Proteolysis targeting chimera compound targeting EGFR, and composition thereof and use thereof

Abstract

The present invention relates to a proteolysis targeting chimera compound of formula (I) having a degradation and / or inhibitory activity against mutant EGFR, 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

Targeted chimeric compounds for EGFR protein degradation, their compositions and uses Technical Field

[0001] This invention belongs to the pharmaceutical field, and particularly relates to chimeric compounds that target protein degradation, including induced degradation and / or inhibited activity against mutant EGFR, as well as pharmaceutical compositions comprising them, and methods for their preparation and uses. Background Technology

[0002] 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.

[0003] Epidermal growth factor receptor (EGFR, ErbB-1, or HER1), belonging to the ErbB family, is a transmembrane receptor tyrosine kinase that is widely expressed in normal tissues. EGFR binds to its ligands, such as epidermal growth factor (EGF), forming homodimers or heterodimers on the cell membrane, undergoing autophosphorylation, thereby activating downstream signaling pathways and ultimately playing an important regulatory role in cellular physiological processes.

[0004] Dysregulation of EGFR overexpression or mutations is associated with many types of human cancer, including prostate cancer, breast cancer, kidney cancer, colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, particularly non-small cell lung cancer (NSCLC). EGFR mutations primarily occur in the kinase domains located in exons 18–24, with approximately 90% being exon 19 deletions (Del19) and codon 858 missense mutations in exon 21 (L858R).

[0005] Marketed EGFR tyrosine kinase inhibitors (TKIs) include first-generation drugs such as gefitinib, erlotinib, and itotinib; second-generation drugs such as afatinib and dacomitinib; and third-generation drugs such as osimertinib, almonertinib, and furmonertinib. Although patients benefit from EGFR TKI treatment, resistance to these drugs typically develops within about one year, including resistance to first- and second-generation EGFR TKIs due to the T790M mutation, and resistance to third-generation EGFR TKIs due to the C797S / G / N, L718Q, and L792F / H / Y mutations. Furthermore, patients with Del19 / T790M / C797S or L858R / T790M / C797S mutants are no longer responsive to third-generation EGFR TKIs after treatment with third-generation EGFR TKIs. EGFR-targeting protacodes could be a potential strategy to overcome these mutant-mediated resistance.

[0006] In 2019, Boehringer Ingelheim of Germany reported an EGFR inhibitor, BI-4020, in [J.Med.Chem.2019,62,22,10272-10293]. This compound could overcome the EGFR Del19 / T790M / C797S triple mutation and also inhibit the Del19 / T790M double mutation and the Del19 single mutation, while showing good selectivity for wild-type EGFR. However, it ultimately did not enter clinical trials. Novartis reported an allosteric inhibitor, EAI0450, targeting EGFR C797S resistance. When combined with an EGFR monoclonal antibody such as cetuximab, it showed good antitumor efficacy in a mouse model of L858R / T790M / C797S mutation. However, this compound was ineffective as a monotherapy and could not inhibit the Del19 / C797S mutation, thus failing to enter clinical trials.

[0007] Currently, there is a lack of drugs on the market targeting EGFR C797S, Del19 / T790M / C797S, or L858R / T790M / C797S mutations, highlighting the medical need for novel EGFR-targeting therapies. Developing PROTACs capable of ubiquitinizing and degrading EGFR proteins could be a novel approach to treating abnormal EGFR-mediated diseases. Therefore, the development of novel EGFR PROTAC compounds remains crucial in this field to enhance their clinical value. This invention provides such compounds.

[0008] Invention Overview

[0009] 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 against EGFR including mutations (e.g., Del19, L858R, T790M, C797S, etc.) or combinations of mutations (e.g., Del19 / T790M, Del19 / C797S, L858R / T790M, L858R / C797S, T790M / C797S, Del19 / T790M / C797S, or L858R / T790M / C797S), blood-brain barrier permeability, high selectivity, and / or excellent pharmacokinetic properties. It can be used to treat diseases and / or conditions mediated by mutant EGFR and their metastases (especially central nervous system metastases such as brain metastases).

[0010] To address this, the present invention adopts the following technical solution:

[0011] In one aspect, the present invention relates to compounds of formula (I), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:

[0012] in,

[0013] Ring A is an optional area bounded by 1-3 Rs A Substituted 6-12-membered heteroaryl or 6-12-membered heterocyclic group;

[0014] Ring B is an optional area bounded by 1-3 R's. B Substituted 5-12 heteroaryl groups;

[0015] p is 1, 2, or 3;

[0016] For each R, R A and R B Each can be independently represented as H, D, halogen, -OH, -CN, =O, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, -OC 3-8 Cycloalkyl or -O-4-9-membered heterocyclic groups;

[0017] X is -O-, -CR a R b -,-NR c -or -S(O) q -;

[0018] q is 0, 1, or 2;

[0019] m is 0 or 1;

[0020] n is 1, 2, 3 or 4;

[0021] Each E is independently for -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -,-CR 3a R 3b -,-O-,-NR c -, -C(O)- or -S(O) q -;

[0022] R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1- 6-acetylenic, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0023] R c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0024] i is 0 or 1; j is 0 or 1;

[0025] S1 and S2 are independent chemical bonds, -O-, -S-, -CR. d R e -,-(CR d R e ) j NR f -,-(CR d R e ) j C(O)-, -(CR) d R e ) j C(O)NR f -,-NR f (CR d R e ) j -,-C(O)(CR d R e ) j -or-C(O)NR f (CR d R e ) j -;

[0026] Each R d and R e Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R d and R e Together with the C atoms they are attached to, they form C3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1- 6-Hydroalkyl substitution;

[0027] Each R f Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0028] L1 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L1 replace;

[0029] L2 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L2 replace;

[0030] L3 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L3 replace;

[0031] L4 is C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatic hydrocarbons or 6-12 membered heterocyclic groups, wherein the C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatics or 6-12 membered heterocyclic groups optionally surrounded by 1-6 R groups L4replace;

[0032] L1 and L2 can share an atom or a chemical bond;

[0033] When S1 is a chemical bond, L2 and L3 can share an atom or a chemical bond;

[0034] When S2 is a chemical bond and i is 1, L3 and L4 can share an atom or a chemical bond;

[0035] Each R L1 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L1 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0036] Each R L2 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0037] Each R L3 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L3 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0038] Each R L4 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L4 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0039] Each U is independent as follows:

[0040] in,

[0041] Indicates a single bond or a double bond;

[0042] Each Q1 is independently C(O) or C(R). U4 )2;

[0043] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0044] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0045] Each Q2 is independently either N or CH;

[0046] Q3 and Q4 are each independently N or CH;

[0047] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0048] P1 is N, C, or CR U4 ;

[0049] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0050] P4 and P5 are each independently N or C;

[0051] z is 0, 1, or 2;

[0052] H1 is N or CR U4 ;

[0053] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0054] Each h is independently 0, 1, 2, 3 or 4;

[0055] Each k is independently 0, 1, 2, or 3;

[0056] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0057] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0058] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0059] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0060] 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.

[0061] 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%.

[0062] 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.

[0063] 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 EGFR inhibitor, an EGFR antibody, a c-MET inhibitor, an immune checkpoint inhibitor, a RAF inhibitor, an ALK inhibitor, or a MEK inhibitor. In specific embodiments, the other EGFR inhibitor is gefitinib, erlotinib, icotinib, afatinib, dacomitinib, neratinib, osimertinib, lazetinib, ametinib, or vormetinib. In specific embodiments, the EGFR antibody is cetuximab, panitumumab, or nexituzumab. In specific embodiments, the c-MET inhibitor is gumetinib, terpoxtinib, carmatinib, or cevotinib. In specific implementation schemes, the immune checkpoint inhibitors are nivolumab, pembrolizumab, pidilimumab, atezolizumab, durvalumab, ipilimumab, or tramemumab. In specific implementation schemes, the RAF inhibitors are sorafenib, vemurafenib, dabrafenib, or encofenib. In specific implementation schemes, the ALK inhibitors are crizotinib, ceritinib, alectinib, brigatinib, ensartinib, loratinib, or ilurac. In specific implementation schemes, the MEK inhibitors are trametinib, selmetinib, or refatinib.

[0064] In another aspect, the present invention provides a method for treating EGFR-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.

[0065] 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 EGFR-mediated diseases.

[0066] 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 diseases mediated by mutant EGFR.

[0067] 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 EGFR-mediated diseases.

[0068] In a specific implementation, the mutated EGFR is non-restricted and present in exon 18, exon 19, exon 20, or exon 21, or any combination thereof. In a more specific implementation, the mutated EGFR is non-restricted and selected from E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, Del19, L747S, L747P, D761Y, M766Q, S768I, T790M, L7 92F, L792H, L792V, G796R, G796S, G796C, G796D, C797S, C797G, C797N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R, or any combination thereof. In a more specific embodiment, the mutated EGFR is Del19, L858R, T790M, C797S, C797G, C797N, L718Q, L792H, or L861Q, or any combination thereof.

[0069] In a more specific implementation, the mutated EGFR is Del19 and another mutation.

[0070] In a more specific implementation, the mutated EGFR is Del19 and two additional mutations.

[0071] In a more specific implementation, the mutated EGFR is L858R and another mutation.

[0072] In a more specific implementation, the mutated EGFR is L858R and two additional mutations.

[0073] In a more specific implementation, the mutated EGFR is the Del19 mutation.

[0074] In a more specific implementation, the mutated EGFR is the L858R mutation.

[0075] In a more specific implementation, the mutated EGFR is the T790M mutation.

[0076] In a more specific implementation, the mutated EGFR is the C797S mutation.

[0077] In a more specific implementation, the mutated EGFR is the L718Q mutation.

[0078] In a more specific implementation, the mutated EGFR is the L792H mutation.

[0079] In a more specific implementation, the mutated EGFR is the L861Q mutation.

[0080] In a more specific implementation, the mutated EGFR is a Del19 / T790M double mutation.

[0081] In a more specific implementation, the mutated EGFR is a Del19 / C797S double mutation.

[0082] In a more specific implementation, the mutated EGFR is a double mutation of L858R / T790M.

[0083] In a more specific implementation, the mutated EGFR is a double mutation of L858R / C797S.

[0084] In a more specific implementation, the mutated EGFR is a T790M / C797S double mutation.

[0085] In a more specific implementation, the mutated EGFR is a triple mutation of Del19 / T790M / C797S.

[0086] In a more specific implementation, the mutated EGFR is a triple mutation of L858R / T790M / C797S.

[0087] In a specific implementation, EGFR-mutated diseases are cancers. In a specific implementation, EGFR-mutated diseases are central nervous system (CNS) metastases, such as brain metastases. In a more specific implementation, EGFR-mutated diseases include lung cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, urothelial carcinoma, kidney cancer, bladder cancer, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial tumor, colorectal cancer, head and neck cancer, esophageal cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, gastric cancer, leukemia, lymphoma, neuroblastoma, glioma, melanoma, sarcoma, thyroid cancer, glioblastoma, solid tumors, oropharyngeal carcinoma, bronchial tumors, skin cancer, brain metastases, and mesothelioma. In a more specific implementation, EGFR-mutated diseases are lung cancer and its metastases (especially CNS metastases, such as brain metastases). In a more specific implementation, EGFR-mutated diseases are non-small cell lung cancer and its metastases (especially CNS metastases, such as brain metastases).

[0088] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed description, embodiments, and claims.

[0089] definition

[0090] Chemical definition

[0091] The definitions of specific functional groups and chemical terms are described in more detail below.

[0092] When listing a range of values, it is assumed that each value and the subranges within that range are 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.

[0093] “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.

[0094] “C 1-6 "Alkylide group" refers to =CRR, where R is H or C. 1-5 alkyl.

[0095] “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.

[0096] “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.

[0097] “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.

[0098] "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.

[0099] 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 Haloalkyl 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 groups are even 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.

[0100] “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.

[0101] “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.

[0102] "3-14 membered heterocyclic group" refers to a group having a cyclic carbon atom and 1 to 5 cyclic heteroatoms, comprising a 3- to 14-membered non-aromatic ring system, 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 may be a carbon or nitrogen atom, provided the valence allows. In some embodiments, 4-10 membered heterocyclic groups are preferred, comprising a 4- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; in some embodiments, 3-7 membered heterocyclic groups are preferred, comprising a 3- to 7-membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; in some embodiments, 3-6 membered heterocyclic groups are particularly preferred, comprising a 3- to 6-membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably, 5-6 membered heterocyclic groups are comprising a 5- to 6-membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. The heterocyclic group may 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.

[0103] 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.

[0104] “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 (“C”). 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.

[0105] "5-14 membered heteroaryl" refers to a group comprising a 5-14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having a cyclic carbon atom and 1-5 cyclic heteroatoms, 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, 5-10 membered heteroaryl are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having a cyclic carbon atom and 1-4 cyclic heteroatoms. In some embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6 membered monocyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. In some embodiments, 5 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5 membered monocyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. Regardless of whether the heteroaryl group is preceded by a "substituted" modification, each heteroaryl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0106] 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.

[0107] "Cycloalkylene", "heterocyclic", "aryl", and "heteroaryl" refer to divalent groups formed by removing one hydrogen atom from cycloalkyl, heterocyclic, aryl, or heteroaryl groups. For example, "C..." 3-10 "Hypercyclic alkyl", "3-14 membered heterocyclic", "C" 6-14 "Aromatic" and "5-14 heteroaryl" refer to those with C removed. 3-10 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 A divalent group formed by the aryl group and another hydrogen atom of a 5-14 membered heteroaryl group. In some embodiments, C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-10 Arylene and 5-12 heteroaryl compounds are preferred. In some embodiments, C 3-8 Cycloalkylene is preferred, C 3-6 Cycloalkylene groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkylene groups. In some embodiments, 4-9-membered heterocyclic groups are preferred, 4-6-membered heterocyclic groups are particularly preferred, and 5-6-membered heterocyclic groups are more preferred. In some embodiments, C 6-10Aryl groups are preferred, and C6 arylene groups are particularly preferred. In some embodiments, 5-12-membered heteroarylene groups are preferred, 5-10-membered heteroarylene groups are particularly preferred, and 5-6-membered heteroarylene groups are more preferred. Regardless of whether the cycloalkyl, heterocyclic, arylene, and heteroarylene groups are pre-modified with "substituted", each of the cycloalkyl, heterocyclic, arylene, and heteroarylene groups may be independently substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] Unless otherwise stated, "cycloalkyl" and "cycloalkane" in this invention may refer to...

[0112] 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(Rbb )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)NR bb 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;

[0113] 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;

[0114] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R aaGroups 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;

[0115] 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;

[0116] 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;

[0117] 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 ee2. 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;

[0118] 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;

[0119] 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;

[0120] 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(C 1-6 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 1-6Haloalkyl, 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.

[0121] 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. cc 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. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0122] "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.

[0123] "Non-deuterated compounds" refer to compounds containing a deuterium atom ratio no higher than the natural deuterium isotope content (0.015%).

[0124] 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%.

[0125] 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.

[0126] 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.

[0127] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0128] 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”).

[0129] 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

[0130] compound

[0131] In this document, “compound of the present invention” refers to the following compounds of formula (I), (II), (III) or (IV) (including subsets of each formula), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0132] This invention provides compounds that specifically degrade mutant EGFR through targeted ubiquitination of the EGFR 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 mutant EGFR (specifically, for example, EGFR Del19 mutation, L858R mutation, Del19 / T790M double mutation, Del19 / C797S double mutation, L858R / T790M double mutation, L858R / C797S double mutation, T790M / C797S double mutation, Del19 / T790M / C797S triple mutation, and L858R / T790M / C797S triple mutation).

[0133] The present invention provides compounds having the activity of inhibiting mutant EGFRs, wherein the mutant EGFRs are, for example, EGFR Del19 mutation, L858R mutation, Del19 / T790M double mutation, Del19 / C797S double mutation, L858R / T790M double mutation, L858R / C797S double mutation, T790M / C797S double mutation, Del19 / T790M / C797S triple mutation, and L858R / T790M / C797S triple mutation.

[0134] This invention provides compounds that selectively degrade EGFR (e.g., EGFR Del19 mutation, L858R mutation, Del19 / T790M double mutation, Del19 / C797S double mutation, L858R / T790M double mutation, L858R / C797S double mutation, T790M / C797S double mutation, Del19 / T790M / C797S triple mutation, and L858R / T790M / C797S triple mutation) in tumors that have metastasized to the central nervous system (CNS), such as brain metastases, and may have mutations or combinations of mutations.

[0135] In one 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:

[0136] in,

[0137] Ring A is an optional area bounded by 1-3 Rs A Substituted 6-12-membered heteroaryl or 6-12-membered heterocyclic group;

[0138] Ring B is an optional area bounded by 1-3 R's. B Substituted 5-12 heteroaryl groups;

[0139] p is 1, 2, or 3;

[0140] For each R, R A and R B Each can be independently represented as H, D, halogen, -OH, -CN, =O, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, -OC 3-8 Cycloalkyl or -O-4-9-membered heterocyclic groups;

[0141] X is -O-, -CR a R b -,-NR c-or -S(O) q -;

[0142] q is 0, 1, or 2;

[0143] m is 0 or 1;

[0144] n is 1, 2, 3 or 4;

[0145] Each E is independently for -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -,-CR 3a R 3b -,-O-,-NR c -, -C(O)- or -S(O) q -;

[0146] R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1- 6-acetylenic, C 3-8The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0147] R c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0148] i is 0 or 1; j is 0 or 1;

[0149] S1 and S2 are independent chemical bonds, -O-, -S-, -CR. d R e -,-(CR d R e ) j NR f -,-(CR d R e ) j C(O)-, -(CR) d R e ) j C(O)NR f -,-NR f (CR d R e ) j -,-C(O)(CR d R e ) j -or-C(O)NR f (CR d R e ) j -;

[0150] Each R d and R e Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R d and R e Together with the C atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1- 6-Hydroalkyl substitution;

[0151] Each R f Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0152] L1 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L1 replace;

[0153] L2 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L2 replace;

[0154] L3 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L3 replace;

[0155] L4 is C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatic hydrocarbons or 6-12 membered heterocyclic groups, wherein the C3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatics or 6-12 membered heterocyclic groups optionally surrounded by 1-6 R groups L4 replace;

[0156] L1 and L2 can share an atom or a chemical bond;

[0157] When S1 is a chemical bond, L2 and L3 can share an atom or a chemical bond;

[0158] When S2 is a chemical bond and i is 1, L3 and L4 can share an atom or a chemical bond;

[0159] Each R L1 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L1 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0160] Each R L2 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0161] Each R L3 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L3Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0162] Each R L4 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L4 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0163] Each U is independent as follows:

[0164] in,

[0165] Indicates a single bond or a double bond;

[0166] Each Q1 is independently C(O) or C(R). U4 )2;

[0167] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0168] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0169] Each Q2 is independently either N or CH;

[0170] Q3 and Q4 are each independently N or CH;

[0171] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0172] P1 is N, C, or CR U4 ;

[0173] P2 and P3 are each independently C(O), N, O, S, NR.U4 CR U4 or C(R) U4 )2;

[0174] P4 and P5 are each independently N or C;

[0175] z is 0, 1, or 2;

[0176] H1 is N or CR U4 ;

[0177] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0178] Each h is independently 0, 1, 2, 3 or 4;

[0179] Each k is independently 0, 1, 2, or 3;

[0180] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0181] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0182] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0183] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0184] 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 ring A is optionally surrounded by 1-3 R... A Substituted 6-12 heteroaryl groups.

[0185] 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 ring A is optionally surrounded by 1-3 R... A Replaced 6-9 hydroxyl heteroaryl groups.

[0186] 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 ring A is optionally surrounded by 1-3 R... A The substituted 6-membered heteroaryl group.

[0187] In one specific 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 ring A is optionally surrounded by 1-3 R... A Substituted 6-membered heteroaryl groups containing 1-3 N atoms.

[0188] In another specific 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 ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein said group is optionally surrounded by 1-3 R... A replace.

[0189] In another specific 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 ring A is Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0190] In another specific 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 ring A is Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0191] 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 ring A is optionally surrounded by 1-3 R... A The 9-membered heteroaryl group is replaced.

