Proteolysis targeting chimera compound targeting alk or ros1, and composition and use thereof

Abstract

Provided are a compound represented by formula (A), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, a pharmaceutical composition thereof, and use thereof in the treatment and / or prevention of related diseases.

Description

Protein degradation targeting chimeric compounds targeting ALK or ROS1, their compositions, and their uses

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese Patent Application No. 202411828154X, filed on December 11, 2024, and Chinese Patent Application No. 2025118255677, filed on December 5, 2025, the entire contents of which are incorporated herein by reference as a part of the specification. Technical Field

[0003] This invention belongs to the pharmaceutical field, and particularly relates to a protein degradation-targeting chimeric compound, pharmaceutical compositions comprising them, and their preparation methods and uses. Background Technology

[0004] Receptor tyrosine kinases (RTKs) are cell surface enzymes that receive external signals, such as whether to grow and divide, and transmit these signals within the cell through kinase activity. The RTK family regulates cell growth, and when they are mutated, translocated, or otherwise aberrantly expressed, they can also trigger tumor transformation. Many RTKs are proto-oncogenes, and aberrant RTK activity can drive cell survival, growth, and proliferation, leading to cancer and related diseases. This aberrant kinase activity can be caused by mutations, such as activating mutations in the kinase domain, gene rearrangements leading to fusion proteins containing the complete kinase domain, amplification, and other mechanisms.

[0005] Anaplastic lymphoma kinase (ALK) is a member of the RTK family. At the amino acid sequence level, ALK is most closely associated with members such as ROS-1, leukocyte tyrosine kinase, insulin receptor, and cMet (liver growth factor receptor). Like all members of this gene family, it possesses an extracellular ligand-binding domain, a transmembrane sequence, and an intracellular kinase catalytic / signal transduction domain.

[0006] Multiple mutations involving the ALK gene are associated with the pathogenesis of various cancers. ALK rearrangements have been detected in many cancers, including non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), diffuse large B-cell lymphoma (DLBCL), esophageal squamous cell carcinoma (ESCC), renal medullary carcinoma, renal cell carcinoma, breast cancer, colon cancer, serous ovarian cancer, papillary thyroid carcinoma, and Spitz nevus-like tumors. ALK activating mutations have also been detected in neuroblastoma.

[0007] Oncogenic ALK gene fusions contain fusions of the kinase domain (3' region) of ALK with the 5' region of more than 20 different somatic genes, the most common of which are EML4 in NSCLC and NPM in ALCL. Other somatic genes include TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, and KIF5B.

[0008] Currently, the FDA has approved five kinase inhibitors for the treatment of ALK-positive NSCLC: crizotinib, ceritinib, alectinib, brigatinib, and lolatinib. ALK-positive tumors are highly sensitive to ALK inhibition, indicating that these tumors depend on ALK kinase activity. However, although the duration of the initial significant response varies, resistance to treatment often develops. Newer-generation ALK inhibitors such as lolatinib have successfully targeted resistant tumors and have shown improved efficacy and overall response rates compared to approved inhibitors; however, patients still continue to develop resistance to these inhibitors.

[0009] A variety of ALK resistance mutations, occurring alone or in combination, have been reported, including G1202R, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V.

[0010] ROS1 is an RTK proto-oncogene, and ROS1 rearrangements have been detected in non-small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, and spitzoid melanoma. Oncogenic ROS1 gene fusions contain fusions of the kinase domain of ROS1 (3' region) with the 5' region of various partner genes. Examples of ROS1 fusion-coupled genes observed in NSCLC include SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC, GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 (presumed), SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8, and CCDC6. Other fusion partners include CAPRIN1, CEP85L, CHCHD3, CLIP1 (presumed), EEF1G, KIF21A (presumed), KLC1, SART3, ST13 (presumed), TRIM24 (presumed), ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1.

[0011] Acquired resistance mutations in ROS1 typically occur alone or in combination, including G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F.

[0012] Proteolysis-targeting chimeras (PROTACs) are a targeted protein degradation technology that uses small molecule compounds to modulate protein levels. PROTACs differ from traditional small molecule drugs in their mode of action, delivering proteins to the proteasome via unique targets to achieve chemical protein degradation. The core concept involves using artificial small molecule compounds to recruit a specific ubiquitin ligase, which then degrades the target protein through ubiquitination. Because this technology employs an iterative degradation process, it exhibits better tolerability compared to traditional drugs, especially in cases of target protein mutation.

[0013] PROTACs can overcome some of the drug resistance mechanisms faced by small molecule inhibitors, such as mutations in target proteins, upregulation of expression, and changes in active sites, because PROTACs do not need to bind tightly to the target protein or inhibit its enzyme activity. They only need to recruit it to the vicinity of the E3 ligase, so that it can be ubiquitinated and degraded.

[0014] Existing drugs for treating oncogenic ALK and ROS1 have substantial deficiencies. These deficiencies may manifest as one or more of the following: associated TRK inhibition, limited CNS activity, and insufficient activity against resistance mutations. Treatment with TRK inhibition in ROS1-positive or ALK-positive patients is associated with adverse reactions, particularly in the CNS, including dizziness / ataxia / gait disturbances, paresthesia, weight gain, and cognitive changes. PROTACs are a promising anticancer strategy that can overcome the limitations of traditional small-molecule inhibitors, offering more target options and higher therapeutic efficacy. Currently, several drugs developed based on PROTAC technology have entered clinical trials, demonstrating some antitumor activity. Therefore, it is necessary to further develop new PROTACs for the treatment of ALK and ROS1-related diseases. Summary of the Invention

[0015] This invention provides a novel ALK or ROS1 protein degradation-targeting chimeric compound (also known as a "protein degrader"), compositions containing the compound, and their uses. The protein degrader provided by this invention has a novel structure, good efficacy, high bioavailability, and is safer. It can inhibit or degrade ALK and / or ROS1 and their mutants, and can be used to treat ALK or ROS1-related diseases, such as tumors.

[0016] To address this, the present invention adopts the following technical solution:

[0017] In one aspect, the present invention relates to compounds of formula (A), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:

[0018] in,

[0019] X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R;

[0020] Y1 is -NR c -CO-, a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein said group is optionally substituted by one or more groups selected from R' groups;

[0021] Z1 is either CR3 or N;

[0022] Z2 can be CH, CD, or N;

[0023] Z3 is either CR4R5 or NR4;

[0024] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0025] l can be 0, 1, or 2;

[0026] R4 and R5 are independently H, D, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally substituted with one or more D atoms until it is fully deuterated;

[0027] Or R4 and an R, along with the atoms they are attached to, form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0028] Or R4 and an R' together with the atoms they are attached to form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0029] Or an R and an R' together with the atoms they are attached to form C. 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0030] Or an R and R c Together with the atoms they are attached to, they form C 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0031] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0032] m can be 0, 1, 2, 3, or 4;

[0033] n is 0, 1, 2, or 3;

[0034] R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0035] Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0036] L represents a chemical bond or a divalent linking group;

[0037] U is a group that binds to E3 ubiquitin ligase.

[0038] In another respect, the present invention relates to compounds of formula (B), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:

[0039] in,

[0040] X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is optionally substituted by one or more groups selected from R;

[0041] Y2 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R' groups;

[0042] Z1 is either CR3 or N;

[0043] Z2 can be CH, CD, or N;

[0044] Z3 is either CR4R5 or NR4;

[0045] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0046] l can be 0, 1, or 2;

[0047] R4 and R5 are independently H, D, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally substituted with one or more D atoms until it is fully deuterated;

[0048] Or R4 and an R, along with the atoms they are attached to, form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0049] Or R4 and an R' together with the atoms they are attached to form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0050] Or an R and an R' together with the atoms they are attached to form C. 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0051] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0052] m can be 0, 1, 2, 3, or 4;

[0053] n is 0, 1, 2, or 3;

[0054] Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0055] L represents a chemical bond or a divalent linking group;

[0056] U is a group that binds to E3 ubiquitin ligase.

[0057] In another aspect, the present invention relates to a pharmaceutical composition comprising the compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient.

[0058] In another aspect, the present invention relates to a kit comprising a first container containing the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutical compositions thereof; and optionally, a second container containing other therapeutic agents; and optionally, a third container containing pharmaceutical excipients for diluting or suspending said compound and / or other therapeutic agents.

[0059] In another aspect, the present invention relates to the use of the compounds of the present invention, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutical compositions of the present invention, or kits of the present invention, in the preparation of medicaments for the treatment and / or prevention of ALK and / or ROS1-related diseases.

[0060] In another aspect, the present invention relates to a method for inducing ALK and / or ROS1 inhibition and / or degradation in cells, the method comprising contacting cells with a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of the present invention, or a kit of the present invention. In a particular embodiment, the contact may be performed in vitro or in vivo.

[0061] In another aspect, the present invention relates to a method for treating and / or preventing ALK and / or ROS1-related diseases in a subject, the method comprising administering to the subject a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention.

[0062] In another aspect, the present invention relates to the use of the compounds of the present invention, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutical compositions of the present invention, or kits of the present invention, in the treatment and / or prevention of diseases caused by ALK and / or ROS1.

[0063] In a specific embodiment, the diseases caused by ALK and / or ROS1 according to the present invention include the expression of the oncogene ALK gene or an oncogene ALK gene fusion; in a more specific embodiment, the oncogene ALK gene or oncogene ALK gene fusion contains one or more mutations in the human ALK gene; in a more specific embodiment, the mutations in the oncogene ALK gene or oncogene ALK gene fusion result in the expression of an ALK protein having one or more mutations selected from the group consisting of G1202R, L1196M, G1269A, D1203N and I1171N.

[0064] In a specific embodiment, the ALK and / or ROS1-induced diseases of the present invention include the expression of an oncogenic ROS1 gene or an oncogenic ROS1 gene fusion; in a more specific embodiment, the oncogenic ROS1 gene or the oncogenic ROS1 gene fusion contains one or more mutations in the human ROS1 gene; in a more specific embodiment, the mutations in the oncogenic ROS1 gene or the oncogenic ROS1 gene fusion result in the expression of a ROS1 protein with a G2032R mutation.

[0065] In a specific embodiment, the ALK and / or ROS1-induced disease involved in this invention is a tumor. In a specific embodiment, the tumor is selected from solid tumors or hematologic malignancies. In a more specific embodiment, the solid tumor is selected from lung cancer, glioblastoma, inflammatory myofibroblastoma, cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid angioendothelioma, esophageal cancer, renal cancer, breast cancer, colon cancer, thyroid cancer, Spitz nevus-like tumor, and neuroblastoma. In a more specific implementation plan, the hematologic malignancies are selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic lymphoma (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ALL), and acute myeloid leukemia with trilineage myelodysplastic syndromes. AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, splenic marginal zone lymphoma, extranodal marginal zone B-cell lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-cell lymphoblastic leukemia, hairy cell leukemia, mucosa-associated lymphoid tissue lymphoma, plasmacytoma, plasmacytoma, and multiple myeloma. In a more specific implementation, the tumor is an ALK-positive tumor. In a more specific implementation, the tumor is a ROS1-positive tumor.

[0066] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed description, embodiments, and claims.

[0067] definition

[0068] Chemical definition

[0069] The definitions of specific functional groups and chemical terms are described in more detail below.

[0070] When listing a range of values, it is assumed that each value and a subrange within that range will be included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0071] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and is also referred to in this invention as "lower alkyl". In some embodiments, C 1-4 Alkyl 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.

[0072] “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 2-4Alkenyl 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.

[0073] “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.

[0074] “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 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.

[0075] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by the other hydrogen atom of the alkyl group, and can be a substituted or unsubstituted alkylene group. In some embodiments, C 1-4Alkylenes are particularly preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0076] “C 0-6 "alkylene" includes chemical bonds and C as defined above. 1-6 Alkylene.

[0077] "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.

[0078] Therefore, "C" 1-6 "Halogenated alkyl" and "C" 1-6 "Haloalkoxy" refers to the above "C" 1-6 "alkyl" and "C" 1-6 "Alkoxy" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1- 2-Haloalkyl. In some embodiments, C 1-4 Halogenated alkoxy groups are particularly preferred, and C4 groups are even more preferred. 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.

[0079] “C3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 Cycloalkyl groups are preferred, C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent 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), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (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.

[0080] "3- to 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, 3- to 7-membered heterocyclic groups are preferred, which are 3- to 7-membered non-aromatic ring systems having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; in some embodiments, 3- to 6-membered heterocyclic groups are particularly preferred, which are 3- to 6-membered non-aromatic ring systems having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably, 5- to 6-membered heterocyclic groups are 5- to 6-membered non-aromatic ring systems having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include cyclic systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the connection point is on the heterocyclic ring; and 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 the word "substituted," each of the heterocyclic groups may be optionally substituted independently, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0081] 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 (also referred to as 5,6-bicyclic heterocyclic groups in this invention) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (this invention also refers to 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0082] “C 6-14 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C... 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C14”). 14 "Aryl"; for example, anthracene). In some embodiments, C 6-10Aryl groups are particularly preferred, and more preferably C6 aryl groups. Aryl groups also include ring systems in which the aforementioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is preceded by the word "substituted," each aryl group may be optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0083] "5- to 10-membered heteroaryl" refers to a group comprising a 4n+2 aromatic ring system of a 5- to 10-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6 or 10 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl are particularly preferred, which are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having a ring carbon atom and 1-4 ring heteroatoms. Regardless of whether the term "substituted" is used before the heteroaryl group, each of the heteroaryl groups is independently and optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents defined as follows.

[0084] 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.

[0085] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb)2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)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)(NRbb )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;

[0086] 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;

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

[0088] 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;

[0089] 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;

[0090] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee-OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0091] 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;

[0092] 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;

[0093] 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 1-6Alkyl 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 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0094] 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、-SO2Rcc -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.

[0095] "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.

[0096] "Non-deuterated compounds" refer to compounds containing a deuterium atom ratio no higher than the natural deuterium isotope content (0.015%).

[0097] 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%.

[0098] Other definitions

[0099] 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.

[0100] The term "subject" for drug 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 in this invention.

[0101] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this invention.

[0102] Unless otherwise stated, the term "treatment" as used in this invention 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 the subject begins to have a specific disease, disorder, or condition ("preventive treatment").

[0103] 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.

[0104] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a response in the target organism. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include both therapeutic and prophylactic effective amounts.

[0105] Unless otherwise stated, the "therapeuticly effective amount" of a compound used in this invention is the amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic efficacy of other therapeutic agents.

[0106] Unless otherwise stated, the "preventively effective amount" of a compound used in this invention is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventative benefit in the prevention of a disease, disorder, or condition. The term "preventively effective amount" may include amounts that improve overall prevention or enhance the preventative efficacy of other preventative agents. Detailed Implementation

[0107] compound

[0108] In this invention, "compound of this invention" refers to the following compounds of formula (A), formula (B), formula (I) to formula (V) (including subsets of each formula, such as formula (II)). A2 (a compound), or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0109] In one embodiment, the present invention relates to a compound of formula (A), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0110] in,

[0111] X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R;

[0112] Y1 is -NR c -CO-, a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein said group is optionally substituted by one or more groups selected from R' groups;

[0113] Z1 is either CR3 or N;

[0114] Z2 can be CH, CD, or N;

[0115] Z3 is either CR4R5 or NR4;

[0116] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0117] l can be 0, 1, or 2;

[0118] R4 and R5 are independently H, D, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally substituted with one or more D atoms until it is fully deuterated;

[0119] Or R4 and an R, along with the atoms they are attached to, form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0120] Or R4 and an R' together with the atoms they are attached to form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0121] Or an R and an R' together with the atoms they are attached to form C. 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0122] Or an R and R c Together with the atoms they are attached to, they form C 5-8cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0123] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0124] m can be 0, 1, 2, 3, or 4;

[0125] n is 0, 1, 2, or 3;

[0126] R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0127] Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0128] L represents a chemical bond or a divalent linking group;

[0129] U is a group that binds to E3 ubiquitin ligase.

[0130] 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:

[0131] in,

[0132] X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R;

[0133] Y1 is -NR c -CO-, a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein said group is optionally substituted by one or more groups selected from R' groups;

[0134] Z1 is either CR3 or N;

[0135] Z2 can be CH, CD, or N;

[0136] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0137] l can be 0, 1, or 2;

[0138] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0139] m can be 0, 1, 2, 3, or 4;

[0140] n is 0, 1, 2, or 3;

[0141] R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0142] Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0143] L represents a chemical bond or a divalent linking group;

[0144] U is a group that binds to E3 ubiquitin ligase.

[0145] In another embodiment, the present invention relates to a compound of formula (B), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0146] in,

[0147] X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is optionally substituted by one or more groups selected from R;

[0148] Y2 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R' groups;

[0149] Z1 is either CR3 or N;

[0150] Z2 can be CH, CD, or N;

[0151] Z3 is either CR4R5 or NR4;

[0152] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0153] l can be 0, 1, or 2;

[0154] R4 and R5 are independently H, D, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally substituted with one or more D atoms until it is fully deuterated;

[0155] Or R4 and an R, along with the atoms they are attached to, form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0156] Or R4 and an R' together with the atoms they are attached to form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0157] Or an R and an R' together with the atoms they are attached to form C. 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0158] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0159] m can be 0, 1, 2, 3, or 4;

[0160] n is 0, 1, 2, or 3;

[0161] Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0162] L represents a chemical bond or a divalent linking group;

[0163] U is a group that binds to E3 ubiquitin ligase.

[0164] In another embodiment, the present invention relates to compounds of formula (II), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0165] in,

[0166] X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is optionally substituted by one or more groups selected from R;

[0167] Y2 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein the group is substituted by a -LU group and optionally by one or more groups selected from R';

[0168] Z1 is either CR3 or N;

[0169] Z2 can be CH, CD, or N;

[0170] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0171] l can be 0, 1, or 2;

[0172] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0173] m can be 0, 1, 2, 3, or 4;

[0174] n is 0, 1, 2, or 3;

[0175] R and R' are independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0176] L represents a chemical bond or a divalent linking group;

[0177] U is a group that binds to E3 ubiquitin ligase.

[0178] X1

[0179] In one embodiment, X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is substituted with a -LU group and optionally substituted with one or more groups selected from R; in another embodiment, X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon containing 1 to 3 heteroatoms selected from N, S and O, wherein the group is substituted with a -LU group and optionally substituted with 1, 2 or 3 groups selected from R.

[0180] In one specific implementation plan, X1 is: The aforementioned group is substituted by a -LU group, and optionally substituted by 1, 2 or 3 groups selected from R;

[0181] In another specific implementation, X1 is:

[0182] In another specific implementation, X1 is:

[0183] ^Represents the connection points of formula X and the methylene groups bonded to X and Y;

[0184] In a more specific implementation plan, X1 is:

[0185] ^Represents the connection point of formula X1 with the methylene group bonded to X1 and Y1.

[0186] X2

[0187] In one embodiment, X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is optionally substituted by one or more groups selected from R; in another embodiment, X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon containing 1 to 3 heteroatoms selected from N, S and O, wherein the group is optionally substituted by 1, 2 or 3 groups selected from R.

[0188] In one specific implementation plan, X2 is: The aforementioned groups are optionally replaced by 1, 2 or 3 groups selected from R;

[0189] In another specific implementation, X2 is:

[0190] In another specific implementation, X2 is:

[0191] ^The connection point of the methylene group bonded to X2 and Y2;

[0192] In a more specific implementation plan, X2 is:

[0193] ^Represents the connection point of formula X2 with the methylene group bonded to X2 and Y2.

[0194] Y1

[0195] In one implementation, Y1 is -NR c -CO-, a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein said group is optionally substituted by one or more groups selected from R' groups; in another embodiment, Y1 is -NR. c -CO-, wherein the group is optionally substituted with one or more groups selected from R'; in another embodiment, Y1 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein the group is optionally substituted with one or more groups selected from R'; in another embodiment, Y1 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon, wherein the group is optionally substituted with one or more groups selected from R'; in another embodiment, Y1 is a divalent group of a benzene ring, wherein the group is optionally substituted with one or more groups selected from R';

[0196] In another embodiment, Y1 is a divalent group of a 5- to 6-membered heteroaromatic hydrocarbon or benzene ring containing 1 to 3 heteroatoms selected from N, S, and O, wherein said group is optionally substituted by 1, 2, 3, or 4 groups selected from R'; in another embodiment, Y1 is a divalent group of a benzene ring, wherein said group is optionally substituted by 1, 2, 3, or 4 groups selected from R';

[0197] In one specific implementation plan, Y1 is: The aforementioned groups are optionally replaced by 1, 2, 3 or 4 groups selected from R';

[0198] In another specific implementation scheme, Y1 is:

[0199] Where W1 is N or CR';

[0200] In another specific implementation scheme, Y1 is:

[0201] *The connection site of formula Y1 to the methylene group bonded to X1 and Y1; in a more specific embodiment, Y1 is:

[0202] Where W1 is N or CR';

[0203] *The connection point of formula Y1 to the methylene group bonded to X1 and Y1.

[0204] In another, more specific implementation, Y1 is -NR c -CO-.

[0205] W1

[0206] In one embodiment, W1 is N or CR'; in another embodiment, W1 is N; in yet another embodiment, W1 is CR'.

[0207] Y2

[0208] In one embodiment, Y2 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or benzene ring, wherein the group is substituted with a -LU group and optionally substituted with one or more groups selected from R'; in another embodiment, Y2 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or benzene ring containing 1 to 3 heteroatoms selected from N, S and O, wherein the group is substituted with a -LU group and optionally substituted with one or more groups selected from R'.

[0209] In one specific implementation plan, Y2 is: The aforementioned group is substituted by a -LU group, and optionally substituted by 1, 2 or 3 groups selected from R';

[0210] In another specific implementation scheme, Y2 is:

[0211] In another specific implementation scheme, Y2 is:

[0212] In a more specific implementation plan, Y2 is:

[0213] Where W2 is N or CR';

[0214] *The connection point of formula Y2 to the methylene group bonded to X2 and Y2.

[0215] W2

[0216] In one embodiment, W2 is N or CR'; in another embodiment, W2 is N; in yet another embodiment, W2 is CR'.

[0217] Z1

[0218] In one embodiment, Z1 is CR3 or N; in another embodiment, Z1 is CR3; in yet another embodiment, Z1 is N.

[0219] Z2

[0220] In one embodiment, Z2 is CH, CD, or N; in another embodiment, Z2 is CH; in another embodiment, Z2 is CD; in yet another embodiment, Z2 is N.

[0221] R1

[0222] In one implementation, R1 is independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0223] In one specific implementation, R1 is H, D, halogen, -CH2-OH, C 1-3 Alkyl groups, wherein the -CH2-OH, C 1-3 The alkyl group is optionally substituted with one or more D molecules until fully deuterated; in another specific embodiment, R1 is H, D, F, -CH3, -CD3, -CH2-OH, -CD2-OH, -CH2-OD, or -CD2-OD; in another specific embodiment, R1 is H, D, F, Cl, -CH3, -CD3, or -CF3; in another specific embodiment, R1 is H, -CH3, or -CH2-OH.

