optionally substituted with one or more halogens, and “*” represents attachment to the PTM.

[0160] In some embodiments, L is selected from

[0161] In some embodiments, L is selected from

[0162] In some embodiments, represents a single bond; X A , X B , X C is selected from CH or N.

[0163] In some embodiments, represents a double bond; X A , XB , X C is selected from C.

[0164] In some embodiments, the compound of Formula (A) is represents a single bond; X A is selected from CH or N.

[0165] In some embodiments, the compound of Formula (B) is represents a double bond; X B is selected from C.

[0166] In some embodiments, the compound of Formula (C) is represents a single bond; X C is selected from N.

[0167] In some embodiments, E A1 and E A2 are each independently selected from O, E B1 , E B2 , and E B3 are each independently selected from O, E C1 , and E C2 are each independently selected from O.

[0168] In some embodiments, when X A , X B , X C is selected from N, E A2 , E B3 , and E C2 are each independently selected from -CR E1 R E2 -.

[0169] In some embodiments, each R E1 and R E2 is each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.

[0170] In some embodiments, each R E1 and R E2 is each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino.

[0171] In some embodiments, each R E1 and R E2 are each independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0172] In some embodiments, each R E1 and R E2 are each independently selected from H, deuterium, -F, -Cl, or methyl.

[0173] In some embodiments, each R E1 and R E2 are each independently selected from H or methyl.

[0174] In some embodiments, E A1 , E A2 are each independently selected from -O- or -CR E1 R E2 -.

[0175] In some embodiments, E A1 , E A2 are each independently selected from -O-, -CH2-, -CHF-, -CF2-, or -CH(CH3)-.

[0176] In some embodiments, E A1 , E A2 are each independently selected from -O-, -CH2-, or -CH(CH3)-.

[0177] In some embodiments, E A1 is selected from -O-, or -CH2-, E A2 is selected from -CH2-, or -CH(CH3)-.

[0178] In some embodiments, E B1 , E B2 , E B3each independently selected from -O- or -CR E1 R E2 -.

[0179] In some embodiments, E B1 , E B2 , E B3 each independently selected from -CH2- or -CH(CH3)-.

[0180] In some embodiments, E B1 and E B2 each independently selected from -CH2-, E B3 selected from -CH2-, or -CH(CH3)-.

[0181] In some embodiments, E C1 , E C2 each independently selected from -O- or -CR E1 R E2 -.

[0182] In some embodiments, E C1 , E C2 each independently selected from -CH2- or -CH(CH3)-.

[0183] In some embodiments, E C1 selected from -CH2-, E C2 selected from -CH2-, or -CH(CH3)-.

[0184] In some embodiments, R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 , R B4 , R C1 , R C2 , R C3 and R C4 each independently selected from H, halogen, -OH, -NH2, -CN, -COOH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino;

[0185] or, R A3R and R A4 together form a group that is optionally substituted by one or more R A6 phenyl or 5-6 membered heteroaryl;

[0186] or, R B3 and R B4 together form a group that is optionally substituted by one or more R B6 phenyl or 5-6 membered heteroaryl.

[0187] In some embodiments, R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 , R B4 , R C1 , R C2 , R C3 and R C4 are each independently selected from H, halogen, -OH, -NH2, -CN, -COOH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3 alkylamino, or halogenated diC 1-3 alkylamino;

[0188] or, R A3 and R A4 together form a group that is optionally substituted by one or more R A6 phenyl or 5-6 membered heteroaryl;

[0189] or, R B3 and R B4 together form a group that is optionally substituted by one or more R B6 phenyl or 5-6 membered heteroaryl.

[0190] In some embodiments, R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 , R B4 , R C1 , R C2 , R C3 and RC4 Each is independently selected from H, -F, -Cl, -Br, -OH, -NH2, -CN, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuterylmethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino;

[0191] Or, R A3 and R A4 Together they form an optional combination of one or more R A6 The following groups may be substituted: phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyrazinyl;

[0192] Or, R B3 and R B4 Together they form an optional combination of one or more R B6 The following groups may be substituted: phenyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

[0193] In some implementation schemes, R A1 R A2 and R A4 Each is independently selected from H, -F, -Cl, or methyl.

[0194] In some implementation schemes, R A1 R A2 and R A4 Each is independently selected from H.

[0195] In some implementation schemes, R A3 Selected from H, -OH, -CN, or -COOH.

[0196] In some implementation schemes, R A3 Selected from -OH.

[0197] In some implementation schemes, R A3 and R A4 Together they form an optional combination of one or more R A6 The following groups are substituted: pyrrole or pyrazol.

[0198] In some implementation schemes, R A3 and R A4 Together they form an optional combination of one or more R A6 The following groups are substituted:

[0199] In some embodiments, R A6 each is independently selected from halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.

[0200] In some embodiments, R A6 each is independently selected from halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3 alkylamino, or halogenated diC 1-3 alkylamino.

[0201] In some embodiments, R A6 each is independently selected from -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n- propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0202] In some embodiments, R A6 each is independently selected from -F, -Cl, or methyl.

[0203] In some embodiments, R A6 each is independently selected from -F.

[0204] In some embodiments, R A3 and R A4 are taken together to form a group:

[0205] In some embodiments, R B1 , R B2 , and R B4 are each independently selected from H, -F, -Cl, or methyl.

[0206] In some embodiments, R B1 , R B2 , and R B4 are each independently selected from H.

[0207] In some embodiments, R B3 is selected from H, -OH, -CN, or -COOH.

[0208] In some embodiments, R B3 is selected from -OH.

[0209] In some embodiments, R B3 and R B4 together form a group optionally substituted with one or more R B6 pyrrolyl or pyrazolyl.

[0210] In some embodiments, R B3 and R B4 together form a group optionally substituted with one or more R B6

[0211] In some embodiments, R B6 are each independently selected from halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.

[0212] In some embodiments, R B6 are each independently selected from halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3 alkylamino, or halogenated diC 1-3 alkylamino.

[0213] In some embodiments, R B6 ​each independently selected from -F, -CI, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0214] In some embodiments, R B6 each independently selected from -F, -CI, or methyl.

[0215] In some embodiments, R B6 each independently selected from -F.

[0216] In some embodiments, R B3 and R B4 are taken together to form a group:

[0217] In some embodiments, R C1 , R C2 , R C3 and R C4 are each independently selected from H, -F, -CI, or methyl.

[0218] In some embodiments, R C1 , R C2 , R C3 and R C4 are each independently selected from H.

[0219] In some embodiments, R A5 is selected from H or a group optionally substituted with one or more R A7 substituents: C 1-4 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-3 alkylene 3-10 membered cycloalkyl, C 1-3 alkylene 3-10 membered cycloalkenyl, C 1-3 alkylene 4-10 membered heterocyclyl, C 1-3 alkylene 6-10 membered aryl, or C 1-3 alkylene 5-10 membered heteroaryl.

[0220] In some embodiments, R A5 is selected from H or a group optionally substituted with one or more R A7 substituents: C 1-4 alkyl, 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 1-2alkylene, 3-6 membered cycloalkyl, C 1-2 alkylene 4-6 membered cycloalkenyl, C 1-2 alkylene 4-6 membered heterocyclic groups, C 1-2 alkylenephenyl, or C 1-2 Alkylene 5-6-membered heteroaryl.

[0221] In some implementation schemes, R A5 Selected from H or arbitrarily selected by one or more R A7 The following groups are substituted: C 1-4 Alkyl, 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C 1-2 alkylene, 3-6 membered cycloalkyl, C 1-2 alkylene 4-6 membered cycloalkenyl, or C 1-2 Alkylene 4-6 membered heterocyclic groups.

[0222] In some embodiments, the 3-12, 3-10, 4-8, or 4-6 heterocyclic groups are selected from 3-12, 3-10, 4-8, or 4-6 heterocyclic alkyl groups.

[0223] In some implementation schemes, R A5 Selected from H or arbitrarily selected by one or more R A7 The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydrocyclopentadienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, benzocyclobutenyl, oxacyclobutyl, aziridine, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyranyl, tetrahydropyridinyl, phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methyleneoxacyclobutyl, methyleneaziridine, methylenetetrahydrofuranyl, or methylenetetrahydropyrrolyl.

[0224] In some implementation schemes, R A5 Selected from H or arbitrarily selected by one or more R A7 The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl, benzocyclobutenyl, tetrahydropyranyl, phenyl, pyrazolyl, pyridyl, methylenecyclopropyl, or methyleneoxetyl.

[0225] In some implementation schemes, R A5 Selected from one or more R A7The following groups are substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl. phenyl, methylenecyclopropyl, or

[0226] In some implementation schemes, R A5 Selected from one or more R A7 The following groups can be substituted: ethyl, n-propyl, isobutyl, cyclohexyl, phenyl, methylenecyclopropyl.

[0227] In some implementation schemes, R A3 and R A4 Together they form an optional combination of one or more R A6 The following groups are substituted: pyrrole or pyrazol; R A5 Selected from one or more R A7 The following groups are substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylenecyclopropyl, or

[0228] In some implementation schemes, R A3 and R A4 Together they form an optional combination of one or more R A6 The following groups are substituted: pyrrole or pyrazol; R A5 Selected from one or more R A7 The following groups may be substituted: ethyl, n-propyl, isobutyl, or methylenecyclopropyl.

[0229] In some implementations, each R A7 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R groups. A8 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino.

[0230] In some implementations, each R A7 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R groups. A8 The following groups are substituted: C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, or di-C 1-3 Alkylamino.

[0231] In some implementations, each R A7each independently selected from deuterium, oxo, -F, -CI, -Br, -OH, -NH2, or -CN. A8 substituted methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0232] In some embodiments, each R A7 each independently selected from -F, -OH, or optionally substituted methyl. A8 substituted methyl or methoxy.

[0233] In some embodiments, each R A8 each independently selected from deuterium, oxo, -F, -CI, -Br, -OH, -NH2, or -CN.

[0234] In some embodiments, each R A8 each independently selected from deuterium, -F, -CI, -OH, or -NH2.

[0235] In some embodiments, each R A8 each independently selected from -F or -OH.

[0236] In some embodiments, each R A7 each independently selected from deuterium, -F, -CI, -OH, -NH2, methyl, trifluoromethyl, methylenehydroxyl, or methoxy.

[0237] In some embodiments, each R A7 each independently selected from -F or -OH.

[0238] In some embodiments, R A5 is selected from

[0239] In some embodiments, R A5 is selected from

[0240] In some embodiments, R A3 and R A4 together form a group: R A5 is selected from

[0241] In some embodiments, R A3 and R A4 together form a group: R A5 is selected from

[0242] In some embodiments, R is selected from H or a group optionally substituted with one or more R B5 In some embodiments, R is selected from H or a group optionally substituted with one or more R B7 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-4 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-3 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-3 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-3 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-3 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-3 In some embodiments, R is selected from H or a group optionally substituted with one or more R

[0243] In some embodiments, R is selected from H or a group optionally substituted with one or more R B5 In some embodiments, R is selected from H or a group optionally substituted with one or more R B7 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-4 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-2 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-2 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-2 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-2 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-2 In some embodiments, R is selected from H or a group optionally substituted with one or more R

[0244] In some embodiments, R is selected from H or a group optionally substituted with one or more R B5 In some embodiments, R is selected from H or a group optionally substituted with one or more R B7 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-4 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-2 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-2 In some embodiments, R is selected from H or a group optionally substituted with one or more R 1-2 In some embodiments, R is selected from H or a group optionally substituted with one or more R

[0245] In some embodiments, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-6 membered heterocyclyl is selected from 3-12 membered, 3-10 membered, 4-8 membered, or 4-6 membered heterocycloalkyl.

[0246] In some embodiments, R is selected from H or a group optionally substituted with one or more R B5 In some embodiments, R is selected from H or a group optionally substituted with one or more R B7substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydrocyclopenta-dienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, benzocyclobutenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, dihydropyranyl, tetrahydropyridinyl, phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenoxetanyl, methyleneazetidinyl, methylenetetrahydrofuranyl, or methylenetetrahydropyrrolyl.

[0247] In some embodiments, R B5 is selected from H or optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclohexyl, benzocyclobutenyl, tetrahydropyranyl, phenyl, pyrazolyl, pyridinyl, methylenecyclopropyl, or methylenoxetanyl. B7 is selected from H or optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclohexyl, benzocyclobutenyl, tetrahydropyranyl, phenyl, pyrazolyl, pyridinyl, methylenecyclopropyl, or methylenoxetanyl.

[0248] In some embodiments, R B5 is selected from H or optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclohexyl, benzocyclobutenyl, tetrahydropyranyl, phenyl, pyrazolyl, pyridinyl, methylenecyclopropyl, or methylenoxetanyl. B7 is selected from H or optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclohexyl, benzocyclobutenyl, tetrahydropyranyl, phenyl, pyrazolyl, pyridinyl, methylenecyclopropyl, or methylenoxetanyl. phenyl, methylenecyclopropyl, or

[0249] In some embodiments, R B5 is selected from H or optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclohexyl, benzocyclobutenyl, tetrahydropyranyl, phenyl, pyrazolyl, pyridinyl, methylenecyclopropyl, or methylenoxetanyl. B7 is selected from H or optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclohexyl, benzocyclobutenyl, tetrahydropyranyl, phenyl, pyrazolyl, pyridinyl, methylenecyclopropyl, or methylenoxetanyl.

[0250] In some embodiments, each R B7 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally substituted C B8 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, or diC 1-4 alkyl.

[0251] In some embodiments, each R B7 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally substituted C B8 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3alkylamino, or diC 1-3 alkylamino.

[0252] In some embodiments, each R B7 is each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, or a group optionally substituted with one or more R B8 substituted with one or more R

[0253] In some embodiments, each R B7 is each independently selected from -F, or -OH, or a group optionally substituted with one or more R B8 substituted with one or more R

[0254] In some embodiments, each R B8 is each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, or -CN.

[0255] In some embodiments, each R B8 is each independently selected from deuterium, -F, -Cl, -OH, or -NH2.

[0256] In some embodiments, each R B7 is each independently selected from deuterium, -F, -Cl, -OH, -NH2, methyl, trifluoromethyl, methylenehydroxyl, or methoxy.

[0257] In some embodiments, each R B7 is each independently selected from -F, -OH, or methyl.

[0258] In some embodiments, R B5 is selected from H,

[0259] In some embodiments, R B5 is selected from H,

[0260] In some embodiments, R C5 is selected from H or a group optionally substituted with one or more R C7 substituted with one or more R 1-4 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-3 alkylene 3-10 membered cycloalkyl, C 1-3 alkylene 3-10 membered cycloalkenyl, C 1-3 alkylene 4-10 membered heterocyclyl, C 1-3alkylene 6-10 aryl, or C 1-3 Alkylene 5-10-membered heteroaryl groups.

[0261] In some implementation schemes, R C5 Selected from H or arbitrarily selected by one or more R C7 The following groups are substituted: C 1-4 Alkyl, 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C 1-2 alkylene, 3-6 membered cycloalkyl, C 1-2 alkylene 4-6 membered cycloalkenyl, C 1-2 alkylene 4-6 membered heterocyclic groups, C 1-2 alkylenephenyl, or C 1-2 Alkylene 5-6-membered heteroaryl.

[0262] In some implementation schemes, R C5 Selected from H or arbitrarily selected by one or more R C7 The following groups are substituted: C 1-4 Alkyl, 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C 1-2 alkylene, 3-6 membered cycloalkyl, C 1-2 alkylene 4-6 membered cycloalkenyl, or C 1-2 Alkylene 4-6 membered heterocyclic groups.

[0263] In some embodiments, the 3-12, 3-10, 4-8, or 4-6 heterocyclic groups are selected from 3-12, 3-10, 4-8, or 4-6 heterocyclic alkyl groups.

[0264] In some implementation schemes, R C5 Selected from H or arbitrarily selected by one or more R C7 The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydrocyclopentadienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, benzocyclobutenyl, oxacyclobutyl, aziridine, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyranyl, tetrahydropyridinyl, phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methyleneoxacyclobutyl, methyleneaziridine, methylenetetrahydrofuranyl, or methylenetetrahydropyrrolyl.

[0265] In some implementation schemes, R C5 Selected from H or arbitrarily selected by one or more R C7The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylenecyclopropyl, or methyleneoxetyl.

[0266] In some implementation schemes, R C5 Selected from H or arbitrarily selected by one or more R C7 The following groups are substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylenecyclopropyl, or

[0267] In some implementation schemes, R C5 Selected from H or arbitrarily selected by one or more R C7 The following groups are substituted: ethyl or n-propyl.

[0268] In some implementations, each R C7 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R groups. C8 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino.

[0269] In some implementations, each R C7 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R groups. C8 The following groups are substituted: C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, or di-C 1-3 Alkylamino.

[0270] In some implementations, each R C7 Each is independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, or optionally influenced by one or more R. C8 The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0271] In some implementations, each R C8 Each is independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, or -CN.

[0272] In some implementations, each R C8 Each is independently selected from deuterium, -F, -Cl, -OH, or -NH2.

[0273] In some embodiments, each R C7 is each independently selected from deuterium, -F, -CI, -OH, -NH2, methyl, trifluoromethyl, methylenehydroxyl, or methoxy.

[0274] In some embodiments, each R C7 is each independently selected from -F, or -OH.

[0275] In some embodiments, R C5 is selected from

[0276] In some embodiments, R C5 is selected from

[0277] In some embodiments, ring D, ring E, and ring F are each independently selected from phenyl or 5-6 membered heteroaryl.

[0278] In some embodiments, ring D, ring E, and ring F are each independently selected from phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

[0279] In some embodiments, ring D, ring E, and ring F are each independently selected from wherein the end with “*” is attached to the L moiety.

[0280] In some embodiments, ring D, ring E, and ring F are each independently selected from wherein the end with “*” is attached to the L moiety.

[0281] In some embodiments, each R D , R E , and R F are each independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.

[0282] In some embodiments, each R D , R E , and R Feach independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, di-C 1-3 alkylamino, deuterated C 1-3 alkyl, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, halo-C 1-3 alkylamino, or halo-di-C 1-3 alkylamino.

[0283] In some embodiments, each R D , R E , and R F is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0284] In some embodiments, each R D , R E , and R F is independently selected from deuterium, -F, -Cl, methyl, or methoxy.

[0285] In some embodiments, each R D , R E , and R F is independently selected from -F.

[0286] In some embodiments, m is selected from 0, 1, or 2.

[0287] In some embodiments, p is selected from 0, 1, or 2. In some embodiments, p is selected from 0 or 1.

[0288] In some embodiments, q is selected from 0, 1, or 2.

[0289] In some embodiments, structural unit is selected from wherein the end with “*” is connected to the L moiety.

[0290] In some embodiments, structural unit is selected from wherein the end with “*” is connected to the L moiety.

[0291] In some embodiments, structural unit selected from wherein the end with the "*" is attached to the L moiety.

[0292] In some embodiments, the structural unit selected from wherein the end with the "*" is attached to the L moiety.

[0293] In some embodiments, the structural unit selected from wherein the end with the "*" is attached to the L moiety.

[0294] In some embodiments, the structural unit selected from wherein the end with the "*" is attached to the L moiety.

[0295] In some embodiments, the structural unit selected from wherein the end with the "*" is attached to the L moiety.

[0296] In some embodiments, Formula (A) is selected from

[0297] In some embodiments, Formula (A) is selected from

[0298] In some embodiments, Formula (A) is selected from

[0299] In some embodiments, Formula (A) is selected from

[0300] In some embodiments, Formula (A) is selected from

[0301] In some embodiments, Formula (A) is selected from

[0302] In some embodiments, Formula (A) is selected from

[0303] In some embodiments, Formula (B) is selected from

[0304] In some implementations, formula (B) is selected from...

[0305] In some implementations, formula (C) is selected from...

[0306] In some implementations, formula (C) is selected from...

[0307] In some implementations, formula (C) is selected from...

[0308] In some implementations, formula (C) is selected from...

[0309] In some embodiments, the heterocyclic group is selected from heterocyclic alkyl groups. In some embodiments, the heterocyclic group in this application is selected from partially unsaturated heterocyclic groups.

[0310] In some implementations, the 3-12 yuan is selected from 3-10 yuan, 3-8 yuan, 3-6 yuan, 4-7 yuan, 4-6 yuan, 5-8 yuan, 5-7 yuan, or 5-6 yuan.

[0311] In some implementations, the C 1-6 Selected from C 1-5 C 1-4 C 1-3 or C 1-2 .

[0312] In some implementations, the C 1-6 Alkyl groups are selected from C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0313] In some implementations, the C 1-6 Alkylene is selected from C 1-5 Alkylene, C 1-4 Alkylene, C 1-3 alkylene, or C 1-2 Alkylene.

[0314] In some implementations, the C 1-6 Heteroalkylene groups are selected from C 1-5 Heteroalkylene, C 1-4 Heteroalkylene, C 1-3 Heteroalkylene, or C 1-2 Heteroalkylene.

[0315] In some embodiments, the halogen is selected from F, CI, Br, or I.

[0316] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is fluoro.

[0317] In some embodiments, "one or more" can refer to an integer from one to less than ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, three, or four.

[0318] In some embodiments, the heterocycloalkenyl or heterocycloalkyl, wherein the heteroatom is selected from N, NH, O, or S. In some embodiments, the heterocycloalkenyl or heterocycloalkyl, wherein the heteroatom is selected from N, O, or S. In some embodiments, the heteroaryl, wherein the heteroatom is selected from N, O, S. In some embodiments, the heteroalkylene, wherein the heteroatom is selected from N, NH, O, S, S(O), or S(O)2.

[0319] In some embodiments, the heterocycloalkenyl, heterocycloalkyl, heteroalkylene, or heteroaryl, wherein the number of heteroatoms is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the heterocycloalkenyl, heterocycloalkyl, heteroalkylene, or heteroaryl, wherein the number of heteroatoms is selected from 1, 2, 3, or 4. In some embodiments, the heterocycloalkenyl, heterocycloalkyl, heteroalkylene, or heteroaryl, wherein the number of heteroatoms is selected from 1, 2, or 3.

[0320] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl contains 1 or 2 heteroatoms selected from N, O, or S.

[0321] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl contains 1 or 2 N atoms.

[0322] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl contains 1 O atom.

[0323] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl contains 1 N atom and 1 O atom.

[0324] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl contains 1 N atom and 1 S atom.

[0325] In some embodiments, the heterocyclyl or heterocycloalkyl group comprises a monocyclic, spiro, fused or bridged ring. In some embodiments, the heterocycloalkyl group comprises a monocyclic or spiro ring. In some embodiments, the heterocyclyl or heterocycloalkyl group described herein comprises a monocyclic or bridged ring.

[0326] The present application provides a compound of Formula (I-A), Formula (I-B), Formula (I-C), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0327] wherein, L, ring A, ring B, R 1 , n, X A , E A1 , E A2 , R A1 , R A2 , R A3 , R A4 , R A5 , ring D, R D , m, X B , E B1 , E B2 , E B3 , R B1 , R B2 , R B3 , R B4 , R B5 , ring E, R E , p, X C , E C1 , E C2 , R C1 , R C2 , R C3 , R C4 , R C5 , ring F, R F and q are as described herein.

[0328] The present application provides a compound of Formula (I-A-1), Formula (I-B-1), Formula (I-C-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0329] wherein, L, ring A, ring B, R 1 , n, X A , E A1 , E A2 , R A1 , R A2 , R A3 , R A4 , R A5 , ring D, R D , m, X B , E B1 , EB2 , E B3 , R B1 , R B2 , R B3 , R B4 , R B5 , ring E, R E , p, X C , E C1 , E C2 , R C1 , R C2 , R C3 , R C4 , R C5 , ring F, R F and q are as described herein.

[0330] In some embodiments, the present application includes the above-defined variables and embodiments thereof, and any combination thereof.

[0331] The present application provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0332] In another aspect, the present application provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0333] In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0334] In another aspect, the present application also provides the use of a compound of the present application, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment or prevention of a disease.

[0335] The present application also provides a method for treating or preventing a disease, comprising administering to a mammal (preferably a human) in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0336] The present application also provides the use of a compound described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the treatment or prevention of a disease.

[0337] The present application also provides a compound described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a disease. The present application also provides a compound described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a disease.

[0338] In some embodiments, the disease is selected from diseases associated with the estrogen receptor.

[0339] In some embodiments, the disease is selected from diseases associated with the estrogen receptor alpha protein.

[0340] In some embodiments, the disease is selected from breast cancer.

[0341] In some embodiments, the disease is selected from estrogen receptor positive breast cancer.

[0342] Technical effects

[0343] The compounds of the present application have good ERa protein degradation activity, exhibit good cell proliferation inhibition effect (e.g. MCF-7 cells or T47D cells); and exhibit good pharmacodynamics properties, pharmacokinetic properties and drugability in animals in vivo.

[0344] Definitions

[0345] The following terms as used in the present application have the following meanings, unless otherwise specified. A particular term should not be construed as indefinite or unclear if not specifically defined, but should be understood in accordance with the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0346] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced with a substituent, provided that the valency of the particular atom is normal and that the substituted compound is stable. When the substituent is oxo (i.e., =0), it is meant that two hydrogen atoms are replaced, and oxo cannot occur on an aromatic group.

[0347] The term "displace" or "displaced" means that a particular atom or group can be replaced or replaced by a designated other atom or group. For example, 1 or 2 or 3 -CH2- in -CH2CH2CH2- can be replaced by O, S, NH to get -O-CH2-CH2-, -O-CH2-, -CH2-O-CH2-, -CH2-O-, -CH2-CH2-O-, -O-, etc.

[0348] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. A group "optionally substituted" means that the group is substituted or unsubstituted. For example, ethyl "optionally" substituted with halogen means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (such as CH2CH2F), poly-substituted (such as CHFCH2F, CH2CHF2, and the like), or fully substituted (CF2CF3). It will be understood by those skilled in the art that, for any group containing one or more substituents, such group does not include any substitution or substitution pattern that is not

[0349] C in this document m-n is that the moiety has an integer number of carbon atoms in the given range (m-n). For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0350] When any variable (e.g., R) occurs more than one time in a compound; each definition is independent. For example, if a group has 2 R's, each R is independently selected.

[0351] When one of the variables is selected from a covalent bond, it means that the two groups to which it is attached are directly connected, such as L represents a covalent bond in A-L-Z means that the structure is actually A-Z.

[0352] When a linking group is listed without specifying its direction of attachment, its direction of attachment is arbitrary, such as in A-L-Z, where the linking group L is -M-W-, this means that the structure can be either A-M-W-Z or A-W-M-Z.

[0353] When a bond crosslinks to two atoms of a ring (including monocyclic, fused ring, or spirocyclic), the bond can be to any atom on the ring (including monocyclic, fused ring, or spirocyclic). For example, when a substituent's bond crosslinks to two atoms of a ring, the substituent can be bonded to any atom on the ring. For example, the structural element means that it can be substituted at any position on the cyclohexyl or cyclohexadiene.

[0354] The term "halo" or "halogen" means fluoro, chloro, bromo, and iodo.

[0355] The term "hydroxy" means an -OH group.

[0356] The term "cyano" means a -CN group.

[0357] The term "mercapto" means an -SH group.

[0358] The term "amino" refers to a -NH2group.

[0359] The term "nitro" refers to a -NO2group.

[0360] The term "alkylene" refers to a saturated straight or branched chain divalent hydrocarbon radical of the general formula -C n H 2n having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 alkylene" refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, or -CH2CH2CH(CH3)-), and the like. The alkylene group is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0361] The term "alkyl" refers to a saturated hydrocarbon radical of the general formula -C n H 2n+1 having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl group can be straight or branched, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). The alkyl group is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy. Similarly, the alkyl moieties (i.e., alkyl groups) of alkoxy, alkylamino, dialkylamino, and alkylthio groups have the same definition as above.

[0362] The term "heteroalkylene" refers to an alkylene in which one or more carbon atoms are replaced by a heteroatom, and contains at least one carbon atom, having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The specific heteroatom can be selected from N, NH, O, S, S(O), or S(O)2. The number of heteroatoms is selected from 1, 2, 3, 4, 5, or 6. For example, C 1-12 Heteroalkylene indicates that the heteroalkylene contains 1 to 12 carbon atoms and one or more heteroatoms. For example, C 1-6 Heteroalkylene indicates that the heteroalkylene contains 1 to 6 carbon atoms and one or more (e.g., 1-6, 1-3, 1, 2, or 3 heteroatoms) heteroatoms.

[0363] The term "alkoxy" refers to -O-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl portion is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0364] The term "alkylamino" refers to -NH-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl portion is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0365] The term "dialkylamino" refers to -N(alkyl)2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl portion is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0366] The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0367] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and has at least one double bond and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, benzocyclobutene, and the like. The cycloalkenyl group is optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0368] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, azirrobutyl, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazine, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, azirrospironyl, diazirrospironyl, azirrospirodecyl, azirrospirodecyl, diazirrospirodecyl, azirrospiroundecyl, or diazirrospiroundecyl, etc. The heterocyclic group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0369] The term "heterocyclic alkenyl" refers to a partially unsaturated (but not fully unsaturated) heteroaromatic ring that can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic alkenyl groups include, but are not limited to, dihydrofuranyl, dihydropyrrolyl, 2H-pyranyl, dihydrothiophenyl, dihydrooxazolyl, dihydrothiazolyl, dihydrooxazinyl, dihydropyridyl, tetrahydropyridyl, and dihydroazapyrrolyl. basal or tetrahydrozaza Heteroaryl is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heteroaryl, heteroaryloxy, aryl, aryloxy, or aralkyloxy.

[0370] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle typically is a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, examples of other heterocycloalkyl groups include, but are not limited to, monoazaspiro nonanyl, diazaspiro nonanyl, monoazaspiro decanyl, monoazamonooxaspiro decanyl, diazaspiro decanyl, monoazaspiro undecanyl, or diazaspiro undecanyl. The heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0371] The term "aryl" refers to all-carbon monocyclic or fused polycyclic aromatic ring groups having a conjugated pi-electron system. For example, aryl groups can have from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracyl groups, and the like. The aryl group is optionally substituted with one or more substituents selected from hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(0)0-alkyl, -OC(O)-alkyl, -C(0)NH2, -C(0)NH-alkyl, -C(0)N(alkyl)2, -NHC(0)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(0)2-alkyl, -S(0)2NH2, -S(0)2NH-alkyl, -S(0)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0372] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, typically having from 5 to 14 members, from 5 to 12 members, from 5 to 10 members, from 5 to 8 members, from 5 to 7 members, or from 5 to 6 members in the ring. Preferred heteroaryl groups have a single 4 to 8 member ring, especially a 5 to 6 member ring, or multiple fused rings comprising from 5 to 14, especially from 5 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl, and the like. The heteroaryl group is optionally substituted with one or more substituents selected from hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(0)0-alkyl, -OC(O)-alkyl, -C(0)NH2, -C(0)NH-alkyl, -C(0)N(alkyl)2, -NHC(0)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(0)2-alkyl, -S(0)2NH2, -S(0)2NH-alkyl, -S(0)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0373] Unless otherwise specified, the term "deuterated C 1-6 alkyl" refers to any number and position of H atoms in the above "C 1-6 alkyl" groups being replaced by deuterium atoms. The deuterated C 1-6 alkyl group can be a deuterated C 1-4 alkyl or a deuterated C 1-3 alkyl. Examples of deuterated alkyl groups include, but are not limited to, -CH2D, -CHD2, -CD3, and the like.

[0374] The groups L, LNK 1 , Cy 1 , LNK 2 , Cy 2 , LNK 3 read from left to right or right to left, for example, the group L corresponds to the left group and the right group connected to the group in the general formula when read from left to right or right to left, specifically for example, when L is selected from -LNK 1 -Cy 1 -LNK 2 -Cy 2 -LNK 3 , the structure is

[0375] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0376] (i) inhibiting the disease or condition, i.e., arresting its development;

[0377] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0378] The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition, but has not yet been diagnosed as having it.

[0379] The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present application that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner by a consideration of the factors relevant to the choice of an appropriate dose of a therapeutic compound.

[0380] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0381] As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.

[0382] The term "pharmaceutical composition" means a mixture of one or more compounds of the present application or salts thereof with a pharmaceutically acceptable excipient. The objective of a pharmaceutical composition is to facilitate the administration of a compound of the present application to an organism.

[0383] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The presence of an excipient in a composition does not interfere with any of the biological activity or properties of the active compound.

[0384] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising", when used in relation to a list of items or steps, are to be interpreted as "including but not limited to".

[0385] The compounds and intermediates of the present application can also exist in different tautomeric forms and all such forms are embraced within the scope of the present application. The term "tautomers" or "tautomeric forms" refers to different energy structures that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton transfer tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerization. A specific example of prototropic tautomers is the imidazole moiety, wherein a proton can migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0386] In this document, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0387] Unless otherwise indicated, in this document, the parameter values representing the amount or a physico-chemical property of a component or a reaction condition etc. should be understood to be modified in all cases by the term "about". When the term "about" is used in describing the present application, the term "about" means that there is an acceptable margin of error, for example within ±5%, such as ±1% or ±0.1% of a certain value.

[0388] The present application also includes isotope-labeled compounds of the present application which are the same as those described herein, but for the inclusion of one or more atoms which are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, and the like.

[0389] Certain isotopically-labeled compounds of the present application (for example those 3 H, and 14 C) are useful in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H), and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, are useful in positron emission tomography (PET) studies for measurement of substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by

[0390] Further, substitution with heavier isotopes such as deuterium (i.e. 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances, wherein deuterium substitution can be partial or complete, partial deuterium substitution refers to replacement of at least one hydrogen with at least one deuterium.

