Heteroaryl compound, and preparation method therefor and pharmaceutical use thereof

Abstract

The present disclosure relates to a heteroaryl compound, and a preparation method therefor and the pharmaceutical use thereof. Specifically, the present disclosure relates to a heteroaryl compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the heteroaryl compound, and the use thereof as a therapeutic agent, in particular as a BTK inhibitor or degradant, and the use thereof in the preparation of a drug for treating and / or preventing BTK-mediated or BTK-dependent diseases or conditions. Each group in the general formula (I) is as defined in the description.

Description

A heteroaryl compound, a preparation method thereof and a pharmaceutical use thereof TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine, and relates to a heteroaryl compound represented by a general formula (I), a preparation method thereof, a pharmaceutical composition containing the heteroaryl compound, and a use of the heteroaryl compound as a therapeutic agent, in particular, a use as a BTK inhibitor or degrader and a use in preparing a drug for treating and / or preventing a BTK-mediated or dependent disease or disorder. BACKGROUND

[0002] Bruton's tyrosine kinase (BTK) is a cytoplasmic non-receptor tyrosine kinase belonging to the TEC family. Its protein structure comprises an N-terminal Plekloke substrate homology (PH) domain, a TEC homology (TH) domain, SRC homology (SH) domains SH2 and SH3, and a kinase domain with enzymatic activity (Hendriks RW et al., Nat Rev Cancer. 2014, 14:219-232). Its PH domain recruits BTK to the cell membrane by interacting with phosphatidylinositol-3,4,5-triphosphate (PIP3) generated from phosphatidylinositol-3 kinase (PI3K). Transmembrane proteins (such as the B cell receptor (BCR) complex) promote phosphorylation of BTK at Y551 via SYK or SRC family kinases, leading to BTK kinase activation and subsequent autophosphorylation at Y223 within the SH3 domain (Rawlings DJ et al., Science. 1996, 271:822-825). BTK is expressed in B lymphocytes and is essential at all stages of B lymphocyte development (Burger JA et al., Nat Rev Cancer. 2018, 18:148-167). BTK mutations were initially shown in human primary immunodeficiency X-linked agammaglobulinemia (XLA). Patients with XLA are characterized by low B cell numbers and virtually no circulating antibodies (Vetrie D et al., Nature. 1993, 361:226-233; Tsukada S et al., Cell, 1993, 72:279-290). BTK can also be expressed in certain types of myeloid cells, such as macrophages, neutrophils, and mast cells. In these innate immune cells, BTK is involved in toll-like receptor (TLR), Fc receptor (FCR), and chemokine receptor-mediated signaling (Crofford et al., Expert Rev Clin Immunol, 2016, 12:763-773). BTK activation stimulates several downstream signaling pathways, such as the NF-κB and MAP (mitogen-activated protein) kinase pathways. Aberrant expression and / or activation of BTK have been found in various B-cell malignancies, which are crucial for cancer cell survival and autoimmune diseases.

[0003] BTK inhibitors have been developed to treat cancer and autoimmune diseases such as chronic lymphocytic leukemia (CLL) and chronic spontaneous urticaria (CSU) or multiple sclerosis (MS). Five covalent BTK inhibitors are currently used clinically for B-cell malignancies. However, these inhibitors target the cysteine ​​residue C481 in the BTK kinase domain, covalently binding to the side-chain thiol group. With the clinical use of covalent inhibitors, a certain proportion of patients have developed resistance. Mutations within the BTK protein, such as C481S, C481Y, C481R, and C481F, have been reported in relapsed cancers, showing a loss of the drug's covalent binding site (Liu L et al., Future Med Chem, 2018, 10:343-356). In response to mutations resulting from the use of covalent inhibitors, the non-covalent inhibitor pirtobrutinib has been approved for marketing as a second-line treatment. With the use of Pirtobrutinib, although the resulting C481 mutation is effectively suppressed in patients, new resistance mutations against Pirtobrutinib, such as L528W, are subsequently generated (Jennifer AWoyach et al., Clin Oncol. 2017 May 1; 35(13):1437-1443; Piers Blombery et al., Blood Adv (2022) 6(20):5589–5592). All marketed and investigational BTK covalent or non-covalent inhibitors bind to the ATP pocket, with Novartis' Remibrutinib and Roche's Fenebrutinib additionally binding to the H3 pocket, improving inhibitor selectivity. However, molecules with different binding modes have significant overlap in the amino acid residues that bind to BTK, for example, they all interact with sites such as M477, E475, and D539. Most of the resistance mutations that arise are related to the binding pocket. Clinically, the main mutations, such as C481S, T474I, L528W, and A428D, show reduced or absent binding activity to one or more of these mutations by existing covalent and non-covalent inhibitors (Eric Wang et al., N Engl J Med. 2022 Feb 24; 386(8):735-743). This means that new mutations generated by new inhibitors cannot be completely covered by existing inhibitors. Besides its inherent tyrosine kinase function, BTK also has a scaffold function (Skye Montoya et al., Science. 2024 Feb 2; 383(6682):eadi5798). Kinase inhibitors cannot completely inhibit its scaffold function.

[0004] PROTAC (Proteolysis-Targeting Chimera) is a drug form that utilizes the intracellular ubiquitin-proteasome system. Its basic principle is that the molecule binds to the target protein at one end and to E3 ubiquitin ligase at the other, connected by a linker. This allows the molecule to draw the target protein and E3 ubiquitin ligase closer, promoting the ubiquitination of the target protein by the E3 ubiquitin linker, thereby degrading the target protein (Lin Zhao et al., Signal Transduct Target Ther. 2022 Apr 4; 7(1):113). Therefore, after PROTAC molecules degrade the protein, they can not only remove the protein's enzymatic function but also its scaffold function. PROTAC molecules have a high tolerance for target protein binding activity; studies have shown that a molecular affinity for the target protein within 500 nM can lead to protein degradation. (Nat Rev Drug Discov. 2022 Mar; 21(3): 181-200), therefore, mutations that cause weak binding to small molecule inhibitors may also be effective for PROTAC molecules.

[0005] Relapse of cancers such as CLL or mantle cell lymphoma (MCL) after covalent BTK inhibitor therapy is an increasingly important and clinically significant issue (Wayach JA et al., J Clin Oncol, 2017, 35:1437-1443). Therefore, one objective of this disclosure is to provide a BTKPROTAC degradation molecule that is effective against a variety of BTK mutants. Summary of the Invention

[0006] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0007] in:

[0008] B is

[0009] B 1 For N or CR 1 B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 1 B 2 B 3 and B 4 At least one of them is N;

[0010] R1 R 2a R 2b and R 2c The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0011] R 3 and R 3a The same or different, and each independently selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 3 and R 3a Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0012] Or, R 1 and R 3 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0013] R 4 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0014] R 5 Selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. 5a replace;

[0015] Or, R 4 and R 5 Together with their respective attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms.5c replace;

[0016] Each R 5a and each R 5c The same or different, and each independently selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 -OC(O)R 17 -OC(O)OR 17 -NR 20 C(O)R 17 -NR 20 C(O)OR 17 -S(O) v R 17 -S(O) v NR 18 R 19 =O, =CR 22 R 23 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0017] W is N or CR 6 ;

[0018] R 6 Selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0019] R wSelected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuteralkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuteralkyl groups, cyano groups, amino groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups;

[0020] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0021] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. A replace;

[0022] Each R A The same or different, and each independently selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0023] Or, two Rs A Together with the attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R... 0 replace;

[0024] Cy1, Cy2, and Cy3 may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0025] s1, s2 and s3 may be the same or different, and each is independently 0 or 1;

[0026] Each R 9 R 10 and R 11 The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R17 -C(O)OR 17 -C(O)NR 18 R 19 =O, =CR 22 R 23 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0027] Or, two Rs 9 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0028] Or, two Rs 10 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0029] Or, two Rs 11 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0030] Or, two non-adjacent R 9 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 10 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 11 They connect to form bridging alkylene groups;

[0031] L a L b L c and L d Same or different, and each independently selected from bonds, alkenyl, alkynyl, (CR) a R b ) x O, S(O) v C(O), NR c C(O)NR c and NR c C(O);

[0032] E is

[0033] The ring G is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. G replace;

[0034] R G The same or different, and each independently selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace;

[0035] Or, two Rs G Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0036] R 13 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0037] X 1 For N or CR 15 ;

[0038] R 15 Selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteralkyl, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl;

[0039] L 1 Selected from bond, O, S, NR c C(O), C(O)NR c and NR c C(O);

[0040] R a and R b They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl;

[0041] Or, R a and R b Together with the attached atoms, they form cycloalkyl or heterocyclic groups;

[0042] Rc Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0043] R 17 R 18 and R 19 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 18 and R 19 and together with the attached nitrogen atom, form a heterocyclic group, which is optionally surrounded by one or more R atoms. 0 replace;

[0044] R 20 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0045] R 22 and R 23 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuteralkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0046] R 0 They may be the same or different, and each is independently selected from deuterium, =O, =S, =CH2, =CHF, =CF2, halogen, hydroxyl, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkoxyalkyl, aminoalkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0047] m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0048] x is 0, 1, 2, 3, 4 or 5;

[0049] v is 0, 1, or 2;

[0050] The condition is that,

[0051] When ring A is a single ring, ring G is a triple ring;

[0052] When ring G is monocyclic or bicyclic, ring A is a polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, or polycyclic heteroaryl.

[0053] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0054] in:

[0055] B is

[0056] B 1 For N or CR 1 B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 1 B 2 B 3 and B 4 At least one of them is N;

[0057] R 1 R 2a R 2b and R 2c The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0058] R 3 and R 3a The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 3 and R 3a Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0replace;

[0059] Or, R 1 and R 3 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0060] R 4 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0061] R 5 Selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. 5a replace;

[0062] Or, R 4 and R 5 Together with their respective attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 5c replace;

[0063] Each R 5a and each R 5c The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 -OC(O)R 17 -OC(O)OR 17 -NR 20 C(O)R 17 -NR 20 C(O)OR 17 -S(O) v R 17 -S(O) v NR 18 R 19 =O, =CR 22 R 23 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0064] W is N or CR 6 ;

[0065] R 6 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0066] R w Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups;

[0067] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0068] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. A replace;

[0069] Each R A The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0070] Or, two Rs A Together with the attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R... 0 replace;

[0071] Cy1, Cy2, and Cy3 may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0072] s1, s2 and s3 may be the same or different, and each is independently 0 or 1;

[0073] Each R 9 R 10 and R 11 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 =O, =CR 22 R 23 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0074] Or, two Rs 9 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0075] Or, two Rs 10 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0076] Or, two Rs 11 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0077] Or, two non-adjacent R 9 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 10 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 11 They connect to form bridging alkylene groups;

[0078] L a L b L cand L d Same or different, and each independently selected from bonds, alkenyl, alkynyl, (CR) a R b ) x O, S(O) v C(O), NR c C(O)NR c and NR c C(O);

[0079] E is

[0080] The ring G is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. G replace;

[0081] R G The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace;

[0082] Or, two Rs G Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0083] R 13 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0084] X 1 For N or CR 15 ;

[0085] R 15 Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl;

[0086] L 1 Selected from bond, O, S, NR cC(O), C(O)NR c and NR c C(O);

[0087] R a and R b They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl;

[0088] Or, R a and R b Together with the attached atoms, they form cycloalkyl or heterocyclic groups;

[0089] R c Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0090] R 17 R 18 and R 19 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 18 and R 19 and together with the attached nitrogen atom, form a heterocyclic group, which is optionally surrounded by one or more R atoms. 0 replace;

[0091] R 20 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0092] R 22 and R 23 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0093] R 0 They may be the same or different, and each is independently selected from =O, =S, =CH2, =CHF, =CF2, halogen, hydroxyl, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0094] m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0095] x is 0, 1, 2, 3, 4 or 5;

[0096] v is 0, 1, or 2;

[0097] The condition is that,

[0098] When ring A is a single ring, ring G is a triple ring;

[0099] When ring G is monocyclic or bicyclic, ring A is a polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, or polycyclic heteroaryl group.

[0100] In some embodiments disclosed herein, B 1 For CR 1 B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c ;R 1 R 2a R 2b and R 2c As defined in general formula (I); the condition is that B 2 B 3 and B 4 At least one of them is N; in some implementations, B 1 For CR 1 B 2 For N; B 3 For CR 2b B 4 For CR 2c Or, B 1 For CR 1 B 2 For CR 2a B 3 For N; B 4 For CR 2c Or, B 1 For CR 1 B 2 For CR 2a B 3 For CR 2b B 4 For N; R 1 R 2a R 2b and R 2c As defined in general formula (I); in some implementations, B 1 For CR 1 B2 For N; B 3 For CH; B 4 For CH; or, B 1 For CR 1 B 2 For CH; B 3 For N; B 4 For CH; or, B 1 For CR 1 B 2 For CH; B 3 For CH; B 4 For N; R 1 As defined in general formula (I); in some implementations, B 1 For CR 1 B 2 For CH; B 3 For N; B 4 For CH; R 1 As defined in general formula (I); in some implementations, B 1 For CR 1 ;R 1 Methyl; B 2 For CH; B 3 For N; B 4 For CH.

[0101] In some implementation schemes, R w Selected from hydrogen atoms, deuterium atoms, and C atoms 1-6 Alkyl; in some embodiments, R w It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R w It is a hydrogen atom or a deuterium atom; in some embodiments, R w For hydrogen atoms; in some implementations, R w It is a deuterium atom.

[0102] In some embodiments disclosed herein, R 7 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 7 It is a hydrogen atom.

[0103] In some embodiments of this disclosure, s1 is 1; in other embodiments, s1 is 0.

[0104] In some embodiments of this disclosure, s2 is 0.

[0105] In some embodiments of this disclosure, s3 is 0.

[0106] In some embodiments of this disclosure, s1 is 0 or 1; s2 is 0; s3 is 0; in some embodiments, s1 is 1; s2 is 0; s3 is 0; in some embodiments, s1 is 0; s2 is 0; s3 is 0.

[0107] In some embodiments disclosed herein, L a L b L c and L d The same or different, and each is independent (CR) a R b ) x ;R a R b And x is as defined in general formula (I); in some implementations, L a L b L c and L d They are the same or different, and each is independent of the other (CH2). x ;x as defined in general formula (I); in some implementations, L a L b L c and L d They may be the same or different, and each is an independent bond or CH2; in some implementations, L a For key; in some implementations, L a For CH2; in some implementations, L b For key; in some implementations, L b For CH2; in some implementations, L c For key; in some implementations, L c For CH2; in some implementations, L d For key; in some implementations, L d It is CH2.

[0108] In some embodiments of this disclosure, cyclic Cy2 and cyclic Cy3 may be the same or different, and each is independently a 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic group; in some embodiments, cyclic Cy2 and cyclic Cy3 may be the same or different, and each is independently a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group; in some embodiments, cyclic Cy2 and cyclic Cy3 may be the same or different, and each is independently a 6-membered heterocyclic group; in some embodiments, cyclic Cy2 and cyclic Cy3 may be the same or different, and each is independently selected from cyclobutyl, aziridine, cyclopentyl, pyrrolyl, cyclohexyl, piperidinyl, and piperazine; in some embodiments, cyclic Cy2 and cyclic Cy3 may be the same or different, and each is independently selected from aziridine, piperidinyl, and piperazine; in some embodiments, cyclic Cy2 and cyclic Cy3 may be the same or different, and each is independently a piperidinyl or piperazine.

[0109] In some embodiments of this disclosure, ring Cy2 and ring Cy3 may be the same or different, and each is independently selected from...

[0110] In some embodiments disclosed herein, Cy2 is selected from In some implementations, Cy2 is... In some implementations, Cy2 is... In the above implementation schemes, *terminal and L c Connected; End and L b Connected.

[0111] In some embodiments disclosed herein, Cy3 is selected from... In some implementations, Cy3 is selected from... In the aforementioned implementation plan, *end and L d Connected; End and L c Connected.

[0112] In some embodiments disclosed herein, R 13 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 13 It is a hydrogen atom.

[0113] In some embodiments disclosed herein, L 1 Selected from bonds, NH and C(O)NH; in some embodiments, L 1 As a key. In some embodiments of this disclosure, R c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R c It is a hydrogen atom.

