Heteroaryl compound, preparation method therefor, and pharmaceutical use thereof

Abstract

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

Description

A heteroaryl compound, its preparation method and its pharmaceutical application Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a heteroaryl compound of general formula (I), a method for its preparation, a pharmaceutical composition containing the heteroaryl compound, and its use as a therapeutic agent, particularly as a BTK inhibitor or degrader, and in the preparation of medicaments for the treatment and / or prevention of BTK-mediated or dependent diseases or conditions. Background Technology

[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 C481 mutation generated in patients has been effectively suppressed, new resistance mutations against Pirtobrutinib have emerged, such as L528W (Jennifer A. Woyach et al., Clin Oncol. 2017 May 1; 35(13):1437-1443; Piers Blombery et al., Blood Adv (2022) 6(20):5589–5592). Marketed and investigational BTK covalent or non-covalent inhibitors all bind to the ATP pocket, with Novartis' Remibrutinib and Roche's Fenebrutinib additionally binding to the H3 pocket, improving inhibitor selectivity. However, molecules with several 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 this scaffold function.

[0004] PROTAC (Proteolysis-Targeting Chimera) is a drug formulation 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, prompting the E3 ubiquitin ligase to ubiquitinate the target protein, thereby degrading it (Lin Zhao et al., Signal Transduct Target Ther. 2022 Apr 4; 7(1):113). Therefore, after PROTAC molecules degrade the protein, they 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 molecules with an affinity for target proteins below 500 nM may cause protein degradation (Miklós Békés et al., Nat Rev Drug Discov. 2022 Mar; 21(3):181-200). Therefore, PROTAC molecules may also be effective against mutations that cause weak binding of small molecule inhibitors.

[0005] Relapse of cancers such as CLL or mantle cell lymphoma (MCL) after covalent BTK inhibitor therapy is an increasingly important and clinically significant problem (Wayach JA et al., J Clin Oncol, 2017, 35:1437-1443). Therefore, one object of this disclosure is to provide a BTK PROTAC 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 They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0012] Or, R 3 and R 3a 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;

[0013] 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;

[0014] R 4 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0015] 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;

[0016] Or, R 4 and R 5Together 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;

[0017] 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;

[0018] W is N or CR 6 ;

[0019] R 6 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; each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R0 replace;

[0020] 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;

[0021] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0022] Cy, Cy1, Cy2 and Cy3 may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0023] s1, s2 and s3 may be the same or different, and each is independently 0 or 1;

[0024] Each R 8 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 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;

[0025] Or, two Rs 8 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;

[0026] Or, two Rs 9 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;

[0027] Or, two Rs 10Together 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;

[0028] Or, two Rs 11 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;

[0029] Or, two non-adjacent R 8 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 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;

[0030] 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);

[0031] E is selected from

[0032] 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 ;

[0033] Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom and is related to L d Connected, the other three are the same or different, and each is independently N or CR. 12 ;

[0034] R 12The 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;

[0035] R 13 and R 14 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and heterocyclic groups;

[0036] X 1 For N or CR 15 ;

[0037] R 15 Selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteralkyl, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl;

[0038] Y 1 and Y 2 Same or different, and each is independently selected from the key, (CR a R b ) y O, S, NR c and C(O);

[0039] L 1 Selected from key, (CR) a R b ) z 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] R c 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 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] m, m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0048] x, y, and z are each independently 0, 1, 2, 3, 4, or 5;

[0049] v can be 0, 1, or 2.

[0050] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0051] in:

[0052] B is

[0053] 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;

[0054] 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 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;

[0055] R 3 and R 3a They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0056] Or, R 3 and R 3a 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;

[0057] Or, R1 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;

[0058] R 4 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0059] 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;

[0060] 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;

[0061] 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 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;

[0062] W is N or CR 6 ;

[0063] R 6 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; 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] 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;

[0065] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0066] Cy, Cy1, Cy2 and Cy3 may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0067] s1, s2 and s3 may be the same or different, and each is independently 0 or 1;

[0068] Each R 8 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;

[0069] Or, two Rs 8 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;

[0070] Or, two Rs 9 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] Or, two Rs 10 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;

[0072] Or, two Rs 11 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;

[0073] Or, two non-adjacent R 8 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 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;

[0074] 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);

[0075] E is selected from

[0076] 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;

[0077] Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom and is related to L d Connected, the other three are the same or different, and each is independently N or CR. 12 ;

[0078] 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 0 replace;

[0079] R 13 and R 14 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and heterocyclic groups;

[0080] X 1 For N or CR 15 ;

[0081] R 15 Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl;

[0082] Y 1 and Y 2 Same or different, and each is independently selected from the key, (CR a R b ) y O, S, NR c and C(O);

[0083] L 1 Selected from key, (CR) a R b ) z O, S, NR c C(O), C(O)NR c and NRc C(O);

[0084] 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;

[0085] Or, R a and R b Together with the attached atoms, they form cycloalkyl or heterocyclic groups;

[0086] R c Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0087] 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;

[0088] R 20 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0089] R 22 and R 23 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0090] 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;

[0091] m, m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0092] x, y, and z are each independently 0, 1, 2, 3, 4, or 5;

[0093] v can be 0, 1, or 2.

[0094] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein 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 B 2 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, B1 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.

[0095] 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.

[0096] 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.

[0097] In some embodiments of this disclosure, s1 is 1.

[0098] In some embodiments of this disclosure, s2 is 1.

[0099] In some embodiments of this disclosure, s3 is 0.

[0100] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein s1 is 1; s2 is 1; and s3 is 0.

[0101] In some embodiments disclosed herein, L a For (CR) a R b ) x ;R a R b And x is as defined in general formula (I); in some implementations, La (CH2) x ;x as defined in general formula (I); in some implementations, L a For a bond or CH2; in some implementations, L a For key; in some implementations, L a It is CH2.

[0102] In some embodiments disclosed herein, L b For (CR) a R b ) x ;R a R b And x is as defined in general formula (I); in some implementations, L b (CH2) x ;x as defined in general formula (I); in some implementations, L b For a bond or CH2; in some implementations, L b For key; in some implementations, L b It is CH2.

[0103] In some embodiments disclosed herein, L d For (CR) a R b ) x ;R a R b And x is as defined in general formula (I); in some implementations, L d (CH2) x ;x as defined in general formula (I); in some implementations, L d For a bond or CH2; in some implementations, L d For key; in some implementations, L d It is CH2.

[0104] In some embodiments of this disclosure, cycloCy3 is a 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic group; in some embodiments, cycloCy3 is a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group; in some embodiments, cycloCy3 is a 4- to 12-membered heterocyclic group; in some embodiments, cycloCy3 is a 4- to 6-membered heterocyclic group; in some embodiments, cycloCy3 is a 6-membered cycloalkyl or a 6-membered heterocyclic group; in some embodiments, cycloCy3 is selected from cyclobutane, azacyclobutane, pyrrolidinyl, cyclohexyl, piperidinyl, and piperazine; in some embodiments, cycloCy3 is selected from piperazine, piperidinyl, and azacyclobutane.

[0105] In some embodiments disclosed herein, Cy3 is selected from... In some implementations, Cy3 is selected from... In some implementations, 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.

[0106] In some embodiments of this disclosure, E is G 1 G 2 G 3 G 4 G 5 L 1 X 1 and R 13 As defined in general formula (I); in some implementations, E is r is 0, 1, 2, 3, or 4; R 12 and X 1 As defined in general formula (I); in some implementations, E is r is 0, 1, 2, 3, or 4; R 12 As defined in general formula (I); in some implementations, E is r is 0, 1, 2, 3, or 4; R 12 As defined in general formula (I); in some implementations, E is 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 group; r is 0, 1, or 2; in some embodiments, E is... R 12 As defined in general formula (I); in some implementations, E is selected from... In some implementations, E is In some implementations, E is

[0107] In some embodiments of this disclosure, E is Q 1 Q 3 and Q 4 Each is independently N or CR 12 ;Y 2 and R12 As defined in general formula (I); in some implementations, E is r is 0, 1, 2, or 3; R 12 As defined in general formula (I); in some implementations, E is r is 0, 1, 2, or 3; R 12 As defined in general formula (I); in some implementations, E is selected from... In some implementations, E is selected from

[0108] 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 in general formula (I); 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 Whether the same or different, and each independently constitutes a CR 12 ;R 12 As defined in general formula (I); 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 in general formula (I); 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.

[0109] In some embodiments disclosed herein, Q 2 It is a carbon atom and is related to L d Connected, Q 1 Q 3 and Q4 Whether they are the same or different, and each is independently N or CR 12 ;R 12 As defined in general formula (I); in some implementations, Q 2 It is a carbon atom and is related to L d Connected, Q 1 Q 3 and Q 4 Whether the same or different, and each independently constitutes a CR 12 ;R 12 As defined in general formula (I); in some implementations, Q 2 It is a carbon atom and is related to L d Connected, Q 1 Q 3 and Q 4 For CH; in some implementations, Q 1 It is a carbon atom and is related to L d Connected, Q 2 Q 3 and Q 4 Whether they are the same or different, and each is independently N or CR 12 ;R 12 As defined in general formula (I); in some implementations, Q 1 It is a carbon atom and is related to L d Connected, Q 2 Q 3 and Q 4 Whether the same or different, and each independently constitutes a CR 12 ;R 12 As defined in general formula (I); in some implementations, Q 1 It is a carbon atom and is related to L d Connected, Q 2 Q 3 and Q 4 For CH.

[0110] 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.

[0111] In some embodiments disclosed herein, R 14 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 14 C 1-6 Alkyl; in some embodiments, R 14 It is a methyl group.

[0112] In some embodiments disclosed herein, L 1Selected from bonds, NH and C(O)NH; in some embodiments, L 1 For key.

[0113] In some embodiments disclosed herein, Y 1 and Y 2 They may be the same or different, and each is independently C(O) or CH2; in some implementations, Y 1 and Y 2 For C(O); in some implementations, Y 1 For C(O); Y 2 For CH2; in some implementations, Y 1 CH2; Y 2 It is C(O).

[0114] In some embodiments of this disclosure, y is 1.

[0115] In some embodiments of this disclosure, z is 0 or 1; in other embodiments, z is 0.

[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) or general formula (III) or a pharmaceutically acceptable salt thereof.

[0117] in:

[0118] 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;

[0119] r can be 0, 1, 2, 3, or 4;

[0120] R 1 R 2a R 2b R 2c R 3a R 3 To R 5 W, Cy, R 8 m, Cy1, R 9 m1, R a R b x, Cy2, R 10 m2, L c R 12 and X 1As defined in general formula (I).

[0121] In some embodiments disclosed herein, L c For (CR) a R b ) x ;R a R b And x is as defined in general formula (I); in some implementations, L c (CH2) x ;x as defined in general formula (I); in some implementations, L c For a bond or CH2; in some implementations, L c For key; in some implementations, L c It is CH2.

[0122] 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 8-membered cycloalkyl or a 4- to 8-membered heterocyclic group; in some embodiments, cycloCy1 is a 4- to 8-membered heterocyclic group; in some embodiments, cycloCy1 is a 6-membered cycloalkyl or a 6-membered heterocyclic group; in some embodiments, cycloCy1 is a 6-membered heterocyclic group; in some embodiments, cycloCy1 is selected from cyclobutane, aziridine, cyclopentyl, pyrrolidinyl, cyclohexyl, piperidinyl, and piperazine; in some embodiments, cycloCy1 is piperazine or piperidinyl; in some embodiments, cycloCy1 is piperazine.

[0123] In some embodiments disclosed herein, Cy1 is X a X b q1 and q2 are as defined in general formula (IV) or general formula (V); in some implementations, ring Cy1 is X a q1 and q2 are as defined in general formula (IV) or general formula (V); in some embodiments, ring Cy1 is selected from In some implementations, the ring Cy1 is selected from In some implementations, 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 Or connected to the Cy ring.