[0224] In a more specific implementation, R1 is -CH3.

[0225] R2

[0226] In one implementation, R2 is independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0227] In one embodiment, R2 is H, D, F, Cl, or Br; in another embodiment, R2 is H, D, F, Cl, -CH3, -CD3, or -CF3; in yet another embodiment, R2 is H or F.

[0228] In a more specific implementation, R2 is F.

[0229] R3

[0230] In one implementation, R2 is independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0231] In one specific implementation scheme, R3 is H, D, F, Cl, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 The haloalkoxy group is optionally substituted with one or more D groups until fully deuterated; in another specific embodiment, R3 is H, D, F, Cl, -CH3, -CD3 or -CF3; in another specific embodiment, R3 is H or F.

[0232] In a more specific implementation, R3 is H.

[0233] l

[0234] In one embodiment, l is 0, 1, or 2; in another embodiment, l is 0 or 1; in another embodiment, l is 1 or 2; in another embodiment, l is 0; in another embodiment, l is 1; in another embodiment, l is 2.

[0235] R a and R b

[0236] In one implementation, R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with one or more D molecules, up to full deuteration; in one specific embodiment, R… a and R b Independently, it is H, D, F, Cl, -CH3, -CD3, or -CF3; in another specific embodiment, R a and R b Independently, it is F, -CH3, or -CD3; in another specific embodiment, R a and R b Independently, it is either H or F.

[0237] m

[0238] In one implementation, m is 0, 1, 2, 3, or 4; in another implementation, m is 0; in yet another implementation, m is 1; in yet another implementation, m is 2; in yet another implementation, m is 3; in yet another implementation, m is 4.

[0239] n

[0240] In one implementation, n is 0, 1, 2, or 3; in another implementation, n is 0; in another implementation, n is 1; in another implementation, n is 2; and in another implementation, n is 3.

[0241] R c

[0242] In one implementation, R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3- 7-cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0243] In one specific implementation plan, R c It is -CH3, -CH2CH3, -CD3, or -CD2CD3; in another specific embodiment, R c For H, D, F, -CH3, -CF3, or -CD3; in another specific embodiment, R c It is -CH3 or -CD3;

[0244] In a more specific implementation plan, R c -CH3;

[0245] R

[0246] In one implementation, each R is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0247] In another implementation, each R is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 0-3 Alkylene-C 3-6 cycloalkyl or C 0-3 alkylene-3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 0-3 Alkylene-C 3-6 cycloalkyl or C 0-3 The alkylene-3 to 6-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0248] In another implementation, H, D, halogen, -CN, C 1-6 Alkyl or C 0-6 Alkylene-C 3-7 cycloalkyl, wherein the C 1-6 Alkyl or C 0-6 Alkylene-C 3-7 The cycloalkyl group may optionally be substituted with one or more D molecules until fully deuterated;

[0249] In one specific embodiment, each R is independently H, D, F, Cl, -CN, -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxacyclobutyl, wherein -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxacyclobutyl is optionally substituted by one or more Ds until fully deuterated; in another specific embodiment, each R is independently H, D, F, Cl, -CN, -CH2CH3, cyclopropyl, or cyclopropylmethyl, wherein -CH2CH3, cyclopropyl, isopropylmethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxacyclobutyl is optionally substituted by one or more Ds until fully deuterated; The methyl group or cyclopropylmethyl group is optionally substituted with one or more D groups until fully deuterated; in another embodiment, each R is independently H, D, F, Cl, -CN, -CH3, -CH2CH3, methoxy, or ethoxy, wherein the -CH3, -CH2CH3, methoxy, or ethoxy group is optionally substituted with one or more D groups until fully deuterated; in another embodiment, each R is independently H, D, F, Cl, -CN, -CH2CH3, cyclopropyl, or cyclopropylmethyl; in another embodiment, each R is independently H, D, F, Cl, -CN, or -CH2CH3; in another embodiment, each R is independently -CH3, -CH2CH3, -CD3, or -CD2CD3; in another embodiment, each R is independently -CN.

[0250] R'

[0251] In one implementation, each R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0252] In another implementation, each R' is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group may optionally be substituted with one or more D molecules, up to complete deuteration;

[0253] In one embodiment, H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CHF2, -CF3, or methoxy, wherein the -CH3, -CH2CH3, -CHF2, -CF3, or methoxy is optionally substituted by one or more D until fully deuterated; in another embodiment, H, D, F, Cl, -CH3, or -CD3; in yet another embodiment, each R' is independently -CH3 or -CD3.

[0254] In a more specific implementation, each R' is independently -CH3.

[0255] L

[0256] In one embodiment, L is a chemical bond or a divalent linking group; in another embodiment, L is a chemical bond; in yet another embodiment, L is a divalent linking group.

[0257] In another embodiment, L is the divalent linker shown in formula (III):

[0258] -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-■(III)

[0259] in,

[0260] i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0.

[0261] L1, L2, and L3 are each chemical bonds that can be formed independently, or are selected from C. 3-7 A divalent group consisting of a cycloalkanes, a 4- to 7-membered heterocycle, or a 5- to 7-membered heteroaryl group, wherein the divalent group is optionally surrounded by one or more elements selected from D, halogens, -OH, -CN, and C. 1- 3-alkyl and C 1-3 Substitution of alkyl groups;

[0262] S0, S1, S2, and S3 are each independently a chemical bond, namely -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, and -C(O)NH(CH2). p -、-C(O)(CH2) p -、-NHC(O)(CH2) p -、-(CH2) p -、-(CH2CH2O) q -、C 1-6 imide or C 1-6 Alynyl group; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0263] ■ indicates the end connected to U;

[0264] In one specific implementation, L is Equation (III) A The divalent linker shown is:

[0265] -(L1) i -(L2) j -(L3) k -■(III A );

[0266] In another specific implementation, L is Equation (IIII) B The divalent linker shown is:

[0267] -(L1) i -S1-(L2) j -S2-(L3) k -■(III B );

[0268] In another specific implementation, L is Equation (III) C The divalent linker shown is:

[0269] -S0-(L1) i (L2) j -S2-(L3) k -S3-■(III C )

[0270] Among them, (L1) i and (L2) j Sharing an atom and / or a chemical bond;

[0271] In another specific implementation, L is Equation (III) D The divalent linker shown is:

[0272] -S0-(L1) i -S1-(L2)j (L3) k -S3-■(III D )

[0273] Among them, (L2) j and (L3) k They share an atom and / or a chemical bond.

[0274] In a more specific embodiment, one or two of L1, L2, and L3 are chemically bonded, and the remaining groups are each independently divalent groups selected from 4- to 7-membered heterocycles containing 1 or 2 N atoms, wherein the divalent groups are optionally bonded by one or more groups selected from D, halogens, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups;

[0275] In another, more specific embodiment, L1 is a chemical bond, and L2 and L3 are each independently a divalent group selected from 4- to 7-membered heterocycles containing 1 or 2 N atoms, wherein the divalent group is optionally bonded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups;

[0276] In another, more specific embodiment, L2 is a chemical bond, and L1 and L3 are each independently a divalent group selected from 4- to 7-membered heterocycles containing 1 or 2 N atoms, wherein the divalent group is optionally bonded by one or more bonds selected from D, halogens, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups;

[0277] In another, more specific embodiment, L3 is a chemical bond, and L1 and L2 are each independently a divalent group selected from 4- to 7-membered heterocycles containing 1 or 2 N atoms, wherein the divalent group is optionally bonded by one or more bonds selected from D, halogens, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups;

[0278] In another, more specific embodiment, L1 and L2 are chemical bonds, and L3 is a divalent group selected from 4- to 7-membered heterocycles containing 1 or 2 N atoms, wherein the divalent group is optionally bonded by one or more bonds selected from D, halogens, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups;

[0279] In another, more specific embodiment, L1 and L3 are chemical bonds, and L2 is a divalent group selected from 4- to 7-membered heterocycles containing 1 or 2 N atoms, wherein the divalent group is optionally bonded by one or more bonds selected from D, halogens, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups;

[0280] In another, more specific embodiment, L2 and L3 are chemical bonds, and L1 is a divalent group selected from 4- to 7-membered heterocycles containing 1 or 2 N atoms, wherein the divalent group is optionally bonded by one or more bonds selected from D, halogens, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0281] L1, L2 and L3

[0282] In one implementation, L1, L2, and L3 are each independently a chemical bond, or selected from C 3-7 Cycloalkanes, with a divalent group consisting of a 4- to 7-membered heterocycle or a 5- to 7-membered heteroaryl group, wherein the divalent group is optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 The alkyl group is substituted; in another embodiment, L1, L2, and L3 are each independently chemically bonded; in another embodiment, L1, L2, and L3 are each independently selected from C 3-7 A divalent group consisting of a cycloalkane, a 4- to 7-membered heterocycle, or a 5- to 7-membered heteroaryl group, wherein the above groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 The alkyl group is substituted; in another embodiment, L1, L2, and L3 are each independently C1. 3-7 The divalent group of the cycloalkanes, wherein the above group is optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 The alkyl group is substituted; in another embodiment, L1, L2, and L3 are each independently a divalent group of a 4- to 7-membered heterocyclic ring, wherein the aforementioned groups are optionally replaced by one or more groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 The alkyl group is substituted; in another embodiment, L1, L2, and L3 are each independently a divalent group of a 5- to 7-membered heteroaryl group, wherein the above groups are optionally replaced by one or more groups selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups;

[0283] In one specific implementation plan, L1, L2, and L3 are each independently: The above-mentioned groups are optionally surrounded by 1-6 elements selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0284] In another specific implementation, L1, L2, and L3 are each independently: The above-mentioned groups are optionally surrounded by 1-6 elements selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0285] In another specific implementation, L1, L2, and L3 are each independently: The above-mentioned groups are optionally surrounded by 1-6 elements selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0286] In another specific implementation scheme, (L1) i and (L2) j Sharing an atom and / or a chemical bond;

[0287] In another specific implementation scheme, (L2) j and (L3) k Sharing an atom and / or a chemical bond;

[0288] In a more specific implementation plan, (L1) i (L2) j and (L2) j (L3) k Each independently is: The above-mentioned groups are optionally surrounded by 1-6 elements selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0289] i, j and k

[0290] In one embodiment, i is 0 or 1, j is 0 or 1, and k is 0 or 1, provided that at least one of i, j, and k is not 0; in another embodiment, i is 1, j is 0, and k is 0; in another embodiment, i is 1, j is 1, and k is 0; in another embodiment, i is 1, j is 0, and k is 1; in another embodiment, i is 1, j is 1, and k is 1; in another embodiment, i is 0, j is 0, and k is 1; in another embodiment, i is 0, j is 1, and k is 0; in another embodiment, i is 0, j is 1, and k is 1.

[0291] S0, S1, S2 and S3

[0292] In one implementation, S0, S1, S2, and S3 are each independently a chemical bond, -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, or -C(O)NH(CH2). p -、-C(O)(CH2) p -、-NHC(O)(CH2) p -、-(CH2) p -、-(CH2CH2O) q -、C 1-6 imide or C 1-6The ynylene group, wherein p is 1, 2, 3 or 4, and q is 1, 2 or 3; in another embodiment, S0, S1, S2 and S3 are each independently chemically bonded; in another embodiment, S0, S1, S2 and S3 are each independently -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-; in another embodiment, S0, S1, S2 and S3 are each independently vinylene, propyneene, ethynene or propyneene; in another embodiment, S0, S1, S2 and S3 are each independently -C(O)NHCH2-, -C(O)NH(CH2)2-, -C(O)NH(CH2)3- or -C(O)NH(CH2)4-; in another embodiment, S0, S1 S0, S1, S2, and S3 are each independently -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, or -C(O)(CH2)4-; in another embodiment, S0, S1, S2, and S3 are each independently -NHC(O)CH2-, -NHC(O)(CH2)2-, -NHC(O)(CH2)3-, or -NHC(O)(CH2)4-; in another embodiment, S0, S1, S2, and S3 are each independently -CH2-, -(CH2)2-, -(CH2)3-, or -(CH2)4-; in another embodiment, S0, S1, S2, and S3 are each independently -CH2CH2O-, -(CH2CH2O)2-, or -(CH2CH2O)3-.

[0293] In one specific implementation plan, L is:

[0294] The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0295] In a more specific implementation plan, L is:

[0296] The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0297] In a particularly specific implementation scheme, L is:

[0298] The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0299] U

[0300] In one implementation scheme, U is:

[0301] in,

[0302] Indicates a single bond or a double bond;

[0303] Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0304] Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0305] Each Q1 is independently C(O) or C(R9)2;

[0306] Each Q2 is independently either N or CH;

[0307] Each Q3 and Q4 is independently either N or CR9;

[0308] Each of K1, K2, and K3 is independently either N or CR9;

[0309] K4 and K5 are each independently N or C;

[0310] H1 is N, C, or CR9;

[0311] H2 and H3 are each independently C(O), N, O, S, NR9, CR9 or C(R9)2;

[0312] H4 and H8 are each independently N or CR9;

[0313] H5, H6, and H7 are each independently C(O), O, S, NR9, or C(R9)2; each R7 is independently H or C. 1-6 alkyl;

[0314] Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 Cycloalkanes or 4- to 7-membered heterocycles;

[0315] Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkanes, 4- to 7-membered heterocycles, C 6-10 Aromatic hydrocarbons or 5- to 10-membered heteroaromatic hydrocarbons;

[0316] Each 'o' is independently 0, 1, or 2;

[0317] Each h is independently 0, 1, 2, 3 or 4;

[0318] Each z is independently 0, 1, or 2;

[0319] Each r and s is independently 0, 1, 2, or 3; and r and s are not both 0 at the same time;

[0320] Each t and u is independently 0, 1, 2, or 3; and t and u are not both 0 at the same time.

[0321] In another implementation, U is:

[0322] in,

[0323] Indicates a single bond or a double bond;

[0324] Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0325] Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0326] Each Q1 is independently C(O) or C(R9)2;

[0327] Each Q2 is independently either N or CH;

[0328] Each Q3 and Q4 is independently either N or CR9;

[0329] Each R7 is independently either H or C. 1-6 alkyl;

[0330] Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 Cycloalkanes or 4- to 7-membered heterocycles;

[0331] Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkanes, 4- to 7-membered heterocycles, C 6-10 Aromatic hydrocarbons or 5- to 10-membered heteroaromatic hydrocarbons;

[0332] Each h is independently 0, 1, 2, 3 or 4;

[0333] Each k is independently 0, 1, 2, 3 or 4;

[0334] Each z is independently 0, 1, or 2;

[0335] Each 'o' is independently 0, 1, or 2;

[0336] Each r and s is independently 1, 2, or 3;

[0337] Each t and u is independently 1, 2, or 3.

[0338] In one specific implementation plan, U is:

[0339] in,

[0340] Q3 is either N or CR9;

[0341] Each R9 is independently H, D, or halogen;

[0342] Each k is independently 0, 1, or 2.

[0343] In another specific implementation scheme, U is:

[0344] in,

[0345] Q3 is either N or CR9;

[0346] Each R9 is independently H, D, or halogen;

[0347] Each k is independently 0, 1, or 2.

[0348] In another specific implementation scheme, U is:

[0349] in,

[0350] Q3 is either N or CR9;

[0351] Each R9 is independently H, D, or halogen;

[0352] Each k is independently 0, 1, or 2.

[0353] In a more specific implementation scheme, U is:

[0354] In another, more specific implementation scheme, U is

[0355] In one implementation scheme, U is:

[0356] in,

[0357] Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0358] Each R 10 Each can be independently H, -CH3, -OCH2CH2OH, -(OCH2CH2)2OH,

[0359] Each R 11 Each can be independently H, Cl, -CN, ethynyl, phenyl,

[0360] In another specific implementation scheme, U is:

[0361] in,

[0362] V, R 10 and R 11 As defined above;

[0363] Each R 12 Each independently constitutes -CH3,

[0364] Each R 13 Each can be independently -CH3, -CH(CH3)2, -C(CH3)3 or -OCH3.

[0365] In a more specific implementation scheme, U is:

[0366] In another, more specific implementation, U is:

[0367] In another, more specific implementation, U is:

[0368] 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 X1 can be combined with X2, Y1, Y2, Z1, Z2, Z3, W1, W2, R1, R2, R3, R4, R5, l, R a R b m, n, R c , R, R', L, L1, L2, L3, i, j, k, S0, S1, S2, S3, p, q, U, V, W, Q1, Q2, Q3, Q4, K1, K 2. K3, K4, K5, H1, H2, H3, H4, H5, H6, H7, H8, R7, R8, R9, o, h, r, s, t, u, k, z, R 10 R 11 R 12 and R 13 This invention involves combining any technical solution or any combination thereof. The present invention aims to include combinations of all these technical solutions; however, due to space limitations, they will not be listed individually.

[0369] In one embodiment, the present invention relates to a compound of formula (A), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0370] in,

[0371] X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R;

[0372] Y1 is -NR c -CO-, a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein said group is optionally substituted by one or more groups selected from R' groups;

[0373] Z1 is either CR3 or N;

[0374] Z2 can be CH, CD, or N;

[0375] Z3 is either CR4R5 or NR4;

[0376] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0377] l can be 0, 1, or 2;

[0378] R4 and R5 are independently H, D, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally substituted with one or more D atoms until it is fully deuterated;

[0379] Or R4 and an R, along with the atoms they are attached to, form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0380] Or R4 and an R' together with the atoms they are attached to form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0381] Or an R and an R' together with the atoms they are attached to form C. 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0382] Or an R and R c Together with the atoms they are attached to, they form C 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0383] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0384] m can be 0, 1, 2, 3, or 4;

[0385] n is 0, 1, 2, or 3;

[0386] R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0387] Each R and R' is independently H, D, halogen, -CN, C.1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0388] L represents a chemical bond or a divalent linking group;

[0389] U is a group that binds to E3 ubiquitin ligase.

[0390] 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:

[0391] in,

[0392] X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R;

[0393] Y1 is -NR c -CO-, a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein said group is optionally substituted by one or more groups selected from R' groups;

[0394] Z1 is either CR3 or N;

[0395] Z2 can be CH, CD, or N;

[0396] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0397] l can be 0, 1, or 2;

[0398] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0399] m can be 0, 1, 2, 3, or 4;

[0400] n is 0, 1, 2, or 3;

[0401] R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0402] Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0403] L represents a chemical bond or a divalent linking group;

[0404] U is a group that binds to E3 ubiquitin ligase.

[0405] In one embodiment, the present invention relates to formula (I) A Compounds, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0406] In another embodiment, the present invention relates to formula (I) B Compounds, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0407] In one embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) BThe compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon containing 1 to 3 heteroatoms selected from N, S and O, wherein the group is substituted by a -LU group and optionally substituted by 1, 2 or 3 groups selected from R.

[0408] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I B A compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein X1 is:

[0409] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I B A compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein X1 is:

[0410] ^Represents the connection point of formula X1 with the methylene group bonded to X1 and Y1.

[0411] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R is independently H, D, F, Cl, -CN, -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxecyclobutyl, wherein the -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxecyclobutyl is optionally substituted by one or more Ds until fully deuterated.

[0412] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R is independently H, D, F, Cl, -CN, -CH2CH3, cyclopropyl, or cyclopropylmethyl.

[0413] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Y1 is a divalent group of a 5- to 6-membered heteroaromatic hydrocarbon or benzene ring containing 1 to 3 heteroatoms selected from N, S, and O, wherein said group is optionally substituted by 1, 2, 3, or 4 groups selected from R'.

[0414] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Y1 is:

[0415] Where W1 is N or CR'.

[0416] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B A compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein Y1 is:

[0417] Where W1 is N or CR';

[0418] *The connection point of formula Y1 to the methylene group bonded to X1 and Y1.

[0419] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R' is independently H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CHF2, -CF3, or methoxy, wherein the -CH3, -CH2CH3, -CHF2, -CF3, or methoxy group is optionally substituted by one or more D groups up to complete deuteration.

[0420] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R' is independently H, D, F, Cl, -CH3 or -CD3.

[0421] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B A compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein Y1 is -NR c -CO-.

[0422] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein R c It can be -CH3 or -CD3.

[0423] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B ( ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein Z1 is CR3; Z2 is CH.

[0424] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, R2 and R3 are independently H, D, F, Cl, -CH3, -CD3 or -CF3.

[0425] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B A compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein R1 is -CH3; R2 is F; and R3 is H.

[0426] In another embodiment, the present invention relates to formula (I), formula (I) A ) or formula (I) B (a) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein m and n are both 0.

[0427] In one embodiment, the present invention relates to formula (I) A1 ) to formula (I A5 ') compounds, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0428] in,

[0429] W1 is either N or CR';

[0430] R and R' are independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0431] L represents a chemical bond or a divalent linking group;

[0432] U is a group that binds to E3 ubiquitin ligase.

[0433] In another embodiment, the present invention relates to formula (I) A1 ) to formula (I A5 ') A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R is independently H, D, halogen, -CN, C 1-6 Alkyl or C 0-6 Alkylene-C 3-7 cycloalkyl, wherein the C 1-6 Alkyl or C 0-6 Alkylene-C 3-7 The cycloalkyl group is optionally substituted with one or more D molecules, up to complete deuteration.

[0434] In another embodiment, the present invention relates to formula (I) A1 ) to formula (I A5A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R is independently H, D, F, Cl, -CN, -CH2CH3, cyclopropyl, or cyclopropylmethyl, wherein the -CH2CH3, cyclopropyl, or cyclopropylmethyl is optionally substituted by one or more Ds up to complete deuteration.

[0435] In another embodiment, the present invention relates to formula (I) A1 ) to formula (I A5 A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R' is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with one or more D molecules, up to and including complete deuteration.

[0436] In another embodiment, the present invention relates to formula (I) A1 ) to formula (I A5 R') a compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R' is independently H, D, F, Cl, -CH3 or -CD3.

[0437] In one embodiment, the present invention relates to formula (I) A6 Compounds, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0438] in,

[0439] R can be independently H, D, halogen, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0- 6-alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0- The 6-alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0440] R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0441] L represents a chemical bond or a divalent linking group;

[0442] U is a group that binds to E3 ubiquitin ligase.

[0443] In another embodiment, the present invention relates to formula (I) A6 A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R is independently -CN.

[0444] In another embodiment, the present invention relates to formula (I) A6 ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein R c It can be -CH3 or -CD3 independently.

[0445] In one embodiment, the present invention relates to a compound of formula (B), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0446] in,

[0447] X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is optionally substituted by one or more groups selected from R;

[0448] Y2 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R' groups;

[0449] Z1 is either CR3 or N;

[0450] Z2 can be CH, CD, or N;

[0451] Z3 is either CR4R5 or NR4;

[0452] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0453] l can be 0, 1, or 2;

[0454] R4 and R5 are independently H, D, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally substituted with one or more D atoms until it is fully deuterated;

[0455] Or R4 and an R, along with the atoms they are attached to, form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0456] Or R4 and an R' together with the atoms they are attached to form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0457] Or an R and an R' together with the atoms they are attached to form C. 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated;

[0458] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0459] m can be 0, 1, 2, 3, or 4;

[0460] n is 0, 1, 2, or 3;

[0461] Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0462] L represents a chemical bond or a divalent linking group;

[0463] U is a group that binds to E3 ubiquitin ligase.