[0391] The compounds of the present application can be asymmetric, for example, having one or more stereocenters. Unless otherwise indicated, all stereoisomers, including enantiomers and diastereomers, are included within the scope of the present application. Compounds of the present application containing an asymmetric carbon atom can be isolated in optically active or racemic forms. The optically active forms can be obtained by separation from a racemic mixture or by using chiral starting materials or chiral reagents in the synthetic sequence.

[0392] The compounds of the present application can have one or more atropisomers, which refers to optically active isomers resulting from the restriction of free rotation about a single bond due to an energy barrier. Compounds of the present application containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation of a single bond of a compound of the present application containing a chiral axis is sufficiently high, its atropisomers can be isolated in optically active form.

[0393] The pharmaceutical compositions of the present application can be prepared by combining a compound of the present application with a suitable pharmaceutically acceptable excipient, such as can be formulated into solid, semi-solid, liquid, or gaseous dosage forms, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, and aerosols.

[0394] Typical routes of administering a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalant, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0395] The pharmaceutical compositions of the present application can be manufactured in a manner appropriate to the type of composition by methods known to those skilled in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, or lyophilizing processes.

[0396] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients can enable the compounds of the present application to be formulated as tablets, pills, capsules, dragees, gelcaps, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0397] Solid oral compositions can be prepared by conventional mixing, encapsulating, or tabletting processes. For example, the active compound can be mixed with a solid diluent and optionally ground, and if desired, other suitable excipients can be added and the mixture tabletted or encapsulated to form a tablet or capsule core. Suitable excipients include, but are not limited to, binders, diluents, disintegrating agents, lubricants, glidants, sweeteners, or flavorants.

[0398] The pharmaceutical compositions can also be in a form suitable for parenteral administration, such as by injection, as a sterile solution, suspension or lyophilized powder, or by implantation (see, e.g., U.S. Patent No. 4,490,226).

[0399] In all methods of administration of the compounds of Formula I described herein, the dosage administered is from 0.001 to 2000 mg / kg body weight per day in single or divided doses.

[0400] The compounds of the present application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments set forth below with other chemical synthetic methods known to those skilled in the art, and equivalents thereof known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.

[0401] The chemical reactions of the specific embodiments of the present application are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the synthesis of the compounds of the present application, it is sometimes necessary to protect sensitive or reactive groups on the compounds, such as the amino group in the present application, using methods known to those skilled in the art. The protecting groups can be removed at a convenient stage using methods known from the art.

[0402] One important consideration in the planning of synthetic routes in the art is the selection of an appropriate protecting group for a reactive functional group, such as the amino group in the present application, for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0403] In some embodiments, the compounds of the present application can be prepared by the following routes, wherein ring A, ring B, R 1 , n, LNK 1 , Cy 1 , LNK 2 , Cy 2 , LNK 3 , Cy 1 , Cy 2 , X A , X B , XC , E A1 , E A2 , E B1 , E B2 , E B3 , E C1 , E C2 , R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 , R B4 , R C1 , R C2 , R C3 , R C4 , R A5 , R B5 , R C5 , ring D, ring E, ring F, R D , R E , R F , m, p and q are as described herein:

[0404] Each product resulting from the reactions in the above routes can be isolated by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Starting materials can be obtained commercially or synthesized by conventional methods. These materials can be characterized using conventional means such as physical constants and spectral data. The compounds described herein can be obtained as single isomers or as mixtures of isomers using the synthetic methods described.

[0405] The following abbreviations are used herein:

[0406] THP represents tetrahydropyranyl; Boc represents tert-butoxycarbonyl; Me represents methyl; Bn represents benzyl; Cbz represents benzyloxycarbonyl; DMSO represents dimethylsulfoxide; Tf represents trifluoromethanesulfonyl; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DMSO represents dimethylsulfoxide; Xphos Pd G3 represents (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate; TBDPS represents tert-butyldiphenylsilyl; Ts represents p-toluenesulfonic acid; TBDPS represents tert-butyldiphenylsilyl; PinB represents pinacolborane; Piv represents pivaloyl.

[0407] For purposes of United States patent practice, the contents of all patents, patent applications, and other documents, published or otherwise, mentioned anywhere in this application are hereby expressly incorporated by reference in their entirety. Such publications are only provided for their disclosure prior to the filing date of this application. All statements as to the date or dates of publication of documents are based on the dates of issuance of the U.S. Patent and Trademark Office, and are subject to change upon the correction of patent application processing errors. Furthermore, the references cited herein are not admitted to be prior art to this application, in any country, by virtue of their mention in this application.

[0408] For the purposes of description and disclosure, all patents, patent applications, and other publications, whether prior to or contemporaneous with the application, are expressly incorporated herein by reference in their entirety. These publications are provided solely for their disclosure prior to the filing date of the application. All statements as to the date or dates of publication of documents are based on the dates of issuance of the U.S. Patent and Trademark Office, and are subject to change upon the correction of patent application processing errors. Furthermore, the references cited herein are not admitted to be prior art to this application, in any country, by virtue of their mention in this application. DETAILED DESCRIPTION

[0409] Example 1

[0410] Step 1:

[0411] Intermediate A-1 (100 mg), 1-Boc-3-azetidinone (212 mg), sodium acetate (51 mg) and N,N-dimethylacetamide (10 mL) were mixed and stirred at 80°C for 2 hours. The reaction solution was poured into saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to obtain 106 mg of intermediate 1-1.

[0412] MS (ESI, [M+Na] + )m / z: 463.32

[0413] 1 H-NMR (500MHz, DMSO-d6): δ 11.07 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 3.97 (s, 2H), 3.82 (s, 2H), 3.76 (s, 2H), 3.38 (ddd, J = 7.2, 5.0, 1.9 Hz, 1H), 2.96 (t, J = 5.8 Hz, 2H), 2.77 (ddd, J = 17.2, 12.0, 5.3 Hz, 1H), 2.67 (t, J = 5.8 Hz, 2H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.46 (dd, J = 12.1, 4.2 Hz, 1H), 2.24 - 2.15 (m, 1H), 1.39 (s, 9H).

[0414] Step two:

[0415] Intermediate 1-1 (110 mg) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was directly concentrated to obtain 190 mg of intermediate 1-2.

[0416] MS (ESI, [M+H] + )m / z: 341.26

[0417] Step three:

[0418] Intermediate B-1 (50 mg), intermediate 1-2 (86 mg), sodium acetate (31 mg), 1,2-dichloroethane (5 mL), and isopropanol (1 mL) were mixed, and the reaction was stirred at 60°C for 30 minutes. Sodium triacetoxyborohydride (80 mg) was added, and the reaction was stirred at 60°C for 2 hours. Saturated aqueous ammonium chloride solution was added to quench, and the organic layer was extracted with dichloromethane, washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column (dichloromethane:methanol = 10:1) to obtain 20 mg of compound 1.

[0419] MS (ESI, [M+H] + )m / z: 722.56

[0420] 1 H-NMR (500MHz, DMSO-d6): δ 11.07 (s, 1H), 9.08 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.13 (p, J = 6.4 Hz, 4H), 6.96-6.74 (m, 2H), 6.72-6.57 (m, 2H), 6.57-6.32 (m, 3H), 6.20 (d, J = 8.3 Hz, 2H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.69 (s, 2H), 3.50 (s, 2H), 3.39 (d, J = 11.8 Hz, 2H), 3.30-3.24 (m, 2H), 3.15 (d, J = 9.7 Hz, 1H), 2.97-2.88 (m, 5H), 2.80-2.72 (m, 1H), 2.63-2.57 (m, 5H), 2.47 (d, J = 4.0 Hz, 1H), 2.23-1.98 (m, 3H), 1.76-1.61 (m, 3H), 1.23 (dd, J = 13.1, 8.4 Hz, 2H).

[0421] Example 2

[0422] Step one:

[0423] Intermediate A-2 (200 mg), 1-Boc-3-azetidinone (252 mg), sodium acetate (121 mg), 1,2-dichloroethane (5 mL) and isopropanol (1 mL) were mixed and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (313 mg) was added and stirring was continued at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was washed successively with water, saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give 160 mg of intermediate 2-1.

[0424] 1 H-NMR (500 MHz, DMSO-d6): δ 11.09 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.60 (dd, J = 11.9, 5.0 Hz, 1H), 4.18 (d, J = 2.4 Hz, 2H), 4.09-4.07 (m, 2H), 3.97 (s, 2H), 3.86 (s, 2H), 3.72-3.70 (m, 1H), 2.78-2.74 (m, 1H), 2.64-2.60 (m, 1H), 2.56-2.46 (m, 1H), 2.24-2.16 (m, 1H), 1.39 (s, 9H).

[0425] Step two:

[0426] Intermediate 2-1 (140 mg) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was directly concentrated to give 150 mg of intermediate 2-2.

[0427] MS (ESI, [M+H] + )m / z: 327.20

[0428] Step three:

[0429] Intermediate B-1 (57 mg), intermediate 2-2 (73 mg), sodium acetate (23.5 mg), 1,2-dichloroethane (5 mL) and isopropanol (1 mL) were mixed and stirred at 60 °C for 30 minutes. Sodium triacetoxyborohydride (60.8 mg) was added and stirring was continued at 60 °C for 2 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was washed successively with water, saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 63 mg of compound 2.

[0430] MS (ESI, [M+H] +m / z: 708.35

[0431] 1 H-NMR (500 MHz, DMSO-d6): δ 11.09 (s, 1H), 9.09 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 12.5, 7.0 Hz, 3H), 6.83 (d, J = 7.3 Hz, 2H), 6.64 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.52 (d, J = 8.3 Hz, 2H), 6.48 (dd, J = 8.3, 2.6 Hz, 1H), 6.20 (d, J = 8.2 Hz, 2H), 4.61-4.58 (m, 1H), 4.14-4.12 (m, 3H), 4.03 (s, 2H), 3.53-3.48 (m, 1H), 3.42-3.36 (m, 4H), 3.31-3.24 (m, 2H), 3.03-2.85 (m, 4H), 2.80-2.73 (m, 1H), 2.65-2.56 (m, 3H), 2.22-2.18 (m, 1H), 2.15-2.09 (m, 2H), 1.71-1.66 (m, 3H), 1.25-1.18 (m, 2H).

[0432] Example 3

[0433] Step one:

[0434] ( methoxymethyl) triphenylphosphonium chloride (752 mg), tetrahydrofuran (5 mL) and potassium tert-butoxide (246 mg) were mixed, and reacted at 0 °C for 2 hours under nitrogen atmosphere, cooled to -78 °C, and benzyl 2-oxo-7- azaspiro [3.5] nonane-7-carboxylate (200 mg) was added, and the reaction was continued at 0 °C for 1 h. Saturated aqueous ammonium chloride solution was added, and the organic phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: ethyl acetate = 90:10) to obtain 205 mg of intermediate 3-1.

[0435] MS (ESI, [M+H] + m / z: 302.17

[0436] 1H-NMR (500 MHz, DMSO-d6): δ 7.38 (dt, J = 6.8, 1.3 Hz, 1H), 7.36-7.28 (m, 4H), 5.91 (p, J = 2.2 Hz, 1H), 5.06 (s, 2H), 3.47 (s, 3H), 3.34 (s, 2H), 3.30 (s, 2H), 2.34 (d, J = 2.5 Hz, 2H), 2.30 (t, J = 2.0 Hz, 2H), 1.51-1.45 (m, 4H).

[0437] Step two:

[0438] Intermediate 3-1 (1.0 g) was mixed with acetonitrile (5 mL), 4M hydrochloric acid in dioxane (5 mL) was added, and the mixture was stirred at room temperature for 2 h. The solvent was evaporated by concentration, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 940 mg of intermediate 3-2.

[0439] 1 H-NMR (500 MHz, DMSO-d6): δ 9.67 (d, J = 1.6 Hz, 1H), 7.45-7.27 (m, 5H), 5.06 (s, 2H), 3.34 (s, 2H), 3.27 (s, 2H), 3.22-3.14 (m, 1H), 1.95 (d, J = 4.0 Hz, 2H), 1.93 (d, J = 5.4 Hz, 2H), 1.61-1.50 (m, 2H), 1.43-1.34 (m, 2H).

[0440] Step three:

[0441] Intermediate 3-2 (500 mg), trimethyl orthoformate (2.2 g), p-toluenesulfonic acid hydrate (16 mg), and methanol (5 mL) were mixed, and the mixture was stirred at room temperature for 12 h. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90: 10) to give 1.1 g of intermediate 3-3.

[0442] 1H-NMR (500 MHz, DMSO-d6): δ 7.39-7.29 (m, 5H), 5.05 (s, 2H), 4.28 (d, J = 7.0 Hz, 1H), 3.35 (d, J = 6.9 Hz, 2H), 3.25 (s, 2H), 3.20 (s, 6H), 2.53 (d, J = 8.7 Hz, 1H), 1.81-1.74 (m, 2H), 1.61-1.54 (m, 2H), 1.53-1.48 (m, 2H), 1.42-1.36 (m, 2H).

[0443] Step four:

[0444] Intermediate 3-3 (1 g), palladium on carbon (32 mg) and methanol (5 mL) were mixed and reacted under hydrogen atmosphere at room temperature for 12 h. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column (petroleum ether: ethyl acetate = 5: 1) to obtain 507 mg of intermediate 3-4.

[0445] 1 H-NMR (500 MHz, DMSO-d6): δ 4.25 (d, J = 7.1 Hz, 1H), 3.20 (s, 6H), 2.60 (s, 2H), 2.52 (s, 2H), 2.45 (dt, J = 17.2, 8.7 Hz, 1H), 1.78-1.69 (m, 2H), 1.54-1.48 (m, 2H), 1.45 (t, J = 5.5 Hz, 2H), 1.37-1.31 (m, 2H).

[0446] Step five:

[0447] Intermediate 3-4 (218 mg), intermediate B-2 (500 mg), sodium tert-butoxide (210 mg), palladium acetate (32.7 mg), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (84 mg) and toluene (5 ml) were mixed, and the reaction mixture was heated to 90°C under nitrogen atmosphere for 3 h. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: ethyl acetate = 85: 15) to obtain 226 mg of intermediate 3-5.

[0448] MS (ESI, [M+H] + )m / z: 586.44

[0449] 1H-NMR (500 MHz, DMSO-d6): δ 7.42 (dd, J = 21.9, 7.6 Hz, 4H), 7.33 (d, J = 7.3 Hz, 1H), 7.10 (d, J = 7.7 Hz, 2H), 7.01 (d, J = 8.0 Hz, 3H), 6.92 (s, 1H), 6.79 (s, 4H), 6.72 (d, J = 8.5 Hz, 1H), 6.57 (d, J = 8.7 Hz, 1H), 5.09 (s, 2H), 4.29 (d, J = 7.2 Hz, 1H), 3.22 (s, 6H), 3.07 (s, 2H), 2.98 (s, 2H), 2.87 (s, 2H), 2.68 (d, J = 8.6 Hz, 2H), 1.79 (m, 2H), 1.64 (s, 2H), 1.60 (m, 2H), 1.53 (s, 2H), 1.24 (s, 1H).

[0450] Step six:

[0451] Intermediate 3-5 (100 mg), palladium on carbon (18 mg) and methanol (5 mL) were mixed and stirred under hydrogen atmosphere at room temperature for 12 h. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was separated by supercritical fluid chromatography (chiral resolution) (column: CHIRALART Amylose SA 30*250 mm; mobile phase A: carbon dioxide B: ethanol; flow rate: 75 mL / min) to give 420 mg of intermediate 3-6.

[0452] Intermediate 3-6, R t = 3.147 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 ml / min; column temperature: 40 °C).

[0453] 1H-NMR (500 MHz, DMSO-d6): δ 9.11 (s, 1H), 7.17-6.97 (m, 4H), 6.82 (d, J = 6.6 Hz, 2H), 6.65-6.61 (m, 1H), 6.59 (s, 1H), 6.51 (d, J = 8.7 Hz, 2H), 6.47 (d, J = 8.2 Hz, 1H), 6.19 (d, J = 8.7 Hz, 2H), 4.27 (d, J = 6.9 Hz, 1H), 4.11 (d, J = 5.0 Hz, 1H), 3.27 (dd, J = 13.4, 5.3 Hz, 1H), 3.20 (d, J = 2.0 Hz, 6H), 2.98-2.87 (m, 4H), 2.84 (t, J = 5.6 Hz, 2H), 2.09 (dd, J = 12.6, 6.4 Hz, 1H), 1.76 (t, J = 10.8 Hz, 2H), 1.72-1.66 (m, 1H), 1.58 (d, J = 7.9 Hz, 2H), 1.54 (d, J = 10.8 Hz, 2H), 1.50-1.44 (m, 2H).

[0454] Step seven:

[0455] Intermediate 3-6 (79 mg), tetrahydrofuran (2 mL) and 2M aqueous sulfuric acid (1.2 mL) were mixed and heated to 70 °C for 1 h. The pH was adjusted to 7 by adding saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with water, saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 65 mg of intermediate 3-7.

[0456] Step eight:

[0457] Intermediate 3-7 (130 mg), intermediate A-2 (112 mg), sodium acetate (50 mg), sodium triacetoxyborohydride (183 mg), 1,2-dichloroethane (3.5 mL), and isopropanol (3.5 mL) were mixed and stirred at room temperature for 16 h under nitrogen protection. Water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water, saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 8:1) to give 36 mg of compound 3.

[0458] MS (ESI, [M+H] + )m / z: 707.51.

[0459] 1H-NMR (500 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.08 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.18-7.09 (m, 3H), 6.83 (d, J = 6.6 Hz, 2H), 6.69-6.58 (m, 2H), 6.53 (d, J = 8.9 Hz, 2H), 6.48 (dd, J = 8.3, 2.7 Hz, 1H), 6.20 (d, J = 8.9 Hz, 2H), 4.59 (dd, J = 11.9, 5.0 Hz, 1H), 4.17-4.07 (m, 3H), 3.99 (s, 2H), 3.30-3.22 (m, 1H), 3.06-2.71 (m, 9H), 2.65-2.57 (m, 1H), 2.55-2.51 (m, 1H), 2.49-2.45 (m, 1H), 2.23-2.04 (m, 2H), 2.01-1.93 (m, 2H), 1.70 (dd, J = 12.1, 5.5 Hz, 1H), 1.67-1.60 (m, 2H), 1.56-1.43 (m, 4H).

[0460] Example 4

[0461] Intermediate 3-7 (109 mg), intermediate A-1 (78 mg), sodium acetate (40 mg), 1,2-dichloroethane (3 mL) and isopropanol (0.6 mL) were mixed and reacted at 70 °C for 30 min. Sodium triacetoxyborohydride (153 mg) was added and the reaction was continued at 70 °C for 2 h. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The combined organic phase was washed with water, saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 92:8) to give 110 mg of compound 4.

[0462] MS (ESI, [M+H] + )m / z: 721.46.

[0463] 1H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.08 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.45-6.99 (m, 5H), 6.87-6.80 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.52 (d, J = 8.5 Hz, 2H), 6.47 (dd, J = 8.3, 2.6 Hz, 1H), 6.19 (d, J = 8.4 Hz, 2H), 4.54 (dd, J = 11.8, 5.0 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.66 (s, 2H), 3.27 (ddd, J = 13.1, 5.0, 2.3 Hz, 1H), 3.01-2.96 (m, 2H), 2.96 -2.94 (m, 2H), 2.90 (s, 2H), 2.86 (t, J = 5.5 Hz, 2H), 2.74 (q, J = 5.5 Hz, 2H), 2.61 (t, J = 4.3 Hz, 1H), 2.49-2.43 (m, 1H), 2.18 (dq, J = 13.6, 4.9 Hz, 1H), 2.09 (dd, J = 12.6, 6.4 Hz, 1H), 1.98-1.92 (m, 2H), 1.91 (s, 2H), 1.69 (dd, J = 13.1, 6.0 Hz, 1H), 1.63 (t, J = 5.4 Hz, 2H), 1.54-1.49 (m, 2H), 1.48-1.41 (m, 2H), 1.17 (t, J = 7.1 Hz, 1H).

[0464] Example 5

[0465] Intermediate 3-7 (65 mg), intermediate A-3 (46 mg), sodium acetate (23 mg), 1,2-dichloroethane (2 mL) and isopropanol (0.4 mL) were mixed and reacted at 70 °C for 30 min. Sodium triacetoxyborohydride (92 mg) was added and the reaction was continued at 70 °C for 2 h. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The combined organic phase was washed with water, saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 92:8) to obtain 40 mg of compound 5.

[0466] MS (ESI, [M+H] + )m / z:721.37

[0467] 1H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.08 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.22-7.08 (m, 5H), 6.82 (d, J = 6.6 Hz, 2H), 6.63 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H), 6.52 (d, J = 8.9 Hz, 2H), 6.47 (dd, J = 8.2, 2.7 Hz, 1H), 6.19 (d, J = 8.7 Hz, 2H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.11 (d, J = 5.0 Hz, 1H), 3.75 (s, 2H), 3.27 (dd, J = 14.1, 4.0 Hz, 1H), 2.98 (d, J = 17.0 Hz, 2H), 2.95 (d, J = 5.6 Hz, 2H), 2.92 (d, J = 5.3 Hz, 2H), 2.86 (dd, J = 7.3, 4.3 Hz, 2H), 2.72 (d, J = 5.0 Hz, 2H), 2.58 (t, J = 4.3 Hz, 1H), 2.45 (dd, J = 12.1, 4.4 Hz, 1H), 2.20-2.14 (m, 1H), 2.09 (dd, J = 12.2, 6.4 Hz, 1H), 1.96 (d, J = 12.7 Hz, 2H), 1.91 (s, 2H), 1.69 (d, J = 7.2 Hz, 1H), 1.64 (s, 2H), 1.56-1.50 (m, 2H), 1.49-1.44 (m, 2H), 0.84 (t, J = 7.3 Hz, 1H).

[0468] Example 6

[0469] Intermediate 3-7 (130 mg), intermediate A-4 (112 mg) were dissolved in 1,2-dichloroethane (3.5 mL) and isopropanol (3.5 mL), sodium acetate (50 mg), sodium triacetoxyborohydride (183 mg) were added successively, stirred at room temperature for 16 hours under nitrogen protection. Water was added, extracted with dichloromethane, the organic layer was washed with water, saturated brine successively, dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column (dichloromethane:methanol = 7:1) to give 37 mg of compound 6.

[0470] MS (ESI, [M+H] + )m / z: 735.53.

[0471] 1H-NMR (500MHz, DMSO-d6): δ 11.07 (s, 1H), 9.08 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.23-7.07 (m, 4H), 6.89-6.79 (m, 2H), 6.68-6.57 (m, 2H), 6.55-6.44 (m, 3H), 6.19 (d, J = 8.9 Hz, 2H), 4.53 (dd, J = 11.9, 5.0 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.30-3.23 (m, 2H), 3.12 (s, 2H), 3.00 (s, 2H), 2.95 (d, J = 5.5 Hz, 3H), 2.89-2.83 (m, 2H), 2.82-2.70 (m, 1H), 2.65-2.50 (m, 7H), 2.46 (dd, J = 12.4, 4.3 Hz, 1H), 2.22-2.03 (m, 2H), 1.90 (d, J = 11.6 Hz, 3H), 1.71 (d, J = 5.6 Hz, 1H), 1.64-1.57 (m, 2H), 1.53-1.46 (m, 2H), 1.42-1.30 (m, 2H).

[0472] Example 7

[0473] Intermediate B-3 (112 mg), intermediate A-2 (100 mg) were dissolved in 1,2-dichloroethane (4 mL) and isopropanol (4 mL), sodium acetate (45 mg), sodium triacetoxyborohydride (173 mg) were added successively, stirred at room temperature for 16 hours under nitrogen protection. Water was added, extracted with dichloromethane, the organic layer was washed successively with water, saturated brine, dried over anhydrous sodium sulfate. Filtration under suction, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column (dichloromethane:methanol = 10:1) to obtain 60 mg of compound 7.

[0474] MS (ESI, [M+H] + )m / z: 667.36.

[0475] 1H-NMR (500 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.09 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.22-7.03 (m, 3H), 6.83 (d, J = 7.3 Hz, 2H), 6.71-6.40 (m, 5H), 6.21 (d, J = 8.5 Hz, 2H), 4.59 (dd, J = 12.0, 5.0 Hz, 1H), 4.13 (s, 3H), 4.02 (s, 2H), 3.53 (d, J = 12.8 Hz, 2H), 3.27 (s, 1H), 3.10-2.86 (m, 2H), 2.80-2.65 (m, 1H), 2.63 (d, J = 5.2 Hz, 3H), 2.55 (d, J = 11.4 Hz, 3H), 2.29-2.03 (m, 2H), 1.82 (d, J = 13.1 Hz, 2H), 1.77-1.53 (m, 2H), 1.36-1.05 (m, 2H).

[0476] Example 8

[0477] Step one:

[0478] A mixture of 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (100 mg), intermediate A-4 (168 mg), sodium acetate (77 mg), sodium triacetoxyborohydride (300 mg), 1,2-dichloroethane (3.5 mL) and isopropanol (3.5 mL) was stirred at room temperature for 16 hours under nitrogen protection. Water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane:methanol = 20:1) to give 130 mg of intermediate 8-1.

[0479] MS (ESI, [M+H] + )m / z: 497.37.

[0480] 1H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.54 (dd, J = 12.0, 4.9 Hz, 1H), 3.94 (d, J = 12.8 Hz, 2H), 3.14 (s, 2H), 3.03 (s, 2H), 2.82-2.65 (m, 2H), 2.63-2.53 (m, 5H), 2.46 (dd, J = 12.3, 4.4 Hz, 1H), 2.31 (s, 2H), 2.22-2.13 (m, 1H), 1.73 (d, J = 12.3 Hz, 3H), 1.40 (s, 10H), 0.98 (d, J = 11.9 Hz, 2H).

[0481] Step two:

[0482] Intermediate 8-1 (130 mg), 1,4-dioxane (1.5 mL) and 4 M hydrochloric acid in dioxane (3.5 mL) were mixed, and the reaction was stirred at room temperature for 2 h. The reaction was directly concentrated to give 100 mg of intermediate 8-2.

[0483] MS (ESI, [M+H] + )m / z: 397.32.

[0484] Step three:

[0485] Intermediate B-1 (50 mg), intermediate 8-2 (65 mg), sodium acetate (21 mg), sodium triacetoxyborohydride (80 mg), 1,2-dichloroethane (2 mL) and isopropanol (2 mL) were mixed, and the reaction was stirred at room temperature for 16 h under nitrogen protection. Water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane:methanol = 6:1) to give 15 mg of compound 8.

[0486] MS (ESI, [M+H] + )m / z: 778.53.

[0487] 1H-NMR (500 MHz, CD3OD): δ 7.39 (d, J = 8.1 Hz, 1H), 7.09-6.98 (m, 4H), 6.61-6.81 (m, 2H), 6.63-6.48 (m, 4H), 6.41 (dd, J = 8.3, 2.7 Hz, 1H), 6.22 (d, J = 8.7 Hz, 2H), 4.50-4.31 (m, 1H), 4.08 (d, J = 5.2 Hz, 1H), 3.60 (d, J = 11.0 Hz, 2H), 3.39 (d, J = 12.1 Hz, 2H), 3.26-3.22 (m, 1H), 3.16 (dd, J = 6.9, 3.3 Hz, 2H), 3.01 (dd, J = 6.6, 3.4 Hz, 3H), 2.98-2.80 (m, 4H), 2.77-2.67 (m, 2H), 2.66 -2.51 (m, 6H), 2.50-2.39 (m, 1H), 2.34 (d, J = 7.0 Hz, 2H), 2.23-2.28 (m, 1H), 2.19-2.08 (m, 1H), 2.06-1.95 (m, 4H), 1.93-1.78 (m, 1H), 1.75-1.62 (m, 3H), 1.40-1.25 (m, 2H).

[0488] Example 9

[0489] Step one:

[0490] (S)-1-Boc-3-hydroxymethylpyrrolidine (0.5 g) was dissolved in dimethyl sulfoxide (10 ml), 2-iodoxybenzoic acid (0.7 g) was added, and stirring was performed at room temperature for 3 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine water, and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated to obtain 0.42 g of Intermediate 9-1.

[0491] Step two:

[0492] Intermediate A-2 (150 mg), Intermediate 9-1 (194 mg), sodium acetate (80 mg), 1,2-dichloroethane (5 ml), and isopropyl alcohol (1 ml) were mixed, and stirring was performed at room temperature for 30 min. Sodium triacetoxyborohydride (207 mg) was added, and stirring was performed at room temperature for 2 h. Saturated aqueous ammonium chloride solution was added, extraction was performed with dichloromethane, and the organic layer was washed with water and saturated brine water, and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column (dichloromethane:methanol = 98:2) to obtain 160 mg of Intermediate 9-2.

[0493] MS (ESI, [M+H] + )m / z: 455.37

[0494] 1 H-NMR (500MHz, DMSO-d6): δ 11.09 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 4.61-4.58 (m, 1H), 4.19-4.12 (m, 2H), 4.08-4.01 (m, 2H), 3.48-3.45 (m, 1H), 3.38-3.33 (m, 1H), 3.26-3.18 (m, 1H), 3.01-2.96 (m, 1H), 2.82-2.71 (m, 3H), 2.63-2.58 (m, 1H), 2.54 (s, 1H), 2.48-2.35 (m, 1H), 2.23-2.17 (m, 1H), 2.05-1.94 (m, 1H), 1.65-1.52 (m, 1H), 1.40 (s, 9H).

[0495] Step three:

[0496] Intermediate 9-2 (150 mg) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (1 mL) was added dropwise, and stirring was performed at room temperature for 2 h. The reaction solution was directly concentrated to obtain 150 mg of intermediate 9-3.

[0497] MS (ESI, [M+H] + )m / z: 355.29

[0498] Step four:

[0499] Intermediate B-1 (100 mg), intermediate 9-3 (140 mg), sodium acetate (41.3 mg), 1,2-dichloroethane (5 ml), isopropyl alcohol (1 ml), and N,N-dimethylacetamide (1 mL) were mixed, and reaction was performed at 60 °C for 20 min. Sodium triacetoxyborohydride (107 mg) was added, and reaction was performed at 60 °C for 2 h. Saturated aqueous ammonium chloride solution was added, extraction was performed with dichloromethane, the organic layer was washed with water and saturated brine in turn, and dried over anhydrous sodium sulfate. Filtration under suction, and concentration of the filtrate under reduced pressure, and purification of the residue on a silica gel column (dichloromethane:methanol = 10:1) yielded 58 mg of compound 9.

[0500] 1H-NMR (500 MHz, CDC13): δ 7.55 (t, J = 7.1 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.0 Hz, 3H), 6.80 (d, J = 7.6 Hz, 3H), 6.70 (d, J = 2.6 Hz, 1H), 6.59-6.56 (m, 1H), 6.53 (d, J = 8.3 Hz, 2H), 6.27 (d, J = 8.2 Hz, 2H), 4.33-4.30 (m, 1H), 4.25-4.18 (m, 3H), 4.11-4.08 (s, 3H), 3.60-3.58 (s, 2H), 3.35-3.32 (m, 1H), 3.03-2.99 (m, 4H), 2.85 (s, 2H), 2.78-2.73 (s, 2H), 2.62-2.57 (m, 5H), 2.45 (s, 2H), 2.18-2.14 (m, 3H), 2.06-2.02 (m, 3H), 1.26 (s, 2H).

[0501] Example 10

[0502] Step one:

[0503] (R)-1-Boc-3-hydroxymethylpyrrolidine (0.5 g) was dissolved in dimethyl sulfoxide (10 ml), 2-iodoxybenzoic acid (0.67 g) was added, and stirring was performed at room temperature for 3 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine water, and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was directly concentrated to obtain 0.49 g of Intermediate 10-1.

[0504] Step two:

[0505] Intermediate A-2 (150 mg), Intermediate 10-1 (194 mg), sodium acetate (80 mg), 1,2-dichloroethane (5 ml), and isopropyl alcohol (1 ml) were mixed, and stirring was performed at room temperature for 30 min. Sodium triacetoxyborohydride (207 mg) was added, and stirring was performed at room temperature for 2 h. Saturated aqueous ammonium chloride solution was added, extraction was performed with dichloromethane, and the organic layer was washed with water, saturated brine water, and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The residue was purified with a silica gel column (dichloromethane:methanol = 98:2) to obtain 161 mg of Intermediate 10-2.

[0506] MS (ESI, [M+H] + )m / z: 455.37

[0507] 1H-NMR (500 MHz, DMSO-d6): δ 11.08 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 4.61-4.58 (m, 1H), 4.19-4.15 (m, 2H), 4.08-4.04 (m, 2H), 3.48-3.45 (m, 1H), 3.40-3.33 (m, 1H), 3.24-3.20 (m, 1H), 2.99-2.95 (m, 1H), 2.82-2.68 (m, 3H), 2.63-2.58 (m, 1H), 2.54 (s, 1H), 2.48-2.44 (m, 1H), 2.23-2.17 (m, 1H), 1.99 (s, 1H), 1.64-1.53 (m, 1H), 1.40 (s, 9H).

[0508] Step three:

[0509] Intermediate 10-2 (150 mg) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated to obtain 260 mg of intermediate 10-3.

[0510] MS (ESI, [M+H] + )m / z: 355.29

[0511] Step four:

[0512] Intermediate B-1 (140 mg), intermediate 10-3 (190 mg), sodium acetate (57.8 mg), 1,2-dichloroethane (5 ml), isopropyl alcohol (1 ml), and N,N-dimethylacetamide (1 mL) were added successively, and the mixture was mixed at 60°C for 20 min. Sodium triacetoxyborohydride (149 mg) was added, and the mixture was stirred at 60°C for 1 h. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 100 mg of compound 10.