[0114] In some embodiments of this disclosure, ring A is ring A1, which is defined below.

[0115] In some embodiments of this disclosure, ring G is ring G1, which is defined below.

[0116] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof:

[0117] in:

[0118] Cyclone A1 is selected from polycyclic alkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups, each of which is independently selected by one or more R groups. A replace;

[0119] B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 2 B 3 and B 4 At least one of them is N;

[0120] R 1 R 2a R 2b R 2c R 3a R 3 To R 5 W, R A R a R b x, Cy1, R 9 m1, L b Ring G and X 1 As defined in general formula (I).

[0121] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II-3) or general formula (II-4) or a pharmaceutically acceptable salt thereof:

[0122] in:

[0123] Ring G1 is a three-ring structure, wherein the three rings are arbitrarily connected by one or more R... G replace;

[0124] B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 2 B 3 and B 4 At least one of them is N;

[0125] R 1 R 2a R 2b R 2c R 3aR 3 To R 5 W, ring A, R 9 m1, s1, R a R b x, R G and X 1 As defined in general formula (I).

[0126] In some embodiments of this disclosure, cycloCy1 is a 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic group; in some embodiments, cycloCy1 is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocyclic group; in some embodiments, cycloCy1 is a 4- to 7-membered heterocyclic group; in some embodiments, cycloCy1 is a 6-membered heterocyclic group; in some embodiments, cycloCy1 is selected from cyclobutane, azirane, cyclopentyl, pyrrolidinyl, cyclohexyl, piperidinyl, and piperazine; in some embodiments, cycloCy1 is piperazine or piperidinyl; in some embodiments, cycloCy1 is piperidinyl.

[0127] In some embodiments disclosed herein, Cy1 is X a X b q1 and q2 are as defined in general formula (III-1); in some implementations, ring Cy1 is X a q1 and q2 are as defined in general formula (III-1); in some embodiments, ring Cy1 is selected from In some implementations, the ring Cy1 is selected from In some implementations, the ring Cy1 is selected from In some implementations, the ring Cy1 is selected from In some implementations, Cy1 is... *End and L b or (CR) a R b ) connected; End and L a 、(CR a R b ) x Or connected to ring A.

[0128] In some embodiments of this disclosure, ring G is phenyl or pyridyl, said phenyl and pyridyl groups being independently and optionally converted by one or more R groups. G Replace; R G As defined in general formula (I); in some implementations, ring G is optionally controlled by one or more R G Substituted phenyl; RG As defined in general formula (I); in some embodiments, ring G is phenyl or pyridyl; in some embodiments, ring G is phenyl; in some embodiments, ring G is... G 1 G 2 G 3 G 4 and G 5 One of them is a carbon atom and is related to L d Connected, the other four are the same or different, and each is independently N or CR. 12 ;R 12 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 Replace; L 1 X 1 R 13 R 17 -R 19 and R 0 As defined in general formula (I); in some implementations, ring G is r is 0, 1, 2, 3, or 4; R 12 As defined above; in some implementations, ring G is r and R 12 As defined above; in some implementations, ring G is selected from... In some implementation schemes, ring G is *End and L 1 or X 1 Connected. In some embodiments of this disclosure, ring A is a phenyl or a 5- or 6-membered heteroaryl group, each of which is independently optionally converted by one or more R groups. A Replace; R A As defined in general formula (I); in some embodiments, ring A is phenyl or pyridyl, said phenyl and pyridyl groups being optionally independently converted by one or more R groups. A Replace; R AAs defined in general formula (I); in some implementations, ring A is optionally bounded by one or more R A Substituted pyridinyl group; R A As defined in general formula (I); in some embodiments, ring A is phenyl or pyridinyl; in some embodiments, ring A is pyridinyl; in some embodiments, ring A is... A 1 A 2 A 3 and A 4 As defined in general formula (III-3); in some implementations, ring A is selected from... m is 0, 1, 2, or 3; R 8 A 1 A 2 A 3 and A 4 As defined in general formula (III-3); in some implementations, ring A is selected from... A 2 A 3 and A 4 As defined in general formula (III-3); in some implementations, ring A is selected from... In some implementations, ring A is *End and L a Or connected to Cy1.

[0129] In some embodiments disclosed herein, R a and R b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R a and R b It is a hydrogen atom.

[0130] In some embodiments disclosed herein, R 15 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 15 It is a hydrogen atom.

[0131] In some embodiments disclosed herein, X 1 For N or CH; in some implementations, X 1 For N; in some implementations, X 1 For CH.

[0132] In some embodiments of this disclosure, the compound represented by general formula (I), (II-1) or (II-2) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof.

[0133] in:

[0134] Cyclone A1 is selected from polycyclic alkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups, each of which is independently selected by one or more R groups. A replace;

[0135] B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 2 B 3 and B 4 At least one of them is N;

[0136] R 12 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace;

[0137] r can be 0, 1, 2, 3, or 4;

[0138] m1 can be 0, 1, 2, 3 or 4;

[0139] X a and X b Whether they are the same or different, and each is independently N or CR x ;

[0140] R x Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cyano and hydroxyl;

[0141] q1 and q2 may be the same or different, and each is independently 0, 1, 2, 3 or 4;

[0142] R 1 R 2a R 2b R 2c R 3a R 3 To R 5 W, R A x, R 9 R 17 -R 19 and R 0 As defined in general formula (I).

[0143] In some embodiments of this disclosure, the compound represented by general formula (I), (II-3) or (II-4), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III-3) or (III-4), or a pharmaceutically acceptable salt thereof.

[0144] in:

[0145] Ring G1 is a three-ring structure, wherein the three rings are arbitrarily connected by one or more R... G replace;

[0146] B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 2 B 3 and B 4 At least one of them is N;

[0147] A 1 A 2 A 3 and A 4 Whether they are the same or different, and each is independently N or CR 8 ;R 8 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0148] m1 can be 0, 1, 2, 3 or 4;

[0149] X a and X b Whether they are the same or different, and each is independently N or CR x ;

[0150] R x Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cyano and hydroxyl;

[0151] q1 and q2 may be the same or different, and each is independently 0, 1, 2, 3 or 4;

[0152] R 1 R 2a R 2b R 2c R 3a R 3 To R 5 W, R 9 x, R G R 17 -R 19 and R 0 As defined in general formula (I).

[0153] In some embodiments of this disclosure, ring A1 is optionally controlled by one or more R A Substituted 8-15 membered polycyclic heteroaryl groups; R A As defined in general formula (I); in some embodiments, ring A1 is a 9- to 10-membered bicyclic heteroaryl or an 11- to 15-membered tricyclic heteroaryl; the 9- to 10-membered bicyclic heteroaryl and the 11- to 15-membered tricyclic heteroaryl are each independently and optionally converted by one or more R A Replace; R A Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and =O; or, two Rs A Together with the attached atoms, they form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; in some embodiments, ring A1 is a 5-membered heteroaryl-fused 6-membered heterocyclic group or a 14- or 15-membered tricyclic-fused heteroaryl group; the 5-membered heteroaryl-fused 6-membered heterocyclic group and the 14- or 15-membered tricyclic-fused heteroaryl group are each independently and optionally converted by one or more R A Replace; R A C 1-6Alkyl; or, two Rs A Together with the attached carbon atom, they form a cyclopropyl group.

[0154] In some implementations, ring A1 is selected from In some implementations, ring A1 is

[0155] Among them, Z 1 For N or CR 8k Z 2 For N or CR 8m Z 3 For N or CR 8n ;D 1 For N or CR 8p ;D 2 For N or CR 8q ;D 3 For N or CR 8r M is selected from bonds, O, S, and C. 8s R 8t and NR 8w ;R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h R 8i R 8j R 8k R 8m R 8n R 8p R 8q R 8r R 8s R 8t and R 8x The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replace; or, R8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8g and R 8h Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8i and R 8j Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8s and R 8t Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, two R... 8x Together with the attached atoms, they form cycloalkyl or heterocyclic groups; R 8w Selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace;

[0156] X, X c and X d Whether the same or different, and each independently constitutes a CR x Or N; R x Selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, alkoxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, cyano groups, and hydroxyl groups; q3 and q4 may be the same or different, and each is independently 0, 1, 2, 3, or 4; n1 and n2 may be the same or different, and each is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, 5, or 6; R 17 -R 19 and R 0 As defined in general formula (I).

[0157] In some embodiments of this disclosure, ring A1 is selected from *End and (CR) a R b ) x Or (CH2) x Connected; Z 1For N or CR 8k Z 2 For N or CR 8m Z 3 For N or CR 8n ;D 1 For N or CR 8p ;D 2 For N or CR 8q ;D 3 For N or CR 8r M is selected from bonds, O, S, and C. 8s R 8t and NR 8w ;R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h R 8i R 8j R 8k R 8m R 8n R 8p R 8q R 8r R 8s R 8t and R 8x The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replace; or, R 8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8g and R 8hTogether with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8i and R 8j Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8s and R 8t Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, two R... 8x Together with the attached atoms, they form cycloalkyl or heterocyclic groups; R 8w Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace;

[0158] X, X c and X d Whether the same or different, and each independently constitutes a CR x Or N; R x Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, cyano groups, and hydroxyl groups; q3 and q4 may be the same or different, and each is independently 0, 1, 2, 3, or 4; n1 and n2 may be the same or different, and each is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, 5, or 6; R 17 -R 19 and R 0 As defined in general formula (I);

[0159] In some implementations, ring A1 is selected from *End and (CR) a R b ) x Or (CH2) x Connected; in some implementations, ring A1 is selected from *End and (CR) a R b ) x Or (CH2) x Connected; in some implementations, ring A1 is selected from *End and (CR) a Rb ) x Or (CH2) x Connected; in some implementations, ring A1 is selected from *End and (CR) a R b ) x Or (CH2) x Connected; in some implementations, ring A1 is selected from *End and (CR) a R b ) x Or (CH2) x Connected; in some implementations, ring A1 is selected from *End and (CR) a R b ) x Or (CH2) x Connected.

[0160] In some embodiments of this disclosure, ring G1 is optionally controlled by one or more R... G Replaced 11 to 15-membered tricyclic heteroaryl groups; R G As defined in general formula (I); in some implementations, ring G1 is optionally bounded by one or more R G Substituted 14 or 15-membered tricyclic heteroaryl groups; R G As defined in general formula (I); in some implementations, ring G1 is optionally bounded by one or more R G Substituted 14 or 15-membered tricyclic fused heteroaryl groups; R G As defined in general formula (I); in some embodiments, ring G1 is a 14- or 15-membered tricyclic fused heteroaryl group. In some embodiments of this disclosure, ring G1 is... *Terminal and X 1 Or N connected; G 6 For N or CR 12e G 7 For N or CR 12f G 8 For N or CR 12g Q is selected from bonds, O, S, and C. 12h R 12i and NR 12j ;R 12a R 12b R 12c R 12d R 12e R 12f R 12g R 12h R12i and R 12x The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replace; or, R 12a and R 12b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 12c and R 12d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 12h and R 12i Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, two R... 12x Together with the attached atoms, they form cycloalkyl or heterocyclic groups; R 12j Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 Replace; X e and X f Whether the same or different, and each independently constitutes a CR x Or N; R x Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, cyano groups, and hydroxyl groups; q5 and q6 may be the same or different, and each is independently 0, 1, 2, 3, or 4; n3 and n4 may be the same or different, and each is independently 0, 1, 2, 3, or 4; a is 0, 1, 2, 3, 4, 5, or 6; R 17 -R 19 and R 0 As defined in general formula (I);

[0161] In some implementations, ring G1 is selected from *Terminal and X 1 Or N connected.

[0162] In some embodiments disclosed herein, R 12a R 12b R 12c and R 12d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 12a R 12b R 12c and R 12d It is a hydrogen atom.

[0163] In some embodiments disclosed herein, R 12e R 12f and R 12g They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 12e For hydrogen atoms; in some implementations, R 12f For hydrogen atoms; in some implementations, R 12g For hydrogen atoms; in some implementations, R 12e R 12f and R 12g It is a hydrogen atom.

[0164] In some embodiments disclosed herein, R 12h and R 12i It is a hydrogen atom.

[0165] In some embodiments disclosed herein, R 12j It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0166] In some embodiments disclosed herein, R 12x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 12x It is a hydrogen atom.

[0167] In some embodiments of this disclosure, a is 0 or 1; in other embodiments, a is 0.

[0168] In some embodiments of this disclosure, Q is O or CH2; in other embodiments, Q is O.

[0169] In some embodiments disclosed herein, G 6 G 7 and G 8They may be the same or different, and each is independently CH or N; in some implementations, G 6 G 7 and G 8 For CH.

[0170] In some embodiments of this disclosure, q5 and q6 may be the same or different, and each is independently 0, 1 or 2; in some embodiments, q5 and q6 may be the same or different, and each is independently 0 or 1; in some embodiments, q5 is 1; q6 is 1.

[0171] In some embodiments of this disclosure, n3 and n4 may be the same or different, and each is independently 0 or 1; in some embodiments, n3 is 1 and n4 is 0 or 1; in some embodiments, n3 is 1 and n4 is 0.

[0172] In some embodiments disclosed herein, X e and X f Each is independently N or CH; in some implementations, X e For CH; in some implementations, X f Let N be the number of elements in the array.

[0173] In some implementation schemes, R 3a Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Deuterated alkyl; in some embodiments, R 3a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 3a It is a hydrogen atom or a deuterium atom; in some embodiments, R 3a For hydrogen atoms; in some implementations, R 3a It is a deuterium atom.

[0174] In some embodiments disclosed herein, R 3a and R 3 Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 3a and R 3 Together with the attached carbon atom, they form a cyclopropyl group.

[0175] In some embodiments disclosed herein, R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 4 It is a hydrogen atom.

[0176] In some embodiments disclosed herein, R 4 and R 5Together with their respective attached atoms, they form a 5- to 15-membered heterocyclic group or a 5- to 15-membered heteroaryl group, wherein each of the 5- to 15-membered heterocyclic group and the 5- to 15-membered heteroaryl group is independently and optionally converted by one or more R 5c Replace; in some implementations, R 4 and R 5 Together with the connected atoms, they form an optional structure formed by one or more R atoms. 5c The substituted 5- or 6-membered heterocyclic group; in some embodiments, R 4 and R 5 Together with the connected atoms, they form an optional structure formed by one or more R atoms. 5c The substituted 6-membered heterocyclic group; in the above schemes, R 5c As defined in general formula (I).

[0177] In some embodiments disclosed herein, R 4 and R 5 Together with the connected atoms, they form In some implementation schemes, R 4 and R 5 Together with the connected atoms, they form In the above implementation schemes, It can be a single or double bond; Y can be N or CR. 5e ;R 5m R 5n R 5x R 5j R 5d and R 5e They may be the same or different, and each is independently a hydrogen atom or R. 5c Or, two Rs 5m Together with their respective attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R groups. 5c Replace; or, two Rs 5n Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R groups. 5c Replace; R 5f Selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclic alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; k1 is 0, 1, 2, or 3; k2 is 0, 1, 2, or 3; k3 is 0, 1, 2, or 3; t is 0, 1, 2, or 3; f1 is 0, 1, 2, or 3; f2 is 0, 1, 2, or 3; R 5c As defined in general formula (I);

[0178] In some implementation schemes, R 4 and R 5 Together with the connected atoms, they form In some implementation schemes, R 4 and R 5 Together with the connected atoms, they form

[0179] In some embodiments disclosed herein, Y represents CR 5e ;R 5e Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, Y is CH or CF; in some embodiments, Y is CH.

[0180] In some embodiments disclosed herein, R 5c They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 5c The same or different, and each independently is C. 1-6 Alkyl or 3- to 6-membered cycloalkyl C 1-6 alkyl.

[0181] In some embodiments disclosed herein, R 5n Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1- 6-alkyl; in some embodiments, R 5n It is a 3- to 6-membered cycloalkyl group; in some embodiments, R 5n It is cyclopropyl.