[0124] In some implementation schemes disclosed herein, for X a X b and R 9 As defined in general formula (IV) or general formula (V); in some implementations, Selected from In some implementation schemes, for *End and L b or (CR) a R b ) x Connected; End and L a Or connected to the Cy ring.

[0125] In some embodiments of this disclosure, cycloCy2 is a 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclic group; in some embodiments, cycloCy2 is a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group; in some embodiments, cycloCy2 is a 4- to 12-membered heterocyclic group; in some embodiments, cycloCy2 is a 4- to 6-membered heterocyclic group; in some embodiments, cycloCy2 is a 6-membered cycloalkyl or a 6-membered heterocyclic group; in some embodiments, cycloCy2 is selected from cyclobutane, aziridine, cyclopentyl, pyrrolidinyl, cyclohexyl, piperidinyl, and piperazine; in some embodiments, cycloCy2 is aziridine, piperidinyl, and piperazine; in some embodiments, cycloCy2 is piperidinyl or piperazine; in some embodiments, cycloCy2 is piperidinyl.

[0126] In some embodiments disclosed herein, Cy2 is X c X d q3 and q4 are as defined in general formula (IV) or general formula (V); in some implementations, ring Cy2 is q3 and q4 are each independently 0, 1, 2, 3, or 4; in some implementations, ring Cy2 is q3 and q4 are each independently 0, 1, 2, 3, or 4; in some implementations, ring Cy2 is selected from... In some implementations, Cy2 is selected from... In some implementations, Cy2 is... In some implementations, Cy2 is... In some implementations, Cy2 is... In the above implementation schemes, *terminal and L c Connected; End and L b or (CR) a R b (connected)

[0127] 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.

[0128] 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.

[0129] 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.

[0130] In some implementation schemes disclosed herein, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for

[0131] In some embodiments of this disclosure, m is 0, 1, or 2; in some embodiments, m is 0 or 1; in some embodiments, m is 1; and in some embodiments, m is 0.

[0132] In some embodiments of this disclosure, the cyclic Cy is phenyl or a 5- or 6-membered heteroaryl group; in some embodiments, the cyclic Cy is a 5- or 6-membered heteroaryl group; in some embodiments, the cyclic Cy is a 6-membered heteroaryl group; in some embodiments, the cyclic Cy is pyridyl or phenyl; in some embodiments, the cyclic Cy is pyridyl; in some embodiments, the cyclic Cy is selected from... In some implementations, the Cy ring is In some implementations, the Cy ring is *End and L a Or connected to Cy1.

[0133] In some implementation schemes disclosed herein, Selected from m is 0, 1, 2, or 3; 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 As defined in general formula (I); in some implementations, Selected from A 2 A 3 and A 4 Whether they are the same or different, and each is independently N or CR 8 ;R 8 As defined in general formula (I); in some implementations, Selected from In some implementation schemes, for In some implementation schemes, for *End and L a Or connected to Cy1.

[0134] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), or general formula (III), or pharmaceutically acceptable salts thereof, are compounds represented by general formula (IV) or general formula (V), or pharmaceutically acceptable salts thereof.

[0135] in:

[0136] A 1 A 2 A 3 and A 4 Whether they are the same or different, and each is independently N or CR 8 ;

[0137] 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;

[0138] X a X b X c and X d Whether they are the same or different, and each is independently N or CR x ;

[0139] R x Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cyano and hydroxyl;

[0140] q1, q2, q3 and q4 may be the same or different, and each is independently 0, 1, 2, 3 or 4;

[0141] m1 and m2 may be the same or different, and each can be 0, 1, 2, 3 or 4 independently;

[0142] r can be 0, 1, 2, 3, or 4;

[0143] R 1 R 2a R 2b R 2c R 3a R 3 To R 5 W, R 8 R 9 x, R 10 and R 12 As defined in general formula (I).

[0144] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (II), or general formula (IV), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof.

[0145] in:

[0146] R 1 B 2 B 3 B 4 R 3 R 5 A 4 R 9 X a X b X c X d x, q3 and q4 are as defined in general formula (IV).

[0147] In some implementation schemes disclosed herein, for R 9As defined in general formula (I); in some implementations, for *Terminal and (CH2) x Connected.

[0148] In some implementation schemes, R 1 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 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 Selected from 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, R 1 It is a deuterated methyl group.

[0149] 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 1-6Halogenated 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.

[0150] 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 CR 2a 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; B4 For CH.

[0151] In some implementation schemes, R 3a Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 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.

[0152] In some embodiments disclosed herein, R 3 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 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;

[0153] In some implementation schemes, 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 It is methyl;

[0154] In some implementation schemes, R 3 It is a deuterated methyl group.

[0155] 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.

[0156] 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.

[0157] In some embodiments disclosed herein, R 3a It is a hydrogen atom; and / or R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; and / or R 4 It is a hydrogen atom.

[0158] In some implementation schemes disclosed herein, Selected from In some implementation schemes, for *Terminal and B 2 The rings they belong to are connected.

[0159] 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 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 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

[0160] 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 1-6Halogenated 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

[0161] In some embodiments disclosed herein, R 5b Selected from hydrogen atoms, 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 5b Selected from hydrogen atoms, C 1-6 Alkyl groups and optionally one or more C 1-6 Alkyl-substituted 3- to 6-membered cycloalkyl groups; in some embodiments, R 5b It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 5b 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, R5b tert-butyl or In some implementation schemes, R 5b For hydrogen atoms; in some implementations, R 5b It is a hydrogen atom or a tert-butyl group; in some embodiments, R 5b For tert-butyl; in some implementations, R 5b for

[0162] In some embodiments disclosed herein, R 4 and R 5 Together with their respective connected 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- to 15-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 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 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 8- to 10-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 9-membered heterocyclic group; 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 11- to 13-membered heterocyclic groups; 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 12-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 13- to 15-membered heterocyclic group is replaced; in some embodiments, R 4 and R 5Together with the connected atoms, they form an optional structure formed by one or more R atoms. 5c The substituted 14-membered heterocyclic group; R in the above schemes 5c As defined in general formula (I).

[0163] 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; R 5m For R 5c Or, two Rs 5m Together with their respective attached atoms, they form cycloalkyl or heterocyclic groups; each cycloalkyl and heterocyclic group is independently and optionally influenced by one or more R groups. 5c Replace; R 5n For R 5c Or, two Rs 5n Together with the attached atoms, they form cycloalkyl or heterocyclic groups; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 5c Replacement; Y is N or CR 5e ;R 5j R 5d and R 5e They may be the same or different, and each is independently a hydrogen atom or R. 5c ;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);

[0164] 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

[0165] In some embodiments disclosed herein, Y represents CR 5e ;R 5eFor hydrogen atoms or R 5c ;R 5c As defined in general formula (I); in some implementations, Y is CR 5e ;R 5e Y is a hydrogen atom or a halogen; in some embodiments, Y is CH or CF; in some embodiments, Y is CH.

[0166] 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 and 3- to 6-membered cycloalkyl; in some embodiments, R 5c They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 5c They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 5c They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and cyclopropyl; in some embodiments, R 5c They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; in some embodiments, R 5c They may be the same or different, and each is independently selected from F, methyl and cyclopropyl.

[0167] In some embodiments disclosed herein, R 5m 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 and 3- to 6-membered cycloalkyl; in some embodiments, R 5m Selected from halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 5m Selected from halogens, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 5m It is a 3- to 6-membered cycloalkyl group; in some embodiments, R 5m It is cyclopropyl.

[0168] In some embodiments disclosed herein, R5n 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 and 3- to 6-membered cycloalkyl; or, two R atoms on the same carbon atom 5n Together they form 3- to 6-membered cycloalkyl groups; in some embodiments, R 5n C 1-6 Alkyl group; or, two R atoms on the same carbon atom. 5n Together they form 3- to 6-membered cycloalkyl groups; in some embodiments, R 5n C 1-6 Alkyl group; or, two R atoms on the same carbon atom. 5n Together they form a cyclopropyl group; in some embodiments, R 5n It is a methyl group; or, two R atoms on the same carbon atom. 5n Together they form a cyclopropyl group; in some embodiments, R 5n C 1-6 Alkyl; in some embodiments, R 5n For methyl; in some embodiments, the two R atoms on the same carbon atom 5n Together they form 3- to 6-membered cycloalkyl groups; in some embodiments, the two R atoms on the same carbon atom 5n Together they form a cyclopropyl group.

[0169] In some embodiments disclosed herein, R 5j 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 5j Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; in some embodiments, R 5j Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; in some embodiments, R 5j It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 5j Selected from hydrogen atoms, methyl groups, and hydroxymethyl groups; in some embodiments, R 5j It is a hydrogen atom.

[0170] In some embodiments disclosed herein, R 5d Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C1-6 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 5d Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; in some embodiments, R 5d Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; in some embodiments, R 5d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 5d Selected from hydrogen atoms, methyl groups, and hydroxymethyl groups; in some embodiments, R 5d It is a hydrogen atom.

[0171] 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 It is a hydrogen atom or F; in some implementations, R 5e For hydrogen atoms; in some implementations, R 5e It is F.

[0172] 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 1-6 Alkyl 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

[0173] In some embodiments of this disclosure, t is 1 or 2; in other embodiments, t is 1.

[0174] In some embodiments of this disclosure, f1 is 0, 1, or 2; in some embodiments, f1 is 0 or 1; in some embodiments, f1 is 1; and in some embodiments, f1 is 0.

[0175] In some embodiments of this disclosure, f2 is 0, 1, or 2; in some embodiments, f2 is 0 or 1; in some embodiments, f2 is 1; and in some embodiments, f2 is 0.

[0176] In some embodiments of this disclosure, f1 is 1; f2 is 1.

[0177] 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.

[0178] In some embodiments of this disclosure, k2 is 0, 1, or 2; in some embodiments, k2 is 2.

[0179] In some embodiments of this disclosure, k3 is 0, 1, or 2; in some embodiments, k3 is 0 or 1; and in some embodiments, k3 is 0.

[0180] In some implementation schemes disclosed herein, It is a single key; in some implementations, It is a double bond.

[0181] 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.

[0182] 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.

[0183] In some embodiments disclosed herein, A 1 A 2 and A 3 Whether the same or different, and each independently constitutes a CR 8 A 4 For N; or, A 1 A 2 and A 4 Whether the same or different, and each independently constitutes a CR 8 A3 For N; R 8 As defined in general formula (I); 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 For N; in some implementations, A 1 A 2 and A 3 For CH, A 4 For CH or 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 It can be CH or N.

[0184] 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.

[0185] 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.

[0186] In some embodiments disclosed herein, X a For N or CH; in some implementations, X a For N; in some implementations, X a For CH.

[0187] In some embodiments disclosed herein, X b For N or CH; in some implementations, X b For N; in some implementations, X b For CH.

[0188] In some embodiments disclosed herein, X c For N or CH; in some implementations, X c For N; in some implementations, X c For CH.

[0189] In some embodiments disclosed herein, X d For N or CH; in some implementations, X d For N; in some implementations, X d For CH.

[0190] In some embodiments of this disclosure, q1 and q2, q3 and q4 are the same or different, and each is independently 0, 1 or 2; in some embodiments, q1 and q2, q3 and q4 are the same or different, and each is independently 0 or 1; in some embodiments, q1 and q2 are the same or different, and each is independently 0, 1 or 2; in some embodiments, q1 and q2 are 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; in some embodiments, q3 and q4 are the same or different, and each is independently 0, 1 or 2; in some embodiments, q3 and q4 are the same or different, and each is independently 0 or 1; in some embodiments, q3 is 1; q4 is 1; in some embodiments, q3 is 0; q4 is 0.

[0191] In some embodiments of this disclosure, x is 0 or 1; in some embodiments, x is 0; and in some embodiments, x is 1.

[0192] In some embodiments disclosed herein, X a For N or CH; X b For N or CH; X c For N or CH; X d It is N or CH; and / or q1, q2, q3, and q4 are the same or different, and each is independently 0 or 1; and / or x is 0 or 1; in some implementations, X a For N; Xb For N; X c For CH; X d The q1, q2, q3, and q4 are N; and / or q1, q2, q3, and q4 are 1.