[0513] 1H-NMR (500 MHz, CDC13): δ 7.55-7.51 (m, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 6.6 Hz, 3H), 6.83-6.77 (m, 3H), 6.69 (s, 1H), 6.55 (t, J = 9.3 Hz, 3H), 6.27 (d, J = 8.1 Hz, 2H), 4.31 (s, 1H), 4.26-4.15 (m, 3H), 4.15-4.01 (m, 3H), 3.55 (s, 2H), 3.36-3.29 (m, 1H), 3.02-2.96 (m, 4H), 2.80 (s, 4H), 2.60-2.58 (m, 5H), 2.44 (s, 2H), 2.14 (s, 3H), 2.14-1.80 (m, 3H), 1.27 (d, J = 7.6 Hz, 2H).

[0514] Example 11

[0515] Step one:

[0516] The intermediate A-5-1 (15.6 g) was dissolved in dichloromethane (100 mL), 4N hydrogen chloride dioxane solution (105 mL) was added, and stirring was performed at room temperature for 2 h. The reaction solution was directly concentrated to obtain 12.5 g of the intermediate A-5.

[0517] 1 H-NMR (500 MHz, DMSO-d6): δ 11.12 (s, 1H), 10.20 (s, 2H), 7.86 (s, 1H), 7.80 (s, 1H), 4.68-4.53 (m, 5H), 2.81 (td, J = 12.2, 6.2 Hz, 1H), 2.62 (dt, J = 17.5, 4.1 Hz, 1H), 2.47 (dd, J = 12.5, 4.3 Hz, 1H), 2.25-2.17 (m, 1H).

[0518] Step two:

[0519] The intermediate A-5 (120 mg) was dissolved in 1,2-dichloroethane (5 mL) and isopropyl alcohol (1 mL), and the intermediate 1-Boc-3-azetidinone (164 mg) and sodium acetate (72.6 mg) were sequentially added, and stirring was performed at room temperature for 30 min. Sodium triacetoxyborohydride (188 mg) was added, and stirring was performed at room temperature for 2 h. Saturated aqueous ammonium chloride solution was added, and extraction was performed with dichloromethane, and the organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtration under suction, and concentration of the filtrate under reduced pressure, and purification of the residue on a silica gel column (dichloromethane:methanol = 98:2) were performed to obtain 130 mg of the intermediate 11-1.

[0520] 1 H-NMR (500MHz, DMSO-d6): δ 11.07 (s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 4.54 (dd, J = 11.9, 5.0 Hz, 1H), 3.92 (s, 4H), 3.87 (s, 2H), 3.56 (s, 2H), 2.89 (d, J = 7.6 Hz, 2H), 2.79-2.76 (m, 2H), 2.62-2.59 (m, 1H), 2.48-2.45 (m, 1H), 2.21-2.16 (m, 1H), 1.38 (s, 9H).

[0521] Step three:

[0522] Intermediate 11-1 (75 mg) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated to obtain 130 mg of intermediate 11-2.

[0523] MS (ESI, [M+H] + )m / z: 341.23

[0524] Step four:

[0525] Intermediate B-1 (50 mg), intermediate 11-2 (130 mg), sodium acetate (20.64 mg), 1,2-dichloroethane (2.5 ml), isopropyl alcohol (1 ml), and N,N-dimethylacetamide (0.5 mL) were mixed, and the mixture was reacted at 60 °C for 20 min. Sodium triacetoxyborohydride (60.8 mg) was added, and the mixture was reacted at 60 °C for 2 h. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 43 mg of compound 11.

[0526] MS (ESI, [M+H] + )m / z: 722.37

[0527] 1H-NMR (500MHz, DMSO-d6): δ 11.07 (s, 1H), 9.10 (s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.16-7.10 (m, 3H), 6.83 (d, J = 7.3 Hz, 2H), 6.66-6.59 (m, 2H), 6.54 (d, J = 8.3 Hz, 2H), 6.48 (dd, J = 8.4, 2.6 Hz, 1H), 6.21 (d, J = 8.2 Hz, 2H), 4.56-4.53 (m, 1H), 4.13 (d, J = 5.0 Hz, 1H), 3.92-3.87 (m, 3H), 3.51 (s, 2H), 3.02-2.85 (m, 4H), 2.80-2.73 (m, 2H), 2.51-2.47 (m, 8H), 2.21-2.16 (m, 1H), 2.11-2.07 (m, 1H), 1.78-1.74 (m, 3H), 1.37-1.16 (m, 5H).

[0528] Example 12

[0529] Step one:

[0530] Intermediate A-3 (200 mg), 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (199 mg), sodium acetate (76 mg), 1,2-dichloroethane (10 mL) and isopropanol (2 mL) were mixed and reacted at 25 °C for 30 min. Sodium triacetoxyborohydride (395 mg) was added and the reaction was continued at 25 °C for 3 h. Saturated aqueous sodium bicarbonate solution was added and the organic phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to obtain 259 mg of intermediate 12-1.

[0531] MS (ESI, [M+H] + )m / z: 483.39

[0532] 1H-NMR (500 MHz, DMSO-d6): δ 11.10 (s, 1H), 10.06 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 4.77 (s, 1H), 4.61 (dd, J = 12.2, 5.0 Hz, 1H), 4.48 (s, 1H), 3.95 (d, J = 13.1 Hz, 2H), 3.84 (s, 1H), 3.33 (s, 2H), 3.19 (s, 2H), 2.84 - 2.79 (m, 1H), 2.77 (dd, J = 12.1, 5.3 Hz, 2H), 2.66 - 2.58 (m, 1H), 2.54 (dd, J = 12.7, 4.4 Hz, 1H), 2.24 - 2.17 (m, 1H), 2.13 (s, 1H), 1.78 (s, 2H), 1.40 (s, 9H), 1.16 - 1.04 (m, 2H).

[0533] Step two:

[0534] Intermediate 12-1 (259 mg), 1,4-dioxane (2 mL) and 4 M hydrochloric acid in dioxane (2 mL) were mixed and reacted at 25 °C for 6 h. The reaction solution was directly concentrated to give 169 mg of intermediate 12-2.

[0535] MS (ESI, [M+H] + )m / z: 383.30

[0536] 1 H-NMR (500 MHz, DMSO-d6): δ 11.55 (s, 1H), 11.11 (s, 1H), 9.26 - 9.12 (m, 1H), 9.05 (m, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.76 (m, 1H), 4.63 (m, 1H), 4.45 (dd, J = 16.2, 6.5 Hz, 1H), 3.79 (dd, J = 11.5, 6.0 Hz, 1H), 3.48 (d, J = 19.5 Hz, 2H), 3.30 - 3.25 (m, 2H), 3.18 (tt, J = 13.6, 6.4 Hz, 2H), 2.91 - 2.83 (m, 2H), 2.78 (m, 1H), 2.62 (m, 1H), 2.30 (s, 1H), 2.23 - 2.16 (m, 1H), 2.12 (d, J = 13.9 Hz, 1H), 2.05 (d, J = 13.8 Hz, 1H), 1.57 - 1.46 (m, 2H).

[0537] Step three:

[0538] Intermediate 12-2 (85 mg), intermediate B-1 (80 mg), sodium acetate (66 mg) and N,N-dimethylacetamide (2 mL) were mixed and reacted at 60 °C for 30 min. Sodium cyanoborohydride (50 mg) was added and the reaction was continued at 60 °C for 2 h. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 92:8) to give 48 mg of compound 12.

[0539] MS (ESI, [M+H] + m / z: 764.42

[0540] 1 H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.10 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.12 (dd, J = 10.5, 7.0 Hz, 3H), 7.08 (d, J = 8.3 Hz, 1H), 6.85-6.81 (m, 2H), 6.63 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.57 (d, J = 8.3 Hz, 2H), 6.48 (dd, J = 8.3, 2.5 Hz, 1H), 6.22 (d, J = 8.3 Hz, 2H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.14 (d, J = 5.0 Hz, 1H), 3.70 (s, 4H), 3.47 (s, 2H), 3.28 (s, 1H), 2.98 (dd, J = 15.1, 7.6 Hz, 6H), 2.77 (d, J = 5.2 Hz, 3H), 2.61 (d, J = 4.4 Hz, 1H), 2.57 (dd, J = 11.9, 7.8 Hz, 2H), 2.52 (s, 1H), 2.38 (d, J = 6.4 Hz, 2H), 2.21-2.15 (m, 1H), 2.08 (dd, J = 12.4, 6.3 Hz, 1H), 1.98 (d, J = 1.3 Hz, 3H), 1.90 (s, 2H), 1.76-1.52 (m, 4H), 1.33 (s, 2H).

[0541] Example 13

[0542] Step one:

[0543] Intermediate C-1 (200 mg), 4-piperidone ethylene glycol (130 mg), sodium tert-butoxide (174 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (42 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl methanesulfonic acid (2-amino-1,1'-biphenyl-2-yl)palladium (76 mg) and dioxane (5 mL) were mixed and the reaction was heated by microwave at 110 °C for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated brine successively, and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to give 88 mg of intermediate 13-1.

[0544] MS (ESI, [M+H] + )m / z: 505.28

[0545] 1 H-NMR (500 MHz, DMSO-d6): δ 13.06-12.86 (m, 1H), 8.06 (s, 1H), 7.24-7.22 (m, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.56 (d, J = 13.5 Hz, 2H), 6.01-5.59 (m, 1H), 5.16 (s, 1H), 3.90 (s, 4H), 3.49-3.45 (m, 1H), 3.31 (d, J = 3.7 Hz, 4H), 3.19 (dd, J = 16.6, 4.9 Hz, 1H), 3.12-2.96 (m, 1H), 2.89 (dd, J = 16.5, 5.4 Hz, 1H), 2.71-2.61 (m, 1H), 1.75-1.57 (m, 4H), 1.05 (d, J = 6.5 Hz, 3H).

[0546] Step two:

[0547] Intermediate 13-1 (80 mg), 2M sulfuric acid aqueous solution (0.5 mL) and tetrahydrofuran (1 mL) were mixed and stirred at 70 °C for 2 h. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated brine successively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give 55 mg of intermediate 13-2.

[0548] MS (ESI, [M+H] + )m / z: 461.33

[0549] Step three:

[0550] Intermediate 2-2 (85 mg), intermediate 13-2 (80 mg), sodium acetate (66 mg), 1,2-dichloroethane (10 mL) and isopropanol (2 mL) were mixed and reacted at 60 °C for 30 min. Sodium triacetoxyborohydride (50 mg) was added and the reaction was continued at 60 °C for 2 h. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 92:8) to give 40 mg of compound 13.

[0551] MS (ESI, [M+H] + )m / z: 771.34

[0552] 1 H-NMR (500 MHz, DMSO-d6): δ 12.97 (s, 1H), 11.08 (s, 1H), 8.06 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.53 (d, J = 13.3 Hz, 2H), 5.86-5.74 (m, 1H), 5.16 (s, 1H), 4.60 (dd, J = 11.9, 5.0 Hz, 1H), 4.16 (s, 2H), 4.05 (d, J = 2.6 Hz, 2H), 3.62-3.59 (m, 2H), 3.58-3.52 (s, 1H), 3.49-3.44 (m, 2H), 3.25-2.95 (m, 4H), 2.94-2.79 (m, 3H), 2.79-2.71 (m, 1H), 2.71-2.55 (m, 2H), 2.55-2.51 (m, 1H), 2.49-2.46 (m, 1H), 2.38-2.14 (m, 2H), 1.81-1.62 (m, 2H), 1.26-1.21 (m, 2H), 1.05 (d, J = 6.5 Hz, 3H).

[0553] Example 14

[0554] Step one:

[0555] Intermediate C-2-1 (400 mg), dichloromethane (1 mL) and 4 M hydrochloric acid in dioxane (7 mL) were mixed and stirred at room temperature for 1 h. The solvent was evaporated by distillation to give 460 mg of intermediate C-2.

[0556] MS (ESI, [M+H] + )m / z: 516.34.

[0557] Step two:

[0558] Intermediate A-2 (200 mg), acetonitrile (5 mL) and N,N-diisopropyl ethylamine (280 mg) were mixed, and tert-butyl bromoacetate (170 mg) was added. The reaction was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column (dichloromethane:methanol = 15:1) to obtain 186 mg of intermediate 14-1.

[0559] MS (ESI, [M+H] + )m / z: 386.32.

[0560] 1 H-NMR (500MHz, DMSO-d6): δ 11.09 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.60 (dd, J = 11.9, 5.0 Hz, 1H), 4.33 (t, J = 2.6 Hz, 2H), 4.22 (t, J = 2.6 Hz, 2H), 3.58 (s, 2H), 2.85-2.70 (m, 1H), 2.68-2.57 (m, 1H), 2.54-2.51 (m, 1H), 2.29-2.14 (m, 1H), 1.43 (s, 9H).

[0561] Step three:

[0562] Intermediate 14-1 (186 mg) and trifluoroacetic acid (5 mL) were mixed, and the reaction was stirred at room temperature for 4 hours. The solvent was evaporated by concentration to obtain 150 mg of intermediate 14-2.

[0563] MS (ESI, [M+H] + )m / z: 330.14.

[0564] Step four:

[0565] Intermediate 14-2 (186 mg) was dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (192 mg) and N,N-diisopropyl ethylamine (543 mg) were added in sequence. The reaction was stirred at room temperature for 10 minutes. Intermediate C-2 (330 mg) was added, and the reaction was stirred for 12 hours. After stirring for 10 minutes after adding water (10 mL), the filter cake was collected by suction filtration, and the filter cake was purified by C18 reverse phase column (acetonitrile:water = 1:1). The obtained solid was dissolved in dichloromethane (2 mL), and 4M hydrochloric acid in dioxane (5 mL) was slowly added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated by concentration to obtain 50 mg of hydrochloride of compound 14.

[0566] MS (ESI, [M+H] + m / z: 827.48.

[0567] 1 H-NMR (500MHz, DMSO-d6): δ 11.45 (s, 1H), 11.11 (s, 1H), 8.09 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 13.3 Hz, 2H), 5.87 (br s, 1H), 5.31-4.99 (m, 3H), 4.90 (s, 1H), 4.79-4.60 (m, 4H), 3.96-3.90 (m, 2H), 3.56 -3.54 (m, 3H), 3.33-3.22 (m, 7H), 2.96-2.92 (m, 1H), 2.87-2.76 (m, 1H), 2.66-2.62 (m, 1H), 2.56-2.54 (m, 1H), 2.24-2.19 (m, 1H), 1.58-1.46 (m, 8H), 1.25-0.94 (m, 3H).

[0568] Example 15

[0569] Step one:

[0570] Intermediate A-3 (150 mg), tert-butyl bromoacetate (109 mg) were dissolved in acetonitrile (5 mL), potassium carbonate (129 mg) was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column (dichloromethane:methanol = 15:1) to obtain 160 mg of intermediate 15-1.

[0571] MS (ESI, [M+H] + m / z: 400.28

[0572] 1 H-NMR (500MHz, DMSO-d6): δ 11.07 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 3.87 (s, 2H), 3.38 (s, 2H), 3.00-2.91 (m, 4H), 2.76 (ddd, J = 17.3, 11.9, 5.3 Hz, 1H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.53-2.46 (m, 1H), 2.19-2.17 (m, 1H), 1.44 (s, 9H).

[0573] Step two:

[0574] Intermediate 15-1 (160 mg), dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were mixed and stirred at room temperature for 4 h. The solvent was evaporated by concentration to give 230 mg of intermediate 15-2.

[0575] MS (ESI, [M+H] + )m / z: 344.21.

[0576] Step three:

[0577] Intermediate 15-2 (40 mg) was dissolved in N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (33 mg) and N,N-diisopropylethylamine (113 mg) were added successively, and the reaction was stirred at room temperature for 10 min. Intermediate C-2 (72 mg) was added, and the reaction was stirred for 12 h. After stirring in water (10 mL) for 10 min, the filter cake was collected by suction filtration, and the filter cake was purified by high-pressure preparative chromatography (conditions: column: XB-Phenyl, 20 x 250 mm, 5 μm; mobile phase: water (containing 10 mM ammonium acetate): acetonitrile = 1:1, flow rate: 20 mL / min) to give 25 mg of compound 15.

[0578] MS (ESI, [M+H] + )m / z: 841.49.

[0579] 1H-NMR (500 MHz, DMSO-d6): δ 12.96 (s, 1H), 11.07 (s, 1H), 8.05 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 13.9 Hz, 2H), 5.79 (t, J = 56.3 Hz, 1H), 5.15 (s, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 3.78 (s, 2H), 3.49 (d, J = 21.4 Hz, 5H), 3.40 (s, 2H), 3.25 - 3.08 (m, 6H), 3.01 (q, J = 9.9 Hz, 3H), 2.95 - 2.81 (m, 3H), 2.76 (ddd, J = 17.2, 11.9, 5.3 Hz, 1H), 2.69 - 2.55 (m, 2H), 2.18 (dd, J = 13.4, 5.0 Hz, 1H), 1.51 (t, J = 5.7 Hz, 4H), 1.41 (d, J = 15.8 Hz, 4H), 1.04 (d, J = 6.5 Hz, 3H).

[0580] Example 16

[0581] Step one:

[0582] Intermediate A-1 (183 mg), tert-butyl bromoacetate (150 mg) were dissolved in acetonitrile (5 mL), N,N-diisopropylethylamine (250 mg) was added, and the reaction was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column (dichloromethane:methanol = 15:1) to obtain 255 mg of intermediate 16-1.

[0583] MS (ESI, [M+H] + )m / z: 400.30.

[0584] 1 H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 3.97 (s, 2H), 3.42 (s, 2H), 3.00 - 2.93 (m, 2H), 2.90 (d, J = 4.9 Hz, 2H), 2.80 - 2.70 (m, 2H), 2.68 - 2.53 (m, 2H), 1.45 (s, 9H).

[0585] Step two:

[0586] Intermediate 16-1 (255 mg), dichloromethane (3 mL) and trifluoroacetic acid (771 mg) were mixed and stirred at room temperature for 4 h. The solvent was evaporated by concentration to give 220 mg of intermediate 16-2.

[0587] MS (ESI, [M-H] - )m / z: 342.06.

[0588] Step three:

[0589] Intermediate 16-2 (220 mg) was dissolved in N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (220 mg) and N,N-diisopropylethylamine (827 mg) were added successively, and the reaction was stirred at room temperature for 10 min. Intermediate C-2 (330 mg) was added, and the reaction was stirred for 12 h. After stirring for 10 min after adding water (10 mL), the filter cake was collected by suction filtration, and the filter cake was purified with a C18 reverse phase column (acetonitrile: water = 1: 1) to give 86 mg of compound 16.

[0590] MS (ESI, [M+H] + )m / z: 841.46.

[0591] 1 H-NMR (500MHz, DMSO-d6): δ 12.96 (s, 1H), 11.08 (s, 1H), 8.05 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.32-7.11 (m, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.50 (d, J = 13.1 Hz, 2H), 6.00-5.64 (m, 1H), 5.15 (s, 1H), 4.56 (dd, J = 12.0, 5.0 Hz, 1H), 3.90 (s, 2H), 3.62-3.41 (m, 7H), 3.26-3.10 (m, 5H), 3.08-2.93 (m, 3H), 2.92-2.81 (m, 3H), 2.79-2.73 (m, 1H), 2.71-2.57 (m, 2H), 2.46 (dd, J = 12.2, 4.1 Hz, 1H), 2.26-2.14 (m, 1H), 1.71-1.50 (t, J = 6.0 Hz, 4H), 1.50-1.38 (m, 4H), 1.04 (d, J = 6.6 Hz, 3H).

[0592] Example 17

[0593] Step one:

[0594] Intermediate C-1 (1 g), N-tert-butoxycarbonyl-piperazine (0.844 g), (2- dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(0) (0.38 g), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (0.212 g), sodium tert-butoxide (0.868 g) and 1,4-dioxane (40 mL) were mixed and reacted under nitrogen atmosphere at 100 °C in an oil bath for 4 hours. After cooling to room temperature, the mixture was filtered through celite, the filtrate was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic phase was concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to give 1.17 g of intermediate 17-1.

[0595] MS (ESI, [M+H]+) m / z: 548.19.

[0596] 1 H-NMR (500 MHz, CDC13): δ 10.06 (s, 1H), 8.08-8.04 (m, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.36-6.29 (m, 2H), 5.55 (dd, J = 5.7, 3.2 Hz, 1H), 5.25 (s, 1H), 3.55 (t, J = 5.3 Hz, 4H), 3.42 (dd, J = 16.1, 5.0 Hz, 1H), 3.14 (t, J = 5.3 Hz, 4H), 3.06-2.95 (m, 1H), 2.91 (dd, J = 16.1, 4.5 Hz, 1H), 2.85-2.72 (m, 1H), 1.48 (s, 9H), 1.12 (d, J = 6.6 Hz, 3H).

[0597] Step two:

[0598] Intermediate 17-1 (1.17 g) was dissolved in a mixture of dichloromethane (10 mL) and trifluoroacetic acid (2 mL) and reacted at room temperature for 1 hour. The solvent was directly evaporated to give 0.5 g of intermediate 17-2.

[0599] MS (ESI, [M+H]+) m / z: 448.31.

[0600] 1H-NMR (500 MHz, CDC13): δ 8.06 (s, 1H), 7.18 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.32 (d, J = 12.5 Hz, 2H), 5.71-5.39 (m, 1H), 5.25 (s, 1H), 3.57 (q, J = 5.7 Hz, 1H), 3.42 (dd, J = 16.2, 5.0 Hz, 1H), 3.14 (dd, J = 6.6, 3.8 Hz, 3H), 3.00 (t, J = 5.1 Hz, 4H), 2.91 (dd, J = 16.2, 4.6 Hz, 1H), 2.86-2.71 (m, 1H), 1.69 (s, 3H), 1.32-1.23 (m, 1H), 1.12 (d, J = 6.5 Hz, 3H).

[0601] Step three:

[0602] Intermediate 14-2 (150 mg) was dissolved in N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (170 mg) and N,N-diisopropylethylamine (588 mg) were added successively, and the reaction was stirred at room temperature for 10 min. Intermediate 17-2 (204 mg) was added, and the reaction was stirred for 12 h. Water (10 mL) was added, and after stirring for 10 min, the filter cake was collected by suction filtration and purified by high-pressure preparative chromatography (chromatography column: Ultimate Polar RP, 21.2*250 mm, 5 μm; mobile phase: water (containing 10 mM ammonium acetate): acetonitrile = 1:1; flow rate: 20 mL / min) to obtain a solid, which was dissolved in dichloromethane (1 mL), 4M hydrochloric acid in dioxane (5 mL) was slowly added, and the mixture was stirred at room temperature for 1 h. The solvent was removed by concentration and evaporation to obtain 40 mg of the hydrochloride salt of compound 17.

[0603] MS (ESI, [M+H] + )m / z: 759.38.

[0604] 1H-NMR (500MHz, DMSO-d6): δ11.60(s,1H),11.10(s,1H),8.08(s,1H),7.92(d,J=8.2Hz,1H),7.47(d,J=8 .4Hz,1H),7.25(d,J=7.5Hz,1H),6.83-6.41(m,3H),5.43-5.00(m,3H),4.92(s,1H),4.72(s,3H),4.66( dd,J=12.2,5.0Hz,1H),3.73-3.61(m,3H),3.59-3.42(m,4H),3.29(t,J=5.5Hz,5H),2.96(s,1H),2.83- 2.63(m,2H),2.69-2.60(m,1H),2.55(dd,J=12.6,4.3Hz,1H),2.20(dd,J=8.7,4.1Hz,1H),1.11(s,3H).

[0605] Example 18

[0606] Step 1:

[0607] Intermediate 17-2 (221 mg), potassium carbonate (137 mg), and N,N-dimethylformamide (5 mL) were mixed, and tert-butyl bromoacetate (96 mg) was added. The reaction was continued at room temperature for 2 h. The mixture was poured into water (5 mL), stirred for 30 min, filtered, and the filter cake was washed with water (5 mL) and dried to obtain 161 mg of intermediate 18-1.

[0608] Step Two:

[0609] Intermediate 18-1 (161 mg) and trifluoroacetic acid (5 mL) were mixed and reacted at room temperature for 2 h. The mixture was then concentrated to give 130 mg of intermediate 18-2.

[0610] Step 3:

[0611] Intermediate 18-2 (60 mg), intermediate A-2 (32 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (58 mg), N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (160 mg) were mixed and reacted at room temperature for 6 h. Water was added, and the mixture was extracted with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 92:8). The resulting solid was dissolved in dichloromethane (1 mL), and a 4M hydrochloric acid solution of dioxane (1 mL) was slowly added. The mixture was stirred at room temperature for 30 min. The mixture was filtered, and the filter cake was washed with n-hexane (2 mL) and dried to give 23 mg of the hydrochloride salt of compound 18.

[0612] MS (ESI, [M+H] + m / z: 759.30

[0613] 1 H-NMR (500MHz, DMSO-d6): δ 11.12 (s, 1H), 10.53 (s, 1H), 8.09 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.2, 2.6 Hz, 1H), 7.24 (dd, J = 18.9, 8.5 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 13.1 Hz, 2H), 5.16 (s, 1H), 5.03 (d, J = 9.7 Hz, 2H), 4.93 (s, 1H), 4.66 (ddd, J = 12.0, 4.9, 2.3 Hz, 1H), 4.49 (d, J = 12.1 Hz, 2H), 3.92 (s, 3H), 3.82 (s, 1H), 3.64-3.58 (m, 3H), 3.57 (s, 1H), 3.29 (s, 4H), 2.95 (d, J = 10.1 Hz, 1H), 2.84-2.71 (m, 2H), 2.65 (t, J = 4.3 Hz, 1H), 2.62-2.53 (m, 1H), 2.25-2.17 (m, 1H), 2.05-1.95 (m, 1H), 1.10 (s, 3H).

[0614] Example 19

[0615] Step one:

[0616] Intermediate A-2 (200 mg) was dissolved in 1,2-dichloroethane (10 mL) and isopropyl alcohol (2 mL), and 3-formylazetidine-1-carboxylic acid tert-butyl ester (241 mg) and sodium acetate (107 mg) were added in turn. After stirring at room temperature for 30 min, sodium triacetoxyborohydride (275 mg) was added, and stirring was performed at room temperature for 2 h. The reaction solution was poured into saturated sodium bicarbonate solution, dichloromethane was added for extraction, and the organic layer was washed with water and saturated brine in turn, and dried over anhydrous sodium sulfate. Filtration under suction, and concentration of the filtrate under reduced pressure, and purification of the residue on a silica gel column (dichloromethane:methanol = 98:2) gave 200 mg of intermediate 19-1.

[0617] MS (ESI, [M+Na] + m / z: 463.32

[0618] Step two:

[0619] Intermediate 19-1 (200 mg) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (3 ml) was added dropwise, and stirred at room temperature for 2 h. Concentration under reduced pressure gave 300 mg of intermediate 19-2.

[0620] MS (ESI, [M+H] + )m / z: 341.25

[0621] Step three:

[0622] Intermediate B-1 (70 mg), intermediate 19-2 (113 mg), sodium acetate (57.8 mg), 1,2-dichloroethane (10 ml) and isopropanol (2 ml) were mixed and reacted at 60 °C for 20 min. Sodium triacetoxyborohydride (74.6 mg) was added and reacted at 60 °C for 2 h. The reaction solution was poured into saturated sodium bicarbonate solution, dichloromethane was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Filtration under suction, and concentration of the filtrate under reduced pressure gave a residue, which was purified by silica gel column (dichloromethane:methanol = 10:1) to give 94 mg of compound 19.

[0623] HRMS (ESI, [M+H] + )m / z: 722.3724

[0624] 1 H-NMR (500 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.09 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.16-7.07 (m, 3H), 6.83 (d, J = 7.2 Hz, 2H), 6.64 (d, J = 8.2 Hz, 1H), 6.60 (s, 1H), 6.53 (d, J = 8.7 Hz, 2H), 6.49-6.47 (m, 1H), 6.20 (d, J = 8.7 Hz, 2H), 4.61-4.57 (m, 1H), 4.11 (s, 3H), 4.05-4.01 (m, 2H), 3.43-3.40 (m, 3H), 3.27-3.17 (m, 4H), 3.00-2.91 (m, 5H), 2.80-2.73 (m, 1H), 2.73-2.63 (m, 1H), 2.62-2.55 (m, 4H), 2.21-2.18 (m, 1H), 2.14-2.05 (m, 1H), 1.71-1.69 (m, 3H), 1.25-1.19 (s, 2H).

[0625] Example 20

[0626] Step one:

[0627] A mixture of 1-benzyloxycarbonylazetidin-3-one (5 g), 4-(dimethoxymethyl)- piperidine (5.82 g), glacial acetic acid (0.59 g) and 1,2-dichloroethane (100 ml) was stirred at room temperature for 20 minutes, then sodium triacetoxyborohydride (10.33 g) was added and the reaction was stirred at room temperature for 1 hour. The reaction was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate (50 ml). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to give 2.5 g of intermediate 20-1.

[0628] MS (ESI, [M+H] + )m / z: 349.25

[0629] 1 H-NMR (500MHz, DMSO-d6): δ 7.39-7.29 (m, 5H), 5.02 (s, 2H), 4.02 (d, J = 6.9 Hz, 1H), 3.91 (brs, 2H), 3.72 (brs, 2H), 3.23 (s, 6H), 3.07-3.00 (m, 1H), 2.78-2.70 (m, 2H), 1.73-1.67 (m, 2H), 1.63-1.57 (m, 2H), 1.55-1.48 (m, 1H), 1.23-1.13 (m, 2H).

[0630] Step two:

[0631] A mixture of intermediate 20-1 (2 g) was dissolved in methanol (60 ml), 10% palladium-carbon (0.4 g) was added and the reaction was stirred at 40°C under hydrogen atmosphere for 12 hours. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure to give 1.1 g of intermediate 20-2.

[0632] HRMS (ESI, [M+H] + )m / z: 215.1754

[0633] Step three:

[0634] A mixture of intermediate B-2 (1 g), intermediate 20-2 (0.62 g), tris(dibenzylideneacetone)dipalladium (0.13 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.169 g), cesium carbonate (0.95 g) and 1,4-dioxane (50 ml) was stirred at 120°C under nitrogen atmosphere for 12 hours. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to give 0.71 g of intermediate 20-3.

[0635] MS (ESI, [M+H] +m / z: 601.42

[0636] Step four:

[0637] Intermediate 20-3 (0.56 g) was dissolved in methanol (6 mL) and tetrahydrofuran (6 ml), 10% palladium carbon (0.1 g) was added, the reaction was stirred at 40 °C for 5 days under hydrogen atmosphere. Celite was filtered, the filtrate was concentrated under reduced pressure, the residue was separated by chiral HPLC (column: CHIRALPAK IG, 30 x 250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:3): n-hexane = 26:74; flow rate: 40 mL / min) to give 246 mg of intermediate 20-4.

[0638] Intermediate 20-4: R t = 3.094 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia water) = 50:50; flow rate: 2.0 ml / min; column temperature: 40 °C).

[0639] MS (ESI, [M+H] + )m / z: 513.00

[0640] Step five:

[0641] Intermediate 20-4 (120 mg), 2M aqueous sulfuric acid (5 ml) and tetrahydrofuran (2.5 ml) were mixed, the reaction was stirred at 70 °C for 2 hours. The reaction was poured into saturated sodium bicarbonate solution, ethyl acetate (50 mL) was added to extract, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure to give 100 mg of intermediate 20-5.

[0642] MS (ESI, [M+H] + )m / z: 467.42

[0643] Step six:

[0644] Intermediate A-2 (50 mg), intermediate 20-4 (91 mg), sodium acetate (26.7 mg), 1,2-dichloroethane (2.5 ml) and isopropanol (0.5 ml) were mixed, the reaction was stirred at room temperature for 20 minutes, then sodium triacetoxyborohydride (68.9 mg) was added, the reaction was stirred at room temperature for 2 hours. The reaction was poured into saturated sodium bicarbonate solution, dichloromethane was added to extract, the organic layer was washed with water, saturated brine successively, dried over anhydrous sodium sulfate. Suction filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column (dichloromethane:methanol = 10:1) to give 87 mg of compound 20.

[0645] HRMS (ESI, [M+H]+) calcd for C48H53F2N7O8 948.3950, found 948.3950. + ) m / z: 722.3717

[0646] 1 H-NMR (500MHz, DMSO-d6): δ 11.08 (s, 1H), 9.08 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.18-7.09 (m, 3H), 6.82 (d, J = 6.9 Hz, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.60-6.58 (m, 1H), 6.51-6.44 (m, 1H), 6.17 (d, J = 8.7 Hz, 2H), 6.04 (d, J = 8.5 Hz, 2H), 4.61-4.54 (m, 1H), 4.11-4.08 (m, 3H), 4.00 (s, 2H), 3.81-3.77 (m, 2H), 3.44-3.34 (m, 2H), 3.29-3.25 (m, 1H), 3.15-3.12 (m, 1H), 3.00-2.87 (m, 2H), 2.80-2.73 (m, 3H), 2.63-2.58 (m, 3H), 2.21-2.14 (m, 1H), 2.12-2.01 (m, 1H), 1.87-1.75 (m, 4H), 1.71-1.65 (m, 1H), 1.58-1.49 (m, 1H), 1.33-1.23 (m, 1H), 1.16-1.09 (m, 2H).

[0647] Example 21

[0648] Step one: Preparation of intermediate 21-1

[0649] Intermediate A-4 (220 mg), 3-formylazetidine-1-carboxylic acid tert-butyl ester (182 mg), sodium acetate (107 mg), 1,2-dichloroethane (10 mL) and isopropanol (2 mL) were mixed and reacted at room temperature for 20 minutes. Sodium triacetoxyborohydride (278 mg) was added and reacted at room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate solution was added, extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration under suction, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column (dichloromethane:methanol 97:3) to obtain 300 mg of intermediate 21-1.

