Proteolysis-targeting chimeric compound targeting c-met, and composition thereof and use thereof

Abstract

The present invention relates to a proteolysis-targeting chimeric compound of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV') or (V') which has a degrading and / or inhibitory activity against aberrant c-MET, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and further relates to a pharmaceutical composition containing same, and a preparation method therefor and the therapeutic use thereof.

Description

Chimeric compounds targeting c-MET protein degradation, their compositions, and their uses Technical Field

[0001] This invention belongs to the pharmaceutical field, and particularly relates to protein degradation-targeting chimeric compounds that induce and / or inhibit c-MET degradation, as well as pharmaceutical compositions comprising them, and methods for their preparation and uses. Background Technology

[0002] c-Mesenchymal-epithelial transition factor (c-MET) is a transmembrane receptor tyrosine kinase encoded by the MET gene located on the long arm of human chromosome 7, also known as hepatocyte growth factor receptor (HGFR). The c-MET protein is a heterodimer consisting of a 50kD α subunit and a 145kD β subunit linked by a disulfide bond. It mainly comprises an N-terminal extracellular binding domain, a single transmembrane domain, and an intracellular domain. The extracellular domain includes a signaling symptom domain (SEMA), a nerve plexus signaling integrin (PSI) domain, and an immunoglobulin plexus transcription (IPT) domain. The intracellular domain includes a juxtamembrane domain with a Y1003 phosphorylation site, a kinase domain with Y1234 and Y1235 phosphorylation sites, and a C-terminal multifunctional docking site domain containing Y1349 and Y1356 binding tyrosine residues. Under normal circumstances, hepatocyte growth factor (HGF) binds to the SEMA domain of the extracellular domain of c-MET protein, leading to receptor dimerization and phosphorylation of tyrosine residues in the kinase domain and autophosphorylation of tyrosine residues at the C-terminus. This further activates numerous downstream signaling pathways such as RAS / MAPK, PI3K / AKT, and STAT, thereby promoting cell proliferation, cell migration, invasion, angiogenesis, and epithelial-mesenchymal transition.

[0003] Dysregulation of the c-MET signaling pathway is closely related to the proliferation, invasion, and metastasis of tumors such as lung cancer, gastric cancer, renal cancer, osteosarcoma, thyroid cancer, and pancreatic cancer. Furthermore, c-MET abnormalities are often associated with poor tumor prognosis and play a significant role in the development and progression of non-small cell lung cancer (NSCLC) and resistance to EGFR inhibitors. Abnormal activation of the c-MET signaling pathway mainly includes c-MET amplification, c-MET mutation, c-MET fusion, and c-MET overexpression. Among these, c-MET amplification and MET exon 14 skipping mutation (MET ex14) are the main types of c-MET gene mutations. c-MET amplification, including polyploid amplification and localized amplification, is one of the primary tumor driver gene mutations and has been found in various tumors, including NSCLC. Simultaneously, c-MET amplification often occurs secondary to treatment of other driver gene-positive tumors and is one of the resistance mechanisms to EGFR TKIs, ALK TKIs, etc. c-MET mutations occur at multiple sites in c-MET, primarily in exon 14 and the kinase domain. MET ex14 is a typical oncogenic mutation, present in various tumors, such as NSCLC (3-4%) and pulmonary sarcomatoid carcinoma (9-22%). Kinase domain mutations include G1163R, L1195V, D1228H, D1228N, D1228V, Y1230H, Y1230A, Y1230C, and Y1230D. c-MET fusions lead to ligand-independent constitutive activation, including TPR-MET fusions in osteosarcoma, and other fusions such as PTPRZ1-MET, CLIP2-MET, CAPZA2-MET, and ST7-MET in gastric cancer, thyroid cancer, lung cancer, and hepatocellular carcinoma.

[0004] Currently, various c-MET tyrosine kinase inhibitors (TKIs) have emerged in clinical practice, mainly divided into two types. Type I inhibitors bind to the ATP pocket of the active c-MET conformation, including crizotinib, tepotinib, capmatinib, savolitinib, glutmetinib, and vebrereltinib, primarily used for NSCLC with MET ex14. Type II inhibitors are mainly multi-kinase inhibitors, binding to the ATP pocket of the inactive c-MET conformation; a representative drug is cabozantinib. Although TKIs have shown good clinical efficacy, drug resistance is a significant issue, necessitating the development of new drugs targeting c-MET. The main mechanisms of c-MET resistance include c-MET amplification, c-MET mutation, and c-MET fusion.

[0005] Protein degradation-targeting chimeras (PROTACs) are bifunctional molecules composed of a target protein ligand and an E3 ubiquitin ligase ligand linked by an appropriate linker strand. PROTACs chemically mediate the polyubiquitination of target proteins through the ubiquitin-proteasome system (UPS), specifically degrading the target protein and possessing broad application prospects and development potential.

[0006] Developing protacos capable of ubiquitinizing and degrading c-MET proteins may offer a novel approach to treating abnormal c-MET-mediated diseases and holds promise for overcoming resistance to small molecule inhibitors, thus better meeting clinical needs. Therefore, the development of novel c-MET protaco compounds remains crucial in this field to enhance their clinical value. This invention provides such compounds.

[0007] Invention Overview

[0008] This invention provides a novel protein degradation-targeting chimeric compound, compositions comprising the compound, methods for their preparation, and uses. The compound exhibits degradative and / or inhibitory activity, high selectivity, and / or excellent pharmacokinetic properties against aberrant c-MET proteins, such as c-MET amplification, c-MET mutation, c-MET fusion, and / or c-MET overexpression, and can be used to treat diseases and / or conditions mediated and metastasized by aberrant c-MET.

[0009] To address this, the present invention adopts the following technical solution:

[0010] In one aspect, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), or (V'), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0011] in,

[0012] X1 is N or CR X1 ;where R X1 It can be H, D, CN, NO2, or halogen;

[0013] X2 is N or CR X2 ;where R X2 It can be H, D, CN, NO2, or halogen;

[0014] X3 is N or CR X3 ;where R X3It can be H, D, CN, NO2, or halogen;

[0015] Y is C(R) Y )2, O, S, NH or S(O)2; where each R Y Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0016] p is 0, 1, 2, 3, 4, 5 or 6;

[0017] Each R1 is independently D, CN, NO2, or a halogen, or two adjacent R1s together with the atoms they are attached to form a 5-6 membered monocyclic heterocycle, wherein the 5-6 membered monocyclic heterocycle is optionally composed of one or more atoms selected from oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Substitution of alkyl groups;

[0018] Each of R2, R3, and R5 is independently H, C 1-6 Alkyl or 3-6 membered monocyclic carbon ring; wherein the group is optionally substituted by one or more groups selected from D or halogens;

[0019] R4 can be H, D, CN, NO2, or a halogen;

[0020] Each A is independently C. 1-6 The ynyl group is a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more R groups.

[0021] Each m is independently either 0 or 1;

[0022] Each B is independently a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more Rs;

[0023] Each C is independently a chemical bond, a phenylene group, or a 5-6 membered heteroaryl group; wherein the phenylene group and the 5-6 membered heteroaryl group are optionally substituted by one or more R groups;

[0024] m' is 0 or 1;

[0025] When m' is 1, B' is B; or

[0026] When m' is 0, ring B' is a divalent group selected from 3-6 member monocyclic carbon rings, 6-10 member fused carbon rings, 6-10 member fused heterocycles, 6-10 member bridged carbon rings, 6-10 member bridged heterocycles, 6-9 member spirocyclic carbon rings, and 6-9 member spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R;

[0027] n is 0 or 1;

[0028] D is a chemical bond, a phenylene group, or a 5-6-membered heteroaryl group; wherein the phenylene group and the 5-6-membered heteroaryl group are optionally substituted by one or more R groups;

[0029] Each R is independently H, D, OH, CN, NO2, NH2, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two Rs together with the atoms they are attached to form a 3-6 membered monocyclic carbon ring or a 4-7 membered monocyclic heterocycle;

[0030] Each U is independent as follows:

[0031] in,

[0032] Indicates a single bond or a double bond;

[0033] Each Q1 is independently C(O) or C(R). U4 )2;

[0034] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0035] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0036] Each Q2 is independently either N or CH;

[0037] Q3 and Q4 are each independently N or CH;

[0038] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0039] P1 is N, C, or CR U4 ;

[0040] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4or C(R) U4 )2;

[0041] P4 and P5 are each independently N or C;

[0042] z is 0, 1, or 2;

[0043] H1 is N or CR U4 ;

[0044] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0045] Each h is independently 0, 1, 2, 3 or 4;

[0046] Each k is independently 0, 1, 2, or 3;

[0047] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0048] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0049] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0050] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0051] In some embodiments, the compounds of the present invention have at least one desired atom substituted with the isotope D in an amount higher than the natural abundance of the isotope, i.e., enriched.

[0052] In some embodiments, the compounds of the present invention comprise one or more deuterium atoms. In specific embodiments, the deuterium isotope content at the deuterated position is at least greater than 0.015% of the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, and more preferably greater than 99%.

[0053] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, and pharmaceutically acceptable excipients. In a specific embodiment, the present invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compound of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the present invention is provided in a preventatively effective amount.

[0054] In another aspect, the present invention provides a compound comprising the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, and pharmaceutically acceptable excipients, further comprising other therapeutic agents. In specific embodiments, the other therapeutic agents are another c-MET inhibitor, a c-MET antibody, an EGFR inhibitor, an ALK inhibitor, a RAF inhibitor, a MEK inhibitor, or an immune checkpoint inhibitor. In specific embodiments, the other c-MET inhibitor is terpoxtinib, carmatinib, cevotinib, gumetinib, or beritinib. In specific embodiments, the c-MET antibody is ervantumab. In specific embodiments, the EGFR inhibitor is gefitinib, erlotinib, icotinib, afatinib, dacomitinib, neratinib, osimertinib, lazetinib, ametinib, or vormetinib. In specific implementation schemes, the ALK inhibitor is crizotinib, ceritinib, alectinib, brigatinib, ensartinib, loratinib, or ilurac. In specific implementation schemes, the RAF inhibitor is sorafenib, vemurafenib, dabrafenib, or encofenib. In specific implementation schemes, the MEK inhibitor is trametinib, selumetinib, or refatinib. In specific implementation schemes, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilimumab, atezolilimumab, durvalumab, ipilimumab, or tramemumab.

[0055] In another aspect, the present invention provides a method for treating c-MET-mediated diseases, comprising administering to a subject an effective amount of the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or compositions of the present invention.

[0056] In another aspect, the present invention provides compounds of the present invention or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or compositions thereof, for the treatment of c-MET-mediated diseases.

[0057] In another aspect, the present invention provides the use of the compounds of the present invention or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or compositions of the present invention in the preparation of medicaments for treating c-MET-mediated diseases.

[0058] In another aspect, the present invention provides the use of the compounds of the present invention or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or compositions of the present invention in the treatment of subjects with c-MET-mediated diseases.

[0059] In a specific embodiment, the c-MET is an aberrant c-MET. In a more specific embodiment, the aberrant c-MET is c-MET amplification, c-MET mutation, c-MET fusion, or c-MET overexpression. In a more specific embodiment, the aberrant c-MET is c-MET amplification, wherein the c-MET amplification is polyploid amplification or local amplification. In a more specific embodiment, the aberrant c-MET is a c-MET mutation, wherein the c-MET mutation, without limitation, includes MET exon 14 skipping mutations (MET...). ex14), Y1003C, Y1003F, Y1003N, Y1003S, G1090A, G1090S, V1092I, V1092L, H1094L, H1094R, H1094Y, N1100Y, N1106D, M1131T, D1133V, M1149T, V1155L, Y1159H, V1188L, G1163R, G1163E, D1164G, L1195V, L1195F, F1200I, F1200L, V1206L, M1211T, L1213V, 1220I, D1228N, D1228H, D1228A, D1228E, D1228G, D1228Y, Y1230H, Y1230C, Y1230S, Y1230D, Y1230N, Y1230S, D1246N, D1246H, Y1248C, Y1248H, or M1268T. In a more specific embodiment, the aberrant c-MET is a c-MET fusion, wherein the c-MET fusion is TPR-MET, PTPRZ1-MET, CLIP2-MET, KIF5B-MET, TFG-MET, CAPZA2-MET, ST7-MET, BAIAP2L1-MET, C8orf34-MET, TRIM4-MET, STARD3NL-MET, or OXR1-MET. In a more specific embodiment, the aberrant c-MET is a c-MET fusion mutation, wherein the fusion mutation, without limitation, includes TPR-MET-G1163R, TPR-MET-L1195V, TPR-MET-L1195F, TPR-MET-D1228N, or TPR-MET-Y1230H. In a more specific embodiment, the aberrant c-MET is c-MET overexpression.

[0060] In a specific implementation plan, c-MET-mediated diseases and their metastases are cancers. In a more specific implementation plan, c-MET-mediated diseases include lung cancer, gastric cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, thyroid cancer, bladder cancer, bile duct cancer, colorectal cancer, head and neck cancer, nasopharyngeal carcinoma, ovarian cancer, breast cancer, cervical cancer, salivary gland cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, soft tissue sarcoma, multiple myeloma, lymphoma, leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma, and nephroblastoma, and their metastases. In a more specific implementation plan, c-MET-mediated diseases include lung cancer and its metastases. In a more specific implementation plan, c-MET-mediated diseases include non-small cell lung cancer and its metastases. In a more specific implementation plan, c-MET-mediated diseases include gastric cancer and its metastases. In a more specific implementation plan, c-MET-mediated diseases include pancreatic cancer and its metastases.

[0061] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed description, embodiments, and claims.

[0062] definition

[0063] Chemical definition

[0064] The definitions of specific functional groups and chemical terms are described in more detail below.

[0065] When listing a range of values, it is assumed that each value and a subrange within that range will be included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0066] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C 1-4 Alkyl and C 1-3Alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Regardless of whether the alkyl group is preceded by "substituted," each alkyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0067] “C 1-6 "Alkylide group" refers to =CRR, where R is H or C. 1-5 alkyl.

[0068] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). In some embodiments, C 2-4 Alkenyl groups are particularly preferred. Examples of such alkenyl groups include, but are not limited to: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. Regardless of whether the alkenyl group is preceded by "substituted," each alkenyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0069] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, C 2-4 The alkynyl group is particularly preferred. In some embodiments, the alkynyl group does not contain any double bonds. One or more carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of the alkynyl group include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), and so on. Regardless of whether the alkynyl group is preceded by the word "substituted," each alkynyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0070] “C 1-6 "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted carbon group. 1-6 Alkyl group. In some embodiments, C 1-4 Alkoxy and C 1-3 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0071] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

[0072] Therefore, "C" 1-6 "Halogenated alkyl" and "C" 1-6 "Haloalkoxy" refers to the above "C" 1-6 "alkyl" and "C" 1-6 "Alkoxy" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1- 3-Hydroalkyl and C 1-2 Halogenated alkyl groups. In some embodiments, C 1-4 Halogenated alkoxy groups are particularly preferred, and C4 is more preferred. 1-3 Halogenated alkoxy groups and C 1-2 Haloalkoxy groups. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Exemplary haloalkoxy groups include, but are not limited to: -OCH2F, -OCHF2, -OCF3, etc.

[0073] “C 1-6 Alkylene, C 1-6 "Ideinyl" and "C" 1-6 "Iso-ynyl" refers to the group that has the C group removed. 1-6 Alkyl, C 1-6 alkenyl and C 1-6 The other hydrogen atom of the alkynyl group forms a divalent group. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-2 Alkylene is preferred. In some embodiments, C 2-4 C1- and C2-olefinic groups are preferred. In some embodiments, C1-olefinic groups are preferred.2-4 Alkyneyl groups and C2 alkyneyl groups are preferred. Examples of the alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, and -CH2C(CH3). 2- Examples of the alkenyl group include, but are not limited to: -CH=CH-, -CH=CH-CH2-, -CH=C(CH3)-CH2-, -CH=CH-CH(CH3)-, -CH=CH-CH2-CH2-, -CH2-CH=CH-CH2-, and -CH2-CH=C(CH3)-CH2-. Examples of the alkyne group include, but are not limited to: -C≡C-, -C≡C-CH2-, -C≡C-CH(CH3)-, -C≡C-CH2-CH2-, -CH2-C≡C-CH2-, and -CH2-C≡C-CH(CH3)-. Regardless of whether the alkylene, alkenyl, and alkyne groups are modified with "substituted", each of the alkylene, alkenyl, and alkyne groups is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0074] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-8 Cycloalkyl groups are preferred, C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl. Cycloalkyl can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic can be fused, spirocyclic, bridged, or a combination thereof. Bicyclic or polycyclic may include one or more aromatic rings, but the ring system as a whole is not aromatic, and in such cases, the number of carbons continues to indicate the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), bicyclo[1.1.1]pentyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), bicyclo[2.1.1]hexyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), etc. 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10), spiro[4.5]decyl(C 10 ), etc. Regardless of whether the cycloalkyl group is modified with "substituted", each of the cycloalkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, with suitable substituents defined as follows.

[0075] "3-10 membered heterocyclic group" refers to a group having a 3- to 10 membered non-aromatic ring system with a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, 4- to 10 membered heterocyclic groups are preferred, which are 4- to 10 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 4 cyclic heteroatoms; in some embodiments, 3- to 7 membered heterocyclic groups are preferred, which are 3- to 7 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms; in some embodiments, 3- to 6 membered heterocyclic groups are particularly preferred, which are 3- to 6 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably, 5- to 6 membered heterocyclic groups are 5- to 6 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms. The heterocyclic group can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be fused rings, spirocyclic rings, bridged rings, or combinations thereof. A bicyclic or polycyclic ring may include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic. In such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. Regardless of whether the heterocyclic group is preceded by "substituted," each of the heterocyclic groups is independently and optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0076] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclopropane, oxacyclopropane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclobutane, oxacyclobutane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxeheptanyl, and thionylheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxeheptanyl, and thionylheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0077] “C 6-14 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C... 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C14”). 14 "Aryl"; for example, anthracene). In some embodiments, C 6-10Aryl groups are particularly preferred, and more preferably C6 aryl groups. Aryl groups also include ring systems in which the aforementioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is preceded by the word "substituted," each aryl group may be optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0078] "5-10-membered heteroaryl" refers to a group comprising a 4n+2 aromatic ring system of a 5-10-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6 or 10 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6-membered heteroaryl is particularly preferred, which is a 4n+2 aromatic ring system of a 5-6-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. In some embodiments, a 5-membered heteroaryl group is particularly preferred, which is a 4n+2 aromatic ring system of a 5-membered monocyclic or bicyclic ring having a cyclic carbon atom and 1-4 cyclic heteroatoms. Regardless of whether the heteroaryl group is preceded by "substituted", each of the heteroaryl groups is optionally substituted independently, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined as follows.

[0079] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirheptatrienyl, oxaheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0080] A "fused ring" refers to a polycyclic group in which rings share two adjacent ring atoms and a chemical bond. It may contain one or more double or triple bonds and can contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Fused rings are typically 5-20 membered, 5-14 membered, 5-12 membered, 6-12 membered, 5-10 membered, or 6-10 membered. Regardless of whether the fused ring is preceded by a "substituted" designation, each element of the fused ring can be independently and optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are defined as follows.

[0081] A "spirocyclic ring" is a polycyclic group that shares a single carbon atom (called a spiro atom) between its rings. It can contain 0 or 1 double or triple bonds and 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Spirocyclic rings are typically 6-14 membered, 6-12 membered, or 6-10 membered. Regardless of whether the spirocyclic ring is pre-modified with "substituents," each member of the spirocyclic ring can be independently and optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are defined as follows.

[0082] A "bridged ring" refers to two rings sharing two non-adjacent ring atoms. It can contain one or more double or triple bonds and 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Bridged rings are typically 5-20 membered, 5-14 membered, 5-12 membered, 6-12 membered, 5-10 membered, or 6-10 membered. Regardless of whether the bridged ring is preceded by a "substituted" modification, each member of the bridged ring can be independently and optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are defined as follows.

[0083] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X-, -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -OC(=NR) bb )R aa -OC(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NRbb SO2R aa -NR bb SO2R aa -SO2N(R) bb )2、-SO2R aa -SO2OR aa -OSO2R aa -S(=O)R aa -OS(=O)R aa 、-Si(R aa )3、-OSi(R aa 3. -C(=S)N(R) bb )2、-C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0084] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0085] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0086] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0087] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0088] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee-SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0089] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0090] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0091] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl)+ X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1- 6-alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1- 6-alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0092] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. ccThe groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0093] "Deuterated" or "D" refers to the substitution of one or more hydrogen atoms in a compound or group by deuterium; deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms "one or more deuterated" and "one or more deuterated" are used interchangeably.

[0094] Therefore, "C" 1-6 "Deuterated alkyl" refers to the above "C 1-6 The alkyl group is replaced by one or more deuterium atoms. In some embodiments, C 1-4 Deuterated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-3 Deuterated alkyl and C 1-2 Deuterated alkyl groups. Exemplary deuterated alkyl groups include, but are not limited to: -CD3, -CH2D, -CHD2, -CHDCH2D, -CD2CHD2, -CD2CD3, etc.

[0095] "Non-deuterated compounds" refer to compounds containing a deuterium atom ratio no higher than the natural deuterium isotope content (0.015%).

[0096] The content of deuterium isotopes at the deuterated position is at least 0.015% greater than the content of natural deuterium isotopes, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, and more preferably greater than 99%.

[0097] The term "pharmaceutically acceptable salt" refers to those salts that, within the bounds of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Salts formed using methods conventional in the art are also included, such as ion exchange methods. Other pharmaceutically acceptable salts include: adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentylpropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, gluconate salts, glyceryl phosphate salts, glucuronate salts, hemisulfate salts, heptarate salts, hexanoate salts, hydroiodate salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, dihydroxynaphthalate salts, pectin ester salts, persulfate salts, 3-phenylpropionate salts, phosphate salts, picrate salts, p-pentanoate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts, if appropriate, include non-toxic ammonium salts, quaternary ammonium salts, and amine cations that form with counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonates, and aryl sulfonates.

[0098] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0099] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0100] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0101] The term "combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form. Detailed Implementation

[0102] compound

[0103] In this document, “compound of the present invention” refers to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV') or (V') (including subsets of each formula, such as compounds of formula (III-1)), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0104] This invention provides compounds that specifically degrade c-MET through targeted ubiquitination of the c-MET protein and subsequent proteasome degradation. The compounds of this invention bind to the universally expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, thereby leading to the recruitment and ubiquitination of c-MET (specifically, for example, amplified c-MET, mutant c-MET, fused c-MET, and / or overexpressed c-MET).

[0105] The present invention provides compounds that inhibit abnormal c-MET activity, including c-MET amplification, c-MET mutation, c-MET fusion and / or c-MET overexpression.

[0106] In one embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), or (V'), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0107] in,

[0108] X1 is N or CR X1 ;where R X1 It can be H, D, CN, NO2, or halogen;

[0109] X2 is N or CR X2 ;where R X2 It can be H, D, CN, NO2, or halogen;

[0110] X3 is N or CR X3 ;where R X3 It can be H, D, CN, NO2, or halogen;

[0111] Y is C(R) Y )2, O, S, NH or S(O)2; where each R Y Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0112] p is 0, 1, 2, 3, 4, 5 or 6;

[0113] Each R1 is independently D, CN, NO2, or a halogen, or two adjacent R1s together with the atoms they are attached to form a 5-6 membered monocyclic heterocycle, wherein the 5-6 membered monocyclic heterocycle is optionally composed of one or more atoms selected from oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Substitution of alkyl groups;

[0114] Each of R2, R3, and R5 is independently H, C 1-6 Alkyl or 3-6 membered monocyclic carbon ring; wherein the group is optionally substituted by one or more groups selected from D or halogens;

[0115] R4 can be H, D, CN, NO2, or a halogen;

[0116] Each A is independently C. 1-6 The ynyl group is a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more R groups.

[0117] Each m is independently either 0 or 1;

[0118] Each B is independently a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more Rs;

[0119] Each C is independently a chemical bond, a phenylene group, or a 5-6 membered heteroaryl group; wherein the phenylene group and the 5-6 membered heteroaryl group are optionally substituted by one or more R groups;

[0120] m' is 0 or 1;

[0121] When m' is 1, B' is B; or

[0122] When m' is 0, ring B' is a divalent group selected from 3-6 member monocyclic carbon rings, 6-10 member fused carbon rings, 6-10 member fused heterocycles, 6-10 member bridged carbon rings, 6-10 member bridged heterocycles, 6-9 member spirocyclic carbon rings, and 6-9 member spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R;

[0123] n is 0 or 1;

[0124] D is a chemical bond, a phenylene group, or a 5-6-membered heteroaryl group; wherein the phenylene group and the 5-6-membered heteroaryl group are optionally substituted by one or more R groups;

[0125] Each R is independently H, D, OH, CN, NO2, NH2, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two Rs together with the atoms they are attached to form a 3-6 membered monocyclic carbon ring or a 4-7 membered monocyclic heterocycle;

[0126] Each U is independent as follows:

[0127] in,

[0128] Indicates a single bond or a double bond;

[0129] Each Q1 is independently C(O) or C(R). U4 )2;

[0130] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0131] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0132] Each Q2 is independently either N or CH;

[0133] Q3 and Q4 are each independently N or CH;

[0134] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0135] P1 is N, C, or CR U4 ;

[0136] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0137] P4 and P5 are each independently N or C;

[0138] z is 0, 1, or 2;

[0139] H1 is N or CR U4 ;

[0140] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0141] Each h is independently 0, 1, 2, 3 or 4;

[0142] Each k is independently 0, 1, 2, or 3;

[0143] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0144] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0145] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0146] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0147] In another embodiment, the present invention relates to a compound of formula (I) or formula (I'), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X1 is N, CH, CD or CF, X2 is N, CH, CD or CF, and X3 is N, CH, CD or CF.