[0193] In some embodiments disclosed herein, each R 9 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 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; in some embodiments, each R 9 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 Halogenated alkyl; in some embodiments, R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 9 For methyl; in some embodiments, R 9 It is a hydrogen atom.

[0194] 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 of this disclosure, two R atoms on the same carbon atom... 9 Together with the attached carbon atom, they form a cyclopropyl group.

[0195] 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 ethylene (-CH2CH2-).

[0196] In some embodiments of this disclosure, m1 is 0, 1, or 2; in some embodiments, m1 is 0 or 1; in some embodiments, m1 is 1; and in some embodiments, m1 is 0.

[0197] In some embodiments disclosed herein, each R 10 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 R10 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; in some embodiments, each R 10 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 Halogenated alkyl; in some embodiments, R 10 It is a hydrogen atom.

[0198] In some embodiments disclosed herein, two R 10 Together with the adjacent atoms, they form a 3- to 6-membered cycloalkyl group; in some embodiments of this disclosure, two R atoms on the same carbon atom... 10 Together with the attached carbon atom, they form a cyclopropyl group.

[0199] In some embodiments of this disclosure, 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 ethylene (-CH2CH2-).

[0200] In some embodiments of this disclosure, m2 is 0, 1, or 2; in some embodiments, m2 is 0 or 1; and in some embodiments, m2 is 0.

[0201] In some embodiments disclosed herein, each 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 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; in some embodiments, each 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 1-6 Halogenated alkyl; in some embodiments, R 11 It is a hydrogen atom.

[0202] In some embodiments of this disclosure, m3 is 0, 1, or 2; in some embodiments, m3 is 0 or 1; and in some embodiments, m3 is 0.

[0203] 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.

[0204] 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 It is a hydrogen atom or F; in some implementations, R 12 It is a hydrogen atom.

[0205] In some embodiments disclosed herein, R 12 r is a hydrogen atom or a halogen; and / or r is 0 or 1.

[0206] In some embodiments disclosed herein, R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; and / or m1 is 0 or 1; and / or R 10 It is a hydrogen atom; and / or R 12 r is a hydrogen atom or a halogen; and / or r is 0 or 1.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] In some embodiments of this disclosure, v is 0; in some embodiments, v is 1; and in some embodiments, v is 2.

[0212] In some embodiments disclosed herein, R c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R c It is a hydrogen atom.

[0213] 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 Halogenated alkyl groups 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 halogen or =O; in some implementations, R 0 It is a halogen.

[0214] In some implementation schemes disclosed herein, Each independently selected

[0215] In some implementation schemes, selected from In some implementation schemes, for In each of the above embodiments, the * end is connected to E or a phenyl group.

[0216] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof,

[0217] Where: R 1 C 1-6 Alkyl; 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 CR 2a B 3 For CR 2b B 4 For N; 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; R 3a For hydrogen atoms; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 4 For hydrogen atoms; 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; W is CH; 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 atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; X a For N or CH; X b For N or CH; X c For N or CH; X d It is N or CH; q1 and q2, q3 and q4 are the same or different, and each is independently 0 or 1; x is 0 or 1; each R 9 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 Haloalkyl; m1 is 0, 1 or 2; each R 10 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 Haloalkyl; m2 is 0, 1 or 2; each R 12They may be the same or different, and each is independently a hydrogen atom or a halogen; r is 0 or 1.

[0218] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof,

[0219] 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 3a For hydrogen atoms; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 4 For hydrogen atoms; R 5 for W stands for CH; 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; X a For N or CH; X b For N or CH; X c For N or CH; X d It is N or CH; q1 and q2, q3 and q4 are the same or different, and each is 0 or 1 independently; x is 0 or 1; m1 is 0; m2 is 0; r is 0.

[0220] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof,

[0221] 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 4For CH; or, B 2 For CH; B 3 For CH; B 4 For N; R 3a For hydrogen atoms; R 3 It is a hydrogen atom or a methyl group; R 4 For hydrogen atoms; R 5 for W stands for CH; A 1 A 2 and A 3 For CH; A 4 For CH or N; X a For N or CH; X b For N or CH; X c For N or CH; X d For N or CH; q1 and q2 are 1; m1 is 0 or 1; R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl group; x is 1; q3 and q4 are each independently 0 or 1; m2 is 0; r is 0.

[0222] In some embodiments of this disclosure, the compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof,

[0223] Where: R 1 Methyl; 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 methyl group; R 5 for A 4 For CH or N; X a For N; X b For N; X c For CH; X d For N; R 9 It represents a hydrogen atom or a methyl group; x is 1; q3 and q4 are 1.

[0224] Table A lists typical compounds disclosed herein, including but not limited to:

[0225] This disclosure provides a compound of general formula (IVa) or a salt thereof.

[0226] in:

[0227] R w1 and R w2 Each is independently protected by a hydrogen atom or an amino group;

[0228] R 1 B 2 B 3 B 4 R 3a R 3 To R 5 W, A 1 A 2 A 3 A 4 X a q1, q2, R 9 m1 is as defined in general formula (IV).

[0229] This disclosure provides a compound of general formula (IVA) or general formula (VA) or a salt thereof.

[0230] in:

[0231] R 1 B 2 B 3 B 4 R 3a R 3 To R 5 W, A 1 A 2 A 3 A 4 X a q1, q2, R 9 m1 is as defined in general formula (IV) or general formula (V).

[0232] This disclosure provides a compound of general formula (VIa) or a salt thereof.

[0233] in:

[0234] R w1 and R w2 Each is independently protected by a hydrogen atom or an amino group;

[0235] R 1 B 2 B 3 B 4 R 3 R 5 A 4 Xa and R 9 As defined in general formula (VI).

[0236] In some embodiments, the amino protecting group is Boc or -SO2Ph; in some embodiments, the amino protecting group is Boc.

[0237] In some embodiments of this disclosure, R w1 and R w2 Each is an independent amino protecting group; in some embodiments, R w1 For Boc; R w2 For -SO2Ph; in some implementations, R w1 R is an amino protecting group. w2 For hydrogen atoms; in some implementations, R w1 For Boc, R w2 For hydrogen atoms; in some implementations, R w1 For hydrogen atoms, R w2 It is a hydrogen atom.

[0238] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0239] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0240] The compound represented by general formula (IVA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (IVB-1) or its salt to give the compound represented by general formula (IV) or its pharmaceutically usable salt.

[0241] in:

[0242] x is 0; X b For N; X c For CH;

[0243] R 1 B 2 B 3 B 4 R 3a R 3 To R 5 W, A 1 A 2 A 3 A 4 X a q1, q2, R 9m1, q3, q4, R 10 m2, X d R 12 And r as defined in general formula (IV);

[0244] or,

[0245] The compound represented by general formula (IVA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (IVB-2) or its salt to give the compound represented by general formula (IV) or its pharmaceutically usable salt.

[0246] in:

[0247] X b Let N be the number of people in the group.

[0248] x6 is 0, 1, 2, 3, or 4; in some implementations, x6 is 0;

[0249] x is 1, 2, 3, 4 or 5;

[0250] R 1 B 2 B 3 B 4 R 3a R 3 To R 5 W, A 1 A 2 A 3 A 4 X a q1, q2, R 9 m1, q3, q4, R 10 m2, X c X d R 12 And r are as defined in general formula (IV).

[0251] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0252] The compound represented by general formula (IVA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (IVB-2) or its salt to give the compound represented by general formula (IV) or its pharmaceutically usable salt.

[0253] in:

[0254] X b Let N be the number of people in the group.

[0255] x6 is 0, 1, 2, 3, or 4; in some implementations, x6 is 0;

[0256] x is 1, 2, 3, 4 or 5;

[0257] R 1 B 2 B 3 B 4 R 3a R 3 To R 5 W, A 1 A 2 A 3 A 4 X a q1, q2, R 9 m1, q3, q4, R 10 m2, X c X d R 12 And r are as defined in general formula (IV).

[0258] Another aspect of this disclosure relates to a method for preparing a compound of general formula (VI) or a pharmaceutically acceptable salt thereof, comprising:

[0259] The compound of general formula (VIa) or its salt undergoes a reductive amination reaction with the compound of general formula (VIb) or its salt to give the compound of general formula (VI) or its pharmaceutically usable salt.

[0260] in:

[0261] R w1 It is a hydrogen atom;

[0262] R w2 It is a hydrogen atom;

[0263] X b For N; X c For CH;

[0264] x is 1;

[0265] R 1 B 2 B 3 B 4 R 3 R 5 A 4 X a R 9 X d q3 and q4 are as defined in general formula (VI).

[0266] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V) or a pharmaceutically acceptable salt thereof, comprising:

[0267] The compound represented by general formula (VA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (IVB-1) or its salt to give the compound represented by general formula (V) or its pharmaceutically usable salt.

[0268] in:

[0269] x is 0; X b For N; X c For CH;

[0270] R 1 B 2 B 3 B 4 R 3a R 3 To R 5 A 1 A 2 A 3 A 4 X a q1, q2, R 9 m1, q3, q4, R 10 m2, X d R 12 And r is as defined in general formula (V);

[0271] or,

[0272] The compound represented by general formula (VA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (IVB-2) or its salt to give the compound represented by general formula (V) or its pharmaceutically usable salt.

[0273] in:

[0274] X b Let N be the number of people in the group.

[0275] x6 is 0, 1, 2, 3, or 4; in some implementations, x6 is 0;

[0276] x is 1, 2, 3, 4 or 5;

[0277] R 1 B 2 B 3 B 4 R 3a R 3 To R 5 A 1 A 2 A 3 A 4 X a q1, q2, R 9 m1, q3, q4, R 10m2, X c X d R 12 And r is as defined in general formula (V).

[0278] In some embodiments of this disclosure, x6 is 0; x is 1; in other embodiments, x6 is 1; x is 2.

[0279] In some embodiments of this disclosure, the reductive amination reaction occurs under acidic conditions and in the presence of a reducing agent.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of the above-described general formulas (I), (II), (III), (IV), (V), (VI) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0284] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III), (IV), (V), (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for inhibiting or degrading BTK.

[0285] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for regulating BTK protein ubiquitination and degradation in a subject.

[0286] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III), (IV), (V), (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on BTK.

[0287] This disclosure further relates to the use of compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, 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.

[0288] 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), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0289] This disclosure also relates to a method for inhibiting or degrading BTK in a subject, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0290] 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), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0291] This disclosure also relates to a method of treating and / or preventing tumors or autoimmune diseases, comprising administering to a desired patient a compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above-described general formulas (I), (II), (III), (IV), (V), (VI) or Table A, to treat and / or prevent leukemia or lymphoma, and in some embodiments, 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.

[0292] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicine.

[0293] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicament for regulating the ubiquitination and degradation of BTK protein in a subject.

[0294] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on BTK.

[0295] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IV), (V), (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for regulating BTK protein ubiquitination and degradation in a subject.

[0296] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IV), (V), (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for use in inhibiting or degrading BTK in a subject.

[0297] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IV), (V), (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for the treatment and / or prevention of diseases or conditions mediated or dependent on BTK.

[0298] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IV), (V), (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, 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.

[0299] In some implementations, the tumor described in this disclosure is cancer.

[0300] In some embodiments, the tumors described in this disclosure are hematologic malignancies.

[0301] In some embodiments, the tumor described in this disclosure is a B-cell malignant tumor.

[0302] 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).

[0303] 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).

[0304] In some embodiments, the BTK described in this disclosure also includes mutations within the BTK protein, such as C481S, C481Y, C481R, and C481F.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0310] 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.

[0311] 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.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] Terminology Explanation

[0321] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0322] 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., C164 ... 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 deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0323] 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 deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0324] 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-).