[0192] In one specific 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 ring A is optionally surrounded by 1-3 R... A Substituted 9-membered heteroaryl groups containing 1-3 N or O atoms.

[0193] In another specific 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 ring A is optionally surrounded by 1-3 R... A Replacement Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0194] In another specific 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 ring A is optionally surrounded by 1-3 R... A Replacement Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0195] In another specific 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 ring A is optionally surrounded by 1-3 R... A Replacement Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0196] 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 ring A is optionally surrounded by 1-3 R... A Substituted 6-12-membered heterocyclic groups.

[0197] 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 ring A is optionally surrounded by 1-3 R... A Substituted 6-membered heterocyclic group.

[0198] In one specific 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 ring A is Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0199] 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, which is a compound of formula (II):

[0200] in,

[0201] Ring B is an optional area bounded by 1-3 R's. B Substituted 5-12 heteroaryl groups;

[0202] p is 1, 2, or 3;

[0203] For each R, R A and R B Each can be independently represented as H, D, halogen, -OH, -CN, =O, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, -OC 3-8 Cycloalkyl or -O-4-9-membered heterocyclic groups;

[0204] X is -O-, -CR a R b -,-NR c -or -S(O) q -;

[0205] q is 0, 1, or 2;

[0206] m is 0 or 1;

[0207] n is 1, 2, 3 or 4;

[0208] Each E is independently for -CR 3a R 3b -CR 4a R 4b-CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -,-CR 3a R 3b -,-O-,-NR c -, -C(O)- or -S(O) q -;

[0209] R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1- 6-acetylenic, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0210] R c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0211] i is 0 or 1; j is 0 or 1;

[0212] S1 and S2 are independent chemical bonds, -O-, -S-, -CR. d R e -,-(CR d R e ) j NR f -,-(CR d R e ) j C(O)-, -(CR) d R e ) j C(O)NR f -,-NR f (CR d R e ) j -,-C(O)(CR d R e ) j -or-C(O)NR f (CR d R e ) j -;

[0213] Each R d and R e Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R d and R e Together with the C atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6-Hydroalkyl substitution;

[0214] Each R f Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0215] L1 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L1 replace;

[0216] L2 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L2 replace;

[0217] L3 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L3 replace;

[0218] L4 is C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatic hydrocarbons or 6-12 membered heterocyclic groups, wherein the C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatics or 6-12 membered heterocyclic groups optionally surrounded by 1-6 R groups L4 replace;

[0219] L1 and L2 can share an atom or a chemical bond;

[0220] When S1 is a chemical bond, L2 and L3 can share an atom or a chemical bond;

[0221] When S2 is a chemical bond and i is 1, L3 and L4 can share an atom or a chemical bond;

[0222] Each R L1 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L1 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0223] Each R L2 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0224] Each R L3 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L3 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0225] Each R L4 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L4 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0226] Each U is independent as follows:

[0227] in,

[0228] Indicates a single bond or a double bond;

[0229] Each Q1 is independently C(O) or C(R). U4 )2;

[0230] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0231] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0232] Each Q2 is independently either N or CH;

[0233] Q3 and Q4 are each independently N or CH;

[0234] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0235] P1 is N, C, or CR U4 ;

[0236] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0237] P4 and P5 are each independently N or C;

[0238] z is 0, 1, or 2;

[0239] H1 is N or CR U4 ;

[0240] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R)U4 )2;

[0241] Each h is independently 0, 1, 2, 3 or 4;

[0242] Each k is independently 0, 1, 2, or 3;

[0243] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0244] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0245] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0246] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0247] 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 ring B is optionally surrounded by 1-3 R... B Substituted 5-12 heteroaryl groups.

[0248] 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 ring B is optionally surrounded by 1-3 R... B Substituted 5-9 quinone heteroaryl groups.

[0249] 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 ring B is optionally surrounded by 1-3 R... B The substituted 5-membered heteroaryl group.

[0250] In one specific 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 ring B is optionally surrounded by 1-3 R... B Substituted 5-membered heteroaryl groups containing 1-3 N atoms.

[0251] In another specific 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 ring B is pyrazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isothiazolyl, or isoxazolyl, wherein said group is optionally surrounded by 1-3 R... B replace.

[0252] In another specific 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 ring B is * indicates that it is connected to X. This indicates that it is connected to ring A.

[0253] In another specific 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 ring B is * indicates that it is connected to X. This indicates that it is connected to ring A.

[0254] 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 ring B is optionally surrounded by 1-3 R... B Replaced 6-9 hydroxyl heteroaryl groups.

[0255] 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 ring B is optionally surrounded by 1-3 R...B Substituted 6-membered heteroaryl groups containing 1-3 N atoms.

[0256] In one specific 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 ring B is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein said group is optionally surrounded by 1-3 R... B replace.

[0257] In another specific 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 ring B is * indicates that it is connected to X. This indicates that it is connected to ring A.

[0258] In another specific 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 ring B is * indicates that it is connected to X. This indicates that it is connected to ring A.

[0259] 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 ring B is optionally surrounded by 1-3 R... B Substituted 9-membered heteroaryl groups containing 1-3 N or O atoms.

[0260] In one specific 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 ring B is * indicates that it is connected to X. This indicates that it is connected to ring A.

[0261] 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, which is a compound of formula (III) or formula (V):

[0262] in,

[0263] p is 1, 2, or 3;

[0264] For each R, RA and R B Each can be independently represented as H, D, halogen, -OH, -CN, =O, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, -OC 3-8 Cycloalkyl or -O-4-9-membered heterocyclic groups;

[0265] X is -O-, -CR a R b -,-NR c -or -S(O) q -;

[0266] q is 0, 1, or 2;

[0267] m is 0 or 1;

[0268] n is 1, 2, 3 or 4;

[0269] Each E is independently for -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -,-CR 3a R 3b -,-O-,-NR c -, -C(O)- or -S(O) q -;

[0270] R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R 2a R2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1- 6-acetylenic, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0271] R c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0272] i is 0 or 1; j is 0 or 1;

[0273] S1 and S2 are independent chemical bonds, -O-, -S-, -CR. d R e -,-(CR d R e ) j NR f -,-(CR d R e ) j C(O)-, -(CR) d R e ) j C(O)NR f -,-NR f (CR d R e ) j -,-C(O)(CR d R e) j -or-C(O)NR f (CR d R e ) j -;

[0274] Each R d and R e Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R d and R e Together with the C atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1- 6-Hydroalkyl substitution;

[0275] Each R f Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0276] L1 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L1 replace;

[0277] L2 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups.L2 replace;

[0278] L3 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L3 replace;

[0279] L4 is C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatic hydrocarbons or 6-12 membered heterocyclic groups, wherein the C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatics or 6-12 membered heterocyclic groups optionally surrounded by 1-6 R groups L4 replace;

[0280] L1 and L2 can share an atom or a chemical bond;

[0281] When S1 is a chemical bond, L2 and L3 can share an atom or a chemical bond;

[0282] When S2 is a chemical bond and i is 1, L3 and L4 can share an atom or a chemical bond;

[0283] Each R L1 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L1 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0284] Each R L2 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0285] Each R L3 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L3 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0286] Each R L4 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L4 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0287] Each U is independent as follows:

[0288] in,

[0289] Indicates a single bond or a double bond;

[0290] Each Q1 is independently C(O) or C(R). U4 )2;

[0291] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0292] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0293] Each Q2 is independently either N or CH;

[0294] Q3 and Q4 are each independently N or CH;

[0295] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0296] P1 is N, C, or CR U4 ;

[0297] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0298] P4 and P5 are each independently N or C;

[0299] z is 0, 1, or 2;

[0300] H1 is N or CR U4 ;

[0301] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0302] Each h is independently 0, 1, 2, 3 or 4;

[0303] Each k is independently 0, 1, 2, or 3;

[0304] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0305] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0306] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10Aryl or 5-10 heteroaryl groups;

[0307] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0308] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein,

[0309] X is either -O- or -CR a R b -;

[0310] m is 0 or 1;

[0311] n is 1 or 2;

[0312] Each E is independently for -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -,-CR 3a R 3b -,-O-,-NR c -or -C(O)-;

[0313] R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 2a R 2b R 3a R 3b R4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally substituted by 1-3 groups selected from D, F or OH;

[0314] R c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl.

[0315] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein,

[0316] X is either -O- or -CR a R b -;

[0317] m is 0 or 1;

[0318] n is 1 or 2;

[0319] Each E is independently for -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -or-CR 3a R 3b -;

[0320] R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl or C 1-6Halogenated alkyl, or R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl or 4-9 membered heterocyclic group is optionally substituted by 1-3 groups selected from D, F or OH.

[0321] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein,

[0322] X is either -O- or -CR a R b -;

[0323] m is 0 or 1;

[0324] n is 1 or 2;

[0325] Each E is independently for -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -or-CR 3a R 3b -;

[0326] R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each is independently H, D, halogen, or C. 1-6 Alkyl, or R 3a R 3b R 4a R4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl; wherein the C 1-6 Alkyl or C 3-8 The cycloalkyl group is optionally substituted by 1 to 3 substituted groups selected from D, F or OH.

[0327] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein,

[0328] X is either -O- or -CH2-;

[0329] m is 0 or 1;

[0330] n is 1 or 2;

[0331] R 1a and R 1b For H;

[0332] R 2a For H and R 2b It is -CH3 or -CD3;

[0333] Each E is independently -CH2-CH2-CH2-, -CH2-CH2-, -CH2-, cyclobutylene, cyclopentylene, or cyclohexylene, wherein said groups are optionally substituted by 1 to 3 groups selected from D, F, or OH.

[0334] In one specific embodiment, the present invention relates to a compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X is -O-.

[0335] In another specific embodiment, the present invention relates to a compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X is -CH2-.

[0336] In another specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein R 1a and R 1b For H.

[0337] In another specific embodiment, the present invention relates to a compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein m is 0.

[0338] In another specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein m is 1; R 2a For H and R 2b It can be -CH3 or -CD3.

[0339] In another specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein m is 1; R 2a For H and R 2b It is -CH3.

[0340] In another specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein m is 1; R 2a For H and R 2b It is -CD3.

[0341] In another specific embodiment, the present invention relates to a compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 1; E is -CH2-CH2-CH2-, -CH2-CH2-, -CH2-, cyclobutylene, cyclopentylene or cyclohexylene, wherein said groups are optionally substituted by 1 to 3 groups selected from D, F or OH.

[0342] In another specific embodiment, the present invention relates to a compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 1; E is -CH2-CH2-CH2-, -CH2-CH2-, cyclobutylene, cyclopentylene or cyclohexylene, wherein said groups are optionally substituted by 1 to 3 groups selected from D, F or OH.

[0343] In another specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein n is 2; each E is independently -CH2-CH2-CH2-, -CH2-CH2-, -CH2-, cyclobutylene, cyclopentylene or cyclohexylene, wherein said groups are optionally substituted by 1 to 3 groups selected from D, F or OH.

[0344] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i -for-L1-L2-L3-(L4) i -

[0345] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-L3-.

[0346] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i -for-L1-L2-L3-(L4) i - where L1 and L2 share an atom.

[0347] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-L3-L4-, where L1 and L2 share an atom.

[0348] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i- is -L1-L2-CH2-L3-(L4) i -

[0349] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-CH2-L3-.

[0350] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-CH2-L3-(L4) i - where L1 and L2 share an atom.

[0351] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-CH2-L3-, where L1 and L2 share an atom.

[0352] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-C(O)-CH2-L3-(L4) i -

[0353] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-C(O)-CH2-L3-.

[0354] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-C(O)-CH2-L3-(L4) i - where L1 and L2 share an atom.

[0355] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-C(O)-CH2-L3-, where L1 and L2 share an atom.

[0356] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each L1, L2, L3 and L4 is independently a 4-9 membered heterocyclic group containing 1 or 2 N atoms, wherein the 4-9 membered heterocyclic group may optionally be surrounded by 1-3 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0357] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each L1, L2, L3 and L4 is independently […]. The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0358] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each L1, L2, L3 and L4 is independently […]. The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0359] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each L1, L2, L3 and L4 is independently... The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0360] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the group sharing an atom between L1 and L2 is:

[0361] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0362] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the group sharing an atom between L1 and L2 is:

[0363] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0364] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i -for:

[0365] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3- 6-Cycloalkyl-substituted.

[0366] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i -for:

[0367] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3- 6-Cycloalkyl-substituted.

[0368] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i -for:

[0369] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0370] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i -for:

[0371] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0372] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein -L1-L2-S1-L3-S2-(L4) i -for:

[0373] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3- 6-Cycloalkyl-substituted.

[0374] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0375] in,

[0376] Indicates a single bond or a double bond;

[0377] Each Q1 is independently C(O) or C(R). U4 )2;

[0378] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0379] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0380] Each Q2 is independently either N or CH;

[0381] Q3 and Q4 are each independently N or CH;

[0382] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0383] P1 is N, C, or CR U4 ;

[0384] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0385] P4 and P5 are each independently N or C;

[0386] z is 0, 1, or 2;

[0387] H1 is N or CR U4 ;

[0388] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0389] Each h is independently 0, 1, 2, 3 or 4;

[0390] Each k is independently 0, 1, 2, or 3;

[0391] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0392] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0393] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0394] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0395] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0396] in,

[0397] Indicates a single bond or a double bond;

[0398] Each Q1 is independently C(O) or C(R). U4 )2;

[0399] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0400] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0401] Each Q2 is independently either N or CH;

[0402] Q3 and Q4 are each independently N or CH;

[0403] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0404] P1 is N, C, or CR U4 ;

[0405] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0406] P4 and P5 are each independently N or C;

[0407] Each h is independently 0, 1, 2, 3 or 4;

[0408] Each k is independently 0, 1, 2, or 3;

[0409] Each R U1 Each independently represents H and C. 1-6Alkyl or C 3-8 cycloalkyl;

[0410] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0411] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0412] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0413] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0414] in,

[0415] Each Q1 is independently C(O) or C(R). U4 )2;

[0416] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0417] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0418] Each h is independently 0, 1, 2, 3 or 4;

[0419] Each k is independently 0, 1, 2, or 3;

[0420] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0421] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0422] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0423] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0424] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0425] in,

[0426] Each Q1 is independently C(O) or C(R). U4 )2;

[0427] Each k is independently 0, 1, or 2;

[0428] Each R U3 Each is independently either D or halogen;

[0429] Each R U4 Each can be H, D, or halogen independently.

[0430] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0431] in,

[0432] Q2 is either N or CH;

[0433] Q3 is either N or CH;

[0434] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0435] h can be 0, 1, 2, 3, or 4;

[0436] k can be 0, 1, 2, or 3;

[0437] R U1 For H, C 1-6 Alkyl or C 3-8 cycloalkyl;

[0438] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0439] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0440] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0441] in,

[0442] Q2 is either N or CH;

[0443] Q3 is either N or CH;

[0444] Each k is independently 0, 1, or 2;

[0445] Each R U3 Each is independently either D or halogen.

[0446] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0447] in,

[0448] Indicates a single bond or a double bond;

[0449] Q2 is either N or CH;

[0450] P1 is N, C, or CR U4 ;

[0451] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0452] P4 and P5 are each independently N or C;

[0453] h can be 0, 1, 2, 3, or 4;

[0454] k can be 0, 1, 2, or 3;

[0455] R U1 For H, C 1-6 Alkyl or C 3-8 cycloalkyl;

[0456] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0457] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groupsU3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0458] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkanes or 4-9 membered heterocycles.

[0459] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0460] in,

[0461] Q2 is either N or CH;

[0462] Each P2 is independently either N or CR. U4 ;

[0463] Each P3 is independently N, O, S, NR. U4 or CR U4 ;

[0464] Each k is independently 0, 1, or 2;

[0465] Each R U3 Each is independently either D or halogen;

[0466] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0467] In another specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0468] in,

[0469] Q2 is either N or CH;

[0470] P2 is N or CR U4 ;

[0471] P3 is O, S, or NR. U4 ;

[0472] k is 0, 1, or 2;

[0473] Each R U3 Each is independently either D or halogen;

[0474] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0475] In a more specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each U is independently:

[0476] in,

[0477] k is 0, 1, or 2;

[0478] Each R U3 Each is independently either D or halogen;

[0479] R U4 For H, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0480] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein,

[0481] p is 1 or 2;

[0482] For each R, R A and R B Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl.

[0483] In another embodiment, the present invention relates to a compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein p is 1 or 2.

[0484] In one specific embodiment, the present invention relates to a compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein p is 1.

[0485] In another specific embodiment, the present invention relates to a compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein p is 2.

[0486] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each R, R A and R B Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl.

[0487] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each R, R A and R B Each is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0488] In another embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each R, R A and R B Each is independently H, D, halogen, or C. 1-6 alkyl.

[0489] In one specific embodiment, the present invention relates to compounds of formula (I), formula (II), formula (III) or formula (IV), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein each R A and R B Each of the following can be independently H, D, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, F, Cl, -CF3, -CHF2 or -CH2CF3.

[0490] Ring A

[0491] In one implementation, ring A is optionally bounded by 1-3 R... A Substituted 6-12-membered heteroaryl or 6-12-membered heterocyclic group.

[0492] In another implementation, ring A is optionally bounded by 1-3 R A Substituted 6-12 heteroaryl groups.

[0493] In another implementation, ring A is optionally bounded by 1-3 R A Replaced 6-9 hydroxyl heteroaryl groups.

[0494] In another implementation, ring A is optionally bounded by 1-3 R A The substituted 6-membered heteroaryl group.

[0495] In one specific implementation, ring A is optionally bounded by 1-3 R... A A substituted 6-membered heteroaryl group containing 1-3 N atoms; in another specific embodiment, ring A is optionally surrounded by 1-3 R atoms. A Substituted pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0496] In another specific implementation scheme, ring A is Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0497] In another specific implementation scheme, ring A is Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0498] In another specific implementation scheme, ring A is Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0499] In another specific implementation scheme, ring A is Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0500] In another implementation, ring A is optionally bounded by 1-3 R A The 9-membered heteroaryl group is replaced.

[0501] In one specific implementation, ring A is optionally bounded by 1-3 R... A Substituted 9-membered heteroaryl groups containing 1-3 N or O atoms.

[0502] In another specific implementation, ring A is optionally bounded by 1-3 R A Replacement Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0503] In another specific implementation, ring A is optionally bounded by 1-3 R A Replacement Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0504] In another specific implementation, ring A is optionally bounded by 1-3 R A Replacement Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0505] In another implementation, ring A is optionally bounded by 1-3 R A Substituted 6-12-membered heterocyclic groups.

[0506] In another implementation, ring A is optionally bounded by 1-3 R A Substituted 6-9 member heterocyclic groups.

[0507] In another implementation, ring A is optionally bounded by 1-3 R A Substituted 6-membered heterocyclic group.

[0508] In one specific implementation scheme, ring A is... Where * indicates connection to ring B, This indicates that it is connected to -C(O)-.

[0509] Ring B

[0510] In one implementation, ring B is optionally bounded by 1-3 Rs. B Substituted 5-12 heteroaryl groups.

[0511] In another implementation, ring B is optionally bounded by 1-3 R... B Substituted 5-9 quinone heteroaryl groups.

[0512] In another implementation, ring B is optionally bounded by 1-3 R... B Replaced 6-9 hydroxyl heteroaryl groups.

[0513] In another implementation, ring B is optionally bounded by 1-3 R... B The substituted 5-membered heteroaryl group.

[0514] In one specific implementation, ring B is optionally bounded by 1-3 Rs. B Substituted 5-membered heteroaryl groups containing 1-3 N atoms.

[0515] In another specific implementation, ring B is optionally bounded by 1-3 R... B Substituted with pyrazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isothiazolyl, or isoxazolyl.

[0516] In another specific implementation scheme, ring B is * indicates that it is connected to X. This indicates that it is connected to ring A.

[0517] In another specific implementation scheme, ring B is * indicates that it is connected to X. This indicates that it is connected to ring A.

[0518] In another implementation, ring B is optionally bounded by 1-3 R B The substituted 6-membered heteroaryl group.