[0148] In one specific embodiment, the present invention relates to a compound of formula (I) or formula (I'), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X1 is CH, X2 is N and X3 is N.

[0149] In another specific embodiment, the present invention relates to a compound of formula (I) or formula (I'), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X1 is N, X2 is CH and X3 is N.

[0150] In another specific embodiment, the present invention relates to a compound of formula (I) or formula (I'), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X1 is N, X2 is CF and X3 is CH.

[0151] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein D is a chemical bond, a phenylene or a 5-6-membered heteroaryl group; wherein the phenylene and the 5-6-membered heteroaryl group are optionally substituted with one or more R groups.

[0152] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein D is a chemical bond.

[0153] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein D is a phenylene, wherein the aforementioned group is optionally substituted with one or more R; in a specific embodiment of D, D is a phenylene optionally substituted with one or more D or F.

[0154] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein D is a 5-6-membered heteroaryl group, wherein the aforementioned group is optionally substituted by one or more R groups; in a specific embodiment of D, D is a 5-6-membered heteroaryl group optionally substituted by one or more D or F groups; in a more specific embodiment of D, D is a 5-6-membered heteroaryl group containing one or more N atoms; in another more specific embodiment of D, D is a pyrazolyl group.

[0155] In another embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein p is 0 or 1 and R1 is D or a halogen; in one embodiment of formula (I), p is 0 and R1 is D or a halogen; in another embodiment of formula (I), p is 1 and R1 is D or a halogen; in yet another embodiment of formula (I), p is 1 and R1 is D or F.

[0156] In another embodiment, the present invention relates to a compound of formula (I') or formula (II'), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R3 is C 1-6 Alkyl; in one specific embodiment of R3, R3 is methyl.

[0157] In another embodiment, the present invention relates to a compound of formula (II'), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R4 is H, D, CN or F; in a specific embodiment of R4, R4 is H or CN.

[0158] In another embodiment, the present invention relates to a compound of formula (I) or formula (II'), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 0 or 1; in one specific embodiment of n, n is 0; in another specific embodiment of n, n is 1.

[0159] In another embodiment, the present invention relates to a compound of formula (III), formula (IV) or formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2 is methyl or cyclopropane.

[0160] In another embodiment, the present invention relates to a compound of formula (III'), formula (IV') or formula (V'), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R5 is H or methyl.

[0161] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), or (V'), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein Y is CH2, CF2, CH(CH3), S, or S(O)2; in one specific embodiment of Y, Y is CH2; in another specific embodiment of Y, Y is CF2; in another specific embodiment of Y, Y is CH(CH3); in another specific embodiment of Y, Y is S; in another specific embodiment of Y, Y is S(O)2.

[0162] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), or (V'), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein the compounds are compounds of formula (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1):

[0163] Each A is independently C. 1-6 The ynyl group is a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more R groups.

[0164] Each m is independently either 0 or 1;

[0165] Each B is independently a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more Rs;

[0166] Each C is independently a chemical bond, a phenylene group, or a 5-6 membered heteroaryl group; wherein the phenylene group and the 5-6 membered heteroaryl group are optionally substituted by one or more R groups;

[0167] m' is 0 or 1;

[0168] When m' is 1, B' is B; or

[0169] When m' is 0, ring B' is a divalent group selected from 3-6 member monocyclic carbon rings, 6-10 member fused carbon rings, 6-10 member fused heterocycles, 6-10 member bridged carbon rings, 6-10 member bridged heterocycles, 6-9 member spirocyclic carbon rings, and 6-9 member spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R;

[0170] n is 0 or 1;

[0171] Each R is independently H, D, OH, CN, NO2, NH2, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two Rs together with the atoms they are attached to form a 3-6 membered monocyclic carbon ring or a 4-7 membered monocyclic heterocycle;

[0172] Each U is independent as follows:

[0173] in,

[0174] Indicates a single bond or a double bond;

[0175] Each Q1 is independently C(O) or C(R).U4 )2;

[0176] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0177] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0178] Each Q2 is independently either N or CH;

[0179] Q3 and Q4 are each independently N or CH;

[0180] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0181] P1 is N, C, or CR U4 ;

[0182] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0183] P4 and P5 are each independently N or C;

[0184] z is 0, 1, or 2;

[0185] H1 is N or CR U4 ;

[0186] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0187] Each h is independently 0, 1, 2, 3 or 4;

[0188] Each k is independently 0, 1, 2, or 3;

[0189] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0190] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0191] Each R U3Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0192] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0193] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0194] in,

[0195] Indicates a single bond or a double bond;

[0196] Each Q1 is independently C(O) or C(R). U4 )2;

[0197] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0198] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0199] Each Q2 is independently either N or CH;

[0200] Q3 and Q4 are each independently N or CH;

[0201] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0202] P1 is N, C, or CR. U4 ;

[0203] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0204] P4 and P5 are each independently N or C;

[0205] Each h is independently 0, 1, 2, 3 or 4;

[0206] Each k is independently 0, 1, 2, or 3;

[0207] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0208] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0209] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0210] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0211] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0212] in,

[0213] Each Q1 is independently C(O) or C(R). U4 )2;

[0214] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0215] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0216] Each h is independently 0, 1, 2, 3 or 4;

[0217] Each k is independently 0, 1, 2, or 3;

[0218] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0219] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0220] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0221] Each R U4Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkanes or 4-7 membered heterocycles; or two Rs U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0222] In one specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0223] in,

[0224] Each Q1 is independently C(O) or C(R). U4 )2;

[0225] Each k is independently 0, 1, or 2;

[0226] Each R U3 Each is independently either D or halogen;

[0227] Each R U4 Each can be H, D, or halogen independently.

[0228] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0229] in,

[0230] Q2 is either N or CH;

[0231] Q3 is either N or CH;

[0232] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0233] h can be 0, 1, 2, 3, or 4;

[0234] k can be 0, 1, 2, or 3;

[0235] R U1 For H, C 1-6 Alkyl or C 3-7 cycloalkyl;

[0236] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0237] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quinary aromatic hydrocarbons.

[0238] In one specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0239] in,

[0240] Q2 is either N or CH;

[0241] Q3 is either N or CH;

[0242] Each k is independently 0, 1, or 2;

[0243] Each R U3 Each is independently either D or halogen.

[0244] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0245] in,

[0246] Indicates a single bond or a double bond;

[0247] Q2 is either N or CH;

[0248] P1 is N, C, or CR. U4 ;

[0249] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0250] P4 and P5 are each independently N or C;

[0251] h can be 0, 1, 2, 3, or 4;

[0252] k can be 0, 1, 2, or 3;

[0253] R U1 For H, C 1-6 Alkyl or C 3-7 cycloalkyl;

[0254] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0255] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0256] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0257] In one specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0258] in,

[0259] Q2 is either N or CH;

[0260] Each P2 is independently either N or CR. U4 ;

[0261] Each P3 is independently N, O, S, NR. U4 or CR U4 ;

[0262] Each k is independently 0, 1, or 2;

[0263] Each R U3 Each is independently either D or halogen;

[0264] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups.

[0265] In another specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0266] in,

[0267] Q2 is either N or CH;

[0268] P2 is N or CR U4 ;

[0269] P3 is O, S, or NR. U4 ;

[0270] k is 0, 1, or 2;

[0271] Each R U3 Each is independently either D or halogen;

[0272] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic rings.

[0273] In a more specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0274] in,

[0275] k is 0, 1, or 2;

[0276] Each R U3 Each is independently either D or halogen;

[0277] R U4 For H, C 1-6 Alkyl, C 3-7Cycloalkyl or 4-7 membered heterocyclic groups.

[0278] In another more specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each U is independently:

[0279] in,

[0280] k is 0, 1, or 2;

[0281] Each R U3 Each is independently either D or halogen.

[0282] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1) or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein m and m' are each independently 0 or 1.

[0283] In one specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1) or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein m and m' are both 0.

[0284] In another specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1) or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein m and m' are both 1.

[0285] In another embodiment, the invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each A is independently C. 1-6 The ynyl group is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more R.

[0286] In another embodiment, the invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each A is independently C. 1-6 The group is acetylenoid, wherein the group is optionally substituted with one or more R; in a specific embodiment of A, A is acetylenoid.

[0287] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each A is independently a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more R.

[0288] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each A is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, and 6-9 membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0289] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each A is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered bridged heterocycles, and 6-9 membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0290] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each A is independently a divalent group selected from 4-7 membered monocyclic heterocycles and 6-9 membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0291] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each A is independently a divalent group selected from 4-7 membered monocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more R.

[0292] In one specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each A is independently... The aforementioned groups may optionally be substituted with one or more R groups.

[0293] In another specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each A is independently... The aforementioned groups may optionally be substituted with one or more R groups.

[0294] In a preferred embodiment of A, each R is independently D, -OH, F, or C. 1-3 Alkyl groups, or two R groups together with the atoms they are attached to, form 3-6 membered monocyclic carbon rings.

[0295] In another preferred embodiment of A, each A is independently...

[0296] In another preferred embodiment of A, each A is independently...

[0297] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each B is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, and 6-9 membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0298] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each B is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, and 6-9 membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0299] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each B is independently a divalent group selected from 4-7 membered monocyclic heterocycles and 6-9 membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0300] In a preferred embodiment of B, each B is independently configured as follows: The aforementioned groups may optionally be substituted with one or more R groups.

[0301] In another preferred embodiment of B, each B is independently configured as follows: The aforementioned groups may optionally be substituted with one or more R groups.

[0302] In another preferred embodiment of B, each R is independently D, -OH, F, or C. 1-3 Alkyl groups, or two R groups together with the atoms they are attached to, form 3-6 membered monocyclic carbon rings.

[0303] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein, when m' is 0, B' is a divalent group selected from 6-10 fused heterocycles, 6-10 bridged heterocycles, and 6-9 spirocyclic heterocycles; wherein the above-mentioned groups are optionally substituted by one or more R.

[0304] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein, when m' is 0, B' is a divalent group selected from 6-10 fused heterocycles and 6-9 spirocyclic heterocycles; wherein the above-mentioned groups are optionally substituted by one or more R.

[0305] In a preferred embodiment of B', B' is The aforementioned groups may optionally be substituted with one or more R groups.

[0306] In another preferred embodiment of B', B' is The aforementioned groups may optionally be substituted with one or more R groups.

[0307] In another preferred embodiment of B', each R is independently D, -OH, F, or C. 1-3 Alkyl groups, or two R groups together with the atoms they are attached to, form 3-6 membered monocyclic carbon rings.

[0308] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each C is independently a chemical bond, a phenylene group, or a 5-6-membered heteroaryl group; wherein the phenylene group and the 5-6-membered heteroaryl group are optionally substituted with one or more R groups.

[0309] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each C is a chemical bond.

[0310] In another embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein each C is independently phenylene or a 5-6 membered heteroaryl group; wherein the above groups are optionally substituted by one or more R groups.

[0311] In one specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1) or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein each C is independently phenylene, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrazoloyl, pyrrolyl, thiopheneyl, imidazoyl, oxazolyl, isoxazolyl, furanyl, thiazoyl or isothiazolyl.

[0312] In another specific embodiment, the present invention relates to compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1) or (V'-1), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein each C is independently phenylene, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazinyl, pyrazolyl or imidazolyl.

[0313] X1, X2 and X3

[0314] In one implementation, X1 is N or CR X1 , where R X1 X1 is H, D, CN, NO2, or a halogen; in another embodiment, X1 is N; in another embodiment, X1 is CR. X1 .

[0315] In one implementation, X2 is N or CR X2 , where R X2 X2 is H, D, CN, NO2, or a halogen; in another embodiment, X2 is N; in another embodiment, X2 is CR. X2 .

[0316] In one implementation, X3 is N or CR X3 , where R X3 X3 is H, D, CN, NO2, or a halogen; in another embodiment, X3 is N; in another embodiment, X3 is CR. X3 .

[0317] R X1 R X2 and R X3

[0318] In one implementation, R X1 It is H, D, CN, NO2, or halogen; in one specific embodiment, R X1 For H; in another specific implementation, R X1 For D; in another specific implementation, R X1 For CN; in another specific implementation, R X1 For NO2; in another specific implementation, R X1 For halogen; in another specific implementation, R X1 For F, Cl, Br, or I; in another specific embodiment, R X1 It is F.

[0319] In one implementation, R X2 It is H, D, CN, NO2, or halogen; in one specific embodiment, R X2 For H; in another specific implementation, R X2 For D; in another specific implementation, R X2 For CN; in another specific implementation, R X2 For NO2; in another specific implementation, R X2 For halogen; in another specific implementation, RX2 For F, Cl, Br, or I; in another specific embodiment, R X2 It is F.

[0320] In one implementation, R X3 It is H, D, CN, NO2, or halogen; in one specific embodiment, R X3 For H; in another specific implementation, R X3 For D; in another specific implementation, R X3 For CN; in another specific implementation, R X3 For NO2; in another specific implementation, R X3 For halogen; in another specific implementation, R X3 For F, Cl, Br, or I; in another specific embodiment, R X3 It is F.

[0321] In one specific embodiment, X1, X2, and X3 are each independently N, CH, CD, C(CN), C(NO2), CF, CCl, CBr, or CI; in another specific embodiment, X1, X2, and X3 are each independently N, CH, CD, or CF; in a preferred embodiment, X1 is CH, X2 is N, and X3 is N; in another preferred embodiment, X1 is N, X2 is CH, and X3 is N; in yet another preferred embodiment, X1 is N, X2 is CF, and X3 is CH.

[0322] Y and R Y

[0323] In one implementation, Y is C(R) Y )2, O, S, NH or S(O)2; where each R Y Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups.

[0324] In another embodiment, Y is O, S, NH, or S(O)2; in one specific embodiment of Y, Y is O; in another specific embodiment of Y, Y is S; in another specific embodiment of Y, Y is NH; in another specific embodiment of Y, Y is S(O)2.

[0325] In another implementation, Y is C(R) Y )2, where each R Y Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6Halogenated alkyl; in another embodiment, each R Y Each is independently H, D, halogen, or C. 1-6 Alkyl; in one specific embodiment, an R Y For H, another R Y For D; in another specific implementation, an R Y For H, another R Y For halogen; in another specific embodiment, an R Y For H, another R Y C 1-6 Alkyl; in another specific embodiment, an R Y For H, another R Y C 1- 6-Deuterated alkyl; in another specific embodiment, an R Y For H, another R Y C 1-6 Halogenated alkyl; in another specific embodiment, an R Y For D, another R Y For halogen; in another specific embodiment, an R Y For D, another R Y C 1-6 Alkyl; in another specific embodiment, an R Y For D, another R Y C 1-6 Deuterated alkyl; in another specific embodiment, an R Y For D, another R Y C 1-6 Halogenated alkyl; in another specific embodiment, an R Y For halogens, another R Y C 1-6 Alkyl; in another specific embodiment, an R Y For halogens, another R Y C 1-6 Deuterated alkyl; in another specific embodiment, an R Y For halogens, another R Y C 1-6 Halogenated alkyl; in another specific embodiment, an R Y C 1-6 Alkyl, another R Y C 1-6 Deuterated alkyl; in another specific embodiment, an R Y C 1-6 Alkyl, another R Y C 1-6Halogenated alkyl; in another specific embodiment, an R Y C 1-6 Deuterated alkyl, another R Y C 1- 6-Hydroalkyl; in another specific embodiment, the two Rs Y Both are H; in another specific implementation, both R Y Both are D; in another specific implementation, both R Y All are F.

[0326] In one specific embodiment of Y, Y is CH2, CD2, CF2, CHD, CHF or CH(CH3); in another specific embodiment of Y, Y is CH2, CF2 or CH(CH3); in another specific embodiment of Y, Y is CH2; in another specific embodiment of Y, Y is CF2; in another specific embodiment of Y, Y is CH(CH3).

[0327] p

[0328] In one implementation, p is 0, 1, 2, 3, 4, 5, or 6; in another implementation, p is 0; in yet another implementation, p is 1; in yet another implementation, p is 2; in yet another implementation, p is 3; in yet another implementation, p is 4; in yet another implementation, p is 5; in yet another implementation, p is 6.

[0329] R1

[0330] In one embodiment, each R1 is independently D, CN, NO2, or a halogen, or two adjacent R1s together with the atoms they are attached to form a 5-6 membered monocyclic heterocycle, wherein the 5-6 membered monocyclic heterocycle is optionally selected from one or more atoms selected from oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Substitution of alkyl groups with haloalkyl groups.

[0331] In another embodiment, each R1 is independently D, CN, NO2, or a halogen; in one specific embodiment, each R1 is independently D or a halogen; in another specific embodiment, R1 is D; in another specific embodiment, each R1 is independently F, Cl, Br, or I; in another specific embodiment, R1 is F; in another specific embodiment, R1 is CN; in another specific embodiment, R1 is NO2.

[0332] In another embodiment, two adjacent R1 atoms, together with the atoms they are attached to, form a 5-6 membered monocyclic heterocycle, wherein the 5-6 membered monocyclic heterocycle is optionally composed of one or more atoms selected from oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Substitution of alkyl groups with haloalkyl groups.

[0333] R2

[0334] In one implementation, each R2 is independently H, C 1-6 Alkyl or 3-6 membered monocyclic carbon ring; wherein the group is optionally substituted by one or more groups selected from D or halogens.

[0335] In another embodiment, R2 is H, which is optionally substituted with a group selected from D or halogens.

[0336] In another implementation, each R2 is independently C 1-6 Alkyl groups, optionally substituted with one or more groups selected from D or halogens; in one embodiment, each R2 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; in another embodiment, each R2 is independently methyl, ethyl, n-propyl, or isopropyl; in a preferred embodiment, R2 is methyl.

[0337] In another embodiment, each R2 is independently a 3-6 membered monocyclic carbon ring, optionally substituted with one or more groups selected from D or halogens; in a specific embodiment, each R2 is independently cyclopropane, cyclobutane, cyclopentane, or cyclohexane; in a preferred embodiment, R2 is cyclopropane.

[0338] R3

[0339] In one implementation, each R3 is independently H, C 1-6 Alkyl or 3-6 membered monocyclic carbon ring; wherein the group is optionally substituted by one or more groups selected from D or halogens.

[0340] In another embodiment, R3 is H, which is optionally substituted with a group selected from D or halogens.

[0341] In another implementation, each R3 is independently C 1-6Alkyl groups, optionally substituted with one or more groups selected from D or halogens; in one embodiment, each R3 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; in another embodiment, each R3 is independently methyl, ethyl, n-propyl, or isopropyl; in a preferred embodiment, R3 is methyl.

[0342] In another embodiment, each R3 is independently a 3-6 membered monocyclic carbon ring, optionally substituted with one or more groups selected from D or halogens; in one specific embodiment, each R3 is independently cyclopropane, cyclobutane, cyclopentane, or cyclohexane; in another specific embodiment, R3 is cyclopropane.

[0343] R4

[0344] In one embodiment, R4 is H, D, CN, NO2, or a halogen; in another embodiment, R4 is H, D, CN, or NO2; in another embodiment, R4 is H or CN; in one specific embodiment, R4 is H; in another specific embodiment, R4 is D; in another specific embodiment, R4 is CN; in another specific embodiment, R4 is NO2; in another specific embodiment, R4 is a halogen; in another specific embodiment, R4 is F, Cl, Br, or I; in another specific embodiment, R4 is F.

[0345] R5

[0346] In one implementation, each R5 is independently H, C 1-6 Alkyl or 3-6 membered monocyclic carbon ring; wherein the group is optionally substituted by one or more groups selected from D or halogens.

[0347] In another implementation, R5 is H.

[0348] In another implementation, each R5 is independently C 1-6 Alkyl groups, optionally substituted with one or more groups selected from D or halogens; in one embodiment, each R5 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; in another embodiment, each R5 is independently methyl, ethyl, n-propyl, or isopropyl; in a preferred embodiment, R5 is methyl.

[0349] In another embodiment, each R5 is independently a 3-6 membered monocyclic carbon ring, optionally substituted with one or more groups selected from D or halogens; in one specific embodiment, each R5 is independently cyclopropane, cyclobutane, cyclopentane, or cyclohexane; in another specific embodiment, R5 is cyclopropane.

[0350] A

[0351] In one implementation scheme, each A is independently C. 1-6 The ynyl group is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more R.

[0352] In another implementation, each A is independently C. 1-6 The group is acetylenoid, wherein the group is optionally substituted with one or more R; in one specific embodiment, A is acetylenoid.

[0353] In another embodiment, each A is independently a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocycles, 6-10 membered fused carbon rings, 6-10 membered fused heterocycles, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocycles, 6-9 membered spirocyclic carbon rings, and 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R.

[0354] In another embodiment, each A is independently a divalent group selected from 4-7-membered monocyclic heterocycles, 6-10-membered fused heterocycles, 6-10-membered bridged heterocycles, and 6-9-membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more Rs.

[0355] In another embodiment, each A is independently a divalent group selected from 4-7-membered monocyclic heterocycles, 6-10-membered bridged heterocycles, and 6-9-membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0356] In another embodiment, each A is independently a divalent group selected from 4-7 membered monocyclic heterocycles and 6-9 membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0357] In another embodiment, each A is independently a divalent group of a 4-7 member monocyclic heterocycle, wherein the aforementioned group is optionally substituted by one or more R.

[0358] In another embodiment, each A is independently a divalent group of a 6-9 membered spirocyclic heterocycle, wherein the aforementioned group is optionally substituted by one or more R.

[0359] In one specific implementation plan, each A is independently for The aforementioned groups may optionally be substituted with one or more R groups.

[0360] In another specific implementation, each A is independently for The aforementioned groups may optionally be substituted with one or more R groups.

[0361] In a preferred embodiment of A, each A is independently... The aforementioned groups may optionally be substituted with one or more R groups.

[0362] In another preferred embodiment of A, each R is independently D, -OH, F, or C. 1-3 Alkyl groups, or two R groups together with the atoms they are attached to, form 3-6 membered monocyclic carbon rings.

[0363] In another preferred embodiment of A, each A is independently...

[0364] In another preferred embodiment of A, each A is independently...

[0365] In a particularly preferred embodiment of A, each A is independently...

[0366] In another particularly preferred embodiment of A, each A is independently...

[0367] In another particularly preferred embodiment of A, each A is independently...

[0368] B

[0369] In one embodiment, each B is independently a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocycles, 6-10 membered fused carbon rings, 6-10 membered fused heterocycles, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocycles, 6-9 membered spirocyclic carbon rings, and 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R.

[0370] In another embodiment, each B is independently a divalent group selected from 4-7-membered monocyclic heterocycles, 6-10-membered fused heterocycles, 6-10-membered bridged heterocycles, and 6-9-membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more Rs.

[0371] In another embodiment, each B is independently a divalent group selected from 4-7-membered monocyclic heterocycles, 6-10-membered fused heterocycles, and 6-9-membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0372] In another embodiment, each B is independently a divalent group selected from 4-7 membered monocyclic heterocycles and 6-9 membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs.

[0373] In another embodiment, each B is independently a divalent group of a 4-7 member monocyclic heterocycle, wherein the aforementioned group is optionally substituted by one or more R.

[0374] In another embodiment, each B is independently a divalent group of a 6-9 membered spirocyclic heterocycle, wherein the aforementioned group is optionally substituted by one or more R.

[0375] In another embodiment, each B is independently a divalent group of a 6-10 fused heterocycle, wherein the aforementioned group is optionally substituted by one or more R.

[0376] In one specific implementation plan, each B independently serves as... The aforementioned groups may optionally be substituted with one or more R groups.

[0377] In another specific implementation scheme, each B independently serves as... The aforementioned groups may optionally be substituted with one or more R groups.

[0378] In a preferred embodiment of B, each B is independently configured as follows: The aforementioned groups may optionally be substituted with one or more R groups.

[0379] In another preferred embodiment of B, each R is independently D, -OH, F, or C. 1-3 Alkyl groups, or two R groups together with the atoms they are attached to, form 3-6 membered monocyclic carbon rings.

[0380] m'

[0381] In one implementation, m' is 0 or 1; in another implementation, m' is 0; in yet another implementation, m' is 1.