[0325] 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 deuterium, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0326] 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 deuterium, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0327] 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 deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0328] 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). In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl) or a cycloalkyl group having 4 to 11 ring atoms (i.e., 4 to 11 membered cycloalkyl), in some embodiments, a cycloalkyl group having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), and in some embodiments, a cycloalkyl group having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0329] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0330] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0331] 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:

[0332] Its connection point can be anywhere;

[0333] wait.

[0334] 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:

[0335] Its connection point can be anywhere;

[0336] wait.

[0337] 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: Its connection point can be anywhere.

[0338] 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: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0339] 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 with 5 to 15 ring atoms (i.e., a 5 to 15-membered heterocyclic group); in some embodiments, it is a heterocyclic group with 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group); in some embodiments, it is a heterocyclic group with 4 to 12 ring atoms (i.e., a 4 to 12-membered heterocyclic group); in some embodiments, it is a heterocyclic group with 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in some embodiments, it is a heterocyclic group with 4 to 8 ring atoms (i.e., a 4 to 8-membered heterocyclic group); in some embodiments, it is a heterocyclic group with 4 to 6 ring atoms (i.e., a 4 to 6-membered heterocyclic group); in some embodiments, it is a heterocyclic group with 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); in some embodiments, it is a heterocyclic group with 5 to 7 ring atoms (i.e., a 5 to 15-membered heterocyclic group). In some embodiments, a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 6 ring atoms (i.e., a 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 8 to 10 ring atoms (i.e., an 8 to 10-membered heterocyclic group); in some embodiments, a heterocyclic group having 9 ring atoms (i.e., a 9-membered heterocyclic group); in some embodiments, a heterocyclic group having 11 to 13 ring atoms (i.e., an 11 to 13-membered heterocyclic group); in some embodiments, a heterocyclic group having 12 ring atoms (i.e., a 12-membered heterocyclic group); in some embodiments, a heterocyclic group having 13 to 15 ring atoms (i.e., a 13 to 15-membered heterocyclic group); in some embodiments, a heterocyclic group having 14 ring atoms (i.e., a 14-membered heterocyclic group).

[0340] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0341] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0342] 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:

[0343] wait.

[0344] 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:

[0345] wait.

[0346] 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:

[0347] wait.

[0348] 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: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0349] 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:

[0350] wait.

[0351] 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: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0352] 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). In some embodiments, the heteroaryl has 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), and in some embodiments, it has 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0353] 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.

[0354] 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: wait.

[0355] 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: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0362] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0363] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0364] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0365] 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.

[0366] 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.

[0367] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0368] 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.

[0369] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0370] 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.

[0371] 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.

[0372] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0373] The term "hydroxyl group" refers to -OH.

[0374] The term "thiol" refers to -SH.

[0375] The term "amino" refers to -NH2.

[0376] The term "cyano" refers to -CN.

[0377] The term "nitro" refers to -NO2.

[0378] The term "oxo" or "oxo group" refers to =O.

[0379] The term "carbonyl" refers to C=O.

[0380] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0381] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0382] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0383] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0384] 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.

[0385] 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.

[0386] 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 simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0387] 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:

[0388] 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:

[0389] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0390] 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.

[0391] 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.

[0392] 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.

[0393] When a position is specifically designated as deuterium (D), the position 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.

[0394] "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.

[0395] "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).

[0396] "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.

[0397] "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.

[0398] 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.

[0399] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0400] 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. Attached Figure Description

[0401] Figure 1 shows the efficacy data of compound 9-1 against TMD-8-L528W xenografts in C.B17 / SCID mice.

[0402] Figure 2 shows the effect of compound 9-1 on body weight in C.B17 / SCID mice. Detailed Implementation

[0403] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0404] Example

[0405] 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).

[0406] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS). Other instruments used included: a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector); and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0407] 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.

[0408] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0409] High-performance liquid chromatography (HPLC) preparative chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0410] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0411] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0412] 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.

[0413] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0414] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0415] 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.

[0416] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0417] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0418] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0419] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0420] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0421] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0422] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0423] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0424] 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.

[0425] Example 1

[0426] 3-(tert-butyl)-N-((6-(6-(6-(4-((1-(4-((2-4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide1

[0427] first step

[0428] (6-Bromo-2-methylpyridin-3-yl)methylamine 1b

[0429] 6-Bromo-2-methylpyridin-3-carboxynitrile 1a (2.4 g, 12.2 mmol, Leyan) was dissolved in a boranetetrahydrofuran complex (121.8 mL, 1 M, 121.8 mmol, Leyan), stirred overnight at room temperature under a nitrogen atmosphere, 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 1b (1.3 g, yield: 53%).

[0430] MS m / z(ESI): 201.1 [M+1] + .

[0431] Step 2

[0432] N-((6-bromo-2-methylpyridin-3-yl)methyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide 1d

[0433] Compound 1b (1.3 g, 6.5 mmol) and potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate 1c (1.6 g, 7.8 mmol, prepared by the same intermediate method described on page 58 of patent application WO2021087112) were dissolved in N,N-dimethylformamide (30 mL). 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. 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 title compound 1d (1.48 g, yield: 64.8%).

[0434] MS m / z(ESI): 353.2 [M+1] + .

[0435] Step 3

[0436] 4-(5-(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)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester 1f

[0437] Compound 1d (400 mg, 1.13 mmol), hexamethyldistin (816 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 4-(5-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester 1e (340 mg, 0.61 mmol, prepared by the same intermediate method described on page 51 of patent application WO2021219070A1), cuprous iodide (117 mg, 0.61 mmol, Adamas), and bis(triphenylphosphine)palladium dichloride (85 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 1f (270 mg, yield: 55.6%).

[0438] MS m / z(ESI): 793.6 [M+1] + .

[0439] Step 4

[0440] 1 g of 4-(5-(4-(5-((3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)methyl)-6-methylpyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0441] Compound 1f (270 mg, 0.34 mmol) was dissolved in tetrahydrofuran (5 mL, Adamas) and methanol (2 mL), and sodium hydroxide (54 mg, 1.35 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 1 g (220 mg, yield: 99.0%) of the title compound.

[0442] MS m / z (ESI): 653.7 [M+1] + .

[0443] Step 5

[0444] 3-(tert-butyl)-N-((2-methyl-6-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 1h

[0445] 1 g (220 mg, 0.34 mmol) of the compound was dissolved in dioxane hydrochloride solution (2 mL, 8 mmol, 4 M, Adamas) and reacted at room temperature for 1 h. The mixture was concentrated under reduced pressure, and 2 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 1 h (185 mg, yield: 99.2%).

[0446] MS m / z (ESI): 553.7 [M+1] + .

[0447] Step 6

[0448] 3-(tert-butyl)-N-((6-(6-(6-(4-((1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide1

[0449] Compound 1h (185 mg, 0.33 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-carboxaldehyde 1i (110 mg, 0.37 mmol, prepared by the method disclosed in intermediate 0423 on page 107 of patent application WO2023125908A1), glacial acetic acid (60 mg, 1.00 mmol, Sinopharm), and sodium acetate (55 mg, 0.67 mmol, Adamas) were dissolved in dichloromethane (5 mL) and ethanol (5 mL) and stirred at room temperature for 2 hours. Sodium borohydride acetate (354 mg, 1.67 mmol, Shaoyuan) was added, and stirring was continued for 1 hour. The extract was concentrated under reduced pressure, 10 mL of water was added, and it 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 with eluent system A to give title compound 1 (18 mg, yield: 6.4%).

[0450] MS m / z(ESI): 838.9 [M+1] + .

[0451] 1 H NMR (500MHz, DMSO-d6): δ12.56(s,1H),10.26(s,1H),9.98-9.87(m,1H),8.80(s,1H), 8.44-8.35(m,1H),8.22-8.10(m,1H),7.92-7.84(m,1H),7.71(s,1H),7.25-7.10(m,2 H),7.06-6.90(m,2H),4.67-4.50(m,2H),3.84-3.43(m,12H),3.31-3.16(m,4H),2.84 -2.57(m,7H),2.24(s,1H),2.05-1.96(m,1H),1.88-1.70(m,2H),1.44-1.20(m,10H).

[0452] Example 2

[0453] 3-(tert-butyl)-N-((6-(6-(6-(4-((1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 2

[0454] first step

[0455] 4-(5-(4-(5-((3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)methyl)-4-methylpyridin-2-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester 2b

[0456] Compound 1e (720 mg, 1.30 mmol), hexamethyldistin (552.5 mg, 1.69 mmol, Adamas) and tetra(triphenylphosphine)palladium (149.9 mg, 0.13 mmol, Adamas) were placed in 1,4-dioxane (8 mL), purged with nitrogen three times, and heated to 100 °C for 6 hours. The reaction mixture was cooled to room temperature, and N-((6-bromo-4-methylpyridin-3-yl)methyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide 2a (360 mg, 1.0 mmol, prepared by replacing the first-step compound 1a with the starting material 6-bromo-4-methylpyridin-3-carboxylonite), cuprous iodide (194.1 mg, 1.0 mmol, Adamas), and bis(triphenylphosphine)palladium dichloride (143.1 mg, 0.2 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 2b (630 mg, yield: 77.96%).

[0457] MS m / z(ESI): 793.3 [M+1] + .

[0458] Step 2

[0459] 3-(tert-butyl)-N-((6-(6-(6-(4-((1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 2

[0460] Using the synthetic route from step four to step six in Example 1, the compound 1f in step four was replaced with compound 2b to obtain title compound 2 (28 mg, yield: 4.29%).

[0461] MS m / z(ESI): 838.9 [M+1] + .

[0462] 1H NMR (500MHz, DMSO-d6): δ12.59(s,1H),10.26(s,1H),9.95-9.92(m,1H),8.81(s,1H),8.77-8. 76(m,1H),8.72(s,1H),8.42(s,1H),8.14-8.12(m,1H),7.66-7.63(m,1H),7.15-7.14(m,2H),6 .98-6.93(m,3H),4.63-4.62(m,2H),3.72-3.61(m,7H),3.39-3.33(m,1H),2.70-2.64(m,4H),2 .56-2.53(m,2H),2.24-2.23(m,2H),2.02-1.85(m,2H),1.82-1.76(m,4H),1.38-1.25(m,13H).

[0463] Example 3

[0464] 3-(tert-butyl)-N-((5-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpyridin-2-yl)methyl)-1,2,4-oxadiazole-5-carboxamide3

[0465] first step

[0466] ((5-bromo-3-methylpyridin-2-yl)methyl)tert-butyl carbamate 3b

[0467] 5-Bromo-3-methylpyridin-2-carboxynitrile 3a (1.45 g, 7.36 mmol, Leyan) and cobalt chloride hexahydrate (2.62 g, 11.0 mmol, Adamas) were dissolved in methanol (20 mL). Sodium borohydride (835 mg, 22.1 mmol, Shaoyuan) was added at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Water (2.4 mL) and di-tert-butyl dicarbonate (3.21 g, 14.7 mmol, Adamas) were added, and the mixture was heated to 70 °C and reacted for another 15 hours. The mixture was concentrated under reduced pressure, and water (10 mL) and dichloromethane (10 mL) were added. The mixture was filtered, and the filtrate was extracted with dichloromethane (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 B to give the title compound 3b (1.12 g, yield: 50.5%).

[0468] MS m / z(ESI): 301.2 [M+1] +.

[0469] Step 2

[0470] (5-Bromo-3-methylpyridin-2-yl)methylamine hydrochloride 3c

[0471] Compound 3b (1.12 g, 3.72 mmol) was dissolved in dichloromethane (5 mL, Sinopharm), and dioxane hydrochloride solution (5 mL, 20 mmol, 4 M, Adamas) was added. The reaction was carried out at room temperature for 1 hour. The solution was concentrated under reduced pressure to give crude title compound 3c (740 mg), which was used directly in the next reaction without purification.

[0472] MS m / z(ESI): 201.1 [M+1] + .