[0519] In one specific implementation, ring B is optionally bounded by 1-3 Rs. B A substituted 6-membered heteroaryl group containing 1-3 N atoms; in another specific embodiment, ring B is optionally replaced by 1-3 R atoms. B Substituted pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0520] In another specific implementation scheme, ring B is * indicates that it is connected to X. This indicates that it is connected to ring A.

[0521] In another specific implementation scheme, ring B is... * indicates that it is connected to X. This indicates that it is connected to ring A.

[0522] In another implementation, ring B is optionally bounded by 1-3 R B The 9-membered heteroaryl group is replaced.

[0523] In one specific implementation, ring B is optionally bounded by 1-3 Rs. B Substituted 9-membered heteroaryl groups containing 1-3 N or O atoms.

[0524] In another specific implementation scheme, ring B is... * indicates that it is connected to X. This indicates that it is connected to ring A.

[0525] p

[0526] In one implementation, p is 1, 2, or 3.

[0527] In another implementation, p is 1 or 2.

[0528] In one specific implementation, p is 1; in another specific implementation, p is 2; in yet another specific implementation, p is 3.

[0529] R, R A and R B

[0530] In one implementation scheme, each R, R A and R B Each can be independently represented as H, D, halogen, -OH, -CN, =O, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, -OC 3-8 Cycloalkyl or -O-4-9-membered heterocyclic groups.

[0531] In another implementation, each R, R A and R B Each can be independently represented as H, D, halogen, -OH, -CN, =O, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0532] In another implementation, each R, R A and R B Each can be independently represented as H, D, halogen, -OH, -CN, =O, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Cycloalkyl.

[0533] In another implementation, each R, R A and R B Each is independently H, D, halogen, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Cycloalkyl.

[0534] In another implementation, each R, R A and R B Each is independently H, D, halogen, C 1-6 Alkyl, C 1- 6-halogenated alkyl or C 3-8 Cycloalkyl.

[0535] In another implementation, each R, R A and R B Each is independently H, D, halogen, C 1-6 Alkyl or C 1- 6-Hydroalkyl group.

[0536] In another implementation, each R, R A and R B Each is independently H, D, halogen, or C. 1-6 alkyl.

[0537] In one specific implementation scheme, each R, R A and R B Each of the following can be independently H, D, -OH, -CN, =O, -NH2, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -O-cyclopropyl, methoxy, F, Cl, Br, -CF3, -CHF2 or -CH2CF3.

[0538] In another specific implementation, each R, R A and R B Each of the following can be independently H, D, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, F, Cl, -CF3, -CHF2 or -CH2CF3.

[0539] In another specific implementation, each R, R A and R B Each of the following can be independently H, D, CN, methyl, ethyl, isopropyl, cyclopropyl, methoxy, F, -CF3, -CHF2 or -CH2CF3.

[0540] In another specific implementation, each R, R A and R B Each can be independently H, D, CN, F, methyl, ethyl, isopropyl, cyclopropyl, or methoxy.

[0541] In another specific implementation, each R, R A and R B Each can be independently H, D, methyl, isopropyl, cyclopropyl, or methoxy.

[0542] In one more specific embodiment, R is H, D, methyl, isopropyl, cyclopropyl, or methoxy; in another more specific embodiment, R is H; in another more specific embodiment, R is D; in another more specific embodiment, R is methyl; in another more specific embodiment, R is isopropyl; in another more specific embodiment, R is cyclopropyl; in another more specific embodiment, R is methoxy.

[0543] In a more specific implementation scheme, R A H, D, CN, methyl, ethyl, isopropyl, cyclopropyl, methoxy, F, -CF3, -CHF2, or -CH2CF3; in another more specific embodiment, R A For H; in another more specific implementation, R A For D; in another more specific implementation, R A For CN; in another more specific implementation, R A For methyl; in another more specific embodiment, R A It is isopropyl; in another more specific embodiment, R A It is cyclopropyl; in another more specific embodiment, R A It is methoxylated; in another more specific embodiment, R A For F; in another more specific implementation, R A For -CF3; in another more specific implementation, R A For -CHF2; in another more specific implementation, R A It is -CH2CF3.

[0544] In a more specific implementation plan, R BH, D, CN, methyl, ethyl, isopropyl, cyclopropyl, methoxy, F, -CF3, -CHF2, or -CH2CF3; in another more specific embodiment, R B For H; in another more specific implementation, R B For D; in another more specific implementation, R B For CN; in another more specific implementation, R B For methyl; in another more specific embodiment, R B It is isopropyl; in another more specific embodiment, R B It is cyclopropyl; in another more specific embodiment, R B It is methoxylated; in another more specific embodiment, R B For F; in another more specific implementation, R B For -CF3; in another more specific implementation, R B For -CHF2; in another more specific implementation, R B It is -CH2CF3.

[0545] q

[0546] In one implementation, q is 0, 1, or 2.

[0547] In one specific implementation, q is 0; in another specific implementation, q is 1; in yet another specific implementation, q is 2.

[0548] X

[0549] In one implementation, X is -O-, -CR a R b -,-NR c -or -S(O) q -;

[0550] Where q is 0, 1, or 2;

[0551] R a and R b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1- 6-acetylenic, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1- 6-acetylenic, C 3-8The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0552] R c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0553] In another implementation, X is -O- or -CR a R b -

[0554] In another implementation, X is -O-.

[0555] In another implementation, X is -CR a R b -

[0556] In one specific embodiment, X is -CH2-, -CHD-, -CD2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CF3)-, or -CH(CH2CF3)-; in another specific embodiment, X is -CH2-, -CHD-, -CD2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH2CH3)-, -CH(CF3)-, or -CH(CH2CF3)-; in another specific embodiment, X is -CH2-, -CHD-, -CD2-, -CH(OH)-, -CHF-, or -CF2-; in another specific embodiment, X is -CH2-, -CHD-, or -CD2-; in another specific embodiment, X is -CH2-; in another specific embodiment, X is -CHD-; in another specific embodiment, X is -CD2-.

[0557] In another implementation, X is -NR c -or -S(O) q -

[0558] In another implementation, X is -NR c -

[0559] In one specific embodiment, X is -NH-, -N(CH3)-, -N(CH2CH3)-, -N(CH2OH)-, -N(CF3)-, or -N(CH2CF3)-; in another specific embodiment, X is -NH-; in another specific embodiment, X is -N(CH3)-; in another specific embodiment, X is -N(CH2CH3)-; in another specific embodiment, X is -N(CH2OH)-; in another specific embodiment, X is -N(CF3)-; in another specific embodiment, X is -N(CH2CF3)-.

[0560] In another implementation, X is -S(O). q -

[0561] In one specific embodiment, X is -S-, -S(O)-, or -S(O)2-; in another specific embodiment, X is -S-; in yet another specific embodiment, X is -S(O)-; in yet another specific embodiment, X is -S(O)2-.

[0562] R a and R b

[0563] In one implementation, R a and R b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0564] In another implementation, R a and R b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl; wherein the C 1-6Alkyl and C 1-6 The alkyl halide is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0565] In another implementation, R a and R b Each can be independently H, D, halogen, or -OH.

[0566] In another implementation, R a and R b Each independently is C 1-6 Alkyl or C 1-6 Haloalkyl; wherein the above groups are optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0567] In one specific implementation plan, R a and R b Each of the following is independently H, D, F, Cl, Br, I, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R a and R b Each is independently H, D, F, -OH, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R a and R b Each is independently H, D, F, -OH, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R a and R b Each is independently H, D, F, or -OH; in another specific embodiment, R a and R b For H; in another specific implementation, R a and R b For D; in another specific implementation, R a and R b It is F.

[0568] In another implementation, R a and R b Each is independently H, D, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0569] In another implementation, R a and R b Each is independently H, D, C 1-6 alkenyl or C 1-6 Alkyne group; wherein the C 1-6 alkenyl and C 1-6 The alkynyl group is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0570] In one specific implementation plan, R a and R b Each of these is independently H, D, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, butadiynyl, pentynyl, pentadiynyl, or hexynyl; in another specific embodiment, R a and R b Each is independently H, D, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, or 2-propynyl.

[0571] In another implementation, R a and R b Each is independently H, D, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0572] In one specific implementation plan, R a and R b Each of the following is independently H, D, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridine, oxadiolyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; in another specific embodiment, R a and R b Each can be independently H, D, cyclopropyl, cyclobutyl, aziridine, piperidinyl, or morpholinyl.

[0573] Rc

[0574] In one implementation, R c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3- 8-cycloalkyl or 4-9-membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3- The 8-cyclic alkyl group and the 4-9-membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0575] In another implementation, R c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 cycloalkyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-8 The cycloalkyl group is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1- 6-alkyl or C 1-6 Halogenated alkyl substitution.

[0576] In another implementation, R c Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl; wherein the C 1-6 Alkyl and C 1-6 The alkyl halide is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0577] In one specific implementation plan, R c Selected from H, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CF3, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; in another specific embodiment, R c Selected from H, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3.

[0578] m

[0579] In one implementation, m is 0 or 1.

[0580] In one specific implementation, m is 0; in another specific implementation, m is 1.

[0581] n

[0582] In one implementation, n is 1, 2, 3, or 4.

[0583] In another implementation, n is 1, 2, or 3;

[0584] In another implementation, n is 1 or 2.

[0585] In one specific implementation, n is 1; in another specific implementation, n is 2; in another specific implementation, n is 3; in another specific implementation, n is 4.

[0586] R 1a and R 1b

[0587] In one implementation, R 1a and R 1b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0588] In another implementation, R 1a and R 1b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl or C 1- 6-Hydroalkyl; wherein the C 1-6 Alkyl and C 1-6 The alkyl halide is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0589] In another implementation, R 1a and R 1bEach can be independently H, D, halogen, or -OH.

[0590] In another implementation, R 1a and R 1b Each independently is C 1-6 Alkyl or C 1-6 Haloalkyl; wherein the above groups are optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0591] In one specific implementation plan, R 1a and R 1b Each of the following is independently H, D, F, Cl, Br, I, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R 1a and R 1b Each is independently H, D, F, -OH, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R 1a and R 1b Each is independently H, D, F, -OH, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R 1a and R 1b Each is independently H, D, F, or -OH; in another specific embodiment, R 1a and R 1b For H; in another specific implementation, R 1a and R 1b For D; in another specific implementation, R 1a and R 1b It is F.

[0592] In another implementation, R 1a and R 1b Each is independently H, D, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0593] In another implementation, R 1a and R 1b Each is independently H, D, C 1-6 alkenyl or C 1-6 Alkyne group; wherein the C 1-6 alkenyl and C 1-6 The alkynyl group is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0594] In one specific implementation plan, R 1a and R 1b Each of these is independently H, D, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, butadiynyl, pentynyl, pentadiynyl, or hexynyl; in another specific embodiment, R 1a and R 1b Each is independently H, D, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, or 2-propynyl.

[0595] In another implementation, R 1a and R 1b Each is independently H, D, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0596] In one specific implementation plan, R 1a and R 1b Each of the following is independently H, D, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridine, oxadiolyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; in another specific embodiment, R 1a and R 1b Each can be independently H, D, cyclopropyl, cyclobutyl, aziridine, piperidinyl, or morpholinyl.

[0597] R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b

[0598] In one implementation, R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1- 6-acetylenic, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0599] In another implementation, R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0600] In another implementation, R 2a and R 2b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0601] In another implementation, R 2a and R 2b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl or C 1- 6-Hydroalkyl; wherein the C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted by 1 to 7 substituted groups selected from D, F, OH or CN.

[0602] In one specific implementation plan, R 2a and R 2b Each of these is independently H, D, F, Cl, Br, I, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, -CD3, -CH2CD3, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R 2a and R 2b Each is independently H, D, F, -OH, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R 2a and R 2b Each is independently H, D, F, -OH, methyl, ethyl, isopropyl, -CD3, -CH2CD3, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R 2a and R 2b Each is independently H, D, F, -OH, methyl, ethyl, isopropyl, -CD3, -CF3 or -CH2CF3; in another specific embodiment, R 2a For H, R2b The derivatives are H, D, F, -OH, methyl, ethyl, isopropyl, -CD3, -CF3, or -CH2CF3; in another specific embodiment, R 2a For H, R 2b It is methyl, ethyl, isopropyl, -CD3, -CF3 or -CH2CF3; in another specific embodiment, R 2a For H, R 2b It is methyl, -CD3 or -CF3; in another specific embodiment, R 2a For H, R 2b It is methyl or -CD3; in another specific embodiment, R 2a For H, R 2b For methyl; in another specific embodiment, R 2a For H, R 2b It is -CD3.

[0603] In another implementation, R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0604] In another implementation, R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl; wherein the C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted by 1 to 7 substituted groups selected from D, F, OH or CN.

[0605] In one specific implementation plan, R 3a R 3b R 4a R 4b R 5a and R 5b Each of these is independently H, D, F, Cl, Br, I, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, -CD3, -CH2CD3, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, R 3a R 3b R 4a R 4b R 5a and R 5b Each of these is independently H, D, F, -OH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CD3, -CH2CD3, -CH2F, -CHF2, -CF3, or -CH2CF3; in another specific embodiment, R 3a R 3b R 4a R 4b R 5a and R 5b Each is independently H, D, F, -OH, methyl, isopropyl, cyclopropyl, -CD3, -CF3, or -CH2CF3; in another specific embodiment, R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, F, -OH, methyl, -CD3, -CF3 or -CH2CF3.

[0606] In another implementation, R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; wherein 1-7 of the above groups are selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0607] In another implementation, R 2a R 2b R 3aR 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl; wherein 1 to 7 of the above groups are selected from D, halogen, OH, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0608] In one specific implementation plan, R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclopentadienylene, cyclohexadienylene, cycloheptene, cycloheptadienylene, cycloheptanetrienylene, cyclooctenylene, or cyclooctadienyl, wherein the above groups are optionally substituted by 1-3 groups selected from D, F, or OH; in another specific embodiment, R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group, wherein the aforementioned groups are optionally substituted by 1-3 atoms selected from D, F, or OH; in another specific embodiment, R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form a cyclobutylene, cyclopentylene, or cyclohexylene group, wherein the above groups are optionally replaced by 1-3 atoms selected from D, F, or OH.

[0609] In another implementation, R 2a R 2b R 3a R 3b R 4a R 4b R5a and R 5b Any two groups together with the atoms they are attached to form a 4-9 membered heterocyclic group; wherein 1-7 of the above groups are selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0610] E

[0611] In one implementation, each E is independently designated as -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -,-CR 3a R 3b -,-O-,-NR c -, -C(O)- or -S(O) q -

[0612] In another implementation, each E is independently -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -,-CR 3a R 3b -,-O-,-NR c -or -C(O)-.

[0613] In another implementation, E is -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -or-CR 3a R 3b -

[0614] In another implementation, E is -CR 3a R 3b -CR 4a R4b -CR 5a R 5b -

[0615] In another implementation, E is -CR 3a R 3b -CR 4a R 4b -

[0616] In another implementation, E is -CR 3a R 3b -

[0617] In another implementation, E is -O-.

[0618] In another implementation, E is -NR c -

[0619] In another implementation, E is -C(O)-.

[0620] In another implementation, E is -S(O). q - In one specific embodiment, E is -S-, -S(O)- or -S(O)2-; in another specific embodiment, E is -S-; in yet another specific embodiment, E is -S(O)-; in yet another specific embodiment, E is -S(O)2-.

[0621] In one specific embodiment, each E is independently -CH2-CH2-CH2-, -CH2-CH2-, -CH2-, cyclobutylene, cyclopentylene, or cyclohexylene, wherein the group is optionally substituted by 1 to 3 groups selected from D, F, or OH.

[0622] i and j

[0623] In one implementation, i is 0 or 1.

[0624] In one specific implementation, i is 0; in another specific implementation, i is 1.

[0625] In one implementation, j is 0 or 1.

[0626] In one specific implementation, j is 0; in another specific implementation, j is 1.

[0627] R d and R e

[0628] In one implementation scheme, each R d and R e Each can be independently H, D, halogen, -OH, C 1-6Alkyl, C 1- 6-Hydroalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R d and R e Together with the C atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0629] In another implementation, each R d and R e Each can be independently H, D, halogen, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl; wherein the C 1-6 Alkyl and C 1-6 The alkyl halide is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0630] In another implementation, each R d and R e Each can be independently H, D, halogen, or -OH.

[0631] In another implementation, each R d and R e Each independently is C 1-6 Alkyl or C 1-6 Haloalkyl; wherein the above groups are optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0632] In one specific implementation plan, each R d and R e Each of the following is independently H, D, F, Cl, Br, I, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, each R d and R eEach is independently H, D, F, -OH, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, each R d and R e Each is independently H, D, F, -OH, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, each R d and R e Each is independently H, D, F, or -OH; in another specific embodiment, R d and R e For H; in another specific implementation, R d and R e For D; in another specific implementation, R d and R e It is F.

[0633] In another implementation, each R d and R e Each is independently H, D, C 1-6 alkenyl, C 1-6 alkynyl group, C 3- 8-cycloalkyl or 4-9-membered heterocyclic group; wherein the C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0634] In another implementation, each R d and R e Each is independently H, D, C 1-6 alkenyl or C 1-6 Alkyne group; wherein the C 1-6 alkenyl and C 1-6 The alkynyl group is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0635] In one specific implementation plan, each R d and R e Each is independently H, D, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, butadiynyl, pentynyl, pentadiynyl or hexynyl; in another specific embodiment, each Rd and R e Each is independently H, D, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, or 2-propynyl.

[0636] In another implementation, each R d and R e Each is independently H, D, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1- 6-alkyl or C 1-6 Halogenated alkyl substitution.

[0637] In one specific implementation plan, each R d and R e Each of the following is independently H, D, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridine, oxadiolyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; in another specific embodiment, each R d and R e Each can be independently H, D, cyclopropyl, cyclobutyl, aziridine, piperidinyl, or morpholinyl.

[0638] R f

[0639] In one implementation scheme, each R f Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0640] In another implementation, each R f Each independently represents H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 cycloalkyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-8The cycloalkyl group is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0641] In another implementation, each R f Each independently represents H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl; wherein the C 1-6 Alkyl and C 1-6 The alkyl halide is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0642] In one specific implementation plan, each R f Each of the following is independently H, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CF3, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; in another specific embodiment, each R f Each can be independently H, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3.

[0643] -L1-L2-S1-L3-S2-(L4) i -

[0644] In one implementation, -L1-L2-S1-L3-S2-(L4) i - is - L1-L2-S1-L3-S2-(L4) i -,-L1-L2-S1-L3-(L4) i -,-L1-L2-L3-S2-(L4) i -or-L1-L2-L3-(L4) i -; where L1 and L2 can share an atom or a chemical bond;

[0645] When S1 is a chemical bond, L2 and L3 can share an atom or a chemical bond;

[0646] When S2 is a chemical bond and i is 1, L3 and L4 can share an atom or a chemical bond.

[0647] In another implementation, -L1-L2-S1-L3-S2-(L4) i-for -L1-L2-S1-L3-S2-L4-, -L1-L2-S1-L3-S2-, -L1-L2-S1-L3-L4-, -L1-L2- S1-L3-, -L1-L2-L3-S2-L4-, -L1-L2-L3-S2-, -L1-L2-L3-L4- or -L1-L2-L3-.

[0648] In another implementation, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-S1-L3-S2-L4-; where L1 and L2 can share an atom or a chemical bond.

[0649] In another implementation, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-S1-L3-S2-; where L1 and L2 can share an atom or a chemical bond.

[0650] In another implementation, -L1-L2-S1-L3-S2-(L4) i - is - L1-L2-S1-L3-(L4) i -; where L1 and L2 can share an atom or a chemical bond.

[0651] In one specific implementation, -L1-L2-S1-L3-S2-(L4) i The form is -L1-L2-S1-L3-L4-, where L1 and L2 may share an atom or a chemical bond. In another specific embodiment, -L1-L2-S1-L3-S2-(L4) i The expression is -L1-L2-S1-L3-L4-, where L3 and L4 may share an atom or a chemical bond. In another specific embodiment, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-S1-L3-L4-, where L1 and L2 share an atom or a chemical bond, and L3 and L4 share an atom or a chemical bond.