[0464] In one embodiment, the present invention relates to compounds of formula (II), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0465] in,

[0466] X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is optionally substituted by one or more groups selected from R;

[0467] Y2 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein the group is substituted by a -LU group and optionally by one or more groups selected from R';

[0468] Z1 is either CR3 or N;

[0469] Z2 can be CH, CD, or N;

[0470] R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0471] l can be 0, 1, or 2;

[0472] R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated;

[0473] m can be 0, 1, 2, 3, or 4;

[0474] n is 0, 1, 2, or 3;

[0475] R and R' are independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0476] L represents a chemical bond or a divalent linking group;

[0477] U is a group that binds to E3 ubiquitin ligase.

[0478] In one embodiment, the present invention relates to formula (II) A Compounds, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0479] In another embodiment, the present invention relates to formula (II) BCompounds, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0480] In one embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B The compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon containing 1 to 3 heteroatoms selected from N, S and O, wherein the group is optionally substituted by 1, 2 or 3 groups selected from R.

[0481] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein X2 is:

[0482] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein X2 is:

[0483] ^Represents the connection point of formula X2 with the methylene group bonded to X2 and Y2.

[0484] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R is independently H, D, F, Cl, -CN, -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxecyclobutyl, wherein the -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxecyclobutyl is optionally substituted by one or more Ds until fully deuterated.

[0485] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II)B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R is independently H, D, F, Cl, -CN, or -CH2CH3.

[0486] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B The compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein Y2 is a divalent group of a 5- to 6-membered heteroaromatic or benzene ring containing 1 to 3 heteroatoms selected from N, S and O, wherein the group is substituted by a -LU group and optionally substituted by 1, 2 or 3 groups selected from R'.

[0487] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein Y2 is:

[0488] Where W2 is N or CR'.

[0489] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein Y2 is:

[0490] Where W2 is N or CR';

[0491] *The connection point of formula Y2 to the methylene group bonded to X2 and Y2.

[0492] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R' is independently H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CHF2, -CF3, or methoxy, wherein the -CH3, -CH2CH3, -CHF2, -CF3, or methoxy group is optionally substituted by one or more D groups up to complete deuteration.

[0493] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R' is independently H, D, F, Cl, -CH3, or -CD3.

[0494] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B ( ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein Z1 is CR3; Z2 is CH.

[0495] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, R2 and R3 are independently H, D, F, Cl, -CH3, -CD3 or -CF3.

[0496] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B A compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein R1 is -CH3; R2 is F; and R3 is H.

[0497] In another embodiment, the present invention relates to formula (II), formula (II) A ) or formula (II) B (a) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein m and n are both 0.

[0498] In one embodiment, the present invention relates to formula (II) A1 ) to formula (II) A3 Compounds, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0499] in,

[0500] W2 is either N or CR';

[0501] R and R' are independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated;

[0502] L represents a chemical bond or a divalent linking group;

[0503] U is a group that binds to E3 ubiquitin ligase.

[0504] In another embodiment, the present invention relates to formula (II) A1 ) to formula (II) A3 Compounds, or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein each R is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 The alkoxy group is optionally substituted with one or more D atoms, up to complete deuteration.

[0505] In another embodiment, the present invention relates to formula (II) A1 ) to formula (II) A3 A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R is independently H, D, F, Cl, -CN, -CH3, -CH2CH3, methoxy, or ethoxy, wherein the -CH3, -CH2CH3, methoxy, or ethoxy is optionally substituted by one or more Ds up to complete deuteration.

[0506] In another embodiment, the present invention relates to (II) A1) to formula (II) A3 A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R is independently -CH3, -CH2CH3, -CD3 or -CD2CD3.

[0507] In another embodiment, the present invention relates to (II) A1 ) to formula (II) A3 A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R' is independently H, D, F, Cl, -CH3 or -CD3.

[0508] In one embodiment, the present invention relates to formula (A), formula (I), and formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein L is a divalent linking group as shown in formula (III):

[0509] -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-■(III)

[0510] in,

[0511] i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0.

[0512] L1, L2, and L3 are each chemical bonds that can be formed independently, or are selected from C. 3-7 A divalent group consisting of a cycloalkanes, a 4- to 7-membered heterocycle, or a 5- to 7-membered heteroaryl group, wherein the divalent group is optionally surrounded by one or more elements selected from D, halogens, -OH, -CN, C. 1- 3-alkyl and C 1-3 Substitution of alkyl groups;

[0513] S0, S1, S2, and S3 are each independently a chemical bond, namely -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, and -C(O)NH(CH2). p -、-C(O)(CH2) p-、-NHC(O)(CH2) p -、-(CH2) p -、-(CH2CH2O) q -、C 1-6 imide or C 1-6 Alynyl group; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0514] ■ indicates the end connected to U.

[0515] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein L is of formula (III A The divalent linker shown is:

[0516] -(L1) i -(L2) j -(L3) k -■(III A ).

[0517] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein L is of formula (III B The divalent linker shown is:

[0518] -(L1) i -S1-(L2) j -S2-(L3) k -■(III B ).

[0519] In another embodiment, the present invention relates to formula (A), formula (I), formula (I)A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein L is of formula (III C The divalent linker shown is:

[0520] -S0-(L1) i (L2) j -S2-(L3) k -S3-■(III C )

[0521] Among them, (L1) i and (L2) j They share an atom and / or a chemical bond.

[0522] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein L is of formula (III D The divalent linker shown is:

[0523] -S0-(L1) i -S1-(L2) j (L3) k -S3-■(III D )

[0524] Among them, (L2) j and (L3) k They share an atom and / or a chemical bond.

[0525] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (IA6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein one or two of L1, L2, and L3 are chemically bonded, and the remaining individual groups are each selected from a 4- to 7-membered heterocycle containing one or two nitrogen atoms; wherein the divalent groups are optionally bonded by one or more of D, halogens, -OH, -CN, C 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0526] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein L is:

[0527] The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0528] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II)A3 ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein L is:

[0529] The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0530] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein L is:

[0531] The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

[0532] In one embodiment, the present invention relates to formula (A), formula (I), and formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein U is:

[0533] in,

[0534] Indicates a single bond or a double bond;

[0535] Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0536] Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0537] Each Q1 is independently C(O) or C(R9)2;

[0538] Each Q2 is independently either N or CH;

[0539] Each Q3 and Q4 is independently either N or CR9;

[0540] Each of K1, K2, and K3 is independently either N or CR9;

[0541] K4 and K5 are each independently N or C;

[0542] H1 is N, C, or CR9;

[0543] H2 and H3 are each independently C(O), N, O, S, NR9, CR9 or C(R9)2;

[0544] H4 and H8 are each independently N or CR9;

[0545] H5, H6, and H7 are each independently C(O), O, S, NR9, or C(R9)2; each R7 is independently H or C. 1-6 alkyl;

[0546] Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 Cycloalkanes or 4- to 7-membered heterocycles;

[0547] Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkanes, 4- to 7-membered heterocycles, C 6-10 Aromatic hydrocarbons or 5- to 10-membered heteroaromatic hydrocarbons;

[0548] Each 'o' is independently 0, 1, or 2;

[0549] Each h is independently 0, 1, 2, 3 or 4;

[0550] Each z is independently 0, 1, or 2;

[0551] Each r and s is independently 0, 1, 2, or 3; and r and s are not both 0 at the same time;

[0552] Each t and u is independently 0, 1, 2, or 3; and t and u are not both 0 at the same time.

[0553] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein U is:

[0554] in,

[0555] Indicates a single bond or a double bond;

[0556] Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0557] Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0558] Each Q1 is independently C(O) or C(R9)2;

[0559] Each Q2 is independently either N or CH;

[0560] Each Q3 and Q4 is independently either N or CR9;

[0561] Each R7 is independently either H or C. 1-6 alkyl;

[0562] Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 Cycloalkanes or 4- to 7-membered heterocycles;

[0563] Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkanes, 4- to 7-membered heterocycles, C 6-10 Aromatic hydrocarbons or 5- to 10-membered heteroaromatic hydrocarbons;

[0564] Each h is independently 0, 1, 2, 3 or 4;

[0565] Each k is independently 0, 1, 2, 3 or 4;

[0566] Each z is independently 0, 1, or 2;

[0567] Each 'o' is independently 0, 1, or 2;

[0568] Each r and s is independently 1, 2, or 3;

[0569] Each t and u is independently 1, 2, or 3.

[0570] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein U is:

[0571] in,

[0572] Q3 is either N or CR9;

[0573] Each R9 is independently H, D, or halogen;

[0574] Each k is independently 0, 1, or 2.

[0575] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II)A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein U is:

[0576] in,

[0577] Q3 is either N or CR9;

[0578] Each R9 is independently H, D, or halogen;

[0579] Each k is independently 0, 1, or 2.

[0580] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein U is:

[0581] in,

[0582] Q3 is either N or CR9;

[0583] Each R9 is independently H, D, or halogen;

[0584] Each k is independently 0, 1, or 2.

[0585] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein U is:

[0586] In one embodiment, the present invention relates to formula (A), formula (I), and formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein U is

[0587] In one embodiment, the present invention relates to formula (A), formula (I), and formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein U is:

[0588] in,

[0589] Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0590] Each R 10 Each can be independently H, -CH3, -OCH2CH2OH, -(OCH2CH2)2OH,

[0591] Each R 11 Each can be independently H, Cl, -CN, ethynyl, phenyl,

[0592] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II)A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein U is:

[0593] in,

[0594] Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0595] Each R 10 Each can be independently H, -CH3, -OCH2CH2OH, -(OCH2CH2)2OH,

[0596] Each R 11 Each can be independently H, Cl, -CN, ethynyl, phenyl,

[0597] Each R 12 Each independently constitutes -CH3,

[0598] Each R 13 Each can be independently -CH3, -CH(CH3)2, -C(CH3)3 or -OCH3.

[0599] In one embodiment, the present invention relates to formula (A), formula (I), and formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3 ) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein U is:

[0600] In another embodiment, the present invention relates to formula (A), formula (I), formula (I) A ), formula (I B ), formula (I A1 ) to formula (I A6 Formula (B), Formula (II), Formula (II) A Formula (II) B ) or formula (II) A1 ) to formula (II) A3) compound, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein U is:

[0601] In one embodiment, the present invention relates to a compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotope variant, hydrate, or solvate thereof, wherein the compound is selected from compounds of the following formula:

[0602] 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.

[0603] "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.

[0604] 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.

[0605] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed 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 in this invention can be prepared, for example, in a 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.

[0606] 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)).

[0607] 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.

[0608] 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.

[0609] 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 incorporates this invention by reference.

[0610] 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.

[0611] Pharmaceutical compositions, formulations and kits

[0612] 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.

[0613] 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.

[0614] 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.

[0615] The pharmaceutical compositions provided by this invention also include other therapeutic agents. In some embodiments, the other therapeutic agents are tyrosine kinase inhibitors (TKIs). In some embodiments, the tyrosine kinase inhibitors include: crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, taletrectinib, merestinib, masitetinib, or ensartinib.

[0616] 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, the parenteral administration methods used in this invention include 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.

[0617] Typically, an effective amount of the compound provided by this invention is administered. The amount of compound actually administered can be determined by a physician, depending 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.

[0618] When used to prevent the conditions described in this invention, the compound provided by this invention is administered to subjects at risk of developing the condition, 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.

[0619] The pharmaceutical compositions provided by this invention 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, for example, 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, for example, within a therapeutic window.

[0620] 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.

[0621] 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.

[0622] 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.

[0623] 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.

[0624] 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.

[0625] 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.

[0626] 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.

[0627] 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.

[0628] 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.

[0629] 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.

[0630] 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.

[0631] 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).

[0632] Indications

[0633] In another aspect, the present invention provides the use of the compounds of the present invention (including all individual embodiments and subsets of the species disclosed herein) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as the use of the pharmaceutical compositions or kits of the present invention as medicines.

[0634] In another aspect, the present invention provides a method for treating cancer, comprising administering compounds of the present invention (including all individual embodiments and subsets of the species disclosed herein) or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates thereof, as well as pharmaceutical compositions or kits of the present invention.

[0635] Cancer is a disease caused by uncontrolled cell proliferation due to changes in certain genes. Some of these changes occur in genes encoding receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that can transmit signals from outside the cell to promote cell survival, growth, and proliferation. Abnormal RTK activation leads to excessive cell growth, which in turn leads to cancer. Typically, RTKs contain an N-terminal domain that binds extracellular ligands, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signal transduction.

[0636] In one embodiment, the present invention provides a method for reducing ALK and / or ROS1 levels in cells, comprising contacting cells with compounds of the present invention (including all individual embodiments and subsets thereof disclosed herein) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as pharmaceutical compositions or kits of the present invention. In one embodiment, such contact occurs in cells of mammals such as humans. In one embodiment, such contact occurs in cells of a human patient suffering from a cancer provided by the present invention.

[0637] As described in this invention, unless otherwise stated, inhibition of ALK includes inhibition of wild-type ALK or its mutations; inhibition of ROS1 includes inhibition of wild-type ROS1 or its mutations.

[0638] Cancers treated by the methods of this invention include, but are not limited to, lung cancer (e.g., non-small cell lung cancer), inflammatory myofibroblastic tumor, ovarian cancer (e.g., serous ovarian cancer), melanoma (e.g., Spitz nevus-like melanoma), glioblastoma, cholangiocarcinoma (e.g., cholangiocarcinoma), gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, large B-cell lymphoma, esophageal cancer (e.g., esophageal squamous cell carcinoma), renal cancer (e.g., renal medullary carcinoma or renal cell carcinoma), breast cancer (e.g., triple-negative breast cancer), thyroid cancer (e.g., papillary thyroid carcinoma), neuroblastoma, epithelioid hemangioendothelioma, colon cancer, and Spitz nevus-like tumors.

[0639] Cancers treated by the methods of the present invention include cancers originating from one or more oncogenes selected from ALK and / or ROS1. In some embodiments, cancers treated by the methods of the present invention include cancers resistant to treatment against one or more oncogenes selected from ALK and / or ROS1.

[0640] In one embodiment, the cancer in the method provided by this invention is anaplastic lymphoma kinase positive (ALK+). As described in this invention, unless otherwise stated, "ALK-positive" (ALK+) cancer, disease, or condition refers to a cancer, disease, or condition characterized by inappropriate overexpression of the ALK gene and / or the presence of mutations in the ALK gene. In one embodiment, the mutation alters the biological activity of the ALK nucleic acid molecule or polypeptide. As described in this invention, unless otherwise stated, a "mutation" or "mutant" of ALK comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications of an amino acid or nucleotide sequence or fragment thereof of ALK. As described in this invention, unless otherwise stated, an ALK "rearrangement" refers to a genetic translocation involving the ALK gene that can produce an ALK fusion gene and / or an ALK fusion protein. ALK fusions may also comprise one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or fragments thereof, as long as the mutant retains kinase phosphorylation activity.

[0641] In one embodiment, the ALK mutation includes one or more ALK point mutations. In some embodiments, the cancer treated by the method of the present invention includes one or more mutations in the ALK kinase. In one embodiment, the one or more ALK point mutations are selected from point mutations at L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202, D1203, S1206, E1210, F1245, G1269, and R1275. In one implementation, one or more ALK point mutations are selected from G1202R, G1202K, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V.

[0642] In one embodiment, the ALK mutation includes one or more ALK rearrangements (in one embodiment, a rearrangement). In one embodiment, the ALK mutation includes one or more ALK fusions (in one embodiment, a fusion). In some embodiments, the cancer treated by the method of the present invention includes an ALK fusion. In one embodiment, the ALK fusion is a fusion with one of the following fusion partners: NPM1, ALO17, TFG, MSN, TPM3, TPM4, ATIC, MYH9, CLTC, TRAF1, EML4, KIF5B, KLC1, PTPN3, HIP1, TPR, STRN, SEC31A, RANBP2, PPFIBP1, CARS, SQSTM1, VCL, C2orf44, FN1, GFPT1, TMP1, WDCP, GTF2IRD1, LMNA, PRKAR1A, DCTN1, CRIM1, and FBXO36. In one embodiment, the ALK mutation is a fusion between the cytoplasmic domain of ALK and the N-terminus of nucleolar phosphoprotein 1 (NPM1). In another embodiment, the ALK mutation is a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain, known as EML4-ALK. There are many variants of EML4-ALK, differing in their breakpoint connections, with variant 1 (V1) and variants 3a / 3b (V3a / 3b) being the most common clinically.

[0643] In one embodiment, the ALK mutation includes an ALK rearrangement and one or more ALK point mutations. In one embodiment, the ALK mutation is EML4-ALK wt (variant 1). In one embodiment, the ALK mutation is EML4-ALKG1202R (variant 1). In one embodiment, the ALK mutation is EML4-ALK L1196M / G1202R (variant 1). In one embodiment, the ALK mutation is EML4-ALK G1202R / G1269A (variant 1). In one embodiment, the ALK mutation is EML4-ALK G1202R / L1198F (variant 1).

[0644] A method for treating a subject with cancer (e.g., ALK-positive cancer) is also provided, comprising: determining whether cancer cells in a sample obtained from a subject with cancer who has previously been treated with a first ALK inhibitor have one or more ALK inhibitor resistance mutations; and if the subject has cancer cells with one or more ALK inhibitor resistance mutations, administering to the subject a compound of the present invention (including all individual embodiments and subsets of the class disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as a pharmaceutical composition or kit of the present invention, as a monotherapy or in combination with another anticancer agent. In some embodiments, one or more ALK inhibitor resistance mutations confer increased resistance to treatment with a first ALK inhibitor. In some embodiments, one or more ALK inhibitor resistance mutations comprise one or more ALK inhibitor resistance mutations. For example, resistance mutations to one or more ALK inhibitors may include substitutions at one or more of the following amino acid positions: 1202, 1196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1151, 1174, 1203, 1206, 1152, 1196, 1198, 1275, 1152, 1156, and 1245, such as G1202R, L1196M, and G1269. A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the other anticancer agent may be another ALK inhibitor (e.g., a second ALK inhibitor).

[0645] In one embodiment, the cancer in the method provided by this invention is a ROS1-positive (ROS1+) cancer. As described in this invention, unless otherwise stated, “ROS1-positive (ROS1+) cancer, disease, or condition” refers to a cancer, disease, or condition characterized by inappropriate high expression of the ROS1 gene and / or the presence of mutations in the ROS1 gene. In one embodiment, the mutation alters the biological activity of the ROS1 nucleic acid molecule or polypeptide. As described in this invention, unless otherwise stated, a “mutation” or “mutant” of ROS1 comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications of an amino acid or nucleotide sequence or fragment thereof of ROS1. As described in this invention, unless otherwise stated, a “ROS1 rearrangement” refers to a genetic translocation involving the ROS1 gene that can produce a ROS1 fusion gene and / or a ROS1 fusion protein. ROS1 fusions may also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or fragments thereof, provided that the mutant retains kinase phosphorylation activity.

[0646] In one embodiment, the ROS1 mutation includes one or more ROS1 point mutations. In some embodiments, the cancer treated by the method of the present invention includes one or more mutations in the ROS1 kinase. In one embodiment, the one or more ROS1 point mutations are selected from point mutations at E1935, L1947, L1951, G1971, E1974, L1982, S1986, F2004, E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101, D2113, and L2155. In one implementation, one or more ROS1 point mutations are selected from G2032R, G2032K, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, and L2086F.

[0647] In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements (in one embodiment, a rearrangement). In one embodiment, the ROS1 mutation comprises one or more ROS1 fusions (in one embodiment, a fusion). In some embodiments, cancers treated by the methods of the present invention comprise ROS1 fusions. In one embodiment, the ROS1 fusion is a fusion with one of the following fusion partners: SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC (e.g., GOPC-S, GOPC-L), GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17. SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8, CCDC6, CAPRIN1, CEP85L, CHCHD3, CLIP1, EEF1G, KIF21A, KLC1, SART3, ST13, TRIM24, ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1. In one embodiment, the ROS1 fusion is a CD74-ROS1 fusion. In one embodiment, the ROS1 fusion is an SDC4-ROS1 fusion. In one embodiment, the ROS1 fusion is an EZR-ROS1 fusion. In one embodiment, the ROS1 fusion is an SLC34A2-ROS1 fusion. In one embodiment, the ROS1 fusion is a GOPC-ROS1 fusion (e.g., GOPC-ROS1-S, GOPC-ROS1-L). In another embodiment, the ROS1 fusion is a CEP85L-ROS1 fusion.

[0648] In one embodiment, the ROS1 mutation includes a ROS1 rearrangement and one or more ROS1 point mutations. In one embodiment, the ROS1 mutation includes one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (e.g., GOPC-ROS1-S, GOPC-ROS1-L), and CEP85L-ROS1, and one or more ROS1 point mutations selected from F2004C, F2004V, and G2032R. In one embodiment, the ROS1 mutation includes one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, and SLC34A2-ROS1, and a ROS1 point mutation from G2101A.

[0649] In one embodiment, ROS1 is mutated to CD74-ROS1 F2004C. In one embodiment, ROS1 is mutated to CD74-ROS1 F2004V. In one embodiment, ROS1 is mutated to CD74-ROS1 G2101A. In one embodiment, ROS1 is mutated to CD74-ROS1 G2032R. In one embodiment, ROS1 is mutated to CD74-ROS1 S1986F. In one embodiment, ROS1 is mutated to CD74-ROS1 L2026M. In one embodiment, ROS1 is mutated to CD74-ROS1 D2033N. In one embodiment, ROS1 is mutated to EZR-ROS1 F2004C. In one embodiment, ROS1 is mutated to EZR-ROS1 F2004V. In one embodiment, ROS1 is mutated to EZR-ROS1 G2101A. In one embodiment, ROS1 is mutated to EZR-ROS1 G2032R. In one embodiment, ROS1 is mutated to SLC34A2-ROS1F2004C. In one embodiment, ROS1 is mutated to SLC34A2-ROS1 F2004V. In one embodiment, ROS1 is mutated to SLC34A2-ROS1 G2101A. In one embodiment, ROS1 is mutated to SLC34A2-ROS1 G2032R. In one embodiment, ROS1 is mutated to GOPC-ROS1 F2004C (e.g., GOPC-ROS1-S F2004C, GOPC-ROS1-LF2004C). In one embodiment, ROS1 is mutated to GOPC-ROS1 F2004V (e.g., GOPC-ROS1-S F2004V, GOPC-ROS1-L F2004V). In one embodiment, ROS1 is mutated to GOPC-ROS1 G2032R (e.g., GOPC-ROS1-S G2032R, GOPC-ROS1-L G2032R). In one embodiment, ROS1 is mutated to CEP85L-ROS1F2004C. In one embodiment, ROS1 is mutated to CEP85L-ROS1 F2004V. In one embodiment, ROS1 is mutated to CEP85L-ROS1 G2032R. In one embodiment, ROS1 is mutated to GOPC-ROS1 L1982F (e.g., GOPC-ROS1-S L1982F, GOPC-ROS1-L L1982F). In one embodiment, ROS1 is mutated to CD74-ROS1L1982F.