[0473] Step 3

[0474] N-((5-bromo-3-methylpyridin-2-yl)methyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide 3d

[0475] Compound 3c (620 mg, 2.61 mmol) and ethyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (620 mg, 3.13 mmol, Bio-D) were dissolved in ethanol (12 mL), and potassium carbonate (1.08 g, 7.81 mmol, Sinopharm) was added. The reaction mixture was stirred at 80 °C for 16 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 3d (764 mg, yield: 82.9%).

[0476] MS m / z(ESI): 353.3 [M+1] + .

[0477] Step 4

[0478] 3-(tert-butyl)-N-((3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridin-2-yl)methyl)-1,2,4-oxadiazol-5-carboxamide 3e

[0479] Compound 3d (764 mg, 2.16 mmol) was dissolved in 1,4-dioxane (20 mL, Anaiji), and bis(diphenylphosphino)diborane (1.37 g, 5.40 mmol, Shaoyuan), potassium acetate (636 mg, 6.48 mmol, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (316 mg, 0.43 mmol, Adamas) were added. The mixture was purged with nitrogen three times and heated to 90 °C for 1.5 h. 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 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 purified by column chromatography with eluent system C to give the title compound 3e (480 mg, yield: 55.4%).

[0480] MS m / z (ESI): 401.4 [M+1] + .

[0481] Step 5

[0482] 4-(5-(4-(6-((3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)methyl)-5-methylpyridin-3-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester 3f

[0483] Compound 3e (247 mg, 0.62 mmol) was dissolved in 1,4-dioxane (5 mL, Adamas) and water (1 mL). Compound 1e (376 mg, 0.68 mmol), potassium carbonate (255 mg, 1.85 mmol, Sinopharm), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (90 mg, 0.12 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 3f (321 mg, yield: 65.6%).

[0484] MS m / z(ESI): 793.7 [M+1] + .

[0485] Step 6

[0486] 3-(tert-butyl)-N-((5-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpyridin-2-yl)methyl)-1,2,4-oxadiazole-5-carboxamide3

[0487] Using the synthetic route of steps four to six of Example 1, the starting compound 1f in step four was replaced with compound 3f to obtain title compound 3 (50 mg, yield: 17.4%).

[0488] MS m / z(ESI): 839.1 [M+1] + .

[0489] 1 H NMR (500MHz, DMSO-d6): δ12.71(s,1H),10.26(s,1H),9.73-9.65(m,1H),9.28-9.19(m ,1H),8.92-8.78(m,2H),8.46-8.42(m,1H),8.29-8.20(m,1H),7.46-7.39(m,1H),7.18 -7.10(m,2H),7.04-6.87(m,3H),4.77-4.67(m,2H),3.84-3.47(m,7H),3.33-3.11(m,7 H),2.73-2.56(m,5H),2.44-2.16(m,3H),1.89-1.68(m,3H),1.40(s,6H),1.24(s,4H).

[0490] Example 4

[0491] 3-(tert-butyl)-N-((6-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide

[0492] Using the synthetic route of Example 1, the third-step compound 1e was replaced with (4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.27 mmol, prepared by the method disclosed in intermediates 1-3 on page 9 of the specification in patent application WO2021 / 219071A1), to obtain title compound 4 (131 mg, yield: 55.3%).

[0493] MS m / z (ESI): 837.7 [M+1] + .

[0494] 1H NMR(500MHz,DMSO-d6)δ12.49(s,1H),10.34-10.19(m,1H),9.99-9.85(m,1H),8.83-8.71(m,1H) ),8.43-8.33(m,1H),7.97-7.80(m,3H),7.71-7.63(m,1H),7.21-7.04(m,4H),6.97-6.85(m,2H) ,4.68-4.52(m,2H),3.78-3.65(m,4H),3.31-3.22(m,4H),2.81-2.73(m,3H),2.72-2.63(m,4H) ,2.57-2.53(m,2H),2.29-2.20(m,2H),1.87-1.70(m,3H),1.51-1.35(m,9H),1.33-1.18(m,4H).

[0495] Example 5

[0496] (S)-3-(tert-butyl)-N-((6-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide5

[0497] first step

[0498] (S)-3-methyl-4-phenylpiperazine-1-carboxylic acid tert-butyl ester 5c

[0499] (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester 5b (7.60 g, 37.95 mmol, Shanghai Bide), bromobenzene 5a (5 g, 31.84 mmol), cesium carbonate (20 g, 61.38 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (584 mg, 698 mg) 1.55 g (1.85 mmol) of 2-dicyclohexylphosphine-2”,6”-diisopropoxy-1,1”-biphenyl (1.55 g, 1.85 mmol) was dissolved in 1,4-dioxane (100 mL). The reaction mixture was heated to 110 °C for 16 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 5c (7.6 g, yield: 86.3%).

[0500] MS m / z(ESI): 277.3 [M+1]+ .

[0501] Step 2

[0502] (S)-4-(4-bromophenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester 5d

[0503] Compound 5c (7.60 g, 27.50 mmol) was dissolved in chloroform (100 mL), and tetrabutylammonium tribromide (14.60 g, 30.27 mmol, Shanghai Titan) was slowly added. The reaction mixture was stirred for 16 hours. The reaction solution was quenched with saturated sodium sulfite solution, extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed successively with saturated sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 5d (4.8 g, yield 49.1%).

[0504] MS m / z(ESI): 299.1 [M-55] + .

[0505] Step 3

[0506] (S)-3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0507] 5e

[0508] Compound 5d (4.80 g, 13.51 mmol) was dissolved in 1,4-dioxane (100 mL), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (1 g, 1.37 mmol), potassium acetate (4 g, 40.76 mmol), and pinacol boryl ester (6.80 g, 26.78 mmol) were added. The mixture was purged with nitrogen three times and stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 5e (5 g, 92.0% yield).

[0509] MS m / z(ESI): 403.3 [M+1] + .

[0510] Step 4

[0511] (S)-4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester 5g

[0512] Compound 5e (2 g, 4.98 mmol) was dissolved in a mixed solvent of 1,4-dioxane (50 mL) and water (5 mL), and 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine 5f (2.10 g, 5.00 mmol), potassium carbonate (2 g, 14.47 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (600 mg, 820 μmol) were added. The mixture was stirred at 90 °C for 10 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 5 g (1.5 g, 53.1%).

[0513] MS m / z(ESI): 568.2 [M+1] + .

[0514] Step 5

[0515] (S)-3-(tert-butyl)-N-((6-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide5

[0516] Using the synthetic route of steps three to six of Example 1, the starting material compound 1e in step three was replaced with compound 5g to obtain title compound 5 (100mg, yield: 65.2%).

[0517] MS m / z (ESI): 851.7 [M+1] + .

[0518] 1H NMR(500MHz,DMSO-d6)δ12.47(s,1H),10.26(s,1H),9.96-9.89(m,1H),8.78(s,1H),8.42-8.34(m,1H),7.92 -7.83(m,3H),7.66(s,1H),7.18-7.11(m,2H),7.07-6.99(m,2H),6.97-6.90(m,2H),4.65-4.57(m,2H),4.17( s,1H),3.76-3.66(m,4H),3.51-3.44(m,1H),3.09-3.00(m,1H),2.96-2.90(m,1H),2.77(s,4H),2.72-2.63( m,4H),2.29-2.10(m,4H),1.90-1.81(m,2H),1.74(s,1H),1.38(s,9H),1.26-1.24(m,2H),1.15-1.08(m,3H).

[0519] Example 6

[0520] (R)-3-(tert-butyl)-N-((6-(6-(4-(4-((1-(4-(2-4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 6

[0521] Using the synthetic route of Example 5, the first-step compound 5b was replaced with (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (7.60 g, 37.95 mmol, Shanghai Bide) to obtain title compound 6 (121 mg, yield: 59.6%).

[0522] MS m / z (ESI): 851.7 [M+1] + .

[0523] 1H NMR(500MHz,DMSO-d6)δ12.50-12.44(m,1H),10.26(s,1H),9.96-9.90(m,1H),8.78(s,1H),8.42-8.35(m,1H),7 .91-7.83(m,3H),7.68-7.63(m,1H),7.18-7.11(m,2H),7.04-6.98(m,2H),6.96-6.90(m,2H),4.65-4.56(m,2H) ,4.16(s,1H),3.76-3.66(m,4H),3.50-3.44(m,1H),3.08-2.99(m,1H),2.93-2.88(m,1H),2.77(s,4H),2.73-2. 63(m,4H),2.28-2.09(m,4H),1.88-1.79(m,2H),1.72(s,1H),1.38(s,9H),1.27-1.23(m,2H),1.15-1.09(m,3H).

[0524] Example 7

[0525] (S)-3-(tert-butyl)-N-((6-(6-(6-(4-((1-(4-(2-4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 7

[0526] first step

[0527] (S)-4-(5-(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)pyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester 7b

[0528] In a sealed tube, (S)-4-(5-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester 7a (600 mg, 1.05 mmol, prepared by replacing the starting material piperazine-1-carboxylic acid tert-butyl ester with (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester using the same intermediate method described on page 51 of patent application WO2021219070A1), hexamethyldistin (449 mg, 1.37 mmol, Adamas) and tetra(triphenylphosphine)palladium (122 mg, 0.11 mmol, Adamas) were placed in 1,4-dioxane (8 mL), purged with nitrogen for 5 minutes, sealed, and heated to 100 °C for 6 hours. The reaction mixture was cooled to room temperature, and compound 1d (350 mg, 0.99 mmol), cuprous iodide (189 mg, 0.99 mmol, Adamas), and bis(triphenylphosphine)palladium dichloride (139 mg, 0.2 mmol, Adamas) were added. The mixture was purged with nitrogen for 5 minutes, sealed, 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 7b (799 mg, yield: 99.9%).

[0529] MS m / z (ESI): 807.4 [M+1] + .

[0530] Step 2

[0531] (S)-3-(tert-butyl)-N-((6-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 7

[0532] Using the synthetic route from step four to step six in Example 1, the compound 1f in step four was replaced with compound 7b to obtain title compound 7 (175 mg, yield: 60.94%).

[0533] MS m / z (ESI): 852.6 [M+1] + .

[0534] 1H NMR (500MHz, DMSO-d6): δ12.55(s,1H),10.27(s,1H),9.94-9.91(m,1H),8.80(s,2H),8.39-8.37(m,1 H),8.14-8.12(m,1H),7.87-7.85(m,1H),7.70(s,1H),7.15-7.13(m,2H),6.94-6.90(m,3H),4.61-4. 59(m,3H),4.13-4.11(m,1H),3.71-3.69(m,4H),3.11-3.07(m,1H),2.94-2.91(m,1H),2.82-2.65(m, 8H),2.24-2.20(m,3H),2.17-1.99(m,1H),1.86-1.83(m,2H),1.80-1.71(m,1H),1.38-1.20(m,14H).

[0535] Example 8

[0536] (R)-3-(tert-butyl)-N-((6-(6-(6-(4-((1-(4-(2-4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 8

[0537] first step

[0538] (R)-4-(5-(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)pyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester 8b

[0539] In a sealed tube, (R)-4-(5-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester 8a (600 mg, 1.05 mmol, prepared by replacing the starting material piperazine-1-carboxylic acid tert-butyl ester with (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester using the same intermediate method described on page 51 of patent application WO2021219070A1), hexamethyldistin (449 mg, 1.37 mmol, Adamas) and tetra(triphenylphosphine)palladium (122 mg, 0.11 mmol, Adamas) were placed in 1,4-dioxane (8 mL), purged with nitrogen for 5 minutes, sealed, and heated to 100 °C for 6 hours. The reaction mixture was cooled to room temperature, and compound 1d (350 mg, 0.99 mmol), cuprous iodide (189 mg, 0.99 mmol, Adamas), and bis(triphenylphosphine)palladium dichloride (139 mg, 0.2 mmol, Adamas) were added. The mixture was purged with nitrogen for 5 minutes, sealed, 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 title compound 8b (799 mg, yield: 99.9%).