[0650] MS (ESI, [M-100+H]+) m / z: 369.32

[0651] Step two: Preparation of intermediate 21-2

[0652] Intermediate 21-1 (350 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated directly to give 450 mg of intermediate 21-2.

[0653] MS (ESI, [M+H] + )m / z: 369.25

[0654] Step three: Preparation of compound 21

[0655] Intermediate B-1 (70 mg), intermediate 21-2 (126 mg), sodium acetate (28.9 mg), 1,2-dichloroethane (5 mL), and isopropanol (1 mL) were mixed and the reaction was stirred at 60 °C for 20 minutes. Sodium triacetoxyborohydride (74.6 mg) was added and the reaction was stirred at 60 °C for 2 hours. The reaction was completed, saturated sodium bicarbonate solution was added, and the reaction was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane: dichloromethane / methanol (10 / 1) = 80:20) to give 35 mg of compound 21.

[0656] HRMS (ESI, [M+H] + )m / z: 750.4028

[0657] 1 H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.09 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.19-7.09 (m, 4H), 6.85-6.81 (m, 2H), 6.64 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 8.7 Hz, 2H), 6.47 (dd, J = 8.3, 2.6 Hz, 1H), 6.19 (d, J = 8.4 Hz, 2H), 4.53 (dd, J = 11.9, 5.0 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.40-3.34 (m, 3H), 3.31-3.24 (m, 4H), 3.12 (dd, J = 6.8, 3.3 Hz, 2H), 3.03-2.98 (m, 2H), 2.98-2.93 (m, 1H), 2.74-2.69 (m, 2H), 2.67-2.63 (m, 2H), 2.63-2.59 (m, 3H), 2.59-2.54 (m, 5H), 2.48-2.42 (m, 1H), 2.21-2.14 (m, 1H), 2.11-2.00 (m, 2H), 1.72-1.67 (m, 1H), 1.65-1.59 (m, 2H), 1.26-1.22 (m, 2H).

[0658] Example 22

[0659] Step one:

[0660] Intermediate A-3 (200 mg), 3-formylazetidine-1-carboxylic acid tert-butyl ester (173 mg), sodium acetate (102 mg), 1,2-dichloroethane (10 mL) and isopropanol (2 mL) were mixed and reacted at room temperature for 20 minutes. Sodium triacetoxyborohydride (263 mg) was added and reacted at room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate solution was added and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. It was filtered under suction and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane:methanol 97:3) to obtain 270 mg of intermediate 22-1.

[0661] MS (ESI, [M+H]+) m / z: 355.28 + ) m / z: 355.28

[0662] Step two:

[0663] Intermediate 22-1 (260 mg) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated to obtain 300 mg of intermediate 22-2.

[0664] MS (ESI, [M+H]+) m / z: 355.29 + ) m / z: 355.29

[0665] Step three:

[0666] Intermediate B-1 (70 mg), intermediate 22-2 (145 mg), sodium acetate (57.8 mg), 1,2-dichloroethane (5 mL) and isopropanol (1 mL) were mixed and reacted at 60°C for 20 minutes. Sodium triacetoxyborohydride (74.6 mg) was added and reacted at 60°C for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. It was filtered under suction and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane:dichloromethane / methanol (10 / 1) = 0:100) to obtain 65 mg of compound 22.

[0667] HRMS (ESI, [M+H]+) m / z: 736.3881 + ) m / z: 736.3881

[0668] 1H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.11 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.18-7.06 (m, 4H), 6.87-6.79 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 8.3 Hz, 2H), 6.48 (dd, J = 8.3, 2.5 Hz, 1H), 6.20 (d, J = 8.3 Hz, 2H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.13 (d, J = 5.0 Hz, 1H), 3.68 (s, 2H), 3.47 (s, 3H), 3.32-3.22 (m, 3H), 3.17 (s, 1H), 3.03-2.91 (m, 4H), 2.84-2.67 (m, 6H), 2.66-2.60 (m, 1H), 2.60-2.56 (m, 1H), 2.56-2.51 (m, 2H), 2.49-2.42 (m, 1H), 2.21-2.15 (m, 1H), 2.12-2.04 (m, 1H), 1.82-1.64 (m, 3H), 1.32-1.24 (m, 2H).

[0669] Example 23

[0670] Step one:

[0671] Intermediate A-5 (200 mg), 3-formylazetidine-1-carboxylic acid tert-butyl ester (241 mg), sodium acetate (107 mg), 1,2-dichloroethane (10 mL) and isopropanol (2 mL) were mixed and reacted at room temperature for 20 minutes. Sodium triacetoxyborohydride (275 mg) was added and reacted at room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate solution was added, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. Filtration under suction, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column (dichloromethane:methanol 97:3) to obtain 220 mg of intermediate 23-1.

[0672] MS (ESI, [M+H]+) at m / z: 385.25 + ) m / z: 385.25

[0673] Step two:

[0674] Intermediate 23-1 (220 mg) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added, and reacted at room temperature for 1 hour. The reaction solution was directly concentrated to obtain 200 mg of intermediate 23-2.

[0675] MS (ESI, [M+H]+) at m / z: 385.25 +m / z: 341.23

[0676] Step three:

[0677] Intermediate B-3 (100 mg), intermediate 23-2 (196 mg), sodium acetate (39.9 mg), 1,2-dichloroethane (5 mL) and isopropanol (1 mL) were mixed and reacted at 60 °C for 20 min. Sodium triacetoxyborohydride (103 mg) was added and the reaction was carried out at room temperature overnight. After the reaction was completed, saturated sodium bicarbonate solution was added and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column (dichloromethane: dichloromethane / methanol (10 / 1) = 0:100) to obtain 15 mg of compound 23.

[0678] HRMS (ESI, [M+H] + m / z: 736.3861

[0679] 1 H-NMR (500MHz, DMSO-d6): δ 11.07 (s, 1H), 9.09 (s, 1H), 7.67-7.53 (m, 2H), 7.16-7.09 (m, 3H), 6.82 (d, J = 7.3 Hz, 2H), 6.64 (d, J = 8.3 Hz, 1H), 6.59 (s, 1H), 6.51 (d, J = 8.3 Hz, 2H), 6.47 (d, J = 8.1 Hz, 1H), 6.19 (d, J = 8.2 Hz, 2H), 4.54 (dd, J = 11.9, 5.1 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.88 (s, 2H), 3.83 (s, 2H), 3.47 (d, J = 11.9 Hz, 2H), 3.38-3.34 (m, 3H), 3.02-2.89 (m, 2H), 2.85-2.81 (m, 2H), 2.79-2.72 (m, 3H), 2.62-2.57 (m, 2H), 2.46-2.40 (m, 2H), 2.24 (d, J = 6.7 Hz, 2H), 2.20-2.15 (m, 1H), 2.12-2.04 (m, 1H), 1.73-1.63 (m, 3H), 1.38-1.28 (m, 2H), 1.15-1.08 (m, 2H).

[0680] Example 24

[0681] Step one:

[0682] Acetyl chloride (2.065 g) was dissolved in dichloromethane (60 mL) and cooled to -70 °C. A solution of dimethyl sulfoxide (1.271 g) in dichloromethane (5 mL) was slowly added to the system, and the reaction was maintained at -70 °C for 0.5 h. Then, triethylamine (4.12 g) and a solution of 3-hydroxymethyl-azetidine-1-carboxylic acid benzyl ester (3 g) in dichloromethane (20 mL) were added, and the reaction was allowed to recover to room temperature for 0.5 h. After the reaction was completed, water was added for extraction, and the organic phase was washed with saturated brine, filtered, and concentrated to give 2.8 g of intermediate 24-1.

[0683] 1 H-NMR (500 MHz, DMSO-d6): δ 9.74 (d, J = 1.7 Hz, 1H), 7.37-7.34 (m, 5H), 5.04 (s, 2H), 4.12-4.01 (m, 4H), 3.56-3.44 (m, 1H).

[0684] Step two:

[0685] Intermediate 24-1 (2.5 g), 4-piperidone glycol (2.449 g), acetic acid (2.054 g), 1,2-dichloroethane (20 mL), and isopropanol (5 mL) were mixed and reacted at room temperature for 20 min. Sodium triacetoxyborohydride (7.25 g) was added, and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was completed, saturated sodium bicarbonate solution was added, and extraction was performed with dichloromethane. The organic phase was washed with saturated brine, dried, and concentrated. The residue was purified with a C18 column (water:acetonitrile = 50:50) to give 2.3 g of intermediate 24-2.

[0686] MS (ESI, [M+H] + )m / z: 347.25

[0687] 1 H-NMR (500 MHz, DMSO-d6): δ 7.41-7.24 (m, 5H), 5.01 (s, 2H), 4.05-3.92 (m, 2H), 3.84 (s, 4H), 3.62-3.48 (m, 2H), 2.79-2.70 (m, 1H), 2.52 (d, J = 7.4 Hz, 2H), 2.45-2.34 (m, 4H), 1.57 (t, J = 5.7 Hz, 4H).

[0688] Step three:

[0689] Intermediate 24-2 (2 g) was dissolved in methanol (30 mL), and palladium on carbon (10%, 0.614 g) was added. The reaction was allowed to proceed at 40 °C for 12 h under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated to give 1.3 g of intermediate 24-3.

[0690] 1 H-NMR (500 MHz, DMSO-d6): δ 4.08 (s, 2H), 3.84 (s, 4H), 3.61 (s, 2H), 3.36-3.26 (m, 2H), 2.50-2.46 (m, 2H), 2.43-2.30 (m, 4H), 1.57 (t, J = 5.7 Hz, 4H).

[0691] Step four:

[0692] Step four:

[0693] MS (ESI, [M+H] + )m / z: 599.42

[0694] 1 H-NMR (500 MHz, DMSO-d6): δ 7.46-7.43 (m, 2H), 7.41-7.37 (m, 2H), 7.35-7.30 (m, 1H), 7.13-7.08 (m, 2H), 7.05-6.99 (m, 3H), 6.91 (d, J = 2.7 Hz, 1H), 6.79-6.74 (m, 2H), 6.71 (dd, J = 8.6, 2.7 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 6.29-6.22 (m, 2H), 5.09 (s, 2H), 3.88-3.83 (m, 6H), 3.43-3.39 (m, 2H), 2.89-2.81 (m, 3H), 2.69-2.64 (m, 2H), 2.57 (d, J = 7.4 Hz, 2H), 2.48-2.39 (m, 4H), 1.59 (t, J = 5.6 Hz, 4H).

[0695] Step four:

[0696] Intermediate 24-4 was dissolved in methanol (15 mL), tetrahydrofuran (15 mL), and palladium on carbon (10%, 89 mg) was added. The reaction was stirred at 40 °C under hydrogen atmosphere for 4 days. The reaction was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated, and the residue was separated by chiral HPLC (column: CHIRALPAK IK, 4.6 x 250 mm, 5 μm; mobile phase: n-hexane: ethanol / dichloromethane (1 / 1, containing 0.05% ammonia water) = 80:20; flow rate: 20 mL / min) to give 90 mg of intermediate 24-5.

[0697] Intermediate 24-5: R t = 4.189 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 x 100 mm, 3 μm; mobile phase: carbon dioxide: methanol (containing 0.1% ammonia water) = 60:40; flow rate: 2.0 mL / min; column temperature: 40 °C).

[0698] MS (ESI, [M+H] + )m / z: 511.43

[0699] 1 H-NMR (500 MHz, DMSO-d6): δ 9.06 (s, 1H), 7.16-7.06 (m, 3H), 6.83-6.77 (m, 2H), 6.65-6.55 (m, 2H), 6.45 (dd, J = 8.3, 2.6 Hz, 1H), 6.14 (d, J = 8.4 Hz, 2H), 6.05-5.96 (m, 2H), 4.08 (d, J = 5.0 Hz, 1H), 3.82 (s, 4H), 3.73 (q, J = 7.3 Hz, 2H), 3.28-3.21 (m, 3H), 3.01-2.84 (m, 2H), 2.81-2.74 (m, 1H), 2.53-2.49 (m, 2H), 2.44-2.31 (m, 4H), 2.11-2.01 (m, 1H), 1.71-1.64 (m, 1H), 1.55 (t, J = 5.6 Hz, 4H).

[0700] Step six:

[0701] Intermediate 24-5 (90 mg) was dissolved in tetrahydrofuran (5 mL), and 2 M dilute sulfuric acid solution (5 mL) was added. The reaction was stirred at 60 °C for 2 hours. The reaction was adjusted to neutral pH by adding saturated sodium bicarbonate solution, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 60 mg of intermediate 24-6.

[0702] Step seven:

[0703] Intermediate 24-6 (50 mg), intermediate A-1 (51.7 mg), sodium acetate (17.58 mg), N,N-dimethylformamide (3 mL) were mixed and reacted at 60 °C for 20 min. Sodium cyanoborohydride (13.47 mg) was added and the reaction was carried out at room temperature for 12 h. After the reaction was completed, saturated sodium bicarbonate solution was added and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (dichloromethane: dichloromethane / methanol (10 / 1) = 0:100) to obtain 13 mg of compound 24.

[0704] HRMS (ESI, [M+H] + )m / z: 736.3888

[0705] 1 H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.08 (s, 1H), 7.61-7.53 (m, 1H), 7.18 (s, 1H), 7.16-7.07 (m, 3H), 6.82 (d, J = 7.2 Hz, 1H), 6.67-6.61 (m, 1H), 6.59 (d, J = 2.6 Hz, 1H), 6.51-6.42 (m, 1H), 6.16 (d, J = 8.1 Hz, 1H), 6.02 (d, J = 8.1 Hz, 1H), 5.38-5.25 (m, 1H), 4.55 (dd, J = 11.8, 4.9 Hz, 1H), 4.12-4.07 (m, 1H), 3.92 (s, 1H), 3.80-3.74 (m, 1H), 3.03-2.97 (m, 1H), 2.97-2.85 (m, 4H), 2.84-2.79 (m, 2H), 2.77-2.71 (m, 1H), 2.66-2.57 (m, 3H), 2.36 (s, 1H), 2.21-2.15 (m, 1H), 2.13-2.06 (m, 1H), 2.01-1.92 (m, 3H), 1.81 (d, J = 12.0 Hz, 2H), 1.72-1.65 (m, 1H), 1.57-1.43 (m, 4H), 1.26-1.22 (m, 7H).

[0706] Example 25

[0707] Step one:

[0708] Intermediate 25-1 (6.5 g), p-hydroxybenzeneboronic acid (2.78 g), potassium carbonate (4.65 g), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.616 g) and 1,4-dioxane (60 mL), water (10 mL) were mixed and reacted at 100 °C for 6 hours under nitrogen protection. After the reaction was completed, the reaction solution was extracted with saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration were performed, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain 2.6 g of intermediate 25-2.

[0709] MS (ESI, [M+H] + )m / z: 330.93

[0710] 1 H-NMR (500MHz, DMSO-d6): δ 9.54 (s, 1H), 7.46-7.42 (m, 2H), 7.41-7.37 (m, 2H), 7.35-7.31 (m, 1H), 7.11 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 9.2 Hz, 1H), 6.82-6.78 (m, 2H), 6.61-6.51 (m, 2H), 5.65 (t, J = 4.0 Hz, 1H), 5.09 (s, 2H), 4.74 (d, J = 4.0 Hz, 2H).

[0711] Step two:

[0712] Intermediate 25-2 (2.6 g) was dissolved in acetonitrile (30 mL), and N-bromosuccinimide (1.261 g) was added portionwise under ice bath, and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration were performed, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain 2.18 g of intermediate 25-3.

[0713] MS (ESI, [M-H] - )m / z: 407.06

[0714] 1 H-NMR (500MHz, DMSO-d6): δ 9.63 (s, 1H), 7.45-7.36 (m, 4H), 7.35-7.30 (m, 1H), 7.05-6.99 (m, 2H), 6.89-6.82 (m, 2H), 6.60-6.55 (m, 1H), 6.54-6.51 (m, 2H), 5.07 (s, 2H), 4.99 (s, 2H).

[0715] Step three:

[0716] Intermediate 25-3 (2 g), phenylboronic acid (0.626 g), potassium carbonate (1.351 g), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.179 g) were mixed with 1,4-dioxane (50 mL), water (10 mL) and reacted at 100 °C for 5 hours under nitrogen protection. After the reaction, the reaction solution was extracted with saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration and purification of the residue by column chromatography (petroleum ether: ethyl acetate = 80:20) gave 1.7 g of intermediate 25-4.

[0717] MS (ESI, [M-H] - )m / z: 405.13

[0718] 1 H-NMR (500 MHz, DMSO-d6): δ 9.43 (s, 1H), 7.46-7.42 (m, 2H), 7.42-7.37 (m, 2H), 7.35-7.31 (m, 1H), 7.19-7.14 (m, 2H), 7.14-7.09 (m, 1H), 7.04-6.99 (m, 2H), 6.88-6.83 (m, 2H), 6.71-6.67 (m, 2H), 6.65 (d, J = 8.5 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 6.53 (dd, J = 8.6, 2.5 Hz, 1H), 5.09 (s, 2H), 5.03 (s, 2H).

[0719] Step four:

[0720] Intermediate 25-4 (1.7 g), potassium carbonate (0.867 g), tetrahydrofuran (20 mL) and acetonitrile (20 mL) were mixed, and perfluorobutylsulfonyl fluoride (1.390 g) was added. The reaction was carried out at room temperature for 15 hours. After the reaction, the filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 95:5) to give 2.6 g of intermediate 25-5.

[0721] MS (ESI, [M-H] - )m / z: 687.23

[0722] 1H-NMR (500 MHz, CDC13): δ 7.45-7.41 (m, 2H), 7.41-7.36 (m, 2H), 7.35-7.30 (m, 1H), 7.22-7.18 (m, 4H), 7.16-7.10 (m, 3H), 6.95-6.88 (m, 2H), 6.67 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.48 (dd, J = 8.6, 2.6 Hz, 1H), 5.08 (s, 2H), 5.06 (s, 2H).

[0723] Step five:

[0724] Intermediate 25-5 (1.5 g), 4-piperidone acetal (0.468 g), cesium carbonate (1.420 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.252 g), tris(dibenzylideneacetone)dipalladium (0.199 g) and 1,4-dioxane (30 mL) were mixed and reacted at 100 °C for 12 h under nitrogen atmosphere. After the reaction, it was extracted by filtration, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 75:25) to obtain 650 mg of intermediate 25-6.

[0725] MS (ESI, [M+H] + )m / z: 532.32

[0726] 1 H-NMR (500 MHz, DMSO-d6): δ 7.45-7.43 (m, 2H), 7.41-7.37 (m, 2H), 7.35-7.32 (m, 1H), 7.17-7.14 (m, 2H), 7.13-7.10 (m, 1H), 7.03-7.01 (m, 2H), 6.87 (d, J = 1.8 Hz, 4H), 6.67 (d, J = 8.6 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 6.54 (dd, J = 8.6, 2.5 Hz, 1H), 5.09 (s, 2H), 5.02 (s, 2H), 3.91 (s, 4H), 3.28-3.24 (m, 4H), 1.70-1.67 (m, 4H).

[0727] Step six:

[0728] Intermediate 25-6 (650 mg) was dissolved in methanol (20 mL), tetrahydrofuran (20 mL), and palladium on carbon (10%, 130 mg) was added. The reaction was carried out under hydrogen atmosphere at 40 °C for 30 hours. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated, and the residue was separated by chiral HPLC (column: CHIRALART Amylose-SA; system: ethanol / dichloromethane (1 / 1): n-hexane = 30:70; flow rate: 40 mL / min) to give 180 mg of intermediate 25-7.

[0729] Intermediate 25-7: R t = 3.231 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 x 100 mm, 3 μm; mobile phase: carbon dioxide: methanol (containing 0.1% ammonia water) = 50:50; flow rate: 2.0 mL / min; column temperature: 40 °C).

[0730] MS (ESI, [M+H] + )m / z: 444.33

[0731] 1 H-NMR (500 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.16-7.09 (m, 3H), 6.76-6.72 (m, 2H), 6.66 (d, J = 8.2 Hz, 1H), 6.63-6.59 (m, 2H), 6.39-6.35 (m, 2H), 6.29 (d, J = 2.4 Hz, 1H), 6.26 (dd, J = 8.2, 2.4 Hz, 1H), 4.31 (t, J = 11.1 Hz, 1H), 4.21-4.13 (m, 2H), 3.87 (s, 4H), 3.53-3.45 (m, 1H), 3.17-3.09 (m, 4H), 1.66-1.59 (m, 4H).

[0732] Step Seven:

[0733] Intermediate 25-7 (130 mg) was dissolved in tetrahydrofuran (5 mL), and 4M dilute sulfuric acid (5 mL) was added. The reaction was carried out at 70 °C for 4 hours. After the reaction was completed, the pH was adjusted to neutral by adding saturated sodium bicarbonate solution, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to give 100 mg of intermediate 25-8.

[0734] MS (ESI, [M+H] + )m / z: 400.31

[0735] Step Eight:

[0736] Intermediate 25-8 (100 mg), intermediate 2-2 (159 mg), sodium acetate (41.1 mg), 1,2-dichloroethane (5 mL) and isopropanol (1 mL) were mixed and reacted at 60 °C for 20 minutes. Sodium triacetoxyborohydride (106 mg) was added and reacted at 60 °C for 2 hours. After the reaction, saturated sodium bicarbonate solution was added and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (dichloromethane: dichloromethane / methanol (10 / 1) = 35:65) to obtain 90 mg of compound 25.

[0737] HRMS (ESI, [M+H] + )m / z: 710.3368

[0738] 1 H-NMR (500MHz, DMSO-d6): δ 11.08 (s, 1H), 9.26 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.17-7.12 (m, 3H), 6.78-6.74 (m, 2H), 6.66 (d, J=8.3 Hz, 1H), 6.61 (d, J=8.7 Hz, 2H), 6.38 (d, J=8.4 Hz, 2H), 6.31 (d, J=2.4 Hz, 1H), 6.27 (dd, J=8.2, 2.4 Hz, 1H), 4.60 (dd, J=11.9, 5.0 Hz, 1H), 4.33 (t, J=11.0 Hz, 1H), 4.20-4.14 (m, 4H), 4.07-4.02 (m, 2H), 3.62-3.48 (m, 3H), 3.44 (d, J=11.5 Hz, 3H), 3.07 (s, 2H), 2.81-2.73 (m, 1H), 2.67-2.57 (m, 3H), 2.28-2.12 (m, 2H), 1.75-1.65 (m, 2H), 1.31-1.19 (m, 3H).

[0739] Example 26

[0740] Step one:

[0741] To a solution of intermediate 26-1 (1.32 g) in ethanol (25 mL) was added 10% palladium on carbon (0.13 g) and the reaction mixture was stirred at 70 °C under hydrogen atmosphere for 12 h. The palladium on carbon was removed by celite filtration and the filtrate was concentrated to give 0.66 g of intermediate 26-2.

[0742] MS (ESI, [M+H] + )m / z: 333.22.

[0743] Step two:

[0744] To a solution of intermediate 26-1 (1.32 g) in ethanol (25 mL) was added 10% palladium on carbon (0.13 g) and the reaction mixture was stirred at 70 °C under hydrogen atmosphere for 12 h. The palladium on carbon was removed by celite filtration and the filtrate was concentrated to give 0.66 g of intermediate 26-2.

[0745] HRMS (ESI, [M+H] + )m / z: 199.1436.

[0746] Step three:

[0747] To a solution of intermediate C-1 (0.2 g), intermediate 26-2 (0.27 g), and 2- dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.044 g) in anhydrous 1,4- dioxane (10 mL) was added XPhos Pd G3 (0.076 g) and sodium tert-butoxide (0.17 g) after the solution was purged with nitrogen for 5 min. The reaction mixture was stirred at 120 °C under nitrogen atmosphere for 3 h by microwave heating. The reaction mixture was cooled to room temperature, filtered by celite and the filtrate was concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 25:1) to give 0.12 g of intermediate 26-3.

[0748] MS (ESI, [M+H] + )m / z: 560.31.

[0749] Step four:

[0750] To a solution of intermediate 26-3 (0.12 g) in tetrahydrofuran (1 mL) was added 4 M sulfuric acid (1 mL) and the reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature, adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with water, saturated brine, dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to give 0.1 g of intermediate 26-4.

[0751] MS (ESI, [M+H] + m / z: 516.35.

[0752] Step five:

[0753] To a solution of intermediate 26-4 (0.1 g), intermediate A-2 (0.07 g) and sodium acetate (0.065 g) in 1,2-dichloroethane (5 mL) and isopropanol (1 mL) was added sodium triacetoxyborohydride (0.165 g) portionwise with stirring at room temperature. The reaction mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed successively with water, saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 50:1) to give 0.012 g of compound 26.

[0754] HRMS (ESI, [M+H] + m / z: 771.3400.

[0755] 1 H-NMR (500 MHz, DMSO-d6): δ 12.97 (s, 1H), 11.10 (s, 1H), 8.05 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.7 Hz, 2H), 6.73-6.68 (m, 1H), 6.66-6.53 (m, 1H), 6.07-6.01 (m, 2H), 5.93-5.63 (m, 1H), 5.32 (s, 1H), 5.14 (s, 1H), 4.59 (m, 1H), 4.17 (s, 2H), 4.06 (s, 2H), 3.92 (s, 2H), 3.63 (s, 2H), 3.49-3.43 (m, 2H), 3.25-3.18 (m, 2H), 3.08-2.98 (m, 1H), 2.91-2.86 (m, 1H), 2.77 (s, 3H), 2.62 (s, 2H), 2.18 (s, 1H), 2.08-1.84 (m, 7H).

[0756] Example 27

[0757] Step one:

[0758] To a solution of intermediate 27-1 (3.53 g) in ethanol (60 mL) was added 10% palladium on carbon (0.35 g) and the reaction mixture was stirred at 70 °C under hydrogen atmosphere for 12 h. The palladium on carbon was removed by celite filtration and the filtrate was concentrated to give 1.73 g of intermediate 27-2.

[0759] MS (ESI, [M+H] + )m / z: 361.26.

[0760] Step two:

[0761] To a solution of intermediate 27-1 (3.53 g) in ethanol (60 mL) was added 10% palladium on carbon (0.35 g) and the reaction mixture was stirred at 70 °C under hydrogen atmosphere for 12 h. The palladium on carbon was removed by celite filtration and the filtrate was concentrated to give 1.73 g of intermediate 27-2.

[0762] HRMS (ESI, [M+H] + )m / z: 227.1763.

[0763] Step three:

[0764] To a solution of intermediate C-1 (0.2 g), intermediate 27-2 (0.31 g), and 2- dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.042 g) in anhydrous 1,4- dioxane (10 mL) was added XPhos Pd G3 (0.077 g) and sodium tert-butoxide (0.17 g) after the solution was purged with nitrogen for 5 min. The reaction mixture was stirred at 120 °C under nitrogen atmosphere for 3 h. The reaction mixture was cooled to room temperature, filtered by celite to remove the salts and catalyst, and the filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 25:1) to give 0.18 g of intermediate 27-3.

[0765] MS (ESI, [M+H] + )m / z: 588.40.

[0766] Step four:

[0767] To a solution of intermediate 27-3 (0.18 g) in tetrahydrofuran (1 mL) was added 4 M sulfuric acid (1 mL) and the reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature, adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.092 g of intermediate 27-4.

[0768] MS (ESI, [M+H] + m / z: 544.29.

[0769] Step five:

[0770] Intermediate 27-4 (0.1 g), intermediate A-2 (0.07 g) and sodium acetate (0.06 g) were added into a mixture of 1,2-dichloroethane (5 mL) and isopropanol (1 mL), and sodium triacetoxyborohydride (0.155 g) was added portionwise with stirring at room temperature. The reaction was stirred at 80 °C for 1 h. After cooling to room temperature, saturated sodium bicarbonate was added to quench, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 50:1) to give 0.033 g of compound 27.

[0771] HRMS (ESI, [M+H] + m / z: 799.3714.

[0772] 1 H-NMR (500 MHz, DMSO-d6): δ 12.97 (s, 1H), 11.09 (s, 1H), 8.06 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.7 Hz, 1H), 6.53 (d, J = 13.1 Hz, 2H), 5.91-5.70 (m, 1H), 5.16 (s, 1H), 4.60 (dd, J = 11.7, 5.0 Hz, 1H), 4.19-4.02 (m, 4H), 3.78 (d, J = 12.0 Hz, 2H), 3.47 (d, J = 6.1 Hz, 1H), 3.19 (dd, J = 16.9, 4.8 Hz, 1H), 3.12-3.00 (m, 2H), 2.97-2.84 (m, 3H), 2.84-2.55 (m, 6H), 2.33-2.15 (m, 3H), 1.97-1.79 (m, 4H), 1.48 (t, J = 12.1 Hz, 4H), 1.33-1.26 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H).

[0773] Example 28

[0774] Step one:

[0775] Intermediate B-2 (1 g), intermediate 26-2 (0.87 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 g) were dissolved in anhydrous 1,4-dioxane (20 mL), and after nitrogen bubbling for 5 minutes, tris(dibenzylideneacetone)dipalladium (0.12 g) and cesium carbonate (1.41 g) were added to the solution. The reaction was stirred under a nitrogen atmosphere and heated to 120 °C in a microwave for 3 h. After cooling to room temperature, the salt and catalyst were removed by suction filtration over celite, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 0.53 g of intermediate 28-1.

[0776] MS (ESI, [M+H] + )m / z: 585.37.

[0777] Step two:

[0778] Intermediate 28-1 (0.53 g) was dissolved in ethanol (50 mL), and 10% palladium carbon (0.04 g) was added. The reaction was stirred under a hydrogen atmosphere at 70 °C for 72 h. The palladium carbon was removed by suction filtration over celite, and the filtrate was concentrated. The residue was separated by chiral column (column: CHIRALPAK IG, 30 x 250 mm, 10 μm; system: ethanol: n-hexane = 27:73; flow rate: 40 mL / min) to give 0.147 g of intermediate 28-2.

[0779] Intermediate 28-2: R t = 2.981 min (UPCC conditions: column: CHIRALPAK IE-3, 4.6 x 150 mm, 3 μm; mobile phase: carbon dioxide: ethanol (containing 0.1% ammonia water) = 50:50; flow rate: 2.0 mL / min; column temperature: 40 °C).

[0780] MS (ESI, [M+H] + )m / z: 497.37.

[0781] 1H-NMR (500MHz, DMSO-d6) δ 9.08 (s, 1H), 7.17-7.13 (m, 2H), 7.12-7.09 (m, 1H), 6.82 (d, J = 6.7 Hz, 2H), 6.63 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 6.47 (dd, J = 8.3, 2.7 Hz, 1H), 6.17 (d, J = 8.5 Hz, 2H), 6.03 (d, J = 8.4 Hz, 2H), 4.11 (d, J = 5.2 Hz, 1H), 3.84 (s, 4H), 3.80-3.75 (m, 2H), 3.40-3.35 (m, 2H), 3.28-3.24 (m, 1H), 3.19-3.15 (m, 1H), 3.01-2.89 (m, 2H), 2.32 (s, 4H), 2.13-2.05 (m, 1H), 1.71-1.68 (m, 1H), 1.61-1.57 (m, 4H).

[0782] Step three:

[0783] Intermediate 28-2 (0.077 g) was added to 4M sulfuric acid (2 mL) in tetrahydrofuran (2 mL) and stirred at 70 °C for 2 h. After cooling to room temperature, the pH was adjusted to 8 with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with water, saturated brine solution successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 0.05 g of intermediate 28-3.

[0784] MS (ESI, [M+H] + )m / z: 453.18.

[0785] Step four:

[0786] Intermediate 28-3 (0.05 g), intermediate A-2 (0.04 g) and sodium acetate (0.018 g) were added to a mixture of 1,2-dichloroethane (2.5 mL) and isopropyl alcohol (0.5 mL), and then sodium triacetoxyborohydride (0.035 g) was added portionwise with stirring at room temperature. The reaction mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, saturated brine solution successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (dichloromethane:methanol = 40:1) to give 0.04 g of compound 28.

[0787] HRMS (ESI, [M+H] + )m / z: 708.3551.

[0788] 1H-NMR (500 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.08 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.32-7.28 (m, 1H), 7.18-7.13 (m, 2H), 7.13-7.10 (m, 1H), 6.83 (d, J = 7.3 Hz, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), 6.47 (dd, J = 8.3, 2.5 Hz, 1H), 6.17 (d, J = 8.5 Hz, 2H), 6.05 (d, J = 8.4 Hz, 2H), 4.61-4.58 (m, 1H), 4.36 (s, 1H), 4.25 (s, 1H), 4.15 (s, 2H), 4.12-4.09 (m, 1H), 4.05 (s, 2H), 3.83-3.76 (m, 2H), 3.46-3.37 (m, 2H), 3.18-3.14 (m, 1H), 3.00-2.87 (m, 2H), 2.76 (s, 4H), 2.65-2.55 (m, 2H), 2.22-2.18 (m, 1H), 2.14-2.03 (m, 1H), 1.98-1.87 (m, 4H), 1.70 (s, 1H), 1.54-1.44 (m, 1H).

[0789] Example 29

[0790] Step one:

[0791] Intermediate A-1 (0.2 g) was dissolved in a mixed solvent of 1,2-dichloroethane (20 mL) and isopropyl alcohol (4 mL), and 3-formylazetidine-1-carboxylic acid tert-butyl ester (0.164 mL) and sodium acetate (0.115 g) were added, and the reaction was allowed to proceed at room temperature for 20 minutes. Sodium triacetylboration hydride (0.297 g) was added, and the reaction was allowed to proceed at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added, and the pH of the system was adjusted to weak alkalinity. Water was added, and extraction was performed with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. Filtration and concentration gave 0.319 g of intermediate 29-1.