[0652] In another specific implementation, -L1-L2-S1-L3-S2-(L4) i The form is -L1-L2-S1-L3-; where L1 and L2 may share an atom or a chemical bond. In another specific embodiment, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-CH2-L3-. In another specific implementation, -L1-L2-S1-L3-S2-(L4) iThe symbol is -L1-L2-CH2-L3-, where L1 and L2 share a single atom. In another specific embodiment, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-C(O)-CH2-L3-. In another specific embodiment, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-C(O)-CH2-L3-, where L1 and L2 share an atom.

[0653] In another implementation, -L1-L2-S1-L3-S2-(L4) i - is - L1-L2-L3-S2-(L4) i -; where L1 and L2 may share an atom or a chemical bond; or L2 and L3 may share an atom or a chemical bond.

[0654] In one specific implementation, -L1-L2-S1-L3-S2-(L4) i - can be -L1-L2-L3-S2-L4- or -L1-L2-L3-S2-, where L1 and L2 may share an atom or a chemical bond; or L2 and L3 may share an atom or a chemical bond.

[0655] In another implementation, -L1-L2-S1-L3-S2-(L4) i -for-L1-L2-L3-(L4) i -; where L1 and L2 can share an atom or a chemical bond.

[0656] In one specific implementation, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-L3-L4-. In another specific implementation, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-L3-. In another specific implementation, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-L3-L4-, where L1 and L2 share an atom.

[0657] S1 and S2

[0658] In one implementation, S1 and S2 are each independently a chemical bond, -O-, -S-, -CR. d R e -,-(CR d R e ) j NR f -,-(CRd R e ) j C(O)-, -(CR) d R e ) j C(O)NR f -,-NR f (CR d R e ) j -,-C(O)(CR d R e ) j -or-C(O)NR f (CR d R e ) j -

[0659] In another embodiment, S1 and S2 are each independently chemical bonds, -O-, -S-, -CR d R e -,-(CR d R e )NR f -,-(CR d R e )C(O)-,-(CR d R e )C(O)NR f -,-NR f (CR d R e )-,-C(O)(CR d R e )-,-C(O)NR f (CR d R e )-,-NR f -,-C(O)- or -C(O)NR f -

[0660] In another embodiment, S1 and S2 are each independently chemical bonds, -O-, -S-, -CR d R e -,-(CR d R e )C(O)-,-C(O)(CR d R e )- or -C(O)-.

[0661] In another implementation, S1 and S2 are each independently -(CR d R e )NR f -,-(CR d Re )C(O)NR f -,-NR f (CR d R e )-,-C(O)NR f (CR d R e )-,-NR f -or-C(O)NR f -

[0662] In one specific implementation, S1 and S2 are each independently a chemical bond, -O-, -S-, -CH2-, -CH2C(O)-, -C(O)-, -C(O)CH2-, -CH2NH-, -CH2C(O)NH-, -NHCH2-, -C(O)NHCH2-, -NH- or -C(O)NH-.

[0663] In another specific embodiment, S1 and S2 are each independently a chemical bond, -O-, -S-, -CH2-, -CH2C(O)-, -C(O)- or -C(O)CH2-.

[0664] In another specific embodiment, S1 is a chemical bond, -O-, -S-, -CH2-, -CH2C(O)-, -C(O)- or -C(O)CH2-.

[0665] In one more specific embodiment, S1 is a chemical bond; in another more specific embodiment, S1 is -O-; in another more specific embodiment, S1 is -S-; in another more specific embodiment, S1 is -CH2-; in another more specific embodiment, S1 is -CH2C(O)-; in another more specific embodiment, S1 is -C(O)-; in another more specific embodiment, S1 is -C(O)CH2-.

[0666] In another specific embodiment, S2 is a chemical bond, -O-, -S-, -CH2-, -CH2C(O)-, -C(O)- or -C(O)CH2-.

[0667] In one more specific embodiment, S2 is a chemical bond; in another more specific embodiment, S2 is -O-; in another more specific embodiment, S2 is -S-; in another more specific embodiment, S2 is -CH2-; in another more specific embodiment, S2 is -CH2C(O)-; in another more specific embodiment, S2 is -C(O)-; in another more specific embodiment, S2 is -C(O)CH2-.

[0668] R L1 RL2 R L3 and R L4

[0669] In one implementation scheme, each R L1 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L1 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0670] In another implementation, each R L1 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0671] In another implementation, each R L1 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl; wherein the C 1-6 Alkyl and C 1-6 The alkyl halide is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0672] In one specific implementation plan, each R L1 Each is independently D, F, Cl, Br, I, OH, CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, each R L1Each can be independently D, F, OH, CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3.

[0673] In another implementation, any two R L1 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; wherein the above groups are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0674] In one implementation scheme, each R L2 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0675] In another implementation, each R L2 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0676] In another implementation, each R L2 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl; wherein the C 1-6 Alkyl and C 1-6 The alkyl halide is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0677] In one specific implementation plan, each R L2 Each is independently D, F, Cl, Br, I, OH, CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, each R L2 Each can be independently D, F, OH, CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3.

[0678] In another implementation, any two R L2 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; wherein the above groups are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0679] In one implementation scheme, each R L3 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L3 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0680] In another implementation, each R L3 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0681] In another implementation, each R L3 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C1-6 Halogenated alkyl; wherein the C 1-6 Alkyl and C 1-6 The alkyl halide is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0682] In one specific implementation plan, each R L3 Each is independently D, F, Cl, Br, I, OH, CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, each R L3 Each can be independently D, F, OH, CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3.

[0683] In another implementation, any two R L3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; wherein the above groups are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0684] In one implementation scheme, each R L4 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L4 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0685] In another implementation, each R L4 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C.1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0686] In another implementation, each R L4 Each is independently D, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl; wherein the C 1-6 Alkyl and C 1-6 The alkyl halide is optionally surrounded by 1-7 atoms selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0687] In one specific implementation plan, each R L4 Each is independently D, F, Cl, Br, I, OH, CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3; in another specific embodiment, each R L4 Each can be independently D, F, OH, CN, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3 or -CH2CF3.

[0688] In another implementation, any two R L4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; wherein the above groups are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0689] L1, L2, L3 and L4

[0690] In one implementation, L1 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L1 replace;

[0691] L2 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L2 replace;

[0692] L3 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L3 replace;

[0693] L4 is C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatic hydrocarbons or 6-12 membered heterocyclic groups, wherein the C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatics or 6-12 membered heterocyclic groups optionally surrounded by 1-6 R groups L4 replace.

[0694] In another implementation, each L1, L2, L3, and L4 is independently designated as C. 3-8 Cycloalkylene groups, wherein the above groups may optionally be surrounded by 1-3 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0695] In another implementation, each L1, L2, L3, and L4 is independently... The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0696] In another embodiment, each L1, L2, L3, and L4 is independently a 4-9 membered heterocyclic group containing one or two N atoms, wherein the 4-9 membered heterocyclic group may optionally be composed of one to three atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0697] In another implementation, each L1, L2, L3, and L4 is independently... The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1- 3-Hydroalkyl or C 3-6 Cycloalkyl substitution.

[0698] In another implementation, each L1, L2, L3, and L4 is independently... The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1- 3-Hydroalkyl or C 3-6Cycloalkyl substitution.

[0699] In one specific implementation, each L1, L2, L3, and L4 is independently... The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0700] In -L1-L2-S1-L3-S2-(L4) i In one specific implementation, L1 and L2 share an atom or a chemical bond.

[0701] In -L1-L2-S1-L3-S2-(L4) i In another specific implementation, L2 and L3 share an atom or a chemical bond.

[0702] In -L1-L2-S1-L3-S2-(L4) i In another specific implementation, L3 and L4 share an atom or a chemical bond.

[0703] In -L1-L2-S1-L3-S2-(L4) i In another specific embodiment, the groups that share an atom among L1 and L2, L2 and L3, and L3 and L4 are:

[0704] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0705] In -L1-L2-S1-L3-S2-(L4) i In another specific embodiment, the groups that share an atom among L1 and L2, L2 and L3, and L3 and L4 are:

[0706] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0707] In -L1-L2-S1-L3-S2-(L4) iIn one specific implementation, -L1-L2-S1-L3-S2-(L4) i -for:

[0708] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3- 6-Cycloalkyl-substituted.

[0709] In -L1-L2-S1-L3-S2-(L4) i In another specific implementation, -L1-L2-S1-L3-S2-(L4) i -for:

[0710] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3- 6-Cycloalkyl-substituted.

[0711] In -L1-L2-S1-L3-S2-(L4) i In another specific implementation, -L1-L2-S1-L3-S2-(L4) i -for:

[0712] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0713] In -L1-L2-S1-L3-S2-(L4) i In another specific implementation, -L1-L2-S1-L3-S2-(L4) i -for:

[0714] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution.

[0715] In -L1-L2-S1-L3-S2-(L4) i In another specific implementation, -L1-L2-S1-L3-S2-(L4) i -for:

[0716] The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3- 6-Cycloalkyl-substituted.

[0717] U

[0718] In one implementation scheme, each U is independently:

[0719] in,

[0720] Indicates a single bond or a double bond;

[0721] Each Q1 is independently C(O) or C(R). U4 )2;

[0722] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0723] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0724] Each Q2 is independently either N or CH;

[0725] Q3 and Q4 are each independently N or CH;

[0726] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0727] P1 is N, C, or CR U4 ;

[0728] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0729] P4 and P5 are each independently N or C;

[0730] z is 0, 1, or 2;

[0731] H1 is N or CRU4 ;

[0732] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0733] Each h is independently 0, 1, 2, 3 or 4;

[0734] Each k is independently 0, 1, 2, or 3;

[0735] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0736] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0737] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0738] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0739] In another implementation, each U is independently:

[0740] in,

[0741] Indicates a single bond or a double bond;

[0742] Each Q1 is independently C(O) or C(R).U4 )2;

[0743] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0744] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0745] Each Q2 is independently either N or CH;

[0746] Q3 and Q4 are each independently N or CH;

[0747] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0748] P1 is N, C, or CR U4 ;

[0749] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0750] P4 and P5 are each independently N or C;

[0751] Each h is independently 0, 1, 2, 3 or 4;

[0752] Each k is independently 0, 1, 2, or 3;

[0753] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0754] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0755] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0756] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0757] In another implementation, each U is independently:

[0758] in,

[0759] Each Q1 is independently C(O) or C(R). U4 )2;

[0760] Each r and s is independently 0, 1, 2 or 3; and r and s are not both 0 at the same time;

[0761] t and u are each independently 0, 1, 2 or 3; and t and u are not both 0 at the same time;

[0762] Each h is independently 0, 1, 2, 3 or 4;

[0763] Each k is independently 0, 1, 2, or 3;

[0764] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0765] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0766] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0767] Each R U4Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0768] In one specific implementation scheme, each U is independently:

[0769] in,

[0770] Each Q1 is independently C(O) or C(R). U4 )2;

[0771] Each k is independently 0, 1, or 2;

[0772] Each R U3 Each is independently either D or halogen;

[0773] Each R U4 Each can be H, D, or halogen independently.

[0774] In another specific implementation, each U is independently:

[0775] in,

[0776] Each k is independently 0, 1, or 2;

[0777] Each R U3 Each is independently either D or halogen.

[0778] In another specific implementation, each U is independently:

[0779] in,

[0780] Each k is independently 0, 1, or 2;

[0781] Each R U3 Each is independently either D or halogen.

[0782] In another specific implementation, each U is independently:

[0783] in,

[0784] Each k is independently 0, 1, or 2;

[0785] Each R U3Each is independently either D or halogen.

[0786] In a more specific implementation, each U is independently:

[0787] In another implementation, each U is independently:

[0788] in,

[0789] Q2 is either N or CH;

[0790] Q3 is either N or CH;

[0791] W is a chemical bond, such as NH, O, S, C(O)NH or NHC(O);

[0792] h can be 0, 1, 2, 3, or 4;

[0793] k can be 0, 1, 2, or 3;

[0794] R U1 For H, C 1-6 Alkyl or C 3-8 cycloalkyl;

[0795] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0796] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0797] In one specific implementation scheme, each U is independently:

[0798] in,

[0799] Q2 is either N or CH;

[0800] Q3 is either N or CH;

[0801] Each k is independently 0, 1, or 2;

[0802] Each R U3 Each is independently either D or halogen.

[0803] In another specific implementation, each U is independently:

[0804] in,

[0805] Q3 is either N or CH;

[0806] Each k is independently 0, 1, or 2;

[0807] Each R U3 Each is independently either D or halogen.

[0808] In a more specific implementation, each U is independently:

[0809] In another implementation, each U is independently:

[0810] in,

[0811] Indicates a single bond or a double bond;

[0812] Q2 is either N or CH;

[0813] P1 is N, C, or CR U4 ;

[0814] P2 and P3 are each independently C(O), N, O, S, NR. U4 CR U4 or C(R) U4 )2;

[0815] P4 and P5 are each independently N or C;

[0816] h can be 0, 1, 2, 3, or 4;

[0817] k can be 0, 1, 2, or 3;

[0818] R U1 For H, C 1-6 Alkyl or C 3-8 cycloalkyl;

[0819] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups;

[0820] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0821] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkanes or 4-9 membered heterocycles.

[0822] In one specific implementation scheme, each U is independently:

[0823] in,

[0824] Q2 is either N or CH;

[0825] Each P2 is independently either N or CR. U4 ;

[0826] Each P3 is independently N, O, S, NR. U4 or CR U4 ;

[0827] Each k is independently 0, 1, or 2;

[0828] Each R U1 Each independently is H or C 1-6 alkyl;

[0829] Each R U3 Each is independently either D or halogen;

[0830] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0831] In another specific implementation, each U is independently:

[0832] in,

[0833] Q2 is either N or CH;

[0834] Each P2 is independently either N or CR. U4 ;

[0835] Each P3 is independently N, O, S, NR. U4 or CR U4 ;

[0836] Each k is independently 0, 1, or 2;

[0837] Each R U3 Each is independently either D or halogen;

[0838] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0839] In another specific implementation, each U is independently:

[0840] in,

[0841] Q2 is either N or CH;

[0842] Each k is independently 0, 1, or 2;

[0843] Each R U1 Each independently is H or C 1-6 alkyl;

[0844] Each R U3 Each is independently either D or halogen;

[0845] R U4 For H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0846] In another specific implementation, each U is independently:

[0847] in,

[0848] Q2 is either N or CH;

[0849] P2 is N or CR U4;

[0850] P3 is O, S, or NR. U4 ;

[0851] k is 0, 1, or 2;

[0852] Each R U3 Each is independently either D or halogen;

[0853] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0854] In a more specific implementation, each U is independently:

[0855] in,

[0856] Each k is independently 0, 1, or 2;

[0857] Each R U3 Each is independently either D or halogen;

[0858] Each R U4 Each independently represents H and C. 1-6 Alkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0859] In another, more specific implementation, each U is independently:

[0860] in,

[0861] k is 0, 1, or 2;

[0862] Each R U3 Each is independently either D or halogen;

[0863] R U4 For H, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups.

[0864] In another, more specific implementation, each U is independently:

[0865] In another implementation, each U is independently:

[0866] in,

[0867] Q2 is either N or CH;

[0868] Q3 is either N or CH;

[0869] z is 0, 1, or 2;

[0870] H1 is N or CR U4 ;

[0871] H2, H3, and H4 are each independently C(O), O, S, NR. U4 or C(R) U4 )2;

[0872] Each h is independently 0, 1, 2, 3 or 4;

[0873] Each k is independently 0, 1, 2, or 3;

[0874] Each R U1 Each independently represents H and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0875] Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 Cycloalkanes or 4-9 membered heterocycles;

[0876] Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkanes, 4-9 membered heterocycles, C 6-10 Aromatic hydrocarbons or 5-10 quintone aromatic hydrocarbons;

[0877] Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkanes or 4-9 membered heterocyclic groups.

[0878] In one specific implementation scheme, each U is independently:

[0879] in,

[0880] Q3 is either N or CH;

[0881] z is 0, 1, or 2;

[0882] Each k is independently 0, 1, 2, or 3;

[0883] Each R U1 Each independently is H or C 1-6 alkyl;

[0884] Each R U3 Each is independently either D or halogen.

[0885] In another specific implementation, each U is independently:

[0886] in,

[0887] Each k is independently 0, 1, 2, or 3;

[0888] Each R U3 Each is independently either D or halogen.

[0889] 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 ring A can be combined with rings B, R, and R A R B X, E, R a R b R c R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R d R e R f R L1 R L2 R L3 R L4 , S1, S2, L1, L2, L3, L4, i, j, m, n, p, q, U, Q1, Q2, Q3, Q4, P1, P2, P3, P4, P5, H1, H2, H3, H4, W, R U1 R U2 R U3 R U4The 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.

[0890] 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 selected from:

[0891] 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.

[0892] "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.

[0893] 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.

[0894] 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.

[0895] 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)).

[0896] 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.

[0897] 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.

[0898] 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.

[0899] 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.

[0900] Pharmaceutical compositions, formulations and kits

[0901] 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.

[0902] 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.

[0903] 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.

[0904] 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.

[0905] 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.

[0906] 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.

[0907] 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.

[0908] 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.

[0909] 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.

[0910] 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.

[0911] 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.

[0912] 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.

[0913] 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.

[0914] 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.

[0915] 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.

[0916] 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.

[0917] 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.

[0918] 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.

[0919] 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).

[0920] Indications

[0921] On the other hand, the use of compounds of formula (I), (II), (III), and (IV) disclosed herein (including all individual embodiments and subsets thereof) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents in pharmaceuticals.

[0922] In one embodiment, the present invention provides compounds that specifically degrade mutant EGFR through targeted ubiquitination of the EGFR 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 mutant EGFR (specifically, for example, EGFR Del19 mutation, L858R mutation, T790M mutation, C797S mutation, Del19 / T790M double mutation, Del19 / C797S double mutation, L858R / T790M double mutation, L858R / C797S double mutation, T790M / C797S double mutation, Del19 / T790M / C797S triple mutation, and L858R / T790M / C797S triple mutation).

[0923] In another embodiment, the present invention provides a compound having the activity of inhibiting mutant EGFR, wherein the mutant EGFR specifically includes, for example, EGFR Del19 mutation, L858R mutation, T790M mutation, C797S mutation, Del19 / T790M double mutation, Del19 / C797S double mutation, L858R / T790M double mutation, L858R / C797S double mutation, T790M / C797S double mutation, Del19 / T790M / C797S triple mutation, or L858R / T790M / C797S triple mutation.

[0924] In another embodiment, the compounds of the present invention can be used to treat diseases mediated by mutated EGFR, wherein EGFR has been mutated from the wild-type. In another embodiment, the compounds of the present invention are used to treat EGFR-mediated cancers that have metastasized to the central nervous system (CNS), such as those metastasizing to the peripheral nervous system, brain, cerebrospinal fluid, spinal cord, pia mater, epidural space, and / or dura mater, wherein EGFR has been mutated from the wild-type. EGFR mutations are possible in many ways. In one specific embodiment, the EGFR mutation is not limited to being present in exon 18, exon 19, exon 20, or exon 21, or any combination thereof. In a more specific implementation, the EGFR mutation is not limited to positions E709, L718, G719, G724, Del19, L747, D761, M766, S768, T790, L792, G796, C797, ex20ins, G834, V843, L844, T854, L858, or L861, or any combination thereof. In a more specific implementation, the EGFR mutation is not limited to being selected from E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, Del19, L747S, L747P, D761Y, M766Q, S768I, T790M, L792F, L792H, L792V, G796R, G796S, G796C, G796D, C797S, C797G, C797N, ex20ins, G834L, V843I, L844V, T854A, L858R, or L861Q, or any combination thereof. In another, more specific embodiment, the EGFR mutation is Del19, L858R, T790M, C797S, C797G, C797N, L718Q, L792H, or L861Q, or any combination thereof. In another, more specific embodiment, the EGFR mutation is not an exon 18, exon 19, exon 20, or exon 21 mutation. In another, more specific embodiment, the non-exon 18, non-exon 19, exon 20, or exon 21 mutation is non-restrictively selected from G119A, R531Q, V948R, or I941R.

