Pyrimidine or pyridine derivatives and their medical use

Abstract

The application relates to a focal adhesion kinase (FAK) inhibitor compound, a composition containing the compound, and the use of the compound. The compound has a good therapeutic effect on cancer, pulmonary arterial hypertension and pathological angiogenesis, and has a good clinical application prospect.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese patent application No. 202111522765.8, filed on December 13, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of pharmaceuticals, specifically relating to a pyrimidine or pyridine derivative and its pharmaceutical uses, particularly in the preparation of drugs for the treatment or prevention of cancer, pulmonary hypertension, and pathological angiogenesis. Background Technology

[0004] Focal adhesion kinase (FAK), also known as PTK2 (protein tyrosine kinase 2), is a non-receptor tyrosine kinase located at the intersection of multiple signal transduction pathways. It can be activated by integrins, growth factor receptors, G protein-coupled receptors, and cytokines. Besides its role as a cytoplasmic kinase in signal transduction, research has shown that FAK also plays an important role in the cell nucleus. FAK can promote p53 degradation through ubiquitination, thereby leading to cancer cell growth and proliferation. Tang et al. reported that FAK can also regulate the expression of GATA4 and IL-33, thereby reducing inflammatory responses and immune escape. In the tumor microenvironment, nuclear FAK can regulate angiogenesis, affecting tumor blood supply.

[0005] FAK is widely expressed in vivo and plays an important role in cell growth, proliferation, migration, and adhesion, participating in embryonic development and the occurrence and development of diseases (such as cancer and cardiovascular diseases). Overexpression of FAK has been found in many types of cancer, including colon cancer, breast cancer, prostate cancer, thyroid cancer, neuroblastoma, ovarian cancer, cervical cancer, brain cancer, head and neck cancer, liver cancer, esophageal cancer, pancreatic cancer, lung cancer, gastric cancer, and acute leukemia. High FAK expression often predicts a poor prognosis. For example, studies have found that FAK expression is associated with the GTPase RHOA. Y42C The mutation is one of the most common gain-of-function mutations in diffuse gastric cancer, and RHOA is one of them. Y42C The mutant mice were sensitive to FAK inhibitors, suggesting that inhibiting FAK activity may be a new strategy for treating diffuse gastric cancer.

[0006] In the process of FAK's function, the binding of the transmembrane integrin receptor to the extracellular matrix (ECM) recruits FAK to the site of integrin accumulation. FAK does not interact directly with integrins, but rather binds to the cell membrane and other adhesion proteins through its C-terminal FAT domain. Once recruited, the inactive state of FAK activates its catalytic activity through autophosphorylation at Y397. After phosphorylation, FAK acts as a molecular scaffold, recruiting Src family kinases. Src can phosphorylate FAK at Y576 and Y577 sites, further enhancing FAK activity and promoting the recruitment of downstream proteins containing the SH2 domain, such as Grb2 and PI3K. When Grb2 binds to FAK, it can further recruit SOS to form a complex, thereby further activating the downstream Ras-MAPK signaling pathway.

[0007] Based on the above, FAK and its signaling pathway-related targets are considered potential targets for anticancer drug development. However, there are currently no marketed inhibitors of FAK, with only a few drugs in clinical trials, such as Defactinib, IN10018, and GSK-2256098. Therefore, developing new compounds that regulate the FAK signaling pathway is crucial.

[0008] YAP (Yes-associated protein), a downstream signaling pathway of FAK, is a Yes-related protein and a transcriptional coactivator of the Hippo pathway. Located on human chromosome 11q22, it promotes gene expression by enhancing the activity of transcription factors. External signals activate MST1 / 2, which binds to the regulatory protein SAV1, phosphorylating LATS1 / 2 and MOB, subsequently directly phosphorylating YAP / TAZ. Phosphorylated YAP / TAZ is arrested in the cytoplasm, repressing transcription. When this signaling pathway is blocked or inactivated, unphosphorylated YAP / TAZ translocates from the cytoplasm to the nucleus, where it binds to transcription factors such as TEADs, Smad, Runx1 / 2, p63 / p73, and ErbB4, promoting gene transcription.

[0009] The Hippo-YAP pathway is a signaling pathway discovered in recent years that regulates organ volume and maintains the balance between cell proliferation and apoptosis, and is closely related to the uncontrolled proliferation of tumor cells. In mammals, the main function of the Hippo-YAP pathway is to negatively regulate tumor progression by inhibiting the activity of transcription factors YAP and TAZ; therefore, the Hippo pathway is also considered a tumor suppressor pathway. Specifically, the core members of this pathway include serine / threonine kinases MST1, MST2, LATS1, and LATS2; scaffold proteins SAV1 (binding to MST1 and MST2) and MOB1 (binding to LATS1 and LATS2); the transcriptional coactivator YAP; and the transcription factor TEAD, which contains a TEA-binding domain. In short, when the Hippo pathway is activated, MST1 / 2 kinases phosphorylate and activate LATS1 / 2. Activated LATS1 / 2 then phosphorylates YAP. Phosphorylated YAP is inactivated and subsequently exits the nucleus, while cytoplasmic YAP is degraded by the proteasome.

[0010] Studies have confirmed that the Hippo pathway is involved in the progression of various tumors, such as lung cancer, colon cancer, ovarian cancer, prostate cancer, and liver cancer. However, gene mutations in the Hippo pathway are relatively rare in human tumors. Based on this, it is concluded that Hippo pathway dysregulation in human tumors stems not only from mutations in key proteins of the Hippo pathway itself, but more significantly from cross-communication between the Hippo pathway and other abnormally expressed proteins or signaling pathways within tumor cells. Furthermore, the role of the Hippo signaling pathway in tumors is closely related to the nuclear translocation of YAP / TAZ. Recently, high expression of YAP has been found in various tumors, which is associated with high pathological grade, advanced TNM stage, lymph node metastasis, and nuclear localization.

[0011] Based on this, the inhibition of active YAP can block related signaling pathways, potentially playing a role in inhibiting tumors and providing guidance for drug development. Summary of the Invention

[0012] This invention provides a compound that can be used as a focal adhesion kinase (FAK) inhibitor, a composition containing such a compound, and the uses of such compounds. In addition to its good inhibitory effect on FAK, the compound of this invention unexpectedly exhibits good inhibitory effect on YAP. The compound provided by this invention shows good therapeutic effects and promising clinical application prospects for cancer, pulmonary hypertension, and pathological angiogenesis.

[0013] On one hand, the present invention provides a compound, which is a compound of Formula I or a stereoisomer, tautomer, enantiomer, diastereomer, racemate, geometric isomer, nitroxide compound, solvate, hydrate, crystal form, ester, isotopically labeled compound (preferably deuterated), metabolite, pharmaceutically acceptable salt or prodrug:

[0014]

[0015] in,

[0016] M represents a covalent warhead; A represents an aryl or heteroaryl warhead.

[0017] L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independently, it is a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, or nitrogen-protecting group; wherein R L1a The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, and oxo.

[0018] L 2 It is a single bond, alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group, aryl or heteroaryl; wherein, L 2 The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved may each be independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, alkyl, alkenyl, ynyl, heteroalkyl, or haloheteroalkyl.

[0019] L 3 It is a single bond, aryl or heteroaryl; wherein, L 3 The aryl or heteroaryl groups involved may optionally be substituted independently by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl or haloheteroalkyl.

[0020] L 4 It is a carbon chain or heterochain with 2-6 atoms; where L 4The carbon chain or heterochain involved may optionally be substituted independently by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, aminoalkoxy, alkylamino, and nitrogen protecting group.

[0021] L 5 For -NR L5a -, -O-, -S-, alkyl or heteroalkyl; wherein, L 5 The alkyl and heteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), amino, hydroxyl, oxo, cyano, halogen, alkenyl, or alkynyl; each R L5a It is independently a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or nitrogen-protected group;

[0022] L 6 For -NR L6a -, -O-, -S-, alkyl or heteroalkyl; wherein, L 6 The alkyl and heteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen, amino, hydroxyl, oxo, cyano, halogen, alkenyl, or alkynyl; each R L6a It is independently a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or nitrogen-protected group;

[0023] X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 and Y 5 Each can be independently CH or N;

[0024] Each R 1 Independently, it is hydrogen, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, alkoxy, haloalkoxy, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 1 Adjacent, the two adjacent R 1 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 1The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, alkoxy, haloalkoxy, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, optionally each independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, alkyl;

[0025] Each R 2 Independently, it is hydrogen, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, alkoxy, haloalkoxy, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 2 Adjacent, the two adjacent R 2 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, alkoxy, haloalkoxy, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be substituted independently by one or more substituents selected from hydroxyl, amino, cyano, halogen, oxo, alkyl.

[0026] Each R 3 Independently, it is hydrogen, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, alkoxy, haloalkoxy, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 3The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, alkoxy, haloalkoxy, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydroxyl, amino, cyano, halogen, oxo, and alkyl groups; and

[0027] m and p are each independently 0, 1, 2, 3 or 4.

[0028] In some embodiments, the compounds provided by the present invention are compounds of Formula I or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0029]

[0030] in,

[0031] M represents a covalent warhead;

[0032] A is aryl or heteroaryl;

[0033] L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independently, it is a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, or nitrogen-protecting group; wherein R L1a The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, and oxo.

[0034] L 2 It is a single bond, alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group, aryl or heteroaryl; wherein, L 2 The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved may each be independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, alkyl, alkenyl, ynyl, heteroalkyl, or haloheteroalkyl.

[0035] L 3 It is a single bond, aryl or heteroaryl; wherein, L3 The aryl or heteroaryl groups involved may optionally be independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl or haloheteroalkyl.

[0036] L 4 It is a carbon chain or heterochain with 2-6 atoms; where L 4 The carbon chain or heterochain involved may optionally be independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, aminoalkoxy, alkylamino, and nitrogen-protecting groups.

[0037] L 5 For -NR L5a -, -O-, -S-, alkyl or heteroalkyl; wherein, L 5 The alkyl and heteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen, amino, hydroxyl, oxo, cyano, halogen, alkenyl, or ynyl; each R L5a Independently hydrogen (e.g., deuterium), alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, or nitrogen-protecting group;

[0038] L 6 For -NR L6a -, -O-, -S-, alkyl or heteroalkyl; wherein, L 6 The alkyl and heteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), amino, hydroxyl, oxo, cyano, halogen, alkenyl, or ynyl; each R L6a It is independently a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or nitrogen-protected group;

[0039] X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 and Y 5 Each can be independently CH or N;

[0040] Each R 1 Independently, it is hydrogen, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present1 Adjacent, the two adjacent R 1 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 1 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, optionally each independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, alkyl;

[0041] Each R 2 Independently, it is hydrogen, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 2 Adjacent, the two adjacent R 2 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently substituted by one or more substituents selected from hydroxyl, amino, cyano, halogen, oxo, alkyl.

[0042] Each R 3 Independently, it is hydrogen, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 3The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydroxyl, amino, cyano, halogen, oxo, and alkyl groups; and

[0043] m and p are each independently 0, 1, 2, 3 or 4.

[0044] In some embodiments, X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 and Y 5 At least one of them is an N atom. In some embodiments, X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 and Y 5 At least two of them are N atoms.

[0045] In some embodiments, X 1 X 2 X 3 X 4 At least one of them is an N atom. In some embodiments, X 1 X 2 X 3 X 4 At least two of them are N atoms. In some embodiments, X 1 X 2 X 3 X 4 At least one of them is an N atom. In some embodiments, X 1 X 2 X 3 X 4 At least two of them are N atoms.

[0046] In some embodiments, Y 1 Y 2 Y 3 Y 4 and Y 5 At least one of them is an N atom. In some embodiments, Y 1 Y2 Y 3 Y 4 and Y 5 At least two of them are N atoms.

[0047] In some embodiments, M is

[0048]

[0049]

[0050] in,

[0051] L 7 For a key, -O-, -S-, -NR L7a -or C 1-4 Alkyl, wherein the C 1-4 One or more carbon units of an alkyl group are optionally and independently separated by -O-, -S-, -NR-. L7a -、-NR L7a C(=O)-、-C(=O)NR L7a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L7a C(=S)-、-C(=S)NR L7a - Trans CR L7b =CR L7b - Cis-CR L7b =CR L7b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L7a -、-NR L7a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR L7a -or-NR L7a S(=O)2-replacement; where each R L7a Independently hydrogen, C 1-4 Alkyl or nitrogen protecting groups; each R L7b Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two adjacent R groups L7b The groups and the atoms attached to them connect to form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each L 7 R L7a RL7b The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0052] L 8 For a key or C 1-4 Alkyl, wherein L 8 The alkyl group involved may optionally be substituted by one or more substituents selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, and oxo;

[0053] Each R M1 Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M1a -CH2N(R) M1a )2、-CH2SR M1a -OR M1a -N(R) M1a )2、-Si(R M1a )3 or -SR M1a , where each R M1a Independently hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M1a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M1 R M1a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0054] Each R M2 Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M2a -CH2N(R) M2a )2、-CH2SR M2a -OR M2a -N(R) M2a )2 or -SR M2a , where each R M2a Independently hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M2a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M2 R M2a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0055] Each R M3 Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M3a -CH2N(R) M3a )2、-CH2SR M3a -OR M3a -N(R) M3a )2 or -SR M3a , where each R M3a Independently hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M3a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M3 R M3aThe alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0056] Optional, R M1 and R M3 , or R M2 and R M3 , or R M1 and R M2 Optionally linked to form saturated or partially unsaturated carbocyclic groups or saturated or partially unsaturated heterocyclic groups, wherein the saturated or partially unsaturated carbocyclic groups or saturated or partially unsaturated heterocyclic groups are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0057] R M4 R is a leaving group; M5 It is a halogen; Z is O, S, or NR. Z ;where R Z For hydrogen, deuterium, C 1-4 Alkyl or nitrogen protecting group; R Z The alkyl group involved is optionally substituted with one or more substituents selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, or oxo; q is 0, 1, 2, 3, 4, 5, or 6; r is 1 or 2.

[0058] In some embodiments, M is

[0059]

[0060] in,

[0061] L 7 For a key, -O-, -S-, -NR L7a -or C 1-4 Alkyl, wherein the C 1-4 One or more carbon units of an alkyl group are optionally and independently separated by -O-, -S-, -NR-. L7a -、-NR L7a C(=O)-、-C(=O)NR L7a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L7a C(=S)-、-C(=S)NR L7a - Trans CR L7b =CR L7b - Cis-CR L7b =CRL7b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L7a -、-NR L7a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR L7a -or-NR L7a S(=O)2-replacement; where each R L7a Independent of hydrogen, deuterium, and C 1-4 Alkyl or nitrogen protecting groups; each R L7b Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two adjacent R groups. L7b The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each L 7 R L7a R L7b The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0062] Z represents O, S, or NR. Z ;where R Z For hydrogen, C 1-4 Alkyl or nitrogen protecting group; R Z The alkyl group involved may optionally be substituted by one or more substituents selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, and oxo;

[0063] Each R M1 Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M1a -CH2N(R) M1a )2、-CH2SR M1a -OR M1a -N(R) M1a )2、-Si(R M1a )3 or -SRM1a , where each R M1a Independently hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. M1a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; where R in each group... M1 R M1a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0064] Each R M2 Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M2a -CH2N(R) M2a )2、-CH2SR M2a -OR M2a -N(R) M2a )2 or -SR M2a , where each R M2a Independently hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. M2a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M2 R M2a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0065] Each R M3 Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M3a -CH2N(R) M3a )2、-CH2SR M3a -OR M3a -N(R) M3a )2 or -SR M3a , where each R M3a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. M3a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M3 R M3a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0066] In some embodiments, M is

[0067]

[0068] In some embodiments, A is a 6-10 aryl or a 5-10 heteroaryl. In some embodiments, A is a 6-10 aryl or a 5-10 azaaryl. In some embodiments, A is a phenyl or a 6-azaaryl. In some embodiments, A is a phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, furanyl, thiophene, pyrroleyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or the following groups:

[0069] For A and L 6 The connected end.

[0070] In some embodiments, A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, A is phenyl or pyrazinyl.

[0071] In some embodiments, L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a-、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independently hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Haloalkyl, C 1-4 Halogenated heteroalkyl or nitrogen-protected groups; wherein R L1a The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, and oxo; L 2 For a key, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups; wherein, L 2 The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; L 3 It is a single bond, a 6-10 aryl group or a 5-10 heteroaryl group; wherein, L 3 The aryl or heteroaryl groups involved are optionally and independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; L 4 It is a carbon chain or heterochain with 2-6 atoms; where L 4 The carbon chains or heterochains involved are optionally and independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkoxy, C 1-4 aminoalkoxy, C 1-4 One or more substituents of an alkylamino group or a nitrogen protecting group are used for substitution.

[0072] In some embodiments, L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independently hydrogen, methyl, ethyl, vinyl, ethynyl, or trifluoromethyl; L 2 For a key, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups; wherein, L 2 The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently substituted by a substituent selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, fluorine, chlorine, oxo, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, or methylamino. 3 It is a single bond, a 6-10 aryl group or a 5-10 heteroaryl group; wherein, L 3 The aryl or heteroaryl groups involved are optionally and independently substituted by a substituent selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, fluorine, chlorine, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, and methylamino; L 4 It is a carbon chain or heterochain with 2-4 atoms; where L 4 The carbon chain or heterochain involved may optionally be independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, methylamino, and nitrogen protecting group.

[0073] In some embodiments, L 1 For a single bond, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NH-, -NHC(=O)-, -S(=O)2NH- or -NHS(=O)2-; L 2It is a single-bonded, 3-6 member saturated or partially unsaturated carbocyclic group or a 3-6 member saturated or partially unsaturated heterocyclic group; wherein, L 2 The saturated or partially unsaturated carbocyclic groups and saturated or partially unsaturated heterocyclic groups involved may optionally be independently substituted by one or more substituents selected from hydroxyl, amino, cyano, fluorine, chlorine, oxo, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, and methylamino; L 3 It is a single bond, a 6-10 aryl group or a 5-10 heteroaryl group; wherein, L 3 The aryl or heteroaryl groups involved are optionally substituted with one or more hydroxyl, amino, cyano, fluorine, chlorine, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, or methylamino substituents; L 4 It is a carbon chain or heterochain with 2-4 atoms; where L 4 The carbon chain or heterochain involved may optionally be independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, methylamino, and nitrogen protecting group.

