STAT protein degrader, and preparation method therefor and use thereof

Abstract

A compound having a structure of formula (I) or formula (II) and a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and the use thereof as a STAT protein degrader in the treatment of STAT3- or STAT6-related diseases. Further provided is a method for preparing the compound having the structure of formula (I) or formula (II).

Description

STAT protein degraders, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of biomedicine. This application provides a compound having the structure of formula (I), its pharmaceutically acceptable salt, pharmaceutical composition, and its use as a STAT protein degrader in the prevention and / or treatment of STAT3 or STAT6 related diseases. A method for preparing the compound described in this application is also provided. Background Technology

[0002] Targeted protein degradation (TPD) technology has become an effective strategy in drug development, emerging as a novel treatment approach for diseases such as cancer, inflammation, immune disorders, and infections. TPD agents can induce the degradation and clearance of pathogenic proteins, offering advantages such as better efficacy, targeting previously "undruggable" targets, and overcoming drug resistance.

[0003] Signal transducers and activators of transcription (STAT) proteins play crucial roles in biological processes. Abnormally activated STAT signaling pathways are associated with a variety of human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma, and diabetes. The STAT protein family comprises seven members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. Structurally, they share five domains: an N-terminal domain, a coiled-coil domain, a DNA-binding domain, an SH2 (Src homology 2) domain, and a C-terminal transcription activation domain. The transcription activation domain contains one or two key amino acid residues that are essential for the activity of STAT proteins. In particular, phosphorylation of specific tyrosine residues promotes dimerization, while phosphorylation of specific serine residues enhances transcriptional activation. STAT proteins promote fundamental cellular processes such as cell growth, differentiation, apoptosis, immune responses, and inflammation.

[0004] STAT6 plays a crucial role in IL-4 and IL-13-mediated Th2 cell development and function. Inhibition of the STAT6 signaling pathway can reduce cytokine production (such as IL-4, IL-13, and IL-5) by Th2 cells, thereby suppressing diseases such as allergic reactions and asthma. Abnormally activated STAT6 signaling is associated with the development and progression of various tumors. Inhibition of STAT6 may block its promoting effects on tumor cell growth, invasion, and metastasis, thereby inhibiting tumor development. STAT6 can also regulate the type and intensity of immune responses by influencing the activation state of immune cells (such as macrophages and T cells). Inhibition of STAT6 may regulate the balance of immune responses, potentially aiding in the treatment of autoimmune diseases or enhancing immune surveillance.

[0005] STAT3 is another important signal transduction protein that plays a crucial role in various physiological and pathological processes. STAT3 participates in regulating the expression of multiple growth factors and apoptosis-related genes, such as c-Myc, Bcl-2, and Bcl-XL. In cancer cells, abnormally activated STAT3 can promote tumor cell growth and survival while inhibiting apoptosis, thereby driving tumor development and progression. STAT3 regulates the expression of various inflammatory factors, including IL-6, IL-17, and IL-23, participating in the regulation of inflammatory responses and the occurrence of persistent inflammation. In immune-mediated inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, abnormal activation of STAT3 is closely related to the pathological process. STAT3 also plays an important role in regulating T cell differentiation, Th17 cell development, and the function of suppressor T cells (Treg cells); abnormal STAT3 signaling pathways may lead to immune dysregulation and the development of autoimmune diseases. Summary of the Invention

[0006] The purpose of this invention is to provide a compound that functions as a protein regulator and can be used to treat related conditions, such as inflammation, autoimmune diseases, and cancer.

[0007] Another object of the present invention is to provide a protein regulator, said protein including STAT6 and / or STAT3.

[0008] Specifically, the present invention provides a compound having a structure of formula (I) or formula (II), or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotope derivative, N-oxide, or prodrug thereof:

[0009] in,

[0010] Indicates a single bond or a double bond;

[0011] q is 0, 1, or 2; r is 0, 1, or 2; t is 1 or 2;

[0012] m can be 0, 1, 2, 3, or 4; n can be 0, 1, 2, 3, or 4.

[0013] X is independently selected from CH, CH2, O, and NR. 8 ,S,SO,S(O)2,S(=O)(=NR 9 ), where X in equation (I) is not CH or CH2;

[0014] T is independently selected from CH or N;

[0015] Ring A is selected from 6-10-membered aromatic rings or 5-10-membered heteroaromatic rings, wherein each of the 6-10-membered aromatic rings or 5-10-membered heteroaromatic rings may be optionally divided by p R. 7 replace;

[0016] p is 0, 1, 2 or 3;

[0017] R 1 The group is selected from (C1-C4) alkyl, phenyl, 4-9 membered heterocyclic alkyl, and 5-10 membered heteroaryl, wherein the (C1-C4) alkyl group may optionally be selected from 0, 1, 2 or 3 R groups. Y The phenyl group, 4-9-membered heterocyclic alkyl group, and 5-10-membered heteroaryl group can be monocyclic or bicyclic, and the phenyl, 4-9-membered heterocyclic alkyl group, and 5-10-membered heteroaryl group can each be independently replaced by 0, 1, 2, or 3 groups selected from R. Z Substitution of groups;

[0018] R 2 and R 3 Each group is independently selected from hydrogen, phenyl, (C1-C4)alkyl, C3-C6 cycloalkyl or 4-6 heterocyclic alkyl, wherein the phenyl, (C1-C4)alkyl, C3-C6 cycloalkyl or 4-6 heterocyclic alkyl can be independently substituted by 0, 1 or 2 groups selected from the following: halogen, (C1-C4)alkyl;

[0019] R 1 and R 2 Together with the nitrogen atoms they are attached to, they form 4-14-membered heterocyclic alkyl groups or 5-12-membered heteroaryl groups, which can be monocyclic or bicyclic, and the 4-14-membered heterocyclic alkyl groups or 5-12-membered heteroaryl groups can be further surrounded by 0, 1, 2, or 3 atoms selected from R. Q Substitution of groups;

[0020] R 4 Each is independently selected from naphthyl, 8-10 fused bicyclic heteroaryl, 8-10 fused bicyclic heterocyclic alkyl, or -CR 1b =CR 2b -phenyl, the naphthyl group, 8-10 fused bicyclic heteroaryl group, 8-10 fused bicyclic heterocyclic group or -CR 1b =CR 2b -Phenyl groups may be optionally substituted by 0, 1, 2, 3, or 4 substituents selected from the following: halogen, CN, OH, -(C1-C4)alkyl, -(C1-C4)hydroxyalkyl, -[(C0-C4)alkylene]-O-[(C1-C4)alkyl], -CR 1a R 2a P(O)OR 1b OR 2b-CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b -P(O)[OR 1b ][NH(AA)C(O)OR T ]、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ]、-[P(O)[NH(AA)C(O)OR T ][NH(AA)C(O)OR T ];

[0021] R 1a and R 2a Each is independently selected from hydrogen, cyano, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, -[(C0-C4)alkylene]-O-[(C1-C4)alkyl], OH, and halogen, or R 1a and R 2a Together they form an oxygen group; R 1a and R 2a H, (C1-C4) alkyl groups, and halogens are preferred; fluorine is preferred among halogens.

[0022] R 1b and R 2b Each is independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, -[(C1-C4)alkylene]-O- ... 20 [(C1-C4)alkylene]-JR v 5-6-membered heteroaryl and phenyl groups, wherein -J- are each independently selected from -OC(O)-, -C(O)O-, -OC(O)O-, -SC(O)-, -OC(O)NH- or -OC(O)N(R) v )-;R v Each is independently selected from H, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C3-C6)cycloalkyl, -(5-7 membered heterocyclic alkyl), -[(C1-C4)alkylene]-OR a The 5-6-membered heteroaryl and phenyl groups are each independently substituted by 0, 1, or 2 groups selected from halogens, cyano groups, and (C1-C4)alkyl groups; the 5-7-membered heterocyclic alkyl groups are each independently substituted by 0, 1, or 2 -C(O)OR groups. h replace;

[0023] AA represents α or β natural or non-natural amino acid residues;

[0024] R T and R Ty Each group is independently selected from H, (C1-C4)alkyl, phenyl, and benzyl, wherein the phenyl and benzyl groups may each be optionally substituted by 0, 1, or 2 groups selected from the following: H, halogen, (C1-C4)alkyl, and (C1-C4)haloalkyl;

[0025] Optional, R 1b and R 2b Together with the P atom and the atoms between them, they can form 5-9 membered heterocyclic alkyl groups; optionally, R 1b and R T Together with the P atom and the atoms between them, they can form 5-9 membered heterocyclic alkyl groups; optionally, the two R atoms... T Together with the P atom and the atoms between them, they can form 5-9 membered heterocyclic alkyl groups; optionally, R Ty and R T Together with the P atom and the atoms between them, they can form 5-9 membered heterocyclic alkyl groups;

[0026] R 5 Each is independently selected from H, halogen, CN, OH, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, (C2-C4)alkenyl;

[0027] Two Rs 5 The intermediate atoms therein can form 3-6 membered alkyl rings, 3-6 membered heterocyclic alkyl rings, benzene rings or 5-6 membered heteroaromatic rings, wherein each of the 3-6 membered alkyl rings or 3-6 membered heterocyclic alkyl rings may be optionally substituted by 1, 2 or 3 of the following groups: H, F, methyl; and each of the benzene rings or 5-6 membered heteroaromatic rings may be optionally substituted by 1, 2 or 3 of the following groups: H, halogen, CN.

[0028] R 6 Each is independently selected from H, halogen, CN, -OH, -NR. a R b (C1-C4)alkyl, (C1-C4)haloalkyl, -(C0-C4)alkylene-O-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl, wherein the phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, and 4-6-membered heterocyclic alkyl may each optionally be surrounded by 0, 1, 2, or 3 R's. S replace;

[0029] Two Rs 6The intermediate atoms thereon can form 3-6 membered alkyl rings or 3-6 membered heterocyclic alkyl rings, wherein the 3-6 membered alkyl rings or 3-6 membered heterocyclic alkyl rings can be optionally substituted by 0, 1, 2 or 3 groups selected from the following: H, F, methyl;

[0030] R 7 Each occurrence is independently selected from H, halogen, CN, OH, -NR. a R b (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, C3-C6 cycloalkyl, 4-6 heterocyclic alkyl, wherein the C3-C6 cycloalkyl and 4-6 heterocyclic alkyl may each be optionally substituted by 0, 1, 2 or 3 groups selected from the following: H, F, methyl;

[0031] R 8 or R 9 Each occurrence is independently selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, -(C0-C4)alkylene-(C3-C6 cycloalkyl), -(C0-C4)alkylene-(4-7 heterocyclic alkyl), -(C0-C4)alkylene-phenyl, -(C0-C4)alkylene-(5-10 heteroaryl), -C(O)R Ha -C(O)OR Ha -C(O)NR Ha R Hb -SOR Ha SO2R Ha The -(C0-C4)alkylene-(C3-C6 cycloalkyl), -(C0-C4)alkylene-(4-7 heterocycloalkyl), -(C0-C4)alkylene-phenyl, and -(C0-C4)alkylene-(5-10 heteroaryl) groups may each be optionally surrounded by 0, 1, 2, or 3 R groups. U replace;

[0032] R Ha Each is independently selected from H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, phenyl, 5-10 membered heteroaryl, (C3-C8)cycloalkyl, 4-10 membered heterocycloalkyl, wherein C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 The alkynyl groups can each be optionally surrounded by 0, 1, or 2 R groups. OThe phenyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic alkyl or (C3-C8) cycloalkyl groups may each be optionally substituted with 0, 1, 2 or 3 groups selected from the following: H, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, CN, oxo, 4-6-membered heterocyclic alkyl;

[0033] R O Each group is independently selected from halogen, OH, NH2, phenyl, (C1-C4)alkyl, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, C3-C6 cycloalkyl, 4-10 heterocyclic alkyl, 5-10 heteroaryl. Optionally, the 4-10 heterocyclic alkyl and 5-10 heteroaryl groups may be independently substituted by 0, 1, 2, or 3 groups selected from the following: H, halogen, CN, oxo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy.

[0034] R Hb Each is independently selected from H, (C1-C4) alkyl, or (C3-C5) cycloalkyl;

[0035] R Q and R U Each is independently selected from H, halogen, CN, OH, NH2, oxo, C2-C4 alkenyl, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, phenyl, 4-9 membered heterocyclic alkyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, -OR e -C(O)R g -C(O)OR e ,NHC(O)R e -C(O)NR c R d -NR a R b -S(O)2R f -S(O)=NH(C1-C4 alkyl), -S(O)NR e R f -S(O)2NR e R f Optionally, the C2-C4 alkenyl and (C1-C4) alkyl groups may each be independently surrounded by 0, 1, 2, or 3 R groups. M Optionally, the phenyl, 4-9 membered heterocyclic alkyl, 5-10 membered heteroaryl, and C3-C6 cycloalkyl groups may each be independently replaced by 0, 1, 2, or 3 R groups. F replace;

[0036] RY R J and R M Each is independently selected from H, halogen, CN, OH, (C1-C4)alkoxy, (C1-C4)haloalkoxy, -C(O)R g -C(O)OR e -NHC(O)R e -C(O)NR c R d -NR a R b -S(O)2R f -S(O)=NH(C1-C4 alkyl), -S(O)NR e R f -S(O)2NR e R f phenyl, 4-6-membered heterocyclic alkyl, 5-10-membered heteroaryl, optionally, the phenyl, 4-6-membered heterocyclic alkyl, and 5-10-membered heteroaryl groups may each be independently surrounded by 0, 1, 2, or 3 R groups. X replace;

[0037] R F R S R X R Z Each is independently selected from H, halogen, CN, OH, NH2, NO2, oxo, (C1-C4)alkyl, (C1-C4)haloalkyl, -(C0-C4 alkylene)-(C1-C4 alkoxy), (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, -(C0-C4 alkylene)-phenyl, -(C0-C4 alkylene)-(5-10-membered heteroaryl), -(C0-C4 alkylene)-(4-6-membered heterocyclic alkyl), C2-C4 alkenyl, C2-C4 alkynyl, -OR e -C(O)R g -C(O)OR e ,NHC(O)R e -(C0-C4 alkylene)-C(O)NR c R d -NR a R b -S(O)2R f -S(O)=NH(C1-C4 alkyl), -S(O)NR e R f -S(O)2NR e R fOptionally, the (C1-C4) alkyl group may be substituted with CN, and the -(C0-C4 alkylene)-phenyl and -(C0-C4 alkylene)-(4-6-membered heterocyclic alkyl groups may each be independently substituted with 0, 1, 2, or 3 groups selected from the following: H, halogen, CN, oxo, C1-C4. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, optionally, the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 The alkynyl group may be optionally substituted with a 5-10-membered heteroaryl group or a 4-10-membered heterocyclic alkyl group; the 5-10-membered heteroaryl group or the 4-10-membered heterocyclic alkyl group may be optionally substituted with an oxo group or a 4-7-membered heterocyclic alkyl group.

[0038] R a R b R c R d R e R f R g R h Each group is independently selected from H, (C1-C4)alkyl, C2-C4 alkynyl, -(C0-C4 alkylene)-phenyl, C3-C6 cycloalkyl, 4-6 heterocyclic alkyl, and 5-6 heteroaryl groups. The (C1-C4)alkyl, -(C0-C4 alkylene)-phenyl, C3-C6 cycloalkyl, 4-6 heterocyclic alkyl, and 5-6 heteroaryl groups may each be optionally substituted by 0, 1, 2, or 3 groups selected from the following: H, halogen, CN, OH, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, phenyl, and benzyl.

[0039] In the structural formula, brackets [] indicate that one H atom in the chemical formula shown inside is bonded to one end of L;

[0040] L represents -(C1-C 50 The alkylene group (-, L) is connected by a covalent bond and C, N, O, or S atoms on both sides of the group. Optionally, the 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 methylene units are each independently replaced by the following subunits: -(4-12 membered heterocyclic alkyl)-, -(C3-C 12Cycloalkyl), -(5-6-membered heteroaryl), -phenyl, -O, -NR, -S, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, -CH=CH- or -C≡C-, wherein the 4-12-membered heterocycloalkyl, C3-C 12 Cycloalkyl, 5-6-membered heteroaryl, phenyl, -CH=CH- can each be independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, methyl or oxo (=O), wherein each R independently represents H, C1-C4 alkyl or C3-C5 cycloalkyl; optionally, L can also be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, -(C0-C3)alkylene-OR, -(C0-C3)alkylene-N(R)2, -(C0-C3)alkylene-SR or oxo (=O);

[0041] EBM is a fragment of CRBN or VHL E3 ubiquitin ligase ligand, wherein:

[0042] (a) When EBM is a CRBN E3 ubiquitin ligase ligand fragment, it is selected from:

[0043] Wherein, W represents a direct bond, a benzene ring, or a 5-6 membered heteroaromatic ring, and the benzene ring or the 5-6 membered heteroaromatic ring may be optionally surrounded by 0, 1, 2, or 3 R groups. 13 replace;

[0044] Ring B represents phenyl, naphthyl, 5-12-membered heteroaryl, or 4-14-membered heterocyclic alkyl, wherein the phenyl, naphthyl, 5-12-membered heteroaryl, or 4-14-membered heterocyclic alkyl may each optionally be surrounded by 0, 1, 2, or 3 R's. 13 replace;

[0045] R 13 Each can be independently represented by H, fluorine, chlorine, oxo, C1-C4 alkyl, methoxy, or trifluoromethyl.

[0046] Z can independently represent a direct bond, -NH-, -O-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, or -CH2-;

[0047] Y can independently represent CH, CD, CF, CMe, or N;

[0048] Indicates a single bond or a double bond;

[0049] Y1 Each can be independently represented as CH2, CH, or CMe;

[0050] Y 2 Each can independently represent CH2, CH, NH, N, O, CMe, or a direct bond;

[0051] Furthermore, -L-EBM is not or,

[0052] (b) When EBM is a VHL E3 ubiquitin ligase ligand fragment, it is selected from:

[0053] Wherein, V is selected from NHR 41 Or a 5-membered heteroaryl ring, wherein each of the 5-membered heteroaryl rings may be optionally substituted with 0, 1 or 2 H, halogen or methyl;

[0054] R 41 Each of these groups independently represents H, -C(O)-(C1-C4 alkyl), and -C(O)-(C3-C5 cycloalkyl), wherein the -C(O)-(C3-C5 cycloalkyl) group may be optionally substituted by 0, 1, or 2 groups selected from the following: H, halogen, CN, and methyl.

[0055] R 31 Each can be independently represented as a C1-C4 alkyl or a C3-C6 cycloalkyl;

[0056] R 32 and R 33 Each of the following can be independently represented as H, halogen, or C1-C4 alkyl, wherein each C1-C4 alkyl group may be optionally substituted by 0, 1, 2 or 3 groups selected from the following: H, F, OH, OMe, NH(Me), NH(Me)2;

[0057] R 32 and R 33 The carbon atoms attached to it can form C3-C5 cycloalkyl groups;

[0058] The ring C is selected from phenyl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl may optionally be substituted by 0, 1 or 2 groups selected from the following: H, halogen, OH, OMe, NH(Me), NH(Me)2, C1-C4 alkyl, C3-C6 cycloalkyl; and

[0059] R 34Each of the following groups independently represents H, ethynyl, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, phenyl, 5-6 heteroaryl, and 5-6 heterocyclic alkyl. The phenyl and 5-6 heteroaryl groups may each be optionally substituted by 0, 1, or 2 groups selected from the following: H, halogen, methyl, and cyclopropyl. The 5-6 heterocyclic alkyl groups may each be optionally substituted by 1 or 2 groups selected from the following: H, halogen, methyl, cyclopropyl, and oxo.

[0060] In some implementation schemes, R 3 Selected from H.

[0061] In some implementations, q is independently selected from 0 or 1.

[0062] In some implementations, m is 0.

[0063] In some implementation schemes, R 6 Each is independently selected from H, F, or methyl.

[0064] In some embodiments, ring A is selected from a benzene ring, which may optionally be divided by p R groups. 7 replace.

[0065] In some implementations, ring A is selected from 5-6 membered heteroaryl rings, each of which may optionally be divided by p R 7 replace.

[0066] In some implementation schemes, R 4 Each is selected independently from: Among them, R 3a Each group is independently selected from CN, OH, halogen, -(C1-C4)alkyl, -(C1-C4)hydroxyalkyl, -[(C0-C4)alkylene]-O-[(C1-C4)alkyl], n1 is selected from 1, 2 or 3, and the remaining groups are as defined above.

[0067] In some implementation schemes, R 4 Each is selected independently from: and / or

[0068] In some implementations, L is -(C1-C 20The alkylene group (-, L) is connected by a covalent bond and C, N, O, or S atoms on both sides of the group. Optionally, the 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 methylene units are each independently replaced by the following subunits: -(4-12 membered heterocyclic alkyl)-, -(C3-C 12 Cycloalkyl), -(5-6-membered heteroaryl), -phenyl, -O, -NR, -S, -C(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -CH=CH- or -C≡C-, wherein the 4-12-membered heterocycloalkyl, C3-C 12 Cycloalkyl, 5-6 heteroaryl, phenyl, -CH=CH- can each be independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, methyl or oxo (=O), wherein each R independently represents H, C1-C4 alkyl or C3-C5 cycloalkyl.

[0069] In some embodiments, L may optionally be substituted by 0, 1, 2, 3 or 4 of the following substituents: halogen, C1-C3 alkyl, C3-C6 cycloalkyl or oxo (=O).

[0070] In some implementation schemes, L is selected from:

[0071] In some implementations, L does not include the following structural segments:

[0072] In some implementations, EBM is a CRBN E3 ubiquitin ligase ligand fragment selected from:

[0073] Wherein, W represents a direct linker, a benzene ring, or a 5-6 membered heteroaromatic ring, wherein the benzene ring or the 5-6 membered heteroaromatic ring may be optionally surrounded by 1, 2, or 3 R groups. 13 replace;

[0074] Ring B represents phenyl, naphthyl, 5-12-membered heteroaryl, or 4-14-membered heterocyclic alkyl, wherein the phenyl, naphthyl, 5-12-membered heteroaryl, or 4-14-membered heterocyclic alkyl may each optionally be surrounded by 1, 2, or 3 R's. 13 replace;

[0075] R 13 Each can be independently represented by H, fluorine, chlorine, oxo, C1-C4 alkyl, methoxy, or trifluoromethyl.

[0076] Z can independently represent a direct bond, -NH-, -O-, -C(O)NH-, -NHC(O)-, or -CH2-;

[0077] Y can independently represent CH, CD, CF, CMe, or N.

[0078] In some implementations, EBM is an E3 ubiquitin ligase ligand fragment selected from:

[0079] Among them, X 3 X 4 X 5 X 6 and X 8 Each can be represented independently as CH, N, or CR. 13 , where R 13 Each can independently represent H, fluorine, chlorine, methyl, methoxy, and trifluoromethyl;

[0080] X 7 Each can be independently represented as -CH2- or -C(O)-;

[0081] X 9 Each can be independently represented as -NH-, -N(Me)-, or -O-;

[0082] X 10 Each can be represented independently as N or CH;

[0083] X 11 Each can be independently represented as -O-, -NH-, -N(Me)-, -CH2-, or -C(Me)2-;

[0084] X 12 Each can independently represent N, CH, CF, C=O, C(Me), CH2 or CF2;

[0085] X 13 Each can independently represent N, CH, CF, C=O, C(Me), CH2 or NH;

[0086] Y can independently represent CH, CD, CF, CMe, or N;

[0087] Y a Each can be independently represented as CH, CD, CF, or CMe;

[0088] Z can independently represent a direct bond, -NH-, -O-, -C(O)NH-, -NHC(O)-, or -CH2-.

[0089] In some implementations, the EBM is selected from the following structures: Where R 13 Each can be represented independently as H, fluorine, chlorine, methyl, methoxy, or trifluoromethyl.

[0090] In some implementations, the EBM is selected from the following structures:

[0091] In some implementations, EBM is not

[0092] In some implementations, EBM is a VHL E3 ubiquitin ligase ligand fragment selected from:

[0093] Wherein, V is selected from NHR 41 Or a 5-membered heteroaryl ring, wherein each of the 5-membered heteroaryl rings may be optionally substituted with 0, 1 or 2 H, halogen or methyl;

[0094] R 41 Each of these groups independently represents H, -C(O)-(C1-C4 alkyl), and -C(O)-(C3-C5 cycloalkyl), wherein the -C(O)-(C3-C5 cycloalkyl) group may be optionally substituted by 0, 1, or 2 groups selected from the following: H, halogen, CN, and methyl.

[0095] R 31 Each can be independently represented as a C1-C4 alkyl or a C3-C6 cycloalkyl;

[0096] R 32 and R 33 Each of the following can be independently represented as H, halogen, or C1-C4 alkyl, wherein each C1-C4 alkyl group may be optionally substituted by 0, 1, 2 or 3 groups selected from the following: H, F, OH, OMe, NH(Me), NH(Me)2;

[0097] R 32 and R 33 And the carbon atoms attached to it can form C3-C5 cycloalkyl groups; and

[0098] R 34 Each of the following groups independently represents H, ethynyl, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, phenyl, 5-6 heteroaryl, and 5-6 heterocyclic alkyl. The phenyl and 5-6 heteroaryl groups may each be optionally substituted by 0, 1, or 2 groups selected from the following: H, halogen, methyl, and cyclopropyl. The 5-6 heterocyclic alkyl groups may each be optionally substituted by 0, 1, or 2 groups selected from the following: H, halogen, methyl, cyclopropyl, and oxo.

[0099] In some implementations, EBM is selected from:

[0100] In some embodiments, the compounds of the present invention have the structure shown in formula (Ia) or formula (Ib):

[0101] Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0102] In some embodiments, the compounds of the present invention have the structure shown in formula (Ic) or formula (Id):

[0103] Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0104] In some embodiments, the compounds of the present invention have the structure shown in formula (IIa) or formula (IIb):

[0105] Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0106] In some embodiments, the compounds of the present invention have the structures shown in formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), or (Ia-8): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0107] In some embodiments, the compounds of the present invention have the structures shown in formula (Iaa-1), (Iaa-2), (Iaa-3), (Iaa-4), (Iaa-5), (Iaa-6), (Iaa-7), or (Iaa-8): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0108] In some embodiments, the compounds of the present invention have structures shown in formulas (Iaaa-1) to (Iaaa-24): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0109] In some embodiments, the compounds of the present invention have the structures shown in formula (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), or (Ib-8): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0110] In some embodiments, the compounds of the present invention have the structures shown in formula (Ibb-1), (Ibb-2), (Ibb-3), (Ibb-4), (Ibb-5), (Ibb-6), (Ibb-7), or (Ibb-8): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each q is independently selected from 0 or 1, preferably q is 0, and the remaining groups are as defined above.

[0111] In some embodiments, the compounds of the present invention have structures shown in formulas (Ibbb-1) to (Ibbb-16): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0112] In some embodiments, the compounds of the present invention have the structure shown in formula (IIa) or formula (IIb): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0113] In some embodiments, the compounds of the present invention have the structures shown in formula (IIa-1), (IIa-2), (IIa-3), (IIa-4), (IIa-5), (IIa-6), (IIa-7), or (IIa-8): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each q is independently selected from 0 or 1, and the remaining groups are as defined above.

[0114] In some embodiments, the compound of the present invention has the structure shown in formula (III): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0115] In some embodiments, the compounds of the present invention have the structures shown in formula (IIIa), (IIIb), (IIIc), (IIId), or (IIIe): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0116] In some embodiments, the compound of the present invention has the structure shown in formula (IV): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0117] In some embodiments, the compounds of the present invention have the structures shown in formula (IVa), (IVb), (IVc), (IVd), or (IVe): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0118] In some embodiments, the compound of the present invention has the structure shown in formula (V): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0119] In some embodiments, the compound of the present invention has the structure shown in formula (VI): Or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, wherein each group is as defined above.

[0120] This invention covers any combination of the above embodiments.

[0121] More preferably, in some embodiments of the present invention, the compound is any of the following compounds:

[0122] In another aspect, the present invention also provides a pharmaceutical composition comprising the compound as described above, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotope derivative, N-oxide, or prodrug, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0123] In another aspect, the present invention also provides the use of the compounds described above, or their stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, or pharmaceutical compositions, in medicaments for the prevention and / or treatment of diseases associated with STAT6 and / or STAT3 activity. These STAT6 and / or STAT3 activity-related diseases include, for example, cancer, inflammatory diseases, and autoimmune diseases.

[0124] In one aspect, the present invention also provides a method for preventing and / or treating diseases associated with STAT6 and / or STAT3 activity, comprising administering to a patient in need a therapeutically effective amount of the compound as described above, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotope derivative, N-oxide, or prodrug, or pharmaceutical composition thereof. The STAT6 and / or STAT3 activity-related diseases include, for example, cancer, inflammatory diseases, autoimmune diseases, etc.

[0125] In another aspect, in the above-described uses or methods, the compound described above, or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotope derivatives, N-oxides or prodrugs, or pharmaceutical compositions, may be used alone or in combination with other types of pharmaceutical preparations and / or treatment methods.

[0126] It is particularly noteworthy that, in this article, when referring to a "compound" having a specific structural formula, it generally also includes its stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives.

[0127] As is known to those skilled in the art, the salts, solvates, and hydrates of a compound are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noteworthy that when a compound is mentioned herein, its pharmaceutically usable salts are generally also included, and consequently its solvates and hydrates are also included.

[0128] Similarly, when referring to a compound in this article, its prodrug, metabolites, and nitrogen oxides are generally also included.

[0129] The term "stereoisomer" in the compounds of this invention refers to the enantiomers produced when the compound contains asymmetric carbon atoms; the cis-trans isomers produced when the compound contains carbon-carbon double bonds or cyclic structures; and the tautomers produced when the compound contains ketones or oximes. All enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of this invention.

[0130] The "pharmaceutically acceptable salts" described in this invention refer to pharmaceutically acceptable addition salts of acids and bases or their solvates. Such pharmaceutically acceptable salts include salts of the following acids: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, and alkanes (such as acetic acid, HOOC-(CH2)n-COOH (where n is 0-4)). Salts of bases include: sodium salts, potassium salts, calcium salts, ammonium salts, etc. Many non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.

[0131] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example by dissolving the compounds of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, and acetonitrile), adding an excess of an aqueous solution of an organic or inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid, and then separating the precipitated salt.

[0132] The precursors or metabolites described in this invention can be precursors or metabolites known in the art, as long as they are metabolized and transformed in vivo to form compounds. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly converted in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism.

[0133] This invention provides the use of a compound of specific formula (I) and its pharmaceutically acceptable salts, solvates, stereoisomers, prodrugs, and metabolites in the prevention and / or treatment of diseases related to STAT6 and / or STAT3 activity.

[0134] The diseases associated with STAT6 and / or STAT3 activity described in this invention include cancer, inflammatory diseases, autoimmune diseases, etc.

[0135] The compounds of this invention can be used alone or in combination with other types of pharmaceutical preparations and / or treatments for the prevention and / or treatment of STAT6 and / or STAT3-related diseases.

[0136] The present invention also provides the use of the compounds of the present invention in the preparation of medicaments for the prevention and / or treatment of STAT6 and / or STAT3-related diseases.

[0137] Furthermore, the present invention provides pharmaceutical compositions for the prevention and / or treatment of STAT6 and / or STAT3-related diseases, comprising compounds of the present invention as active ingredients. Attached Figure Description

[0138] Figure 1 shows the results of the compound's degradation activity against STAT protein (Western Blot).

