Amide compound as well as preparation method and medical application thereof

Abstract

The invention relates to an amide compound, a preparation method thereof and application of the amide compound in medicine. Specifically, the invention relates to an amide compound as shown in a general formula (I), a preparation method of the amide compound, a pharmaceutical composition containing the amide compound and application of the amide compound as a therapeutic agent. The invention also relates to a use thereof, in particular as a BTK inhibitor or degradation agent and in the preparation of a medicament for the treatment and / or prevention of BTK-mediated or dependent diseases or conditions. Wherein each group in the general formula (I) is defined in the specification.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to an amide compound of general formula (I), a method for its preparation, a pharmaceutical composition containing the amide 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 C481 mutation was effectively suppressed in patients, new resistance mutations against Pirtobrutinib, such as L528W, subsequently emerged (Jennifer AWoyach et al., Clin Oncol. 2017 May 1; 35(13):1437-1443; Piers Blombery et al., Blood Adv (2022) 6(20):5589-5592). All marketed and investigational BTK covalent or non-covalent inhibitors bind to the ATP pocket, with Novartis' Remibrutinib and Roche's Fenebrutinib additionally binding to the H3 pocket, thus improving inhibitor selectivity. However, molecules with different binding modes have significant overlap in the amino acid residues that interact with BTK, for example, they all interact with sites such as M477, E475, and D539. Most of the resistance mutations that arise are related to the binding pocket. Clinically, the main mutations, such as C481S, T474I, L528W, and A428D, show reduced or absent binding activity to one or more of these mutations by existing covalent and non-covalent inhibitors (Eric Wang et al., N Engl J Med. 2022 Feb 24; 386(8):735-743). This means that new mutations generated by new inhibitors cannot be completely covered by existing inhibitors. Besides its inherent tyrosine kinase function, BTK also has a scaffold function (Skye Montoya et al., Science. 2024 Feb 2; 383(6682):eadi5798). Kinase inhibitors cannot completely inhibit its scaffold function.

[0004] PROTAC (Proteolysis-Targeting Chimera) is a drug 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 an E3 ligase at the other, with a linker connecting them. This allows the molecule to draw the target protein and the E3 ligase closer, prompting the E2 enzyme to ubiquitinate the target protein, thereby degrading it. Therefore, after degrading a protein, PROTAC molecules not only remove its enzymatic function but also its scaffold function. PROTAC molecules have a high tolerance for target protein binding activity; studies have shown that a molecular affinity for the target protein below 500 nM can lead to protein degradation. Therefore, even with mutations that inhibit weak binding of small molecule inhibitors, PROTAC molecules may also be effective.

[0005] Relapse of cancers such as CLL or mantle cell lymphoma (MCL) after covalent BTK inhibitor therapy is an increasingly important clinical concern. Therefore, one objective of this disclosure is to provide a BTK PROTAC degradation molecule that is effective against multiple 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]

[0008] in:

[0009] Ring A is *The end is connected to NH;

[0010] B 1 B 2 B 3 and B 4 One of them is a carbon atom bonded to NH, and the other three are the same or different, and each is independently either N or CR. 1 ;

[0011] R 1 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 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16alkyl, 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;

[0012] Z 1 For (CR) a R b ) q1 M;

[0013] Z 2 For (CR) a R b ) q2 ;

[0014] M is selected from bond, O, S(O). v C(O), C(O)O, OC(O), NR c C(O)NR c and NR c C(O);

[0015] 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;

[0016] R c Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0017] q1 and q2 are each independently 0, 1, 2, 3 or 4;

[0018] k1 and k2 are each independently 0, 1, 2, 3 or 4;

[0019] A 1 For N or CR A1 ;

[0020] A 2 For N or CR A2 ;

[0021] R A1 and R A2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, hydroxyalkyl groups, haloalkyl groups, hydroxyl groups, cyano groups, alkoxy groups, alkoxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0022] a can be 0, 1, 2, 3, 4, or 5;

[0023] R 2The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, oxo, -OR 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 =CR 17 R 18 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;

[0024] W 1 For N or CR 3a ;

[0025] W 2 For N or CR 3b ;

[0026] W 3 For N or CR 3c ;

[0027] R 3a R 3b and R 3c 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 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 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;

[0028] D is selected from bonds, O, and NH;

[0029] Cyclone B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. B Replaced;