[0540] MS m / z (ESI): 807.4 [M+1] + .

[0541] Step 2

[0542] (R)-3-(tert-butyl)-N-((6-(6-(6-(4-((1-(4-(2-4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide 8

[0543] Using the synthetic route from step four to step six in Example 1, the compound 1f in step four was replaced with compound 8b to obtain title compound 8 (180 mg, yield: 62.68%).

[0544] MS m / z (ESI): 852.6 [M+1] + .

[0545] 1H NMR (500MHz, DMSO-d6): δ12.55(s,1H),10.26(s,1H),9.94-9.91(m,1H),8.80(s,2H),8.39-8.37(m,1 H),8.15-8.12(m,1H),7.87-7.85(m,1H),7.70(s,1H),7.15-7.13(m,2H),6.95-6.91(m,3H),4.61-4. 60(m,3H),4.14-4.12(m,1H),3.72-3.69(m,4H),3.12-3.07(m,1H),2.95-2.93(m,1H),2.84-2.66(m, 8H),2.26-2.19(m,3H),2.17-2.20(m,1H),1.87-1.85(m,2H),1.82-1.74(m,1H),1.38-1.21(m,14H).

[0546] Example 9

[0547] 3-(tert-butyl)-N-(1-(6-(6-(6-(4-((1-(4-((2-4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 9

[0548] first step

[0549] N-((6-bromo-2-methylpyridin-3-yl)methylethylene)-2-methylpropane-2-sulfinamide 9b

[0550] 6-Bromo-2-methylnicotinaldehyde 9a (4.74 g, 23.7 mmol, Bide), 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 reaction mixture was concentrated, and 40 mL of saturated ammonium chloride solution was added. Extraction was performed 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 the filtrate was concentrated under reduced pressure to give crude title compound 9b (7 g, yield: 97.4%). This product was used directly in the next reaction without purification.

[0551] MS m / z(ESI): 303.2 [M+1] + .

[0552] Step 2

[0553] N-(1-(6-bromo-2-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide 9c

[0554] Compound 9b (7 g, 23.1 mmol, Bide) was dissolved in tetrahydrofuran (150 mL, Anegig), purged three times with nitrogen, and cooled to 0 °C. Methylmagnesium bromide (23 mL, 3 M, 69 mmol, Anegig) was added dropwise, and the reaction was continued at 0 °C for 3 hours. The reaction solution was concentrated, and 30 mL of saturated ammonium chloride solution was added. Extraction was performed 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 the filtrate was concentrated under reduced pressure to give crude title compound 9c (5.5 g, yield: 74.6%). This product was used directly in the next reaction without purification.

[0555] MS m / z(ESI): 319.2 [M+1] + .

[0556] Step 3

[0557] 1-(6-bromo-2-methylpyridin-3-yl)ethyl-1-amine 9d

[0558] Compound 9c (5.5 g, 17.2 mmol) was dissolved in 1,4-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 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 9d (2.5 g, yield: 57.7%).

[0559] MS m / z(ESI): 215.0 [M+1] + .

[0560] Step 4

[0561] N-(1-(6-bromo-2-methylpyridin-3-yl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide 9e

[0562] Compound 9d (2.42 g, 11.3 mmol) and compound 1c (4.68 g, 22.5 mmol) were 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 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 9e (3.5 g, yield: 84.7%).

[0563] MS m / z(ESI): 367.2 [M+1] + .

[0564] Step 5

[0565] 4-(5-(4-(5-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-6-methylpyridin-2-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester 9f

[0566] Compound 1e (11 g, 19.8 mmol), hexamethyldistin (8.44 g, 25.8 mmol, Adamas), and tetra(triphenylphosphine)palladium (2.29 g, 1.98 mmol, Adamas) were placed in 1,4-dioxane (100 mL), purged with nitrogen three times, and heated to 100 °C for 6 hours. The reaction mixture was cooled to room temperature, and compound 9e (6 g, 16.3 mmol), cuprous iodide (3.11 g, 16.3 mmol, Adamas), and bis(triphenylphosphine)palladium dichloride (2.29 g, 3.27 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 9f (13 g, yield: 98.6%).

[0567] MS m / z (ESI): 807.5 [M+1] + .

[0568] Step 6

[0569] 9g of 4-(5-(4-(5-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-6-methylpyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0570] Compound 9f (13 g, 16.1 mmol) was dissolved in tetrahydrofuran (200 mL, Adamas) and methanol (50 mL), and sodium hydroxide (2.58 g, 64.4 mmol, Adamas) was added. The reaction mixture was stirred at room temperature for 15 minutes. 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with 100 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 the title compound 9f (3.22 g, yield: 30.0%).

[0571] MS m / z (ESI): 667.5 [M+1] + .

[0572] Step 7

[0573] 3-(tert-butyl)-N-(1-(2-methyl-6-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 9h

[0574] 9 g (3.22 g, 4.83 mmol) of the compound was dissolved in 1,4-dioxane hydrochloric acid solution (40 mL, 145 mmol, 4 M, Adamas) and reacted at room temperature for 1 h. The solution was concentrated under reduced pressure, and 20 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (40 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 to give the title compound 9h (2.73 g, yield: 99.8%).

[0575] MS m / z (ESI): 567.4 [M+1] + .

[0576] Step 8

[0577] 3-(tert-butyl)-N-(1-(6-(6-(6-(4-((1-(4-((2-4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 9

[0578] Compound 9h (333 mg, 0.59 mmol), compound 1i (177 mg, 0.59 mmol), glacial acetic acid (105 mg, 1.75 mmol, Sinopharm), and sodium acetate (96 mg, 1.17 mmol, Adamas) were dissolved in dichloromethane (10 mL) and ethanol (10 mL) and stirred at room temperature for 2 hours. Sodium borohydride acetate (622 mg, 2.93 mmol, Shaoyuan) was added, and stirring was 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) (20 mL × 3). The organic phases were combined, washed with 10 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 9 (300 mg, yield: 59.9%).

[0579] MS m / z (ESI): 852.6 [M+1] + .

[0580] 1 H NMR (500MHz, DMSO-d6): δ12.56(s,1H),10.26(s,1H),9.99-9.93(m,1H),8.86-8.76(m,2H),8.45-8 .38(m,1H),8.18-8.11(m,1H),8.07-8.00(m,1H),7.70(s,1H),7.20-7.11(m,2H),7.03-6.90(m,3H) ,5.44-5.36(m,1H),3.74-3.57(m,8H),2.86-2.78(m,3H),2.71-2.63(m,4H),2.49-2.47(m,2H),2. 29-2.19(m,2H),1.88-1.79(m,2H),1.74(s,1H),1.60-1.56(m,2H),1.37(s,9H),1.30-1.22(m,5H).

[0581] Examples 9-1 and 9-2

[0582] (R)-3-(tert-butyl)-N-(1-(6-(6-(6-(4-((1-(4-(2-4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazol-5-carboxamide 9-1

[0583] (S)-3-(tert-butyl)-N-(1-(6-(6-(6-(4-((1-(4-(2-4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazol-5-carboxamide 9-2

[0584] Compound 9 (300 mg) was purified by chiral high performance liquid chromatography (instrument model: Gilson-281Pre system; column: (S,S)-Whelk-O1, 10 μm, 20 mm * 250 mm; elution system: acetonitrile and ethanol (0.5% 7 M NH3 in MEOH), flow rate: 20 mL / min) to give compounds 9-1 (87 mg, yield: 29.0%) and 9-2 (52 mg, yield: 17.3%).

[0585] Single-configuration compound 9-1 (retention time: 14.72 minutes):

[0586] MS m / z (ESI): 852.7 [M+1] + .

[0587] 1 H NMR (500MHz, DMSO-d6): δ12.56(s,1H),10.31-10.24(m,1H),10.01-9.91(m,1H),8.86-8.74(m,2H),8.45- 8.38(m,1H),8.21-8.12(m,1H),8.07-8.00(m,1H),7.74-7.66(m,1H),7.22-7.10(m,2H),7.03-6.90(m,3H ),5.44-5.35(m,1H),3.76-3.57(m,8H),2.86-2.78(m,3H),2.72-2.65(m,4H),2.48(s,2H),2.27-2.19(m, 2H),2.10-2.07(m,1H),1.86-1.79(m,2H),1.74(s,1H),1.62-1.55(m,3H),1.45-1.34(m,9H),1.24(s,3H).

[0588] Compound 9-2 with a single configuration (retention time: 24.164 minutes):

[0589] MS m / z (ESI): 852.7 [M+1] + .

[0590] 1 H NMR (500MHz, DMSO-d6): δ12.56(s,1H),10.27(s,1H),9.99-9.93(m,1H),8.85-8.77(m,2H),8.45-8.38( m,1H),8.17-8.11(m,1H),8.07-8.01(m,1H),7.70(s,1H),7.16-7.10(m,2H),7.00-6.88(m,3H),5.44-5. 35(m,1H),3.74-3.65(m,4H),3.64-3.54(m,4H),2.82(s,3H),2.71-2.63(m,4H),2.49-2.37(m,4H),2.2 6-2.16(m,2H),1.86-1.77(m,2H),1.75-1.67(m,1H),1.62-1.53(m,3H),1.37(s,9H),1.26-1.20(m,2H).

[0591] Example 10

[0592] 3-(tert-butyl)-N-(1-(6-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 10

[0593] Using the synthetic route of Example 9, the fifth step compound 1e was replaced with (4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.27 mmol, prepared by the method disclosed in intermediates 1-3 on page 9 of the specification in patent application WO2021 / 219071A1), yielding title compound 10 (67 mg, yield: 36.2%).

[0594] MS m / z (ESI): 851.6 [M+1] + .

[0595] 1H NMR (500MHz, DMSO-d6): δ12.49(s,1H),10.26(s,1H),9.97-9.95(m,1H),8.79(s,1H),8.43-8.39(m,1H) ,8.07-8.00(m,1H),7.90-7.84(m,2H),7.68-7.65(m,1H),7.16-7.11(m,2H),7.09-7.05(m,2H),6.97-6. 91(m,2H),5.43-5.37(m,1H),3.75-3.67(m,4H),3.32-3.24(m,4H),2.80(s,3H),2.71-2.63(m,4H),2.5 8-2.53(m,3H),2.28-2.19(m,2H),1.86-1.69(m,3H),1.61-1.57(m,3H),1.37(s,9H),1.27-1.21(m,3H).

[0596] Examples 10-1 and 10-2

[0597] (R)-3-(tert-butyl)-N-(1-(6-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 10-1

[0598] (S)-3-(tert-butyl)-N-(1-(6-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 10-2

[0599] Compound 10 (64 mg, 75.20 μmol) was prepared chirally (separation conditions: chiral preparation column: (S,S)-Whelk-O1, 10 μm, 20 mm * 250 mm (Regis Technologies, in-house packed)); mobile phase 1: ACN (30%); mobile phase 2: EtOH (0.1% 7 M NH3 in MeOH) (70%), flow rate: 20 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds 10-1 (22.3 mg) and 10-2 (17.5 mg).

[0600] Single-configuration compound 10⁻¹ (shorter retention time: 14.871 min)

[0601] MS m / z (ESI): 851.6 [M+1] + .

[0602] 1 H NMR (500MHz, DMSO-d6): δ12.49(s,1H),10.26(s,1H),9.97-9.95(m,1H),8.78(s,1H),8.43-8.41(m,1H) ,8.05-8.02(m,1H),7.89-7.87(m,2H),7.68-7.65(m,1H),7.15-7.11(m,2H),7.08-7.05(m,2H),6.95-6. 93(m,2H),5.41-5.38(m,1H),3.72-3.67(m,4H),3.32-3.24(m,4H),2.81(s,3H),2.71-2.66(m,4H),2.5 8-2.53(m,3H),2.32-2.17(m,2H),2.08-1.74(m,3H),1.59-1.57(m,3H),1.37(s,9H),1.28-1.21(m,3H).

