Heteroaryl compound, preparation method therefor, and pharmaceutical use thereof

Abstract

The present application relates to a heteroaryl compound, a preparation method therefor, and the pharmaceutical use thereof. Specifically, the present application relates to a heteroaryl compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the heteroaryl compound, the use thereof as a therapeutic agent, particularly as a BTK inhibitor or degrader, and the use thereof in the preparation of a drug for treating and / or preventing BTK-mediated or dependent diseases or conditions. 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, resistance has emerged in cancer patients treated with these inhibitors, as they target the cysteine ​​residue C481 in the BTK kinase domain to covalently bind to the side-chain thiol group. 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 second-line treatment. With the use of Pirtobrutinib, although the resulting C481 mutation is effectively suppressed in patients, new resistance mutations against Pirtobrutinib, such as L528W, have subsequently emerged (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). All marketed and investigational BTK covalent or non-covalent inhibitors bind to the ATP pocket, with Novartis' Remibrutinib and Roche's Fenebrutinib additionally binding to the H3 pocket, thus improving inhibitor selectivity. However, molecules with different binding modes exhibit significant overlap in the amino acid residues that bind to BTK, such as interacting with sites like 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] R 3 and R 3a The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 3 and R 3a Together with the carbon atom to which it is attached, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R atoms. 0 replace;

[0010] 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;

[0011] R 4 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0012] 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;

[0013] 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;

[0014] 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;

[0015] W is N or CR 6 ;

[0016] R 1 and 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;

[0017] 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;

[0018] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0019] Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups;

[0020] Cy1, Cy2, and Cy3 may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0021] s1, s2 and s3 may be the same or different, and each is independently 0 or 1;

[0022] L a L b L c and L d They may be the same or different, and each is independently selected from bonds, alkenyl groups, alkynyl groups, and -(CR groups). a R b ) x -、-O-、-S(O) v -、-C(O)-、-NR c -、-C(O)NR c -and-NR c C(O)-;

[0023] E is selected from

[0024] G1 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 selected from N, CH and CR. 12 ;

[0025] 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 selected from N, CH and CR. 12 ;

[0026] X 1 For N or CR 15 ;

[0027] 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)-;

[0028] 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)-;

[0029] R 15 Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl;

[0030] 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;

[0031] Or, R a and R b Together with the attached atoms, they form cycloalkyl or heterocyclic groups;

[0032] Each R 2 and R12 The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0033] R 13 R 14 and R c They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and heterocyclic groups;

[0034] Each R 8 R 9 R 10 and R 11 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 =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;

[0035] Or, two Rs 8 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0036] Or, two Rs 9 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0037] Or, two Rs 10 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0038] 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;

[0039] Or, R 6 and R 8 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 0 replace;

[0040] Or, R 8 and R 9 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 0 replace;

[0041] 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 Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally bonded by one or more R atoms. 0 replace;

[0042] R 20 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0043] R 22 and R 23 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0044] R 0They 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;

[0045] n is 0, 1, 2, or 3;

[0046] m, m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0047] x, y, and z are each independently 0, 1, 2, 3, 4, or 5;

[0048] v can be 0, 1, or 2.

[0049] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0050] in:

[0051] B is

[0052] 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.

[0053] 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;

[0054] R 4 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0055] 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;

[0056] 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;

[0057] 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;

[0058] W is N or CR 6 ;

[0059] R 1 and 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 19alkyl, 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;

[0060] 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;

[0061] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, and heterocyclic groups;

[0062] Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups;

[0063] Cy1, Cy2, and Cy3 may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0064] s1, s2 and s3 may be the same or different, and each is independently 0 or 1;

[0065] L a L b L c and L d They may be the same or different, and each is independently selected from bonds, alkenyl groups, alkynyl groups, and -(CR groups). a R b ) x -、-O-、-S(O) v -、-C(O)-、-NR c -、-C(O)NR c -and-NR c C(O)-;

[0066] E is selected from

[0067] 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 selected from N, CH and CR. 12 ;

[0068] Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom and is related to L dConnected, the other three are the same or different, and each is independently selected from N, CH and CR. 12 ;

[0069] X 1 For N or CR 15 ;

[0070] 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)-;

[0071] 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)-;

[0072] R 15 Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl;

[0073] 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;

[0074] Or, R a and R b Together with the attached atoms, they form cycloalkyl or heterocyclic groups;

[0075] Each R 2 and R 12 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 19cycloalkyl, 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;

[0076] R 13 R 14 and R c They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and heterocyclic groups;

[0077] Each R 8 R 9 R 10 and R 11 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 =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;

[0078] 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;

[0079] Or, R 6 and R 8 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 0 replace;

[0080] Or, R 8 and R 9 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 0 replace;

[0081] 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 Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally bonded by one or more R atoms. 0 replace;

[0082] R 20 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0083] R 22 and R 23 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0084] 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;

[0085] n is 0, 1, 2, or 3;

[0086] m, m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0087] x, y, and z are each independently 0, 1, 2, 3, 4, or 5;

[0088] v can be 0, 1, or 2.

[0089] In some embodiments disclosed herein, B is R 1 -R 5 , n, W, Cy, R 8 And m are as defined in general formula (I).

[0090] In some embodiments disclosed herein, R 3aSelected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 3a It is a hydrogen atom.

[0091] In some embodiments disclosed herein, R w It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R w It is a hydrogen atom.

[0092] 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.

[0093] In some embodiments of this disclosure, s1 is 1.

[0094] In some embodiments of this disclosure, s2 is 0.

[0095] In some embodiments of this disclosure, s3 is 0.

[0096] In some embodiments of this disclosure, s1 is 1; s2 is 0; and s3 is 0.

[0097] In some embodiments disclosed herein, L a -(CR) a R b ) x -;R a R b And x is as defined in general formula (I); in some implementations, L a -(CH2) x -; x as defined in general formula (I); in some implementations, L a For the key or -CH2-; in some implementations, L a For key; in some implementations, L a It is -CH2-.

[0098] In some embodiments disclosed herein, L c -(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 the key or -CH2-; in some implementations, L cFor key; in some implementations, L c It is -CH2-.

[0099] In some embodiments disclosed herein, L d -(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 the key or -CH2-; in some implementations, L d For key; in some implementations, L d It is -CH2-.

[0100] 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 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 piperidinyl or aziridine; in some embodiments, cycloCy1 is piperidinyl; in some embodiments, cycloCy1 is aziridine.

[0101] In some embodiments disclosed herein, ring Cy1 is X a X b q1 and q2 are as defined in general formula (II) or general formula (III); in some embodiments, ring Cy1 is X a q1 and q2 are as defined in general formula (II) or general formula (III); in some embodiments, ring Cy1 is selected from In some implementations, the ring Cy1 is selected from In some implementations, the ring Cy1 is selected from In some implementations, the ring Cy1 is selected from *End and L b Connected; End and L aConnected; in some implementations, ring Cy1 is *End and L b Connected; End and L a Connected; in some implementations, ring Cy1 is *End and L b Connected; End and L a Connected.

[0102] 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.

[0103] In some embodiments disclosed herein, Cy2 is X c Selected from N, CH and CR 10 ;X d Selected from N, CH and CR 10 ;q3 and q4 are each independently 0, 1, 2, 3 or 4; R 10 As defined in general formula (I); 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 schemes, *end and L c Connected; End and L bConnected.

[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 above schemes, *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 halogens, C 1-6 Alkyl and C 1-6 alkoxy group, r is 0, 1 or 2; in some embodiments, E is... R 12a For hydrogen atoms or R 12 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 selected from N, CH and CR 12 Y 2 and 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 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 They may be the same or different, and each is independently selected from N, CH and 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 two are the same or different, and each is independently CH or CR 12 R 12 As defined in general formula (I); in some implementations, G3 It is a carbon atom and is related to L d Connected, G 1 For CR 12a R 12a For hydrogen atoms or R 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 Q 4 They may be the same or different, and each is independently selected from N, CH and 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 two are the same or different, and each is independently CH 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 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 They may be the same or different, and each is independently selected from N, CH and 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 two are the same or different, and each is independently CH or CR 12 R 12As 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 1 Selected 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 -C(O)-; Y 2 For -CH2-; in some implementations, Y 1 For -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] X a Selected from N, CH and CR 9 ;

[0119] X b Selected from N, CH and CR 9 ;

[0120] q1 and q2 are each independently 0, 1, 2, 3 or 4;

[0121] m1 can be 0, 1, 2, 3 or 4;

[0122] r can be 0, 1, 2, 3, or 4;

[0123] R 1 To R 5 , n, W, Cy, R 8 m, R a R b x, R 9 L b R 12 and X 1 As defined in general formula (I).

[0124] In some embodiments disclosed herein, L b -(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 the key or -CH2-; in some implementations, L b For key; in some implementations, L b It is -CH2-.

[0125] 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.

[0126] 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.

[0127] In some embodiments disclosed herein, X 1 For N or CH; in some implementations, X 1 For N; in some implementations, X 1For CH.

[0128] 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

[0129] 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.

[0130] in:

[0131] R 1 To R 5 , n, W, Cy, R 8 m, x, X a X b R 9 m1, q1, q2, R 12 And r as defined in general formula (II) or general formula (III).

[0132] In some implementation schemes disclosed herein, for *End and L a or -(CR) a R b ) x -or-(CH2) x - Linked; Cy0 is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group; m and R 8 As defined in general formula (I).

[0133] In some embodiments of this disclosure, cyclic Cy is an 8- to 15-membered polycyclic heteroaryl group; in some embodiments, cyclic Cy is a 9- to 11-membered polycyclic heteroaryl group; in some embodiments, cyclic Cy is a 9-membered bicyclic heteroaryl group or an 11-membered tricyclic heteroaryl group; in some embodiments, cyclic Cy is selected from... In some implementations, the Cy ring is In some implementations, the Cy ring is In some implementations, the Cy ring is *End and L a or -(CR) a R b ) x -or-(CH2) x - Connected; The terminal is connected to the ring where W is located or to N.

[0134] In some embodiments of this disclosure, the cyclic Cy is a 7- to 11-membered bicyclic fused heterocyclic group or a 7- to 11-membered bicyclic fused heterocyclic group; in some embodiments, the cyclic Cy is a 7- to 11-membered bicyclic fused heterocyclic group; in some embodiments, the cyclic Cy is a 9-membered bicyclic fused heterocyclic group; in some embodiments, the cyclic Cy is a 5-membered heterocyclic group fused with a 5- to 8-membered heterocyclic group; in some embodiments, the cyclic Cy is a 5- or 6-membered heterocyclic group fused with a 5- to 7-membered heterocyclic group; in some embodiments, the cyclic Cy is a 5-membered heterocyclic group fused with a 6-membered heterocyclic group; in some embodiments, the cyclic Cy is a pyrazolyl group fused with a piperazine group; in some embodiments, the cyclic Cy is a 5- to 7-membered heterocyclic group fused with a 5- to 7-membered heterocyclic group; in some embodiments, the cyclic Cy is... g is 0, 1, or 2; ring A1 is a 5- or 6-membered heteroaryl or a 5- to 7-membered heterocyclic group; in some embodiments, ring Cy is Cy is a 5- or 6-membered heteroaryl group or a 5- to 7-membered heterocyclic group; in some embodiments, Cy is... Cy is a 5- or 6-membered heteroaryl group; in some embodiments, cycloCy is selected from... In some implementations, the Cy ring is In some implementations, the Cy ring is selected from... In some implementations, the Cy ring is In some implementations, the Cy ring is selected from... In the above schemes, *end and L a or -(CR) a R b ) x -or-(CH2) x - Connected; The terminal is connected to the ring where W is located or to N.

[0135] In some embodiments disclosed herein, each R 8Same or different, and each independently selected from =O, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; or, two R groups 8 Together with the attached atoms, they form a 3- to 8-membered cycloalkyl ring; in some embodiments, R 8 C 1-6 Alkyl; or two R 8 Together with the attached atoms, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 8 It can be methyl or ethyl; or two R atoms on the same carbon atom. 8 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R 8 It is a methyl group; or two R atoms on the same carbon atom. 8 Together with the attached carbon atom, they form a cyclopropyl group.

[0136] In some embodiments disclosed herein, each R 8 Same or different, and each independently selected from =O, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 8 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O; in some embodiments, each R 8 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 8 Halogen or C 1-6 Alkyl; in some embodiments, R 8 =O or C 1-6 Alkyl; in some embodiments, R 8 C 1-6 Alkyl; in some embodiments, R 8 It is methyl or ethyl; in some embodiments, R 8 For methyl; in some embodiments, R 8 It is a halogen.

[0137] 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 or 2; in some embodiments, m is 1; and in some embodiments, m is 0.

[0138] In some embodiments of this disclosure, the cyclic Cy is a 5-membered heteroaryl fused to a 6-membered heterocyclic group, and R 8 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and =O, m is 0 or 1; in some embodiments, the cyclic Cy is m is 0; in some implementations, Cy is m is 0, *terminal and L a or -(CR) a R b ) x -or-(CH2) x -connected, The terminal is connected to the ring where W is located or to N.

[0139] In some embodiments of this disclosure, g is 1 or 2; in other embodiments, g is 1.

[0140] In some embodiments of this disclosure, ring A1 is a 5-membered heterocyclic group or a 5-membered heteroaryl group; in some embodiments, ring A1 is a 5- or 6-membered heteroaryl group; in some embodiments, ring A1 is a 5-membered heteroaryl group; in some embodiments, ring A1 is selected from pyrroleyl, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, isothiazolyl, furanyl, oxazolyl, isoxazolyl, and pyridinyl; in some embodiments, ring A1 is pyrazolyl; in some embodiments, ring A1 is a 5-membered heterocyclic group; in some embodiments, ring A1 is 3-oxohexahydroimidazolyl.

[0141] In some implementation schemes disclosed herein, for In some implementation schemes, for In the above implementation schemes, Z 1 For N or CR 8g Z 2 For N or CR 8h Z 3 For N or CR 8i X is CR 8j Or N; R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h R 8i and R 8jThe same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0142] In some implementation schemes, Selected from

[0143] In some implementation schemes, Selected from In some implementation schemes, Selected from In some implementation schemes, Selected from In some implementation schemes, Selected from In some implementation schemes, Selected from In some implementation schemes, for *End and L a or -(CR) a R b ) x -or-(CH2) x - Connected; The terminal is connected to the ring where W is located or to N.

[0144] In some embodiments disclosed herein, R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; or, R 8aand R 8b Together with the adjacent carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R 8c and R 8d Together with the adjacent carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together with the attached carbon atom, they form a cyclopropyl group; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R 8a R 8b R 8c and R 8f For hydrogen atoms; R 8d and R 8e They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R 8a R 8b R 8c R 8d and R 8f For hydrogen atoms; R 8e It is a methyl group.

[0145] In some embodiments disclosed herein, R 8g Selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0146] In some embodiments disclosed herein, R 8h Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 8h It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 8h It is a hydrogen atom or a methyl group; in some embodiments, R 8hIt is a hydrogen atom.

[0147] In some embodiments disclosed herein, R 8i Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 8i It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 8i It is a hydrogen atom.

[0148] In some embodiments disclosed herein, R 8j It is a hydrogen atom.

[0149] In some embodiments disclosed herein, Z 1 For N or CH; in some implementations, Z 1 Let N be the number of elements in the array.

[0150] In some embodiments disclosed herein, Z 2 For N or CH; in some implementations, Z 2 For CR 8h ;R 8h It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, Z 2 For CH.

[0151] In some embodiments disclosed herein, Z 3 For N or CH; in some implementations, Z 3 For CH.

[0152] In some embodiments of this disclosure, X is N or CH; in other embodiments, X is N.

[0153] In some embodiments of this disclosure, the compound represented by general formula (I), (III), or (V), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof.

[0154] in:

[0155] Z 1 For N or CR 8g Z 2 For N or CR 8h X is CR 8j Or N; R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h and R 8jThe same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0156] X a Selected from N, CH and CR 9 ;

[0157] X b Selected from N, CH and CR 9 ;

[0158] q1 and q2 are each independently 0, 1, 2, 3 or 4;

[0159] m1 can be 0, 1, 2, 3 or 4;

[0160] r can be 0, 1, 2, 3, or 4;

[0161] R 1 To R 5 n, x, R 9 and R 12 As defined in general formula (I).