[0030] R BSelected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, oxo, -OR 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 =CR 17 R 18 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 4 replace;

[0031] R 4 Selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, oxo, -OR 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 =CR 17 R 18 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;

[0032] L is -L 1 -L 2 -L 3 -L 4 -L 5 -;L 5 Connected to E;

[0033] L 1 L 2 L 3 L 4 and L 5 They may be the same or different, and each is independently selected from the bond, O, and S(O). v NR d C(O), C(O)NR d NR dC(O), C(O)O, OC(O), alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected by one or more R L replace;

[0034] R d Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0035] R L The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, oxo, -OR 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 =CR 17 R 18 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;

[0036] E is selected from

[0037] G 1 G 2 G 3 G 4 and G 5 One of them is a carbon atom bonded to L, and the other four are the same or different, and each is independently either N or C. 5 ;

[0038] Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom bonded to L, and the other three are the same or different, and each is independently either N or CR. 5 ;

[0039] R 5 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 14 -NR15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 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;

[0040] X 1 For N or CR 6 ;

[0041] R 6 Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl;

[0042] L a Selected from key, (CR) 7 R 8 ) m O, S, C(O), NR 9 C(O)NR 9 and NR 9 C(O);

[0043] m can be 0, 1, 2, or 3;

[0044] R 7 and R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups; or, R 7 and R 8 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0045] R 9 Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, and cycloalkylalkyl;

[0046] Z is CR 10 R 11 Or C(O);

[0047] R 10 and R 11 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups; or, R 10 and R 11 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0048] R12 and R 13 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and cycloalkylalkyl;

[0049] R 14 R 15 and R 16 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 15 and R 16 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally surrounded by one or more R atoms. 0 replace;

[0050] R 17 and R 18 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or R 17 and R 18 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0051] R 0 They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0052] v can be 0, 1, or 2.

[0053] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein D is a bond or NH; in some embodiments, D is a bond.

[0054] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein W 1 For N; in some implementations, W 1 For CR 3a ;R 3a Selected from hydrogen atoms, halogens and C 1-6Alkyl; in some embodiments, W 1 For N or CH; in some implementations, W 1 For CH.

[0055] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein W 3 For N; in some implementations, W 3 For CR 3c ;R 3c Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, W 3 For N or CH; in some implementations, W 3 For CH.

[0056] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein W 1 For N; W 2 For N or CR 3b ;R 3b As defined in general formula (I); W 3 For CH; in some implementations, W 1 For N; W 2 For CH or N; W 3 For CH; in some implementations, W 1 For N; W 2 For N; W 3 For CH.

[0057] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3a It is a hydrogen atom.

[0058] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3c Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3c It is a hydrogen atom.

[0059] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally surrounded by one or more R B Replacement; in some implementations, ring B is optionally replaced by one or more R BReplacement of 3- to 8-membered heterocyclic groups; in some embodiments, ring B is a 6-membered cycloalkyl or 6-membered heterocyclic group, wherein the 6-membered cycloalkyl or 6-membered heterocyclic group is optionally replaced by one or more R... B Substitution; in some embodiments, ring B is cyclohexyl or piperidinyl, said cyclohexyl or piperidinyl is optionally replaced by one or more R B Replacement; in some implementations, ring B is optionally replaced by one or more R B Substituted piperidinyl group; in some embodiments, ring B is selected from... Y is either N or CH; in some implementations, ring B is selected from... Y is either N or CH; in some implementations, ring B is selected from... In some implementation schemes, ring B is In some implementation schemes, ring B is In the above implementation schemes, R B As defined in general formula (I).

[0060] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from... Y is N or CH; R 4 As defined in general formula (I); in some implementations, ring B is Y is N or CH; R 4 As defined in general formula (I); in some implementations, ring B is selected from... R 4 As defined in general formula (I); in some implementations, ring B is R 4 As defined in general formula (I); in some implementations, ring B is selected from... In some implementation schemes, ring B is

[0061] 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 a pharmaceutically acceptable salt thereof.

[0062]

[0063] in:

[0064] Y is either N or CH;

[0065] R B W 2 Rings A, L, and E are as defined in general formula (I).