[0650] A method for treating a subject with cancer (e.g., ROS1-positive cancer) is also provided, comprising: determining whether cancer cells in a sample obtained from a subject with cancer who has previously been treated with a first ROS1 inhibitor have one or more ROS1 inhibitor resistance mutations; and if the subject has cancer cells with one or more ROS1 inhibitor resistance mutations, administering the compound of the present invention (including all individual embodiments and subsets of the class disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as the pharmaceutical composition or kit of the present invention, to the subject as a monotherapy or in combination with another anticancer agent. In some embodiments, one or more ROS1 inhibitor resistance mutations confer increased resistance of cancer cells or tumors to treatment with a first ROS1 inhibitor. In some embodiments, one or more ROS1 inhibitor resistance mutations comprise one or more ROS1 inhibitor resistance mutations. For example, resistance mutations to one or more ROS1 inhibitors may include substitutions at one or more of the following amino acid positions: 2032, 2033, 1986, 2026, 1951, 1935, 1947, 1971, 1974, 1982, 2004, 2020, 2060, 2075, 2089, 2098, 2101, 2113, 2155, 2032, and 2086, such as G2032R, D203. 3N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the other anticancer agent may be another ROS1 inhibitor (e.g., a second ROS1 inhibitor).

[0651] In one embodiment, the compound provided by the present invention is a compound that penetrates the CNS. In one embodiment, after administration of an effective amount of the compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, and pharmaceutical compositions or kits of the present invention, said compound is able to penetrate the CNS (e.g., the blood-brain barrier) and reach concentrations in the CNS (e.g., the brain) sufficient to inhibit (e.g., selectively inhibit) both ALK and ROS1.

[0652] In one embodiment, the present invention provides a method for treating CNS metastases of cancer, comprising administering to a subject in need an effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as the pharmaceutical compositions or kits of the present invention. In one embodiment, the CNS metastasis is a brain metastasis. In one embodiment, the cancer is an ALK+ cancer. In one embodiment, the cancer is a ROS1+ cancer.

[0653] In one embodiment, the present invention provides a method for treating cancer, comprising administering to a subject in need a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as the pharmaceutical compositions or kits of the present invention. In one embodiment, the cancer is ALK-related cancer. In one embodiment, the cancer is ALK+ cancer. In one embodiment, the cancer is identified as ALK+. In one embodiment, the cancer is ROS1-related cancer. In one embodiment, the cancer is ROS1+ cancer. In one embodiment, the cancer is identified as ROS1+.

[0654] In one embodiment, the present invention provides a method for treating ALK+ cancer, comprising administering to a subject in need a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as the pharmaceutical compositions or kits of the present invention.

[0655] In one embodiment, the present invention provides a method for treating ROS1+ cancer, comprising administering to a subject in need a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as the pharmaceutical compositions or kits of the present invention.

[0656] In one embodiment, the present invention provides a method for treating a subject's cancer, comprising: (i) identifying the subject's cancer as ALK+, and (ii) administering to the subject a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as the pharmaceutical compositions or kits of the present invention.

[0657] In one embodiment, the present invention provides a method for treating a subject's cancer, comprising: (i) identifying the subject's cancer as ROS1+, and (ii) administering to the subject a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the class disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as the pharmaceutical composition or kit of the present invention.

[0658] In one implementation, the cancer (or ALK+ cancer or ROS1+ cancer) is a solid tumor. In another implementation, the cancer (or ALK+ cancer or ROS1+ cancer) is lung cancer (e.g., non-small cell lung cancer), glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma (e.g., cholangiocarcinoma), ovarian cancer (e.g., serous ovarian cancer), gastric cancer, colorectal cancer, angiosarcoma, melanoma (e.g., Spitz nevus-like melanoma), epithelioid hemangioendothelioma, esophageal cancer (e.g., esophageal squamous cell carcinoma), renal cancer (e.g., renal medullary carcinoma or renal cell carcinoma), breast cancer (e.g., triple-negative breast cancer), colon cancer, thyroid cancer (e.g., papillary thyroid carcinoma), Spitz nevus-like tumor, or neuroblastoma.

[0659] In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is ALK+ non-small cell lung cancer. In one embodiment, the cancer is ROS1+ non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory ALK+ non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ALK+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ROS1+ non-small cell lung cancer.

[0660] In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is ALK+ glioblastoma. In one embodiment, the cancer is ROS1+ glioblastoma. In one embodiment, the cancer is relapsed or refractory glioblastoma. In one embodiment, the cancer is relapsed or refractory ALK+ glioblastoma. In one embodiment, the cancer is relapsed or refractory ROS1+ glioblastoma. In one embodiment, the cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed ALK+ glioblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ glioblastoma.

[0661] In one embodiment, the cancer is IMT. In one embodiment, the cancer is ALK+IMT. In one embodiment, the cancer is ROS1+IMT. In one embodiment, the cancer is relapsed or refractory IMT. In one embodiment, the cancer is relapsed or refractory ALK+IMT. In one embodiment, the cancer is relapsed or refractory ROS1+IMT. In one embodiment, the cancer is newly diagnosed IMT. In one embodiment, the cancer is newly diagnosed ALK+IMT. In one embodiment, the cancer is newly diagnosed ROS1+IMT.

[0662] In one embodiment, the cancer is bile duct cancer. In another embodiment, the cancer is cholangiocarcinoma. In one embodiment, the cancer is ALK+ cholangiocarcinoma. In one embodiment, the cancer is ROS1+ cholangiocarcinoma. In one embodiment, the cancer is recurrent or refractory cholangiocarcinoma. In one embodiment, the cancer is recurrent or refractory ALK+ cholangiocarcinoma. In one embodiment, the cancer is recurrent or refractory ROS1+ cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed ALK+ cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ cholangiocarcinoma.

[0663] In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is ALK+ ovarian cancer. In one embodiment, the cancer is ROS1+ ovarian cancer. In one embodiment, the cancer is recurrent or refractory ovarian cancer. In one embodiment, the cancer is recurrent or refractory ALK+ ovarian cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ovarian cancer. In one embodiment, the cancer is newly diagnosed ALK+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ROS1+ ovarian cancer. In one embodiment, the ovarian cancer is serous ovarian cancer. In one embodiment, the ovarian cancer is high-grade serous ovarian cancer.

[0664] In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is ALK+ gastric cancer. In one embodiment, the cancer is ROS1+ gastric cancer. In one embodiment, the cancer is recurrent or refractory gastric cancer. In one embodiment, the cancer is recurrent or refractory ALK+ gastric cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ gastric cancer. In one embodiment, the cancer is newly diagnosed gastric cancer. In one embodiment, the cancer is newly diagnosed ALK+ gastric cancer. In one embodiment, the cancer is newly diagnosed ROS1+ gastric cancer.

[0665] In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is ALK+ colorectal cancer. In one embodiment, the cancer is ROS1+ colorectal cancer. In one embodiment, the cancer is recurrent or refractory colorectal cancer. In one embodiment, the cancer is recurrent or refractory ALK+ colorectal cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ colorectal cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is newly diagnosed ALK+ colorectal cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colorectal cancer.

[0666] In one embodiment, the cancer is angiosarcoma. In one embodiment, the cancer is ALK+ angiosarcoma. In one embodiment, the cancer is ROS1+ angiosarcoma. In one embodiment, the cancer is relapsed or refractory angiosarcoma. In one embodiment, the cancer is relapsed or refractory ALK+ angiosarcoma. In one embodiment, the cancer is relapsed or refractory ROS1+ angiosarcoma. In one embodiment, the cancer is a newly diagnosed angiosarcoma. In one embodiment, the cancer is a newly diagnosed ALK+ angiosarcoma. In one embodiment, the cancer is a newly diagnosed ROS1+ angiosarcoma.

[0667] In one embodiment, the cancer is melanoma. In one embodiment, the cancer is a Spitz nevus-like tumor. In one embodiment, the cancer is a Spitz nevus-like melanoma. In one embodiment, the cancer is ALK+ Spitz nevus-like melanoma. In one embodiment, the cancer is ROS1+ Spitz nevus-like melanoma. In one embodiment, the cancer is relapsed or refractory Spitz nevus-like melanoma. In one embodiment, the cancer is relapsed or refractory ALK+ Spitz nevus-like melanoma. In one embodiment, the cancer is relapsed or refractory ROS1+ Spitz nevus-like melanoma. In one embodiment, the cancer is a newly diagnosed Spitz nevus-like melanoma. In one embodiment, the cancer is a newly diagnosed ALK+ Spitz nevus-like melanoma. In one embodiment, the cancer is a newly diagnosed ROS1+ Spitz nevus-like melanoma.

[0668] In one embodiment, the cancer is an epithelioid hemangioendothelioma. In one embodiment, the cancer is an ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a relapsed or refractory epithelioid hemangioendothelioma. In one embodiment, the cancer is a relapsed or refractory ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a relapsed or refractory ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed ROS1+ epithelioid hemangioendothelioma.

[0669] In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is esophageal squamous cell carcinoma. In one embodiment, the cancer is ALK+ esophageal squamous cell carcinoma. In one embodiment, the cancer is ROS1+ esophageal squamous cell carcinoma. In one embodiment, the cancer is recurrent or refractory esophageal squamous cell carcinoma. In one embodiment, the cancer is recurrent or refractory ALK+ esophageal squamous cell carcinoma. In one embodiment, the cancer is recurrent or refractory ROS1+ esophageal squamous cell carcinoma. In one embodiment, the cancer is newly diagnosed esophageal squamous cell carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ esophageal squamous cell carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ esophageal squamous cell carcinoma.

[0670] In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is renal medullary carcinoma. In one embodiment, the cancer is ALK+ renal medullary carcinoma. In one embodiment, the cancer is ROS1+ renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory ALK+ renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory ROS1+ renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ renal medullary carcinoma. In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is ALK+ renal cell carcinoma. In one embodiment, the cancer is ROS1+ renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory ALK+ renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory ROS1+ renal cell carcinoma. In one embodiment, the cancer is newly diagnosed renal cell carcinoma. In one implementation, the cancer is a newly diagnosed ALK+ renal cell carcinoma. In another implementation, the cancer is a newly diagnosed ROS1+ renal cell carcinoma.

[0671] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ALK+ breast cancer. In one embodiment, the cancer is ROS1+ breast cancer. In one embodiment, the cancer is recurrent or refractory breast cancer. In one embodiment, the cancer is recurrent or refractory ALK+ breast cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ breast cancer. In one embodiment, the cancer is newly diagnosed breast cancer. In one embodiment, the cancer is newly diagnosed ALK+ breast cancer. In one embodiment, the cancer is newly diagnosed ROS1+ breast cancer. In one embodiment, the breast cancer is triple-negative breast cancer.

[0672] In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is ALK+ colon cancer. In one embodiment, the cancer is ROS1+ colon cancer. In one embodiment, the cancer is recurrent or refractory colon cancer. In one embodiment, the cancer is recurrent or refractory ALK+ colon cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ colon cancer. In one embodiment, the cancer is newly diagnosed colon cancer. In one embodiment, the cancer is newly diagnosed ALK+ colon cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colon cancer.

[0673] In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is papillary thyroid carcinoma. In one embodiment, the cancer is ALK+ papillary thyroid carcinoma. In one embodiment, the cancer is ROS1+ papillary thyroid carcinoma. In one embodiment, the cancer is recurrent or refractory papillary thyroid carcinoma. In one embodiment, the cancer is recurrent or refractory ALK+ papillary thyroid carcinoma. In one embodiment, the cancer is recurrent or refractory ROS1+ papillary thyroid carcinoma. In one embodiment, the cancer is newly diagnosed papillary thyroid carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ papillary thyroid carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ papillary thyroid carcinoma.

[0674] In one embodiment, the cancer is a neuroblastoma. In one embodiment, the cancer is an ALK+ neuroblastoma. In one embodiment, the cancer is a ROS1+ neuroblastoma. In one embodiment, the cancer is a relapsed or refractory neuroblastoma. In one embodiment, the cancer is a relapsed or refractory ALK+ neuroblastoma. In one embodiment, the cancer is a relapsed or refractory ROS1+ neuroblastoma. In one embodiment, the cancer is a newly diagnosed neuroblastoma. In one embodiment, the cancer is a newly diagnosed ALK+ neuroblastoma. In one embodiment, the cancer is a newly diagnosed ROS1+ neuroblastoma.

[0675] In one embodiment, the cancer (or ALK+ cancer or ROS1+ cancer) is a hematologic cancer. In one embodiment, the cancer (or ALK+ cancer or ROS1+ cancer) is a lymphoma. In one embodiment, the lymphoma is non-Hodgkin's lymphoma. In one embodiment, the lymphoma is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma. In addition to hematologic cancers, the present invention also provides methods for treating other hematologic disorders or hematologic malignancies that are ALK+ or ROS1+.

[0676] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is ALK+ALCL. In one embodiment, the cancer is ROS1+ALCL. In one embodiment, the cancer is relapsed or refractory ALCL. In one embodiment, the cancer is relapsed or refractory ALK+ALCL. In one embodiment, the cancer is relapsed or refractory ROS1+ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ALK+ALCL. In one embodiment, the cancer is newly diagnosed ROS1+ALCL.

[0677] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is ALK+DLBCL. In one embodiment, the cancer is ROS1+DLBCL. In one embodiment, the cancer is relapsed or refractory DLBCL. In one embodiment, the cancer is relapsed or refractory ALK+DLBCL. In one embodiment, the cancer is relapsed or refractory ROS1+DLBCL. In one embodiment, the cancer is newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed ALK+DLBCL. In one embodiment, the cancer is newly diagnosed ROS1+DLBCL.

[0678] In one embodiment, the cancer is large B-cell lymphoma. In one embodiment, the cancer is ALK+ large B-cell lymphoma. In one embodiment, the cancer is ROS1+ large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory ALK+ large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory ROS1+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed ALK+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed ROS1+ large B-cell lymphoma.

[0679] In one implementation, the cancer (or ALK+ cancer or ROS1+ cancer) is newly diagnosed. In another implementation, the cancer (or ALK+ cancer or ROS1+ cancer) has not been previously treated.

[0680] In one implementation, the cancer (or ALK+ cancer or ROS1+ cancer) is relapsed or refractory. In one implementation, the cancer is relapsed. In one implementation, the cancer (or ALK+ cancer or ROS1+ cancer) is refractory.

[0681] In one embodiment, the subject has not received prior treatment. In one embodiment, the subject has not been treated with a tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the subject has received one or more prior therapies. In one embodiment, the subject has received two or more prior therapies. In one embodiment, the subject has developed resistance to one or more prior therapies. In one embodiment, the prior therapy includes a tyrosine kinase inhibitor (TKI). In one embodiment, the prior therapy includes one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, and ensartinib. In one embodiment, the prior therapy includes one or more chemotherapy therapies. In one embodiment, one or more chemotherapy therapies are supplemental to TKI therapy.

[0682] In one implementation, the cancer (or ALK+ cancer or ROS1+ cancer) is resistant to tyrosine kinase inhibitors (TKIs).

[0683] In one embodiment, the cancer is drug-resistant lung cancer. In one embodiment, the cancer is drug-resistant non-small cell lung cancer. In one embodiment, the cancer is non-small cell lung cancer resistant to TKI. In one embodiment, the cancer is ALK+ non-small cell lung cancer resistant to TKI. In one embodiment, the cancer is ROS1+ non-small cell lung cancer resistant to TKI.

[0684] In one implementation, the cancer is lung cancer (e.g., non-small cell lung cancer), and the cancer has relapsed after treatment with a TKI or was refractory before the treatment.

[0685] In one embodiment, the compound provided by the present invention is administered as a first-line treatment. In one embodiment, the compound provided by the present invention is administered as a second-line treatment. In one embodiment, the compound provided by the present invention is administered as a third- or fourth-line treatment.

[0686] In one embodiment, the cancer (or ALK+ cancer or ROS1+ cancer) is metastatic. In one embodiment, the cancer has CNS metastases. In one embodiment, the cancer has brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer (NSCLC). In one embodiment, the cancer is metastatic ALK+ NSCLC. In one embodiment, the cancer is metastatic ROS1+ NSCLC.

[0687] In one embodiment, the present invention provides a method for treating a patient with metastatic ALK+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as a pharmaceutical composition or kit of the present invention.

[0688] In one embodiment, the present invention provides a method for treating a patient with metastatic ROS1+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as a pharmaceutical composition or kit of the present invention.

[0689] In one implementation, the patient is an adult patient. In another implementation, the patient is a pediatric patient.

[0690] In one embodiment, the present invention provides a method for treating ALK-related (or ALK+) cancer in a subject of need, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as a pharmaceutical composition or kit of the present invention.

[0691] In one embodiment, the present invention provides a method for treating ALK-related (or ALK+) cancer in a subject of need, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ALK inhibitor resistance mutations. The method comprises administering to the subject a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as a pharmaceutical composition or kit of the present invention.

[0692] In one embodiment, one or more ALK inhibitor resistance mutations comprise one or more amino acid substitutions at positions selected from amino acids 1196, 1198, 1202, and 1269. In one embodiment, one or more ALK inhibitor resistance mutations comprise one or more amino acid substitutions selected from L1196M, L1198F, G1202R, and G1269A. In one embodiment, one or more ALK inhibitor resistance mutations are G1202R. In one embodiment, one or more ALK inhibitor resistance mutations comprise G1202R and one or more of L1196M, L1198F, and G1269A.

[0693] In one embodiment, the present invention provides a method for treating an adult patient with metastatic NSCLC, the metastatic NSCLC being ALK+ with the G1202R mutation, the method comprising administering to the patient a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the class disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as the pharmaceutical compositions or kits of the present invention.

[0694] In one embodiment, the present invention provides a method for treating ALK-related (or ALK+) cancer in a subject of need, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as a pharmaceutical composition or kit of the present invention.

[0695] In one embodiment, the present invention provides a method for treating an adult patient with metastatic ROS1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as a pharmaceutical composition or kit of the present invention.

[0696] In one embodiment, the present invention provides a method for treating an adult patient with metastatic ROS1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as a pharmaceutical composition or kit of the present invention.

[0697] In one embodiment, the present invention provides a method for treating an adult patient with metastatic NSCLC, the metastatic NSCLC being ROS1+ and having a solvation front mutation G2032R, the method comprising administering to the patient a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the class disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as the pharmaceutical compositions or kits of the present invention.

[0698] In one embodiment, the present invention provides a method for treating ROS1-related (or ROS1+) cancer in a subject of need, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as a pharmaceutical composition or kit of the present invention.

[0699] In one embodiment, the present invention provides a method for treating ROS1-related (or ROS1+) cancer in a subject of need, wherein the cancer is resistant to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ROS1 inhibitor resistance mutations. The method comprises administering to the subject a therapeutically effective amount of a compound provided by the present invention (including all individual embodiments and subsets of the species disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as a pharmaceutical composition or kit of the present invention. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise amino acid substitutions at positions selected from amino acids 1986, 2004, 2026, 2032, and 2033. In one embodiment, one or more ROS1 inhibitor resistance mutations comprise one or more amino acid substitutions selected from S1986F, S1986Y, F2004C, F2004V, L2026M, G2032R, D2033N, L2086F, and G2101A. In one embodiment, one or more ROS1 inhibitor resistance mutations are G2032R. In one embodiment, one or more ROS1 inhibitor resistance mutations comprise G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101A. In one embodiment, the ROS1 inhibitor resistance mutation is L2086F.

[0700] In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib.

[0701] In some implementations, the subject experienced cancer recurrence after first-line cancer treatment. In other implementations, the subject experienced cancer recurrence after second-line cancer treatment.

[0702] In one implementation, the cancer or disease occurs in a pediatric patient (including an infant). In one implementation, the cancer in pediatric patients aged 1 year or older and young adults is ALK+ systemic anaplastic large cell lymphoma (ALCL). In another implementation, the cancer in pediatric patients aged 1 year or older and young adults is ALK+ relapsed or refractory systemic anaplastic large cell lymphoma (ALCL). In one implementation, the cancer in pediatric patients aged 1 year or older and young adults is ROS1+ systemic anaplastic large cell lymphoma (ALCL). In another implementation, the cancer in pediatric patients aged 1 year or older and young adults is ROS1+ relapsed or refractory systemic anaplastic large cell lymphoma (ALCL).

[0703] In some implementations, the method for treating or preventing cancer can be demonstrated through one or more reactions, such as increased apoptosis, inhibition of tumor growth, reduction of tumor metastasis, inhibition of tumor metastasis, reduction of microvascular density, reduction of neovascularization, inhibition of tumor migration, tumor regression, and increased subject survival.

[0704] In some embodiments, the compounds of the present invention (including all individual embodiments and subsets thereof disclosed herein) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as the pharmaceutical compositions or kits of the present invention, can be administered to patients, such as cancer patients, as monotherapy or combination therapy. The therapy can be “first-line,” i.e., as initial treatment for patients who have not received an anticancer treatment regimen, used alone or in combination with other treatments; or “second-line,” i.e., as treatment for patients who have received an anticancer treatment regimen, used alone or in combination with other treatments; or as “third-line,” “fourth-line,” etc., i.e., used alone or in combination with other treatments. The therapy can also be used for patients who have received partially successful prior treatments but are intolerant to certain treatments. The therapy can also be used as adjuvant therapy, i.e., to prevent cancer recurrence in patients with currently undetectable disease or after surgical removal of a tumor.

[0705] In some embodiments, the compounds of the present invention (including all individual embodiments and subsets thereof disclosed herein) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as the pharmaceutical compositions or kits of the present invention, may be administered to patients who have received another therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiotherapy, targeted therapy, or any combination thereof.

[0706] Combination therapy

[0707] On the other hand, the compounds of the present invention (including all individual embodiments and subsets thereof disclosed herein) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotope variants, hydrates or solvates, as well as the pharmaceutical compositions or kits of the present invention, may be used in combination with or simultaneously with at least one other active agent (e.g., an anticancer agent or regimen) to treat diseases and conditions.

[0708] The terms “combination” and “simultaneous” in this context refer to the co-administration of agents, including substantially simultaneous administration, in the same or separate dosage forms, in the same or different manner of administration, or sequential administration, such as as part of the same treatment regimen or through a series of treatment regimens. Thus, if administered sequentially, in some cases, when the second compound is initiated, the first of the two compounds may still be detectable at the treatment site at an effective concentration. The order and time intervals can be determined such that they can act together (e.g., synergistically to provide a greater benefit than when administered in other ways). For example, therapeutic agents can be administered simultaneously or sequentially at different time points in any order; however, if not administered simultaneously, they can be administered at sufficiently close times to provide the desired therapeutic effect, which may be synergistic. Therefore, these terms are not limited to administering the active agent at exactly the same time.