[0139] Invention Details

[0140] definition

[0141] Unless otherwise specified, the terms used in this application (including the specification and claims) are defined as follows. It should be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0142] In the specification and claims, the given chemical formula or name shall cover all stereo and optical isomers and racemic products containing such isomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of this invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc., may also be present in the compounds, and all such stable isomers are covered within this invention. This invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of this invention, which can be separated into mixtures of isomers or separate isomeric forms. The compounds of this invention can be separated in optically active or racemic forms. All methods used to prepare the compounds of this invention and the intermediates prepared therein are considered part of this invention. In the preparation of enantiomers or diastereomers, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the method conditions, the end products of this invention are obtained in free (neutral) or salt form. Both the free form and salts of these end products are within the scope of this invention. If necessary, one form of the compound can be converted into another. A free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; a mixture of isomers of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms, and salts can exist in a variety of tautomer forms, wherein hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all possible tautomer forms are included within the scope of this invention.

[0143] In this invention, when the connection direction of the listed linking groups is not specified, the connection direction is arbitrary, for example... In this case, L stands for -C(O)NH-. -C(O)NH- can be formed by connecting the phenyl group and the cyclohexyl group in a left-to-right reading order. Alternatively, the phenyl and cyclohexyl groups can be connected in the reverse reading order from left to right to form the structure. The combination of the linking group and the linked group is only permitted if it produces a stable compound.

[0144] Unless otherwise defined, the definitions of substituents in this invention are independent and not related to each other. For example, for R in a substituent...a (or R) b For R, the definitions of different substituents are independent. Specifically, for R a (or R) b Choosing a definition for a substituent does not mean that R a (or R) b The same definition applies to all other substituents. More specifically, for example (a non-exhaustive list only) for NR... a R b In the middle, when R a (or R) b When the definition of ) is taken from hydrogen, it does not mean that in -C(O)-NR a R b In the middle, R a (or R) b It must be hydrogen. On the other hand, when a substituent contains more than one R... a (or R) b When these R a (or R) b They are also independent. For example, in the substituent -(CR) a R b ) m -O-(CR a R b ) n In the case where m+n is greater than or equal to 2, there are m+n R values. a (or R) b Each of these is independent; they can have the same or different meanings.

[0145] Unless otherwise defined, when a substituent is labeled “optionally substituted,” the substituent is selected from, for example, alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine group (where the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arylanoylamino, arylalkylamino, substituted alkanoylamino, substituted arylamino, substituted arylalkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamide (e.g., -SO2NH2), substituted sulfonamide, nitro, cyano, carboxyl, carbamoyl (e.g., -CONH2), substituted carbamoyl (e.g., -CONHalkyl), -CONHaryl, -CONHarylalkyl, or having two substituents selected from alkyl, aryl, or arylalkyl on nitrogen, alkoxycarbonyl, aryl, substituted aryl, guanidine, heterocyclic, such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazine, homopiperazine, etc., and substituted heterocyclic groups.

[0146] In this invention, the structural formula is as follows: This indicates that one H atom in the chemical formula shown in [] is connected to one end of L by a bond, which means that one C, N, O or S atom in the chemical formula shown in [] is connected to L by a covalent bond.

[0147] In this invention, the structure This indicates that the phenyl and cyano groups are trans-substituted on the ring, which represents... A mixture of two configurations.

[0148] In this invention, the term "alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and neopentyl. Alkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable link, preferably from one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Preferred alkyl groups in this invention include C1-C6 alkyl or C1-C4 alkyl groups.

[0149] In this invention, the term "haloalkyl" refers to an alkyl group that is substituted with one or more halogens, wherein the alkyl group is as defined above.

[0150] In this invention, the term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0151] In this invention, the term "alkylene" is intended to include branched, straight-chain, saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, containing or not containing cyclic alkyl groups, which are residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, "C0-C6 alkylene" indicates an alkylene having 0 to 6 carbon atoms, and C0 alkylene indicates that the alkylene is absent (one bond). Examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. In this document, alkylene atoms are preferably alkylene atoms having 0-6, 0-4, 0-3, 1-6, 1-4, or 1-3 carbon atoms. Preferably, alkylene atoms do not contain cyclic alkyl groups.

[0152] In this invention, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, polycyclic, or branched cycloalkyl group. For example, C3-C 12 Cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornel. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Polycyclic cycloalkyl groups, such as bicyclic and tricyclic, include bridged, spirocyclic, or fused cycloalkyl groups. The cycloalkyl ring includes fused rings formed by cycloalkyl groups (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aromatic ring, heteroaromatic ring, or heterocyclic alkyl ring as described above, wherein the ring connected to the parent structure is a cycloalkyl group. Non-limiting examples: etc. The cycloalkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the present invention, the cycloalkyl group is preferably C3-C. 12 Cycloalkyl, more preferably C3-C8 cycloalkyl.

[0153] In this invention, the term "3-12 membered cycloalkyl" or "C3-C" is used. 12 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic alkyl system consisting of 3 to 12 ring atoms, all of which are carbon atoms. It includes monocyclic alkyl, fused cycloalkyl, spirocyclic alkyl, and bridged cycloalkyl. The term "3-12 membered cycloalkyl" or "C3-C" is used. 12"Cycloalkyl" can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered cycloalkyl. Specific examples of 3-12-membered cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl-cyclopentyl, cyclobutylspirobutyl, or... wait.

[0154] In this invention, the term "heterocyclic alkyl" refers to a saturated or partially unsaturated cyclic structure in which at least one carbon atom in a cycloalkyl ring is replaced by a heteroatom selected from N, O, S, and P. The N atom may optionally be quaternized, and the N and S atoms may optionally be oxidized (i.e., NO, SO, and SO2). It includes monocyclic, bicyclic, and tricyclic heterocyclic systems, wherein bicyclic and tricyclic heterocyclic systems include spirocyclic, fused, and bridged heterocyclic rings. The heterocyclic alkyl ring includes a fused ring formed by the fusion of heterocyclic alkyl groups (including monocyclic, spirocyclic, fused, and bridged rings) onto an aromatic ring, heteroaromatic ring, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic alkyl group. Non-limiting examples: The heterocyclic alkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl. In the present invention, the heterocyclic alkyl group is preferably a 4-12 membered heterocyclic alkyl group, more preferably a 4-8 membered heterocyclic alkyl group.

[0155] In this invention, the term "4-12 membered heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic alkyl system consisting of 4 to 12 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from N, O, and S, and the remainder are carbon atoms, wherein the N atom may optionally be quaternized, and the N and S atoms may optionally be oxidized (i.e., NO, SO, and SO2). When the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. It includes monocyclic, bicyclic, and tricyclic heterocyclic systems, wherein bicyclic and tricyclic heterocyclic systems include spirocyclic, fused, and bridged heterocyclic rings. The "4-12 membered heterocyclic alkyl" can be 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered heterocyclic alkyl. Specific examples of 4-12 membered heterocyclic alkyl groups include, but are not limited to, aziridine, oxadiazinyl, pyrrolidine (including 2-pyrrolidine and 3-pyrrolidine), piperidinyl (including 2-piperidinyl, 3-piperidinyl and 4-piperidinyl, etc.), piperazinyl, hexahydropyridazinyl, morpholinyl, dioxane, hexahydropyridazinyl, aziridine-heptane, 1,4-diazacycloheptane, cyclopentyl-pyrrolidine, pyrrolidine-pyrrolidine, cyclopropylspiroperazinyl, cyclobutylspiroaziridine, aziridine-butylspiroaziridine, cyclobutylspiroaziridine-butyl, cyclobutylspiroaziridine-pentyl, aziridine-butylspiroaziridine-pentyl, cyclobutylspiroaziridine-pentyl, cyclobutylspiroaziridine-hexyl, aziridine-butylspiroaziridine-hexyl, aziridine-butylspiroaziridine-hexyl, cyclopentylspiroaziridine-pentyl, aziridine- ... wait.

[0156] In this invention, the term "cyclic" refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms.

[0157] In this invention, the term "bridged ring" refers to a polycyclic group in which two rings in the system share two or more ring atoms.

[0158] In this invention, the term "spirocyclic" refers to a polycyclic group in which single rings share a single carbon atom (called a spiro atom).

[0159] In this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. Preferred alkenyl groups in this invention include C2-C6 alkenyl groups.

[0160] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl groups refer to C3-C8 cyclic alkenyl groups, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norcamphenyl. Branched cyclic alkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl." Bicyclic cyclic alkenyl groups include bridged, spiro, or fused ring cyclic alkenyl groups.

[0161] In this invention, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, etc. Preferred alkynyl groups in this invention include C2-C6 alkynyl groups.

[0162] In this invention, the term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above, connected by a sulfur bridge having a specified number of carbon atoms; for example, methyl-S- and ethyl-S-. Preferred alkoxy groups in this invention include C1-C6 or C1-C4 alkoxy groups. Alkoxy groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable connection point, preferably from one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0163] In this invention, the term "carbonyl" refers to an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0164] In this invention, the term "aryl" or "aryl ring" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heterocyclic alkyl or cycloalkyl ring as described above, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include: The dashed lines drawn from the ring system indicate that the bond can be attached to any suitable ring atom. The aryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0165] In this invention, the term "heteroaryl" or "heteroary ring" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur, and can be a monocyclic, fused bicyclic, or tricyclic system. The heteroaryl is preferably a 5- to 10-membered heteroaryl (e.g., 5, 6, 7, 8, 9, or 10-membered heteroaryl), such as furanyl, thiophene, pyridinyl, pyrrolithyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, benzopyrimidinyl, benzothiophene, benzopyrazolyl, benzothiazolyl, benzopyrrolithyl, pyridothiophene, pyridopyrazolyl, imidazole, pyrazole, triazole, tetrazolyl, etc. The heteroaryl ring includes a fused ring formed by a heteroaryl group fused to a heterocyclic alkyl or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include: The heteroaryl group can be unsubstituted or substituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0166] In this invention, the term "substitution" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution yields a stable compound. The cyclic double bond used herein is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0167] In this invention, one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0168] In this invention, the terms "halogenated" or "halogen" include fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of halogenated alkyl groups also include "fluoroalkyl" groups intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms. "Halogenated cycloalkyl" / "halogenated heterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having a specified number of carbon atoms and substituted with one or more halogens. In this invention, the halogen atom is preferably fluorine or chlorine, more preferably fluorine.

[0169] In this invention, the term "haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above, which is oxygen-bridged and has a specified number of carbon atoms. For example, "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a haloalkyl group as defined above, which is sulfur-bridged and has a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0170] In this invention, C is used when referring to certain substituent groups. x1 -C x2 The statement indicates that the number of carbon atoms in the substituent group can be [number missing]. x1 to x2 For example, C 0- C8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C1-C8 indicates that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C2-C8 indicates that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C3-C8 indicates that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms; C4-C8 indicates that the group contains 4, 5, 6, 7, or 8 carbon atoms; C0-C6 indicates that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 indicates that the group contains 2, 3, 4, 5, or 6 carbon atoms; C3-C6 indicates that the group contains 3, 4, 5, or 6 carbon atoms.

[0171] In this invention, when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), the expression "x1-x2 membered ring" is used, indicating that the number of ring atoms in the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; a 3-6 membered ring indicates that the cyclic group can be a 3, 4, 5, or 6 membered ring, and its number of ring atoms can be 3, 4, 5, or 6; a 3-8 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, or 8; a 3-9 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; 8 or 9; 4-7 membered ring indicates that the cyclic group can be a 4, 5, 6, or 7 membered ring, and its number of ring atoms can be 4, 5, 6, or 7; 5-8 membered ring indicates that the cyclic group can be a 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 5, 6, 7, or 8; 5-12 membered ring indicates that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 5, 6, 7, 8, 9, 10, 11, or 12; 6-12 membered ring indicates that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 6, 7, 8, 9, 10, 11, or 12. The ring atoms can be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3 or 4 cyclic heteroatoms, for example, heteroatoms chosen from N, O and S.

[0172] In cases where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxides to obtain derivatives of the present invention.

[0173] When any variable appears more than once in any composition or formula of a compound, its definition for each occurrence is independent of its definition for each other occurrence. Thus, for example, if a substituent group is shown to have 0-3 R groups, the substituent group may optionally be substituted with up to three R groups, and each occurrence of R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are only permitted if such combinations produce a stable compound.

[0174] In this invention, the term "patient" refers to an organism treated by the method of this invention. Such organisms preferably include, but are not limited to, mammals (e.g., rodents, apes / monkeys, horses, cattle, pigs, dogs, cats, etc.), and most preferably, humans.

[0175] In this invention, the term "effective amount" means the amount of a drug or agent (i.e., the compound of this invention) that will elicit a biological or medical response in a tissue, system, animal, or human, as sought by, for example, a researcher or clinician. Furthermore, the term "therapeutic effective amount" means an amount that, compared to a corresponding subject who has not received the aforementioned amount, results in improved treatment, cure, prevention, or reduction of a disease, symptom, or side effect, or a slower rate of progression of a disease or symptom. Effective amounts may be administered, applied, or dosed in one or more administrations and are not intended to be limited to a specific formulation or route of administration. The term also includes effective amounts within its scope that enhance normal physiological function.

[0176] In this invention, the term "treatment" has a broad meaning, encompassing therapeutic and / or preventative treatment of an object. Specifically, "treatment" includes any treatment that results in the mitigation, suppression, elimination, improvement, and / or prevention of symptoms, diseases, disorders, etc., such as alleviating, reducing, regulating, improving, eliminating, preventing, or improving their symptoms. Therapeutic treatment includes alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving underlying metabolic syndrome; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom; or treating signs caused by a disease or symptom. Preventative treatment includes pre-treatment to prevent, block, delay, slow the occurrence or development of a disease or condition, or reduce its severity.

[0177] Similarly, "therapeutic agents" also include medicines or reagents that provide therapeutic and / or preventative treatment to a subject.

[0178] In this invention, the terms "pharmaceutical" or "pharmaceutical acceptable" are used herein to refer to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, and / or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0179] In this invention, the term "pharmaceutically acceptable carrier" or "pharmaceutical carrier" means a pharmaceutical substance, composition, or medium, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, zinc stearate, or stearic acid), or solvent encapsulation substance, relating to carrying or delivering a subject compound from one part of an organ or body to another part of an organ or body. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation and harmlessness to the patient.

[0180] In this invention, the term "pharmaceutical composition" means a composition comprising the compounds of this invention and at least one other pharmaceutical carrier. "Pharmaceutical carrier" refers to a medium commonly accepted in the art for delivering a bioactive agent to an animal (specifically a mammal), including (i.e.) adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form.

[0181] Specific pharmaceutical and medical terms

[0182] In this invention, the term "acceptable," as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on the health of a general therapeutic target.

[0183] In this invention, the term "cancer," as used herein, refers to an uncontrolled abnormal growth of cells that, under certain conditions, is capable of metastasis (spread). This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestines, brain, chest, uterus, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or hematologic malignancies (such as non-leukemic leukemia).

[0184] In this invention, the term "autoimmune disease," as used herein, refers to a disease in which the body's immune system abnormally attacks its own normal tissues, causing inflammation and damage. Common autoimmune diseases include: systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, psoriasis, type 1 diabetes, Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease, scleroderma, and thrombocytopenic purpura.

[0185] In this invention, the term "inflammatory disease," as used herein, refers to a class of diseases caused by inflammation of tissues due to a response of the immune system. Inflammation can be acute or chronic. Common inflammatory diseases include: autoimmune inflammatory diseases (such as multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, psoriasis, type 1 diabetes, Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease, scleroderma, thrombocytopenic purpura, etc.), allergic diseases (asthma, eczema, allergic rhinitis, etc.), non-infectious inflammatory diseases (osteoarthritis, gouty arthritis, etc.), infectious inflammatory diseases, and metabolic inflammatory diseases.

[0186] In this invention, the term "combined administration" or similar terms, as used herein, refers to administering several selected therapeutic agents to a patient in the same or different manners of administration at the same or different times.

[0187] In this invention, the terms "enhancement" or "capability to enhance," as used herein, refer to the expected increase or prolongation of either potency or duration of effect. Therefore, in terms of enhancing the therapeutic effect of a drug, the term "capability to enhance" refers to the ability of a drug in a system to increase or prolong its potency or duration of effect. The term "synergistic value," as used herein, refers to the ability of an ideal system to maximize the enhancement of another therapeutic agent.

[0188] In this invention, the term "immune disease" refers to a disease or symptom that results from an adverse or harmful reaction to endogenous or exogenous antigens. This typically results in cellular dysfunction, or damage leading to functional impairment, or damage to organs or tissues that may produce immune symptoms.

[0189] In this invention, the terms "reagent kit" and "product packaging" are synonyms.

[0190] In this invention, the terms "subject," "subject," or "patient" include both mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In a preferred embodiment, the selected mammal is a human.

[0191] As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. This may be attributable to or related to the administration, whether the administration is fixed or intermittent, continuous or discontinuous. Specific Implementation

[0192] The present invention can be better understood by referring to the following specific embodiments, which are for illustrative purposes only and not for limiting the invention. In the present invention, when the preparation method is not mentioned, the relevant raw materials and intermediates are all purchased from commercial reagents (e.g., from Bioderm, Pharmaron, etc.).

[0193] The abbreviations used in this invention have the following meanings:

[0194] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-35°C).

[0195] The compounds of this invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or fast column chromatography (Flash column chromatography), and their structures are obtained by... 1 Confirmation was performed using 1H NMR and / or MS. Reaction monitoring was performed using TLC or LC-MS.

[0196] 1 H-NMR spectra were recorded at 500 MHz on a Bruker instrument. Chemical shift values ​​are expressed in parts per million (ppm), i.e., δ values. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad peak, d = doublet, t = triplet, m = multiplet. Coupling constants are listed in J values ​​and measured in Hz. LC-MS experimental conditions were as follows: Instrument: Thermo U3000, ALLtech ELSD, MSQ, UV detector combined with ELSD and MSD (elution ratio 4:1). Column: Waters X-Bridge C-18, 3.5 μm, 4.6 x 50 mm; column temperature: 30 °C. Gradient [time (min) / solvent B in A (%)]: 0.00 / 5.0, 1.40 / 95, 2.80 / 95, 2.82 / 5, 3.00 / 5. (Solvent A = 0.01% trifluoroacetic acid in water; Solvent B = 0.01% trifluoroacetic acid in acetonitrile). UV detection: 214 / 254 / 280 / 300nm; DAD detection: 210-350nm; Flow rate: 2mL / min; MS: ESI, 100-1500m / z.

[0197] Preparative HPLC used basic, acidic, or neutral methods (basic method mobile phase: acetonitrile / 0.05% ammonium bicarbonate aqueous solution; acidic method mobile phase: acetonitrile / 0.05% formic acid aqueous solution or acetonitrile / 0.05% TFA aqueous solution; neutral method mobile phase: acetonitrile / pure water); the instrument was a Thermo U3000 AFC-3000; the column was a Globalsil C-18 12nm, 250x20mm, 10μm, or equivalent; the flow rate was 20mL / min, and gradient elution separation was performed.

[0198] Synthesis of intermediates

[0199] Intermediate INT-1

[0200] Synthesis steps:

[0201] Step 1: Compound INT-1a (3.0 g, 28.30 mmol) was dissolved in tetrahydrofuran (30 mL). INT-1b (5.02 g, 28.30 mmol) and potassium tert-butoxide (6.34 g, 56.60 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LC-MS until completion. The reaction mixture was poured into water (40 mL), extracted with ethyl acetate (40 mL x 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-1c (1.60 g, yield 44%). ESI-MS (m / z): 130.1 [M+H] + .

[0202] Step 2: Compound INT-1c (1.60 g, 12.40 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of INT-1d (2.94 g, 12.40 mmol) and TFA (140.0 mg, 1.24 mmol). The reaction mixture was stirred at room temperature for 12 hours, and the reaction was monitored by LCMS until completion. Dichloromethane (30 mL) was then added to the reaction mixture, and the solution was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-1e (1.70 g, 53% yield). ESI-MS (m / z): 263.2 [M+H] + .

[0203] Step 3: Compound INT-1e (1.70 g, 6.48 mmol) was dissolved in dichloromethane (20 mL), and 1-chloroethyl chloroformate (9.20 g, 64.80 mmol) was added. The reaction mixture was stirred at 70°C for 12 hours, and the starting material disappeared as monitored by LCMS. The reaction mixture was concentrated, and the residue was dissolved in methanol (15 mL). The mixture was stirred at 70°C for another hour, and the reaction was considered complete as monitored by LCMS. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative liquid chromatography to obtain compound INT-1 (1.0 g, 91% yield). ESI-MS (m / z): 173.3 [M+H] + .

[0204] Intermediate INT-2

[0205] Synthesis steps:

[0206] Step 1: Compound INT-2a (25.0 g, 97.24 mmol) and benzyl bromide (19.96 g, 116.68 mmol, 13.86 mL) were dissolved in DMF (300 mL), and potassium carbonate (40.32 g, 291.71 mmol) was added. The reaction mixture was stirred at 80°C for 1 hour, and the reaction was monitored by LCMS until completion. The reaction mixture was cooled to room temperature and slowly poured into water (500 mL). Extraction was performed with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound INT-2b (25.0 g, 74% yield). ESI-MS (m / z): 367.2 [M+H] + .

[0207] Step 2: Compound INT-2b (5.0 g, 14.40 mmol), cuprous iodide (822.74 mg, 4.32 mmol), sodium iodide (6.48 g, 43.20 mmol), and N,N'-dimethylethylenediamine (380.81 mg, 4.32 mmol) were dissolved in dioxane (50 mL). The reaction system was purged with nitrogen, and the mixture was stirred at 115°C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-2c (4.8 g, yield 84%). ESI-MS (m / z): 189.0 [M+H] + .

[0208] Step 3: Cadmium (17.96 g, 159.81 mmol) and TMSCl (578.71 mg, 5.33 mmol) were dissolved in DMF (200 mL), and diethyl bromodifluoromethylphosphonate (42.67 g, 159.81 mmol) was added. The reaction system was purged with nitrogen gas, and the mixture was stirred at room temperature for 3 hours. The reaction solution was then filtered under nitrogen protection. INT-2c (21 g, 53.27 mmol) and cuprous chloride (15.82 g, 159.81 mmol) were dissolved in DMF (200 mL) and added to the filtrate under nitrogen protection. The mixture was stirred at room temperature for another 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was cooled to room temperature and slowly poured into water (500 mL). Extraction was performed with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give compound INT-2d (18.0 g, 74% yield). ESI-MS (m / z): 455.0 [M+H] + .

[0209] Step 4: Dissolve compound INT-2d (16.5 g, 36.31 mmol) in methanol (160 mL), add Pd / C (3.86 g, 36.31 mmol), replace the reaction system with hydrogen gas, stir at room temperature for 16 hours, and monitor the reaction for completion using LCMS. Filter and concentrate the reaction solution, and use C2000 for further processing. 18 Purification by reverse-phase column chromatography (water / acetonitrile = 75 / 25) yielded compound INT-2 (4.20 g, 32% yield). ESI-MS (m / z): 365.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.06(d,J=8.0Hz,2H),7.88(s,1H),7.48(d,J=8.8Hz,1H),4.17–4.03(m,4H),1.21(t,J=7.2Hz,6H).

[0210] intermediate INT-3

[0211] Synthesis steps:

[0212] Step 1: Compound INT-3a (750.0 mg, 2.09 mmol) was dissolved in DMF (15 mL), and DMAP (255 mg, 2.09 mmol), p-nitrophenol (290.0 mg, 2.09 mmol), and EDCI (397.0 mg, 2.09 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound INT-3b (550.0 mg, yield 54%). ESI-MS (m / z): 480.0 [M+H] + .

[0213] Step 2: Compound INT-3b (550.0 mg, 1.15 mmol) was dissolved in dichloromethane (6 mL). TMSI (229 mg, 1.15 mmol) and BSTFA (29.5 mg, 114 μmol) were added at 0°C. The reaction system was purged with nitrogen and stirred at 0°C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (30 mL), extracted with dichloromethane (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound INT-3c (300.0 mg, yield 61%). ESI-MS (m / z): 424.2 [M+H] + .

[0214] Step 3: Compound INT-3c (300.0 mg, 708.0 μmol) was placed in water (5 mL), and sodium hydroxide (51.0 mg, 1.28 mmol) and silver nitrate (264 mg, 1.56 mmol) were added at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was monitored by LCMS until the reaction was complete. The reaction solution was filtered, and the filter cake was dried to obtain compound INT-3d (360.0 mg, yield 79%).

[0215] Step 4: 2-Mercaptoethanol (10.0 g, 127 mmol) and triethylamine (15.5 g, 153 mmol) were dissolved in dichloromethane (100 mL). The reaction system was purged with nitrogen. Pivaloyl chloride (18.5 g, 152 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for 3 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (300 mL), extracted with dichloromethane (300 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to give compound INT-3f (11.0 g, yield 53%).

[0216] Step 5: Compound INT-3f (5.00 g, 30.8 mmol), triphenylphosphine (16.1 g, 61.6 mmol), and imidazole (15.6 g, 61.63 mmol) were dissolved in tetrahydrofuran (100 mL). The reaction system was replaced with nitrogen gas. Iodine (15.6 g, 61.63 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (100 mL), extracted with dichloromethane (100 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to give compound INT-3g (7.0 g, yield 83%).

[0217] Step 6: Dissolve compound INT-3d (160 mg, 251 μmol) in toluene (3 mL), add compound INT-3g (205 mg, 753 μmol), replace the reaction system with nitrogen, and stir at room temperature in the dark for 18 hours. Monitor the reaction completion by LC-MS. Filter the reaction solution, concentrate the filtrate, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound INT-3 (24.60 mg, yield 12%). ESI-MS (m / z): 734.2 [M+Na] + ; 1H NMR (400MHz, DMSO-d6): δ9.11(s,1H),8.52(s,1H),8.43–8.37(m,2H),8.31–8.21(m,3H), 7.85–7.79(m,1H),7.72–7.67(m,2H),4.22–4.14(m,4H),3.13–3.08(m,4H),1.14(s,18H).

[0218] intermediate INT-4

[0219] The synthesis method of intermediate INT-4 is the same as that of INT-3.

[0220] 1 H NMR (400MHz, DMSO-d6): δ9.11(s,1H),8.53(s,1H),8.44–8.37(m,2H),8.31–8.24(m,3H),7.86–7.79(m,1H),7.7 5–7.66(m,2H),4.24–4.14(m,4H),3.19–3.13(m,4H),2.44–2.40(m,4H),2.05–1.96(m,2H),0.87–0.83(m,12H).

[0221] Intermediate INT-5

[0222] Synthesis steps:

[0223] Compound INT-5a (966.0 mg, 3 mmol) and 7-octynoic acid (840.0 mg, 6 mmol) were dissolved in DMF (6 mL) and triethylamine (6 mL). Bistriphenylphosphine palladium dichloride (210.0 mg, 0.30 mmol) and cuprous iodide (114.0 mg, 0.60 mmol) were added. The reaction system was purged with nitrogen and stirred at 80°C for 4 hours. The reaction was monitored by LCMS until completion. The reaction solution was quenched with water (30 mL), and the pH was adjusted to 6–7 with 4 M HCl aqueous solution. The mixture was extracted with ethyl acetate (50 mL * 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-5 (607.0 mg, yield 53%). ESI-MS (m / z): 383.2 [M+H] + .

[0224] Intermediate INT-6

[0225] The synthesis method of intermediate INT-6 is the same as that of INT-2.

[0226] 1 H NMR (400MHz, DMSO) δ8.72(s,1H),8.30(s,1H),8.17(d,J=8.4Hz,1H),8.12(d,J=8.4Hz,1H ),8.03(d,J=8.4Hz,1H),7.68(d,J=8.4Hz,1H),4.19–4.09(m,4H),1.22(t,J=7.2Hz,6H).

[0227] Intermediate INT-7

[0228] The synthesis method for intermediate INT-7 is the same as that for INT-3.

[0229] intermediate INT-8

[0230] The synthesis method of intermediate INT-8 is the same as that of INT-3.

[0231] 1 H NMR (400MHz, DMSO-d6): δ9.08(s,1H),8.50(s,1H),8.42–8.39(m,2H),8.30–8.24(m, 3H),7.79(d,J=8.8Hz,1H),7.72–7.69(m,2H),5.77–5.70(m,4H),1.13–1.11(m,18H).

[0232] Intermediate INT-9

[0233] Synthesis steps:

[0234] Step 1: Compound INT-2d (908.0 mg, 2.0 mmol) was dissolved in dichloromethane (10 mL), and TMSI (2.0 g, 10 mmol) and BSTFA (3.08 g, 12 μmol) were added. The reaction system was purged with nitrogen and stirred at 0°C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (30 mL), extracted with dichloromethane (30 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-9a (558.0 mg, yield 70%). ESI-MS (m / z): 399.2 [M+H] + .

[0235] Step 2: Compound INT-9a (558.0 mg, 1.4 mmol) was placed in water (6 mL), sodium carbonate (1.0 g, 9.61 mmol) and silver nitrate (1.18 g, 7.0 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until the reaction was complete. The reaction solution was filtered, and the filter cake was dried to obtain compound INT-9b (800.0 mg, yield 93%).

[0236] Step 3: Compound INT-9b (800 mg, 1.31 mmol) was dissolved in toluene (8 mL), and sodium bicarbonate (330.0 mg, 3.93 mmol) and methyl iodide pentovalinate (951.0 mg, 3.93 mmol) were added. The reaction system was purged with nitrogen and stirred at room temperature in the dark for 18 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a colorless oily compound INT-9c (490.0 mg, yield 60%). ESI-MS (m / z): 627.2 [M+H] + .

[0237] Step 4: Compound INT-9c (490.0 mg, 0.78 mmol) was dissolved in tetrahydrofuran (10 mL), and Pd / C (50 mg) was added. The reaction system was replaced with hydrogen gas, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-9 (230.0 mg, yield 55%). ESI-MS (m / z): 537.2 [M+H] + .

[0238] Intermediate INT-10

[0239] The synthesis method of intermediate INT-10 is the same as that of intermediate INT-11.

[0240] Intermediate INT-11

[0241] Synthesis steps:

[0242] Step 1: Compound INT-11a (100 mg), potassium iodide (12 mg), and sodium bicarbonate (61 mg) were added to DMF (2 mL). Tert-butyl 5-bromopentanoate (95 mg) was then added to the reaction system. The reaction system was heated to 80 °C and stirred overnight. The reaction system was cooled to room temperature, diluted with ethyl acetate, and extracted three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol) to obtain compound INT-11b (150 mg, 95% yield). ESI-MS (m / z): 431.1 [M+H] + .

[0243] Step 2: Compound INT-11b (150 mg) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (2 mL) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated and evaporated to dryness to obtain compound INT-11 (130 mg, yield 99%). ESI-MS (m / z): 375.6 [M+H] + .

[0244] Intermediate INT-12

[0245] Synthesis steps:

[0246] Step 1: 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (1.0 g, 3.62 mmol) and 1-(tert-butyloxycarbonyl)piperazine (846.60 mg, 3.80 mmol) were dissolved in DMF (5 mL), and DIPEA (1.40 g, 10.86 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. The reaction solution was cooled to room temperature. The reaction solution was diluted with dichloromethane and washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol) to give compound INT-12a (1.6 g, 99% yield). ESI-MS (m / z): 443.5 [M+H] + .