[0066] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R B For optional use by one or more R 4 The substituted 5- or 6-membered heterocyclic group; in some embodiments, R B For optional use by one or more R 4 The substituted 5-membered heterocyclic group; in some implementations, R B Selected from In some implementation schemes, R B for In the above implementation schemes, R 4 As defined in general formula (I); in some implementations, R B for

[0067] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein B 2 B is a carbon atom bonded to NH. 1 B 3 and B 4 They are the same or different, and each is independently N or CR. 1 In some implementation schemes, B 3 B is a carbon atom bonded to NH. 1 B 2 and B 4 They are the same or different, and each is independently N or CR. 1 In some implementation schemes, B 1 B is a carbon atom bonded to NH. 2 B 3 and B 4 They are the same or different, and each is independently N or CR. 1 In some implementation schemes, B 4 B is a carbon atom bonded to NH. 1 B 2 and B 3 They are the same or different, and each is independently N or CR. 1 In some implementation schemes, B 2 B is a carbon atom bonded to NH. 1 B 3 and B 4 Whether they are the same or different, and each is an independent CR 1 In the above implementation schemes, R 1 As defined in general formula (I); in some implementations, B 2 B is a carbon atom bonded to NH. 1 B 3 and B4 Both are the same or different, and each is independently CH.

[0068] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein ring A is B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 1 Z 1 Z 2 k1, k2, A 1 A 2 R 1 R 2 And a is as defined in general formula (I); in some implementations, ring A is B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 1 Z 1 k1, k2, A 1 A 2 and R 1 As defined in general formula (I); in some implementations, ring A is r is 0, 1, 2, or 3; k1, k2, A 1 A 2 and R 1 As defined in general formula (I); in some implementations, ring A is selected from... In some implementations, ring A is In each of the above implementation schemes, the * terminal is connected to NH.

[0069] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is used, wherein r is 0 or 1; in some embodiments, r is 0.

[0070] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof.

[0071]

[0072] in:

[0073] Y is either N or CH;

[0074] B1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 1 ;

[0075] R 4 W 2 Z 1 Z 2 k1, k2, A 2 R 1 R 2 a, L and E are as defined in general formula (I).

[0076] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof.

[0077]

[0078] in:

[0079] Y is either N or CH;

[0080] B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 1 ;

[0081] R 4 W 2 Z 1 Z 2 k1, k2, A 1 A 2 R 1 R 2 a, L and E are as defined in general formula (I).

[0082] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein for Y is N or CH; R 4 As defined in general formula (I); in some implementations, for Y is N or CH; R 4 As defined in general formula (I); in some implementations, Selected from In some implementation schemes, for In some implementation schemes, for

[0083] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV) or their pharmaceutically acceptable salts are used, wherein Y is N; in some embodiments, Y is CH.

[0084] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV) or their pharmaceutically acceptable salts are used, wherein q2 is 0, 1 or 2; in some embodiments, q2 is 1 or 2; and in some embodiments, q2 is 1.

[0085] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV) or their pharmaceutically acceptable salts, wherein Z 2 For (CHR) a ) q2 ;R a And q2 as defined in general formula (I); in some implementations, Z 2 For CHR a ;R a As defined in general formula (I); in some implementations, Z 2 (CH2) q2 ;q2 is as defined in general formula (I); in some implementations, Z 2 Selected from Z, CH2 and CH2CH2; in some embodiments, Z 2 It is CH2 or CH2CH2; in some implementations, Z 2 It is CH2.

[0086] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein R 2 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 2 It is a hydrogen atom.

[0087] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV) or their pharmaceutically acceptable salts are used, wherein a is 0 or 1; in some embodiments, a is 0.

[0088] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein R d It is a hydrogen atom or a carbon atom. 1-6Alkyl; in some embodiments, R d It is a hydrogen atom.

[0089] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein R L 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 Hydroxyl alkyl, oxo group, and hydroxyl group; in some embodiments, R L The same or different, and each independently is C. 1-6 alkyl.