[0792] MS (ESI, [M+H] + )m / z: 455.26.

[0793] Step two:

[0794] Intermediate 29-1 (0.319 g) was dissolved in a mixed solvent of dichloromethane (6 mL) and trifluoroacetic acid (2 mL), and the reaction was allowed to proceed at room temperature for 1 hour. The solvent was directly evaporated to give 0.674 g of intermediate 29-2.

[0795] MS (ESI, [M+H] + m / z: 355.26.

[0796] 1 H-NMR (500MHz, DMSO-d6): δ 9.10 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 4.62 (dd, J = 12.1, 4.9 Hz, 2H), 4.12-4.03 (m, 2H), 3.98-3.89 (m, 3H), 3.80-3.71 (m, 2H), 3.63 (d, J = 7.0 Hz, 2H), 3.50 (d, J = 5.2 Hz, 2H), 3.25 (t, J = 6.1 Hz, 2H), 2.91-2.73 (m, 2H), 2.66-2.56 (m, 1H), 2.25-2.15 (m, 1H), 1.04 (d, J = 6.1 Hz, 1H).

[0797] Step three:

[0798] Intermediate 29-2 (0.082 g) and intermediate B-1 (0.07 g) were dissolved in a mixed solvent of 1,2-dichloroethane (1 mL) and isopropyl alcohol (0.2 mL), sodium acetate (0.029 g) was added, and the reaction was carried out at 60°C for 30 minutes. Sodium triacetyloxyborohydride (0.075 g) was added, and the reaction was carried out at 60°C for 2 hours. Saturated aqueous sodium bicarbonate solution was added, and the pH of the system was adjusted to weak alkaline. Water was added, and extraction was carried out with dichloromethane, and anhydrous sodium sulfate was added for drying. Filtration and concentration were carried out, and the residue was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 0.0732 g of compound 29.

[0799] MS (ESI, [M+H] + m / z: 736.36.

[0800] 1H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.09 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.17-7.07 (m, 4H), 6.82 (d, J = 6.8 Hz, 2H), 6.63 (d, J = 8.3 Hz, 1H), 6.60 (s, 1H), 6.52 (d, J = 8.4 Hz, 2H), 6.47 (dd, J = 8.3, 2.6 Hz, 1H), 6.19 (d, J = 8.4 Hz, 2H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.77 (s, 2H), 3.44 (s, 3H), 3.26 (t, J = 3.5 Hz, 2H), 3.17 (s, 1H), 3.02-2.82 (m, 5H), 2.82-2.67 (m, 6H), 2.63-2.52 (m, 3H), 2.45 (dd, J = 12.3, 4.4 Hz, 1H), 2.21-2.12 (m, 1H), 2.12 -2.01 (m, 1H), 1.69 (dd, J = 12.6, 6.5 Hz, 3H), 1.28-1.14 (m, 3H).

[0801] Example 30

[0802] Step one:

[0803] Intermediate A-5 (0.05 g) and N-tert-butoxycarbonyl-4-piperidone (0.073 g) were dissolved in a mixed solvent of 1,2-dichloroethane (2 mL) and isopropyl alcohol (2 mL), sodium acetate (0.015 g) was added, and the reaction was allowed to proceed at room temperature for 30 minutes. Sodium triacetyloxyborohydride (0.078 g) was added, and the reaction was allowed to proceed at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added, and the pH of the system was adjusted to weak alkalinity. Water was added, and extraction was performed with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. Filtration and concentration were performed, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 0.058 g of intermediate 30-1.

[0804] MS (ESI, [M+H] + )m / z: 455.37.

[0805] Step two:

[0806] Intermediate 30-1 (0.058 g) was dissolved in a mixed solvent of dichloromethane (2 mL) and trifluoroacetic acid (0.4 mL), and the reaction was allowed to proceed at room temperature for 1 hour. The solvent was directly evaporated to obtain 0.065 g of intermediate 30-2.

[0807] MS (ESI, [M+H] +m / z: 355.25.

[0808] Step three:

[0809] Intermediate B-3 (0.075 g) and intermediate 30-2 (0.065 g) were dissolved in a mixed solvent of 1,2-dichloroethane (2 mL) and isopropyl alcohol (2 mL), sodium acetate (0.045 g) was added, and the reaction was allowed to proceed at room temperature for 30 minutes. Sodium triacetylboration hydride (0.117 g) was added, and the reaction was allowed to proceed at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added, and the pH of the system was adjusted to weak alkalinity. Water was added, and extraction was performed with dichloromethane, followed by drying over anhydrous sodium sulfate. Filtration and concentration of the filtrate yielded a residue, which was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 0.047 g of compound 30.

[0810] MS (ESI, [M+H] + m / z: 750.49.

[0811] 1 H-NMR (500MHz, CDCl3): δ 8.21 (s, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 7.18-7.10 (m, 3H), 6.85 - 6.76 (m, 3H), 6.67 (d, J = 2.6 Hz, 1H), 6.58-6.50 (m, 3H), 6.27 (d, J = 8.6 Hz, 2H), 4.28 (dd, J = 8.6, 5.2 Hz, 1H), 4.18 (d, J = 5.0 Hz, 1H), 4.05 (d, J = 4.9 Hz, 2H), 4.01 (s, 2H), 3.53 (s, 2H), 3.37 - 2.91 (m, 5H), 2.82-2.68 (m, 2H), 2.67-2.50 (m, 4H), 2.51-2.36 (m, 2H), 2.28 (s, 1H), 2.24-2.08 (m, 3H), 2.00 (s, 2H), 1.87-1.74 (m, 5H), 1.30 (s, 2H), 1.26 (d, J = 1.9 Hz, 1H).

[0812] Example 31

[0813] Step one:

[0814] Intermediate 17-2 (0.25 g) was dissolved in acetonitrile (20 mL), and potassium carbonate (0.386 g) and 2-bromo-1,1-dimethoxyethane (1.321 mL) were added successively, and the reaction was allowed to proceed at 83°C in an oil bath for 12 h. The reaction was quenched by adding water, and extraction was performed with ethyl acetate. The organic phase was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 50:1) to obtain 0.2 g of intermediate 31-1.

[0815] MS (ESI, [M+H]+) m / z: 536.28.

[0816] Step two:

[0817] Intermediate 31-1 (0.1 g) was dissolved in acetonitrile (5 mL), 3M aqueous hydrochloric acid (1 mL) was added, and the reaction was heated at 80 °C for 2 h. After the reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added to quench the reaction. Ethyl acetate was added, and the organic phase was concentrated to give 0.053 g of intermediate 31-2.

[0818] Step three:

[0819] Intermediate 31-2 (0.091 g) and intermediate A-1 (0.053 g) were dissolved in a mixture of 1,2-dichloroethane (2 mL) and isopropyl alcohol (2 mL), sodium acetate (0.046 g) was added, and the reaction was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (0.118 g) was added, and the reaction was stirred at room temperature for 12 h. Saturated aqueous sodium bicarbonate solution was added to adjust the pH of the system to weak alkaline. Water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 15:1) to give 0.075 g of compound 31.

[0820] MS (ESI, [M+H]+) m / z: 536.28. +

[0821] 1 ​H-NMR (500 MHz, DMSO-d6): δ 12.97 (s, 1H), 11.07 (s, 1H), 8.05 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 13.5 Hz, 2H), 5.96-5.67 (m, 1H), 5.16 (s, 1H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 3.87 (s, 2H), 3.47 (q, J = 5.7 Hz, 1H), 3.17 (d, J = 5.3 Hz, 3H), 3.06-3.00 (m, 1H), 2.94 (d, J = 5.8 Hz, 1H), 2.89 (dd, J = 16.6, 5.2 Hz, 1H), 2.80 (t, J = 5.8 Hz, 2H), 2.74 (t, J = 6.6 Hz, 2H), 2.62-2.60 (m, 2H), 2.55 (t, J = 5.0 Hz, 3H), 2.23-2.13 (m, 1H), 1.35 (s, 1H), 1.30 (s, 2H), 1.26 (s, 2H), 1.23 (d, J = 3.0 Hz, 3H), 1.05 (d, J = 6.5 Hz, 3H).

[0822] Example 32

[0823] Intermediate 31-2 (0.091 g) and intermediate A-2 (0.050 g) were dissolved in a mixed solvent of 1,2-dichloroethane (2 mL) and isopropanol (2 mL), sodium acetate (0.046 g) was added, and the reaction was allowed to proceed at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.118 g) was added, and the reaction was allowed to proceed at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added, and the pH of the system was adjusted to weak alkalinity. Water was added, and extraction was performed with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. Filtration and concentration were performed, and the residue was purified by column chromatography (dichloromethane:methanol = 15:1) to obtain 0.096 g of compound 32.

[0824] MS (ESI, [M+H] + )m / z: 745.38.

[0825] 1H-NMR (500 MHz, DMSO-d6): δ 12.97 (s, 1H), 11.08 (s, 1H), 8.06 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 13.4 Hz, 2H), 5.96-5.68 (m, 2H), 5.17 (s, 1H), 4.59 (dd, J = 11.9, 5.0 Hz, 1H), 4.19 (s, 2H), 4.08 (s, 2H), 3.47 (q, J = 5.8 Hz, 1H), 3.21-3.17 (m, 4H), 3.03 (d, J = 15.0 Hz, 1H), 2.92 (q, J = 6.1 Hz, 2H), 2.81-2.72 (m, 1H), 2.62 (t, J = 4.5 Hz, 1H), 2.58 (d, J = 9.3 Hz, 4H), 2.24-2.16 (m, 1H), 2.04-1.95 (m, 1H), 1.37 (s, 1H), 1.24 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 6.5 Hz, 3H).

[0826] Example 33

[0827] Step one:

[0828] Intermediate A-5 (50 mg) and 1-tert-butoxycarbonyl-3-azetidinone (63 mg) were dissolved in a mixed solution of 1,2-dichloroethane (2 mL) and isopropanol (0.5 mL), sodium acetate (45 mg) and sodium triacetoxyborohydride (117 mg) were added, and the reaction was stirred at 80 °C for 2 h. Saturated sodium bicarbonate solution was added, and the organic layer was extracted with dichloromethane, washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 94:6) to give 70 mg of intermediate 33-1.

[0829] MS (ESI, [M+H] + )m / z: 427.34.

[0830] 1H-NMR (500 MHz, DMSO-d6): δ 11.10 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 4.61 (dd, J = 11.9, 5.0 Hz, 1H), 4.19 (d, J = 2.4 Hz, 2H), 4.08 (d, J = 2.4 Hz, 2H), 3.97 (d, J = 9.4 Hz, 2H), 3.86 (s, 2H), 3.72 (ddd, J = 7.2, 5.9, 3.5 Hz, 1H), 2.78 (ddd, J = 17.3, 11.9, 5.4 Hz, 1H), 2.62 (dt, J = 17.2, 4.0 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.25 - 2.17 (m, 1H), 1.40 (s, 9H).

[0831] Step two:

[0832] Intermediate 33-1 (70 mg) was dissolved in dichloromethane (3 mL), 4M hydrochloric acid in dioxane (0.5 mL) was added, and stirred at room temperature for 30 minutes. The solvent was removed by concentration to obtain 64 mg of intermediate 33-2.

[0833] MS (ESI, [M+H] + )m / z: 327.18.

[0834] 1 H-NMR (500 MHz, DMSO-d6): δ 11.02 (s, 1H), 8.85 (s, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 4.55 (dd, J = 12.0, 5.0 Hz, 1H), 4.41 (s, 2H), 4.27 (s, 2H), 4.07 (q, J = 4.7 Hz, 5H), 2.70 (ddd, J = 17.4, 12.1, 5.4 Hz, 1H), 2.54 (dt, J = 17.3, 4.2 Hz, 1H), 2.49 - 2.44 (m, 1H), 2.17 - 2.09 (m, 1H).

[0835] Step three:

[0836] Intermediate 33-2 (64 mg) and intermediate B-3 (97 mg) were dissolved in a mixed solution of 1,2-dichloroethane (2 mL) and isopropanol (0.5 mL), sodium acetate (48 mg) was added, and stirring was performed at 50°C for 30 min. Sodium triacetoxyborohydride (125 mg) was added, and stirring was performed at 50°C for 2 h. Saturated sodium bicarbonate solution was added, and extraction was performed with dichloromethane. The organic layer was washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. Filtration and concentration were performed, and the residue was purified by column chromatography (dichloromethane:methanol = 91:9) to obtain 50 mg of compound 33.

[0837] MS (ESI, [M+H] + ) m / z: 722.37

[0838] 1 H-NMR (500MHz, DMSO-d6): δ 11.07 (s, 1H), 9.09 (s, 1H), 7.63 (d, J = 20.0 Hz, 2H), 7.19-7.07 (m, 3H), 6.83 (d, J = 6.5 Hz, 2H), 6.69-6.57 (m, 2H), 6.55-6.45 (m, 3H), 6.19 (d, J = 8.5 Hz, 2H), 4.59-4.51 (m, 1H), 4.12 (d, J = 4.0 Hz, 1H), 3.92-3.88 (m, 4H), 3.54-3.45 (m, 3H), 3.02-2.88 (m, 3H), 2.78-2.69 (m, 1H), 2.66-2.56 (m, 1H), 2.47-2.42 (m, 1H), 2.22-2.05 (m, 2H), 1.73-1.64 (m, 2H), 1.42-1.09 (m, 9H), 1.02-0.90 (m, 1H), 0.88-0.76 (m, 2H).

[0839] Example 34

[0840] Step one:

[0841] Intermediate A-2 (50 mg) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (88 mg) were dissolved in a mixed solution of 1,2-dichloroethane (2 mL) and isopropanol (0.5 mL), sodium acetate (64 mg) and sodium triacetoxyborohydride (164 mg) were added, and stirring was performed at 80°C for 2 h. Saturated sodium bicarbonate solution was added, and extraction was performed with dichloromethane. The organic layer was washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. Filtration and concentration were performed, and the residue was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 80 mg of intermediate 34-1.

[0842] MS (ESI, [M+H] + )m / z: 495.36

[0843] Step two:

[0844] Intermediate 34-1 (80 mg) was dissolved in dichloromethane (3 mL), 4M hydrochloric acid solution in dioxane (0.5 mL) was added, stirred at room temperature for 30 min. The solvent was removed by concentration to give 75 mg of intermediate 34-2.

[0845] MS (ESI, [M+H] + )m / z: 395.34

[0846] Step three:

[0847] Intermediate 34-2 (74 mg) and intermediate B-3 (93 mg) were dissolved in a mixture of 1,2-dichloroethane (2 mL) and isopropyl alcohol (0.5 mL), sodium acetate (48 mg) was added, stirred at 50 °C for 30 min. Sodium triacetoxyborohydride (125 mg) was added, stirred at 50 °C for 2 h. Saturated sodium bicarbonate solution was added, extracted with dichloromethane, the organic layer was washed with water, saturated brine successively, dried over anhydrous sodium sulfate. The filtrate was concentrated, the residue was purified by column chromatography (dichloromethane:methanol = 95:5) to give 50 mg of compound 34.

[0848] MS (ESI, [M+H] + )m / z: 790.44

[0849] 1 H-NMR (500MHz, DMSO-d6): δ 11.08 (s, 1H), 9.09 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.19-7.06 (m, 3H), 6.83 (d, J = 7.0 Hz, 2H), 6.71-6.57 (m, 2H), 6.56-6.44 (m, 3H), 6.19 (d, J = 9.0 Hz, 2H), 4.67-4.52 (m, 1H), 4.22-4.04 (m, 3H), 4.05-3.91 (m, 2H), 3.55-3.42 (m, 2H), 3.04-2.84 (m, 3H), 2.82-2.73 (m, 2H), 2.68-2.57 (m, 1H), 2.51-2.42 (m, 1H), 2.34-2.04 (m, 6H), 2.02-1.93 (m, 2H), 1.79-1.64 (m, 5H), 1.62-1.43 (m, 5H), 1.39-0.94 (m, 3H), 0.88-0.63 (m, 3H).

[0850] Example 35

[0851] Step one:

[0852] Intermediate C-1 (0.5 g) and 3,4-dihydro-2H-pyran (0.14 g) were dissolved in dichloromethane (5 mL), p-toluenesulfonic acid (0.01 g) was added, stirred at room temperature for 2 h. Saturated sodium bicarbonate solution was added, extracted with ethyl acetate, the organic layer was washed with water, saturated brine successively, dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated to give 0.5 g of intermediate 35-1.

[0853] MS (ESI, [M+H] + )m / z: 526.15

[0854] Step two:

[0855] Intermediate 35-1 (0.5 g), intermediate 3-4 (0.28 g), sodium tert-butoxide (0.37 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.15 g), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (0.09 g), dioxane (16 mL) and water (3 mL) were mixed, stirred at 110 °C for 2 h under microwave in nitrogen atmosphere. After cooling to room temperature, concentrated, the residue was purified by silica gel column chromatography (dichloromethane:methanol = 97:3) to give 0.5 g of intermediate 35-2.

[0856] MS (ESI, [M+H] + )m / z: 644.99

[0857] Step three:

[0858] Intermediate 35-2 (0.5 g) was dissolved in isopropyl alcohol (2 mL), concentrated hydrochloric acid (2 mL) was added, stirred at 55 °C for 4 h. Methyl tert-butyl ether (4 mL) was added, stirred at room temperature for 0.5 h. Filtration, the filter cake was rinsed with methyl tert-butyl ether solution containing 10% isopropyl alcohol to give 0.45 g of intermediate 35-3.

[0859] MS (ESI, [M+H] + )m / z: 561.25

[0860] Step four:

[0861] Intermediate 35-3 (0.45 g) was dissolved in tetrahydrofuran (5 mL), 2M diluted sulfuric acid (2 mL) was added, and stirring was performed at 60°C for 4 h. Saturated sodium bicarbonate solution was added, and extraction was performed with dichloromethane. The organic layer was washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 0.4 g of intermediate 35-4.

[0862] MS (ESI, [M+H] + m / z: 515.35

[0863] Step five:

[0864] Intermediate 35-4 (100 mg) and intermediate A-2 (53 mg) were dissolved in a mixed solution of 1,2-dichloroethane (4 mL) and isopropanol (2 mL), and sodium acetate (48 mg) was added. Stirring was performed at 50°C for 30 min. Sodium triacetoxyborohydride (124 mg) was added, and stirring was performed at 50°C for 2 h. Saturated sodium bicarbonate solution was added, and extraction was performed with dichloromethane. The organic layer was washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. Filtration was performed, and the residue was concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 92:8) to obtain 40 mg of compound 35.

[0865] MS (ESI, [M+H] + m / z: 770.46

[0866] 1 H-NMR (500MHz, DMSO-d6): δ 12.97 (s, 1H), 11.08 (s, 1H), 8.05 (s, 1H), 7.70 (d, J=10.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.73 (d, J=8.65 Hz, 1H), 6.53 (d, J=13.0 Hz, 2H), 5.95-5.64 (m, 1H), 5.16 (s, 1H), 4.67-4.54 (m, 1H), 4.12-4.00 (m, 4H), 3.53-3.42 (m, 1H), 3.22-3.08 (m, 5H), 3.06-2.97 (m, 1H), 2.94-2.86 (m, 1H), 2.84-2.73 (m, 2H), 2.69-2.60 (m, 1H), 2.24-2.15 (m, 1H), 2.04-1.96 (m, 4H), 1.70-1.61 (m, 2H), 1.56-1.50 (m, 3H), 1.20-1.13 (m, 3H), 1.05 (d, J=6.5 Hz, 3H).

[0867] Example 36

[0868] Step one:

[0869] Intermediate B-2 (6.6 g), 1,4-dioxane (100 mL), 4-piperidone glycol (2.065 g), cesium carbonate (6.26 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.556 g) and tris(dibenzylideneacetone) palladium (0.440 g) were mixed and reacted at 100 °C for 4 hours under nitrogen atmosphere. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL*3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80:20) to obtain 3 g of intermediate 36-1. MS (ESI, [M+H]+) m / z: 530.36.

[0870] Step two:

[0871] Intermediate 36-1 (1 g), THF (40 mL) and 2M dilute sulfuric acid solution (38.0 mL) were mixed and reacted at 70 °C for 3 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL*3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90:10) to obtain 0.8 g of intermediate 36-2.

[0872] MS (ESI, [M+H]+) m / z: 486.4.

[0873] Step three:

[0874] Intermediate 36-2 (0.8 g), dichloroethane (10 mL), 4-(dimethoxymethyl)-piperidine (0.393 g) and sodium acetate (0.270 g) were mixed and heated to 50 °C for 1 hour. The heating was stopped and cooled to room temperature, and then sodium triacetoxyborohydride (0.524 g) was added thereto, and stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL*3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 90:10) to obtain 0.72 g of intermediate 36-3.

[0875] MS (ESI, [M+H]+) m / z: 629.51.

[0876] Step four:

[0877] A mixture of intermediate 36-3 (0.72 g), methanol (2.000 mL) and tetrahydrofuran (2 mL) was stirred at room temperature under hydrogen atmosphere for 2 hours. Filtration, concentration, the obtained solid was purified by preparative HPLC (column: CHIRALPAK IK, 4.6 x 250 mm, 5 μm; mobile phase: ethanol / dichloromethane / n-hexane = 10 / 80 / 10) to give 0.21 g of intermediate 36-4.

[0878] Intermediate 36-4: Rf = 2.756 min (UPCC condition: column: CHIRALPAK IK-3 (4.6 x 150 mm, 3.0 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia water) = 50:50; flow rate: 2.0 ml / min; column temperature: 40 °C). t = 2.756 min (UPCC condition: column: CHIRALPAK IK-3 (4.6 x 150 mm, 3.0 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia water) = 50:50; flow rate: 2.0 ml / min; column temperature: 40 °C).

[0879] MS (ESI, [M+H] + )m / z: 541.39.

[0880] Step five:

[0881] A mixture of intermediate 36-4 (0.21 g), tetrahydrofuran (8 mL) and 2M dilute sulfuric acid solution (7.76 mL) was heated to 70 °C for 1 hour. The reaction was poured into water (50 mL), extracted with ethyl acetate (50 mL*3), the combined organic phase was washed with saturated sodium bicarbonate solution (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, purified by silica gel column chromatography (dichloromethane / methanol = 90:10) to give 0.15 g of intermediate 36-5.

[0882] 1 H-NMR (500 MHz, DMSO-d6): δ 9.57 (d, J = 1.0 Hz, 1H), 9.09 (s, 1H), 7.17-7.08 (m, 3H), 6.86-6.77 (m, 2H), 6.67-6.58 (m, 2H), 6.55-6.44 (m, 3H), 6.24-6.16 (m, 2H), 4.12 (d, J = 5.0 Hz, 1H), 3.66-3.59 (m, 1H), 3.57-3.51 (m, 2H), 3.30-3.25 (m, 1H), 3.01-2.86 (m, 2H), 2.80-2.73 (m, 2H), 2.49-2.42 (m, 1H), 2.34-2.17 (m, 4H), 2.15-2.07 (m, 1H), 1.82-1.77 (m, 2H), 1.73-1.68 (m, 2H), 1.49-1.40 (m, 4H), 1.37-1.34 (m, 1H).

[0883] Step six

[0884] Intermediate 36-5 (80 mg), intermediate A-2 (64.7 mg), dichloroethane (3 mL), isopropanol (0.5 mL) and sodium acetate (53.1 mg) were mixed and heated to 60 °C for 0.5 h, then sodium triacetoxyborohydride (68.6 mg) was added, stirred at 25 °C for 12 h. The reaction was poured into water (50 mL), extracted with dichloromethane (50 mL*3), the combined organic phase was washed with saturated sodium bicarbonate solution (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, purified by silica gel column chromatography (dichloromethane / methanol = 90:10) to give 50 mg of compound 36.

[0885] MS (ESI, [M+H] + )m / z: 750.401.

[0886] 1 H-NMR (500 MHz, DMSO-d6): δ 11.09 (s, 1H), 9.12 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.19-7.08 (m, 3H), 6.83 (d, J = 6.7 Hz, 2H), 6.67-6.54 (m, 4H), 6.52-6.45 (m, 1H), 6.22 (d, J = 8.7 Hz, 2H), 4.67-4.54 (m, 1H), 4.14 (s, 3H), 4.09-4.00 (m, 2H), 3.65 (s, 2H), 3.31-3.18 (m, 3H), 3.05-2.85 (m, 4H), 2.83-2.70 (m, 2H), 2.69-2.58 (m, 3H), 2.57-2.51 (m, 4H), 2.25-2.16 (m, 1H), 2.15-2.03 (m, 2H), 1.97-1.89 (m, 2H), 1.86-1.63 (m, 4H), 1.49 (s, 2H).

[0887] Example 37

[0888] Intermediate 36-5 (90 mg), intermediate A-1 (76 mg), dichloromethane (5 mL), isopropanol (1 mL) and sodium acetate (59.7 mg) were mixed and heated to 60 °C for 1 hour. Then sodium triacetoxyborohydride (77 mg) was added and stirred at 25 °C for 1 hour. The reaction was poured into water (50 mL) and extracted with dichloromethane (50 mL*3). The combined organic phase was washed with saturated sodium bicarbonate solution (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified on silica gel column (dichloromethane / methanol = 90:10) to give 50 mg of compound 37.

[0889] MS (ESI, [M+H] + m / z: 764.418.

[0890] 1 H-NMR (500MHz, DMSO-d6): δ 11.08 (s, 1H), 9.12 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.18-7.08 (m, 4H), 6.87-6.79 (m, 2H), 6.66-6.53 (m, 4H), 6.50-6.45 (m, 1H), 6.22 (d, J = 8.4 Hz, 2H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.14 (d, J = 5.0 Hz, 1H), 3.80 (s, 2H), 3.71-3.59 (m, 2H), 3.31-3.20 (m, 3H), 3.04-2.87 (m, 5H), 2.82-2.69 (m, 3H), 2.62 (s, 1H), 2.58 (s, 4H), 2.42 (s, 3H), 2.23-2.13 (m, 1H), 2.12-1.99 (m, 3H), 1.97-1.85 (m, 3H), 1.76-1.59 (m, 3H), 1.46 (s, 2H).

[0891] Example 38

[0892] Step one:

[0893] Intermediate A-2 (200 mg), N-tert-butoxy-4-piperidinone (194 mg), isopropanol (2 mL), dichloroethane (10 mL) and sodium acetate (320 mg) were mixed and heated to 60 °C for 0.5 h. Then sodium triacetoxyborohydride (413 mg) was added and the reaction was continued at 60 °C for 1 h. The reaction was poured into water (50 mL) and extracted with dichloromethane (50 mL*3). The combined organic phase was washed with saturated sodium bicarbonate solution (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification on silica gel column (petroleum ether / ethyl acetate = 70:30) gave 0.15 g of intermediate 38-1.

[0894] MS (ESI, [M+H]+) m / z: 455.38. +

[0895] Step two:

[0896] Intermediate 38-1 (240 mg), ethyl acetate (10 mL) and 4 M hydrochloric acid in dioxane (6.60 mL) were mixed and stirred at room temperature for 2 h. Concentration under reduced pressure gave 0.24 g of intermediate 38-2.

[0897] MS (ESI, [M+H]+) m / z: 355.27.

[0898] Step three:

[0899] Intermediate 38-2 (106 mg), intermediate B-1 (70 mg), N,N-dimethylformamide (1 mL) and sodium acetate (57.8 mg) were mixed and heated to 80 °C for 10 min. Then sodium cyanoborohydride (6.32 mg) was added and the reaction was continued at 80 °C for 2 h. The reaction was poured into water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (50 mL), saturated sodium bicarbonate solution (50 mL) respectively, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by preparative HPLC (column: CHIRALART Cellulose-SB, 30x250mm, 5μm; mobile phase: dichloromethane-ethanol (1:1) / n-hexane = 50 / 50) gave 11 mg of compound 38.

[0900] MS (ESI, [M+H]+) m / z: 736.387. +

[0901] 1 ​​H-NMR (500 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.09 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.21-7.05 (m, 3H), 6.83 (d, J = 7.2 Hz, 2H), 6.74-6.39 (m, 5H), 6.20 (d, J = 8.2 Hz, 2H), 4.68-4.52 (m, 1H), 4.21-3.98 (m, 4H), 3.56 (d, J = 11.6 Hz, 2H), 3.30-3.21 (m, 2H), 3.06-2.84 (m, 4H), 2.83-2.71 (m, 1H), 2.67-2.55 (m, 2H), 2.37-2.17 (m, 4H), 2.13-2.04 (m, 1H), 1.97-1.89 (m, 2H), 1.83-1.67 (m, 3H), 1.59-1.40 (m, 5H), 1.38-1.27 (m, 2H).

[0902] Example 39

[0903] Step one:

[0904] Intermediate A-3 (100 mg), N,N-dimethylformamide (1 mL), 1-Boc-azetidine-3- carboxylic acid (61.8 mg), diisopropylethylamine (108 mg) and 2-(7-azobenzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg) were mixed and stirred at room temperature for 1 hour. The stirring was stopped and the reaction solution was poured into water (30 mL) and ethyl acetate (30 mL), saturated ammonium chloride solution (30 mL) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (20 mL*2), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 95:5) to give 0.14 g of intermediate 39-1.

[0905] MS (ESI, [M-100+H]+) m / z: 369.24. +

[0906] Step two:

[0907] Intermediate 39-1 (0.14 g), dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) were mixed and stirred at room temperature for 1.5 hours. The stirring was stopped and concentrated under reduced pressure to give 0.18 g of intermediate 39-2.

[0908] MS (ESI, [M+H]+) m / z: 369.27. ​

[0909] Step three:

[0910] Intermediate 39-2 (0.178 g), isopropanol (0.5 mL), dichloroethane (1 mL), sodium acetate (0.147 g) and intermediate B-1 (0.095 g) were mixed and heated to 60 °C for 0.5 h. The heating was stopped and the reaction was cooled to room temperature. The reaction was poured into water (20 mL), then DCM (20 mL), saturated sodium bicarbonate solution (20 mL) was added. The organic phase was separated and the aqueous phase was extracted with DCM (20 mL*2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, purified by silica gel column chromatography (dichloromethane / methanol = 95:5) to give 68 mg of compound 39.

[0911] MS (ESI, [M+H] + )m / z: 750.368.

[0912] 1 H-NMR (500 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.08 (s, 1H), 7.68-7.56 (m, 1H), 7.26-7.18 (m, 1H), 7.17-7.07 (m, 3H), 6.86-6.79 (m, 2H), 6.66-6.58 (m, 2H), 6.54-6.44 (m, 3H), 6.24-6.15 (m, 2H), 4.77 (s, 1H), 4.67 (s, 1H), 4.57 (dd, J = 12.0, 5.0 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.81 (t, J = 6.2 Hz, 1H), 3.70-3.43 (m, 4H), 3.41-3.32 (m, 3H), 3.31-3.23 (m, 2H), 3.22-3.05 (m, 2H), 3.05-2.86 (m, 4H), 2.82-2.72 (m, 1H), 2.65-2.55 (m, 3H), 2.54-2.51 (m, 1H), 2.22-2.15 (m, 1H), 2.13-2.02 (m, 2H), 1.74-1.55 (m, 3H).

[0913] Example 40

[0914] Step one:

[0915] Intermediate A-1 (115 mg), 1-Boc-4-piperidone (285 mg), sodium cyanoborohydride (135 mg), sodium acetate (147 mg) and N,N-dimethylacetamide (5 mL) were mixed and stirred at 60 °C for 12 h. The system was cooled to room temperature. Ethyl acetate and sodium bicarbonate solution were added to the system. The aqueous phase was extracted with ethyl acetate twice and the combined organic phase was washed with saturated sodium chloride solution. It was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by medium pressure preparative chromatography (dichloromethane / methanol = 90:10) gave 113.6 mg of intermediate 40-1.

[0916] MS (ESI, [M+H] + )m / z: 469.34.

[0917] Step two:

[0918] Intermediate 40-1 (113.6 mg) and 4 M hydrogen chloride in dioxane (5 mL) were mixed and stirred at room temperature for 16 h. The reaction was directly concentrated to give 157.5 mg of intermediate 40-2.

[0919] MS (ESI, [M+H] + )m / z: 369.16.

[0920] Step three:

[0921] Intermediate 40-2 (157.5 mg), intermediate B-1 (95.4 mg), sodium cyanoborohydride (121 mg), sodium acetate (118 mg) and N,N-dimethylacetamide (5 mL) were mixed and heated to 60 °C for 16 h. The heating was stopped and the system was cooled to room temperature. Ethyl acetate and aqueous ammonium chloride solution were added to the system. The phases were separated and the aqueous phase was extracted with ethyl acetate twice. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by medium pressure preparative chromatography (dichloromethane / methanol = 90:10) and C18 reverse phase chromatography (water / acetonitrile = 30:70) to give 40 mg of compound 40.

[0922] MS (ESI, [M+H] + )m / z: 750.402.

[0923] 1H-NMR (500 MHz, CDC13): δ 7.41 (dd, J = 8.2, 4.0 Hz, 1 H), 7.14 (d, J = 6.2 Hz, 3 H), 7.07 (dd, J = 8.4, 2.0 Hz, 1 H), 6.85 - 6.76 (m, 3 H), 6.68 (d, J = 2.6 Hz, 1 H), 6.54 (dd, J = 11.6, 7.3 Hz, 3 H), 6.27 (d, J = 8.3 Hz, 2 H), 4.28 (dd, J = 8.6, 5.2 Hz, 1 H), 4.18 (d, J = 5.0 Hz, 1 H), 4.05 (s, 2 H), 3.61 (d, J = 11.8 Hz, 2 H), 3.37 - 3.30 (m, 1 H), 3.10 (d, J = 10.9 Hz, 2 H), 3.00 (tq, J = 16.2, 8.0 Hz, 6 H), 2.89 (dt, J = 11.5, 5.1 Hz, 2 H), 2.73 (ddd, J = 17.7, 8.9, 5.2 Hz, 1 H), 2.58 (qd, J = 10.1, 5.7 Hz, 4 H), 2.43 (dd, J = 13.6, 7.4 Hz, 2 H), 2.32 (s, 2 H), 2.16 (qd, J = 12.7, 6.5 Hz, 1 H), 2.00 (s, 1 H), 1.97 (d, J = 11.8 Hz, 2 H), 1.89 (d, J = 12.0 Hz, 2 H), 1.67 (s, 2 H), 1.26 (t, J = 11.9 Hz, 1 H).