[0074] In some embodiments, L 1 For a single bond, -C(=O)- or -C(=O)NH-; L 2 It is a single bond, cyclohexyl, piperidinyl, phenyl, or pyridinyl; L 3 For one bond, phenyl or pyridinyl; L 4 -NHCH2-, -CH2NH-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -SCH2CH2-, -CH2SCH2-, -CH2CH2S-, -NHCH2CH2CH2-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -CH2C H2CH2NH-, -OCH2CH2CH2-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -SCH2CH2CH2-, -CH2SCH2CH2-, -CH2C H2SCH2-, -CH2CH2CH2S-, -CH2OCH2O-, -OCH2OCH2-, -OCH2CH2O-, -NHCH2CH2O-, -CH2NHCH2O- or -NHCH2OCH2-; where L 4The hydrogen atoms in CH2 involved are optionally and independently replaced by substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, and methylamino; L 4 The hydrogens in NH involved are optionally and independently replaced by substituents selected from deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, and nitrogen protecting groups.

[0075] In some embodiments, L 1 For a single bond, -C(=O)- or -C(=O)NH-; L 2 It is a single bond, cyclohexyl, piperidinyl, phenyl, or pyridinyl; L 3 For one bond, phenyl or pyridinyl; L 4 It can be -NHCH2-, -CH2NHCH2-, -NHC(=O)-, -CH2NHC(=O)-, -C(=O)NHCH2- or -NHCH(CH3)-.

[0076] In some embodiments, L 5 For -NR L5a -、-O-、-S-、C 1-6 Alkyl or C 1-6 Heteroalkyl; wherein, L 5 The alkyl and heteroalkyl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), amino, hydroxyl, oxo, cyano, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of the haloalkyl group are substituted; each R L5a Independent of hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or nitrogen-protected groups; L 6 For -NR L6a -、-O-、-S-、C 1-6 Alkyl or C 1-6 Heteroalkyl; wherein, L 6 The alkyl and heteroalkyl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), amino, hydroxyl, oxo, cyano, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C1-4 Halogenated alkyl or C 1-4 One or more substituents of the haloalkyl group are substituted; each R L6a Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or nitrogen-protected groups.

[0077] In some embodiments, L 5 For -NR L5a -CR L5b R L5c -、-O-、-S-、-CR L5b R L5c NR L5a -、-NR L5a CR L5b R L5c -、-CR L5b R L5c O-、-OCR L5b R L5c -、-CR L5b R L5c S- or -SCR L5b R L5c -; where each R L5b and R L5c Each can be independently represented by hydrogen, amino, hydroxyl, oxo, cyano, halogen, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; each R L5a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or nitrogen-protected groups; L 6 For -NR L6a -CR L6b R L6c -、-O-、-S-、-CR L6b R L6c NR L6a -、-NR L6a CR L6b R L6c -、-CR L6b R L6c O-、-OCR L6b RL6c -、-CR L6b R L6c S- or -SCR L6b R L6c -; where each R L6b and R L6c Each can be independently represented by hydrogen, amino, hydroxyl, oxo, cyano, halogen, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; each R L6a Independently hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or nitrogen-protected groups.

[0078] In some embodiments, L 5 -NH-, -O-, -S-, -NHCH2-, -OCH2-, -SCH2-, -CH2NH-, -CH2O-, or -CH2S-; L 6 It can be -NH-, -O-, -S-, -NHCH2-, -OCH2-, -SCH2-, -CH2NH-, -CH2O-, or -CH2S-. In some embodiments, L 5 -NH-; L 6 It is -NH- or -NHCH2-.

[0079] In some embodiments, each R 1 Independently hydrogen, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated heteroalkyl groups, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated carbocyclic groups C 1-6 Alkyl groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups C 1-6 Alkyl, 6-10 aryl, 6-10 aryl C 1-6 Alkyl, 6-10 heteroaryl or 6-10 heteroaryl C 1-6 Alkyl; if two R are present 1 Adjacent, the two adjacent R1 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 1 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0080] Each R 2 Independently hydrogen, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, 3-6 member saturated or partially unsaturated carbocyclic groups, 3-6 member saturated or partially unsaturated carbocyclic groups (C) 1-6 Alkyl groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups C 1-6 Alkyl, 6-10 aryl, 6-10 aryl C 1-6 Alkyl, 6-10 heteroaryl or 6-10 heteroaryl C 1-6 Alkyl; if two R are present 2 Adjacent, the two adjacent R 2 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of the alkyl group are substituted; and

[0081] Each R 3 Independently hydrogen, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, 3-6 member saturated or partially unsaturated carbocyclic groups, 3-6 member saturated or partially unsaturated carbocyclic groups (C) 1-6 Alkyl groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups C 1-6 Alkyl, 6-10 aryl, 6-10 aryl C 1-6 Alkyl, 6-10 heteroaryl or 6-10 heteroaryl C 1-6 Alkyl; if two R are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 3 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0082] In some embodiments, each R 1 Independently hydrogen, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; if two R groups are present 1 Adjacent, the two adjacent R 1 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 1 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4One or more substituents of the alkyl group are substituted; each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; if two R groups are present 2 Adjacent, the two adjacent R 2 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of the alkyl group are substituted; and each R 3 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl groups; if two R groups are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 3 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0083] In some embodiments, each R 1 Independently hydrogen, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; wherein R 1The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, and oxo; each R 2 Independently hydrogen, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; wherein R 2 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, and oxo; and each R 3 Independently hydrogen, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; if two R groups are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein R 3 The alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, 3-6 membered saturated or partially unsaturated carbocyclic groups, and 3-6 membered saturated or partially unsaturated heterocyclic groups involved are optionally each independently selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0084] In some embodiments, each R 1 Independently hydrogen, amino, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; wherein R 1 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, and oxo; each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; wherein R 2 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, and oxo; and each R3 Independently hydrogen, amino, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; if two R groups are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein R 3 The alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, 3-6 saturated or partially unsaturated carbocyclic groups and 3-6 saturated or partially unsaturated heterocyclic groups involved may each be independently substituted by one or more substituents selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, methyl, ethyl, isopropyl.

[0085] In some embodiments, each R 1Independently, they are hydrogen, amino, hydroxy, cyano, fluoro, chloro, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)O-, CH3C(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S(=O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)-, (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHON(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S(=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(CH2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-,(CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-, (CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P(=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)- or (CH3)2CH(CH3CH2)P(=O)-;,

[0086] Each R 2Independently, it can be hydrogen, amino, hydroxyl, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-. CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S( =O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)-, (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHO N(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S (=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(C H2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-,(CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-, (CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P(=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)- or (CH3)2CH(CH3CH2)P(=O)-; and also,

[0087] Each R 3Independently selected from hydrogen, amino, hydroxy, cyano, fluoro, chloro, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)O-, CH3C(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S(=O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)-, (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHON(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S(=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(CH2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-,(CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-, (CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P(=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)- or (CH3)2CH(CH3CH2)P(=O)-; if two R, 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form the following groups:

[0088]

[0089] In some embodiments, the saturated or partially unsaturated carbocyclic group is selected from formulas ii-1 to ii-6; formulas ii-1 to ii-6 are monovalent when they are connected to the remainder of the molecule by one bond; formulas ii-1 to ii-6 are divalent when they are connected to the remainder of the molecule by two bonds; the saturated or partially unsaturated carbocyclic groups represented by formulas ii-1 to ii-6 are optionally each independently substituted by one or more substituents defined by the corresponding groups described above in this invention;

[0090]

[0091] The saturated or partially unsaturated heterocyclic groups are selected from formulas iii-1 to iii-16; when formulas iii-1 to iii-16 are connected to the rest of the molecule by one bond, formulas iii-1 to iii-16 are monovalent; when formulas iii-1 to iii-16 are connected to the rest of the molecule by two bonds, formulas iii-1 to iii-16 are divalent; the saturated or partially unsaturated heterocyclic groups represented by formulas iii-1 to iii-16 are optionally and independently substituted by one or more substituents defined by the corresponding groups described above in this invention;

[0092]

[0093] Each t1 is independently 0, 1, 2, 3, 4 or 5; each t2 and t3 is independently 1, 2, 3, 4 or 5.

[0094] "Substituent substitution as defined in the aforementioned corresponding groups of this invention" refers to the substituent mentioned in the aforementioned groups involving "saturated or partially unsaturated carbocyclic groups" and "saturated or partially unsaturated heterocyclic groups" that are being substituted.

[0095] In some embodiments, the saturated or partially unsaturated carbocyclic group is selected from the following groups: when the saturated or partially unsaturated carbocyclic group is connected to the rest of the molecule by one bond, the following groups are monovalent; when the saturated or partially unsaturated carbocyclic group is connected to the rest of the molecule by two bonds, the following groups are divalent; the saturated or partially unsaturated carbocyclic groups represented below are optionally each independently substituted by one or more substituents defined by the corresponding groups described above in this invention;

[0096]

[0097] The saturated or partially unsaturated heterocyclic group is selected from the following groups; when the saturated or partially unsaturated heterocyclic group is connected to the rest of the molecule by one bond, the following groups are monovalent; when the saturated or partially unsaturated heterocyclic group is connected to the rest of the molecule by two bonds, the following groups are divalent; the saturated or partially unsaturated heterocyclic groups represented below are optionally and independently substituted by one or more substituents defined by the corresponding groups described above in this invention.

[0098]

[0099]

[0100] "Substituent substitution as defined in the aforementioned corresponding groups of this invention" refers to the substituent mentioned in the aforementioned groups involving "saturated or partially unsaturated carbocyclic groups" and "saturated or partially unsaturated heterocyclic groups" that are being substituted.

[0101] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas II-1 to II-6, or their stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitroxides, solvates, hydrates, crystal forms, esters, isotopically labeled compounds (preferably deuterated), metabolites, pharmaceutically acceptable salts, or prodrugs.

[0102]

[0103] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, wherein the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are used for substitution.

[0104] In some embodiments, the compounds of the present invention are compounds of Formula III or their stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitroxides, solvates, hydrates, crystal forms, esters, isotopically labeled compounds (preferably deuterated), metabolites, pharmaceutically acceptable salts, or prodrugs.

[0105]

[0106] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation can be optionally formed; k and v are each independently 0, 1 or 2.

[0107] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas IV-1 to IV-6, or their stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitroxides, solvates, hydrates, crystal forms, esters, isotopically labeled compounds (preferably deuterated), metabolites, pharmaceutically acceptable salts, or prodrugs.

[0108]

[0109]

[0110] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, wherein the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b RL4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation can be optionally formed; k and v are each independently 0, 1 or 2.

[0111] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas V-1 to V-7, or their stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitroxides, solvates, hydrates, crystal forms, esters, isotopically labeled compounds (preferably deuterated), metabolites, pharmaceutically acceptable salts, or prodrugs.

[0112]

[0113]

[0114] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas VI-1 to VI-5 or their stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitroxides, solvates, hydrates, crystal forms, esters, isotopically labeled compounds (preferably deuterated), metabolites, pharmaceutically acceptable salts, or prodrugs.

[0115]

[0116] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas VII-1 to VII-6, or their stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitroxides, solvates, hydrates, crystal forms, esters, isotopically labeled compounds (preferably deuterated), metabolites, pharmaceutically acceptable salts, or prodrugs.

[0117]

[0118] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, wherein the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from hydrogen (e.g., deuterium), hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1 or 2.

[0119] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas VIII-1 to VIII-6, or their stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitroxides, solvates, hydrates, crystal forms, esters, isotopically labeled compounds (preferably deuterated), metabolites, pharmaceutically acceptable salts, or prodrugs.

[0120]

[0121] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4eOptional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1 or 2.

[0122] The present invention also relates to methods for the preparation, separation and purification of the compounds described herein.

[0123] This invention also relates to a method for preparing the compound described herein, the method comprising one or more of the following steps (1) to (3):

[0124] (1) React compound a1 with compound a2 to generate compound a3; (2) React compound a3 with compound a4 to generate compound a5; (3) React compound a5 with compound a6 to generate compound a7;

[0125]

[0126] Alternatively, the preparation method may include one or more of the following steps (4) to (9):

[0127] (4) React compound b1 with compound b2 to form compound b3; (5) Convert compound b3 to compound b4; (6) Convert compound b4 to compound b5; (7) React compound b5 with compound b3 to form compound b6; (8) Convert compound b6 to compound b7; (9) Convert compound b7 to compound b8.

[0128]

[0129]

[0130] Where Hal represents a halogen, Cy indicates a ring system (including but not limited to 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups), and Pg indicates a protecting group; A, R 1 R 2 R 3 R 4 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 L 1 L 2 L 5 L6 M, n, m, and p have the definitions described in this invention.

[0131] On the other hand, the present invention relates to intermediates for preparing compounds of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, and VIII-1 to VIII-6.

[0132] On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein and pharmaceutically acceptable excipients thereof.

[0133] On the other hand, the present invention provides the use of the compounds or pharmaceutical compositions described herein in the preparation of medicaments for the prevention or treatment of FAK-related diseases.

[0134] On the other hand, the present invention provides the use of the compounds or pharmaceutical compositions described herein in the prevention or treatment of FAK-related diseases.

[0135] On the other hand, the present invention provides a method for preventing or treating FAK-related diseases using the compounds or pharmaceutical compositions described herein.

[0136] On the other hand, the present invention provides a method for administering an effective amount of the compound or pharmaceutical composition described herein to prevent or treat FAK-related diseases.

[0137] In some implementation schemes, FAK-related diseases include: cancer, pulmonary hypertension, and pathological angiogenesis.

[0138] In some implementation schemes, FAK-related diseases include lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, uterine sheath cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, cancers of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis cancer, brainstem glioma, pituitary adenoma, or one or more combinations of the aforementioned cancers.

[0139] On the other hand, the present invention provides a method for modulating the Hippo-YAP signaling pathway, comprising administering the compound or pharmaceutical composition described in the present invention.

[0140] On the other hand, the present invention provides the use of the compounds or pharmaceutical compositions described herein in the preparation of Hippo-YAP signaling pathway inhibitors.

[0141] On the other hand, the present invention provides the use of the compounds or pharmaceutical compositions described herein in the preparation of medicaments for the prevention or treatment of YAP-related diseases.

[0142] On the other hand, the present invention provides the use of the compounds or pharmaceutical compositions described herein in the prevention or treatment of YAP-related diseases.

[0143] On the other hand, the present invention provides a method for preventing or treating YAP-related diseases, comprising administering an effective amount of the compound or pharmaceutical composition described in the present invention.

[0144] In some implementations, YAP-related diseases are selected from cancers. In some implementations, YAP-related diseases include one or more combinations of skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematologic malignancies, Hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, and uterine cancer.

[0145] On the other hand, the present invention provides a method for inhibiting the activity of FAK kinase and / or YAP protein in cells or a subject, the method comprising the steps of contacting the cells with or administering to the subject a compound or pharmaceutical composition as described in the present invention.

[0146] In some embodiments, the cells are mammalian cells. In some embodiments, the subject is a mammal, preferably a human.

[0147] Detailed description

[0148] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural or chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0149] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0150] Definitions and general terms

[0151] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0152] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0153] As used in this invention, "one or more" means one or more. In some embodiments, "one or more" means 1-5; in some embodiments, "one or more" means 1-4; in some embodiments, "one or more" means 1-3; in some embodiments, "one or more" means 1-2; in some embodiments, "one or more" means 1; in other embodiments, "one or more" means 1, 2, 3, 4 or 5.

[0154] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0155] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0156] The term "comprising" as used in this invention is an open-ended expression, meaning it includes the contents specified in this invention but does not exclude other aspects.

[0157] Unless otherwise expressly indicated, the descriptive terms “each…independently,” “…independently,” “…independently,” and “each…independently” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0158] Unless otherwise expressly indicated, the descriptive terms “optionally” and “arbitrarily” used in this invention mean that the following action may or may not occur. For example, “optionally substituted,” “arbitrarily substituted,” and “optionally substituted by…” indicate that the group may or may not be substituted. Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group.

[0159] Unless otherwise explicitly stated, when “each…independently,” “…independently,” “…independently,” or “each…independently” can be used with “optionally” or “arbitrarily,” the order of the collocation does not matter, and they have the same meaning. For example, “optionally each independently” and “independently optional” indicate that in different groups, the specific options expressed by the same symbols do not affect each other, and the subsequent action may or may not occur.

[0160] The term "C" used alone as a prefix m-n "A group refers to any group having m to n carbon atoms, C" m This refers to any group having m carbon atoms. For example, C 1-20 Alkyl groups refer to alkyl groups containing 1 to 20 carbon atoms; C 1-8 Alkoxy groups refer to alkoxy groups containing 1 to 8 carbon atoms; C 2-6 Alkenyl refers to an alkenyl group containing 2 to 6 carbon atoms; C6 haloalkyl refers to a haloalkyl group containing 6 carbon atoms.

[0161] The term "mn-membered" as a prefix refers to a ring having m to n ring atoms. For example, "3-6-membered saturated or partially unsaturated carbocyclic group" means that the carbocyclic group has 3 to 6 ring atoms; "3-6-membered saturated or partially unsaturated heterocyclic group" means that the heterocyclic group has 3 to 6 ring atoms; "6-10-membered aryl" means that the aryl group has 6 to 10 ring atoms; and "5-10-membered heteroaryl" means that the heteroaryl group has 5 to 10 ring atoms.

[0162] As used in this invention, the term "substitution" means that one or more carbon units in the given structure are replaced by a specific substitution group. When more than one carbon unit in the given structural formula can be replaced by one or more substitution groups selected from a specific group, the substitution groups can be substituted at various positions, either identically or differently. The substitution groups may be, but are not limited to, -O-, -S-, and -NR. L7a -、-NR L7a C(=O)-、-C(=O)NR L7a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L7a C(=S)-、-C(=S)NR L7a - Trans CR L7b =CR L7b - Cis-CR L7b =CR L7b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L7a -、-NR L7a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR L7a -or-NR L7a S(=O)2-, where R L7a It is hydrogen, deuterium, and carbon. 1-4 Alkyl or nitrogen protecting groups; R L7b For hydrogen, deuterium, halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. L7b The groups are arbitrarily linked to form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein L 7 R L7a R L7b The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are each arbitrarily and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0163] The term "substituted" or "substituted" as used in this invention means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents described may be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, amide, aminoacyl, sulfonyl, cyano, oxo (=O), nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 alkenyloxy group, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Haloalkyl, 3-12 membered heterocyclic, 3-10 membered carbon cyclic, C 6-10 Aryl, C 1-9 heteroaryl, 3-12 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl groups, etc.