[0090] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV), or their pharmaceutically acceptable salts, wherein L 1 L 2 L 3 L 4 and L 5 They are the same or different, and each is independently selected from the bond, O, S, NR. d C(O), C(O)NR d NR d C(O), C 1-6 Alkylene, C 2-6 alkenyl, C 2-6 Alkyne group, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group; the C 1-6 Alkylene, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups are each independently and optionally influenced by one or more R groups. L Replace; R d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R L Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl, oxo, and hydroxyl groups;

[0091] In some implementations, L 1 L 2 L 3 L 4 and L 5 Same or different, and each independently selected from bond, O, C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 8-membered cycloalkyl group, and 3- to 8-membered heterocyclic group; each of the 3- to 8-membered cycloalkyl group and the 3- to 8-membered heterocyclic group is independently optionally divided by one or more R groups. L Replace; RL C 1-6 alkyl;

[0092] In some implementations, L 1 L 2 L 3 L 4 and L 5 Same or different, and each independently selected from key, C 1-6 Alkylene, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups;

[0093] In some implementations, L 1 L 2 L 3 L 4 and L 5 Same or different, and each independently selected from key, C 1-6 Alkylenes and 4- to 6-membered heterocyclic groups;

[0094] In some implementations, L 1 L 2 L 3 L 4 and L 5 They may be the same or different, and each is independently selected from the following groups: bond, CH2, CH2CH2, aziridine, pyrrolidinyl, piperidinyl, and piperazine.

[0095] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV), or their pharmaceutically acceptable salts, wherein L 1 Selected from key, C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups; in some embodiments, L 1 For key or C 1-6 Alkylene; in some embodiments, L 1 C 1-6 Alkylene; in some embodiments, L 1 (CH2) n n is 0, 1, 2, 3, or 4; in some implementations, L 1 Selected from the bond, CH2 and CH2CH2; in some embodiments, L 1 It is CH2 or CH2CH2; in some implementations, L 1 It is CH2.

[0096] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV), or their pharmaceutically acceptable salts, wherein L 2It is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups is independently optionally converted by one or more R L Replace; R L C 1-6 Alkyl; in some embodiments, L 2 It is a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group; in some embodiments, L 2 It is a 4- to 6-membered heterocyclic group; in some implementations, L 2 for X a For N or CR B1 ;X b For N or CR B2 ;R B1 and R B2 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and hydroxyl groups; b1 is 0, 1, or 2; b2 is 0, 1, or 2; in some embodiments, L 2 Selected from aziridine, pyrrolidinyl, piperidinyl, piperazine, cyclobutyl, cyclopentyl, and cyclohexyl; in some embodiments, L 2 Selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, and piperazineyl; in some embodiments, L 2 Selected from In some implementations, L 2 Selected from In some implementations, L 2 for In the above implementation schemes, *terminal and L 3 Connected.

[0097] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV), or their pharmaceutically acceptable salts, wherein L 3 For key.

[0098] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV), or their pharmaceutically acceptable salts, wherein L 4 For key.

[0099] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV), or their pharmaceutically acceptable salts, wherein L 5 For key.

[0100] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein L is -L1 -L 2 -;L 2 Connected to E; L 1 Selected from key, C 1-6 Alkylene, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; L 2 It is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups is independently optionally converted by one or more R L Replace; R L C 1-6 Alkyl; in some embodiments, L is -L 1 -L 2 -;L 2 Connected to E; L 1 For key or C 1-6 Alkylene; L 2 It is a 4- to 6-membered heterocyclic group; in some implementations, L is n is 0, 1, 2, 3, or 4; X a For N or CH; X b b1 is N or CH; b2 is 0, 1, or 2; in some implementations, L is selected from N or CH. In some implementations, L is In some implementation schemes, L is selected from In some implementations, L is or In some implementations, L is In each of the above implementation schemes, the * terminal is connected to E.

[0101] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein R 6 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 6 It is a hydrogen atom.

[0102] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 9 It is a hydrogen atom.

[0103] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV), or their pharmaceutically acceptable salts, wherein L aSelected from key, NR 9 and C(O)NR 9 ;R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, L a Selected from bonds, NH and C(O)NH; in some embodiments, L a It is C(O)NH.

[0104] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein X 1 For CH or N; in some implementations, X 1 For CH; in some implementations, X 1 Let N be the number of elements in the array.

[0105] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III) and (IV), or their pharmaceutically acceptable salts, wherein G 2 It is a carbon atom bonded to L; G 1 G 3 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 5 Or, G 3 It is a carbon atom bonded to L; G 1 G 2 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 5 ;R 5 As defined in general formula (I);

[0106] In some implementations, G 3 It is a carbon atom bonded to L; G 1 G 2 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 5 ;R 5 As defined in general formula (I);

[0107] In some implementations, G 3 It is a carbon atom bonded to L; G 1 G 2 and G 4 Whether the two are the same or different, and each is an independent CR 5 G 5 For N or CR 5 ;R 5 As defined in general formula (I);

[0108] In some implementations, G 3 It is a carbon atom bonded to L; G 1 G 2 and G 4 Whether the two are the same or different, and each is an independent CR 5 G 5 For N; R 5 As defined in general formula (I);

[0109] In some implementations, G 3 It is a carbon atom bonded to L; G 1 G 2 and G 4 For CH; G 5 Let N be the number of elements in the array.