[0162] In some embodiments disclosed herein, R 4 and R 5 Together with their respective attached atoms, they form a 5- to 15-membered heterocyclic group or a 5- to 15-membered heteroaryl group, wherein each of the 5- to 15-membered heterocyclic group and the 5- to 15-membered heteroaryl group is independently and optionally converted by one or more R 5c Replace; in some implementations, R 4 and R 5 Together with the connected atoms, they form an optional structure formed by one or more R atoms. 5c The substituted 5- 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 4and 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 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 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 5 Together 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 5fSelected 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 5e For 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 5cThey 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; in some embodiments, the two R atoms on the same carbon atom 5m Together they form a cyclopropyl group.

[0168] In some embodiments disclosed herein, R 5n 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, 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 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, R5e It is a hydrogen atom or a halogen; in some implementations, R 5e For hydrogen atoms 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 groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 5f Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 5f It is a hydrogen atom or a carbon atom. 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, f1 is 1; f2 is 1.

[0176] 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.

[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 disclosed herein, 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; in some embodiments, R 1 It is a methyl group.

[0182] In some embodiments disclosed herein, each R 2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 2 They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; in some embodiments, each R 2 They may be the same or different, and each is independently a halogen; in some implementations, R 2 It is F.

[0183] In some embodiments of this disclosure, n is 0 or 1; in some embodiments, n is 0; and in some embodiments, n is 1.

[0184] In some embodiments disclosed herein, R 2 It is a halogen; and / or n is 0 or 1.

[0185] In some embodiments disclosed herein, R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 For methyl; in some embodiments, R 3 It is a hydrogen atom.

[0186] 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.

[0187] In some embodiments disclosed herein, R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; and / or R 4 It is a hydrogen atom.

[0188] 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

[0189] In some embodiments disclosed herein, each R 5a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally oxidized by one or more C14 groups. 1-6 Alkyl, C 1-6 Halogenated alkyl 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; in some embodiments, R 5a It is tert-butyl.

[0190] 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 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; in some embodiments, 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 It is tert-butyl.

[0191] 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.

[0192] 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.

[0193] In some embodiments disclosed herein, each R 9 Same or different, and each independently selected from =O, halogen, 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 Same or different, and each independently selected from =O, halogen, C 1-6 Alkyl and C 1-6Halogenated alkyl groups; in some embodiments, each R 9 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, each R 9 They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; in some embodiments, R 9 For halogen; in some implementations, R 9 C 1-6 alkyl.

[0194] 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-).

[0195] In some embodiments of this disclosure, q1 and q2 may be the same or different, and each is independently 0, 1 or 2; in some embodiments, q1 and q2 may be the same or different, and each is independently 0 or 1; in some embodiments, q1 is 1; q2 is 1; in some embodiments, q0 is 0; q2 is 0.

[0196] In some embodiments of this disclosure, q3 and q4 may be the same or different, and each is independently 0, 1 or 2; in some embodiments, q3 and q4 may be the same or different, and each is independently 0 or 1; in some embodiments, q3 is 1; q4 is 1; in some embodiments, q3 is 0; q4 is 0.

[0197] In some embodiments of this disclosure, m1 is 0, 1, or 2; in some embodiments, m1 is 0 or 2; in some embodiments, m1 is 0 or 1; in some embodiments, m1 is 0; in some embodiments, m1 is 2.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] In some embodiments disclosed herein, X a For CH; X b Let N be the number of elements in the array.

[0205] In some embodiments disclosed herein, X a For N or CH; X b It is N or CH; and / or q1 and q2 are the same or different, and each is independently 0 or 1.

[0206] In some embodiments of this disclosure, x is 0 or 1; in some embodiments, x is 0; and in some embodiments, x is 1.

[0207] 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.

[0208] In some embodiments disclosed herein, each R 12 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl 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 halogens, C 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 halogen or a carbon. 1-6 Alkyl; in some embodiments, each R 12 They may be the same or different, and each is independently a halogen; in some implementations, R 12 It is F.

[0209] In some embodiments disclosed herein, R 12 It is a halogen; and / or r is 0 or 1.

[0210] In some embodiments disclosed herein, R 12a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; in some embodiments, R 12a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R 12a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 12a It is a hydrogen atom or a halogen; in some implementations, R 12a For hydrogen atoms or F; in some implementations, R 12a It is a hydrogen atom.

[0211] In some embodiments disclosed herein, each R 10 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 10 Same or different, and each independently selected from =O, halogen, 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 halogens, 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 a halogen or a carbon. 1-6 Alkyl; in some embodiments, each R 10 They may be the same or different, and each is an independent halogen.

[0212] In some embodiments disclosed herein, each R 11 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 11Same or different, and each independently selected from =O, halogen, 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 halogens, 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 a halogen or a carbon. 1-6 Alkyl; in some embodiments, each R 11 They may be the same or different, and each is an independent halogen.

[0213] 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.

[0214] In some embodiments disclosed herein, R 18 and R 19 They may be 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.

[0215] 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.

[0216] 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.

[0217] In some embodiments of this disclosure, v is 0; in some embodiments, v is 1; and in some embodiments, v is 2.

[0218] In some embodiments disclosed herein, R c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, Rc It is a hydrogen atom.

[0219] 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 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 For halogen or =O; in some implementations, R 0 For halogen; in some implementations, R 0 It is a 3- to 6-membered cycloalkyl group; in some embodiments, R 0 It is cyclopropyl.

[0220] In some implementation schemes disclosed herein, Each independently selected In some implementation schemes, each is independently selected The * end is connected to E or a phenyl group.

[0221] In some implementation schemes disclosed herein, Selected from In some implementation schemes, selected from In some implementation schemes, for In some implementation schemes, for In each of the above implementation schemes, the * terminal is connected to E.

[0222] In some implementation schemes disclosed herein, Selected from In some implementation schemes, selected from In some implementation schemes, for In some implementation schemes, for In each of the above embodiments, the * end is connected to the phenyl group.

[0223] In some implementation schemes disclosed herein, Selected from In some implementation schemes, selected from In some implementation schemes, for In some implementation schemes, for In each of the above embodiments, the * end is connected to the phenyl group.

[0224] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

[0225] Where B is R 1 C 1-6 Alkyl; R 2 It is a halogen; n is 0 or 1; 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; or, R 4 and R 5 Together with the connected atoms, they form R 5f C 1-6 Alkyl or 3- to 6-membered cycloalkyl C 1-6 Alkyl; f1 is 1; f2 is 1; k3 is 0; W is CH; for *End and L a Connected; R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together with the attached carbon atom, they form a cyclopropyl group; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; Z 1 For N; Z 2 For CR 8h ;R 8h It is a hydrogen atom or a carbon atom. 1-6 Alkyl; Z 3 CH; X is N; L a For bonds or -CH2-; Cy1 is a 4- to 12-membered heterocyclic group; m1 is 0; s1 is 1; L bs1 is the key; s2 is 0; L c s3 is 0; L is the key; d E is the key; E is the key. Each R 12 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy group; r is 0, 1 or 2.

[0226] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 2 It is a halogen; n is 0 or 1; 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; or, R 4 and R 5 Together with the connected atoms, they form R 5f C 1-6 Alkyl or 3- to 6-membered cycloalkyl C 1-6 Alkyl; f1 is 1; f2 is 1; k3 is 0; W is CH; for *Terminal and (CH2) x Connected; R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together with the attached carbon atom, they form a cyclopropyl group; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; Z 1 For N; Z 2 For CR 8h ;R 8h It is a hydrogen atom or a carbon atom. 1-6 Alkyl; Z 3 CH; X is N; x is 0 or 1; m1 is 0, 1 or 2; R 9 C1-6 Alkyl groups; or, two non-adjacent R groups. 9 The connection forms a bridging ethylene group; X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is independently 0 or 1; R 12 It is a halogen; r is 0 or 1.

[0227] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 2 It is a halogen; n is 0 or 1; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 4 For hydrogen atoms; R 5 for Or, R 4 and R 5 Together with the connected atoms, they form R 5f C 1-6 Alkyl or 3- to 6-membered cycloalkyl C 1-6 Alkyl; f1 is 1; f2 is 1; k3 is 0; W is CH; Cy is m is 0 or 1; R 8 C 1-6 Alkyl; x is 0 or 1; m1 is 0, 1 or 2; R 9 C 1-6 Alkyl group; or, two non-adjacent R groups. 9 The connection forms a bridging ethylene group; X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is independently 0 or 1; R 12 It is a halogen; r is 0 or 1.

[0228] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 2 It is a halogen; n is 0 or 1; 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 CR 6 ;R 6 Selected from hydrogen atoms, halogens and C1-6 Alkyl group; Cy is a 5-membered heteroaryl fused to a 6-membered heterocyclic group; R 8 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl group and =O; m is 0 or 1; x is 0 or 1; m1 is 0 or 1; R 9 Halogen or C 1-6 Alkyl; X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is independently 0 or 1; R 12 It is a halogen; r is 0 or 1.

[0229] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; n is 0; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; R 5 for W represents CH; Cy represents *Terminal and (CH2) x Connected; m is 0; x is 0 or 1; m1 is 0; X a For CH; X b The inequality is N; q1 and q2 are the same or different, and each is independently 0 or 1; r is 0.

[0230] In some embodiments of this disclosure, the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 2 It is a halogen; n is 0 or 1; 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 group; Cy is a 5-membered heteroaryl fused to a 6-membered heterocyclic group; R 8 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl group and =O; m is 0 or 1; x is 0 or 1; m1 is 0 or 1; R 9 Halogen or C 1-6 Alkyl; X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is independently 0 or 1; R 12It is a halogen; r is 0 or 1.

[0231] In some embodiments of this disclosure, the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 2 It is a halogen; n is 0 or 1; 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; or, R 4 and R 5 Together with the connected atoms, they form R 5f C 1-6 Alkyl or 3- to 6-membered cycloalkyl C 1-6 Alkyl; f1 is 1; f2 is 1; k3 is 0; for *The terminal is connected to (CH2)x; R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together with the attached carbon atom, they form a cyclopropyl group; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; Z 1 For N; Z 2 For CR 8h ;R 8h It is a hydrogen atom or a carbon atom. 1-6 Alkyl; Z 3 CH; X is N; x is 0 or 1; m1 is 0, 1 or 2; R 9 C 1-6 Alkyl group; or, two non-adjacent R groups. 9 The connection forms a bridging ethylene group; X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is independently 0 or 1; R 12 It is a halogen; r is 0 or 1.

[0232] In some embodiments of this disclosure, the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 2 It is a halogen; n is 0 or 1; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 4 For hydrogen atoms; R 5 for Or, R 4 and R 5 Together with the connected atoms, they form R 5f C 1-6 Alkyl or 3- to 6-membered cycloalkyl C 1-6 Alkyl; f1 is 1; f2 is 1; k3 is 0; Cy is m is 1 or 2; R 8 C 1-6 Alkyl group; or, two R atoms on the same carbon atom. 8 Together with the adjacent carbon atom, they form a cyclopropyl group; x is 0 or 1; m1 is 0, 1, or 2; R 9 C 1-6 Alkyl group; or, two non-adjacent R groups. 9 The connection forms a bridging ethylene group; X a For N or CH; X b It is N or CH; q1 and q2 are the same or different, and each is independently 0 or 1; R 12 It is a halogen; r is 0 or 1.

[0233] In some embodiments of this disclosure, the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; n is 0; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; R 5 for Cy ring is *Terminal and (CH2) x Connected; m is 0; x is 0 or 1; m1 is 0; X a For CH; X b The inequality is N; q1 and q2 are the same or different, and each is independently 0 or 1; r is 0.

[0234] In some embodiments of this disclosure, the compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 2It is a halogen; n is 0 or 1; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 4 For hydrogen atoms; R 5 for Or, R 4 and R 5 Together with the connected atoms, they form R 5f C 1-6 Alkyl or 3- to 6-membered cycloalkyl C 1-6 Alkyl; f1 is 1; f2 is 1; k3 is 0; Z 1 For N; Z 2 For CR 8h ;R 8h It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together with the attached carbon atom, they form a cyclopropyl group; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the adjacent carbon atom, they form a cyclopropyl group; X is N; x is 0 or 1; m1 is 0; or, m1 is 2, two non-adjacent R atoms. 9 The connection forms a bridging ethylidene (-CH2CH2-); X a For CH or N; X b It is CH or N; q1 and q2 are the same or different, and each is independently 0 or 1; R 12 It is a halogen; r is 0 or 1.

[0235] In some embodiments of this disclosure, the compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 2 It is a halogen; n is 0 or 1; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 4 For hydrogen atoms; R 5 for Z 1 For N; Z 2 For CR 8h ;R 8h It is a hydrogen atom or a carbon atom. 1-6Alkyl; R 8a R 8b R 8c R 8d R 8e and R 8f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, or R 8a and R 8b Together with the attached carbon atom, they form a cyclopropyl group; or, R 8c and R 8d Together with the attached carbon atom, they form a cyclopropyl group; or, R 8e and R 8f Together with the attached carbon atom, they form a cyclopropyl group; X is N; x is 0 or 1; m1 is 0; X a For CH or N; X b It is CH or N; q1 and q2 are the same or different, and each is independently 0 or 1; R 12 It is a halogen; r is 0 or 1.

[0236] Table A lists typical compounds disclosed herein, including but not limited to:

[0237] This disclosure provides a compound of general formula (IIa) or general formula (IIIa) or a salt thereof.

[0238] in:

[0239] R m It is a hydrogen atom or an amino protecting group;

[0240] R 5 It is aryl or heteroaryl; each of the aryl and heteroaryl groups is independently and optionally converted by one or more R 5a replace;

[0241] CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0242] R 1 To R 4 R 5a n, W, R 8 And m as defined in general formula (II) or general formula (III).

[0243] This disclosure provides a compound of general formula (IIA) or general formula (IIIA) or a salt thereof.

[0244] in:

[0245] R 5 It is aryl or heteroaryl; each of the aryl and heteroaryl groups is independently and optionally converted by one or more R 5a replace;

[0246] CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0247] R 1 To R 4 R 5a n, W, R 8 And m as defined in general formula (II) or general formula (III).

[0248] This disclosure provides a compound of general formula (VIA) or a salt thereof.

[0249] in:

[0250] R m It is a hydrogen atom or an amino protecting group;

[0251] R 1 To R 5 , n, Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e and R 8f As defined in general formula (VI).

[0252] In some embodiments disclosed herein, R m For hydrogen atoms; in some implementations, R m For Boc.

[0253] In some embodiments of this disclosure, the compounds represented by formula (IIa), formula (IIA), formula (IIIa), formula (IIIA) or formula (IVA) are not compounds disclosed in WO2015089337 A1.

[0254] In some embodiments of this disclosure, the compound or its salt represented by general formula (IIA) is not...

[0255] In some embodiments of this disclosure, the compound represented by general formula (IIIA) is not...

[0256] In some embodiments of this disclosure, the compound represented by the general formula (IVA) is not...

[0257] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

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

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

[0260] in:

[0261] x is 0; X a For CH;

[0262] for *End and (CR) a R b ) x Linked; CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0263] R 1 To R 5 n, W, R 8 m, X b R 9 m1, q1, q2, L b X 1 R 12 and r are as defined in general formula (II);

[0264] or,

[0265] The compound of general formula (IIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IIC) or its salt to give the compound of general formula (II) or its pharmaceutically usable salt.

[0266] in:

[0267] x6 can be 0, 1, 2, 3, or 4;

[0268] x is 1, 2, 3, 4, or 5; R a and R b It is a hydrogen atom;

[0269] for *End and (CR) a R b ) x Linked; CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0270] R 1 To R 5 n, W, R 8 m, X a X b R 9 m1, q1, q2, L b X 1 R 12 And r is as defined in general formula (II).

[0271] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0272] The compound of general formula (IIIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IIB) or its salt to give the compound of general formula (III) or its pharmaceutically usable salt.

[0273] in:

[0274] x is 0; X a For CH;

[0275] for *End and (CR) a R b ) x Connected;

[0276] CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0277] R 1 To R 5 n, R 8 m, X b R 9 m1, q1, q2, L b X 1 R 12and r as defined in general formula (III); or,

[0278] The compound of general formula (IIIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IIC) or its salt to give the compound of general formula (III) or its pharmaceutically usable salt.

[0279] in:

[0280] x6 can be 0, 1, 2, 3, or 4;

[0281] x is 1, 2, 3, 4, or 5; R a and R b It is a hydrogen atom;

[0282] for *End and (CR) a R b ) x Linked; CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0283] R 1 To R 5 n, R 8 m, X a X b R 9 m1, q1, q2, L b X 1 R 12 And r is as defined in general formula (III).