[0709] In some embodiments, the treatment regimen may include the administration of compounds of the present invention (including all individual embodiments and subsets thereof disclosed herein) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as pharmaceutical compositions or kits of the present invention, in combination with one or more adjunctive therapeutic agents known for treating diseases or conditions (e.g., cancer). The dose of the adjunctive anticancer therapeutic agent may be the same as or even lower than known or recommended doses. Representative examples of other active agents and treatment regimens include radiotherapy, chemotherapy agents (e.g., mitotic inhibitors, angiogenesis inhibitors, anti-hormones, autophagy inhibitors, alkylating agents, inserting antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti-microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0710] In some embodiments, the compounds of the present invention (including all individual embodiments and subsets thereof disclosed herein) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates or solvates, as well as the pharmaceutical compositions or kits of the present invention and additional anticancer therapeutic agents, may be used at intervals of less than 5 minutes, less than 30 minutes, less than 1 hour, about 1 hour, about 1 to about 2 hours, about 2 hours to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 5 hours, about 5 hours to about 6 hours, etc. Intervals of approximately 6 to 7 hours, approximately 7 to 8 hours, approximately 8 to 9 hours, approximately 9 to 10 hours, approximately 10 to 11 hours, approximately 11 to 12 hours, approximately 12 to 18 hours, 18 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 ​​to 52 hours, 52 to 60 hours, 60 to 72 hours, 72 to 84 hours, 84 to 96 hours, or 96 to 120 hours. Two or more anticancer treatments may be administered during the same patient's visit.

[0711] In some embodiments, the compounds of the present invention (including all individual embodiments and subsets thereof disclosed herein) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as the pharmaceutical compositions or kits of the present invention and additional agents or therapeutics (e.g., anticancer therapeutics) are administered periodically. For example, in the context of cancer treatment, cyclic therapy involves administering one anticancer therapeutic for a period of time, followed by administering a second anticancer therapeutic for a period of time, and repeating this sequence of administration, i.e., cycling, to reduce the development of resistance to one or two anticancer therapeutics, avoid or reduce the side effects of one or two anticancer therapeutics, and / or improve the efficacy of treatment. In one embodiment, cyclic therapy involves administering a first anticancer therapeutic for a period of time, followed by administering a second anticancer therapeutic for a period of time, optionally followed by administering a third anticancer therapeutic for a period of time, and so on, and repeating this sequence of administration, i.e., cycling, to reduce the development of resistance to one of the anticancer therapeutics, avoid or reduce the side effects of one of the anticancer therapeutics, and / or improve the efficacy of the anticancer therapeutic.

[0712] In some embodiments, the compounds of the present invention (including all individual embodiments and subsets thereof disclosed herein) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates, as well as the pharmaceutical compositions or kits of the present invention, can be used in combination with other anticancer agents. Examples include Durvalumab (e.g., for NSCLC), LEE011 (e.g., for NSCLC), cisplatin, gemcitabine hydrochloride, or paclitaxel albumin-stabilized nanoparticle formulations (e.g., for advanced malignant solid tumors, metastatic pancreatic adenocarcinoma, and stage III and IV pancreatic cancer), trametinib (e.g., for NSCLC and neuroblastoma), axitinib (e.g., for advanced solid tumors), cobimetinib (e.g., for NSCLC), and brentuximab. Vedotin (e.g., for ALK-positive anaplastic large cell lymphoma, CD30-positive tumor cells, and systemic anaplastic large cell lymphoma), nivolumab (e.g., for ALK-positive NSCLC), everolimus (e.g., for head and neck cancer), pemetrexed, cisplatin, and carboplatin (e.g., for NSCLC), pemetrexed, cisplatin, and docetaxel (e.g., for NSCLC), pemetrexed and docetaxel (e.g., for NSCLC), bevacizumab (e.g., for NSCLC), and in combination with atezolizumab and erlotinib (e.g., for NSCLC). In some embodiments, the bispecific compounds of the present invention may be used alone or in combination with one or more of alectinib, brigatinib, crizotinib, and ceritinib (e.g., for non-metastatic or metastatic lung cancer, NSCLC, ALK-positive NSCLC, NSCLC with ROS1 rearrangements, lung adenocarcinoma, and squamous cell lung cancer).

[0713] Example

[0714] 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.

[0715] 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.

[0716] The abbreviations used in this invention have the following meanings:

[0717] Preparation of related intermediate compounds

[0718] Preparation of intermediate A-1 compound (R)-5-bromo-3-(1-(5-fluoro-2-iodophenyl)ethoxy)pyridine-2-amine

[0719] Synthesized using the following route:

[0720] Step 1: Synthesis of compound (S)-1-(5-fluoro-2-iodophenyl)methanesulfonate ethyl ester

[0721] To a 500 mL three-necked flask, add (S)-1-(5-fluoro-2-iodophenyl)ethane-1-ol (26.6 g, 0.10 mol), triethylamine (15.2 g, 0.15 mol), and dichloromethane (260 mL) sequentially. Stir until dissolved, cool in an ice-water bath, and add methanesulfonyl chloride (13.7 g, 0.12 mol) dropwise under a nitrogen atmosphere. After the addition is complete, remove the ice bath and stir at room temperature for 2 hours. Add isopropanol (3.0 g, 0.05 mol), stir for 30 minutes, add water (200 mL), stir for 5 minutes, separate the organic phase, extract the aqueous phase with dichloromethane (60 mL), combine the organic phases, wash successively with hydrochloric acid (50 mL, 1 M) and saturated sodium bicarbonate aqueous solution (50 mL), dry to anhydrous sodium sulfate, filter, and concentrate to dryness to obtain 30.1 g of a colorless oil, yield 87.2%. Use directly for the next step.

[0722] Synthesis of intermediate A-1 in step 2

[0723] To a 500 mL three-necked flask, 16.5 g (87 mmol) of 2-amino-3-hydroxy-5-bromopyridine, 150 mL of ethylene glycol dimethyl ether, and 20 mL of N-methylpyrrolidone were added sequentially. The mixture was stirred until dissolved. Cesium carbonate (42.5 g, 130.5 mmol) was added, and the mixture was heated to 60 °C under a nitrogen atmosphere. While stirring, a solution of (S)-1-(5-fluoro-2-iodophenyl)methanesulfonate (30 g, 87 mmol) in ethylene glycol dimethyl ether (50 mL) was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 2 hours. The mixture was cooled to room temperature, and the insoluble solids were filtered off. The filter cake was washed with ethyl acetate (50 mL), concentrated under reduced pressure, and then washed with ethyl acetate (200 mL). The mixture was washed with water (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 31.5 g of a white solid, with a yield of 82.8%. LC-MS: m / z = 437.1(M+1) + .

[0724] Preparation of intermediate A-2 compound (5-(benzyloxy)-6-(bis(tert-butoxycarbonyl)amino)pyridin-3-yl)boronic acid

[0725] Synthesized using the following route:

[0726] Step 1: Synthesis of compound (3-(benzyloxy)-5-bromopyridin-2-yl)(tert-butoxycarbonyl)aminocarboxylic acid tert-butyl ester

[0727] To a 2000 mL three-necked flask equipped with a magnetic stirrer, dichloromethane (200 mL), 2-amino-3-benzyloxy-5-bromopyridine (80 g, 287 mmol), N,N-diisopropylethylamine (110 g, 860 mmol), 4-dimethylaminopyridine (35 g, 287 mmol), and di-tert-butyl dicarbonate (187 g, 860 mmol) were added sequentially, and the mixture was reacted overnight at room temperature. Water (400 mL) was added, and the mixture was stirred for 5 minutes. The organic phase was separated, extracted with dichloromethane (200 mL), and the combined organic phases were washed successively with aqueous hydrochloric acid (200 mL × 2, 1 M) and saturated sodium bicarbonate solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 140 g of a yellow oil, yield 102%. LC-MS: m / z = 479.1 (M+1) + .

[0728] Synthesis of intermediate A-2 in step 2

[0729] Anhydrous toluene (300 mL), 3-(benzyloxy)-5-bromopyridin-2-yl)(tert-butoxycarbonyl)aminocarboxylic acid tert-butyl ester (140 g, 287 mmol), pinacol diboronate (94.6 g, 373 mmol), palladium acetate (3.2 g, 14.3 mmol), potassium acetate (84 g, 860 mmol), and n-butylbis(1-adamantyl)phosphine (10 g, 28.7 mmol) were added sequentially to a 1000 mL three-necked flask equipped with a magnetic stirrer. The mixture was evacuated under vacuum and purged with nitrogen three times, then heated to 100 °C and reacted overnight. After cooling to room temperature, the insoluble solids were filtered off, and water (300 mL) was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 110 g of a yellowish-white solid, with a yield of 86%. LC-MS (APCI): m / z = 445.2(M+1) + .

[0730] Preparation of intermediate A-3 compound (S)-5-fluoro-3-methylbenzo[c][1,2]oxaporborane-1(3H)-ol

[0731] Synthesized using the following route:

[0732] Add (S)-1-(2-iodo-5-fluorophenyl)ethanol (60.0 g, 225.6 mmol) and anhydrous tetrahydrofuran (600 mL) sequentially to a 2000 mL three-necked flask equipped with a magnetic stirrer. Stir until dissolved, cool to -40 °C under nitrogen protection, and slowly add isopropyl magnesium chloride tetrahydrofuran solution (282 mL, 564 mmol, 2 M) dropwise over 30 minutes. Stir the reaction at -40 °C for 1 hour, then raise the temperature to -10 °C and stir for 30 minutes. Subsequently, slowly add trimethyl borate (63 mL, 564 mmol) dropwise over 30 minutes. Allow the mixture to warm to room temperature naturally and stir overnight. The reaction was monitored by TLC until it was complete. A saturated ammonium chloride solution (50 mL) was added to quench the reaction. The reaction solution was diluted with water (200 mL), extracted with ethyl acetate (300 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 30.0 g of a pale gray solid, with a yield of 80.1%. LC-MS: m / z = 167.2 (M+1) + .

[0733] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 7.75-7.63 (m, 1H), 7.31-7.24 (m, 1H), 7.18-7.12 (m, 1H), 5.30-5.18 (m, 1H), 1.55-1.37 (m, 3H).

[0734] Preparation of intermediate A-4 compound (S)-5-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-2-methyl-2H-1,2,3-triazol-4-carboxaldehyde

[0735] Synthesized using the following route:

[0736] Step 1: Synthesis of compound 5-bromo-2-methyl-2H-1,2,3-triazole-4-carboxylic acid

[0737] Add 50.0 g (207.5 mmol) of 4,5-dibromo-2-methyl-2H-1,2,3-triazole and 500 mL of tetrahydrofuran to a 2000 mL three-necked flask equipped with a magnetic stirrer. Stir until dissolved. Under nitrogen protection, cool to -30 °C and slowly add 109 mL (218 mmol, 2 M) of isopropyl magnesium chloride tetrahydrofuran solution over 1 hour. Stir the reaction at -30 °C for 1 hour. Then, bubble carbon dioxide into the reaction system and heat to -10 °C. After bubbling carbon dioxide for 2 hours, allow the temperature to rise naturally to room temperature and stir overnight under a carbon dioxide atmosphere. The reaction was monitored by LCMS until it was complete. The reaction was quenched by adding saturated ammonium chloride solution (100 mL). The reaction solution was diluted with water (300 mL), extracted with ethyl acetate (300 mL × 2), the pH of the aqueous phase was adjusted to 2-3 with acetic acid, and then extracted with dichloromethane (500 mL × 2). The dichloromethane phase was dried with anhydrous sodium sulfate, filtered, and concentrated to give 32.0 g of white solid, with a yield of 74.9%.

[0738] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 13.57 (br s, 1H), 4.20 (s, 3H).

[0739] Step 2: Synthesis of compound (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methanol

[0740] To a 2000 mL single-necked flask equipped with a magnetic stirrer, 32.0 g (155.34 mmol) of 5-bromo-2-methyl-2H-1,2,3-triazol-4-carboxylic acid and 300 mL of tetrahydrofuran were added sequentially. After stirring until dissolved, a tetrahydrofuran solution of borane (620 mL, 620 mmol, 1 M) was added, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched with water in an ice bath, stirred at room temperature for 1 hour, extracted with methyl tert-butyl ether (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and the concentrated reaction solution was used directly for the next reaction step.

[0741] Step 3: Synthesis of compound 4-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2H-1,2,3-triazole

[0742] To a 1000 mL single-necked flask equipped with a magnetic stirrer, add sequentially the (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methanol obtained in step 2, dichloromethane (300 mL), imidazole (21.1 g, 310 mmol), and 4-dimethylaminopyridine (1.96 g, 16.0 mmol). Stir until dissolved, and cool to 0 °C in an ice bath. Then, dissolve tert-butyldimethylchlorosilane (28 g, 186 mmol) in dichloromethane (100 mL) and add it to the reaction system in an ice bath. Stir overnight at room temperature. Monitor the reaction for completion by LCMS. Quench the reaction with water (200 mL) in an ice bath, separate the organic phase, extract the aqueous phase with dichloromethane (200 mL × 2), dry to anhydrous sodium sulfate, filter, concentrate the reaction solution, and purify by silica gel column chromatography to obtain 40.7 g of a colorless oil. The two-step yield is 85.2%. LCMS(ESI): m / z = 306.1(M+1) + .

[0743] Step 4: Synthesis of compound (S)-1-(2-(5-((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-5-fluorophenyl)ethane-1-ol

[0744] To a 1000 mL single-necked flask equipped with a magnetic stirrer, 4-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2H-1,2,3-triazole (40.7 g, 132.1 mmol), 1,4-dioxane (400 mL), water (100 mL), intermediate A-3 (26.3 g, 158 mmol), potassium carbonate (54.8 g, 396.3 mmol), and [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (4.64 g, 6.6 mmol) were added sequentially. The mixture was purged with nitrogen three times, stirred thoroughly, and then heated to 100 °C in an oil bath overnight. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filter cake was washed with dichloromethane (200 mL × 2). The filtrates were combined, concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain 43.5 g of a white solid, with a yield of 90.1%. LCMS(ESI): m / z = 366.4(M+1) + .

[0745] Step 5: Synthesis of compound (S)-4-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-5-((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2H-1,2,3-triazole

[0746] (S)-1-(2-(5-((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-5-fluorophenyl)ethane-1-ol (43.5 g, 119 mmol) and tetrahydrofuran (400 mL) were added sequentially to a 1000 mL single-necked flask equipped with a magnetic stirrer. The mixture was cooled to 0 °C in an ice bath, and sodium hydride (9.52 g, 238 mmol) was added in portions. The reaction was carried out under a nitrogen atmosphere in an ice bath for 1 hour. Benzyl bromide (24.5 g, 143 mmol) was added to the reaction system, and the mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction was quenched by adding 100 mL of saturated ammonium chloride solution under ice bath conditions. The mixture was diluted with 200 mL of water, extracted with ethyl acetate (300 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 46.3 g of a white solid, with a yield of 85.5%. LCMS (ESI): m / z = 456.3 (M+1) + .

[0747] Step 6: Synthesis of compound (S)-(5-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methanol

[0748] To a 2000 mL single-necked flask equipped with a magnetic stirrer, (S)-4-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-5-((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-2H-1,2,3-triazole (46.3 g, 101.7 mmol) and dichloromethane (400 mL) were added sequentially. The mixture was cooled to 0 °C in an ice bath, and isopropanol hydrochloride solution (300 mL, 4 M) was added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS until completion. The solution was concentrated, and the crude product was used directly for the next reaction. LCMS (ESI): m / z = 342 (M+1) + .

[0749] Step 7 Synthesis of intermediate A-4

[0750] To a 2000 mL single-necked flask equipped with a magnetic stirrer, crude ((S)-(5-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methanol obtained in step 6 and dichloromethane (600 mL) were added sequentially. The mixture was stirred until dissolved, followed by the addition of Dys-Martin oxidant (64.7 g, 152.6 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LC-MS until completion. The reaction was quenched with water (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 30.93 g of a white solid. The two-step yield was 89.7%. LC-MS (ESI): m / z = 340 (M+1) + . 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.97(s,1H),7.46-7.39(m,2H),7.31-7.22(m,4H) ,7.18-7.16(m,2H),4.49-4.46(m,1H),4.29-4.13(m,5H),1.30(d,J=6.0Hz,3H).

[0751] Preparation of intermediate A-5 compound (S)-4-(2-(1-(benzyloxyethyl)-4-fluorophenyl)-5-bromo-2-methyl-2H-1,2,3-triazole

[0752] Synthesized using the following route:

[0753] Step 1: Synthesis of compound (S)-1-(2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-5-fluorophenyl)ethane-1-ol

[0754] To a 1000 mL single-necked flask equipped with a magnetic stirrer, 4,5-dibromo-2-methyl-2H-1,2,3-triazole (20.0 g, 83.06 mmol), 1,4-dioxane (300 mL), water (70 mL), intermediate A-3 (12.4 g, 74.7 mmol), sodium carbonate (36.6 g, 345 mmol), and [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.92 g, 4.15 mmol) were added sequentially. The mixture was purged with nitrogen three times, stirred thoroughly, and then heated to 90 °C in an oil bath overnight. The reaction was monitored by LC-MS until completion. The reaction solution was filtered, and the filter cake was washed with dichloromethane (50 mL × 2). The filtrates were combined, concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography to give 18.1 g of a white solid, yield 72.6%. LC-MS (ESI): m / z = 300.2 (M+1) + .1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.42 (dd, J=10.4Hz, J=2.8Hz, 1H), 7.34-7.31 (m, 1H), 7.21- 7.16(m,1H),5.30(d,J=4.0Hz,1H),4.73-4.70(m,1H),4.21(s,3H),1.17(d,J=6.0Hz,3H).

[0755] Synthesis of intermediate A-5 in step 2

[0756] (S)-1-(2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-5-fluorophenyl)ethane-1-ol (18.1 g, 60.3 mmol) and tetrahydrofuran (400 mL) were added sequentially to a 1000 mL single-necked flask equipped with a magnetic stirrer. The mixture was cooled to 0 °C in an ice bath, and sodium hydride (4.84 g, 121 mmol) was added in portions. The reaction was carried out in an ice bath for 1 hour. Benzyl bromide (12.4 g, 72.36 mmol) was then added to the reaction system, and the mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS until completion. The reaction was quenched by adding saturated ammonium chloride solution (50 mL) in an ice bath. The mixture was diluted with water (200 mL), extracted with ethyl acetate (300 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 20.5 g of a white solid, with a yield of 87.2%. LCMS(ESI): m / z = 390(M+1) + . 1 H NMR(400MHz,DMSO-d6)δ(ppm):7.45-7.41(m,2H),7.32-7.27(m,4H),7.23-7.21(m,2H),4.52-4 .48(m,1H),4.32(d,J=12.0Hz,1H),4.19(d,J=12.0Hz,1H),4.18(s,3H),1.33(d,J=6.4Hz,3H).

[0757] Preparation of intermediate A-6 compound 3-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde

[0758] Synthesized using the following route:

[0759] N,N-dimethylformamide (60 mL) was added to a 1000 mL single-necked flask equipped with a magnetic stirrer. Phosphorus oxychloride (60 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. Then, 40.0 g (192 mmol) of 3-iodo-1-methyl-1H-pyrazole was diluted in 20 mL of N,N-dimethylformamide and added dropwise to the reaction mixture. After the addition was complete, the reaction flask was placed in an oil bath and heated to 95 °C for 3 hours. The mixture was cooled to room temperature, and the reaction solution was slowly added dropwise to a saturated ammonium chloride solution (100 mL). Saturated sodium bicarbonate solution was added to adjust the pH to 9. The mixture was extracted with dichloromethane (200 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 36.0 g of a light brown solid, with a yield of 79.45%. LCMS (APCI): m / z = 236 (M+1) + .

[0760] Preparation of intermediate A-7 compound ethyl 3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-1H-pyrazole-5-carboxylic acid

[0761] Synthesized using the following route:

[0762] Step 1: Synthesis of compound ethyl 5-((tert-Butoxycarbonyl)(methyl)amino)-2,4-dioxovalerate

[0763] To a 250 mL three-necked flask equipped with a magnetic stirrer, add an ethanol solution of sodium ethoxide (10.36 g, 30.45 mmol, w / w 20%) and anhydrous ethanol (15 mL), stirring until homogeneous. Evacuate the mixture three times with nitrogen, cool in an ice-water bath, and then add dropwise a solution of methyl (2-oxopropyl)aminocarboxylic acid tert-butyl ester (5.0 g, 26.71 mmol) and diethyl oxalate in ethanol (4.68 g, 32.05 mmol, 10 mL). After the addition is complete, remove the ice bath and stir the mixture at room temperature under a nitrogen atmosphere for 3 hours. Proceed directly to the next step.

[0764] Synthesis of intermediate A-7 in step 2

[0765] The reaction solution from step 1 was cooled in an ice-water bath, and hydrazine hydrochloride (2.20 g, 32.05 mmol) was added dropwise. The reaction was stirred for 2 hours. The reaction was quenched with water (50 mL), concentrated, extracted with ethyl acetate (60 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 7.2 g of a white solid, yield 95.2%. LC-MS (APCI): m / z = 284.0 (M+1) + .

[0766] Preparation of intermediate B-1 compound (tert-butyloxycarbonyl)((10R)-3-cyano-12-fluoro-10,16-dimethyl-15-oxo-2-(piperidin-4-yl)-10,15,16,17-tetrahydro-2H-4,8-(methylbridged)pyrazole[4,3-h][2,5,11]benzoxazadiazetatetracyclo-7-yl)aminocarboxylic acid tert-butyl ester

[0767] Synthesized using the following route:

[0768] Step 1: Synthesis of compound 4-(3-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid benzyl ester

[0769] Intermediate A-7 (7.2 g, 25.44 mmol), benzyl 4-hydroxy-1-piperidincarnate (7.2 g, 30.53 mmol), triphenylphosphine (10 g, 38.10 mmol), and tetrahydrofuran (100 mL) were added sequentially to a 250 mL three-necked flask equipped with a magnetic stirrer. The mixture was cooled in an ice-water bath, and diisopropyl azodicarbonate (10.27 g, 50.88 mmol) was added dropwise. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 12 g of a white solid, yield 94.4%. LC-MS (APCI): m / z = 501.0 (M+1) + .

[0770] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.39-7.36 (m, 4H), 7.35-7.30 (m, 1H), 6.65 (d, J = 8.8Hz, 1H), 5.22-5.16 (m, 1H), 5.09 (s, 2H), 4.31-4.25(m,4H),4.13-4.25(m,2H),3.08-2.90(m,2H),2.75(s,3H),1.93-1.84(m,4H),1.37(s,9H),1.27(t,J=6.8Hz,3H).