[0925] In another specific embodiment, the mutated EGFR includes a combination of mutations, wherein the combination comprises two, three, four, or more mutations, optionally selected from E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, Del19, L747S, L747P, and D76. 1Y, M766Q, S768I, T790M, L792F, L792H, L792V, G796R, G796S, G796C, G796D, C797S, C797G, C797N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R or I941R.

[0926] In another specific implementation, the mutation combinations are Del19 / L718Q, Del19 / T790M, Del19 / C797S, Del19 / C797G, Del19 / C797N, Del19 / L792F, Del19 / L792H, Del19 / L792Y, Del19 / L844V, Del19 / T790M / L718Q, Del19 / T790M / C797S, Del19 / T790M / C797G, and Del19 / T790M / C797N. Del19 / T790M / L792F, Del19 / T790M / L792H, Del19 / T790M / L792Y, Del19 / T790M / L844V, L858R / L718Q, L858R / T790M, L858R / C797S, L858R / C797G, L858R / C797N, L858R / L844V, L858R / T790M / C797S, L858R / T790M / L718Q, or L858R / T790M / I941R.

[0927] In another, more specific embodiment, the mutated EGFR is the Del19 mutation and additional mutations, which may be one, two, or three additional mutations, optionally selected from E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, L747S, and L747P. D761Y, M766Q, S768I, T790M, L792F, L792H, L792V, G796R, G796S, G796C, G796D, C797S, C797G, C797N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R or I941R.

[0928] In another, more specific embodiment, the mutated EGFR is the L858R mutation and additional mutations, which may be one, two, or three additional mutations, optionally selected from E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, Del19, and L747S. L747P, D761Y, M766Q, S768I, T790M, L792F, L792H, L792V, G796R, G796S, G796C, G796D, C797S, C797G, C797N, ex20ins, G834L, V843I, L844V, T854A, L861Q, G119A, R531Q, V948R or I941R.

[0929] In another, more specific embodiment, the mutated EGFR is the T790M mutation and additional mutations, which may be one, two, or three additional mutations, optionally selected from E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, Del19, and L747S. L747P, D761Y, M766Q, S768I, L792F, L792H, L792V, G796R, G796S, G796C, G796D, C797S, C797G, C797N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R or I941R.

[0930] In another, more specific embodiment, the mutated EGFR is the C797S mutation and additional mutations, which may be one, two, or three additional mutations, optionally selected from E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, Del19 L747S, L747P, D761Y, M766Q, S768I, T790M, L792F, L792H, L792V, G796R, G796S, G796C, G796D, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R or I941R.

[0931] In another specific implementation, the EGFR mutation is S768I, L718V, L792H, G796S, G796C, G724S, or G719A.

[0932] In another specific implementation, the EGFR mutation is a deletion of one or more exon 18 (Del18) mutations.

[0933] In another specific embodiment, the EGFR mutation is one or more Del19, wherein the exon 19 deletion mutation is not limited to the deletion of amino acid LREA (L747-A750) or amino acid ELREA (E746-A750).

[0934] In another specific implementation, the EGFR mutation is an E709 mutation, such as E709A, E709G, E709K, or E709V.

[0935] In another specific implementation, the EGFR mutation is an L718 mutation, such as L718Q or L718V.

[0936] In another specific implementation, the EGFR mutation is a G719 mutation, such as G719C, G719S, G719A, or G719D.

[0937] In another specific implementation, the EGFR mutation is the L861Q mutation.

[0938] In another specific implementation, the EGFR mutation is the L858R mutation.

[0939] In another specific implementation, the EGFR mutation is the T790M mutation.

[0940] In another specific implementation, the EGFR mutation is the C797 mutation.

[0941] In another specific implementation, the EGFR mutation is the C797S mutation.

[0942] In another specific implementation, the EGFR mutation is the C797G mutation.

[0943] In another specific implementation, the EGFR mutation is the C797N mutation.

[0944] In another specific implementation, the EGFR mutation is the L792 mutation.

[0945] In another specific implementation, the EGFR mutation is the L792F mutation.

[0946] In another specific implementation, the EGFR mutation is the L792H mutation.

[0947] In another specific implementation, the EGFR mutation is the L792V mutation.

[0948] In another specific implementation, the EGFR mutation is the L718Q mutation.

[0949] In another specific implementation, the EGFR mutation is a Del19 / T790M combined mutation.

[0950] In another specific implementation, the EGFR mutation is a Del19 / C797 combined mutation.

[0951] In another specific implementation, the EGFR mutation is a Del19 / C797S combined mutation.

[0952] In another specific implementation, the EGFR mutation is a Del19 / L718Q combined mutation.

[0953] In another specific implementation, the EGFR mutation is a Del19 / L792H combined mutation.

[0954] In another specific implementation, the EGFR mutation is the L858R / T790M combined mutation.

[0955] In another specific implementation, the EGFR mutation is the L858R / C797 combined mutation.

[0956] In another specific implementation, the EGFR mutation is the L858R / C797S combined mutation.

[0957] In another specific implementation, the EGFR mutation is the L858R / L718Q combined mutation.

[0958] In another specific implementation, the EGFR mutation is the L858R / L792H combined mutation.

[0959] In another specific implementation, the EGFR mutation is a T790M / C797 combined mutation.

[0960] In another specific implementation, the EGFR mutation is a T790M / C797S combined mutation.

[0961] In another specific implementation, the EGFR mutation is a Del19 / T790M / C797 combined mutation.

[0962] In another specific implementation, the EGFR mutation is a Del19 / T790M / C797S combined mutation.

[0963] In another specific implementation, the EGFR mutation is a combined L858R / T790M / C797 mutation.

[0964] In another specific implementation, the EGFR mutation is a combined L858R / T790M / C797S mutation.

[0965] In another embodiment, the compounds of the present invention are used to treat diseases in which escape mutations (one or more mutations) have developed after treatment with at least one EGFR inhibitor, said inhibitor being a non-covalent inhibitor (including, but not limited to, gefitinib, erlotinib, lapatinib, or vandetanib) or a covalent inhibitor (including, but not limited to, afatinib, osimertinib, or dacomitinib). In another embodiment, the compounds of the present invention are used to treat diseases in which escape mutations (one or more mutations) have developed after treatment with an antibody, said antibody being non-limitingly included in the categories of cetuximab, panitumumab, or nexituzumab. In another embodiment, the compounds of the present invention are used to treat diseases with intrinsic resistance to EGFR mutations or non-EGFR mutations, such as somatic exon 20 insertions, MET amplification, somatic PIK3CA mutations, PTEN loss of expression, or KRAS mutations.

[0966] In another embodiment, the compounds of the present invention are used to treat cancers that are resistant to or have acquired resistance to at least one EGFR inhibitor, such as diseases resistant to or have acquired resistance to first-generation EGFR inhibitors such as gefitinib, erlotinib, and / or icotinib. In one specific embodiment, the compounds of the present invention are used to treat diseases resistant to or have acquired resistance to first-generation EGFR inhibitors such as gefitinib, erlotinib, and / or icotinib. In another specific embodiment, the compounds of the present invention are used to treat diseases resistant to or have acquired resistance to second-generation EGFR inhibitors such as afatinib and / or dacomitinib. In another specific embodiment, the compounds of the present invention are used to treat diseases resistant to or have acquired resistance to third-generation EGFR inhibitors such as osimertinib.

[0967] In another embodiment, the compounds of the present invention are used to treat EGFR-mediated diseases and their metastases (especially CNS metastases such as brain metastases), said diseases being cancer or proliferative disorders.

[0968] In one specific implementation, the cancers include, but are not limited to: lung cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, urothelial carcinoma, kidney cancer, bladder cancer, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial tumor, colorectal cancer, head and neck cancer, esophageal cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, gastric cancer, leukemia, lymphoma, neuroblastoma, glioma, melanoma, sarcoma, thyroid cancer, glioblastoma, solid tumor, oropharyngeal cancer, bronchial tumor, skin cancer, brain metastases, and mesothelioma.

[0969] In another embodiment, the compounds of the present invention are used to treat lung cancer, which is not limited to small cell lung cancer and non-small cell lung cancer, each of which can be primary or metastatic (especially CNS metastases such as brain metastases).

[0970] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer and its metastases (especially CNS metastases such as brain metastases), for example, non-small cell lung cancer and its metastases having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0971] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with Del19 mutations and its metastases (especially CNS metastases such as brain metastases).

[0972] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R mutation and its metastases (especially CNS metastases such as brain metastases).

[0973] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the T790M mutation and its metastases (especially CNS metastases such as brain metastases).

[0974] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with C797S mutation and its metastases (especially CNS metastases such as brain metastases).

[0975] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the C797G mutation and its metastases (especially CNS metastases such as brain metastases).

[0976] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the C797N mutation and its metastases (especially CNS metastases such as brain metastases).

[0977] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the Del19 / T790M combined mutation and its metastases (especially CNS metastases such as brain metastases).

[0978] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the Del19 / C797S combined mutation and its metastases (especially CNS metastases such as brain metastases).

[0979] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R / T790M combined mutation and its metastases (especially CNS metastases such as brain metastases).

[0980] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R / C797S combined mutation and its metastases (especially CNS metastases such as brain metastases).

[0981] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the Del19 / T790M / C797S combined mutation and its metastases (especially CNS metastases such as brain metastases).

[0982] In another embodiment, the compounds of the present invention are used to treat non-small cell lung cancer with the L858R / T790M / C797S combined mutation and its metastases (especially CNS metastases such as brain metastases).

[0983] In another embodiment, the compounds of the present invention are used to treat colorectal cancer and its metastases (especially CNS metastases such as brain metastases), for example, colorectal cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0984] In another embodiment, the compounds of the present invention are used to treat head and neck cancer and its metastases (especially CNS metastases such as brain metastases), for example, head and neck cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0985] In another embodiment, the compounds of the present invention are used to treat breast cancer and its metastases (especially CNS metastases such as brain metastases), for example, HER-2 positive breast cancer, ER+ (estrogen-positive) breast cancer, PR+ (progesterone-positive) breast cancer, or triple-negative breast cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V, or L718Q mutations, or any combination thereof.

[0986] In another embodiment, the compounds of the present invention are used to treat gliomas and their metastases (especially CNS metastases such as brain metastases), for example gliomas having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0987] In another embodiment, the compounds of the present invention are used to treat squamous cell carcinoma and its metastases (especially CNS metastases such as brain metastases), for example squamous cell carcinoma having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0988] In another embodiment, the compounds of the present invention are used to treat prostate cancer and its metastases (especially CNS metastases such as brain metastases), for example, prostate cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0989] In another embodiment, the compounds of the present invention are used to treat gastric cancer and its metastases (especially CNS metastases such as brain metastases), for example, gastric cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0990] In another embodiment, the compounds of the present invention are used to treat esophageal cancer and its metastases (especially CNS metastases such as brain metastases), for example, esophageal cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0991] In another embodiment, the compounds of the present invention are used to treat pancreatic cancer and its metastases (especially CNS metastases such as brain metastases), for example pancreatic cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0992] In another embodiment, the compounds of the present invention are used to treat thyroid cancer and its metastases (especially CNS metastases such as brain metastases), for example, thyroid cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0993] In another embodiment, the compounds of the present invention are used to treat ovarian cancer and its metastases (especially CNS metastases such as brain metastases), for example, ovarian cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0994] In another embodiment, the compounds of the present invention are used to treat uterine cancer and its metastases (especially CNS metastases such as brain metastases), for example, uterine cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0995] In another embodiment, the compounds of the present invention are used to treat cervical cancer and its metastases (especially CNS metastases such as brain metastases), for example, cervical cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0996] In another embodiment, the compounds of the present invention are used to treat liver cancer and its metastases (especially CNS metastases such as brain metastases), for example, liver cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0997] In another embodiment, the compounds of the present invention are used to treat renal cell carcinoma and its metastases (especially CNS metastases such as brain metastases), for example, renal cell carcinoma having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0998] In another embodiment, the compounds of the present invention are used to treat bladder cancer and its metastases (especially CNS metastases such as brain metastases), for example, bladder cancer having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[0999] In another embodiment, the compounds of the present invention are used to treat melanoma and its metastases (especially CNS metastases such as brain metastases), for example melanoma having Del19, L861Q, L858R, T790M, C797S, C797G, C797N, L792F, L792H, L792V or L718Q mutations, or any combination of mutations thereof.

[1000] In another implementation, EGFR-mediated disease is abnormal cell proliferation, including but not limited to solid or blood cancers.

[1001] 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).

[1002] 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.

[1003] In another embodiment, the compounds of the present invention are used to treat inflammation, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritis, neuroinflammatory diseases, allergic reactions, pain, neuropathic pain, fever, lung diseases, pneumonia, adult respiratory distress syndrome, chronic inflammatory lung disease and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal diseases, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, and ulcerative diseases. Gastric ulcers, autoimmune diseases, graft-host reactions and allogeneic graft rejection, cancer, leukemia, lymphoma, brain cancer, bone cancer, epithelial cell carcinoma (epithelial carcinoma), basal cell carcinoma, gastrointestinal cancer, lip cancer, oral cancer, esophageal cancer, small bowel cancer, bladder cancer, cervical cancer, skin cancer, renal cell carcinoma and other known cancers affecting epithelial cells throughout the body, angiogenesis (including tumor formation, metastasis, central nervous system disorders), central nervous system disorders with inflammatory or apoptotic components, peripheral neuropathy, or B-cell lymphoma.

[1004] In another embodiment, the compounds of the present invention are used to treat autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immune-mediated diseases.

[1005] 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.

[1006] combination therapy

[1007] 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 EGFR-mediated diseases, including but not limited to those described herein.

[1008] 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.

[1009] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with another EGFR inhibitor, said other 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.

[1010] In another embodiment, the inventive compound or a pharmaceutically acceptable salt thereof is used in combination with an EGFR antibody. In another specific embodiment, the EGFR antibody is cetuximab. In another specific embodiment, the EGFR antibody is panitumumab. In another specific embodiment, the EGFR antibody is nexituzumab.

[1011] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a c-MET inhibitor. In yet another specific embodiment, the c-MET inhibitor is terpoxtinib, carmatinib, cevotinib, gumetinib, or beritinib.

[1012] 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.

[1013] 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.

[1014] 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.

[1015] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a MEK inhibitor. In yet another specific embodiment, the MEK inhibitor is trametinib, selmetinib, or refatinib.

[1016] 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.

[1017] 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, PI3K inhibitors, SYK inhibitors, AKT inhibitors, mTOR inhibitors, RAS inhibitors or HSP inhibitors, or any combination thereof.

[1018] 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.

[1019] Example

[1020] 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.

[1021] 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.

[1022] The abbreviations used in this invention have the following meanings:

[1023] Synthesis of related intermediate compounds

[1024] Preparation of intermediate A-1 compound 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester hydrochloride

[1025] Synthesized using the following route:

[1026] 2-Chloro-6-methylisonicotinic acid methyl ester (10.0 g, 53.9 mmol) and anisole (200 mL) were added sequentially to a 500 mL single-necked flask equipped with a magnetic stirrer and stirred until dissolved. Then, 1-methyl-5-hydroxypyrazole (10.6 g, 108.1 mmol), sodium carbonate (12.6 g, 118.9 mmol), and Pd(dppf)Cl2 (3.95 g, 5.4 mmol) were added. The mixture was purged with nitrogen three times. After stirring until homogeneous, the mixture was heated to 130 °C in an oil bath and reacted overnight. The reaction was monitored by LCMS until completion. The reaction solution was cooled to room temperature and filtered through a sintered glass funnel. The filter cake was washed with toluene (400 mL), and the filtrates were combined. Methanol (30 mL) was added, and hydrochloric acid / 1,4-dioxane solution (20 mL, 4 M) was added dropwise to the mixture. The mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was washed several times with toluene and petroleum ether. The residue was then dried to obtain 14.0 g of a brownish-yellow solid, with a yield of 91.5%. LCMS (ESI): m / z = 248.3 (M+1) + .

[1027] Preparation of intermediate A-2 compound methyl 2-(5-bromo-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1028] Synthesized using the following route:

[1029] Intermediate A-1 (7.6 g, 26.8 mmol) and acetonitrile (100 mL) were added sequentially to a 250 mL single-necked flask equipped with a magnetic stirrer. After stirring until dissolved, phosphorus oxybromide (61.0 g, 212.8 mmol) was added. The mixture was stirred thoroughly and then refluxed at 85 °C in an oil bath for 60 hours. The reaction was monitored by LC-MS until completion. The reaction solution was cooled to 0 °C, and the reaction was quenched dropwise with saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were concentrated and purified by silica gel column chromatography to obtain 3.4 g of solid, with a yield of 40.9%. LC-MS (ESI): m / z = 310.4 (M+1) + .

[1030] Preparation of intermediate A-3 compound (R)-9-(3-((2-methyl-5-((methylsulfonyl)oxy)pentyl)amino)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[1031] Synthesized using the following route:

[1032] Step 1: Synthesis of compound 9-(3-chloro-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[1033] 2-Chloro-4-fluoronitrobenzene (10.5 g, 60 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (15.3 g, 60 mmol), DIPEA (15.5 g, 120 mmol), and DMF (100 mL) were added to a 500 mL two-necked flask equipped with a magnetic stirrer and a condenser. The mixture was purged with nitrogen three times, and the temperature was raised to 100 °C and reacted overnight. The reaction mixture was cooled to room temperature, and water (200 mL) was slowly added dropwise. A large amount of yellow solid precipitated from the system. The mixture was filtered, and the filter cake was washed with water (100 mL). The filter cake was dried to obtain 20.9 g of yellow solid, with a yield of 81.7%. LC-MS (APCI): 176.0 [M+1] + .

[1034] Synthesis of compound (R)-9-(3-((5-hydroxy-2-methylpentyl)amino)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester in step 2

[1035] (R)-5-amino-4-methylpentane-1-ol hydrochloride (3.1 g, 20 mmol), 9-(3-chloro-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (4.1 g, 10 mmol), DIPEA (3.9 g, 30 mmol), and DMSO (60 mL) were added to a 250 mL two-necked flask equipped with a magnetic stirrer and a condenser. The mixture was purged with nitrogen three times and heated to 120 °C overnight. The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL × 3), washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 3.7 g of a yellow oil, yield 75.5%. LC-MS (APCI): 491.3 [M+1] + .

[1036] Step 3: Synthesis of intermediate A-3

[1037] (R)-9-(3-((5-hydroxy-2-methylpentyl)amino)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (2.7 g, 5.4 mmol), dichloromethane (100 mL), and triethylamine (1.1 g, 10.8 mmol) were added to a 250 mL two-necked flask equipped with a magnetic stirrer. The mixture was purged with nitrogen three times and cooled to 0 °C in an ice-water bath. Methylsulfonyl chloride (928 mg, 8.1 mmol) was slowly added dropwise, and the mixture was heated to room temperature for 1 hour after the addition was complete. The reaction mixture was quenched with water (100 mL), and the mixture was separated. The aqueous phase was extracted with dichloromethane (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 2.9 g of a yellow oily substance, with a yield of 94.4%. LC-MS (APCI): 569.3 [M+1] + .

[1038] Preparation of intermediate A-4 compound 9-(3-((5-(((methanesulfonyl)oxy)pentyl)amino)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[1039] According to the preparation method of intermediate A-3, 5-amino-1-pentanol hydrochloride was used to replace (R)-5-amino-4-methylpentanol-1-ol hydrochloride in step 2 as the raw material to prepare intermediate A-4.

[1040] Preparation of intermediate A-5 compound (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate

[1041] Synthesized using the following route:

[1042] Step 1: Synthesis of compound (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentane-1-ol

[1043] Compound (R)-5-amino-4-methylpentane-1-ol hydrochloride (5.5 g, 35.79 mmol), 2-fluoro-4-bromonitrobenzene (7.87 g, 35.79 mmol), potassium carbonate (9.87 g, 71.58 mmol), and DMF (100 mL) were added to a 250 mL three-necked flask equipped with a magnetic stirrer. The mixture was evacuated and purged with nitrogen three times. The reaction was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated and passed through a silica gel column to give 10 g of a white solid, with a yield of 88.5%. LC-MS (APCI): m / z = 317.0 (M+1) + .