[0924] Example 41

[0925] Step one:

[0926] Intermediate A-4 (160 mg), 1-Boc-4-piperidone (190 mg), sodium cyanoborohydride (240 mg), sodium acetate (235 mg) and DMA (10 mL) were mixed and stirred at 60 °C for 12 h. The system was cooled to room temperature, ethyl acetate and sodium bicarbonate solution were added to the system. The aqueous phase was extracted with ethyl acetate twice, the organic phase was combined and washed with saturated sodium chloride solution. It was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by medium pressure preparative chromatography (dichloromethane / methanol = 90:10) to give 158 mg of intermediate 41-1.

[0927] MS (ESI, [M+H] + )m / z: 483.39.

[0928] Step two:

[0929] Intermediate 41-1 (158 mg) and 4 M hydrogen chloride solution in dioxane (6 mL) were mixed and stirred at room temperature for 16 hours. The reaction was concentrated directly to give 148.9 mg of intermediate 41-2.

[0930] MS (ESI, [M+H]+) m / z: 383.26.

[0931] Step three:

[0932] Intermediate 41-2 (148.9 mg), intermediate B-1 (130 mg), sodium cyanoborohydride (164 mg), sodium acetate (161 mg) and N,N-dimethylacetamide (6.5 mL) were mixed and heated to 60 °C for 6 hours. The heating was stopped and the system was cooled to room temperature. Ethyl acetate and aqueous ammonium chloride were added to the system, the mixture was separated, the aqueous phase was extracted with ethyl acetate twice, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by medium pressure preparative chromatography (dichloromethane / methanol = 90:10) and C18 reverse phase column chromatography (water / acetonitrile = 20:80) to give 50 mg of compound 41.

[0933] MS (ESI, [M+H] + )m / z: 764.417.

[0934] 1 H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.09 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.15-7.08 (m, 3H), 6.85-6.80 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 8.3 Hz, 2H), 6.47 (dd, J = 8.3, 2.6 Hz, 1H), 6.20 (d, J = 8.2 Hz, 2H), 4.54 (dd, J = 11.9, 5.0 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.57 (s, 2H), 3.30-3.24 (m, 2H), 3.13 (s, 2H), 3.01 (d, J = 8.2 Hz, 2H), 3.00-2.84 (m, 4H), 2.76 (td, J = 12.0, 6.0 Hz, 5H), 2.65-2.52 (m, 3H), 2.48-2.42 (m, 2H), 2.18 (dq, J = 8.7, 4.6 Hz, 1H), 2.12-2.05 (m, 2H), 1.70 (d, J = 12.9 Hz, 5H), 1.47 (s, 4H), 1.24 (d, J = 6.7 Hz, 1H).

[0935] Example 42

[0936] Intermediate 40-2 (53.6 mg), intermediate B-3 (55 mg), sodium acetate (40 mg), isopropanol (0.4 mL) and 1,2-dichloroethane (2 mL) were mixed and heated to 60 °C for 1 hour. To the system was added sodium triacetoxyborohydride (103 mg) and the reaction was continued at 60 °C for 5 hours. The heating was stopped and the system was cooled to room temperature. To the system was added ethyl acetate and aqueous ammonium chloride solution, the mixture was separated, the aqueous phase was extracted with ethyl acetate twice, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by medium pressure preparative chromatography (dichloromethane / methanol = 90:10) to give 23 mg of compound 42.

[0937] MS (ESI, [M+H] + )m / z: 764.419.

[0938] 1 H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.09 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.14 (qd, J = 7.9, 2.3 Hz, 4H), 6.86-6.80 (m, 2H), 6.64 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 8.2 Hz, 2H), 6.48 (dd, J = 8.2, 2.6 Hz, 1H), 6.20 (d, J = 8.3 Hz, 2H), 4.55 (dd, J = 11.8, 4.9 Hz, 1H), 4.13 (d, J = 5.0 Hz, 1H), 3.95 (s, 2H), 3.52 (d, J = 10.2 Hz, 2H), 3.27 (d, J = 4.2 Hz, 1H), 2.95 (qt, J = 16.6, 8.4 Hz, 5H), 2.85 (s, 2H), 2.76 (ddd, J = 17.2, 11.8, 5.3 Hz, 2H), 2.66-2.56 (m, 2H), 2.48 (s, 1H), 2.23-2.14 (m, 2H), 2.10 (dd, J = 12.5, 6.2 Hz, 2H), 1.90 (d, J = 11.3 Hz, 3H), 1.72 (t, J = 15.5 Hz, 6H), 1.24 (d, J = 4.6 Hz, 4H), 1.15 (s, 1H).

[0939] Example 43

[0940] Step one:

[0941] Intermediate A-2 (120 mg), 1-Boc-azetidine-3-carboxylic acid (84 mg), N,N- dimethylformamide (5 mL), N,N-diisopropyl ethylamine (135 mg) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (200 mg) were mixed and reacted at 25 °C for 1 hour. Ammonium chloride solution and ethyl acetate were added to the system, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the filtrate was concentrated, and purified by column chromatography (dichloromethane:methanol = 90:10) to give 150 mg of intermediate 43-1.

[0942] MS (ESI, [M+H-100] + )m / z: 355.22.

[0943] Step two:

[0944] Intermediate 43-1 (63.6 mg) and 4M hydrochloric acid in dioxane (2 mL) were mixed and stirred at room temperature for 16 hours. The reaction solution was directly concentrated to give 54.7 mg of intermediate 43-2.

[0945] MS (ESI, [M+H] + )m / z: 355.27.

[0946] Step three:

[0947] Intermediate 43-2 (54.7 mg), intermediate B-1 (55.7 mg), sodium acetate (46 mg), isopropyl alcohol (0.8 mL), 1,2-dichloroethane (4 mL) and sodium triacetoxyborohydride (59.3 mg) were mixed and heated to 60 °C for 3 hours. The heating was stopped and the system was cooled to room temperature. Ethyl acetate and aqueous sodium bicarbonate solution were added to the system, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by medium pressure preparative chromatography (dichloromethane / methanol = 90:10) and C18 reverse phase column chromatography (water / acetonitrile = 40:60) to give 20 mg of compound 43.

[0948] MS (ESI, [M+H] + )m / z: 736.3516.

[0949] 1H-NMR (500 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.09 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 21.4, 8.1 Hz, 1H), 7.14 (d, J = 9.8 Hz, 3H), 6.83 (d, J = 7.2 Hz, 2H), 6.70-6.41 (m, 5H), 6.20 (d, J = 8.0 Hz, 2H), 5.02 (s, 1H), 4.90 (s, 2H), 4.80 (s, 1H), 4.69-4.58 (m, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.68-3.36 (m, 5H), 3.28-3.12 (m, 2H), 2.96 (s, 2H), 2.76 (d, J = 12.7 Hz, 1H), 2.62 (d, J = 13.8 Hz, 3H), 2.26-2.04 (m, 3H), 1.69 (s, 3H), 1.23 (s, 4H).

[0950] Example 44

[0951] Step one:

[0952] A mixture of 1,4-diiodobenzene (19.8 g), 4-piperidone glycol (8.6 g), dimethyl sulfoxide (75 mL), L-proline (2.8 g), potassium carbonate (16.6 g) and cuprous iodide (2.3 g) was stirred at 75 °C for 36 h under nitrogen atmosphere. The mixture was cooled to room temperature, and then ammonium chloride solution (10 mL) and ethyl acetate were added. The solid was dissolved by adding water, and then the mixture was filtered through celite. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate twice. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to give 13.4 g of intermediate 44-1.

[0953] MS (ESI, [M+H] + )m / z: 346.06.

[0954] 1 H-NMR (500 MHz, CDCl3): δ 7.51-7.47 (m, 2H), 6.72-6.68 (m, 2H), 3.99 (s, 4H), 3.35-3.27 (m, 4H), 1.85-1.79 (m, 4H).

[0955] Step two:

[0956] Intermediate 44-1 (10.35 g), acetonitrile (75 mL), triethylamine (10.62 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (330 mg,) and 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (7.68 g) were mixed and reacted at 75 °C for 3 hours under nitrogen atmosphere. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 90:10) to give 9.8 g of intermediate 44-2.

[0957] MS (ESI, [M+H] + m / z: 346.27.

[0958] 1 H-NMR (500 MHz, CDC13): δ 7.69 (d, J = 8.6 Hz, 2H), 6.92-6.88 (m, 2H), 3.99 (s, 4H), 3.44 - 3.39 (m, 4H), 1.85-1.77 (m, 4H), 1.32 (s, 12H).

[0959] Step three:

[0960] Intermediate D-1 (8.93 g), intermediate 44-2 (9.56 g), 1,4-dioxane (230 mL), water (50 mL), potassium carbonate (7.66 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1.02 g) were mixed and reacted at 90 °C for 2 hours under nitrogen atmosphere. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 90:10) to give 10.5 g of intermediate 44-3.

[0961] MS (ESI, [M+H] + m / z: 392.25.

[0962] 1 H-NMR (500 MHz, CDC13): δ 7.19-7.14 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.89-6.84 (m, 2H), 6.82 (d, J = 2.7 Hz, 1H), 6.73 (dd, J = 8.5, 2.7 Hz, 1H), 6.29 (t, J = 7.3 Hz, 1H), 3.99 (s, 4H), 3.83 (s, 3H), 3.37-3.30 (m, 4H), 2.62 (t, J = 7.0 Hz, 2H), 2.14 (p, J = 7.1 Hz, 2H), 1.94 (q, J = 7.2 Hz, 2H), 1.87-1.81 (m, 4H).

[0963] Step four:

[0964] Intermediate 44-3 (750 mg) was dissolved in dichloromethane (75 mL), 1M boron tribromide in dichloromethane (9.6 mL) was added dropwise, and the mixture was stirred at 25°C for 14 hours. The mixture was diluted with dichloromethane (300 mL) and poured into water (500 mL), and the aqueous phase was adjusted to pH 7 with sodium bicarbonate solid. The phases were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give 100 mg of intermediate 44-4.

[0965] MS (ESI, [M+H] + )m / z: 334.25.

[0966] 1 H NMR (500 MHz, CDC13): δ 7.23-7.19 (m, 2H), 6.95-6.88 (m, 3H), 6.76 (d, J = 2.7 Hz, 1H), 6.66 (dd, J = 8.3, 2.7 Hz, 1H), 6.30 (t, J = 7.3 Hz, 1H), 3.62 (t, J = 6.0 Hz, 4H), 2.58 (dt, J = 16.5, 6.5 Hz, 6H), 2.14 (q, J = 7.1 Hz, 2H), 1.95 (q, J = 7.2 Hz, 2H).

[0967] Step five:

[0968] Intermediate 44-4 (100 mg), intermediate 2-2 (97.9 mg), sodium acetate (98.4 mg), isopropanol (1.7 mL), 1,2-dichloroethane (8.3 mL), and sodium triacetoxyborohydride (127 mg) were mixed and heated to 60°C for 7 hours. Sodium cyanoborohydride (37.7 mg) was added to the mixture, which was stirred at 60°C for 4 hours. The mixture was cooled to room temperature. Ethyl acetate and aqueous sodium bicarbonate solution were added to the mixture, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by medium pressure preparative chromatography (dichloromethane / methanol = 90:10) to give 23 mg of compound 44.

[0969] MS (ESI, [M+H] + )m / z: 644.3240.

[0970] 1H-NMR (500 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.36 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.72-6.68 (m, 2H), 6.60 (dd, J = 8.3, 2.6 Hz, 1H), 6.20 (t, J = 7.3 Hz, 1H), 4.61 (dd, J = 11.9, 5.0 Hz, 1H), 4.26 (s, 2H), 4.13 (s, 3H), 3.76 (s, 4H), 2.84-2.58 (m, 5H), 2.54 (dd, J = 10.6, 3.2 Hz, 2H), 2.47 (d, J = 5.8 Hz, 3H), 2.21 (dt, J = 13.2, 4.6 Hz, 1H), 2.06 (p, J = 7.1 Hz, 2H), 1.91 (s, 2H), 1.85 (q, J = 7.2 Hz, 2H), 1.45-1.30 (m, 2H).

[0971] Example 45

[0972] Intermediate B-3 (108.6 mg), intermediate A-4 (60.5 mg), sodium acetate (49.8 mg), isopropanol (2 mL) and 1,2-dichloroethane (10 mL) were mixed and reacted at 50 °C for 30 min. Triacetoxyborohydride sodium (86 mg) was added at room temperature and stirred at room temperature for 1 h. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL*3), the organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, purified by silica gel column chromatography (dichloromethane / methanol = 70:30) to give 123 mg of compound 45.

[0973] MS (ESI, [M+H] + )m / z: 695.3601.

[0974] 1H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.09 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.14 (td, J = 12.7, 6.9 Hz, 4H), 6.84 (d, J = 6.6 Hz, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.54 (d, J = 9.0 Hz, 2H), 6.48 (dd, J = 8.3, 2.7 Hz, 1H), 6.21 (d, J = 8.9 Hz, 2H), 5.75 (s, 1H), 4.54 (dd, J = 11.9, 5.0 Hz, 1H), 4.13 (d, J = 5.0 Hz, 1H), 3.52 (d, J = 8.7 Hz, 2H), 3.26 (s, 1H), 3.14 (d, J = 6.7 Hz, 2H), 3.03 (d, J = 9.2 Hz, 2H), 2.99 - 2.87 (m, 2H), 2.76 (ddd, J = 17.2, 12.0, 5.3 Hz, 1H), 2.67 - 2.56 (m, 5H), 2.31 (d, J = 6.9 Hz, 2H), 2.23 - 2.14 (m, 1H), 2.09 (dd, J = 19.1, 6.5 Hz, 1H), 1.78 (d, J = 11.4 Hz, 2H), 1.74 - 1.60 (m, 2H), 1.26 - 1.13 (m, 4H).

[0975] Example 46

[0976] Step one:

[0977] Intermediate C-2 (176 mg), potassium carbonate (94 mg), tert-butyl bromoacetate (100 mg) and acetonitrile (10 mL) were mixed and reacted at room temperature for 2 hours. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL*3), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 85:15) to obtain 82.8 mg of intermediate 46-1.

[0978] MS (ESI, [M+H] + )m / z: 630.32.

[0979] 1H-NMR (500MHz, MeOD): δ 8.05 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 6.46 (s, 1H), 6.44 (s, 1H), 5.67-5.42 (m, 1H), 5.25 (s, 1H), 3.58-3.55 (m, 1H), 3.21-3.19 (m, 4H), 3.14 (s, 2H), 3.08-2.88 (m, 3H), 2.82-2.69 (m, 1H), 2.59-2.57 (m, 4H), 1.62-1.58 (m, 8H), 1.47 (s, 9H), 1.12 (d, J = 6.6 Hz, 3H).

[0980] Step two:

[0981] Intermediate 46-1 (75 mg), dichloromethane (5 mL) and trifluoroacetic acid (5 mL) were mixed and stirred at room temperature for 4 hours. The reaction solution was directly concentrated under reduced pressure to obtain 120 mg of intermediate 46-2.

[0982] MS (ESI, [M+H] + )m / z: 574.27.

[0983] Step three:

[0984] Intermediate 46-2 (90 mg), intermediate A-2 (62.8 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (119 mg), N,N-diisopropyl ethylamine (122 mg) and N,N-dimethylformamide (10 mL) were mixed and reacted at 25°C for 2 hours. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL*3), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, purified by silica gel column chromatography (dichloromethane / methanol = 50:50) and C18 column chromatography (acetonitrile / water = 65:35) to obtain 40.8 mg of compound 46.

[0985] MS (ESI, [M+H] + )m / z: 827.3656.

[0986] 1H-NMR (500MHz, DMSO-d6): δ 12.97 (s, 1H), 11.12 (s, 1H), 8.06 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 8.5, 5.0 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.52 (s, 1H), 6.50 (s, 1H), 5.93-5.67 (m, 1H), 5.23 (s, 1H), 5.16 (s, 1H), 5.09 (s, 1H), 4.91 (s, 1H), 4.81 (s, 1H), 4.64 (dd, J = 12.5, 5.5 Hz, 1H), 3.50-3.44 (m, 1H), 3.31-3.25 (m, 2H), 3.24-3.11 (m, 6H), 3.07-2.98 (m, 1H), 2.94-2.85 (m, 1H), 2.81-2.75 (m, 1H), 2.70-2.60 (m, 2H), 2.58-2.52 (m, 4H), 2.26-2.17 (m, 1H), 1.56-1.42 (m, 8H), 1.05 (d, J = 6.5 Hz, 3H).

[0987] Example 47

[0988] Step one:

[0989] Intermediate D-2 (250 mg), 8-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)- 1,4-dioxa-8-azaspiro[4.5]decane (250 mg), potassium carbonate (173 mg), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (36.4 mg), 1,4-dioxane (4 mL) and water (1 mL) were mixed, heated under microwave at 120 °C for 2 hours. The reaction was filtered with celite, the filtrate was poured into water (10 mL), extracted with ethyl acetate (10 mL*3), the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 72:28) to give 255 mg of intermediate 47-1.

[0990] MS (ESI, [M+H] + )m / z: 568.29.

[0991] 1H-NMR (500MHz, DMSO-d6): δ 8.27 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 6.96-6.89 (m, 4H), 6.75 (d, J = 8.7 Hz, 1H), 5.76 (dd, J = 9.6, 2.6 Hz, 1H), 4.03 (q, J = 7.2 Hz, 1H), 3.91 (d, J = 3.4 Hz, 5H), 3.88-3.83 (m, 1H), 3.73-3.66 (m, 1H), 3.28 (q, J = 5.7 Hz, 5H), 2.99 (t, J = 7.0 Hz, 2H), 2.45-2.36 (m, 1H), 2.30 (q, J = 7.2 Hz, 2H), 2.03 (q, J = 6.9 Hz, 3H), 1.97-1.91 (m, 1H), 1.73-1.68 (m, 4H), 1.60-1.52 (m, 2H).

[0992] Step two:

[0993] Intermediate 47-1 (200 mg), tetrahydrofuran (3 mL) and 2M sulfuric acid (5.64 mL) were mixed and stirred at 70 °C for 3 hours. The reaction solution was adjusted to neutral pH with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 175.8 mg of intermediate 47-2.

[0994] MS (ESI, [M+H] + )m / z: 440.37.

[0995] Step three:

[0996] Intermediate 47-2 (150 mg), intermediate 2-2 (186 mg), sodium acetate (56.0 mg), isopropyl alcohol (1 mL) and 1,2-dichloroethane (1 mL) were mixed and stirred at 60 °C for 30 minutes, then sodium triacetoxyborohydride (217 mg) was added and stirred at 60 °C for 1 hour. The reaction solution was poured into water (10 mL) and extracted with dichloromethane (10 mL*3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, then purified by silica gel column chromatography (dichloromethane / methanol = 65:35) to give 96.5 mg of compound 47.

[0997] MS (ESI, [M+H] + )m / z: 750.338.

[0998] 1H-NMR (500 MHz, DMSO-d6): δ 12.99 (s, 1H), 11.09 (s, 1H), 8.22 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.91 (s, 4H), 6.70 (d, J = 8.5 Hz, 1H), 4.60 (dd, J = 11.9, 5.0 Hz, 1H), 4.16 (s, 2H), 4.05 (s, 2H), 3.59 (d, J = 12.8 Hz, 2H), 3.54 (t, J = 6.5 Hz, 1H), 3.44 (s, 2H), 3.24 (t, J = 11.6 Hz, 2H), 3.10 - 2.96 (m, 4H), 2.78 (q, J = 11.8 Hz, 3H), 2.61 (dt, J = 17.2, 4.0 Hz, 1H), 2.31 (p, J = 7.0 Hz, 2H), 2.20 (dq, J = 8.2, 4.5 Hz, 2H), 2.03 (t, J = 7.1 Hz, 2H), 1.75 (d, J = 9.5 Hz, 2H), 1.36 - 1.19 (m, 3H).

[0999] Example 48

[1000] Intermediate 16-2 (95 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (210 mg), N,N-dimethylformamide (5 ml) and 1-hydroxybenzotriazole (37.4 mg) were mixed, stirred at room temperature for 10 minutes, then intermediate B-4 (130 mg) was added, stirred at room temperature for 1.5 hours, the reaction solution was poured into a mixture of ethyl acetate (20 mL) and water (20 mL), the two phases were separated, the aqueous phase was extracted with ethyl acetate (2*10 mL), the combined organic phases were then washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, purified by medium-low pressure preparative chromatography (dichloromethane / methanol = 90:10), the combined organic phases were concentrated under reduced pressure, and purified by C18 column chromatography (acetonitrile: water = 70:30) to give 40 mg of compound 48.

[1001] MS (ESI, [M+H] + )m / z: 710.334

[1002] 1H-NMR (500MHz, DMSO-d6): δ 11.07 (s, 1H), 9.09 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.19-7.06 (m, 4H), 6.82 (d, J = 6.6 Hz, 2H), 6.67-6.58 (m, 2H), 6.54 (d, J = 8.9 Hz, 2H), 6.48 (d, J = 2.6 Hz, 1H), 6.21 (d, J = 8.7 Hz, 2H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.13 (d, J = 4.9 Hz, 1H), 3.90 (s, 2H), 3.60 (d, J = 33.4 Hz, 4H), 3.48 (s, 2H), 3.04-2.87 (m, 8H), 2.78 (dt, J = 33.4, 6.1 Hz, 3H), 2.60 (dt, J = 17.4, 4.3 Hz, 1H), 2.49-2.42 (m, 2H), 2.18 (dt, J = 8.2, 4.1 Hz, 1H), 2.07 (td, J = 12.4, 6.2 Hz, 1H), 1.69 (d, J = 6.3 Hz, 1H).

[1003] Example 49

[1004] Step one:

[1005] Intermediate A-1 (120 mg), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (179 mg), sodium acetate (31 mg), sodium triacetoxyborohydride (158 mg), 2-propanol (2 ml) and 1,2-dichloroethane (2 ml) were mixed and stirred at room temperature for 2 h. The reaction was poured into a mixture of ethyl acetate (20 mL) and water (20 mL), the two phases were separated, the aqueous phase was extracted with ethyl acetate (2*10 mL), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by medium pressure preparative chromatography (dichloromethane / methanol = 90:10) to give 220 mg of intermediate 49-1.

[1006] MS (ESI, [M+H] + )m / z: 509.37

[1007] Step two:

[1008] Intermediate 49-1 (220 mg), dichloromethane (6 ml) and 4M hydrochloric acid in dioxane (8 mL) were mixed and stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give 210 mg of intermediate 49-2.

[1009] MS (ESI, [M+H]+ m / z: 409.30

[1010] Step three:

[1011] Intermediate 49-2 (85 mg), intermediate B-3 (85 mg), sodium acetate (25.8 mg), 2-propanol (2 ml) and 1,2-dichloroethane (2 ml) were mixed and stirred at 50 °C for 20 min. Sodium triacetoxyborohydride (100 mg) was added and stirring was continued for 2 h. The reaction was poured into a mixture of ethyl acetate (20 mL) and water (20 mL), the two phases were separated, the aqueous phase was extracted with ethyl acetate (2*10 mL), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, purified by medium pressure preparative chromatography (dichloromethane / methanol = 70:30), the combined organic phases were concentrated under reduced pressure to give 70 mg of compound 49.

[1012] MS (ESI, [M+H] + m / z: 804.451

[1013] 1 H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.08 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.19-7.08 (m, 4H), 6.83 (d, J = 6.6 Hz, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.52 (d, J = 9.0 Hz, 2H), 6.47 (dd, J = 8.2, 2.6 Hz, 1H), 6.19 (d, J = 8.9 Hz, 2H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.66 (s, 2H), 3.49 (d, J = 15.7 Hz, 2H), 3.17 (d, J = 4.3 Hz, 1H), 3.03 - 2.86 (m, 5H), 2.80 - 2.73 (m, 1H), 2.66 - 2.56 (m, 3H), 2.46 (d, J = 11.7 Hz, 5H), 2.34 - 2.13 (m, 4H), 2.14 - 2.00 (m, 4H), 1.91 (s, 1H), 1.75 - 1.41 (m, 9H), 1.17 - 1.05 (m, 2H).

[1014] Example 50

[1015] Intermediate B-3 (70 mg), intermediate 1-2 (80 mg), sodium acetate (41.9 mg), isopropanol (3 ml) and 1,2-dichloroethane (3.00 ml) were mixed and stirred at 60 °C for 20 minutes. Sodium triacetoxyborohydride (108 mg) was added and stirred at 60 °C for 2 hours. The reaction solution was poured into a mixture of ethyl acetate (20 mL) and water (20 mL), the two phases were separated, the aqueous phase was extracted with ethyl acetate (2*10 mL), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, purified by medium pressure preparative chromatography (dichloromethane / methanol = 80:20), the combined organic phases were concentrated under reduced pressure to give 30 mg of compound 50.

[1016] MS (ESI, [M+H] + m / z: 736.386

[1017] 1 H-NMR (500MHz, DMSO-d6): δ 11.09 (s, 1H), 9.13 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 7.6 Hz, 4H), 6.82 (d, J = 7.5 Hz, 2H), 6.70-6.40 (m, 5H), 6.19 (d, J = 8.5 Hz, 2H), 4.56 (s, 1H), 4.19-3.93 (m, 2H), 3.67 (s, 2H), 3.48 (d, J = 16.0 Hz, 4H), 3.25 (s, 3H), 3.15 (s, 1H), 3.01-2.82 (m, 5H), 2.82-2.69 (m, 1H), 2.60 (s, 3H), 2.45 (s, 3H), 2.29 (d, J = 6.6 Hz, 2H), 2.23-2.04 (m, 2H), 1.99 (s, 1H), 1.69 (d, J = 11.6 Hz, 3H).

[1018] Example 51

[1019] Step one:

[1020] 9-oxo-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (500 mg) was dissolved in hexafluoroisopropanol (8 ml) and reacted at 130 °C for 5 hours under microwave. Concentrated under reduced pressure to give 1 g of intermediate 51-1

[1021] 1H-NMR (500 MHz, DMSO-d6): δ 2.76-2.74 (m, 1H), 2.73-2.66 (m, 4H), 2.58-2.22 (m, 4H), 1.67-1.64 (m, 4H), 1.49-1.42 (m, 4H).

[1022] Step two:

[1023] Step two:

[1024] MS (ESI, [M+H] + m / z: 554.38

[1025] 1 H-NMR (500 MHz, DMSO-d6): δ 7.44 (d, J = 7.0 Hz, 2H), 7.42-7.37 (m, 2H), 7.35-7.30 (m, 1H), 7.30-7.21 (m, 1H), 7.11 (q, J = 7.6 Hz, 2H), 7.04-7.01 (m, 2H), 6.92 (d, J = 4.6 Hz, 2H), 6.82 (s, 3H), 6.72 (dd, J = 8.5, 2.9 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 5.09 (s, 2H), 3.15 (t, J = 5.8 Hz, 2H), 2.92-2.85 (m, 2H), 2.68 (d, J = 9.0 Hz, 2H), 2.51-2.49 (m, 6H), 1.71 (t, J = 6.8 Hz, 2H), 1.65 (t, J = 5.8 Hz, 2H), 1.24 (d, J = 6.9 Hz, 4H).

[1026] Step three:

[1027] Intermediate 51-2 (400 mg), palladium on carbon (63.4 mg), tetrahydrofuran (4 ml) and methanol (4.00 ml) were mixed, stirred at 40 °C under hydrogen atmosphere for 16 h, concentrated under reduced pressure to give 120 mg of mixture product, which was purified by preparative HPLC (column: CHIRALART Amylose-A, 30 x 250 mm, 10 pm; mobile phase: mobile phase: n-hexane: dichloromethane: ethanol = 70: 15: 15, isocratic elution) to give 50 mg of intermediate 51-3.

[1028] MS (ESI, [M+H] + )m / z: 466.51

[1029] 1 H-NMR (500 MHz, DMSO-d6): δ 9.08 (s, 1H), 7.22-7.07 (m, 3H), 6.83 (d, J = 6.6 Hz, 2H), 6.67-6.53 (m, 4H), 6.50-6.45 (m, 1H), 6.21 (d, J = 8.7 Hz, 2H), 4.13 (d, J = 5.2 Hz, 1H), 3.01 (t, J = 5.7 Hz, 4H), 2.98-2.85 (m, 2H), 2.25 (t, J = 6.9 Hz, 4H), 2.10 (qd, J = 12.4, 6.1 Hz, 1H), 1.67 (t, J = 6.9 Hz, 3H), 1.60 (t, J = 6.0 Hz, 3H), 1.25 (d, J = 11.3 Hz, 4H).

[1030] Step four:

[1031] Intermediate 51-3 (45 mg), intermediate A-2 (40 mg), sodium acetate (15.86 mg), sodium cyanoborohydride (12.15 mg) and N,N-dimethylacetamide (4 ml) were mixed, stirred at 60 °C for 1.5 h. The reaction was poured into a mixture of ethyl acetate (20 mL) and water (20 mL), the two phases were separated, the aqueous phase was extracted with ethyl acetate (2*10 mL), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, purified by silica gel column chromatography (dichloromethane / methanol = 80:20) and C18 column chromatography (acetonitrile: water = 75:25) to give 20 mg of compound 51

[1032] HRMS (ESI, [M+H] + )m / z: 721.3747

[1033] 1H-NMR (500 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.09 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.13 (dd, J = 11.9, 7.2 Hz, 3H), 6.83 (d, J = 6.6 Hz, 2H), 6.68 - 6.58 (m, 2H), 6.53 (d, J = 9.0 Hz, 2H), 6.48 (dd, J = 8.3, 2.7 Hz, 1H), 6.20 (d, J = 8.7 Hz, 2H), 4.59 (dd, J = 11.8, 5.0 Hz, 1H), 4.22 - 4.10 (m, 3H), 4.05 (s, 2H), 3.31 - 3.24 (m, 2H), 3.03 - 2.86 (m, 6H), 2.77 (ddd, J = 17.2, 11.9, 5.3 Hz, 1H), 2.67 - 2.56 (m, 1H), 2.19 (dd, J = 8.9, 4.1 Hz, 1H), 2.10 (dq, J = 12.5, 6.4 Hz, 1H), 1.79 (d, J = 9.8 Hz, 2H), 1.66 (d, J = 14.8 Hz, 3H), 1.54 (d, J = 5.3 Hz, 2H), 1.44 (t, J = 11.7 Hz, 4H), 1.30 - 1.13 (m, 3H).

[1034] Example 52

[1035] Step one:

[1036] Dissolve 8-(4-bromophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (657 mg) in tetrahydrofuran (3 ml), add 2M n-butyllithium in n-hexane (211.8 mg, 1.323 ml) at -60 ℃, keep the temperature at -60 ℃ for 0.5 hour after the addition is completed. Dissolve intermediate D-3 (600 mg) in tetrahydrofuran (3 ml), dropwise add to the above reaction solution, continue to stir at -60 ℃ for 2 hours. Pour the reaction solution into water, add ethyl acetate (50 mL) to extract, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, purify the residue on a silica gel column (petroleum ether: ethyl acetate = 85:15) to obtain 800 mg of intermediate 52-1

[1037] MS (ESI, [M+H] + )m / z: 492.37

[1038] 1H-NMR (500 MHz, DMSO-d6): δ 7.62 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 8.2 Hz, 2H), 6.90-6.86 (m, 2H), 6.82 (dd, J = 8.7, 2.7 Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H), 5.51 (s, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 3.27-3.22 (m, 4H), 2.88 (dd, J = 10.1, 5.1 Hz, 1H), 2.45 (dd, J = 13.7, 5.5 Hz, 1H), 2.33 (td, J = 13.9, 2.7 Hz, 2H), 1.81-1.76 (m, 1H), 1.72-1.64 (m, 6H), 1.57-1.49 (m, 1H), 1.41 (t, J = 12.9 Hz, 1H).

[1039] Step two:

[1040] Intermediate 52-1 (400 mg) was dissolved in dichloromethane (7 ml), and boron tribromide (4.07 ml) was added under ice bath. The reaction was stirred under ice bath for 1 hour. The reaction solution was poured into water, and ethyl acetate (50 mL) was added to extract. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 80:20) to obtain 200 mg of intermediate 52-2.

[1041] MS (ESI, [M+H] + )m / z: 416.38

[1042] 1 H-NMR (500 MHz, DMSO-d6): δ 9.36 (s, 1H), 7.03-6.88 (m, 4H), 6.65 (d, J = 2.2 Hz, 1H), 6.56 -6.49 (m, 2H), 3.60 (t, J = 6.1 Hz, 4H), 3.18 (q, J = 11.6 Hz, 2H), 2.57 (t, J = 6.9 Hz, 2H), 2.44 (t, J = 6.0 Hz, 4H), 2.13 (p, J = 7.0 Hz, 2H), 2.07-1.96 (m, 2H).

[1043] Step three:

[1044] Intermediate 52-2 (150 mg), intermediate 2-2 (168 mg), sodium acetate (70.2 mg), 1,2-dichloroethane (4.00 mL), and isopropanol (4 mL) were mixed and stirred at 60 °C for 20 minutes. Sodium triacetoxyborohydride (181 mg) was added to the mixture, and the reaction was continued to stir at 60 °C for 1 hour. The reaction solution was poured into water, and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 85:15) to obtain 110 mg of compound 52.