[0110] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein E is... G 1 G 2 G 3 G 4 and G 5 As defined in general formula (I); in some implementations, E is G 1 G 2 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 5 ;R 5 As defined in general formula (I); in some implementations, E is q is 0, 1, 2, or 3; G 5 For N or CR 5 ;R 5 As defined in general formula (I); in some implementations, E is q is 0, 1, 2, or 3; G 5 For N or CR 5 ;R 5 As defined in general formula (I); in some implementations, E is selected from...

[0111] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, wherein E is... q is 0, 1, 2, or 3; R 5 As defined in general formula (I); in some implementations, E is q is 0, 1, 2, or 3; R 5As defined in general formula (I); in some implementations, E is selected from...

[0112] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV) or their pharmaceutically acceptable salts, wherein E is selected from...

[0113]

[0114]

[0115]

[0116] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1; in some embodiments, q is 0.

[0117] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), and (III), or pharmaceutically acceptable salts thereof, are compounds represented by general formula (V) or pharmaceutically acceptable salts thereof.

[0118]

[0119] in:

[0120] n can be 0, 1, 2, 3, or 4;

[0121] X a For N or CR B1 ;

[0122] X b For N or CR B2 ;

[0123] R B1 and R B2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and hydroxyl groups;

[0124] b1 is 0, 1, or 2;

[0125] b2 is 0, 1, or 2;

[0126] B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 1 ;

[0127] G 1G 2 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 5 ;

[0128] R 4 W 2 Z 1 k1, k2, A 2 R 1 and R 5 As defined in general formula (I).

[0129] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), and (IV), or pharmaceutically acceptable salts thereof, are compounds represented by general formula (VI), or pharmaceutically acceptable salts thereof.

[0130]

[0131] in:

[0132] n can be 0, 1, 2, 3, or 4;

[0133] X a For N or CR B1 ;

[0134] X b For N or CR B2 ;

[0135] R B1 and R B2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and hydroxyl groups;

[0136] b1 is 0, 1, or 2;

[0137] b2 is 0, 1, or 2;

[0138] B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 1 ;

[0139] G 1 G 2 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 5 ;

[0140] R 4 W 2 Z 1 k1, k2, A 1 A2 R 1 and R 5 As defined in general formula (I).

[0141] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI), or their pharmaceutically acceptable salts, wherein for R 4 As defined in general formula (I); in some implementations, for R 4 As defined in general formula (I); in some implementations, Selected from In some implementation schemes, for

[0142] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI), or their pharmaceutically acceptable salts, wherein for In some implementation schemes, for In some implementation schemes, for

[0143] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from oxo groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 4 It is an oxygen group or C 1-6 Alkyl; in some embodiments, R 4 Selected from oxo, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl; in some embodiments, R 4 It can be an oxo group or a methyl group.

[0144] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein R 4 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 4 C1-6 Alkyl; in some embodiments, R 4 Selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl; in some embodiments, R 4 It is a methyl group.

[0145] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein W 2 For CH or N; in some implementations, W 2 For N; in some implementations, W 2 For CR 3b ;R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, W 2 For CH.

[0146] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3b It is a hydrogen atom.

[0147] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein B 1 B 3 and B 4 Whether the two are the same or different, and each is an independent CR 1 In some implementation schemes, B 1 For N; B 3 and B 4 Whether the two are the same or different, and each is an independent CR 1 In some implementation schemes, B 3 For N; B 1 and B 4 Whether the two are the same or different, and each is an independent CR 1 In some implementation schemes, B 4 For N; B 1 and B 3 Whether the two are the same or different, and each is an independent CR 1 In the above implementation schemes, R 1 As defined in general formula (I); in some implementations, B 1 B 3 and B 4 For CH.

[0148] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein R 1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 1 It is a hydrogen atom.

[0149] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein q1 is 0, 1 or 2; in some embodiments, q1 is 0 or 1; in some embodiments, q1 is 0.