[0164] This invention uses the phrase "a certain group involved in a certain Markush variable" in some group descriptions to distinguish the same group in different Markush variables, such as "R". L1a "alkyl group" refers to the alkyl group defined as R L1a Alkyl group. When the alkyl group is prefixed with "C", it indicates that the alkyl group is an alkyl group. m-n ", i.e., C m-n Alkyl, for simplicity, "R" L1a C involved in m-n Alkyl group is written as "R" L1a The alkyl group involved in the text, "R" L1a The "alkyl group" mentioned refers to the definition of R. L1a C m-n alkyl.

[0165] As used in this invention, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans isomers), trans-blocking isomers, etc. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structures described in this invention are within the scope of this invention. The term "enantiomer" as used in this invention refers to stereoisomers that are mirror images of each other and cannot be superimposed. "Diastereomer" refers to stereoisomers in which the molecules have two or more chiral centers and are not mirror images of each other.

[0166] The term "geometric isomer" as used in this invention includes: cis-trans isomers, isomeric stereoisomers and syndiomeric stereoisomers, rotational isomers caused by stereobarriers, etc.

[0167] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0168] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0169] As used in this invention, the terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0170] As used in this invention, the term "nitrogen oxide" refers to a compound containing several amine functional groups, which can oxidize one or more nitrogen atoms to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen atoms in nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), wherein the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane.

[0171] As used in this invention, the term "solvent" refers to an association formed by one or more solvent molecules with the compounds of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0172] As used in this invention, the term "metabolite" refers to the product obtained in vivo through the metabolism of a specific compound or its salt. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0173] The term "ester" includes compounds or segments containing carbon atoms or heteroatoms bonded to oxygen atoms bonded to carbonyl groups. The term "ester" includes alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.

[0174] It should be understood that the compounds of the present invention can be described as different tautomers. It should also be understood that when a compound has tautomer forms, all tautomer forms are intended to be included within the scope of the present invention, and the naming of the compound does not exclude any tautomer form. It should be understood that some tautomers may have higher levels of activity than others.

[0175] The term "crystal form" refers to the crystalline structure of a compound (or its salt or solvate) that can crystallize in different crystalline packing arrangements, all of which have the same elemental composition. Different crystal forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. The crystal form of a compound can be obtained by crystallization under different conditions.

[0176] The term "isotope labeling" refers to the process of replacing a corresponding element in a compound molecule with an isotope. An "isotope" is the same element with different masses but identical chemical properties. The method of replacing a specific atom in a molecule with its isotope is called isotope labeling.

[0177] As used in this invention, the term "pharmaceutically acceptable" means a compound, raw material, composition, and / or dosage form that, within the limits of reasonable medical judgment, is suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems and complications commensurate with a reasonable benefit / risk ratio, and is effective for its intended use.

[0178] The term "pharmaceutically acceptable salt" as used in this invention refers to both organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobroms, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (R)4 salts, such as R being H or C 1-4 Alkyl, C 6-10 Aryl groups, etc., and cyclic amines, such as piperidine, morpholine, and piperazine. The present invention also envisions quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C... 1-8 Sulfonates and aromatic sulfonates.

[0179] As used in this invention, the term "prodrug" refers to the in vivo conversion of a compound into compounds represented by formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, and VIII-1 to VIII-6. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion to the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0180] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0181] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0182] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0183] The term "covalent warhead" refers to a group that can interact with a specific target protein and form a covalent bond. This includes, but is not limited to:

[0184]

[0185]

[0186] in,

[0187] L 7 For a key, -O-, -S-, -NR L7a -or C 1-4 Alkyl, wherein the C 1-4 One or more carbon units of an alkyl group are optionally and independently separated by -O-, -S-, -NR-. L7a -、-NR L7a C(=O)-、-C(=O)NR L7a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L7a C(=S)-、-C(=S)NR L7a - Trans CR L7b =CR L7b - Cis-CR L7b =CR L7b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L7a -、-NR L7a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR L7a -or-NR L7a S(=O)2-replacement; where each R L7a Independently hydrogen, C 1-4Alkyl or nitrogen protecting groups; each R L7b Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two adjacent R groups L7b The groups and the atoms attached to them connect to form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each L 7 R L7a R L7b The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0188] L 8 For a key or C 1-4 Alkyl, wherein L 8 The alkyl group involved may optionally be substituted by one or more substituents selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, and oxo;

[0189] Each R M1 Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M1a -CH2N(R) M1a )2、-CH2SR M1a -OR M1a -N(R) M1a )2、-Si(R M1a )3 or -SR M1a , where each R M1a Independently hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M1a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M1 R M1aThe alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0190] Each R M2 Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M2a -CH2N(R) M2a )2、-CH2SR M2a -OR M2a -N(R) M2a )2 or -SR M2a , where each R M2a Independently hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M2a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M2 R M2a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0191] Each R M3 Independently hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M3a -CH2N(R) M3a )2、-CH2SR M3a -OR M3a -N(R) M3a )2 or -SR M3a , where each R M3a Independently hydrogen, C1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M3a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M3 R M3a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0192] Optional, R M1 and R M3 , or R M2 and R M3 , or R M1 and R M2 Optionally linked to form saturated or partially unsaturated carbocyclic groups or saturated or partially unsaturated heterocyclic groups, wherein the saturated or partially unsaturated carbocyclic groups or saturated or partially unsaturated heterocyclic groups are optionally each independently selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0193] R M4 R is a leaving group; M5 It is a halogen; Z is O, S, or NR. Z ;where R Z For hydrogen, C 1-4 Alkyl or nitrogen protecting group; R Z The alkyl group involved is optionally substituted with one or more substituents selected from hydrogen (e.g., deuterium), halogen, hydroxyl, amino, cyano, or oxo; q is 0, 1, 2, 3, 4, 5, or 6; r is 1 or 2.

[0194] The term "alkyl" or "alkyl group" refers to a saturated straight-chain or branched hydrocarbon group, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl group is C10. 1-20 Alkyl; in some embodiments, the alkyl group is C10. 1-10 Alkyl; in another embodiment, the alkyl group is C10. 1-6 Alkyl; in yet another embodiment, the alkyl group is C10. 1-4 Alkyl; in yet another embodiment, the alkyl group is C10. 1-3Alkyl group. In some specific structures, when the alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group, for example, in the structural formula (C... 6-10 aryl)-(C 1-6 C in alkyl)- 1-6 Alkyl should be understood as C 1-6 Alkylene. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH2CH3). tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2 -Methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2) CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0195] The term "heteroalkyl" refers to a group obtained by inserting one or more heteroatoms into an alkyl group, wherein the alkyl group and heteroatom have the meanings as described in this invention. The heteroalkyl group may optionally be substituted with one or more substituents described in this invention. The heteroalkyl group may be attached to the remainder of the molecule via its carbon atom or via its heteroatom. In some embodiments, the heteroalkyl group is C10-C20. 1-20 Heteroalkyl; in some embodiments, the heteroalkyl group is C1-10 Heteroalkyl; in another embodiment, the heteroalkyl group is C 1-6 Heteroalkyl; in yet another embodiment, the heteroalkyl group is C 1-4 Heteroalkyl; in yet another embodiment, the heteroalkyl group is C 1-3Heteroalkyl. Heteroalkyl examples include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)O-, CH3C(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S(=O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)-, (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHON(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S(=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(CH2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-, (CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-(CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P(=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)-, or (CH3)2CH(CH3CH2)P(=O)-. When a heteroalkyl group is the linking group, and the definition of "heteroalkyl" lists the group for that Markush group, then "heteroalkyl" refers to the linked heteroalkylene group. Heteroalkyl examples include, but are not limited to, -NHCH2-, -CH2NH-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -SCH2CH2-, -CH2SCH2-, -CH2CH2S-, -NHCH2CH2CH2-, -CH2NHCH2CH2-, -CH2CH2NHC H2-, -CH2CH2CH2NH-, -OCH2CH2CH2-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -SCH2CH2CH2-, -CH2SCH2CH2-, -CH2CH2SCH2-, -CH2CH2CH2S-, -CH2OCH2O-, -OCH2OCH2-, -OCH2CH2O-, -NHCH2CH2O-, -CH2NHCH2O- or -NHCH2OCH2-.

[0196] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group having at least one unsaturated site, i.e., one carbon-carbon sp2 double bond. The alkenyl group may optionally be substituted by one or more substituents described in this invention, including "cis" and "tans" orientations, or "E" and "Z" orientations. The alkenyl group can be attached to the remainder of the molecule via an atom that forms a double bond, or via an atom that does not form a double bond. In some embodiments, the alkenyl group is C. 2-12 Alkenyl; in one embodiment, the alkenyl group is C 2-8 Alkenyl; in another embodiment, the alkenyl group is C 2-6 Alkenyl; in yet another embodiment, the alkenyl group is C 2-4Alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc. When the alkenyl group is a linking group, and the definition of "alkenyl" lists the linking subalkenyl group, then "alkenyl" refers to the linked subalkenyl group. Examples of alkenyl groups represented as linked subalkenyl groups include, but are not limited to: -CH=CH-, -CH2CH=CH-, -CH2CH=CHCH2-, etc.

[0197] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group having at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention; the alkynyl group may be attached to the remainder of the molecule by a triple-bonded atom or by a non-triple-bonded atom. In some embodiments, the alkynyl group is C 2-12 alkynyl group; in one embodiment, the alkynyl group is C 2-8 Alkyne group; in another embodiment, the alkynyl group is C 2-6 Alkyne group; in yet another embodiment, the alkynyl group is C 2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc. When the alkynyl group is a linking group, and the definition of "alkynyl" lists it, then "alkynyl" refers to a linked alkynyl group. Examples of alkynyl groups represented as linked alkynyl groups include, but are not limited to: -C≡C-, -CH2C≡C-, -CH2C≡CCH2-, etc.

[0198] The term "alkoxy" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Unless otherwise specified, in some embodiments, the alkoxy group is C0. 1-20 Alkoxy group; in some embodiments, the alkoxy group is C 1-10 Alkoxy group; in another embodiment, the alkoxy group is C60. 1-6 Alkoxy group; in yet another embodiment, the alkoxy group is C 1-4 Alkoxy group; in yet another embodiment, the alkoxy group is C 1-3Alkoxy group. When an alkoxy group is a linking group, and the definition of "alkoxy" lists "alkoxy" for that Markush group, then "alkoxy" refers to the linked alkeneoxy group. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy Oxygen groups (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0199] The term "alkylamino" indicates that an alkyl group is attached to the remainder of the molecule by a nitrogen atom, wherein the alkyl group has the meaning as described in this invention. The alkylamino group may optionally be substituted with one or more substituents described in this invention. In some embodiments, the alkylamino group is C10. 1-20 Alkylamino; in some embodiments, the alkylamino group is C 1-10 Alkylamino; in another embodiment, the alkylamino group is C 1-6 Alkylamino; in yet another embodiment, the alkylamino group is C 1-4 Alkylamino; in yet another embodiment, the alkylamino group is C 1-3 Alkylamino. When alkylamino is a linking group, and the definition of "alkylamino" includes "alkylamino" for that Markush group, then "alkylamino" means the linked alkyleneamino group. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, and isopropylamino.

[0200] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group has the meaning as described in this invention. In some embodiments, the haloalkyl group is C10. 1-20 Halogenated alkyl group; in some embodiments, the halogenated alkyl group is C10. 1-10 Haloalkyl; in another embodiment, the haloalkyl is C10. 1-6Haloalkyl; in yet another embodiment, the haloalkyl group is C10. 1-4 Haloalkyl; in yet another embodiment, the haloalkyl group is C10. 1-3 Haloalkyl. When a haloalkyl group is a linking group, and the definition of "haloalkyl" is listed for that Markush group, then "haloalkyl" means the linked haloalkyl group. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, etc.

[0201] The term "haloalkoxy" indicates that an alkoxy group is replaced by one or more halogen atoms, wherein the alkoxy group has the meaning as described in this invention. In some embodiments, the haloalkoxy group is C10. 1-20 Halogenated alkoxy group; in some embodiments, the halogenated alkoxy group is C60. 1-10 Haloalkoxy group; in another embodiment, the haloalkoxy group is C10. 1-6 Haloalkoxy group; in yet another embodiment, the haloalkoxy group is C 1-4 Haloalkoxy group; in yet another embodiment, the haloalkoxy group is C 1-3 Haloalkoxy groups. When a haloalkoxy group is a linking group, and the definition of "haloalkoxy" lists "haloalkoxy" for that Markush group, then "haloalkoxy" refers to the linked haloalkoxy group. Examples of haloalkoxy groups include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, monochloromethoxy, dichloromethoxy, trichloromethoxy, 2-chloroethoxy, 1,2-dichloroethoxy, 1,1-dichloroethoxy, 2,2-dichloroethoxy, 1,1-dibromoethoxy, etc.

[0202] The term "halogenated heteroalkyl" means that a heteroalkyl group is replaced by one or more halogen atoms, wherein the heteroalkyl group has the meaning as described in this invention. In some embodiments, the haloalkyl group is C10. 1-20 Halogenated heteroalkyl groups; in some embodiments, the halogenated heteroalkyl group is C10. 1-10 Halogenated heteroalkyl group; in another embodiment, the haloalkyl group is C10. 1-6 Halo-heteroalkyl; in yet another embodiment, the halo-heteroalkyl group is C10. 1-4 Halo-heteroalkyl; in yet another embodiment, the halo-heteroalkyl group is C10. 1-3Haloalkyl. When a haloalkyl is a linking group, and the definition of "haloalkyl" is listed for that Markush group, then "haloalkyl" refers to the linked haloalkylene group.

[0203] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). The term "hydroxyl" refers to "-OH". The term "amino" refers to "-NH2". The term "cyano" refers to "-CN" or "-C≡N". The term "hydrogen" refers to H, containing... 1 H, 2 H, 3 H. In some embodiments, hydrogen refers to 1 H. In some embodiments, hydrogen refers to 2 H (i.e., deuterium). The term "oxo" means "=O". The term "heteroatom" refers to N, O, S, and P. In some embodiments, a heteroatom refers to N, O, and S. In some embodiments, a heteroatom refers to N.

[0204] The terms "saturated or partially unsaturated carbocyclic group" and "saturated or partially unsaturated carbocyclic group" are used interchangeably to refer to non-aromatic saturated or partially unsaturated monocyclic or polycyclic systems composed of carbon atoms as ring atoms. In some embodiments, the polycyclic system is a bicyclic or tricyclic system. Saturated or partially unsaturated carbocyclic groups include saturated or partially unsaturated monocyclic groups, saturated or partially unsaturated spirocyclic groups, saturated or partially unsaturated fused carbocyclic groups, and saturated or partially unsaturated bridged carbocyclic groups. In some embodiments, a saturated or partially unsaturated carbocyclic group represents a 3-12 member saturated or partially unsaturated carbocyclic group; in other embodiments, a saturated or partially unsaturated carbocyclic group represents a 3-10 member saturated or partially unsaturated carbocyclic group; and in still other embodiments, a saturated or partially unsaturated carbocyclic group represents a 3-7 member saturated or partially unsaturated carbocyclic group. The saturated or partially unsaturated carbocyclic group may be independently and optionally substituted by one or more substituents described in this invention. When a saturated or partially unsaturated carbocyclic group is a linking group, the term "saturated or partially unsaturated carbocyclic group" is expressed as "saturated or partially unsaturated subcarbonylcyclic group".

[0205] In other embodiments, saturated or partially unsaturated carbocyclic groups represent 3- to 6-membered saturated or partially unsaturated carbocyclic groups. In other embodiments, "saturated or partially unsaturated carbocyclic groups" are selected from formulas ii-1 to ii-6; formulas ii-1 to ii-6 are monovalent when they are connected to the remainder of the molecule by one bond; formulas ii-1 to ii-6 are divalent when they are connected to the remainder of the molecule by two bonds; the saturated or partially unsaturated carbocyclic groups represented by formulas ii-1 to ii-6 are optionally each independently substituted by one or more substituents as described in this invention;

[0206]

[0207] Each t1 is independently 0, 1, 2, 3, 4 or 5; each t2 and t3 is independently 1, 2, 3, 4 or 5.

[0208] In other embodiments, the saturated or partially unsaturated carbocyclic group is selected from the following groups: when the saturated or partially unsaturated carbocyclic group is connected to the rest of the molecule by one bond, the following groups are monovalent; when the saturated or partially unsaturated carbocyclic group is connected to the rest of the molecule by two bonds, the following groups are divalent; the saturated or partially unsaturated carbocyclic groups represented below are optionally each independently substituted by one or more substituents as described in this invention;

[0209]

[0210] "Saturated or partially unsaturated monocyclic group" refers to a monocyclic system and is used interchangeably with "saturated or partially unsaturated monocyclic ring". In some embodiments, the saturated or partially unsaturated monocyclic group is a 3-8 member saturated or partially unsaturated monocyclic group; in other embodiments, it is a 3-7 member saturated or partially unsaturated monocyclic group; in still other embodiments, it is a 3-6 member saturated or partially unsaturated monocyclic group; and in yet another embodiment, it is a 5-6 member saturated or partially unsaturated monocyclic group. Examples of saturated or partially unsaturated monocyclic groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentadienyl, cyclohexenyl, etc. When the saturated or partially unsaturated monocyclic group is a linking group, it refers to a linked saturated or partially unsaturated sub-monocyclic group. The saturated or partially unsaturated monocarbonyl group may be independently and optionally replaced by one or more substituents described in this invention.

[0211] "Saturated or partially unsaturated spirocyclic group" refers to a polycyclic system and is used interchangeably with "saturated or partially unsaturated spirocyclic ring," wherein at least one such ring system is a saturated or partially unsaturated non-aromatic ring system formed by two carbon rings sharing a single carbon atom. In some embodiments, the saturated or partially unsaturated spirocyclic group is a 7-12 member saturated or partially unsaturated spirocyclic group; in other embodiments, the saturated or partially unsaturated spirocyclic group is a 7-10 member saturated or partially unsaturated spirocyclic group. Examples of saturated or partially unsaturated spirocyclic groups include, but are not limited to, spiro[4,4]nonyl, spiro[3,4]octyl, spiro[4,5]decyl, etc. When the saturated or partially unsaturated spirocyclic group is a linking group, the saturated or partially unsaturated spirocyclic group refers to a linked saturated or partially unsaturated subspirocyclic group. The saturated or partially unsaturated spirocyclic group may be independently and optionally substituted by one or more substituents described in this invention.