[0284] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0285] The compound of general formula (IIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB) or its salt to give the compound of general formula (IV) or its pharmaceutically usable salt.

[0286] in:

[0287] x is 0; X a For CH;

[0288] for *Terminal and (CH2) x Connected;

[0289] CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0290] R 1 To R 5 n, W, R8 m, X b R 9 m1, q1, q2, R 12 and r as defined in general formula (IV); or,

[0291] The compound of general formula (IIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IVC) or its salt to give the compound of general formula (IV) or its pharmaceutically usable salt.

[0292] in:

[0293] x6 is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5;

[0294] for *Terminal and (CH2) x Connected;

[0295] CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0296] R 1 To R 5 n, W, R 8 m, X a X b R 9 m1, q1, q2, R 12 And r are as defined in general formula (IV).

[0297] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V) or a pharmaceutically acceptable salt thereof, comprising:

[0298] The compound of general formula (IIIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB) or its salt to give the compound of general formula (V) or its pharmaceutically usable salt.

[0299] in:

[0300] x is 0; X a For CH;

[0301] for *Terminal and (CH2) x Connected;

[0302] CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0303] R 1 To R 5 n, R 8 m, X bR 9 m1, q1, q2, R 12 And r as defined in general formula (V);

[0304] or,

[0305] The compound of general formula (IIIA) or its salt undergoes a reductive amination reaction with the compound of general formula (VC) or its salt to give the compound of general formula (V) or its pharmaceutically usable salt.

[0306] in:

[0307] x6 can be 0, 1, 2, 3, or 4;

[0308] x is 1, 2, 3, 4 or 5;

[0309] for *Terminal and (CH2) x Connected;

[0310] CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group;

[0311] R 1 To R 5 n, R 8 m, X a X b R 9 m1, q1, q2, R 12 And r is as defined in general formula (V).

[0312] Another aspect of this disclosure relates to a method for preparing a compound of general formula (VI) or a pharmaceutically acceptable salt thereof, comprising:

[0313] The compound of general formula (VIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB) or its salt to give the compound of general formula (VI) or its pharmaceutically usable salt.

[0314] in:

[0315] R m It is a hydrogen atom;

[0316] x is 0; X a CH; X is N;

[0317] R 1 To R 5 , n, Z 1 Z 2 R 8a R 8b R 8c R 8dR 8e R 8f X b q1, q2, R 9 m1, R 12 and r as defined in general formula (VI); or,

[0318] The compound of general formula (VIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IVC) or its salt to give the compound of general formula (VI) or its pharmaceutically usable salt.

[0319] in:

[0320] x6 can be 0, 1, 2, 3, or 4;

[0321] x is 1, 2, 3, 4 or 5;

[0322] R m It is a hydrogen atom;

[0323] X is N;

[0324] R 1 To R 5 , n, Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e R 8f X a X b q1, q2, R 9 m1, R 12 And r are as defined in general formula (VI).

[0325] Another aspect of this disclosure relates to a method for preparing a compound of general formula (VI) or a pharmaceutically acceptable salt thereof, comprising:

[0326] The compound of general formula (VIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IVB) or its salt to give the compound of general formula (VI) or its pharmaceutically usable salt.

[0327] in:

[0328] R m It is a hydrogen atom;

[0329] x is 0; X a CH; X is N;

[0330] R 1 To R 5 , n, Z 1Z 2 R 8a R 8b R 8c R 8d R 8e R 8f X b q1, q2, R 9 m1, R 12 And r are as defined in general formula (VI).

[0331] Another aspect of this disclosure relates to a method for preparing a compound of general formula (VI) or a pharmaceutically acceptable salt thereof, comprising:

[0332] The compound of general formula (VIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IVC) or its salt to give the compound of general formula (VI) or its pharmaceutically usable salt.

[0333] in:

[0334] x6 can be 0, 1, 2, 3, or 4;

[0335] x is 1, 2, 3, 4 or 5;

[0336] R m It is a hydrogen atom;

[0337] X is N;

[0338] R 1 To R 5 , n, Z 1 Z 2 R 8a R 8b R 8c R 8d R 8e R 8f X a X b q1, q2, R 9 m1, R 12 And r are as defined in general formula (VI).

[0339] In some embodiments of this disclosure, x6 is 0; in some embodiments, x6 is 0; x is 1; in some embodiments, x6 is 1; x is 2.

[0340] In some embodiments of this disclosure, the reductive amination reaction occurs under acidic conditions and in the presence of a reducing agent; in some embodiments, the reagents providing the acidic conditions include, but are not limited to, acetic acid, glacial acetic acid, Ti(i-PrO)3, and BF3·Et2O; in some embodiments, the reagents providing the acidic conditions are acetic acid or glacial acetic acid; in some embodiments, the acidic conditions are provided by an acid generated during the reaction.

[0341] 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.

[0342] 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.

[0343] In some embodiments of this disclosure, the cyclic CyO is a 7- to 11-membered nitrogen-containing bicyclic fused heterocyclic group or a 7- to 11-membered nitrogen-containing bicyclic fused heterocyclic aryl group; in some embodiments, the cyclic CyO is a 7- to 11-membered nitrogen-containing bicyclic fused heterocyclic aryl group; in some embodiments, the cyclic CyO is a 9-membered nitrogen-containing bicyclic fused heterocyclic aryl group; in some embodiments, the cyclic CyO is a 5- or 6-membered heterocyclic group fused with a 5- to 7-membered nitrogen-containing heterocyclic group; in some embodiments, the cyclic CyO is a 5-membered heterocyclic group fused with a 6-membered nitrogen-containing heterocyclic group; in some embodiments, the cyclic CyO is a 5- to 7-membered heterocyclic group fused with a 5- to 7-membered nitrogen-containing heterocyclic group; in some embodiments, the cyclic CyO is a 5-membered heterocyclic group fused with a 6-membered nitrogen-containing heterocyclic group; in some embodiments... for g is 0, 1, or 2; ring A1 is a 5- or 6-membered heteroaryl group or a 5- to 7-membered heterocyclic group; in some embodiments, ... for Ring A1 is a 5- or 6-membered heteroaryl group or a 5- to 7-membered heterocyclic group; in some embodiments, for Cyclone A1 is a 5- or 6-membered heteroaryl group; in some embodiments, Selected from In some implementation schemes, for In some implementation schemes, Selected from In the above schemes, the * terminal is connected to H or R m Connected; The end is connected to the ring where W is located or to NH.

[0344] In some implementation schemes, for; *Terminal and H or R m Connected; The terminal is connected to the ring containing W or N; X is N; Z 1 Z 2 Z 3 R 8a R 8b R 8c R 8d R 8e and R 8f As defined above.

[0345] In some implementation schemes, Selected from *Terminal and H or R m Connected; The end is connected to the ring where W is located or to NH.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] This disclosure also relates to a method for regulating the ubiquitination and degradation of BTK protein in a subject, comprising administering to a patient in need 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.

[0352] This disclosure also relates to methods for inhibiting or degrading BTK in a subject, comprising administering to a patient in need 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.

[0353] This disclosure also relates to a method of treating and / or preventing diseases or conditions mediated or dependent on BTK, comprising administering to a patient in need 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] In some implementations, the tumor described in this disclosure is cancer.

[0363] In some embodiments, the tumors described in this disclosure are hematologic malignancies.

[0364] In some embodiments, the tumor described in this disclosure is a B-cell malignant tumor.

[0365] 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).

[0366] 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).

[0367] In some embodiments, the BTK described in this disclosure also includes mutations within the BTK protein, such as C481S, C481Y, C481R, and C481F.

[0368] The active compound can be formulated in a form suitable for administration via any appropriate route, in some embodiments in the form of a unit dose or in a form that a patient can self-administer as a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0369] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0370] 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.

[0371] As a general guideline, the active compounds of this disclosure are, in some embodiments, expressed as unit doses or in a manner that allows patients to self-administer a single dose. The unit dose of the disclosed compounds or compositions may be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. Suitable unit doses may range from 0.1 to 1000 mg.

[0372] 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.

[0373] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0374] 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.

[0375] 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.

[0376] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0377] 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.

[0378] 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.

[0379] 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.

[0380] 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.

[0381] 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.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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.

[0386] 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.

[0387] Terminology Explanation

[0388] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0389] 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 the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0390] 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 alkylenes having 1 to 8 carbon atoms (i.e., C164-C ... 1-8 Alkylenes), in some embodiments having 2 to 7 carbon atoms (i.e., C164-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0391] 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-).

[0392] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group, in some embodiments, has 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0393] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 The alkynyl group (in some embodiments) has 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0394] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0395] 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).

[0396] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0397] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0398] 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:

[0399] Its connection point can be anywhere;

[0400] wait.

[0401] 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:

[0402] Its connection point can be anywhere;

[0403] wait.

[0404] 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:

[0405] Its connection point can be anywhere.

[0406] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0407] 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).

[0408] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0409] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0410] 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 is, in some embodiments, a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, a spiroheterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered spiroheterocyclic group). The spiroheterocyclic group includes mono-spiroheterocyclic groups and poly-spiroheterocyclic groups (such as bi-spiroheterocyclic groups), and in some embodiments is a mono-spiroheterocyclic group or a bi-spiroheterocyclic group, and more particularly 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 mono-spiroheterocyclic group. Non-limiting examples include:

[0411] wait.

[0412] 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:

[0413] wait.

[0414] 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:

[0415] wait.

[0416] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0417] 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:

[0418] wait.

[0419] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0420] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) ring atoms (i.e., 5 to 15-membered heteroaryl). The heteroaryl group is, in some embodiments, a heteroaryl group with 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), in some embodiments a heteroaryl group with 8 to 15 ring atoms (i.e., an 8 to 15-membered heteroaryl group), in some embodiments a heteroaryl group with 9 to 11 ring atoms (i.e., a 9 to 11-membered heteroaryl group), in some embodiments a heteroaryl group with 9 ring atoms (i.e., a 9-membered heteroaryl group), in some embodiments a heteroaryl group with 11 ring atoms (i.e., an 11-membered heteroaryl group), and in some embodiments a heteroaryl group with 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group).

[0421] 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.

[0422] 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:

[0423] wait.

[0424] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0425] 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.

[0426] When a polycyclic system formed by the fusion of a monocyclic heteroaryl group with a cycloalkyl group, a heterocyclic group, or an aryl group is divalent, the polycyclic system is classified as "heteroaryl" or "fused heteroaryl" as long as one of the linking sites is on the monocyclic heteroaryl group; non-limiting examples include:

[0427] 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.

[0428] 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.

[0429] 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.

[0430] 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.

[0431] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0432] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0433] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0434] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0439] 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.

[0440] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0441] The term "hydroxyl group" refers to -OH.

[0442] The term "thiol" refers to -SH.

[0443] The term "amino" refers to -NH2.

[0444] The term "cyano" refers to -CN.

[0445] The term "nitro" refers to -NO2.

[0446] The term "oxo" or "oxo group" refers to "=O".

[0447] The term "carbonyl" refers to C=O.

[0448] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0449] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0450] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0451] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0452] The term "amino protecting group" refers to a group that is easily removed from the amino group, introduced onto the amino group to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), tert-butylsulfinyl, trifluoroacetyl (Tfa), trichloroacetyl, triphenylmethyl (Trt), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.; in some embodiments, it is Boc.

[0453] 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.

[0454] 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.

[0455] 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:

[0456] 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:

[0457] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0458] 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.

[0459] 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.

[0460] 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.

[0461] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0462] "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.

[0463] "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).

[0464] "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.

[0465] "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.

[0466] 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.

[0467] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0468] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations. Detailed Implementation

[0469] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0470] Example

[0471] 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. -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).

[0472] MS measurements were performed using an Agilent 1200 / 1290 DAD-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).

[0473] 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.

[0474] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0475] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0476] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0477] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0478] 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.

[0479] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0480] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0481] 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.

[0482] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0483] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0484] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0485] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0486] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0487] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0488] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0489] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0490] 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.

[0491] Example 1

[0492] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide1

[0493] first step

[0494] 2-((6-chloropyrimidin-4-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 1b

[0495] 2-Amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 1a (500 mg, 2.10 mmol, Bioderm) was dissolved in 1,4-dioxane (8 mL), and 4,6-dichloropyrimidine (376 mg, 2.52 mmol) and N,N-diisopropylethylamine (1.36 g, 10.52 mmol, Sinopharm) were added. The mixture was sealed and reacted at 100 °C for 12 hours. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give title compound 1b (130 mg, yield: 17.7%).

[0496] MS m / z (ESI): 351.4 [M+1] + .

[0497] Step 2

[0498] (R)-2-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 1d

[0499] Compound 1b (130 mg, 0.37 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.6 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (55 mg, 0.08 mmol, Bioderm), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopent-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 1c (169 mg, 0.41 mmol) (prepared by the method disclosed in intermediate 0127 on page 48 of patent application WO2023125908A1), and potassium carbonate (103 mg, 0.75 mmol, Sinopharm) were added. The mixture was purged with nitrogen three times and reacted at 80 °C for 12 hours. Add 10 mL of water, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with 10 mL of saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by column chromatography with eluent system B to give the title compound 1d (150 mg, yield: 67.3%).

[0500] MS m / z (ESI): 602.7 [M+1] + .

[0501] Step 3

[0502] (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 1e

[0503] Compound 1d (150 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), and dioxane hydrochloride solution (0.62 mL, 2.50 mmol, 4 M, Adamas) was added. The mixture was reacted at room temperature for 2 hours. The solution was concentrated under reduced pressure, and 5 mL of saturated sodium bicarbonate was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 1e (125 mg, yield: 99.9%). The product was directly used in the next reaction without purification.

[0504] MS m / z (ESI): 502.6 [M+1] + .

[0505] Step 4

[0506] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide1

[0507] Compound 1e (125 mg, 0.25 mmol) was dissolved in ethanol (2 mL) and dichloromethane (2 mL). Acetic acid (45 mg, 0.75 mmol, Sinopharm), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-carboxaldehyde 1f (83 mg, 0.28 mmol) (prepared using the method disclosed in intermediate 0423 on page 107 of patent application WO2023125908A1), and sodium acetate (41 mg, 0.50 mmol, Sinopharm) were added, and the mixture was reacted at room temperature for 2 hours. Sodium borohydride acetate (265 mg, 1.25 mmol, Biotin) was then added, and the mixture was reacted at room temperature for 2 hours. Add 20 mL of water and extract with a mixture of isopropanol / dichloromethane (V / V = 1:3) (20 mL × 3). Combine the organic phases, wash with 20 mL of saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography with eluent system A to give title compound 1 (98 mg, yield: 50.0%).

[0508] MS m / z(ESI): 787.8 [M+1] + .

[0509] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),9.94-9.87(m,2H),8.65(s,1H),7.83-7.81(m,2H),7 .65-7.59(m,2H),7.20-7.12(m,2H),6.95-6.92(m,2H),6.24-6.23(m,1H),5.36-5.31(m,1H) ,4.04-4.01(m,2H),3.71-3.63(m,5H),2.92-2.89(m,2H),2.71-2.66(m,4H),2.47-2.45(m,3 H),2.41-2.40(m,2H),1.84-1.81(m,2H),1.52-1.50(m,3H),1.37(s,9H),1.29-1.27(m,4H).

[0510] Example 2

[0511] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobut-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 2

[0512] first step

[0513] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobut-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 2b

[0514] Compound 1e (100 mg, 0.20 mmol) was dissolved in methanol (1.5 mL) and dichloromethane (1.5 mL). Acetic acid (36 mg, 0.6 mmol, Sinopharm), 1-(4-(3-oxoazacyclobut-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione 2a (85 mg, 0.22 mmol) (prepared using the method disclosed in intermediate 0801 on page 179 of patent application WO2022143856A1), and anhydrous sodium acetate (33 mg, 0.40 mmol, Sinopharm) were added, and the reaction was carried out at room temperature for 12 hours. Sodium borohydride acetate (212 mg, 1.00 mmol, Bigeter) was added, and the reaction was carried out at room temperature for 1 hour. Sodium cyanoborohydride (19 mg, 0.30 mmol, Bigeter) was added, and the reaction was carried out at room temperature for 1 hour. Add 10 mL of water, extract with dichloromethane (10 mL × 3), combine the organic phases, wash with 10 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give title compound 2b (174 mg, yield: 99.7%). The product was directly used in the next reaction without purification.