[0382] B'

[0383] In one implementation, when m' is 1, B' is B.

[0384] In another embodiment, when m' is 0, B' is a divalent group selected from 3-6 membered monocyclic carbon rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocycles, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocycles, 6-9 membered spirocyclic carbon rings, and 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R.

[0385] In another embodiment, when m' is 0, B' is a divalent group selected from 6-10 fused heterocycles and 6-9 spirocyclic heterocycles; wherein the above group is optionally substituted by one or more R.

[0386] In another embodiment, when m' is 0, B' is a divalent group of a 6-10 fused heterocycle, wherein the group is optionally substituted by one or more R.

[0387] In another embodiment, when m' is 0, B' is a divalent group of a 6-9 membered spirocyclic heterocycle, wherein the group is optionally substituted by one or more R.

[0388] In one specific implementation plan, B' is... The aforementioned groups may optionally be substituted with one or more R groups.

[0389] In another specific implementation scheme, B' is The aforementioned groups may optionally be substituted with one or more R groups.

[0390] In a preferred embodiment of B', each R is independently D, -OH, F, or C. 1-3 Alkyl groups, or two R groups together with the atoms they are attached to, form 3-6 membered monocyclic carbon rings.

[0391] C

[0392] In one embodiment, each C is independently a chemical bond, a phenylene group, or a 5-6 membered heteroaryl group; wherein the phenylene group and the 5-6 membered heteroaryl group are optionally substituted by one or more R groups.

[0393] In another implementation, each C is a chemical bond.

[0394] In another embodiment, each C is independently a phenylene or a 5-6 membered heteroaryl group; wherein the above groups are optionally substituted by one or more R groups.

[0395] In one specific embodiment, each C is independently phenylene, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrazoloyl, pyrroleyl, thiophenyl, imidazoyl, oxazolyl, isoxazolyl, furanyl, thiazolyl, or isothiazolyl, wherein the above groups are optionally substituted by one or more R.

[0396] In another specific embodiment, each C is independently phenylene, pyridinyl, pyrimidinyl, pyridazinyl, pyridazinyl, pyridazolyl, or imidazolyl, wherein the above groups are optionally substituted by one or more Rs.

[0397] In another specific embodiment, each C is independently phenylene, pyridinyl, pyridazinyl, pyridazinyl, pyridazolyl, or imidazolyl, wherein the above groups are optionally substituted by one or more Rs.

[0398] In a preferred embodiment of C, C is phenylene, which is optionally substituted with one or more R.

[0399] In another preferred embodiment of C, C is pyridylene, which is optionally substituted with one or more R.

[0400] In another preferred embodiment of C, C is pyridazine group, which is optionally substituted with one or more R.

[0401] In another preferred embodiment of C, C is a pyrazine group, which is optionally substituted with one or more R.

[0402] In another preferred embodiment of C, C is an imidazolyl group, which is optionally substituted with one or more R groups.

[0403] In another preferred embodiment of C, C is an imidazolyl group, which is optionally substituted with one or more R groups.

[0404] D

[0405] In one embodiment, D is a chemical bond, a phenylene group, or a 5-6-membered heteroaryl group; wherein the phenylene group and the 5-6-membered heteroaryl group are optionally substituted with one or more R groups.

[0406] In another implementation, D represents a chemical bond.

[0407] In another embodiment, D is a phenylene or a 5-6-membered heteroaryl group; wherein the phenylene and the 5-6-membered heteroaryl group are optionally substituted with one or more R groups.

[0408] In another embodiment, D is a phenylene, wherein the aforementioned group is optionally substituted with one or more R groups; in one specific embodiment, D is a phenylene optionally substituted with one or more D or F groups; in another specific embodiment, D is a phenylene optionally substituted with one or more D groups; in a more specific embodiment, D is a phenylene substituted with one, two, three, or four D groups; in another more specific embodiment, D is a phenylene substituted with one D group; in another specific embodiment, D is a phenylene optionally substituted with one or more F groups; in a more specific embodiment, D is a phenylene substituted with one, two, three, or four F groups; in another more specific embodiment, D is a phenylene substituted with one F group.

[0409] In another embodiment, D is a 5-6 membered heteroaryl group, wherein the group is optionally substituted by one or more R groups; in one specific embodiment, D is a 5-6 membered heteroaryl group optionally substituted by one or more D or F groups; in another specific embodiment, D is a pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrazoleyl, pyrroloyl, thiopheneyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, thiazolyl, or isothiazolyl group, wherein the group is optionally substituted by one or more D or F groups; in another specific embodiment, D contains one or more R groups. A 5-6 membered heteroaryl group with multiple N atoms; in another specific embodiment, D is pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrazolyl, or imidazolyl, wherein the above groups are optionally substituted by one or more D or F groups; in a more specific embodiment, D is pyridinyl; in another more specific embodiment, D is pyrimidinyl; in another more specific embodiment, D is pyridazinyl; in another more specific embodiment, D is pyrazolyl; in another more specific embodiment, D is imidazolyl.

[0410] m

[0411] In one implementation, each m is independently 0 or 1; in another implementation, m is 0; and in yet another implementation, m is 1.

[0412] n

[0413] In one implementation, each n is independently 0 or 1; in another implementation, n is 0; and in yet another implementation, n is 1.

[0414] R

[0415] In one implementation, each R is independently H, D, OH, CN, NO2, NH2, halogen, oxo, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two Rs together with the atoms they are attached to form a 3-6 membered monocyclic carbon ring or a 4-7 membered monocyclic heterocycle.

[0416] In another embodiment, each R is independently H, D, OH, CN, NO2, NH2, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0417] In another embodiment, each R is independently H, D, OH, CN, NO2, NH2, halogen, or oxo. In one specific embodiment, R is H; in another specific embodiment, R is D; in another specific embodiment, R is OH; in another specific embodiment, R is CN; in another specific embodiment, R is NO2; in another specific embodiment, R is NH2; in another specific embodiment, R is halogen; in another specific embodiment, R is F, Cl, Br, or I; in another specific embodiment, R is F; in another specific embodiment, R is oxo.

[0418] In another implementation, each R is independently C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups. In one specific embodiment, each R is independently C. 1-6 Alkyl; in another specific embodiment, each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, or n-hexyl. In another specific embodiment, each R is independently C 1-6 Halogenated alkyl; in another specific embodiment, each R is independently C. 1-4 Halogenated alkyl; in another specific embodiment, each R is independently C. 1- 3-Haloalkyl; in another specific embodiment, each R is independently C. 1-2Haloalkyl; in another specific embodiment, each R is independently -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl or -CHCl2. In another specific embodiment, each R is independently C 1-6 Alkyl group; in another specific embodiment, each R is independently C. 1-4 Alkyl group; in another specific embodiment, each R is independently C. 1-3 Alkyloxy; in another specific embodiment, each R is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy. In another specific embodiment, each R is independently C 1-6 Haloalkoxy; in another specific embodiment, each R is independently C 1-4 Haloalkoxy; in another specific embodiment, each R is independently C 1-3 Haloalkoxy; in another specific embodiment, each R is independently C 1-2 Halogenated alkoxy groups; in another specific embodiment, each R is independently -OCH2F, -OCHF2, or -OCF3.

[0419] In another implementation, each R is independently C. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups. In one specific embodiment, each R is independently C. 3-6 Cycloalkyl; in another specific embodiment, each R is independently cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, bicyclo[1.1.1]pentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, or bicyclo[2.1.1]hexyl. In another specific embodiment, each R is independently a 4-7 membered heterocyclic group; in another specific embodiment, each R is independently a 4-membered heterocyclic group; in another specific embodiment, each R is independently an azahexacyclobutyl, oxacyclobutyl, or thiohexacyclobutyl; in another specific embodiment, each R is independently a 5-membered heterocyclic group; in another specific embodiment, each R is independently a 6-membered heterocyclic group; in another specific embodiment, each R is independently piperidinyl, piperazinyl, morpholinyl, dithiohexacyclohexyl, or dioxane; in another specific embodiment, each R is independently a 7-membered heterocyclic group.

[0420] In another embodiment, the two R atoms, together with the atoms they are attached to, form a 3-6 membered monocyclic carbon ring or a 4-7 membered monocyclic heterocyclic ring. In one specific embodiment, the two R atoms, together with the atoms they are attached to, form a 3-6 membered monocyclic carbon ring; in another specific embodiment, the two R atoms, together with the atoms they are attached to, form a 3-membered monocyclic carbon ring; in another specific embodiment, the two R atoms, together with the atoms they are attached to, form a 4-membered monocyclic carbon ring; in another specific embodiment, the two R atoms, together with the atoms they are attached to, form a 5-membered monocyclic carbon ring; and in yet another specific embodiment, the two R atoms, together with the atoms they are attached to, form a 6-membered monocyclic carbon ring. In another specific embodiment, the two Rs together with the atoms they are attached to form a 4-7 member monocyclic heterocycle; in another specific embodiment, the two Rs together with the atoms they are attached to form a 4 member monocyclic heterocycle; in another specific embodiment, the two Rs together with the atoms they are attached to form a 5 member monocyclic heterocycle; in another specific embodiment, the two Rs together with the atoms they are attached to form a 6 member monocyclic heterocycle; in another specific embodiment, the two Rs together with the atoms they are attached to form a 7 member monocyclic heterocycle.

[0421] U

[0422] In one implementation scheme, each U is independently:

[0423] in,

[0424] Indicates a single bond or a double bond;

[0425] Each Q1 is independently C(O) or C(R). U4 )2;

[0426] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0427] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0428] Each Q2 is independently either N or CH;

[0429] Q3 and Q4 are each independently N or CH;

[0430] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0431] P1 is N, C, or CR U4 ;

[0432] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4or C(R) U4 )2;

[0433] P4 and P5 are each independently N or C;

[0434] z is 0, 1, or 2;

[0435] H1 is N or CR U4 ;

[0436] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0437] Each h is independently 0, 1, 2, 3 or 4;

[0438] Each k is independently 0, 1, 2, or 3;

[0439] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0440] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0441] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0442] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0443] In another implementation, each U is independently:

[0444] in,

[0445] Indicates a single bond or a double bond;

[0446] Each Q1 is independently C(O) or C(R). U4 )2;

[0447] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0448] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0449] Each Q2 is independently either N or CH;

[0450] Q3 and Q4 are each independently N or CH;

[0451] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0452] P1 is N, C, or CR U4 ;

[0453] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0454] Each h is independently 0, 1, 2, 3 or 4;

[0455] Each k is independently 0, 1, 2, or 3;

[0456] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0457] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0458] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0459] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0460] In another implementation, each U is independently:

[0461] in,

[0462] Each Q1 is independently C(O) or C(R). U4 )2;

[0463] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0464] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0465] Each h is independently 0, 1, 2, 3 or 4;

[0466] Each k is independently 0, 1, 2, or 3;

[0467] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0468] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0469] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0470] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0471] In one specific implementation scheme, each U is independently:

[0472] in,

[0473] Each Q1 is independently C(O) or C(R). U4 )2;

[0474] Each k is independently 0, 1, or 2;

[0475] Each R U3 Each is independently either D or halogen;

[0476] Each R U4 Each can be H, D, or halogen independently.

[0477] In another specific implementation, each U is independently:

[0478] in,

[0479] Each k is independently 0, 1, or 2;

[0480] Each R U3 Each is independently either D or halogen.

[0481] In another specific implementation, each U is independently:

[0482] in,

[0483] Each k is independently 0, 1, or 2;

[0484] Each R U3 Each is independently either D or halogen.

[0485] In another specific implementation, each U is independently:

[0486] in,

[0487] Each k is independently 0, 1, or 2;

[0488] Each R U3 Each is independently either D or halogen.

[0489] In a more specific implementation, each U is independently:

[0490] In another implementation, each U is independently:

[0491] in,

[0492] Q2 is either N or CH;

[0493] Q3 is either N or CH;

[0494] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0495] h can be 0, 1, 2, 3, or 4;

[0496] k can be 0, 1, 2, or 3;

[0497] R U1 For H, C 1-6 Alkyl or C 3-7 cycloalkyl;

[0498] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0499] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 heteroaryl aromatic hydrocarbons.

[0500] In one specific implementation scheme, each U is independently:

[0501] in,

[0502] Q2 is either N or CH;

[0503] Q3 is either N or CH;

[0504] Each k is independently 0, 1, or 2;

[0505] Each R U3 Each is independently either D or halogen.

[0506] In another specific implementation, each U is independently:

[0507] in,

[0508] Q3 is either N or CH;

[0509] Each k is independently 0, 1, or 2;

[0510] Each R U3 Each is independently either D or halogen.

[0511] In a more specific implementation, each U is independently:

[0512] In another implementation, each U is independently:

[0513] in,

[0514] Indicates a single bond or a double bond;

[0515] Q2 is either N or CH;

[0516] P1 is N, C, or CR U4 ;

[0517] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0518] P4 and P5 are each independently N or C;

[0519] h can be 0, 1, 2, 3, or 4;

[0520] k can be 0, 1, 2, or 3;

[0521] R U1 For H, C 1-6 Alkyl or C 3-7 cycloalkyl;

[0522] Each R U2 Each is independently D, halogen, C 1-6Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0523] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0524] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

[0525] In one specific implementation scheme, each U is independently:

[0526] in,

[0527] Q2 is either N or CH;

[0528] Each P2 is independently either N or CR. U4 ;

[0529] Each P3 is independently N, O, S, NR. U4 or CR U4 ;

[0530] Each k is independently 0, 1, or 2;

[0531] Each R U1 Each independently is H or C 1-6 alkyl;

[0532] Each R U3 Each is independently either D or halogen;

[0533] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl or 4-7 membered heterocyclic groups.

[0534] In another specific implementation, each U is independently:

[0535] in,

[0536] Q2 is either N or CH;

[0537] Each P2 is independently either N or CR. U4 ;

[0538] Each P3 is independently N, O, S, NR. U4 or CR U4 ;

[0539] Each k is independently 0, 1, or 2;

[0540] Each R U3 Each is independently either D or halogen;

[0541] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups.

[0542] In another specific implementation, each U is independently:

[0543] in,

[0544] Q2 is either N or CH;

[0545] Each k is independently 0, 1, or 2;

[0546] Each R U1 Each independently is H or C 1-6 alkyl;

[0547] Each R U3 Each is independently either D or halogen;

[0548] R U4 For H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups.

[0549] In another specific implementation, each U is independently:

[0550] in,

[0551] Each Q2 is independently either N or CH;

[0552] Each P2 is independently either N or CR. U4 ;

[0553] Each P3 is independently O, S, or NR. U4 ;

[0554] Each k is independently 0, 1, or 2;

[0555] Each R U3 Each is independently either D or halogen;

[0556] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic rings.

[0557] In a more specific implementation, each U is independently:

[0558] in,

[0559] Each k is independently 0, 1, or 2;

[0560] Each R U3 Each is independently either D or halogen;

[0561] Each R U4 Each independently represents H and C. 1-6 Alkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups.

[0562] In another, more specific implementation, each U is independently:

[0563] in,

[0564] Each k is independently 0, 1, or 2;

[0565] Each R U3 Each is independently either D or halogen;

[0566] Each R U4 Each is independent as H, C 1-6 Alkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups.

[0567] In another, more specific implementation, each U is independently:

[0568] In another implementation, each U is independently:

[0569] in,

[0570] Q2 is either N or CH;

[0571] Q3 is either N or CH;

[0572] z is 0, 1, or 2;

[0573] H1 is N or CR U4 ;

[0574] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0575] Each h is independently 0, 1, 2, 3 or 4;

[0576] Each k is independently 0, 1, 2, or 3;

[0577] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0578] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles;

[0579] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0580] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7Cycloalkanes or 4-7 membered heterocycles.

[0581] In one specific implementation scheme, each U is independently:

[0582] in,

[0583] Q3 is either N or CH;

[0584] z is 0, 1, or 2;

[0585] Each k is independently 0, 1, 2, or 3;

[0586] Each R U1 Each independently is H or C 1-6 alkyl;

[0587] Each R U3 Each is independently either D or halogen.

[0588] In another specific implementation, each U is independently:

[0589] in,

[0590] Each k is independently 0, 1, 2, or 3;

[0591] Each R U3 Each is independently either D or halogen.

[0592] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of A can be combined with B, B', C, D, X1, X2, X3, R. X1 R X2 R X3 Y, R Y , R, R1, R2, R3, R4, R5, m, m', n, p, U, Q1, Q2, Q3, Q4, P1, P2, P3, P4, P5, H1, H2, H3, H4, W, R U1 R U2 R U3 R U4 The invention may combine any of the following technical solutions: h, k, r, s, t, u, and z, or any combination thereof. This invention aims to include combinations of all these technical solutions; however, due to space limitations, they will not be listed individually.

[0593] In another embodiment, the present invention relates to a compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopic variant, hydrate, or solvate thereof, wherein the compound is:

[0594] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0595] "Tautomers" refer to compounds in which one functional group changes its structure to become another functional group isomer, and can rapidly interconvert to each other, becoming two isomers in dynamic equilibrium. These two isomers are called tautomers.

[0596] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[0597] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed typically by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0598] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0599] The compounds of this invention can be in amorphous or crystalline forms (crystalline or polymorphic). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0600] The present invention also includes isotopically labeled compounds that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e.14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0601] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0602] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[0603] Pharmaceutical compositions, formulations and kits

[0604] In another aspect, the present invention provides pharmaceutical compositions comprising the compound of the present invention (also referred to as the "active ingredient") and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the active ingredient.

[0605] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0606] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0607] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0608] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0609] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0610] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0611] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active ingredient, while a bolus dose delivered directly to a vein (e.g., via IV infusion) allows for a more rapid delivery, causing the concentration of the active ingredient in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0612] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0613] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0614] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0615] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0616] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0617] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0618] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0619] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0620] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0621] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0622] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0623] Indications

[0624] In another aspect, the use of the compounds of formulas (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), (V'), (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1) disclosed herein (including all individual embodiments and subsets thereof) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvent compounds, as well as the pharmaceutical compositions or kits of the present invention, in the context of pharmaceuticals.

[0625] In one embodiment, the present invention provides compounds that specifically degrade aberrant c-MET through targeted ubiquitination of the c-MET protein and subsequent proteasome degradation. The compounds of the present invention bind to the universally expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, thereby leading to the recruitment and ubiquitination of aberrant c-MET.

[0626] In another embodiment, the present invention provides a compound having the ability to inhibit aberrant c-MET activity, said aberrant c-MET including c-MET amplification, c-MET mutation, c-MET fusion, or c-MET overexpression.

[0627] In another embodiment, the compounds of the present invention can be used to treat diseases mediated by and metastasizing with c-MET, wherein the c-MET has been altered or is abnormal. c-MET abnormalities can be varied. In one specific embodiment, the c-MET abnormality is c-MET amplification, which may be polyploid or localized. In another specific embodiment, the c-MET abnormality is a c-MET mutation, which, without limitation, includes mutations in MET exon 14, kinase domains, extracellular domains, or splicing. In yet another specific embodiment, the c-MET abnormality is a c-MET fusion, which, without limitation, includes TPR-MET, PTPRZ1-MET, CLIP2-MET, KIF5B-MET, TFG-MET, CAPZA2-MET, ST7-MET, BAIAP2L1-MET, C8orf34-MET, TRIM4-MET, STARD3NL-MET, or OXR1-MET. In another specific implementation, the c-MET abnormality is c-MET overexpression. In yet another specific implementation, the c-MET abnormality is a MET exon 14 skipping mutation (MET ex14), Y1003C, Y1003F, Y1003N, Y1003S, R970C, T992I, P991S, D1010H, D1010N, or D1010Y, wherein the MET ex14 mainly occurs in branching site regions, polypyrimidine regions, splice acceptor sites, and splice donor sites. In another specific embodiment, the c-MET abnormality is a kinase domain mutation, and the non-restricted kinase domain mutations include G1090A, G1090S, V1092I, V1092L, H1094L, H1094R, H1094Y, N1100Y, N1106D, M1131T, D1133V, M1149T, V1155L, Y1159H, V1188L, G1163R, G1163E, D1164G, and L119. 5V, L1195F, F1200I, F1200L, V1206L, M1211T, L1213V, 1220I, D1228N, D1228H, D1228A, D1228E, D1228G, D1228Y, Y1230H, Y1230C, Y1230S, Y1230D, Y1230N, Y1230S, D1246N, D1246H, Y1248C, Y1248H or M1268T.In another specific embodiment, the c-MET aberration is a c-MET fusion mutation, which, without limitation, includes TPR-MET-G1163R, TPR-MET-L1157T, TPR-MET-L1195V, TPR-MET-L1195F, TPR-MET-D1228N, TPR-MET-D1228Y, or TPR-MET-Y1230H. In yet another specific embodiment, the c-MET aberration is c-MET overexpression.

[0628] In another specific implementation, the c-MET abnormality is a MET ex14 mutation.

[0629] In another specific implementation, the c-MET abnormality is a G1163R or G1163E mutation.

[0630] In another specific implementation, the c-MET abnormality is an L1195V or L1195F mutation.

[0631] In another specific implementation, the c-MET abnormality is an F1200I or F1200L mutation.

[0632] In another specific implementation, the c-MET abnormality is a mutation of D1228N, D1228H, D1228A, D1228E, D1228G, or D1228Y.

[0633] In another specific implementation, the c-MET abnormality is a mutation of Y1230H, Y1230C, Y1230S, Y1230D, Y1230N, or Y1230S.

[0634] In another specific implementation, the c-MET abnormality is a D1246N or D1246H mutation.

[0635] In another specific implementation, the c-MET abnormality is a Y1248C or Y1248H mutation.

[0636] In another specific implementation, the c-MET anomaly is a fusion of TPR-MET, PTPRZ1-MET, or CLIP2-MET.

[0637] In another specific implementation, the c-MET abnormality is a TPR-MET-G1163R fusion mutation.

[0638] In another specific implementation, the c-MET abnormality is a TPR-MET-L1195V fusion mutation.

[0639] In another specific implementation, the c-MET abnormality is a TPR-MET-L1195F fusion mutation.

[0640] In another specific implementation, the c-MET abnormality is a TPR-MET-D1228N fusion mutation.

[0641] In another embodiment, the compounds of the present invention are used to treat diseases in which escape mutations have occurred after treatment with at least one c-MET inhibitor, said inhibitor being non-limitingly included are terpoxtinib, carmatinib, cevotinib, gumetinib, or berilatinib. In another embodiment, the compounds of the present invention are used to treat diseases in which escape mutations have occurred after treatment with an antibody, said antibody being non-limitingly included is ervantuzumab.

[0642] In another embodiment, the compounds of the present invention are used to treat diseases that are resistant to or have acquired resistance to at least one c-MET inhibitor, such as diseases that are resistant to or have acquired resistance to terpoxtinib, carmatinib, cevotinib, gumetinib, and / or beritinib.

[0643] In another embodiment, the compounds of the present invention are used to treat diseases associated with dysregulation of the HGF / c-MET signaling pathway, the mechanisms of which, without limitation, include HGF-dependent autocrine and paracrine activation, c-MET gene mutations, deletions, truncations, rearrangements, and overexpression, as well as aberrant c-MET receptor processing and defective negative regulatory mechanisms.

[0644] In another embodiment, the compounds of the present invention are used to treat c-MET-mediated and metastatic diseases, said diseases being cancer or proliferative diseases.

[0645] In one specific implementation, the cancers include, but are not limited to: lung cancer, stomach cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, thyroid cancer, bladder cancer, bile duct cancer, colorectal cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, breast cancer, cervical cancer, salivary gland cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, soft tissue sarcoma, multiple myeloma, lymphoma, leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma, and nephroblastoma.

[0646] In another implementation, c-MET-mediated diseases are abnormal cell proliferations, including but not limited to solid or blood cancers.

[0647] In one specific implementation plan, hematologic malignancies include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, and acute megakaryoblastic leukemia. Diseases, promyelocytic leukemia, mixed spectrum leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL) 2 and / or CL6 rearrangement / overexpression [double and triple hit lymphomas], myelodyplastic / myeloproliferative neoplasms, mantle cell lymphoma (including bortezomib-resistant mantle cell lymphoma).

[0648] In another specific implementation, solid cancers include, but are not limited to, lung cancer (including small cell lung cancer and non-small cell lung cancer), breast cancer (including inflammatory breast cancer, ER-positive breast cancer, and triple-negative breast cancer), colon cancer, midline cancer, liver cancer, kidney cancer, prostate cancer (including castration-resistant prostate cancer), brain cancer (including glioma, glioblastoma, neuroblastoma, and medulloblastoma (including MYC-amplified medulloblastoma)), colorectal cancer, nephroblastoma, and Ewing's sarcoma. Tumors, rhabdomyosarcomas, ependymomas, head and neck cancers, melanomas, squamous cell carcinomas, ovarian cancers, pancreatic cancers (including pancreatic ductal carcinomas and pancreatic neuroendocrine tumors), osteosarcomas, giant cell tumors of bone, thyroid cancers, bladder cancers, urothelial carcinomas, vulvar cancers, cervical cancers, endometrial cancers, mesotheliomas, esophageal cancers, salivary gland cancers, gastric cancers, nasopharyngeal carcinomas, buccal cancers, oral cancers, gastrointestinal stromal tumors, NUT-midline carcinomas, testicular cancers, squamous cell carcinomas, hepatocellular carcinomas, MYCN-driven solid tumors, and NUT-midline carcinomas.