[0212] "Saturated or partially unsaturated fused carbon cyclic group" refers to a polycyclic system and is interchangeable with "saturated or partially unsaturated fused carbon ring," wherein at least one such ring system is a non-aromatic saturated or partially unsaturated ring system in which two carbon rings share two carbon atoms. In some embodiments, the saturated or partially unsaturated fused carbon cyclic group is a 6-12 member saturated or partially unsaturated fused carbon cyclic group; in other embodiments, the saturated or partially unsaturated fused carbon cyclic group is a 6-10 member saturated or partially unsaturated fused carbon cyclic group; in still other embodiments, the saturated or partially unsaturated fused carbon cyclic group is an 8-10 member saturated or partially unsaturated fused carbon cyclic group. Examples of saturated or partially unsaturated fused carbon cyclic groups include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, etc. When the saturated or partially unsaturated fused carbocyclic group is the linking group, the saturated or partially unsaturated fused carbocyclic group refers to the linked saturated or partially unsaturated subfused carbocyclic group. The saturated or partially unsaturated fused carbocyclic group may be independently and optionally replaced by one or more substituents described in this invention.

[0213] "Saturated or partially unsaturated bridged carbocyclic group" refers to a polycyclic system and is used interchangeably with "saturated or partially unsaturated bridged carbocyclic ring." It contains at least one such ring system, which is a non-aromatic saturated or partially unsaturated ring system in which two carbocyclic rings share three or more carbon atoms. In some embodiments, the saturated or partially unsaturated bridged carbocyclic group is a 5-12 member saturated or partially unsaturated bridged carbocyclic group; in other embodiments, it is a 5-10 member saturated or partially unsaturated bridged carbocyclic group; and in still other embodiments, it is a 5-8 member saturated or partially unsaturated bridged carbocyclic group. Examples of saturated or partially unsaturated bridged carbocyclic groups include, but are not limited to: bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, etc. When the saturated or partially unsaturated bridging carbocyclic group is the linking group, the saturated or partially unsaturated bridging carbocyclic group represents the linked saturated or partially unsaturated subbridged carbocyclic group. The saturated or partially unsaturated bridging carbocyclic group may be independently and optionally replaced by one or more substituents described in this invention.

[0214] The terms "saturated or partially unsaturated heterocyclic group" and "saturated or partially unsaturated heterocycle" are used interchangeably to refer to non-aromatic saturated or partially unsaturated monocyclic or polycyclic systems in which the ring atom comprises at least one carbon atom and one or more heteroatoms. The heteroatoms have the meaning as described in this invention. Unless otherwise stated, a saturated or partially unsaturated heterocyclic group may be connected to the remainder of the molecule via its carbon atom or via a heteroatom. In some embodiments, the polycyclic system is a bicyclic or tricyclic system. Saturated or partially unsaturated heterocyclic groups include saturated or partially unsaturated monocyclic groups, saturated or partially unsaturated spirocyclic groups, saturated or partially unsaturated fused heterocyclic groups, and saturated or partially unsaturated bridged heterocyclic groups. In some embodiments, a saturated or partially unsaturated heterocyclic group represents a 3-12 member saturated or partially unsaturated heterocyclic group; in other embodiments, a saturated or partially unsaturated heterocyclic group represents a 3-10 member saturated or partially unsaturated heterocyclic group; in still other embodiments, a saturated or partially unsaturated heterocyclic group represents a 3-7 member saturated or partially unsaturated heterocyclic group; and in yet another embodiment, a saturated or partially unsaturated heterocyclic group represents a 3-6 member saturated or partially unsaturated heterocyclic group. The saturated or partially unsaturated heterocyclic group may be independently and optionally substituted by one or more substituents described in this invention. When the saturated or partially unsaturated heterocyclic group is a linking group, the term "saturated or partially unsaturated heterocyclic group" is used to refer to a "saturated or partially unsaturated subheterocyclic group".

[0215] In other embodiments, the saturated or partially unsaturated heterocyclic group is selected from formulas iii-1 to iii-16; formulas iii-1 to iii-16 are monovalent when they are connected to the remainder of the molecule by one bond; formulas iii-1 to iii-16 are divalent when they are connected to the remainder of the molecule by two bonds; the saturated or partially unsaturated heterocyclic group represented by formulas iii-1 to iii-16 is optionally, each independently, substituted by one or more substituents defined by the corresponding groups described above in this invention;

[0216]

[0217] Each t1 is independently 0, 1, 2, 3, 4 or 5; each t2 and t3 is independently 1, 2, 3, 4 or 5.

[0218] "Substituent substitution as defined in the aforementioned corresponding groups of this invention" refers to the substituent mentioned in the aforementioned groups involving "saturated or partially unsaturated carbocyclic groups" and "saturated or partially unsaturated heterocyclic groups" that are being substituted.

[0219] In other embodiments, the saturated or partially unsaturated heterocyclic group is selected from the following groups: when the saturated or partially unsaturated heterocyclic group is connected to the remainder of the molecule by one bond, the following groups are monovalent; when the saturated or partially unsaturated heterocyclic group is connected to the remainder of the molecule by two bonds, the following groups are divalent; the saturated or partially unsaturated heterocyclic groups represented below are optionally each independently substituted by one or more substituents defined by the corresponding groups described above in this invention;

[0220]

[0221] "Saturated or partially unsaturated monoheterocyclic group" refers to a monocyclic system and is used interchangeably with "saturated or partially unsaturated monoheterocyclic group". In some embodiments, the saturated or partially unsaturated monoheterocyclic group is a 3-8 member saturated or partially unsaturated monoheterocyclic group; in other embodiments, the saturated or partially unsaturated monoheterocyclic group is a 3-7 member saturated or partially unsaturated monoheterocyclic group; in still other embodiments, the saturated or partially unsaturated monoheterocyclic group is a 3-6 member saturated or partially unsaturated monoheterocyclic group; and in still other embodiments, the saturated or partially unsaturated monoheterocyclic group is a 5-6 member saturated or partially unsaturated monoheterocyclic group. Examples of saturated or partially unsaturated monoheterocyclic groups include, but are not limited to: ethylene oxide, azirrobutyl, oxacyclobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxane, dithiaalkyl, thiaoxane, homopiperazine, homopiperidinyl, 1,1-dioxo-1,3-thiomorpholine, etc. Examples of heterocyclic groups where the -CH2- group is substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridine, etc. When the saturated or partially unsaturated monoheterocyclic group is the linking group, the saturated or partially unsaturated monoheterocyclic group refers to a linked saturated or partially unsaturated submonoheterocyclic group. The saturated or partially unsaturated monoheterocyclic group may be independently and optionally substituted by one or more substituents described in this invention.

[0222] "Saturated or partially unsaturated spiroheterocyclic group" refers to a polycyclic system and is used interchangeably with "saturated or partially unsaturated spiroheterocycle." It contains at least one such ring system, which is a saturated or partially unsaturated non-aromatic ring system formed by two heterocycles sharing a single heteroatom. In some embodiments, the saturated or partially unsaturated spiroheterocyclic group is a 7-12 member saturated or partially unsaturated spiroheterocyclic group; in other embodiments, the saturated or partially unsaturated spiroheterocyclic group is a 7-10 member saturated or partially unsaturated spiroheterocyclic group. Examples of saturated or partially unsaturated spirochetal groups include, but are not limited to: 4,7-diazaspiro[2.5]octyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.5]decyl, 2,7-diazaspiro[3.5]decyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[4.4]nonyl, 3-azaspiro[5.5]undecyl, 2,7-diazaspiro[4.4]nonyl-1-one, etc. When the saturated or partially unsaturated spirochetal group is a linking group, the saturated or partially unsaturated spirochetal group refers to a linked saturated or partially unsaturated spiroheterocyclic group. The saturated or partially unsaturated spirochetal group may be independently and optionally substituted by one or more substituents described in this invention.

[0223] "Saturated or partially unsaturated fused heterocyclic group" refers to a polycyclic system and is used interchangeably with "saturated or partially unsaturated fused heterocycle." It contains at least one such ring system, which is a non-aromatic saturated or partially unsaturated ring system in which two heterocycles share two heteroatoms. In some embodiments, the saturated or partially unsaturated fused heterocyclic group is a 6-12 member saturated or partially unsaturated fused heterocyclic group; in other embodiments, it is a 6-10 member saturated or partially unsaturated fused heterocyclic group; and in still other embodiments, it is an 8-10 member saturated or partially unsaturated fused heterocyclic group. Examples of saturated or partially unsaturated fused heterocyclic groups include, but are not limited to, octahydroimidazolo[1,5-c]pyrimidine, etc. When the saturated or partially unsaturated fused heterocyclic group is a linking group, it refers to a linked saturated or partially unsaturated sub-fused heterocyclic group. The saturated or partially unsaturated fused heterocyclic group may be independently and optionally replaced by one or more substituents described in this invention.

[0224] "Saturated or partially unsaturated bridged heterocyclic group" refers to a polycyclic system and is used interchangeably with "saturated or partially unsaturated bridged heterocycle." It contains at least one such ring system, which is a non-aromatic saturated or partially unsaturated ring system in which two heterocycles share three or more heteroatoms. In some embodiments, the saturated or partially unsaturated bridged heterocyclic group is a 5-12 member saturated or partially unsaturated bridged heterocyclic group; in other embodiments, it is a 5-10 member saturated or partially unsaturated bridged heterocyclic group; and in still other embodiments, it is a 5-8 member saturated or partially unsaturated bridged heterocyclic group. Examples of saturated or partially unsaturated bridged heterocyclic groups include, but are not limited to: 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2-diazabicyclo[2.2.1]heptane, 6-diazabicyclo[3.1.1]heptane, 3-diazabicyclo[3.1.1]heptane, 8-diazabicyclo[3.2.1]octane, 3-diazabicyclo[3.2.1]octane, 2-diazabicyclo[2.2.2]octane, etc. When the saturated or partially unsaturated bridged heterocyclic group is a linking group, the saturated or partially unsaturated bridged heterocyclic group refers to a linked saturated or partially unsaturated subbridged heterocyclic group. The saturated or partially unsaturated bridged heterocyclic group may be independently and optionally substituted by one or more substituents described in this invention.

[0225] The terms "aryl" and "aromatic ring" are used interchangeably to refer to aromatic monocyclic or polycyclic systems composed of carbon atoms as ring atoms. In some embodiments, the polycyclic system is bicyclic or tricyclic. In some embodiments, the aryl group is a 6-14-membered aryl group; in other embodiments, it is a 6-10-membered aryl group; in still other embodiments, it is a phenyl or naphthyl group. When the aryl group is a linking group, it indicates a linked arylide group. The aryl group may be independently and optionally substituted by one or more substituents described in this invention.

[0226] The terms "heteroaryl" and "heteroary ring" are used interchangeably to refer to aromatic monocyclic or polycyclic systems consisting of at least one carbon atom and one or more heteroatoms as ring atoms. The heteroatoms have the meaning as described in this invention. In some embodiments, the polycyclic system is bicyclic or tricyclic. In some embodiments, the heteroaryl group is a 5-14-membered heteroaryl group; in other embodiments, it is a 5-10-membered heteroaryl group; in other embodiments, it is a 5-6-membered heteroaryl group. In other embodiments, it is a 5-10-membered nitrogen-containing heteroaryl group; in other embodiments, it is a 5-6-membered nitrogen-containing heteroaryl group; in other embodiments, it is a 6-membered nitrogen-containing heteroaryl group. Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrroleyl, 2-pyrroleyl, pyrazinyl, 3-pyrroleyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl pyridyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purineyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-... Isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc. When the aryl group is a linking group, the aryl group represents a linked aryl group. The aryl group may be independently and optionally substituted by one or more substituents described in this invention.

[0227] The term "carbon chain" refers to a saturated or unsaturated group consisting of carbon atoms that acts as a linking element. The carbon chain may optionally be substituted by one or more substituents described in this invention. In some embodiments, the carbon chain is saturated; in other embodiments, the carbon chain contains one or more double or triple bonds. In some embodiments, the carbon chain is a carbon chain having 2-6 atoms; in other embodiments, the carbon chain is a carbon chain having 2-4 atoms; in other embodiments, the carbon chain is a carbon chain having 2-3 atoms; in other embodiments, the carbon chain is a carbon chain having 2 atoms; in other embodiments, the carbon chain is a carbon chain having 3 atoms; and in other embodiments, the carbon chain is a carbon chain having 4 atoms.

[0228] The term "hybrid" refers to a saturated or unsaturated group consisting of carbon atoms and heteroatoms that act as a linker, wherein at least one heteroatom is present. The heterochain may optionally be substituted by one or more substituents described in this invention. In some embodiments, the heterochain is saturated; in other embodiments, the heterochain contains one or more double or triple bonds. In some embodiments, the heterochain is a heterochain having 2-6 atoms; in other embodiments, the heterochain has 2-4 atoms; in other embodiments, the heterochain has 2-3 atoms; in other embodiments, the heterochain has 2 atoms; in other embodiments, the heterochain has 3 atoms; in other embodiments, the heterochain has 4 atoms.

[0229] The term "nitrogen protecting group" has the same connotation as "amino saturated group" and can be used interchangeably with it. A nitrogen protecting group refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenemethoxycarbonyl (Fmoc).

[0230] The term "leaving group," or "leaving radical," refers to an atom or functional group that breaks off from a larger molecule during a chemical reaction. It is used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Common leaving groups include, but are not limited to, halogen atoms, ester groups, sulfonate groups, nitro groups, azide groups, or hydroxyl groups.

[0231] The term "carbon unit" refers to CH2, or substituted CH2.

[0232] As described in this invention, unless otherwise specified, the combined groups used in this invention, such as hydroxyalkyl, aminoalkyl, hydroxyalkoxy, aminoalkoxy, alkylamino, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic alkyl, arylalkyl, heteroarylalkyl, and aminoalkyl groups, such as amino, hydroxy, alkyl, alkoxy, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, and heteroaryl, have the definitions described in this invention.

[0233] As described in this invention, unless otherwise specified, cyclic substituents, such as saturated or partially unsaturated carbocyclic groups, saturated or partially unsaturated heterocyclic groups, aryl groups, and heteroaryl groups, can be attached to the remainder of the molecule at any connectable position on the ring. For example, piperidinyl groups include piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl. As described in this invention, a ring system formed by a substituent R being bonded to a central ring represents that the substituent R can be substituted at any substituted or reasonable position on the ring to which it is attached. As described in this invention, a ring system formed by a bond bonded to the center of a ring represents that this bond can be attached to the remainder of the molecule at any connectable position on the ring system. As described in this invention, if a ring has two attachment points attached to the remainder of the molecule, then these two attachment points can be attached to the remainder of the molecule at any connectable position on the ring, and the two ends of the attachment can be interchanged.

[0234] As used in this invention, "pharmaceuticalally acceptable excipient" refers to a pharmaceutically acceptable material, mixture, or solvent related to the consistency of the dosage form or pharmaceutical composition. Each excipient must be compatible with the other components of the pharmaceutical composition when mixed to avoid interactions that would significantly reduce the efficacy of the disclosed compounds when administered to a patient, and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition. Furthermore, each excipient must be pharmaceutically acceptable, for example, having sufficiently high purity. Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form chosen. In addition, pharmaceutically acceptable excipients may be selected based on their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that contribute to the production of a homogeneous dosage form. Certain pharmaceutically acceptable excipients may be selected that contribute to the production of a stable dosage form. Certain pharmaceutically acceptable excipients may be selected that facilitate the carrying or transport of the compounds of this invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

[0235] Examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, flavoring agents, anti-adhesion agents, antioxidants, chelating agents, penetration enhancers, pH adjusters, plasticizers, surfactants, foaming agents, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and deflocculators, and filter aids. Those skilled in the art will recognize that certain pharmaceutically acceptable excipients can provide more than one function and offer alternative functions, depending on the amount of that excipient present in the formulation and what other excipients are present in the formulation. The compounds of the present invention can be formulated using methods known in the art to enable rapid, sustained, or delayed release of the active ingredient after administration to a patient.

[0236] Those skilled in the art possess the knowledge and skills to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in this invention. Furthermore, numerous resources available to those skilled in the art describe pharmaceutically acceptable excipients and are used for selecting suitable pharmaceutically acceptable excipients. Examples include Remington’s Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0237] As used in this invention, "pharmaceutically acceptable carriers" include any and all solvents and solvent mixtures, coatings, complexing agents, solid carriers, dispersion media, surfactant excipients, antibacterial and antifungal agents, isotonic and absorption delay agents for pharmaceutically active substances, and mixtures thereof, which are also known in the art.

[0238] Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference. Except for any commonly used carriers that are incompatible with the compounds of the present invention due to any undesirable biological effects or harmful interactions with any other component of a pharmaceutically acceptable composition, interest in their use is within the scope of this invention.

[0239] Suitable pharmaceutically acceptable carriers depend on the form of the drug and are known to those skilled in the art. Non-limiting examples of pharmaceutically acceptable carriers include those having components selected from: lactose, gelatin, sugar alcohols (e.g., starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, colloidal silica, carboxymethyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, Tween buffered aqueous solution, copovidone, polysorbate, ethanol, propylene glycol, polyethylene glycol (preferably polyethylene glycol, e.g., PEG400), 80 (i.e., PEG(20), sorbitol monooleate), DMSO, A mixture of water and a cosolvent, such as an aqueous solution of alcohols such as ethanol and / or polyethylene glycol such as polyethylene glycol, polyols such as glycerol and / or esters of polyethylene glycol with fatty acids, surfactants such as anionic, cationic, nonionic and amphoteric surfactants, complexing agents such as cyclodextrins, such as α-cyclodextrin (α-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD), bile acids or lipids, such as salts of animal or plant phospholipids, micellar agents, and oils such as corn oil, or a mixture of two or more of the aforementioned components.