[0247] Step 2: Dissolve INT-12a (1.6 g, 3.62 mmol) in dioxane (10 mL), add 4 M HCl dioxane solution (5 mL), and stir at room temperature for 3 hours. Concentrate the reaction mixture to obtain INT-12 (1.2 g, 96% yield). ESI-MS (m / z): 343.6 [M+H] + .

[0248] Intermediate INT-13

[0249] The preparation method of intermediate INT-13 is the same as that of intermediate INT-12.

[0250] Intermediate INT-14

[0251] Synthesis steps:

[0252] Step 1: Methyltriphenylphosphine bromide (27.9 g, 81.4 mmol) was dissolved in tetrahydrofuran (300 mL), and potassium tert-butoxide (11 g, 97.7 mmol) was added under ice bath conditions. The reaction system was then brought to room temperature and stirred for 2 hours. Then, ethane-4-oxycyclohexane acetate (10 g, 54.3 mmol) was added under ice bath conditions, and the reaction system was stirred at room temperature for 2 hours, followed by heating to 50 °C and stirring for 14 hours. After the reaction was complete, the reaction system was cooled to room temperature, diluted with water (1000 mL), and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound INT-14a (5.0 g, 50% yield). ESI-MS (m / z): 183.5 [M+H] + .

[0253] Step 2: Compound INT-14a (5.0 g, 27.5 mmol) was dissolved in tetrahydrofuran (20 mL), ethanol (3 mL), and water (20 mL). Lithium hydroxide (3.3 g, 137 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water, the pH was adjusted to 2.0 with hydrochloric acid, and then extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound INT-14b (3.75 g, 88% yield). ESI-MS (m / z): 155.4 [M+H] + .

[0254] Step 3: Compound INT-14b (3.2 g, 20.7 mmol) was dissolved in tert-butanol (30 mL). DMAP (253 mg, 2.1 mmol) and Boc anhydride (9.0 g, 41.5 mmol) were added sequentially at room temperature. The reaction mixture was heated to 40 °C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound 14c (2.2 g, 50% yield). ESI-MS (m / z): 211.3 [M+H] + .

[0255] Step 4: Compound 14c (1.4 g, 6.5 mmol) and 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.1 g, 3.3 mmol) were dissolved in DMF (15 mL). Pd2(dba)3 (297 mg, 0.33 mmol), DIEA (1.1 mL, 6.5 mmol), and tri-tert-butylphosphine (132 mg, 0.65 mmol) were added at room temperature. The reaction mixture was heated to 80 °C and stirred for 16 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted three times with dichloromethane (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol) to obtain compound INT-14d (1.0 g, 65% yield). ESI-MS (m / z): 468.4 [M+H] + .

[0256] Step 5: Compound INT-14d (1.0 g, 2.1 mmol) was dissolved in isopropanol (10 mL), and palladium on carbon (227 mg) was added at room temperature. The reaction system was heated to 40 °C and stirred for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction system was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain compound INT-14e (0.7 g, 90% yield). ESI-MS (m / z): 470.7 [M+H] + .

[0257] Step 6: Compound INT-14e (450 mg, 0.96 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated to obtain compound INT-14 (390 mg, 99% yield). ESI-MS (m / z): 414.2 [M+H] +.

[0258] Intermediate INT-15

[0259] Synthesis steps:

[0260] Step 1: 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (3.0 g, 8.87 mmol) and compound INT-15a (3.41 g, 26.61 mmol) were dissolved in DMSO (35 mL), and Pd(PPh3)4 (1.03 g, 0.88 mmol), CuI (169.0 mg, 0.88 mmol), and triethylamine (5.39 g, 53.30 mmol) were added. The reaction system was purged with nitrogen, and the reaction solution was stirred at 80 °C for 3 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water (80 mL), extracted with ethyl acetate (80 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-15b (1.0 g, yield 23%). ESI-MS (m / z): 384.2 [M + H] + .

[0261] Step 2: Compound INT-15b (1.0 g, 2.61 mmol) was dissolved in DMF (3 mL) and tetrahydrofuran (15 mL), and palladium on carbon (250.0 mg) was added. The reaction system was replaced with hydrogen gas, and the reaction solution was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by preparative liquid chromatography to obtain compound INT-15 (500.0 mg, yield 49%). ESI-MS (m / z): 388.5 [M+H] + .

[0262] Intermediate INT-16

[0263] Synthesis steps:

[0264] Step 1: Compound INT-16a (2.0 g, 9.57 mmol) and tert-butyl acrylate (1.47 g, 11.48 mmol) were dissolved in acetonitrile (20 mL), and potassium carbonate (3.30 g, 23.9 mmol) was added. The reaction system was purged with nitrogen, and the reaction mixture was stirred at 70 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-16b (1.8 g, yield 56%). ESI-MS (m / z): 338.1 [M + H] + .

[0265] Step 2: 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.0 g, 2.97 mmol) and compound INT-16b (1.5 g, 4.45 mmol) were dissolved in 1,4-dioxane (20 mL) and water (1 mL). Palladium acetate (67.0 mg, 0.29 mmol), n-butyldi(1-adamantyl)phosphine (107.0 mg, 0.29 mmol) and cesium carbonate (2.42 g, 7.41 mmol) were added. The reaction system was replaced with nitrogen gas. The reaction solution was stirred at 100 degrees Celsius for 2 hours. The reaction was monitored by LCMS until it ended. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-16c (1.0 g, yield 72%). ESI-MS (m / z): 469.2 [M+H] + .

[0266] Step 3: Compound INT-16c (1.0 g, 2.13 mmol) was dissolved in tetrahydrofuran (10 mL), and palladium on carbon (200.0 mg) was added. The reaction system was replaced with hydrogen gas, and the reaction solution was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filtrate was concentrated to obtain compound INT-16d (900.0 mg, yield 85%). ESI-MS (m / z): 471.7 [M+H] + .

[0267] Step 4: Compound INT-16d (900.0 mg, 1.91 mmol) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (3 mL) was added. The reaction system was purged with nitrogen gas, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to obtain compound INT-16 (460.0 mg, yield 58%). ESI-MS (m / z): 415.3 [M+H] + .

[0268] Intermediate INT-17

[0269] Synthesis steps:

[0270] Step 1: Compound INT-17a (230 mg, 1.8 mmol) and tert-butyl 4-piperidine acetate (339 mg, 2.2 mmol) were dissolved in 1,4-dioxane (2 mL), followed by the addition of RuPhos Pd G3 (57 mg, 0.07 mmol), RuPhos (32 mg, 0.07 mmol), and LiHMDS (3.4 mmol, 3.4 mL, 1 M in THF). The system was stirred in a microwave oven at 80 °C for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with saturated ammonium chloride, diluted and extracted with ethyl acetate, and the organic phase was concentrated by rotary evaporation under reduced pressure. The residue was purified by Prep-HPLC to obtain compound INT-17b (75 mg, yield 24%). ESI-MS (m / z): 457.2 [M+H] + .

[0271] Step 2: Compound INT-17b (60 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to obtain compound INT-17 (30 mg, yield 57%). ESI-MS (m / z): 401.2 [M+H] + .

[0272] Intermediate INT-18

[0273] The preparation method of intermediate INT-18 is the same as that of intermediate INT-17.

[0274] Intermediate INT-19

[0275] Synthesis steps:

[0276] Step 1: Compound INT-19a (2.88 g, 15.47 mmol) was dissolved in tert-butanol (30 mL). Di-tert-butyl dicarbonate (8.78 g, 40.21 mmol) and 4-dimethylaminopyridine (0.75 g, 6.19 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with sodium bicarbonate (60 mL) aqueous solution, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give compound INT-19b (3.60 g, 96% yield). ESI-MS (m / z): 243.15 [M+H] + .

[0277] Step 2: Compound INT-19b (2.00 g, 7.43 mmol) was dissolved in water (5 mL) and methanol (25 mL). Lithium hydroxide monohydrate (1.25 g, 29.71 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (60 mL), extracted with ethyl acetate (40 mL * 2), and the aqueous phase was retained. The aqueous phase was adjusted to pH 3 with 1 M hydrochloric acid solution, extracted with ethyl acetate (50 mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-19c (1.20 g, 70% yield). ESI-MS (m / z): 227.10 [MH] + .

[0278] Step 3: Compound INT-19c (1.00 g, 4.67 mmol) was dissolved in THF (15 mL), and boranetetrahydrofuran (1.36 g, 15.77 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours under nitrogen protection. The reaction mixture was quenched in water (80 mL), extracted with ethyl acetate (50 mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound INT-19d (1 g, 88% yield). ESI-MS (m / z): 215.2 [M + H] + .

[0279] Step 4: Compound INT-19d (1.20 g, 5.25 mmol) was dissolved in DCM (40 mL), and Dysmartin oxidant (2.97 g, 7.00 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-19e (0.32 g, yield 32%). ESI-MS (m / z): 213.14 [M+H] + .

[0280] Step 5: Compound INT-19e (33.62 mg, 158.37 μmol) was dissolved in THF (2 mL), and INT-1f (60.00 mg, 158.37 μmol), potassium acetate (155.43 mg, 1.58 mmol), and acetic acid (9.51 mg, 158.37 μmol) were added. After 10 minutes, sodium borohydride acetate (50.35 mg, 237.56 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-19g (0.04 g, yield 47%). ESI-MS (m / z): 539.32 [M+H] + .

[0281] Step 6: Dissolve compound INT-19 g (40.00 mg, 74.26 μmol) in DCM (1 mL), and add trifluoroacetic acid (1.49 g, 13.07 mmol). Stir the reaction mixture at room temperature for 4 hours, and monitor the reaction completion by LCMS. Concentrate the reaction mixture directly, add water (10 mL) and acetonitrile (10 mL), and lyophilize to obtain compound INT-19 (36.00 mg, 90% yield). ESI-MS (m / z): 483.25 [M+H] + .

[0282] Intermediate INT-20

[0283] Synthesis steps:

[0284] Step 1: Methyl phenylacetate (1.50 g, 10.0 mmol) was dissolved in tetrahydrofuran (15 mL). The reaction system was purged with nitrogen. A 2 M LDA (6 mL, 12.0 mmol) THF solution was added dropwise at -78°C. After stirring at -78°C for 1 hour, bromoacetonitrile (1.30 g, 11.0 mmol) was slowly added dropwise to the reaction system. Stirring was continued at -78°C for another 1 hour. The reaction was monitored by LCMS until completion. A saturated ammonium chloride aqueous solution (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a colorless oily compound INT-20a (1.40 g, 74% yield). ESI-MS (m / z): 190.1 [M+H] + ;

[0285] Step 2: Compound INT-20a (1.40 g, 7.41 mmol) and tetraisopropyl titanate (2.52 g, 8.87 mmol) were dissolved in tetrahydrofuran (30 mL). 3M ethyl magnesium bromide (5.6 mL, 16.80 mmol) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and the reaction was monitored by LCMS until completion. 2N HCl aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a white solid compound INT-20b (770.0 mg, yield 55%). ESI-MS (m / z): 188.1 [M+H] + ;

[0286] Step 3: Compound INT-20b (200.0 mg, 1.07 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium borohydride (202.0 mg, 5.34 mmol) was added in portions. Then, boron trifluoride diethyl ether (0.63 mL, 5.34 mmol) was added dropwise to the reaction system. The reaction mixture was stirred at 60°C for 16 hours, and the starting material was observed to disappear via LC-MS. The reaction system was cooled to room temperature, and 2N HCl aqueous solution (3 mL) was slowly added to the reaction mixture. Extraction was performed with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give a white solid compound INT-20 (150.0 mg, yield 81%). ESI-MS (m / z): 174.3 [M+H] + .

[0287] Intermediate INT-21

[0288] Synthesis steps:

[0289] Step 1: Compound 1d (240.0 mg, 0.50 mmol) and INT-17 (200.0 mg, 0.5 mmol) were dissolved in DMF (4 mL). DIPEA (193.0 mg, 1.50 mmol) and HATU (190.0 mg, 0.50 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. Water (25 mL) and ethyl acetate (25 mL) were added to the reaction solution. The organic phase was separated, and the aqueous phase was extracted twice again with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound INT-21a (259.0 mg, yield 60%). ESI-MS (m / z): 864.2 [M+H] + .

[0290] Step 2: Compound INT-21a (250.0 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated to obtain compound INT-21 (210.0 mg, 95% yield). ESI-MS (m / z): 764.2 [M+H] + .

[0291] Intermediate INT-22

[0292] Synthesis steps:

[0293] Step 1: Methyl (5S,8S,10AR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-A][1,5]diazaoctyl-8-carboxylic acid ester (2.0 g, 5.86 mmol) was dissolved in water (10 mL) and tetrahydrofuran (10 mL). Lithium hydroxide monohydrate (370 mg, 8.81 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved in water (30 mL). The pH was adjusted to 7-8 with 4M hydrochloric acid. 1,4-dioxane (30 mL), sodium bicarbonate (985 mg, 11.72 mmol), and Fmoc-OSU (2.96 g, 8.78 mmol) were added to the reaction system, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-22a (2.60 g, yield 81%). ESI-MS (m / z): 550.7 [M+H] + .

[0294] Step 2: Compounds INT-22a (2.60 g, 4.73 mmol) and INT-20 (818.50 mg, 4.73 mmol) were dissolved in DMF (25 mL), and DIPEA (2.47 mL, 14.20 mmol) and HATU (1.80 g, 4.73 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (100 mL), extracted with dichloromethane (100 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-22b (2.50 g, yield 75%). ESI-MS (m / z): 705.2 [M + H] + .

[0295] Step 3: Compound INT-22b (2.50 g, 3.55 mmol) was dissolved in DCM (25 mL), and diethylamine (20 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give compound INT-22 (1.28 g, yield 75%). ESI-MS (m / z): 483.3 [M+H] + .

[0296] Intermediate INT-23

[0297] Synthesis steps:

[0298] Step 1: Compound INT-23a (50.0 g, 406 mmol) was dissolved in tetrahydrofuran (500 mL). The reaction system was purged with nitrogen. LDA (2.0 M in THF / n-hexane) (243.5 mL, 487 mmol) was added at -78°C, and the mixture was stirred at -78°C for 1 hour. Dimethyl carbonate (40.2 g, 446 mmol) was added to the reaction system, and the mixture was stirred at -78°C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (1000 mL), extracted with ethyl acetate (500 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily compound INT-23b (29.0 g, yield 39%). ESI-MS (m / z): 182.2 [M+H] + ;

[0299] Step 2: Compound INT-23b (29.0 g, 160 mmol) was dissolved in tetrahydrofuran (300 mL). The reaction system was purged with nitrogen. LDA (2.0 M in THF / n-hexane) (120 mL, 240 mmol) and bromoacetonitrile (19.0 g, 160 mmol) were added at -65°C. The mixture was stirred at -65°C for 1 hour. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was poured into a saturated ammonium chloride aqueous solution (1000 mL), extracted with ethyl acetate (800 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a colorless oily compound INT-23c (12.0 g, yield 34%). ESI-MS (m / z): 221.2 [M+H] + ;

[0300] Step 3: Compound INT-23c (13.0 g, 59.0 mmol) and tetraisopropyl titanate (18.7 g, 59.0 mmol) were dissolved in tetrahydrofuran (120 mL). The reaction system was purged with nitrogen, and ethyl magnesium bromide (147 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into a saturated ammonium chloride aqueous solution (1000 mL), extracted with ethyl acetate (800 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a colorless oily compound INT-23d (3.43 g, yield 21%). ESI-MS (m / z): 219.2 [M+H] + ;

[0301] Step 4: Compound INT-23d (3.00 g, 13.7 mmol) and rhodium tris(triphenylphosphine)carbonylhydrazine (1.10 g, 687 μmol) were dissolved in 1,4-dioxane (30 mL). The reaction system was purged with nitrogen gas, and phenylsilane (8.92 g, 82.4 mmol) was added at room temperature. The mixture was stirred at 100 °C for 12 hours, and the reaction was monitored by LCMS until completion. The reaction system was quenched in 2N HCl solution, filtered, and the filtrate was concentrated to give a yellow oily compound INT-23e (1.8 g, yield 64%). This compound was used directly in the next step. ESI-MS (m / z): 205.4 [M+H] + ;

[0302] Step 5: Compound INT-23e (1.8 g, 8.80 mmol) was dissolved in 20 mL of 30% HBr acetic acid solution and stirred at 100°C for 12 hours. The reaction was monitored by LCMS until completion. The reaction system was neutralized with saturated sodium bicarbonate aqueous solution, concentrated, and the residue was purified by preparative liquid chromatography to obtain a yellow oily compound INT-23 (1.6 g, 95% yield). ESI-MS (m / z): 191.1 [M+H] + .

[0303] Intermediate INT-24

[0304] Synthesis steps:

[0305] Step 1: Compound INT-23 (1.90 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL), and (Boc)₂O (3.27 g, 15 mmol) and triethylamine (3.0 g, 30 mmol) were added. The mixture was stirred at room temperature for 18 hours, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (200 mL), extracted with ethyl acetate (150 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give a white solid compound INT-24a (650.0 mg, yield 23%). ESI-MS (m / z): 291.2 [M + H] + ;

[0306] Step 2: Compound INT-24a (600 mg, 2.07 mmol) and iodomethane (674 mg, 4.75 mmol) were dissolved in DMF (6 mL), and cesium carbonate (2.09 g, 6.41 mmol) was added. The mixture was stirred at room temperature for 18 hours, and the reaction was monitored by LCMS to ensure complete reaction of the starting material. The reaction solution was poured into water (80 mL), extracted with ethyl acetate (80 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give the oil-free compound INT-24b (300.0 mg, yield 47%). ESI-MS (m / z): 306.2 [M + H] + ;1H NMR (400MHz, DMSO-d6): δ7.62(d,J=6.8Hz,1H),6.32–6.17(m,2H),3.83–3.75(m,1H),3.38(s,3H),3.31–3.15(m,2H) ),2.24–2.16(m,1H),2.01–1.93(m,1H),1.85–1.54(m,1H),1.41–1.33(m,9H),1.30–1.18(m,1H),0.54–0.41(m,2H).

[0307] Step 3: Compound INT-24b (300.0 mg, 0.98 mmol) was dissolved in dichloromethane (6 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The reaction solution was concentrated to give a colorless oily compound INT-24 (180.0 mg, yield 89%). ESI-MS (m / z): 205.1 [M+H] + .

[0308] Intermediate INT-25

[0309] Synthesis steps:

[0310] Step 1: Compound INT-2 (8.0 g, 21.96 mmol) was dissolved in anhydrous dichloromethane (50 mL). Oxaloyl chloride (4.18 g, 32.94 mmol) and DMF (5 drops) were slowly added dropwise at 25°C. The reaction mixture was stirred at 35°C for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated to remove the organic solvent, yielding a yellow oily crude compound, INT-25a (8.41 g, 100% yield). ESI-MS (m / z): 383.5 [M+H] + ;

[0311] Step 2: Compound INT-25a (8.41 g, 21.96 mmol) was dissolved in anhydrous dichloromethane (50 mL). Pentafluorophenol (4.85 g, 26.35 mmol) and triethylamine (8.0 g, 79.06 mmol) were added at room temperature, and the mixture was stirred for 0.5 hours. The reaction was monitored by LC-MS until complete. The reaction solution was poured into water (25 mL), extracted with dichloromethane (50 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a yellow oily compound INT-25b (9.5 g, yield 82%). ESI-MS (m / z): 531.5 [M+H] + ;

[0312] Step 3: Compound INT-25b (9.5 g, 17.91 mmol) was dissolved in DCM (100 mL). After being placed in an ice-water bath, BSTFA (27.66 g, 107.48 mmol) and TMSI (17.92 g, 89.56 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-25 (5.2 g, yield 61%). ESI-MS (m / z): 475.6 [M+H] + .

[0313] Intermediate INT-26

[0314] The preparation method for intermediate INT-26 is the same as that for INT-25, except that 5-((diethoxyphospho)difluoromethyl)benzo[B]thiophene-2-carboxylic acid is replaced with 7-((diethoxyphospho)difluoromethyl)-2-naphthoic acid. Following a similar method and steps, intermediate INT-26 can be obtained. ESI-MS (m / z): 475.6 [M+H] + .

[0315] Intermediate INT-27

[0316] Synthesis steps:

[0317] Step 1: 2-Fluoro-5-methylbenzaldehyde (20.0 g, 145.0 mmol) and ethyl mercaptoacetate (21.8 g, 145.0 mmol) were dissolved in DMF (300 mL). Potassium carbonate (40.0 g, 290.0 mmol) was added at 0°C, and the mixture was stirred at 80°C for 4 hours. The reaction was monitored by LCMS until completion. The reaction solution was added to water (900 mL), filtered, and the filter cake was washed with water and dried to give a white solid compound INT-27a (28.0 g, yield 88%). 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.93(d,J=8.4Hz,1H),7.81(s,1H),7.3 7(d,J=8.4Hz,1H),4.35(q,J=7.2Hz,2H),2.43(s,3H),1.34(t,J=7.2Hz,3H).

[0318] Step 2: Compound INT-27a (28.0 g, 127.0 mmol) was dissolved in water (150 mL), tetrahydrofuran (150 mL), and methanol (150 mL). Lithium hydroxide (9.13 g, 381.0 mmol) was added at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The pH of the reaction solution was adjusted to 3-4, filtered, and the filter cake was washed with water and dried to obtain a white solid compound INT-27b (23.0 g, yield 94%); ESI-MS (m / z): 193.0 [M+H]. + ;

[0319] Step 3: Compound INT-27b (24.0 g, 125.0 mmol) was dissolved in DMF (250 mL), and benzyl bromide (23.5 g, 137.0 mmol) and potassium carbonate (34.5 g, 250.0 mmol) were added at 0°C. The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was added to water (800 mL), filtered, and the filter cake was washed with water and dried to obtain a white solid compound INT-27c (31.0 g, yield 88%).

[0320] Step 4: Compound INT-27c (21.0 g, 74.40 mmol) was dissolved in carbon tetrachloride (250 mL). BPO (1.80 g, 7.44 mmol) and NBS (17.2 g, 96.7 mmol) were added at 0°C, and the mixture was stirred at 80°C for 16 hours. The reaction was monitored by LC-MS until completion. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give a yellow solid compound INT-27d (650.0 mg, yield 23%). ESI-MS (m / z): 383.2 [M+Na] + ;

[0321] Step 5: Compound INT-27d (16.0 g, 44.30 mmol) was added to triethyl phosphite (60 mL) at 0°C, and stirred at 100°C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give a yellow oily compound INT-27e (12.0 g, yield 65%). 1 H NMR (400MHz, CDCl3) δ8.09–8.04(m,1H),7.82(d,J=8.4Hz,2H),7.53–7.35(m,6 H),5.41(s,2H),4.10–3.98(m,4H),3.28(d,J=21.6Hz,2H),1.29–1.22(m,6H).

[0322] Step 6: Compound INT-27e (5.0 g, 11.90 mmol) was dissolved in tetrahydrofuran (25 mL), and Pd / C (500 mg) was added. The reaction system was replaced with hydrogen gas, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to obtain a white solid compound INT-27f (3.60 g, yield 92%). ESI-MS (m / z): 329.0 [M+H]+;

[0323] Step 7: Compound INT-27f (3.0 g, 9.14 mmol) and pentafluorophenol (2.52 g, 13.7 mmol) were dissolved in tetrahydrofuran (50 mL). DCC (3.77 g, 18.30 mmol) was added at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (80 mL), extracted with dichloromethane (80 mL * 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the oil-free compound INT-27f (3.0 g, 70% yield). ESI-MS (m / z): 495.2 [M+H] + ;

[0324] Step 8: Dissolve compound INT-27 g (3.00 g, 6.07 mmol) in DCM (40 mL), add TMSBr (10 mL) at 0°C, stir at room temperature for 16 hours, and monitor the reaction for completion using LC-MS. Concentrate the reaction solution, and purify the residue directly by preparative liquid chromatography to obtain a white solid compound INT-27 (2.49 g, yield 93%). ESI-MS (m / z): 439.0 [M+H] + .

[0325] 1 H NMR (400MHz, CD3OD) δ8.39 (s, 1H), 8.18–7.69 (m, 2H), 7.57 (d, J = 8.4Hz, 1H), 3.28 (d, J = 21.6Hz, 2H).

[0326] Intermediate INT-28

[0327] Synthesis steps:

[0328] Step 1: Compound INT-25 (474.0 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (0.25 mL, 3.0 mmol) and DMF (1 drop) were added. The reaction solution was stirred at 50°C for 2 hours, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to give a yellow solid compound INT-28a (407.0 mg, yield 80%).

[0329] Step 2: Compound INT-28a (400.0 mg, 0.78 mmol), triethylamine (0.32 mL, 2.35 mmol), and DMAP (10.0 mg, 0.08 mmol) were dissolved in dichloromethane (10 mL). S-(2-hydroxyethyl)-2,2-dimethylpropane sulfate (380.0 mg, 2.35 mmol) was added at 0°C. The reaction mixture was stirred overnight at room temperature, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give a yellow solid compound INT-28 (377.0 mg, yield 63%). ESI-MS (m / z): 763.1 [M+H] + .

[0330] Intermediate INT-29

[0331] Synthesis steps:

[0332] Step 1: Compound INT-2d (454.0 mg, 1 mmol) was dissolved in DCM (10 mL). The reaction mixture was placed in an ice bath under nitrogen protection, and BSTFA (1.54 g, 6.0 mmol) and TMSI (1.0 g, 5.0 mmol) were added. The mixture was stirred at room temperature for 0.5 hours. The reaction was monitored by LCMS until completion. Water (40 mL) and ethyl acetate (40 mL) were added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted twice again with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-29a (298.0 mg, 75% yield). ESI-MS (m / z): 399.2 [M+H] + .

[0333] Step 2: Compound INT-29a (298.0 mg, 0.75 mmol) was dissolved in dichloromethane (5 mL), and oxaloyl chloride (0.2 mL, 2.25 mmol) and DMF (1 drop) were added. The mixture was stirred at 40°C for 2 hours, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the resulting yellow solid was dissolved in dichloromethane (5 mL). Under nitrogen protection, TEA (225.0 mg, 2.25 mmol) and L-alanine propyl ester (196.0 mg, 1.5 mmol) were added. The mixture was stirred overnight at room temperature, and the reaction was monitored by LCMS until completion. After the reaction solution was concentrated to dryness, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-29b (115.0 mg, yield 30%). ESI-MS (m / z): 512.2 [M+H] + .

[0334] Step 3: Compound INT-29b (115.0 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL). Under nitrogen protection, TEA (225.0 mg, 0.66 mmol), DMAP (2.50 mg, 0.02 mmol), and phenol (41.0 mg, 0.44 mmol) were added. The mixture was stirred overnight at room temperature, and the reaction was monitored by LCMS until completion. After the reaction solution was concentrated to dryness, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound INT-29c (60.0 mg, yield 45%). ESI-MS (m / z): 588.3 [M+H] + .

[0335] Step 4: Compound INT-29c (60.0 mg, 0.10 mmol) was dissolved in tetrahydrofuran (3 mL), and Pd / C (20.0 mg) was added. The reaction system was replaced with hydrogen gas. The mixture was stirred at room temperature for 5 hours, and the reaction was monitored by LCMS until completion. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by preparative liquid chromatography to obtain compound INT-29 (35.0 mg, yield 70%). ESI-MS (m / z): 498.3 [M+H] + .

[0336] Intermediate INT-30

[0337] Synthesis steps:

[0338] Step 1: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (200 mg, 0.6 mmol) and 4-(dimethoxymethyl)piperidine (376.7 mg, 2.4 mmol) were dissolved in 1,4-dioxane (4 mL), followed by the addition of RuPhos Pd G3 (74.2 mg, 0.09 mmol), RuPhos (82.8 mg, 0.18 mmol), and LiHMDS (0.5 mmol, 0.5 mL, 1 M in THF). The reaction was stirred at 80 °C under microwave conditions for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with saturated ammonium chloride, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography to obtain compound INT-30a (170.9 mg, yield 69%). ESI-MS (m / z): 416.9 [M+H] + .

[0339] Step 2: Compound INT-30a (80 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and potassium peroxide monosulfonate (232.8 mg, 0.67 mmol) was added under ice bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred overnight. After the reaction was complete, the reaction solution was purified by pre-hplc to give compound INT-30 (5 mg, yield 7%). ESI-MS (m / z): 385.0 [MH] - .

[0340] Intermediate INT-31

[0341] Synthesis steps:

[0342] Step 1: Compound INT-31a (500 mg, 2.04 mmol) and tert-butyl chloroacetate (369.5 mg, 2.45 mmol) were dissolved in acetonitrile (5 mL), and then triethylamine (517 mg, 712 μL, 5.11 mmol) was added. The system was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-31b (609 mg, yield 92%). ESI-MS (m / z): 324.1 [M+H] + .

[0343] Step 2: Compound INT-31b (172 mg, 0.53 mmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (150 mg, 0.44 mmol), XPhos Pd G2 (34.9 mg, 44.4 μmol), and potassium phosphate (188.3 mg, 0.89 mmol) were dissolved in a mixed solution of 1,4-dioxane and water (3 mL / 0.3 mL). The reaction system was purged with nitrogen for protection and stirred at 80 °C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-31c (173.8 mg, yield 86%). ESI-MS (m / z): 455.2 [M + H] + .

[0344] Step 3: Compound INT-31c (173 mg, 0.38 mmol) was dissolved in tetrahydrofuran (10 mL), and Pd / C (40.5 mg, 0.04 mmol, 10% w / w) and Pd(OH)₂ / C (53.5 mg, 0.04 mmol, 10% w / w) were added. The reaction system was purged with hydrogen and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was concentrated and purified by preparative liquid chromatography to obtain compound INT-31d (48 mg, yield 27%). ESI-MS (m / z): 457.0 [M+H] + .

[0345] Step 4: Compound INT-31d (20 mg, 43.8 μmol) was dissolved in dichloromethane (1 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound INT-31 (15.7 mg, 90% yield). ESI-MS (m / z): 398.6 [MH] - .

[0346] Intermediate INT-32

[0347] Synthesis steps:

[0348] Step 1: Compound INT-32a (500 mg, 1.55 mmol) was dissolved in tetrahydrofuran (5 mL), and potassium tert-butoxide (347.5 mg, 3.1 mmol) and methyl iodide (329.7 mg, 2.32 mmol) were added under ice bath conditions. The reaction was then brought to room temperature and stirred overnight. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-32b (341 mg, 65% yield). ESI-MS (m / z): 336.6 [M+H] + .

[0349] Step 2: Compound INT-32b (150 mg, 0.45 mmol), compound INT-7b (172 mg, 0.53 mmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (185.8 mg, 0.45 mmol), Pd(dppf)Cl2 (32.6 mg, 44.5 μmol), and cesium carbonate (290.1 ​​mg, 0.89 mmol) were dissolved in a mixed solution of 1,4-dioxane and water (5 mL / 0.5 mL). The reaction was carried out under nitrogen protection and stirred overnight at 90 °C. After the reaction was complete, the reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give compound INT-32c (158 mg, yield 70%). ESI-MS (m / z): 500.8 [M+H]+.

[0350] Step 3: Compound INT-32c (100 mg, 0.2 mmol), tert-butyl 4-piperidine acetate (79.7 mg, 0.4 mmol), Pd-PEPPSI-iPentCl (19.5 mg, 20.0 μmol), and cesium carbonate (195.4 mg, 0.6 mmol) were dissolved in dioxane (3 mL). The reaction mixture was purged under nitrogen protection and stirred overnight at 100 °C. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated, and the residue was purified by silica gel column chromatography to obtain compound INT-32d (98.5 mg, yield 79%). ESI-MS (m / z): 619.0 [M+H] + .