[0515] MS m / z (ESI): 875.8 [M+1] + .

[0516] Step 2

[0517] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobut-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 2

[0518] The crude compound 2b (174 mg, 0.20 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1.54 g, 13.51 mmol, Adamas) was added. The mixture was reacted at room temperature for 2 hours. The solution was concentrated under reduced pressure, and methanol (2 mL) and potassium carbonate (138 mg, 1.00 mmol, Sinopharm) were added. The mixture was reacted at room temperature for 1 hour, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 2 (45 mg, yield: 30.4%).

[0519] MS m / z (ESI): 745.9 [M+1] + .

[0520] 1 H NMR (500MHz, DMSO-d6): δ10.24(s,1H),9.95-9.87(m,2H),8.65(s,1H),7.83-7.8 1(m,2H),7.61-7.60(m,2H),7.15-7.12(m,2H),6.47-6.45(m,2H),6.24-6.23(m,1 H),5.34-5.32(m,1H),4.06-4.01(m,4H),3.72-3.67(m,5H),3.61-3.59(m,1H),2 .93-2.90(m,2H),2.70-2.67(m,2H),2.47(s,4H),1.52-1.49(m,3H),1.36(s,9H).

[0521] Example 3

[0522] (R)-3-(tert-butyl)-N-(1-(4-(6-(5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 3

[0523] first step

[0524] 3-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 3b

[0525] 3-Bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 3a (500 mg, 1.65 mmol) was dissolved in 1,4-dioxane (8 mL), and pinacol diboronate (841 mg, 3.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (243 mg, 0.33 mmol, Bioderm), and potassium acetate (488 mg, 4.97 mmol, Sinopharm) were added. The mixture was purged with nitrogen three times and stirred at 90 °C for 12 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 3b (330 mg, yield: 57.1%).

[0526] MS m / z (ESI): 350.3 [M+1] + .

[0527] Step 2

[0528] 3-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 3d

[0529] Compound 3b (330 mg, 0.95 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (139 mg, 0.19 mmol, BIDE), 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine 3c (437 mg, 1.04 mmol, BIDE), and potassium carbonate (262 mg, 1.90 mmol, Sinopharm) were added. The mixture was purged with nitrogen three times and reacted at 90 °C for 5 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 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 B to give the title compound 3d (170 mg, yield: 34.9%).

[0530] MS m / z (ESI): 515.4 [M+1] + .

[0531] Step 3: (R)-3-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 3e

[0532] Compound 3d (170 mg, 0.33 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (49 mg, 0.07 mmol, Bioderm), compound 1c (151 mg, 0.37 mmol), and potassium carbonate (92 mg, 0.67 mmol, Sinopharm) were added. The mixture was purged with nitrogen three times and reacted at 80 °C for 12 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 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 B to give the title compound 3e (180 mg, yield: 71.2%).

[0533] MS m / z(ESI): 766.6 [M+1] + .

[0534] Step 4 (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 3f

[0535] Compound 3e (180 mg, 0.24 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (1 mL), and sodium hydroxide (66 mg, 1.65 mmol, Sinopharm) was added. The reaction was carried out at room temperature for 0.5 h. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 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 crude product was dissolved in dichloromethane (2 mL), and dioxane hydrochloride solution (1.00 mL, 4.00 mmol, 4 M, Adamas) was added. The reaction was carried out at room temperature for 2 h. The mixture was concentrated under reduced pressure, and 5 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 3f (123 mg, yield: 99.6%). The product was directly used in the next reaction without purification.

[0536] MS m / z(ESI): 526.6 [M+1] +.

[0537] Step 5

[0538] (R)-3-(tert-butyl)-N-(1-(4-(6-(5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 3

[0539] Compound 3f (123 mg, 0.23 mmol) was dissolved in ethanol (3 mL) and dichloromethane (3 mL). Acetic acid (43 mg, 0.72 mmol, Sinopharm), compound 1f (78 mg, 0.26 mmol), and sodium acetate (39 mg, 0.48 mmol, Sinopharm) were added, and the mixture was reacted at room temperature for 2 hours. Sodium borohydride acetate (248 mg, 1.17 mmol, Bioderm) was added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with a 20 mL × 3 mixture of isopropanol / dichloromethane (V / V = 1:3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give title compound 3 (102 mg, yield: 53.7%).

[0540] MS m / z(ESI): 811.9 [M+1] + .

[0541] 1 H NMR (500MHz, DMSO-d6): δ12.64(s,1H),10.28(s,1H),9.96-9.94(m,1H),8.82(s,1H),8.06-8.0 4(m,2H),7.69-7.67(m,1H),7.25-7.24(m,2H),7.18-7.14(m,2H),7.04-7.03(m,2H),5.36-5.31 (m,1H),4.04-4.01(m,2H),3.71-3.63(m,5H),2.92-2.89(m,2H),2.71-2.66(m,4H),2.47-2.45( m,3H),2.41-2.40(m,2H),1.84-1.81(m,2H),1.52-1.50(m,3H),1.37(s,9H),1.29-1.27(m,4H).

[0542] Example 4

[0543] (R)-3-(tert-butyl)-N-(1-(4-(6-(5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 4

[0544] first step

[0545] 2-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 4c

[0546] 2-Bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 4a (100 mg, 0.33 mmol, Icon) was dissolved in 1,4-dioxane (3 mL), and 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 4b (177 mg, 0.43 mmol) (prepared by the method disclosed in intermediate F1 on page 36 of patent application WO2024088379A1), hexamethyldistin (141 mg, 0.43 mmol, Bitden), and tetra(triphenylphosphine)palladium (39 mg, 0.03 mmol, Bitden) were added. The mixture was purged with nitrogen three times and stirred at 100 °C for 6 hours. Add bis(triphenylphosphine)palladium dichloride (47 mg, 0.07 mmol, BIDE), purge with nitrogen three times, and stir at 100 °C for 12 hours. Add 10 mL of water, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with 10 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography with eluent system B to give the title compound 4c (150 mg, yield: 89.7%).

[0547] MS m / z (ESI): 505.5 [M+1] + .

[0548] Step 2

[0549] (R)-2-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 4d

[0550] Compound 4c (150 mg, 0.30 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.06 mmol, Bioderm), compound 1c (135 mg, 0.33 mmol), and potassium carbonate (83 mg, 0.60 mmol, Sinopharm) were added. The mixture was purged with nitrogen three times and reacted at 95 °C for 4 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 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 B to give the title compound 4d (100 mg, yield: 44.5%).

[0551] MS m / z(ESI): 756.9 [M+1] + .

[0552] Step 3

[0553] (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 4e

[0554] The crude compound 4d (100 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (3.08 g, 27.01 mmol, Adamas) was added. The mixture was reacted at room temperature for 2 hours. The solution was concentrated under reduced pressure, and 5 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 4e (69 mg, yield: 99.2%). The product was directly proceeded to the next reaction without purification.

[0555] MS m / z(ESI): 526.5 [M+1] + .

[0556] Step 4

[0557] (R)-3-(tert-butyl)-N-(1-(4-(6-(5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 4

[0558] Compound 4e (69 mg, 0.13 mmol) was dissolved in ethanol (2 mL) and dichloromethane (2 mL). Acetic acid (24 mg, 0.40 mmol, Sinopharm), compound 1f (44 mg, 0.15 mmol), and sodium acetate (22 mg, 0.27 mmol, Sinopharm) were added, and the mixture was reacted at room temperature for 2 hours. Sodium borohydride acetate (140 mg, 0.66 mmol, Bioderm) was added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with a 20 mL × 3 isopropanol / dichloromethane (V / V = 1:3) mixed solvent. The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give title compound 4 (33 mg, yield: 31.0%).

[0559] MS m / z(ESI): 811.8 [M+1] + .

[0560] 1 H NMR (500MHz, DMSO-d6): δ12.64(s,1H),10.26(s,1H),9.95-9.94(m,1H),8.78(s,1H),8.05-8.0 0(m,2H),7.69-7.67(m,1H),7.16-7.13(m,3H),6.95-6.93(m,2H),6.72-6.66(m,2H),5.41-5.37 (m,1H),4.21-4.18(m,2H),3.72-3.69(m,4H),2.98-2.95(m,2H),2.72-2.67(m,4H),2.47-2.45( m,3H),1.99-1.97(m,2H),1.86-1.83(m,2H),1.56-1.55(m,3H),1.37(s,9H),1.29-1.27(m,4H).

[0561] Example 5

[0562] 3-(tert-butyl)-N-((1R)-1-(4-(6-(5-((8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-8-azabicyclo[3.2.1]oct-3-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 5

[0563] Compound 4e (100 mg, 0.19 mmol) was dissolved in ethanol (2 mL) and dichloromethane (2 mL), and acetic acid (34 mg, 0.57 mmol, Sinopharm), 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-8-azabicyclo[3.2.1]octane-3-carboxaldehyde 5a (68.5 mg, 0.21 mmol, prepared by replacing piperidine-4-ylmethanol with 8-azabicyclo[3.2.1]octane-3-ylmethanol using the same method as intermediate 0133 on page 34 of patent application WO2021 / 219070), and sodium acetate (31 mg, 0.38 mmol, Sinopharm) were added. The reaction was carried out at room temperature for 2 hours. Sodium borohydride acetate (202 mg, 0.95 mmol, BIDE) was added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with a 20 mL × 3 solution of isopropanol / dichloromethane (V / V = 1:3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give title compound 5 (42 mg, yield: 26.4%).

[0564] MS m / z(ESI): 837[M+1] + .

[0565] 1 H NMR(500MHz,DMSO-d6)δ12.62(s,1H),10.24(s,1H),9.94(d,1H),8.78(s,1H),8.04(d, 1H),8.00(s,1H),7.68(d,1H),7.14-7.10(m,3H),6.77(d,2H),6.68(s,1H),5.40-5.37 (m,1H),4.25(s,2H),4.15-4.13(m,2H),3.71-3.67(m,4H),2.91-2.90(m,3H),2.70-2. 65(m,3H),2.37-2.22(m,5H),1.98-1.86(m,5H),1.56-1.49(m,5H),1.42-1.38(m,9H).

[0566] Example 6

[0567] (R)-3-(tert-butyl)-N-(1-(4-(6-(5-((7-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-7-azaspiro[3.5]non-2-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 6

[0568] Compound 4e (150 mg, 0.29 mmol) was dissolved in ethanol (2 mL) and dichloromethane (2 mL), and acetic acid (51.4 mg, 0.86 mmol, Sinopharm), 7-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-7-azaspiro[3.5]nonane-2-carboxaldehyde 6a (98 mg, 0.29 mmol, prepared by replacing piperidine-4-ylmethanol with (7-azaspiro[3.5]non-2-yl)methanol using the same method as intermediate 0133 on page 34 of patent application WO2021 / 219070), and sodium acetate (46.8 mg, 0.57 mmol, Sinopharm) were added, and the reaction was carried out at room temperature for 2 hours. Sodium borohydride acetate (302 mg, 1.43 mmol, Biotin) was added, and the reaction was carried out at room temperature for 2 hours. Add 25 mL of water and extract with a mixture of isopropanol / dichloromethane (V / V = 1:3) (25 mL × 3). Combine the organic phases, wash with 20 mL of saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography with eluent system A to give title compound 6 (31 mg, yield: 12.8%).

[0569] MS m / z(ESI): 851[M+1] + .

[0570] 1H NMR(500MHz,DMSO-d6)δ12.62(s,1H),10.25(s,1H),9.94(d,1H),8.78(s,1H),8.04(d,1H),8 .00(s,1H),7.68(d,1H),7.21-7.14(m,3H),6.93(d,2H),6.71-6.66(m,1H),5.40-5.32(m,1H) ,4.17-4.15(m,2H),3.71-3.65(m,4H),3.15-3.14(m,2H),3.05-3.03(m,2H),2.94(s,2H),2. 70-2.63(m,4H),2.48-2.43(m,1H),2.03-1.98(m,4H),1.72-1.50(m,10H),1.48-1.38(m,9H).

[0571] Example 7

[0572] (R)-3-(tert-butyl)-N-(1-(4-(6-(5'-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4',5'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-2'-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 7

[0573] first step

[0574] 3-Bromo-1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrazole-5-carboxylic acid ethyl ester 7c

[0575] Ethyl 3-bromo-1H-pyrazole-5-carboxylate 7b (2.5 g, 11.4 mmol, BIDE), (1-(hydroxymethyl)cyclopropyl)carbamate tert-butyl 7a (2.4 g, 12.82 mmol, Shaoyuan), and triphenylphosphine (3.8 g, 14.49 mmol, BIDE) were dissolved in tetrahydrofuran (45 mL). Diisopropyl azodicarbonate (3 g, 14.83 mmol, Shaoyuan) was added under ice bath conditions. The mixture was allowed to return to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 7c (3.5 g, yield: 79%).

[0576] MS m / z(ESI): 388.2 [M+1] + .

[0577] Step 2

[0578] 2'-Bromo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 7d

[0579] Compound 7c (2.5 g, 6.44 mmol) was dissolved in 1,4-dioxane (10 mL), and a 4M hydrogen chloride solution of 1,4-dioxane (4 mL, 16 mmol, Sinopharm) was added. The mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (30 mL). Sodium methoxide (347.8 mg, 6.44 mmol, Anaiji) was added, and the mixture was stirred at 80 °C for 6 hours. The reaction solution was cooled to room temperature, adjusted to neutral with a 4M hydrogen chloride solution of 1,4-dioxane, and concentrated under reduced pressure. A dichloromethane / methanol (v:v = 15:1) mixture was added to the residue, and the mixture was stirred for 0.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7d (1.9 g). The product was used directly in the next reaction without purification.

[0580] MS m / z(ESI): 242.1 [M+1] + .

[0581] Step 3

[0582] 2'-Bromo-4',5'-Dihydro-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]7e

[0583] The crude compound 7d (1.9 g, 8.1 mmol) was dissolved in tetrahydrofuran (10 mL), and 1 M borane tetrahydrofuran solution (24.5 mL, 24.5 mol, Anegir) was added. The mixture was stirred at 45 °C for 16 hours. The reaction solution was cooled to room temperature, quenched dropwise with methanol under ice bath, and concentrated under reduced pressure to obtain the crude title compound 7e (1.8 g). The product was used directly in the next reaction without purification.

[0584] MS m / z(ESI): 228.0 [M+1] + .

[0585] Step 4

[0586] 2'-Bromo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-tert-butyl carboxylate 7f

[0587] The crude compound 7e (1.85 g, 8.11 mmol) was dissolved in dichloromethane (25 mL) and methanol (3 mL), and di-tert-butyl dicarbonate (2.66 g, 12.2 mmol, Adamas) and triethylamine (1.65 g, 16.3 mmol, Sinopharm) were added. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 7f (1.56 g, yield: 58.6%).

[0588] MS m / z(ESI): 328.0 [M+1] + .

[0589] Step 5

[0590] (R)-3-(tert-butyl)-N-(1-(4-(6-(5'-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4',5'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-2'-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 7

[0591] Using the synthetic route of Example 4, the first step compound 4a was replaced with compound 7f to obtain title compound 7 (8 mg, yield: 3.0%).

[0592] MS m / z (ESI): 837.8 [M+1] + .

[0593] 1 H NMR(500MHz,DMSO-d6)δ12.63(s,1H),10.26(s,1H),9.97-9.91(m,1H),8.79(s,1H),8.08-8.02(m,1 H),8.01-7.96(m,1H),7.70-7.65(m,1H),7.20-7.10(m,3H),6.96-6.89(m,2H),6.80(s,1H),5.41-5. 34(m,1H),4.15-3.99(m,4H),3.73-3.62(m,4H),2.72-2.62(m,4H),2.53(s,3H),1.82-1.71(m,2H),1 .63(s,1H),1.58-1.51(m,3H),1.37(s,9H),1.28-1.22(m,3H),1.22-1.13(m,2H),0.79-0.73(m,3H).

[0594] Example 8

[0595] 1-(4-(4-((2'-(4-(4-(((4-isobutyl-2-oxopiperazin-1-yl)methyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidin-2,4(1H,3H)-dione8

[0596] Using the synthetic route of Example 4, the first-step compound 4a was replaced with compound 7f, and the second-step starting compound 1c was replaced with 4-isobutyl-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzyl)piperazin-2-one (prepared using the same method as compound 51 in Bioorganic and Medicinal Chemistry Letters, 2022, vol.60, art.no.128549), to obtain title compound 8 (15 mg, yield: 7.5%).