[0182] In some embodiments disclosed herein, R 5m Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1- 6-alkyl; or, two R atoms on the same carbon atom 5m Together they form 3- to 6-membered cycloalkyl groups; in some embodiments, R 5m It is a hydrogen atom or a carbon atom.1-6 Alkyl group; or, two R atoms on the same carbon atom. 5m Together they form a cyclopropyl group; in some embodiments, R 5m It can be a hydrogen atom or a methyl group; or, two R atoms on the same carbon atom. 5m Together they form a cyclopropyl group.

[0183] In some embodiments disclosed herein, R 5j and R 5d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 5j and R 5d Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Hydroxyalkyl; in some embodiments, R 5j and R 5d They may be the same or different, and each is independently selected from hydrogen atoms, methyl groups, and hydroxymethyl groups; in some embodiments, R 5j For hydrogen atoms; in some implementations, R 5d It is a hydrogen atom.

[0184] In some embodiments disclosed herein, R 5e Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 5e Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 5e It is a hydrogen atom or a halogen; in some implementations, R 5e For hydrogen atoms or F; in some implementations, R 5e It is a hydrogen atom.

[0185] In some embodiments disclosed herein, R 5f Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 5f C 1-6Alkyl or 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 5f C 1-6 Alkyl; in some embodiments, R 5f Selected from In some implementation schemes, R 5f for

[0186] In some embodiments of this disclosure, t is 1 or 2; in other embodiments, t is 1.

[0187] In some embodiments of this disclosure, f1 and f2 are each independently 0, 1, or 2; in some embodiments, f1 and f2 are each independently 0 or 1; in some embodiments, f1 is 1 and f2 is 1.

[0188] In some embodiments of this disclosure, k1 is 0, 1, or 2; in some embodiments, k1 is 0 or 1; and in some embodiments, k1 is 1.

[0189] In some embodiments of this disclosure, k2 is 0, 1, or 2; in some embodiments, k2 is 2.

[0190] In some embodiments of this disclosure, k3 is 0 or 1; in other embodiments, k3 is 0.

[0191] In some implementation schemes disclosed herein, It is a single key; in some implementations, It is a double bond.

[0192] In some embodiments of this disclosure, W is CH or N; in some embodiments, W is CH; in some embodiments, W is CR 6 ;R 6 Selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0193] In some embodiments disclosed herein, R 6 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6 It is a hydrogen atom.

[0194] In some embodiments disclosed herein, A 1 A 2 and A 3 Whether the two are the same or different, and each is an independent CR 8 A 4 For N; or, A 1 A 2 and A 4Whether the two are the same or different, and each is an independent CR 8 A 3 For N; R 8 As defined in general formula (III-1); in some implementations, A 1 A 2 A 3 and A 4 They may be the same or different, and each is independently N or CH; in some implementations, A 1 A 2 and A 3 For CH; A 4 For N; or; A 1 A 2 and A 4 For CH; A 3 For N; or, A 1 A 2 A 3 and A 4 For CH; in some implementations, A 1 A 2 and A 3 For CH; A 4 Let N be the number of elements in the array.

[0195] In some embodiments disclosed herein, each R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; in some embodiments, R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 8 It is a hydrogen atom.

[0196] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II-1), (II-2), (III-1), or (III-2), or pharmaceutically acceptable salts thereof, are compounds represented by general formula (IV-3) or pharmaceutically acceptable salts thereof.

[0197] in:

[0198] B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 2 B 3and B 4 At least one of them is N;

[0199] R 12 The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace;

[0200] r can be 0, 1, 2, 3, or 4;

[0201] Z 1 For N or CR 8k Z 2 For N or CR 8m ;D 1 For N or CR 8p ;D 2 For N or CR 8q ;D 3 For N or CR 8r M is selected from bonds, O, S, and C. 8s R 8t and NR 8w ;R 8a R 8b R 8c R 8d R 8e R 8f R 8k R 8m R 8p R 8q R 8r R 8s and R 8t The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR17 -C(O)NR 18 R 19 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replace; or, R 8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8s and R 8t Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R 8w Selected from hydrogen atoms, deuterium atoms, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxyalkyl, deuteroxy, aminoalkyl, -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace;

[0202] X, X a X b X c and X d Whether they are the same or different, and each is independently N or CR x ;

[0203] R x Selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuteralkyl, cycloalkyl, cycloalkylalkyl, cyano, and hydroxyl;

[0204] q1 and q2 may be the same or different, and each is independently 0, 1, 2, 3 or 4;

[0205] n1 and n2 may be the same or different, and each can be 0, 1, 2, 3 or 4 independently;

[0206] m1 can be 0, 1, 2, 3 or 4;

[0207] R 1 R 2a R 2b R2c R 3 R 5 x, R 9 R 17 -R 19 and R 0 As defined in general formula (I).

[0208] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II-1), (II-2), (III-1), or (III-2), or pharmaceutically acceptable salts thereof, are compounds represented by general formulas (IV-1), (IV-2), (IV-3), or (IV-4), or pharmaceutically acceptable salts thereof.

[0209] in:

[0210] B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 2 B 3 and B 4 At least one of them is N;

[0211] R 12 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace;

[0212] r can be 0, 1, 2, 3, or 4;

[0213] Z 1 For N or CR 8k Z 2 For N or CR 8m ;D 1 For N or CR 8p ;D 2 For N or CR 8q ;D 3For N or CR 8r M is selected from bonds, O, S, and C. 8s R 8t and NR 8w ;R 8a R 8b R 8c R 8d R 8e R 8f R 8k R 8m R 8p R 8q R 8r R 8s and R 8t The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replace; or, R 8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8s and R 8t Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R 8w Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace;

[0214] X, X a Xb X c and X d Whether they are the same or different, and each is independently N or CR x ;

[0215] R x Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cyano and hydroxyl;

[0216] q1 and q2 may be the same or different, and each is independently 0, 1, 2, 3 or 4;

[0217] n1 and n2 may be the same or different, and each can be 0, 1, 2, 3 or 4 independently;

[0218] m1 can be 0, 1, 2, 3 or 4;

[0219] R 1 R 2a R 2b R 2c R 3 R 5 x, R 9 R 17 -R 19 and R 0 As defined in general formula (I).

[0220] In some implementation schemes, R 1 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Deuterated alkyl; in some embodiments, R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 1 It is a hydrogen atom or a carbon atom. 1- 6-alkyl; in some embodiments, R 1 C 1-6 Alkyl or C 1-6 Deuterated alkyl; in some embodiments, R 1 C 1-6 Alkyl; in some embodiments, R 1 C 1-6 Deuterated alkyl; in some embodiments, R 1 It is methyl or deuterated methyl; in some embodiments, R 1 For methyl; in some embodiments, R1 It is a deuterated methyl group.

[0221] In some implementation schemes, R 2a R 2b and R 2c They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl and C 1-6 Haloalkoxy; in some embodiments, R 2a R 2b and R 2c They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; in some embodiments, R 2a R 2b and R 2c They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 2a R 2b and R 2c For hydrogen atoms; in some implementations, R 2a It is a hydrogen atom or a deuterium atom; in some embodiments, R 2a For hydrogen atoms; in some implementations, R 2a For deuterium atoms; in some implementations, R 2b It is a hydrogen atom or a deuterium atom; in some embodiments, R 2b For hydrogen atoms; in some implementations, R 2b For deuterium atoms; in some implementations, R 2c It is a hydrogen atom or a deuterium atom; in some embodiments, R 2c For hydrogen atoms; in some implementations, R 2c It is a deuterium atom.

[0222] In some embodiments disclosed herein, B 2 For N; B 3 For CR 2b B 4 For CR 2c Or, B 2 For CR 2a B 3 For N; B 4 For CR 2c Or, B 2 For CR2a B 3 For CR 2b B 4 For N; R 2a R 2b and R 2c As defined in general formula (I); in some implementations, B 2 For N; B 3 For CH; B 4 For CH; or, B 2 For CH; B 3 For N; B 4 For CH; or, B 2 For CH; B 3 For CH; B 4 For N; in some implementations, B 2 For CH; B 3 For N; B 4 For CH.

[0223] In some implementation schemes, R 3 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Deuterated alkyl; in some embodiments, R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 3 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 Selected from hydrogen atoms, methyl groups, and deuterated methyl groups; in some embodiments, R 3 It is a hydrogen atom or a methyl group; in some embodiments, R 3 For hydrogen atoms; in some implementations, R 3 For methyl; in some embodiments, R 3 It is a deuterated methyl group.

[0224] In some embodiments disclosed herein, R 5 It is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is optionally surrounded by one or more R groups. 5a Replace; R 5a As defined in general formula (I); in some implementations, R 5It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally coupled with one or more R groups. 5a Replace; R 5a As defined in general formula (I); in some implementations, R 5 Selected from R 5b For hydrogen atoms or R 5a ;R 5a As defined in general formula (I); in some implementations, R 5 for R 5b For hydrogen atoms or R 5a ;R 5a As defined in general formula (I); in some implementations, R 5 for In some implementation schemes, R 5 for In some implementation schemes, R 5 for

[0225] In some embodiments disclosed herein, each R 5a They may be the same or different, and each is independently selected from halogens, C 1- 6-alkyl, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally oxidized by one or more C14 groups. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The hydroxyalkyl group is substituted; in some embodiments, R 5a C 1-6 Alkyl or optionally with one or more C 1-6 Alkyl-substituted 3- to 6-membered cycloalkyl groups; in some embodiments, R 5a C 1-6 Alkyl or C 1-6 Deuterated alkyl; in some embodiments, R 5a C 1-6 Alkyl; in some embodiments, R 5a C 1-6 Deuterated alkyl; in some embodiments, R 5a tert-butyl or In some implementation schemes, R 5a For tert-butyl; in some implementations, R 5a for

[0226] In some embodiments disclosed herein, R 5bSelected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2- 6-olefin, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally oxidized by one or more C14 groups. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The hydroxyalkyl group is substituted; in some embodiments, R 5b Selected from C 1-6 Alkyl or optionally with one or more C 1-6 Alkyl-substituted 3- to 6-membered cycloalkyl groups; in some embodiments, R 5b C 1-6 Alkyl or C 1-6 Deuterated alkyl; in some embodiments, R 5b C 1-6 Alkyl; in some embodiments, R 5b C 1-6 Deuterated alkyl; in some embodiments, R 5b tert-butyl or In some implementation schemes, R 5b For tert-butyl; in some implementations, R 5b for

[0227] In some embodiments disclosed herein, R x Selected from hydrogen atoms, halogens, C 1-6 Alkyl and hydroxyl; in some embodiments, R x It is a hydrogen atom.

[0228] In some embodiments disclosed herein, X, X a X b X c and X d They may be the same or different, and each is independently N or CH; in some implementations, X is N; in some implementations, X is... a For CH; in some implementations, X b For N; in some implementations, X c For N; in some implementations, X d Let N be the number of elements in the array.

[0229] In some embodiments of this disclosure, q1 and q2 may be the same or different, and each is independently 0, 1 or 2; in some embodiments, q1 and q2 may be the same or different, and each is independently 0 or 1; in some embodiments, q1 is 1; q2 is 1; in some embodiments, q0 is 0; q2 is 0.

[0230] In some embodiments of this disclosure, q3 and q4 may be the same or different, and each is independently 0, 1 or 2; in some embodiments, q3 and q4 may be the same or different, and each is independently 0 or 1; in some embodiments, q3 is 1; q4 is 1.

[0231] In some embodiments disclosed herein, each R 12 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 12 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, each R 12 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 12 For hydrogen atoms or F; in some implementations, R 12 It is a hydrogen atom.

[0232] In some embodiments of this disclosure, r is 0, 1, or 2; in some embodiments, r is 0 or 1; in some embodiments, r is 0; and in some embodiments, r is 1.

[0233] In some embodiments disclosed herein, X a For N or CH; and / or X b For N or CH; and / or q1 and q2 are the same or different, and each is independently 0 or 1; and / or R 12 r is a hydrogen atom or a halogen; and / or r is 0 or 1.

[0234] In some embodiments of this disclosure, x is 0 or 1; in some embodiments, x is 0; and in some embodiments, x is 1.

[0235] In some implementation schemes, R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Deuterated alkoxy group; or, R 8a and R8b Together with the adjacent carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R 8c and R 8d Together with the adjacent carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; or, R 8a and R 8b Together with the adjacent carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R 8c and R 8d Together with the adjacent carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together with the attached carbon atom, they form a cyclopropyl group; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R 8a R 8b R 8c and R 8f For hydrogen atoms; R 8d and R 8e They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R8a R 8b R 8c R 8d R 8e and R 8f Each is independently a hydrogen atom or a carbon atom. 1-6 Deuterated alkyl; or, or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R 8a R 8b R 8c R 8d R 8e and R 8f Each is independently a hydrogen atom or a carbon atom. 1-6 Deuterated alkyl; in some embodiments, R 8a R 8b R 8c R 8d R 8e and R 8f For hydrogen atoms; in some implementations, R 8e C 1-6 Alkyl or C 1-6 Deuterated alkyl, R 8a R 8b R 8c R 8d and R 8f For hydrogen atoms; in some implementations, R 8e C 1-6 Alkyl, R 8a R 8b R 8c R 8d and R 8f For hydrogen atoms; in some implementations, R 8e C 1-6 Deuterated alkyl, R 8a R 8b R 8c R 8d and R 8f For hydrogen atoms; in some implementations, R 8e It is methyl or deuterated methyl, R 8a R 8b R 8c R 8d and R 8f For hydrogen atoms; in some implementations, R 8e For methyl, R 8a R 8b R8c R 8d and R 8f For hydrogen atoms; in some implementations, R 8e It is a deuterated methyl group, R 8a R 8b R 8c R 8d and R 8f It is a hydrogen atom.

[0236] In some embodiments disclosed herein, R 8g R 8h R 8i and R 8j They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 8g For hydrogen atoms; in some implementations, R 8h For hydrogen atoms; in some implementations, R 8i For hydrogen atoms; in some implementations, R 8j For hydrogen atoms; in some implementations, R 8g R 8h R 8i and R 8j It is a hydrogen atom.

[0237] In some implementation schemes, R 8k R 8m R 8n R 8p R 8q and R 8r They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 8k R 8m R 8n R 8p R 8q and R 8r They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 8k For hydrogen atoms; in some implementations, R 8m It is a hydrogen atom or a deuterium atom; in some embodiments, R 8m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 8m For hydrogen atoms; in some implementations, R 8m For deuterium atoms; in some implementations, R 8n It is a hydrogen atom or a deuterium atom; in some embodiments, R8n For hydrogen atoms; in some implementations, R 8n For deuterium atoms; in some implementations, R 8p For hydrogen atoms; in some implementations, R 8q For hydrogen atoms; in some implementations, R 8r It is a hydrogen atom.

[0238] In some embodiments disclosed herein, R 8s and R 8t It is a hydrogen atom.

[0239] In some embodiments disclosed herein, R 8w It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0240] In some embodiments disclosed herein, R 8x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 8x It is a hydrogen atom.

[0241] In some embodiments of this disclosure, n is 0 or 1; in other embodiments, n is 0.

[0242] In some embodiments disclosed herein, Z 1 For N or CH; in some implementations, Z 1 Let N be the number of elements in the array.

[0243] In some embodiments disclosed herein, Z 2 For N or CH; in some implementations, Z 2 For CR 8m ;R 8m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, Z 2 For CH.

[0244] In some embodiments disclosed herein, Z 3 For N or CH; in some implementations, Z 3 For CH.

[0245] In some embodiments of this disclosure, M is CH2 or O; in other embodiments, M is O.

[0246] In some embodiments of this disclosure, n1 and n2 may be the same or different, and each is independently 0 or 1; in some embodiments, n1 is 0 or 1; n2 is 1; in some embodiments, n1 is 0; n2 is 1.

[0247] In some embodiments disclosed herein, D 1 D2 and D 3 They may be the same or different, and each is independently CH or N; in some implementations, D 1 For CH; D 2 For CH; D 3 For N; or, for D 1 For CH; D 2 For CH; D 3 For CH; in some implementations, D 1 For CH; D 2 For CH; D 3 Let N be the number of elements in the array.

[0248] In some embodiments of this disclosure, X is N; and / or Z. 1 For N; and / or Z 2 For CH; and / or R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together with the attached carbon atom, they form a cyclopropyl group; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group;

[0249] And / or M is 0; and / or n1 and n2 are the same or different, and each is independently 0 or 1; and / or X c For N or CH; and / or X d For N or CH; and / or D 1 For CH; D 2 For CH; D 3 Let N be the number of elements in the array.