[0351] Step 4: Compound INT-32d (50 mg, 80.8 μmol) was dissolved in ethyl acetate (2 mL), and Pd / C (8.6 mg, 80.8 μmol, 10% w / w) was added. The system was purged with hydrogen and stirred overnight at 50 °C. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was concentrated to give compound INT-32e (35 mg, 98% yield). ESI-MS (m / z): 441.2 [M+H] + .

[0352] Step 5: Dissolve compound INT-32e (35 mg, 79.5 μmol) in dichloromethane (2 mL), add TFA (0.5 mL), stir at room temperature for 2 hours, and monitor the reaction for completion using LCMS. The reaction solution was then concentrated under reduced pressure to obtain compound INT-32 (25 mg, 92% yield).

[0353] Intermediate INT-33

[0354] Synthesis steps:

[0355] Step 1: Compound INT-33a (500 mg, 1.73 mmol) was dissolved in tert-butanol (10 mL), followed by the addition of (Boc)₂O (942.9 mg, 4.32 mmol) and DMAP (63.34 mg, 0.52 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain compound INT-33b (512 mg, 85% yield). ESI-MS (m / z): 346.0 [M+H] + .

[0356] Step 2: Compound INT-33b (300 mg, 0.87 mmol) was dissolved in methanol (2 mL), and Pd / C (92.4 mg, 0.87 mmol, 10% w / w) was added. The system was purged with hydrogen and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was concentrated to give compound INT-33c (170 mg, 92% yield). ESI-MS (m / z): 212.4 [M+H] + .

[0357] Step 3: Compound INT-33c (81.8 mg, 0.39 mmol), 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (100 mg, 0.19 mmol), Pd-PEPPSI-iPentCl (18.8 mg, 19.4 μmol), and cesium carbonate (189.3 mg, 0.58 mmol) were dissolved in dioxane (3 mL). The reaction mixture was stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated, and the residue was purified by silica gel column chromatography to give compound INT-33d (72.1 mg, yield 57%). ESI-MS (m / z): 647.0 [M+H] + .

[0358] Step 4: Compound INT-33d (342 mg, 528.8 μmol) was dissolved in ethyl acetate (5 mL) and methanol (5 mL), and Pd(OH)₂ / C (222.8 mg, 0.16 mmol, 10% w / w) was added. The reaction mixture was purged with hydrogen and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the residue was washed with ethyl acetate. The filtrate was concentrated to give compound INT-33e (233 mg, 94% yield). ESI-MS (m / z): 469.4 [M+H] + .

[0359] Step 5: Compound INT-33e (233 mg, 497.3 μmol) was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound INT-33 (165 mg, 80% yield). ESI-MS (m / z): 412.7 [M+H] + .

[0360] Intermediate INT-34

[0361] Synthesis steps:

[0362] Step 1: Compound INT-34a (1 g, 4.29 mmol) was dissolved in tetrahydrofuran (10 mL). LDA (0.64 mL, 0.64 mmol, 1 M in THF) was added at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, tert-butyl propionate (837.2 mg, 6.43 mmol) was added, and the reaction was brought to room temperature and stirred overnight. After the reaction was complete, the reaction was quenched with 1 M HCl aqueous solution and extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound INT-34b (1.24 g, 79% yield). ESI-MS (m / z): 364.2 [M+H] + .

[0363] Step 2: Compound INT-34b (500 mg, 1.38 mmol) was dissolved in toluene (10 mL), and Burgess reagent (491.8 mg, 2.06 mmol) was added. The reaction mixture was stirred at 100 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-34c (258 mg, yield 54%). ESI-MS (m / z): 346.2 [M+H] + .

[0364] Step 3: Compound INT-34c (310 mg, 897.4 μmol) was dissolved in ethanol (5 mL), and Pd(OH)₂ / C (252.1 mg, 0.18 mmol, 10% w / w) was added. The reaction mixture was purged with hydrogen and stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was concentrated to give compound INT-34 (150 mg, yield 78%). ESI-MS (m / z): 214.0 [M+H] + .

[0365] Intermediate INT-35

[0366] Synthesis steps:

[0367] Step 1: Compound INT-35a (67.4 mg, 0.25 mmol) and tert-butyl 4-piperidine acetate (50 mg, 0.25 mmol) were dissolved in DMF (1 mL), and DIPEA (87.4 μL, 0.5 mmol) and HATU (143.1 mg, 0.38 mmol) were added. The mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (5 mL), extracted with ethyl acetate (5 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography to give compound INT-35b (106.8 mg, yield 94%). ESI-MS (m / z): 449.9 [M + H] + .

[0368] Step 2: Compound INT-35b (50 mg, 111 μmol) was dissolved in dichloromethane (2 mL), and TFA (0.25 mL) was added. The mixture was stirred at room temperature for 4 hours, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound INT-35 (35.8 mg, yield 81%). ESI-MS (m / z): 393.6 [M+H] + .

[0369] Intermediate INT-36

[0370] Synthesis steps:

[0371] Step 1: Compound INT-36a (200 mg, 0.62 mmol), tert-butyl 4-piperidine acetate (246.7 mg, 1.24 mmol), Pd-PEPPSI-iPentCl (60.2 mg, 61.9 μmol), and cesium carbonate (605.0 mg, 1.86 mmol) were dissolved in a mixed solution of DMF and dioxane (1.5 mL / 3 mL). The reaction mixture was purged under nitrogen protection and stirred in a microwave at 120 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound INT-36b (147 mg, yield 53%). ESI-MS (m / z): 442.2 [M+H] + .

[0372] Step 2: Compound INT-36b (50 mg, 113.2 μmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound INT-36 (32 mg, 75% yield). ESI-MS (m / z): 384.2 [MH] - .

[0373] Intermediate INT-37

[0374] Synthesis steps:

[0375] Step 1: 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.40 g, 1.24 mmol) was dissolved in DMF (4 mL) and TEA (4 mL). At room temperature, 5-hexyneic acid (121 mg, 1.24 mmol), palladium dichloride bis(triphenylphosphine) (94.30 mg, 495.14 μmol), and cuprous iodide (173.77 mg, 247.57 μmol) were added. The reaction system was purged with nitrogen gas. The reaction mixture was stirred at 90 °C for 4 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was then poured into water (30 mL), and 1 M HCl aqueous solution was added to adjust the pH to 1. Extracted with dichloromethane (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-34 (0.06 g, yield 14%). ESI-MS (m / z): 355.3 [M+H] + .

[0376] Intermediate INT-38

[0377] Synthesis steps:

[0378] Step 1: 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.40 g, 1.24 mmol) was dissolved in DMF (6 mL) and TEA (3 mL). INT-38b (0.414 g, 1.86 mmol), palladium dichloride (94.30 mg, 495.14 μmol), and cuprous iodide (173.77 mg, 247.57 μmol) were added at room temperature. The reaction system was purged with nitrogen. The reaction mixture was stirred at 90 °C for 4 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (40 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound INT-38c (0.45 g, yield 54%). ESI-MS (m / z): 466.1 [M+H] + .

[0379] Step 2: Compound INT-38c (0.45 g, 966.96 μmol) was dissolved in dichloromethane (4 mL), and 4 M dioxane hydrochloride (4 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-38 (0.32 g, 90% yield). ESI-MS (m / z): 366.2 [M+H] + .

[0380] Intermediate INT-39

[0381] Synthesis steps:

[0382] Step 1: Compound INT-5 (50.0 mg, 130.75 μmol) was dissolved in DMF (1 mL), and piperazine-1-carboxylic acid tert-butyl ester (24.35 mg, 130.75 μmol) and DIPEA (50.69 mg, 392.25 μmol) were added. After stirring for ten minutes, HATU (74.57 mg, 196.13 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. Compound INT-39a (51.0 mg, 70% yield) was purified by preparative liquid chromatography. ESI-MS (m / z): 550.9 [M+H] + .

[0383] Step 2: Compound INT-39a (51.0 mg, 92.62 mmol) was dissolved in dichloromethane (4 mL), and 4 M dioxane hydrochloride (4 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-39 (33.4 mg, 95% yield). ESI-MS (m / z): 450.7 [M+H] + .

[0384] Intermediate INT-40

[0385] Synthesis steps:

[0386] Step 1: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (0.20 g, 591.44 μmol) was dissolved in DMSO (5 mL) and TEA (2.5 mL). 4-tert-butyl 4-pentyneate (0.456 g, 2.96 mmol), palladium dichloride bis(triphenylphosphine) (68.34 mg, 59.14 μmol), and cuprous iodide (11.26 mg, 59.14 μmol) were added at room temperature. The reaction system was replaced with nitrogen gas. The reaction solution was stirred at 80 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water (40 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-40a (0.23 g, yield 85%). ESI-MS (m / z): 411.9 [M+H] + .

[0387] Step 2: Compound INT-40a (100.0 mg, 92.62 mmol) was dissolved in dichloromethane (2 mL), and TFA (2 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-40 (70.0 mg, yield 81%). ESI-MS (m / z): 356.1 [M+H] + .

[0388] Intermediate INT-41

[0389] Synthesis steps:

[0390] Step 1: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (500.0 mg, 1.48 mmol) and tert-butyl 4-piperidinate (884.01 mg, 4.44 mmol) were dissolved in toluene (6 mL). RuPhos Pd G3 (123.67 mg, 147.86 μmol), Ruphos (69.00 mg, 147.86 μmol), and LiHMDS (1.24 g, 7.39 mmol) were added. The reaction system was purged with nitrogen, and the mixture was stirred in a microwave oven at 80°C for 3 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-41a (100.0 mg, yield 14%). ESI-MS (m / z): 457.0 [M+H] + .

[0391] Step 2: Compound INT-41a (100.0 mg, 219.04 μmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-41b (80.0 mg, yield 91%). ESI-MS (m / z): 401.5 [M+H] + .

[0392] Step 3: Compound INT-41b (80.0 mg, 199.79 μmol) was dissolved in DMF (6 mL), and tert-butyl piperazine-1-carboxylate (44.65 mg, 239.74 μmol) and DIPEA (77.46 mg, 599.36 μmol) were added. After ten minutes, HATU (113.95 mg, 299.68 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (40 mL), extracted with ethyl acetate (30 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-41c (0.09 g, yield 79%). ESI-MS (m / z): 569.0 [M + H] + .

[0393] Step 4: Compound INT-41c (0.09 g, 158.27 μmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-41 (72.0 mg, yield 97%). ESI-MS (m / z): 468.1 [M+H] + .

[0394] Intermediate INT-42

[0395] Synthesis steps:

[0396] Step 1: 3-(5-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (500.0 mg, 1.55 mmol) and tert-butyl piperazine-1-carboxylate (432.28 mg, 2.32 mmol) were dissolved in dioxane (4 mL). RuPhos Pd G2 (240.37 mg, 309.46 μmol), Ruphos (144.41 mg, 309.46 μmol), 4A molecular sieve (50.0 mg, 29.33 μmol), and cesium carbonate (1.01 g, 3.09 mmol) were added. The reaction system was purged with nitrogen, and the mixture was stirred at 120°C in a microwave oven for 4 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (40 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-42a (100.0 mg, yield 15%). ESI-MS (m / z): 429.0 [M+H] + .

[0397] Step 2: Compound INT-42a (100.0 mg, 233.38 μmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-42b (72.0 mg, yield 93%). ESI-MS (m / z): 329.2 [M+H] + .

[0398] Step 3: Compound INT-42b (72.0 mg, 219.27 μmol) was dissolved in DMF (4 mL), and 1-BOC-pyrrolidine-3-carboxylic acid (56.64 mg, 263.12 μmol) and DIPEA (85.01 mg, 657.80 μmol) were added. After stirring for ten minutes, HATU (125.06 mg, 328.90 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-42c (0.08 g, yield 69%). ESI-MS (m / z): 526.0 [M+H] + .

[0399] Step 4: Compound INT-42c (0.08 g, 152.21 μmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-42 (59.5 mg, yield 91%). ESI-MS (m / z): 426.1 [M+H] + .

[0400] Intermediate INT-43

[0401] Synthesis steps:

[0402] Step 1: Aluminum trichloride (14.53 g, 108.96 mmol) was added to dichloromethane (200 mL). Oxaloyl chloride monoethyl ester (13.02 g, 95.34 mmol) and p-fluorotoluene (10.0 g, 90.80 mmol) were slowly added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. The reaction mixture was quenched with water (500 mL), extracted with dichloromethane (300 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound INT-43a (8.50 g, 44% yield).

[0403] Step 2: Compound INT-43a (8.50 g, 40.44 mmol) was dissolved in ethanol (100 mL), and hydroxylamine hydrochloride (3.37 g, 48.52 mmol) and sodium acetate (4.98 g, 60.66 mmol) were added. The reaction mixture was stirred at 50 °C for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was filtered and concentrated, and water (500 mL) was added. The mixture was extracted with ethyl acetate (300 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-43b (7.05 g, yield 77%).

[0404] Step 3: Compound INT-43b (7.0 g, 31.07 mmol) was dissolved in DMSO (30 mL), and potassium carbonate (6.44 g, 46.62 mmol) was added. The reaction mixture was stirred at 50 °C for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was filtered and concentrated, then water (300 mL) was added, and the mixture was extracted with ethyl acetate (200 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-43c (3.8 g, yield 59%).

[0405] Step 4: Compound INT-43c (1.0 g, 4.87 mmol) was dissolved in 70% sulfuric acid aqueous solution (10 mL), and the reaction solution was stirred at 60 °C for 3 hours. The reaction was monitored by TLC until it was complete. Ice water (80 mL) was added to the reaction solution, the mixture was filtered, and the solid product was collected. The product was then dried using an oil pump to obtain compound INT-43 (0.4 g, yield 46%).

[0406] Intermediate INT-44

[0407] Synthesis steps:

[0408] Step 1: 10.0 g (53.7 mmol) of cis-1,4-cyclohexanedicarboxylic acid monomethyl ester was dissolved in 100 mL of tert-butanol. DMAP (3.28 g, 26.9 mmol) and (Boc)₂O (23.4 g, 107 mmol) were slowly added under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC until completion. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a yellow oily compound INT-44a (11.0 g, 84% yield). 1H NMR (400MHz, CDCl3) δ3.60(s,3H),2.50–2.21(m,2H),1.91–1.73(m,4H),1.68–1.49(m,4H),1.37(s,9H).

[0409] Step 2: Compound INT-44a (8.00 g, 33.1 mmol) was dissolved in THF (40 mL), and LiBH4 (2.0 mol / L THF, 50 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC until completion. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (200 mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily compound INT-44b (6.0 g, yield 85%). 1 H NMR(400MHz, CDCl3)δ3.42(d,J=6.4Hz,2H),2.47–2.31(m,1H),1.96–1.81(m ,2H),1.59–1.50(m,3H),1.48–1.41(m,2H),1.37(s,9H),1.29–1.17(m,2H).

[0410] Step 3: Compound INT-44b (8.00 g, 33.1 mmol) was dissolved in DCM (60 mL), and Dys-Martin oxidant (10.9 g, 25.7 mmol) was added. The mixture was stirred at 0°C for 2 hours. The reaction was monitored by TLC until completion. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a yellow oily compound INT-44c (2.7 g, yield 84%). 1 H NMR (400MHz, CDCl3) δ9.59(s,1H),2.33–2.21(m,2H),1.91–1.82(m,2H),1.68–1.57(m,4H),1.41–1.29(m,11H).

[0411] Step 4: Compound INT-44c (2.30 g, 10.8 mmol) was dissolved in THF (20 mL), and t-BuOK (3.65 g, 32.5 mmol) and methyltriphenylphosphine bromide (14.2 g, 32.5 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (50 mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily compound INT-44d (6.0 g, yield 85%). 1H NMR (400MHz, CDCl3) δ5.89–5.62(m,1H),5.00–4.73(m,2H),2.46–2.27(m,1H) ,2.11–1.98(m,1H),1.94–1.80(m,2H),1.61–1.43(m,4H),1.41–1.33(m,11H).

[0412] Step 5: Compound INT-44d (1.87 g, 8.87 mmol) and 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (1.50 g, 4.44 mmol) were dissolved in DMF (20 mL). Pd2(dba)3 (406 mg, 443 μmol), tri-tert-butylphosphine (179 mg, 887 μmol), and DIEA (1.15 g, 8.87 mmol) were added. The reaction mixture was stirred overnight at 80°C under nitrogen protection. The reaction was monitored by LCMS until completion. The reaction mixture was extracted with water and ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid compound INT-44e (1.50 g, yield 58%). ESI-MS (m / z): 468.4 [M+H] + .

[0413] Step 6: Dissolve compound INT-44e (1.50 g, 3.21 mmol) in i-PrOH (20 mL), add Pd / C (10% w / w, 500 mg), and stir the reaction mixture overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, and the filtrate was concentrated to obtain a yellow solid compound INT-44f (1.2 g). ESI-MS (m / z): 492.4 [M+Na] + .

[0414] Step 7: Dissolve compound INT-44f (1.30 g, 2.77 mmol) in DCM (20 mL), add TFA (10 mL), and stir the reaction solution at 0°C for 2 hours. Monitor the reaction completion by LCMS. Concentrate the reaction solution directly, and purify the residue by preparative liquid chromatography to obtain a white solid compound INT-44 (403.0 mg, yield 35%). ESI-MS (m / z): 414.4 [M+H] + .

[0415] 1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),11.08(s,1H),7.04–6.96(m,2H),6.9 0–6.76(m,1H),5.40–5.20(m,1H),3.33–3.31(m,3H),2.97–2.82(m,1H),2. 81–2.65(m,1H),2.65–2.54(m,3H),2.17–2.07(m,1H),2.03–1.95(m,1H),1 .93–1.73(m,2H),1.54–1.37(m,2H),1.35–1.10(m,5H),1.04–0.78(m,2H).

[0416] Intermediate INT-45

[0417] The preparation method for compound INT-45 is the same as that for compound INT-44. ESI-MS (m / z): 414.5 [M+H] + .

[0418] Intermediate INT-46

[0419] Synthesis steps:

[0420] Step 1: Dissolve 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol) and potassium vinyltrifluoroborate (594 mg, 4.44 mmol) in dioxane (30 mL) and water (1.5 mL). Add Cs₂CO₃ (1.93 g, 5.91 mmol) and Pd(dppf)Cl₂ (216 mg, 295 μmol). Stir the reaction mixture at 80°C for 3 hours under nitrogen protection. Monitor the reaction progress using LCMS. The reaction mixture was extracted with water (100 mL) and ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 1) to give a colorless oily compound INT-46a (350.0 mg, yield 41%). ESI-MS (m / z): 286.2 [M+H] + ;

[0421] Step 2: Compound INT-46a (400 mg, 1.40 mmol) was dissolved in dioxane (6 mL) and water (2 mL). NaIO4 (1.20 g, 5.61 mmol) and K2O5O4·2H2O (51.6 mg, 140 μmol) were added at 0°C, and the reaction mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until completion. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 1) to give a white solid compound INT-46b (185.0 mg, yield 45%). ESI-MS (m / z): 288.2 [M+H] + ;

[0422] Step 3: Compound INT-46b (185 mg, 643 μmol) and tert-butyl 4-piperidine acetate (154 mg, 772 μmol) were dissolved in tetrahydrofuran (3 mL), and glacial acetic acid (77.3 mg, 1.29 mmol) was added. The reaction mixture was stirred for 0.5 hours, and then sodium triacetoxyborohydride (409 mg, 1.93 mmol) was added. The mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction mixture was extracted with water (100 mL) and ethyl acetate (100 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 1) to give a white solid compound INT-46c (115.0 mg, yield 37%). ESI-MS (m / z): 471.2 [M + H] + ;

[0423] Step 4: Dissolve compound INT-46c (110 mg, 233 μmol) in DCM (2 mL), add TFA (0.7 mL), stir at room temperature for 1 hour, and monitor the reaction until completion by LCMS. The reaction solution was directly concentrated to obtain a white solid compound INT-46 (105.0 mg). ESI-MS (m / z): 415.4 [M+H] + ;

[0424] 1H NMR (400MHz, DMSO-d6): δ11.13(s,1H),7.33–7.27(m,1H),7.23–7.13(m,2H),5.44–5.37(m,1H),4.30–4.25(m,2H),3.37( s,4H),3.22–2.86(m,4H),2.75–2.61(m,2H),2.22–2.11(m,2H),2.05–1.99(m,1H),1.88–1.65(m,3H),1.44–1.30(m,2H).

[0425] Intermediate INT-47

[0426] Synthesis steps:

[0427] Step 1: Boc-1-aminocyclopropylformic acid (2.00 g, 9.94 mmol), 3-aminopyridine (935 mg, 9.94 mmol), and HATU (4.16 g, 10.9 mmol) were dissolved in DMF (20 mL), and TEA (2.01 g, 19.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was extracted with water (100 mL) and ethyl acetate (100 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 1) to give a yellow solid compound INT-47a (1.7 g, yield 61%). ESI-MS (m / z): 278.4 [M + H] + ;

[0428] Step 2: Dissolve INT-47a (1.20 g, 4.33 mmol) in DCM (10 mL), add TFA (5 mL), and stir the reaction mixture at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The reaction solution was directly concentrated to obtain a colorless oily compound INT-47b (400.0 mg, crude product). ESI-MS (m / z): 178.3 [M+H] + ;

[0429] Step 3: Dissolve INT-47b (400 mg, 2.26 mmol) in DCM (4 mL), add TEA (456 mg, 4.51 mmol) and triphosgene (267 mg, 902 μmol), and stir the reaction mixture at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated, and the residue was purified by preparative liquid chromatography to obtain a yellow solid compound INT-47 (200.0 mg, yield 43%). ESI-MS (m / z): 204.3 [M+H] + ;

[0430] 1 H NMR (400MHz, DMSO-d6): δ8.78(s,1H),8.66–8.61(m,1H),8.57(dd,J=4.8,1.6Hz,1H),7.88( ddd,J=8.2,2.4,1.6Hz,1H),7.54(ddd,J=8.4,4.8,0.8Hz,1H),1.37(dt,J=6.0,3.6Hz,4H).

[0431] Intermediate INT-48

[0432] Synthesis steps:

[0433] Step 1: 1-BOC-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (500 mg, 1.62 mmol) was dissolved in dichloromethane (4 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to give a yellow oily liquid compound INT-48a (338 mg, 99% yield). ESI-MS (m / z): 210.5 [M+H] + ;

[0434] Step 2: Compound INT-48a (338 mg, 1.62 mmol) was dissolved in DCM (6 mL), and tert-butyl bromoacetate (315.31 mg, 1.62 mmol) and DIPEA (633.96 mg, 4.91 mmol) were added. The mixture was stirred at room temperature for 18 hours, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (15 mL), extracted with dichloromethane (30 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a white solid compound INT-48b (380 mg, yield 73%). ESI-MS (m / z): 324.3 [M + H] + ;

[0435] Step 3: Compound INT-48b (172.1 mg, 0.532 mmol) and 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (150.0 mg, 0.444 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.4 mL). XPhos Pd G2 (34.90 mg, 0.044 mmol) and potassium phosphate (188.3 mg, 0.887 mmol) were added. The reaction system was replaced with nitrogen gas. The reaction solution was stirred at 80 degrees Celsius for 3 hours. The reaction was monitored by LCMS until it ended. The reaction mixture was poured into water (15 mL), extracted with ethyl acetate (25 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-48c (195 mg, 97% yield). ESI-MS (m / z): 455.5 [M+H] + ;

[0436] Step 4: Compound INT-48c (50 mg, 0.110 mmol) was dissolved in dichloromethane (1 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain a yellow oily liquid compound INT-48 (43 mg, 98% yield). ESI-MS (m / z): 399.5 [M+H] + ;

[0437] Intermediate INT-49

[0438] Compound INT-49 was prepared by referring to the method for compound INT-48, except that 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione was replaced with 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione, and compound INT-49 was obtained by following similar methods and steps. ESI-MS (m / z): 399.4 [M+H] + .

[0439] Intermediate INT-50

[0440] Synthesis steps:

[0441] Step 1: 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (100 mg, 0.194 mmol) and compound 2-(pyrrolidine-3-yl) tert-butyl acetate (71.75 mg, 0.387 mmol) were dissolved in 1,4-dioxane (3 mL), and Pd-PEPPSI-iPentCl (18.84 mg, 0.019 mmol) and cesium carbonate (189.29 mg, 0.581 mmol) were added. The reaction system was replaced with nitrogen gas, and the reaction solution was stirred at 100 degrees Celsius for 16 hours. The reaction was monitored by LCMS until it ended. The reaction mixture was poured into water (15 mL), extracted with ethyl acetate (25 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-50a (100 mg, yield 83%). ESI-MS (m / z): 621.5 [M + H] + ;

[0442] Step 2: Compound INT-50a (90 mg, 0.145 mmol) was dissolved in ethyl acetate (3 mL), and palladium / carbon (9 mg) was added at room temperature. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 16 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain compound INT-50b (64 mg, 99% yield). ESI-MS (m / z): 443.5 [M+H] + ;

[0443] Step 3: Compound INT-50b (60 mg, 0.145 mmol) was dissolved in DCM (3 mL), and TFA (0.5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound INT-50 (47 mg, yield 85%). ESI-MS (m / z): 387.5 [M+H] + ;

[0444] Intermediate INT-51

[0445] Synthesis steps:

[0446] Step 1: Compound INT-48c (50 mg, 0.110 mmol) was dissolved in methanol (1 mL), and palladium / carbon (5 mg) was added at room temperature. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 16 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain compound INT-51a (50 mg, 99% yield). ESI-MS (m / z): 457.5 [M+H] + ;

[0447] Step 2: Compound INT-51a (50 mg, 0.10 mmol) was dissolved in DCM (3 mL), and TFA (0.5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound INT-51 (39 mg, 90% yield). ESI-MS (m / z): 401.5 [M+H] + ;

[0448] Intermediate INT-52

[0449] The preparation method for compound INT-52 is the same as that for compound INT-51. ESI-MS (m / z): 401.6 [M+H] + ;

[0450] Intermediate INT-53

[0451] Synthesis steps:

[0452] Step 1: (1-hydroxymethylcyclopropyl)-tert-butoxycarbonylamino (5.00 g, 26.7 mmol) was dissolved in DCM (50 mL). TEA (5.40 g, 53.4 mmol) and methanesulfonyl chloride (4.59 g, 40.1 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with DCM (80 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid compound INT-53a (6.5 g, 92% yield). 1 H NMR (400MHz, CDCl3) δ5.08(s,1H),4.23(s,2H),3.01(s,3H),1.43(s,9H),1.00–0.84(m,4H).

[0453] Step 2: Compound INT-53a (12.0 g, 45.2 mmol) was dissolved in DMSO (120 mL), and sodium cyanide (11.1 g, 226 mmol) was added. The mixture was stirred at 50 °C for 3 hours. The reaction was monitored by LCMS until completion. The reaction solution was extracted with water (100 mL) and ethyl acetate (100 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give a yellow solid compound INT-53b (8.5 g, purity 30 °C, yield 28%). 1 H NMR (400MHz, CDCl3) δ2.66(s,2H),1.38(s,9H),0.93–0.71(m,4H).

[0454] Step 3: Compound INT-53b (11.0 g, 14.0 mmol) was dissolved in DCM (80 mL), and HCl dioxane solution (20 mL, 4 M) was added. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until it was complete. The reaction solution was concentrated to give a yellow solid compound INT-53c (4.0 g, yield 72%).

[0455] Step 4: Compound INT-53c (4.00 g, 10.4 mmol) was dissolved in DMF (40 mL), and 2-bromoacetophenone (2.07 g, 10.4 mmol) and K3PO4 (6.62 g, 31.21 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS until completion. The reaction solution was extracted with water (100 mL) and ethyl acetate (100 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to give a yellow oily compound INT-53d (1.05 g, yield 47%). ESI-MS (m / z): 215.2 [M + H] + .

[0456] Step 5: Compound INT-53d (1.05 g, 4.90 mmol) was dissolved in THF (5 mL) and water (5 mL), and sodium bicarbonate (823 mg, 9.80 mmol) and (Boc)₂O (2.14 g, 9.80 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction solution was extracted with water (100 mL) and ethyl acetate (100 mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 4 / 1) to give a yellow oily compound INT-53e (660.0 mg, yield 43%).

[0457] Step 6: Dissolve compound INT-53e (660 mg, 2.10 mmol) in MeOH (8 mL), add sodium borohydride (79.4 mg, 2.10 mmol) at 0°C, and stir at room temperature for 1 hour. Monitor the reaction end by LCMS. Quench the reaction solution with 1N HCl, extract with ethyl acetate (30 mL * 2), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter and concentrate to obtain a pale pink oily compound INT-53f (660.0 mg, 99% yield). ESI-MS (m / z): 339.2 [M + Na] + ;

[0458] Step 7: Dissolve compound INT-53f (200.0 mg, 632 μmol) in THF (5 mL), add diethyl chlorophosphate (192 mg, 948 μmol) at -15°C, then add LiHMDS (1.58 mL, 1.58 mmol) dropwise. Stir the reaction mixture at -15°C for 1 hour. Monitor the reaction for completion by TLC. Quench the reaction mixture with 1N HCl and concentrate it. Purify the residue by silica gel column chromatography (PE / EA = 9 / 1) to obtain a colorless oily compound INT-53g (60.0 mg, yield 31%). 1 H NMR (400MHz, CDCl3) δ7.41–7.31(m,5H),4.09–3.98(m,1H),3.67–3.58(m,2H),3.36(d,J= 9.6Hz,1H),2.02(s,1H),1.55(s,1H),1.44(s,9H),1.09–1.02(m,1H),0.72–0.67(m,1H).

[0459] Step 8: Dissolve compound INT-53 g (150 mg, 502 μmol) in DCM (4 mL), add TFA (2 mL), and stir at room temperature for 2 hours. Monitor the reaction end by LCMS. Concentrate the reaction solution, and purify the residue by preparative liquid chromatography to obtain a white solid compound INT-53 (95.0 mg, 95% yield). ESI-MS (m / z): 199.2 [M+H] + ;

[0460] 1 H NMR (400MHz, DMSO-d6) δ9.79 (s, 1H), 7.64–7.28 (m, 5H), 4.01–3.80 (m, 3H), 3.49 (t, J = 10.8Hz, 1H), 1.47–1.34 (m, 2H), 1.20–1.06 (m, 2H).

[0461] Intermediate INT-54

[0462] Synthesis steps:

[0463] Step 1: 4-Bromo-2-fluorobenzoic acid (150 mg, 0.685 mmol) and 4-piperidine acetate tert-butyl oxalate (136.49 mg, 0.685 mmol) were dissolved in 1,4-dioxane (3 mL). Brettphos Pd G3 (62.09 mg, 0.069 mmol), Brettphos (73.53 mg, 0.137 mmol), and cesium carbonate (446.31 mg, 1.37 mmol) were added. The reaction system was purged with nitrogen. The reaction mixture was stirred at 100°C for 16 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (15 mL), extracted with ethyl acetate (25 mL x 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-54a (130 mg, 56% yield). ESI-MS (m / z): 338.5 [M+H] + ;

[0464] Step 2: Compound INT-54a (88 mg, 0.261 mmol) and 3-amino-2,6-piperidinidone (43 mg, 0.261 mmol) were dissolved in THF (2 mL) and ACN (2 mL), and NMI (107.25 mg, 1.31 mmol) and TCFH (109.95 mg, 0.392 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (10 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-54b (50 mg, yield 43%). ESI-MS (m / z): 448.5 [M + H] + ;

[0465] Step 3: Compound INT-54b (50 mg, 0.11 mmol) was dissolved in DCM (3 mL), and TFA (0.5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound INT-54 (39 mg, 90% yield). ESI-MS (m / z): 392.5 [M+H] + .