[0597] MS m / z (ESI): 810.8 [M+1] + .

[0598] 1 H NMR(500MHz,DMSO-d6)δ12.66(s,1H),10.26(s,1H),8.79(s,1H),8.11-7.98(m,2H),7.33-7.2 8(m,1H),7.19-7.09(m,3H),6.98-6.88(m,2H),6.80(s,1H),4.64(s,2H),4.14-3.96(m,4H),3. 73-3.64(m,4H),3.25-3.19(m,2H),3.10(s,2H),2.70-2.63(m,5H),2.40(s,3H),2.18-2.11(m ,2H),1.84-1.72(m,3H),1.63(s,1H),1.34-1.12(m,5H),0.93-0.84(m,6H),0.81-0.69(m,4H).

[0599] Example 9

[0600] 1-(4-(4-((2'-(4-(3-methyl-4-((4-neopentyl-2-oxopiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidin-2,4(1H,3H)-dione9

[0601] Using the synthetic route of Example 4, the first-step compound 4a was replaced with compound 7f, and the second-step starting compound 1c was replaced with 1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzyl)-4-neopentylpiperazin-2-one (prepared by the same method as the second step on page 276 of patent application WO2022 / 235945), to obtain title compound 9 (55 mg, yield: 18%).

[0602] MS m / z (ESI): 825.1 [M+1] + .

[0603] 1 H NMR(500MHz,DMSO-d6)δ12.66(s,1H),10.26(s,1H),8.79(s,1H),8.04-8.02(m,2H),7.31-7.30(m,1 H),7.21-7.09(m,3H),6.94-6.92(m,2H),6.80-6.79(m,1H),4.64(s,2H),4.07-3.97(m,4H),3.71-3. 66(m,4H),3.29-3.21(m,4H),2.79-2.64(m,6H),2.40-2.37(m,3H),2.28-2.15(m,2H),2.08-1.98(m ,2H),1.78-1.75(m,2H),1.63-1.45(m,2H),1.24-1.17(m,1H),0.88-0.85(m,9H),0.80-0.71(m,4H).

[0604] Example 10

[0605] 1-(4-(4-((2'-(4-(4-((4-(cyclopropylmethyl)-2-oxopiperazin-1-yl)methyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)methyl]piperidin-1-yl)phenyl)dihydropyrimidin-2,4(1H,3H)-dione 10

[0606] Using the synthetic route of Example 4, the first-step compound 4a was replaced with compound 7f, and the second-step starting compound 1c was replaced with 4-(cyclopropylmethyl)-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzyl)piperazin-2-one (prepared by replacing 4-neopentylpiperazin-2-one with 4-(cyclopropylmethyl)piperazin-2-one using the same method as described on page 276 of patent application WO2022 / 235945), to obtain title compound 10 (27 mg, yield: 9.2%).

[0607] MS m / z(ESI): 808[M+1] + .

[0608] 1 H NMR(500MHz,DMSO-d6)δ12.66(s,1H),10.26(s,1H),8.79(s,1H),8.03-8.02(m,2H),7.30-7.29(m,1H),7.16-7.13 (m,3H),6.94-6.92(m,2H),6.80(s,1H),4.64(s,2H),4.07-4.03(m,4H),3.71-3.66(m,4H),3.33-3.22(m,4H),2.77 (s,2H),2.70-2.64(m,4H),2.41-2.37(m,3H),2.31-2.29(m,2H),2.08-1.98(m,2H),1.78-1.75(m,2H),1.63(s,1H) ,1.48-1.46(m,1H),1.19-1.14(m,1H),0.88-0.85(m,2H),0.80-0.75(m,3H),0.52-0.48(m,2H),0.13-0.12(m,2H).

[0609] Example 11

[0610] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 11

[0611] first step

[0612] 2-Amino-3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 11b

[0613] 2-Amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 11a (500 mg, 2.10 mmol, lysine) was dissolved in dichloromethane (10 mL), and N-bromosuccinimide (411 mg, 2.31 mmol) was added. The mixture was stirred at room temperature for 12 hours. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give title compound 11b (650 mg, yield: 97.7%).

[0614] MS m / z(ESI): 317.2 [M+1] + .

[0615] Step 2

[0616] 2-Amino-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 11c

[0617] Compound 11b (300 mg, 0.95 mmol) was dissolved in toluene (6 mL) and water (0.6 mL). Methylboric acid (288 mg, 4.81 mmol, Shaoyuan), palladium acetate (43 mg, 0.19 mmol, Bide), tricyclohexylphosphine (80 mg, 0.29 mmol, Adamas), and cesium carbonate (930 mg, 2.85 mmol, Sinopharm) were added. The mixture was purged with nitrogen three times and reacted at 100 °C for 3 hours. After returning to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 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 the title compound 11c (200 mg, yield: 83.8%).

[0618] MS m / z(ESI): 253.2 [M+1] + .

[0619] Step 3

[0620] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 11

[0621] Using the synthetic route from step one to step four in Example 1, starting compound 1a was replaced with starting compound 11c to obtain title compound 11 (30 mg, yield: 30.8%).

[0622] MS m / z(ESI): 801.9 [M+1] + .

[0623] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),9.88-9.87(m,1H),9.28(s,1H),8.59-8.58(m,1H),7 .81-7.79(m,2H),7.59-7.58(m,2H),7.15-7.13(m,2H),6.96-6.93(m,2H),5.36-5.31(m,1H) ,4.04-4.02(m,2H),3.72-3.56(m,5H),2.91-2.89(m,2H),2.73-2.67(m,4H),2.46-2.43(m,4 H),2.03-2.00(m,1H),1.85-1.83(m,5H),1.52-1.50(m,3H),1.37(s,9H),1.29-1.27(m,4H).

[0624] Example 12

[0625] 1-(4-(4-((2-((6-(4-((4-isobutyl-2-oxopiperazin-1-yl)methyl)-3-methylphenyl)pyrimidin-4-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidin-2,4(1H,3H)-dione 12

[0626] Using the synthetic route of Example 1, the second-step compound 1c was replaced with 4-isobutyl-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzin-2-one (prepared by the same method as compound 51 in Bioorganic and Medicinal Chemistry Letters, 2022, vol.60, art.no.128549) to obtain title compound 12 (29 mg, yield: 42.1%).

[0627] MS m / z(ESI): 760.9 [M+1] + .

[0628] 1H NMR(500MHz,DMSO-d6)δ10.26(s,1H),9.94(s,1H),8.68-8.61(m,1H),7.86(s,1H),7.81-7.77(m,1H),7.64(s,1H) ,7.25-7.19(m,1H),7.17-7.09(m,2H),6.98-6.88(m,2H),6.24(s,1H),4.60(s,2H),4.05-4.01(m,2H),3.72-3.67( m,5H),3.63(s,2H),3.20-3.16(m,2H),3.08(s,2H),2.94-2.88(m,2H),2.70-2.66(m,4H),2.64-2.62(m,2H),2.44- 2.39(m,2H),2.34(s,3H),2.17-2.11(m,2H),2.10-2.07(m,1H),1.86-1.81(m,2H),1.24(s,2H),0.94-0.85(m,6H).

[0629] Example 13

[0630] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 13

[0631] Compound 1e (100 mg, 0.2 mmol) was dissolved in ethanol (2 mL) and dichloromethane (2 mL), and acetic acid (36 mg, 0.6 mmol, Sinopharm), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperidine-4-carboxaldehyde 13a (76.4 mg, 0.24 mmol, prepared by the method disclosed in step 6 of Example 82 on page 171 of patent application WO2022 / 12622), and sodium acetate (32.7 mg, 0.40 mmol, Sinopharm) were added. The mixture was reacted at room temperature for 2 hours. Sodium borohydride acetate (211.3 mg, 1 mmol, BIDE) was added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with a 10 mL × 3 solution of isopropanol / dichloromethane (V / V = 1:3). 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 the title compound 13 (9 mg, yield: 5.6%).

[0632] MS m / z (ESI): 805.3 [M+1] + .

[0633] 1 H NMR (500MHz, DMSO-d6): δ10.36(s,1H),9.94(s,2H),9.89-9.87(d,1H),8.65(s,1H),7.83-7.82(m,2H) ,7.61-7.60(m,1H),7.19-7.16(m,2H),7.08-7.03(m,2H),6.24(s,1H),5.35-5.32(m,1H),4.03-4.02( m,2H),3.76-3.73(m,2H),3.64(s,2H),2.92-2.90(m,2H),2.71-2.68(m,3H),2.66-2.64(m,2H),2.47- 2.43(m,3H),2.38-2.37(m,2H),1.86-1.84(m,3H),1.75(s,2H),1.53-1.51(m,3H),1.37-1.31(m,9H).

[0634] Example 14

[0635] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 14

[0636] first step

[0637] (R)-N-(1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide 14c

[0638] (R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethyl-1-amine hydrochloride 14a (2.32 g, 8.64 mmol, prepared by the same intermediate method as on page 105 of patent application WO2021 / 87112) and potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate 14b (3.61 g, 17.3 mmol, prepared by the same intermediate method as on page 58 of patent application WO2021087112) were dissolved in N,N-dimethylformamide (30 mL), and triethylamine (6.00 mL, 43.3 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.29 g, 11.3 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 14c (1.34 g, yield: 40.4%).

[0639] MS m / z(ESI): 384.3 [M+1] + .

[0640] Step 2

[0641] (R)-3-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 14d

[0642] Compound 14c (1.13 g, 2.94 mmol) was dissolved in 1,4-dioxane (15 mL, Adamas), and bis(diphenylphosphine) diborane (1.50 g, 5.91 mmol), potassium acetate (870 mg, 8.86 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (440 mg, 0.60 mmol, Adamas) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 2 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system C to give the title compound 14d (960 mg, yield: 75.7%).

[0643] MS m / z(ESI): 432.2 [M+1] + .

[0644] Step 3

[0645] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 14

[0646] Using the synthetic route of Example 1, the second step compound 1c was replaced with compound 14d to obtain title compound 14 (45 mg, yield: 25.5%).

[0647] MS m / z (ESI): 805.9 [M+1] + .

[0648] 1 H NMR(500MHz,DMSO-d6)δ10.26(s,1H),10.03(s,1H),9.98-9.88(m,1H),8.67(s,1H),7.88-7.78(m ,1H),7.67-7.39(m,2H),7.19-7.11(m,2H),6.98-6.90(m,2H),6.28(s,1H),5.40-5.30(m,1H),4. 07-3.94(m,2H),3.72-3.67(m,4H),3.63(s,2H),2.92-2.86(m,2H),2.72-2.64(m,4H),2.43-2.38 (m,2H),2.37-2.32(m,3H),1.86-1.73(m,3H),1.55-1.50(m,3H),1.37(s,9H),1.26-1.22(m,2H).

[0649] Example 15

[0650] 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 15

[0651] first step

[0652] 2-((diphenylmethyl)amino)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 15b

[0653] 2-Bromo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 15a (2.42 g, 7.64 mmol, prepared by replacing starting material 7a with (1-hydroxypropyl-2-yl)carbamate tert-butyl ester in steps one to four of the synthetic route of Example 7) was dissolved in toluene (35 mL), and benzophenone imine (1.8 g, 9.93 mmol, Shaoyuan), tris(dibenzylideneacetone) dipalladium (699.1 mg, 0.76 mmol, Bide), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.43 g, 2.3 mmol, Shaoyuan), and sodium tert-butoxide (1.03 g, 10.7 mmol, Shaoyuan) were added. The mixture was stirred at 80 °C for 6 hours under a nitrogen atmosphere. After restoring to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 15b (3.18 g, yield: 99.96%).

[0654] MS m / z(ESI): 417.3 [M+1] + .

[0655] Step 2

[0656] 2-Amino-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 15c

[0657] Compound 15b (3.18 g, 7.63 mmol) was dissolved in methanol (30 mL), and hydroxylamine (1.51 g, 22.9 mmol, Sinopharm) was added. The mixture was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give the title compound 15c (1.78 g, yield: 92.4%).

[0658] MS m / z(ESI): 253.4 [M+1] + .

[0659] Step 3

[0660] 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 15

[0661] Using the synthetic route from step one to step four in Example 1, the first-step compound 1a was replaced with compound 15c to obtain title compound 15 (180 mg, yield: 59.73%).

[0662] MS m / z(ESI): 802.0 [M+1] + .

[0663] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),9.95(s,2H),9.89-9.88(d,1H),8.65(s,1H),7.82(s, 2H),7.61-7.60(m,2H),7.15-7.13(m,2H),6.94-6.93(m,2H),6.26(s,1H),5.36-5.33(m,1H) ,4.06-4.04(m,2H),3.85-3.82(m,2H),3.75-3.69(m,5H),2.70-2.66(m,4H),2.48-2.44(m,2 H),2.41-2.36(m,2H),1.86-1.83(m,2H),1.81(s,1H),1.53-1.51(m,3H),1.37-1.11(m,14H).

[0664] Example 16

[0665] 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 16

[0666] first step

[0667] 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid methyl ester 16c

[0668] Methyl 3-bromo-1H-pyrazole-5-carboxylic acid 16a (5 g, 24.39 mmol, Adamas) was dissolved in tetrahydrofuran (200 mL). N-(tert-Butoxycarbonyl)ethanolamine 16b (5.11 g, 31.70 mmol, Adamas), triphenylphosphine (12.8 g, 48.80 mmol, Adamas), and diisopropyl azodicarbonate (9.9 g, 48.96 mmol, Adamas) were added, and the mixture was stirred at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16c (8.49 g, yield: 99.9%).

[0669] MS m / z(ESI): 348.3 [M+1] + .

[0670] Step 2

[0671] 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid 16d

[0672] Compound 16c (8.5 g, 24.41 mmol) was dissolved in tetrahydrofuran (120 mL) and water (30 mL). Lithium hydroxide (2.05 g, 48.85 mmol, Adamas) was added at 0 °C, and the mixture was allowed to return to room temperature. The mixture was stirred for 16 hours. The tetrahydrofuran was removed by concentration under reduced pressure. The pH of the reaction solution was adjusted to 4 with hydrochloric acid. The mixture was filtered, and the filter cake was collected to give the title compound 16d (8.1 g, yield: 99.3%).

[0673] MS m / z(ESI): 334.1 [M+1] + .

[0674] Step 3

[0675] (2-(3-bromo-5-(methoxy(methyl)aminocarbonyl)-1H-pyrazole-1-yl)ethyl)tert-butyl carbamate 16e

[0676] Compound 16d (7.8 g, 23.34 mmol) was dissolved in N,N-dimethylformamide (80 mL), and N,O-dimethylhydroxylamine hydrochloride (3.43 g, 35.16 mmol, Adamas), N,N-diisopropylethylamine (9.05 g, 70.02 mmol, Adamas), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (13.31 g, 35.01 mmol, Adamas) were added. The mixture was stirred at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 16e (8.8 g, yield: 99.9%).

[0677] MS m / z(ESI): 377.3 [M+1] + .

[0678] Step 4

[0679] (2-(5-acetyl-3-bromo-1H-pyrazole-1-yl)ethyl)tert-butyl carbamate 16f

[0680] Compound 16e (8 g, 21.21 mmol) was dissolved in tetrahydrofuran (80 mL). Under a nitrogen atmosphere, methyl magnesium bromide (28.23 mL, 84.70 mmol, 3 M, Adamas) was added at 0 °C, and the mixture was stirred at room temperature for 16 hours. 100 mL of saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16f (6.65 g, yield: 94.4%).

[0681] MS m / z(ESI): 332.3 [M+1] + .

[0682] Step 5

[0683] 16g of 2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine

[0684] Compound 16f (3.3 g, 9.93 mmol) was dissolved in 1,4-dioxane (30 mL), and dioxane hydrochloride solution (18 mL, 72.00 mmol, 4 M, Adamas) was added. The mixture was stirred at room temperature for 16 hours. The solution was concentrated, and extracted with ethyl acetate (50 mL × 3) by adding 50 mL of saturated sodium bicarbonate solution. The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 16f (1.97 g, yield: 92.6%).

[0685] MS m / z(ESI): 214.2 [M+1] + .

[0686] Step 6

[0687] 2-Bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 16h

[0688] 16 g (1.97 g, 9.20 mmol) of the compound was dissolved in methanol (18 mL). Sodium borohydride (1.4 g, 84.70 mmol, Adamas) was added at 0 °C under a nitrogen atmosphere. The mixture was allowed to return to room temperature and stirred for 1 h. 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 16h (1.98 g, yield: 99.6%).