[0250] In some embodiments disclosed herein, each R A and R G They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; or, two R groups A Together with the adjacent carbon atom, they form a 3- to 6-membered cycloalkyl group; or, two R... G Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, each R A and RG The same or different, and each independently is C. 1-6 Alkyl group; or, two R atoms on the same carbon atom. A Together with the adjacent carbon atom, they form a cyclopropyl group; or, two R atoms on the same carbon atom... G Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R A Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and =O; or, two Rs A Together with the attached atoms, they form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, R A C 1-6 Alkyl or C 1-6 Deuterated alkyl; or, two Rs A Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R A C 1-6 Alkyl; or, two Rs A Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R A C 1-6 Alkyl or C 1-6 Deuterated alkyl; in some embodiments, R A C 1-6 Deuterated alkyl; in some embodiments, R A It is methyl or deuterated methyl; in some embodiments, R A For methyl; in some embodiments, R A It is a deuterated methyl group.

[0251] In some embodiments disclosed herein, each R 9 R 10 and R 11 They may be the same or different, and each is independently selected from hydrogen atoms, =O, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 9 R 10 and R 11 They may be the same or different, and each is independently selected from hydrogen atoms, =O, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; in some embodiments, each R 9 R 10 and R 11 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6Halogenated alkyl; in some embodiments, R 9 For hydrogen atoms; in some implementations, R 10 For hydrogen atoms; in some implementations, R 11 It is a hydrogen atom.

[0252] In some embodiments disclosed herein, two R 9 Together with the adjacent atoms, they form a 3- to 6-membered cycloalkyl group; in some embodiments, two R atoms on the same carbon atom 9 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, the two R groups... 10 Together with the adjacent atoms, they form a 3- to 6-membered cycloalkyl group; in some embodiments, two R atoms on the same carbon atom 10 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, the two R groups... 11 Together with the adjacent atoms, they form a 3- to 6-membered cycloalkyl group; in some embodiments, two R atoms on the same carbon atom 11 Together with the attached carbon atom, they form a cyclopropyl group.

[0253] In some embodiments of this disclosure, two non-adjacent R 9 Connection forms a bridge C 1-3 Alkylene; in some embodiments, two non-adjacent R 9 The connection forms a bridging ethylidene (-CH2CH2-); in some embodiments, two non-adjacent R... 10 Connection forms a bridge C 1-3 Alkylene; in some embodiments, two non-adjacent R 10 The connection forms a bridging ethylidene (-CH2CH2-); in some embodiments, two non-adjacent R... 11 Connection forms a bridge C 1-3 Alkylene; in some embodiments, two non-adjacent R 11 The connection forms a bridging ethylidene (-CH2CH2-).

[0254] In some embodiments of this disclosure, m1, m2, and m3 are each independently 0, 1, or 2; in some embodiments, m1, m2, and m3 are each independently 0 or 1; in some embodiments, m1 is 1; in some embodiments, m1 is 0; in some embodiments, m2 is 0; and in some embodiments, m3 is 0.

[0255] In some embodiments disclosed herein, R 17 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 17 It is a hydrogen atom.

[0256] In some embodiments disclosed herein, R 18 and R 19 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 18 and R 19 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 18 and R 19 For hydrogen atoms; in some implementations, R 18 and R 19 It is a methyl group.

[0257] In some embodiments disclosed herein, R 20 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 20 It is a hydrogen atom.

[0258] In some embodiments disclosed herein, R 22 and R 23 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 22 and R 23 They may be the same or different, and each is independently a hydrogen atom or F.

[0259] In some embodiments of this disclosure, v is 0; in some embodiments, v is 1; and in some embodiments, v is 2.

[0260] In some embodiments disclosed herein, R 0 Selected from O, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl and cyano groups; in some embodiments, R 0 Selected from O, halogen, C 1-6 Alkyl, C 1- 6-Hydroalkyl and C 1-6 Alkoxy; in some embodiments, R 0 Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 0 It is a halogen.

[0261] In some implementation schemes disclosed herein, Selected from and CH2; in some implementations, for * The terminal is connected to E.

[0262] In some embodiments of this disclosure, E is G 1 G 2 G 3 G 4 G 5 L 1 X 1 R 13 R 17 -R 19 and R 0 As defined above; in some implementations, E is r、R 12 and X 1 As defined above; in some implementations, E is r and R 12 As defined above; in some implementations, E is selected from... In some implementations, E is

[0263] In some embodiments of this disclosure, E is Q 1 Q 3 and Q 4 Whether they are the same or different, and each is independently N or CR 12 ;Y 2 For C(O) or CH2; R 12 As defined above; in some implementations, E is r is 0, 1, 2, or 3; R 12 As defined above; in some implementations, E is r is 0, 1, 2, or 3; R 12 As defined above; in some implementations, E is selected from...

[0264] In some embodiments disclosed herein, G 3 It is a carbon atom and is related to L d Connected, G 1 G 2 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 12 ;R 12 As defined above; in some implementations, G 3 It is a carbon atom and is related to L d Connected, G 1G 2 G 4 and G 5 Whether the two are the same or different, and each is an independent CR 12 ;R 12 As defined above; in some implementations, G 3 It is a carbon atom and is related to L d Connected, G 1 For CR 12 ;R 12 As defined above; G 2 G 4 and G 5 For CH; in some implementations, G 3 It is a carbon atom and is related to L d Connected, G 1 G 2 G 4 and G 5 For CH.

[0265] In some embodiments of this disclosure, E is R 12a R 12b R 12c R 12d n3, n4, Q, G 6 G 7 G 8 X e X f q5, q6, R 12x a and X 1 As defined above; in some implementations, E is selected from...

[0266] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or pyridyl, said phenyl and pyridyl groups being optionally independently converted by one or more R groups. A Replacement; ring G becomes ring G1; R A And ring G1 as defined above; in some embodiments, ring G is phenyl or pyridyl, wherein the phenyl and pyridyl groups are each independently optionally converted by one or more R groups. G Replacement; ring A becomes ring A1, R G And ring A1 as defined above;

[0267] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is *End and L a Connected; ring G is *End and L 1 Linked; the definitions of each group are as defined above; in some embodiments, ring G is *End and L 1 Connected; Ring A is selected from *End and L a Connected; the definitions of each group are as defined above.

[0268] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... *End and L a Connected; ring G is selected from *End and L 1 Connected;

[0269] In some implementations, ring G is selected from *End and L 1 Connected; Ring A is selected from *End and L a Connected.

[0270] In some embodiments of this disclosure, the compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; B 2 For N; B 3 For CH; B 4 For CH; or, B 2 For CH; B 3 For N; B 4 For CH; or, B 2 For CH; B 3 For CH; B 4 For N; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 5 It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally coupled with one or more R groups. 5a Replace; R 5a C 1-6 Alkyl; Z 1 For N; Z 2 For CR 8m ;R 8m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 8a R 8b R8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together with the attached carbon atom, they form a cyclopropyl group; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; X is N; x is 0 or 1; m1 is 0, 1, or 2; R 9 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is independently 0 or 1; R 12 r represents a hydrogen atom or a halogen; r is 0 or 1.

[0271] In some embodiments of this disclosure, the compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; B 2 For N; B 3 For CH; B 4 For CH; or, B 2 For CH; B 3 For N; B 4 For CH; or, B 2 For CH; B 3 For CH; B 4 For N; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 5 for Z 1 For N; Z 2 For CH; R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together they form a cyclopropyl group; or, R 8c and R 8d Together they form a cyclopropyl group; or, R 8e and R 8f Together they form a cyclopropyl group; X is N; x is 0 or 1; m1 is 0; Xa For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is 0 or 1 independently; r is 0.

[0272] In some embodiments of this disclosure, the compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; B 2 For N; B 3 For CH; B 4 For CH; or, B 2 For CH; B 3 For N; B 4 For CH; or, B 2 For CH; B 3 For CH; B 4 For N; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 5 It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally coupled with one or more R groups. 5a Replace; R 5a C 1-6 Alkyl; D 1 For CH; D 2 For N or CH; D 3 For N or CH; M is O; n1 and n2 may be the same or different, and each is independently 0 or 1; X c For N or CH; X d For N or CH; for x, 0 or 1; for m1, 0, 1 or 2; for R 9 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is independently 0 or 1; R 12 r represents a hydrogen atom or a halogen; r is 0 or 1.

[0273] In some embodiments of this disclosure, the compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; B 2 For N; B 3 For CH; B 4 For CH; or, B 2 For CH; B 3 For N; B 4 For CH; or, B 2 For CH; B 3 For CH; B 4 For N; R 3 It is a hydrogen atom or a carbon atom.1-6 Alkyl; R 5 for D 1 For CH; D 2 For CH; D 3 For N; for M, for O; for n1, for 0 or 1; for n2, for 1; for X c For N or CH; X d For N or CH; for x, 0 or 1; for m1, 0; for X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is 0 or 1 independently; r is 0 or 1.

[0274] In some embodiments of this disclosure, the compound represented by general formula (IV-3) or a pharmaceutically acceptable salt thereof, Where R 1 C 1-6 Alkyl; B 2 For N; B 3 For CH; B 4 For CH; or, B 2 For CH; B 3 For N; B 4 For CH; or, B 2 For CH; B 3 For CH; B 4 For N; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 5 for Z 1 For N; Z 2 For CH; R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together they form a cyclopropyl group; or, R 8c and R 8d Together they form a cyclopropyl group; or, R 8e and R 8f Together they form a cyclopropyl group; X is N; x is 0 or 1; m1 is 0; X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is 0 or 1 independently; r is 0.

[0275] Table A lists typical compounds disclosed herein, including but not limited to:

[0276] This disclosure provides a compound or a salt thereof represented by general formula (IV-1A), general formula (IV-2A), general formula (IV-3A) or general formula (IV-4A).

[0277] in:

[0278] R m1 and R m2 Each is independently protected by a hydrogen atom or an amino group;

[0279] R 1 B 2 B 3 B 4 R 3 R 5 Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e R 8f D 1 D 2 D 3 M, X c n1 and n2 are as defined in general formula (IV-1), general formula (IV-2), general formula (IV-3) or general formula (IV-4).

[0280] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0281] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV-1) or a pharmaceutically acceptable salt thereof, comprising:

[0282] The compound of general formula (IV-1A) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB-1) or its salt to give the compound of general formula (IV-1) or its pharmaceutically usable salt.

[0283] in:

[0284] R m2 For hydrogen atoms; R m1 It is a hydrogen atom or an amino protecting group;

[0285] x is 0; X a CH; X is N;

[0286] R 1 B 2 B 3 B 4 R 3 R 5 Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e R 8f X b R 9 m1, q1, q2, R 12 And r is as defined in general formula (IV-1);

[0287] or,

[0288] The compound of general formula (IV-1A) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB-2) or its salt to give the compound of general formula (IV-1) or its pharmaceutically usable salt.

[0289] in:

[0290] R m2 For hydrogen atoms; R m1 It is a hydrogen atom or an amino protecting group;

[0291] x6 is 0, 1, 2, 3, or 4; in some implementations, x6 is 0;

[0292] x is 1, 2, 3, 4 or 5;

[0293] X is N;

[0294] R 1 B 2 B 3 B 4 R 3 R 5 Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e R 8f X a X b R 9 m1, q1, q2, R12 And r are as defined in general formula (IV-1).

[0295] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV-2) or a pharmaceutically acceptable salt thereof, comprising:

[0296] The compound of general formula (IV-2A) or its salt reacts with the compound of general formula (IVB-1) or its salt to undergo a reductive amination reaction to give the compound of general formula (IV-2) or its pharmaceutically usable salt.

[0297] in:

[0298] R m2 For hydrogen atoms; R m1 It is a hydrogen atom or an amino protecting group;

[0299] x is 0; X a For CH; X d Let N be the number of people in the group.

[0300] R 1 B 2 B 3 B 4 R 3 R 5 D 1 D 2 D 3 M, n1, n2, X c X b R 9 m1, q1, q2, R 12 And r as defined in general formula (IV-2);

[0301] or,

[0302] The compound of general formula (IV-2A) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB-2) or its salt to give the compound of general formula (IV-2) or its pharmaceutically usable salt.

[0303] in:

[0304] R m2 For hydrogen atoms; R m1 It is a hydrogen atom or an amino protecting group;

[0305] x6 is 0, 1, 2, 3, or 4; in some implementations, x6 is 0;

[0306] x is 1, 2, 3, 4 or 5;

[0307] X d Let N be the number of people in the group.

[0308] R 1 B 2 B 3 B 4 R 3 R 5 D 1 D 2 D 3 M, n1, n2, X c X a X b R 9 m1, q1, q2, R 12 And r are as defined in general formula (IV-2).

[0309] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV-3) or a pharmaceutically acceptable salt thereof, comprising:

[0310] The compound of general formula (IV-3A) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB-2) or its salt to give the compound of general formula (IV-3) or its pharmaceutically usable salt.

[0311] in:

[0312] R m2 It is a hydrogen atom;

[0313] x6 is 0, 1, 2, 3, or 4; in some implementations, x6 is 0;

[0314] x is 1, 2, 3, 4 or 5;

[0315] X is N;

[0316] R 1 B 2 B 3 B 4 R 3 R 5 Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e R 8f X a X b R 9 m1, q1, q2, R 12 And r are as defined in general formula (IV-3).

[0317] In some embodiments of this disclosure, x6 is 0; x is 1; in some embodiments of this disclosure, x6 is 1; x is 2.

[0318] In some embodiments of this disclosure, the reductive amination reaction occurs under acidic conditions and in the presence of a reducing agent.

[0319] In some embodiments of this disclosure, the reagents providing acidic conditions include, but are not limited to, acetic acid, glacial acetic acid, Ti(i-PrO)3, and BF3·Et2O; in some embodiments, the reagent providing acidic conditions is acetic acid; in some embodiments, the reagent providing acidic conditions is glacial acetic acid; or, the acidic conditions are provided by an acid produced in the reaction, for example, sodium acetate reacts with hydrochloride to produce acetic acid.

[0320] In some embodiments of this disclosure, the reducing agent includes, but is not limited to, sodium borohydride acetate, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, and sodium acetylborohydride; in some embodiments, the reducing agent is sodium borohydride acetate.

[0321] In some embodiments of this disclosure, the above preparation method is carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.

[0322] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of the above general formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3), or (IV-4) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0323] This disclosure further relates to the use of compounds of the above general formulas (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for inhibiting or degrading BTK.

[0324] This disclosure further relates to the use of compounds of the above general formulas (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3), or (IV-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for regulating BTK protein ubiquitination and degradation in a subject.

[0325] This disclosure further relates to the use of compounds of the above general formulas (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on BTK.

[0326] This disclosure further relates to the use of the compounds of the above general formulas (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the above, in the preparation of medicaments for the treatment and / or prevention of tumors or autoimmune diseases; in some embodiments, in the preparation of medicaments for the treatment and / or prevention of leukemia or lymphoma; and in some embodiments, in the preparation of medicaments for the treatment and / or prevention of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma, follicular lymphoma, lymphoblastic lymphoma, marginal zone lymphoma (MZL), non-Hodgkin lymphoma (NHL), B-cell non-Hodgkin lymphoma, mantle cell lymphoma (MCL), and B-cell lymphoma.

[0327] This disclosure also relates to a method for regulating the ubiquitination and degradation of BTK protein in a subject, comprising administering to a desired patient a compound of the above general formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0328] This disclosure also relates to a method of inhibiting or degrading BTK in a subject, comprising administering to a desired patient a compound of the above general formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0329] This disclosure also relates to a method of treating and / or preventing diseases or conditions mediated or dependent on BTK, comprising administering to a desired patient a compound of the above general formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0330] This disclosure also relates to a method of treating and / or preventing tumors or autoimmune diseases, comprising administering to a desired patient a compound of the above general formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, to treat and / or prevent leukemia or lymphoma in some embodiments, and to treat and / or prevent chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma, follicular lymphoma, lymphoblastic lymphoma, marginal zone lymphoma (MZL), non-Hodgkin lymphoma (NHL), B-cell non-Hodgkin lymphoma, mantle cell lymphoma (MCL), and B-cell lymphoma.