[0240] Unless otherwise indicated, any structural formulas given in this invention are also intended to represent the un-isotopically enriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas given in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C, 13 C,14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0241] It contains radioactive isotopes, such as 3 H, 14 C and 18 Those compounds of F, or those containing non-radioactive isotopes, such as 2 H and 13 C. Compounds enriched by this type of isotope can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) which includes the determination of drug or substrate tissue distribution, may be used in the patient's radiotherapy. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, and VIII-1 to VIII-6 can be prepared using conventional techniques familiar to those skilled in the art or as described in the examples and preparation processes of this invention, replacing the previously used unlabeled reagents with suitable isotopic labeling reagents.

[0242] In addition, heavier isotopes, especially deuterium (i.e., 2Substitution with H or D can provide certain therapeutic advantages resulting from increased metabolic stability. For example, this may lead to an increased half-life in vivo, a reduced dose requirement, or an improved therapeutic index. It should be understood that deuterium in this invention is considered as a substituent in compounds of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, and VIII-1 to VIII-6. The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotope enrichment factor. The term "isotope enrichment factor" as used in this invention refers to the ratio between the isotopic abundance and the native abundance of the specified isotope. If the substituent of the compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) with respect to each designated deuterium atom. The pharmaceutically usable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D2O, acetone-d6, DMSO-d6.

[0243] Compounds, pharmaceutical compositions, formulations and administration

[0244] This invention provides a focal adhesion kinase (FAK) inhibitor compound that has good therapeutic effects on cancer, pulmonary hypertension, and pathological angiogenesis.

[0245] On one hand, the present invention relates to a compound, which is a compound of Formula I or a stereoisomer, tautomer, nitroxide compound, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

[0246]

[0247] Among them, M, A, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y5 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0248] In some embodiments, M is a covalent warhead. In some embodiments, M is...

[0249]

[0250] Among them, Z and L 7 L 8 R M1 R M2 R M3 R M4 R M5 , q, and r have the definitions described in this invention.

[0251] In some embodiments, M is

[0252]

[0253] Among them, Z and L 7 R M1 R M2 R M3 It has the definition as described in this invention.

[0254] In some embodiments, L 7 For a key, -O-, -S-, -NR L7a -or C 1-4 Alkyl, wherein the C 1-4 One or more carbon units of an alkyl group are optionally and independently separated by -O-, -S-, -NR-. L7a -、-NR L7a C(=O)-、-C(=O)NR L7a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L7a C(=S)-、-C(=S)NR L7a - Trans CR L7b =CR L7b - Cis-CR L7b =CR L7b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L7a -、-NR L7a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR L7a -or-NR L7aS(=O)2-replacement; where each R L7a Independent of hydrogen, deuterium, and C 1-4 Alkyl or nitrogen protecting groups; each R L7b Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two adjacent R groups L7b The groups and the atoms attached to them connect to form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each L 7 R L7a R L7b The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0255] In some embodiments, L 7 For a single bond, -O-, -S-, -NH-, or C 1-4 Alkyl, wherein the C 1-4 One or more carbon units of an alkyl group may optionally be independently replaced by -O-, -S-, -NH-, -NHC(=O)-, -C(=O)NH-, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NHC(=S)-, -C(=S)NH-, transCH=CH-, cisCH=CH-, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NH-, -NHS(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NH- or -NHS(=O)2-.

[0256] In some embodiments, L 8 For a key or C 1-4 Alkyl, wherein L 8 The alkyl group involved may optionally be substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, and oxo.

[0257] In some embodiments, each R M1 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M1a -CH2N(R) M1a )2、-CH2SR M1a -OR M1a -N(R) M1a )2、-Si(R M1a )3 or -SR M1a , where each R M1a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M1a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M1 R M1a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0258] In some embodiments, each R M1 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M1a -CH2N(R) M1a )2、-CH2SR M1a -OR M1a -N(R) M1a )2、-Si(R M1a )3 or -SR M1a , where each R M1a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. M1a The groups and the atoms attached to them are optionally linked to form 3-6 saturated or partially unsaturated heterocyclic groups.

[0259] In some embodiments, each R M2 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M2a -CH2N(R) M2a )2、-CH2SR M2a -OR M2a -N(R) M2a )2 or -SR M2a , where each R M2a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M2a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M2 R M2a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0260] In some embodiments, each R M2 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M2a -CH2N(R) M2a )2、-CH2SR M2a -OR M2a -N(R) M2a )2 or -SR M2a , where each R M2a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. M2a The groups and the atoms attached to them are optionally linked to form 3-6 saturated or partially unsaturated heterocyclic groups.

[0261] In some embodiments, each R M3 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M3a -CH2N(R) M3a )2、-CH2SR M3a -OR M3a -N(R) M3a )2 or -SR M3a , where each R M3a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M3a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M3 R M3a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0262] In some embodiments, each R M3 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M3a -CH2N(R) M3a )2、-CH2SR M3a -OR M3a -N(R) M3a )2 or -SR M3a , where each R M3aIndependent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. M3a The groups and the atoms attached to them are optionally linked to form 3-6 saturated or partially unsaturated heterocyclic groups.

[0263] In some embodiments, R M1 and R M3 , or R M2 and R M3 , or R M1 and R M2 Optionally linked to form saturated or partially unsaturated carbocyclic groups or saturated or partially unsaturated heterocyclic groups, wherein the saturated or partially unsaturated carbocyclic groups or saturated or partially unsaturated heterocyclic groups are optionally each independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0264] In some embodiments, R M1 and R M3 , or R M2 and R M3 , or R M1 and R M2 Optionally linked to form a 3-6 member saturated or partially unsaturated carbocyclic group or a saturated or 3-6 member partially unsaturated heterocyclic group, wherein the 3-6 member saturated or partially unsaturated carbocyclic group or the saturated or 3-6 member partially unsaturated heterocyclic group is optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0265] In some embodiments, R M4 R is a leaving group. In some embodiments, R M4 It is a halogen, p-toluenesulfonyl, benzenesulfonyl, or p-nitrobenzenesulfonyl. In some embodiments, R M5 It is a halogen.

[0266] In some embodiments, Z is O, S, or NR. Z ;where R Z For hydrogen, deuterium, C 1-4 Alkyl or nitrogen protecting group; R Z The alkyl group involved may optionally be substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, and oxo. In some embodiments, Z is O, S, or NH.

[0267] In some embodiments, q is 0, 1, 2, 3, 4, 5, or 6.

[0268] In some embodiments, r is 1 or 2.

[0269] In some embodiments, M is

[0270] In some embodiments, A is an aryl or heteroaryl group. In some embodiments, A is a 6-10 aryl or a 5-10 heteroaryl group.

[0271] In some embodiments, A is a 6-10 aryl or a 5-10 azaaryl. In some embodiments, A is a phenyl or a 6-azaaryl. In some embodiments, A is a phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, furanyl, thiophenyl, pyrroleyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or the following groups:

[0272]

[0273] In some other embodiments, A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0274] In some embodiments, L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independently, it is a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, or nitrogen-protecting group; wherein R L1a The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, and oxo.

[0275] In some embodiments, L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independent of hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl or nitrogen-protected groups; wherein R L1a The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, and oxo.

[0276] In some embodiments, L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Haloalkyl, C 1-4 Halogenated heteroalkyl or nitrogen-protected groups; wherein R L1a The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, and oxo. In other embodiments, L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independently, it is hydrogen, methyl, ethyl, vinyl, ethynyl, or trifluoromethyl. In other embodiments, L 1 It is a single bond, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NH-, -NHC(=O)-, -S(=O)2NH-, or -NHS(=O)2-. In other embodiments, L 1 It is a single bond, -C(=O)- or -C(=O)NH-.

[0277] In some embodiments, L 2 It is a single bond, alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group, aryl or heteroaryl; wherein, L 2The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved may each be independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, alkyl, alkenyl, ynyl, heteroalkyl, or haloheteroalkyl.

[0278] In other embodiments, L 2 For a key, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups; wherein, L 2 The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are used for substitution.

[0279] In other embodiments, L 2 For a key, C 1-4 Alkyl, C 1-4 Heteroalkyl, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups; wherein, L 2 The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are used for substitution.

[0280] In other embodiments, L 2 For a key, C 1-4 Alkyl, C 1-4 Heteroalkyl, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups; wherein, L 2The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally and independently substituted by a substituent selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, oxo, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, or methylamino.

[0281] In other embodiments, L 2 It is a single-bonded, 3-6 member saturated or partially unsaturated carbocyclic group or a 3-6 member saturated or partially unsaturated heterocyclic group; wherein, L 2 The saturated or partially unsaturated carbocyclic groups and saturated or partially unsaturated heterocyclic groups involved are optionally each independently substituted by one or more substituents selected from hydroxyl, amino, cyano, fluorine, chlorine, oxo, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, and methylamino. In other embodiments, L 2 It is a single bond, cyclohexyl, piperidinyl, phenyl, or pyridinyl.

[0282] In some embodiments, L 3 It is a single bond, aryl or heteroaryl; wherein, L 3 The aryl or heteroaryl groups involved may optionally be substituted independently by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl or haloheteroalkyl.

[0283] In other embodiments, L 3 It is a single bond, a 6-10 aryl group or a 5-10 heteroaryl group; wherein, L 3 The aryl or heteroaryl groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of the haloheteroalkyl group are substituted. In other embodiments, L 3 It is a single bond, a 6-10 aryl group or a 5-10 heteroaryl group; wherein, L 3 The aryl or heteroaryl groups involved are optionally and independently substituted with substituents selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, and methylamino. In other embodiments, L 3 It is a single bond, a 6-10 aryl group or a 5-10 heteroaryl group; wherein, L 3The aryl or heteroaryl groups involved are optionally substituted with one or more hydroxyl, amino, cyano, fluorine, chlorine, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, or methylamino substituents. In other embodiments, L 3 It is a single bond, phenyl or pyridyl.

[0284] In some embodiments, L 4 It is a carbon chain or heterochain with 2-6 atoms; where L 4 The carbon chain or heterochain involved may optionally be independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, aminoalkoxy, alkylamino, and nitrogen protecting group.

[0285] In other embodiments, L 4 It is a carbon chain or heterochain with 2-6 atoms; where L 4 The carbon chains or heterochains involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 1-6 aminoalkoxy, C 1-6 Alkylamino groups, nitrogen-protecting groups, or one or more substituents are used for substitution. In other embodiments, L... 4 It is a carbon chain or heterochain with 2-6 atoms; where L 4 The carbon chains or heterochains involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkoxy, C 1-4 aminoalkoxy, C 1-4 Alkylamino groups, nitrogen-protecting groups, or one or more substituents are used for substitution. In other embodiments, L... 4 It is a carbon chain or heterochain with 2-4 atoms; where L 4The carbon chain or heterochain involved may optionally be independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, methylamino, and nitrogen protecting group.

[0286] In other embodiments, L 4 -NHCH2-, -CH2NH-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -SCH2CH2-, -CH2SCH2-, -CH2CH2S-, -NHCH2CH2CH2-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -CH2C H2CH2NH-, -OCH2CH2CH2-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -SCH2CH2CH2-, -CH2SCH2CH2-, -CH2C H2SCH2-, -CH2CH2CH2S-, -CH2OCH2O-, -OCH2OCH2-, -OCH2CH2O-, -NHCH2CH2O-, -CH2NHCH2O- or -NHCH2OCH2-; where L 4 The hydrogen atoms in CH2 involved are optionally and independently replaced by hydrogen, deuterium, hydroxyl, amino, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino substituents; L 4 The hydrogen atoms in NH are optionally and independently replaced by hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting substituents. In other embodiments, L 4 It can be -NHCH2-, -CH2NHCH2-, -NHC(=O)-, -CH2NHC(=O)-, -C(=O)NHCH2- or -NHCH(CH3)-.

[0287] In some embodiments, L 5 For -NR L5a -, -O-, -S-, alkyl or heteroalkyl; wherein, L 5 The alkyl and heteroalkyl groups involved are optionally and independently substituted by substituents selected from deuterium, amino, hydroxyl, oxo, cyano, halogen, alkenyl, or alkynyl; each R L5a It is independently a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or nitrogen-protected group.

[0288] In some embodiments, L 5 For -NR L5a -、-O-、-S-、C 1-6 Alkyl or C 1-6 Heteroalkyl; wherein, L 5 The alkyl and heteroalkyl groups involved are optionally each independently selected from deuterium, amino, hydroxyl, oxo, cyano, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of the haloalkyl group are substituted; each R L5a Independent of hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or nitrogen-protected groups.

[0289] In other embodiments, L 5 For -NR L5a -CR L5b R L5c -、-O-、-S-、-CR L5b R L5c NR L5a -、-NR L5a CR L5b R L5c -、-CR L5b R L5c O-、-OCR L5b R L5c -、-CR L5b R L5c S- or -SCR L5b R L5c -; where each R L5b and R L5c Each of these can be independently represented by hydrogen, deuterium, amino, hydroxyl, oxo, cyano, halogen, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; each R L5a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl groups or nitrogen-protected groups. In other embodiments, L5 It can be -NH-, -O-, -S-, -NHCH2-, -OCH2-, -SCH2-, -CH2NH-, -CH2O-, or -CH2S-. In other embodiments, L 5 It is -NH-.

[0290] In some embodiments, L 6 For -NR L6a -, -O-, -S-, alkyl or heteroalkyl; wherein, L 6 The alkyl and heteroalkyl groups involved are optionally and independently substituted by substituents selected from deuterium, amino, hydroxyl, oxo, cyano, halogen, alkenyl, or alkynyl; each R L6a It is independently a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or nitrogen-protected group.

[0291] In other embodiments, L 6 For -NR L6a -、-O-、-S-、C 1-6 Alkyl or C 1-6 Heteroalkyl; wherein, L 6 The alkyl and heteroalkyl groups involved are optionally each independently selected from deuterium, amino, hydroxyl, oxo, cyano, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of the haloalkyl group are substituted; each R L6a Independent of hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or nitrogen-protected groups.

[0292] In other embodiments, L 6 For -NR L6a -CR L6b R L6c -、-O-、-S-、-CR L6b R L6c NR L6a -、-NR L6a CR L6b R L6c -、-CR L6b R L6c O-、-OCR L6b R L6c -、-CR L6b R L6c S- or -SCRL6b R L6c -; where each R L6b and R L6c Each of these can be independently represented by hydrogen, deuterium, amino, hydroxyl, oxo, cyano, halogen, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; each R L6a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl groups or nitrogen-protected groups. In other embodiments, L 6 It can be -NH-, -O-, -S-, -NHCH2-, -OCH2-, -SCH2-, -CH2NH-, -CH2O-, or -CH2S-. In other embodiments, L 6 It is -NH- or -NHCH2-.

[0293] In some embodiments, X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 and Y 5 Each can be CH or N independently.

[0294] In some embodiments, each R 1 Independently, it is hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 1 Adjacent, the two adjacent R 1 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 1The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups may each be independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, and alkyl.

[0295] In some embodiments, each R 1 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl groups, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated carbocyclic groups C 1-6 Alkyl groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups C 1-6 Alkyl, 6-10 aryl, 6-10 aryl C 1-6 Alkyl, 6-10 heteroaryl or 6-10 heteroaryl C 1-6 Alkyl; if two R are present 1 Adjacent, the two adjacent R 1 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 1 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0296] In other embodiments, each R 1 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; if two R groups are present 1 Adjacent, the two adjacent R 1The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 1 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0297] In other embodiments, each R 1 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; wherein R 1 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, and oxo. In other embodiments, each R 1 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; wherein R 1 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, and oxo. In other embodiments, each R 1Independently, it can be hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-. CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S( =O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)-, (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHO N(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S (=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(C H2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-,(CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-, (CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P (=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)-, or (CH3)2CH(CH3CH2)P(=O)-. ,

[0298] In some embodiments, each R 2 Independently, it is hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 2 Adjacent, the two adjacent R 2 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently substituted by one or more substituents of one or more hydroxyl, amino, cyano, halogen, oxo, or alkyl groups.

[0299] In other embodiments, each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl groups, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated carbocyclic groups C 1-6 Alkyl groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups C 1-6 Alkyl, 6-10 aryl, 6-10 aryl C 1-6 Alkyl, 6-10 heteroaryl or 6-10 heteroaryl C 1-6 Alkyl; if two R are present 2 Adjacent, the two adjacent R2 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0300] In other embodiments, each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; if two R groups are present 2 Adjacent, the two adjacent R 2 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of the alkyl group are substituted. In other embodiments, each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; wherein R 2 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, and oxo. In other embodiments, each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; wherein R 2The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, and oxo.

[0301] In other embodiments, each R 2Independently, it is hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)- , CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S (=O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)- , (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHO N(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S (=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(C H2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-,(CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-, (CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P (=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)-, or (CH3)2CH(CH3CH2)P(=O)-. ,

[0302] In some embodiments, each R 3 Independently, it is hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 3 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently substituted by one or more substituents of one or more hydroxyl, amino, cyano, halogen, oxo, or alkyl groups.

[0303] In other embodiments, each R 3 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl groups, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated carbocyclic groups C 1-6 Alkyl groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups C 1-6 Alkyl, 6-10 aryl, 6-10 aryl C 1-6 Alkyl, 6-10 heteroaryl or 6-10 heteroaryl C 1-6 Alkyl; if two R are present 3 Adjacent, the two adjacent R3 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 3 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0304] In other embodiments, each R 3 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl groups; if two R groups are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 3 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of the alkyl group are substituted. In other embodiments, each R 3 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; if two R groups are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein R 3 The alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, 3-6 member saturated or partially unsaturated carbocyclic groups, and 3-6 member saturated or partially unsaturated heterocyclic groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4One or more substituents of the alkyl group are substituted. In other embodiments, each R 3 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; if two R groups are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein R 3 The alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, 3-6 saturated or partially unsaturated carbocyclic groups and 3-6 saturated or partially unsaturated heterocyclic groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, methyl, ethyl, and isopropyl.

[0305] In other embodiments, each R 3Independently, it can be hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-. CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S( =O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)-, (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHO N(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S (=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(C H2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-,(CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-, (CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P(=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)- or (CH3)2CH(CH3CH2)P(=O)-; if two R, 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form the following groups:

[0306]

[0307] In some embodiments, n, m, and p are each independently 0, 1, 2, 3, or 4.