[0466] Intermediate INT-55

[0467] Synthesis steps:

[0468] Step 1: Compound INT-27e (800 mg, 1.91 mmol) was dissolved in tetrahydrofuran (10 mL). 3-Phenyl-2-phenylsulfonyl-1,2-oxazacyclopropane (1.0 g, 3.82 mmol) was added at -78°C, followed by NaHMDS (2.0 M, 1.91 mL, 3.82 mmol). The reaction system was purged with nitrogen, and the reaction mixture was stirred at -78°C for half an hour. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water (25 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a yellow oily compound INT-55a (450 mg, yield 54%). ESI-MS (m / z): 435.2 [M+H] + ;

[0469] Step 2: Compound INT-55a (450 mg, 1.04 mmol) was dissolved in DCM (10 mL), and DAST (200 mg, 1.24 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into saturated sodium bicarbonate solution (30 mL), extracted with dichloromethane (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a pale yellow oily compound INT-55b (220 mg, yield 49%). ESI-MS (m / z): 437.0 [M+H] + ;

[0470] Step 3: Compound INT-55b (220 mg, 504 μmol) was dissolved in tetrahydrofuran (8 mL), and Pd / C (10% w / w, containing 55% water, 107 mg) was added. The reaction mixture was stirred at 50°C for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, and the filtrate was concentrated to obtain compound INT-55c (200.0 mg, yield 97%). ESI-MS (m / z): 347.0 [M+H] + .

[0471] Step 4: Compound INT-55c (140 mg, 344 μmol) was dissolved in tetrahydrofuran (5 mL), and DCC (142 mg, 687 μmol) and pentafluorophenol (94.9 mg, 515 μmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a pale yellow oily compound INT-55d (120 mg, yield 68%). ESI-MS (m / z): 513.2 [M+H] + ;

[0472] Step 5: Compound INT-55d (100 mg, 195 μmol) was dissolved in DCM (6 mL). N,O-bis(trimethylsilyl)trifluoroacetamide (301 mg, 1.17 mmol), TMSI (156 mg, 781 μmol), and pentafluorophenol (94.9 mg, 515 μmol) were added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a pale yellow oily compound INT-55 (42.0 mg, yield 72%). ESI-MS (m / z): 474.0 [M+NH4] + ;

[0473] 1 H NMR (400MHz, CD3OD) δ8.48 (s, 1H), 8.17 (s, 1H), 8.06 (d, J = 8.4Hz, 1H), 7.73 (d, J = 8.4Hz, 1H), 5.86 (dd, J = 44.4, 8.4Hz, 1H).

[0474] Intermediate INT-56

[0475] Synthesis steps:

[0476] Step 1: 1-Fluoro-4-nitrobenzene (100.0 mg, 0.789 mmol) and piperin-4-yl-tert-butyl acetate (141.2 mg, 0.789 mmol) were dissolved in DMF (2 mL). DIPEA (183.2 mg, 1.42 mmol) was added at room temperature, and the mixture was stirred at 100°C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a pale yellow solid compound INT-56a (195 mg, yield 86%). ESI-MS (m / z): 321.0 [M+H] + ;

[0477] Step 2: Compound INT-56a (195.0 mg, 0.609 mmol) was dissolved in ethanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL). Zinc powder (400.0 mg, 6.09 mmol) and ammonium chloride (325.6 mg, 6.09 mmol) were added at room temperature. The mixture was stirred at 60°C for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was filtered, the filter cake was washed with ethyl acetate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a yellow oily compound INT-56b (170 mg, 96% yield). ESI-MS (m / z): 291.4 [M+H] + ;

[0478] Step 3: Compound INT-56b (170 mg, 0.585 mmol) and 1-(4-methoxybenzyl)-2,6-dioxadiazine-3-yltrifluoromethanesulfonate (187 mg, 0.490 mmol) were dissolved in acetonitrile (3 mL). Sodium carbonate (77.97 mg, 0.736 mmol) was added at room temperature, and the mixture was stirred at 65°C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL * 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a pale yellow solid compound INT-56c (228 mg, yield 89%). ESI-MS (m / z): 522.0 [M+H] + ;

[0479] Step 4: Compound INT-56c (198 mg, 0.380 mmol) was dissolved in TFA (1 mL), and TfOH (313.3 mg, 2.09 mmol) was added at room temperature. The mixture was stirred at 65°C for 2 hours, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated and dissolved in DCM (5 mL). The pH was adjusted with DIPEA until a solid precipitated. The mixture was filtered, and the filter cake was washed with DCM and dried to obtain a green solid compound INT-56 (50 mg, yield 38%). ESI-MS (m / z): 346.1 [M+H] + ;

[0480] Intermediate INT-57

[0481] Synthesis steps:

[0482] Step 1: Boc-piperazine (72.1 mg, 0.39 mmol), 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (100 mg, 0.19 mmol), Pd-PEPPSI-iPentCl (18.8 mg, 19.4 μmol), and cesium carbonate (189.3 mg, 0.58 mmol) were dissolved in dioxane (3 mL). The reaction mixture was stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound INT-57a (88.7 mg, 73% yield). ESI-MS (m / z): 621.8 [M+H] + .

[0483] Step 2: Compound INT-57a (44 mg, 70.8 μmol) was dissolved in ethyl acetate (2 mL) and methanol (5 mL), and Pd(OH)₂ / C (29.82 mg, 10% w / w) was added. The reaction mixture was purged with hydrogen and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was concentrated to give compound INT-57b (30 mg, 98% yield). ESI-MS (m / z): 444.0 [M+H] + .

[0484] Step 3: Compound INT-57b (62 mg, 139.8 μmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 6 hours, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound INT-57c (47 mg, 98% yield). ESI-MS (m / z): 344.2 [M+H] + .

[0485] Step 4: Compound INT-57c (48 mg, 139.8 μmol) and tert-butyl chloroacetate (25.3 mg, 167.7 μmol) were dissolved in acetonitrile (2 mL), and then DIPEA (36.1 mg, 49 μL, 279.6 μmol) was added. The system was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound INT-57d (18 mg, yield 28%). ESI-MS (m / z): 458.1 [M+H] + .

[0486] Step 5: Compound INT-57d (14 mg, 30.6 μmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 6 hours, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound INT-57 (16 mg, yield 89%). ESI-MS (m / z): 402.0 [M+H] + .

[0487] Intermediate INT-58

[0488] Synthesis steps:

[0489] Step 1: 7-BOC-7-azaspiro[3.5]nonane-2-carboxylic acid (100 mg, 0.371 mmol) and benzyl bromide (127 mg, 0.0743 mmol) were dissolved in DMF (300 mL), and cesium carbonate (241.9 mg, 0.743 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was slowly poured into water (5 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a pale yellow solid compound INT-58a (130 mg, yield 97%). ESI-MS (m / z): 360.6 [M + H] + .

[0490] Step 2: Compound INT-58a (130 mg, 0.362 mmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated to obtain compound INT-58b (93 mg, 99% yield). ESI-MS (m / z): 260.2 [M+H] + .

[0491] Step 3: 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (93 mg, 0.180 mmol) and compound INT-58b (93 mg, 0.360 mmol) were dissolved in 1,4-dioxane (3 mL), and Pd-PEPPSI-iPentCl (17.52 mg, 0.018 mmol) and cesium carbonate (176.04 mg, 0.540 mmol) were added. The reaction system was replaced with nitrogen gas, and the reaction solution was stirred at 100 degrees Celsius for 16 hours. The reaction was monitored by LCMS until it ended. The reaction mixture was poured into water (15 mL), extracted with ethyl acetate (25 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-58c (55 mg, yield 44%). ESI-MS (m / z): 695.1 [M+H] + ;

[0492] Step 4: Compound INT-58c (55 mg, 0.079 mmol) was dissolved in ethyl acetate (1 mL) and methanol (1 mL). Palladium hydroxide / carbon (33.35 mg, 10% w / w) was added at room temperature. The reaction mixture was stirred at 30°C under a hydrogen atmosphere for 16 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain compound INT-58 (30 mg, yield 89%). ESI-MS (m / z): 427.9 [M+H] + ;

[0493] Intermediate INT-59

[0494] The preparation method for compound INT-59 is the same as that for compound INT-58. Compound INT-59 was obtained by replacing 7-BOC-7-azaspiro[3.5]nonane-2-carboxylic acid with [1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]acetic acid, following a similar method and procedure. ESI-MS (m / z): 415.8 [M+H] + .

[0495] Intermediate INT-60

[0496] The preparation method for compound INT-60 is the same as that for compound INT-20. Compound INT-60 can be obtained by replacing methyl phenylacetate with methyl pyridinyl-3-acetate and following a similar method and procedure. ESI-MS (m / z): 175.0 [M+H] + .

[0497] Intermediate INT-61

[0498] Synthesis steps:

[0499] Compound INT-27e (500.0 mg, 1.19 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Under nitrogen protection at -78 °C, sodium bis(trimethylsilyl)amino (2 M n-hexane solution, 1.8 mL, 3.58 mmol) was added, and the mixture was stirred for 10 min. Then, 1H-benzotriazole-1-methanol (356.0 mg, 2.39 mmol) was added, and the mixture was stirred for another 2 h. The reaction was monitored by LCMS until completion. The reaction solution was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-61 (115.0 mg, 21% yield). ESI-MS (m / z): 449.0 [M+H] + .

[0500] Intermediate INT-62

[0501] Synthesis steps:

[0502] Step 1: 6-Bromo-3-fluoro-2-pyridinecarboxaldehyde (1.0 g, 4.90 mmol) and methyl mercaptoacetate (546.34 mg, 5.15 mmol, 0.471 mL) were dissolved in DMSO (6 mL), and triethylamine (1.24 g, 12.26 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-62a (1.20 g, 89% yield). ESI-MS (m / z): 274.0 [M+H] + .

[0503] Step 2: Compound INT-62a (1.20 g, 4.41 mmol), cuprous iodide (83.99 mg, 0.441 mmol), sodium iodide (1.32 g, 8.82 mmol), and N,N'-dimethylethylenediamine (38.87 mg, 0.441 mmol) were dissolved in dioxane (10 mL). The reaction system was purged with nitrogen gas and stirred at 110°C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound INT-62b (1.3 g, yield 92%). ESI-MS (m / z): 319.9 [M+H] + .

[0504] Step 3: Cadmium powder (3.24 g, 28.84 mmol) and TMSCl (65.10 mg, 0.599 mmol) were dissolved in DMF (10 mL), and diethyl bromodifluoromethylphosphonate (5.0 g, 18.73 mmol) was added. The reaction system was purged with nitrogen gas, and the mixture was stirred at room temperature for 3 hours. The reaction solution was then filtered under nitrogen protection. Compound INT-62b (300.0 mg, 0.940 mmol) and cuprous chloride (139.60 mg, 1.41 mmol) were dissolved in DMF (10 mL) and added to the filtrate under nitrogen protection. The mixture was stirred at room temperature for another 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was slowly poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound INT-62c (259 mg, yield 72%). ESI-MS (m / z): 379.8 [M+H] + .

[0505] Step 4: Compound INT-62c (250 mg, 0.659 mmol) was dissolved in water (4 mL) and tetrahydrofuran (1 mL), and lithium hydroxide monohydrate (138.29 mg, 3.30 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 9 / 1) to give compound INT-62 (140.0 mg, yield 62%). ESI-MS (m / z): 337.9 [M+H] + .

[0506] Intermediate INT-63

[0507] Synthesis steps:

[0508] Step 1: 2-Bromo-5-fluoropyridine-4-carboxaldehyde (1.0 g, 4.90 mmol) and ethyl mercaptoside (648.0 mg, 5.39 mmol) were dissolved in DMF (10 mL). Potassium carbonate (2.71 g, 19.61 mmol) was added at 0°C, and the mixture was stirred at 60°C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (25 mL), extracted with ethyl acetate (35 mL x 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-63a (1.4 g, 99% yield). ESI-MS (m / z): 287.4 [M+H] + ;

[0509] Step 2: Compound INT-63a (1.4 g, 4.89 mmol), cuprous iodide (93.18 mg, 0.489 mmol), sodium iodide (1.47 g, 9.79 mmol), and N,N'-dimethylethylenediamine (4.13 mg, 0.489 mmol) were dissolved in dioxane (15 mL). The reaction system was purged with nitrogen, and the mixture was stirred at 100°C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-63b (0.8 g, yield 49%). ESI-MS (m / z): 334.6 [M+H] + .

[0510] Step 3: Cadmium (17.96 g, 159.81 mmol) and TMSCl (578.71 mg, 5.33 mmol) were dissolved in DMF (200 mL), and diethyl bromodifluoromethylphosphonate (42.67 g, 159.81 mmol) was added. The reaction system was purged with nitrogen, and the mixture was stirred at room temperature for 3 hours. The reaction solution was then filtered under nitrogen protection. INT-63b (0.8 g, 2.02 mmol) and cuprous chloride (300.59 g, 3.04 mmol) were then dissolved in DMF (6 mL) and added to the filtrate (7.68 mL) under nitrogen protection. The mixture was stirred at room temperature for another 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was cooled to room temperature and slowly poured into water (15 mL). Extraction was performed with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give compound INT-63c (608 mg, yield 76%). ESI-MS (m / z): 393.5 [M+H] + ;

[0511] Step 4: Compound INT-63c (608 mg, 1.55 mmol) was dissolved in water (1.6 mL) and tetrahydrofuran (8 mL). 1M lithium hydroxide aqueous solution (74.04 mg, 3.09 mmol) was added at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS until completion. The pH of the reaction solution was adjusted to 3-4, extracted, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a yellow oily compound INT-63d (410 mg, yield 79%); ESI-MS (m / z): 337.6 [M+H] + ;

[0512] Step 5: Compound INT-63d (410 mg, 1.22 mmol) and pentafluorophenol (246.2 mg, 1.34 mmol) were dissolved in tetrahydrofuran (10 mL). DCC (501.7 mg, 2.43 mmol) and DMAP (14.85 mg, 0.122 mmol) were added at 0°C. The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (15 mL), extracted with dichloromethane (25 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the oil-free compound INT-63e (156 mg, yield 26%). ESI-MS (m / z): 504.2 [M+H] + ;

[0513] Step 6: Compound INT-63e (156 mg, 0.310 mmol) was dissolved in DCM (3 mL). After being placed in an ice-water bath, BSTFA (478.71 mg, 1.86 mmol) and TMSI (310.10 mg, 1.55 mmol) were added under nitrogen protection. The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid compound INT-63 (122 mg, yield 83%). ESI-MS (m / z): 475.3 [M+H] + .

[0514] Intermediate INT-64

[0515] Synthesis steps:

[0516] Step 1: 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate (166.77 mg, 774.62 μmol) and 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (0.20 g, 387.31 μmol) were dissolved in dioxane (5 mL). Pd-PEPPSI-iPentCl (37.68 mg, 38.72 μmol) and cesium carbonate (378.58 mg, 1.16 mmol) were added. The reaction system was purged with nitrogen gas, and the reaction was carried out at 100°C for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound INT-64a (210.00 mg, yield 83%). ESI-MS (m / z): 651.3 [M+H] + .

[0517] Step 2: Compound INT-64a (0.01 g, 153.67 μmol) was dissolved in methanol (3 mL) and ethyl acetate (3 mL). Palladium hydroxide (64.74 mg, 10% w / w) was added at room temperature, and the reaction system was replaced with hydrogen gas. The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to obtain compound INT-64b (0.07 g, 96% yield). ESI-MS (m / z): 472.8 [M+H] + .

[0518] Step 3: Compound INT-64b (70.00 mg, 148.14 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-64 (60.00 mg, yield 97%). ESI-MS (m / z): 416.9 [M+H] + .

[0519] Intermediate INT-65

[0520] The preparation method for compound INT-65 is the same as that for compound INT-64. Compound INT-65 was obtained by replacing methyl 3-piperidine acetate hydrochloride with methyl 6-azaspiro[3.4]octane-2-carboxylate, following a similar method and procedure. ESI-MS (m / z): 413.5 [M+H] + ;

[0521] Intermediate INT-66

[0522] Synthesis steps:

[0523] Step 1: Compound INT-64b (100.00 mg, 153.67 μmol) was dissolved in DCM (3 mL), and DAST (37.15 mg, 230.50 μmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-66a (35.00 mg, yield 34%). ESI-MS (m / z): 652.8 [M + H] + .

[0524] Step 2: Compound INT-66a (35.00 mg, 53.62 μmol) was dissolved in methanol (1.5 mL) and ethyl acetate (1.5 mL). Palladium hydroxide (22.59 mg, 10% w / w) was added at room temperature, and the reaction mixture was replaced with hydrogen gas. The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to obtain compound INT-66b (25.00 mg, 98% yield). ESI-MS (m / z): 475.0 [M+H] + .

[0525] Step 3: Compound INT-66b (25.00 mg, 52.68 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-66 (20.00 mg, 90% yield). ESI-MS (m / z): 418.2 [M+H] + .

[0526] Intermediate INT-67

[0527] Synthesis steps:

[0528] Step 1: Methyl 4-amino-2-chlorobenzoate (5.0 g, 26.94 mmol) and calcium carbonate (5.4 g, 53.88 mmol) were dissolved in methanol (50 mL) and dichloromethane (25 mL). Iodine chloride (4.8 g, 29.63 mmol) was added at room temperature, and the mixture was stirred for 16 hours under these conditions. The reaction was monitored by LCMS until completion. The reaction solution was concentrated by diatomaceous earth filtration, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-67a (3.3 g, yield 39%). ESI-MS (m / z): 311.8 [M+H] + .

[0529] Step 2: Compound INT-67a (3.3 g, 10.59 mmol) was dissolved in dichloromethane (20 mL) and anhydrous tetrahydrofuran (5 mL). Under nitrogen protection at -78 °C, diisobutylaluminum hydride (1 M n-hexane solution, 26.5 mL, 26.50 mmol) was slowly added. After completion, the mixture was brought to room temperature and stirred for 30 minutes. The reaction was monitored by LCMS until completion. The reaction solution was quenched with water (50 mL), extracted with dichloromethane (50 mL * 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound INT-67b (2.9 g, 96% yield). ESI-MS (m / z): 283.7 [M + H] + .

[0530] Step 3: Compound INT-67b (2.9 g, 10.23 mmol) was dissolved in chloroform (30 mL), and manganese dioxide (5.4 g, 61.38 mmol) was added at room temperature. The mixture was then heated to 60 °C and stirred for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated by diatomaceous earth filtration to obtain compound INT-67c (2.8 g, 97% yield). ESI-MS (m / z): 281.7 [M+H] + .

[0531] Step 4: Compound INT-67c (2.8 g, 9.95 mmol) and ethyl mercaptoside (2.4 g, 19.90 mmol) were dissolved in DMF (20 mL). Potassium carbonate (2.8 g, 19.90 mmol) was added at room temperature, and the mixture was stirred at 90 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (50 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give compound INT-67d (1.8 g, yield 52%). ESI-MS (m / z): 348.5 [M + H] + .

[0532] Step 5: Compound INT-67d (700.0 mg, 2.02 mmol) was dissolved in acetonitrile (20 mL), and cuprous chloride (399.23 mg, 4.03 mmol) and tert-butyl nitrite (311.0 mg, 3.02 mmol) were added at room temperature. The mixture was stirred at 75 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated by diatomaceous earth filtration, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give compound INT-67 (330 mg, yield 44%). ESI-MS (m / z): 366.6 [M+H] + .

[0533] Intermediate INT-68

[0534] Synthesis steps:

[0535] Compound INT-67d (1.0 g, 2.88 mmol) was dissolved in tetrahydrofuran (10 mL). Fluoroboric acid (6.0 g, 68.3 mmol) and sodium nitrite (178.8 mg, 2.59 mmol) in water (8 mL) were added sequentially under ice bath conditions. The mixture was stirred for 1 hour. A solid precipitated, which was collected by filtration to obtain a yellow solid. The mixture was then stirred at 160 °C for 3 hours, and the reaction was monitored by LC-MS until completion. The mixture was cooled to room temperature, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give compound INT-68 (320.0 mg, yield 32%). ESI-MS (m / z): 351.1 [M+H] + .

[0536] Intermediate INT-69

[0537] Synthesis steps:

[0538] Step 1: Dissolve (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (100 mg, 440.0 μmol) in 2 mL of methanol, and add thionyl chloride (104.7 mg, 880.1 μmol) dropwise at 0 °C. The reaction is then carried out at room temperature for 3 hours. After the reaction is complete, the intermediate INT-69a (80 mg) is concentrated. ESI-MS (m / z): 142.6 [M+H] + .

[0539] Step 2: Compound INT-69a (80 mg, 0.44 mmol), 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (100 mg, 0.19 mmol), Pd-PEPPSI-iPentCl (18.8 mg, 19.4 μmol), and cesium carbonate (315.5 mg, 0.97 mmol) were dissolved in dioxane (3 mL). The reaction mixture was stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated, and the residue was purified by silica gel column chromatography to give compound INT-69b (95 mg, 84% yield). ESI-MS (m / z): 577.2 [M+H] + .

[0540] Step 3: Compound INT-69b (95 mg, 164.4 μmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide (13.8 mg, 328.8 μmol) was added. The reaction was carried out at 25 °C for 16 hours, and the reaction was monitored by LCMS until completion. After the reaction, the pH was adjusted to 3-4 with 4 M hydrochloric acid, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound INT-69c (95 mg). ESI-MS (m / z): 562.7 [M + H] + .

[0541] Step 4: Compound INT-69c (95 mg, 163.5 μmol) was dissolved in ethyl acetate (2 mL) and methanol (2 mL), and Pd(OH)₂ / C (68.9 mg, 10% w / w) was added. The reaction mixture was purged with hydrogen and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was concentrated to give compound INT-69 (21 mg, yield 33%). ESI-MS (m / z): 384.6 [M+H] + .

[0542] Intermediate INT-70

[0543] Synthesis steps:

[0544] Step 1: (4E)-4-(2-ethoxy-2-oxoethylene)-3,3-dimethylpiperidine-1-carboxylic acid tert-butyl ester (100 mg, 336.3 μmol) was dissolved in dichloromethane (2 mL), and HCl (4 M in Dioxane, 0.5 mL) was added. The mixture was stirred at room temperature for 5 hours, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound INT-70a (83 mg). ESI-MS (m / z): 198.4 [M+H] + .

[0545] Step 2: Compound INT-70a (83 mg, 0.34 mmol), 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (100 mg, 0.19 mmol), Pd-PEPPSI-iPentCl (18.8 mg, 19.4 μmol), and cesium carbonate (315.5 mg, 0.97 mmol) were dissolved in dioxane (3 mL). The reaction mixture was stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated, and the residue was purified by silica gel column chromatography to obtain compound INT-70b (92.2 mg, 75% yield). ESI-MS (m / z): 633.2 [M+H] + .

[0546] Step 3: Compound INT-70b (92.2 mg, 145.7 μmol) was dissolved in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL), and potassium hydroxide (24.5 mg, 437 μmol) was added. The reaction was carried out at 65 °C for 3 hours, and the reaction was monitored by LCMS until completion. After the reaction, the pH was adjusted to 3-4 with 4M hydrochloric acid, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound INT-70c (100 mg). ESI-MS (m / z): 604.9 [M + H] + .

[0547] Step 4: Compound INT-70c (100 mg, 145.7 μmol) was dissolved in ethyl acetate (2 mL) and methanol (2 mL), and Pd(OH)₂ / C (61.3 mg, 10% w / w) was added. The reaction mixture was purged with hydrogen and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was concentrated to give compound INT-70 (59 mg, 94% yield). ESI-MS (m / z): 428.7 [M+H] + .

[0548] Intermediate INT-71

[0549] Synthesis steps:

[0550] Step 1: Methyltriphenylphosphine bromide (5.41 g, 15.13 mmol) was dissolved in THF (40 mL), and the reaction system was purged with nitrogen. Butyllithium (775.41 mg, 12.11 mmol) was added at 0°C and stirred for 1 hour. INT-71a (2.00 g, 10.09 mmol) was added to the system, and the reaction mixture was stirred at 0°C for 1 hour. The reaction was monitored by TLC until completion. The reaction mixture was poured into water (60 mL), extracted with ethyl acetate (40 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compound INT-71b (1.10 g, yield 55%).

[0551] Step 2: Compound INT-71b (464.37 mg, 2.37 mmol) and 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (0.40 g, 1.18 mmol) were dissolved in DMF (10 mL). Pd2(dba)3 (108.32 mg, 118.29 μmol), DIEA (305.75 mg, 2.37 mmol), and tri-tert-butylphosphine (478.64 mg, 236.58 μmol) were added. The reaction system was replaced with nitrogen gas and incubated at 90°C for 18 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound INT-71c (440.00 mg, yield 82%). ESI-MS (m / z): 470.9 [M + NH4) + .

[0552] Step 3: Compound INT-71c (250.00 mg, 551.23 μmol) was dissolved in isopropanol (6 mL). Wet palladium on carbon (58.16 mg, 10% w / w, 55% water content) was added at room temperature. The reaction system was replaced with hydrogen gas, and the mixture was stirred at 40°C for 18 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to obtain compound INT-71d (120.00 mg, yield 47%). ESI-MS (m / z): 472.9 [M+NH4] + .

[0553] Step 4: Compound INT-71d (120.00 mg, 263.42 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-71 (100.00 mg, 95% yield). ESI-MS (m / z): 399.4 [M+H] + .

[0554] Intermediate INT-72

[0555] Synthesis steps:

[0556] Step 1: Compound INT-72a (0.20 g, 744.46 μmol) and tert-butyl 5-aminovalerate (144.88 mg, 818.90 μmol) were dissolved in DMF (3 mL), and DIEA (288.64 mg, 2.23 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, DIEA (339.68 mg, 893.35 μmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water (40 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-72b (0.28 g, 88% yield). ESI-MS (m / z): 440.8 [M + NH4] + .

[0557] Step 2: Compound INT-72b (0.01 g, 235.91 μmol) was dissolved in dichloromethane (3 mL), and TFA (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-72 (80.00 mg, yield 92%). ESI-MS (m / z): 367.5 [M+H] + .

[0558] Intermediate INT-73

[0559] The preparation method for intermediate INT-73 is the same as that for compound INT-67. Intermediate INT-73 can be obtained by replacing INT-67a with methyl 2-amino-6-chloro-3-iodobenzoate and following a similar method and procedure. ESI-MS (m / z): 367.5 [M+H] + .

[0560] Intermediate INT-74

[0561] The preparation method of intermediate INT-74 is the same as that of compounds INT-73 and INT-68. ESI-MS (m / z): 351.2 [M+H] + .

[0562] Intermediate INT-75

[0563] Synthesis steps:

[0564] Step 1: 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (0.20 g, 744.46 μmol) and 4-oxopiperidone hydrochloride (111.04 mg, 818.90 μmol) were dissolved in DMF (3 mL), and DIEA (288.64 mg, 2.23 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, DIEA (339.68 mg, 893.35 μmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water (40 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-75b (0.18 g, 69% yield). ESI-MS (m / z): 367.0 [M+NH4] + .

[0565] Step 2: Compound INT-75b (90.00 mg, 257.31 μmol) was dissolved in DCE (4 mL), and sodium triacetoxyborohydride (272.67 mg, 1.29 mmol) and acetic acid (15.45 mg, 257.31 μmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-75c (65.00 mg, yield 48%). ESI-MS (m / z): 518.8 [M + H] + .

[0566] Step 3: Compound INT-75c (65.00 mg, 125.23 μmol) was dissolved in dichloromethane (3 mL), and TFA (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-75 (50.00 mg, yield 86%). ESI-MS (m / z): 462.5 [M+H] + .

[0567] Intermediate INT-76

[0568] Synthesis steps:

[0569] Step 1: 6-BOC-6-azaspiro[2.5]octane-1-carboxylic acid (5 g, 19.58 mmol) and DBU (3.58 g, 23.5 mmol) were dissolved in acetonitrile (100 mL), and benzyl bromide (3.68 g, 21.5 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was concentrated and purified by rapid silica gel chromatography to obtain compound INT-76a (6.68 g, 98% yield). ESI-MS (m / z): 345.9 [M+H] + .

[0570] Step 2: Compound INT-76a (100 mg, 289.5 μmol) was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 4 hours, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound INT-76b (150 mg). ESI-MS (m / z): 246.3 [M+H] + .

[0571] Step 3: Compound INT-76b (150 mg, 0.29 mmol), 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (100 mg, 0.19 mmol), Pd-PEPPSI-iPentCl (18.8 mg, 19.4 μmol), and cesium carbonate (315.5 mg, 0.97 mmol) were dissolved in dioxane (3 mL). The reaction mixture was stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated, and the residue was purified by silica gel column chromatography to give compound INT-76c (113.5 mg, yield 86%). ESI-MS (m / z): 680.6 [M+H] + .

[0572] Step 4: Compound INT-76c (113.5 mg, 166.7 μmol) was dissolved in ethyl acetate (2 mL) and methanol (2 mL), and Pd(OH)₂ / C (70.4 mg, 10% w / w) was added. The reaction mixture was purged with hydrogen and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was concentrated to give compound INT-76 (53 mg, 77% yield). ESI-MS (m / z): 412.7 [M+H]+ .

[0573] Intermediate INT-77

[0574] Synthesis steps:

[0575] Step 1: Methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (1.0 g, 3.89 mmol) was dissolved in DMF (5 mL), and sodium hydride (186.5 mg, 4.66 mmol) was added under ice bath conditions. The mixture was stirred for 0.5 h under these conditions. Then, methyl iodide (827.0 mg, 5.83 mmol) was slowly added, and the mixture was brought to room temperature and stirred for another 16 h. The reaction was monitored by LCMS until completion. The reaction solution was quenched with saturated ammonium chloride solution (20 mL), diluted with ethyl acetate (50 mL), the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound INT-77a (1.0 g, 94% yield). ESI-MS (m / z): 272.1 [M+H] + .

[0576] Step 2: Compound INT-77a (1.0 g, 3.87 mmol) was dissolved in dichloromethane (3 mL), and 4 M HCl dioxane solution (3 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction system was concentrated to give compound INT-77b (662.0 mg, 99% yield). ESI-MS (m / z): 172.4 [M+H] + .

[0577] Step 3: Compound INT-77b (281.0 mg, 1.36 mmol) and 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (350.0 mg, 0.68 mmol) were dissolved in 1,4-dioxane (5 mL), and Pd-PEPPSI-iPentCl (53.7 mg, 67.8 μmol) and cesium carbonate (662.0 mg, 2.03 mmol) were added. The reaction system was replaced with nitrogen gas, and the reaction solution was stirred at 100 °C for 16 hours. The reaction was monitored by LCMS until it ended. The reaction mixture was poured into water (15 mL), extracted with ethyl acetate (25 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give compound INT-77c (101.0 mg, yield 24%). ESI-MS (m / z): 624.3 [M + NH4) + .