[1044] Synthesis of intermediate A-5 in step 2

[1045] Compound (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentane-1-ol (10 g, 31.64 mmol), triethylamine (4.84 g, 47.46 mmol), and DCM (100 mL) were added to a 250 mL three-necked flask equipped with a magnetic stirrer. The flask was evacuated and purged with nitrogen three times. MsCl (4.35 g, 37.97 mmol) was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.5 hours. The reaction was quenched with water (100 mL), extracted with DCM (100 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 12.4 g of crude product, with a yield of 99.0%. LC-MS (APCI): m / z = 395.0 (M+1) + .

[1046] Preparation of intermediate A-6 compound methyl 4'-hydroxy-6-methyl-[2,3'-bipyridine]-4-carboxylic acid

[1047] Synthesized using the following route:

[1048] Step 1: Synthesis of methyl 4'-methoxy-6-methyl-[2,3'-bipyridine]-4-carboxylic acid.

[1049] To a 250 mL flask equipped with a magnetic stirrer, methyl 2-chloro-6-methylisonicotinate (10.0 g, 54.0 mmol), pinacol 4-methoxypyridine-3-boronic acid (13.0 g, 55.3 mmol), and a 1,4-dioxane / H₂O mixed solution (200 mL / 20 mL) were added sequentially. The mixture was stirred until dissolved. Then, sodium carbonate (11.5 g, 108.5 mmol) and Pd(PPh₃)₄ (3.1 g, 5.4 mmol) were added. The mixture was purged three times under nitrogen protection. The reactor was slowly heated to 100 °C and stirred for 12 hours. Ethyl acetate (200 mL) and a saturated saline solution (100 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and passed through a silica gel column to give 13.2 g of a white solid, with a yield of 72.5%. LC-MS (APCI): m / z = 259.1 (M+1) + .

[1050] Synthesis of intermediate A-6 in step 2

[1051] 13.2 g (51.0 mmol) of 4'-methoxy-6-methyl-[2,3'-bipyridine]-4-carboxylic acid methyl ester and 100 mL / 100 mL acetonitrile / DMF mixture were added sequentially to a 250 mL two-necked flask equipped with a magnetic stirrer. The mixture was evacuated and purged with nitrogen three times. TMSI (8.5 g, 61.1 mmol) was then added. The reaction mixture was slowly heated to 80 °C and stirred for 2 hours. Saturated sodium bicarbonate aqueous solution (60 mL) was added, followed by extraction with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 8.5 g of a yellow solid, yield 68.5%. LC-MS (APCI): m / z = 245.08 (M+1) + .

[1052] Intermediate B-1 compound (20E)-5,25-dimethyl-15-(3,9-diazaspiro[5.5]undecane-3-yl)-4,5,12,19,21,26-hexaazapentacyclo[21.3.1.0] 2,6 .0 12,20 .0 13,18 Preparation of heptadecane-1(26),2(6),3,13(18),14,16,20,23(27),24-nonen-22-one

[1053] Synthesized using the following route:

[1054] Step 1: Synthesis of compound methyl 2-(5-(5-((tert-butoxycarbonyl)amino)pent-1-yn-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid ester

[1055] Intermediate A-2 (1.25 g, 3.9 mmol) and DMF (20 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. After stirring until dissolved, N-tert-butoxycarbonyl-4-pentyne-1-amine (1.28 g, 7.0 mmol), triethylamine (2.1 g, 20.6 mmol), cuprous iodide (148 mg, 0.78 mmol), and Pd(PPh3)2Cl2 (547 mg, 0.78 mmol) were added. The mixture was purged with nitrogen three times, stirred thoroughly, and reacted at room temperature for 48 hours. The reaction was monitored by LCMS until completion. The mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, concentrated, and purified by silica gel column chromatography to obtain 1.5 g of a brownish-yellow solid, with a yield of 93.2%. LCMS (ESI): m / z = 413.4 (M+1) + .

[1056] Step 2: Synthesis of compound methyl 2-(5-(5-((tert-butoxycarbonyl)amino)pentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1057] 1.5 g (3.6 mmol) of methyl 2-(5-(5-((tert-butoxycarbonyl)amino)pent-1-yn-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid and 20 mL of methanol were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved, followed by the addition of wet palladium on carbon (1.0 g). The mixture was purged three times with hydrogen, heated to 70 °C under a hydrogen atmosphere, and stirred overnight. The reaction was monitored by LC-MS to confirm completion. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 1.2 g of solid, with a yield of 80.0%. LC-MS (ESI): m / z = 417.4 (M+1) + .

[1058] Step 3: Synthesis of compound methyl 2-(5-(5-aminopentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1059] 1.2 g (2.9 mmol) of methyl 2-(5-(5-((tert-butoxycarbonyl)amino)pentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid was added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer, and the mixture was stirred until dissolved. Then, 5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS to indicate completion, and the solution was directly concentrated to obtain the trifluoroacetate solid of methyl 2-(5-(5-aminopentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid. LCMS (ESI): m / z = 317.4 (M+1) + .

[1060] Step 4: Synthesis of compound methyl 2-(5-(5-((5-bromo-2-nitrophenyl)amino)pentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid ester

[1061] To a 100 mL single-necked flask equipped with a magnetic stirrer, trifluoroacetate of methyl 2-(5-(5-aminopentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid obtained in step 3, DMF (20 mL), and 2-fluoro-4-bromonitrobenzene (667 mg, 3.0 mmol) were added sequentially. The mixture was stirred until dissolved, followed by the addition of potassium carbonate (1.2 g, 8.7 mmol). The reaction was stirred overnight at room temperature. The reaction was monitored by LC-MS to indicate completion. The reaction solution was diluted with water and extracted three times with ethyl acetate. The combined organic phases were concentrated and purified by silica gel column chromatography to obtain 1.12 g (2.17 mmol) of solid, with a yield of 75.3%. LC-MS (ESI): m / z = 516.4 (M+1) + .

[1062] Step 5: Synthesis of compound methyl 2-(5-(5-((2-amino-5-bromophenyl)amino)pentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1063] 2-(5-(5-(((5-bromo-2-nitrophenyl)amino)pentyl)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinic acid methyl ester (1.12 g, 2.17 mmol) and THF (10 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved, followed by the addition of ethanol (10 mL) and water (5 mL). The mixture was cooled to 0 °C in an ice bath, and then zinc powder (1.42 g, 21.7 mmol) and ammonium chloride (1.16 g, 21.7 mmol) were added. The mixture was stirred in an ice bath for 1 hour. The reaction was monitored for completion by LC-MS. The mixture was filtered, and the filtrate was extracted three times with ethyl acetate. The combined organic phases were concentrated and purified by silica gel column chromatography to obtain 1.0 g of solid, with a yield of 96.8%. LC-MS (ESI): m / z = 486.4 (M+1) + .

[1064] Step 6: Synthesis of compound methyl 2-(5-(5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)pentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1065] 2-(5-(5-(((2-amino-5-bromophenyl)amino)pentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester (1.0 g, 2.1 mmol) and DCM (15 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. After stirring until dissolved, tert-butanol (3 mL) was added, and the mixture was cooled to 0 °C in an ice bath. Cyanogen bromide (3.1 mL, 13.9 mmol, 4.5 M) was added, and the mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS until completion. The mixture was diluted with dichloromethane, quenched with saturated sodium bicarbonate solution, and stirred at room temperature for 10 minutes. After separation, the organic phase was concentrated and purified by silica gel column chromatography to obtain 900 mg of solid, with a yield of 83.8%. LC-MS (ESI): m / z = 511.4 (M+1) + .

[1066] Step 7: Synthesis of compound 2-(5-(5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)pentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1067] 2-(5-(5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)pentyl)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinic acid methyl ester (900 mg, 1.76 mmol) and THF (20 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved, followed by the addition of water (10 mL) and sodium hydroxide (948 mg, 23.7 mmol). The reaction was stirred at room temperature for 1 hour, and the reaction was monitored by LC-MS to indicate completion. The tetrahydrofuran was removed by concentration, and the pH was adjusted to approximately 5 by adding 1 M hydrochloric acid solution. A pale pink solid precipitated out. The precipitate was filtered, washed several times with petroleum ether, and dried to obtain 840 mg of solid, with a yield of 95.9%. LC-MS (ESI): m / z = 497.4 (M+1) + .

[1068] Step 8 Compound (20E)-5,25-dimethyl-15-bromo-4,5,12,19,21,26-hexaazapentacyclo[21.3.1.0] 2,6 .0 12,20 .0 13,18 Synthesis of heptadecane-1(26),2(6),3,13(18),14,16,20,23(27),24-nonen-22-one

[1069] To a 100 mL flask equipped with a magnetic stirrer, 2-(5-(5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)pentyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (840 mg, 1.69 mmol), DCM (10 mL), DMF (2 mL), TBTU (812 mg, 2.5 mmol), and triethylamine (850 mg, 8.3 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion. Saturated sodium bicarbonate solution (5 mL) was added, and the mixture was stirred for 10 minutes. The mixture was then extracted three times with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain 620 mg of solid, with a yield of 76.5%. LCMS (ESI): m / z = 479.4 (M+1) + .

[1070] Step 9 Compound 9-((20E)-5,25-dimethyl-22-oxo-4,5,12,19,21,26-hexaazapentacyclo[21.3.1.0] 2,6 .0 12,20 .0 13,18 Synthesis of tert-butyl undecane-3-carboxylic acid ester (26),2(6),3,13(18),14,16,20,23(27),24-nonen-15-yl)-3,9-diazaspiro[5.5]

[1071] (20E)-5,25-dimethyl-15-bromo-4,5,12,19,21,26-hexaazapentacyclo[21.3.1.0] was added sequentially to a 20 mL microwave tube equipped with a magnetic stirrer. 2,6 .0 12,20 .0 13,18 Heptadecane-1 (26),2 (6),3,13 (18),14,16,20,23 (27),24-nonen-22-one (620 mg, 1.29 mmol) and DMA (10 mL) were stirred until dissolved. Then, tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (660 mg, 2.6 mmol), sodium tert-butoxide (250 mg, 2.6 mmol), RuPhos (122 mg, 0.26 mmol), and Pd2(dba)3 (120 mg, 0.13 mmol) were added. The mixture was purged with nitrogen three times and reacted in a microwave oven at 140 °C for 1.5 hours. The reaction was monitored by LCMS until completion. The mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined. After concentration, the mixture was purified by silica gel column chromatography to obtain 520 mg of a brownish-yellow solid, with a yield of 61.8%. LCMS (ESI): m / z = 653.8 (M+1) + .

[1072] Step 10 Synthesis of intermediate B-1

[1073] Add 9-((20E)-5,25-dimethyl-22-oxo-4,5,12,19,21,26-hexaazapentacyclo[21.3.1.0] to a 100 mL flask equipped with a magnetic stirrer. 2,6 .0 12,20 .0 13,18 [520 mg, 0.79 mmol] tert-butyl 3-undecane-3-carboxylate (5,4-heptadecane-1(26),2(6),3,13(18),14,16,20,23(27),24-nonen-15-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate and dichloromethane (20 mL) were stirred until dissolved. Then trifluoroacetic acid (5 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion. 500 mg of trifluoroacetate solid of intermediate B-1 was directly concentrated, with a yield of 94.9%. LCMS (ESI): m / z = 553.7 (M+1) + .

[1074] Intermediate B-2 compound (21E)-5,26-dimethyl-16-(3,9-diazaspiro[5.5]undecane-3-yl)-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] 2,6 .0 13,21 .0 14,19 Preparation of octadecano-1(27),2(6),3,14,16,18,21,24(28),25-nonen-23-one

[1075] Synthesized using the following route:

[1076] Step 1: Synthesis of compound methyl 2-(5-(6-((tert-butoxycarbonyl)amino)hex-1-yn-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid ester

[1077] To a 100 mL three-necked flask equipped with a magnetic stirrer, intermediate A-2 (3.0 g, 9.7 mmol), tert-butyl hexano-5-yn-1-ylcarbamate (3.5 g, 17.5 mmol), Pd(PPh3)Cl2 (350.9 mg, 0.5 mmol), cuprous iodide (190.5 mg, 1.0 mmol), Et3N (4.9 g, 48.5 mmol), and DMF (30 mL) were added sequentially. The mixture was evacuated and purged with nitrogen three times, and stirred overnight at room temperature. The reaction was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 3.0 g of a white solid, yield 72.6%. LC-MS (APCI): m / z = 427.0 (M+1) + .

[1078] Step 2: Synthesis of compound methyl 2-(5-(6-((tert-butoxycarbonyl)amino)hexyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1079] To a 100 mL single-necked flask equipped with a magnetic stirrer, methyl 2-(5-(6-((tert-butoxycarbonyl)amino)hex-1-yn-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (3.0 g, 7.0 mmol), CoSO4-7H2O (2.0 g, 7.0 mmol), methanol (30 mL), and H2O (3 mL) were added sequentially. The mixture was stirred until dissolved, cooled to -10 °C, and NaBH4 (1.1 g, 28.0 mmol) was added. The mixture was slowly heated to room temperature and stirred for 1 hour. The solution was concentrated under reduced pressure, and the mixture was extracted with water (30 mL), followed by extraction with dichloromethane (30 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 1.1 g of a white solid (yield 36.5%). LC-MS (APCI): m / z = 431.0 (M+1) + .

[1080] Step 3: Synthesis of methyl 2-(5-(6-aminohexyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid. Methyl 2-(5-(6-((tert-butoxycarbonyl)amino)hexyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (1.1 g, 2.6 mmol) and HCl / EA (15 mL) were added sequentially to a 50 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain a colorless oily liquid, which was used directly in the next step without further purification. LC-MS (APCI): m / z = 331.0 (M+1) + .

[1081] Step 4: Synthesis of compound methyl 2-(5-(6-((5-bromo-2-nitrophenyl)amino)hexyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1082] 2-(5-(6-aminohexyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester (1.1 g, 2.6 mmol), 2-fluoro-4-bromonitrobenzene (569.2 mg, 2.6 mmol), K₂CO₃ (1.1 g, 7.8 mmol), and DMF (15 mL) were added sequentially to a 50 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred overnight in an oil bath at 60 °C. After cooling to room temperature, the mixture was filtered, washed with ethyl acetate, concentrated, and passed through a silica gel column to give 1.1 g of a yellow solid. The yields of steps 3 and 4 were 80.0%. LC-MS (APCI): m / z = 530.0 (M+1) + .

[1083] Step 5: Synthesis of compound methyl 2-(5-(6-((2-amino-5-bromophenyl)amino)hexyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1084] To a 50 mL single-necked flask equipped with a magnetic stirrer, methyl 2-(5-(6-((5-bromo-2-nitrophenyl)amino)hexyl)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinic acid (1.1 g, 2.1 mmol), zinc powder (1.4 g, 21.0 mmol), EtOH (10 mL), THF (10 mL), and H₂O (5 mL) were added sequentially. The mixture was cooled to 0 °C, and ammonium chloride (1.1 g, 21.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was extracted with dichloromethane (10 mL × 3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a colorless oily liquid. This oil was used directly in the next step without further purification. LC-MS (APCI): m / z = 500.0 (M+1) + .

[1085] Step 6: Synthesis of compound methyl 2-(5-(6-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinic acid

[1086] To a 50 mL single-necked flask equipped with a magnetic stirrer, methyl 2-(5-(6-((2-amino-5-bromophenyl)amino)hexyl)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinic acid (1.0 g, 2.1 mmol) and acetic acid (10 mL) were added sequentially. The mixture was stirred until dissolved, cooled to 0 °C, and cyanogen bromide (1.1 mL, 4.8 mmol, 4.5 M) was added. The mixture was slowly heated to room temperature and stirred for 1 hour. The solution was concentrated under reduced pressure, and extracted with saturated aqueous sodium bicarbonate solution (15 mL) in an ice bath. The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 700.0 mg of a pale purple solid. The two-step yield was 63.6%. LC-MS (APCI): m / z = 525.0 (M+1) + .

[1087] Step 7: Synthesis of compound 2-(5-(6-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[1088] Methyl 2-(5-(6-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (700.0 mg, 1.3 mmol), lithium hydroxide monohydrate (545.5 mg, 13.0 mmol), THF (10 mL), and H₂O (10 mL) were added sequentially to a 50 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred at room temperature for 1 hour. THF was removed by rotary evaporation under reduced pressure. Citric acid (840.6 mg) was added to the aqueous phase, and the mixture was stirred at room temperature for 10 minutes. A precipitate formed in the reaction solution. The precipitate was filtered, washed with water, and dried to give 610.0 mg of a pale yellow solid, with a yield of 92.0%. LC-MS (APCI): m / z = 511.0 (M+1) + .

[1089] Step 8 Compound (21E)-5,26-dimethyl-16-bromo-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] 2,6 .0 13,21 .0 14,19 Synthesis of octadecano-1(27),2(6),3,14,16,18,21,24(28),25-nonen-23-one

[1090] 2-(5-(6-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinic acid (610.0 mg, 1.2 mmol), DIPEA (310.2 mg, 2.4 mmol), and DCM (10 mL) were added sequentially to a 50 mL three-necked flask equipped with a magnetic stirrer. The mixture was stirred at 0 °C for 10 min, then TBTU (578.0 mg, 1.8 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 550.0 mg of a pale yellow solid, yield 93.1%. LC-MS (APCI): m / z = 493.0 (M+1) + .

[1091] Step 9 Compound 9-((21E)-5,26-dimethyl-23-oxo-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] 2,6 .0 13,21 .0 14,19 Synthesis of tert-butyl undecane-3-carboxylic acid ester (28-25-nonen-16-yl)-3,9-diazaspiro[5.5]

[1092] Add (21E)-5,26-dimethyl-16-bromo-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] sequentially to a 50 mL three-necked flask equipped with a magnetic stirrer. 2,6 .0 13,21 .0 14,19 [Octadecano-1(27),2(6),3,14,16,18,21,24(28),25-nonen-23-one (500.0 mg, 1.0 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (508.4 mg, 2.0 mmol), t-BuONa (192.2 mg, 2.0 mmol), RuPhos (186.7 mg, 0.4 mmol), Pd2(dba)3 (183.1 mg, 0.2 mmol) and DMA (10 mL) were added to the reaction mixture under vacuum, purged with nitrogen three times, and stirred overnight at 100 °C. After cooling to room temperature, H2O (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain a pale yellow solid of 475.0 mg, yield 71.3%.] LC-MS (APCI): m / z = 667.0 (M+1) + .

[1093] Step 10 Synthesis of intermediate B-2

[1094] Add 9-((21E)-5,26-dimethyl-23-oxo-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] to a 50 mL single-necked flask equipped with a magnetic stirrer. 2,6 .0 13,21 .0 14,19 [475.0 mg, 0.7 mmol] tert-butyl 3-undecane-3-carboxylic acid (475.0 mg, 0.7 mmol) and HCl / EA (10 mL) were stirred and reacted for 1 hour. The solvent was removed by rotary evaporation under reduced pressure, and the concentrate was extracted with saturated sodium bicarbonate aqueous solution (10 mL) by DCM (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give 339.6 mg of yellow solid, yield 85.7%. LC-MS (APCI): m / z = 567.0 (M+1) + .

[1095] Intermediate B-3 compound (22E)-27-methyl-17-(3,9-diazaspiro[5.5]undecane-3-yl)-4,14,21,23,28-pentazapentane[23.3.1.0] 2,7 .0 14,22 .0 15,20 Preparation of 29-carbon-1(28),2(7),3,5,15,17,19,22,25(29),26-decen-24-one

[1096] Synthesized using the following route:

[1097] Step 1: Synthesis of methyl 4'-chloro-6-methyl-[2,3'-bipyridine]-4-carboxylic acid.