[0308] In some embodiments, the saturated or partially unsaturated carbocyclic group includes saturated or partially unsaturated monocarbocyclic groups, saturated or partially unsaturated spirocarbocyclic groups, saturated or partially unsaturated fused carbocyclic groups, and saturated or partially unsaturated bridged carbocyclic groups.

[0309] In some embodiments, the saturated or partially unsaturated carbocyclic group is selected from formulas ii-1 to ii-6; formulas ii-1 to ii-6 are monovalent when they are connected to the rest of the molecule by one bond; formulas ii-1 to ii-6 are divalent when they are connected to the rest of the molecule by two bonds; the saturated or partially unsaturated carbocyclic group represented by formulas ii-1 to ii-6 is optionally substituted independently by one or more substituents as described in this invention;

[0310]

[0311] Each t1 is independently 0, 1, 2, 3, 4 or 5; each t2 and t3 is independently 1, 2, 3, 4 or 5.

[0312] In some embodiments, the saturated or partially unsaturated heterocyclic group includes a saturated or partially unsaturated mono-heterocyclic group, a saturated or partially unsaturated spiro-heterocyclic group, a saturated or partially unsaturated fused heterocyclic group, and a saturated or partially unsaturated bridged heterocyclic group. In some embodiments, the saturated or partially unsaturated heterocyclic group is selected from formulas iii-1 to iii-16; formulas iii-1 to iii-16 are monovalent when they are connected to the remainder of the molecule by one bond; formulas iii-1 to iii-16 are divalent when they are connected to the remainder of the molecule by two bonds; the saturated or partially unsaturated heterocyclic group represented by formulas iii-1 to iii-16 is optionally and independently substituted by one or more substituents as described in this invention;

[0313]

[0314] Each t1 is independently 0, 1, 2, 3, 4 or 5; each t2 and t3 is independently 1, 2, 3, 4 or 5.

[0315] In other embodiments, the saturated or partially unsaturated carbocyclic group is selected from the following groups: when the saturated or partially unsaturated carbocyclic group is connected to the rest of the molecule by one bond, the following groups are monovalent; when the saturated or partially unsaturated carbocyclic group is connected to the rest of the molecule by two bonds, the following groups are divalent; the saturated or partially unsaturated carbocyclic groups represented below are optionally each independently substituted by one or more substituents as described in this invention;

[0316]

[0317] In other embodiments, the saturated or partially unsaturated heterocyclic group is selected from the following groups: when the saturated or partially unsaturated heterocyclic group is connected to the remainder of the molecule by one bond, the following groups are monovalent; when the saturated or partially unsaturated heterocyclic group is connected to the remainder of the molecule by two bonds, the following groups are divalent; the saturated or partially unsaturated heterocyclic groups represented below are optionally each independently substituted by one or more substituents as described in this invention;

[0318]

[0319] In some embodiments, the compounds of the present invention are compounds represented by Formula II-1 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0320]

[0321] Among them, each R M1 R M2R M3 L 2 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0322] In some embodiments, the compounds of the present invention are compounds represented by Formula II-2 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0323]

[0324] Among them, each R M1 R M2 R M3 R L1a L 2 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0325] In some embodiments, the compounds of the present invention are compounds represented by Formula II-3 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0326]

[0327] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of the haloheteroalkyl group are substituted; wherein each R M1 R M2 R M3 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0328] In some embodiments, the compounds of the present invention are compounds represented by Formula II-4 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0329]

[0330] Among them, each R M1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0331] In some embodiments, the compounds of the present invention are compounds represented by Formulas II-5 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0332]

[0333] Among them, each R M1 R L1a L 2 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0334] In some embodiments, the compounds of the present invention are compounds represented by Formula II-6 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0335]

[0336] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of the haloheteroalkyl group are substituted; wherein each R M1 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0337] In some embodiments, the compounds of the present invention are compounds of Formula III or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0338]

[0339] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation is optionally formed; k and v are each independently 0, 1, or 2; wherein, each M and L 1 L 2 L 3 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, p have the definitions as described in this invention.

[0340] In some embodiments, the compounds of the present invention are compounds of Formula IV-1 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0341]

[0342] Among them, R L4aIt is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation is optionally formed; k and v are each independently 0, 1, or 2; wherein, each R M1 R M2 R M3 L 2 L 3 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0343] In some embodiments, the compounds of the present invention are compounds represented by Formula IV-2 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0344]

[0345] in,

[0346] R L4a It can be hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group;

[0347] Each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and RL4c Optional oxidation; R L4d and R L4e Oxygenation is optionally formed; k and v are each independently 0, 1, or 2; wherein, each R M1 R M2 R M3 R L1a L 2 L 3 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0348] In some embodiments, the compounds of the present invention are compounds of Formula IV-3 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0349]

[0350] in,

[0351] B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, wherein the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are used for substitution;

[0352] R L4a It can be hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group;

[0353] Each R L4b R L4c R L4d and R L4eEach of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation can be selectively formed;

[0354] k and v are each independently 0, 1 or 2;

[0355] Among them, each R M1 R M2 R M3 L 3 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0356] In some embodiments, the compounds of the present invention are compounds represented by Formula IV-4 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0357]

[0358] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation is optionally formed; k and v are each independently 0, 1, or 2; wherein, each R M1 L 2 L 3 L 5 L6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0359] In some embodiments, the compounds of the present invention are compounds of formulas IV-5 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0360]

[0361] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation is optionally formed; k and v are each independently 0, 1, or 2; wherein, each R M1 R L1a L 2 L 3 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0362] In some embodiments, the compounds of the present invention are compounds of formula IV-6 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0363]

[0364] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation can be optionally formed; k and v are each independently 0, 1, or 2;

[0365] Among them, each R M1 L 3 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0366] In some embodiments, the compounds of the present invention are compounds of Formula V-1 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0367]

[0368] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0369] In some embodiments, the compounds of the present invention are compounds of formula V-2 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0370]

[0371] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0372] In some embodiments, the compounds of the present invention are compounds of formula V-3 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0373]

[0374] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0375] In some embodiments, the compounds of the present invention are compounds of formula V-4 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0376]

[0377] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0378] In some embodiments, the compounds of the present invention are compounds of formulas V-5 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0379]

[0380] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0381] In some embodiments, the compounds of the present invention are compounds of formula V-6 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0382]

[0383] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 R 1 R 2 R 3A, n, m, and p have the definitions as described in this invention.

[0384] In some embodiments, the compounds of the present invention are compounds of formula V-7 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0385]

[0386] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 R 1 R 2 R 3 A, n, m, and p have the definitions as described in this invention.

[0387] In some embodiments, the compounds of the present invention are compounds of Formula VI-1 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0388]

[0389] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0390] In some embodiments, the compounds of the present invention are compounds of formula VI-2 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0391]

[0392] Among them, each M, L 1 L2 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0393] In some embodiments, the compounds of the present invention are compounds of formula VI-3 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0394]

[0395] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0396] In some embodiments, the compounds of the present invention are compounds of formula VI-4 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0397]

[0398] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0399] In some embodiments, the compounds of the present invention are compounds of formula VI-5 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0400]

[0401] Among them, each M, L 1 L 2 L 3 L 4 L 5 L 6 X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y 5 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0402] In some embodiments, the compounds of the present invention are compounds represented by Formula VII-1 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0403]

[0404] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and RL4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 R M2 R M3 L 2 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0405] In some embodiments, the compounds of the present invention are compounds represented by Formula VII-2 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0406]

[0407] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 R M2 R M3 R L1a L 2 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3, n, m, p have the definitions as described in this invention.

[0408] In some embodiments, the compounds of the present invention are compounds represented by formula VII-3 or their stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0409]

[0410] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation is formed; G1 and G2 are each independently CH or N; k and v are each independently 0, 1 or 2; wherein, each R M1 R M2 R M3 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0411] In some embodiments, the compounds of the present invention are compounds represented by formulas VII-4 or their stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0412]

[0413] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 L 2 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0414] In some embodiments, the compounds of the present invention are compounds represented by formulas VII-5 or their stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0415]

[0416] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 RL1a L 2 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0417] In some embodiments, the compounds of the present invention are compounds represented by formulas VII-6 or their stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0418]

[0419] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0420] In some embodiments, the compounds of the present invention are compounds of formula VIII-1 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0421]

[0422] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 R M2 R M3 L 2 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0423] In some embodiments, the compounds of the present invention are compounds represented by Formula VIII-2 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0424]

[0425] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4eEach of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 R M2 R M3 R L1a L 2 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0426] In some embodiments, the compounds of the present invention are compounds represented by formula VIII-3 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0427]

[0428] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and RL4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 R M2 R M3 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0429] In some embodiments, the compounds of the present invention are compounds represented by formulas VIII-4 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0430]

[0431] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 L 2 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0432] In some embodiments, the compounds of the present invention are compounds represented by formulas VIII-5 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0433]

[0434] Among them, R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 R L1a L 2 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0435] In some embodiments, the compounds of the present invention are compounds of formulas VIII-6 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0436]

[0437] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4aIt is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1, or 2; among them, each R M1 L 3 L 5 L 6 X 1 X 2 R 1 R 2 R 3 , n, m, p have the definitions as described in this invention.

[0438] On one hand, the present invention provides a compound, which is a compound of Formula I or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

[0439]

[0440] in,

[0441] M represents a covalent warhead;

[0442] A is aryl or heteroaryl;

[0443] L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independently, it is a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, or nitrogen-protecting group; wherein R L1a The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, and oxo.

[0444] L 2 It is a single bond, alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group, aryl or heteroaryl; wherein, L 2 The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved may each be independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, alkyl, alkenyl, ynyl, heteroalkyl, or haloheteroalkyl.

[0445] L 3 It is a single bond, aryl or heteroaryl; wherein, L 3 The aryl or heteroaryl groups involved may optionally be substituted independently by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl or haloheteroalkyl;

[0446] L 4 It is a carbon chain or heterochain with 2-6 atoms; where L 4 The carbon chain or heterochain involved may optionally be substituted independently by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, aminoalkoxy, alkylamino, and nitrogen protecting group.

[0447] L 5 For -NR L5a -, -O-, -S-, alkyl or heteroalkyl; wherein, L 5 The alkyl and heteroalkyl groups involved are optionally and independently substituted by substituents selected from deuterium, amino, hydroxyl, oxo, cyano, halogen, alkenyl, or alkynyl; each R L5a It is independently a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or nitrogen-protected group;

[0448] L 6 For -NR L6a -, -O-, -S-, alkyl or heteroalkyl; wherein, L 6 The alkyl and heteroalkyl groups involved are optionally and independently substituted by substituents selected from deuterium, amino, hydroxyl, oxo, cyano, halogen, alkenyl, or alkynyl; each R L6a It is independently a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or nitrogen-protected group;

[0449] X 1 X 2 X 3 X 4 Y 1 Y 2 Y3 Y 4 and Y 5 Each can be independently CH or N;

[0450] Each R 1 Independently, it is hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 1 Adjacent, the two adjacent R 1 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 1 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, optionally each independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, alkyl;

[0451] Each R 2 Independently, it is hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 2 Adjacent, the two adjacent R 2 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be substituted independently by one or more substituents of one or more hydroxyl, amino, cyano, halogen, oxo, or alkyl groups.

[0452] Each R 3Independently, it is hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, ynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; if two R are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group, or a heteroaryl group; wherein, R 3 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be substituted independently by one or more substituents of one or more hydroxyl, amino, cyano, halogen, oxo, or alkyl groups; and m and p are each independently 0, 1, 2, 3 or 4.

[0453] In some embodiments, M is

[0454]

[0455]

[0456] in,

[0457] L 7 For a key, -O-, -S-, -NR L7a -or C 1-4 Alkyl, wherein the C 1-4 One or more carbon units of an alkyl group are optionally and independently separated by -O-, -S-, -NR-. L7a -、-NR L7a C(=O)-、-C(=O)NR L7a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L7a C(=S)-、-C(=S)NR L7a - Trans CR L7b =CR L7b - Cis-CR L7b =CR L7b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L7a -、-NR L7a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NRL7a -or-NR L7a S(=O)2-replacement; where each R L7a Independent of hydrogen, deuterium, and C 1-4 Alkyl or nitrogen protecting groups; each R L7b Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two adjacent R groups L7b The groups and the atoms attached to them connect to form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each L 7 R L7a R L7b The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0458] L 8 For a key or C 1-4 Alkyl, wherein L 8 The alkyl group involved may optionally be substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, and oxo;

[0459] Each R M1 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M1a -CH2N(R) M1a )2、-CH2SR M1a -OR M1a -N(R) M1a )2、-Si(R M1a )3 or -SR M1a , where each R M1a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M1aThe groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M1 R M1a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0460] Each R M2 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M2a -CH2N(R) M2a )2、-CH2SR M2a -OR M2a -N(R) M2a )2 or -SR M2a , where each R M2a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M2a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M2 R M2a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0461] Each R M3 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M3a -CH2N(R) M3a )2、-CH2SR M3a -OR M3a -N(R)M3a )2 or -SR M3a , where each R M3a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group; or two R groups. M3a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M3 R M3a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0462] Optional, R M1 and R M3 , or R M2 and R M3 , or R M1 and R M2 Optionally linked to form saturated or partially unsaturated carbocyclic groups or saturated or partially unsaturated heterocyclic groups, wherein the saturated or partially unsaturated carbocyclic groups or saturated or partially unsaturated heterocyclic groups are optionally each independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0463] R M4 R is a leaving group; M5 It is a halogen; Z is O, S, or NR. Z ;where R Z For hydrogen, deuterium, C 1-4 Alkyl or nitrogen protecting group; R Z The alkyl group involved is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, and oxo; q is 0, 1, 2, 3, 4, 5, or 6; r is 1 or 2;

[0464] In some embodiments, M is

[0465]

[0466] L 7 For a key, -O-, -S-, -NR L7a -or C 1-4 Alkyl, wherein the C 1-4 One or more carbon units of an alkyl group are optionally and independently separated by -O-, -S-, -NR-.L7a -、-NR L7a C(=O)-、-C(=O)NR L7a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L7a C(=S)-、-C(=S)NR L7a - Trans CR L7b =CR L7b - Cis-CR L7b =CR L7b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L7a -、-NR L7a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR L7a -or-NR L7a S(=O)2-replacement; where each R L7a Independent of hydrogen, deuterium, and C 1-4 Alkyl or nitrogen protecting groups; R L7b For hydrogen, deuterium, halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two adjacent R groups. L7b The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each L 7 R L7a R L7b The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0467] Z represents O, S, or NR. Z ;where R Z For hydrogen, deuterium, C 1-4 Alkyl or nitrogen protecting group; R Z The alkyl group involved may optionally be substituted with one or more substituents such as hydrogen, deuterium, halogen, hydroxyl, amino, cyano, or oxo;

[0468] Each R M1 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M1a -CH2N(R) M1a )2、-CH2SR M1a -OR M1a -N(R) M1a )2、-Si(R M1a )3 or -SR M1a , where each R M1a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. M1a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M1 R M1a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0469] Each R M2 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M2a -CH2N(R) M2a )2、-CH2SR M2a -OR M2a -N(R) M2a )2 or -SR M2a , where each R M2a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. M2a The groups and the atoms attached to them are optionally linked to form 3-6 member saturated or partially unsaturated heterocyclic groups; wherein each R M2 RM2a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0470] Each R M3 Independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -CN, -CH2OR M3a -CH2N(R) M3a )2、-CH2SR M3a -OR M3a -N(R) M3a )2 or -SR M3a , where each R M3a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered saturated or partially unsaturated carbocyclic group, 3-6 membered saturated or partially unsaturated heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, or two R groups. M3a The groups can be selectively linked with any atoms to form 3-6 member saturated or partially unsaturated heterocyclic groups; where each R M3 R M3a The alkyl, alkenyl, alkynyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0471] In some embodiments, M is

[0472]

[0473] In some embodiments, A is a 6-10 aryl or a 5-10 heteroaryl. In some embodiments, A is a 6-10 aryl or a 5-10 azaaryl. In some embodiments, A is a phenyl or a 6-azaaryl. In some embodiments, A is a phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, furanyl, thiophene, pyrroleyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or the following groups:

[0474]

[0475] In some embodiments, A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, A is phenyl or pyrazinyl.

[0476] In some embodiments, L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Haloalkyl, C 1-4 Halogenated heteroalkyl or nitrogen-protected groups; wherein R L1a The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, and oxo; L 2 For a key, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups; wherein, L 2 The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally each independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; L 3 It is a single bond, a 6-10 aryl group or a 5-10 heteroaryl group; wherein, L 3 The aryl or heteroaryl groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; L 4It is a carbon chain or heterochain with 2-6 atoms; where L 4 The carbon chains or heterochains involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkoxy, C 1-4 aminoalkoxy, C 1-4 One or more substituents of an alkylamino group or a nitrogen protecting group are used for substitution.

[0477] In some embodiments, L 1 For a single key, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR L1a -、-NR L1a C(=O)-、-S(=O)2NR L1a -or-NR L1a S(=O)2-; where each R L1a Independently hydrogen, methyl, ethyl, vinyl, ethynyl, or trifluoromethyl; L 2 For a key, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups; wherein, L 2 The alkyl, heteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl, or heteroaryl groups involved are optionally and independently substituted by a substituent selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, oxo, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, or methylamino. 3 It is a single bond, a 6-10 aryl group or a 5-10 heteroaryl group; wherein, L 3 The aryl or heteroaryl groups involved are optionally and independently substituted by substituents selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, and methylamino; L 4 It is a carbon chain or heterochain with 2-4 atoms; where L 4 The carbon chain or heterochain involved may optionally be independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, methylamino, and nitrogen protecting group.

[0478] In some embodiments, L 1 For a single bond, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NH-, -NHC(=O)-, -S(=O)2NH- or -NHS(=O)2-; L 2 It is a single-bonded, 3-6 member saturated or partially unsaturated carbocyclic group or a 3-6 member saturated or partially unsaturated heterocyclic group; wherein, L 2 The saturated or partially unsaturated carbocyclic groups and saturated or partially unsaturated heterocyclic groups involved may optionally be independently substituted by one or more substituents selected from hydroxyl, amino, cyano, fluorine, chlorine, oxo, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, and methylamino; L 3 It is a single bond, a 6-10 aryl group or a 5-10 heteroaryl group; wherein, L 3 The aryl or heteroaryl groups involved are optionally substituted with one or more hydroxyl, amino, cyano, fluorine, chlorine, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, or methylamino substituents; L 4 It is a carbon chain or heterochain with 2-4 atoms; where L 4 The carbon chain or heterochain involved may optionally be independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, methylamino, and nitrogen protecting group.