[0578] Step 4: Compound INT-77c (70.0 mg, 115.0 μmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL). Lithium hydroxide (24.2 mg, 577.0 μmol) was added at room temperature, and the reaction mixture was stirred at 50 °C for 5 hours. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with water, and the pH was adjusted to 2.0 with hydrochloric acid. The mixture was then extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound INT-77d (60.0 mg, 87% yield). ESI-MS (m / z): 593.8 [M+H] + .

[0579] Step 5: Compound INT-77d (60.0 mg, 0.11 mmol) was dissolved in methanol (2 mL) and ethyl acetate (2 mL). Palladium hydroxide on carbon (6.0 mg, 10% w / w) was added, and the reaction system was replaced with hydrogen gas. The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to obtain compound INT-77 (30.2 mg, yield 71%). ESI-MS (m / z): 415.7 [M+H] + .

[0580] Intermediate INT-78

[0581] Synthesis steps:

[0582] Step 1: Compound INT-78a (0.10 g, 336.26 μmol) was dissolved in ACN (2 mL), and benzyl bromide (63.26 mg, 369.89 μmol) and 1,8-diazobisspirocyclic [5.4.0]undec-7-ene (61.43 mg, 403.51 μmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS until completion. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound INT-78b (0.12 g, 92% yield). ESI-MS (m / z): 388.0 [M+H] + .

[0583] Step 2: Compound INT-78b (0.12 g, 309.67 μmol) was dissolved in dichloromethane (3 mL), and TFA (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-78c (80.00 mg, yield 89%). ESI-MS (m / z): 288.1 [M+H]+ .

[0584] Step 3: Compound INT-78c (80.00 mg, 278.36 μmol) and 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (0.10 g, 193.65 μmol) were dissolved in dioxane (3 mL), and Pd-PEPPSI-iPentCl (18.84 mg, 19.37 μmol) and cesium carbonate (315.48 mg, 968.27 μmol) were added. The reaction system was replaced with nitrogen gas, and the reaction was carried out at 100°C for 5 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water (40 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound INT-78d (80.00 mg, yield 57%). ESI-MS (m / z): 722.6 [M+H] + .

[0585] Step 4: Compound INT-78d (80.00 mg, 110.67 μmol) was dissolved in methanol (2 mL) and ethyl acetate (2 mL). Palladium hydroxide on carbon (8.0 mg, 10% w / w) was added at room temperature, and the reaction system was replaced with hydrogen gas. The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to obtain compound INT-78 (0.02 g, yield 39%). ESI-MS (m / z): 454.7 [M+H] + .

[0586] Intermediate INT-79

[0587] Synthesis steps:

[0588] Step 1: 1-O-7-BOC-7-azaspiro[3.5]nonane (200 mg, 835.7 μmol), p-methylbenzenesulfonylmethylisocyanate (163.2 mg, 835.7 μmol), and ethanol (65.5 mg, 1.42 mmol) were added to ethylene glycol dimethyl ether (3 mL). Potassium tert-butoxide (187.6 mg, 1.67 mmol) was added at 0 °C, and the mixture was slowly heated to room temperature and stirred overnight. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and then purified by rapid silica gel chromatography to obtain intermediate INT-79a (120 mg, yield 57%). ESI-MS (m / z): 250.7 [M+H] + .

[0589] Step 2: Compound INT-79a (120 mg, 479.4 μmol) was dissolved in ethanol (2 mL), and HCl solution (3 mL, 4 M in Dioxane) was added. The mixture was reacted at 70 °C for 48 hours. After the reaction was complete, 2 mL of water was added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain INT-79b (45 mg, yield 47%). ESI-MS (m / z): 198.2 [M+H] + .

[0590] Step 3: Compound INT-79b (45 mg, 0.23 mmol), 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (100 mg, 0.19 mmol), Pd-PEPPSI-iPentCl (18.8 mg, 19.4 μmol), and cesium carbonate (185.8 mg, 0.57 mmol) were dissolved in dioxane (3 mL). The reaction mixture was stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated, and the residue was purified by silica gel column chromatography to obtain compound INT-79c (78 mg, yield 64%). ESI-MS (m / z): 632.9 [M+H] + .

[0591] Step 4: Compound INT-79c (78 mg, 123.3 μmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (0.5 mL), and lithium hydroxide (15.5 mg, 369.8 μmol) was added. The reaction was carried out at 60 °C for 16 hours, and the reaction was monitored by LCMS until completion. After the reaction, the pH was adjusted to 3-4 with 4 M hydrochloric acid, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound INT-79d (85 mg). ESI-MS (m / z): 604.9 [M + H] + .

[0592] Step 5: Compound INT-79d (85 mg, 124.7 μmol) was dissolved in ethyl acetate (2 mL) and methanol (2 mL), and Pd(OH)₂ / C (52.6 mg, 10% w / w) was added. The reaction mixture was purged with hydrogen and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was concentrated to give compound INT-79 (50 mg, 93% yield). ESI-MS (m / z): 426.2 [M+H] + .

[0593] Intermediate INT-80

[0594] The preparation method of intermediate INT-80 is the same as that of intermediate INT-79. 1-O-7-BOC-7-azaspiro[3.5]nonane is replaced with cis-5-oxohexahydrocyclopentadieno[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester. Following a similar method and steps, intermediate INT-80 can be obtained. ESI-MS (m / z): 413.0 [M+H] + ;

[0595] Intermediate INT-81

[0596] The preparation method of intermediate INT-81 is the same as that of intermediate INT-9, except that INT-2d is replaced with INT-55b. Following a similar method and steps, intermediate INT-81 can be obtained. ESI-MS (m / z): 536.1 [M+NH4] + ;

[0597] Intermediate INT-82

[0598] The preparation method of intermediate INT-82 is the same as that of intermediate INT-29, except that INT-2d is replaced with INT-55b. Following a similar method and steps, intermediate INT-82 can be obtained. ESI-MS (m / z): 497.0 [M+NH4] + ;

[0599] Intermediate INT-83

[0600] Synthesis steps:

[0601] Step 1: Methyl cis-4-hydroxycyclohexanecarboxylate (500 mg, 3.16 mmol) and p-toluenesulfonyl chloride (723 mg, 3.79 mmol) were dissolved in dichloromethane (5 mL). DMAP (77.2 mg, 0.63 mmol) and triethylamine (1.32 mL, 9.48 mmol) were added sequentially at room temperature, and the mixture was stirred for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was diluted with dichloromethane (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give compound INT-83a (980 mg, 99% yield). ESI-MS (m / z): 330.8 [M+NH4] + .

[0602] Step 2: Dissolve 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[D]imidazol-2-one (1.0 g, 1.94 mmol) in 1,4-dioxane (10 mL) and water (2 mL), add Pd2dba3 (177.3 mg, 0.19 mmol), t-BuXPhos (164.4 mg, 0.38 mmol) and potassium hydroxide (326.0 mg, 5.81 mmol), replace the reaction system with nitrogen gas, stir the reaction solution at 90 °C for 8 hours, and monitor the reaction at LCMS until it ends. The reaction solution was adjusted to pH 3 with hydrochloric acid, extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give compound INT-83b (742 mg, yield 85%). ESI-MS (m / z): 454.8 [M+H] + .

[0603] Step 3: Compound INT-83b (600 mg, 1.32 mmol) and compound 114a (826 mg, 2.65 mmol) were dissolved in DMF (5 mL). Cesium carbonate (1.29 g, 3.97 mmol) was added at room temperature, and the mixture was stirred at 90 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give compound INT-83c (590 mg, 75% yield). ESI-MS (m / z): 594.7 [M+H] + .

[0604] Step 4: Compound INT-83c (590.0 mg, 0.99 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL). Lithium hydroxide (47.7 mg, 1.99 mmol) was added at room temperature, and the reaction mixture was stirred at 50 °C for 5 hours. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with water, and the pH was adjusted to 2.0 with hydrochloric acid. The mixture was then extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound INT-83d (518.0 mg, 90% yield). ESI-MS (m / z): 580.1 [M+H] + .

[0605] Step 5: Compound INT-83d (500.0 mg, 0.86 mmol) was dissolved in methanol (6 mL) and ethyl acetate (6 mL). Palladium hydroxide on carbon (50.0 mg, 10% w / w) was added, and the reaction system was purged with hydrogen gas. The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to obtain compound INT-83 (263.2 mg, yield 76%). ESI-MS (m / z): 402.2 [M+H] + .

[0606] Intermediate INT-84

[0607] The preparation method of intermediate INT-84 is the same as that of intermediate INT-77, except that methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarbamate is replaced with methyl cis-4-(tert-butoxycarbonylamino)cyclohexanecarbamate. Following a similar method and steps, compound INT-84 can be obtained. ESI-MS (m / z): 415.5 [M+H] + .

[0608] Intermediate INT-85

[0609] Synthesis steps:

[0610] Step 1: 3-Benzyl-3-azabicyclo[3.1.1]heptane-6-one (150 mg, 745.29 μmol) was dissolved in DME (3 mL). Sodium hydride (21.94 mg, 914.33 μmol) was added under ice bath conditions, and the mixture was stirred for 0.5 hours. Then, triethyl phosphoroacetate (291.06 mg, 1.30 mmol) was slowly added, and the mixture was stirred for another 1.5 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with ammonium chloride aqueous solution (15 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to give compound INT-85a (180 mg, 89% yield). ESI-MS (m / z): 272.0 [M+H] + .

[0611] Step 2: Compound INT-85a (180 mg, 0.663 mmol) was dissolved in methanol (4 mL), and palladium on carbon (54 mg) was added at room temperature. The reaction system was stirred at 55°C under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction system was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain compound INT-85 (121 mg, yield 99%). ESI-MS (m / z): 184.5 [M+H]+ .

[0612] Intermediate INT-86

[0613] The preparation method of intermediate INT-86 is the same as that of intermediate INT-83, except that methyl trans-4-hydroxycyclohexanecarboxylate is substituted for methyl cis-4-hydroxycyclohexanecarboxylate. Following a similar method and steps, intermediate INT-86 can be obtained. ESI-MS (m / z): 402.1 [M+H] + ;

[0614] Intermediate INT-87

[0615] Synthesis steps:

[0616] Step 1: Methyl cis-3-(tert-butoxycarbonylamino)cyclobutanecarboxylate (500 mg, 2.18 mmol) was dissolved in DMF (10 mL), and sodium hydride (104.68 mg, 2.62 mmol) was added under ice bath conditions. The mixture was stirred for 0.5 h under these conditions. Then, methyl iodoform (827.0 mg, 5.83 mmol) was slowly added, and the mixture was brought to room temperature and stirred for another 16 h. The reaction was monitored by LCMS until completion. The reaction solution was quenched with saturated ammonium chloride solution (20 mL), diluted with ethyl acetate (50 mL), the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound INT-87a (530 mg, 99% yield). ESI-MS (m / z): 244.4 [M+H] + .

[0617] Step 2: Compound INT-87a (530 mg, 2.18 mmol) was dissolved in dichloromethane (4 mL), and TFA (2 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain compound INT-87 (311 mg, 99% yield). ESI-MS (m / z): 144.5 [M+H] + .

[0618] Intermediate INT-88

[0619] Synthesis steps:

[0620] Step 1: Methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (500 mg, 1.94 mmol) was dissolved in dichloromethane (5 mL), and 4 M dioxane hydrochloride (2.5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to give compound INT-88 (305 mg, 99% yield). ESI-MS (m / z): 157.1 [M+H] + .

[0621] Intermediate INT-89

[0622] The preparation method of intermediate INT-89 is the same as that of intermediate INT-87. Methyl trans-3-(tert-butoxycarbonylamino)cyclobutane carboxylate is substituted for methyl cis-3-(tert-butoxycarbonylamino)cyclobutane carboxylate, and intermediate INT-89 is obtained by following similar methods and steps. ESI-MS (m / z): 144.2 [M+H] + .

[0623] Intermediate INT-90

[0624] Synthesis steps:

[0625] Step 1: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (337.0 mg, 1.0 mmol), vinyl borate (308.0 mg, 2.0 mmol), and cesium carbonate (975.0 mg, 3.0 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), and Pd(dppf)Cl2 (73.1 mg, 0.1 mmol) was added. The reaction mixture was stirred at 80 °C for 6 hours. The reaction was monitored by LCMS until completion. The reaction mixture was cooled to room temperature, and 30 mL of ethyl acetate and 10 mL of water were added. The organic phase was concentrated, and the residue was purified by silica gel column chromatography to give a yellow oily compound INT-90a (200.20 mg, 70% yield). ESI-MS (m / z): 286.2 [M+H] + .

[0626] Step 2: Compound INT-90a (200.0 mg, 0.70 mmol) was dissolved in THF (6 mL) and water (2 mL). Sodium periodate (600.0 mg, 2.80 mmol) and potassium osmium tetroxide dihydrate (26.0 mg, 0.07 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours, and the reaction was monitored by LCMS until completion. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily compound INT-90b (157.0 mg, yield 78%). ESI-MS (m / z): 288.1 [M+H] + .

[0627] Step 3: Dissolve INT-90b (150.0 mg, 0.52 mmol) and tert-butyl 4-piperidincarnate (97.0 mg, 0.52 mmol) in dichloromethane (4 mL) and stir at room temperature for 1 hour. Then add sodium triacetoxyborohydride (550.0 mg, 2.60 mmol). Stir the reaction mixture at room temperature overnight. Monitor the reaction end by LCMS. Add water (25 mL) to the reaction mixture and extract with ethyl acetate (30 mL * 3). Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain a yellow oily compound INT-90c (107.0 mg, yield 45%). ESI-MS (m / z): 457.3 [M+H] + .

[0628] Step 4: Dissolve INT-90c (105.0 mg, 0.23 mmol) in dichloromethane (6 mL) and add trifluoroacetic acid (1 mL). Stir the reaction mixture at 50 °C for 1 hour. Monitor the reaction completion by LCMS. Concentrate the reaction mixture directly, and purify the residue by preparative liquid chromatography to obtain a white solid compound INT-90 (58.0 mg, yield 63%). ESI-MS (m / z): 401.2 [M+H] + .

[0629] Intermediate INT-91

[0630] Synthesis steps:

[0631] Step 1: Compound INT-90b (100.0 mg, 0.35 mmol) and sodium dihydrogen phosphate (209.0 mg, 1.74 mmol) were dissolved in acetonitrile (3 mL). 30% hydrogen peroxide (80.0 mg, 0.70 mmol) was added dropwise at 0 °C, followed by an aqueous solution of sodium chlorite (220 mg, 2.45 mmol) (3 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness, and the residue was purified by preparative liquid chromatography to obtain a white solid compound INT-91a (38.0 mg, yield 36%). ESI-MS (m / z): 304.1 [M+H] + .

[0632] Step 2: Compound INT-91a (38.0 mg, 0.12 mmol) and tert-butyl 4-piperidinecarboxylate (23.0 mg, 0.12 mmol) were dissolved in DMF (2 mL). DIPEA (49.0 mg, 0.38 mmol) and HAUT (47.0 mg, 0.12 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain a yellow oily compound INT-91b (37.0 mg, yield 64%). ESI-MS (m / z): 471.2 [M+H] + .

[0633] Step 3: Dissolve INT-91b (37.0 mg, 0.08 mmol) in dichloromethane (2 mL) and add trifluoroacetic acid (0.5 mL). Stir the reaction mixture at 50 °C for 1 hour. Monitor the reaction completion by LCMS. Concentrate the reaction mixture directly, and purify the residue by preparative liquid chromatography to obtain a white solid compound INT-91 (24.0 mg, yield 74%). ESI-MS (m / z): 415.6 [M+H] + .

[0634] Intermediate INT-92

[0635] The preparation method of intermediate INT-92 is the same as that of intermediate INT-29, except that INT-2d is replaced with INT-55b and L-alanine propyl ester is replaced with L-alanine isopropyl ester. Following similar methods and steps, intermediate INT-92 can be obtained. ESI-MS (m / z): 480.0 [M+NH4] + ;

[0636] Intermediate INT-93

[0637] Synthesis steps:

[0638] Step 1: 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (700 mg, 2.17 mmol) was dissolved in DMF (4 mL). Cesium carbonate (1.41 g, 4.33 mmol) and PMB-Cl (508 mg, 3.25 mmol) were added at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography to give compound INT-93a (660 mg, 68% yield). ESI-MS (m / z): 444.3 [M+H] + .

[0639] Step 2: Compound INT-93a (200 mg, 0.45 mmol), trans-4-aminocyclohexylcarboxylate tert-butyl hydrochloride (174 mg, 0.90 mmol), Pd-PEPPSI-iPentCl (44 mg, 45.1 μmol), and cesium carbonate (735 mg, 2.26 mmol) were dissolved in dioxane (10 mL). The reaction mixture was purged under nitrogen protection and stirred overnight at 100 °C. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated, and the residue was purified by rapid column chromatography to obtain compound INT-93b (160 mg, yield 68%). ESI-MS (m / z): 520.2 [M+H] + .

[0640] Step 3: Compound INT-93b (150 mg, 0.29 mmol) and formaldehyde (117 mg, 1.44 mmol) were dissolved in 1,2-dichloroethane (4 mL) and methanol (4 mL), and acetic acid (34.6 mg, 0.58 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then sodium borohydride acetate (183.5 mg, 0.87 mmol) was added, and the reaction was heated to 50 °C and allowed to proceed overnight. After the reaction was complete, 2 mL of water was added to quench the reaction. The reaction mixture was extracted with dichloromethane (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography to obtain compound INT-93c (110 mg, yield 71%). ESI-MS (m / z): 534.1 [M+H] + .

[0641] Step 4: Compound INT-93c (110 mg, 0.2 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL). Lithium hydroxide (17.3 mg, 0.4 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 3-4 with 4 M hydrochloric acid, and extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-93d (93 mg, yield 86%). ESI-MS (m / z): 538.2 [M + NH4] + .

[0642] Step 5: Dissolve compound INT-93d (20 mg, 38 μmol) in trifluoroacetic acid (1 mL), add trifluoromethanesulfonic acid (0.5 mg, 3.8 μmol) at 0 °C, and stir the reaction mixture at 60 °C for 4 hours. After the reaction is complete, concentrate the reaction solution and evaporate to dryness to obtain a yellow oily compound INT-93, which can be used directly in the next step. ESI-MS (m / z): 400.2 [M+H] + .

[0643] Intermediate INT-94

[0644] Synthesis steps:

[0645] Step 1: 7-Bromo-3-iodo-1-methyl-1H-indazole (370 mg, 1.1 mmol), 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (458 mg, 1.1 mmol), PdCl2 (dppf) (80.4 mg, 0.11 mmol), and cesium carbonate (715 mg, 2.2 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL). After purging with nitrogen three times, the reaction mixture was stirred overnight at 90 °C. After the reaction was complete, 5 mL of water was added and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to give compound INT-94a (200 mg, 36% yield). ESI-MS (m / z): 500.7 [M+H] + .

[0646] Step 2: Compound INT-94a (180 mg, 0.36 mmol), trans-4-aminocyclohexylcarboxylate tert-butyl hydrochloride (140 mg, 0.72 mmol), Pd-PEPPSI-iPentCl (35 mg, 36 μmol), and cesium carbonate (586 mg, 1.8 mmol) were dissolved in dioxane (5 mL). The reaction mixture was stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated, and the residue was purified by rapid column chromatography to obtain compound INT-94b (85 mg, 40% yield). ESI-MS (m / z): 577.2 [M+H] + .

[0647] Step 3: Compound INT-94b (85 mg, 0.15 mmol) and formaldehyde (60 mg, 0.75 mmol) were dissolved in 1,2-dichloroethane (3 mL) and methanol (3 mL), and acetic acid (17.7 mg, 0.3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then sodium borohydride acetate (93.7 mg, 0.44 mmol) was added, and the reaction was heated to 50 °C and allowed to proceed overnight. After the reaction was complete, 2 mL of water was added to quench the reaction. The reaction mixture was extracted with dichloromethane (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography to obtain compound INT-94c (40 mg, 45% yield). ESI-MS (m / z): 592.0 [M+H] + .

[0648] Step 4: Compound INT-94c (40 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.5 mL). Lithium hydroxide (5.7 mg, 0.12 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 3-4 with 4 M hydrochloric acid, and extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound INT-94d (39 mg, 99% yield). ESI-MS (m / z): 577.3 [M+H] + .

[0649] Step 5: Compound INT-94d (40 mg, 0.06 mmol) was dissolved in ethyl acetate (2 mL) and methanol (2 mL), and palladium hydroxide (29.2 mg, 0.2 mmol, 10% on carbon) was added. The system was purged with hydrogen and reacted overnight at 40 °C. After the reaction was complete, the reaction solution was filtered through diatomaceous earth and washed with ethyl acetate (5 mL * 3). The solution was concentrated and evaporated to dryness to give a pale yellow oily compound INT-94 (27 mg, 99% yield). ESI-MS (m / z): 399.8 [M+H] + .

[0650] Intermediate INT-95

[0651] Synthesis steps:

[0652] Step 1: Dissolve NaH (1.32 g, 33.0 mmol, 60% w / w) in THF (30 mL), place in an ice-water bath, and then add ethyl 5-methylindole-2-carboxylate (3.0 g, 14.76 mmol) in portions. Stir the mixture at 0°C for half an hour, then add di-tert-butyl dicarbonate (4.86 g, 22.27 mmol). Continue stirring at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-95a (4.4 g, 98% yield). ESI-MS (m / z): 304.2 [M+H] + .

[0653] Step 2: INT-95a (4.4 g, 14.50 mmol) was dissolved in carbon tetrachloride (20 mL), and N-bromosuccinimide (2.58 g, 14.50 mmol) and benzoyl peroxide (175.67 mg, 725.23 μmol) were added sequentially. The mixture was stirred at 80 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered through diatomaceous earth, washed with dichloromethane, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-95b (4.2 g, yield 69%). ESI-MS (m / z): 384.6 [M+H] + .

[0654] Step 3: Dissolve INT-95b (4.2 g, 10.00 mmol) in triethyl phosphite (2.08 mL) and stir at 100 °C for 3 hours. The reaction was monitored by LCMS until completion. The reaction solution was diluted with dichloromethane, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-95c (4.2 g, yield 76%). ESI-MS (m / z): 440.5 [M+H] + .

[0655] Step 4: Dissolve INT-95c (4.2 g, 9.56 mmol) in benzyl alcohol (10 mL), add tetraisopropyl titanate (2.84 mL, 9.56 mmol), and stir the mixture at 100 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was quenched with dilute hydrochloric acid (1 M, 10 mL), extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-95d (3.5 g, 91% yield). ESI-MS (m / z): 402.7 [M+H] + .

[0656] Step 5: Dissolve NaH (627.82 mg, 26.16 mmol, 60% w / w) in THF (20 mL), place in an ice-water bath, and add compound INT-95d (3.5 g, 8.72 mmol) in portions. Stir the system at 0 °C for 10 minutes, then add benzyl chloroformate (2.23 g, 13.08 mmol). Continue stirring at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-95e (2.4 g, 51% yield). ESI-MS (m / z): 536.6 [M+H] + .

[0657] Step 6: Compound INT-95e (2.4 g, 3.59 mmol) and N-fluorobis(benzenesulfonamide) (3.39 g, 10.76 mmol) were dissolved in THF (20 mL). After cooling to -78 °C, NaHMDS (1 M, 10.76 mL) was added dropwise. The mixture was stirred at -78 °C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound INT-95f (2.0 g, 78% yield). ESI-MS (m / z): 572.5 [M+H] + .

[0658] Step 7: Compound INT-95f (2.0 g, 3.50 mmol) was dissolved in tetrahydrofuran (10 mL), and Pd / C (200 mg, 1.88 mmol) was added. The reaction system was purged with hydrogen gas, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to obtain compound INT-95g (1.2 g, 98% yield). ESI-MS (m / z): 348.1 [M+H] + .

[0659] Step 8: Compound INT-95 g (1.2 g, 3.46 mmol) was dissolved in tetrahydrofuran (10 mL). Pentafluorophenol (763.3 mg, 4.15 mmol) and DCC (1.07 g, 5.18 mmol) were added at room temperature, and the mixture was stirred for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 70) to give compound INT-95 h (642.0 mg, yield 36%). ESI-MS (m / z): 531.9 [M + NH4] + .

[0660] Step 9: Compound INT-95h (100 mg, 0.19 mmol) was dissolved in DCM (4 mL). After being placed in an ice-water bath, BSTFA (200.6 mg, 1.17 mmol) and TMSI (194.8 mg, 0.98 mmol) were added under nitrogen protection. The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound INT-95i (42.0 mg, yield 47%). ESI-MS (m / z): 475.0 [M+NH4] + .

[0661] Step 10: Compound INT-95i (42 mg, 91.86 μmol) was dissolved in acetonitrile (3 mL) and water (4.5 mL). Trifluoroacetic acid (1.19 g, 10.45 mmol) was added at room temperature. The mixture was stirred at 60 °C for 48 hours, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation, and the residue was lyophilized to give a white solid compound INT-95 (30.0 mg, yield 75%). ESI-MS (m / z): 453.0 [M+NH4] + .

[0662] Intermediate INT-96

[0663] Synthesis steps:

[0664] Step 1: 3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (200.0 mg, 0.621 mmol) was dissolved in THF (2 mL). Sodium hydride (37.25 mg, 1.55 mmol) and SEM-Cl (124.20 mg, 0.745 mmol) were added at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography to give compound INT-96a (240.0 mg, 85% yield). ESI-MS (m / z): 453.3 [M+H] + .

[0665] Step 2: Compound INT-96a (210 mg, 0.464 mmol), trans-4-aminocyclohexylcarboxylate tert-butyl hydrochloride (185.01 mg, 0.928 mmol), Pd-PEPPSI-iPentCl (45.15 mg, 46.42 μmol), and cesium carbonate (453.71 mg, 1.39 mmol) were dissolved in dioxane (5 mL). The reaction mixture was purged under nitrogen protection and stirred overnight at 100 °C. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated, and the residue was purified by rapid column chromatography to obtain compound INT-96b (80 mg, 30% yield). ESI-MS (m / z): 571.5 [M+H] + .

[0666] Step 3: Compound INT-96b (80 mg, 0.140 mmol) and formaldehyde (21.04 mg, 0.700 mmol) were dissolved in 1,2-dichloroethane (2 mL) and methanol (2 mL), and acetic acid (34.6 mg, 0.58 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then sodium borohydride acetate (89.11 mg, 0.420 mmol) was added, and the reaction was heated to 50 °C and allowed to proceed overnight. After the reaction was complete, 2 mL of water was added to quench the reaction. The reaction mixture was extracted with dichloromethane (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography to obtain compound INT-96c (22 mg, yield 26%). ESI-MS (m / z): 585.5 [M+H] + .

[0667] Step 4: Compound INT-96c (22 mg, 0.038 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1.49 mg, 0.013 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 8 hours. After the reaction was complete, the reaction solution was concentrated and evaporated to dryness to obtain an oily compound INT-96 (12 mg, 80% yield). This compound was used directly in the next reaction without purification. ESI-MS (m / z): 399.4 [M+H] + .

[0668] Intermediate INT-97

[0669] Synthesis steps:

[0670] Step 1: Dissolve (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (219 mg, 1.0 mmol) and DIPEA (258.0 mg, 2.0 mmol) in DMF (5 mL), and add p-toluenesulfonyl chloride (229.0 mg, 1.20 mmol). Stir the reaction mixture at 50 °C for 3 hours. Monitor the reaction completion by LCMS. Cool the reaction mixture to room temperature, quench with water, extract with ethyl acetate, concentrate the organic phase, and purify the residue by silica gel column chromatography to obtain a yellow oily compound INT-97a (290.90 mg, yield 78%). ESI-MS (m / z): 374.2 [M+H] + .

[0671] Step 2: Compound INT-97a (290.0 mg, 0.77 mmol) was dissolved in DMF (5 mL), and INT-83b (352.0 g, 0.77 mmol) and cesium carbonate (505.0 g, 1.55 mmol) were added. The reaction mixture was stirred at 50 °C for 5 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was cooled to room temperature and poured into water (40 mL). It was extracted with ethyl acetate (40 mL * 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give a yellow solid compound INT-97b (346.0 mg, yield 68%). ESI-MS (m / z): 655.1 [M + H] + .

[0672] Step 3: Dissolve INT-97b (345.0 mg, 0.53 mmol) in methanol (5 mL) and ethyl acetate (5 mL), then add palladium hydroxide / carbon (70.0 mg). Stir the reaction mixture overnight at room temperature. Monitor the reaction completion by LCMS. Filter the reaction mixture, and concentrate the filtrate to obtain a pale yellow oily compound INT-97c (200.0 mg, yield 80%). ESI-MS (m / z): 477.2 [M+H] + .

[0673] Step 4: Dissolve INT-97c (200.0 mg, 0.42 mmol) in dichloromethane (5 mL) and add trifluoroacetic acid (1 mL). Stir the reaction mixture at room temperature for 1 hour. Monitor the reaction completion by LCMS. Concentrate the reaction mixture directly to obtain a pale yellow oily compound INT-97d (150.0 mg, 95% yield). ESI-MS (m / z): 377.4 [M+H] + .

[0674] Step 5: Dissolve INT-97d (150.0 mg, 0.39 mmol) in dichloromethane (5 mL), add DIPEA (154.0 mg, 1.19 mmol) and triphosgene (41.0 mg, 0.14 mmol). Stir the reaction mixture at room temperature for 1 hour, then add INT-22 (192.0 mg, 0.39 mmol), and continue stirring at room temperature for another hour. The reaction was monitored by LCMS until completion. The reaction mixture was directly concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 9 / 1) to give a yellow solid compound INT-97 (116.0 mg, two-step yield 33%). ESI-MS (m / z): 885.1 [M+H] + .

[0675] Example 1

[0676] Synthesis steps:

[0677] Step 1: Compound 1a (2.0 g, 5.86 mmol) was dissolved in water (10 mL) and tetrahydrofuran (10 mL). Lithium hydroxide monohydrate (370 mg, 8.81 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved in water (30 mL). The pH was adjusted to 7-8 with 4M hydrochloric acid. 1,4-Dioxane (30 mL), sodium bicarbonate (985 mg, 11.72 mmol), and Fmoc-OSU (2.96 g, 8.78 mmol) were added to the reaction system, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 1b (2.60 g, yield 81%). ESI-MS (m / z): 550.7 [M+H] + .

[0678] Step 2: Compound 1b (2.60 g, 4.73 mmol) and INT-1 (810.50 mg, 4.73 mmol) were dissolved in DMF (25 mL), and DIPEA (2.47 mL, 14.20 mmol) and HATU (1.80 g, 4.73 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (100 mL), extracted with dichloromethane (100 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 1c (2.39 g, yield 72%). ESI-MS (m / z): 704.2 [M+H] + .

[0679] Step 3: Compound 1c (2.39 g, 3.40 mmol) was dissolved in DCM (30 mL), and diethylamine (30 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give compound 1d (1.31 g, 80% yield). ESI-MS (m / z): 482.5 [M+H] + .

[0680] Step 4: Compound 1d (1.31 g, 2.72 mmol) and INT-5 (1.04 g, 2.72 mmol) were dissolved in DMF (15 mL), and DIPEA (1.42 mL, 8.17 mmol) and HATU (1.03 g, 2.72 mmol) were added, respectively. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (80 mL), extracted with ethyl acetate (80 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 1e (1.17 g, yield 51%). ESI-MS (m / z): 846.5 [M + H] + .