[0649] In another embodiment, the compounds of the present invention are used to treat atherosclerosis, pulmonary fibrosis, renal fibrosis, allergic diseases, cerebrovascular diseases, cardiovascular diseases, organ transplant-related diseases, autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immune-mediated diseases.

[0650] Based on the foregoing, the present invention also provides a method for preventing or treating any of the aforementioned diseases or conditions in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of the compound as described herein, or its enantiomers, diastereomers, or stereoisomers, or pharmaceutically acceptable salts, hydrates, or solvates thereof. For any of the above uses, the required dosage will vary depending on the method of administration, the specific patient to be treated, and the desired effect.

[0651] combination therapy

[0652] The compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof may be used alone or in combination with another compound of the present invention or another bioactive agent or a second therapeutic agent to treat subjects, such as subjects with abnormal c-MET-mediated conditions, including but not limited to those described herein.

[0653] The term "bioactive agent" or "additional active agent" is used to describe pharmaceutical agents other than those selected according to the invention, which can be used in combination with or alternately with the compounds of the invention to achieve a desired therapeutic outcome. In one embodiment, the compounds and bioactive agents of the invention are administered in a manner that allows them to be active in vivo during overlapping time periods, such as time periods with overlapping Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, the compounds and bioactive agents of the invention are administered to a subject in need who does not have overlapping pharmacokinetic parameters, but whose therapeutic effect is influenced by the other drug.

[0654] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with another c-MET inhibitor, said other c-MET inhibitor including but not limited to terpoxtinib, carmatinib, cervacinib, gumetinib, beritinib, or carboplatinib.

[0655] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a c-MET antibody. In yet another specific embodiment, the c-MET antibody is ervaltumab.

[0656] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an EGFR inhibitor, including but not limited to gefitinib, erlotinib, icotinib, afatinib, dacomitinib, neratinib, osimertinib, lazatinib, ametinib, vormetinib, lapatinib, vandetanib, omamotinib, befotinib, or brigatinib. In another specific embodiment, the EGFR inhibitor is a first-generation EGFR inhibitor such as gefitinib, erlotinib, or icotinib. In another specific embodiment, the EGFR inhibitor is a second-generation EGFR inhibitor such as afatinib and / or dacomitinib. In another specific embodiment, the EGFR inhibitor is a third-generation EGFR inhibitor such as osimertinib, ametinib, or vormetinib.

[0657] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an immunomodulator, said immunomodulator including, but not limited to, immune checkpoint inhibitors or antibodies. In another specific embodiment, the immunomodulator is an immune checkpoint inhibitor, such as a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, T-cell activation V-domain Ig inhibitor inhibitor inhibitor, small molecule, peptide, nucleotide, or other inhibitor. In yet another more specific embodiment, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, atezolizumab, durvalumab, ipilimumab, or trimemumab.

[0658] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an ALK inhibitor. In yet another specific embodiment, the ALK inhibitor is crizotinib, ceritinib, alectinib, brigatinib, ensartinib, loratinib, or ilurac.

[0659] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a BTK inhibitor. In another specific embodiment, the BTK inhibitor is ibrutinib, acomitinib, zanubrutinib, tabrutinib, or obrutinib or pitutinib.

[0660] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a MEK inhibitor. In another specific embodiment, the MEK inhibitor is trametinib, selmetinib, or refatinib.

[0661] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a RAF inhibitor. In yet another specific embodiment, the RAF inhibitor is sorafenib, vemurafenib, dabrafenib, or encofenib.

[0662] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a PI3K inhibitor. In yet another specific embodiment, the PI3K inhibitor is woumamin, demethylamphenicol, perifolliculin, or ederaris.

[0663] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an optional selection of HER-2 inhibitors, CD20 inhibitors, JAK3 inhibitors, BCL-2 inhibitors, SYK inhibitors, AKT inhibitors, mTOR inhibitors, RAS inhibitors or HSP inhibitors, or any combination thereof.

[0664] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapy agent, or an immunosuppressant.

[0665] Example

[0666] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percentages.

[0667] Typically, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C to 100°C, preferably 0°C to 80°C). The reaction time is usually 0.1-60 hours, preferably 0.5-24 hours.

[0668] The abbreviations used in this article have the following meanings: Pd(dppf)Cl2·DCM: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; Pd2(dba3): tris(dibenzylacetone)dipalladium; PPh3: triphenylphosphine; Pd-PEPPSI-IHept-Cl: (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-diphenylphosphine. [H-2H-imidazol-2-yl subunit]dichloro(3-chloropyridine-KN)palladium Pd(OAc)2:palladium acetate NiBr2·(4,4'-dtbbpy):[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel dibromide 4CzIPN:2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile BINAP:2,2'-bisdiphenylphosphine-1,1'-binaphthyl SPhos:2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl CS2:carbon disulfide POCl3:phosphorus oxychloride H ATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBT: 1-hydroxybenzotriazine DIAD: diisopropyl azodicarbonate DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DCM: dichloromethane DMSO: dimethyl sulfoxide DME: ethylene glycol dimethyl ether DEA: diethanolamine L DA: Lithium diisopropylamino (LiHMDS): Lithium bis(trimethylsilyl)amino (THF): Tetrahydrofuran (TFA): Trifluoroacetic acid (MeOH): Methanol (EtOAc): Ethyl acetate (KOAc): Potassium acetate (PCy3): Tricyclohexylphosphine (NCS): N-chlorosuccinimide (NFSI): N-fluorobis(benzenesulfonamide) (SEMCl): (2-(chloromethoxy)ethyl)trimethylsilane (TBAF): Tetrabutylammonium fluoride (TBAF): Tetrabutylammonium fluoride (TsCl): p-Toluenesulfonyl chloride (NaBH(OAc)3): Sodium borohydride acetate (NMP): N-methylpyrrolidone (Xantphos) Pd G4: (4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene)methanesulfonic acid)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) B2Pin2: pinacol diboronate 9-BBN: 9-boron bicyclo[3.3.1]nonane ACN: acetonitrile rt: room temperature 1 atm: 1 standard atmosphere ee: enantiomeric excess

[0669] Preparation of intermediate A-1 compound 4-(1-tert-butoxycarbonyl-4-piperidinyl)phenylboronic acid pinacol ester

[0670] The following synthetic route was adopted:

[0671] Step 1: Synthesis of compound tert-butyl 4-(4-bromobenzene)-3,6-dihydropyridine-1(2H)formate

[0672] p-Bromoiodobenzene (31.12 g, 110 mmol), N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (34.01 g, 110 mmol), Pd(dppf)Cl2·DCM (8.98 g, 11 mmol), sodium carbonate (29.15 g, 275 mmol), DMF (330 mL), and water (55 mL) were added separately to reaction flasks, and stirred overnight at 90 °C under nitrogen protection. After the reaction was complete, the reaction system was cooled to room temperature, concentrated to remove DMF, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 26.2 g of a pale yellow solid, with a yield of 71%. LC-MS (ESI): m / z = 323 [M+1-Me]. + .

[0673] Step 2: Synthesis of compound 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0674] 26.2 g (77.5 mmol) of tert-butyl 4-(4-bromobenzene)-3,6-dihydropyridine-1(2H)carboxylate, 25.58 g (101 mmol) of pinacol diboronate, 3.16 g (3.88 mmol) of Pd(dppf)Cl2·DCM, 22.82 g (232.5 mmol) of potassium acetate, and 300 mL of DMSO were added to separate reaction flasks and stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, and water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and washed three times with water to remove DMSO. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 27.66 g of a pale yellow solid, with a yield of 93%. LC-MS (ESI): m / z = 386 [M+1] + .

[0675] Synthesis of intermediate A-1 in step 3

[0676] Compound 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (27.16 g, 70.55 mmol), 10% palladium on carbon (5.6 g), and ethyl acetate (750 mL) were added separately to 2 L reaction flasks. The system was purged with hydrogen gas at 1 atm and stirred overnight at room temperature. After the reaction was complete, the palladium on carbon was removed by vacuum filtration, and the filtrate was concentrated to obtain 27.3 g of a colorless oil, which was directly used in the next reaction step. LC-MS (ESI): m / z = 388 [M+1] + .

[0677] Preparation of intermediate A-2 compound tert-butyl 4-(4-(1H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylate

[0678] The following synthetic route was adopted:

[0679] 6-Bromo-1H-pyrazolo[4,3-b]pyridine (300 mg, 1.52 mmol), intermediate A-1 (707 mg, 1.83 mmol), Pd(dppf)Cl2 (144 mg, 0.197 mmol), sodium carbonate (483 mg, 4.56 mmol), acetonitrile (7.6 mL), and water (1.1 mL) were added separately to reaction flasks and reacted under nitrogen protection at 120 °C for 4 h using microwave. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 300 mg of a white solid, yield 52%. LC-MS (ESI): m / z = 379 [M+1] + .

[0680] Preparation of intermediate A-3 compound 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)propyne aldehyde

[0681] The following synthetic route was adopted:

[0682] Step 1: Synthesis of compound 3-(5-(3,3-diethoxyprop-1-yn-1-yl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0683] 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 g, 3.09 mmol), 3,3-diethoxyprop-1-yne (0.67 mL, 4.64 mmol), DIPEA (1.6 mL, 9.27 mmol), cuprous iodide (59 mg, 0.31 mmol), Pd(PPh3)2Cl2 (218 mg, 0.31 mmol), and DMF (7.5 mL) were sequentially added to a reaction flask, and the reaction was carried out at 65 °C under nitrogen protection for 3 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 1.04 g of product, yield 91%. LC-MS (ESI): m / z = 371 [M+1] + .

[0684] Synthesis of intermediate A-3 in step 2

[0685] 3-(5-(3,3-diethoxyprop-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (1.04 g, 2.81 mmol), THF (25 mL), and 1 M H₂SO₄ (25 mL, 25 mmol) were added sequentially to a reaction flask and stirred at room temperature for 2 h. After the reaction was complete, water was added, and the pH was adjusted to 8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 372 mg of a yellow solid, with a yield of 45%. LC-MS (ESI): m / z = 297 [M+1] + .

[0686] Preparation of intermediate A-4 compound 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid

[0687] The following synthetic route was adopted:

[0688] Step 1: Synthesis of compound tert-butyl 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate

[0689] 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4-(1H,3H)-dione (1.3 g, 4.41 mmol), 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate (0.94 g, 4.41 mmol), Pd-PEPPSI-IHept-Cl (210 mg, 0.22 mmol), cesium carbonate (3.6 g, 11 mmol), and 1,4-dioxane (20 mL) were added separately to reaction flasks. The reaction was carried out overnight at 110 °C under nitrogen protection with stirring. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The product was separated by silica gel column chromatography, yielding 1.47 g of product (70%). LC-MS (ESI): m / z = 476 [M+1] + .

[0690] Synthesis of intermediate A-4 in step 2

[0691] 1.47 g (3.09 mmol) of tert-butyl 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate was added to 15 mL of DCM. Under nitrogen protection, 30.9 mL (123.6 mmol) of 4 M 1,4-dioxane hydrogen chloride solution was slowly added dropwise at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred overnight. After the reaction was complete, the system was concentrated to obtain the product, which was directly used in the next reaction.

[0692] Preparation of intermediate A-5 compound 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester

[0693] The following synthetic route was adopted:

[0694] 2-Bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (250 mg, 0.83 mmol), pinacol diboronate (320 mg, 1.26 mmol), Pd(dppf)Cl2·DCM (41 mg, 0.05 mmol), potassium acetate (200 mg, 2.04 mmol), and 1,4-dioxane (8 mL) were added to separate reaction flasks and stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was used directly in the next reaction step. LC-MS (ESI): m / z = 268 [M(RB(OH)2)+1] + .

[0695] Preparation of intermediate A-6 compound 3-(3-bromoquinolin-6-yl)-2-chloropropanal

[0696] The following synthetic route was adopted:

[0697] Step 1: Synthesis of compound 6-(3,3-diethoxypropyl)quinoline

[0698] 0.5 M 9-BBN / THF (680 mL, 340 mmol) was added to the reaction flask. Under nitrogen protection at 0 °C, acrolein diethanolamide (51.8 mL, 340 mmol) was added dropwise to the system. After the addition was complete, the reaction mixture was brought to room temperature and stirred overnight. 6-Bromoquinoline (26.3 mL, 194 mmol), potassium carbonate (53.7 g, 389 mmol), tricyclohexylphosphine (5.5 g, 19.4 mmol), and palladium acetate (4.4 g, 19.4 mmol) were added to the reaction system, and the mixture was stirred at 65 °C under nitrogen protection for 3 h. After the reaction was complete, the mixture was filtered, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 22.8 g of the product, with a yield of 45%. LC-MS (ESI): m / z = 260 [M+1] + .

[0699] Step 2: Synthesis of compound 3-bromo-6-(3,3-diethoxypropyl)quinoline

[0700] Compound 6-(3,3-diethoxypropyl)quinoline (21.1 g, 81.4 mmol), liquid bromine (4.15 mL, 81.4 mmol), and pyridine (7.85 mL, 97.6 mmol) were sequentially added to carbon tetrachloride (200 mL), and the reaction was refluxed under nitrogen protection for 2 h. After the reaction was complete, the mixture was filtered, concentrated, and separated by silica gel column chromatography to give 9.24 g of the product, yield 34%. LC-MS (ESI): m / z = 338 [M+1] + .

[0701] Step 3: Synthesis of compound 3-(3-bromoquinoline-6-yl)propionaldehyde

[0702] Compound 3-bromo-6-(3,3-diethoxypropyl)quinoline (9.24 g, 27.3 mmol) was added to ethyl acetate (109 mL), and then 2M HCl aqueous solution (68.3 mL, 137 mmol) was slowly added dropwise to the reaction mixture at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 30 minutes. After the reaction was complete, the pH was adjusted to 8-9 with 25% sodium hydroxide aqueous solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 4.6 g of the product, yield 64%. LC-MS (ESI): m / z = 264 [M+1] + .

[0703] Synthesis of intermediate A-6 in step 4

[0704] 3-(3-bromoquinoline-6-yl)propionaldehyde (4.6 g, 17.4 mmol) was added to chloroform (25 mL). L-proline (328 mg, 2.84 mmol) and NCS (2.73 g, 20.5 mmol) were then added sequentially to the system under nitrogen protection at 0 °C. The reaction was allowed to proceed to room temperature and stirred for 2 h. After the reaction was complete, the mixture was concentrated, and the resulting solid was used directly in the next reaction step. LC-MS (ESI): m / z = 298 [M+1] + .

[0705] Preparation of intermediate A-7 compound 2-(1-(5-fluoro-1-methyl-3-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid

[0706] The following synthetic route was adopted:

[0707] Step 1: Synthesis of compound 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)-3-methyldihydropyrimidine-2,4(1H,3H)-dione

[0708] 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4-(1H,3H)-dione (850 mg, 2.5 mmol), methyl iodoform (0.87 mL, 14 mmol), and potassium carbonate (1.93 g, 14 mmol) were sequentially added to DMF (10 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, water was added, and the reaction was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 430 mg of product, yield 49%. LC-MS (ESI): m / z = 355 [M+1] + .

[0709] Step 2: Synthesis of compound tert-butyl 2-(1-(5-fluoro-1-methyl-3-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate

[0710] Compounds 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)-3-methyldihydropyrimidin-2,4(1H,3H)-dione (400 mg, 1.16 mmol), 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate (360 mg, 1.67 mmol), Pd-PEPPSI-IHept-Cl (54 mg, 0.056 mmol), cesium carbonate (920 mg, 2.82 mmol), and 1,4-dioxane (10 mL) were added to a reaction flask and stirred overnight at 110 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and separated by silica gel column chromatography to obtain 350 mg of the product, yield 62%. LC-MS (ESI): m / z = 490 [M+1] + .

[0711] Synthesis of intermediate A-7 in step 3

[0712] Compound tert-butyl 2-(1-(5-fluoro-1-methyl-3-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate (350 mg, 0.72 mmol) was added to DCM (15 mL), and 4M 1,4-dioxane hydrogen chloride solution (30.5 mL, 121.0 mmol) was slowly added dropwise under nitrogen protection at 0 °C. The mixture was then heated to room temperature and stirred overnight. After the reaction was complete, the system was concentrated to obtain the product, which was directly used in the next reaction step.

[0713] Preparation of intermediate A-8 compound 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-en-8-carboxylic acid tert-butyl ester

[0714] The following synthetic route was adopted:

[0715] Step 1: Synthesis of compound 3-(((perfluorobutyl)sulfonyl)oxy)-1-oxa-8-azaspiro[4.5]dec-3-en-8-carboxylic acid tert-butyl ester

[0716] 10 g (39.2 mmol) of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was added to 100 mL of THF. DBU (17.6 mL, 117.7 mmol) was added dropwise to the reaction mixture at 0 °C under nitrogen protection. After the addition was complete, the mixture was stirred at 0 °C for 30 min. Then, perfluorobutylsulfonyl fluoride (21.2 mL, 117.7 mmol) was added dropwise at 0 °C, and the mixture was brought to room temperature and stirred for 1 h. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 13.8 g of the product (66% yield). LC-MS (ESI): m / z = 538 [M+1]. + .

[0717] Synthesis of intermediate A-8 in step 2

[0718] Compounds 3-(((perfluorobutyl)sulfonyl)oxy)-1-oxo-8-azaspiro[4.5]dec-3-en-8-carboxylic acid tert-butyl ester (13.8 g, 26 mmol), pinacol diboronate (9.91 g, 39 mmol), Pd(dppf)Cl2·DCM (2.12 g, 2.6 mmol), potassium acetate (7.64 g, 78 mmol), and 1,4-dioxane (125 mL) were added to separate reaction flasks and stirred overnight at 110 °C under nitrogen protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 7.93 g of a yellow oily substance, yield 84%. LC-MS (ESI): m / z = 366 [M+1] + .

[0719] Preparation of intermediate A-9 compound 2-chloro-3-(quinolin-6-yl)propionaldehyde

[0720] The following synthetic route was adopted:

[0721] Step 1: Synthesis of compound 3-(quinolin-6-yl)propionaldehyde

[0722] Pd₂(dba)₃ (3.7 g, 4.0 mmol) and tri-tert-butylphosphine tetrafluoroborate (2.4 g, 8.2 mmol) were added to a reaction flask. Under nitrogen protection, 1,4-dioxane (240 mL), 6-bromoquinoline (56 g, 270 mmol), allyl alcohol (37 mL, 540 mmol), and N-methyldicyclohexylamine (69.5 mL, 324 mmol) were added sequentially. The reaction was stirred at 30 °C for 24 h. After the reaction was complete, diethyl ether was added, the mixture was filtered, the filter cake was washed with diethyl ether, the filtrate was concentrated, and the product was purified by column chromatography.

[0723] Synthesis of intermediate A-9 in step 2

[0724] Compound 3-(quinolin-6-yl)propionaldehyde (4.45 g, 24.1 mmol) was added to chloroform (40 mL). L-proline (0.47 g, 4.1 mmol) and NCS (3.53 g, 26.4 mmol) were added sequentially to the system under nitrogen protection at 0 °C. The reaction was then brought to room temperature and stirred for 2 h. After the reaction was complete, the mixture was concentrated, and the resulting solid was used directly in the next reaction step. LC-MS (ESI): m / z = 220 [M+1] + .

[0725] Preparation of intermediate A-10 compound 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[0726] The following synthetic route was adopted:

[0727] Step 1: Synthesis of compound 1-(2-fluoro-4-nitrophenyl)piperidin-4-one

[0728] Piperidin-4-one (4.95 g, 50.0 mmol) and 1,2-difluoro-4-nitrobenzene (6.4 mL, 57.8 mmol) were added to DMSO (68 mL), followed by slow dropwise addition of DIPEA (8.7 mL, 50 mmol). The reaction was stirred overnight at 80 °C. After the reaction was complete, ice water was added to the reaction system, causing the solid to precipitate. Filtration yielded 8.5 g of product, with a yield of 72%. LC-MS (ESI): m / z = 239 [M+1] + .

[0729] Step 2: Compound 2-(1-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[0730] 4.8 mL (35.7 mmol) of tert-butyl acetate was added to 70 mL of THF. Then, 2 M LDA / THF (35.7 mL, 71.4 mmol) was added dropwise to the system under nitrogen protection and at -78 °C. The system was stirred at -78 °C for 1 h. Next, a solution of 8.5 g (35.7 mmol) of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one in 20 mL of THF was slowly added to the system, and the reaction was continued to be stirred at -78 °C for 2 h. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 6.5 g of product, with a yield of 51%. LC-MS (ESI): m / z = 355 [M+1] + .

[0731] Step 3: Synthesis of compound 2-(1-(4-amino-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[0732] Compound 2-(1-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate (1.98 g, 5.6 mmol), 10% palladium on carbon (190 mg), and ethanol (23 mL) were added to a reaction flask. The system was then purged with hydrogen gas at 1 atm and stirred at room temperature for 5 h. After the reaction was complete, the palladium on carbon was removed by vacuum filtration, and the filtrate was concentrated to give 1.80 g of product, which was directly used in the next reaction. LC-MS (ESI): m / z = 436 [M+1] + .

[0733] Step 4: Synthesis of compound 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[0734] 2-(1-(4-amino-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate (1.86 g, 5.74 mmol), 3-bromopiperidin-2,6-dione (2.22 g, 11.48 mmol), sodium bicarbonate (0.96 g, 114.48 mmol), and DMF (57 mL) were added to a sealed reaction flask, and the system was stirred overnight at 65 °C. After the reaction was complete, the system was cooled to room temperature, filtered, the filtrate was concentrated, diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 1.87 g of product, with a yield of 75%. LC-MS (ESI): m / z = 436 [M+1] + .

[0735] Synthesis of intermediate A-10 in step 5

[0736] 1.77 g (4.07 mmol) of 2-(1-(4-((2,6-dioxopiridine-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and 1,4-dioxane (4N) hydrogen chloride (102 mL, 407 mmol) were added to DCM (40 mL), and the reaction was stirred overnight at room temperature. After the reaction was complete, the reaction system was concentrated to give 1.39 g of product, with a yield of 90%. LC-MS (ESI): m / z = 380 [M+1] + .

[0737] Preparation of intermediate A-11 compound 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-5-oxa-2-azaspiro[3.4]oct-7-ene-2-carboxylic acid tert-butyl ester

[0738] Following the preparation method of intermediate A-8, tert-butyl 3-oxo-1-oxa-8-azaspiro[3.4]octane-2-carboxylic acid was replaced with tert-butyl 3-oxo-8-azaspiro[4.5]decane-8-carboxylic acid (10 g, 39.2 mmol) to prepare 4.4 g of yellow oily substance A-11, with a yield of 64% and LC-MS (ESI): m / z = 338[M+1]+.

[0739] Preparation of intermediate A-12 compound 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-oxa-7-azaspiro[4.4]non-3-ene-7-carboxylic acid tert-butyl ester

[0740] Following the preparation method of intermediate A-8, tert-butyl 3-oxo-1-oxa-7-azaspiro[4.4]nonane-7-carboxylic acid was replaced with tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid (10 g, 39.2 mmol) to prepare 3.5 g of yellow oily substance A-12, with a yield of 49%, LC-MS (ESI): m / z = 352[M+1]+.

[0741] Example 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-((4-(4-(1-(imidazo[1,2-a]pyridin-3-ylsulfonyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-yl)isoindoline-1,3-dione (compound T-1)

[0742] The following synthetic route was adopted:

[0743] Step 1: Synthesis of the compound imidazo[1,2-a]pyridine-3-sulfonic acid

[0744] Chlorosulfonic acid (4 mL, 60 mmol) was dissolved in chloroform (40 mL). A chloroform solution (60 mL) of imidazo[1,2-a]pyridine (2.36 g, 20 mmol) was slowly added at room temperature, and the mixture was refluxed at 60 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain an oily crude product. This product was then crystallized from diethyl ether (180 mL) and ethanol (40 mL) to obtain a white precipitate. The precipitate was filtered, and the filter cake was washed with ethanol to finally obtain 3.8 g of a white solid, with a yield of 97%.

[0745] Step 2: Synthesis of compound imidazo[1,2-a]pyridine-3-sulfonyl chloride

[0746] Imidazolo[1,2-a]pyridine-3-sulfonic acid (3.8 g, 19.2 mmol) and POCl3 (76 mL) were added to a reaction flask, and the reaction system was heated under reflux for 24 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residual solid was added to dichloromethane and ice water. The aqueous layer was extracted with dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was directly used in the next reaction step.