[0689] MS m / z(ESI): 216.0 [M+1] + .

[0690] Step 7

[0691] 2-Bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16i

[0692] Compound 16h (1.98 g, 9.16 mmol) was dissolved in dichloromethane (24 mL), and triethylamine (2.78 g, 27.47 mmol, Sinopharm) and di-tert-butyl dicarbonate (4 g, 18.33 mmol, Shaoyuan) were added at 0 °C. The mixture was then allowed to return to room temperature and stirred for 16 hours. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 16i (2.12 g, yield: 73.2%).

[0693] MS m / z(ESI): 316.2 [M+1] + .

[0694] Step 8

[0695] 2-((diphenylmethyl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16j

[0696] Compound 16i (750 mg, 2.37 mmol) was dissolved in toluene (6 mL), and benzophenone imine (570 mg, 3.15 mmol, Shaoyuan), tris(dibenzylacetone)dipalladium (219 mg, 0.24 mmol, Bide), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (444 mg, 0.71 mmol, Shaoyuan), and sodium tert-butoxide (321 mg, 3.34 mmol, Shaoyuan) were added. The mixture was stirred at 80 °C for 6 hours under a nitrogen atmosphere. After returning to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16j (680 mg, yield: 68.8%).

[0697] MS m / z(ESI): 417.7 [M+1] + .

[0698] Step 9

[0699] 2-Amino-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 16k

[0700] Compound 16j (630 mg, 1.51 mmol) was dissolved in tetrahydrofuran (15 mL) and water (10 mL), and citric acid (1.44 g, 6.85 mmol, Adamas) was added. The mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 16k (363 mg, yield: 95.1%).

[0701] MS m / z(ESI): 253.4 [M+1] + .

[0702] Step 10

[0703] 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 16

[0704] Using the synthetic route from step one to step four in Example 1, starting compound 1a was replaced with starting compound 16k to obtain title compound 16 (89 mg, yield: 50.7%).

[0705] MS m / z (ESI): 801.3 [M+1] + .

[0706] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),9.93(s,1H),9.89-9.87(m,1H),8.66(s,1H),7 .83-7.82(m,2H),7.66-7.60(m,2H),7.15-7.13(m,2H),6.96-6.93(m,2H),5.37-5.32( m,1H),4.04-4.02(m,2H),3.72-3.69(m,5H),3.27-3.25(m,2H),2.78-2.65(m,6H),2.4 7(s,3H),2.30-2.27(m,1H),2.03-1.72(m,5H),1.53-1.51(m,3H),1.29-1.21(m,12H).

[0707] Example 16-1

[0708] 3-(tert-butyl)-N-((R)-1-(4-(6-(((R)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 16-1

[0709] first step

[0710] 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid methyl ester 16c

[0711] Methyl 3-bromo-1H-pyrazole-5-carboxylic acid 16a (5 g, 24.39 mmol, Adamas) was dissolved in tetrahydrofuran (200 mL). N-(tert-Butoxycarbonyl)ethanolamine 16b (5.11 g, 31.70 mmol, Adamas), triphenylphosphine (12.8 g, 48.80 mmol, Adamas), and diisopropyl azodicarbonate (9.9 g, 48.96 mmol, Adamas) were added, and the mixture was stirred at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16c (8.49 g, yield: 99.9%).

[0712] MS m / z(ESI): 348.3 [M+1] + .

[0713] Step 2

[0714] 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid 16d

[0715] Compound 16c (8.5 g, 24.41 mmol) was dissolved in tetrahydrofuran (120 mL) and water (30 mL). Lithium hydroxide (2.05 g, 48.85 mmol, Adamas) was added at 0 °C, and the mixture was allowed to return to room temperature. The mixture was stirred for 16 hours. The tetrahydrofuran was removed by concentration under reduced pressure. The pH of the reaction solution was adjusted to 4 with hydrochloric acid. The mixture was filtered, and the filter cake was collected to give the title compound 16d (8.1 g, yield: 99.3%).

[0716] MS m / z(ESI): 334.1 [M+1] + .

[0717] Step 3

[0718] (2-(3-bromo-5-(methoxy(methyl)aminocarbonyl)-1H-pyrazole-1-yl)ethyl)tert-butyl carbamate 16e

[0719] Compound 16d (7.8 g, 23.34 mmol) was dissolved in N,N-dimethylformamide (80 mL), and N,O-dimethylhydroxylamine hydrochloride (3.43 g, 35.16 mmol, Adamas), N,N-diisopropylethylamine (9.05 g, 70.02 mmol, Adamas), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (13.31 g, 35.01 mmol, Adamas) were added. The mixture was stirred at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 16e (8.8 g, yield: 99.9%).

[0720] MS m / z(ESI): 377.3 [M+1] + .

[0721] Step 4

[0722] (2-(5-acetyl-3-bromo-1H-pyrazole-1-yl)ethyl)tert-butyl carbamate 16f

[0723] Compound 16e (8 g, 21.21 mmol) was dissolved in tetrahydrofuran (80 mL). Under a nitrogen atmosphere, methyl magnesium bromide (28.23 mL, 84.70 mmol, 3 M, Adamas) was added at 0 °C, and the mixture was stirred at room temperature for 16 hours. 100 mL of saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16f (6.65 g, yield: 94.4%).

[0724] MS m / z(ESI): 332.3 [M+1] + .

[0725] Step 5

[0726] 16g of 2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine

[0727] Compound 16f (3.3 g, 9.93 mmol) was dissolved in 1,4-dioxane (30 mL), and dioxane hydrochloride solution (18 mL, 72.00 mmol, 4 M, Adamas) was added. The mixture was stirred at room temperature for 16 hours. The solution was concentrated, and extracted with ethyl acetate (50 mL × 3) by adding 50 mL of saturated sodium bicarbonate solution. The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 16f (1.97 g, yield: 92.6%).

[0728] MS m / z(ESI): 214.2 [M+1] + .

[0729] Step 6

[0730] (R)-2-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 16h-1

[0731] 16 g (2.18 g, 10.21 mmol) of the compound was dissolved in N,N-dimethylformamide (11 mL) and water (11 mL). Sodium formate (2.78 g, 40.83 mmol, Adamas) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (130 mg, 0.20 mmol, Leyan) were added under a nitrogen atmosphere, and the mixture was stirred at 50 °C for 16 h. After returning to room temperature, 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 16h⁻¹ (2.2 g, yield: 99.7%).

[0732] MS m / z(ESI): 216.1 [M+1] + .

[0733] Step 7

[0734] (R)-2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16i-1

[0735] Compound 16h-1 (2.2 g, 10.18 mmol) was dissolved in dichloromethane (22 mL), and triethylamine (3.09 g, 30.55 mmol, Sinopharm) and di-tert-butyl dicarbonate (2.67 g, 12.22 mmol, Shaoyuan) were added at 0 °C. The mixture was stirred at room temperature for 16 hours. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 16i-1 (3.2 g, yield: 99.4%).

[0736] MS m / z(ESI): 316.2 [M+1] + .

[0737] Step 8

[0738] (R)-2-((diphenylmethyl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16j-1

[0739] Compound 16i-1 (730 mg, 2.31 mmol) was dissolved in 1,4-dioxane (15 mL), and benzophenone imine (628 mg, 3.47 mmol, Shaoyuan), tris(dibenzylacetone)dipalladium (212 mg, 0.23 mmol, Bide), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (201 mg, 0.35 mmol, Shaoyuan), and sodium tert-butoxide (666 mg, 6.93 mmol, Shaoyuan) were added. The mixture was stirred at 90 °C for 16 hours under a nitrogen atmosphere. After returning to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16j-1 (740 mg, yield: 77.0%).

[0740] MS m / z (ESI): 417.5 [M+1] + .

[0741] Step 9

[0742] (R)-2-amino-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16kJ

[0743] Compound 16j-1 (740 mg, 1.78 mmol) was dissolved in tetrahydrofuran (15 mL) and water (9 mL), and citric acid (1.68 g, 7.99 mmol, Adamas) was added. The mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 16k-1 (410 mg, yield: 91.5%).

[0744] MS m / z(ESI): 253.4 [M+1] + .

[0745] Step 10

[0746] (R)-2-((6-bromopyrimidin-4-yl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 16l-1

[0747] Compound 16k-1 (650 mg, 2.58 mmol, Bio-D) was dissolved in dimethyl sulfoxide (13 mL), and 4-bromo-6-fluoropyrimidine (548 mg, 3.10 mmol) and N,N-diisopropylethylamine (1.67 g, 12.92 mmol, Sinopharm) were added. The mixture was sealed and reacted at 100 °C for 1 hour. After returning to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16k-1 (510 mg, yield: 48.4%).

[0748] MS m / z(ESI): 409.1 [M+1] + .

[0749] Step 11

[0750] (R)-2-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 16m-1

[0751] Compound 16l-1 (510 mg, 1.25 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (183 mg, 0.25 mmol, Bioderm), compound 1c (618 mg, 1.50 mmol), and potassium carbonate (345 mg, 2.50 mmol, Sinopharm) were added. The mixture was purged with nitrogen three times and reacted at 80 °C for 12 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 16m-1 (450 mg, yield: 58.7%).

[0752] MS m / z (ESI): 616.7 [M+1] + .

[0753] Step Twelve

[0754] 3-(tert-butyl)-N-((R)-1-(2-methyl-4-(6-(((R)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 16n-1

[0755] Compound 16m-1 (450 mg, 0.25 mmol) was dissolved in dichloromethane (6 mL), and dioxane hydrochloride solution (3 mL, 12.01 mmol, 4 M, Adamas) was added. The reaction was carried out at room temperature for 2 hours. The solution was concentrated under reduced pressure, and 15 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with 15 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 16n-1 (376 mg, yield: 99.8%). The product was directly used in the next reaction without purification.

[0756] MS m / z (ESI): 516.4 [M+1] + .

[0757] Step Thirteen

[0758] 3-(tert-butyl)-N-((R)-1-(4-(6-(((R)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 16-1

[0759] Compound 16n-1 (376 mg, 0.73 mmol) was dissolved in dichloromethane (10 mL), and acetic acid (88 mg, 1.47 mmol, Sinopharm), triethylamine (82 mg, 0.81 mmol, Sinopharm), compound 1f (264 mg, 0.88 mmol), and sodium acetate (41 mg, 0.50 mmol, Sinopharm) were added. The mixture was reacted at room temperature for 2 hours. Sodium borohydride acetate (773 mg, 3.65 mmol, Bioderm) was added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with a 20 mL × 3 mixture of isopropanol / dichloromethane (V / V = 1:3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 16-1 (310 mg, yield: 53.1%).

[0760] MS m / z (ESI): 801.7 [M+1] + .

[0761] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),9.93(s,1H),9.89-9.87(m,1H),8.66(s,1H),7 .83-7.82(m,2H),7.62-7.60(m,2H),7.15-7.13(m,2H),6.95-6.92(m,2H),5.35-5.32( m,1H),4.04-4.02(m,2H),3.72-3.69(m,5H),3.27-3.25(m,2H),2.78-2.67(m,6H),2.4 7(s,3H),2.30-2.27(m,1H),2.03-1.72(m,5H),1.53-1.51(m,3H),1.29-1.21(m,12H).

[0762] Example 16-2

[0763] 3-(tert-butyl)-N-((R)-1-(4-(6-(((S)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 16-2

[0764] Method 1: Using the same synthetic route as in Example 16-1, the reagent (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (II) in step 6 was replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (II) (Leyan) to obtain the title compound 16-2 (142 mg, yield: 88.75%).

[0765] Method 2:

[0766] first step

[0767] (R)-2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16i-1

[0768] (S)-2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16i-2

[0769] Compound 16i (11.3 g) was resolved by chiral column chromatography (Shimadzu LC-20AP Prep system, column: ChiralPak IG, 10 μm, 50 mm ID*300 mm L (Daicel, in-house packed); mobile phase A: n-hexane, mobile phase B: ethanol; gradient ratio: A:B = 70:30, flow rate: 80 mL / min) to obtain compound 16i-1 (5.5 g, yield: 49%) and compound 16i-2 (5.5 g, yield: 49%).

[0770] Compound 16i-1 (5.5 g, yield: 49%, single configuration compound, retention time 8.875 min in chiral resolution).

[0771] MS m / z(ESI): 316.2 [M+1] + .

[0772] Compound 16i-2 (5.5 g, yield: 49%, single configuration compound, retention time 12.931 min in chiral resolution).

[0773] MS m / z(ESI): 316.2 [M+1] + .

[0774] Step 2

[0775] 3-(tert-butyl)-N-((R)-1-(4-(6-(((S)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 16-2

[0776] Using the synthetic route from step 8 to step 13 of Example 16-1, the compound 16i-1 in step 8 was replaced with compound 16i-2 to obtain the title compound 16-2 (290 mg, yield: 43.1%).

[0777] MS m / z (ESI): 801.7 [M+1] + .

[0778] 1H NMR (500MHz, DMSO-d6): δ10.26(s,1H),9.93(s,1H),9.89-9.87(m,1H),8.66(s,1H),7 .83-7.82(m,2H),7.62-7.60(m,2H),7.15-7.13(m,2H),6.95-6.92(m,2H),5.35-5.32( m,1H),4.04-4.02(m,2H),3.72-3.69(m,5H),3.27-3.25(m,2H),2.78-2.67(m,6H),2.4 7(s,3H),2.30-2.27(m,1H),2.03-1.72(m,5H),1.53-1.51(m,3H),1.29-1.21(m,12H).

[0779] Example 17-1

[0780] 3-(tert-butyl)-N-((R)-1-(4-(6-(((R)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 17-1

[0781] first step

[0782] (R)-N-(1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide 14c

[0783] (R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethyl-1-amine hydrochloride 14a (2.32 g, 8.64 mmol, prepared by the same intermediate method as on page 105 of patent application WO2021 / 87112), potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate 14b (3.61 g, 17.3 mmol, prepared by the same intermediate method as on page 58 of patent application WO2021087112), were dissolved in N,N-dimethylformamide (30 mL), and triethylamine (6.00 mL, 43.3 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.29 g, 11.3 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 14c (1.34 g, yield: 40.4%).

[0784] MS m / z(ESI): 384.3 [M+1] + .

[0785] Step 2

[0786] (R)-3-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 14d

[0787] Compound 14c (1.13 g, 2.94 mmol) was dissolved in 1,4-dioxane (15 mL, Adamas), and bis(diphenylphosphino)diborane (1.50 g, 5.91 mmol, Shaoyuan), potassium acetate (870 mg, 8.86 mmol, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (440 mg, 0.60 mmol, Adamas) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 2 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system C to give the title compound 14d (960 mg, yield: 75.7%).

[0788] MS m / z(ESI): 432.2 [M+1] + .

[0789] Step 3

[0790] 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid methyl ester 16c

[0791] Methyl 3-bromo-1H-pyrazole-5-carboxylic acid 16a (5 g, 24.39 mmol, Adamas) was dissolved in tetrahydrofuran (200 mL), and N-(tert-butoxycarbonyl)ethanolamine 16b (5.11 g, 31.70 mmol, Adamas), triphenylphosphine (12.8 g, 48.80 mmol, Adamas), and diisopropyl azodicarbonate (9.9 g, 48.96 mmol, Adamas) were added. The mixture was stirred at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16c (8.49 g, yield: 99.9%).

[0792] MS m / z(ESI): 348.3 [M+1] + .

[0793] Step 4

[0794] 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid 16d

[0795] Compound 16c (8.5 g, 24.41 mmol) was dissolved in tetrahydrofuran (120 mL) and water (30 mL). Lithium hydroxide (2.05 g, 48.85 mmol, Adamas) was added at 0 °C, and the mixture was allowed to return to room temperature. The mixture was stirred for 16 hours. The tetrahydrofuran was removed by concentration under reduced pressure. The pH of the reaction solution was adjusted to 4 with hydrochloric acid. The mixture was filtered, and the filter cake was collected to give the title compound 16d (8.1 g, yield: 99.3%).

[0796] MS m / z(ESI): 334.1 [M+1] + .