[0331] This disclosure further relates to a compound of the above general formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which is used as a medicine.

[0332] This disclosure further relates to a compound of the above general formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which is used as a medicament for regulating the ubiquitination and degradation of BTK protein in a subject.

[0333] This disclosure further relates to a compound of the above general formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which is used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on BTK.

[0334] This disclosure further relates to compounds of the above general formulas (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the purpose of regulating BTK protein ubiquitination and degradation in a subject.

[0335] This disclosure further relates to compounds of the above general formulas (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for use in inhibiting or degrading BTK in a subject.

[0336] This disclosure further relates to compounds of the above general formulas (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on BTK.

[0337] This disclosure further relates to compounds of the above general formulas (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3) or (IV-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of tumors or autoimmune diseases; in some embodiments for the treatment and / or prevention of leukemia or lymphoma; in some embodiments for the treatment and / or prevention of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma, follicular lymphoma, lymphoblastic lymphoma, marginal zone lymphoma (MZL), non-Hodgkin lymphoma (NHL), B-cell non-Hodgkin lymphoma, mantle cell lymphoma (MCL), and B-cell lymphoma.

[0338] In some implementations, the tumor described in this disclosure is cancer.

[0339] In some embodiments, the tumors described in this disclosure are hematologic malignancies.

[0340] In some embodiments, the tumor described in this disclosure is a B-cell malignant tumor.

[0341] In some embodiments, the autoimmune disease described in this disclosure is urticaria; in some embodiments, the autoimmune disease is chronic spontaneous urticaria (CSU); and in some embodiments, the autoimmune disease is multiple sclerosis (MS).

[0342] In some embodiments, the BTK-mediated or dependent diseases or conditions described in this disclosure are tumors or autoimmune diseases; in some embodiments, the BTK-mediated or dependent diseases or conditions described in this disclosure are tumors; in some embodiments, the BTK-mediated or dependent diseases or conditions described in this disclosure are hematologic malignancies; in some embodiments, the BTK-mediated or dependent diseases or conditions described in this disclosure are B-cell malignancies; in some embodiments, the BTK-mediated or dependent diseases or conditions described in this disclosure are leukemia or lymphoma; in some embodiments... In this disclosure, the diseases or conditions mediated or dependent on BTK are selected from chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma, follicular lymphoma, lymphoblastic lymphoma, marginal zone lymphoma (MZL), non-Hodgkin lymphoma (NHL), B-cell non-Hodgkin lymphoma, mantle cell lymphoma (MCL), and B-cell lymphoma; in some embodiments, the diseases or conditions mediated or dependent on BTK as described in this disclosure are chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL).

[0343] In some embodiments, the BTK described in this disclosure also includes mutations within the BTK protein, such as C481S, C481Y, C481R, and C481F.

[0344] The active compounds can be formulated into forms suitable for administration via any appropriate route. As a general guideline, the active compounds of this disclosure are, in some embodiments, expressed as unit doses or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compounds or compositions can be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg; in some embodiments, a suitable unit dose may be 0.1 to 1000 mg.

[0345] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0346] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0347] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0348] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0349] Pharmaceutical compositions containing active ingredients may be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation.

[0350] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0351] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0352] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0353] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0354] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0355] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0356] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0357] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0358] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0359] Terminology Explanation

[0360] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0361] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). The alkyl group, in some embodiments, is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, in some embodiments having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. In some embodiments, the substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0362] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). The alkylene is, in some embodiments, an alkylene having 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), in some embodiments having 1 to 8 carbon atoms (i.e., C164-C ... 1-8 Alkylenes), in some embodiments having 2 to 7 carbon atoms (i.e., C164-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0363] The term "bridged alkylene" refers to an alkylene ring formed by the connection of two non-adjacent atoms, as defined above. Non-limiting examples include: bridged ethylene (-CH2CH2-) and bridged methylene (-CH2-).

[0364] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group, in some embodiments, has 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0365] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 The alkynyl group (in some embodiments) has 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0366] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0367] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). The cycloalkyl group is, in some embodiments, a cycloalkyl group with 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl); in some embodiments, a cycloalkyl group with 4 to 12 ring atoms (i.e., 4 to 12 membered cycloalkyl); in some embodiments, a cycloalkyl group with 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl); in some embodiments, a cycloalkyl group with 4 to 6 ring atoms (i.e., 4 to 6 membered cycloalkyl); and in some embodiments, a cycloalkyl group with 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0368] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0369] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0370] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl with 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl with 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), and in some embodiments is a monospirocyclic alkyl or bispirocyclic alkyl group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocyclic alkyl group. Non-limiting examples include:

[0371] Its connection point can be anywhere;

[0372] wait.

[0373] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0374] Its connection point can be anywhere;

[0375] wait.

[0376] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system sharing two non-directly linked carbon atoms between rings, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl with 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl with 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0377] Its connection point can be anywhere.

[0378] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0379] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). In some embodiments, the heterocyclic group is a heterocyclic group having 5 to 15 ring atoms (i.e., a 5 to 15-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group); in some embodiments, a heterocyclic group having 4 to 12 ring atoms (i.e., a 4 to 12-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in some embodiments, a heterocyclic group having 4 to 6 ring atoms (i.e., a 4 to 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 4 to 7 ring atoms (i.e., a 4 to 7-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); and in some embodiments, a heterocyclic group having 6 ring atoms (i.e., a 6-membered heterocyclic group).

[0380] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0381] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0382] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). The spiroheterocyclic group has 6 to 14 ring atoms in some embodiments (i.e., 6 to 14-membered spiroheterocyclic groups), and 7 to 11 ring atoms in some embodiments (i.e., 7 to 11-membered spiroheterocyclic groups). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups), and in some embodiments is a monospirocyclic or bispirocyclic group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic group. Non-limiting examples include:

[0383] wait.

[0384] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). The fused heterocyclic group has, in some embodiments, 6 to 14 ring atoms (i.e., 6 to 14-membered fused heterocyclic group); in some embodiments, 7 to 11 ring atoms (i.e., 7 to 11-membered fused heterocyclic group); in some embodiments, 7 to 10 ring atoms (i.e., 7 to 10-membered fused heterocyclic group); and in some embodiments, 9 ring atoms (i.e., 9-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), and in some embodiments is a bicyclic or tricyclic fused heterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include:

[0385] wait.

[0386] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). In some embodiments, the bridged heterocyclic group has 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0387] wait.

[0388] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0389] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14-membered aryl). In some embodiments, the aryl group has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl group further includes fusion of the phenyl group with one or more heterocyclic groups or cycloalkyl groups, or fusion of the naphthyl group with one or more heterocyclic groups or cycloalkyl groups, wherein the bonding point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0390] wait.

[0391] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0392] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) ring atoms (i.e., 5 to 15-membered heteroaryl). The heteroaryl group is, in some embodiments, a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group); in some embodiments, a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group); in some embodiments, a heteroaryl group having 9 or 10 ring atoms (i.e., a 9 or 10-membered heteroaryl group); in some embodiments, a heteroaryl group having 11 to 15 ring atoms (i.e., an 11 to 15-membered heteroaryl group); in some embodiments, a heteroaryl group having 9 ring atoms (i.e., a 9-membered heteroaryl group); and in some embodiments, a heteroaryl group having 14 or 15 ring atoms (i.e., a 14 or 15-membered heteroaryl group).

[0393] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0394] Non-limiting examples of the aforementioned polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system; in some embodiments, the heteroaryl group is a fused heteroaryl group having 7 to 11 ring atoms (i.e., a 7 to 11-membered fused heteroaryl group); in some embodiments, the heteroaryl group is a fused heterocyclic group having 9 ring atoms (i.e., a 9-membered fused heteroaryl group). Non-limiting examples of polycyclic heteroaryl groups include:

[0395] wait.

[0396] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0397] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent ring, i.e., "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene". Non-limiting examples include: wait.

[0398] The term "tricyclic" refers to a multicyclic system containing three rings, which can be connected by fusion, bridging, or helical means. In some embodiments, the "tricyclic" has 11 to 15 ring atoms (i.e., an 11- to 15-membered tricyclic), and in other embodiments, it has 14 or 15 ring atoms (i.e., a 14- or 15-membered tricyclic).

[0399] The term "tricyclic heteroaryl" refers to a polycyclic system with three rings, which can be connected by fusion, bridging, or helical linkages, and at least one monocyclic ring is a heteroaryl group, with the linkage site located on the monocyclic heteroaryl group. In some embodiments, the "tricyclic heteroaryl" has 11 to 15 ring atoms (i.e., an 11 to 15-membered tricyclic heteroaryl), and in other embodiments, it has 14 or 15 ring atoms (i.e., a 14 or 15-membered tricyclic heteroaryl). "Fused tricyclic heteroaryl" refers to a system where all three rings are connected by fusion.

[0400] When a polycyclic system formed by the fusion of a monocyclic heteroaryl group with a cycloalkyl group, a heterocyclic group, or an aryl group is divalent, the polycyclic system is classified as "heteroaryl" or "fused heteroaryl" as long as one of the linking sites is on the monocyclic heteroaryl group; non-limiting examples include:

[0401] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0402] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0403] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0404] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0405] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0406] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0407] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0408] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0409] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined above.

[0410] The term "alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy groups, wherein the alkoxy groups and alkyl groups are as defined above.

[0411] The term "haloalkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0412] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0413] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0414] The term “deuterated alkoxy” refers to an alkoxy group that is replaced by one or more deuterium atoms, where the alkoxy group is as defined above.

[0415] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0416] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0417] The term "hydroxyl group" refers to -OH.

[0418] The term "thiol" refers to -SH.

[0419] The term "amino" refers to -NH2.

[0420] The term "cyano" refers to -CN.

[0421] The term "nitro" refers to -NO2.

[0422] The term "oxo" or "oxo group" refers to "=O".

[0423] The term "carbonyl" refers to C=O.

[0424] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0425] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0426] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0427] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0428] The term "amino protecting group" refers to a group that is easily removed from the amino group, introduced onto the amino group to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), tert-butylsulfinyl, trifluoroacetyl (Tfa), trichloroacetyl, triphenylmethyl (Trt), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.; in some embodiments, it is Boc.

[0429] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0430] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0431] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0432] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0433] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0434] The compounds disclosed herein may comprise transisomers. The term "transisomer" refers to a conformational stereoisomer resulting from restricted or significantly slowed rotation around a single bond in a molecule (as a result of steric interactions with other parts of the molecule and asymmetric substituents at the ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, some compounds of this disclosure may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0435] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I,124 I, 125 I, 129 I and 131 In some implementations, I is deuterium.

[0436] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0437] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0438] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6 "Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0439] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0440] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0441] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0442] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0443] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0444] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations. Detailed Implementation

[0445] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0446] Example

[0447] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms.-6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0448] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS);

[0449] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector);

[0450] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive).

[0451] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0452] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0453] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0454] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0455] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0456] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0457] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0458] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0459] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0460] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0461] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0462] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0463] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0464] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0465] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0466] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0467] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0468] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0469] Example 1

[0470] (R)-3-(tert-butyl)-N-(1-(6-(6-(5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide1

[0471] first step

[0472] (S,E)-N-((6-bromo-2-methylpyridin-3-yl)methylethylene)-2-methylpropane-2-sulfinamide 1b

[0473] 6-Bromo-2-methylnicotinaldehyde 1a (4.74 g, 23.7 mmol, Bide), S-tert-butylsulfinamide (7.46 g, 61.6 mmol, Shaoyuan), and tetraethyl titanate (13.0 mL, 62.0 mmol, Adamas) were dissolved in tetrahydrofuran (100 mL, Anage), purged with nitrogen three times, and reacted at 80 °C for 6 hours. After cooling to room temperature, the system was concentrated, and 40 mL of saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with 40 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title compound 1b (7 g, yield: 97.4%).

[0474] MS m / z(ESI): 303.2 [M+1].

[0475] Step 2

[0476] (S)-N-((R)-1-(6-bromo-2-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide 1c

[0477] Compound 1b (7 g, 23.1 mmol, BIDE) was dissolved in tetrahydrofuran (150 mL, ANGE), purged with nitrogen three times, and the reaction was cooled to 0 °C. Methylmagnesium bromide (23 mL, 3 M, 69 mmol, ANGE) was added dropwise, and the reaction was continued at 0 °C for 3 hours. The system was concentrated, and 30 mL of saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 40 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound 1c (5.5 g, yield: 74.6%).

[0478] MS m / z(ESI): 319.2 [M+1].

[0479] Step 3

[0480] (R)-1-(6-bromo-2-methylpyridin-3-yl)ethyl-1-amine 1d

[0481] Compound 1c (5.5 g, 17.2 mmol) was dissolved in dioxane hydrochloride (50 mL, 4 M, 200 mmol, Adamas) and reacted at room temperature for 2 hours. The solution was concentrated under reduced pressure, and N,N-diisopropylethylamine (10 mL) was added. The solution was then concentrated again under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 1d (2.5 g, yield: 57.7%). MS m / z (ESI): 215.0 [M+1].

[0482] Step 4

[0483] (R)-N-(1-(6-bromo-2-methylpyridin-3-yl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide 1e

[0484] Compound 1d (2.42 g, 11.3 mmol), potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (4.68 g, 22.5 mmol, prepared by the same intermediate method described on page 58 of patent application WO2021087112), was dissolved in N,N-dimethylformamide (50 mL), and triethylamine (3.42 g, 33.8 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (8.56 g, 22.5 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give title compound 1e (3.5 g, yield: 84.7%).

[0485] MS m / z(ESI): 367.2 [M+1].

[0486] Step 5

[0487] 2-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 1h

[0488] 1f of 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (100 mg, 0.33 mmol, Icon) was dissolved in 1,4-dioxane (3 mL), and 1g of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (177 mg, 0.43 mmol, prepared by the method disclosed in intermediate F1 on page 36 of patent application WO2024088379A1), hexamethyldistin (141 mg, 0.43 mmol, BIDE), and tetra(triphenylphosphine)palladium (39 mg, 0.03 mmol, BIDE) were added. The mixture was purged with nitrogen three times and stirred at 100 °C for 6 hours. Add bis(triphenylphosphine)palladium dichloride (47 mg, 0.07 mmol, BIDE), purge with nitrogen three times, and stir at 100 °C for 12 hours. Add 10 mL of water, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with 10 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography with eluent system B to give the title compound 1h (150 mg, yield: 89.7%).

[0489] MS m / z(ESI): 505.5 [M+1].

[0490] Step 6

[0491] (R)-2-(4-(5-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-6-methylpyridin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate

[0492] Compound 1e (400 mg, 1.09 mmol), hexamethyldistin (785 mg, 2.40 mmol, Adamas), and tetra(triphenylphosphine)palladium (251 mg, 0.22 mmol, Adamas) were placed in 1,4-dioxane (5 mL), purged with nitrogen three times, and heated to 100 °C for 6 hours. The reaction mixture was cooled to room temperature, and compound 1h (300 mg, 0.59 mmol), cuprous iodide (113 mg, 0.59 mmol, Adamas), and bis(triphenylphosphine)palladium dichloride (83 mg, 0.12 mmol, Adamas) were added. The mixture was purged with nitrogen three times, and the reaction mixture was heated to 100 °C and stirred overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 1i (80 mg, yield: 17.8%).

[0493] MS m / z(ESI): 757.9 [M+1].

[0494] Step 7

[0495] (R)-3-(tert-butyl)-N-(1-(2-methyl-6-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide1j

[0496] Compound 1i (80 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (3.08 g, 27.01 mmol, Adamas) was added. The reaction was carried out at room temperature for 2 hours. The solution was concentrated under reduced pressure, and 5 mL of saturated sodium bicarbonate solution was added. The solution was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 1j (12 mg, yield: 21.6%). The product was used directly for the next reaction without purification.

[0497] MS m / z(ESI): 527.5 [M+1].