[0771] Step 2: Synthesis of compound 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-((tert-butoxycarbonyl)(methyl)amino)methyl)-1H-pyrazole-5-carboxylic acid

[0772] 4-(3-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid benzyl ester (12 g, 24.00 mmol), water (100 mL), and tetrahydrofuran (100 mL) were added sequentially to a 250 mL single-necked flask equipped with a magnetic stirrer and a condenser. The mixture was stirred until dissolved, and lithium hydroxide monohydrate (11.76 g, 240.00 mmol) was added. The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. Water (100 mL) was added, and the pH was adjusted to approximately 5 with hydrochloric acid (1 N). 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 11 g of a white solid, with a yield of 97.1%. LC-MS (APCI): m / z = 473.0 (M+1) + .

[0773] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.37-7.32 (m, 5H), 7.29-7.27 (m, 1H), 6.53 (d, J = 13.6Hz, 1H), 5.30-5.22 (m, 1H), 5.06 (s, 2H) ,4.25(s,2H),4.07(d,J=13.2Hz,2H),2.97-2.89(m,2H),2.72(s,3H),1.87-1.78(m,4H),1.34(s,9H),1.27(t,J=6.8Hz,3H).

[0774] Step 3: Synthesis of compound 4-(3-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-carbamoyl-1H-pyrazol-1-yl)piperidine-1-carboxylic acid benzyl ester

[0775] Compound 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-((tert-butoxycarbonyl)(methyl)amino)methyl)-1H-pyrazole-5-carboxylic acid (11 g, 23.30 mmol) and tetrahydrofuran (55 mL) were added sequentially to a 250 mL three-necked flask equipped with a magnetic stirrer and a condenser. After stirring until dissolved, N,N'-carbonyldiimidazole (7.56 g, 46.60 mmol) was added. The mixture was stirred at 70 °C for 1 hour under a nitrogen atmosphere, cooled to room temperature, and ammonia water (60 mL) was added. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was quenched with water (100 mL), extracted with ethyl acetate (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 10.3 g of a white solid, yield 93.9%. LC-MS (APCI): m / z = 472.0 (M+1) + .

[0776] Step 4: Synthesis of compound 4-(3-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylic acid benzyl ester

[0777] 4-(3-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-carbamoyl-1H-pyrazol-1-yl)piperidin-1-carboxylic acid benzyl ester (10.3 g, 21.86 mmol), tetrahydrofuran (100 mL), and triethylamine (6.69 g, 65.58 mmol) were added sequentially to a 250 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved, cooled in an ice-water bath, and trifluoroacetic anhydride (6.88 g, 32.79 mmol) was added dropwise under a nitrogen atmosphere. The reaction was stirred at 0 °C for 2 hours. The reaction was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 9.7 g of a white solid, yield 97.9%. LC-MS (APCI): m / z = 454.0 (M+1) + .

[0778] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.41-7.32 (m, 5H), 6.99 (d, J = 13.6Hz, 1H), 5.11 (s, 2H), 4.68-4.63 (m, 1H), 4.34 (s ,2H),4.10(d,J=13.2Hz,2H),3.11-3.07(m,2H),2.78(s,3H),2.02-1.98(m,2H),1.91-1.82(m,2H),1.37(s,9H).

[0779] Step 5: Synthesis of compound 4-(5-cyano-3-((methylamino)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid benzyl ester hydrochloride

[0780] 4-(3-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylic acid benzyl ester (9.7 g, 21.41 mmol) and dichloromethane (10 mL) were added sequentially to a 250 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved, and then 50 mL (4 M) of ethyl acetate solution of hydrogen chloride was added under ice-water bath. The reaction was stirred at room temperature for 1 hour, and the solution was concentrated to give 7.26 g of a white solid, with a yield of 99.0%. LC-MS (APCI): m / z = 354.0 (M+1) + .

[0781] Step 6: Synthesis of compound (R)-4-(3-((2-(1-(((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluoro-N-methylbenzoylamino)methyl)-5-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylic acid benzyl ester

[0782] To a 250 mL single-necked flask equipped with a magnetic stirrer and condenser, 4-(5-cyano-3-((methylamino)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid benzyl ester hydrochloride (4 g, 11.33 mmol), intermediate A-1 (6.42 g, 14.73 mmol), N,N-diisopropylethylamine (4.38 g, 33.99 mmol), di(tri-tert-butylphosphine)palladium (578.9 mg, 1.13 mmol), and 1,4-dioxane (40 mL) were added sequentially. The mixture was evacuated under vacuum and purged three times with carbon monoxide. The mixture was stirred at 80 °C for 12 hours under a carbon monoxide atmosphere. The solution was concentrated and purified by silica gel column chromatography to give 4 g of a white solid, yield 51.2%. LC-MS (APCI): m / z = 690.0 (M+1) + .

[0783] Step 7: Synthesis of compound (R)-4-(3-((2-(1-((2-(bis(tert-butoxycarbonyl)amino)-5-bromopyridin-3-yl)oxy)ethyl)-4-fluoro-N-methylbenzoylamino)methyl)-5-cyano-1H-pyrazole-1-yl)piperidine-1-carboxylic acid benzyl ester

[0784] Di-tert-butyl dicarbonate (8.85 g, 40.60 mmol) and dichloromethane (20 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. Then, (R)-4-(3-((2-(1-(((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluoro-N-methylbenzoylamino)methyl)-5-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate benzyl ester (4.0 g, 5.80 mmol) and N,N A mixed solution of diisopropylethylamine (2.24 g, 17.40 mmol), 4-dimethylaminopyridine (141 mg, 1.16 mmol), and dichloromethane (20 mL) was stirred at room temperature for 12 hours. The reaction was quenched with water (50 mL), extracted with dichloromethane (50 mL × 2), 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 4 g of a white solid, yield 77.5%. LC-MS (APCI): m / z = 890.0 (M+1) + .

[0785] Step 8: Synthesis of compound 4-((10R)-7-(bis(tert-butoxycarbonyl)amino)-3-cyano-12-fluoro-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-(methylbridged)pyrazole[4,3-h][2,5,11]benzoxazadiazetatetracyclo-2-yl)piperidine-1-carboxylic acid benzyl ester

[0786] To a 500 mL single-necked flask equipped with a magnetic stirrer and a condenser, benzyl (R)-4-(3-((2-(1-(((2-(bis(tert-butoxycarbonyl)amino)-5-bromopyridin-3-yl)oxy)ethyl)-4-fluoro-N-methylbenzoylamino)methyl)-5-cyano-1H-pyrazol-1-yl)piperidin-1-carboxylate (4 g, 4.50 mmol), palladium acetate (101.7 mg, 0.45 mmol), n-butyldi(1-adamantyl)phosphine (161.3 mg, 0.45 mmol), potassium acetate (1.32 g, 13.5 mmol), and 2-methyl-2-butanol (200 mL) were added sequentially. The reaction mixture was stirred at 110 °C for 12 hours under a nitrogen atmosphere. The mixture was concentrated and purified by silica gel column chromatography to give 2.5 g of a white solid, yield 68.6%. LC-MS (APCI): m / z = 810.0 (M+1) + .

[0787] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.13 (d, J = 2.0Hz, 1H), 7.51-7.49 (m, 1H), 7.40-7.32 ( m,6H),7.23(d,J=9.2Hz,2H),5.80-5.74(m,1H),5.13(s,2H),4.82-4.78(m,1H),4.5 4(d,J=15.2Hz,1H),4.25(d,J=14.4Hz,1H),4.18-4.12(m,2H),3.20-3.07(m,2H),2. 99(s,3H),2.13-2.09(m,2H),1.97-1.92(m,2H),1.65(d,J=6.0Hz,3H),1.39(s,18H).

[0788] Step 9 Synthesis of intermediate B-1

[0789] 4-((10R)-7-(bis(tert-butyloxycarbonyl)amino)-3-cyano-12-fluoro-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-(methylbridged)pyrazole[4,3-h][2,5,11]benzoxazadiazetatetracyclo-2-yl)piperidine-1-carboxylic acid benzyl ester (2.5 g, 3.09 mmol) and methanol (50 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved, and palladium on carbon (1 g, 10%) was added. The mixture was evacuated and purged three times with hydrogen. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The solution was concentrated by filtration to give 1.9 g of a white solid, yield 91.3%. LC-MS (APCI): m / z = 676.0 (M+1) + .

[0790] Preparation of intermediate B-2 compound (10R)-7-amino-12-fluoro-2-(1-(azacyclobutan-3-yl)piperidin-4-yl)-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-(methylbridged)pyrazole[4,3-h][2,5,11]benzoxazadiacetetrazolium-3-carboxynitrile

[0791] Synthesized using the following route:

[0792] Step 1: Synthesis of compound 3-(((10R)-7-(bis(tert-butyloxycarbonyl)amino)-3-cyano-12-fluoro-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-(methylbridged)pyrazole[4,3-h][2,5,11]benzoxazadiazatetetradecanoyl-2-yl)piperidin-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0793] Intermediate B-1 (675 mg, 1.0 mmol), N,N-dimethylformamide (15 mL), and glacial acetic acid (180 mg, 3.0 mmol) were added sequentially to a 50 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved. Then, 1-tert-butoxycarbonyl-3-azacyclobutanone (342 mg, 2.0 mmol) and sodium tri(acetoxy)borohydride (636 mg, 3.0 mmol) were added. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water (80 mL), extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 770 mg of a white solid, in 92.7% yield. LC-MS (APCI): m / z = 831.0 (M+1) + .

[0794] Synthesis of intermediate B-2 in step 2

[0795] To a 50 mL single-necked flask equipped with a magnetic stirrer, 3-(((10R)-7-(bis(tert-butyloxycarbonyl)amino)-3-cyano-12-fluoro-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-(methylbridged)pyrazole[4,3-h][2,5,11]benzoxazadiatetradecanoyl-2-yl)piperidin-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (350 mg, 0.42 mmol), ethyl hydrogen chloride solution (5 mL), and dichloromethane (1 mL) were added sequentially. The mixture was stirred at room temperature for 30 minutes, and the solution was concentrated to give 220 mg of a white solid, with a yield of 98.6%. LC-MS (APCI): m / z = 531.0 (M+1) + .

[0796] Intermediate B-3 compound (19R)-16-fluoro-10-methyl-3-(piperidin-4-yl)-20-oxa-3,4,9,10,11,23-hexaazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18 Preparation of pentacarbal-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine

[0797] Synthesized using the following route:

[0798] Step 1: Synthesis of compound 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0799] 4-Iodopyrazole (1.94 g, 10 mmol), 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (3.55 g, 10 mmol), and N,N-dimethylacetamide (30 mL) were added sequentially to the reaction vessel. The mixture was stirred until dissolved, and then cesium carbonate (4.89 g, 15 mmol) was added. The mixture was purged with nitrogen three times, and the temperature was raised to 100 °C for 16 hours. After cooling to room temperature, saturated brine (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 3 g of a white solid, with a yield of 80%. LC-MS (APCI): m / z = 378.2 (M+1) + .

[0800] Step 2: Synthesis of compound 4-(5-bromo-4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0801] 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (7.55 g, 20 mmol) and anhydrous tetrahydrofuran (75 mL) were added sequentially to the reaction vessel. The mixture was stirred until dissolved, purged with nitrogen three times, and cooled to -70 °C. Diisopropylaminolithium (12 mL, 24 mmol, 2 M) was slowly added dropwise while maintaining the temperature below -60 °C. After the addition was complete, the reaction was carried out at -70 °C for 30 minutes. A tetrahydrofuran solution of carbon tetrabromide (7.96 g, 24 mmol) (80 mL) was slowly added dropwise while maintaining the temperature below -60 °C. After the addition was complete, the reaction was carried out at -60 °C for 3 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (80 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 6.1 g of a brownish-red solid, yield 66.9%. LC-MS (APCI): m / z = 456.2(M+1) + .

[0802] Step 3: Synthesis of compound 4-(4-((5-(2-((S)-1-(benzyloxy)ethyl)-4-fluorophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)(hydroxy)methyl)-5-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0803] 4-(5-bromo-4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (3.3 g, 7.2 mmol) and anhydrous tetrahydrofuran (50 mL) were added sequentially to the reaction vessel. The mixture was stirred until dissolved, purged with nitrogen three times, and cooled to -10 °C. Isopropyl magnesium chloride solution (3.34 mL, 9.36 mmol, 2.8 M) was slowly added dropwise while maintaining the temperature below -5 °C. After the addition was complete, the reaction was carried out at -10 °C for 30 minutes. Then, a tetrahydrofuran solution (30 mL) of intermediate A-4 (2.68 g, 7.92 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at -10 °C for 3 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 2.66 g of a brownish-red solid, with a yield of 55.3%. LC-MS (APCI): m / z = 669.2 (M+1) + .

[0804] Step 4: Synthesis of compound (S)-4-(4-((5-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-bromo-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0805] Add 2.66 g (3.98 mmol) of 4-(4-((5-(2-((S)-1-(benzyloxy)ethyl)-4-fluorophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)(hydroxy)methyl)-5-bromo-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester and 30 mL of dichloromethane sequentially to the reaction vessel, stir until dissolved, and cool to 0 °C. Slowly add 2.32 g (20 mmol) of triethylsilane, and react at 0 °C for 10 minutes after the addition is complete. Slowly add 10 mL of trifluoroacetic acid, and react at 0 °C for 1 hour after the addition is complete. Slowly add 15 mL of triethylamine, keeping the temperature below 10 °C. Slowly add 1.75 g (8 mmol) of ditert-butyl dicarbonate, keeping the temperature below 10 °C, and react at room temperature for 1 hour after the addition is complete. Water (50 mL) was added to the reaction solution, and the mixture was stirred. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 2.08 g of a brownish-red solid, with a yield of 80.1%. LC-MS (APCI): m / z = 653.2 (M+1) + .

[0806] Step 5: Synthesis of compound (S)-4-(5-(5-benzyloxy)-6-(bis(tert-butoxycarbonyl)amino)pyridin-3-yl)-4-((5-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0807] To a 50 mL single-necked flask, (S)-4-(4-((5-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-bromo-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester (2.08 g, 3.19 mmol), intermediate A-2 (1.55 g, 3.5 mmol), sodium carbonate (1 g, 9.43 mmol), tetrakis(triphenylphosphine)palladium (0.368 g, 0.32 mmol), ethanol (15 mL), and water (3 mL) were added sequentially. The mixture was purged with nitrogen three times, and the temperature was raised to 85 °C for 16 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), and the insoluble solids were filtered off. The mixture was washed with ethyl acetate (20 mL), and the filtrate was concentrated to dryness. The residue was separated by silica gel column chromatography to give 2.1 g of a brown solid, with a yield of 67.7%. LC-MS (APCI): m / z = 973.3 (M+1) + .

[0808] Step 6: Synthesis of compound (S)-4-(5-(6-(bis(tert-butyloxycarbonyl)amino)-5-hydroxypyridin-3-yl)-4-((5-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester. (S)-4-(5-(5-benzyloxy)-6-(bis(tert-butyloxycarbonyl)amino)-5-hydroxypyridin-3-yl)-4-((5-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester was added sequentially to the reaction vessel. (2.1 g, 2.16 mmol) tert-butyl ester (5-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazole-1-yl)piperidin-1-carboxylic acid was dissolved in methanol (40 mL) by stirring. Palladium on carbon (1 g, 10%) was added, and the mixture was purged three times with hydrogen. The reaction was stirred overnight at room temperature under a hydrogen atmosphere. The solution was filtered, concentrated, and purified by silica gel column chromatography to give 983 mg of a grayish-white solid, yield 59%. LC-MS (APCI): m / z = 793.2 (M+1) + .

[0809] Step 7 Compound 4-((19R)-22-(bis(tert-butoxycarbonyl)amino)-16-fluoro-10-methyl-20-oxa-3,4,9,10,11,23-hexaazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18 Synthesis of pentacarboxylic acid tert-butyl 1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-3-yl)piperidine-1-carboxylic acid

[0810] (S)-4-(5-(6-(bis(tert-butyloxycarbonyl)amino)-5-hydroxypyridin-3-yl)-4-((5-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazole-1-yl)piperidin-1-carboxylic acid tert-butyl ester (983 mg, 1.24 mmol), triphenylphosphine (487 mg, 1.86 mmol), and anhydrous tetrahydrofuran (20 mL) were added sequentially to the reaction vessel. The mixture was stirred until dissolved, purged with nitrogen three times, and diisopropyl azodicarbonate (376 mg, 1.86 mmol) was slowly added dropwise at 0 °C. The reaction was stirred overnight at room temperature. The reaction was quenched with saturated brine (40 mL), extracted with ethyl acetate (40 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 631 mg of a white solid, yield 65.7%. LC-MS (APCI): m / z = 775.1 (M+1) + .

[0811] Step 8 Synthesis of intermediate B-3

[0812] 4-((19R)-22-(bis(tert-butyloxycarbonyl)amino)-16-fluoro-10-methyl-20-oxa-3,4,9,10,11,23-hexaazapentacyclo[19.3.1.0] were added sequentially to the reaction vessel. 2,6 .0 8,12 .0 13,18 [630 mg, 0.81 mmol] tert-butyl piperidine-1-carboxylate (630 mg, 0.81 mmol) and dichloromethane (10 mL) were dissolved by stirring, and ethyl hydrogen chloride solution (5 mL, 5 M) was added dropwise. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure and used directly in subsequent reaction steps. LC-MS (APCI): m / z = 475 (M+1) + .

[0813] Intermediate B-4 compound (19R)-3-ethyl-16-fluoro-10-(piperidin-4-yl)-19-methyl-20-oxa-3,4,9,10,11,23-hexaazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18 Preparation of pentacarbal-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine

[0814] Synthesized using the following route:

[0815] Step 1: Synthesis of compound 4-(4,5-dibromo-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0816] To a 500 mL single-necked flask equipped with a magnetic stirrer, 4,5-dibromo-1H-1,2,3-triazole (11 g, 48.48 mmol), 1-tert-butoxycarbonyl-4-methanesulfonyloxypiperidine (13.54 g, 48.48 mmol), cesium carbonate (31.6 g, 96.96 mmol), and N,N-dimethylformamide (200 mL) were added sequentially. The mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched with water (200 mL), extracted with ethyl acetate (200 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 15.3 g of a white solid, yield 77.3%. LC-MS (ESI): m / z = 409.0 (M+1) + .

[0817] Step 2: Synthesis of compound 5-bromo-2-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-2H-1,2,3-triazol-4-carboxylic acid

[0818] 4-(4,5-dibromo-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (15.3 g, 37.50 mmol) and tetrahydrofuran (150 mL) were added sequentially to a 500 mL three-necked flask equipped with a magnetic stirrer. The mixture was cooled to -30 °C, and isopropyl magnesium chloride (22.5 mL, 45 mmol, 2 M) was added dropwise. After the addition was complete, the mixture was stirred at -10 °C under a nitrogen atmosphere for 30 minutes. Then, carbon dioxide gas was introduced, and the mixture was stirred at -10 °C under a carbon dioxide atmosphere for 2 hours. The reaction was quenched with water (150 mL), and the pH was adjusted to 2 with hydrochloric acid aqueous solution (1 N). The mixture was extracted with ethyl acetate (200 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and yielded 14 g of white solid, with a yield of 99.9%. LC-MS (ESI): m / z = 375.0 (M+1) + .

[0819] Step 3: Synthesis of compound 4-(4-bromo-5-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0820] 5-Bromo-2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-2H-1,2,3-triazol-4-carboxylic acid (14 g, 37.40 mmol) and tetrahydrofuran (50 mL) were added sequentially to a 250 mL three-necked flask equipped with a magnetic stirrer. The mixture was cooled in an ice-water bath, and a borane tetrahydrofuran solution (152 mL, 149.6 mmol, 1 M) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was then cooled in an ice-water bath, and the reaction was quenched by slow addition of water (100 mL). After the addition was complete, the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate (200 mL × 2), and the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column filtered to give 10.8 g of a white solid, with a yield of 80.1%. LC-MS (ESI): m / z = 361.0 (M+1) + .

[0821] Step 4: Synthesis of compound 4-(4-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0822] To a 250 mL three-necked flask equipped with a magnetic stirrer, 10.8 g (30.0 mmol) of 4-(4-bromo-5-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester, 6.13 g (90.0 mmol), and 110 mL of dichloromethane were added sequentially. The mixture was cooled in an ice-water bath, and 6.78 g (45.0 mmol) of tert-butyldimethylchlorosilane was added dropwise. After the addition was complete, the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was quenched with 100 mL of water, extracted with 100 mL of dichloromethane (2 times), and the organic phases were combined. The mixture was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column filtered to give 11.3 g of a white solid, with a yield of 79.5%. LC-MS (APCI): m / z = 475.0 (M+1) + .

[0823] Step 5: Synthesis of compound (S)-4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0824] To a 250 mL three-necked flask equipped with a magnetic stirrer, add 5.0 g (10.54 mmol) of 4-(4-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester, intermediate A-3 (2.27 g (13.70 mmol), and 0.77 g (1.05 mmol) of [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. Sodium carbonate (3.35 g, 31.62 mmol), 1,4-dioxane (60 mL), and water (15 mL) were reacted overnight at 100 °C under a nitrogen atmosphere with stirring. After cooling to room temperature, the insoluble solids were filtered off, and the mixture was extracted with saturated brine (50 mL) and ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give 5.4 g of white solid, yield 95.9%. LC-MS (ESI): m / z = 535.0 (M+1) + .

[0825] Step 6: Synthesis of compound (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-5-((tert-butyldimethylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0826] To a 250 mL three-necked flask equipped with a magnetic stirrer, add (S)-4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2H-1,2,3-triazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester (5.4 g, 10.11 mmol) and tetrahydrofuran (60 mL). Cool in an ice-water bath, then add sodium hydride (0.81 g, 20.22 mmol) in portions under a nitrogen atmosphere. After stirring at room temperature for 1 hour, tetrabutylammonium iodide (1.12 g, 3.03 mmol) and benzyl bromide (2.59 g, 15.16 mmol) were added. The reaction was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with saturated brine (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give 5.6 g of white solid, yield 88.7%. LC-MS (ESI): m / z = 625.0 (M+1) + .

[0827] Step 7: Synthesis of compound (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-5-hydroxymethyl-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0828] (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-5-((tert-butyldimethylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester (5.6 g, 8.97 mmol) and tetrahydrofuran (25 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. The mixture was cooled in an ice-water bath, and tetrabutylammonium fluoride tetrahydrofuran solution (18 mL, 17.94 mmol, 1 M) was added dropwise. After the addition was complete, the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solution was concentrated and column chromatography to give 4.5 g of a white solid, with a yield of 98.4%. LC-MS (ESI): m / z = 511.0 (M+1) + .