[0797] Step 5

[0798] (2-(3-bromo-5-(methoxy(methyl)aminocarbonyl)-1H-pyrazole-1-yl)ethyl)tert-butyl carbamate 16e

[0799] Compound 16d (7.8 g, 23.34 mmol) was dissolved in N,N-dimethylformamide (80 mL), and N,O-dimethylhydroxylamine hydrochloride (3.43 g, 35.16 mmol, Adamas), N,N-diisopropylethylamine (9.05 g, 70.02 mmol, Adamas), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (13.31 g, 35.01 mmol, Adamas) were added. The mixture was stirred at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 16e (8.8 g, yield: 99.9%).

[0800] MS m / z(ESI): 377.3 [M+1] + .

[0801] Step 6

[0802] (2-(5-acetyl-3-bromo-1H-pyrazole-1-yl)ethyl)tert-butyl carbamate 16f

[0803] Compound 16e (8 g, 21.21 mmol) was dissolved in tetrahydrofuran (80 mL), and methyl magnesium bromide (28.23 mL, 84.70 mmol, 3 M, Adamas) was added at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. 100 mL of saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16f (6.65 g, yield: 94.4%).

[0804] MS m / z(ESI): 332.3 [M+1] + .

[0805] Step 7

[0806] 16g of 2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine

[0807] Compound 16f (3.3 g, 9.93 mmol) was dissolved in 1,4-dioxane (30 mL), and dioxane hydrochloride solution (18 mL, 72.00 mmol, 4 M, Adamas) was added. The mixture was stirred at room temperature for 16 hours. The solution was concentrated, and 50 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 16f (1.97 g, yield: 92.6%).

[0808] MS m / z(ESI): 214.2 [M+1] + .

[0809] Step 8

[0810] (R)-2-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 16h-1

[0811] 16 g (2.18 g, 10.21 mmol) of the compound was dissolved in N,N-dimethylformamide (11 mL), and sodium formate (2.78 g, 40.83 mmol, Adamas) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (130 mg, 0.20 mmol, Leyan) were added under a nitrogen atmosphere. The mixture was stirred at 50 °C for 16 h. After returning to room temperature, 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 16h⁻¹ (2.2 g, yield: 99.7%).

[0812] MS m / z(ESI): 216.1 [M+1] + .

[0813] Step 9

[0814] (R)-2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16i-1

[0815] Compound 16h-1 (2.2 g, 10.18 mmol) was dissolved in dichloromethane (22 mL), and triethylamine (3.09 g, 30.55 mmol, Sinopharm) and di-tert-butyl dicarbonate (2.67 g, 12.22 mmol, Shaoyuan) were added at 0 °C. The mixture was stirred at room temperature for 16 hours. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 16i-1 (3.2 g, yield: 99.4%).

[0816] MS m / z(ESI): 316.2 [M+1] + .

[0817] Step 10

[0818] (R)-2-((diphenylmethyl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16j-1

[0819] Compound 16i-1 (730 mg, 2.31 mmol) was dissolved in 1,4-dioxane (15 mL), and benzophenone imine (628 mg, 3.47 mmol, Shaoyuan), tris(dibenzylacetone)dipalladium (212 mg, 0.23 mmol, Bide), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (201 mg, 0.35 mmol, Shaoyuan), and sodium tert-butoxide (666 mg, 6.93 mmol, Shaoyuan) were added. The mixture was stirred at 90 °C for 16 hours under a nitrogen atmosphere. After returning to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16j-1 (740 mg, yield: 77.0%).

[0820] MS m / z (ESI): 417.5 [M+1] + .

[0821] Step 11

[0822] (R)-2-amino-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl carboxylate 16kJ

[0823] Compound 16j-1 (740 mg, 1.78 mmol) was dissolved in tetrahydrofuran (15 mL) and water (9 mL), and citric acid (1.68 g, 7.99 mmol, Adamas) was added. The mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 16k-1 (410 mg, yield: 91.5%).

[0824] MS m / z(ESI): 253.4 [M+1] + .

[0825] Step Twelve

[0826] (R)-2-((6-bromopyrimidin-4-yl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 16l-1

[0827] Compound 16k-1 (650 mg, 2.58 mmol, Bioderm) was dissolved in dimethyl sulfoxide (13 mL), and 4-bromo-6-fluoropyrimidine (548 mg, 3.10 mmol) and N,N-diisopropylethylamine (1.67 g, 12.92 mmol, Sinopharm) were added. The mixture was sealed and reacted at 100 °C for 1 hour. After returning to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 16k-1 (510 mg, yield: 48.4%).

[0828] MS m / z(ESI): 409.1 [M+1] + .

[0829] Step Thirteen

[0830] (R)-2-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-2-fluoro-3-methylphenyl)pyrimidin-4-yl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 17a-1

[0831] Compound 16l-1 (245 mg, 1.25 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (88 mg, 0.12 mmol, Bioderm), compound 14d (310 mg, 0.72 mmol), and potassium carbonate (165 mg, 1.20 mmol, Sinopharm) were added. The mixture was purged with nitrogen three times and reacted at 80 °C for 12 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 17a-1 (192 mg, yield: 50.6%).

[0832] MS m / z(ESI): 634.6 [M+1] + .

[0833] Step Fourteen

[0834] 3-(tert-butyl)-N-((R)-1-(3-fluoro-2-methyl-4-(6-(((R)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 17b-1

[0835] Compound 17a-1 (192 mg, 0.30 mmol) was dissolved in dichloromethane (5 mL), and 1,4-dioxane hydrochloride solution (3 mL, 12.0 mmol, 4 M, Adamas) was added. The mixture was reacted at room temperature for 2 hours. The solution was concentrated under reduced pressure, and 15 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with 15 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 17b-1 (160 mg, yield: 99.0%). The product was directly used in the next reaction without purification.

[0836] MS m / z(ESI): 534.3 [M+1] + .

[0837] Step 15

[0838] 3-(tert-butyl)-N-((R)-1-(4-(6-(((R)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 17-1

[0839] Compound 17b-1 (160 mg, 0.30 mmol) was dissolved in dichloromethane (5 mL), and acetic acid (36 mg, 0.60 mmol, Sinopharm), triethylamine (36 mg, 0.36 mmol, Sinopharm), and compound 1f (181 mg, 0.60 mmol) were added. The mixture was reacted at room temperature for 2 hours. Sodium borohydride acetate (191 mg, 0.90 mmol, Bioderm) was added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with a 20 mL × 3 mixture of isopropanol / dichloromethane (V / V = 1:3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 17-1 (123 mg, yield: 50.1%).

[0840] MS m / z(ESI): 819.7 [M+1] + .

[0841] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),10.03(s,1H),9.97-9.89(m,1H),8.71-8.65(m,1H),7.86-7.79(m,1H),7.63( s,1H),7.47-7.41(m,1H),7.16-7.11(m,2H),6.97-6.90(m,2H),6.30(s,1H),5.37-5.28(m,1H),4.04-3.90(m,2H),3 .76-3.63(m,5H),3.29-3.21(m,1H),2.79-2.64(m,5H),2.58-2.53(m,1H),2.39-2.33(m,3H),2.32-2.24(m,1H),1.9 2-1.84(m,1H),1.82-1.76(m,1H),1.71(s,1H),1.56-1.49(m,3H),1.37(s,9H),1.36-1.31(m,3H),1.28-1.22(m,2H).

[0842] Example 17-2

[0843] 3-(tert-butyl)-N-((R)-1-(4-(6-(((S)-5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 17-2

[0844] Method 1:

[0845] Using the same synthetic route as in Example 17-1, the reagent in step 8, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (II), was replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (II) (Leyan), to obtain the title compound 17-2 (35 mg, yield: 31.9%).

[0846] Method 2:

[0847] Using the same synthetic route as Method 2 in Example 16-2, but replacing compound 1c with compound 14d, we obtained title compound 17-2 (35 mg, yield: 31.9%).

[0848] MS m / z(ESI): 819.7 [M+1] + .

[0849] 1 H NMR (500MHz, DMSO-d6): δ10.26(s,1H),10.03(s,1H),9.97-9.89(m,1H),8.71-8.65(m,1H),7.86-7.79(m,1H),7.63( s,1H),7.47-7.41(m,1H),7.16-7.11(m,2H),6.97-6.90(m,2H),6.30(s,1H),5.37-5.28(m,1H),4.04-3.90(m,2H),3 .76-3.63(m,5H),3.29-3.21(m,1H),2.79-2.64(m,5H),2.58-2.53(m,1H),2.39-2.33(m,3H),2.32-2.24(m,1H),1.9 2-1.84(m,1H),1.82-1.76(m,1H),1.71(s,1H),1.56-1.49(m,3H),1.37(s,9H),1.36-1.31(m,3H),1.28-1.22(m,2H).

[0850] Example 18

[0851] (R)-3-(tert-butyl)-N-(1-(4-(5-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 18

[0852] first step

[0853] 2-((5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 18b

[0854] 3,5-Dibromo-1-methylpyridin-2(1H)-one 18a (840 mg, 3.15 mmol, Leyan), compound 1a (500 mg, 2.10 mmol), cesium carbonate (1.74 g, 5.34 mmol, Shaoyuan), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (61 mg, 0.11 mmol, Adamas), and tris(dibenzylacetone)dipalladium (96 mg, 0.10 mmol, Adamas) were dissolved in 1,4-dioxane (7.5 mL, Adamas). The mixture was purged with nitrogen three times, and the reaction was heated to 100 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give title compound 18b (569 mg, yield: 63.9%).

[0855] MS m / z(ESI): 424.3 [M+1] + .

[0856] Step 2

[0857] (R)-2-((5-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 18c

[0858] Compound 18b (470 mg, 1.11 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (112 mg, 0.15 mmol, Bioderm), compound 1c (460 mg, 1.11 mmol), and potassium carbonate (460 mg, 0.33 mmol, Sinopharm) were added. The mixture was purged with nitrogen three times and reacted at 100 °C for 4 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 10 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 18c (224 mg, yield: 32.1%).

[0859] MS m / z (ESI): 631.7 [M+1] + .

[0860] Step 3

[0861] (R)-3-(tert-butyl)-N-(1-(4-(5-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 18

[0862] Using the synthetic route from step 3 to step 4 of Example 1, the compound 1d in step 3 was replaced with compound 18c to obtain title compound 18 (123 mg, yield: 50.1%).

[0863] MS m / z (ESI): 816.9 [M+1] + .

[0864] 1H NMR (500MHz, DMSO-d6): δ10.26(s,1H),9.82(d,1H),8.27(d,1H),8.14(s,1H),7.53(d, 1H),7.45(d,1H),7.38-7.32(m,2H),7.14(d,2H),6.94(d,2H),5.89(s,1H),5.34-5.31 (m,1H),4.00(t,2H),3.73-3.66m,4H),3.62-3.52(m,5H),2.88(t,2H),2.73-2.65(m,4 H),2.43(s,3H),2.39(d,2H),2.04-1.94(m,3H),1.82(d,2H),1.51(d,3H),1.37(s,9H).

[0865] Example 19

[0866] (R)-3-(tert-butyl)-N-(1-(4-(5-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 19

[0867] Using the synthetic route of Example 18, the first-step compound 18a was replaced with 4-bromo-6-chloro-2-methylpyridazine-3(2H)-one (Biode) to prepare the title compound 19 (29 mg, yield: 42.1%).

[0868] MS m / z (ESI): 817.9 [M+1] + .

[0869] 1 H NMR(500MHz,DMSO-d6)δ10.23(s,1H),9.84(d,1H),9.21(s,1H),8.20(d,1H) ,7.56(d,3H),7.12(d,2H),6.92(d,2H),6.00(s,1H),5.31(p,1H),4.05(t,2H ),3.76(s,3H),3.68(t,3H),3.59(s,3H),2.88(t,2H),2.71-2.61(m,4H),2. 44(s,3H),2.38(d,2H),1.98(dt,2H),1.80(d,3H),1.49(d,3H),1.35(s,9H).

[0870] Examples 20-1 and 20-2

[0871] (R)-3-(tert-butyl)-N-(1-(4-(6-((5'-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-2'-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 20-1

[0872] 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 20-2

[0873] first step

[0874] 3-Bromo-1H-pyrazole-5-carboxamide 20b

[0875] Methyl 3-bromo-1H-pyrazole-5-carboxylic acid ester 20a (5 g, 24.39 mmol, Adamas) was dissolved in methanol (80 mL), and ammonia water (35 g, 250 mmol, 25%, Sinopharm) was added. The reaction mixture was reacted at 60 °C for 3 days. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, title compound 20b, which was used directly in the next step without purification.

[0876] MS m / z(ESI): 189.9 [M+1] + .

[0877] Step 2

[0878] 3-Bromo-1H-pyrazole-5-carboxynitrile 20c

[0879] Compound 20b (4.56 g, 24 mmol) was dissolved in pyridine (80 mL), and trifluoroacetic anhydride (20 g, 95 mmol, Sinopharm) was added at 0 °C and stirred for 40 minutes. The reaction solution was diluted with 100 mL of ethyl acetate, washed successively with saturated sodium bicarbonate solution (100 mL × 2), 1 M hydrochloric acid solution (100 mL × 2), and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give title compound 20c (2 g, yield: 48.4%).

[0880] MS m / z (ESI): 169.9 [M⁻¹] - .

[0881] Step 3

[0882] 2-(3-bromo-5-cyano-1H-pyrazole-1-yl)methyl acetate 20d

[0883] Compound 20c (2 g, 11.63 mmol) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (3.21 g, 23.22 mmol, Sinopharm) and methyl chloroacetate (1.89 g, 17.41 mmol, Adamas) were added. The mixture was stirred at 80 °C for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 20d (1.14 g, yield: 40.2%).

[0884] Step 4

[0885] 2'-Bromo-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-6'(7'H)-one 20e

[0886] Compound 20d (1 g, 4.1 mmol) was dissolved in tetrahydrofuran (30 mL), and tetraisopropyl titanate (1.28 g, 4.5 mmol, Adamas) and ethyl magnesium bromide (1.09 g, 8.17 mmol, Adamas) were added at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding 10 mL of saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 20e (280 mg, yield: 28.2%).

[0887] MS m / z(ESI): 242.0 [M+1] + .

[0888] Step 5

[0889] 2'-Bromo-6',7'-Dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]20f-12-bromo-4-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine20f-2

[0890] Compound 20e (280 mg, 1.15 mmol) was dissolved in tetrahydrofuran (8 mL), and a borane tetrahydrofuran complex (200 mg, 2.33 mmol, Adamas) was added. The mixture was stirred at 60 °C for 16 hours. The reaction was cooled to room temperature, quenched dropwise with methanol in an ice bath, and concentrated under reduced pressure to give a crude mixture of the title compounds 20f-1 and 20f-2 (250 mg). The product was used directly in the next step without purification.

[0891] MS m / z(ESI): 228.0 [M+1] + ; 230.0 [M+1] + .

[0892] Step 6

[0893] 2'-Bromo-6',7'-Dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-5'-carboxylic acid tert-butyl ester 20g - 12-Bromo-4-ethyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 20g - 2

[0894] A mixture of compounds 20f-1 and 20f-2 (250 mg, 21.21 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (200 mg, 1.97 mmol, Sinopharm) and di-tert-butyl dicarbonate (263 mg, 1.21 mmol, Shaoyuan) were added at 0 °C. The mixture was then allowed to return to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give a mixture of the title compounds 20g-1 and 20g-2 (110 mg, yield: 30.5%).

[0895] MS m / z(ESI): 328.1 [M+1] + 330.1[M+1] + .

[0896] Step 7

[0897] (R)-3-(tert-butyl)-N-(1-(4-(6-((5'-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-2'-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 20-1

[0898] 3-(tert-butyl)-N-((1R)1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 20-2

[0899] Using the synthetic route from step 8 to step 10 in Example 16, compound 16i was replaced with a mixture of compounds 20g-1 and 20g-2 to obtain title compound 20-1 (3 mg, yield: 4.6%) and title compound 20-2 (5 mg, yield: 7.7%).

[0900] Title compound 20-1:

[0901] MS m / z (ESI): 813.6 [M+1] + .

[0902] 1 H NMR(500MHz, CDCl3)δ8.78(s,1H),7.90(d,2H),7.62(s,1H),7.55(s,1H),7.52(d,1H), 7.38(s,1H),7.22(d,1H),7.19-7.16(m,2H),6.98-6.94(m,2H),5.81(s,1H),5.56-5.52 (m,1H),4.17(t,2H),3.85(d,2H),3.71(d,2H),3.46(t,2H),2.84(t,2H),2.75(t,2H),2 .60(d,2H),2.54(s,3H),2.25(t,2H),1.85(d,2H),1.70-1.64(m,4H),1.41(s,9H),1.18 -1.15(m,2H),1.08-1.06(m,2H).