[0498] Step 8

[0499] (R)-3-(tert-butyl)-N-(1-(6-(6-(5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide1

[0500] Compound 1j (12 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL), and acetic acid (2.7 mg, 0.05 mmol, Sinopharm), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carboxaldehyde 1k (13.7 mg, 0.05 mmol prepared by the method disclosed in intermediate 0423 on page 107 of patent application WO2023125908A1), and triethylamine (2.8 mg, 0.03 mmol, Sinopharm) were added. The mixture was reacted at room temperature for 2 hours. Sodium borohydride acetate (14 mg, 0.07 mmol, BIDE) was added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with a 20 mL × 3 solution of isopropanol / dichloromethane (V / V = 1:3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give title compound 1 (4 mg, yield: 21.6%).

[0501] MS m / z(ESI): 812.7 [M+1].

[0502] 1 H NMR (500MHz, DMSO-d6): δ12.58(s,1H),10.28-10.23(m,1H),10.00-9.92(m,1H),8.81(s,1H),8.46-8.41(m,1H),8. 08-8.01(m,1H),7.70-7.64(m,1H),7.21(s,1H),7.17-7.10(m,2H),6.98-6.90(m,2H),6.71(s,1H),6.66(s,1H),5.4 3-5.32(m,2H),4.22(s,1H),3.74-3.67(m,4H),2.97(s,2H),2.79(s,2H),2.71-2.65(m,4H),2.47-2.43(m,1H),2.39 -2.35(m,1H),2.24-2.19(m,1H),1.89-1.77(m,3H),1.69-1.56(m,3H),1.51-1.42(m,2H),1.37(s,4H),1.24(s,5H).

[0503] Example 2

[0504] (R)-3-(tert-butyl)-N-(1-(6-(6-(5'-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4',5'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-2'-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazol-5-carboxamide 2

[0505] first step

[0506] 3-Bromo-1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrazole-5-carboxylic acid ethyl ester 2c

[0507] Ethyl 3-bromo-1H-pyrazole-5-carboxylate 2b (2.5 g, 11.4 mmol, BIDE), (1-(hydroxymethyl)cyclopropyl)carbamate tert-butyl ester 2a (2.4 g, 12.82 mmol, SHAOYUAN), and triphenylphosphine (3.8 g, 14.49 mmol, BIDE) were dissolved in tetrahydrofuran (45 mL). Diisopropyl azodicarbonate (3 g, 14.83 mmol, SHAOYUAN) was added under ice bath. The mixture was allowed to return to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 2c (3.5 g, yield: 79%).

[0508] MS m / z(ESI): 388.2 [M+1].

[0509] Step 2

[0510] 2'-Bromo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 2d

[0511] Compound 2c (2.5 g, 6.44 mmol) was dissolved in 1,4-dioxane (10 mL), and a 4M hydrogen chloride solution of 1,4-dioxane (4 mL, 16 mmol, Sinopharm) was added. The mixture was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in methanol (30 mL), and sodium methoxide (347.8 mg, 6.44 mmol, Anaiji) was added. The mixture was stirred at 80 °C for 6 hours, and the reaction solution was cooled to room temperature. The pH of the reaction solution was adjusted to neutral with a 4M hydrogen chloride solution of 1,4-dioxane. The mixture was concentrated under reduced pressure, and a dichloromethane / methanol (V:V = 15:1) solution was added to the residue. The mixture was stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2d (1.9 g). The product was used directly in the next reaction without purification.

[0512] MS m / z(ESI):242.1[M+1].

[0513] Step 3

[0514] 2'-Bromo-4',5'-Dihydro-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]2e

[0515] The crude compound 2d (1.9 g, 8.1 mmol) was dissolved in tetrahydrofuran (10 mL), and 1 M borane tetrahydrofuran solution (24.5 mL, 24.5 mol, Anegir) was added. The mixture was stirred at 45 °C for 16 hours. The reaction solution was cooled to room temperature, quenched dropwise with methanol under ice bath, and concentrated under reduced pressure to obtain the crude title compound 2e (1.8 g). The product was used directly in the next reaction without purification.

[0516] MS m / z(ESI):228.0[M+1].

[0517] Step 4

[0518] 2'-Bromo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-tert-butyl carboxylate 2f

[0519] The crude compound 2e (1.85 g, 8.11 mmol) was dissolved in dichloromethane (25 mL) and methanol (3 mL), and di-tert-butyl dicarbonate (2.66 g, 12.2 mmol, Adamas) and triethylamine (1.65 g, 16.3 mmol, Sinopharm) were added. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 2f (1.56 g, yield: 58.6%).

[0520] MS m / z(ESI):328.0[M+1].

[0521] Step 5

[0522] (R)-3-(tert-butyl)-N-(1-(6-(6-(5'-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4',5'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-2'-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazol-5-carboxamide 2

[0523] Using the synthetic route of Example 1, the fifth step compound 1f was replaced with compound 2f to obtain title compound 2 (5 mg, yield: 11.0%).

[0524] MS m / z(ESI): 838.7 [M+1].

[0525] 1 H NMR (500MHz, DMSO-d6): δ12.60(s,1H),10.26(s,1H),9.99-9.92(m,1H),8.81(s,1H),8.48-8 .40(m,1H),8.08-8.01(m,1H),7.72-7.66(m,1H),7.21-7.10(m,2H),6.98-6.89(m,2H),6.79( s,1H),5.44-5.34(m,1H),4.17-4.00(m,4H),3.74-3.63(m,4H),2.79(s,3H),2.73-2.63(m,4 H),1.83-1.73(m,2H),1.69-1.55(m,4H),1.47(s,1H),1.42-1.20(m,13H),0.82-0.71(m,3H).

[0526] Example 3

[0527] 3-(tert-butyl)-N-((6-(6-(5'-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4',5'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-2'-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 3

[0528] first step

[0529] (6-Bromo-2-methylpyridin-3-yl)methylamine 3b

[0530] 6-Bromo-2-methylpyridin-3-carboxynitrile 3a (2.4 g, 12.2 mmol, Leyan) was dissolved in a boranetetrahydrofuran complex (121.8 mL, 1 M, 121.8 mmol), stirred overnight at room temperature under nitrogen protection, quenched by slow dropwise addition of methanol, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give title compound 3b (1.3 g, yield: 53%).

[0531] MS m / z(ESI):201.1[M+1].

[0532] Step 2

[0533] N-((6-bromo-2-methylpyridin-3-yl)methyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide 3c

[0534] Compound 3b (1.3 g, 6.5 mmol), potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (1.6 g, 7.8 mmol), and N,N-dimethylformamide (30 mL) were dissolved in water. Triethylamine (1.96 g, 19.4 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.2 g, 8.4 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 3c (1.48 g, yield: 64.8%).

[0535] MS m / z(ESI): 353.2 [M+1].

[0536] Step 3

[0537] 3-(tert-butyl)-N-((6-(6-(5'-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4',5'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-2'-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 3

[0538] Using the synthetic route of steps five through eight of Example 1, the title compound 3 (8 mg, yield: 17.4%) was obtained by replacing compound 1f in step five with compound 2f and compound 1e in step six with compound 3c. MS m / z (ESI): 824.7 [M+1].

[0539] 1 H NMR (500MHz, DMSO-d6): δ12.65-12.55(m,1H),10.26(s,1H),9.99-9.86(m,1H),8.81(s,1H),8 .44-8.35(m,1H),7.92-7.80(m,1H),7.74-7.63(m,1H),7.25-7.06(m,2H),7.00-6.88(m,2H),6 .79(s,1H),4.67-4.54(m,2H),4.23-3.97(m,4H),3.76-3.61(m,4H),3.33-3.30(m,1H),2.79-2 .60(m,7H),1.82-1.72(m,2H),1.64(s,1H),1.38(s,9H),1.29-1.13(m,4H),0.80-0.72(m,3H).

[0540] Example 4

[0541] 3-(tert-butyl)-N-((6-(6-(5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 4

[0542] Using the synthetic route from steps 5 to 8 of Example 1, the title compound 4 (19 mg, yield: 23.0%) was obtained by replacing compound 1e in step 6 with compound 3c.

[0543] MS m / z(ESI):798.8[M+1].

[0544] 1 H NMR (500MHz, DMSO-d6): δ12.58(s,1H),10.26(s,1H),9.93(s,1H),8.81(s,1H),8.42-8. 37(m,1H),7.89-7.85(m,1H),7.68(s,1H),7.17-7.10(m,2H),6.99-6.92(m,2H),6.72(s, 1H),5.36-5.30(m,2H),4.63-4.56(m,2H),4.22(s,2H),3.76-3.68(m,4H),2.98(s,2H),2 .77-2.64(m,6H),2.37(s,1H),2.08(s,1H),1.49-1.44(m,2H),1.38(s,4H),1.25(s,9H).

[0545] Example 5

[0546] (R)-3-(tert-butyl)-N-((6-(6-(8-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide5

[0547] first step

[0548] (R)-4-(5-bromo-3-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester 5c

[0549] 5-Bromo-2,3-difluoropyridine 5a (20 g, 103.1 mmol, Shaoyuan), (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester 5b (22.3 g, 103.1 mmol, Bide), and N,N-diisopropylethylamine (15.9 g, 123.7 mmol, Adamas) were dissolved in dimethyl sulfoxide (100 mL, Adamas) and reacted at 100 °C for 48 h. The reaction mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system C to give the title compound 5c (20.7 g, yield: 51.4%).

[0550] MS m / z(ESI): 390.1 [M+1].

[0551] Step 2

[0552] (R)-3-bromo-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester 5d

[0553] Compound 5c (20.7 g, 53.01 mmol) was dissolved in N,N-dimethylformamide (120 mL, Adamas), and sodium hydrogen hydrate (3.05 g, 79.61 mmol, Adamas) was added under ice bath conditions. The reaction mixture was allowed to rise naturally to room temperature and stirred for 15 hours. 50 mL of saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 5d (18.9 g, yield: 96.2%).

[0554] MS m / z(ESI): 370.1 [M+1].

[0555] Step 3

[0556] (R)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester 5e

[0557] Compound 5d (2.27 g, 6.13 mmol) was dissolved in 1,4-dioxane (30 mL, Adamas), and bis(diphenylphosphine) diborane (3.7 g, 15.42 mmol), potassium acetate (1.8 g, 18.34 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (897 mg, 1.22 mmol, Adamas) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 2 hours. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system C to give the title compound 5e (2.85 g, yield: 99.6%).

[0558] MS m / z(ESI):418.2[M+1].

[0559] Step 4

[0560] (R)-3-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester 5f

[0561] Compound 5e (2.55 g, 6.10 mmol) was dissolved in 1,4-dioxane (40 mL, Adamas) and water (8 mL). 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (2.56 g, 6.10 mmol, WuXi AppTec), potassium carbonate (2.53 g, 18.31 mmol, Sinopharm), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (894 mg, 1.22 mmol, Adamas) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 3 hours. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system C to give the title compound 5f (2.3 g, yield: 64.5%).

[0562] MS m / z(ESI): 583.1 [M+1].

[0563] Step 5

[0564] (R)-3-(4-(5-((3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)methyl)-6-methylpyridin-2-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazin-8(6H)-carboxylic acid tert-butyl ester 5g

[0565] Compound 3c (400 mg, 1.13 mmol), hexamethyldistin (861.3 mg, 2.5 mmol, Adamas), and tetra(triphenylphosphine)palladium (261.7 mg, 0.23 mmol, Adamas) were placed in 1,4-dioxane (5 mL), purged with nitrogen three times, and heated to 100 °C for 6 hours. The reaction mixture was cooled to room temperature, and compound 5f (360 mg, 0.62 mmol), cuprous iodide (117.6 mg, 0.62 mmol, Adamas), and bis(triphenylphosphine)palladium dichloride (86.7 mg, 0.12 mmol, Adamas) were added. The mixture was purged with nitrogen three times, and the reaction mixture was heated to 100 °C and stirred overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give 5 g (460 mg, yield: 90.75%) of the title compound.

[0566] MS m / z(ESI): 821.3 [M+1].

[0567] Step 6

[0568] (R)-3-(4-(5-((3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)methyl)-6-methylpyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazin-8(6H)-carboxylic acid tert-butyl ester 5h

[0569] 5 g (460 mg, 0.56 mmol) of the compound was dissolved in tetrahydrofuran (6 mL, Adamas) and methanol (3 mL), and sodium hydroxide (156.9 mg, 3.92 mmol, Adamas) was added. The reaction mixture was stirred at room temperature for 15 minutes. 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 5 h (380 mg, yield: 99.6%). MS m / z (ESI): 681.3 [M+1].

[0570] Step 7

[0571] (R)-3-(tert-butyl)-N-((6-(6-(6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide5i

[0572] Compound 5h (380 mg, 0.56 mmol) was dissolved in dichloromethane (4 mL, Sinopharm), and dioxane hydrochloride (4 mL, 16 mmol, 4 M, Adamas) was added. The reaction was carried out at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 10 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 5i (300 mg, yield: 92.56%).

[0573] MS m / z(ESI): 581.3 [M+1].

[0574] Step 8

[0575] (R)-3-(tert-butyl)-N-((6-(6-(8-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide5

[0576] Compound 5i (300 mg, 0.52 mmol), compound 1k (155.7 mg, 0.52 mmol), glacial acetic acid (93.1 mg, 1.55 mmol, Sinopharm), and sodium acetate (106 mg, 1.29 mmol, Adamas) were dissolved in dichloromethane (3 mL) and ethanol (3 mL) and stirred at room temperature for 2 hours. Sodium borohydride acetate (547.5 mg, 2.58 mmol, Shaoyuan) was added and stirring continued for 1 hour. The mixture was concentrated under reduced pressure, and 10 mL of water was added. The mixture was extracted with a mixture of isopropanol and chloroform (V / V = 1:3) (10 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give title compound 5 (9 mg, yield: 2%).

[0577] MS m / z(ESI): 866.4 [M+1].

[0578] 1H NMR (500MHz, DMSO-d6): δ12.59(s,1H),10.26(s,1H),9.94(s,1H),8.82(s,1H),8.45-8. 44(m,2H),7.89(s,1H),7.71(s,1H),7.64(s,1H),7.14(d,2H),6.94(d,2H),4.61(s,2H), 4.46-4.37(m,2H),4.00-3.96(m,2H),3.71-3.69(m,6H),2.99(s,2H),2.87-2.79(m,2H), 2.70-2.65(m,4H),2.25(s,2H),2.06-1.99(m,3H),1.84-1.74(m,4H),1.46-1.38(m,9H).

[0579] Example 6

[0580] 3-(tert-butyl)-N-(1-(6-(6-(((R)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 6

[0581] first step

[0582] N-(1-(6-bromo-2-methylpyridin-3-yl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide 6a

[0583] Following the synthetic route of steps one through four in Example 1, the title compound 6a (6.3 g, yield: 83.1%) was obtained by replacing the first-step compound S-tert-butylsulfinamide with tert-butylsulfinamide (Adamas). MS m / z (ESI): 367.2 [M+1] + .

[0584] Step 2

[0585] 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid methyl ester 6d

[0586] Methyl 3-bromo-1H-pyrazole-5-carboxylic acid 6b (5 g, 24.39 mmol, Adamas) was dissolved in tetrahydrofuran (200 mL). N-(tert-butoxycarbonyl)ethanolamine 6c (5.11 g, 31.70 mmol, Adamas), triphenylphosphine (12.8 g, 48.80 mmol, Adamas), and diisopropyl azodicarbonate (9.9 g, 48.96 mmol, Adamas) were added, and the mixture was stirred at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 6d (8.49 g, yield: 99.9%).

[0587] MS m / z(ESI): 348.3 [M+1] + .

[0588] Step 3

[0589] 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid 6e

[0590] Compound 6d (8.5 g, 24.41 mmol) was dissolved in tetrahydrofuran (120 mL) and water (30 mL). Lithium hydroxide (2.05 g, 48.85 mmol, Adamas) was added at 0 °C, and the mixture was allowed to return to room temperature. The mixture was stirred for 16 hours. The tetrahydrofuran was removed by concentration under reduced pressure. The pH of the reaction solution was adjusted to 4 with hydrochloric acid. The mixture was filtered, and the filter cake was collected to give the title compound 6e (8.1 g, yield: 99.3%).

[0591] MS m / z(ESI): 334.1 [M+1] + .