[1045] MS (ESI, [M+H] + m / z: 726.327.

[1046] 1 H-NMR (500MHz, DMSO-d6): δ 11.10 (s, 1H), 9.38 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.95-6.86 (m, 4H), 6.65 (s, 1H), 6.51 (s, 2H), 4.61 (dd, J = 11.9, 5.0 Hz, 1H), 4.24 (s, 2H), 4.11 (s, 3H), 3.73 (s, 5H), 3.16 (q, J = 11.6 Hz, 3H), 2.83-2.69 (m, 3H), 2.63 (t, J = 4.1 Hz, 1H), 2.62-2.53 (m, 3H), 2.26-2.17 (m, 1H), 2.13 (p, J = 6.8 Hz, 2H), 2.00 (t, J = 7.0 Hz, 2H), 1.90 (d, J = 8.1 Hz, 2H), 1.41 (s, 2H), 1.27-1.17 (m, 1H).

[1047] Example 53

[1048] Step one:

[1049] Intermediate 46-2 (100 mg), intermediate A-1 (54.7 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (88 mg), N,N-diisopropylethylamine (300 mg), and N,N-dimethylformamide (5 mL) were mixed and reacted at 25 °C for 2 hours. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL*3), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50:50) to obtain 50 mg of compound 53.

[1050] HRMS (ESI, [M+H] + )m / z: 841.3828.

[1051] 1 H-NMR (500MHz, DMSO-d6): δ 12.96 (s, 1H), 11.08 (s, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.23-7.17 (m, 2H), 6.72-6.70 (m, 1H), 6.52-6.45 (m, 2H), 5.90-5.67 (m, 1H), 5.15 (s, 1H), 5.11-5.01 (m, 1H), 4.84 (s, 1H), 4.60-4.56 (m, 1H), 3.87-3.82 (m, 1H), 3.81-3.72 (m, 1H), 3.47-3.26 (m, 1H), 3.30-3.26 (m, 3H), 3.20-3.15 (m, 3H), 3.07-2.98 (m, 4H), 2.90-2.87 (m, 2H), 2.81-2.75 (m, 1H), 2.70-2.59 (m, 2H), 2.46-2.36 (m, 2H), 2.34-2.26 (m, 2H), 2.23-2.15 (m, 1H), 1.52-1.42 (m, 4H), 1.35-1.27 (m, 2H), 1.15-1.09 (m, 2H), 1.04 (d, J = 6.6 Hz, 3H).

[1052] Example 54

[1053] Step one:

[1054] Intermediate C-4 (230 mg), N,N-diisopropyl ethylamine (780 mg), tert-butyl bromoacetate (86 mg) and acetonitrile (6 mL) were mixed and reacted at room temperature for 2 hours. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 85:15) to obtain 194 mg of intermediate 54-1.

[1055] MS (ESI, [M+H] + )m / z: 613.51.

[1056] 1H-NMR (500MHz, DMSO-d6): δ 12.97 (s, 1H), 8.12 (d, J = 3.1 Hz, 1H), 8.05 (s, 1H), 7.28-7.26 (m, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 4.99 (s, 1H), 3.59-3.45 (m, 2H), 3.15-3.13 (m, 4H), 3.09-3.06 (m, 3H), 3.03-2.95 (m, 1H), 2.88-2.83 (m, 1H), 2.49-2.47 (m, 4H), 1.53-1.50 (m, 4H), 1.47-1.42 (m, 4H), 1.41 (s, 9H), 1.09 (d, J = 6.7 Hz, 3H).

[1057] Step two:

[1058] Intermediate 54-1 (170 mg), dichloromethane (2.5 mL) and 4N hydrogen chloride solution in dioxane (5 mL) were mixed and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain 170 mg of intermediate 54-2.

[1059] MS (ESI, [M+H] + )m / z: 557.38.

[1060] Step three:

[1061] Intermediate 54-2 (100 mg), intermediate A-1 (66.4 mg), 2-(7-azobenzo triazole)-N,N,N',N'-tetramethyl urea hexafluorophosphate (79 mg), N,N-diisopropyl ethylamine (308 mg) and N,N-dimethyl formamide (5 mL) were mixed and reacted at 25°C for 2 hours. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL*3), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, purified by silica gel column chromatography (dichloromethane / methanol = 50:50) to obtain 54 mg of compound 54.

[1062] HRMS (ESI, [M+H] + )m / z: 824.3886.

[1063] 1H NMR (500 MHz, DMSO-d6): δ 12.97 (s, 1H), 11.08 (s, 1H), 8.11-8.08 (m, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.28-7.17 (m, 3H), 7.08-7.05 (m, 1H), 6.82-3.80 (m, 1H), 5.11-5.02 (m, 1H), 4.99 (s, 1H), 4.84 (s, 1H), 4.60-4.56 (m, 1H), 3.87-3.85 (m, 1H), 3.82-3.73 (m, 1H), 3.58-3.41 (m, 2H), 3.29-3.24 (m, 2H), 3.15-3.12 (m, 2H), 3.09-3.01 (m, 4H), 2.99-2.94 (m, 1H), 2.90-2.83 (m, 2H), 2.81-2.74 (m, 1H), 2.64-2.59 (m, 1H), 2.48-2.36 (m, 3H), 2.35-2.27 (m, 2H), 2.20-2.15 (m, 1H), 1.71-1.54 (m, 1H), 1.54-1.40 (m, 5H), 1.38-1.32 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H).

[1064] Example 55

[1065] Step one:

[1066] Bromobenzeneboronic acid (0.947 g), tert-butyl 3,9-diazaspiro[5.5]undecane-3- carboxylate (1 g), copper acetate (1.071 g) and pyridine (5 ml) were mixed and reacted at 40 °C overnight under oxygen atmosphere. Water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 3:1) to give 660 mg of intermediate 55-1.

[1067] MS (ESI, [M+H] + )m / z: 409.25.

[1068] 1 H NMR (500 MHz, CDCl3): δ 7.35-7.28 (m, 2H), 6.82-6.75 (m, 2H), 3.41-3.39 (m, 4H), 3.17-3.11 (m, 4H), 1.64 (t, J = 5.8 Hz, 4H), 1.48 (t, J = 5.8 Hz, 4H), 1.46 (s, 9H).

[1069] Step two:

[1070] Intermediate 55-1 (200 mg) was dissolved in THF (3 ml), n-butyllithium (0.3 mL, 2.5 M in hexane) was added dropwise at -60 °C, and the reaction was allowed to proceed at -60 °C for 30 min. Then a THF (3 ml) solution of intermediate D-3 (200 mg) was added dropwise to the reaction solution, and the reaction was allowed to proceed at -60 °C for 2 h. Water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 247 mg of compound intermediate 55-2.

[1071] MS (ESI, [M+H] + )m / z: 603.47.

[1072] 1 H NMR (500 MHz, CDCl3): δ 7.68 (dd, J = 9.0, 3.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 17.1, 9.1 Hz, 3H), 6.67 (s, 1H), 3.83 (s, 3H), 3.41-3.80 (m, 4H), 3.20-3.14 (m, 4H), 3.02-2.99 (m, 1H), 2.50-2.34 (m, 3H), 1.96-1.90 (m, 3H), 1.77-1.69 (m, 1H), 1.67-1.61 (m, 5H), 1.48-1.45 (m, 13H).

[1073] Step three:

[1074] Intermediate 55-2 (220 mg) was dissolved in dichloromethane (2 ml), and boron tribromide (0.539 ml, 2 M in DCM) was added dropwise in an ice bath. The reaction was allowed to proceed at room temperature for 2 h. Water was added to quench the reaction, and extraction was performed with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain 130 mg of intermediate 55-3.

[1075] MS (ESI, [M+H] + )m / z: 471.40.

[1076] Step four:

[1077] Intermediate 55-3 (126 mg), intermediate 14-2 (80 mg), diisopropylethylamine (314 mg), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (111 mg) and N,N-dimethylformamide (2 mL) were mixed, stirred at room temperature, and reacted overnight. Water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 80 mg of compound 55.

[1078] MS (ESI, [M+H] + )m / z: 782.40.

[1079] 1 H NMR (500 MHz, DMSO-d6): δ 11.09 (s, 1H), 9.38 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.03-6.82 (m, 4H), 6.65 (s, 1H), 6.51 (s, 2H), 4.66-4.57 (m, 1H), 4.34 (s, 2H), 4.23 (s, 2H), 3.77 (s, 2H), 3.49 (s, 4H), 3.20-3.15 (m, 4H), 2.77 (s, 1H), 2.63 (s, 2H), 2.21-2.12 (m, 3H), 1.99 (s, 2H), 1.60 (s, 4H), 1.49 (s, 2H), 1.44 (s, 2H), 1.27-1.17 (m, 4H).

[1080] Example 56

[1081] Step one:

[1082] Intermediate A-4 (300 mg), acetonitrile (5 mL) and N,N-diisopropylethylamine (389 mg) were mixed, and tert-butyl bromoacetate (235 mg) was added. The reaction was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain 244 mg of intermediate 56-1.

[1083] MS (ESI, [M+H] + )m / z: 414.37.

[1084] Step two:

[1085] Intermediate 56-1 (244 mg) and trifluoroacetic acid (5 mL) were mixed, and the reaction was stirred at room temperature for 4 h. The solvent was evaporated by concentration, and 148 mg of intermediate 56-2 was obtained.

[1086] MS (ESI, [M+H] + )m / z: 358.27.

[1087] Step three:

[1088] Intermediate 56-2 (148 mg) was dissolved in N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (189 mg) and N,N-diisopropyl ethylamine (534 mg) were added successively, and the reaction was stirred at room temperature for 10 min. Intermediate B-4 (159 mg) was added, and the reaction was stirred for 12 h. After stirring in water (10 mL) for 10 min, the filter cake was collected by suction filtration, and the filter cake was purified by high-pressure preparative chromatography (conditions: column: Xtimeate C18, 20 x 250 mm, 5 μm); mobile phase: water (containing 10 mM ammonium acetate): acetonitrile = 1:1, flow rate: 20 mL / min) to give 91 mg of compound 56.

[1089] MS (ESI, [M+H] + )m / z: 724.35.

[1090] 1 H-NMR (500 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.09 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.14 (td, J = 14.8, 7.6 Hz, 4H), 6.87-6.80 (m, 2H), 6.66-6.59 (m, 2H), 6.58 (d, J = 8.4 Hz, 2H), 6.47 (dd, J = 8.2, 2.6 Hz, 1H), 6.23 (d, J = 8.4 Hz, 2H), 4.54 (dd, J = 11.9, 5.0 Hz, 1H), 4.15 (d, J = 5.0 Hz, 1H), 3.69 (d, J = 5.3 Hz, 2H), 3.54 (d, J = 6.0 Hz, 2H), 3.36 (s, 2H), 3.27 (dd, J = 5.5, 2.9 Hz, 1H), 3.16-3.10 (m, 2H), 3.06-3.03 (m, 2H), 3.02 (s, 2H), 2.96 (s, 2H), 2.70 (s, 2H), 2.67 (s, 2H), 2.60 (dt, J = 17.4, 4.3 Hz, 2H), 2.22-2.06 (m, 2H), 1.71 (s, 2H), 0.84 (dd, J = 10.5, 7.1 Hz, 2H).

[1091] Example 57

[1092] Step one:

[1093] Intermediate E-1 (1 g), 4-tert-butoxycarbonylaminopiperidine (0.847 g), cesium carbonate (1.377 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.163 g), tris(dibenzylideneacetone) palladium (0.129 g) and 1,4-dioxane (30 mL) were reacted at 100 °C for 15 hours under nitrogen atmosphere. After the reaction, the reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to obtain 770 mg of intermediate 57-1.

[1094] MS (ESI, [M+H]+) m / z: 829.41

[1095] 1 H NMR (500 MHz, DMSO-d6): δ 10.50 (s, 1H), 7.59-7.53 (m, 4H), 7.49-7.44 (m, 2H), 7.44-7.39 (m, 4H), 7.36 (d, J = 7.7 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.00-6.95 (m, 1H), 6.94-6.90 (m, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.39 (d, J = 13.1 Hz, 2H), 5.06 (s, 1H), 4.04-3.94 (m, 1H), 3.63-3.56 (m, 2H), 3.55-3.48 (m, 1H), 3.47-3.43 (m, 1H), 3.39 (s, 1H), 3.23-3.11 (m, 1H), 2.80-2.65 (m, 4H), 2.52 (d, J = 5.3 Hz, 1H), 1.74 (d, J = 12.4 Hz, 2H), 1.37 (s, 9H), 1.35-1.28 (m, 1H), 1.27-1.20 (m, 1H), 1.04 (d, J = 6.5 Hz, 3H), 0.97 (s, 9H).

[1096] Step two:

[1097] Intermediate 57-1 (550 mg), dichloromethane (10 mL) and trifluoroacetic acid (10 mL) were mixed and reacted at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated, and the residue was extracted with saturated sodium bicarbonate solution and dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (dichloromethane: dichloromethane / methanol (10 / 1) = 70:30) to obtain 410 mg of intermediate 57-2.

[1098] MS (ESI, [M+H]+) m / z: 729.46

[1099] Step three:

[1100] Intermediate 57-2 (400 mg), 1,5-dichloro-3-pentanone (170 mg), sodium carbonate (116 mg) and methanol (15 mL) were mixed and reacted at 65 °C for 1 hour. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to obtain 350 mg of intermediate 57-3.

[1101] MS (ESI, [M+H] + )m / z: 811.50

[1102] 1 H NMR (500 MHz, DMSO-d6): δ 10.50 (s, 1H), 7.60-7.54 (m, 4H), 7.50-7.45 (m, 2H), 7.45-7.40 (m, 4H), 7.40-7.36 (m, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.03-6.97 (m, 1H), 6.96-6.92 (m, 1H), 6.42 (d, J = 13.2 Hz, 2H), 5.08 (s, 1H), 4.02-3.95 (m, 1H), 3.76-3.68 (m, 2H), 3.54-3.50 (m, 1H), 3.50-3.45 (m, 1H), 3.22-3.14 (m, 2H), 2.83-2.74 (m, 5H), 2.72-2.60 (m, 4H), 2.36-2.27 (m, 4H), 1.80 (d, J = 12.4 Hz, 2H), 1.49-1.40 (m, 2H), 1.05 (d, J = 6.5 Hz, 3H), 0.98 (s, 9H).

[1103] Step four:

[1104] Intermediate 57-3 (200 mg), tetrahydrofuran (10 mL) and tetrabutylammonium fluoride (200 mg) were mixed and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated and the residue was purified by column chromatography (dichloromethane: dichloromethane / methanol (10 / 1) = 70:30) to obtain 120 mg of intermediate 57-4.

[1105] MS (ESI, [M+H] + )m / z: 573.30

[1106] 1H NMR (500 MHz, DMSO-d6): δ 10.54 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.01 - 6.97 (m, 1H), 6.96 - 6.92 (m, 1H), 6.55 (d, J = 13.1 Hz, 2H), 5.25 (t, J = 6.1 Hz, 1H), 5.11 (s, 1H), 3.82 (d, J = 12.6 Hz, 2H), 3.69 - 3.59 (m, 1H), 3.48 - 3.37 (m, 2H), 3.15 - 3.05 (m, 1H), 2.87 - 2.81 (m, 1H), 2.81 - 2.70 (m, 6H), 2.68 - 2.60 (m, 2H), 2.55 (dd, J = 15.2, 5.7 Hz, 1H), 2.34 - 2.29 (m, 4H), 1.84 - 1.78 (m, 2H), 1.52 - 1.43 (m, 2H), 1.08 (d, J = 6.6 Hz, 3H).

[1107] Step five:

[1108] Intermediate 57-4 (100 mg), intermediate A-2 (81 mg), sodium acetate (43 mg), 1,2-dichloroethane (5 mL) and isopropanol (1 mL) were mixed and reacted at room temperature for 20 minutes. Sodium triacetoxyborohydride (111 mg) was added and reacted at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added, extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: dichloromethane / methanol (10 / 1) = 40:60) to obtain 70 mg of compound 57.

[1109] MS (ESI, [M+H] + )m / z: 828.14

[1110] 1H NMR (500 MHz, DMSO-d6): δ 11.09 (s, 1H), 10.54 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.02-6.97 (m, 1H), 6.96-6.90 (m, 1H), 6.54 (d, J = 13.3 Hz, 2H), 5.25 (t, J = 6.1 Hz, 1H), 5.11 (s, 1H), 4.59 (dd, J = 11.9, 5.0 Hz, 1H), 4.16 (s, 2H), 4.05 (s, 2H), 3.80 (d, J = 12.2 Hz, 2H), 3.72-3.60 (m, 1H), 3.49-3.43 (m, 1H), 3.43-3.35 (m, 1H), 3.17-3.04 (m, 1H), 2.91 (s, 2H), 2.86-2.80 (m, 1H), 2.78-2.67 (m, 3H), 2.67-2.53 (m, 3H), 2.50-2.41 (m, 3H), 2.33-2.12 (m, 3H), 1.98-1.87 (m, 2H), 1.81 (d, J = 12.1 Hz, 2H), 1.58-1.41 (m, 4H), 1.08 (d, J = 6.5 Hz, 3H).

[1111] Example 58

[1112] Step one:

[1113] (R)-1-Cbz-3-hydroxymethylpyrrolidine (10 g) and dichloromethane (100 mL) were mixed, and Dess-Martin oxidant (21.63 g) was added in batches at 0 °C. The reaction was continued at room temperature for 2 hours. After the reaction was completed, the filter cake was washed with dichloromethane, and the filtrate was washed with saturated sodium bicarbonate solution and saturated sodium sulfite solution, respectively, and dried over anhydrous sodium sulfate. Filtration and concentration gave 10 g of intermediate 58-1.

[1114] Step two:

[1115] Intermediate 58-1 (10 g), trimethyl orthoformate (13.65 g), p-toluenesulfonic acid (0.738 g), and methanol (100 mL) were mixed, and the reaction was continued at room temperature for 10 hours. After the reaction was completed, saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave a residue, which was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give 7.5 g of intermediate 58-2.

[1116] 1H NMR (500 MHz, DMSO-d6): δ 7.44-7.26 (m, 5H), 5.05 (d, J = 1.5 Hz, 2H), 4.26 (d, J = 7.4 Hz, 1H), 3.45-3.33 (m, 2H), 3.30-3.19 (m, 7H), 3.14-3.04 (m, 1H), 2.57-2.51 (m, 1H), 1.93-1.81 (m, 1H), 1.76-1.60 (m, 1H).

[1117] Step three:

[1118] Intermediate 58-2 (1 g), 10% palladium carbon (0.381 g) and methanol (20 mL) were mixed and reacted at room temperature for 4 hours under hydrogen atmosphere. After the reaction was completed, the filter cake was washed with methanol, and the filtrate was concentrated to obtain 460 mg of intermediate 58-3.

[1119] 1 H NMR (500 MHz, DMSO-d6): δ 4.20 (d, J = 8.1 Hz, 1H), 3.78 (s, 6H), 3.22 (s, 1H), 2.86-2.80 (m, 2H), 2.75-2.69 (m, 1H), 2.62-2.58 (m, 1H), 2.33 (q, J = 7.7 Hz, 1H), 1.78-1.72 (m, 1H), 1.50-1.42 (m, 1H).

[1120] Step four:

[1121] Intermediate D-2 (1.8 g), 4-bromophenylboronic acid (1.088 g), tetrakis triphenylphosphine palladium (0.417 g), potassium carbonate (0.998 g), 1,4-dioxane (20 mL) and water (4 mL) were mixed and reacted at 90°C for 5 hours under nitrogen atmosphere. After the reaction was completed, water was added, and the organic phase was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain 450 mg of intermediate 58-4.

[1122] MS (ESI, [M+H] + )m / z: 505.20

[1123] 1H NMR (500 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.50-7.42 (m, 1H), 7.11-7.02 (m, 2H), 6.72 (d, J = 8.7 Hz, 1H), 5.77 (dd, J = 9.7, 2.6 Hz, 1H), 3.89-3.82 (m, 1H), 3.74-3.65 (m, 1H), 3.24 (q, J = 11.4 Hz, 2H), 3.02 (t, J = 7.1 Hz, 2H), 2.43-2.28 (m, 3H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 1H), 1.97-1.91 (m, 1H), 1.78-1.68 (m, 1H), 1.63-1.53 (m, 2H).

[1124] Step five:

[1125] Intermediate 58-4 (400 mg), intermediate 58-3 (345 mg), cesium carbonate (516 mg), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (92 mg), tris(dibenzylideneacetone)dipalladium (72.5 mg) and 1,4-dioxane (10 mL) were reacted under nitrogen atmosphere at 90 °C for 5 hours. After reaction, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give 300 mg of intermediate 58-5.

[1126] MS (ESI, [M+H] + )m / z: 570.34

[1127] 1H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 8.4 Hz, 2H), 5.76 (dd, J = 9.6, 2.6 Hz, 1H), 4.32 (d, J = 7.6 Hz, 1H), 3.91 - 3.82 (m, 1H), 3.75 - 3.65 (m, 1H), 3.35 - 3.32 (m, 2H), 3.29 (d, J = 4.3 Hz, 7H), 3.28 - 3.18 (m, 2H), 3.09 - 3.04 (m, 1H), 2.99 (t, J = 7.1 Hz, 2H), 2.64 (q, J = 7.9 Hz, 1H), 2.42 - 2.36 (m, 1H), 2.33 - 2.27 (m, 2H), 2.08 - 1.99 (m, 4H), 1.97 - 1.91 (m, 1H), 1.85 - 1.78 (m, 1H), 1.76 - 1.67 (m, 1H), 1.60 - 1.53 (m, 2H).

[1128] Step six:

[1129] Intermediate 58-5 (300 mg), dichloromethane (5 mL) and trifluoroacetic acid (5 mL) were mixed and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was added with saturated sodium bicarbonate solution and dichloromethane was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure to give 200 mg of intermediate 58-6.

[1130] MS (ESI, [M+H] + )m / z: 440.39

[1131] Step seven:

[1132] Intermediate 58-6 (110 mg), intermediate 2-2 (262 mg), sodium acetate (41.1 mg), 1,2-dichloroethane (5 mL) and isopropyl alcohol (1 mL) were mixed and reacted at room temperature for 20 minutes. Sodium triacetoxyborohydride (106 mg) was added and reacted at 60°C for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: dichloromethane / methanol (10 / 1) = 35:65) to give 60 mg of compound 58.

[1133] MS (ESI, [M+H] + )m / z: 750.55

[1134] 1 H NMR (500 MHz, DMSO-d6) δ 12.96 (s, 1H), 11.07 (s, 1H), 8.19 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 8.1 Hz, 2H), 6.68 (d, J = 8.7 Hz, 1H), 6.47 (d, J = 8.3 Hz, 2H), 4.57 (dd, J = 11.9, 5.0 Hz, 1H), 4.13 (s, 2H), 4.02 (d, J = 2.6 Hz, 2H), 3.57-3.51 (m, 1H), 3.51-3.41 (m, 2H), 3.29-3.17 (m, 6H), 3.06 (s, 2H), 3.00-2.90 (m, 3H), 2.79-2.70 (m, 1H), 2.62-2.55 (m, 1H), 2.52-2.49 (m, 2H), 2.32-2.24 (m, 3H), 2.21-2.14 (m, 1H), 2.09-2.03 (m, 1H), 2.03-1.98 (m, 2H), 1.70-1.61 (m, 1H).

[1135] Example 59

[1136] Step one:

[1137] Intermediate D-2 (290 mg), 4-(4-Boc-l-piperazinyl)benzeneboronic acid pinacol ester (240 mg), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (40 mg) and potassium carbonate (230 mg) and 1.5 ml water and 15 ml dioxane were mixed, heated at 90 °C for 4 h. Water was added, extracted with ethyl acetate, the organic layer was washed with water, saturated brine successively, dried over anhydrous sodium sulfate. Filtration under suction, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column (petroleum ether: ethyl acetate = 80:20) to give 280 mg of intermediate 59-1.

[1138] MS (ESI, [M+H] + )m / z: 611.41.

[1139] Step two:

[1140] Intermediate 59-1 (280 mg), tetrahydrofuran (3 mL) and 4M hydrochloric acid dioxane solution (4 ml) were mixed, stirred at room temperature for 3 h. The solvent was evaporated by concentration to give 200 mg of intermediate 59-2.

[1141] MS (ESI, [M+H] + )m / z: 427.39.

[1142] Step three:

[1143] Intermediate 59-2 (180 mg), intermediate 16-2 (170 mg), 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (267 mg), triethylamine (237 mg) and N,N-dimethylformamide (2 ml) were mixed and reacted at room temperature for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse phase column (acetonitrile: water = 1:1) to give 50 mg of compound 59.

[1144] MS (ESI, [M+H] + )m / z: 752.56.

[1145] 1 H NMR (500 MHz, DMSO-d6): δ 12.99 (s, 1H), 11.07 (s, 1H), 8.22 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.93 (s, 4H), 6.68 (d, J = 8.5 Hz, 1H), 4.55 (dd, J = 12.0, 5.0 Hz, 1H), 3.93 (s, 2H), 3.72 (s, 2H), 3.63 (s, 2H), 3.52 (s, 2H), 3.23-3.12 (m, 5H), 3.04-2.92 (m, 4H), 2.89-2.72 (m, 3H), 2.64-2.56 (m, 1H), 2.37-2.25 (m, 2H), 2.22-2.13 (m, 1H), 2.11-2.00 (m, 4H).

[1146] Example 60

[1147] Step one:

[1148] Intermediate 46-2 (57 mg), intermediate A-3 (29 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (47 mg), N,N-diisopropyl ethylamine (21 mg) and N,N-dimethylformamide (2 mL) were mixed and reacted at 25 °C for 3 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL*3), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, purified by silica gel column chromatography (dichloromethane / methanol = 95:5) and C18 column chromatography (acetonitrile / water = 65:35) to give 17 mg of compound 60.

[1149] HRMS (ESI, [M+H] + )m / z: 841.3809.

[1150] 1 H NMR (500 MHz, DMSO-d6): δ 12.96 (s, 1H), 11.08 (s, 1H), 8.05 (s, 1H), 7.68-7.62 (m, 1H), 7.25-7.17 (m, 2H), 6.74-6.69 (m, 1H), 6.55-6.45 (m, 2H), 5.95-5.60 (m, 2H), 5.15 (s, 1H), 4.92 (s, 1H), 4.77 (s, 1H), 4.57 (dd, J = 12.0, 5.0 Hz, 1H), 3.90-3.87 (m, 1H), 3.84-3.77 (m, 1H), 3.49-3.44 (m, 1H), 3.29 (s, 2H), 3.20 (s, 4H), 3.13-3.09 (m, 2H), 3.05-2.99 (m, 1H), 2.99-2.93 (m, 1H), 2.92-2.86 (m, 1H), 2.80-2.74 (m, 1H), 2.67-2.59 (m, 2H), 2.42 (s, 2H), 2.36 (s, 1H), 2.20-2.16 (m, 1H), 1.48 (s, 4H), 1.40 (s, 2H), 1.34-1.26 (m, 3H), 1.07-1.02 (m, 3H).

[1151] Example 61

[1152] Step one:

[1153] Intermediate 24-6 (0.1 g), intermediate A-2 (0.079 g) and sodium acetate (0.035 g) were added into a mixture of 1,2-dichloroethane (5 mL) and isopropanol (1 mL), and sodium triacetoxy cyanoborohydride (0.068 g) was added portionwise with stirring at room temperature. The reaction mixture was stirred at 50 °C for 3 h. After cooling to room temperature, the reaction was quenched by the addition of 20 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL*3). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 98:2) and then by C18 column chromatography (acetonitrile:water = 60:40) to give 29 mg of compound 61.

[1154] HRMS (ESI, [M+H] + )m / z: 722.3699.

[1155] 1 H NMR (500 MHz, DMSO-d6): δ 11.09 (s, 1H), 9.09 (s, 1H), 7.72 (s, 1H), 7.31 (s, 1H), 7.14 (s, 3H), 6.83 (s, 2H), 6.67-6.56 (m, 2H), 6.49 (s, 1H), 6.18 (s, 2H), 6.04 (s, 2H), 4.60 (s, 1H), 4.17 (s, 2H), 4.13-3.99 (m, 3H), 3.81 (s, 2H), 3.05-2.85 (m, 5H), 2.76 (s, 2H), 2.67-2.56 (m, 3H), 2.20 (s, 2H), 2.09 (s, 2H), 1.96 (s, 2H), 1.69 (s, 1H), 1.23 (s, 5H), 0.85 (s, 1H).

[1156] Example 62

[1157] Step one:

[1158] Intermediate E-2 (300 mg), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (486 mg), cesium carbonate (622 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73.7 mg), tris(dibenzylideneacetone)dipalladium (58.3 mg), 1,4-dioxane (5 mL) were mixed and stirred at 110 °C for 4 h under nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water, saturated brine successively, and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 65:35) to give 176.7 mg of intermediate 62-1.

[1159] 1H NMR (500 MHz, CDC13): δ 7.53-7.49 (m, 1H), 7.44 (s, 1H), 7.22 (dd, J = 7.2, 1.9 Hz, 1H), 7.14-7.08 (m, 2H), 6.42-6.34 (m, 2H), 5.13 (s, 1H), 3.8-3.60 (m, 4H), 3.46-3.37 (m, 4H), 3.28-3.24 (m, 1H), 3.23-3.18 (m, 4H), 3.15-3.10 (m, 1H), 2.97-2.88 (m, 1H), 2.67 (dd, J = 15.4, 1.7 Hz, 1H), 1.63 (t, J = 5.9 Hz, 4H), 1.46 (s, 13H), 1.17 (d, J = 6.6 Hz, 3H).

[1160] Step two:

[1161] To intermediate 62-1 (147.4 mg) was added hydrogen chloride-ethyl acetate solution (4 M, 2 mL) dropwise and stirred for 15 minutes. The reaction solution was directly concentrated to obtain 208.7 mg of intermediate 62-2.

[1162] MS (ESI, [M+H] + )m / z: 545.34.

[1163] Step three:

[1164] Intermediate 62-2 (118 mg), triethylamine (132 mg), tert-butyl bromoacetate (46.5 mg), dichloromethane (2 mL) were mixed and stirred at room temperature for 3 hours. Extraction was performed with dichloromethane, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Filtration under suction and concentration of the filtrate under reduced pressure, and purification of the residue on a silica gel column (petroleum ether: ethyl acetate = 65:35) yielded 94 mg of intermediate 62-3.

[1165] 1H NMR (500 MHz, CDC13): δ 7.51 (d, J = 7.0 Hz, 1H), 7.44 (s, 1H), 7.21 (dd, J = 6.9, 1.7 Hz, 1H), 7.16-7.06 (m, 2H), 6.37 (d, J = 12.7 Hz, 2H), 5.12 (s, 1H), 3.85-3.57 (m, 4H), 3.28-3.22 (m, 1H), 3.19 (t, J = 6.0 Hz, 4H), 3.11 (d, J = 7.2 Hz, 1H), 2.94-2.90 (m, 1H), 2.67 (dd, J = 14.0, 2.8 Hz, 1H), 2.60 (t, J = 5.8 Hz, 4H), 1.61 (t, J = 6.0 Hz, 10H), 1.47 (s, 9H), 1.17 (d, J = 6.6 Hz, 3H).

[1166] Step four:

[1167] Intermediate 62-3 (147.4 mg) was dissolved with ethyl acetate (1 mL), hydrogen chloride-ethyl acetate solution (4 M, 2 mL) was added dropwise, and stirred for 1 hour. The reaction solution was directly concentrated to obtain 104.7 mg of intermediate 62-4.

[1168] MS (ESI, [M+H]+) m / z: 603.34.

[1169] Step five:

[1170] Intermediate 62-4 (88 mg), N,N-diisopropylethylamine (71.6 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (70.2 mg), intermediate A-2 (34.1 mg), N,N-dimethylformamide (1 mL) were stirred at room temperature for 16 hours. Extraction was performed with dichloromethane, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Filtration under suction, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column (dichloromethane:methanol = 27:73) to obtain 18.8 mg of compound 62.

[1171] HRMS (ESI, [M+H] + ) m / z: 856.3803.

[1172] 1H NMR (500 MHz, CDC13): δ 8.04 (s, 1H), 7.68 (dd, J = 8.2, 5.5 Hz, 1H), 7.50 (d, J = 6.9 Hz, 1H), 7.45 (s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.16-7.06 (m, 2H), 6.38 (d, J = 12.7 Hz, 2H), 5.23 (s, 1H), 5.11 (d, J = 17.1 Hz, 2H), 4.97 (s, 1H), 4.37-4.30 (m, 1H), 3.85-3.57 (m, 4H), 3.32 (d, J = 8.1 Hz, 2H), 3.25 (s, 1H), 3.23-3.16 (m, 4H), 3.15-3.09 (m, 1H), 3.09-2.99 (m, 1H), 2.98-2.87 (m, 1H), 2.84-2.73 (m, 1H), 2.67 (d, J = 9.6 Hz, 1H), 2.66-2.58 (m, 4H), 2.47 (dd, J = 13.7, 5.9 Hz, 1H), 1.61 (t, J = 5.7 Hz, 10H), 1.17 (d, J = 6.6 Hz, 3H).

[1173] Example 63

[1174] Intermediate 62-2 (90 mg), N,N-diisopropylethylamine (120 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (118 mg), intermediate 14-2 (82 mg), N,N-dimethylformamide (1 mL), stirred at room temperature for 16 hours. Extracted with dichloromethane, the organic layer was washed with water, saturated brine successively, dried over anhydrous sodium sulfate. Poured out, concentrated under reduced pressure, the residue was purified by silica gel column (dichloromethane:methanol = 74:26) to give 35.8 mg of compound 63.