[0479] In some embodiments, L 1 For a single bond, -C(=O)- or -C(=O)NH-; L 2 It is a single bond, cyclohexyl, piperidinyl, phenyl, or pyridinyl; L 3 For one bond, phenyl or pyridinyl; L 4-NHCH2-, -CH2NH-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -SCH2CH2-, -CH2SCH2-, -CH2CH2S-, -NHCH2CH2CH2-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -CH2C H2CH2NH-, -OCH2CH2CH2-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -SCH2CH2CH2-, -CH2SCH2CH2-, -CH2C H2SCH2-, -CH2CH2CH2S-, -CH2OCH2O-, -OCH2OCH2-, -OCH2CH2O-, -NHCH2CH2O-, -CH2NHCH2O- or -NHCH2OCH2-; where L 4 The hydrogen atoms in CH2 involved are optionally and independently replaced by hydrogen, deuterium, hydroxyl, amino, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino substituents; L 4 The hydrogens in NH involved are optionally and independently replaced by hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, nitrogen protecting group substituents.

[0480] In some embodiments, L 1 For a single bond, -C(=O)- or -C(=O)NH-; L 2 It is a single bond, cyclohexyl, piperidinyl, phenyl, or pyridinyl; L 3 For one bond, phenyl or pyridinyl; L 4 It can be -NHCH2-, -CH2NHCH2-, -NHC(=O)-, -CH2NHC(=O)-, -C(=O)NHCH2- or -NHCH(CH3)-.

[0481] In some embodiments, L 5 For -NR L5a -、-O-、-S-、C 1-6 Alkyl or C 1-6 Heteroalkyl; wherein, L 5 The alkyl and heteroalkyl groups involved are optionally each independently selected from deuterium, amino, hydroxyl, oxo, cyano, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C1-4 Halogenated alkyl or C 1-4 One or more substituents of the haloalkyl group are substituted; each R L5a Independent of hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or nitrogen-protected groups; L 6 For -NR L6a -、-O-、-S-、C 1-6 Alkyl or C 1-6 Heteroalkyl; wherein, L 6 The alkyl and heteroalkyl groups involved are optionally each independently selected from deuterium, amino, hydroxyl, oxo, cyano, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of the haloalkyl group are substituted; each R L6a Independent of hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or nitrogen-protected groups.

[0482] In some embodiments, L 5 For -NR L5a -CR L5b R L5c -、-O-、-S-、-CR L5b R L5c NR L5a -、-NR L5a CR L5b R L5c -、-CR L5b R L5c O-、-OCR L5b R L5c -、-CR L5b R L5c S- or -SCR L5b R L5c -; where each R L5b and R L5c Each of these can be independently represented by hydrogen, deuterium, amino, hydroxyl, oxo, cyano, halogen, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; each R L5a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or nitrogen-protected groups; L 6 For -NR L6a -CR L6b R L6c -、-O-、-S-、-CR L6b R L6c NR L6a -、-NR L6a CR L6b R L6c -、-CR L6b R L6c O-、-OCR L6b R L6c -、-CR L6b R L6c S- or -SCR L6b R L6c -; where each R L6b and R L6c Each of these can be independently represented by hydrogen, deuterium, amino, hydroxyl, oxo, cyano, halogen, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; each R L6a Independent of hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or nitrogen-protected groups.

[0483] In some embodiments, L 5 -NH-, -O-, -S-, -NHCH2-, -OCH2-, -SCH2-, -CH2NH-, -CH2O-, or -CH2S-; L 6 It can be -NH-, -O-, -S-, -NHCH2-, -OCH2-, -SCH2-, -CH2NH-, -CH2O-, or -CH2S-.

[0484] In some embodiments, L 5 -NH-; L 6 It is -NH- or -NHCH2-.

[0485] In some embodiments,

[0486] Each R 1 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl groups, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated carbocyclic groups C 1-6 Alkyl groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups C 1-6 Alkyl, 6-10 aryl, 6-10 aryl C 1-6 Alkyl, 6-10 heteroaryl or 6-10 heteroaryl C 1-6 Alkyl; if two R are present 1 Adjacent, the two adjacent R 1 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 1 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0487] Each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl groups, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated carbocyclic groups C 1-6 Alkyl groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups C 1-6 Alkyl, 6-10 aryl, 6-10 aryl C 1-6 Alkyl, 6-10 heteroaryl or 6-10 heteroaryl C 1-6 Alkyl; if two R are present2 Adjacent, the two adjacent R 2 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of the alkyl group are used for substitution;

[0488] Each R 3 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl groups, 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated carbocyclic groups C 1-6 Alkyl groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups C 1-6 Alkyl, 6-10 aryl, 6-10 aryl C 1-6 Alkyl, 6-10 heteroaryl or 6-10 heteroaryl C 1-6 Alkyl; if two R are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 3 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated carbocyclic alkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups may optionally be independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0489] In some embodiments, each R 1 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; if two R groups are present 1 Adjacent, the two adjacent R 1 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 1 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of the alkyl group are substituted; each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; if two R groups are present 2 Adjacent, the two adjacent R 2 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 2 The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of the alkyl group are substituted; each R 3 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated heteroalkyl groups; if two R groups are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 membered saturated or partially unsaturated carbocyclic groups, 3-6 membered saturated or partially unsaturated heterocyclic groups, 6-10 membered aryl groups, or 6-10 membered heteroaryl groups; wherein, R 3The alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloheteroalkyl, saturated or partially unsaturated carbocyclic, saturated or partially unsaturated heterocyclic, aryl or heteroaryl groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0490] In some embodiments, each R 1 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; wherein R 1 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, and oxo; each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; wherein R 2 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, and oxo; each R 3 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated heteroalkyl groups; if two R groups are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein R 3 The alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, 3-6 member saturated or partially unsaturated carbocyclic groups, and 3-6 member saturated or partially unsaturated heterocyclic groups involved are optionally and independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 One or more substituents of an alkyl group are used for substitution.

[0491] In some embodiments, each R 1 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; wherein R1 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, and oxo; each R 2 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; wherein R 2 The alkyl, heteroalkyl, haloalkyl, and haloheteroalkyl groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, and oxo; each R 3 Independently hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 Halogenated heteroalkyl groups; if two R groups are present 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form 3-6 member saturated or partially unsaturated carbocyclic groups or 3-6 member saturated or partially unsaturated heterocyclic groups; wherein R 3 The alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, 3-6 saturated or partially unsaturated carbocyclic groups and 3-6 saturated or partially unsaturated heterocyclic groups involved are optionally and independently substituted by one or more substituents selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, methyl, ethyl, and isopropyl.

[0492] In some embodiments, each R 1Independently, it can be hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-. CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S( =O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)-, (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHO N(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S (=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(C H2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-,(CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-, (CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P(=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)- or (CH3)2CH(CH3CH2)P(=O)-;,

[0493] Each R 2Independently, it is hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)- , CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S (=O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)- , (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHO N(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S (=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(C H2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-,(CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-, (CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P(=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)- or (CH3)2CH(CH3CH2)P(=O)-; and also,

[0494] Each R 3Independently, it can be hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, CH3C(=O)O-, CH3CH2C(=O)O-, (CH3)2CHC(=O)NH-, CH3CH2C(=O)NH-, (CH3)2CHC(=O)NH-, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-. CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3S(=O)2-, CH3CH2S(=O)2-, (CH3)2CHS(=O)2-, CH3S(=O)2O-, CH3CH2S(=O)2O-, (CH3)2CHS(=O)2O-, CH3S( =O)2NH-, CH3CH2S(=O)2NH-, (CH3)2CHS(=O)2NH-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3C(=O)N(CH3)-, CH3CH2C(=O)N(CH3)-, (CH3)2CHC(=O)N(CH3)-, CH3N(CH3)C(=O)-, CH3CH2N(CH3)C(=O)-, (CH3)2CHN(CH3)C(=O)-, CH3ON(CH3)C(=O)-, CH3CH2ON(CH3)C(=O)-, (CH3)2CHO N(CH3)C(=O)-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-, CH3N(CH3)S(=O)2-, CH3CH2N(CH3)S(=O)2-, (CH3)2CHN(CH3)S (=O)2-, CH3C(=O)N(CH2CH3)-, CH3CH2C(=O)N(CH2CH3)-, (CH3)2CHC(=O)N(CH2CH3)-, CH3N(CH2CH3)C(=O)-, CH3CH2N(CH2CH3)C(=O)-, (CH3)2CHN(C H2CH3)C(=O)-, CH3ON(CH2CH3)C(=O)-, CH3CH2ON(CH2CH3)C(=O)-, (CH3)2CHON(CH2CH3)C(=O)-, CH3S(=O)2N(CH2CH3)-, CH3CH2S(=O)2N(CH2CH3)-,(CH3)2CHS(=O)2N(CH2CH3)-, CH3N(CH2CH3)S(=O)2-, CH3CH2N(CH2CH3)S(=O)2-, (CH3)2CHN(CH2CH3)S(=O)2-, (CH3)2P(=O)-, CH3CH2(CH3)P(=O)-, (CH3)2CH(CH3)P(=O)-, (CH3CH2)2P(=O)-, CH3CH2(CH3)P(=O)- or (CH3)2CH(CH3CH2)P(=O)-; if two R, 3 Adjacent, the two adjacent R 3 The atoms to which it is attached may optionally form the following groups:

[0495]

[0496] In some embodiments, the saturated or partially unsaturated carbocyclic group is selected from formulas ii-1 to ii-6; formulas ii-1 to ii-6 are monovalent when they are connected to the remainder of the molecule by one bond; formulas ii-1 to ii-6 are divalent when they are connected to the remainder of the molecule by two bonds; the saturated or partially unsaturated carbocyclic group represented by formulas ii-1 to ii-6 is optionally, each independently, substituted by one or more substituents as defined herein.

[0497]

[0498] The saturated or partially unsaturated heterocyclic groups are selected from formulas iii-1 to iii-16; formulas iii-1 to iii-16 are monovalent when they are connected to the rest of the molecule by one bond; formulas iii-1 to iii-16 are divalent when they are connected to the rest of the molecule by two bonds; the saturated or partially unsaturated heterocyclic groups represented by formulas iii-1 to iii-16 are optionally each independently substituted by one or more substituents defined herein.

[0499]

[0500] Each t1 is independently 0, 1, 2, 3, 4 or 5; each t2 and t3 is independently 1, 2, 3, 4 or 5.

[0501] In some embodiments, the saturated or partially unsaturated carbocyclic group is selected from the following groups: when the saturated or partially unsaturated carbocyclic group is connected to the remainder of the molecule by one bond, the following groups are monovalent; when the saturated or partially unsaturated carbocyclic group is connected to the remainder of the molecule by two bonds, the following groups are divalent; the saturated or partially unsaturated carbocyclic groups represented below are optionally each independently substituted by one or more substituents as defined herein.

[0502]

[0503] The saturated or partially unsaturated heterocyclic group is selected from the following groups; when the saturated or partially unsaturated heterocyclic group is connected to the rest of the molecule by one bond, the following groups are monovalent; when the saturated or partially unsaturated heterocyclic group is connected to the rest of the molecule by two bonds, the following groups are divalent; the saturated or partially unsaturated heterocyclic groups represented below are optionally each independently substituted by one or more substituents as defined herein.

[0504]

[0505] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas II-1 to II-6, or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0506]

[0507]

[0508] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are used for substitution.

[0509] In some embodiments, the compounds of the present invention are compounds of Formula III or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0510]

[0511] Among them, R L4aIt is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation can be optionally formed; k and v are each independently 0, 1 or 2.

[0512] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas IV-1 to IV-6, or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0513]

[0514] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Oxygenation can be optionally formed; k and v are each independently 0, 1 or 2.

[0515] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas V-1 to V-7 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0516]

[0517]

[0518] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas VI-1 to VI-5 or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0519]

[0520] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas VII-1 to VII-6, or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0521]

[0522]

[0523] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1 or 2.

[0524] In some embodiments, the compounds of the present invention are compounds represented by any one of formulas VIII-1 to VIII-6, or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0525]

[0526]

[0527] Wherein, B is a 3-6 member saturated or partially unsaturated N-containing heterocyclic group, and the 3-6 member saturated or partially unsaturated N-containing heterocyclic group is optionally selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Heteroalkyl, C 1-4 Halogenated alkyl or C 1-4 One or more substituents of a haloalkyl group are substituted; R L4a It is a hydrogen, deuterium, hydroxyl, cyano, halogen, oxo, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or nitrogen-protecting group; each R L4b R L4c R L4d and R L4e Each of these can be independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, vinyl, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, or methylamino; wherein, R L4b and R L4c Optional oxidation; R L4d and R L4e Optional oxidation; G 1 G2 and G2 are each independently CH or N; k and v are each independently 0, 1 or 2.

[0528] In some embodiments, the compounds of the present invention are the following compounds or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0529]

[0530]

[0531] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds described herein and pharmaceutically acceptable excipients thereof. The amounts of the compounds in the compositions of the present invention are effective in treating or alleviating FAK and / or YAP-related diseases in patients.

[0532] In some embodiments, the present invention provides a pharmaceutical composition that further comprises an additional therapeutic agent, wherein the additional therapeutic agent includes other anticancer agents, other drugs for treating pulmonary arterial hypertension, or combinations thereof.

[0533] As described in this invention, the pharmaceutical compositions of this invention further comprise pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21 st The contents of this literature, including edition 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, demonstrate that various excipients can be used in formulations of pharmaceutically acceptable compositions and their known methods of preparation. The use of any conventional excipients, except those incompatible with the compounds of this invention, for example, any adverse biological effects or harmful interactions with any other component of a pharmaceutically acceptable composition, is also within the scope of this invention.

[0534] The pharmaceutical composition of the present invention further comprises i) one or more other FAK inhibitors and / or ii) one or more other types of protein kinase inhibitors and / or one or more other types of therapeutic agents. The one or more other types of protein kinase inhibitors include, for example, PYK2 or src inhibitors, and the other types of therapeutic agents include other anticancer agents, other drugs for treating pulmonary hypertension, etc.

[0535] As used herein, the term "therapeuticly effective amount" refers to the total amount of each active component sufficient to demonstrate a meaningful patient benefit (e.g., reduction of viral load). When available for treatment, therapeutically effective amounts of the compounds of the present invention, particularly compounds of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, VIII-1 to VIII-6, and their pharmaceutically acceptable salts, may be administered as unprocessed chemicals or provided as active ingredients in pharmaceutical compositions. Therefore, the present invention also provides pharmaceutical compositions comprising therapeutically effective amounts of the compounds of the present invention, particularly compounds of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, VIII-1 to VIII-6, or their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0536] When a single active ingredient is administered alone, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that produce a therapeutic effect regardless of whether they are administered sequentially or simultaneously. The compounds of the present invention, particularly compounds of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, VIII-1 to VIII-6, and their pharmaceutically acceptable salts, are described above. The carrier, diluent, or excipient must be acceptable in the sense of compatibility with other components of the formulation and harmlessness to the recipient. According to another aspect of the present invention, a method for preparing a pharmaceutical formulation is also provided, comprising mixing the compounds of the present invention, particularly compounds of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, VIII-1 to VIII-6, or their pharmaceutically acceptable salts, with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0537] The amount of active ingredient combined with one or more excipients to prepare a single dosage form will need to vary depending on the host being treated and the specific route of administration. For example, formulations intended for oral administration to humans typically contain, for example, 0.5 mg to 2 g of the active ingredient combined with a suitable and convenient amount of excipient (suitable 0.5 mg to 1 g of active ingredient, e.g., 0.5 mg to 0.5 g of active agent, more suitable 0.5 to 100 mg, e.g., 1 to 30 mg), said excipient may be about 5% to about 98% by weight of the total composition. The amount of active ingredient mixed with a carrier material to prepare a single dosage form of compounds of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, VIII-1 to VIII-6 will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the duration of treatment, and the patient's age, sex, weight, and condition. Preferred unit dosage forms are those containing a daily dose or fractional dose, or an appropriate fraction thereof, of the active ingredient described herein. Treatment may begin with a small dose, obviously below the optimal dose of the compound. Thereafter, the dose may be increased in small increments until optimal efficacy is achieved in this case. Generally, the most ideal concentration level of the compound administered is one that typically provides effective results in antitumor activity without causing any harmful or toxic side effects.

[0538] In the course of treatment or prevention using the compounds of the present invention, if separate doses are required, they are typically administered to achieve a daily dose of, for example, 0.1 mg / kg to 75 mg / kg body weight. Generally, a lower dose will be given when administered via the parenteral route. Therefore, for example, in the case of intravenous or intraperitoneal administration, the dose typically used is, for example, 0.1 mg / kg to 30 mg / kg body weight. Similarly, in the case of inhalation administration, the dose used will be, for example, 0.05 mg / kg to 25 mg / kg body weight. Oral administration is also suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of the present invention, and the unit dosage form can be administered once, twice, three times, or four times daily, or more frequently if necessary.

[0539] Pharmaceutical dosage forms of the compounds and compositions thereof of the present invention can be provided in the form of immediate-release, controlled-release, sustained-release, or targeted drug delivery systems. Common dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated pills, soft-shell or hard-shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized preparations. Depending on the route of administration used, special devices may be required to administer or deliver the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms often consist of the drug, excipients, and a container / sealing system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration, and safety of the drug, and to provide a method for obtaining the desired drug release profile. Therefore, the type of excipient added to the drug can be determined by various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. Pharmaceutical excipients exist in this field and include those listed in various pharmacopoeias. (See the United States Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); publications of the Center for Drug Evaluation and Research (CEDR) of the US Food and Drug Administration (www.fda.gov), such as the Inactive Ingredient Guide (1996); and the Handbook of Pharmaceutical Additives (2002, Synapse Information Resources, Inc., Endicott NY, etc.)).

[0540] The pharmaceutical composition is suitable for administration via any suitable route, such as oral (including oral or sublingual), rectal, nasal, local (including oral, sublingual, or percutaneous), vaginal, or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or subdermal injection or infusion). Such formulations can be prepared by any method known in the field of pharmaceutical science, for example, by mixing the active ingredient with a carrier or excipient. Oral or injectable administration is preferred.