[0603] Single-configuration compound 10⁻² (longer retention time: 23.117 min)

[0604] MS m / z (ESI): 851.6 [M+1] + .

[0605] 1 H NMR (500MHz, DMSO-d6): δ12.49(s,1H),10.26(s,1H),9.97-9.95(m,1H),8.78(s,1H),8.43-8.41(m,1H) ,8.05-8.03(m,1H),7.90-7.87(m,2H),7.68-7.66(m,1H),7.15-7.13(m,2H),7.08-7.06(m,2H),6.95-6. 93(m,2H),5.42-5.37(m,1H),3.71-3.69(m,4H),3.35-3.25(m,4H),2.81(s,3H),2.70-2.65(m,4H),2.5 8-2.53(m,3H),2.25-2.19(m,2H),1.84-1.69(m,3H),1.59-1.55(m,3H),1.37(s,9H),1.28-1.21(m,3H).

[0606] Example 11

[0607] 3-(tert-butyl)-N-(1-(6-(6-(4-((S)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 11

[0608] Using the synthetic route of Example 9, the fifth step compound 1e was replaced with compound 5g to obtain title compound 11 (58mg, yield: 28.6%).

[0609] MS m / z (ESI): 865.6 [M+1] + .

[0610] 1 H NMR (500MHz, DMSO-d6): δ12.47(s,1H),10.26(s,1H),9.97-9.95(m,1H),8.79(s,1H),8.43-8.39(m,1H),8.07-8.02(m, 1H),7.90-7.84(m,2H),7.68-7.65(m,1H),7.16-7.11(m,2H),7.04-6.99(m,2H),6.96-6.91(m,2H),5.43-5.37(m,1H),4 .19-4.12(m,1H),3.75-3.67(m,4H),3.50-3.44(m,1H),3.08-3.01(m,1H),2.94-2.88(m,1H),2.84-2.76(m,4H),2.72-2 .65(m,4H),2.28-1.97(m,4H),1.88-1.71(m,3H),1.62-1.55(m,3H),1.37(s,9H),1.28-1.21(m,2H),1.14-1.09(m,3H).

[0611] Examples 11-1 and 11-2

[0612] 3-(tert-butyl)-N-((R)-1-(6-(6-(4-((S)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 11-1

[0613] 3-(tert-butyl)-N-((S)-1-(6-(6-(4-((S)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 11-2

[0614] Compound 11 (55 mg, 63.58 μmol) was prepared chirally (separation conditions: chiral preparation column: (S,S)-Whelk-O1, 10 μm, 20 mm * 250 mm (Regis Technologies, in-house packed)); mobile phase 1: ACN (30%); mobile phase 2: EtOH (0.1% 7 M NH3 in MeOH) (70%), flow rate: 20 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to obtain title compounds 11-1 (13.2 mg) and 11-2 (14.5 mg).

[0615] Compound 11-1 with a single configuration (shorter retention time: 14.201 min)

[0616] MS m / z (ESI): 865.6 [M+1] +

[0617] 1H NMR (500MHz, DMSO-d6): δ12.47(s,1H),10.26(s,1H),9.97-9.95(m,1H),8.78(s,1H),8.43-8.41(m,1H),8.05-8.03(m, 1H),7.88-7.86(m,2H),7.68-7.65(m,1H),7.15-7.13(m,2H),7.02-7.00(m,2H),6.95-6.93(m,2H),5.42-5.37(m,1H),4 .16-4.12(m,1H),3.73-3.69(m,4H),3.49-3.46(m,1H),3.06-3.02(m,1H),2.93-2.91(m,1H),2.81-2.78(m,4H),2.69-2 .66(m,4H),2.26-1.97(m,4H),1.86-1.73(m,3H),1.59-1.55(m,3H),1.37(s,9H),1.26-1.21(m,2H),1.14-1.09(m,3H).

[0618] Compound 11-2 with a single configuration (longer retention time: 22.009 min)

[0619] MS m / z (ESI): 865.6 [M+1] +

[0620] 1H NMR (500MHz, DMSO-d6): δ12.47(s,1H),10.26(s,1H),9.97-9.95(m,1H),8.78(s,1H),8.43-8.41(m,1H),8.05-8.03(m, 1H),7.88-7.86(m,2H),7.67-7.65(m,1H),7.15-7.13(m,2H),7.02-7.00(m,2H),6.95-6.93(m,2H),5.42-5.37(m,1H),4 .17-4.14(m,1H),3.72-3.69(m,4H),3.49-3.46(m,1H),3.07-3.02(m,1H),2.93-2.91(m,1H),2.81-2.78(m,4H),2.70-2 .68(m,4H),2.26-1.97(m,4H),1.87-1.73(m,3H),1.59-1.50(m,3H),1.37(s,9H),1.27-1.21(m,2H),1.14-1.11(m,3H).

[0621] Example 12

[0622] 3-(tert-butyl)-N-(1-(6-(6-(4-((R)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 12

[0623] Using the synthetic route from step one to step four of Example 5, the compound 5b in step one was replaced with (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (7.1 g, 35.45 mmol, Shanghai Bide) to prepare (R)-4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester.

[0624] Using the synthetic route of Example 9, the fifth step compound 1e was replaced with compound (R)-4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester to obtain compound 12 (128 mg, yield: 63.1%).

[0625] MS m / z (ESI): 865.7 [M+1] + .

[0626] 1 H NMR (500MHz, DMSO-d6): δ12.47(s,1H),10.26(s,1H),9.97-9.95(m,1H),8.78(s,1H),8.43-8.41(m,1H),8.05-8.03(m, 1H),7.86-7.84(m,2H),7.67-7.65(m,1H),7.16-7.11(m,2H),7.02-6.99(m,2H),6.96-6.93(m,2H),5.43-5.37(m,1H),4 .16-4.14(m,1H),3.72-3.68(m,4H),3.48-3.46(m,1H),3.06-3.01(m,1H),2.93-2.90(m,1H),2.81-2.76(m,4H),2.71-2 .66(m,4H),2.25-2.08(m,4H),1.86-1.71(m,3H),1.59-1.55(m,3H),1.37(s,9H),1.28-1.21(m,2H),1.14-1.09(m,3H).

[0627] Examples 12-1 and 12-2

[0628] 3-(tert-butyl)-N-((R)-1-(6-(6-(4-((R)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 12-1

[0629] 3-(tert-butyl)-N-((S)-1-(6-(6-(4-((R)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpyridin-3-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide 12-2

[0630] Compound 12 (128 mg, 147.9 μmol) was prepared chirally (separation conditions: chiral preparation column: (S,S)-Whelk-O1, 10 μm, 20 mm * 250 mm (Regis Technologies, in-house packed)); mobile phase 1: ACN (30%); mobile phase 2: EtOH (0.1% 7 M NH3 in MeOH) (70%), flow rate: 20 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to obtain title compounds 12-1 (41 mg) and 12-2 (37 mg).

[0631] Single-configuration compound 12-1 (shorter retention time: 14.630 min)

[0632] MS m / z (ESI): 865.7 [M+1] +

[0633] 1H NMR(500MHz,DMSO-d6)δ12.49(s,1H),10.26(s,1H),9.99-9.93(m,1H),8.78(s,1H),8.45-8.39(m,1H),8.07-8.01(m,1H) ,7.92-7.84(m,2H),7.65(d,1H),7.19-7.11(m,2H),7.04-6.98(m,2H),6.96-6.90(m,2H),5.42-5.35(m,1H),4.16(s,1H) ,3.76-3.66(m,4H),3.51-3.43(m,1H),3.09-3.00(m,1H),2.96-2.89(m,1H),2.81(s,4H),2.73-2.65(m,4H),2.28-2.21( m,2H),2.20-2.09(m,2H),1.89-1.80(m,2H),1.73(s,1H),1.63-1.55(m,3H),1.37(s,9H),1.24(s,2H),1.16-1.09(m,3H).

[0634] Single-configuration compound 12-2 (longer retention time: 22.527 min)

[0635] MS m / z (ESI): 865.7 [M+1] +

[0636] 1H NMR (500MHz, DMSO-d6): δ12.47(s,1H),10.26(s,1H),9.98-9.93(m,1H),8.80-8.76(m,1H),8.44-8.40(m,1H),8.06-8.02(m,1 H),7.90-7.85(m,2H),7.67-7.64(m,1H),7.18-7.12(m,2H),7.04-6.99(m,2H),6.97-6.91(m,2H),5.42-5.37(m,1H),4.17(s, 1H),3.74-3.67(m,4H),3.50-3.45(m,1H),3.07-3.01(m,1H),2.94-2.90(m,1H),2.81(s,4H),2.71-2.64(m,4H),2.29-2.21(m ,2H),2.20-2.09(m,2H),1.90-1.81(m,2H),1.73(s,1H),1.63-1.56(m,3H),1.37(s,9H),1.25-1.24(m,2H),1.15-1.09(m,3H).

[0637] Comparative Example 1

[0638] 3-(tert-butyl)-N-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (Comparative Example 1)

[0639] Using the synthetic route of steps five and six of Example 3, the starting compound 3e was replaced with 3-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (prepared using the same intermediate method described on page 44 of patent application WO2022 / 32019) to obtain the title compound Comparative Example 1 (95 mg, yield: 67.33%).

[0640] MS m / z (ESI): 837.4 [M+1] + .

[0641] 1 H NMR (500MHz, DMSO-d6): δ12.59(s,1H),10.26(s,1H),9.91-9.89(m,1H),8.81-8.77(m,2H),8.19-8. 17(m,1H),8.08-8.07(m,2H),7.48-7.47(m,1H),7.29-7.28(m,1H),7.15-7.13(m,2H),6.97-6.93(m, 3H),4.57-4.56(m,2H),3.71-3.69(m,4H),3.60(s,4H),3.33-3.24(m,2H),2.70-2.66(m,4H),2.50-2 .47(m,3H),2.24-2.22(m,2H),1.84-1.82(m,2H),1.76-1.74(m,2H),1.38(s,9H),1.28-1.23(m,3H).

[0642] Comparative Example 2

[0643] The synthesis was performed using the route from example 14 in the published patent WO2021219070A1.

[0644] Biological evaluation

[0645] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0646] Test Example 1: Test of the proliferative activity of the disclosed compound against cells carrying the BTK-C481S mutation.

[0647] This assay assesses compound activity by detecting the proliferation of BA / F3 cells carrying the BTK C481S mutation. (The assay is performed using...) The 2.0 kit employs a homogenization method for cell viability detection, which measures cell viability by quantifying ATP and analyzes the inhibition of BTK mutant cell proliferation.

[0648] BA / F3 cells carrying the BTK C481S mutation were constructed by Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd. Cells were cultured in RPMI 1640 complete medium containing 10% FBS. 90 μL of cell suspension was seeded into each well of a 96-well plate, for a total of 3000 cells / well. A 10-fold drug solution was prepared, with the highest working concentration of the test compound being 1 μM. Nine concentrations were prepared and diluted 3-fold. Then, 10 μL of each serially diluted compound was transferred to the corresponding well of the 96-well cell plate to achieve a final DMSO concentration of 0.1%. Three replicates were set up for each drug concentration. The drug-treated cells were cultured at 37°C and 5% CO2 for 72 hours. After 72 hours, an equal volume of cell viability assay reagent (CellCounting-Lite 2.0 Luminescent Cell Viability Assay) was added to each well, and the cells were lysed by shaking on a track-mounted shaker for 5 minutes. The cell plate was placed at room temperature for 20 minutes to stabilize the cryo-luminescence signal. The cryo-luminescence values ​​were read, and data were collected.

[0649] Data was analyzed using GraphPad Prism 7.0 software. A nonlinear S-curve regression was used to fit the data to derive the dose-response curve, from which the IC was calculated. 50 value.