[1098] To a 250 mL three-necked flask equipped with a magnetic stirrer, methyl 2-chloro-6-methylisonicotinate (5.0 g, 27.0 mmol), pinacol 4-chloropyridin-3-boronic acid (7.7 g, 32.4 mmol), Pd(dppf)₂Cl₂ (1.2 g, 1.6 mmol), K₂CO₃ (7.5 g, 54.0 mmol), 1,4-dioxane (60 mL), and H₂O (15 mL) were added sequentially. The mixture was evacuated to a vacuum, purged three times with nitrogen, and stirred overnight at 90 °C. After cooling to room temperature, H₂O (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (60 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 4.8 g of a white solid, yield 67.8%. LC-MS (APCI): m / z = 263.0 (M+1) + .

[1099] Step 2: Synthesis of methyl 4'-(6-((tert-butoxycarbonyl)amino)hex-1-yn-1-yl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid

[1100] To a 100 mL three-necked flask equipped with a magnetic stirrer, methyl 4'-chloro-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (4.8 g, 18.3 mmol), tert-butyl hex-5-yn-1-ylcarbamate (3.5 g, 17.5 mmol), Pd(PPh3)4 (2.1 g, 1.8 mmol), cuprous iodide (685.6 mg, 3.6 mmol), Et3N (7.4 g, 73.2 mmol), and DMF (50 mL) were added sequentially. The mixture was evacuated and purged with nitrogen three times, and reacted overnight in an oil bath at 120 °C. After cooling to room temperature, the reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 5.3 g of a white solid, yield 68.4%. LC-MS (APCI): m / z = 424.0 (M+1) + .

[1101] Step 3: Synthesis of methyl 4'-(6-((tert-butoxycarbonyl)amino)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid

[1102] To a 100 mL single-necked flask equipped with a magnetic stirrer, methyl 4'-(6-((tert-butoxycarbonyl)amino)hex-1-yn-1-yl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (5.3 g, 12.5 mmol), CoSO4-7H2O (3.5 g, 12.5 mmol), methanol (50 mL), and H2O (5 mL) were added sequentially. The mixture was stirred until dissolved, cooled to -10 °C, and NaBH4 (1.9 g, 50.0 mmol) was added. The mixture was slowly heated to room temperature and stirred for 1 hour. The solution was concentrated under reduced pressure, and the mixture was extracted with water (50 mL), followed by extraction with dichloromethane (50 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 1.6 g of a yellow solid (yield 30.0%). LC-MS (APCI): m / z = 428.0 (M+1) + .

[1103] Step 4: Synthesis of methyl 4'-(6-aminohexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid.

[1104] To a 50 mL single-necked flask equipped with a magnetic stirrer, methyl 4'-(6-((tert-butoxycarbonyl)amino)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (1.6 g, 3.7 mmol) and HCl / EA (20 mL) were added sequentially, and the mixture was stirred for 1 hour. The solvent was removed by rotary evaporation under reduced pressure; no purification was required, and the mixture was used directly in the next step. LC-MS (APCI): m / z = 328.0 (M+1) + .

[1105] Step 5: Synthesis of methyl 4'-(6-((5-bromo-2-nitrophenyl)amino)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid.

[1106] To a 50 mL single-necked flask equipped with a magnetic stirrer, methyl 4'-(6-aminohexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (1.4 g, 3.7 mmol), 2-fluoro-4-bromonitrobenzene (810.0 mg, 3.7 mmol), K₂CO₃ (1.5 g, 11.1 mmol), and DMF (20 mL) were added sequentially. The mixture was stirred overnight in an oil bath at 50 °C. After cooling to room temperature, the mixture was filtered, washed with ethyl acetate, concentrated, and purified by silica gel column chromatography to give 950.0 mg of a yellow solid. The two-step yield was 48.8%. LC-MS (APCI): m / z = 527.0 (M+1) + .

[1107] Step 6: Synthesis of methyl 4'-(6-((2-amino-5-bromophenyl)amino)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid.

[1108] To a 50 mL single-necked flask equipped with a magnetic stirrer, methyl 4'-(6-((5-bromo-2-nitrophenyl)amino)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (950.0 mg, 1.8 mmol), zinc powder (1.2 g, 18.0 mmol), EtOH (10 mL), THF (10 mL), and H₂O (5 mL) were added sequentially. The mixture was cooled to 0 °C, and ammonium chloride (1.0 g, 18.0 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was extracted with dichloromethane (50 mL × 3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a colorless oily liquid. No purification was required, and the liquid was used directly in the next step. LC-MS (APCI): m / z = 497.0 (M+1) + .

[1109] Step 7: Synthesis of methyl 4'-(6-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid.

[1110] To a 50 mL single-necked flask equipped with a magnetic stirrer, methyl 4'-(6-((2-amino-5-bromophenyl)amino)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (1.0 g, 1.8 mmol) and acetic acid (10 mL) were added sequentially. The mixture was stirred until dissolved, cooled to 0 °C, and cyanogen bromide (0.8 mL, 3.6 mmol, 4.5 M) was added. The mixture was slowly heated to room temperature and stirred for 1 hour. The solution was concentrated under reduced pressure, and extracted with saturated aqueous sodium bicarbonate solution (15 mL) in an ice bath. The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 310.0 mg of a yellow solid. The two-step yield was 33.3%. LC-MS (APCI): m / z = 522.0 (M+1) + .

[1111] Step 8: Synthesis of compound 4'-(6-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid

[1112] To a 50 mL single-necked flask equipped with a magnetic stirrer, methyl 4'-(6-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (310.0 mg, 0.6 mmol), lithium hydroxide monohydrate (251.8 mg, 6.0 mmol), THF (5 mL), and H₂O (5 mL) were added sequentially. The mixture was stirred at room temperature for 1 hour. THF was removed by rotary evaporation under reduced pressure. Citric acid (840.6 mg) was added to the aqueous phase, and the mixture was stirred at room temperature for 10 minutes. Extraction was performed with dichloromethane (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give 147.1 mg of a pale yellow solid, yield 48.3%. LC-MS (APCI): m / z = 508.0 (M+1) + .

[1113] Step 9: Compound (22E)-27-methyl-17-bromo-4,14,21,23,28-pentazapentacyclo[23.3.1.0] 2,7 .0 14,22 .0 15,20 Synthesis of 29-carbon-1(28),2(7),3,5,15,17,19,22,25(29),26-decen-24-one

[1114] To a 50 mL three-necked flask equipped with a magnetic stirrer, 4'-(6-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (147.1 mg, 0.3 mmol), DIPEA (77.5 mg, 0.6 mmol), and DCM (5 mL) were added sequentially. The mixture was stirred at 0 °C for 10 min, then TBTU (160.5 mg, 0.5 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. H₂O (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 130.6 mg of a pale yellow solid, yield 89.0%. LC-MS (APCI): m / z = 490.0 (M+1) + .

[1115] Step 10 Compound 9-((22E)-27-methyl-24-oxo-4,14,21,23,28-pentazapentacyclo[23.3.1.0] 2,7 .0 14,22 .0 15,20 Synthesis of tert-butyl undecen-3-carboxylic acid ester (26-decen-1(28),2(7),3,5,15,17,19,22,25(29),26-decen-17-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid)

[1116] (22E)-27-methyl-17-bromo-4,14,21,23,28-pentaazapentacyclo[23.3.1.0] was added sequentially to a 50 mL three-necked flask equipped with a magnetic stirrer. 2,7 .0 14,22 .0 15,20 [28),2(7),3,5,15,17,19,22,25(29),26-decen-24-one (80.6 mg, 0.2 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (101.7 mg, 0.4 mmol), t-BuONa (38.4 mg, 0.4 mmol), RuPhos (18.7 mg, 0.04 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol) and DMA (5 mL) were added to the reaction mixture under vacuum, purged three times with nitrogen, and stirred overnight at 100 °C. After cooling to room temperature, H2O (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 73.0 mg of a pale yellow solid, yield 55.0%.] LC-MS (APCI): m / z = 664.0 (M+1) + .

[1117] Synthesis of intermediate B-3 in step 11

[1118] 9-((22E)-27-methyl-24-oxo-4,14,21,23,28-pentazapentacyclo[23.3.1.0]) was added sequentially to a 50 mL single-necked flask equipped with a magnetic stirrer. 2,7 .0 14,22 .0 15,20 [73.0 mg, 0.1 mmol] tert-butyl 3-undecen-1(28),2(7),3,5,15,17,19,22,25(29),26-decen-17-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid was reacted with HCl / EA (5 mL) for 1 hour. The solvent was removed by rotary evaporation under reduced pressure. The concentrate was extracted with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (5 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated to give 50 mg of yellow solid, yield 88.7%. LC-MS (APCI): m / z = 564.0 (M+1) + .

[1119] Intermediate B-4 compound (11R,21E)-5,11,26-trimethyl-16-bromo-7-oxa-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] 2,6 .0 13,21 .0 14,19Preparation of octadecano-1(27),2(6),3,14,16,18,21,24(28),25-nonen-23-one

[1120] Synthesized using the following route:

[1121] Step 1: Synthesis of compound (R)-2-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-5-methylisonicotinic acid methyl ester

[1122] Compound intermediates A-5 (12.4 g, 31.47 mmol), A-1 (7.77 g, 31.47 mmol), potassium carbonate (8.68 g, 62.94 mmol), and DMF (120 mL) were added to a 250 mL three-necked flask equipped with a magnetic stirrer. The mixture was evacuated and purged with nitrogen three times. The mixture was stirred overnight at 60 °C under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water (100 mL). The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 11.0 g of a white solid, yield 64.1%. LC-MS (APCI): m / z = 546.0 (M+1) + .

[1123] Step 2: Synthesis of compound (R)-2-(5-((5-(((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-5-methylisonicotinic acid methyl ester

[1124] Compound (R)-2-(5-((5-(((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-5-methylisonicotinic acid methyl ester (11.0 g, 20.18 mmol), ethanol (110 mL), THF (110 mL), and water (55 mL) were added to a 500 mL three-necked flask equipped with a magnetic stirrer. Zinc powder (13.12 g, 201.8 mmol) and ammonium chloride (10.90 g, 201.8 mmol) were added under an ice-water bath. The mixture was evacuated and purged with nitrogen three times. The mixture was stirred at 0 °C under a nitrogen atmosphere for 1.5 h. After concentration, the reaction was quenched with water (100 mL). The mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 10.0 g of crude product, with a yield of 96.2%. LC-MS (APCI): m / z = 516.0 (M+1) + .

[1125] Step 3: Synthesis of compound (R)-2-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazole-4-yl)-5-methylisonicotinic acid methyl ester

[1126] Compound (R)-2-(5-((5-(((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-5-methylisonicotinic acid methyl ester (10.0 g, 19.42 mmol) and glacial acetic acid (40 mL) were added to a 100 mL three-necked flask equipped with a magnetic stirrer. A solution of cyanogen bromide in acetonitrile (8.6 mL, 38.84 mmol, 4.5 M) was added under an ice-water bath. The mixture was evacuated and purged with nitrogen three times. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was quenched with water (50 mL), and the solution was adjusted to alkali with sodium bicarbonate solution. The mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 9.5 g of a white solid, yield 90.6%. LC-MS (APCI): m / z = 541.0 (M+1) + .

[1127] Step 4: Synthesis of compound (R)-2-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-5-methylisonicotinic acid

[1128] Compound (R)-2-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazole-4-yl)-5-methylisonicotinic acid methyl ester (9.5 g, 17.59 mmol), THF (50 mL), and water (50 mL) were added to a 250 mL single-necked flask equipped with a magnetic stirrer. Lithium hydroxide (7.39 g, 175.9 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After concentrating the THF, citric acid (11.3 g, 58.6 mmol) was added to adjust the pH. A large amount of solid precipitated out. The solid was filtered, washed with water, and dried to give 8.5 g of white solid, with a yield of 91.9%. LC-MS (APCI): m / z = 527.0 (M+1) + .

[1129] Synthesis of intermediate B-4 in step 5

[1130] Compound (R)-2-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazole-4-yl)-5-methylisonicotinic acid (8.5 g, 16.16 mmol), triethylamine (2.5 g, 24.24 mmol), and DCM (170 mL) were added to a 250 mL single-necked flask equipped with a magnetic stirrer. TBTU (6.23 g, 19.39 mmol) was added under an ice-water bath. The mixture was evacuated and purged with nitrogen three times. The mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 h. The reaction was quenched with water (100 mL), extracted with DCM (100 mL × 2), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 6.2 g of a white solid, yield 75.5%. LC-MS (APCI): m / z = 509.0 (M+1) + .

[1131] Intermediate B-5 compound (11R,21E)-5,11,26-trimethyl-23-oxo-7-oxa-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] 2,6 .0 13,21 .0 14,19 Preparation of octadecano-1(27),2(6),3,14,16,18,21,24(28),25-nonene-16-carboxaldehyde

[1132] Synthesized using the following route:

[1133] Intermediate B-4 (1.0 g, 1.97 mmol), N-formylsaccharin (1.7 g, 7.88 mmol), palladium acetate (132.7 mg, 0.59 mmol), DPPB (251.6 mg, 0.59 mmol), sodium carbonate (626.5 mg, 5.91 mmol), TESiH (801.7 mg, 6.9 mmol), and DMF (20 mL) were added to a 100 mL single-necked flask equipped with a magnetic stirrer. The mixture was evacuated and purged with nitrogen three times. The mixture was stirred at 80 °C for 12 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water (50 mL). The mixture was extracted with EA (50 mL × 2), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 586.0 mg of white solid, yield 65.0%. LC-MS (APCI): m / z = 459.0 (M+1) + .

[1134] Intermediate B-6 compound (11R,21E)-5,11,26-trimethyl-16-(3,9-diazaspiro[5.5]undecane-3-yl)-7-oxa-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] 2,6 .0 13,21 .0 14,19 Preparation of octadecano-1(27),2(6),3,14,16,18,21,24(28),25-nonen-23-one

[1135] Synthesized using the following route:

[1136] Step 1: Synthesis of compound (R)-9-(3-((5-((4-(4-(4-(methoxycarbonyl)-5-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2-methylpentyl)amino)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[1137] To a 250 mL two-necked flask equipped with a magnetic stirrer and condenser, intermediates A-3 (2.0 g, 3.5 mmol), potassium carbonate (1.2 g, 8.8 mmol), intermediate A-1 (1.2 g, 4.2 mmol), and DMF (50 mL) were added sequentially. The mixture was purged with nitrogen three times, and the temperature was raised to 60 °C and reacted overnight. The reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (50 mL × 3), washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 1.9 g of a yellow oily substance, yield 75.5%. LC-MS (APCI): 720.4 [M+1] + .

[1138] Synthesis of compound (R)-9-(4-amino-3-((5-((4-(4-(4-((methoxycarbonyl)-5-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2-methylpentyl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[1139] To a 250 mL single-necked flask equipped with a magnetic stirrer, (R)-9-(3-((5-(((4-(4-((methoxycarbonyl)-5-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2-methylpentyl)amino)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.9 g, 2.6 mmol), palladium on carbon (1 g, 10%), and methanol (100 mL) were added sequentially. The mixture was purged with hydrogen three times and reacted at room temperature for 2 hours. The reaction solution was filtered, and the filter cake was washed with dichloromethane (100 mL) and concentrated to give 1.7 g of a yellow oil, yield 94.9%. LC-MS (APCI): 690.4 [M+1] + .

[1140] Synthesis of compound (R)-9-(2-amino-1-(5-((4-(4-((methoxycarbonyl)-5-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2-methylpentyl)-1H-benzo[d]imidazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester in step 3

[1141] To a 100 mL two-necked flask equipped with a magnetic stirrer, add (R)-9-(4-amino-3-((5-((4-(4-(4-(methoxycarbonyl)-5-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2-methylpentyl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.7 g, 2.5 mmol) and glacial acetic acid (30 mL). Purge with nitrogen three times and cool to 0 °C in an ice-water bath. Slowly add cyanogen bromide solution (1.1 mL, 5 mmol, 4.5 M). After the addition is complete, heat to room temperature and react for 1 hour. The reaction solution was concentrated, most of the glacial acetic acid was evaporated, and saturated sodium bicarbonate solution (50 mL) was added and stirred for 5 minutes. The mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 0.9 g of a brown oily substance, with a yield of 50.3%. LC-MS (APCI): 715.4 [M+1] + .

[1142] Synthesis of compound (R)-2-(5-((5-(2-amino-6-(9-(tert-butoxycarbonyl)-3,9-diazaspiro[5.5]undecane-3-yl)-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-5-methylisonicotinic acid in step 4

[1143] To a 100 mL single-necked flask equipped with a magnetic stirrer, (R)-9-(2-amino-1-(5-((4-(4-((methoxycarbonyl)-5-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2-methylpentyl)-1H-benzo[d]imidazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (0.9 g, 1.3 mmol), lithium hydroxide monohydrate (164 mg, 3.9 mmol), tetrahydrofuran (20 mL), and water (20 mL) were added sequentially, and the reaction was carried out at room temperature for 1 hour. Citric acid (250 mg, 1.3 mmol) was added, and the mixture was stirred for 5 minutes. The mixture was extracted with dichloromethane (30 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 0.8 g of a brown oily substance, with a yield of 87.9%. LC-MS (APCI): 701.4 [M+1] + .

[1144] Step 5 Compound 9-((11R,21E)-5,11,26-trimethyl-23-oxo-7-oxa-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] 2,6 .0 13,21 .0 14,19 Synthesis of tert-butyl undecane-3-carboxylic acid ester (28-25-nonen-16-yl)-3,9-diazaspiro[5.5]

[1145] (R)-2-(5-((5-(2-amino-6-(9-(tert-butoxycarbonyl)-3,9-diazaspiro[5.5]undecane-3-yl)-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-5-methylisonicotinic acid (700 mg, 1 mmol), triethylamine (151.5 mg, 1.5 mmol), TBTU (417.3 mg, 1.3 mmol), and dichloromethane (20 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. The mixture was purged with nitrogen three times and reacted at room temperature for 1 hour. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 383.1 mg of a brown solid, yield 56.1%. LC-MS (APCI): 683.4 [M+1] + .

[1146] Synthesis of intermediate B-6 in step 6

[1147] Add 9-((11R,21E)-5,11,26-trimethyl-23-oxo-7-oxa-4,5,13,20,22,27-hexaazapentacyclo[22.3.1.0] to a 100 mL single-necked flask equipped with a magnetic stirrer. 2,6 .0 13,21 .0 14,19 [340 mg, 0.5 mmol] tert-butyl 3-undecane-3-carboxylic acid (35.5) was dissolved in dichloromethane (5 mL) by stirring at room temperature. Hydrochloric acid / 1,4-dioxane solution (5 mL, 4 M) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added and stirred for 5 minutes. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 280 mg of brown solid (96.2% yield). LC-MS (APCI): 583.3 [M+1] + .

[1148] Intermediate B-7 compound (12R,22E)-12,27-dimethyl-17-(3,9-diazaspiro[5.5]undecane-3-yl)-8-oxa-4,14,21,23,28-pentazapentane[23.3.1.0] 2,7 .0 14,22 .0 15,20 Preparation of 29-carbon-1(28),2(7),3,5,15,17,19,22,25(29),26-decen-24-one

[1149] Synthesized using the following route:

[1150] Step 1: Synthesis of compound (R)-9-(3-((5-((4-(methoxycarbonyl)-6-methyl-[2,3'-bipyridin]-4'-yl)oxy)-2-methylpentyl)amino)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[1151] Intermediate A-6 (8.5 g, 34.6 mmol), intermediate A-3 (25.7 g, 45.2 mmol), cesium carbonate (22.7 g, 69.2 mmol), and DMF (100 mL) were added sequentially to a 250 mL flask equipped with a magnetic stirrer. The mixture was stirred until dissolved, evacuated under vacuum and purged with nitrogen three times, and the mixture was heated to 25 °C and stirred for 12 hours. The mixture was then extracted with saturated brine (100 mL) and ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was passed through a silica gel column chromatography column to give 10.3 g of a white solid, yield 41.2%. LC-MS (APCI): m / z = 717.4 (M+1) + .