[1175] HRMS (ESI, [M+H] + )m / z: 856.3806.

[1176] 1H NMR (500 MHz, DMSO-de) d 11.09 (s, 1H), 10.54 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.01 - 6.96 (m, 1H), 6.93 (t, J = 6.8 Hz, 1H), 6.53 (d, J = 13.3 Hz, 2H), 5.24 (t, J = 6.1 Hz, 1H), 5.10 (s, 1H), 4.60 (dd, J = 11.9, 5.0 Hz, 1H), 4.28 (s, 2H), 4.17 (s, 2H), 3.73 - 3.61 (m, 3H), 3.46 (dt, J = 18.9, 6.1 Hz, 6H), 3.20 (t, J = 6.6 Hz, 4H), 3.14 - 3.06 (m, 1H), 2.84 - 2.74 (m, 2H), 2.69 - 2.52 (m, 4H), 2.24 - 2.16 (m, 1H), 1.53 (t, J = 5.8 Hz, 4H), 1.47 - 1.42 (m, 4H), 1.07 (d, J = 6.7 Hz, 3H).

[1177] Example 64

[1178] Step one:

[1179] Intermediate B-4 (110 mg), N,N-diisopropyl ethylamine (137 mg), tert-butyl bromoacetate (63.3 mg), dichloromethane (2 mL) were mixed and stirred at room temperature for 3 hours. Extraction was performed with dichloromethane, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Filtration under suction, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane:methanol = 80:20) to obtain 106.8 mg of intermediate 64-1.

[1180] MS (ESI, [M+H] + )m / z: 499.41.

[1181] 1H NMR (500 MHz, DMSO-d6): δ 9.08 (s, 1H), 7.14 (dt, J = 13.6, 6.9 Hz, 3H), 6.84 (d, J = 6.7 Hz, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.52 (d, J = 8.9 Hz, 2H), 6.47 (dd, J = 8.2, 2.7 Hz, 1H), 6.21 (d, J = 8.9 Hz, 2H), 4.13 (d, J = 5.0 Hz, 1H), 3.28 (d, J = 8.0 Hz, 1H), 3.11 (s, 2H), 2.96 (d, J = 5.4 Hz, 4H), 2.93-2.87 (m, 1H), 2.56 (t, J = 5.0 Hz, 4H), 2.12-2.06 (m, 1H), 1.74-1.67 (m, 1H), 1.42 (d, J = 3.6 Hz, 1H), 1.40 (s, 9H).

[1182] Step two:

[1183] Intermediate 64-1 (106 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (2 mL) was added dropwise, and stirring was performed for 2 hours. The reaction solution was directly concentrated to obtain 298.8 mg of intermediate 64-2.

[1184] MS (ESI, [M+H] + )m / z: 443.37.

[1185] Step three:

[1186] Intermediate 64-2 (500 mg), N,N-diisopropylethylamine (482 mg), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (473 mg), intermediate A-2 (249 mg), N,N-dimethylformamide (5 mL) were stirred at room temperature for 16 hours. Extraction was performed with dichloromethane, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Filtration under suction, and concentration of the filtrate under reduced pressure, and purification of the residue on a silica gel column (dichloromethane:methanol = 74:26) yielded 48.4 mg of compound 64.

[1187] HRMS (ESI, [M+H] + )m / z: 696.3174.

[1188] 1H NMR (500 MHz, DMSO-d6): δ 11.11 (s, 1H), 9.10 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.14 (dt, J = 13.1, 6.7 Hz, 3H), 6.84 (d, J = 7.2 Hz, 2H), 6.68 - 6.55 (m, 4H), 6.48 (d, J = 8.2 Hz, 1H), 6.25 (d, J = 8.2 Hz, 2H), 5.17 (s, 1H), 5.04 (s, 1H), 4.98 (s, 1H), 4.88 (s, 1H), 4.64 (dd, J = 12.1, 4.8 Hz, 1H), 4.16 (s, 1H), 3.36 - 3.33 (m, 4H), 3.29 (d, J = 2.7 Hz, 4H), 3.03 - 2.89 (m, 4H), 2.83 - 2.72 (m, 2H), 2.65 - 2.59 (m, 2H), 2.22 (s, 1H), 2.11 (s, 1H), 1.72 (s, 1H).

[1189] Example 65

[1190] Step one:

[1191] Intermediate B-2 (6 g), 2-(piperidin-4-yl)ethyl acetate hydrochloride (2.01 g), cesium carbonate (9.03 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.80 g), tris(dibenzylideneacetone)dipalladium (0.64 g), 1,4-dioxane (50 mL) were mixed, protected by N2, heated and stirred at 100 °C for 5 hours. Extracted with ethyl acetate, the organic layer was washed with water, saturated brine successively, dried over anhydrous sodium sulfate. Poured into a filter funnel, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column (petroleum ether: ethyl acetate = 75:25) to give 0.8 g of intermediate 65-1.

[1192] MS (ESI, [M+H] + )m / z: 544.39.

[1193] Step two:

[1194] Intermediate 65-1 (0.8 g), palladium on carbon (0.225 g), methanol (4 mL), tetrahydrofuran (4 mL) were mixed, reacted in a hydrogen atmosphere at room temperature for 4 days. Filtered through diatomite, the filtrate was concentrated under reduced pressure, the residue was separated by high pressure preparative chromatography (column: IG 30*250mm, 10μm; mobile phase: ethanol: n-hexane = 32:68; flow rate: 40 mL / min) to give 232.3 mg of intermediate 65-2.

[1195] Intermediate 65-2, Rt = 2.859 min (UPCC condition: Column: ACQUITY TORUS2-PIC (4.6 x 100 mm, 5 μm); Mobile phase: Carbon dioxide: methanol (containing 0.1% ammonia water) = 50:50; Flow rate: 2.0 ml / min; Column temperature: 40 °C).

[1196] MS (ESI, [M+H] + )m / z: 456.40.

[1197] 1 H NMR (500 MHz, DMSO-d6): δ 9.10 (s, 1H), 7.12 (dd, J = 11.8, 7.1 Hz, 3H), 6.86-6.79 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.52 (d, J = 9.0 Hz, 2H), 6.47 (dd, J = 8.2, 2.6 Hz, 1H), 6.19 (d, J = 8.9 Hz, 2H), 4.12 (d, J = 5.0 Hz, 1H), 3.58 (s, 3H), 3.48 (d, J = 13.7 Hz, 2H), 3.27 (dd, J = 13.2, 5.1 Hz, 1H), 3.02-2.87 (m, 2H), 2.46 (t, J = 3.0 Hz, 1H), 2.25 (d, J = 7.0 Hz, 2H), 2.10 (tt, J = 13.0, 6.5 Hz, 1H), 1.78-1.63 (m, 4H), 1.30 (s, 1H), 1.26 (s, 2H).

[1198] Step three:

[1199] Intermediate 65-2 (100 mg), lithium hydroxide monohydrate (36.8 mg), methanol (1 mL), water (0.25 mL) were mixed, and the reaction was carried out at room temperature for 4 hours. The residue was diluted with water and dispersed, and the pH was adjusted to 2 with 2M HCl. The product was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate to obtain 48.8 mg of intermediate 65-3.

[1200] MS (ESI, [M+H] + )m / z: 442.35

[1201] Step four:

[1202] Intermediate 65-3 (48 mg), N,N-diisopropylethylamine (84 mg), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (83 mg), intermediate A-2 (40.1 mg), N,N-dimethylformamide (1 mL), stirred at room temperature for 2 hours. Extracted with dichloromethane, the organic layer was washed with water, saturated brine in turn, dried over anhydrous sodium sulfate. Filtration under reduced pressure, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column (dichloromethane:methanol = 45:55), the chromatogram was concentrated under reduced pressure, the residue was purified by high performance liquid chromatography (chromatographic column: C18 4.6*250mm, 8μm; mobile phase A: water (0.1% trifluoroacetic acid) B: acetonitrile; flow rate: 1.0 mL / min), the preparation liquid was freeze-dried to obtain 19.2 mg of compound 65.

[1203] HRMS (ESI, [M+H] + )m / z: 695.3224.

[1204] 1 H NMR (500 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.09 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.41-7.35 (m, 1H), 7.16-7.00 (m, 3H), 6.86-6.81 (m, 2H), 6.64 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.53 (d, J = 8.9 Hz, 2H), 6.48 (dd, J = 8.2, 2.7 Hz, 1H), 6.20 (d, J = 8.9 Hz, 2H), 5.13 (s, 1H), 5.00 (s, 1H), 4.90 (s, 1H), 4.79 (s, 1H), 4.65-4.61 (m, 1H), 4.13 (d, J = 5.0 Hz, 1H), 3.52-3.49 (m, 2H), 3.27-3.26 (m, 1H), 3.02-2.86 (m, 2H), 2.81-2.74 (m, 1H), 2.63-2.60 (m, 1H), 2.54-2.52 (m, 2H), 2.40-2.35 (m, 2H), 2.24-2.17 (m, 1H), 2.16-2.08 (m, 1H), 1.96-1.86 (m, 1H), 1.79-1.70 (m, 3H), 1.29-1.23 (m, 3H).

[1205] Example 66

[1206] Step one:

[1207] Ethoxycarbonylmethylidenetriphenylphosphonium bromide (21 g) was dissolved in toluene (70 mL) and heated to 100 °C for 4 hours. The reaction was poured into water and extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slurried with petroleum ether / ethyl acetate (10:1), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 90:10) to give 10 g of intermediate 66-1.

[1208] 1 H NMR (500 MHz, DMSO-d6): δ 5.80 (t, J = 1.3 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.93 (td, J = 6.5, 1.2 Hz, 2H), 2.39 (td, J = 6.6, 1.2 Hz, 2H), 2.10-1.94 (m, 4H), 1.20 (t, J = 7.1 Hz, 3H).

[1209] Step two:

[1210] Intermediate 66-1 (10 g) was dissolved in methanol (600 mL) and then palladium on carbon (1 g, 10%) was added. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 8.69 g of intermediate 66-2.

[1211] 1 H NMR (500 MHz, DMSO-d6): δ 4.06 (q, J = 7.1 Hz, 2H), 2.25 (d, J = 7.0 Hz, 2H), 2.03-1.90 (m, 2H), 1.89-1.70 (m, 5H), 1.26-1.14 (m, 5H).

[1212] Step three:

[1213] Diisopropyl amine (7.02 g) was dissolved in tetrahydrofuran (100 mL) and cooled to 0 °C under nitrogen protection. Then 1M n-butyllithium n-hexane solution (25.04 mL) was added dropwise. After the addition, the mixture was stirred at 0 °C for 0.5 hours and then cooled to -70 °C. Then a tetrahydrofuran (100 mL) solution of intermediate 66-2 (11 g) was added dropwise. After the addition, the mixture was stirred at -70 °C for 0.5 hours. Then 3-bromopropene (8.39 g) was added dropwise. After the addition, the mixture was stirred at -70 °C for 0.5 hours. The mixture was then allowed to warm to room temperature and stirred overnight. The reaction was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 90:10) to give 12 g of intermediate 66-3.

[1214] 1 H NMR (500 MHz, DMSO-d6): δ 5.76-5.66 (m, 1H), 5.07-4.96 (m, 2H), 4.13-3.99 (m, 2H), 2.36-2.20 (m, 3H), 2.07-1.93 (m, 2H), 1.87-1.70 (m, 3H), 1.69-1.60 (m, 2H), 1.29-1.21 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H).

[1215] Step four:

[1216] Intermediate 66-3 (3.4 g) was dissolved in N,N-dimethylformamide (40 mL), then 3-benzyloxybromobenzene (4.00 g), N,N-diisopropylethylamine (3.57 g), tris(o-tolyl)phosphine (0.420 g) and palladium acetate (0.155 g) were added. The mixture was heated to 100 °C for 5 hours under nitrogen protection. The reaction was poured into water, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 80:20) gave 4.8 g of intermediate 66-4.

[1217] 1 H NMR (500 MHz, DMSO-d6): δ 7.47-7.43 (m, 2H), 7.41-7.37 (m, 2H), 7.35-7.30 (m, 1H), 7.24-7.19 (m, 1H), 7.01-6.97 (m, 1H), 6.95-6.91 (m, 1H), 6.88-6.84 (m, 1H), 6.40-6.34 (m, 1H), 6.22-6.14 (m, 1H), 5.10 (s, 2H), 4.05 (q, J = 7.1 Hz, 2H), 2.47-2.35 (m, 3H), 2.05-1.94 (m, 2H), 1.89-1.80 (m, 2H), 1.80-1.73 (m, 1H), 1.72-1.63 (m, 2H), 1.33-1.22 (m, 2H), 1.13 (t, J = 7.1 Hz, 3H).

[1218] Step five:

[1219] Intermediate 66-4 (4.8 g) was dissolved in methanol (60 mL), then palladium on carbon (1.192 g, 10%) was added. After stirring overnight under a hydrogen atmosphere (15 psi), the mixture was filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 80:20) gave 3 g of intermediate 66-5.

[1220] MS (ESI, [M-H] -m / z: 339.25.

[1221] 1 H NMR (500 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.07-7.02 (m, 1H), 6.61-6.52 (m, 3H), 4.16-4.00 (m, 2H), 2.47-2.39 (m, 1H), 2.23 (q, J = 7.3 Hz, 1H), 1.97 (s, 2H), 1.85-1.67 (m, 3H), 1.64-1.55 (m, 2H), 1.54-1.42 (m, 4H), 1.27-1.10 (m, 6H).

[1222] Step six:

[1223] Intermediate 66-5 (3.5 g) was dissolved in methanol (30 mL), then sodium hydroxide (4.11 g) aqueous solution (30 mL) was added, and the mixture was heated to 70 °C for 8 hours. The reaction solution was poured into 2M hydrochloric acid solution, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3.2 g of intermediate 66-6.

[1224] MS (ESI, [M-H] - )m / z: 311.01.

[1225] 1 H NMR (500 MHz, DMSO-d6): δ 12.12 (s, 1H), 9.19 (s, 1H), 7.08-7.01 (m, 1H), 6.62-6.52 (m, 3H), 2.47-2.40 (m, 1H), 2.16-2.09 (m, 1H), 2.00-1.93 (m, 3H), 1.84-1.70 (m, 3H), 1.67-1.54 (m, 2H), 1.53-1.42 (m, 4H), 1.30-1.18 (m, 2H).

[1226] Step seven:

[1227] Intermediate 66-6 (0.2 g) was dissolved in trifluoroacetic acid (30 mL), cooled to 0 °C, and trifluoroacetic anhydride (0.336 g) was added dropwise under nitrogen protection. The mixture was stirred at 0 °C for 1 hour. The stirring was stopped, and the reaction solution was poured into water-saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 70:30) gave 0.15 g of intermediate 66-7.

[1228] MS (ESI, [M+H] +m / z: 295.2.

[1229] 1 H NMR (500 MHz, DMSO-d6): δ 10.00 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 6.71-6.61 (m, 2H), 3.03-2.91 (m, 1H), 2.82-2.74 (m, 1H), 2.70-2.61 (m, 1H), 2.10-1.91 (m, 5H), 1.87-1.82 (m, 1H), 1.79-1.69 (m, 2H), 1.66-1.61 (m, 1H), 1.52-1.40 (m, 1H), 1.39-1.32 (m, 1H), 1.26-1.15 (m, 2H).

[1230] Step Eight:

[1231] Intermediate 66-7 (0.1 g) was dissolved in dichloromethane (2 mL), then triethylamine (0.034 g) and pivaloyl chloride (0.041 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to give 60 mg of intermediate 66-8.

[1232] 1 H NMR (500 MHz, DMSO-d6): δ 10.00 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 6.71-6.61 (m, 2H), 3.03-2.91 (m, 1H), 2.82-2.74 (m, 1H), 2.70-2.61 (m, 1H), 2.10-1.91 (m, 5H), 1.87-1.82 (m, 1H), 1.79-1.69 (m, 2H), 1.66-1.61 (m, 1H), 1.52-1.40 (m, 1H), 1.39-1.32 (m, 1H), 1.26-1.15 (m, 2H).

[1233] Step Nine:

[1234] Intermediate 66-8 (0.4 g) was dissolved in tetrahydrofuran (4 mL) and cooled to -60 °C under nitrogen protection, then 1 M potassium bis(trimethylsilyl)amide tetrahydrofuran solution (1.6 mL) was added dropwise. After the addition, the mixture was stirred at -60 °C for 5 min, then N-phenyl bis(trifluoromethanesulfonyl)imide (0.566 g) in tetrahydrofuran (4 mL) was added dropwise. After the addition, the mixture was stirred at -60 °C for 0.5 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 90: 10) to give 0.53 g of intermediate 66-9.

[1235] 1 H NMR (500 MHz, DMSO-d6): δ 7.47-7.43 (m, 1H), 7.15-7.10 (m, 2H), 2.90-2.81 (m, 1H), 2.62 (t, J = 7.1 Hz, 2H), 2.20-2.08 (m, 4H), 1.98-1.89 (m, 1H), 1.88-1.80 (m, 3H), 1.74-1.62 (m, 4H), 1.31 (s, 9H).

[1236] Step ten:

[1237] Intermediate 66-9 (500 mg) was dissolved in 1,4-dioxane (10 mL), then water (1 mL), intermediate 44-2 (406 mg), potassium carbonate (271 mg), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (71.7 mg) were added. The mixture was heated to 100 °C under nitrogen protection for 4 h. The reaction mixture was poured into water solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to give 0.23 g of intermediate 66-10.

[1238] MS (ESI, [M+H] + )m / z: 580.43.

[1239] 1H NMR (500 MHz, DMSO-de): δ 6.97 (d, J = 2.5 Hz, 1H), 6.93-6.86 (m, 4H), 6.84-6.79 (m, 1H), 6.69-6.64 (m, 1H), 3.93-3.90 (m, 4H), 3.38-3.33 (m, 1H), 3.29-3.23 (m, 4H), 2.68-2.54 (m, 3H), 2.14-1.93 (m, 4H), 1.82 (t, J = 7.0 Hz, 2H), 1.73-1.69 (m, 5H), 1.68-1.62 (m, 4H), 1.28 (s, 9H).

[1240] Step eleven:

[1241] Intermediate 66-10 (0.21 g) was dissolved in methanol (5 mL), and 5M sodium hydroxide solution (2 mL) was added dropwise under ice water bath cooling (T < 5°C). The ice bath was removed, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into saturated ammonium chloride aqueous solution, and extracted with ethyl acetate. The combined organic phase was washed with satu...

Claims

1. A compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from 5-10 membered cycloalkenyl or 5-10 membered heterocycloalkenyl; Ring B is selected from phenyl; Each R 1 Independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; n is selected from 0, 1, 2, or 3; L is selected from -LNK 1 -Cy 1 -LNK 2 -Cy 2 -LNK 3 -; Cy 1 is selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or Cy 2 is selected from a single bond, or a group optionally substituted with one or more R Cy2 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or each R Cy1 and R Cy2 are each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated di-C 1-6 alkylamino; LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 substituted with one or more R 1-6 alkylene or C 1-6 heteroalkylene; LNK 2 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 substituted with one or more R 1-6 alkylene or C 1-6 heteroalkylene; LNK 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 substituted with one or more R 1-6 alkylene or C 1-6 heteroalkylene; Each R LNK1 R LNK2 and R LNK3 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; PTM is selected from: represents a single bond or a double bond; X A , X B , X C is selected from C, CH or N; E A1 、E A2 、E B1 、E B2 、E B3 、E C1 、E C2 each independently is selected from -O- or -CR E1 R E2 -; each R E1 and R E2 are each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated di-C 1-6 alkylamino; R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 , R B4 , R C1 , R C2 , R C3 , and R C4 are each independently selected from H, halogen, -OH, -NH2, -CN, -COOH, C 1-6 1-6alkyl, C 1-6 1-6alkoxy, C 1-6 1-6alkylamino, diC 1-6 1-6alkylamino, deuterated C 1-6 1-6alkyl, halogenated C 1-6 1-6alkyl, halogenated C 1-6 1-6alkoxy, halogenated C 1-6 1-6alkylamino, or halogenated diC 1-6 1-6alkylamino; or R A3 and R A4 together form a group selected from phenyl or 5-6 membered heteroaryl, optionally substituted by one or more R A6 ; or R B3 and R B4 together form a group selected from phenyl or 5-6 membered heteroaryl, optionally substituted by one or more R B6 groups; each R A6 and R B6 are each independently selected from halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated di-C 1-6 alkylamino; R A5 Selected from H or arbitrarily selected by one or more R A7 The following groups are substituted: C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 alkylene, 3-12 membered cycloalkyl, C 1-4 alkylene 3-12-membered cycloalkenyl, C 1-4 alkylene 4-12-membered heterocyclic groups, C 1-4 alkylene 6-10 aryl, or C 1-4 alkylene 5-10-membered heteroaryl groups; Each R A7 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R groups. A8 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino; Each R A8 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, or -CN; R B5 is selected from H or an optionally substituted group consisting of C B7 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 alkylene 3-12 membered cycloalkyl, C 1-4 alkylene 3-12 membered cycloalkenyl, C 1-4 alkylene 3-12 membered cycloalkenyl, C 1-4 alkylene 4-12 membered heterocyclyl, C 1-4 alkylene 6-10 membered aryl, or C 1-4 alkylene 5-10 membered heteroaryl; Each R B7 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R groups. B8 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino; Each R B8 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, or -CN; R C5 is selected from H or an optionally substituted group consisting of C C7 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 alkylene 3-12 membered cycloalkyl, C 1-4 alkylene 3-12 membered cycloalkenyl, C 1-4 alkylene 3-12 membered cycloalkenyl, C 1-4 alkylene 4-12 membered heterocyclyl, C 1-4 alkylene 6-10 membered aryl, or C 1-4 alkylene 5-10 membered heteroaryl; Each R C7 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R groups. C8 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino; Each R C8 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, or -CN; Ring D, Ring E, and Ring F are each independently selected from 6-10 membered aryl or 5-10 membered heteroaryl; Each R D R E and R F Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; m, p, and q are each independently selected from 0, 1, 2, or 3; C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino is optionally substituted with one or more groups independently selected from deuterium, oxo, halogen, -OH, -NH2, or -CN.

2. The compound of formula (I) according to claim 1, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein, Ring A is selected from 5-8 membered cycloalkenyl or 5-8 membered heterocycloalkenyl; Alternatively, ring A is selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, dihydrofuranyl, dihydrothiophenyl, dihydropyrroleyl, dihydrooxazolyl, dihydrothiazolyl, dihydrooxazinyl, dihydropyridyl, tetrahydropyridyl, and dihydroazapyridine. benzyl, or tetrahydroazepin Group ; Alternatively, ring A is selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, dihydropyrrolyl, tetrahydropyridinyl, or tetrahydroazepinyl Group ; or a structural unit of formula (II) selected from the group consisting of or a structural unit of formula (II) selected from the group consisting of or a structural unit of formula (II) selected from the group consisting of 3. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein, Cy 1 is selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or Or, Cy 1 Selected from a single key, or optionally by one or more R keys Cy1 The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, azaspirononyl, diazaspirononyl, azaspirodecanyl, azaoxospirodecanyl, diazaspirodecanyl, azaspiroundecyl, or diazaspiroundecyl; or, Cy is selected from the group consisting of a single bond, or a group optionally substituted as follows: 1 is selected from the group consisting of a single bond, or a group optionally substituted as follows: Cy1 substituted as follows: or Cy is selected from the group consisting of a single bond, 1 selected from the group consisting of a single bond, or, Cy is selected from the group consisting of a single bond, or a substituted or unsubstituted 3-10 membered cycloalkyl or 4-12 membered heterocycloalkyl; 2 is selected from the group consisting of a single bond, or a substituted or unsubstituted 3-10 membered cycloalkyl or 4-12 membered heterocycloalkyl; Cy2 substituted or unsubstituted 3-10 membered cyclo Or, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolithyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, azaspironyl, diazaspironyl, azaspirodealkyl, diazaspirodealkyl, azaspirodealkyl, azaspiroundecyl, or diazaspiroundecyl; or, Cy is selected from the group consisting of a single bond, or a group optionally substituted as follows: 2 is selected from the group consisting of a single bond, or a group optionally substituted as follows: Cy2 is selected from the group consisting of a single bond, or a group optionally substituted as follows: or Cy is selected from the group consisting of a single bond, 2 selected from the group consisting of a single bond, 4. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein, LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 substituted C 1-4 alkylene or C 1-4 heteroalkylene; or LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 -CH2-, -CH2CH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, or -CH2CH2NH-; or LNK 1 is selected from a single bond, -O-, or is optionally substituted with one or more R LNK1 substituted -CH2-, or -CH2CH2-; or LNK 1 is selected from a single bond, -0-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, or -C(O)CH2-; or LNK 2 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 substituted with one or more R 1-4 alkylene or C 1-4 heteroalkylene; or LNK 2 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 -CH2-, -CH2CH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, or -CH2CH2NH-; or LNK 2 is selected from a single bond, -O-, or is optionally substituted with one or more R LNK2 substituted with one or more R substituted with one or more R or LNK 2 is selected from a single bond, -0-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, -CH(CH3)C(O)-, -C(O)CH2-, or -C(O)CH(CH3)-; or LNK 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 substituted with one or more R 1-4 alkylene or C 1-4 heteroalkylene; or LNK 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 -CH2-, -CH2CH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, or -CH2CH2NH-; or LNK 3 is selected from a single bond, -O-, or is optionally substituted with one or more R LNK3 substituted -CH2-, or -CH2CH2-; or LNK 3 is selected from a single bond, -0-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, or -C(O)CH2-.

5. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein, E A1 , E A2 each independently is selected from -O- or -CR E1 R E2 -; or E A1 , E A2 are each independently selected from -0-, -CH2-, -CHF-, -CF2-, or -CH(CH3)-; or E is selected from -O-, or -CH2-, A1 E is selected from -O-, or -CH2-, A2 E is selected from -CH2-, or -CH(CH3)-; or E B1 , E B2 , E B3 are each independently selected from -O- or -CR E1 R E2 -; or E B1 , E B2 , E B3 are each independently selected from -CH2- or -CH(CH3)-; or E B1 and E B2 each independently is selected from -CH2-, E B3 is selected from -CH2-, or -CH(CH3)-; or E C1 , E C2 are each independently selected from -O- or -CR E1 R E2 -; or E C1 , E C2 are each independently selected from -CH2- or -CH(CH3)-; Or, E C1 Selected from -CH2-, E C2 Selected from -CH2- or -CH(CH3)-; Or, E A1 and E A2 At most one of them is selected from O, E B1 E B2 and E B3 At most one of them is selected from O, E C1 and E C2 At most one of them can be selected from O; or, when X A , X B , X C is selected from N, E A2 , E B3 , E C2 are each independently selected from -CR E1 R E2 - 6. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein, R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 , R B4 , R C1 , R C2 , R C3 , and R C4 are each independently selected from H, halogen, -OH, -NH2, -CN, -COOH, C 1-4 1-6 alkyl, C 1-4 1-6 alkoxy, C 1-4 1-6 alkylamino, diC 1-4 1-6 alkylamino, deuterated C 1-4 1-6 alkyl, halogenated C 1-4 1-6 alkyl, halogenated C 1-4 1-6 alkoxy, halogenated C 1-4 1-6 alkylamino, or halogenated diC 1-4 1-6 alkylamino; or, R A3 and R A4 together form a phenyl or 5-6 membered heteroaryl group optionally substituted with one or more R A6 ; or, R B3 and R B4 together form a phenyl or 5-6 membered heteroaryl group optionally substituted with one or more R B6 ; or, R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 , R B4 , R C1 , R C2 , R C3 and R C4 are each independently selected from H, -F, -CI, -Br, -OH, -NH2, -CN, -COOH, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, trifluoromethyl, monofluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino; or, R A3 and R A4 together form a group selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, optionally substituted with one or more R A6 ; or, R B3 and R B4 together form a group selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, optionally substituted with one or more R B6 ; or R A1 , R A2 , and R A4 are each independently selected from H, -F, -Cl, or methyl; Or, R A3 Selected from H, -OH, -CN, or -COOH; Or, R A3 and R A4 Together they form an optional combination of one or more R A6 The following groups are substituted: pyrrole or pyrazolyl; or R A3 and R A4 together form a group: or R B1 , R B2 , and R B4 are each independently selected from H, -F, -Cl, or methyl; Or, R B3 Selected from H, -OH, -CN, or -COOH; or R B3 and R B4 together form a group selected from pyrrolyl or pyrazolyl, optionally substituted by one or more R B6 groups; or R B3 and R B4 together form a group: or R C1 , R C2 , R C3 and R C4 are each independently selected from H, -F, -Cl, or methyl.

7. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-6, wherein, R A5 is selected from H or an optionally substituted group selected from C A7 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 alkylene 3-10 membered cycloalkyl, C 1-3 alkylene 3-10 membered cycloalkenyl, C 1-3 alkylene 3-10 membered cycloalkenyl, C 1-3 alkylene 4-10 membered heterocyclyl, C 1-3 alkylene 6-10 membered aryl, or C 1-3 alkylene 5-10 membered heteroaryl; Or, R A5 Selected from H or arbitrarily selected by one or more R A7 The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydrocyclopentadienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, benzocyclobutenyl, oxacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyranyl, tetrahydropyridinyl, phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazine, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methyleneoxacyclobutyl, methyleneazacyclobutyl, methylenetetrahydrofuranyl, or methylenetetrahydropyrrolyl; or R A5 is selected from the group consisting of optionally substituted methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclohexyl, A7 is selected from the group consisting of optionally substituted methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclohexyl, phenyl, methylenecyclopropyl, or or R A5 selected from 8. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein, R B5 Selected from H or arbitrarily selected by one or more R B7 The following groups are substituted: C 1-4 Alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-3 alkylene, 3-10 membered cycloalkyl, C 1-3 alkylene 3-10-membered cycloalkenyl, C 1-3 alkylene 4-10 membered heterocyclic groups, C 1-3 alkylene 6-10 aryl, or C 1-3 alkylene 5-10-membered heteroaryl groups; Or, R B5 Selected from H or arbitrarily selected by one or more R B7 The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydrocyclopentadienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, benzocyclobutenyl, oxacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyranyl, tetrahydropyridinyl, phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazine, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methyleneoxacyclobutyl, methyleneazacyclobutyl, methylenetetrahydrofuranyl, or methylenetetrahydropyrrolyl; or R B5 is selected from H or an optionally substituted group selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclohexyl, B7 is selected from H or an optionally substituted group selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclohexyl, phenyl, methylenecyclopropyl, or R B5 selected from H, 9. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, wherein, R C5 Selected from H or arbitrarily selected by one or more R C7 The following groups are substituted: C 1-4 Alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-3 alkylene, 3-10 membered cycloalkyl, C 1-3 alkylene 3-10-membered cycloalkenyl, C 1-3 alkylene 4-10 membered heterocyclic groups, C 1-3 alkylene 6-10 aryl, or C 1-3 alkylene 5-10-membered heteroaryl groups; Or, R C5 Selected from H or arbitrarily selected by one or more R C7 The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydrocyclopentadienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, benzocyclobutenyl, oxacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyranyl, tetrahydropyridinyl, phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazine, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methyleneoxacyclobutyl, methyleneazacyclobutyl, methylenetetrahydrofuranyl, or methylenetetrahydropyrrolyl; or R C5 is selected from H or an optionally substituted group selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methylenecyclopropyl, or C7 is selected from H or an optionally substituted group selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methylenecyclopropyl, or or R C5 selected from 10. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-9, wherein, Ring D, Ring E, and Ring F are each independently selected from phenyl or 5-6 membered heteroaryl; or, Ring D, Ring E, and Ring F are each independently selected from phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl; or each of ring D, ring E, and ring F is independently selected from wherein the asterisk (*) end is attached to the L moiety; or a structural unit of formula (II) selected from the group consisting of wherein the asterisk (*) end is attached to the L moiety; or a structural unit of formula (II) selected from the group consisting of wherein the asterisk (*) end is attached to the L moiety; or a structural unit of formula (III) selected from the group consisting of wherein the asterisk (*) end is attached to the L moiety.

11. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-10, wherein, L is selected from Alternatively, the PTM is selected from Alternatively, the PTM is selected from 12. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-11, selected from the group consisting of a compound of formula (I-A), formula (I-B), formula (I-C), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L, Ring A, Ring B, R 1 , n, X A , E A1 , E A2 , R A1 , R A2 , R A3 , R A4 , R A5 , ring D, R D , m, X B , E B1 , E B2 , E B3 , R B1 , R B2 , R B3 , R B4 , R B5 , ring E, R E , p, X C , E C1 , E C2 , R C1 , R C2 , R C3 , R C4 , R C5 , ring F, R F and q are as defined in any one of claims 1 to 11; or it is selected from the group consisting of a compound of formula (I-A-1), formula (I-B-1), formula (I-C-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L, ring A, ring B, R 1 , n, X A , E A1 , E A2 , R A1 , R A2 , R A3 , R A4 , R A5 , ring D, R D , m, X B , E B1 , E B2 , E B3 , R B1 , R B2 , R B3 , R B4 , R B5 , ring E, R E , p, X C , E C1 , E C2 , R C1 , R C2 , R C3 , R C4 , R C5 , ring F, R F and q are as defined in any one of claims 1 to 11.

13. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, which is the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

14. A pharmaceutical composition comprising a compound of Formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-13; optionally, further comprising a pharmaceutically acceptable excipient.

15. Use of a compound of Formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-13, or a pharmaceutical composition of claim 14, in the manufacture of a medicament for the treatment of a disease.

Images