[0747] Step 3: Synthesis of compound 6-bromo-1-(imidazo[1,2-a]pyridin-3-ylsulfonyl)-1H-pyrazolo[4,3-b]pyridine

[0748] Sodium hydride (720 mg, 18 mmol) was dissolved in DMF (70 mL). A DMF solution (15 mL) of 6-bromo-1H-pyrazolo[4,3-b]pyridine (3.56 g, 18 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. Subsequently, a DMF solution (15 mL) of imidazo[1,2-a]pyridine-3-sulfonyl chloride (3.24 g, 15 mmol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 4 hours. After the reaction was complete, 0.1 N hydrochloric acid was added, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 820 mg of the product, a yield of 14%. LC-MS (ESI): m / z = 378 [M+1] + .

[0749] Step 4: Synthesis of compound tert-butyl 4-(4-(1-(imidazo[1,2-a]pyridin-3-ylsulfonyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid

[0750] Compound 6-bromo-1-(imidazo[1,2-a]pyridin-3-ylsulfonyl)-1H-pyrazolo[4,3-b]pyridine (800 mg, 2.12 mmol), intermediate A-1 (900 mg, 2.43 mmol), Pd(dppf)Cl2·DCM (87 mg, 0.106 mmol), potassium carbonate (880 mg, 6.36 mmol), 1,4-dioxane (20 mL), and water (6 mL) were added to a reaction flask and reacted overnight at 90 °C under nitrogen protection using microwave. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 550 mg of product, yield 46%. LC-MS (ESI): m / z = 559 [M+1] + .

[0751] Step 5: Synthesis of compound 1-(imidazo[1,2-a]pyridin 3-ylsulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

[0752] Compound tert-butyl 4-(4-(1-(imidazo[1,2-a]pyridin-3-ylsulfonyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid (170 mg, 0.30 mmol) was added to a mixed solvent of trifluoroacetic acid (1.5 mL) and dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the crude product obtained by concentrating the reaction system was used directly in the next step.

[0753] Step 6: Synthesis of compound (R)-3-((4-(4-(1-(imidazo[1,2-a]pyridin-3-ylsulfonyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0754] The crude product from the previous step, 1-(imidazo[1,2-a]pyridinyl3-ylsulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine, (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (43 mg, 0.165 mmol), and DIPEA (0.1 mL, 0.45 mmol) were sequentially added to DCM (2 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (170 mg, 0.6 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 90 mg of product, yield 47%, LC-MS (ESI): m / z = 642 [M+1]. + .

[0755] Step 7: Synthesis of compound (S)-1-(imidazo[1,2-a]pyridin-3-ylsulfonyl)-6-(4-(1-(pyrrolidine-3-ylmethyl)pyridin-4-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

[0756] Compound (R)-3-((4-(4-(1-(imidazo[1,2-a]pyridin-3-ylsulfonyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 0.14 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (0.7 mL) and dichloromethane (0.7 mL) and stirred at room temperature for 2 h. After the reaction was complete, the crude product obtained by concentrating the reaction system was directly used in the next step.

[0757] Step 8: Synthesis of compound T-1

[0758] The crude product from the previous step, (S)-1-(imidazo[1,2-a]pyridin-3-ylsulfonyl)-6-(4-(1-(pyrrolidine-3-ylmethyl)pyridin-4-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (64 mg, 0.196 mmol), and DIPEA (0.26 mL, 1.26 mmol) were sequentially added to DMSO (2 mL), and the mixture was heated to 120 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 25 mg of the product, yield 22%. LC-MS (ESI): m / z = 798 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),9.06(d,J=1.9Hz,1H),8.98(d,J=6.8Hz,1H),8.79(s,1H),8.70(s,1H),8.62(d,J=2.0Hz,1 H),7.84(t,J=9.1Hz,3H),7.67(dd,J=16.6,8.0Hz,2H),7.48(d,J=8.0Hz,2H),7.39(t,J=7.0Hz,1H),6.92(d,J=2.2Hz,1H),6.83( dd,J=8.4,2.2Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),3.60(t,J=8.9Hz,1H),3.52(q,J=7.8,4.5Hz,1H),3.45–3.37(m,1H),3.21–2 .97(m,3H),2.89(ddd,J=17.0,13.9,5.5Hz,1H),2.73–2.55(m,4H),2.38(d,J=38.8Hz,2H),2.22–1.96(m,4H),1.90–1.69(m,5H).

[0759] Example 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-((4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-yl)isoindoline-1,3-dione (compound T-2)

[0760] The following synthetic route was adopted:

[0761] Step 1: Synthesis of compound 6-bromoimidazolo[1,2-a]pyridine-3-sulfonic acid

[0762] Chlorosulfonic acid (4 mL, 60.9 mmol) was dissolved in chloroform (50 mL), and a chloroform solution (50 mL) of 6-bromoimidazolo[1,2-a]pyridine (4 g, 20.3 mmol) was slowly added at room temperature. The mixture was refluxed at 60 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain an oily crude product. This product was then crystallized from diethyl ether (180 mL) and ethanol (40 mL) to obtain a white precipitate. The precipitate was filtered and washed with ethanol to give 5.3 g of a white solid, with a yield of 95%.

[0763] Step 2: Synthesis of compound 6-bromoimidazolo[1,2-a]pyridine-3-sulfonyl chloride

[0764] 6-Bromoimidazolo[1,2-a]pyridine-3-sulfonic acid (1.0 g, 3.68 mmol) and POCl3 (20 mL) were added to a reaction flask and heated under reflux for 24 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residual solid was treated with dichloromethane and ice water. The aqueous layer was extracted with dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was directly used in the next reaction. LC-MS (ESI): m / z = 295 [M+1] + .

[0765] Step 3: Synthesis of compound tert-butyl 4-(4-(1-(6-bromoimidazolo[1,2-a]pyridin-3-ylsulfonyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid.

[0766] Sodium hydride (75 mg, 1.86 mmol) was dissolved in DMF (3.5 mL). A solution of intermediate A-2 (232 mg, 0.62 mmol) in DMF (3.5 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 30 min. Subsequently, a solution of 6-bromoimidazolo[1,2-a]pyridine-3-sulfonyl chloride (217 mg, 0.74 mmol) in DMF (3.5 mL) was slowly added, and the reaction was stirred at room temperature for 4 h. After the reaction was complete, 0.1 N hydrochloric acid was added, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 211 mg of the product, yield 54%. LC-MS (ESI): m / z = 637 [M+1] + .

[0767] Step 4: Synthesis of compound tert-butyl 4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid

[0768] Compounds tert-butyl 4-(4-(1-(6-bromoimidazolo[1,2-a]pyridin-3-ylsulfonyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)piperidin-1-carboxylic acid (211 mg, 0.33 mmol), pinacol 1-methyl-4-pyrazolboronic acid (79 mg, 0.38 mmol), Pd(dppf)Cl2·DCM (18 mg, 0.022 mmol), potassium carbonate (141 mg, 1.02 mmol), 1,4-dioxane (4 mL), and water (2 mL) were added to a reaction flask and reacted under nitrogen protection at 90 °C with microwave for 1 h. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the product was separated by silica gel column chromatography to obtain 111 mg of product, yield 53%, LC-MS (ESI): m / z = 639 [M+1]. + .

[0769] Step 5: Synthesis of compound 1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine

[0770] Compound tert-butyl 4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-carboxylic acid (93 mg, 0.146 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (0.7 mL) and dichloromethane (0.7 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the crude product was concentrated and used directly in the next reaction.

[0771] Step 6: Synthesis of compound (R)-3-((4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0772] 1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (44 mg, 0.169 mmol), and DIPEA (92 μL, 0.53 mmol) were added sequentially to DCM (2 mL), and the mixture was stirred at room temperature for 1 h. Then, NaBH(OAc)3 (150 mg, 0.71 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 118 mg of the product (95% yield). LC-MS (ESI): m / z = 722 [M+1] + .

[0773] Synthesis of compound (S)-1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(1-pyrrolidine-3-ylmethyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine in step 7

[0774] Compound (R)-3-((4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (127 mg, 0.176 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (1.4 mL) and dichloromethane (6 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the concentrated crude product was directly used for the next reaction.

[0775] Step 8: Synthesis of compound T-2

[0776] The crude product from the previous step, (S)-1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(1-pyrrolidine-3-ylmethyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (73 mg, 0.264 mmol) and DIPEA (462 μL, 2.66 mmol) were added to DMSO (2 mL) and the mixture was heated to 120 °C and reacted for 4 h. After the reaction was complete, the system was cooled to room temperature, the reaction was quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 28 mg of product, yield 18%, LC-MS (ESI): m / z = 878 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),9.06(d,J=2.0Hz,1H),9.00(s,1H),8.83(s,1H),8.65(s,2H),8.25(s,1H), 7.94–7.85(m,3H),7.82(d,J=8.1Hz,2H),7.65(d,J=8.4Hz,1H),7.48(d,J=7.9Hz,2H),6.92(d,J=2.2Hz,1H),6.8 4(dd,J=8.6,2.2Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),3.89(s,3H),3.64–3.40(m,5H),3.22–2.98(m,2H),2.93–2 .79(m,1H),2.73–2.54(m,5H),2.41(d,J=7.3Hz,1H),2.23–2.04(m,3H),1.87–1.76(m,4H),1.46(d,J=7.8Hz,1H).

[0777] Example 3: Preparation of 5-((R)-3-((4-(4-(1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound T-3)

[0778] The following synthetic route was adopted:

[0779] Step 1: Synthesis of compound 6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-sulfonic acid

[0780] Compound 6-bromoimidazolo[1,2-a]pyridine-3-sulfonic acid (600 mg, 2.16 mmol), 1-cyclopropyl-4-pyrazoleboronic acid pinacol ester (555 mg, 2.37 mmol), Pd(dppf)Cl2·DCM (62 mg, 0.076 mmol), potassium carbonate (894 mg, 6.48 mmol), 1,4-dioxane (9 mL), and water (4.5 mL) were added to a reaction flask and stirred overnight at 120 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the product was separated by silica gel column chromatography to obtain 491 mg of product, yield 75%, LC-MS (ESI): m / z = 303 [M-1]. - .

[0781] Step 2: Synthesis of compound 6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-sulfonyl chloride

[0782] 6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-sulfonic acid (480 mg, 1.58 mmol) and POCl3 (9.0 mL) were added to a reaction flask and the mixture was heated under reflux for 24 h. After the reaction was complete, the mixture was cooled to room temperature and then concentrated under reduced pressure using a rotary evaporator. The residual solid was added to dichloromethane and ice water, and the aqueous layer was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 240 mg of crude product, with a yield of 47%.

[0783] Step 3: Synthesis of compound 6-bromo-1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridine

[0784] Sodium hydride (89 mg, 2.23 mmol) was dissolved in DMF (2.5 mL). A solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (154 mg, 0.782 mmol) in DMF (2.5 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 30 min. Then, a solution of 6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-sulfonyl chloride (240 mg, 0.745 mmol) in DMF (2.5 mL) was slowly added at room temperature, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, 0.1 N hydrochloric acid was added, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 30 mg of a white solid, yield 8.3%. LC-MS (ESI): m / z = 484 [M+1] + .

[0785] Step 4: Synthesis of compound tert-butyl 4-(4-(1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid

[0786] Compound 6-bromo-1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridine (30 mg, 0.062 mmol), intermediate A-1 (19 mg, 0.075 mmol), Pd(dppf)Cl2·DCM (4.5 mg, 0.0055 mmol), potassium carbonate (27 mg, 0.20 mmol), 1,4-dioxane (1.5 mL), and water (0.45 mL) were added to a reaction flask and reacted under nitrogen atmosphere at 90 °C for 30 min using microwave. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the product was separated by silica gel column chromatography to obtain 21 mg of product, yield 51%. LC-MS (ESI): m / z = 665 [M+1] + .

[0787] Step 5: Synthesis of compound 1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine

[0788] Compound tert-butyl 4-(4-(1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid (21 mg, 0.032 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (0.4 mL) and dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0789] Step 6: Synthesis of compound (R)-3-((4-(4-(1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0790] The crude product 1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (8 mg, 0.04 mmol), and DIPEA (17 μL, 0.098 mmol) were added to DCM (1.5 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (28 mg, 0.132 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 20 mg of the product, yield 84%. LC-MS (ESI): m / z = 748 [M+1] + .

[0791] Synthesis of compound (S)-1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(1-pyrrolidine-3-ylmethyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine in step 7

[0792] Compound (R)-3-((4-(4-(1-((6-(1-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (20 mg, 0.027 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (0.34 mL) and dichloromethane (1.7 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0793] Step 8: Synthesis of compound T-3

[0794] The crude product from the previous step, (S)-1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(1-pyrrolidine-3-ylmethyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (24 mg, 0.086 mmol) and DIPEA (96 μL, 0.552 mmol) were added to DMSO (0.5 mL), and the mixture was heated to 120 °C and reacted for 4 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 3 mg of product, yield 12%. LC-MS (ESI): m / z = 904 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.06(s,1H),8.99(s,1H),8.84(s,1H),8.65(d,J=4.7H z,2H),8.39(s,1H),7.99–7.77(m,5H),7.67(s,1H),7.48(d,J=8.0Hz,2H),6.93(s,1H),6.85( s,1H),5.12–5.01(m,1H),3.87–3.71(m,3H),3.50(d,J=6.0Hz,6H),2.87(d,J=12.2Hz,2H),2. 62–2.54(m,3H),2.25–2.05(m,1H),1.98(d,J=6.3Hz,5H),1.81(s,3H),1.46(d,J=7.7Hz,4H).

[0795] Example 4: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (compound T-4)

[0796] The following synthetic route was adopted:

[0797] Step 1: Synthesis of compound 1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine

[0798] Compound tert-butyl 4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid (160 mg, 0.25 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0799] Step 2: Synthesis of compound tert-butyl 4-((4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid

[0800] The crude product obtained in the previous step, 1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (61 mg, 0.286 mmol), and DIPEA (100 μL, 0.575 mmol) were added to DCM (7 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (212 mg, 1.0 mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 86 mg of product, yield 47%, LC-MS (ESI): m / z = 736 [M+1]. + .

[0801] Step 3: Synthesis of compound 1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine

[0802] Compound tert-butyl piperidinium-1-carboxylate (86 mg, 0.117 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (0.6 mL) and dichloromethane (2.5 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0803] Step 4: Synthesis of compound T-4

[0804] The crude product obtained in the previous step, 1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (48 mg, 0.176 mmol) and DIPEA (183 μL, 1.05 mmol) were added to DMSO (1.5 mL) and the mixture was heated to 120 °C and reacted for 4 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 36 mg of product, yield 35%. LC-MS (ESI): m / z = 892 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.06(d,J=1.9Hz,1H),9.00(s,1H),8.83(s,1H),8.64(s,2H),8.2 5(s,1H),7.95–7.84(m,3H),7.82(d,J=7.9Hz,2H),7.66(d,J=8.5Hz,1H),7.47(d,J=8.1Hz,2H),7.32(d ,J=2.2Hz,1H),7.24(dd,J=8.6,2.3Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.13–4.00(m,3H),3.89(s,3H ),3.09–2.79(m,5H),2.69–2.54(m,5H),2.21(s,2H),2.10–2.02(m,2H),1.90–1.69(m,6H),1.45(s,1H).

[0805] Example 5: Preparation of 3-(5-(3-(4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound T-5)

[0806] The following synthetic route was adopted:

[0807] Step 1: Synthesis of compound 1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine

[0808] Compound tert-butyl 4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid (80 mg, 0.125 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (1 mL) and dichloromethane (4 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0809] Step 2: Synthesis of compound T-5

[0810] The crude product 1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, intermediate A-3 (47 mg, 0.158 mmol), and DIPEA (54 μL, 0.311 mmol) from the previous step were added to DCM (4 mL), and the mixture was stirred at room temperature for 1 h. Then, NaBH(OAc)3 (106 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 70 mg of the product (68% yield). LC-MS (ESI): m / z = 819 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.06(d,J=1.9Hz,1H),8.99(s,1H),8.83(s,1H),8.65(s,2H),8.25(s,1H) ,7.94–7.85(m,3H),7.83(d,J=8.1Hz,2H),7.76–7.70(m,2H),7.60(d,J=8.2Hz,1H),7.49(d,J=8.1Hz,2H),5.12( dd,J=13.3,5.0Hz,1H),4.48(d,J=17.5Hz,1H),4.40–4.30(m,1H),3.89(s,3H),3.63(s,2H),3.03(d,J=10.5Hz, 2H),2.97–2.86(m,1H),2.71–2.57(m,4H),2.41(t,J=10.1Hz,2H),1.85(t,J=18.0Hz,3H),1.45(t,J=7.2Hz,1H).

[0811] Example 6: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(4-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)azacyclobutane-1-yl)isoindoline-1,3-dione (compound T-6)

[0812] Following the preparation method of Example 4, 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (61 mg, 0.286 mmol) was replaced with 3-formylazetane-1-carboxylic acid tert-butyl ester (56 mg, 0.30 mmol) to obtain 22 mg of compound T-6, with a yield of 14%. LC-MS (ESI): m / z = 864 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),9.06(d,J=2.1Hz,1H),9.00(s,1H),8.83(s,1H),8.65(d,J=2.1Hz,2H),8.25( s,1H),7.94–7.85(m,3H),7.82(d,J=8.1Hz,2H),7.64(d,J=8.4Hz,1H),7.47(d,J=8.1Hz,2H),6.79(d,J=2.2Hz,1H) ,6.66(dd,J=8.3,2.2Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.17(t,J=8.2Hz,2H),3.89(s,3H),3.72(dd,J=8.4,5.5 Hz,2H),3.01(d,J=11.1Hz,3H),2.94–2.80(m,2H),2.72–2.60(m,4H),2.12(s,2H),1.83–1.67(m,4H),1.45(s,1H).

[0813] Example 7: Preparation of 1-(5-fluoro-6-(4-hydroxy-4-(2-(2-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4.5]decane-8-yl)-2-oxoethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound T-7)

[0814] The following synthetic route was adopted:

[0815] Step 1: Synthesis of compound 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

[0816] Sodium hydride (606 mg, 15.2 mmol) was dissolved in DMF (20 mL), and a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.0 g, 10.1 mmol) in DMF (5 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 30 min. Then, SEMCl (2.68 mL, 15.2 mmol) was slowly added, and the reaction was stirred overnight at room temperature. After the reaction was complete, a saturated ammonium chloride aqueous solution was added, and the reaction was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 2.30 g of the product (70% yield). LC-MS (ESI): m / z = 328 [M+1] + .

[0817] Step 2: Synthesis of compound tert-butyl 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4,5]decane-8-carboxylate

[0818] Compound 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine (2.2 g, 6.71 mmol), 8-tert-butoxycarbonyl-2,8-diazaspiro[4.5]decane (1.93 g, 8.0 mmol), Pd(OAc)2 (152 mg, 0.671 mmol), BINAP (685 mg, 1.10 mmol), cesium carbonate (6.56 g, 20.1 mmol), and toluene (45 mL) were added to a reaction flask and stirred overnight at 120 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography to give 2.48 g of the product, yield 76%, LC-MS (ESI): m / z = 488 [M+1]. + .

[0819] Synthesis of compound tert-butyl 2-(1H-pyrazolo[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4,5]decane-8-carboxylate in step 3

[0820] 2.43 g (4.98 mmol) of tert-butyl 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid was added to 60 mL of THF, and the mixture was heated to 70 °C and stirred overnight. After the reaction was complete, the mixture was concentrated and separated by silica gel column chromatography to give 1.3 g of the product, yield 73%. LC-MS (ESI): m / z = 358 [M+1] + .

[0821] Synthesis of compound tert-butyl 2-(1-((6-bromoimidazolo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4,5]decane-8-carboxylate in step 4

[0822] Sodium hydride (268 mg, 6.7 mmol) was dissolved in DMF (5 mL). A solution of tert-butyl 2-(1H-pyrazolo[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid (600 mg, 1.68 mmol) in DMF (5 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 30 min. Then, a solution of 6-bromoimidazolo[1,2-a]pyridine-3-sulfonyl chloride (692 mg, 2.35 mmol) in DMF (5 mL) was slowly added at room temperature, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, 0.1 N hydrochloric acid was added, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 200 mg of a white solid (yield 19%). LC-MS (ESI): m / z = 616 [M+1] + .

[0823] Synthesis of compound tert-butyl 2-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate in step 5

[0824] Compound 2-(1-((6-bromoimidazolo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (200 mg, 0.325 mmol), 1-methyl-4-pyrazolboronic acid pinacol ester (82 mg, 0.394 mmol), Pd(dppf)Cl2·DCM (14 mg, 0.0172 mmol), potassium carbonate (135 mg, 0.978 mmol), 1,4-dioxane (2.5 mL), and water (1.2 mL) were added to a reaction flask and reacted in a microwave-assisted reaction at 110 °C for 1.5 h under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the product was separated by silica gel column chromatography to obtain 190 mg of product, with a yield of 95%. LC-MS (ESI): m / z = 618 [M+1] + .

[0825] Synthesis of compound 2-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4,5]decane in step 6

[0826] 190 mg (0.31 mmol) of tert-butyl 2-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid was dissolved in a mixed solvent of trifluoroacetic acid (1.2 mL) and dichloromethane (4.8 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the crude product obtained by concentration was directly used in the next reaction step.

[0827] Step 7: Synthesis of compound T-7

[0828] Under nitrogen protection, intermediate A-4 (156 mg, 0.372 mmol), HATU (141 mg, 0.371 mmol), and DIPEA (216 μL, 1.24 mmol) were added to DMF (3.0 mL) and stirred at room temperature for 5 min. Then, a DMF (1.5 mL) solution of the crude product 2-(1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazol[4,3-b]pyridin-6-yl)-2,8-diazaspiro[4.5]decane was added and the mixture was stirred at room temperature overnight. After the reaction was complete, the product was concentrated to remove DMF, diluted with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 64 mg of product, yield 22%. LC-MS (ESI): m / z = 919 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.93(s,1H),8.50(d,J=10.7Hz,2H),8.26(s,1H),8.23(d,J=2.5Hz,1H),7.84(d,J= 11.2Hz,3H),7.33(d,J=12.7Hz,1H),7.22(d,J=2.5Hz,1H),7.13(d,J=7.1Hz,1H),5.07(s,1H),3.94(s,3H),3.92(s,3H),3 .89(t,J=6.7Hz,2H),3.72–3.58(m,3H),3.54(t,J=7.1Hz,4H),3.19(d,J=11.2Hz,3H),3.08(t,J=11.0Hz,2H),2.74(t,J=6 .7Hz,2H),2.60(s,2H),1.99(q,J=7.0,5.2Hz,2H),1.83(d,J=11.1Hz,2H),1.74(d,J=14.0Hz,2H),1.60(d,J=27.4Hz,4H). 19F NMR(377MHz,DMSO-d6)δ-129.74.

[0829] Example 8: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(4-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (compound T-8)

[0830] The following synthetic route was adopted:

[0831] Step 1: Synthesis of compound 1-(6-bromoimidazolo[1,2-a]pyridin-3-yl)ethyl-1-one

[0832] 6-Bromoimidazolo[1,2-a]pyridine (4 g, 20.3 mmol) was added to CS2 (24 mL), and anhydrous aluminum chloride (6.75 g, 50 mmol) was slowly added under nitrogen protection at 0 °C. The mixture was then heated to room temperature and stirred for 30 min. The mixture was then heated to reflux, and acetic anhydride (2 mL, 21.2 mmol) was slowly added dropwise. After the addition was complete, the mixture was refluxed and stirred for 5 h. Upon completion of the reaction, the reaction was quenched with ice water, extracted with dichloromethane, and the organic phase was washed successively with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 952 mg of the product (20% yield). LC-MS (ESI): m / z = 239 [M+1] + .

[0833] Step 2: Synthesis of compound 1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl-1-one. Compound 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethyl-1-one (7 g, 29.3 mmol), pinacol ester of 1-methyl-4-pyrazolborate (6.7 g, 32.2 mmol), Pd(dppf)Cl2·DCM (1.2 g, 1.47 mmol), potassium carbonate (12.1 g, 87.7 mmol), 1,4-dioxane (225 mL), and water (112 mL) were added to a reaction flask and stirred overnight at 120 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Separation by silica gel column chromatography yielded 3.9 g of product (55% yield). LC-MS (ESI): m / z = 241 [M+1]. + .

[0834] Step 3: Synthesis of compound 1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethanol-1-ol

[0835] Compound 1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl-1-one (3.9 g, 16.3 mmol), THF (5 mL), and MeOH (5 mL) were added to a reaction flask. Sodium borohydride (620 mg, 16.3 mmol) was added at room temperature, and the mixture was stirred for 1 h. After the reaction was complete, the reaction was quenched by slowly adding saturated ammonium chloride aqueous solution at 0 °C. The mixture was concentrated to remove methanol, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 3 g of product (76% yield). LC-MS (ESI): m / z = 243 [M+1] + .

[0836] Step 4: Synthesis of compound 6-bromo-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridine

[0837] Compounds 1-(6-(1-methyl-1H-pyrazolo-4-yl)imidazo[1,2-a]pyridin-3-yl)ethanol-1-ol (3 g, 12.4 mmol), 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.95 g, 14.9 mmol), and p-toluenesulfonyl chloride (2.84 g, 14.9 mmol) were added to DMF (150 mL). DBU (3.7 mL, 24.8 mmol) was added dropwise at room temperature under nitrogen protection. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 365 mg of the product (7% yield). LC-MS (ESI): m / z = 422 [M+1] + .