[1152] Synthesis of compound (R)-9-(4-amino-3-((5-((4-(methoxycarbonyl)-6-methyl-[2,3'-bipyridin]-4'-yl)oxy)-2-methylpentyl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester in step 2

[1153] Add (R)-9-(3-((5-((4-(methoxycarbonyl)-6-methyl-[2,3'-bipyridin]-4'-yl)oxy)-2-methylpentyl)amino)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (10.3 g, 14.3 mmol) and EtOH / H2O mixed solution (100 mL / 20 mL) to a 100 mL flask equipped with a magnetic stirrer, and stir until dissolved. Ammonium chloride (0.7 g, 12.5 mmol) and zinc powder (3.0 g, 46.1 mmol) were added. The mixture was evacuated under vacuum and purged with nitrogen three times. The mixture was then cooled to 0°C and stirred for 2 hours. The filtrate was filtered and extracted with saturated brine (40 mL) and ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was passed through a silica gel column to give 7.5 g of a white solid, yield 76.5%. LC-MS (APCI): m / z = 687.4 (M+1) + .

[1154] Synthesis of compound (R)-9-(2-amino-1-(5-((4-(methoxycarbonyl)-6-methyl-[2,3'-bipyridin]-4'-yl)oxy)-2-methylpentyl)-1H-benzi[d]imidazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester in step 3

[1155] (R)-9-(4-amino-3-((5-((4-(methoxycarbonyl)-6-methyl-[2,3'-bipyridin]-4'-yl)oxy)-2-methylpentyl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (7.5 g, 10.9 mmol), acetic acid (100 mL), and cyanogen bromide (6.1 mL, 4.5 M) were added sequentially to a 200 mL flask equipped with a magnetic stirrer. The mixture was stirred at 0 °C for 12 hours under nitrogen protection. The solution was concentrated under vacuum and passed through a reverse-phase column to give 4.5 g of a purple solid, yield 58.4%. LC-MS (APCI): m / z = 712.4 (M+1) + .

[1156] Synthesis of compound (R)-4'-((5-(2-amino-6-(9-(tert-butoxycarbonyl)-3,9-diazaspiro[5.5]undecane-3-yl)-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid in step 4

[1157] To a 100 mL single-necked flask equipped with a magnetic stirrer, add (R)-9-(2-amino-1-(5-((4-(methoxycarbonyl)-6-methyl-[2,3'-bipyridin]-4'-yl)oxy)-2-methylpentyl)-1H-benzo[d]imidazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (4.5 g, 6.3 mmol) and lithium hydroxide monohydrate (2.1 g, 50 mmol) sequentially. 0 mmol), then add a THF / H2O mixed solution (50 mL / 5 mL), stir at 25 °C for 2 hours, then add citric acid (3.1 g, 16.5 mmol) and stir for 1 hour. Add saturated brine (20 mL), extract with ethyl acetate (100 mL × 2), combine the organic phases, wash with saturated brine (50 mL), dry to anhydrous sodium sulfate, filter and concentrate to give 3.5 g of gray solid, yield 79.5%. LC-MS (APCI): m / z = 698.4 (M+1) + .

[1158] Step 5 Compound 9-((12R,22E)-12,27-dimethyl-24-oxo-8-oxa-4,14,21,23,28-pentazapentacyclo[23.3.1.0] 2,7 .0 14,22 .0 15,20 Synthesis of tert-butyl undecen-3-carboxylic acid ester (26-decen-1(28),2(7),3,5,15,17,19,22,25(29),26-decen-17-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid)

[1159] (R)-4'-((5-(2-amino-6-(9-(tert-butoxycarbonyl)-3,9-diazaspiro[5.5]undecane-3-yl)-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (3.5 g, 5.0 mmol), DCM (40 mL), TBTU (3.2 g, 10.0 mmol), and DIPEA (1.0 g, 7.7 mmol) were added sequentially to a 100 mL flask equipped with a magnetic stirrer. The mixture was evacuated and purged with nitrogen three times, and stirred at room temperature for 12 hours. Water (30 mL) was added, the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 2.2 g of a purple solid, yield 64.7%. LC-MS (APCI): m / z = 680.4 (M+1) + .

[1160] Synthesis of intermediate B-7 in step 6

[1161] Add 9-((12R,22E)-12,27-dimethyl-24-oxo-8-oxa-4,14,21,23,28-pentazapentacyclo[23.3.1.0] to a 100 mL single-necked flask equipped with a magnetic stirrer. 2,7 .0 14,22 .0 15,25 [2.2 g, 3.2 mmol] tert-butyl 3-carboxylic acid (2.2 g, 3.2 mmol), 1,4-dioxane (20 mL), and hydrochloric acid / 1,4-dioxane (20 mL, 4.0 M) were reacted for 2 hours. The solvent was removed under reduced pressure to give 1.8 g of black solid, yield 96.2%. LC-MS (APCI): m / z = 580.3 (M+1) + .

[1162] Intermediate B-8 compound (12R,22E)-12,27-dimethyl-17-(9-(azacyclobutane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-8-oxa-4,14,21,23,28-pentazapentacyclo[23.3.1.0] 2,7 .0 14,22 .0 15,20 Preparation of 29-carbon-1(28),2(7),3,5,15,17,19,22,25(29),26-decen-24-one

[1163] Synthesized using the following route:

[1164] Step 1 Compound 3-(9-((12R,22E)-12,27-dimethyl-24-oxo-8-oxa-4,14,21,23,28-pentazapentane[23.3.1.0] 2,7 .0 14,22 .0 15,20 Synthesis of tert-butyl 2,9-diazaspiro[5.5]undecane-3-yl]azacyclobutane-1-carboxylic acid

[1165] Intermediate B-7 (0.5 g, 0.8 mmol), DMF (10 mL), acetic acid (1 mL), NaBH(OAc)3 (0.36 g, 1.7 mmol), and 1-tert-butoxycarbonyl-3-azacyclobutanone (410 mg, 2.4 mmol) were added sequentially to a 100 mL flask equipped with a magnetic stirrer. The mixture was evacuated and purged with nitrogen three times, and the reaction was stirred at a low temperature for 12 hours. The pH was adjusted to 7 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 0.4 g of a white solid, yield 62.5%. LC-MS (APCI): m / z = 735.4 (M+1) + .

[1166] Synthesis of intermediate B-8 in step 2

[1167] Add 3-(9-((12R,22E)-12,27-dimethyl-24-oxo-8-oxa-4,14,21,23,28-pentazapentacyclo[23.3.1.0] to a 100 mL single-necked flask equipped with a magnetic stirrer. 2,7 .0 14,22 .0 15,20 [0.4 g, 0.5 mmol] tert-butyl est...

Claims

Compounds of formula (I), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates: in, Ring A is an optional area bounded by 1-3 Rs. A Substituted 6-12-membered heteroaryl or 6-12-membered heterocyclic group; Ring B is an optional area bounded by 1-3 R's. B Substituted 5-12 heteroaryl groups; p is 1, 2, or 3; For each R, R A and R B Each can be independently represented as H, D, halogen, -OH, -CN, =O, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, -OC 3-8 Cycloalkyl or -O-4-9-membered heterocyclic groups; X is -O-, -CR a R b -,-NR c -or -S(O) q -; q is 0, 1, or 2; m is 0 or 1; n is 1, 2, 3 or 4; Each E is independently for -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -,-CR 3a R 3b -,-O-,-NR c -, -C(O)- or -S(O) q -; R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1- 6-acetylenic, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; i is 0 or 1; j is 0 or 1; S1 and S2 are independent chemical bonds, -O-, -S-, -CR. d R e -,-(CR d R e ) j NR f -,-(CR d R e ) j C(O)-, -(CR) d R e ) j C(O)NR f -,-NR f (CR d R e ) j -,-C(O)(CR d R e ) j -or-C(O)NR f (CR d R e ) j -; Each R d and R e Each can be independently H, D, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or R d and R e Together with the C atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1- 6-Hydroalkyl substitution; Each R f Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; L1 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L1 replace; L2 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L2 replace; L3 is C 3-8 Cycloalkylene or 4-9 membered heterocyclic alkylene, wherein the C 3-8 Cycloalkylene and 4-9 membered heterocyclic groups are optionally surrounded by 1-6 R groups. L3 replace; L4 is C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatic hydrocarbons or 6-12 membered heterocyclic groups, wherein the C 3-8 Cycloalkylene, 4-9 membered heterocyclic alkylene, C 6-12 Heterocyclic aromatics or 6-12 membered heterocyclic groups optionally surrounded by 1-6 R groups L4 replace; L1 and L2 can share an atom or a chemical bond; When S1 is a chemical bond, L2 and L3 can share an atom or a chemical bond; When S2 is a chemical bond and i is 1, L3 and L4 can share an atom or a chemical bond; Each R L1 Each of these can be independently represented as D, halogen, OH, CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L1 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; Each R L2 Each of these can be independently represented as D, halogen, OH, CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; Each R L3 Each of these can be independently represented as D, halogen, OH, CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L3 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; Each R L4 Each of these can be independently represented as D, halogen, OH, CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups, or any two R groups L4 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally surrounded by 1-7 groups selected from D, halogen, OH, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; 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 3-8 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, Ring A is an optional area bounded by 1-3 Rs. A Substituted 6-membered heteroaryl group; Preferably, ring A is optionally surrounded by 1-3 R... A Substituted 6-membered heteroaryl groups containing 1-3 N atoms; Preferably, ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein said group is optionally surrounded by 1-3 R groups. A replace; Preferably, ring A is Where * indicates connection to ring B, This indicates that it is connected to -C(O)-. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, Ring A is an optional area bounded by 1-3 Rs. A Substituted 9-membered heteroaryl group; Preferably, ring A is optionally surrounded by 1-3 R... A Substituted 9-membered heteroaryl groups containing 1-3 N or O atoms; Preferably, ring A is optionally surrounded by 1-3 R... A Replacement Where * indicates connection to ring B, This indicates that it is connected to -C(O)-. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, Ring A is an optional area bounded by 1-3 Rs. A Substituted 6-membered heterocyclic group; Preferably, ring A is Where * indicates connection to ring B, This indicates that it is connected to -C(O)-. The compound according to claim 1, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate, is a compound of formula (II): in, Rings B, X, E, R, R A R 1a R 1b R 2a R 2b L1, L2, L3, L4, S1, S2, U, p, m, n, i as defined in claim 1. The compound according to any one of claims 1-5, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate, wherein, Ring B is an optional area bounded by 1-3 R's. B Substituted 5-membered heteroaryl group; Preferably, ring B is optionally surrounded by 1-3 R... B Substituted 5-membered heteroaryl groups containing 1-3 N atoms; Preferably, ring B is pyrazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isothiazolyl, or isoxazolyl, wherein said group is optionally surrounded by 1-3 R groups. B replace; Preferably, ring B is * indicates that it is connected to X. This indicates that it is connected to ring A. The compound according to any one of claims 1-5, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate, wherein, Ring B is an optional area bounded by 1-3 R's. B Substituted 6-9 quinone heteroaryl groups; Preferably, ring B is optionally surrounded by 1-3 R... B Substituted 6-membered heteroaryl groups containing 1-3 N atoms; Preferably, ring B is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein said group is optionally surrounded by 1-3 R groups. B replace; Preferably, ring B is * indicates that it is connected to X. Indicates connection to ring A; Preferably, ring B is optionally surrounded by 1-3 R... B Substituted 9-membered heteroaryl groups containing 1-3 N or O atoms; Preferably, ring B is * indicates that it is connected to X. This indicates that it is connected to ring A. The compound according to claim 1, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate, is a compound of formula (III) or (V): in, X, E, R, R A R B R 1a R 1b R 2a R 2b L1, L2, L3, L4, S1, S2, U, p, m, n, i as defined in claim 1. 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, X is either -O- or -CR a R b -; m is 0 or 1; n is 1 or 2; Each E is independently for -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -,-CR 3a R 3b -CR 4a R 4b -,-CR 3a R 3b -,-O-,-NR c -or -C(O)-; R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 4-9 membered heterocyclic group are optionally substituted by 1-3 groups selected from D, F or OH; R c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl. The compound according to claim 9, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, X is either -O- or -CR a R b -; m is 0 or 1; n is 1 or 2; E is -CR 3a R 3b -CR 4a R 4b -CR 5a R 5b -, -CR 3a R 3b -CR 4a R 4b - or -CR 3a R 3b -; R a R b R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Each can be independently H, D, halogen, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b Any two groups together with the atoms they are attached to form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl or 4-9 membered heterocyclic group is optionally substituted by 1-3 groups selected from D, F or OH. The compound according to claim 10, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X is either -O- or -CH2-; m is 0 or 1; n is 1 or 2; R 1a and R 1b For H; R 2a For H and R 2b It is -CH3 or -CD3; E is -CH2-CH2-CH2-, -CH2-CH2-, -CH2-, cyclobutylene, cyclopentylene, or cyclohexylene, wherein the group is optionally substituted by 1-3 groups selected from D, F, or OH. The compound according to any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, -L1-L2-S1-L3-S2-(L4) i -is -L1-L2-L3-(L4) i -; Preferably, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-L3-. The compound according to any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, -L1-L2-S1-L3-S2-(L4) i - is - L1-L2-L3-(L4) i - where L1 and L2 share a single atom; Preferably, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-L3-L4-, where L1 and L2 share an atom. The compound according to any one of claims 1-11, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate, wherein, -L1-L2-S1-L3-S2-(L4) i -is-L1-L2-CH2-L3-(L4) i -; Preferably, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-CH2-L3-. The compound according to any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-CH2-L3-(L4) i - where L1 and L2 share a single atom; Preferably, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-CH2-L3-, where L1 and L2 share an atom. The compound according to any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, -L1-L2-S1-L3-S2-(L4) i -is-L1-L2-C(O)-CH2-L3-. The compound according to any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, -L1-L2-S1-L3-S2-(L4) i - is -L1-L2-C(O)-CH2-L3-, where L1 and L2 share an atom. The compound according to any one of claims 12-17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each L1, L2, L3, and L4 is independently a 4-9 membered heterocyclic group containing 1 or 2 N atoms, wherein the 4-9 membered heterocyclic group may optionally be composed of 1-3 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution. The compound according to any one of claims 12-17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each L1, L2, L3, and L4 is independently... The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution. The compound according to any one of claims 12-17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, The group in which L1 and L2 share one atom is: The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution. The compound according to any one of claims 12-17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, -L1-L2-S1-L3-S2-(L4) i is: The above-mentioned groups may optionally be replaced by 1-3 groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl substitution. The compound according to any one of claims 1-21, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, 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; 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 3-8 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups. The compound according to any one of claims 1-22, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each U is independent as follows: 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 3-8 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups. The compound according to claim 23, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, Each U is independent as follows: 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. The compound according to any one of claims 1-22, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each U is independent as follows: 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 3-8 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl compounds. The compound according to claim 25, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each U is independent as follows: 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. The compound according to any one of claims 1-22, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each U is independent as follows: 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 3-8 cycloalkyl; Each R U2 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4-9 membered heterocyclic groups; Each R U3 Each is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U3 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups; Each R U4 Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups; or two R groups U4 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 4-9 membered heterocyclic groups. The compound according to claim 27, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each U is independent as follows: 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 3-8 Cycloalkyl or 4-9 membered heterocyclic groups. The compound according to claim 28, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each U is independent as follows: 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 3-8 Cycloalkyl or 4-9 membered heterocyclic groups. The compound of claim 29, 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 3-8 Cycloalkyl or 4-9 membered heterocyclic groups. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, p is 1 or 2; For each R, R A and R B Each is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl. A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is selected from: 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. The pharmaceutical composition according to claim 33 further comprises other therapeutic agents; Preferably, the other therapeutic agent is another EGFR inhibitor, EGFR antibody, c-MET inhibitor, immune checkpoint inhibitor, RAF inhibitor, ALK inhibitor, or MEK inhibitor; Preferably, another EGFR inhibitor is gefitinib, erlotinib, icotinib, afatinib, dacomitinib, neratinib, osimertinib, lazazetinib, ametinib, or vometinib; Preferably, the EGFR antibody is cetuximab, panitumumab, or nexituzumab; Preferably, the c-MET inhibitor is gumetinib, terpoxtinib, carmatinib, or severtinib; Preferably, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, atezolizumab, durvalumab, ipilimumab, or trimemumab. Preferably, the RAF inhibitor is sorafenib, vemurafenib, dabrafenib, or encofenib; Preferably, the ALK inhibitor is crizotinib, ceritinib, alectinib, brigatinib, ensartinib, lolatinib, or iruac; Preferably, the MEK inhibitor is trametinib, selmetinib, or refatinib. 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 diseases mediated by mutant EGFR; Preferably, the mutated EGFR is E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, Del19, L747S, L747P, D761Y, M766Q, S768I, T790M, L792F, L792H, L792V, G796R, G796S, G796C, G796D, C797S, C797G, C797N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R, or any combination thereof; Preferably, the mutated EGFR is Del19, L858R, T790M, C797S, C797G, C797N, L718Q, L792H or L861Q, or any combination thereof; Preferably, the mutated EGFR is the Del19 mutation; Preferably, the mutated EGFR is the L858R mutation; Preferably, the mutated EGFR is a Del19 / T790M double mutation; Preferably, the mutated EGFR is a Del19 / T790M / C797S triple mutation; Preferably, the mutated EGFR is the L858R / T790M double mutation; Preferably, the mutated EGFR is a triple mutation of L858R / T790M / C797S. A method for treating a disease mediated by a mutant EGFR 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 mutated EGFR is E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, Del19, L747S, L747P, D761Y, M766Q, S768I, T790M, L792F, L792H, L792V, G796R, G796S, G796C, G796D, C797S, C797G, C797N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R, or any combination thereof; Preferably, the mutated EGFR is Del19, L858R, T790M, C797S, C797G, C797N, L718Q, L792H or L861Q, or any combination thereof; Preferably, the mutated EGFR is the Del19 mutation; Preferably, the mutated EGFR is the L858R mutation; Preferably, the mutated EGFR is a Del19 / T790M double mutation; Preferably, the mutated EGFR is a Del19 / T790M / C797S triple mutation; Preferably, the mutated EGFR is the L858R / T790M double mutation; Preferably, the mutated EGFR is a triple mutation of L858R / T790M / C797S. The compound of any one of claims 1-32, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of claim 33 or 34, for the treatment of EGFR-mediated diseases; Preferably, the mutated EGFR is E709A, E709G, E709K, E709V, L718Q, L718V, G719C, G719S, G719A, G719D, G724S, Del19, L747S, L747P, D761Y, M766Q, S768I, T790M, L792F, L792H, L792V, G796R, G796S, G796C, G796D, C797S, C797G, C797N, ex20ins, G834L, V843I, L844V, T854A, L858R, L861Q, G119A, R531Q, V948R, or I941R, or any combination thereof; Preferably, the mutated EGFR is Del19, L858R, T790M, C797S, C797G, C797N, L718Q, L792H or L861Q, or any combination thereof; Preferably, the mutated EGFR is the Del19 mutation; Preferably, the mutated EGFR is the L858R mutation; Preferably, the mutated EGFR is a Del19 / T790M double mutation; Preferably, the mutated EGFR is a Del19 / T790M / C797S triple mutation; Preferably, the mutated EGFR is the L858R / T790M double mutation; Preferably, the mutated EGFR is a triple mutation of L858R / T790M / C797S. 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 EGFR-mediated disease is cancer; Preferably, the disease mediated by mutated EGFR is cancer; Preferably, the disease mediated by mutated EGFR is a central nervous system (CNS) metastasis, such as brain metastasis; Preferably, the diseases mediated by mutated EGFR include lung cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, urothelial carcinoma, kidney cancer, bladder cancer, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial tumor, colorectal cancer, head and neck cancer, esophageal cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, gastric cancer, leukemia, lymphoma, neuroblastoma, glioma, melanoma, sarcoma, thyroid cancer, glioblastoma, solid tumor, oropharyngeal carcinoma, bronchial tumor, skin cancer, brain metastases, and mesothelioma. Preferably, the EGFR-mediated disease is lung cancer and its metastases (especially CNS metastases such as brain metastases); Preferably, the EGFR-mediated disease is non-small cell lung cancer and its metastases (especially CNS metastases such as brain metastases).

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