[0592] Step 4

[0593] (2-(3-bromo-5-(methoxy(methyl)aminocarbonyl)-1H-pyrazole-1-yl)ethyl)tert-butyl carbamate 6f

[0594] Compound 6e (7.8 g, 23.34 mmol) was dissolved in N,N-dimethylformamide (80 mL), and N,O-dimethylhydroxylamine hydrochloride (3.43 g, 35.16 mmol, Adamas), N,N-diisopropylethylamine (9.05 g, 70.02 mmol, Adamas), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (13.31 g, 35.01 mmol, Adamas) were added. The mixture was stirred at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6f (8.8 g, yield: 99.9%).

[0595] MS m / z(ESI): 377.3 [M+1] + .

[0596] Step 5

[0597] 6g of tert-butyl (2-(5-acetyl-3-bromo-1H-pyrazole-1-yl)ethyl)carbamate

[0598] Compound 6f (8 g, 21.21 mmol) was dissolved in tetrahydrofuran (80 mL). Under nitrogen atmosphere, methyl magnesium bromide (28.23 mL, 84.70 mmol, 3 M, Adamas) was added at 0 °C, and the mixture was stirred at room temperature for 16 hours. 100 mL of saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 6 g (6.65 g, yield: 94.4%).

[0599] MS m / z(ESI): 332.3 [M+1] + .

[0600] Step 6

[0601] 2-Bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine 6h

[0602] 6 g (3.3 g, 9.93 mmol) of compound was dissolved in 1,4-dioxane (30 mL), and dioxane hydrochloride solution (18 mL, 72.00 mmol, 4 M, Adamas) was added. The mixture was stirred at room temperature for 16 hours. The solution was concentrated, and 50 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6h (1.97 g, yield: 92.6%).

[0603] MS m / z(ESI): 214.2 [M+1] + .

[0604] Step 7

[0605] 2-Bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 6i

[0606] Compound 6h (1.97 g, 9.20 mmol) was dissolved in methanol (18 mL). Sodium borohydride (1.4 g, 84.70 mmol, Adamas) was added at 0 °C under a nitrogen atmosphere. The mixture was allowed to return to room temperature, and the reaction was stirred for 1 hour. 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6i (1.98 g, yield: 99.6%). MS m / z (ESI): 216.0 [M+1] + .

[0607] Step 8

[0608] 2-Bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 6j

[0609] Compound 6i (1.98 g, 9.16 mmol) was dissolved in dichloromethane (24 mL), and triethylamine (2.78 g, 27.47 mmol, Sinopharm) and di-tert-butyl dicarbonate (4 g, 18.33 mmol, Shaoyuan) were added at 0 °C. The mixture was then allowed to return to room temperature and stirred for 16 hours. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 6j (2.12 g, yield: 73.2%).

[0610] MS m / z(ESI): 316.2 [M+1] + .

[0611] Step 9

[0612] (R)-2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 6j-1

[0613] (S)-2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 6j-2

[0614] Compound 6j (11.3 g) was separated by a chiral column (Shimadzu LC-20AP Prep system, column: ChiralPak IG, 10 μm, 50 mm ID*300 mm L (Daicel, in-house packed); mobile phase A: n-hexane, mobile phase B: ethanol; gradient ratio: A:B = 70:30, flow rate: 80 mL / min) to obtain compounds 6j-1 (5.5 g, yield: 49%) and 6j-2 (5.5 g, yield: 49%).

[0615] Compound 6j-1 (5.5 g, yield: 49%, single configuration compound, retention time 8.875 min in chiral resolution).

[0616] MS m / z(ESI): 316.2 [M+1] + .

[0617] Compound 6j-2 (5.5 g, yield: 49%, single configuration compound, retention time 12.931 min in chiral resolution).

[0618] MS m / z(ESI): 316.2 [M+1] + .

[0619] Step 10

[0620] (R)-2-((diphenylmethyl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 6k

[0621] Compound 6j-1 (750 mg, 2.37 mmol) was dissolved in toluene (6 mL), and benzophenone imine (570 mg, 3.15 mmol, Shaoyuan), tris(dibenzylacetone)dipalladium (219 mg, 0.24 mmol, Bide), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (444 mg, 0.71 mmol, Shaoyuan), and sodium tert-butoxide (321 mg, 3.34 mmol, Shaoyuan) were added. The mixture was stirred at 80 °C for 6 hours under a nitrogen atmosphere. After returning to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 6k (680 mg, yield: 68.8%).

[0622] MS m / z(ESI): 417.7 [M+1] + .

[0623] Step 11

[0624] (R)-2-amino-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 6l

[0625] Compound 6k (630 mg, 1.51 mmol) was dissolved in tetrahydrofuran (15 mL) and water (10 mL), and citric acid (1.44 g, 6.85 mmol, Adamas) was added. The mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 6l (363 mg, yield: 95.1%).

[0626] MS m / z(ESI): 253.4 [M+1] + .

[0627] Step Twelve

[0628] (R)-2-((6-bromopyrimidin-4-yl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 6m

[0629] Compound 6l (650 mg, 2.58 mmol, Bioderm) was dissolved in dimethyl sulfoxide (13 mL), and 4-bromo-6-fluoropyrimidine (548 mg, 3.10 mmol) and N,N-diisopropylethylamine (1.67 g, 12.92 mmol, Sinopharm) were added. The mixture was sealed and reacted at 100 °C for 1 hour. After returning to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 6m (510 mg, yield: 48.4%).

[0630] MS m / z(ESI): 409.1 [M+1] + .

[0631] Step Thirteen

[0632] 3-(tert-butyl)-N-(1-(6-(6-(((R)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 6

[0633] Using the synthetic route of steps six to eight of Example 1, the title compound 6 (80 mg, yield: 56.0%) was prepared by replacing compounds 1e and 1h in step six with compounds 6a and 6m.

[0634] MS m / z(ESI):802.8[M+1].

[0635] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),10.02(s,1H),9.94-9.92(m,1H),8.68(s,1H),8.22- 8.20(m,1H),8.01-7.99(m,2H),7.15-7.10(m,2H),6.95-6.93(m,2H),6.35(br,1H),5.36-5. 33(m,1H),4.03-3.96(m,2H),3.74-3.69(m,5H),3.33-3.26(m,2H),2.77-2.56(m,10H),2.3 1-2.29(m,1H),1.90-1.76(m,3H),1.59-1.54(m,3H),1.37-1.34(m,10H),1.24-1.22(m,2H).

[0636] Examples 6-1 and 6-2

[0637] 3-(tert-butyl)-N-((R)-(1-(6-(6-(((R)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 6-1

[0638] 3-(tert-butyl)-N-((S)-(1-(6-(6-(((R)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 6-2

[0639] Compound 6 (75 mg, 93.52 μmol) was prepared chirally (separation conditions: chiral preparation column (S,S)-Whelk-O1, 10 μm, 20 mm * 250 mm (Regis Technologies, lab-filled); mobile phase 1: ACN (20%); mobile phase 2: EtOH (0.1% 7 M NH3 in MeOH) (80%), flow rate: 20 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound (20 mg) and (21 mg). (20 mg) monoform compound (shorter retention time):

[0640] MS m / z(ESI):802.8[M+1].

[0641] Chiral HPLC analysis: retention time 7.577 min, chiral purity: 100% (column: ReGIS(S,S)-Whelk-O1 15cm*4, 6mm, 5μm; mobile phase: EtOH / ACN / DEA=80 / 20 / 0.1(V / V / V), flow rate: 1mL / min).

[0642] 1H NMR (500MHz, DMSO-d6): δ10.26(s,1H),10.02(s,1H),9.94-9.92(m,1H),8.68(s,1H),8.22- 8.20(m,1H),8.08-7.99(m,2H),7.15-7.13(m,2H),6.95-6.93(m,2H),6.35(br,1H),5.36-5. 33(m,1H),4.03-3.96(m,2H),3.74-3.69(m,5H),3.33-3.26(m,2H),2.77-2.56(m,10H),2.3 1-2.29(m,1H),1.90-1.76(m,3H),1.59-1.54(m,3H),1.37-1.34(m,10H),1.27-1.22(m,2H).

[0643] (21mg) Single-configuration compound (longer retention time):

[0644] MS m / z(ESI):802.7[M+1].

[0645] Chiral HPLC analysis: retention time 10.311 min, chiral purity: 100% (column: ReGIS(S,S)-Whelk-O1 15cm*4, 6mm, 5μm; mobile phase: EtOH / ACN / DEA=80 / 20 / 0.1(V / V / V), flow rate: 1mL / min).

[0646] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),10.02(s,1H),9.94-9.92(m,1H),8.68(s,1H),8.22- 8.20(m,1H),8.08-7.99(m,2H),7.15-7.13(m,2H),6.95-6.93(m,2H),6.35(br,1H),5.36-5. 33(m,1H),4.03-3.96(m,2H),3.74-3.69(m,5H),3.33-3.26(m,2H),2.78-2.57(m,10H),2.3 1-2.27(m,1H),1.90-1.76(m,3H),1.59-1.54(m,3H),1.37-1.34(m,10H),1.24-1.21(m,2H).

[0647] Example 7

[0648] 3-(tert-butyl)-N-(1-(6-(6-(((S)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 7

[0649] Using the synthetic route from steps 10 to 13 of Example 6, the title compound 7 (120 mg, yield: 45.2%) was obtained by replacing compound 6j-1 in step 10 with compound 6j-2.

[0650] MS m / z(ESI):802.9[M+1].

[0651] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),10.02(s,1H),9.94-9.92(m,1H),8.68(s,1H),8.22- 8.20(m,1H),8.08-7.99(m,2H),7.15-7.13(m,2H),6.95-6.93(m,2H),6.34(br,1H),5.38-5. 33(m,1H),4.03-3.96(m,2H),3.75-3.69(m,5H),3.33-3.28(m,2H),2.78-2.59(m,10H),2.3 1-2.27(m,1H),1.90-1.72(m,3H),1.56-1.54(m,3H),1.37-1.34(m,10H),1.27-1.22(m,2H).

[0652] Examples 7-1 and 7-2

[0653] 3-(tert-butyl)-N-((R)-(1-(6-(6-(((S)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 7-1

[0654] 3-(tert-butyl)-N-((S)-(1-(6-(6-(((S)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 7-2

[0655] Compound 7 (115 mg, 0.14 mmol) was prepared chirally (separation conditions: chiral preparation column (S,S)-Whelk-O1, 10 μm, 20 mm * 250 mm (Regis Technologies, laboratory-filled); mobile phase 1: ACN (20%); mobile phase 2: EtOH (0.1% 7 M NH3 in MeOH) (80%), flow rate: 20 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound (25 mg) and (26 mg).

[0656] (25mg) Single configuration compound (shorter retention time):

[0657] MS m / z(ESI):802.8[M+1].

[0658] Chiral HPLC analysis: retention time 7.755 min, chiral purity: 100% (column: ReGIS(S,S)-Whelk-O1 15cm*4, 6mm, 5μm; mobile phase: EtOH / ACN / DEA=80 / 20 / 0.1(V / V / V), flow rate: 1mL / min).

[0659] 1 H NMR (500MHz, DMSO-d6): δ10.25(s,1H),10.01(s,1H),9.93-9.91(m,1H),8.68(s,1H),8.22- 8.20(m,1H),8.08-7.99(m,2H),7.15-7.13(m,2H),6.95-6.93(m,2H),6.34(br,1H),5.36-5. 33(m,1H),4.03-3.96(m,2H),3.75-3.69(m,5H),3.28-3.25(m,2H),2.80-2.54(m,10H),2.3 1-2.28(m,1H),1.90-1.72(m,3H),1.56-1.54(m,3H),1.37-1.27(m,10H),1.24-1.22(m,2H).

[0660] (26mg) Single-configuration compound (longer retention time):

[0661] MS m / z(ESI):802.8[M+1].

[0662] Chiral HPLC analysis: retention time 10.704 min, chiral purity: 100% (column: ReGIS(S,S)-Whelk-O1 15cm*4, 6mm, 5μm; mobile phase: EtOH / ACN / DEA=80 / 20 / 0.1(V / V / V), flow rate: 1mL / min).

[0663] 1 H NMR (500MHz, DMSO-d6): δ10.25(s,1H),10.01(s,1H),9.93-9.91(m,1H),8.68(s,1H),8.22- 8.20(m,1H),8.07-7.99(m,2H),7.15-7.13(m,2H),6.95-6.93(m,2H),6.35(br,1H),5.36-5. 33(m,1H),4.03-3.95(m,2H),3.74-3.69(m,5H),3.33-3.26(m,2H),2.80-2.68(m,10H),2.3 1-2.28(m,1H),1.90-1.72(m,3H),1.56-1.54(m,3H),1.37-1.27(m,10H),1.24-1.19(m,2H).

[0664] Biological evaluation

[0665] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0666] Test Example 1: Degradation activity of the disclosed compound against BTK expressed in TMD-8 cells.

[0667] This test uses an HTRF assay to assess the degradation effect of the compound on BTK expressed in TMD-8 cells, based on DC... 50 Size and maximum degradation rate D max Evaluate the in vitro activity of the compound.

[0668] TMD8 cells were cultured in RPMI 1640 complete medium containing 10% FBS. On day 1 of the experiment, all suspension cells were transferred to 15 mL centrifuge tubes, centrifuged at 1000 rpm for 3 min, the medium was removed, and the cells were resuspended in 5-10 mL of fresh cell culture medium and counted. The cell density was adjusted to 5 × 10⁶ cells / mL using phenol-free red blood cell medium. 5Cells / mL: 40.5 μL of cell suspension was added to each well of a 96-well cell culture plate. The plate was incubated for 24 hours (37°C, 5% CO2). The next day, the compound was serially diluted 4-fold with DMSO, then 20-fold with phenol red-free medium, and 4.5 μL was added to each well of the cell culture plate. Wells treated with DMSO were positive controls, and wells without cells in culture medium were negative controls. The final DMSO concentration was 0.5%. The final compound concentrations were: 1000, 250, 62.5, 15.63, 3.91, 0.98, 0.24, 0.06, and 0.02 nM. The cells with the added compound were incubated at 37°C, 5% CO2 for 4 hours.

[0669] After compound incubation, add 15 μL of 4× cell lysis buffer to each well and lyse by shaking at room temperature for 30 minutes. After lysis, centrifuge at 2000 rpm for 10 minutes, and transfer 16 μL of the lysate supernatant to the detection plate. Add 4 μL of detection antibody working solution to each well, centrifuge at 1000 rpm for 1 minute, and seal the plate. Incubate the detection plate at 25°C overnight and then read the fluorescence value.

[0670] The DC was calculated using Graphpad Prism 10 software to perform curve fitting between the logarithm of each concentration of the test compound and the corresponding degradation rate. 50 Value. Using the log(inhibitor) vs. response--Variable slope (four parameters) equation in GraphPad Prism 10's nonlinear regression (a four-parameter fit of nonlinear regression with the logarithm of compound concentration minus the inhibition percentage), the DC of the compound was calculated based on the logarithm of the compound concentration and the degradation rate. 50 Value. Degradation rate (%) = (RLU) 阳性对照 -RLU 化合物浓度 ) / (RLU 阳性对照 -RLU 阴性对照 )×100%.

[0671] Table 1. Degradation activity of the compounds disclosed herein against BTK expressed in TMD-8 cells.

[0672] Conclusion: The compound disclosed herein exhibits degradation activity against BTK expressed in TMD-8 cells.

[0673] Test Example 2: Pharmacokinetic Evaluation

[0674] I. C57 mice

[0675] 1. Abstract

[0676] Using C57 mice as test animals, the drug concentrations in plasma at different time points after intragastric administration (i.g.) or intravenous injection (i.v.) of the compounds in the examples were determined by LC / MS / MS method to study the pharmacokinetic behavior of the compounds of the present disclosure in C57 mice and evaluate their pharmacokinetic characteristics.

[0677] 2. Experimental protocol

[0678] 2.1. Test drugs

[0679] The compounds corresponding to the retention time of 7.577 minutes in 6-1 and 6-2.

[0680] 2.2. Test animals

[0681] 18 C57 mice, female, were evenly divided into 2 groups. Provided by Vital River Laboratory Animal Technology Co., Ltd. (SCXK(Beijing)2021-0006).