[0838] Step 5: Synthesis of compound tert-butyl 4-(4-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid.

[0839] Compound 6-bromo-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridine (400 mg, 0.95 mmol), intermediate A-1 (400 mg, 1.045 mmol), Pd(dppf)Cl2·DCM (38 mg, 0.048 mmol), potassium carbonate (390 mg, 2.85 mmol), 1,4-dioxane (9 mL), and water (2.7 mL) were added to a reaction flask and stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography to give 250 mg of product, yield 44%, LC-MS (ESI): m / z = 603 [M+1]. + .

[0840] Step 6: Synthesis of compound 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine

[0841] 125 mg (0.21 mmol) of tert-butyl piperidine-1-carboxylate was dissolved in a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (2 mL) and stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0842] Step 7: Synthesis of compound tert-butyl 4-((4-(4-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid.

[0843] The crude product from the previous step, 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (56 mg, 0.26 mmol), and DIPEA (120 μL, 0.69 mmol) were sequentially added to DCM (2 mL), and the mixture was stirred at room temperature for 1 h. Then, NaBH(OAc)3 (200 mg, 0.94 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 80 mg of the product (54% yield). LC-MS (ESI): m / z = 700 [M+1] + .

[0844] Step 8: Synthesis of compound 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine

[0845] Compound tert-butyl piperidinium ester (80 mg, 0.114 mmol) was added to a mixed solvent of trifluoroacetic acid (1.1 mL) and dichloromethane (1.1 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the crude product obtained by concentration was directly used in the next reaction.

[0846] Step 9: Synthesis of compound T-8

[0847] 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (52 mg, 0.188 mmol), and DIPEA (200 μL, 1.15 mmol) were added to DMSO (2 mL), and the mixture was heated to 120 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 30 mg of product (31% yield). LC-MS (ESI): m / z = 856 [M+1]+ . 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.85(d,J=2.0Hz,1H),8.52(s,1H),8.36(s,1H),8.19(s,1H),7.91(s,2H),7.7 3(d,J=8.1Hz,2H),7.66(d,J=8.6Hz,1H),7.62–7.55(m,2H),7.43(dd,J=8.8,2.6Hz,3H),7.32(d,J=2.3Hz,1H),7.24( dd,J=8.7,2.4Hz,1H),6.72(q,J=6.9Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.06(d,J=12.9Hz,2H),3.77(s,3H),3.12 –2.78(m,5H),2.72–2.53(m,4H),2.23(s,2H),2.12(d,J=6.9Hz,3H),2.01(dt,J=14.7,7.6Hz,4H),1.94–1.69(m,7H).

[0848] Example 9: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((3R)-3-((4-(4-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-yl)isoindoline-1,3-dione (compound T-9)

[0849] The following synthetic route was adopted:

[0850] Step 1: Synthesis of compound 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine

[0851] Compound tert-butyl 4-(4-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidine-1-carboxylic acid (125 mg, 0.21 mmol) was added to a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the crude product obtained by concentrating the reaction system was directly used in the next reaction step.

[0852] Step 2: Synthesis of compound (3R)-3-((4-(4-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0853] The crude product from the previous step, 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(4-(piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, (S)-3-carboxypyrrolidine-1-carboxylic acid tert-butyl ester (52 mg, 0.26 mmol) and DIPEA (120 μL, 0.69 mmol) were added sequentially to DCM (2 mL), and the mixture was stirred at room temperature for 1 h. Then, sodium borohydride acetate (200 mg, 0.94 mmol) was added, and the reaction was continued to be stirred at room temperature overnight. After the reaction was complete, a saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted with dichloromethane, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 40 mg of product, with a yield of 28%. LC-MS (ESI): m / z = 686 [M+1] + .

[0854] Step 3: Synthesis of compound 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(4-(1-(((S)-pyrrolidine-3-yl)methyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine

[0855] Compound (3R)-3-((4-(4-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)phenyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.058 mmol) was added to a mixed solvent of trifluoroacetic acid (0.6 mL) and dichloromethane (0.6 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the crude product obtained by concentrating the reaction system was directly used in the next reaction step.

[0856] Step 4: Synthesis of compound T-9

[0857] The crude product from the previous step, 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(4-(1-(((S)-pyrrolidine-3-yl)methyl)piperidin-4-yl)phenyl)-1H-pyrazol[4,3-b]pyridine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (23 mg, 0.083 mmol) and DIPEA (94 μL, 0.54 mmol) were added sequentially to DMSO (1 mL), and the mixture was heated to 120 °C and reacted for 4 h. After the reaction was complete, the reaction system was cooled to room temperature, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 4 mg of product, yield 8%. LC-MS (ESI): m / z = 842 [M+1] + .

[0858] Example 10: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((3R)-3-((4-(6-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)pyridin-3-yl)piperidin-1-yl)methyl)pyrrolidine-1-yl)isoindoline-1,3-dione (compound T-10)

[0859] The following synthetic route was adopted:

[0860] Step 1: Synthesis of compound 6-(5-bromopyridin-2-yl)-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridine

[0861] The following compounds were added: 6-bromo-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridine (380 mg, 0.90 mmol), pinacol diboronate (270 mg, 1.1 mmol), Pd2(dba)3 (41 mg, 0.045 mmol), tricyclohexylphosphine (12.6 mg, 0.045 mmol), and potassium acetate (18 mg, 18 mmol). 0 mg (1.8 mmol) and 1,4-dioxane (5 mL) were added to a reaction flask, and the mixture was stirred at 110 °C for 3 h under nitrogen protection. After the reaction was complete, 280 mg (0.99 mmol) of 5-bromo-2-iodopyridine, 370 mg (2.7 mmol) of potassium carbonate, 52 mg (0.064 mmol) of Pd(dppf)Cl2·DCM, and 1.25 mL of water were added sequentially to the system. The reaction was stirred overnight at 80 °C under nitrogen protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, and water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 220 mg of product, yield 25%. LC-MS (ESI): m / z = 499 [M+1] + .

[0862] Step 2: Synthesis of compound tert-butyl 4-(6-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)pyridin-3-ylpiperidine-1-carboxylic acid

[0863] Zinc powder (67 mg, 1.02 mmol) was added to DMF (3 mL), and iodine (13 mg, 0.0512 mmol) was added under nitrogen protection. The mixture was stirred at room temperature for 5 min. N-tert-butoxycarbonyl-4-iodopiperidine (210 mg, 0.675 mmol) was added under nitrogen protection, and the mixture was stirred at room temperature for 1 h. Then, 6-(5-bromopyridin-2-yl)-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridine (170 mg, 0.341 mmol), SPhos (14 mg, 0.0341 mmol), and Pd2(dba)3 (22 mg, 0.0240 mmol) were added sequentially under nitrogen protection. The reaction was stirred overnight at 50 °C. After the reaction was complete, the mixture was filtered, and a saturated ammonium chloride aqueous solution was added. The mixture was extracted with ethyl acetate, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 80 mg of the product (yield 39%). LC-MS (ESI): m / z = 604 [M+1] + .

[0864] Step 3: Synthesis of compound 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(5-(piperidin-4-yl)pyridin-2-yl)-1H-pyrazol[4,3-b]pyridine

[0865] Compound tert-butyl 4-(6-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)pyridin-3-ylpiperidine-1-carboxylate (80 mg, 0.133 mmol) was added to a mixed solvent of trifluoroacetic acid (1.3 mL) and dichloromethane (1.3 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the crude product obtained by concentrating the reaction system was directly used in the next reaction step.

[0866] Synthesis of compound (3R)-3-((4-(6-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)pyridin-3-yl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester in step 4

[0867] The crude product from the previous reaction, 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(5-(piperidin-4-yl)pyridin-2-yl)-1H-pyrazol[4,3-b]pyridine, (S)-3-carboxypyrrolidine-1-carboxylic acid tert-butyl ester (35 mg, 0.176 mmol) and DIPEA (83 μL, 0.477 mmol) were added sequentially to DCM (2 mL) and stirred at room temperature for 1 h; then sodium borohydride acetate (130 mg, 0.613 mmol) was added and stirred at room temperature overnight. After the reaction was complete, a saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted with dichloromethane, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 30 mg of product, with a yield of 33%. LC-MS (ESI): m / z = 687 [M+1] + .

[0868] Step 5: Synthesis of compound 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(5-(1-(((S)-pyrrolidine-3-yl)methyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazol[4,3-b]pyridine)

[0869] Compound (3R)-3-((4-(6-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-1H-pyrazol[4,3-b]pyridin-6-yl)pyridin-3-yl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (30 mg, 0.0437 mmol) was added to a mixed solvent of trifluoroacetic acid (0.4 mL) and dichloromethane (0.4 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the crude product obtained by concentrating the reaction system was directly used in the next reaction step.

[0870] Step 6: Synthesis of compound T-10

[0871] The crude product from the previous step, 1-(1-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)ethyl)-6-(5-(1-(((S)-pyrrolidine-3-yl)methyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazol[4,3-b]pyridine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (23 mg, 0.0833 mmol) and DIPEA (93 μL, 0.534 mmol) were added sequentially to DMSO (1 mL), and the mixture was heated to 120 °C and reacted for 4 h. After the reaction was complete, the reaction system was cooled to room temperature, quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 2 mg of product, yield 5%. LC-MS (ESI): m / z = 843 [M+1] + .

[0872] Example 11: Preparation of 3-(1-(3-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-11)

[0873] The following synthetic route was adopted:

[0874] Step 1: Synthesis of compound 4-(((2-chloropyrimidin-5-yl)-oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0875] 2-Chloro-5-hydroxypyrimidine (3.2 g, 24.5 mmol), N-tert-butoxycarbonyl-4-piperidinemethanol (6.4 g, 29.7 mmol), and triphenylphosphine (7.71 g, 29.4 mmol) were added to THF (40 mL). DIAD (5.8 mL, 28.7 mmol) was slowly added dropwise to the system under nitrogen protection at 0 °C, and the reaction was stirred overnight at room temperature. After the reaction was complete, the reaction system was concentrated, and the product was separated by silica gel column chromatography to obtain 5.6 g of product, yield 70%. LC-MS (ESI): m / z = 328 [M+1] + .

[0876] Step 2: Synthesis of compound tert-butyl 4-(((2-(3-(hydroxymethyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylic acid

[0877] Compound 4-(((2-chloropyrimidin-5-yl)-oxy)methyl)piperidin-1-carboxylic acid tert-butyl ester (5.3 g, 16.2 mmol), 3-hydroxymethylphenylboronic acid pinacol ester (11.4 g, 48.6 mmol), Pd(dppf)Cl2 (710 mg, 0.97 mmol), potassium phosphate (13.76 g, 64.8 mmol), DMF (16 mL), and water (3.2 mL) were added to a reaction flask. The reaction was carried out overnight at 80 °C under nitrogen protection with stirring. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The product was separated by silica gel column chromatography, yielding 4.5 g of product (71%). LC-MS (ESI): m / z = 400 [M+1] + .

[0878] Step 3: Synthesis of compound tert-butyl 4-(((2-(3-(chloromethyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate

[0879] 4.5 g (11.3 mmol) of tert-butyl 4-(((2-(3-(hydroxymethyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-carboxylic acid, 4.43 g (16.9 mmol) of triphenylphosphine, and 1.63 mL (16.9 mmol) of carbon tetrachloride were added to 20 mL of DCM. The reaction was stirred overnight at 45 °C under nitrogen protection. After the reaction was completed, the mixture was concentrated and separated by silica gel column chromatography to give 3.87 g of the product, yield 82%. LC-MS (ESI): m / z = 418 [M+1] + .

[0880] Step 4: Synthesis of compound tert-butyl 4-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazine-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylic acid

[0881] Compound 4-(((2-(3-(chloromethyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-carboxylic acid tert-butyl ester (3.67 g, 8.8 mmol), 3-(6-carbonyl-1,6-dihydro-3-pyridazinyl)phenylcyanide (1.73 g, 8.8 mmol), and potassium carbonate (2.43 g, 17.6 mmol) were added to DMF (10 mL), and the reaction was stirred overnight at 80 °C. After the reaction was complete, ethyl acetate was added, and the organic phase was washed three times with saturated sodium bicarbonate aqueous solution, followed by washing with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 1.8 g of the product, yield 35%. LC-MS (ESI): m / z = 579 [M+1] + .

[0882] Step 5: Synthesis of compound 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile

[0883] Compound tert-butyl 4-(((2-(3-((3-(3-cyanophenyl)-6-oxadiazine-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylic acid (630 mg, 1.09 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (10 mL) and dichloromethane (10 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the concentrated crude product was directly used for the next reaction.

[0884] Step 6: Synthesis of compound tert-butyl 4-((4-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazine-1(6H)-yl)-methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid

[0885] The crude product from the previous step, 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, 1-tert-butyloxycarbonyl-4-piperidinecarboxaldehyde (256 mg, 1.20 mmol), and DIPEA (569 μL, 3.27 mmol) were added to DCM (8 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (924 mg, 4.36 mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 228 mg of product, yield 31%. LC-MS (ESI): m / z = 676 [M+1] + .

[0886] Step 7: Synthesis of compound 3-(6-oxo-1-(3-(5-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile

[0887] Compound tert-butyl 4-((4-(((2-(3-(((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)-methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid (100 mg, 0.15 mmol) was added to a mixed solvent of trifluoroacetic acid (1.5 mL) and dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0888] Step 8: Synthesis of compound T-11

[0889] The crude product from the previous step, 3-(6-oxo-1-(3-(5-(((1-(piperidin-4-ylmethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (67 mg, 0.24 mmol), and DIPEA (270 μL, 1.57 mmol) were added to DMSO (2 mL), and the mixture was heated to 120 °C for 4 h. After the reaction was complete, the reaction system was cooled to room temperature, the reaction was quenched with water, extracted with dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 10 mg of product (8% yield). LC-MS (ESI): m / z = 832 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.64(s,2H),8.38(s,2H),8.24(q,J=5.9,4.4Hz,2H),8.18(d,J=9.9Hz,1H),7.9 4(d,J=7.1Hz,1H),7.72(t,J=7.9Hz,1H),7.65(d,J=8.4Hz,1H),7.48(d,J=4.8Hz,2H),7.30(d,J=2.4Hz,1H),7.23(dd ,J=9.0,2.2Hz,1H),7.16(d,J=9.7Hz,1H),5.44(s,2H),5.06(dd,J=12.9,5.4Hz,1H),4.05(d,J=5.7Hz,5H),3.85–3.8 0(m,1H),2.94(dd,J=28.3,15.3Hz,7H),2.72(s,1H),2.15(d,J=6.9Hz,2H),2.05–1.93(m,4H),1.79(d,J=13.0Hz,6H).

[0890] Example 12: Preparation of 3-(1-(3-(5-(8-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-12)

[0891] The following synthetic route was adopted:

[0892] Step 1: Synthesis of compound (3-(5-bromopyrimidin-2-yl)phenyl)methanol

[0893] 5-Bromo-2-iodopyrimidine (42.7 g, 150 mmol), pinacol ester of 3-hydroxymethylphenylboronic acid (42.1 g, 180 mmol), Pd(PPh3)4 (5.2 g, 4.5 mmol), potassium phosphate (63.4 g, 300 mmol), 1,4-dioxane (500 mL), and water (58 mL) were added to a reaction flask. The reaction was carried out overnight at 90 °C under nitrogen protection with stirring. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The product was separated by silica gel column chromatography, yielding 21.2 g of product (54%). LC-MS (ESI): m / z = 265 [M+1] + .

[0894] Step 2: Synthesis of compound 5-bromo-2-(3-(chloromethyl)phenyl)pyrimidine

[0895] 21.2 g (80 mmol) of the compound (3-(5-bromopyrimidin-2-yl)phenyl)methanol was added to 90 mL of DCM, and SOCl2 (8.7 mL, 120 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 3 h. After the reaction was complete, the mixture was concentrated, and toluene was added for further concentration. This process was repeated three times. Crystallization in diethyl ether yielded 17 g of the product, with a yield of 75%. LC-MS (ESI): m / z = 283 [M+1] + .

[0896] Step 3: Synthesis of compound 3-(1-(3-(5-bromopyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazine-3-yl)benzonitrile

[0897] Compounds 5-bromo-2-(3-(chloromethyl)phenyl)pyrimidine (17 g, 60.3 mmol), 3-(6-carbonyl-1,6-dihydro-3-pyridazinyl)phenylcyanide (14.3 g, 72.5 mmol), and potassium carbonate (10 g, 72.4 mmol) were added to N-methylpyrrolidone (80 mL), and the mixture was stirred overnight at 80 °C. After the reaction was complete, ethyl acetate was added, and the organic phase was washed three times with water, followed by washing with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 12.3 g of the product (46% yield). LC-MS (ESI): m / z = 444 [M+1] + .

[0898] Synthesis of compound tert-butyl 2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1-(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate in step 4

[0899] Compound 3-(1-(3-(5-bromopyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (660 mg, 1.5 mmol), 2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (433 mg, 1.8 mmol), Xantphos Pd G4 (72 mg, 0.075 mmol), cesium carbonate (977 mg, 3.0 mmol), and 1,4-dioxane (15 mL) were added to a reaction flask and stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography to give 215 mg of product, yield 24%, LC-MS (ESI): m / z = 604 [M+1]. + .

[0900] Step 5: Synthesis of compound 3-(1-(3-(5-(2,8-diazaspiro[4.5]decane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

[0901] Compound 2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1-(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (150 mg, 0.25 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2.5 mL) and dichloromethane (2.5 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0902] Step 6: Synthesis of compound tert-butyl 4-((2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1-(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-2,8-diazaspiro[4.5]decane-8-yl)methyl)piperidine-1-carboxylate

[0903] The crude product from the previous step, 3-(1-(3-(5-(2,8-diazaspiro[4.5]decane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (70 mg, 0.32 mmol), and DIPEA (150 μL, 0.89 mmol) were added to DCM (3 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (250 mg, 1.19 mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 35 mg of product (20% yield). LC-MS (ESI): m / z = 701 [M+1] + .

[0904] Step 7: Synthesis of compound 3-(6-oxo-1-(3-(5-(8-(piperidin-4-ylmethyl)-2,8-diazaspiro[4.5]decane-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile

[0905] Compound tert-butyl 4-((2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1-(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-2,8-diazaspiro[4.5]decane-8-yl)methyl)piperidine-1-carboxylate (30 mg, 0.043 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (0.43 mL) and dichloromethane (0.43 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0906] Step 8: Synthesis of compound T-12

[0907] The crude product from the previous reaction, 3-(6-oxo-1-(3-(5-(8-(piperidin-4-ylmethyl)-2,8-diazaspiro[4.5]decane-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (19.5 mg, 0.07 mmol), and DIPEA (78 μL, 0.45 mmol) were added to DMSO (2 mL), and the mixture was heated to 120 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 15 mg of the product (yield 41%). LC-MS (ESI): m / z = 857 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.38(d,J=1.7Hz,1H),8.32(d,J=2.1Hz,1H),8.27–8.22(m,1H),8.22–8.13(m,4H),7.94(d,J =7.7Hz,1H),7.72(t,J=7.9Hz,1H),7.65(d,J=8.6Hz,1H),7.48–7.35(m,2H),7.31(d,J=2.2Hz,1H),7.23(dd,J=8.7,2.3Hz,1H),7. 16(d,J=9.7Hz,1H),5.42(s,2H),5.06(dd,J=13.0,5.4Hz,1H),4.04(d,J=12.8Hz,2H),3.40(t,J=6.9Hz,2H),3.21(s,2H),3.04–2. 81(m,3H),2.70–2.53(m,2H),2.47–2.30(m,4H),2.17(d,J=7.4Hz,2H),2.00(dd,J=9.6,5.2Hz,2H),1.92–1.73(m,5H),1.57(s,5H).

[0908] Example 13: Preparation of 3-(1-(3-(5-(8-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetyl)-2,8-diazaspiro[4.5]decane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-13)

[0909] The following synthetic route was adopted:

[0910] Step 1: Synthesis of compound 3-(1-(3-(5-(2,8-diazaspiro[4.5]decane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazine-3-yl)benzyl nitrile

[0911] Compound 2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1-(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (210 mg, 0.348 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (3.5 mL) and dichloromethane (3.5 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0912] Step 2: Synthesis of compound T-13

[0913] Intermediate A-4 (146 mg, 0.348 mmol), HATU (146 mg, 0.383 mmol), and DIPEA (242 μL, 1.39 mmol) were added to DMF (2.0 mL) under nitrogen protection and stirred at room temperature for 5 min. Then, a DMF (1.5 mL) solution of the crude product from the previous step, 3-(1-(3-(5-(2,8-diazaspiro[4.5]decane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzyl nitrile, was added and stirred overnight at room temperature. After the reaction was complete, the DMF was removed by concentration, water was added, and the reaction was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 48 mg of the product (15% yield). LC-MS (ESI): m / z = 905 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.38(t,J=1.7Hz,1H),8.32(d,J=1. 8Hz,1H),8.28–8.23(m,1H),8.22(s,2H),8.19–8.13(m,2H),7.93(d,J=7. 8Hz,1H),7.72(t,J=7.8Hz,1H),7.47–7.37(m,2H),7.33(d,J=12.7Hz,1H) ,7.16(d,J=9.7Hz,1H),7.12(d,J=7.1Hz,1H),5.42(s,2H),5.05(s,1H),3. 94(s,3H),3.89(t,J=6.7Hz,2H),3.64(q,J=7.5Hz,2H),3.52(dd,J=18.1, 8.0Hz,2H),3.46–3.42(m,2H),3.29(s,2H),3.17(d,J=11.8Hz,2H),3.12– 3.01(m,2H),2.74(t,J=6.6Hz,2H),2.58(s,2H),1.93(t,J=7.0Hz,2H),1. 87–1.78(m,2H),1.74(s,2H),1.59(d,J=5.8Hz,2H),1.52(d,J=5.6Hz,2H). 19 F NMR(377MHz,DMSO-d6)δ-129.74.

[0914] Example 14: Preparation of 3-(1-(3-(5-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-14)

[0915] The following synthetic route was adopted:

[0916] Step 1: Synthesis of compound tert-butyl 4-(4-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazine-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0917] Compound 3-(1-(3-(5-bromopyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (1.6 g, 3.61 mmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (1.36 g, 3.61 mmol), Pd(PPh3)4 (420 mg, 0.36 mmol), 2M sodium carbonate aqueous solution (15 mL, 30 mmol) and DME (10 mL) were added to a reaction flask, and the reaction was carried out overnight at 85 °C under nitrogen protection with stirring. After the reaction was complete, the mixture was filtered, extracted with ethyl acetate, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 798 mg of product, yield 36%. LC-MS (ESI): m / z = 615 [M+1] + .

[0918] Step 2: Synthesis of compound 3-(6-oxo-1-(3-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile

[0919] Compound tert-butyl 4-(4-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (203 mg, 0.33 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (3.3 mL) and dichloromethane (3.3 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the concentrated crude product was directly used in the next reaction step.

[0920] Step 3: Synthesis of compound tert-butyl 3-((4-(4-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-1-ylmethyl)pyrrolidine-1-carboxylic acid.

[0921] The crude product from the previous step, 3-(6-oxo-1-(3-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, tert-butyl 3-formylpyrrolidine-1-carboxylate (72 mg, 0.363 mmol), and DIPEA (174 μL, 1.0 mmol) were added to DCM (4 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (280 mg, 1.32 mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 154 mg of product, yield 67%, LC-MS (ESI): m / z = 698 [M+1]. + .

[0922] Step 4: Synthesis of compound 3-(6-oxo-1-(3-(5-(1-(1-(1-(pyrrolidine-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazine-3-yl)benzonitrile

[0923] Compound tert-butyl pyrrolidine-1-carboxylate (154 mg, 0.22 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2.2 mL) and dichloromethane (2.2 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the crude product obtained by concentration was directly used in the next reaction.

[0924] Step 5: Synthesis of compound T-14

[0925] The crude product from the previous step, 3-(6-oxo-1-(3-(5-(1-(1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (49 mg, 0.31 mmol), and DIPEA (200 μL, 1.98 mmol) were added to DMSO (2 mL), and the mixture was heated to 120 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, the reaction was quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 28 mg of the product (yield 15%). LC-MS (ESI): m / z = 854 [M+1]. + . 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.15(s,2H),8.54(s,1H),8.46(s,1H),8. 39(d,J=1.5Hz,1H),8.32(d,J=6.4Hz,1H),8.26(d,J=8.0Hz,1H),8.19(d,J=9.8 Hz,1H),8.11(s,1H),7.94(d,J=7.7Hz,1H),7.73(t,J=7.9Hz,1H),7.65(d,J=8. 5Hz,1H),7.52(d,J=6.6Hz,2H),7.17(d,J=9.7Hz,1H),6.91(d,J=2.1Hz,1H),6. 82(dd,J=8.6,2.1Hz,1H),5.47(s,2H),5.06(dd,J=12.9,5.4Hz,1H),4.21(dt,J =11.1,6.0Hz,1H),3.63–3.45(m,3H),3.17(dd,J=10.4,6.8Hz,1H),3.03(dd,J= 28.5,10.5Hz,2H),2.95–2.81(m,1H),2.70–2.54(m,3H),2.41(d,J=7.3Hz,2H), 2.22–2.11(m,2H),2.08–1.96(m,5H),1.85–1.72(m,1H),1.44(d,J=7.5Hz,1H).