[0829] Step 8: Synthesis of compound (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-5-formyl-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0830] (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-5-hydroxymethyl-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (4.5 g, 8.82 mmol) and dichloromethane (50 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. The mixture was cooled in an ice-water bath, and Dys-Martin oxidant (5.60 g, 13.23 mmol) was added in portions. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched with an aqueous sodium sulfite solution (50 mL), stirred, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give 4.17 g of white solid, yield 93.0%. LC-MS (ESI): m / z = 509.0 (M+1) + .

[0831] Step 9: Synthesis of compound 4-(4-(2-((S)-1-(benzyloxy)ethyl)-4-fluorophenyl)-5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0832] 5-Bromo-1-ethyl-4-iodo-1H-pyrazole (2.46 g, 8.20 mmol) and tetrahydrofuran (25 mL) were added sequentially to a 100 mL three-necked flask equipped with a magnetic stirrer. The mixture was cooled to -10 °C, and a tetrahydrofuran solution of isopropyl magnesium bromide (3.52 mL, 9.84 mmol, 2.8 M) was added dropwise. The mixture was stirred at 0 °C under a nitrogen atmosphere for 1 hour. Then, (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)- A tetrahydrofuran solution (25 mL) of 4.17 g (8.20 mmol) of 5-formyl-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched by adding saturated brine (50 mL). The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column-secred to give 3 g of white solid, yield 53.6%. LC-MS (ESI): m / z = 683.0 (M+1) + .

[0833] Step 10: Synthesis of compound (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-2H-1,2,3-triazol-2-yl)piperidine

[0834] 4-(4-(2-((S)-1-(benzyloxy)ethyl)-4-fluorophenyl)-5-((5-bromo-1-ethyl-1H-pyrazole-4-yl)(hydroxy)methyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 4.39 mmol) and dichloromethane (24 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer. After stirring until dissolved, triethylsilane (4.08 g, 35.12 mmol) was added, and the mixture was cooled to -10 °C. Trifluoroacetic acid (6 mL) was added dropwise, and the reaction was stirred at 0 °C under a nitrogen atmosphere for 1 hour. The mixture was then concentrated to obtain 2.48 g of crude product. LC-MS (ESI): m / z = 683.0 (M+1) + .

[0835] Step 11: Synthesis of compound (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0836] To a 100 mL single-necked flask equipped with a magnetic stirrer, (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-2H-1,2,3-triazol-2-yl)piperidine (2.48 g, 4.38 mmol), dichloromethane (30 mL), and triethylamine (1.34 g, 13.14 mmol) were added sequentially. After stirring until dissolved, di-tert-butyl dicarbonate (1.43 g, 6.57 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction was quenched with water (50 mL), stirred, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column filtered to give 2.4 g of white solid, with a yield of 82.4%. LC-MS(ESI): m / z = 667.0(M+1) + .

[0837] Step 12: Synthesis of compound (S)-4-(4-((5-(5-benzyloxy)-6-(bis(tert-butoxycarbonyl)amino)pyridin-3-yl)-1-ethyl-1H-pyrazol-4-yl)methyl)-5-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0838] To a 250 mL three-necked flask equipped with a magnetic stirrer, add (S)-4-(4-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (2.4 g, 3.60 mmol), intermediate A-2 (2.39 g, 5.40 mmol), sodium carbonate (1.14 g, 10.8 mmol), tetra(triphenylphosphine)palladium (0.41 g, 0.36 mmol), 1,4-dioxane (40 mL), and water (10 mL). Evacuate the flask and purge with nitrogen three times. Heat the flask to 90 °C under a nitrogen atmosphere and stir overnight. The reaction was quenched by adding saturated brine (50 mL) after cooling to room temperature. Extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column filtered to give 3.0 g of a white solid (yield 84.5%). LC-MS (ESI): m / z = 987.0 (M+1) + .

[0839] Step 13: Synthesis of compound (S)-4-(4-((5-(6-bis(tert-butoxycarbonyl)amino)-5-hydroxypyridin-3-yl)-1-ethyl-1H-pyrazol-4-yl)methyl)-5-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0840] To a 100 mL single-necked flask equipped with a magnetic stirrer, (S)-4-(4-((5-(5-benzyloxy)-6-(bis(tert-butoxycarbonyl)amino)pyridin-3-yl)-1-ethyl-1H-pyrazol-4-yl)methyl)-5-(2-(1-benzyloxy)ethyl)-4-fluorophenyl)-2H-1,2,3-triazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester (3.0 g, 3.04 mmol) and methanol (50 mL) were added sequentially. The mixture was stirred until dissolved, and palladium on carbon (1.5 g, 10%) was added. The mixture was purged three times with hydrogen, stirred overnight at room temperature under a hydrogen atmosphere, and the catalyst was removed by filtration. The sample was washed with methanol (10 mL), and the filtrates were combined and concentrated to dryness to give 1.87 g of a white solid, yield 76.5%. LC-MS (ESI): m / z = 807.0 (M+1) + .

[0841] Step 14 Compound 4-((19R)-22-(bis(tert-butoxycarbonyl)amino)-3-ethyl-16-fluoro-19-methyl-20-oxa-3,4,9,10,11,23-hexaazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18Synthesis of tert-butyl 2,2-pentacarbon-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-10-yl)piperidine-1-carboxylic acid

[0842] To a 50 mL three-necked flask equipped with a magnetic stirrer, add (S)-4-(4-((5-(6-bis(tert-butyloxycarbonyl)amino)-5-hydroxypyridin-3-yl)-1-ethyl-1H-pyrazol-4-yl)methyl)-5-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2H-1,2,3-triazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester (750 mg, 0.93 mmol) and triphenylphosphine (787.3 mg, 1.86 mmol). Evacuate the flask and purge with nitrogen three times. Add anhydrous tetrahydrofuran (15 mL). Cool the flask in an ice-water bath. Slowly add diisopropyl azodicarbonate (375.7 mg, 1.86 mmol). After the addition is complete, remove the ice bath and stir the flask at room temperature under a nitrogen atmosphere overnight. Extracted with 30 mL of saturated brine and ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 476.6 mg of a white solid, yield 65.0%. LC-MS (ESI): m / z = 789.0 (M+1) + .

[0843] Step 15 Synthesis of intermediate B-4

[0844] Compound 4-((19R)-22-(bis(tert-butyloxycarbonyl)amino)-3-ethyl-16-fluoro-19-methyl-20-oxa-3,4,9,10,11,23-hexaazapentacyclo[19.3.1.0] was added sequentially to a 50 mL single-necked flask equipped with a magnetic stirrer. 2,6 .0 8,12 .0 13,18 [476.6 mg, 0.60 mmol] tert-butyl piperidine-1-carboxylate (476.6 mg, 0.60 mmol) and dichloromethane (1 mL) were added to ethyl hydrogen chloride solution (5 mL, 4 M) with stirring. The mixture was stirred at room temperature for 30 minutes and concentrated to give 295 mg of white solid, yield 99.9%. LC-MS (ESI): m / z = 489.0 (M+1) + .

[0845] Intermediate B-5 compound (19R)-22-amino-16-fluoro-10,19-dimethyl-4-(piperidin-4-yl)-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18Preparation of pentacarbamate-1(24),2,5,8,11,13,15,17,21(25),22-decaene-3-carboxynitrile

[0846] The following synthetic route was adopted:

[0847] Step 1: Synthesis of compound 4-(3-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0848] 3-Iodopyrazole (5.0 g, 25.75 mmol) and acetonitrile (100 mL) were added sequentially to a 250 mL single-necked flask equipped with a magnetic stirrer. After stirring until dissolved, 1-tert-butoxycarbonyl-4-methanesulfonyloxypiperidine (8.65 g, 31 mmol) and cesium carbonate (25 g, 77.25 mmol) were added. The mixture was heated to 80 °C overnight under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate (80 mL), and inorganic salts were removed by filtration. The filter cake was washed with ethyl acetate (50 mL × 2). The filtrates were combined, concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography to give 5.5 g of a white solid, with a yield of 53.1%. LCMS (ESI): m / z = 377.3 (M+1) + .

[0849] Step 2: Synthesis of compound 4-(5-cyano-3-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0850] To a 250 mL three-necked flask equipped with a magnetic stirrer, tert-butyl 4-(3-iodo-1H-pyrazol-1-yl)piperidin-1-carboxylic acid was added sequentially (5.5 g, 13.68 mmol) and tetrahydrofuran (100 mL). After stirring until dissolved, under nitrogen protection, a tetrahydrofuran solution of 2,2,6,6-tetramethylpiperidinyl magnesium chloride and lithium chloride (19 mL, 19.0 mmol, 1 M) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour, then cooled to 5 °C, and a tetrahydrofuran solution of toluenesulfonyl nitrile (3.44 g, 18.97 mmol) (20 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution (80 mL), extracted with ethyl acetate (80 mL × 3), and the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 4.3 g of white solid (78.2% yield). LCMS(ESI): m / z = 402.2(M+1) + .

[0851] Step 3: Synthesis of compound tert-butyl 4-(5-cyano-3-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid.

[0852] To a 250 mL three-necked flask equipped with a magnetic stirrer, tert-butyl 4-(5-cyano-3-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid (2.34 g, 5.81 mmol) and tetrahydrofuran (50 mL) were added sequentially. The mixture was stirred until dissolved, and then cooled to -10 °C under nitrogen protection. Isopropyl magnesium bromide tetrahydrofuran solution (2.5 mL, 6.98 mmol, 2.8 M) was added dropwise. After the addition was complete, the mixture was stirred at -10 °C for 1 hour. Then, a tetrahydrofuran solution of intermediate A-6 (1.44 g, 6.1 mmol) (20 mL) was added dropwise. After the addition was complete, the reaction system was allowed to warm naturally to room temperature and stirred overnight. The reaction was monitored by LCMS until completion. The reaction was quenched by adding saturated ammonium chloride solution (60 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 2.0 g of a light brown solid, with a yield of 67.1%. LCMS (ESI): m / z = 512.3 (M+1) + .

[0853] Step 4: Synthesis of compound 3-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-(piperidin-4-yl)-1H-pyrazol-5-nitrile

[0854] To a 1000 mL single-necked flask equipped with a magnetic stirrer, 2.0 g (3.9 mmol) of 4-(5-cyano-3-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester and 40 mL of trifluoroacetic acid were added sequentially. The mixture was stirred until dissolved, followed by the addition of triethylsilane (2.7 g, 23.4 mmol). After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was monitored for completion by LCMS, and the solution was concentrated by vacuum distillation. The residue was used directly in subsequent reaction steps. LCMS (ESI): m / z = 396.3 (M+1) + .

[0855] Step 5: Synthesis of compound 4-(5-cyano-3-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0856] To a 100 mL single-necked flask equipped with a magnetic stirrer, trifluoroacetate of 3-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-(piperidin-4-yl)-1H-pyrazol-5-onitrile and 40 mL of dichloromethane were added sequentially. The mixture was stirred until dissolved, followed by the addition of triethylamine (2.0 g, 19.5 mmol) and di-tert-butyl dicarbonate (4.2 g, 7.8 mmol). The mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS until completion. Water (30 mL) was added to the reaction solution, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 1.76 g of a white solid. The two-step yield was 91.0%. LC-MS (ESI): m / z = 496.2 (M+1) + .

[0857] Step 6: Synthesis of compound (S)-4-(5-cyano-3-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0858] To a 100 mL single-necked flask equipped with a magnetic stirrer, 4-(5-cyano-3-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1.76 g, 3.55 mmol), 1,4-dioxane (30 mL), water (5 mL), intermediate A-3 (710 mg, 4.26 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (260 mg, 0.355 mmol) and sodium carbonate (1.2 g, 10.65 mmol) were added sequentially. The mixture was purged with nitrogen three times, stirred thoroughly, and then heated to 100 °C in an oil bath overnight. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filter cake was treated with dichloromethane (50 mL × 2). The filtrates were combined and concentrated under reduced pressure by distillation. The residue was purified by silica gel column chromatography to obtain 1.67 g of white solid, with a yield of 92.97%. LCMS (ESI): m / z = 509 (M+1) + .

[0859] Step 7: Synthesis of compound (R)-4-(3-((3-(2-(1-((5-bromo-2-((tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-5-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0860] Triphenylphosphine (1.3 g, 4.95 mmol) and tetrahydrofuran (20 mL) were added sequentially to a 100 mL three-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved, and then cooled to 0 °C in an ice bath under nitrogen protection. Diisopropyl azodicarbonate (1.0 g, 4.95 mmol) was added dropwise, and the mixture was stirred in an ice bath until a white solid precipitated. Subsequently, tert-butyl (5-bromo-3-hydroxypyridin-2-yl)aminocarboxylic acid (1.04 g, 3.6 mmol) was added dropwise. A solution of 10 mL of tetrahydrofuran (3.3 mmol) was added, and the mixture was stirred at 0 °C for 30 minutes. Then, a solution of 10 mL of tetrahydrofuran containing (S)-4-(5-cyano-3-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1.67 g, 3.3 mmol) was added dropwise. The mixture was allowed to warm naturally to room temperature and stirred overnight. The reaction was monitored by LCMS until completion. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 2.0 g of a light brown solid, yield 77.6%. LCMS (ESI): m / z = 778.2 (M+1) + .

[0861] Step 8 Compound 4-((19R)-22-((tert-Butoxycarbonyl)amino)-3-cyano-16-fluoro-10,19-dimethyl-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18 Synthesis of tert-butyl 2,2-decen-4-yl)piperidine-1-carboxylic acid

[0862] To a 100 mL single-necked flask equipped with a magnetic stirrer, add (R)-4-(3-((3-(2-(1-((5-bromo-2-((tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-5-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 2.57 mmol) and tert-amyl alcohol (30 mL), stirring until dissolved. Then add palladium acetate (574 mg, 2.56 mmol), n-butyldi(1-adamantyl)phosphine (3.68 g, 10.28 mmol) and potassium acetate (752 mg, 7.68 mmol). Purge the mixture with nitrogen three times. After stirring until homogeneous, heat to 100 °C in an oil bath and react overnight. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filter cake was washed with dichloromethane (50 mL × 2). The filtrates were combined, concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography to give 600 mg of white solid, with a yield of 33.45%. LCMS (ESI): m / z = 699.3 (M+1) + .

[0863] Synthesis of intermediate B-5 in step 9

[0864] Add 4-((19R)-22-((tert-butyloxycarbonyl)amino)-3-cyano-16-fluoro-10,19-dimethyl-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] to a 100 mL single-necked flask equipped with a magnetic stirrer. 2,6 .0 8,12 .0 13,18 [600 mg, 0.86 mmol] tert-butyl piperidine-1-carboxylate (600 mg, 0.86 mmol) and dichloromethane (20 mL) were stirred until dissolved, followed by the addition of trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion, and the reaction solution was concentrated and used directly in subsequent reaction steps. LCMS (ESI): m / z = 499.2 (M+1) + .

[0865] Intermediate B-6 compound (19R)-22-amino-4-(1-(azacyclobutan-3-yl)piperidin-4-yl)-16-fluoro-10,19-dimethyl-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18 Preparation of pentacarbamate-1(24),2,5,8,11,13,15,17,21(25),22-decaene-3-carboxynitrile

[0866] The following synthetic route was adopted:

[0867] Step 1 Compound 3-(4-((19R)-22-amino-3-cyano-16-fluoro-10,19-dimethyl-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18 Synthesis of pentacarboxylic acid tert-butyl ester (24), 2, 5, 8, 11, 13, 15, 17, 21 (25), 22-decaen-4-yl)piperidin-1-yl)azacyclobutane-1-carboxylic acid

[0868] Crude trifluoroacetate of intermediate B-5 (170 mg, 0.335 mmol) and N,N-dimethylformamide (5 mL) were added sequentially to a reaction vessel and stirred until dissolved. Then, 1-tert-butoxycarbonyl-3-azacyclobutanone (86 mg, 0.502 mmol), sodium tris(acetoxy)borohydride (142 mg, 0.67 mmol), and a small drop of acetic acid were added, and the mixture was stirred overnight at room temperature. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 177 mg of a white solid, with a yield of 80.9%. LCMS (ESI): m / z = 654.2 (M+1) + .

[0869] Synthesis of intermediate B-6 in step 2

[0870] Add 3-(4-((19R)-22-amino-3-cyano-16-fluoro-10,19-dimethyl-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] to a 50 mL single-necked flask equipped with a magnetic stirrer. 2,6 .0 8,12 .0 13,18 [177 mg, 0.27 mmol] tert-butyl 1-(24),2,5,8,11,13,15,17,21(25),22-decaen-4-yl)piperidin-1-yl)azacyclobutane-1-carboxylic acid was dissolved in 20 mL of dichloromethane by stirring. Trifluoroacetic acid (4 mL) was then added, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The reaction solution was concentrated and used directly in subsequent reaction steps. LCMS (ESI): m / z = 554.3 (M+1) + .

[0871] Intermediate B-7 compound (19R)-22-amino-16-fluoro-10,19-dimethyl-5-(piperidin-4-yl)-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0]2,6 .0 8,12 .0 13,18 Preparation of pentacarbamate-1(24),2(6),3,8,11,13,15,17,21(25),22-decaene-3-carboxynitrile

[0872] The following synthetic route was adopted:

[0873] Step 1: Synthesis of compound 4-(4-bromo-3-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0874] 3-Cyanopyrazole (4.0 g, 23.2 mmol) and acetonitrile (100 mL) were added sequentially to a 250 mL single-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved, followed by the addition of 1-tert-butoxycarbonyl-4-methanesulfonyloxypiperidine (7.8 g, 27.92 mmol) and cesium carbonate (22.8 g, 69.6 mmol). The mixture was stirred thoroughly and then refluxed overnight at 82 °C in an oil bath. The reaction was monitored by LC-MS until complete. The reaction solution was filtered through a sintered glass funnel, and the filter cake was washed with ethyl acetate (50 mL × 2). The filtrates were combined, concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography to give 5.5 g of a white solid, with a yield of 66.97%. LC-MS (ESI): m / z = 255.1 (M + 1 - 100). + .

[0875] 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.45(s,1H),4.53-4.48(m,1H),4.04-4.01(m ,2H),2.89-2.87(m,2H),2.04-2.00(m,2H),1.81-1.73(m,2H),1.40(s,9H).

[0876] Step 2: Synthesis of compound 4-(4-bromo-3-cyano-5-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0877] To a 250 mL three-necked flask equipped with a magnetic stirrer, 4.0 g (11.3 mmol) of 4-(4-bromo-3-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester and 80 mL of tetrahydrofuran were added sequentially. The mixture was stirred until dissolved, and the temperature was lowered to -78 °C under nitrogen protection. A tetrahydrofuran solution of lithium diisopropylaminoacetate (6.2 mL, 12.4 mmol, 2 M) was added dropwise. After the addition was complete, the reaction mixture was stirred at -78 °C for 1.5 hours. Subsequently, a tetrahydrofuran solution of intermediate A-6 (2.8 g, 11.86 mmol) (20 mL) was slowly added dropwise. After the addition was complete, the reaction system was allowed to warm naturally to room temperature and stirred overnight. The reaction was monitored by LCMS until completion. The reaction was quenched by adding saturated ammonium chloride solution (80 mL), extracted with ethyl acetate (80 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 4.0 g of a light brown solid, with a yield of 60.0%. LCMS (ESI): m / z = 590.3 (M+1) + .

[0878] Step 3: Synthesis of compound 4-bromo-5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-(piperidin-4-yl)-1H-pyrazol-3-carboxynitrile

[0879] To a 100 mL single-necked flask equipped with a magnetic stirrer, 4-(4-bromo-3-cyano-5-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (4.0 g, 6.78 mmol) and trifluoroacetic acid (40 mL) were added sequentially. After stirring until dissolved, triethylsilane (7.8 g, 67.8 mmol) was added. The mixture was stirred overnight at room temperature. The reaction was monitored by LCMS to indicate completion. The solution was concentrated by vacuum distillation, and the residue was used directly in subsequent reaction steps. LCMS (ESI): m / z = 474.2 (M+1) + .

[0880] Step 4: Synthesis of compound tert-butyl 4-(4-bromo-3-cyano-5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid.

[0881] The trifluoroacetate of 4-bromo-5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-(piperidin-4-yl)-1H-pyrazol-3-carboxynitrile obtained in step 3 was added sequentially to the reaction vessel to neutralize dichloromethane (40 mL). Triethylamine (6.91 g, 67.8 mmol) and di-tert-butyl dicarbonate (2.93 g, 13.6 mmol) were added with stirring, and the reaction was carried out overnight at room temperature. The reaction was monitored by LCMS until completion. Water (50 mL) was added, and the mixture was stirred. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (40 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 2.5 g of a white solid. The two-step yield was 64.2%. LCMS (ESI): m / z = 574.2 (M+1) + .

[0882] Step 5: Synthesis of compound (S)-4-(4-bromo-3-cyano-5-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0883] To a 100 mL single-necked flask equipped with a magnetic stirrer, 4-(4-bromo-3-cyano-5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1.94 g, 3.38 mmol), intermediate A-3 (560 mg, 3.38 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (260 mg, 0.355 mmol), sodium carbonate (1.1 g, 10.2 mmol), 1,4-dioxane (30 mL), and water (6 mL) were added sequentially. The mixture was purged with nitrogen three times, stirred thoroughly, and then heated to 85 °C in an oil bath for 2 hours. The reaction was monitored by LCMS until completion. After cooling to room temperature, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (30 mL). The filtrates were combined, concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography to give 1.5 g of a white solid, with a yield of 75.7%. LCMS (ESI): m / z = 586.3 (M+1) + .

[0884] Step 6: Synthesis of compound (S)-4-(4-(5-benzyloxy)-6-(bis(tert-butoxycarbonyl)amino)pyridin-3-yl)-3-cyano-5-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0885] To a 100 mL single-necked flask equipped with a magnetic stirrer, add (S)-4-(4-bromo-3-cyano-5-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 2.56 mmol), intermediate A-2 (1.4 g, 2.81 mmol), tetrakis(triphenylphosphine)palladium (296 mg, 0.256 mmol), sodium carbonate (814 mg, 7.68 mmol), 1,4-dioxane (20 mL), and water (4 mL). Purge the mixture with nitrogen three times, stir thoroughly, and then heat in an oil bath to 85 °C overnight. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filter cake was washed with dichloromethane (100 mL × 2). The filtrates were combined, concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography to give 1.4 g of white solid, with a yield of 60.4%. LCMS (ESI): m / z = 906.2 (M+1) + .

[0886] Step 7: Synthesis of compound (S)-4-(4-(6-(bis(tert-butoxycarbonyl)amino)-5-hydroxypyridin-3-yl)-3-cyano-5-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0887] To a 250 mL single-necked flask equipped with a magnetic stirrer, (S)-4-(4-(5-benzyloxy)-6-(bis(tert-butyloxycarbonyl)amino)pyridin-3-yl)-3-cyano-5-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (1.4 g, 1.547 mmol) and methanol (100 mL) were added sequentially. The mixture was stirred until dissolved, and then wet palladium on carbon (1.0 g, 5%) was added. The mixture was purged three times with hydrogen, and the reaction was stirred overnight under a hydrogen atmosphere. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filter cake was washed with methanol (50 mL × 2). The filtrates were combined, concentrated, and the residue was purified by silica gel column chromatography to give 1.0 g of a white solid, yield 79.3%. LCMS(ESI): m / z = 816.2(M+1) + .