[0682] 2.3. Drug preparation

[0683] Weighed a certain amount of the test compound respectively, added 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a 0.1 mg / mL clear and transparent solution.

[0684] 2.4. Drug administration

[0685] Intragastric administration: The administration dose was 2 mg / kg, and the administration volume was 20 mL / kg;

[0686] Intravenous injection: The administration dose was 1 mg / kg, and the administration volume was 10 mL / kg.

[0687] 3. Operations

[0688] Intragastric administration: C57 mice were administered intragastrically (i.g.) respectively, and 0.1 mL of blood was collected from the orbital venous plexus at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, 11.0 h, 24.0 h after administration, placed in an EDTA anticoagulant test tube, and plasma was collected after centrifugation.

[0689] Intravenous injection: C57 mice were administered intravenously (i.v.) respectively, and 0.1 mL of blood was collected from the orbital venous plexus at 5 minutes, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 11.0 h, 24.0 h after administration, placed in an EDTA anticoagulant test tube, and plasma was collected after centrifugation.

[0690] Analyze the plasma samples at each time point after drug administration by LC / MS / MS.

[0691] Table 2-1, Pharmacokinetic Parameters of the Compounds of the Present Disclosure in C57 Mice

[0692] Conclusion: The compounds of the present disclosure have high blood drug concentration and high exposure in C57 mice, showing pharmacokinetic advantages.

[0693] II. SD Rats

[0694] 1. Abstract

[0695] Using SD rats as test animals, the LC / MS / MS method was applied to determine the drug concentrations in plasma at different time points after the test compounds were administered by gavage (i.g.) or intravenous injection (i.v.) to SD rats, to study the pharmacokinetic behavior of the compounds of the present disclosure in SD rats and evaluate their pharmacokinetic characteristics.

[0696] 2. Test Protocol

[0697] 2.1. Test Drugs

[0698] The compounds corresponding to the retention time of 7.577 minutes in 6-1 and 6-2.

[0699] 2.2. Test Animals

[0700] 8 SD rats, half male and half female, were evenly divided into 2 groups and provided by Vital River Laboratory Animal Technology Co., Ltd. (SCXK(Beijing)2021-0011).

[0701] 2.3. Drug Preparation

[0702] Weighed a certain amount of the test compounds respectively, added 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a 0.2 mg / mL clear and transparent solution.

[0703] 2.4. Drug Administration

[0704] Gavage: The administration dose was 2 mg / kg and the administration volume was 10 mL / kg;

[0705] Intravenous injection: The administration dose was 1 mg / kg and the administration volume was 5 mL / kg.

[0706] 3. Operations

[0707] Gavage: SD rats were respectively administered by gavage (i.g.), and 0.2 mL of blood was collected from the jugular vein at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, 11.0 h, and 24.0 h after administration, placed in an EDTA anticoagulant test tube, and plasma was collected after centrifugation.

[0708] Intravenous injection: SD rats were administered the drug via intravenous injection (iv). At 5 minutes, 0.2 mL of blood was collected from the jugular vein at 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 8.0 hours, 11.0 hours, and 24.0 hours after administration. The blood was placed in EDTA anticoagulant tubes, centrifuged, and the plasma was collected.

[0709] Plasma samples were analyzed at various time points after drug administration using LC / MS / MS.

[0710] Table 2-2 Pharmacokinetic parameters of the compounds disclosed herein in SD rats

[0711] Conclusion: The compound disclosed herein exhibits high blood concentrations and high exposure levels in SD rats, demonstrating pharmacokinetic advantages.

Claims

A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: B is B 1 For N or CR 1 B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 1 B 2 B 3 and B 4 At least one of them is N; R 1 R 2a R 2b and R 2c The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; R 3 and R 3a The same or different, and each independently selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 3 and R 3a Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, R 1 and R 3 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 4 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups; R 5 Selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. 5a replace; Or, R 4 and R 5 Together with their respective attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 5c replace; Each R 5a and each R 5c The same or different, and each independently selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 -OC(O)R 17 -OC(O)OR 17 -NR 20 C(O)R 17 -NR 20 C(O)OR 17 -S(O) v R 17 -S(O) v NR 18 R 19 =O, =CR 22 R 23 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; W is N or CR 6 ; R 6 Selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; R w Selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuteralkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuteralkyl groups, cyano groups, amino groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups; R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. A replace; Each R A The same or different, and each independently selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; Or, two Rs A Together with the attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 0 replace; Cy1, Cy2, and Cy3 may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; s1, s2 and s3 may be the same or different, and each is independently 0 or 1; Each R 9 R 10 and R 11 The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 =O, =CR 22 R 23 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; Or, two Rs 9 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs 10 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs 11 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two non-adjacent R 9 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 10 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 11 They connect to form bridging alkylene groups; L a L b L c and L d Same or different, and each independently selected from bonds, alkenyl, alkynyl, (CR) a R b ) x O, S(O) v C(O), NR c C(O)NR c and NR c C(O); E is The ring G is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. G replace; R G The same or different, and each independently selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace; Or, two Rs G Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 13 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups; X 1 For N or CR 15 ; R 15 Selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteralkyl, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl; L 1 Selected from bond, O, S, NR c C(O), C(O)NR c and NR c C(O); R a and R b They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl; Or, R a and R b Together with the attached atoms, they form cycloalkyl or heterocyclic groups; R c Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups; R 17 R 18 and R 19 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 18 and R 19 and together with the attached nitrogen atom, form a heterocyclic group, which is optionally surrounded by one or more R atoms. 0 replace; R 20 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups; R 22 and R 23 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuteralkyl groups, hydroxyalkyl groups, and cycloalkyl groups; R 0 They may be the same or different, and each is independently selected from deuterium, =O, =S, =CH2, =CHF, =CF2, halogen, hydroxyl, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkoxyalkyl, aminoalkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6; x is 0, 1, 2, 3, 4 or 5; v is 0, 1, or 2; The condition is that, When ring A is a single ring, ring G is a triple ring; When ring G is monocyclic or bicyclic, ring A is a polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, or polycyclic heteroaryl group. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: B is B 1 For N or CR 1 B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 1 B 2 B 3 and B 4 At least one of them is N; R 1 R 2a R 2b and R 2c The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; R 3 and R 3a The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 3 and R 3a Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, R 1 and R 3 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 4 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups; R 5 Selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. 5a replace; Or, R 4 and R 5 Together with their respective attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 5c replace; Each R 5a and each R 5c The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 -OC(O)R 17 -OC(O)OR 17 -NR 20 C(O)R 17 -NR 20 C(O)OR 17 -S(O) v R 17 -S(O) v NR 18 R 19 =O, =CR 22 R 23 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; W is N or CR 6 ; R 6 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; R w Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups; R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. A replace; Each R A The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; Or, two Rs A Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Cy1, Cy2, and Cy3 may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; s1, s2 and s3 may be the same or different, and each is independently 0 or 1; Each R 9 R 10 and R 11 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 =O, =CR 22 R 23 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; Or, two Rs 9 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs 10 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs 11 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two non-adjacent R 9 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 10 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 11 They connect to form bridging alkylene groups; L a L b L c and L d Same or different, and each independently selected from bonds, alkenyl, alkynyl, (CR) a R b ) x O, S(O) v C(O), NR c C(O)NR c and NR c C(O); E is The ring G is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. G replace; R G The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace; Or, two Rs G Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 13 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups; X 1 For N or CR 15 ; R 15 Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl; L 1 Selected from bond, O, S, NR c C(O), C(O)NR c and NR c C(O); R a and R b They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl; Or, R a and R b Together with the attached atoms, they form cycloalkyl or heterocyclic groups; R c Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups; R 17 R 18 and R 19 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 18 and R 19 and together with the attached nitrogen atom, form a heterocyclic group, which is optionally surrounded by one or more R atoms. 0 replace; R 20 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups; R 22 and R 23 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; R 0 They may be the same or different, and each is independently selected from =O, =S, =CH2, =CHF, =CF2, halogen, hydroxyl, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6; x is 0, 1, 2, 3, 4 or 5; v is 0, 1, or 2; The condition is that, When ring A is a single ring, ring G is a triple ring; When ring G is monocyclic or bicyclic, ring A is a polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, or polycyclic heteroaryl group. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof: in: Cyclone A1 is selected from polycyclic alkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups, each of which is independently selected by one or more R groups. A replace; B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 2 B 3 and B 4 At least one of them is N; R 1 R 2a R 2b R 2c R 3a R 3 To R 5 W, R A R a R b x, Cy1, R 9 m1, L b Ring G and X 1 As defined in claim 1. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, is a compound of general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof: in: Cyclone A1 is selected from polycyclic alkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups, each of which is independently selected by one or more R groups. A replace; B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 2 B 3 and B 4 At least one of them is N; R 12 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace; r can be 0, 1, 2, 3, or 4; m1 can be 0, 1, 2, 3 or 4; X a and X b Whether they are the same or different, and each is independently N or CR x ; R x Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cyano and hydroxyl; q1 and q2 may be the same or different, and each is independently 0, 1, 2, 3 or 4; R 1 R 2a R 2b R 2c R 3a R 3 To R 5 W, R A x, R 9 R 17 -R 19 and R 0 As defined in claim 1. The compound of formula (I) according to claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein ring A1 is selected from... *End and (CR) a R b (CH2)x or (CH2)x are connected together; Z 1 For N or CR 8k Z 2 For N or CR 8m Z 3 For N or CR 8n ;D 1 For N or CR 8p ;D 2 For N or CR 8q ;D 3 For N or CR 8r M is selected from bonds, O, S, and C. 8s R 8t and NR 8w ;R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h R 8i R 8j R 8k R 8m R 8n R 8p R 8q R 8r R 8s R 8t and R 8x The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 Replace; or, R 8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8g and R 8h Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8i and R 8j Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8s and R 8t Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, two R... 8x Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R 8w Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace; X, X c and X d Whether the same or different, and each independently constitutes a CR x Or N; R x Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, cyano groups, and hydroxyl groups; q3 and q4 may be the same or different, and each is independently 0, 1, 2, 3, or 4; n1 and n2 may be the same or different, and each is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, 5, or 6; R 17 -R 19 and R 0 As defined in claim 1; Preferably, ring A1 is selected from The compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, is a compound of general formula (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof. in: B 2 For N or CR 2a B 3 For N or CR 2b B 4 For N or CR 2c The condition is that B 2 B 3 and B 4 At least one of them is N; R 12 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace; r can be 0, 1, 2, 3, or 4; Z 1 For N or CR 8k Z 2 For N or CR 8m ;D 1 For N or CR 8p ;D 2 For N or CR 8q ;D 3 For N or CR 8r M is selected from bonds, O, S, and C. 8s R 8t and NR 8w ;R 8a R 8b R 8c R 8d R 8e R 8f R 8k R 8m R 8p R 8q R 8r R 8s and R 8t The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replace; or, R 8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8s and R 8t Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R 8w Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R groups. 0 replace; X, X a X b X c and X d Whether they are the same or different, and each is independently N or CR x ; R x Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cyano and hydroxyl; q1 and q2 may be the same or different, and each is independently 0, 1, 2, 3 or 4; n1 and n2 may be the same or different, and each can be 0, 1, 2, 3 or 4 independently; m1 can be 0, 1, 2, 3 or 4; R 1 R 2a R 2b R 2c R 3 R 5 x, R 9 R 17 -R 19 and R 0 As defined in claim 1. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; preferably, R 1 C 1-6 Alkyl; more preferably, R 1 It is a methyl group. The compound of general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein B 2 For N; B 3 For CH; B 4 For CH; or, B 2 For CH; B 3 For N; B 4 For CH; or, B 2 For CH; B 3 For CH; B 4 N; preferably, B 2 For CH; B 3 For N; B 4 For CH. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a hydrogen atom or a carbon atom. 1-6 alkyl. The compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 5 It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally coupled with one or more R groups. 5a Replace; R 5a As defined in claim 1; preferably, R 5 Selected from R 5b For hydrogen atoms or R 5a ;R 5a As defined in claim 1; more preferably, R 5 for The compound of general formula (I) according to any one of claims 4 to 10, or a pharmaceutically acceptable salt thereof, wherein X a For N or CH; and / or X b For N or CH; and / or q1 and q2 are the same or different, and each is independently 0 or 1; and / or R 12 r is a hydrogen atom or a halogen; and / or r is 0 or 1. The compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein x is 0 or 1. The compound of formula (I) according to any one of claims 5 to 12, or a pharmaceutically acceptable salt thereof, wherein X is N; and / or Z 1 For N; and / or Z 2 For CH; and / or R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together they form a cyclopropyl group; or, R 8c and R 8d Together they form a cyclopropyl group; or, R 8e and R 8f Together they form a cyclopropyl group; And / or M is 0; and / or n1 and n2 are the same or different, and each is independently 0 or 1; and / or X c For N or CH; and / or X d For N or CH; and / or D 1 For CH; D 2 For CH; D 3 Let N be the number of elements in the array. The compound of general formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, is selected from the following compounds: A compound of general formula (IV-1A) or general formula (IV-2A), or a salt thereof. in: R m1 and R m2 Each is independently protected by a hydrogen atom or an amino group; R 1 B 2 B 3 B 4 R 3 R 5 Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e R 8f D 1 D 2 D 3 M, X c n1 and n2 are as defined in claim 6. The compound or a salt thereof according to claim 15 is selected from the following compounds: A method for preparing the compound according to claim 6 or a pharmaceutically acceptable salt thereof, comprising: The compound of general formula (IV-1A) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB-1) or its salt to give the compound of general formula (IV-1) or its pharmaceutically usable salt. in: R m2 For hydrogen atoms; R m1 It is a hydrogen atom or an amino protecting group; x is 0; X a CH; X is N; R 1 B 2 B 3 B 4 R 3 R 5 Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e R 8f X b R 9 m1, q1, q2, R 12 and r as defined in claim 6; or, The compound of general formula (IV-1A) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB-2) or its salt to give the compound of general formula (IV-1) or its pharmaceutically usable salt. in: R m2 For hydrogen atoms; R m1 It is a hydrogen atom or an amino protecting group; x6 can be 0, 1, 2, 3, or 4; x is 1, 2, 3, 4 or 5; X is N; R 1 B 2 B 3 B 4 R 3 R 5 Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e R 8f X a X b R 9 m1, q1, q2, R 12 and r as defined in claim 6; The compound of general formula (IV-2A) or its salt reacts with the compound of general formula (IVB-1) or its salt to undergo a reductive amination reaction to give the compound of general formula (IV-2) or its pharmaceutically usable salt. in: R m2 For hydrogen atoms; R m1 It is a hydrogen atom or an amino protecting group; x is 0; X a For CH; X d Let N be the number of people in the group. R 1 B 2 B 3 B 4 R 3 R 5 D 1 D 2 D 3 M, n1, n2, X c X b R 9 m1, q1, q2, R 12 and r as defined in claim 6; or, The compound of general formula (IV-2A) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB-2) or its salt to give the compound of general formula (IV-2) or its pharmaceutically usable salt. in: R m2 For hydrogen atoms; R m1 It is a hydrogen atom or an amino protecting group; x6 can be 0, 1, 2, 3, or 4; x is 1, 2, 3, 4 or 5; X d Let N be the number of people in the group. R 1 B 2 B 3 B 4 R 3 R 5 D 1 D 2 D 3 M, n1, n2, X c X a X b R 9 m1, q1, q2, R 12 and r as defined in claim 6. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of the compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 18 in the preparation of a medicament for inhibiting or degrading BTK. Use of the compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 18 in the preparation of a medicament for the treatment and / or prevention of diseases or conditions mediated or dependent on BTK. The use of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for the treatment and / or prevention of tumors or autoimmune diseases, preferably in the preparation of a medicament for the treatment and / or prevention of leukemia or lymphoma, more preferably in the preparation of a medicament for the treatment and / or prevention of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma, follicular lymphoma, lymphoblastic lymphoma, marginal zone lymphoma (MZL), non-Hodgkin lymphoma (NHL), B-cell non-Hodgkin lymphoma, mantle cell lymphoma (MCL), and B-cell lymphoma.

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