[0650] Cell viability (%) = (Lum) 待测药 -Lum 培养液对照 ) / (Lum 溶剂对照 -Lum 培养液对照 )×100%

[0651] Inhibition rate % = 1 - Cell viability

[0652] Input the data into GraphPad Prism and calculate the IC using the function "log(inhibitor) vs. response -- variable slope (four parameters)". 50 value.

[0653] Table 1. Inhibitory activity of the compounds disclosed herein against the proliferation of cells carrying the BTK-C481S mutation.

[0654] Conclusion: The compound disclosed herein exhibits significant inhibitory activity against cell proliferation in cells carrying the BTK-C481S mutation.

[0655] Test Example 2: Degradation activity of the disclosed compound against BTK expressed in TMD-8 cells.

[0656] 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.

[0657] 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. 5 Cells / 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 cells and DMSO served as positive controls, and wells without cells served as 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.

[0658] After compound incubation, add 15 μL of 4x 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.

[0659] 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. 50Value. 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%

[0660] Table 2. Degradation activity of the compounds disclosed herein against BTK expressed in TMD-8 cells.

[0661] Conclusion: The compound disclosed herein exhibits degradation activity against BTK expressed in TMD-8 cells.

[0662] Test Example 3: Pharmacokinetic Evaluation

[0663] I. SD Rat Experiment

[0664] 1. Abstract

[0665] Using SD rats as test animals, the plasma drug concentration at different time points after gavage (ig) administration of the compound of the present invention to SD rats was determined by LC / MS / MS method. The pharmacokinetic behavior of the compound of the present invention in SD rats was studied and its pharmacokinetic characteristics were evaluated.

[0666] 2. Test Plan

[0667] 2.1 Test Drugs

[0668] Compound 1, Compound 9-1, Comparative Example 1 and Comparative Example 2.

[0669] 2.2 Experimental Animals

[0670] Sixteen SD rats, half male and half female, were randomly divided into four groups and provided by our company's general-grade animal facility (Animal Use License: SYXK(Su)2020-0018), Vital River Laboratory Animal Technology Co., Ltd. (Animal Production License: SCXK(Beijing)2021-0006), and Shanghai Jihui Laboratory Animal Breeding Co., Ltd. (Animal Production License: SCXK(Hu)2022-0009).

[0671] The patient should fast overnight the night before administration and resume feeding 2 hours after administration.

[0672] 2.3 Drug Preparation

[0673] Weigh out a certain amount of the test compound and add 5% DMSO + 5% Tween 80 + 90% physiological saline to prepare a 0.2 mg / mL pale yellow clear solution.

[0674] 2.4. Administration

[0675] The dosage is 2 mg / kg, and the administration volume is 10 mL / kg.

[0676] 3. Operation

[0677] SD rats were administered the drug by gavage, and 0.2 mL of blood was collected from the jugular vein or orbital cavity at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood samples were placed in EDTA anticoagulant tubes and centrifuged (4℃, 2600g, 10min) within 1 hour after collection. After centrifugation, plasma (approximately 0.1 mL) was collected, temporarily placed on wet ice, and stored at -60℃ or below within 1 hour.

[0678] The drug concentration in rat blood samples was quantitatively detected by LC-MS / MS.

[0679] 4. Pharmacokinetic Parameter Results

[0680] Table 3. Pharmacokinetic parameters of the compounds disclosed herein in SD rats.

[0681] Conclusion: Compared with Comparative Example 1 or Comparative Example 2, the compound disclosed herein exhibits higher blood drug concentrations, higher exposure, and lower clearance in SD rats, demonstrating significant pharmacokinetic advantages.

[0682] Test Example 4: Pharmacodynamic Test

[0683] 1. Experimental Objective

[0684] To evaluate the effect of the disclosed compounds on the growth of subcutaneous xenografts of the drug-resistant human diffuse large B-cell lymphoma cell line TMD-8-L528W in C.B17 / SCID mice.

[0685] 2. Experimental reagents

[0686] Compound 9-1 and Comparative Example 2.

[0687] The solution used was 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMC K100LV).

[0688] 3. Experimental methods and materials

[0689] 3.1 Laboratory animals and their housing conditions

[0690] Experimental animals: C.B17 / SCID female mice, purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. (License number: SCXK(Zhe)2024-0001, Animal certificate number: 20250930Abzz06190000101), with a body weight of approximately 20 g at the time of purchase.

[0691] Feeding conditions: Raised at 5 mice per cage, with a 12 / 12-hour light / dark cycle, temperature 20 - 26°C, humidity 30 - 70%, and free access to food and water.

[0692] [[ID=⑦]]3.2 Animal grouping

[0693] After the adaptive feeding of C.B17 / SCID mice, the grouping and dosing regimens are as follows:

[0694] Table 4. Grouping and dosing regimens of animals in the in vivo efficacy experiment Note: qd means administered once a day; bid means administered twice a day; i.g. means administered by gavage.

[0695] 3.3 Experimental method:

[0696] 1×10 7 cells / mouse / 100 μL (containing 50 μL Matrigel) were inoculated subcutaneously into the right rib of female C.B17 / SCID mice. When the tumor volume of the tumor-bearing mice reached approximately 195 mm 3 , the mice were randomly grouped according to tumor volume and body weight, with 8 mice in each group. Starting from the day of grouping (Day0), they were administered by gavage 1 - 2 times a day for a total of 14 days. The tumor volume of the tumor-bearing mice was measured twice a week with a vernier caliper and the body weight was measured with a balance, and the data were recorded. <##

[0697] 3.4 Data statistics

[0698] All data were plotted and statistically analyzed using Excel and GraphPad Prism 10 software.

[0699] The formula for calculating the tumor volume (V) is: V = 1 / 2 × a × b 2 where a and b represent the length and width, respectively.

[0700] The relative tumor proliferation rate T / C (%) = (T - T0) / (C - C0) × 100 (%), where T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T0 and C0 are the tumor volumes at the start of the experiment.

[0701] The tumor inhibition rate TGI (%) = 100 - T / C (%).

[0702] 4. Results

[0703] The efficacy data of compound 9-1 against TMD-8-L528W xenografts in C.B17 / SCID mice are shown in Table 5 and Figure 1.

[0704] The effect of compound 9-1 on body weight in C.B17 / SCID mice is shown in Figure 2.

[0705] Table 5. Efficacy of the disclosed compounds against TMD-8-L528W xenografts in C.B17 / SCID mice. Note: qd means once a day, bid means twice a day; d means day; ig means gavage; SEM means standard error.

[0706] 5. Conclusion

[0707] Compound 9-1, administered once daily for 14 days, showed a tumor inhibition rate of 65.14% in the low-dose group (2 mpk / qd) and 108.60% in the medium-dose group (6 mpk / qd). The administration had no effect on mouse body weight, demonstrating a significant advantage over control group 2 at the same dosage.

Claims

1. 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 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; R 3 and R 3a They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; Or, R 3 and R 3a 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, 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 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; W is N or CR 6 ; R 6 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; 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; Cy, 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 8 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 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, two Rs 8 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; Or, two Rs 9 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; Or, two Rs 10 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; Or, two Rs 11 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; Or, two non-adjacent R 8 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 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 selected from 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 ; Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom and is related to L d Connected, the other three 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, 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; R 13 and R 14 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl 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; Y 1 and Y 2 Same or different, and each is independently selected from the key, (CR a R b ) y O, S, NR c and C(O); L 1 Selected from key, (CR) a R b ) z 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 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; m, m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6; x, y, and z are each independently 0, 1, 2, 3, 4, or 5; v can be 0, 1, or 2.

2. 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 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; R 3 and R 3a They may be the same or different, and each is independently selected from hydrogen atoms, halogens, 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 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, 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 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; W is N or CR 6 ; R 6 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; 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; Cy, 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 8 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; Or, two Rs 8 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; Or, two Rs 9 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; Or, two Rs 10 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; Or, two Rs 11 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; Or, two non-adjacent R 8 They connect to form a bridging alkylene group; or, two non-adjacent R groups... 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 selected from 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 ; Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom and is related to L d Connected, the other three 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 0 replace; R 13 and R 14 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl 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; Y 1 and Y 2 Same or different, and each is independently selected from the key, (CR a R b ) y O, S, NR c and C(O); L 1 Selected from key, (CR) a R b ) z 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 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; m, m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6; x, y, and z are each independently 0, 1, 2, 3, 4, or 5; v can be 0, 1, or 2.

3. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (II) or general formula (III) 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 can be 0, 1, 2, 3, or 4; R 1 R 2a R 2b R 2c R 3a R 3 To R 5 W, Cy, R 8 m, Cy1, R 9 m1, R a R b x, Cy2, R 10 m2, L c R 12 and X 1 As defined in claim 1.

4. The compound of general formula (I) according to any one of claims 1 to 3, wherein the compound is a compound of general formula (IV) or general formula (V) or a pharmaceutically acceptable salt thereof: in: A 1 A 2 A 3 and A 4 Whether they are the same or different, and each is independently N or CR 8 ; 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; 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, q2, q3 and q4 may be the same or different, and each is independently 0, 1, 2, 3 or 4; m1 and m2 may be the same or different, and each can be 0, 1, 2, 3 or 4 independently; r can be 0, 1, 2, 3, or 4; R 1 R 2a R 2b R 2c R 3a R 3 To R 5 W, R 8 R 9 x, R 10 and R 12 As defined in claim 1.

5. The compound of formula (I) according to any one of claims 1 to 4, 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.

6. The compound of general formula (I) according to any one of claims 1 to 5, 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.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 3a It is a hydrogen atom; and / or R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; and / or R 4 It is a hydrogen atom.

8. The compound of formula (I) according to any one of claims 1 to 7, 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 9. The compound of formula (I) according to any one of claims 4 to 8, or a pharmaceutically acceptable salt thereof, wherein A 1 A 2 A 3 and A 4 They may be the same or different, and each is independently N or CH; preferably, A 1 A 2 and A 3 For CH; A 4 For N; or A 1 A 2 A 3 and A 4 For CH.

10. The compound of formula (I) according to any one of claims 4 to 9, or a pharmaceutically acceptable salt thereof, wherein X a For N or CH; X b For N or CH; X c For N or CH; X d It is N or CH; and / or q1 and q2, q3 and q4 are the same or different, and each is independently 0 or 1; and / or x is 0 or 1.

11. The compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; and / or m1 is 0 or 1; and / or R 10 It is a hydrogen atom; and / or R 12 r is a hydrogen atom or a halogen; and / or r is 0 or 1.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

13. A compound of general formula (IVa) or a salt thereof, in: R w1 and R w2 Each is independently a hydrogen atom or an amino protecting group; preferably, the amino protecting group is Boc or -SO2Ph; R 1 B 2 B 3 B 4 R 3a R 3 To R 5 W, A 1 A 2 A 3 A 4 X a q1, q2, R 9 And m1 as defined in claim 4.

14. The compound of formula (IVa) according to claim 13, or a salt thereof, wherein the compound is selected from the group consisting of:

15. A method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising: The compound represented by general formula (IVA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (IVB-1) or its salt to give the compound represented by general formula (IV) or its pharmaceutically usable salt. in: x is 0; X b For N; X c For CH; R 1 B 2 B 3 B 4 R 3a R 3 To R 5 W, A 1 A 2 A 3 A 4 X a q1, q2, R 9 m1, q3, q4, R 10 m2, X d R 12 and r as defined in claim 4; or, The compound represented by general formula (IVA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (IVB-2) or its salt to give the compound represented by general formula (IV) or its pharmaceutically usable salt. in: X b Let N be the number of people in the group. x6 can be 0, 1, 2, 3, or 4; x is 1, 2, 3, 4 or 5; R 1 B 2 B 3 B 4 R 3a R 3 To R 5 W, A 1 A 2 A 3 A 4 X a q1, q2, R 9 m1, q3, q4, R 10 m2, X c X d R 12 and r as defined in claim 4.

16. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for inhibiting or degrading BTK.

18. Use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for treating and / or preventing diseases or conditions mediated or dependent on BTK.

19. Use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, 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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