[0888] Step 8 Compound 4-((19R)-22-(bis(tert-butoxycarbonyl)amino)-3-cyano-16-fluoro-10,19-dimethyl-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18Synthesis of pentacarboxylic acid tert-butyl 1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-5-yl)piperidine-1-carboxylic acid

[0889] Triphenylphosphine (372 mg, 1.42 mmol) and tetrahydrofuran (20 mL) were added sequentially to a 100 mL three-necked flask equipped with a magnetic stirrer. The mixture was stirred until dissolved and cooled to 0 °C under nitrogen protection in an ice bath. Diisopropyl azodicarbonate (287 mg, 1.42 mmol) was added, and the mixture was stirred in an ice bath until a white solid precipitated. Then, a tetrahydrofuran solution (10 mL) of (S)-4-(4-(6-(bis(tert-butyloxycarbonyl)amino)-5-hydroxypyridin-3-yl)-3-cyano-5-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (770 mg, 0.945 mmol) was added dropwise. After the addition was complete, the mixture was allowed to warm naturally to room temperature and stirred overnight. The reaction was monitored by LCMS until completion. Saturated brine (20 mL) was added, followed by extraction with ethyl acetate (20 mL × 3). 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 obtain 500 mg of a light brown solid, yield 66.4%. LCMS (ESI): m / z = 798.4 (M+1) + .

[0890] Synthesis of intermediate B-7 in step 9

[0891] Add 4-((19R)-22-(bis(tert-butyloxycarbonyl)amino)-3-cyano-16-fluoro-10,19-dimethyl-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] to a 50 mL single-necked flask equipped with a magnetic stirrer. 2,6 .0 8,12 .0 13,18 [500 mg, 0.63 mmol] tert-butyl piperidine-1-carboxylate (500 mg, 0.63 mmol) and dichloromethane (10 mL) were stirred until dissolved, followed by the addition of trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion, and the reaction solution was concentrated and used directly in subsequent reaction steps. LCMS (ESI): m / z = 498.2 (M+1) + .

[0892] Intermediate B-8 compound (19R)-22-amino-16-fluoro-10,19-dimethyl-5-(1-(azacyclobutan-3-yl)piperidin-4-yl)-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18 Preparation of pentacarbamate-1(24),2(6),3,8,11,13,15,17,21(25),22-decaene-3-carboxynitrile

[0893] The following synthetic route was adopted:

[0894] Step 1 Compound 3-(4-((19R)-22-amino-3-cyano-16-fluoro-10,19-dimethyl-20-oxa-4,5,10,11,23-pentazapentacyclo[19.3.1.0] 2,6 .0 8,12 .0 13,18 Synthesis of pentacarboxylic acid tert-butyl ester (1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-5-yl)piperidin-1-yl)azacyclobutane-1-carboxylic acid)

[0895] To a reaction vessel, crude trifluoroacetate of intermediate B-7 (400 mg, 0.8 mmol) and N,N-dimethylformamide (5 mL) were added sequentially. After stirring until dissolved, 1-tert-butoxycarbonyl-3-azacyclobutanone (164 mg, 0.96 mmol), sodium tris(acetoxy)borohydride (509 mg, 2.4 mmol), and a small drop of acetic acid were added. The mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 300 mg of a white solid, with a yield of 57.34%. LCMS (ESI): m / z = 654.2 (M+1) + .

[0896] Synthesis of intermediate B-8 in step 2 [08...

Claims

1. A compound of formula (A), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof: in, X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R; Y1 is -NR c -CO-, a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein said group is optionally substituted by one or more groups selected from R' groups; Z1 is either CR3 or N; Z2 can be CH, CD, or N; Z3 is either CR4R5 or NR4; R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; l can be 0, 1, or 2; R4 and R5 are independently H, D, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally substituted with one or more D atoms until it is fully deuterated; Or R4 and an R, along with the atoms they are attached to, form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated; Or R4 and an R' together with the atoms they are attached to form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated; Or an R and an R' together with the atoms they are attached to form C. 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated; Or an R and R c Together with the atoms they are attached to, they form C 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated; R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated; m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; L represents a chemical bond or a divalent linking group; U is a group that binds to E3 ubiquitin ligase.

2. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, is a compound of formula (I): in, X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R; Y1 is -NR c -CO-, a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein said group is optionally substituted by one or more groups selected from R' groups; Z1 is either CR3 or N; Z2 can be CH, CD, or N; R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; l can be 0, 1, or 2; R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated; m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; L represents a chemical bond or a divalent linking group; U is a group that binds to E3 ubiquitin ligase.

3. The compound according to claim 2, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, having the formula (I... A Compounds:

4. The compound according to claim 2, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, having the formula (I... B Compounds:

5. The compound according to any one of claims 2-4, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X1 is a divalent group of a 5-membered heteroaromatic hydrocarbon containing 1 to 3 heteroatoms selected from N, S and O, wherein the group is substituted by a -LU group and optionally substituted by 1, 2 or 3 groups selected from R.

6. The compound according to any one of claims 2-5, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X1 is:

7. The compound according to any one of claims 2-6, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X1 is: ^Represents the connection point of formula X1 with the methylene group bonded to X1 and Y1.

8. The compound according to any one of claims 2-7, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R is independently H, D, F, Cl, -CN, -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxecyclobutyl, wherein -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxecyclobutyl is optionally substituted by one or more Ds until fully deuterated.

9. The compound according to any one of claims 2-8, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R is independently H, D, F, Cl, -CN, -CH2CH3, cyclopropyl, or cyclopropylmethyl.

10. The compound according to any one of claims 2-9, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Y1 is a divalent group of a 5- to 6-membered heteroaromatic hydrocarbon or benzene ring containing 1 to 3 heteroatoms selected from N, S, and O, wherein said group is optionally substituted by 1, 2, 3, or 4 groups selected from R'.

11. The compound according to any one of claims 2-10, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Y1 is: Where W1 is N or CR'.

12. The compound according to claims 2-11, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, Y1 is: Where W1 is N or CR'; *The connection point of formula Y1 to the methylene group bonded to X1 and Y1.

13. The compound according to any one of claims 2-12, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R' is independently H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CHF2, -CF3, or methoxy, wherein the -CH3, -CH2CH3, -CHF2, -CF3, or methoxy group is optionally substituted by one or more D groups until fully deuterated.

14. The compound according to any one of claims 2-13, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R' is independently H, D, F, Cl, -CH3, or -CD3.

15. The compound according to any one of claims 2-9, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Y1 is -NR c -CO-.

16. The compound according to claim 15, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R c It is -CH3 or -CD3.

17. The compound according to any one of claims 2-16, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Z1 is CR3; Z2 is CH.

18. The compound according to any one of claims 2-17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1, R2, and R3 are independently H, D, F, Cl, -CH3, -CD3, or -CF3.

19. The compound according to any one of claims 2-18, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 is -CH3; R2 is F; R3 is H.

20. The compound according to any one of claims 2-19, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Both m and n are 0.

21. The compound according to claim 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, having the formula (I A1 ) to formula (I A5 ') Compound: in, W1 is either N or CR'; R and R' are independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; L represents a chemical bond or a divalent linking group; U is a group that binds to E3 ubiquitin ligase.

22. The compound according to claim 21, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R is independently H, D, halogen, -CN, C 1- 6-alkyl or C 0-6 Alkylene-C 3-7 cycloalkyl, wherein the C 1-6 Alkyl or C 0-6 Alkylene-C 3-7 The cycloalkyl group is optionally substituted with one or more D molecules, up to complete deuteration.

23. The compound according to claim 21, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R is independently H, D, F, Cl, -CN, -CH2CH3, cyclopropyl, or cyclopropylmethyl, wherein the -CH2CH3, cyclopropyl, or cyclopropylmethyl is optionally substituted by one or more Ds until fully deuterated.

24. The compound according to any one of claims 21-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R' is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with one or more D molecules, up to and including complete deuteration.

25. The compound according to any one of claims 21-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R' is independently H, D, F, Cl, -CH3, or -CD3.

26. The compound according to claim 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, having the formula (I) A6 Compounds: in, R can be independently H, D, halogen, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0- 6-alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0- The 6-alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; R c Independently, it can be H, D, halogen, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl groups, wherein -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; L represents a chemical bond or a divalent linking group; U is a group that binds to E3 ubiquitin ligase.

27. The compound according to claim 26, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R stands for -CN.

28. The compound according to claim 26 or 27, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R c It is -CH3 or -CD3.

29. A compound of formula (B), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof: in, X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is optionally substituted by one or more groups selected from R; Y2 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein the group is substituted by a -LU group and optionally substituted by one or more groups selected from R' groups; Z1 is either CR3 or N; Z2 can be CH, CD, or N; Z3 is either CR4R5 or NR4; R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; l can be 0, 1, or 2; R4 and R5 are independently H, D, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally substituted with one or more D atoms until it is fully deuterated; Or R4 and an R, along with the atoms they are attached to, form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated; Or R4 and an R' together with the atoms they are attached to form C. 4-7 cycloalkyl or 4- to 8-membered heterocyclic groups, wherein the C 4-7 The cycloalkyl or 4- to 8-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated; Or an R and an R' together with the atoms they are attached to form C. 5-8 cycloalkyl or 5- to 9-membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5- to 9-membered heterocyclic group is optionally substituted with one or more D groups until fully deuterated; R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl or C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated; m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; Each R and R' is independently H, D, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; L represents a chemical bond or a divalent linking group; U is a group that binds to E3 ubiquitin ligase.

30. The compound according to claim 29, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound of formula (II): in, X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon, wherein the group is optionally substituted by one or more groups selected from R; Y2 is a divalent group of a 5- or 6-membered heteroaromatic hydrocarbon or a benzene ring, wherein the group is substituted by a -LU group and optionally by one or more groups selected from R'; Z1 is either CR3 or N; Z2 can be CH, CD, or N; R1, R2, and R3 are independently H, D, halogen, or -(CH2). l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 Alkylene-5 to 14-membered heteroaryl groups, wherein the -(CH2) group... l -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; l can be 0, 1, or 2; R a and R b Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl and C 1- The 6-haloalkyl group is optionally substituted with one or more D molecules until fully deuterated; m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; R and R' are independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; L represents a chemical bond or a divalent linking group; U is a group that binds to E3 ubiquitin ligase.

31. The compound according to claim 30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, having the formula (II) A Compounds:

32. The compound according to claim 30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, having the formula (II) B Compounds:

33. The compound according to any one of claims 30-32, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X2 is a divalent group of a 5-membered heteroaromatic hydrocarbon containing 1 to 3 heteroatoms selected from N, S and O, wherein the group is optionally substituted by 1, 2 or 3 groups selected from R.

34. The compound according to any one of claims 30-33, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X2 is:

35. The compound according to any one of claims 30-34, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X2 is: ^Represents the connection point of X2 with the methylene group bonded to X2 and Y2.

36. The compound according to any one of claims 30-35, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R is independently H, D, F, Cl, -CN, -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxecyclobutyl, wherein -CH3, -CH2CH3, isopropyl, isobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, or oxecyclobutyl is optionally substituted by one or more Ds until fully deuterated.

37. The compound according to any one of claims 30-36, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R is independently H, D, F, Cl, -CN, or -CH2CH3.

38. The compound according to any one of claims 30-37, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Y2 is a divalent group of a 5- to 6-membered heteroaromatic hydrocarbon or benzene ring containing 1 to 3 heteroatoms selected from N, S, and O, wherein the group is substituted by a -LU group and optionally substituted by 1, 2, or 3 groups selected from R'.

39. The compound according to any one of claims 30-38, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Y2 is: Where W2 is N or CR'.

40. The compound according to claims 30-39, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Y2 is: Where W2 is N or CR'; *The connection point of formula Y2 to the methylene group bonded to X2 and Y2.

41. The compound according to any one of claims 30-40, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R' is independently H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CHF2, -CF3, or methoxy, wherein the -CH3, -CH2CH3, -CHF2, -CF3, or methoxy group is optionally substituted by one or more D groups until fully deuterated.

42. The compound according to any one of claims 30-41, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R' is independently H, D, F, Cl, -CH3, or -CD3.

43. The compound according to any one of claims 40-42, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Z1 is CR3; Z2 is CH.

44. The compound according to any one of claims 40-43, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1, R2, and R3 are independently H, D, F, Cl, -CH3, -CD3, or -CF3.

45. The compound according to any one of claims 40-44, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 is -CH3; R2 is F; R3 is H.

46. ​​The compound according to any one of claims 40-45, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Both m and n are 0.

47. The compound according to claim 30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, having the formula (II) A1 ) to formula (II) A3 Compounds: in, W2 is either N or CR'; R and R' are independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 alkylene-5 to 14-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 0-6 Alkylene-C 3-7 cycloalkyl, C 0-6 Alkylene-C 6-14 Aryl, C 0-6 alkylene-3 to 7-membered heterocyclic groups or C 0-6 The alkylene-5 to 14-membered heteroaryl groups are optionally substituted with one or more D groups until fully deuterated; L represents a chemical bond or a divalent linking group; U is a group that binds to E3 ubiquitin ligase.

48. The compound according to claim 47, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R is independently H, D, halogen, -CN, C 1- 6-alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 The alkoxy group is optionally substituted with one or more D atoms, up to complete deuteration.

49. The compound according to claim 47, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R is independently H, D, F, Cl, -CN, -CH3, -CH2CH3, methoxy, or ethoxy, wherein the -CH3, -CH2CH3, methoxy, or ethoxy is optionally substituted by one or more Ds until fully deuterated.

50. The compound according to claim 47, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R is independently -CH3, -CH2CH3, -CD3, or -CD2CD3.

51. The compound according to any one of claims 47-50, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Each R' is independently H, D, F, Cl, -CH3, or -CD3.

52. The compound according to any one of claims 1-51, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is the divalent linker shown in formula (III): -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-■ (III) in, i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0. L1, L2, and L3 are each an independent chemical bond, or selected from C 3-7 A divalent group consisting of a cycloalkanes, a 4- to 7-membered heterocycle, or a 5- to 7-membered heteroaryl group, wherein the divalent group is optionally surrounded by one or more elements selected from D, halogens, OH, CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups; S0, S1, S2, and S3 are each independently a chemical bond, namely -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, and -C(O)NH(CH2). p -、-C(O)(CH2) p -、-NHC(O)(CH2) p -、-(CH2) p -、-(CH2CH2O) q -、C 1-6 imide or C 1-6 Alynyl group; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3; ■ indicates the end connected to U.

53. The compound according to claim 52, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is equation (III) A The divalent linker shown is: -(L1) i -(L2) j -(L3) k -■ (III A ).

54. The compound according to claim 52, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is equation (III) B The divalent linker shown is: -(L1) i -S1-(L2) j -S2-(L3) k -■ (III B ).

55. The compound according to claim 52, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is equation (III) C The divalent linker shown is: -S0-(L1) i (L2) j -S2-(L3) k -S3-■ (III C ) Among them, (L1) i and (L2) j They share an atom and / or a chemical bond.

56. The compound according to claim 52, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is equation (III) D The divalent linker shown is: -S0-(L1) i -S1-(L2) j (L3) k -S3-■ (III D ) Among them, (L2) j and (L3) k They share an atom and / or a chemical bond.

57. The compound according to any one of claims 52-56, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, One or two of L1, L2, and L3 are chemical bonds, and the remaining individual groups are divalent groups selected from 4- to 7-membered heterocycles containing 1 or 2 nitrogen atoms; wherein the divalent groups are optionally bonded by one or more bonds selected from D, halogens, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

58. The compound according to any one of claims 52-57, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is: The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

59. The compound according to any one of claims 58, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is: The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

60. The compound according to any one of claims 58, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is: The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, -OH, -CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups with haloalkyl groups.

61. The compound according to any one of claims 1-60, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: in, Indicates a single bond or a double bond; Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2; Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2; Each Q1 is independently C(O) or C(R9)2; Each Q2 is independently either N or CH; Each Q3 and Q4 is independently either N or CR9; Each of K1, K2, and K3 is independently either N or CR9; K4 and K5 are each independently N or C; H1 is N, C, or CR9; H2 and H3 are each independently C(O), N, O, S, NR9, CR9 or C(R9)2; H4 and H8 are each independently N or CR9; H5, H6, and H7 are each independently C(O), O, S, NR9, or C(R9)2; each R7 is independently H or C. 1-6 alkyl; Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 Cycloalkanes or 4- to 7-membered heterocycles; Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkanes, 4- to 7-membered heterocycles, C 6-10 Aromatic hydrocarbons or 5- to 10-membered heteroaromatic hydrocarbons; Each 'o' is independently 0, 1, or 2; Each h is independently 0, 1, 2, 3 or 4; Each z is independently 0, 1, or 2; Each r and s is independently 0, 1, 2, or 3; and r and s are not both 0 at the same time; Each t and u is independently 0, 1, 2, or 3; and t and u are not both 0 at the same time.

62. The compound according to claim 61, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: in, Indicates a single bond or a double bond; Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2; Each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2; Each Q1 is independently C(O) or C(R9)2; Each Q2 is independently either N or CH; Each Q3 and Q4 is independently either N or CR9; Each R7 is independently either H or C. 1-6 alkyl; Each R8 is independently D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R8 atoms together with the atoms they are attached to form C 3-7 Cycloalkanes or 4- to 7-membered heterocycles; Each R9 is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R9s together with the atoms they are attached to form C. 3-7 Cycloalkanes, 4- to 7-membered heterocycles, C 6-10 Aromatic hydrocarbons or 5- to 10-membered heteroaromatic hydrocarbons; Each h is independently 0, 1, 2, 3 or 4; Each k is independently 0, 1, 2, 3 or 4; Each z is independently 0, 1, or 2; Each 'o' is independently 0, 1, or 2; Each r and s is independently 1, 2, or 3; Each t and u is independently 1, 2, or 3.

63. The compound according to claim 62, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: in, Q3 is either N or CR9; Each R9 is independently H, D, or halogen; Each k is independently 0, 1, or 2.

64. The compound according to claim 62, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: in, Q3 is either N or CR9; Each R9 is independently H, D, or halogen; Each k is independently 0, 1, or 2.

65. The compound according to claim 62, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: in, Q3 is either N or CR9; Each R9 is independently H, D, or halogen; Each k is independently 0, 1, or 2.

66. The compound according to any one of claims 1-65, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is:

67. The compound according to any one of claims 1-60, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is 68. The compound according to any one of claims 1-60, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: in, Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2; Each R 10 Each can be independently H, -CH3, -OCH2CH2OH, -(OCH2CH2)2OH, Each R 11 Each can be independently H, Cl, -CN, ethynyl, phenyl, 69. The compound according to any one of claims 1-60, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: in, Each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2; Each R 10 Each can be independently H, -CH3, -OCH2CH2OH, -(OCH2CH2)2OH, Each R 11 Each can be independently H, Cl, -CN, ethynyl, phenyl, Each R 12 Each independently constitutes -CH3, Each R 13 Each can be independently -CH3, -CH(CH3)2, -C(CH3)3 or -OCH3.

70. The compound according to any one of claims 1-60, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is:

71. The compound according to any one of claims 1-60, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is:

72. A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopic variant, hydrate, or solvate thereof, wherein, The compounds are selected from the following formula:

73. A pharmaceutical composition comprising the compound of any one of claims 1-72 or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, and pharmaceutically acceptable excipients.

74. A reagent kit, comprising A first container comprising the compound of any one of claims 1-72 or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of claim 73; and optionally, a second container comprising other therapeutic agents; and optionally, a third container comprising pharmaceutical excipients for diluting or suspending said compound and / or other therapeutic agents.

75. The kit according to claim 74, wherein, The other therapeutic agents are tyrosine kinase inhibitors; Preferably, the tyrosine kinase inhibitors include: crizotinib, ceritinib, alectinib, brigatinib, loratinib, entrectinib, repretinib, carboplatinib, taraditinib, meletinib, masatitinib, and ensartinib.

76. Use of any compound of claims 1-72 or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of claim 73, or the kit of claim 74 or 75 in the preparation of a medicament for the treatment and / or prevention of diseases caused by ALK and / or ROS1.

77. A method for inducing ALK and / or ROS1 inhibition and / or degradation in cells, the method comprising contacting cells with a compound of any one of claims 1-72 or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 73, or a kit of claim 74 or 75, said contact being performed in vitro or in vivo; Preferably, the contact is performed outside the body; Preferably, the contact takes place within the body.

78. A method for treating and / or preventing ALK and / or ROS1-induced diseases in a subject, the method comprising administering to the subject a compound of any one of claims 1-72 or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 73, or a kit of claim 74 or 75.

79. The use of any compound of claims 1-72 or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of claim 73, or the kit of claim 74 or 75, in the treatment and / or prevention of diseases caused by ALK and / or ROS1.

80. The use of claim 76, the method of claim 77 or 78, or the application of claim 79, wherein, The diseases caused by ALK and / or ROS1 include the expression of the oncogene ALK or an oncogene ALK fusion. Preferably, the oncogenic ALK gene or oncogenic ALK gene fusion contains one or more mutations in the human ALK gene; Preferably, the mutation in the oncogenic ALK gene or oncogenic ALK gene fusion results in the expression of an ALK protein with one or more mutations selected from the group consisting of G1202R, L1196M, G1269A, D1203N and I1171N.

81. The use of claim 76, the method of claim 77 or 78, or the application of claim 79, wherein, The diseases caused by ALK and / or ROS1 include the expression of oncogenic ROS1 genes or oncogenic ROS1 gene fusions. Preferably, the oncogenic ROS1 gene or the oncogenic ROS1 gene fusion contains one or more mutations in the human ROS1 gene; Preferably, the mutation in the oncogenic ROS1 gene or the oncogenic ROS1 gene fusion results in the expression of the ROS1 protein with the G2032R mutation.

82. The use of claim 76, the method of claim 77 or 78, or the application of claim 79, wherein, The diseases caused by ALK and / or ROS1 are tumors; Preferably, the tumor is selected from solid tumors or hematologic malignancies; Preferably, the solid tumor is selected from lung cancer, glioblastoma, inflammatory myofibroblastoma, cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid angioendothelioma, esophageal cancer, renal cancer, breast cancer, colon cancer, thyroid cancer, Spitz nevus-like tumor, and neuroblastoma. Preferably, the hematologic malignancy is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic lymphoma (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ALL), and acute myeloid leukemia with trilineage myelodysplastic syndrome (AML). Mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, splenic marginal zone lymphoma, extranodal marginal zone B-cell lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-cell lymphoblastic leukemia, hairy cell leukemia, mucosa-associated lymphoid tissue lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma; Preferably, the tumor is an ALK-positive tumor; Preferably, the tumor is a ROS1-positive tumor.

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