[0903] Title compound 20-2:

[0904] MS m / z (ESI): 815.7 [M+1] + .

[0905] 1H NMR(500MHz, CDCl3)δ8.80(d,1H),8.57(s,1H),8.10(s,1H),7.93-7.87(m,2H),7.55(s,1H),7.51(d ,1H),7.25(d,1H),7.22-7.16(m,2H),7.02-6.95(m,2H),6.17(s,1H),5.54(q,1H),4.16(ddd,1H),4 .05(ddd,1H),3.85(t,2H),3.74(d,2H),3.64(t,1H),3.38(dq,1H),2.85(t,2H),2.77(dt,2H),2.60 -2.50(m,4H),2.39(dd,1H),1.95(d,2H),1.89-1.79(m,2H),1.67(s,3H),1.41(s,13H),0.98(t,3H).

[0906] Examples 21-1 and 21-2

[0907] (R)-3-(tert-butyl)-N-(1-(4-(6-((5'-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-2'-yl)amino)pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 21-1

[0908] 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 21-2

[0909] Using the synthetic route from step 8 to step 10 in Example 16, compound 16i was replaced with a mixture of compounds 20g-1 and 20g-2, and compound 1c was replaced with compound 14d, to obtain title compound 21-1 (28 mg, yield: 12.1%) and title compound 21-2 (80 mg, yield: 34.5%).

[0910] Title compound 21-1:

[0911] MS m / z (ESI): 831.7 [M+1] + .

[0912] 1 H NMR(500MHz, CDCl3)δ10.26(s,1H),10.02(s,1H),9.93(d,1H),8.66(s,1H),7.84-7.81(m,1H) ,7.59(s,1H),7.43(d,1H),7.13(d,2H),6.92(d,2H),6.01(s,1H),5.37-5.31(m,1H),4.07-4. 05(m,2H),3.71-3.66(m,4H),2.70-2.63(m,4H),2.50-2.48(m,2H),2.36-2.31(m,3H),1.78-1 .75(m,2H),1.63(s,1H),1.53-1.50(m,3H),1.37(s,9H),1.26-1.13(m,4H),1.07-1.00(m,4H).

[0913] Title compound 21-2:

[0914] MS m / z (ESI): 833.7 [M+1] + .

[0915] 1 H NMR(500MHz, CDCl3)δ10.26(s,1H),10.03(s,1H),9.93(d,1H),8.68(s,1H),7.85-7.81(m,1H),7.60(s,1 H),7.44(d,1H),7.13(d,2H),6.93(d,2H),6.28(s,1H),5.35-5.32(m,1H),4.04-3.99(m,1H),3.89-3.84( m,1H),3.72-3.69(m,4H),3.63-3.61(m,1H),2.82-2.77(m,1H),2.71-2.65(m,4H),2.47-2.45(m,1H),2. 38-2.32(m,4H),1.88-1.70(m,5H),1.53-1.49(m,3H),1.37(s,9H),1.30-1.21(m,3H),0.90-0.84(m,3H).

[0916] Biological evaluation

[0917] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0918] Test Example 1: Test of the proliferative activity of the disclosed compound against cells carrying the BTK-C481S mutation.

[0919] 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.

[0920] 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.

[0921] 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.

[0922] Cell viability (%) = (Lum) 待测药 -Lum 培养液对照 ) / (Lum 溶剂对照 -Lum 培养液对照 )×100%

[0923] Inhibition rate % = 1 - Cell viability

[0924] Input the data into GraphPad Prism and calculate the IC using the function "log(inhibitor) vs. response -- variable slope (four parameters)". 50 value.

[0925] Table 1. Inhibitory activity of the compounds disclosed herein against the proliferation of cells carrying the BTK-C481S mutation.

[0926] Conclusion: The compound disclosed herein exhibits significant inhibitory activity against cell proliferation in cells carrying the BTK-C481S mutation.

[0927] Test Example 2: Degradation activity of the disclosed compound against BTK expressed in TMD-8 cells.

[0928] 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.

[0929] 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 DMSO were positive controls, and wells without cells in culture medium were negative controls. The final DMSO concentration was 0.5%. The final compound concentrations were: 1000, 250, 62.5, 15.63, 3.91, 0.98, 0.24, 0.06, and 0.02 nM. The cells with the added compound were incubated at 37°C, 5% CO2 for 4 hours.

[0930] 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.

[0931] 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%

[0932] Table 2. Degradation activity of the compounds disclosed herein against BTK expressed in TMD-8 cells.

[0933] Conclusion: The compound disclosed herein exhibits degradation activity against BTK expressed in TMD-8 cells.

[0934] Test Example 3: Test of the inhibitory activity of the disclosed compound on cell proliferation carrying the BTK-T474I mutation.

[0935] This test uses The 2.0 kit employs a homogenization method for cell viability detection, determining cell viability of cultured cells by quantifying ATP, based on IC50. 50 and maximum inhibition rate I max To evaluate the inhibitory activity of the compound on the proliferation of BA / F3 cells carrying the BTK-T474I mutation.

[0936] BA / F3 cells carrying the BTK T474I mutation were constructed by Kangyuan Biotech (Beijing) Co., Ltd., and 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.

[0937] 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.

[0938] Cell viability (%) = (Lum) 待测药 -Lum 培养液对照 ) / (Lum 溶剂对照 -Lum 培养液对照 )×100%

[0939] Inhibition rate % = 1 - Cell viability

[0940] Table 3. Inhibitory activity of the disclosed compounds against the proliferation of BA / F3 cells carrying the BTK-T474I mutation.

[0941] Conclusion: The compound disclosed herein has inhibitory activity against the proliferation of BA / F3 cells carrying the BTK-T474I mutation.

[0942] Test Example 4: Pharmacokinetic Evaluation

[0943] I. SD rats

[0944] 1. Abstract

[0945] Using SD rats as test animals, the plasma drug concentrations at different time points after administration of the compound of the present invention by gavage (ig) or intravenous injection (iv) were determined by LC / MS / MS to study the pharmacokinetic behavior of the compound of the present invention in SD rats and to evaluate its pharmacokinetic characteristics.

[0946] 2. Test Plan

[0947] 2.1 Test Drugs

[0948] Compound 17-1.

[0949] 2.2 Experimental Animals

[0950] Eight SD rats, half male and half female, were randomly divided into two groups and provided by Suzhou Guochen Biotechnology Co., Ltd. (Animal Use License: SYXK(Su)2020-0018).

[0951] 2.3 Drug Preparation

[0952] Weigh out a certain amount of the test compound, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and prepare a clear and transparent solution with a concentration of 0.2 mg / mL.

[0953] 2.4. Administration

[0954] Gavage: The dosage is 2 mg / kg, and the administration volume is 10 mL / kg;

[0955] Intravenous injection: The dosage is 1 mg / kg, and the administration volume is 5 mL / kg.

[0956] 3. Operation

[0957] Gavage: SD rats were administered the drug by gavage (ig), and 0.2 mL of blood was collected from the jugular vein at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, 11.0 h, and 24.0 h after administration. The blood was placed in EDTA anticoagulant tubes, centrifuged, and the plasma was collected.

[0958] Intravenous injection: SD rats were administered the drug via intravenous injection (iv). At 5 minutes, 0.2 mL of blood was collected from the jugular vein at 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 8.0 hours, 11.0 hours, and 24.0 hours after administration. The blood was placed in EDTA anticoagulant tubes, centrifuged, and the plasma was collected.

[0959] Plasma samples were analyzed at various time points after drug administration using LC / MS / MS.

[0960] 4. Pharmacokinetic Parameter Results

[0961] Table 4-1. Pharmacokinetic parameters of the disclosed compounds in SD rats.

[0962] Conclusion: The compound disclosed herein exhibits high blood concentrations and high exposure levels in SD rats, demonstrating pharmacokinetic advantages.

[0963] II. C57 Mice

[0964] 1. Abstract

[0965] Using C57 mice as test animals, the drug concentration in plasma at different time points after administration of the compound of the present invention by gavage (ig) or intravenous injection (iv) was determined by LC / MS / MS. The pharmacokinetic behavior of the compound of the present invention in C57 mice was studied and its pharmacokinetic characteristics were evaluated.

[0966] 2. Test Plan

[0967] 2.1 Test Drugs

[0968] Compound 17-1.

[0969] 2.2 Experimental Animals

[0970] Eighteen female C57 mice were evenly divided into two groups. They were provided by Suzhou Guochen Biotechnology Co., Ltd. (Animal Use License: SYXK (Su) 2020-0018).

[0971] 2.3. Drug preparation

[0972] Weigh a certain amount of the test compound respectively, add 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a 0.1 mg / mL clear and transparent solution.

[0973] 2.4. Drug administration

[0974] Gavage: The drug administration dose was 2 mg / kg, and the administration volume was 20 mL / kg;

[0975] Intravenous injection: The drug administration dose was 1 mg / kg, and the administration volume was 10 mL / kg.

[0976] 3. Operations

[0977] Gavage: C57 mice were respectively gavaged (i.g.) with drugs, and at 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, 11.0 hours, and 24.0 hours after drug administration, 0.1 mL of blood was collected from the orbital venous plexus and placed in an EDTA anticoagulant test tube. Plasma was collected after centrifugation.

[0978] Intravenous injection: C57 mice were respectively intravenously injected (i.v.) with drugs, and at 5 minutes, 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 8.0 hours, 11.0 hours, and 24.0 hours after drug administration, 0.1 mL of blood was collected from the orbital venous plexus and placed in an EDTA anticoagulant test tube. Plasma was collected after centrifugation.

[0979] Analyze the plasma samples at each time point after drug administration by LC / MS / MS.

[0980] Table 4-2. Pharmacokinetic parameters of the compounds of the present disclosure in C57 mice

[0981] Conclusion: The compounds of the present disclosure have high blood drug concentration and high exposure in C57 mice, showing pharmacokinetic advantages.

Claims

A compound of general formula (I) or a pharmaceutically acceptable salt thereof. in: B is R 3 and R 3a The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 3 and R 3a Together with the carbon atom to which it is attached, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted 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 1 and 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 is selected from polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups; 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; L a L b L c and L d They may be the same or different, and each is independently selected from bonds, alkenyl groups, alkynyl groups, and -(CR groups). 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 selected from N, CH and 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 selected from N, CH and CR. 12 ; X 1 For N or CR 15 ; 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 15 Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl; 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; Each R 2 and R 12 The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; R 13 R 14 and R c They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and heterocyclic groups; Each R 8 R 9 R 10 and R 11 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 =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 which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs 9 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs 10 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two 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; Or, R 6 and R 8 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 0 replace; Or, R 8 and R 9 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 0 replace; 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 Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally bonded 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; n is 0, 1, 2, or 3; 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. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: B is 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 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 1 and 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 is selected from polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups; 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; L a L b L c and L d They may be the same or different, and each is independently selected from bonds, alkenyl groups, alkynyl groups, and -(CR groups). 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 selected from N, CH and 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 selected from N, CH and CR. 12 ; X 1 For N or CR 15 ; 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 15 Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl; 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; Each R 2 and R 12 The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 17 -NR 18 R 19 -C(O)R 17 -C(O)OR 17 -C(O)NR 18 R 19 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; R 13 R 14 and R c They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and heterocyclic groups; Each R 8 R 9 R 10 and R 11 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 =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 Replacement; or, two non-adjacent R values 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; Or, R 6 and R 8 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 0 replace; Or, R 8 and R 9 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group; each of the cycloalkyl and heterocyclic groups is independently and optionally influenced by one or more R groups. 0 replace; 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 Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally bonded 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; n is 0, 1, 2, or 3; 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. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof: in: X a Selected from N, CH and CR 9 ; X b Selected from N, CH and CR 9 ; q1 and q2 are each independently 0, 1, 2, 3 or 4; m1 can be 0, 1, 2, 3 or 4; r can be 0, 1, 2, 3, or 4; R 1 To R 5 , n, W, Cy, R 8 m, R a R b x, R 9 L b R 12 and X 1 As defined in claim 1. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof: in: R 1 To R 5 , n, W, Cy, R 8 m, x, X a X b R 9 m1, q1, q2, R 12 and r as defined in claim 2. The compound of general formula (I) according to any one of claims 1 to 4, wherein for Z 1 For N or CR 8g Z 2 For N or CR 8h Z 3 For N or CR 8i X is CR 8j Or N; R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h R 8i and R 8j The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; preferably, Selected from *End and L a or (CR) a R b ) x Or (CH2) x Connected. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the ring Cy is a 5-membered heteroaryl fused to a 6-membered heterocyclic group; R 8 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O; m is 0 or 1. The compound of general formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, is the compound of general formula (VI) or a pharmaceutically acceptable salt thereof: in: Z 1 For N or CR 8g Z 2 For N or CR 8h X is CR 8j Or N; R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h and R 8j The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl; or, R 8a and R 8b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8c and R 8d Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 8e and R 8f Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; X a Selected from N, CH and CR 9 ; X b Selected from N, CH and CR 9 ; q1 and q2 are each independently 0, 1, 2, 3 or 4; m1 can be 0, 1, 2, 3 or 4; r can be 0, 1, 2, 3, or 4; R 1 To R 5 n, x, R 9 and R 12 As defined in claim 1. The compound of general formula (I) according to any one of claims 1 to 7, 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 methyl; and / or R 2 It is a halogen; and / or n is 0 or 1. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; and / or x is 0 or 1. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a hydrogen atom; and / or R 5 It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally coupled with one or more R groups. 5a Replace; R 5a As defined in claim 1; preferably, R 5 Selected from R 5b For hydrogen atoms or R 5a ;R 5a As defined in claim 1; more preferably, R 5 for The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 Together with the atoms connected to it, they form an optional structure formed by one or more R atoms. 5c Substituted 6-membered heterocyclic group; R 5c As defined in claim 1; preferably, R 4 and R 5 Together with the connected atoms, they form The compound of general formula (I) according to any one of claims 3 to 11, or a pharmaceutically acceptable salt thereof, wherein X a For N or CH; X b For N or CH; and / or q1 and q2 are the same or different, and each is independently 0 or 1; and / or R 12 It is a halogen; and / or r is 0 or 1. A compound or a pharmaceutically usable salt thereof, selected from the following compounds: A compound of general formula (IIA) or general formula (IIIA), or a salt thereof. in: R 5 It is aryl or heteroaryl; each of the aryl and heteroaryl groups is independently and optionally converted by one or more R 5a replace; CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group; R 1 To R 4 R 5a n, W, R 8 and m as defined in claim 3. A compound or a salt thereof, selected from the following compounds: A method for preparing a compound of formula (II) or formula (III) according to claim 3, or a pharmaceutically acceptable salt thereof, comprising: The compound of general formula (IIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IIB) or its salt to give the compound of general formula (II) or its pharmaceutically usable salt. in: x is 0; X a For CH; for *End and (CR) a R b ) x connect; CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group; R 1 To R 5 n, W, R 8 m, X b R 9 m1, q1, q2, L b X 1 R 12 and r as defined in claim 3; or, The compound of general formula (IIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IIC) or its salt to give the compound of general formula (II) or its pharmaceutically usable salt. in: x6 can be 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; R a and R b It is a hydrogen atom; for *End and (CR) a R b ) x connect; CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group; R 1 To R 5 n, W, R 8 m, X a X b R 9 m1, q1, q2, L b X 1 R 12 and r as defined in claim 3; The compound of general formula (IIIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IIB) or its salt to give the compound of general formula (III) or its pharmaceutically usable salt. in: x is 0; X a For CH; for *End and (CR) a R b ) x connect; CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group; R 1 To R 5 n, R 8 m, X b R 9 m1, q1, q2, L b X 1 R 12 and r as defined in claim 3; or, The compound of general formula (IIIA) or its salt undergoes a reductive amination reaction with the compound of general formula (IIC) or its salt to give the compound of general formula (III) or its pharmaceutically usable salt. in: x6 can be 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; R a and R b It is a hydrogen atom; for *End and (CR) a R b ) x connect; CyO is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group; R 1 To R 5 n, R 8 m, X a X b R 9 m1, q1, q2, L b X 1 R 12 and r as defined in claim 3. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 17 in the preparation of a medicament for inhibiting or degrading BTK. Use of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 17 in the preparation of a medicament for the treatment and / or prevention of diseases or conditions mediated or dependent on BTK. The use of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 17, 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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