[0681] Step 5: Compound 1e (1.17 g, 1.38 mmol) was dissolved in dichloromethane (15 mL), and TFA (5 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to give compound 1f (928.0 mg, 90% yield). ESI-MS (m / z): 746.3 [M+H] + .

[0682] Step 6: Compound 1f (50.0 mg, 0.07 mmol) and INT-6 (24.0 mg, 0.07 mmol) were dissolved in DMF (2 mL), and DIPEA (28.0 mg, 0.21 mmol) and HATU (27.0 mg, 0.07 mmol) were added respectively. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (15 mL), extracted with ethyl acetate (15 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give 1 g of compound (32.70 mg, yield 45%). ESI-MS (m / z): 1086.1 [M + H] + .

[0683] Step 7: Dissolve 1 g (32.70 mg, 0.03 mmol) of compound in DCM (3 mL), place in an ice-water bath, and then add BSTFA (46.50 mg, 0.18 mmol) and TMSI (30.0 mg, 0.15 mmol) under nitrogen protection. Stir at 0°C for half an hour, and monitor the reaction for completion using LCMS. Remove the organic solvent by rotary evaporation, and purify the residue by preparative liquid chromatography to obtain compound 1 (19.70 mg, yield 65%). ESI-MS (m / z): 1047.6 [M+NH4] + .

[0684] 1 H NMR(500MHz,DMSO-d6)δ11.02(s,1H),8.64–8.44(m,2H),8.18(s,1H),8.05–7.88(m,3H),7.82–7.75(m,1H),7.73–7.60(m,2H),7.51–7.29(m, 6H),5.16–4.97(m,2H),4.64–4.23(m,6H),4.10–3.87(m,8H),2.95–2.8 1(m,1H),2.65–2.55(m,2H),2.38(d,J=2.7Hz,3H),2.13–1.42(m,14H).

[0685] Example 2

[0686] Synthesis steps:

[0687] Step 1: Compound 1c (370 mg, 0.52 mmol) was dissolved in DCM (5 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to give compound 2a (310 mg, 98% yield). ESI-MS (m / z): 604.3 [M+H] + .

[0688] Step 2: Compound 2a (310 mg, 0.51 mmol) and intermediate INT-2 (187.07 mg, 0.51 mmol) were dissolved in DMF (4 mL), and DIPEA (199.09 mg, 1.54 mmol) and HATU (292.87 mg, 0.77 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 2b (436 mg, yield 89%). ESI-MS (m / z): 950.5 [M + H] + .

[0689] Step 3: Compound 2b (436 mg, 0.46 mmol) was dissolved in DMF (4 mL), and diethylamine (100.70 mg, 1.38 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 2c (120 mg, yield 36%). ESI-MS (m / z): 728.7 [M + H] + .

[0690] Step 4: Compound 2c (20 mg, 0.027 mmol) and intermediate INT-10 (13.86 mg, 0.030 mmol) were dissolved in DMF (4 mL), and DIPEA (10.66 mg, 0.083 mmol) and HATU (15.67 mg, 0.082 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 2d (28 mg, yield 87%). ESI-MS (m / z): 1169.5 [M + H] + .

[0691] Step 5: Compound 2d (28 mg, 0.024 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (37.02 mg, 0.144 mmol) and TMSI (23.98 mg, 0.120 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 2 (12.5 mg, yield 47%). ESI-MS (m / z): 1129.5 [M+NH4] + .

[0692] 1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.32–8.21(m,1H),8.09–8.01(m,1H),7.97(d,1H),7.86–7.75( m,1H),7.66–7.60(m,1H),7.48–7.43(m,2H),7.43–7.35(m,4H),7.35–7.29(m,2H),7.23–7.17(m,2H), 5.12–4.77(m,2H),4.71–4.50(m,1H),4.35–4.06(m,4H),4.02–3.77(m,3H),3.73–3.50(m,4H),2.89–2 .82(m,1H),2.62–2.54(m,1H),2.02(s,3H),1.88–1.66(m,8H),1.60–1.36(m,5H),1.35–1.19(m,12H).

[0693] Example 3

[0694] Synthesis steps:

[0695] Step 1: Compound 2c (20 mg, 0.027 mmol) and intermediate INT-11 (11.32 mg, 0.030 mmol) were dissolved in DMF (4 mL), and DIPEA (10.66 mg, 0.083 mmol) and HATU (15.67 mg, 0.082 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 3a (26 mg, yield 87%). ESI-MS (m / z): 1085.5 [M + H] + .

[0696] Step 2: Compound 3a (26 mg, 0.024 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (37.04 mg, 0.144 mmol) and TMSI (23.99 mg, 0.120 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 3 (6.6 mg, yield 27%). ESI-MS (m / z): 1045.6 [M+NH4] + .

[0697] 1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.32–8.21(m,1H),8.09–8.01(m,1H),7.97(d,1H),7.86–7.75(m ,1H),7.66–7.60(m,1H),7.48–7.43(m,2H),7.43–7.35(m,4H),7.35–7.29(m,2H),7.23–7.17(m,2H),5. 16–5.07(m,1H),5.04–4.82(m,1H),4.66–4.54(m,1H),4.36–4.14(m,4H),4.12–3.87(m,3H),3.86–3.60 (m,5H),3.57–3.48(m,3H),2.90–2.82(m,1H),2.67–2.56(m,2H),2.09–1.96(m,3H),1.86–1.70(m,8H).

[0698] Example 4

[0699] Synthesis steps:

[0700] Step 1: Compound INT-12 (100 mg, 0.29 mmol) and tert-butyl bromoacetate (56.98 mg, 0.29 mmol) were dissolved in DCM (4 mL), and DIPEA (114.56 mg, 0.89 mmol) was added. The mixture was stirred at room temperature for 18 hours, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 4a (103 mg, yield 77%). ESI-MS (m / z): 457.5 [M + H] + .

[0701] Step 2: Compound 4a (103 mg, 0.23 mmol) was dissolved in DCM (4 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound 4b (90 mg, 99% yield). ESI-MS (m / z): 401.5 [M+H] + .

[0702] Step 3: Compounds 4b (20 mg, 0.027 mmol) and 2c (15.52 mg, 0.030 mmol) were dissolved in DMF (4 mL), and DIPEA (10.66 mg, 0.083 mmol) and HATU (15.67 mg, 0.082 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 4c (25 mg, yield 82%). ESI-MS (m / z): 1111.5 [M + H] + .

[0703] Step 4: Compound 4c (25 mg, 0.023 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (34.78 mg, 0.135 mmol) and TMSI (22.53 mg, 0.113 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 4 (10.5 mg, yield 44%). ESI-MS (m / z): 1071.6 [M+NH4] + .

[0704] 1 H NMR (500MHz, DMSO-d6) δ11.10(d,J=5.5Hz,1H),8.29(d,J=9.6Hz,1H),8.07(d,J=13.3Hz,1H ),7.98(d,J=8.5Hz,1H),7.63(d,J=9.0Hz,2H),7.49–6.87(m,10H),5.14–4.84(m,2H),4.67– 4.54(m,1H),4.39–4.07(m,3H),4.06–3.88(m,2H),3.88–3.76(m,2H),3.76–3.55(m,4H),3. 55–3.44(m,5H),2.97–2.77(m,2H),2.65–2.53(m,3H),2.44–2.27(m,2H),2.22–1.49(m,8H).

[0705] Example 5

[0706] Synthesis steps:

[0707] Step 1: Compound INT-13 (100 mg, 0.26 mmol) and tert-butyl bromoacetate (51.01 mg, 0.26 mmol) were dissolved in DCM (4 mL), and DIPEA (102.55 mg, 0.79 mmol) was added. The mixture was stirred at room temperature for 18 hours, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 5a (76 mg, yield 59%). ESI-MS (m / z): 497.5 [M + H] + .

[0708] Step 2: Compound 5a (76 mg, 0.15 mmol) was dissolved in DCM (4 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound 5b (67 mg, 99% yield). ESI-MS (m / z): 441.5 [M+H] + .

[0709] Step 3: Compounds 2c (20 mg, 0.027 mmol) and 5b (13.31 mg, 0.030 mmol) were dissolved in DMF (4 mL), and DIPEA (10.66 mg, 0.083 mmol) and HATU (15.67 mg, 0.082 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 5c (29 mg, yield 92%). ESI-MS (m / z): 1111.5 [M + H] + .

[0710] Step 4: Compound 5c (29 mg, 0.025 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (39.94 mg, 0.151 mmol) and TMSI (25.22 mg, 0.126 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 5 (14 mg, yield 51%). ESI-MS (m / z): 1111.5 [M+NH4] + .

[0711] 1H NMR(500MHz,DMSO-d6)δ11.24–11.00(m,1H),8.30–8.12(m,1H),8.11–7.82(m,2H),7.75–7.53(m ,2H),7.45–7.26(m,6H),7.22–7.04(m,4H),5.26–5.09(m,1H),5.09–5.00(m,1H),4.96–4.55(m,2 H),4.54–4.13(m,3H),4.11–3.82(m,5H),3.82–3.68(m,4H),3.68–3.51(m,7H),2.92–2.84(m,1H ),2.66–2.54(m,1H),2.39–2.14(m,4H),2.03–1.95(m,2H),1.95–1.82(m,3H),1.81–1.45(m,4H).

[0712] Example 6

[0713] Synthesis steps:

[0714] Step 1: Compound INT-12 (150 mg, 0.44 mmol) and N-Boc-piperidine-4-carboxaldehyde (140.17 mg, 0.66 mmol) were dissolved in MeOH (4 mL), and glacial acetic acid (13.16 mg, 0.22 mmol), sodium acetate hexahydrate (107.83 mg, 1.31 mmol), and sodium cyanoborohydride (82.60 mg, 1.31 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 6a (226 mg, 96% yield). ESI-MS (m / z): 540.5 [M + H] + .

[0715] Step 2: Compound 6a (226 mg, 0.15 mmol) was dissolved in DCM (6 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to give compound 6b (184 mg, 99% yield). ESI-MS (m / z): 440.5 [M+H] + .

[0716] Step 3: Compound 6b (184 mg, 0.42 mmol) and tert-butyl bromoacetate (81.66 mg, 0.42 mmol) were dissolved in DCM (4 mL), and DIPEA (164.19 mg, 1.27 mmol) was added. The mixture was stirred at room temperature for 18 hours, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 6c (215 mg, yield 93%). ESI-MS (m / z): 554.5 [M + H] + .

[0717] Step 4: Compound 6c (215 mg, 0.15 mmol) was dissolved in DCM (4 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound 6d (190 mg, 99% yield). ESI-MS (m / z): 498.5 [M+H] + .

[0718] Step 5: Compounds 2c (20 mg, 0.027 mmol) and 6d (15.04 mg, 0.030 mmol) were dissolved in DMF (4 mL), and DIPEA (10.66 mg, 0.083 mmol) and HATU (15.67 mg, 0.082 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 6e (31 mg, yield 93%). ESI-MS (m / z): 1208.5 [M + H] + .

[0719] Step 6: Compound 6e (31 mg, 0.026 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (39.66 mg, 0.154 mmol) and TMSI (25.69 mg, 0.128 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 6 (2.5 mg, yield 8.5%). ESI-MS (m / z): 1168.5 [M+NH4] + .

[0720] 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),8.37–8.22(m,1H),8.07(d,J=15.3 Hz,1H),8.03–7.97(m,1H),7.72–6.96(m,12H),5.39–5.04(m,2H),4.72–4 .18(m,4H),4.14–3.58(m,8H),3.55–3.35(m,3H),2.93–2.83(m,2H),2.65 –2.56(m,2H),2.27–1.95(m,10H),1.92–1.37(m,13H),0.87–0.82(m,1H).

[0721] Example 7

[0722] Step 1: Compound 1f (50.0 mg, 0.07 mmol) and INT-2 (24.50 mg, 0.07 mmol) were dissolved in DMF (2 mL). DIPEA (28.0 mg, 0.21 mmol) and HATU (27.0 mg, 0.07 mmol) were added, respectively. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (15 mL), extracted with ethyl acetate (15 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 7a (38.0 mg, yield 52%). ESI-MS (m / z): 1092.3 [M + H] + .

[0723] Step 2: Compound 7a (38.0 mg, 0.03 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (54.0 mg, 0.21 mmol) and TMSI (35.0 mg, 0.17 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 7 (17.70 mg, yield 49%). ESI-MS (m / z): 1053.0 [M+NH4] + .

[0724] 1H NMR(500MHz,DMSO-d6)δ9.05–8.58(m,1H),8.30–8.21(m,1H),8.07–8.01(m,1H),7 .98–7.89(m,1H),7.74–7.60(m,3H),7.54–7.29(m,6H),5.20–5.09(m,1H),5.03–4 .79(m,1H),4.68–4.55(m,1H),4.51–4.41(m,1H),4.39–4.15(m,3H),4.11–3.44(m ,9H),2.95–2.82(m,1H),2.65–2.54(m,2H),2.42–2.24(m,3H),2.10–1.43(m,14H).

[0725] Example 8

[0726] Compound INT-7 (36.0 mg, 0.06 mmol) was dissolved in DMF (2 mL), and DIPEA (17.0 mg, 0.12 mmol) and HOBt (13.50 mg, 0.10 mmol) were added separately. The mixture was stirred at room temperature for 0.5 hours. Then, compound 1f (50.0 mg, 0.06 mmol) and DIPEA (8.00 mg, 0.06 mmol) were dissolved in DMF (1 mL) and added to the reaction mixture. The mixture was stirred at room temperature for 0.5 hours, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography to give compound 8 (14.80 mg, yield 20%). ESI-MS (m / z): 1161.7 [M + NH4] + .

[0727] 1 H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.88–8.45(m,2H),8.23–8.12(m,1H),8.06–7.91(m,3H),7.82–7.59(m,3H),7.56–7.29(m,6H),5.42(d,J =10.8Hz,2H),5.20–4.98(m,2H),4.69–3.43(m,14H),2.94–2.83(m,1H) ,2.66–2.56(m,2H),2.41–2.23(m,3H),2.07–1.41(m,14H),1.14(s,9H).

[0728] Example 9

[0729] Synthesis steps:

[0730] Step 1: Compound 2c (31 mg, 0.043 mmol) and INT-14 (19.37 mg, 0.047 mmol) were dissolved in DMF (4 mL), and DIPEA (16.52 mg, 0.128 mmol) and HATU (24.29 mg, 0.064 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 9a (20 mg, yield 42%). ESI-MS (m / z): 1124.5 [M + H] + .

[0731] Step 2: Compound 9a (20 mg, 0.024 mmol) was dissolved in DCM (3 mL). After being placed in an ice-water bath, BSTFA (27.5 mg, 0.107 mmol) and TMSI (17.81 mg, 0.089 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution. The residue was purified by preparative liquid chromatography to obtain compound 9 (3 mg, yield 16%). ESI-MS (m / z): 1084.5 [M+NH4] + .

[0732] Example 10

[0733] Compound 1f (50.0 mg, 0.07 mmol) and INT-9 (36.0 mg, 0.07 mmol) were dissolved in DMF (2 mL), and DIPEA (28.0 mg, 0.21 mmol) and HATU (27.0 mg, 0.07 mmol) were added, respectively. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (15 mL), extracted with ethyl acetate (15 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography to give compound 10 (26.0 mg, yield 31%). ESI-MS (m / z): 1281.8 [M + NH4] + .

[0734] 1H NMR(500MHz,DMSO-d6)δ11.00(s,1H),9.16–8.60(m,1H),8.41–7.96(m,3H),7.75–7.30(m,9H),5.79–5.39(m,4H),5.18–5.09(m,1H),5.04–4.79 (m,1H),4.71–4.20(m,5H),4.12–3.51(m,9H),2.93–2.87(m,1H),2.64– 2.56(m,2H),2.42–2.23(m,3H),2.06–1.46(m,14H),1.18–1.09(m,18H).

[0735] Example 11

[0736] Compound INT-8 (44.0 mg, 0.06 mmol) was dissolved in DMF (2 mL), and DIPEA (17.0 mg, 0.13 mmol) and HOBt (13.50 mg, 0.10 mmol) were added separately. The mixture was stirred at room temperature for 0.5 hours. Then, compound 1f (50.0 mg, 0.06 mmol) and DIPEA (8.00 mg, 0.06 mmol) were dissolved in DMF (1 mL) and added to the reaction mixture. The mixture was stirred at room temperature for another 0.5 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 11 (25.30 mg, 30% yield). ESI-MS (m / z): 1275.8 [M + NH4] + .

[0737] 1 H NMR(500MHz,DMSO-d6)δ11.04–10.94(m,1H),8.87–8.47(m,2H),8.43–8.2 6(m,1H),8.22–7.93(m,3H),7.80–7.58(m,3H),7.54–7.30(m,6H),5.80–5 .37(m,4H),5.19–4.85(m,2H),4.70–3.46(m,14H),2.97–2.84(m,1H),2.6 8–2.53(m,2H),2.46–2.27(m,3H),2.09–1.43(m,14H),1.19–1.06(m,18H).

[0738] Example 12

[0739] Synthesis steps:

[0740] Step 1: Compound 2c (14 mg, 0.019 mmol) and INT-15 (8.20 mg, 0.021 mmol) were dissolved in DMF (2 mL), and DIPEA (7.46 mg, 0.058 mmol) and HATU (10.97 mg, 0.029 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 12a (3 mg, yield 14%). ESI-MS (m / z): 1097.5 [M + H] + .

[0741] Step 2: Compound 12a (6 mg, 0.006 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (8.5 mg, 0.033 mmol) and TMSI (5.47 mg, 0.027 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 12 (2.5 mg, yield 44%). ESI-MS (m / z): 1058.5 [M+NH4] + .

[0742] 1 H NMR (500MHz, DMSO-d6) δ11.13–10.47(m,2H),8.38–8.25(m,1H),8.13–7.96(m,2H),7.64(d,J=7.7Hz, 1H),7.54–7.44(m,1H),7.33–7.22(m,5H),7.07(d,J=7.9Hz,3H),7.00–6.97(m,1H),5.99(dd,J=7.7,2 .6Hz,1H),5.35(d,J=2.6Hz,2H),4.67–4.28(m,1H),4.06–4.04(m,1H),3.92–3.71(m,6H),2.93–2.89( m,2H),2.78–2.69(m,5H),1.89–1.72(m,7H),1.66–1.61(m,3H),1.25–1.14(m,8H),1.13–1.07(m,3H).

[0743] Example 13

[0744] Synthesis steps:

[0745] Step 1: Compound 2c (14 mg, 0.019 mmol) and intermediate INT-16 (11.16 mg, 0.022 mmol) were dissolved in DMF (2 mL), and DIPEA (7.46 mg, 0.058 mmol) and HATU (10.97 mg, 0.029 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 13a (3 mg, yield 14%). ESI-MS (m / z): 1125.5 [M + H] + .

[0746] Step 2: Compound 13a (6 mg, 0.005 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (8.24 mg, 0.032 mmol) and TMSI (5.34 mg, 0.027 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 13 (4.5 mg, yield 79%). ESI-MS (m / z): 1085.1 [M+NH4] + .

[0747] 1 H NMR(500MHz,DMSO-d6)δ11.13–10.47(m,1H),8.32–8.26(m,1H),8.13–7.96(m,2H),7.7 8–7.39(m,3H),7.37–7.18(m,6H),7.11–6.95(m,3H),6.03–5.96(m,1H),5.38–5.30(m,2 H),4.67–4.28(m,1H),4.08–4.02(m,1H),3.82–3.75(m,4H),2.95–2.90(m,2H),2.78–2 .69(m,8H),1.89–1.72(m,7H),1.66–1.61(m,3H),1.25–1.14(m,8H),1.13–1.07(m,3H).

[0748] Example 14

[0749] Synthesis steps:

[0750] Step 1: Compound 1d (33 mg, 0.056 mmol) and intermediate INT-14 (25.24 mg, 0.061 mmol) were dissolved in THF (1 mL) and ACN (1 mL), and NMI (22.78 mg, 0.278 mmol) and TCFH (23.36 mg, 0.083 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 14a (13 mg, yield 27%). ESI-MS (m / z): 877.6 [M + H] + .

[0751] Step 2: Compound 14a (13 mg, 0.015 mmol) was dissolved in DCM (3 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain compound 14b (11 mg, 96% yield). ESI-MS (m / z): 777.8 [M+H] + .

[0752] Step 3: Compound 14b (11 mg, 0.014 mmol) and intermediate INT-9 (7.60 mg, 0.014 mmol) were dissolved in DMF (1 mL), and DIPEA (5.49 mg, 0.043 mmol) and HATU (8.08 mg, 0.021 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative liquid chromatography to obtain compound 14 (0.49 mg, yield 3%). ESI-MS (m / z): 1312.5 [M + NH4] + .

[0753] Example 15

[0754] Synthesis steps:

[0755] Step 1: Compound 2c (15 mg, 0.021 mmol) and intermediate INT-17 (9.08 mg, 0.023 mmol) were dissolved in THF (1 mL) and ACN (1 mL), and NMI (8.46 mg, 0.103 mmol) and TCFH (8.679 mg, 0.031 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 15a (21 mg, 92% yield). ESI-MS (m / z): 1111.6 [M + H] + .

[0756] Step 2: Compound 15a (21 mg, 0.019 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (29.21 mg, 0.114 mmol) and TMSI (18.92 mg, 0.095 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 15 (9.5 mg, yield 48%). ESI-MS (m / z): 1071.5 [M+NH4] + .

[0757] 1 H NMR(500MHz,DMSO-d6)δ9.13–8.65(m,1H),8.26(q,J=8.0,7.6Hz,1H),8.08–7.93(m,2H),7.64 (d,J=8.3Hz,1H),7.51–7.16(m,5H),7.00–6.81(m,3H),5.08–4.76(m,1H),4.74–4.50(m,1H),4 .33–4.08(m,2H),4.04–3.88(m,2H),3.86–3.66(m,4H),3.66–3.58(m,5H),3.57–3.51(m,3H), 2.92–2.78(m,2H),2.77–2.66(m,3H),2.06–1.69(m,8H),1.54–1.42(m,2H),1.03–0.98(m,5H).

[0758] Example 16

[0759] Synthesis steps:

[0760] Step 1: Compound 2c (15 mg, 0.021 mmol) and intermediate INT-18 (12.38 mg, 0.031 mmol) were dissolved in THF (1 mL) and ACN (1 mL), and NMI (8.46 mg, 0.103 mmol) and TCFH (8.679 mg, 0.031 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 16a (20 mg, yield 87%). ESI-MS (m / z): 1111.6 [M + H] + .

[0761] Step 2: Compound 16a (20 mg, 0.018 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (27.82 mg, 0.108 mmol) and TMSI (18.02 mg, 0.090 mmol) were added under nitrogen protection. The mixture was stirred at 0°C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 16 (10.5 mg, yield 55%). ESI-MS (m / z): 1071.3 [M+NH4] + .

[0762] 1 H NMR(500MHz,DMSO-d6)δ9.07–8.61(m,1H),8.32–8.21(m,1H),8.07–7.94(m,4H),7.69–7.19(m,7H),6.98–6.77(m,2H),6.67–6.56(m,1H ),5.39–4.76(m,2H),4.73–4.18(m,9H),4.15–3.86(m,4H),3.86–3.66(m,6H),2.69–2.61(m,5H),2.05–1.89(m,4H),1.89–1.70(m,7H).

[0763] Example 17 & Example 18

[0764] INT-1e was resolved by SFC, and compound 17 was obtained by using the isomer with the shorter retention time, following the preparation methods for compounds INT-1, 1d, and 14. ESI-MS (m / z): 1311.9 [M+NH4] + .

[0765] 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.71(s,1H),8.44–7.98(m,3H),7.63(d,J=8.6Hz,1H),7.43(dd,J=17. 2,7.0Hz,5H),6.98(s,2H),6.82(s,1H),5.92–5.66(m,2H),5.42(dd,J=11.0,2.5Hz,1H),5.32(t,J=4.9Hz,2H ),4.97(s,1H),4.59(s,1H),4.15(d,J=42.3Hz,2H),3.94(s,2H),3.87–3.36(m,6H),3.29(s,4H),2.89(s,1H ),2.65(dd,J=38.3,12.9Hz,4H),2.03–1.94(m,5H),1.45(d,J=10.1Hz,5H),1.18–1.11(m,18H),0.96(s,2H).

[0766] INT-1e was resolved by SFC, and compound 18 was obtained by using the isomer with the longer retention time, following the preparation methods for compounds INT-1, 1d, and 14. ESI-MS (m / z): 1312.6 [M+NH4] + .

[0767] 1 H NMR(500MHz,DMSO-d6)δ11.08(s,1H),8.76(d,J=16.0Hz,1H),8.43–8.01(m,3H),7.60(dd,J=27.4,8.4Hz,1H),7.50–7.30(m,5H), 6.98(d,J=6.4Hz,2H),6.83(dd,J=13.1,6.2Hz,1H),5.71(dq,J=12.5,5.5Hz,3H),5.50–5.24(m,2H),4.99(s,1H),4.71–4.61(m,1H ),4.41–4.14(m,2H),3.93(d,J=11.5Hz,2H),3.72(dt,J=20.8,8.2Hz,4H),3.35–3.28(m,4H),2.89(t,J=13.6Hz,1H),2.65(dd,J= 40.1,13.2Hz,4H),2.32(d,J=26.2Hz,2H),2.11–1.59(m,10H),1.39(d,J=54.8Hz,5H),1.17–1.07(m,18H),0.97(d,J=17.3Hz,2H).

[0768] Example 19

[0769] Synthesis steps:

[0770] Step 1: Compound INT-19 (40.00 mg, 82.89 μmol) was dissolved in DMF (1 mL), and compound 1d (39.92 mg, 82.89 μmol) and DIPEA (21.43 mg, 165.78 μmol) were added. After stirring for 10 minutes, HATU (37.82 mg, 99.47 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was added to water (30 mL), extracted with ethyl acetate (15 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 19b (60.00 mg, yield 76%). ESI-MS (m / z): 946.5 [M + H] + .

[0771] Step 2: Compound 19b (60.00 mg, 63.42 μmol) was dissolved in DCM (1 mL) and 4 M dioxane hydrochloride (1 mL). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was directly evaporated to dryness to give compound 19c (52.00 mg, yield 97%). ESI-MS (m / z): 846.5 [M+H] + .

[0772] Step 3: Compound 19c (52.00 mg, 30.73 μmol) was dissolved in DMF (3 mL), and compound INT-2 (11.20 mg, 30.73 μmol) and DIPEA (11.92 mg, 92.20 μmol) were added. After stirring for 10 minutes, HATU (17.53 mg, 46.10 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was added to water (30 mL), extracted with ethyl acetate (15 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 19d (10.00 mg, yield 27%). ESI-MS (m / z): 1193.1 [M + H] + .

[0773] Step 4: Compound 19d (10.00 mg, 8.39 μmol) was dissolved in DCM (2 mL), and BSTFA (15.11 mg, 58.71 μmol) was added. TMSI (10.07 mg, 50.32 μmol) was added under nitrogen protection at 0°C. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation, and the residue was purified by preparative liquid chromatography to obtain compound 19 (1.07 mg, yield 11%). ESI-MS (m / z): 1137.2 [M+H] + .

[0774] Example 20

[0775] Following the synthetic method of compound 14, INT-14 was replaced with INT-17, and compound 20 was obtained by following a similar method and procedure. ESI-MS (m / z): 1282.6 [M+H] + .

[0776] Example 21

[0777] Synthesis steps:

[0778] Step 1: Dissolve INT-21 (57 mg, 0.075 mmol) and intermediate INT-9 (40 mg, 0.075 mmol) in DMF (2 mL), and add DIPEA (28.93 mg, 0.224 mmol) and HATU (42.56 mg, 0.112 mmol). Stir at room temperature for 1 hour, and monitor the reaction for completion using LCMS. Pour the reaction solution into water (10 mL), extract with dichloromethane (20 mL * 3), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter and concentrate. Purify the residue by preparative liquid chromatography to obtain compound 21 (7.5 mg, yield 8%). ESI-MS (m / z): 1168.5 [M + H] + ;

[0779] 1H NMR (400MHz, DMSO-d6) δ9.10–8.59(m,1H),8.34–8.23(m,1H),8.12–7.98(m,2H),7.64(d,J=8.2Hz,1H),7.48–7.31( m,5H),7.01–6.69(m,3H),5.48–5.28(m,3H),5.08–4.81(m,1H),4.72–4.52(m,1H),4.29–4.17(m,1H),4.13–4.00(m ,3H),3.99–3.68(m,5H),3.17(d,J=5.2Hz,3H),3.14–3.07(m,2H),2.92–2.84(m,1H),2.84–2.66(m,4H),2.65–2.57 (m,3H),2.40–2.32(m,2H),2.02–1.95(m,4H),1.91–1.83(m,4H),1.55–1.36(m,3H),1.19–1.16(m,2H),1.15(s,9H).

[0780] Example 22

[0781] Synthesis steps:

[0782] Step 1: Compound 1d (50 mg, 0.1 mmol) and INT-44 (51.5 mg, 0.12 mmol) were dissolved in DMF (2 mL), and DIPEA (36.17 μL, 0.2 mmol) and HATU (47.4 mg, 0.12 mmol) were added, respectively. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (5 mL), extracted with ethyl acetate (5 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to thin-layer chromatography with silica gel (dichloromethane / methanol = 20 / 1) to give compound 22a (54.8 mg, yield 60%). ESI-MS (m / z): 876.9 [M+H] + .

[0783] Step 2: Compound 22a (54.8 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated under reduced pressure to obtain crude compound 22b. ESI-MS (m / z): 777.8 [M+H] + .

[0784] Step 3: Compound 22b (53.9 mg, 0.07 mmol) and INT-8 (25.3 mg, 0.07 mmol) were dissolved in DMF (2 mL), and DIPEA (17.9 mg, 0.14 mmol) and HATU (31.6 mg, 0.08 mmol) were added, respectively. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (5 mL), extracted with ethyl acetate (5 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 22c (42.6 mg, yield 54%). ESI-MS (m / z): 1124.0 [M+H] + .

[0785] Step 4: Compound 22c (42.6 mg, 0.04 mmol) was dissolved in DCM (3 mL), placed in an ice-water bath, and then BSTFA (68.3 mg, 0.27 mmol) and TMSI (37.9 mg, 0.19 mmol) were added under nitrogen protection. The mixture was stirred at 0 °C for half an hour, and the reaction was monitored by LCMS until completion. The organic solvent was removed by rotary evaporation of the reaction solution, and the residue was purified by preparative liquid chromatography to obtain compound 22 (30.0 mg, yield 74%). ESI-MS (m / z): 1084.0 [M+NH4] + .

[0786] 1 H NMR(500MHz,DMSO-d6)δ9.14–8.69(m,1H),8.29–8.16(m,1H),8.09–7.90(m,2H),7.68–7.57(m,1H),7 .50–7.25(m,5H),7.08–6.96(m,2H),6.92–6.81(m,1H),5.39–5.30(m,1H),5.06–4.53(m,2H),4.40–4 .18(m,2H),4.02–3.74(m,4H),3.72–3.60(m,2H),3.35–3.30(m,3H),3.26–3.24(m,1H),2.94–2.83(m ,1H),2.79–2.69(m,2H),2.64–2.59(m,3H),2.38–2.28(m,1H),2.08–1.97(m,2H),1.88–1.46(m,17H).