[0926] Example 15: Preparation of 3-(1-(3-(5-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-15)

[0927] The following synthetic route was adopted:

[0928] Step 1: Synthesis of compound 2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester

[0929] Compound 3-(1-(3-(5-bromopyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (600 mg, 1.35 mmol), intermediate A-5 (360 mg, 1.35 mmol), Pd(dppf)Cl2 (79 mg, 0.11 mmol), potassium carbonate (370 mg, 2.70 mmol), DMF (14 mL), and water (2.8 mL) were added to a reaction flask. The reaction was carried out under nitrogen protection and stirred at 100 °C for 4 hours. After the reaction was completed, the mixture was filtered, extracted with ethyl acetate, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 220 mg of product, yield 28%. LC-MS (ESI): m / z = 587 [M+1] + .

[0930] Step 2: Synthesis of compound 3-(6-oxo-1-(3-(5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile

[0931] Compound 2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-carboxylic acid tert-butyl ester (220 mg, 0.38 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (3.8 mL) and dichloromethane (3.8 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0932] Step 3: Synthesis of compound tert-butyl 4-((2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)piperidine-1-carboxylic acid

[0933] The crude product from the previous step, 3-(6-oxo-1-(3-(5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzyl nitrile, 1-tert-butyloxycarbonyl-4-piperidinecarboxaldehyde (96 mg, 0.45 mmol), and DIPEA (210 μL, 1.23 mmol) were added to DCM (3 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (350 mg, 1.64 mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 120 mg of product (46% yield). LC-MS (ESI): m / z = 684 [M+1] + .

[0934] Synthesis of compound 3-(6-oxo-1-(3-(5-(5-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile in step 4

[0935] Compound tert-butyl 4-((2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)piperidine-1-carboxylic acid (120 mg, 0.18 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (1.8 mL) and dichloromethane (1.8 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0936] Step 5: Synthesis of compound T-15

[0937] The crude product from the previous step, 3-(6-oxo-1-(3-(5-(5-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (80 mg, 0.25 mmol), and DIPEA (320 μL, 1.62 mmol) were added to DMSO (2 mL), and the mixture was heated to 120 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 51 mg of the product (34% yield). LC-MS (ESI): m / z = 840 [M+1] + .1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.24(s,2H),8.50(s,1H),8.38(s,1H),8.35(d,J=7.1Hz,1H),8.28–8.23(m,1H),8.18(d,J =9.8Hz,1H),7.93(d,J=7.9Hz,1H),7.72(t,J=7.9Hz,1H),7.65(d,J=8.4Hz,1H),7.58–7.49(m,2H),7.32(d,J=2.2Hz,1H),7.23( dd,J=8.7,2.3Hz,1H),7.17(d,J=9.7Hz,1H),6.71(s,1H),5.47(s,2H),5.06(dd,J=12.9,5.4Hz,1H),4.36(s,3H),4.19(t,J=5.5 Hz,2H),4.06(d,J=12.9Hz,2H),3.70(s,2H),3.05–2.85(m,5H),2.41(d,J=7.1Hz,2H),2.07–1.89(m,3H),1.83(d,J=11.7Hz,2H).

[0938] Example 16: Preparation of 3-(1-(3-(5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-16)

[0939] The following synthetic route was adopted:

[0940] Step 1: Synthesis of compound 2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazine-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0941] In a glove box, 3-(1-(3-(5-bromopyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (1 g, 2.26 mmol), tert-butyl 2-iodo-7-azaspiro[3.5]nonane-7-carboxylate (1 g, 3.16 mmol), 4CzIPN (36 mg, 0.05 mmol), NiBr2·(4,4'-dtbbpy) (100 mg, 0.23 mmol), and triethylamine (0.9 mL, 6.78 mmol) were added to 1,4-dioxane (22 mL), and the bottle was sealed. The reaction flask was then placed in a light reaction chamber equipped with a fan and a 440 nm blue light source, and the reaction was stirred for 24 h at room temperature and under blue light irradiation. After the reaction was completed, the product was concentrated and separated by silica gel column chromatography to obtain 452 mg of product, with a yield of 35%. LC-MS (ESI): m / z = 589 [M+1] + .

[0942] Step 2: Synthesis of compound 3-(1-(3-(5-(7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazine-3-yl)benzonitrile

[0943] Compound 2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (150 mg, 0.255 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2.6 mL) and dichloromethane (2.6 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0944] Step 3: Synthesis of compound tert-butyl 4-((2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazine-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylate

[0945] The crude product from the previous step, 3-(1-(3-(5-(7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (78 mg, 0.33 mmol), and DIPEA (160 μL, 0.93 mmol) were added to DCM (3 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (260 mg, 1.24 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 62 mg of product (35% yield). LC-MS (ESI): m / z = 686 [M+1] + .

[0946] Synthesis of compound 3-(6-oxo-1-(3-(5-(7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazine-3-yl)benzonitrile in step 4

[0947] Compound tert-butyl 4-((2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid (62 mg, 0.09 mmol) was added to a mixed solvent of trifluoroacetic acid (0.9 mL) and dichloromethane (0.9 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0948] Step 5: Synthesis of compound T-16

[0949] The crude product from the previous step, 3-(6-oxo-1-(3-(5-(7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (43 mg, 0.12 mmol), and DIPEA (180 μL, 0.81 mmol) were added to DMSO (2 mL), and the mixture was heated to 120 °C for 4 h. After the reaction was complete, the reaction system was cooled to room temperature, the reaction was quenched with water, extracted with dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 8 mg of product, with a yield of 11%. LC-MS (ESI): m / z = 842 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),8.91(d,J=4.8Hz,2H),8.48(s,2H),8.32(t,J=6.5Hz,2H ),7.94(s,2H),7.71(dd,J=19.8,11.6Hz,2H),7.60–7.49(m,2H),7.46(t,J=4.9Hz,1H),7.36(s ,1H),7.26(s,1H),5.45(s,2H),5.07(dd,J=12.9,5.4Hz,1H),4.08(s,2H),3.49–3.44(m,6H), 2.96(d,J=27.3Hz,5H),2.13(s,3H),1.98(d,J=6.4Hz,5H),1.80(s,4H),1.46(d,J=8.5Hz,3H).

[0950] Example 17: Preparation of 3-(1-(3-(5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-17)

[0951] The following synthetic route was adopted:

[0952] Step 1: Synthesis of compound 3-(1-(3-(5-(7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazine-3-yl)benzonitrile

[0953] Compound 2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (150 mg, 0.255 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2.6 mL) and dichloromethane (2.6 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the concentrated crude product was directly used for the next reaction.

[0954] Step 2: Synthesis of compound tert-butyl 3-((2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazine-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylate

[0955] The crude product from the previous step, 3-(1-(3-(5-(7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, tert-butyl 3-formylpyrrolidine-1-carboxylate (73 mg, 0.33 mmol), and DIPEA (160 μL, 0.93 mmol) were added to DCM (3 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (260 mg, 1.24 mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 65 mg of product, yield 38%, LC-MS (ESI): m / z = 672 [M+1]. + .

[0956] Step 3: Synthesis of compound 3-(6-oxo-1-(3-(5-(7-(pyrrolidine-3-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazine-3-yl)benzonitrile

[0957] Compound tert-butyl 3-((2-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylate (65 mg, 0.09 mmol) was added to a mixed solvent of trifluoroacetic acid (0.9 mL) and dichloromethane (0.9 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0958] Step 4: Synthesis of compound T-17

[0959] The crude product from the previous step, 3-(6-oxo-1-(3-(5-(7-(pyrrolidin-3-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (44 mg, 0.12 mmol), and DIPEA (180 μL, 0.81 mmol) were sequentially added to DMSO (2 mL), and the mixture was heated to 120 °C for 4 h. After the reaction was complete, the reaction system was cooled to room temperature, the reaction was quenched with water, extracted with dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 10 mg of product, with a yield of 13%. LC-MS (ESI): m / z = 828 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.91(d,J=4.8Hz,2H),8.48(d,J=7.4Hz,2H),8.32(t,J=7.0Hz,2H),7.94(d,J=5.1Hz,2H),7.73(t,J=7.9Hz, 1H),7.69(d,J=8.4Hz,1H),7.58–7.48(m,2H),7.46(t,J=4.9Hz,1H),6.94 (d,J=2.2Hz,1H),6.83(dd,J=8.6,2.2Hz,1H),5.46(d,J=2.8Hz,2H),5.06 (dd,J=13.0,5.4Hz,1H),3.72(t,J=8.9Hz,1H),3.64(t,J=9.0Hz,1H),3. 54(d,J=9.5Hz,2H),3.21(d,J=8.5Hz,3H),3.05(s,1H),2.95–2.76(m,3H) ,2.58(dd,J=19.1,5.0Hz,2H),2.35(d,J=20.5Hz,1H),2.24(s,1H),2.16( d,J=11.4Hz,3H),2.05–1.92(m,4H),1.85(d,J=13.5Hz,4H),1.45(s,1H).

[0960] Example 18: Preparation of 3-(1-(3-(5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)-7-azaspiro[3.5]nonane-2-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-18)

[0961] Following the preparation method of Example 17, tert-butyl 3-formylpyrrolidine-1-carboxylate (73 mg, 0.33 mmol) was replaced with tert-butyl 3-formylazetane-1-carboxylate (63 mg, 0.33 mmol) to prepare 8 mg of compound T-18, with a yield of 11%. LC-MS (ESI): m / z = 814 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.91(d,J=5.1Hz,2H),8.48(d,J=2.0Hz,2H),8.31(ddd,J=6.6,3.2,1.8Hz,2H),7.96 –7.90(m,2H),7.71(t,J=7.9Hz,1H),7.63(d,J=8.0Hz,1H),7.57–7.49(m,2H),7.45(t,J=4.8Hz,1H),6.77(d,J=2.0Hz,1H), 6.64(dd,J=8.4,2.1Hz,1H),5.45(s,2H),5.05(dd,J=12.8,5.3Hz,1H),4.12(t,J=4.8Hz,2H),3.74–3.55(m,7H),2.87(ddd, J=17.4,14.2,5.5Hz,1H),2.64–2.53(m,5H),2.16(d,J=11.7Hz,2H),1.96(d,J=6.9Hz,3H),1.71(s,1H),1.58–1.39(m,3H).

[0962] Example 19: Preparation of 3-(1-(3-(5-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptane-6-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-19)

[0963] The following synthetic route was adopted:

[0964] Following the preparation method of Example 16, tert-butyl 2-iodide-7-azaspiro[3.3]heptane-2-carboxylic acid was replaced with tert-butyl 2-iodide-7-nonane-7-carboxylic acid (1 g, 3.16 mmol) in 540 mg of 6-iodo-2-azaspiro[3.3]heptane-2-carboxylic acid (1.70 mmol) to prepare 32 mg of compound T-19, with a yield of 36%. LC-MS (ESI): m / z = 814 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.91(d,J=4.9Hz,2H),8.47(d,J=4.2Hz,2H),8.31(t,J=7.4Hz,2H),7.92(d,J=7.1Hz,2H),7.71(t, J=7.9Hz,1H),7.64(d,J=8.4Hz,1H),7.52(d,J=8.1Hz,2H),7.45(d,J=4.9Hz,1H),7.28(s,1H),7.21(d,J=8.8Hz,1H),5.44(s,2H),5.06( dd,J=12.9,5.4Hz,1H),4.01(d,J=13.0Hz,2H),3.53–3.42(m,2H),3.24(s,2H),3.04(s,2H),2.92(t,J=13.3Hz,2H),2.70–2.55(m,2H),2 .41(t,J=10.1Hz,2H),2.32(t,J=10.4Hz,2H),2.22(d,J=6.7Hz,2H),2.05–1.95(m,1H),1.85(s,2H),1.74(d,J=12.9Hz,2H),1.53(s,1H).

[0965] Example 20: 3-(1-(3-(5-((1r,3r)-3-((((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)amino)methyl)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-20A) and

[0966] Preparation of 3-(1-(3-(5-((1s,3s)-3-((((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)amino)methyl)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-20B)

[0967] The following synthetic route was adopted:

[0968] Step 1: Synthesis of compound 3-(6-oxo-1-(3-(5-(2-(piperidin-4-ylmethyl)-2-azaspiro[3.3]heptane-6-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazine-3-yl)benzonitrile

[0969] Compound tert-butyl 4-((6-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-2-azaspiro[3.3]heptane-2-yl)methyl)piperidine-1-carboxylate (72 mg, 0.11 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (1.1 mL) and dichloromethane (1.1 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0970] Step 2: Synthesis of compounds T-20A and T-20B

[0971] The crude product from the previous step, 3-(6-oxo-1-(3-(5-(2-(piperidin-4-ylmethyl)-2-azaspiro[3.3]heptane-6-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (69 mg, 0.15 mmol), and DIPEA (172 μL, 0.99 mmol) were sequentially added to DMSO (2 mL), and the mixture was heated to 120 °C and reacted overnight. After the reaction was complete, the reaction system was cooled to room temperature, the reaction was quenched with water, extracted with dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 8 mg of product T-20A, yield 9%, LC-MS (ESI): m / z = 832 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.90(d,J=5.0Hz,2H),8.50(s,1H),8.44(s,1H),8.38–8.26(m,2H),7.95(d,J =8.3Hz,2H),7.74(t,J=7.9Hz,1H),7.66(d,J=8.8Hz,1H),7.53(d,J=9.0Hz,2H),7.45(t,J=4.8Hz,1H),7.32(s,1H) ,7.24(s,1H),5.47(s,2H),5.06(dd,J=12.9,5.4Hz,1H),4.08–4.02(m,2H),3.75(s,1H),3.73(s,2H),3.63–3.56(m ,2H),3.09(s,1H),2.98–2.81(m,4H),2.65–2.55(m,3H),2.21(s,3H),1.96(d,J=6.4Hz,6H),1.80(d,J=12.9Hz,2H).

[0972] 8 mg of product T-20B, yield 9%, LC-MS (ESI): m / z = 832 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.91(d,J=4.8Hz,2H),8.48(d,J=9.3Hz,2H),8.31(t,J=8.0Hz,2H),7.94(d,J=6. 3Hz,2H),7.73(t,J=7.8Hz,1H),7.68(d,J=8.5Hz,1H),7.57–7.48(m,2H),7.46(t,J=4.8Hz,1H),7.36(s,1H),7.27(d,J= 8.7Hz,1H),5.46(s,2H),5.07(dd,J=12.9,5.4Hz,1H),4.11(d,J=13.1Hz,2H),3.69(t,J=8.9Hz,1H),3.53(s,2H),3.06– 2.81(m,8H),2.61(s,2H),2.28(d,J=10.1Hz,2H),2.11(t,J=10.9Hz,4H),1.96(d,J=6.5Hz,3H),1.84(d,J=12.9Hz,2H).

[0973] Example 21: Preparation of 3-(1-(3-(5-(8-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetyl)-1-oxa-8-azaspiro[4.5]decane-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-21)

[0974] The following synthetic route was adopted:

[0975] Step 1: Synthesis of compound tert-butyl 3-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylic acid.

[0976] Compound 3-(1-(3-(5-bromopyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (1.2 g, 2.7 mmol), intermediate A-8 (1.48 g, 4.05 mmol), Pd(dppf)Cl2·DCM (220 mg, 0.27 mmol), potassium phosphate (1.15 g, 5.4 mmol), 1,4-dioxane (27 mL), and water (5.4 mL) were added to a reaction flask. The reaction was carried out overnight at 110 °C under nitrogen protection with stirring. After the reaction was complete, the mixture was filtered, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 520 mg of product, yield 32%. LC-MS (ESI): m / z = 603 [M+1] + .

[0977] Step 2: Synthesis of compound tert-butyl 3-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0978] Compound tert-butyl 3-(2-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]dec-3-en-8-carboxylic acid (210 mg, 0.35 mmol) and 10% palladium hydroxide on carbon (670 mg, 0.48 mmol) were added to 1,4-dioxane (10 mL). The reaction was carried out in a high-pressure reactor under 10 bar hydrogen atmosphere and at room temperature with stirring for 24 h. After the reaction was complete, the mixture was filtered, concentrated, and separated by silica gel column chromatography to obtain 118 mg of the product, yield 56%. LC-MS (ESI): m / z = 605 [M+1] + .

[0979] Step 3: Synthesis of compound 3-(1-(3-(5-(1-oxa-8-azaspiro[4.5]decane-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

[0980] Compound tert-butyl 3-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (100 mg, 0.166 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (1.7 mL) and dichloromethane (1.7 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0981] Step 4: Synthesis of compound T-21

[0982] Under nitrogen protection, intermediates A-4 (70 mg, 0.166 mmol), HATU (76 mg, 0.199 mmol), and DIPEA (116 μL, 0.664 mmol) were sequentially added to DMF (1.0 mL), and stirred at room temperature for 5 min. Then, a DMF (0.6 mL) solution of the crude product from the previous step, 3-(1-(3-(5-(1-oxa-8-azaspiro[4.5]decane-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, the DMF was removed by concentration, water was added, and the reaction was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 38 mg of the product, yield 25%. LC-MS (ESI): m / z = 906 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.87(s,2H),8.45(d,J=1.8Hz,1H),8.38(t,J=1.7Hz,1H),8.30(d,J=7.4Hz,1H),8.27–8.23(m,1 H),8.18(d,J=9.7Hz,1H),7.94(d,J=7.7Hz,1H),7.72(t,J=7.9Hz,1H),7.57–7.48(m,2H),7.33(d,J=12.7Hz,1H),7.17(d,J=9.7Hz,1H ),7.12(d,J=7.2Hz,1H),5.46(s,2H),5.05(s,1H),4.19(t,J=7.9Hz,1H),3.94(s,3H),3.89(t,J=6.7Hz,2H),3.84–3.75(m,2H),3.70– 3.46(m,4H),3.17(d,J=11.3Hz,2H),3.06(t,J=10.9Hz,2H),2.73(t,J=6.7Hz,2H),2.58(s,2H),2.39–2.30(m,1H),1.95–1.60(m,9H). 19 F NMR(377MHz,DMSO-d6)δ-129.74.

[0983] Example 22: (S)-3-(1-(3-(5-(8-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetyl)-1-oxa-8-azaspiro[4.5]decane-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-22A) and

[0984] Preparation of (R)-3-(1-(3-(5-(8-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetyl)-1-oxa-8-azaspiro[4.5]decane-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-22B)

[0985] The following synthetic route was adopted:

[0986] Step 1: Synthesis of compounds (S)-3-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester and (R)-3-(2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[0987] Compound 3-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (450 mg, 0.745 mmol) was separated by SFC chiral column to yield 190 mg (99.5% ee) of (S)-3-(2-(3-((3-(3-cyanophenyl)-6-yl)-yl)decane-8-yl)carboxylic acid tert-butyl ester. Oxypyridazine-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester and 200 mg (99.5% ee) of (R)-3-(2-(3-((3-(3-cyanophenyl)-6-oxypyridazine-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester.

[0988] Chromatographic separation conditions:

[0989] Column: Chiralpak IK-3 50*4.6mm ID, 3μm

[0990] Mobile phase: Phase A is CO2, Phase B is EtOH + ACN (0.05% DEA)

[0991] Gradient rinsing: 60% EtOH + ACN (0.05% DEA) in CO2

[0992] Flow rate: 3 mL / min; Detector: Diode array detector;

[0993] Column temperature: 35℃; Back pressure: 100 Bar

[0994] Step 2: Synthesis of compounds (S)-3-(1-(3-(5-(1-oxa-8-azaspiro[4.5]decane-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile and compound (R)-3-(1-(3-(5-(1-oxa-8-azaspiro[4.5]decane-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

[0995] The compound (S)-3-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (190 mg, 0.314 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0996] Compound (R)-3-(2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (200 mg, 0.331 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[0997] Step 3: Synthesis of compounds T-22A and T-22B

[0998] Under nitrogen protection, intermediates A-4 (158 mg, 0.377 mmol), HATU (170 mg, 0.447 mmol), and DIPEA (260 μL, 1.496 mmol) were added sequentially to DMF (2.0 mL) and stirred at room temperature for 5 min. Then, a DMF (1.0 mL) solution of the crude product (S)-3-(1-(3-(5-(1-oxa-8-azaspiro[4.5]decane-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile was added and stirred at room temperature overnight. After the reaction was complete, the DMF was removed by concentration, water was added, and the reaction was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 199 mg (98.9% ee) of compound T-22A, yield 70%. LC-MS (ESI): m / z = 906 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.86(s,2H),8.45(s,1H),8.37(s,1H),8.30(d,J=7.3Hz,1H),8.24(d,J=8.0Hz,1H),8.17(d,J=9 .7Hz,1H),7.93(d,J=7.6Hz,1H),7.71(t,J=7.9Hz,1H),7.58–7.47(m,2H),7.32(d,J=12.7Hz,1H),7.16(d,J=9.8Hz,1H),7.11(d,J=7.0 Hz,1H),5.45(s,2H),5.05(s,1H),4.19(t,J=7.8Hz,1H),3.94(s,3H),3.89(t,J=6.6Hz,2H),3.78(td,J=8.6,2.6Hz,2H),3.66–3.48(m, 4H),3.17(d,J=10.5Hz,2H),3.09–3.01(m,2H),2.74(t,J=6.7Hz,2H),2.58(s,2H),2.34(td,J=9.8,9.0,4.6Hz,1H),1.95–1.62(m,9H). 19 F NMR(377MHz,DMSO-d6)δ-129.72.

[0999] Under nitrogen protection, intermediates A-4 (166 mg, 0.397 mmol), HATU (180 mg, 0.473 mmol), and DIPEA (270 μL, 1.553 mmol) were added sequentially to DMF (2.0 mL) and stirred at room temperature for 5 min. Then, a DMF (1.0 mL) solution of the crude product (R)-3-(1-(3-(5-(1-oxa-8-azaspiro[4.5]decane-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile was added and stirred at room temperature overnight. After the reaction was complete, the DMF was removed by concentration, water was added, and the reaction was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 185 mg (98.0% ee) of compound T-22B, yield 62%. LC-MS (ESI): m / z = 906 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.86(s,2H),8.45(s,1H),8.37(s,1H),8.30(d,J=7.3Hz,1H),8.24(d,J=8.0Hz,1H),8.17(d,J =9.8Hz,1H),7.93(d,J=7.7Hz,1H),7.71(t,J=7.9Hz,1H),7.59–7.46(m,2H),7.32(d,J=12.8Hz,1H),7.16(d,J=9.8Hz,1H),7.12(d,J =7.0Hz,1H),5.45(s,2H),5.05(s,1H),4.19(t,J=7.8Hz,1H),3.94(s,3H),3.89(t,J=6.7Hz,2H),3.78(td,J=8.9,2.5Hz,2H),3.71–3 .42(m,4H),3.17(d,J=10.8Hz,2H),3.06(t,J=10.9Hz,2H),2.73(t,J=6.6Hz,2H),2.58(s,2H),2.41–2.27(m,1H),1.99–1.53(m,9H). 19 F NMR(377MHz,DMSO-d6)δ-129.76.

[1000] Example 23: Preparation of 3-(1-(3-(5-(8-(2-(1-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetyl)-1-oxa-8-azaspiro[4.5]dec-3-en-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (compound T-23)

[1001] The following synthetic route was adopted:

[1002] Step 1: Synthesis of compound 3-(1-(3-(5-(1-oxa-8-azaspiro[4.5]dec-3-en-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazine-3-yl)benzonitrile

[1003] 100 mg (0.166 mmol) of tert-butyl 3-(2-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]dec-3-en-8-carboxylic acid was dissolved in a mixed solvent of trifluoroacetic acid (1.7 mL) and dichloromethane (1.7 mL), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[1004] Step 2: Synthesis of compound T-23

[1005] Under nitrogen protection, intermediates A-4 (83 mg, 0.199 mmol), HATU (76 mg, 0.199 mmol), and DIPEA (116 μL, 0.664 mmol) were sequentially added to DMF (1.0 mL), and stirred at room temperature for 5 min. Then, a DMF (0.6 mL) solution of the crude product from the previous step, 3-(1-(3-(5-(1-oxa-8-azaspiro[4.5]dec-3-en-3-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the DMF was removed by concentration, water was added, and the reaction was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 58 mg of the product, yield 32%. LC-MS (ESI): m / z = 904 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.97(s,2H),8.47(d,J=1.7Hz,1H),8.38(d,J=1.8Hz,1H),8.33(dd,J=7.4,1.8Hz,1H),8.25(dt,J=8.0,1.4Hz,1 H),8.18(d,J=9.7Hz,1H),7.93(dt,J=7.8,1.4Hz,1H),7.72(t,J=7.9Hz,1H ),7.61–7.48(m,2H),7.33(d,J=12.7Hz,1H),7.17(d,J=9.8Hz,1H),7.13(d, J=7.1Hz,1H),6.84(d,J=2.2Hz,1H),5.46(s,2H),5.04(s,1H),5.03(s,2H) ,4.09–4.00(m,1H),3.94(s,3H),3.89(t,J=6.6Hz,2H),3.83(d,J=13.6Hz, 1H),3.52(t,J=10.9Hz,1H),3.29–3.23(m,1H),3.22–3.13(m,2H),3.07(t, J=10.9Hz,2H),2.74(t,J=6.6Hz,2H),2.68–2.56(m,2H),1.89–1.57(m,8H). 19 F NMR (377MHz, DMSO-d6) δ-129.74 (dd, J=13.0, 7.5Hz).