[0541] Pharmaceutical formulations suitable for oral administration are provided in individual units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foaming or bubbling formulations; or oil-in-water emulsions or water-in-oil emulsions.

[0542] For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be mixed with a pharmaceutically acceptable, orally non-toxic, inert carrier (e.g., ethanol, glycerol, water, etc.). Powders are prepared by pulverizing the compound into a suitable fine size and mixing it with a similarly pulverized pharmaceutical carrier (e.g., edible sugars such as starch or mannitol). Flavoring agents, preservatives, dispersants, and colorants may also be present.

[0543] Capsules are prepared by filling the powdered mixture as described above into a formed gelatin shell. Prior to filling, gliding agents and lubricants (e.g., colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) may be added to the powdered mixture. Disintegrants or solubilizers (e.g., agar, calcium carbonate, or sodium carbonate) that improve drug bioavailability when the capsule is ingested may also be added.

[0544] In addition, when needed or necessary, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, etc. Lubricants used in these dosage forms include sodium oleate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc. For example, tablets are made by granulating or pre-compressing a powder mixture, adding lubricants and disintegrants, and compressing into tablets. Powder mixtures are prepared by mixing appropriately pulverized compounds with diluents or bases as described above, optionally with binders (e.g., carboxymethyl cellulose, alginate, gelatin, or polyvinylpyrrolidone), dissolution inhibitors (e.g., paraffin), absorption accelerators (quaternary salts), and / or absorbents (e.g., bentonite, kaolin, or dicalcium phosphate). The powdered mixture can be granulated by wetting it with a binder (e.g., syrup, starch paste, gum arabic, or solutions of cellulose or polymeric materials) and then pressing and sieving it. An alternative method of granulation is to pass the powdered mixture through a tableting machine, resulting in the further breaking down of poorly formed clumps into granules. The granules can be lubricated by adding stearic acid, stearates, talc, or mineral oil to prevent them from sticking to the tableting machine's die. The lubricated mixture is then compressed into tablets. The compounds of this invention can also be mixed with a free-flowing inert carrier, allowing for tableting without granulation or pre-compression steps. Transparent or opaque protective coating materials consisting of shellac sealing, sugar coating, or polymeric material coating and a polished wax coating are available. Dyes can be added to these coating materials to differentiate different unit doses.

[0545] Oral liquid formulations, such as solutions, syrups, and elixirs, can be prepared in dosage units, thus containing a predetermined amount of a compound in a given quantity. Syrups can be prepared by dissolving the compound in an appropriately flavored aqueous solution, while elixirs can be prepared using a non-toxic solvent. Solubilizers and emulsifiers (e.g., ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavoring additives (e.g., peppermint oil or natural sweeteners or saccharin or other artificial sweeteners) may also be added.

[0546] If appropriate, dosage units for oral administration can be microencapsulated. Formulations can also be made for delayed or sustained release, for example, by coating or embedding in particulate materials such as polymers or waxes.

[0547] The compounds of the present invention, especially those of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, and VIII-1 to VIII-6, and their pharmaceutically acceptable salts, can also be administered via liposome delivery systems, such as small monolayer liposomes, large monolayer liposomes, and multilayer liposomes. Liposomes may be composed of various phospholipids (e.g., cholesterol, octadecylamine, or phosphatidylcholine).

[0548] The compounds of the present invention, especially those of formulas I, II-1 to II-6, III, IV-1 to IV-6, V-1 to V-6, VI-1 to VI-5, VII-1 to VII-6, and VIII-1 to VIII-6, and their pharmaceutically acceptable salts, can also be delivered by using monoclonal antibodies as separate carriers (to which the compound molecule is conjugated). The compounds can also be conjugated with soluble polymers that serve as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl asparagine phenol, or polyoxyethylene polylysine substituted with palmitoyl residues. Furthermore, the compounds can be conjugated with a class of biodegradable polymers for controlled drug release, such as crosslinked copolymers or amphiphilic block copolymers of polylactic acid, poly(ε-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and hydrogels.

[0549] Pharmaceutical formulations suitable for transdermal administration can be provided as discrete patches to maintain close contact with the recipient's epidermis for an extended period. For example, the active ingredient can be delivered via iontophoresis patches, as generally described in Pharmaceutical Research 1986, 3(6), 318. Pharmaceutical formulations suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oil preparations, or transdermal patches. Pharmaceutical formulations suitable for rectal administration can be provided as suppositories or enemas. Pharmaceutical formulations suitable for vaginal administration can be provided as vaginal suppositories, vaginal plugs, creams, gels, pastes, foams, or sprays. Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions and aqueous and non-aqueous sterile suspensions. Aqueous and non-aqueous sterile injectable solutions may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the recipient's blood. Aqueous and non-aqueous sterile suspensions may include suspending agents and thickeners. Formulations may be provided in single-dose or multi-dose containers, such as sealed vials and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, just before use. Injectable solutions and suspensions prepared immediately before use may be prepared from sterile powders, granules, and tablets. Pharmaceutical formulations suitable for nasal administration (where the carrier is solid) include coarse powders with particle sizes in the range of, for example, 20-500 micrometers, administered by nasal inhalation, i.e., rapid inhalation through the nasal passage from a coarse powder container near the nose. Suitable formulations, wherein the carrier is a liquid and suitable for administration as a nasal spray or drops, include aqueous or oily solutions of the active ingredient. Pharmaceutical formulations suitable for administration by inhalation include dry powders, aerosols, suspensions, or solution compositions. Dry powder compositions delivered to the lungs by inhalation typically comprise, as a finely ground powder, a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides. Finely ground powders can be prepared, for example, by micronization and milling. Generally, size-reduced (e.g., micronized) compounds can be defined by a D50 value (e.g., as detected by laser diffraction) of about 1 to about 10 micrometers.

[0550] Dry powder inhalers can be administered to patients via a reservoir dry powder inhaler (RDPI), the inhaler having a reservoir suitable for storing multiple-dose (unmeasured doses) of medication in dry powder form. An RDPI typically includes a device for measuring each dose of medication from the reservoir to the delivery location. For example, the measuring device may include a measuring cup movable from a first location to a second location, where the cup may be loaded with medication from the reservoir, and in the second location prepared a measured dose of medication for the patient to inhale. Alternatively, the dry powder may be presented as a capsule (such as gelatin or plastic), cartridge, or blister pack for a multi-dose dry powder inhaler (MDPI). An MDPI is an inhaler in which medication is contained in a multi-dose package containing (or otherwise carrying) multiple defined doses (or portions thereof) of medication. When the dry powder is presented as a blister pack, it includes multiple blister packs for containing medication in dry powder form. The blister packs are typically arranged in a regular pattern to facilitate the release of medication from them. For example, blister packs can typically be arranged in a circular pattern on disc-shaped blister packaging, or the blister packs can be elongated, for example, in the form of strips or bands.

[0551] Aerosols can be formed by suspending or dissolving the compound of Formula I or a pharmaceutically acceptable salt of the present invention in a liquefied propellant. Suitable propellants include halogenated hydrocarbons, hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols containing the polymorphs or salts of the present invention are typically administered to patients via a metered-dose inhaler (MDI). Such devices are known to those skilled in the art. Aerosols may contain additional pharmaceutically acceptable excipients, which are typically used with MDI, such as surfactants, lubricants, cosolvents, and other excipients to improve the physical stability of the formulation, improve valve properties, improve solubility, or improve taste.

[0552] It should be understood that, in addition to the ingredients specifically mentioned above, the formulation may also include other ingredients commonly used in the art in relation to the type of formulation, such as flavoring agents, for example, such formulations suitable for oral administration may include flavoring agents.

[0553] The compounds of this invention, or compositions containing the compounds of this invention, are suitable for the prevention and treatment of FAK-related diseases, including cancer, pulmonary hypertension, autoimmune diseases, arthritis, inflammatory bowel disease, and pathological angiogenesis. The compounds of this invention and their pharmaceutical compositions are particularly useful for the preparation of medicaments for treating cancer, pulmonary hypertension, and pathological angiogenesis. The compounds of this invention or their pharmaceutical compositions can be therapeutically combined with: i) one or more other FAK inhibitors and / or, ii) one or more other types of protein kinase inhibitors and / or one or more other types of therapeutic agents, which can be administered orally in the same dosage form, or orally in separate oral dosage forms (e.g., sequentially or non-sequentially), or injected together or separately (e.g., sequentially or non-sequentially). Other types of therapeutic agents include other anticancer agents and other drugs for treating pulmonary hypertension.

[0554] The compounds or pharmaceutical compositions thereof of the present invention are expected to possess (among other properties) antitumor properties, which are believed to derive from inhibition of FAK, for example, the compounds or pharmaceutical compositions thereof may exhibit antiproliferative and / or pro-apoptotic and / or anti-invasive and / or anti-cell motility and / or anti-angiogenic activities. Such compounds appear to be useful for treating, for example, FAK-induced tumors, specifically as anticancer agents.

[0555] Therefore, the compounds of the present invention or pharmaceutical compositions thereof are expected to be used to treat diseases or medical conditions mediated solely or in part by FAK, i.e., the compounds are expected to produce FAK-inhibiting effects in warm-blooded animals requiring such treatment. Thus, the compounds of the present invention provide a method of treating malignant cells, characterized by FAK inhibition. Specifically, the compounds of the present invention or pharmaceutical compositions thereof are expected to produce antiproliferative and / or pro-apoptotic and / or anti-invasive and / or anti-cell motility and / or anti-angiogenic effects mediated solely or in part by FAK inhibition. Specifically, the compounds of the present invention are expected to be used to prevent or treat tumors sensitive to FAK inhibition, said tumors being associated with, for example, angiogenesis, proliferation, and sign...

Claims

1. A compound that is a compound of formula V-1 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: V-1 in, M is or ; A is a phenyl or a 6-membered nitrogen-containing aryl group; L 1 -C(=O)-; L 2 is pyrrolidinyl or piperidinyl; L 3 It is phenyl; L 4 It is -NHCH2-, -NHCH2CH2-, -CH2NHCH2-, -NHCH2CH2CH2- or -CH2NHCH2CH2-; where L 4 The hydrogen atoms in CH2 involved may be independently replaced by deuterium, methyl, ethyl, or isopropyl groups; L 5 For -NR L5a -; where each R L5a Independently hydrogen or C 1-4 alkyl; L 6 For -NR L6a -or-NR L6a CR L6b R L6c -; where each R L6b and R L6c Each independently is hydrogen, C 1-4 Alkyl groups; each R L6a Independently hydrogen, C 1-4 alkyl; X 1 and X 2 Each is independently represented by N; Each R 1 Independently hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy; Each R 2 Independently hydrogen, deuterium, halogen, C 1-6 Alkyl; wherein, R 2 The alkyl groups involved are optionally each independently substituted by one or more substituents selected from halogens; Each R 3 Independently, it is hydrogen, fluorine, chlorine, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)- or (CH3)2CHS(=O)2N(CH3)-; or the two adjacent R 3 The atoms to which it is attached may optionally form the following groups: , , or ; Each R M1 Independently hydrogen, deuterium, halogen, or C 1-4 alkyl; R M2 It is hydrogen, deuterium, or C 1-4 Alkyl; and R M3 It is hydrogen, deuterium, or C 1-4 Alkyl; and n is 0 or 1; m and p are each independently 1 or 2.

2. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein, M is ; R M2 Independently hydrogen, deuterium, or C 1-4 Alkyl; and R M3 It is hydrogen; or R M2 It is hydrogen and R M3 Independently hydrogen, deuterium, or C 1-4 alkyl.

3. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein, M is , ,or .

4. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein, A can be phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

5. The compound according to claim 4, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein, A is phenyl or pyrazinyl.

6. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein, L 1 -C(=O)-; L 2 Piperidinyl; L 3 It is phenyl; L 4 It is -NHCH2-, -NHCH2CH2-, -CH2NHCH2-, -NHCH2CH2CH2- or -CH2NHCH2CH2-; where L 4 The hydrogen atoms in CH2 involved may be independently replaced by deuterium, methyl, ethyl, or isopropyl groups.

7. The compound according to claim 6, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein, L 1 -C(=O)-; L 2 Piperidinyl; L 3 It is phenyl; L 4 It can be -NHCH2-, -CH2NHCH2-, or -NHCH(CH3)-.

8. The compound according to claim 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, L 1 -C(=O)-; L 2 Piperidinyl; L 3 It is phenyl; L 4 It is -NHCH2-.

9. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein... L 5 It is -NH-, and L 6 It is -NH- or -NHCH2-.

10. The compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein... Each R 1 Independently, it is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, or trifluoromethyl; Each R 2 Independently, it is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl, or trifluoromethyl; and Each R 3 Independently, it is hydrogen, fluorine, chlorine, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-; or the two adjacent R 3 The atoms to which it is attached may optionally form the following groups: , , or .

11. The compound according to claim 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein... Each R 1 Independently, it is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, or trifluoromethyl; Each R 2 Independently, it is hydrogen, fluorine, chlorine, bromine, or trifluoromethyl; and Each R 3 Independently, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-; or the two adjacent R 3 The atoms to which it is attached may optionally form the following groups: , , or .

12. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein, L 4 It can be -NHCH2-, -CH2NHCH2-, or -NHCH(CH3)-.

13. The compound according to claim 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, L 4 It is -NHCH2-.

14. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein, L 5 It is -NH-.

15. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein, L 6 It is -NH- or -NHCH2-.

16. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein, Each R 1 Independently, it is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, or trifluoromethyl.

17. The compound according to claim 16, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Each R 1 It can be hydrogen or methoxy group independently.

18. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein, Each R 2 It can be independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl, or trifluoromethyl.

19. The compound according to claim 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Each R 2 It can be independently hydrogen, chlorine, bromine, or trifluoromethyl.

20. The compound according to claim 19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Each R 2 It can be chlorine, bromine, or trifluoromethyl on its own.

21. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein, Each R 3 Independently, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3CH2ONHC(=O)-, (CH3)2CHONHC(=O)-, CH3NHS(=O)2-, CH3CH2NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3S(=O)2N(CH3)-, CH3CH2S(=O)2N(CH3)-, (CH3)2CHS(=O)2N(CH3)-; or the two adjacent R 3 The atoms to which it is attached may optionally form the following groups: 、 、 、 。 22. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein, Each R 3 Independently, it is hydrogen, fluorine, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3S(=O)2N(CH3)-; or the two adjacent R 3 The atoms to which it is attached may optionally form the following groups: 、 、 、 。 23. The compound according to claim 21, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Each R 3 Independently, it can be CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3S(=O)2N(CH3)-; or the two adjacent R 3 The atoms to which it is attached may optionally form the following groups: 、 、 、 。 24. The compound according to claim 22, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Each R 3 Independently, it is hydrogen, fluorine, CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3S(=O)2N(CH3)-; or the two adjacent R 3 The atoms to which it is attached may optionally form the following groups: 。 25. The compound according to claim 24, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Each R 3 Independently, it can be CH3NHC(=O)-, CH3CH2NHC(=O)-, (CH3)2CHNHC(=O)-, CH3ONHC(=O)-, CH3NHS(=O)2-, (CH3)2CHNHS(=O)2-, CH3S(=O)2N(CH3)-; or the two adjacent R 3 The atoms to which it is attached may optionally form the following groups: 。 26. The compound according to claim 1, wherein it is a compound represented by any one of formula VII-1 or VII-4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: VII-1 or VII-4; in, R L4a For hydrogen, methyl, ethyl, and isopropyl; each R L4b R L4c R L4d and R L4e Each is independently hydrogen, deuterium, methyl, ethyl, or isopropyl; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1 or 2.

27. The compound according to claim 1, wherein it is a compound represented by any one of formula VIII-1 or VIII-4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: VIII-1 or VIII-4; in, R L4a For hydrogen, deuterium, methyl, ethyl, isopropyl; each R L4b R L4c R L4d and R L4e Each is independently hydrogen, deuterium, methyl, ethyl, or isopropyl; G 1 and G 2 Each is independently CH or N; k and v are independently 0, 1 or 2.

28. A compound selected from the following: its stereoisomers, tautomers, or pharmaceutically acceptable salts: 。 29. A pharmaceutical composition comprising the compound of any one of claims 1-28 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

30. Use of the compound of any one of claims 1-28, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29, in the preparation of a medicament for the prevention or treatment of FAK-related diseases.

31. The use according to claim 30, wherein the FAK-related disease is selected from cancer, pulmonary hypertension, or pathological angiogenesis.

32. The use according to claim 31, wherein the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, sheath cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, cancers of the endocrine system, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, central nervous system (CNS) tumors, pituitary adenoma, or one or more combinations of the foregoing cancers.

33. The use according to claim 31, wherein the cancer is selected from melanoma of the skin or eye, endometrial cancer, cervical cancer, thyroid cancer, parathyroid cancer, adrenal cancer, renal cell carcinoma, renal pelvis cancer, primary CNS lymphoma, spinal axis cancer, brainstem glioma, or one or more combinations of the foregoing cancers.

34. Use of a compound as described in any one of claims 1-28, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 29, in the preparation of a medicament for regulating or treating YAP-related diseases.

35. The use according to claim 34, wherein the YAP-related disease is selected from cancer.

36. The use according to claim 35, wherein the cancer is selected from one or more of the following: skin cancer, bone cancer, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, colon cancer, hematologic malignancies, lung cancer, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, and uterine cancer.

37. The use according to claim 35, wherein the cancer is selected from one or more of the following: cervical cancer, endometrial cancer, glioma, chronic or acute leukemia, melanoma, Hodgkin's lymphoma, and lymphocytic lymphoma.

38. The use according to claim 35, wherein the cancer is selected from one or more of lung cancer, colon cancer, ovarian cancer, prostate cancer, and liver cancer.

39. Use of a compound as described in any one of claims 1-28, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 29, in the preparation of a medicament for regulating or treating diseases associated with FAK and YAP.

40. The use according to claim 39, wherein the disease associated with FAK and YAP is selected from cancer.

41. The use of any compound of any one of claims 1-28, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29, in the preparation of an inhibitor of the Hippo-YAP signaling pathway.

42. Use of any compound of any one of claims 1-28, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29, in the preparation of a medicament for inhibiting the activity of FAK kinase and / or YAP protein in cells or subjects.

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