[0787] Example 23

[0788] Synthesis steps:

[0789] Step 1: 4-(dimethoxymethyl)-piperidine (159.0 mg, 1.0 mmol) and 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (168.0 mg, 0.50 mmol) were dissolved in dioxane (5 mL), and Ruphos Pd G3 (41.50 mg, 0.05 mmol), Ruphos (46.60 mg, 0.10 mmol), and LiHMDs (2.5 mL, 2.5 mmol, 1 M in THF) were added. The mixture was heated to 120°C and stirred for 3 hours under microwave conditions. After the reaction was complete, water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution. The organic phase was separated, and the aqueous phase was extracted twice again with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 23a (62.1 mg, 30% yield). ESI-MS (m / z): 417.2 [M+H] + .

[0790] Step 2: Compound 23a (62.0 mg, 0.15 mmol) was dissolved in formic acid (1 mL), and water (0.2 mL) was added. The mixture was stirred at 50°C for 0.5 hours, and the reaction was monitored by LCMS until completion. The reaction solution was directly evaporated to dryness to obtain compound 23b (50.0 mg, 90% yield). ESI-MS (m / z): 371.3 [M+H] + .

[0791] Step 3: Compound 23b (50.0 mg, 0.13 mmol) and INT-3 (65.0 mg, 0.13 mmol) were dissolved in DCM (3 mL). The mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (143.0 mg, 0.67 mmol) was added. The mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 23c (62.0 mg, 55% yield). ESI-MS (m / z): 836.5 [M+H] + .

[0792] Step 4: Compound 23c (62.0 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly concentrated to obtain compound 23d (50.0 mg, yield 91%). ESI-MS (m / z): 746.5 [M+H] + .

[0793] Step 5: Compound 23d (20.0 mg, 0.03 mmol) and DIPEA (17.0 mg, 0.13 mmol) were dissolved in DMF (1 mL), and INT-9 (13.0 mg, 0.03 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, and the reaction was monitored by LCMS until completion. The reaction solution was directly purified by preparative liquid chromatography to obtain compound 23 (17.0 mg, yield 63%). ESI-MS (m / z): 1026.6 [M+H] + .

[0794] 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.24–8.54(m,1H),8.34–8.22(m,1H),8.07–7.98(m,2H),7.64–7.59(m, 1H),7.48–7.37(m,4H),7.35–7.31(m,1H),7.00–6.85(m,3H),5.41–5.29(m,1H),5.01–4.83(m,1H),4.68–4.5 5(m,1H),4.46–3.93(m,4H),3.87–3.79(m,1H),3.74–3.69(m,1H),3.64–3.61(m,3H),3.56–3.50(m,1H),3.07 –3.03(m,2H),2.93–2.87(m,2H),2.76–2.60(m,6H),2.38–2.23(m,1H),2.13–1.58(m,12H),1.39–1.28(m,2H).

[0795] Example 24

[0796] Following the synthetic method of compound 22, INT-44 was obtained by replacing INT-45 with INT-45 and proceeding with similar methods and steps. ESI-MS (m / z): 1067.0 [M+H] + .

[0797] 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.11–8.59(m,1H),8.31–8.20(m,1H),8.10–7.94(m,2H),7.69–7.5 8(m,1H),7.49–7.37(m,4H),7.36–7.29(m,1H),7.25–7.12(m,2H),7.07–6.97(m,2H),6.90–6.83(m,1H), 5.41–5.28(m,1H),5.10–4.71(m,1H),4.68–4.51(m,1H),4.45–4.15(m,2H),4.15–3.77(m,4H),3.75–3.6 4(m,2H),2.96–2.83(m,2H),2.82–2.59(m,4H),2.40–2.30(m,1H),2.12–1.95(m,2H),1.96–1.18(m,17H).

[0798] Example 25

[0799] Synthesis steps:

[0800] Step 1: Compound 1d (40.77 mg, 84.66 μmol) was dissolved in DMF (2 mL), and INT-37 (30.0 mg, 84.66 μmol) and DIPEA (32.83 mg, 253.98 μmol) were added. After ten minutes, HATU (48.29 mg, 126.99 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 25a (40.0 mg, yield 57%). ESI-MS (m / z): 817.7 [M + H] + .

[0801] Step 2: Compound 25a (40.0 mg, 48.90 μmol) was dissolved in dichloromethane (2 mL), and 4 M dioxane hydrochloride (2 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated to give compound 25b (28.0 mg, 80% yield). ESI-MS (m / z): 717.6 [M+H] + .

[0802] Step 3: Compound 25b (20 mg, 27.86 μmol) was dissolved in DMF (2 mL), and INT-25 (13.21 mg, 27.86 μmol) and DIPEA (18.01 mg, 139.31 μmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was directly purified by preparative liquid chromatography to obtain compound 25 (5.8 mg, yield 20%). ESI-MS (m / z): 1007.8 [M+NH4] + .

[0803] 1 HNMR(500MHz,DMSO-d6)δ11.00(d,J=9.1Hz,1H),8.99–8.81(m,1H),8.32–8.19(m,1H),8.04–7.99(m,2H),7.76–7.58(m,3H),7.51–7.12(m ,8H),5.07–4.94(m,2H),4.67–4.25(m,4H),4.12–3.50(m,9H),2.97– 2.74(m,1H),2.70–2.52(m,4H),2.44–2.33(m,4H),2.02–1.71(m,8H).

[0804] Example 26

[0805] Synthesis steps:

[0806] Step 1: Compound 1b (50 mg, 0.091 mmol) and (R)-2-phenylmorpholine (16.33 mg, 0.100 mmol) were dissolved in THF (2 mL) and ACN (2 mL), and NMI (37.34 mg, 0.46 mmol) and TCFH (38.29 mg, 0.14 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction solution was poured into water (10 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound 26a (55 mg, yield 87%). ESI-MS (m / z): 695.5 [M + H] + ;

[0807] Step 2: Compound 26a (55 mg, 0.079 mmol) was dissolved in DCM (2 mL), and diethylamine (1...

Claims

1. A compound of the structure of Formula (I) or Formula (II), or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof: wherein represents a single or double bond; q is 0, 1 or 2; r is 0, 1 or 2; t is 1 or 2; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; X is each independently selected from CH, CH2, O, NR 8 , S, SO, S(O)2, S(=O)(=NR 9 ), and wherein X in formula (I) is not CH or CH2; T is each independently selected from CH or N; Ring A is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring, each of which can be optionally substituted with p instances of R 7 substituents; p is 0, 1, 2 or 3; R 1 selected from the group consisting of (Ci-C4)alkyl, phenyl, 4-9 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said (Ci-C4)alkyl is optionally substituted with 0, 1, 2, or 3 groups selected from R Y Z of R Z ; R 2 and R 3 each independently is selected from hydrogen, phenyl, (Ci-C4)alkyl, C3-C6cycloalkyl or 4-6 membered heterocycloalkyl; said phenyl, (Ci-C4)alkyl, C3-C6cycloalkyl or 4-6 membered heterocycloalkyl can each independently be substituted with 0, 1 or 2 groups selected from halogen, (Ci-C4)alkyl; R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-14 membered heterocycloalkyl or 5-12 membered heteroaryl, which can be monocyclic or bicyclic, and which can be further substituted with 0, 1, 2, 3 groups selected from R Q ; R 4 are each independently selected from a naphthalene ring group, an 8-10 membered fused bicyclic heteroaryl group, an 8-10 membered annelated bicyclic heterocycloalkyl group, or -CR 1b =CR 2b -phenyl, which naphthalene ring group, 8-10 membered fused bicyclic heteroaryl group, 8-10 membered annelated bicyclic heterocycloalkyl group, or -CR 1b =CR 2b -phenyl can each be optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halo, CN, OH, -(Ci-C4)alkyl, -(Ci-C4)hydroxyalkyl, -[(Co-C4)alkylene]-O-[(Ci-C4)alkyl], -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -P(O)[OR 1b ][NH(AA)C(O)OR T ], -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], -[P(O)[NH(AA)C(O)OR T ][NH(AA)C(O)OR T ]; R 1a and R 2a are each independently selected from the group consisting of hydrogen, cyano, (Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, -[(Co-C4)alkylene]-0-[(Ci-C4)alkyl], OH and halogen, or R 1a and R 2a form together an oxo group; R 1a and R 2a are preferably H, (Ci-C4)alkyl, halogen; halogen is preferably fluorine; R 1b and R 2b are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, -[(Ci-C4)alkylene]-0-[(Ci-C 20 )alkyl], -[(Ci-C4)alkylene]-J-R v , 5-6 membered heteroaryl and phenyl, wherein -J- are each independently selected from -OC(O)-, -C(O)O-, -OC(O)O-, -SC(O)-, -OC(O)NH- or -OC(O)N(R v )-; R v are each independently selected from H, -(Ci-C4)alkyl, -halo(Ci-C4)alkyl, -(C3-C6)cycloalkyl, -(5-7 membered heterocycloalkyl), -[(Ci-C4)alkylene]-ORa; wherein said 5-6 membered heteroaryl and phenyl are each independently substituted with 0, 1 or 2 groups selected from halogen, cyano and (Ci-C4)alkyl; wherein said 5-7 membered heterocycloalkyl are each independently substituted with 0, 1 or 2 -C(O)OR h groups. AA represents an alpha or beta natural or unnatural amino acid residue; R T and R Ty each independently is selected from the group consisting of H, (Ci-C4)alkyl, phenyl, benzyl, which phenyl and benzyl can each be optionally substituted with 0, 1, or 2 groups selected from H, halo, (Ci-C4)alkyl, (Ci-C4)haloalkyl; R 1b and R 2b together with the P atom and atoms therebetween can form a 5-9 membered heterocycloalkyl group; optionally, R 1b and R T together with the P atom and atoms therebetween can form a 5-9 membered heterocycloalkyl group; optionally, two R T together with the P atom and atoms therebetween can form a 5-9 membered heterocycloalkyl group; optionally, R Ty and R T together with the P atom and atoms therebetween can form a 5-9 membered heterocycloalkyl group; R 5 each independently selected from H, halogen, CN, OH, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, (Ci-C4)hydroxyalkyl, (C2-C4)alkenyl; two R 5 and wherein the intermediate atoms can form a 3-6 membered alkyl ring, a 3-6 membered heterocycloalkyl ring, a phenyl ring or a 5-6 membered heteroaromatic ring, which 3-6 membered alkyl ring or 3-6 membered heterocycloalkyl ring can each be optionally substituted with 1, 2 or 3 of H, F, methyl, which phenyl ring or 5-6 membered heteroaromatic ring can each be optionally substituted with 1, 2 or 3 of H, halogen, CN; R 6 each independently selected from H, halogen, CN, -OH, -NR a R b , (Ci-C4)alkyl, (Ci-C4)haloalkyl, -(Co-C4)alkylene-O-(Ci-C4)alkyl, (Ci-C4)haloalkoxy, (Ci-C4)hydroxyalkyl, phenyl, C3-C6cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, which phenyl, C3-C6cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl can each be optionally substituted with 0, 1, 2, or 3 R S substituents; two R 6 and wherein the intermediate atoms can form a 3-6 membered alkyl ring or a 3-6 membered heterocycloalkyl ring, which 3-6 membered alkyl ring or 3-6 membered heterocycloalkyl ring can each be optionally substituted with 0, 1, 2, or 3 groups selected from H, F, methyl; R 7 each independently at each occurrence is selected from H, halogen, CN, OH, -NR a R b , (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, wherein said C3-C6cycloalkyl, 4-6 membered heterocycloalkyl can each optionally be substituted with 0, 1, 2, or 3 groups selected from H, F, methyl; R 8 or R 9 each independently at each occurrence is selected from H, (Ci-C4)alkyl, (Ci-C4)haloalkyl, -(Co-C4)alkylene-(C3-C6cycloalkyl), -(Co-C4)alkylene-(4-7 membered heterocycloalkyl), -(Co-C4)alkylene-phenyl, -(Co-C4)alkylene-(5-10 membered heteroaryl), -C(O)R Ha , -C(O)OR Ha , -C(O)NR Ha R Hb , -SOR Ha , SO2R Ha , said -(Co-C4)alkylene-(C3-C6cycloalkyl), -(Co-C4)alkylene-(4-7 membered heterocycloalkyl), -(Co-C4)alkylene-phenyl, -(Co-C4)alkylene-(5-10 membered heteroaryl) can each be optionally substituted with 0, 1, 2, 3 R U ; R Ha each independently selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, phenyl, 5-10 membered heteroaryl, (C3-C8)cycloalkyl, 4-10 membered heterocycloalkyl, said C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl can each be optionally substituted with 0, 1, or 2 R O said phenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or (C3-C8)cycloalkyl can each be optionally substituted with 0, 1, 2, 3 groups selected from H, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, CN, oxo, 4-6 membered heterocycloalkyl; R O each independently selected from halogen, OH, NH2, phenyl, (Ci-C4)alkyl, -NH(Ci-C4alkyl), -N(Ci-C4alkyl)2, C3-C6cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, optionally, said 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl can each independently be substituted with 0, 1, 2, 3 groups selected from H, halogen, CN, oxo, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy; R Hb each independently selected from H, (Ci-C4)alkyl or (C3-C5)cycloalkyl; R Q and R U are each independently selected from the group consisting of H, halogen, CN, OH, NH2, oxo, C2-C4alkenyl, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, phenyl, 4-9 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-C6cycloalkyl, -OR e , -C(O)R g , -C(O)OR e , NHC(O)R e , -C(O)NR c R d , -NR a R b , -S(O)2R f , -S(O)=NH(C1-C4alkyl), -S(O)NR e R f , -S(O)2NR e R f , optionally, said C2-C4alkenyl, (C1-C4)alkyl can each independently be substituted with 0, 1, 2, 3 R M , optionally, said phenyl, 4-9 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-C6cycloalkyl can each independently be substituted with 0, 1, 2, 3 R F ; R Y , R J , and R M are each independently selected from H, halogen, CN, OH, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, -C(0)R g , -C(0)OR e , NHC(0)R e , -C(0)NR c R d , -NR a R b , -S(0)2R f , -S(O)=NH(Ci-C4alkyl), -S(0)NR e R f , -S(0)2NR e R f , phenyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl, optionally, said phenyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl can each independently be substituted with 0, 1, 2, 3 R X ; R F , R S , R X , R Z each independently is selected from H, halogen, CN, OH, NH2, NO2, oxo, (Ci-C4)alkyl, (Ci-C4)haloalkyl, -(Co-C4alkylene)-(Ci-C4alkoxy), (Ci-C4)haloalkoxy, (Ci-C4)hydroxyalkyl, -(Co-C4alkylene)-phenyl, -(Co-C4alkylene)-(5-10 membered heteroaryl), -(Co-C4alkylene)-(4-6 membered heterocycloalkyl), C2-C4alkenyl, C2-C4alkynyl, -OR e , -C(O)R g , -C(O)OR e , NHC(O)R e , -(Co-C4alkylene)-C(O)NR c R d , -NR a R b , -S(O)2R f , -S(O)=NH(Ci-C4alkyl), -S(O)NR e R f , -S(O)2NR e R f , optionally said (Ci-C4)alkyl can be substituted with CN, said -(Co-C4alkylene)-phenyl, -(Co-C4alkylene)-(4-6 membered heterocycloalkyl) can each be independently substituted with 0, 1, 2, 3 groups selected from H, halogen, CN, oxo, Ci-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, Ci-C 10 haloalkyl, Ci-C 10 alkoxy, Ci-C 10 haloalkoxy, optionally said Ci-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl can each optionally be substituted with 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl; said 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl can each optionally be substituted with oxo or 4-7 membered heterocycloalkyl; R a , R b , R c , R d , R e , R f , R g , R h each independently is selected from H, (Ci-C4)alkyl, C2-C4alkynyl, -(Co-C4alkylene)-phenyl, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, which (Ci-C4)alkyl, -(Co-C4alkylene)-phenyl, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl can each be optionally substituted with 0, 1, 2, 3 groups selected from H, halogen, CN, OH, (Ci-C4)alkyl, (Ci-C4)haloalkyl, -(Ci-C4alkoxy), (Ci-C4)haloalkoxy, phenyl, benzyl; the brackets [ ] in the structural formulae indicate that one H atom in the chemical formulae shown within is bonded as a bond to one end of L; L represents -(C1-C 50 )alkylene-, L is attached via a covalent bond and a C, N, O or S atom on both flanking groups, optionally wherein 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 methylene units are each independently replaced by a -(4-12 membered heterocycloalkyl)-, -(C3-C 12 cycloalkyl)-, -(5-6 membered heteroaryl)-, -phenyl-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, -CH=CH- or -C≡C-, wherein said 4-12 membered heterocycloalkyl, C3-C 12 cycloalkyl, 5-6 membered heteroaryl, phenyl, -CH=CH- can each independently be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxy, amino, methyl or oxo (=0), each R independently represents H, C1-C4 alkyl or C3-C5 cycloalkyl; optionally, L can also be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, C1-C3 alkyl, C3-C6 cycloalkyl, -(C0-C3)alkylene-OR, -(C0-C3)alkylene-N(R)2, -(C0-C3)alkylene-SR or oxo (=0); EBM is an E3 ubiquitin ligase ligand fragment; wherein -L-EBM is not 2. The compound of claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, R 4 each independently is selected from a naphthalene ring group, an 8-10 membered fused bicyclic heteroaromatic group, an 8-10 membered annelated bicyclic heterocycloalkyl group, or a -CR 1b =CR 2b -phenyl, which naphthalene ring group, 8-10 membered fused bicyclic heteroaromatic group, 8-10 membered annelated bicyclic heterocycloalkyl group, or -CR 1b =CR 2b -phenyl can each optionally be substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, OH, -(Ci-C4)alkyl, -(Ci-C4)hydroxyalkyl, -[(C0-C4)alkylene]-O-[(Ci-C4)alkyl], -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -P(O)[OR 1b ][NH(AA)C(O)OR T ], -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], -[P(O)[NH(AA)C(O)OR T ][NH(AA)C(O)OR T ], preferably the substituents are selected from halogen, CN, -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -P(O)[OR 1b ][NH(AA)C(O)OR T ], -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], -[P(O)[NH(AA)C(O)OR T ][NH(AA)C(O)OR T ].

3. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, R 1a and R 2a are each independently selected from the group consisting of hydrogen, cyano, (Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, OH and halogen, or R 1a and R 2a form together an oxo group; R 1a and R 2a are preferably H, (Ci-C4)alkyl, halogen; halogen is preferably fluorine.

4. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, R 1a and R 2a are each independently selected from the group consisting of hydrogen, cyano, (Ci-C4)alkyl, hydroxy(Ci-C4)alkyl and halogen, or R 1a and R 2a form together an oxo group; R 1a and R 2a are preferably H, (Ci-C4)alkyl, halogen; halogen is preferably fluorine.

5. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein T is N; and / or R 3 selected from H; and / or R 5 represents H; and / or q is each independently selected from 0 or 1; and / or m is 0; and / or R 6 each independently selected from H, F or methyl; and / or Ring A is selected from a phenyl ring or a 5-6 membered heteroaromatic ring, each of which can be optionally substituted with p R 7 substituents; preferably, ring A is selected from a phenyl ring, each of which can be optionally substituted with p R 7 substituents.

6. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compounds have the structure of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (IIa), or Formula (IIb):

7. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compounds have the structure of Formula (Ia-1), Formula (Ia-2), (Ia-3), Formula (Ia-4), (Ia-5), Formula (Ia-6), Formula (Ia-7), or Formula (Ia-8):

8. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compounds have the structure of Formula (Iaa-1), Formula (Iaa-2), (Iaa-3), Formula (Iaa-4), (Iaa-5), Formula (Iaa-6), Formula (Iaa-7), or Formula (Iaa-8):

9. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compounds have structures represented by Formulas (Iaaa-1) through (Iaaa-16):

10. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, the compound is of Formula (Ib-1), Formula (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), or (Ib-8):

11. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compounds have the structure of Formula (Ibb-1), Formula (Ibb-2), (Ibb-3), Formula (Ibb-4), (Ibb-5), Formula (Ibb-6), Formula (Ibb-7), or Formula (Ibb-8):

12. The compound of the preceding claim 8, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, q is each independently selected from 0 or 1, preferably q is 0.

13. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compounds have the structure of formula (Ibbb-1) to formula (Ibbb-8):

14. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compounds have the structure of Formula (IIa-1), Formula (IIa-2), (IIa-3), Formula (IIa-4), (IIa-5), Formula (IIa-6), Formula (IIa-7), or Formula (IIa-8):

15. The compound of claim 11, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, q is each independently selected from 0 or 1.

16. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, R 4 each independently selected from the group consisting of: wherein R 3a each independently is selected from the group consisting of CN, OH, halogen, -(Ci-C4)alkyl, -(Ci-C4)hydroxyalkyl, -[(Co-C4)alkylene]-0-[(Ci-C4)alkyl], n1 is selected from 1, 2 or 3, and the remaining groups are as defined above.

17. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, R 4 each independently selected from the group consisting of:

18. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, R 1b and R 2b are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, -[(Ci-C4)alkylene]-OC(O)-[(Ci-C4)alkyl], -[(Ci-C4)alkylene]-C(O)O-[(Ci-C 20 )alkyl], -[(Ci-C4)alkylene]-OC(O)-[(Ci-C4)haloalkyl], [(Ci-C4)alkylene]-OC(O)O-[5-7 membered heterocycloalkyl], [(Ci-C4)alkylene]-OC(O)-[5-7 membered heterocycloalkyl], -[(Ci-C4)alkylene]-OC(O)-[(Ci-C4)alkylene]-OH, -[(Ci-C4)alkylene]-OC(O)-[(Ci-C4)alkylene]-O-[(Ci-C4)alkyl], -[(Ci-C4)alkylene]-OC(O)O-[(Ci-C4)alkyl], -[(Ci-C4)alkylene]-OC(O)O-[(Ci-C4)haloalkyl], -[(Ci-C4)alkylene]-OC(O)O-[(Ci-C4)alkylene]-OH, -[(Ci-C4)alkylene]-OC(O)O-[(Ci-C4)alkylene]-O-[(Ci-C4)alkyl], -[(Ci-C4)alkylene]-SC(O)-[(Ci-C4)alkyl], -[(Ci-C4)alkylene]-SC(O)-[(Ci-C4)haloalkyl], -[(Ci-C4)alkylene]-SC(O)-[(Ci-C4)alkylene]-OH, -[(Ci-C4)alkylene]-SC(O)-[(Ci-C4)alkylene]-O-[(Ci-C4)alkyl], -[(Ci-C4)alkylene]-OC(O)NH(Ci-C4)alkyl], -[(Ci-C4)alkylene]-OC(O)N[(Ci-C4)alkyl]2, 5-6 membered heteroaryl, and phenyl, wherein the 5-6 membered heteroaryl and phenyl are each optionally and independently substituted with 0, 1, or 2 groups selected from halogen, cyano, and (Ci-C4)alkyl, and wherein the 5-7 membered heterocycloalkyl of [(Ci-C4)alkyl]-OC(O)O-[5-7 membered heterocycloalkyl] and [(Ci-C4)alkyl]-OC(O)-[5-7 membered heterocycloalkyl] is optionally and independently substituted with 0, 1, or 2 -C(O)OR h groups.

19. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, R 4 each independently selected from the group consisting of:

20. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, R a , R b are each independently selected from H or -(Ci-C4)alkyl.

21. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, L represents -(C1-C 20 )alkylene-, L is attached via a covalent bond and a C, N, O or S atom on both flanking groups, optionally wherein 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 methylene units are each independently replaced by a -(4-12 membered heterocycloalkyl)-, -(C3-C 12 cycloalkyl)-, -(5-6 membered heteroaryl)-, -phenyl-, -O-, -NR-, -S-, -C(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -CH=CH- or -C≡C-, said 4-12 membered heterocycloalkyl, C3-C 12 cycloalkyl, 5-6 membered heteroaryl, phenyl, -CH=CH- can each independently be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxy, amino, methyl or oxo (=0), said R each independently represents H, C1-C4 alkyl or C3-C5 cycloalkyl; optionally, L can also be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, C1-C3 alkyl, C3-C6 cycloalkyl or oxo (=0).

22. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, L is selected from:

23. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, L does not include the following structural fragments:

24. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, EBM is a CRBN E3 ubiquitin ligase ligand fragment selected from: wherein W represents a direct bond, a phenyl ring, or a 5-6 membered heteroaromatic ring, each of which can be optionally substituted with 0, 1, 2, 3 R 13 substituents; Ring B represents phenyl, naphthyl, 5-12 membered heteroaromatic ring group, 4-14 membered heterocycloalkyl, each of which can be optionally substituted with 0, 1, 2, 3 R 13 substituents; R 13 each independently represents H, fluorine, chlorine, oxo, C1-C4alkyl, methoxy, trifluoromethyl; Z is each independently represents a direct bond, -NH-, -0-, -C(0)NH-, -NHC(O)-, -C(0)NMe-, -NMeC(O)-, or -CH2-; Y is each independently represents CH, CD, CF, CMe, or N; represents a single or double bond; Y 1 each independently represents CH2, CH or CMe; Y 2 each independently represents CH2, CH, NH, N, O, CMe or a direct bond.

25. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, EBM is a CRBN E3 ubiquitin ligase ligand fragment selected from: wherein W represents a direct bond, a phenyl ring, or a 5-6 membered heteroaromatic ring, each of which can be optionally substituted with 0, 1, 2, 3 R 13 substituents; Ring B represents phenyl, naphthyl, 5-12 membered heteroaromatic ring group, 4-14 membered heterocycloalkyl, each of which can be optionally substituted with 0, 1, 2, 3 R 13 substituents; R 13 each independently represents H, fluorine, chlorine, oxo, C1-C4alkyl, methoxy, trifluoromethyl; Z is each independently represents a direct bond, -NH-, -0-, -C(0)NH-, -NHC(O)-, or -CH2-; Y is each independently represents CH, CD, CF, CMe, or N.

26. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, EBM is an E3 ubiquitin ligase ligand fragment selected from the group consisting of: wherein X 3 , X 4 , X 5 , X 6 and X 8 each independently represent CH, N or CR 13 wherein R 13 each independently represent H, fluorine, chlorine, methyl, methoxy, trifluoromethyl; X 7 each independently represents -CH2- or -C(O)-; X 9 each independently represents -NH-, -N(Me)- or -O-; X 10 each independently represents N or CH; X 11 each independently represents -O-, -NH-, -N(Me)-, -CH2- or -C(Me)2-; X 12 each independently represents N, CH, CF, C=0, C(Me), CH2or CF2; X 13 each independently represents N, CH, CF, C=0, C(Me), CH2, or NH; Y is each independently represents CH, CD, CF, CMe, or N; Y a each independently represents CH, CD, CF, or CMe; Z is each independently represents a bond, -NH-, -0-, -CF2-, or -CH2-.

27. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, EBM is selected from the following structures: wherein R 13 each independently represents H, fluorine, chlorine, methyl, methoxy, trifluoromethyl.

28. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, EBM is selected from the following structures:

29. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, EBM is not 30. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, EBM is a VHL E3 ubiquitin ligase ligand fragment selected from: wherein V is selected from NHR 41 or a 5-membered heteroaromatic ring, which can each optionally be substituted with 0, 1 or 2 H, halogen or methyl; R 41 each independently represents H, -C(O)-(Ci-C4alkyl), -C(O)-(C3-C5cycloalkyl), which -C(O)-(C3-C5cycloalkyl) can each be optionally substituted with 0, 1, or 2 groups selected from H, halogen, CN, methyl; R 31 each independently represents C1-C4alkyl or C3-C6cycloalkyl; R 32 and R 33 each independently represents H, halo or C1-C4alkyl, which C1-C4alkyl can each be optionally substituted with 0, 1, 2 or 3 groups selected from H, F, OH, OMe, NH(Me), NH(Me)2; R 32 and R 33 and the carbon atom to which they are attached can form a C3-C5cycloalkyl; Ring C is selected from phenyl or 5-6 membered heteroaryl, which phenyl or 5-6 membered heteroaryl can each be optionally substituted with 0, 1, or 2 groups selected from H, halogen, OH, OMe, NH(Me), NH(Me)2, C1-C4 alkyl, C3-C6 cycloalkyl; and R 34 each independently represents H, ethynyl, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, which phenyl, 5-6 membered heteroaryl can each be optionally substituted with 1 or 2 groups selected from H, halogen, methyl, cyclopropyl, which 5-6 membered heterocycloalkyl can each be optionally substituted with 0, 1 or 2 groups selected from H, halogen, methyl, cyclopropyl, oxo.

31. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, EBM is a VHL E3 ubiquitin ligase ligand fragment selected from: wherein V is selected from NHR 41 or a 5-membered heteroaromatic ring, which can each optionally be substituted with 0, 1 or 2 H, halogen or methyl; R 41 each independently represents H, -C(O)-(Ci-C4alkyl), -C(O)-(C3-C5cycloalkyl), which -C(O)-(C3-C5cycloalkyl) can each be optionally substituted with 0, 1, or 2 groups selected from H, halogen, CN, methyl; R 31 each independently represents C1-C4alkyl or C3-C6cycloalkyl; R 32 and R 33 each independently represents H, halo or C1-C4alkyl, which C1-C4alkyl can each be optionally substituted with 0, 1, 2 or 3 groups selected from H, F, OH, OMe, NH(Me), NH(Me)2; R 32 and R 33 and the carbon atom to which they are attached can form a C3-C5cycloalkyl group; and R 34 each independently represents H, ethynyl, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, which phenyl, 5-6 membered heteroaryl can each be optionally substituted with 0, 1 or 2 groups selected from H, halogen, methyl, cyclopropyl, which 5-6 membered heterocycloalkyl can each be optionally substituted with 0, 1 or 2 groups selected from H, halogen, methyl, cyclopropyl, oxo.

32. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, EBM is selected from:

33. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compound has a structure represented by formula (III):

34. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compounds have the structure of Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), or Formula (IIIe):

35. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compound has a structure represented by formula (IV):

36. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compounds have the structure of Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe):

37. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compound has a structure represented by formula (V):

38. The compound of any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, wherein, The compound has a structure shown in formula (VI):

39. A compound, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, which compound can be selected from any one of the following:

40. A pharmaceutical composition comprising a compound according to any one of claims 1-39, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

41. Use of a compound according to any one of claims 1-39, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, or a pharmaceutical composition of claim 40, for the manufacture of a medicament for the prevention and / or treatment of a disease associated with STAT6 activity.

42. Use of a compound according to any one of claims 1-39, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, or a pharmaceutical composition of claim 40, for the manufacture of a medicament for the prevention and / or treatment of a disease associated with STAT3 activity.

43. A method of preventing and / or treating a disease associated with STAT6 activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-39, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, or a pharmaceutical composition of claim 40.

44. A method of preventing and / or treating a disease associated with STAT3 activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-39, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, or a pharmaceutical composition of claim 40.

45. The use of claim 41 or the method of claim 43, wherein, The disease associated with STAT6 activity is, for example, cancer, autoimmune disease, inflammatory disease.

46. The use of claim 42 or the method of claim 44, wherein, The disease associated with STAT3 activity is, for example, cancer, autoimmune disease, inflammatory disease.

47. The use of claim 41 or the method of claim 43, wherein, The compound of any one of claims 1-39, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, or a pharmaceutical composition of claim 40 can be used alone, or can be used in combination with other kinds of pharmaceutical preparations and / or therapeutic methods.

48. The use of claim 42 or the method of claim 44, wherein, The compound of any one of claims 1-39, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof, or a pharmaceutical composition of claim 40 can be used alone, or can be used in combination with other kinds of pharmaceutical preparations and / or therapeutic methods.

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