[1006] Example 24: Preparation of 4-(7-((3-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)quinoline-6-yl)methyl)imidazo[1,2-b][1,2,4]triazin-2-yl)-2-fluoro-N-methylbenzamide (compound T-24)

[1007] The following synthetic route was adopted:

[1008] Step 1: Synthesis of compound 2-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzamide

[1009] N-methyl-4-bromo-2-fluorobenzamide (27.8 g, 120 mmol), pinacol diboronate (36.6 g, 144 mmol), Pd2(dba)3 (2.75 g, 3 mmol), tricyclohexylphosphine (1.92 g, 6.84 mmol), potassium acetate (35.33 g, 360 mmol), and 1,4-dioxane (280 mL) were added to a reaction flask and stirred at 80 °C for 2 h under nitrogen protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, and water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 19.29 g of product (58% yield). LC-MS (ESI): m / z = 280 [M+1] + .

[1010] Step 2: Synthesis of compound 4-(3-amino-1,2,4-triazine-6-yl)-2-fluoro-N-methylbenzamide

[1011] 3-Amino-6-bromo-1,2,4-triazine (11 g, 62.8 mmol), 2-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzamide (19.3 g, 69.1 mmol), Pd(dppf)Cl2 (1.1 g, 1.5 mmol), potassium carbonate (34.8 g, 251 mmol), 1,4-dioxane (130 mL), and water (65 mL) were added to a reaction flask. The reaction was carried out under nitrogen protection and stirred at 80 °C for 2 h. After the reaction was completed, the mixture was filtered, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 14.2 g of product, yield 91%. LC-MS (ESI): m / z = 248 [M+1] + .

[1012] Step 3: Synthesis of compound 4-(7-((3-bromoquinoline-6-yl)methyl)imidazo[1,2-b][1,2,4]triazin-2-yl)-2-fluoro-N-methylbenzamide

[1013] Compound 4-(3-amino-1,2,4-triazin-6-yl)-2-fluoro-N-methylbenzamide (3.5 g, 14.2 mmol) and intermediate A-6 (4.7 g, 17.8 mmol) were added to ethylene glycol (36 mL), and the reaction was stirred at 120 °C under nitrogen protection for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and pure water (57 mL) was added. The system was stirred at room temperature for 30 min, filtered, and the filter cake was dissolved in dichloromethane. The organic phase was then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 3.3 g of the product, yield 38%. LC-MS (ESI): m / z = 491 [M+1] + .

[1014] Step 4: Synthesis of compound tert-butyl 4-(4-(6-((2-(3-fluoro-4-(methylcarbamoyl)phenyl)imidazo[1,2-b][1,2,4]triazine-7-yl)methyl)quinoline-3-yl)phenyl)piperidine-1-carboxylic acid.

[1015] Compound 4-(7-((3-bromoquinoline-6-yl)methyl)imidazo[1,2-b][1,2,4]triazin-2-yl)-2-fluoro-N-methylbenzamide (1.0 g, 2.04 mmol), intermediate A-1 (1.03 g, 2.65 mmol), Pd(dppf)Cl2·DCM (84 mg, 0.10 mmol), potassium carbonate (845 mg, 6.12 mmol), 1,4-dioxane (20 mL), and water (6 mL) were added to a reaction flask. The reaction was carried out overnight at 100 °C under nitrogen protection with stirring. After the reaction was complete, the mixture was filtered, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give 1.0 g of product, yield 73%. LC-MS (ESI): m / z = 672 [M+1] + .

[1016] Step 5: Synthesis of compound 2-fluoro-N-methyl-4-(7-((3-(4-(piperidin-4-yl)phenyl)quinoline-6-yl)methyl)imidazo[1,2-b][1,2,4]triazine-2-yl)benzamide

[1017] Compound tert-butyl 4-(4-(6-((2-(3-fluoro-4-(methylcarbamoyl)phenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline-3-yl)phenyl)piperidine-1-carboxylic acid (150 mg, 0.22 mmol) was added to a mixed solvent of trifluoroacetic acid (1.5 mL) and dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[1018] Step 6: Synthesis of compound tert-butyl 4-((4-(4-(6-((2-(3-fluoro-4-(methylcarbamoyl)phenyl)imidazo[1,2-b][1,2,4]triazine-7-yl)methyl)quinoline-3-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid.

[1019] The crude product from the previous step, 2-fluoro-N-methyl-4-(7-((3-(4-(piperidin-4-yl)phenyl)quinoline-6-yl)methyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide, 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (57 mg, 0.27 mmol), and DIPEA (390 μL, 2.23 mmol) were sequentially added to DCM (5 mL) and stirred at room temperature for 1 h. Then, NaBH(OAc)3 (189 mg, 0.89 mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 86 mg of the product (50% yield). LC-MS (ESI): m / z = 769 [M+1] + .

[1020] Step 7: Synthesis of compound 2-fluoro-N-methyl-4-(7-((3-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)quinoline-6-yl)methyl)imidazo[1,2-b][1,2,4]triazine-2-yl)benzamide

[1021] Compound tert-butyl 4-((4-(4-(6-(((2-(3-fluoro-4-(methylcarbamoyl)phenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline-3-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid (86 mg, 0.11 mmol) was added to a mixed solvent of trifluoroacetic acid (1.5 mL) and dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the concentrated crude product was used directly in the next reaction step.

[1022] Step 8: Synthesis of compound T-24

[1023] The crude product from the previous step, 2-fluoro-N-methyl-4-(7-((3-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)quinoline-6-yl)methyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (46 mg, 0.17 mmol), and DIPEA (191 μL, 1.1 mmol) were sequentially added to DMSO (2 mL), and the mixture was heated to 120 °C for 4 h. After the reaction was complete, the reaction system was cooled to room temperature, the...

Claims

1. Compounds of formula (I), (II), (III), (IV), (V), (I'), (II'), (III'), (IV'), or (V'), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates: in, X1 is N or CR X1 ;where R X1 It can be H, D, CN, NO2, or halogen; X2 is N or CR X2 ;where R X2 It can be H, D, CN, NO2, or halogen; X3 is N or CR X3 ;where R X3 It can be H, D, CN, NO2, or halogen; Y is C(R) Y )2, O, S, NH or S(O)2; where each R Y Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups; p is 0, 1, 2, 3, 4, 5 or 6; Each R1 is independently D, CN, NO2, or a halogen, or two adjacent R1s together with the atoms they are attached to form a 5-6 membered monocyclic heterocycle, wherein the 5-6 membered monocyclic heterocycle is optionally composed of one or more atoms selected from oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Substitution of alkyl groups; Each of R2, R3, and R5 is independently H, C 1-6 Alkyl or 3-6 membered monocyclic carbon ring; wherein the group is optionally substituted by one or more groups selected from D or halogens; R4 can be H, D, CN, NO2, or a halogen; Each A is independently C. 1-6 The ynyl group is a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more R groups. Each m is independently either 0 or 1; Each B is independently a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more Rs; Each C is independently a chemical bond, a phenylene group, or a 5-6 membered heteroaryl group; wherein the phenylene group and the 5-6 membered heteroaryl group are optionally substituted by one or more R groups; m' is 0 or 1; When m' is 1, B' is B; or When m' is 0, ring B' is a divalent group selected from 3-6 member monocyclic carbon rings, 6-10 member fused carbon rings, 6-10 member fused heterocycles, 6-10 member bridged carbon rings, 6-10 member bridged heterocycles, 6-9 member spirocyclic carbon rings, and 6-9 member spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R; n is 0 or 1; D is a chemical bond, a phenylene group, or a 5-6-membered heteroaryl group; wherein the phenylene group and the 5-6-membered heteroaryl group are optionally substituted by one or more R groups; Each R is independently H, D, OH, CN, NO2, NH2, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two Rs together with the atoms they are attached to form a 3-6 membered monocyclic carbon ring or a 4-7 membered monocyclic heterocycle; Each U is independent as follows: in, Indicates a single bond or a double bond; Each Q1 is independently C(O) or C(R). U4 )2; Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time; t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time; Each Q2 is independently either N or CH; Q3 and Q4 are each independently N or CH; W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O); P1 is N, C, or CR. U4 ; P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2; P4 and P5 are each independently N or C; z is 0, 1, or 2; H1 is N or CR U4 ; H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2; Each h is independently 0, 1, 2, 3 or 4; Each k is independently 0, 1, 2, or 3; Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

2. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, X1 is N, CH, CD or CF, X2 is N, CH, CD or CF, and X3 is N, CH, CD or CF; Preferably, X1 is CH, X2 is N and X3 is N; Preferably, X1 is N, X2 is CH and X3 is N; Preferably, X1 is N, X2 is CF and X3 is CH.

3. The compound according to claim 1 or 2, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, D represents a chemical bond.

4. The compound according to claim 1 or 2, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, D is a phenylene that is optionally substituted with one or more D or F.

5. The compound according to claim 1 or 2, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, D is a 5-6 member heteroaryl group optionally substituted with one or more D or F; Preferably, D is a 5-6 membered heteroaryl group containing one or more N atoms; Preferably, D is an imidazolyl group.

6. The compound according to any one of claims 1-5, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, p is 0 or 1, and R1 is D or halogen; Preferably, p is 0; Preferably, p is 1, and R1 is D or F.

7. The compound according to any one of claims 1-5, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R3 is C 1-6 alkyl; Preferably, R3 is a methyl group.

8. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, R4 is H, D, CN, or F; Preferably, R4 is H or CN.

9. The compound according to any one of claims 1-8, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 1.

10. The compound according to any one of claims 1-8, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 0.

11. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, R2 is methyl or cyclopropane.

12. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, R5 is H or methyl.

13. The compound according to any one of claims 1-12, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Y is CH2, CF2, CH(CH3), S or S(O)2; Preferably, Y is CH2; Preferably, Y is CF2; Preferably, Y is CH(CH3); Preferably, Y is S; Preferably, Y is S(O)2.

14. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, The compounds are of formula (I-1), (II-1), (III-1), (IV-1), (V-1), (I'-1), (II'-1), (III'-1), (IV'-1), or (V'-1): Each A is independently C. 1-6 The ynyl group is a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more R groups. Each m is independently either 0 or 1; Each B is independently a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more Rs; Each C is independently a chemical bond, a phenylene group, or a 5-6 membered heteroaryl group; wherein the phenylene group and the 5-6 membered heteroaryl group are optionally substituted by one or more R groups; m' is 0 or 1; When m' is 1, B' is B; or When m' is 0, ring B' is a divalent group selected from 3-6 member monocyclic carbon rings, 6-10 member fused carbon rings, 6-10 member fused heterocycles, 6-10 member bridged carbon rings, 6-10 member bridged heterocycles, 6-9 member spirocyclic carbon rings, and 6-9 member spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R; n is 0 or 1; Each R is independently H, D, OH, CN, NO2, NH2, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two Rs together with the atoms they are attached to form a 3-6 membered monocyclic carbon ring or a 4-7 membered monocyclic heterocycle; Each U is independent as follows: in, Indicates a single bond or a double bond; Each Q1 is independently C(O) or C(R). U4 )2; Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time; t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time; Each Q2 is independently either N or CH; Q3 and Q4 are each independently N or CH; W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O); P1 is N, C, or CR. U4 ; P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2; P4 and P5 are each independently N or C; z is 0, 1, or 2; H1 is N or CR U4 ; H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2; Each h is independently 0, 1, 2, 3 or 4; Each k is independently 0, 1, 2, or 3; Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

15. The compound according to any one of claims 1-14, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each U is independently: in, Indicates a single bond or a double bond; Each Q1 is independently C(O) or C(R). U4 )2; Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time; t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time; Each Q2 is independently either N or CH; Q3 and Q4 are each independently N or CH; W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O); P1 is N, C, or CR. U4 ; P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2; P4 and P5 are each independently N or C; Each h is independently 0, 1, 2, 3 or 4; Each k is independently 0, 1, 2, or 3; Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

16. The compound according to any one of claims 1-15, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each U is independently: in, Each Q1 is independently C(O) or C(R). U4 )2; Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time; t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time; Each h is independently 0, 1, 2, 3 or 4; Each k is independently 0, 1, 2, or 3; Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-7 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkanes or 4-7 membered heterocycles; or two Rs U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

17. The compound of claim 16, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each U is independently: in, Each Q1 is independently C(O) or C(R). U4 )2; Each k is independently 0, 1, or 2; Each R U3 Each is independently either D or halogen; Each R U4 Each can be H, D, or halogen independently.

18. The compound according to any one of claims 1-15, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each U is independently: in, Q2 is either N or CH; Q3 is either N or CH; W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O); h can be 0, 1, 2, 3, or 4; k can be 0, 1, 2, or 3; R U1 For H, C 1-6 Alkyl or C 3-7 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 heteroaryl aromatic hydrocarbons.

19. The compound according to claim 18, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each U is independently: in, Q2 is either N or CH; Q3 is either N or CH; Each k is independently 0, 1, or 2; Each R U3 Each is independently either D or halogen.

20. The compound according to any one of claims 1-15, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each U is independently: in, Indicates a single bond or a double bond; Q2 is either N or CH; P1 is N, C, or CR. U4 ; P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2; P4 and P5 are each independently N or C; h can be 0, 1, 2, 3, or 4; k can be 0, 1, 2, or 3; R U1 For H, C 1-6 Alkyl or C 3-7 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes, 4-7 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-7 Cycloalkanes or 4-7 membered heterocycles.

21. The compound of claim 20, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each U is independently: in, Q2 is either N or CH; Each P2 is independently either N or CR. U4 ; Each P3 is independently N, O, S, NR. U4 or CR U4 ; Each k is independently 0, 1, or 2; Each R U3 Each is independently either D or halogen; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups.

22. The compound of claim 21, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each U is independently: in, Q2 is either N or CH; P2 is N or CR U4 ; P3 is O, S, or NR. U4 ; k is 0, 1, or 2; Each R U3 Each is independently either D or halogen; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic rings.

23. The compound of claim 22, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each U is independently: in, k is 0, 1, or 2; Each R U3 Each is independently either D or halogen; R U4 For H, C 1-6 Alkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclic groups; Preferably, each U is independently... Where k is 0, 1, or 2; Each R U3 Each is independently either D or halogen.

24. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Both m and m' are 0.

25. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Both m and m' are 1.

26. The compound according to any one of claims 1-25, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each A is independently C. 1-6 The ynyl group, wherein the above group is optionally substituted with one or more R groups; Preferably, A is an ethynylene group.

27. The compound according to any one of claims 1-25, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each A is independently a divalent group selected from 3-6 membered monocyclic carbocyclic rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbocyclic rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbocyclic rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbocyclic rings, and 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally substituted by one or more R; Preferably, each A is independently a divalent group selected from 4-7 member monocyclic heterocycles, 6-10 member fused heterocycles, 6-10 member bridged heterocycles, and 6-9 member spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more Rs; Preferably, each A is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered bridged heterocycles, and 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more Rs; Preferably, each A is independently a divalent group selected from 4-7 membered monocyclic heterocycles and 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more R; Preferably, each A is independently a divalent group selected from 4-7 membered monocyclic heterocycles; wherein the above groups are optionally substituted by one or more R; Preferably, each A is independently... The aforementioned groups may optionally be substituted by one or more R groups; Preferably, each A is independently... The aforementioned groups may optionally be substituted by one or more R groups; Preferably, each R is independently D, -OH, F, or C. 1-3 Alkyl groups, or two R groups together with the atoms they are attached to, form 3-6 membered monocyclic carbon rings; Preferably, each A is independently... Preferably, each A is independently...

28. The compound according to any one of claims 1-27, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each B is independently a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, and 6-9 membered spirocyclic heterocycles; wherein the aforementioned groups are optionally substituted by one or more Rs; Preferably, each B is independently a divalent group selected from 4-7 member monocyclic heterocycles, 6-10 member fused heterocycles, and 6-9 member spirocyclic heterocycles; wherein the above groups are optionally substituted by one or more Rs; Preferably, each B is independently... The aforementioned groups may optionally be substituted by one or more R groups; Preferably, each B is independently... The aforementioned groups may optionally be substituted by one or more R groups; Preferably, each R is independently D, -OH, F, or C. 1-3 Alkyl groups, or two R groups together with the atoms they are attached to, form 3-6 membered monocyclic carbon rings.

29. The compound according to any one of claims 1-27, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein when m' is 0, B' is a divalent group selected from 6-10 fused heterocycles, 6-10 bridged heterocycles, and 6-9 spirocyclic heterocycles; wherein the above-mentioned group is optionally substituted by one or more R; Preferably, B' is a divalent group selected from 6-10 fused heterocycles and 6-9 spirocyclic heterocycles; wherein the above group is optionally substituted by one or more R; Preferably, B' is The aforementioned groups may optionally be substituted by one or more R groups; Preferably, B' is The aforementioned groups may optionally be substituted by one or more R groups; Preferably, each R is independently D, -OH, F, or C. 1-3 Alkyl groups, or two R groups together with the atoms they are attached to, form 3-6 membered monocyclic carbon rings.

30. The compound according to any one of claims 1-29, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each C is a chemical bond.

31. The compound according to any one of claims 1-29, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each C is independently phenylene or a 5-6 membered heteroaryl group; wherein the above groups are optionally substituted by one or more R groups; Preferably, each C is independently phenylene, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrazolyl, pyrrolyl, thiopheneyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, thiazolyl, or isothiazolyl. Preferably, each C is independently phenylene, pyridinyl, pyrimidinyl, pyridazinyl, pyridazinyl, pyridazolyl, or imidazolyl.

32. A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is selected from:

33. A pharmaceutical composition comprising the compound of any one of claims 1-32, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient.

34. The pharmaceutical composition of claim 33, further comprising other therapeutic agents; Preferably, the other therapeutic agent is another c-MET inhibitor, c-MET antibody, EGFR inhibitor, ALK inhibitor, RAF inhibitor, MEK inhibitor, or immune checkpoint inhibitor; Preferably, another c-MET inhibitor is terpoxtinib, carmatinib, cervacinib, gumetinib, or beritinib; Preferably, the c-MET antibody is ervaltumab; Preferably, the EGFR inhibitor is gefitinib, erlotinib, icotinib, afatinib, dacomitinib, neratinib, osimertinib, lazazetinib, ametinib, or vormetinib; Preferably, the ALK inhibitor is crizotinib, ceritinib, alectinib, brigatinib, ensartinib, lolatinib, or iruac; Preferably, the RAF inhibitor is sorafenib, vemurafenib, dabrafenib, or encofenib; Preferably, the MEK inhibitor is trametinib, selmetinib, or refatinib; Preferably, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, atezolizumab, durvalumab, ipilimumab, or trimemumab.

35. The use of any compound of claims 1-32, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition of claim 33 or 34, in the preparation of a medicament for treating c-MET-mediated diseases; Preferably, the c-MET is an abnormal c-MET; Preferably, the abnormal c-MET is c-MET amplification, c-MET mutation, c-MET fusion, or c-MET overexpression; Preferably, c-MET amplification is polyploid amplification or local amplification; Preferably, the c-MET mutation is a MET exon 14 skipping mutation (MET ex14), Y1003C, Y1003F, Y1003N, Y1003S, G1090A, G1090S, V1092I, V1092L, H1094L, H1094R, H1094Y, N1100Y, N1106D, M1131T, D1133V, M1149T, V1155L, Y1159H, V1188L, G1163R, G1163E, D1164G, L1195V, L1195F, F1200I, F1200L, V1206L, M1211T, L1213V, 1220I, D1228N, D1228H, D1228A, D1228E, D1228G, D1228Y, Y1230H, Y1230C, Y1230S, Y1230D, Y1230N, Y1230S, D1246N, D1246H, Y1248C, Y1248H, or M1268T; Preferably, c-MET is fused into TPR-MET, PTPRZ1-MET, CLIP2-MET, KIF5B-MET, TFG-MET, CAPZA2-MET, ST7-MET, BAIAP2L1-MET, C8orf34-MET, TRIM4-MET, STARD3NL-MET, or OXR1-MET; Preferably, the c-MET fusion mutation is TPR-MET-G1163R, TPR-MET-L1195V, TPR-MET-L1195F, TPR-MET-D1228N or TPR-MET-Y1230H.

36. A method of treating a c-MET-mediated disease in a subject, the method comprising administering to the subject a compound of any one of claims 1-32, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 33 or 34; Preferably, the c-MET is an abnormal c-MET; Preferably, the abnormal c-MET is c-MET amplification, c-MET mutation, c-MET fusion, or c-MET overexpression; Preferably, c-MET amplification is polyploid amplification or local amplification; Preferably, the c-MET mutation is a MET exon 14 skipping mutation (MET ex14), Y1003C, Y1003F, Y1003N, Y1003S, G1090A, G1090S, V1092I, V1092L, H1094L, H1094R, H1094Y, N1100Y, N1106D, M1131T, D1133V, M1149T, V1155L, Y1159H, V1188L, G1163R, G1163E, D1164G, L1195V, L1195F, F1200I, F1200L, V1206L, M1211T, L1213V, 1220I, D1228N, D1228H, D1228A, D1228E, D1228G, D1228Y, Y1230H, Y1230C, Y1230S, Y1230D, Y1230N, Y1230S, D1246N, D1246H, Y1248C, Y1248H, or M1268T; Preferably, c-MET is fused into TPR-MET, PTPRZ1-MET, CLIP2-MET, KIF5B-MET, TFG-MET, CAPZA2-MET, ST7-MET, BAIAP2L1-MET, C8orf34-MET, TRIM4-MET, STARD3NL-MET, or OXR1-MET; Preferably, the c-MET fusion mutation is TPR-MET-G1163R, TPR-MET-L1195V, TPR-MET-L1195F, TPR-MET-D1228N or TPR-MET-Y1230H.

37. The compound of any one of claims 1-32, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition of claim 33 or 34, for the treatment of c-MET-mediated diseases; Preferably, the c-MET is an abnormal c-MET; Preferably, the abnormal c-MET is c-MET amplification, c-MET mutation, c-MET fusion, or c-MET overexpression; Preferably, c-MET amplification is polyploid amplification or local amplification; Preferably, the c-MET mutation is a MET exon 14 skipping mutation (MET ex14), Y1003C, Y1003F, Y1003N, Y1003S, G1090A, G1090S, V1092I, V1092L, H1094L, H1094R, H1094Y, N1100Y, N1106D, M1131T, D1133V, M1149T, V1155L, Y1159H, V1188L, G1163R, G1163E, D1164G, L1195V, L1195F, F1200I, F1200L, V1206L, M1211T, L1213V, 1220I, D1228N, D1228H, D1228A, D1228E, D1228G, D1228Y, Y1230H, Y1230C, Y1230S, Y1230D, Y1230N, Y1230S, D1246N, D1246H, Y1248C, Y1248H, or M1268T; Preferably, c-MET is fused into TPR-MET, PTPRZ1-MET, CLIP2-MET, KIF5B-MET, TFG-MET, CAPZA2-MET, ST7-MET, BAIAP2L1-MET, C8orf34-MET, TRIM4-MET, STARD3NL-MET, or OXR1-MET; Preferably, the c-MET fusion mutation is TPR-MET-G1163R, TPR-MET-L1195V, TPR-MET-L1195F, TPR-MET-D1228N or TPR-MET-Y1230H.

38. The use according to claim 35, the use of the method according to claim 36, and the use of the compound or composition according to claim 37, wherein the c-MET-mediated disease is cancer; Preferably, c-MET-mediated diseases include lung cancer, gastric cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, thyroid cancer, bladder cancer, bile duct cancer, colorectal cancer, head and neck cancer, nasopharyngeal carcinoma, ovarian cancer, breast cancer, cervical cancer, salivary gland cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, soft tissue sarcoma, multiple myeloma, lymphoma, leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma, and nephroblastoma, as well as their metastases; Preferably, c-MET-mediated diseases are lung cancer and its metastases; Preferably, the c-MET-mediated disease is non-small cell lung cancer and its metastases; Preferably, c-MET-mediated diseases are gastric cancer and its metastases; Preferably, c-MET-mediated diseases are pancreatic cancer and its metastases.

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