[0150] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein M is selected from bond, O and NH; in some embodiments, M is O or NH; in some embodiments, M is O.

[0151] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein Z 1 (CH2) q1 M; q1 is 0 or 1; M is selected from bond, O and NH; in some implementations, Z 1 Selected from Zn, O and CH2O; in some implementations, Zn 1 For O or CH2O; in some implementations, Z 1 It is O.

[0152] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IV) or their pharmaceutically acceptable salts, wherein Z 1 -Z 2 Selected from OCH2, OCH2CH2, NHCH2, CH2OCH2, CH2O, CH2CH2O, CH2NH, and CH2CH2; in some embodiments, Z 1 -Z 2 It is OCH2.

[0153] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts are used, wherein k1 and k2 are each independently 0 or 1; in some embodiments, k1 and k2 are 1.

[0154] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (IV) or (VI) or a pharmaceutically acceptable salt thereof, wherein R A1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R A1 It is a hydrogen atom.

[0155] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein R A2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R A2 It is a hydrogen atom.

[0156] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein A 2 For CH or N; in some implementations, A 2 For N; in some implementations, A 2 For CH.

[0157] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (IV) or (VI) or a pharmaceutically acceptable salt thereof, wherein A 1 For CH or N; in some implementations, A 1 For N; in some implementations, A 1 For CH.

[0158] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein B 1 B 3 and B 4 CH; and / or Z 1 =0; and / or k1 and k2 are 1; and / or A 2 Let N be the number of elements in the array.

[0159] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III), (IV), (V) or (VI) or its pharmaceutically acceptable salt, wherein n is 0, 1 or 2; in some embodiments, n is 0 or 1; in some embodiments, n is 1 or 2; in some embodiments, n is 1; in some embodiments, n is 0.

[0160] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein RB1 and R B2 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 B1 and R B2 Each is an independent hydrogen atom.

[0161] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein X a For N or CH; in some implementations, X a For N; in some implementations, X a For CH.

[0162] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein X b For N or CH; in some implementations, X b For N; in some implementations, X b For CH.

[0163] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein X a For N or CH; X b For N or CH; in some implementations, X a For N or CH; X b For N; in some implementations, X a For CH; X b Let N be the number of elements in the array.

[0164] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts are wherein b1 and b2 are each independently 0 or 1; in some embodiments, b1 and b2 are 1; in some embodiments, b1 and b2 are 0; in some embodiments, b1 is 1 and b2 is 0.

[0165] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein X a For CH; X b For N; and / or for b1 and b2 to be 1.

[0166] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein G 1 G 2 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 5 ;R 5 As defined in general formula (I); G 1 G 2 and G 4 Whether the two are the same or different, and each is an independent CR 5 G 5 For N or CR 5 ;R 5 As defined in general formula (I); G 1 G 2 and G 4 Whether the two are the same or different, and each is an independent CR 5 G 5 For N; R 5 As defined in general formula (I); in some implementations, G 1 G 2 and G 4 For CH; G 5 For N or CH; in some implementations, G 1 G 2 and G 4 For CH; G 5 Let N be the number of elements in the array.

[0167] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein R 5 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 5 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 5 It is a hydrogen atom.

[0168] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 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 7 and R 8 It is a hydrogen atom.

[0169] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; in some embodiments, m is 1.

[0170] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein R 10 and R 11 It is a hydrogen atom.

[0171] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III) or (IV) or its pharmaceutically acceptable salt thereof, wherein Z is CH2 or C(O); in some embodiments, Z is CH2; in some embodiments, Z is C(O).

[0172] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein R 12 C 1-6 Alkyl; in some embodiments, R 12 It is a methyl group.

[0173] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein R 13 C 1-6 Alkyl; in some embodiments, R 13 It is a methyl group.

[0174] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein 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 For hydrogen atoms; in some implementations, R a For hydrogen atoms; in some implementations, R b It is a hydrogen atom.

[0175] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein R c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R c It is a hydrogen atom.

[0176] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein R 14 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0177] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein R 15 and R 16 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 15 and R 16 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 15 and R 16 It is a hydrogen atom.

[0178] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein R 17 and R 18 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 17 and R 18 They may be the same or different, and each is independently a hydrogen atom or F.

[0179] In some embodiments of this disclosure, the compound represented by general formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein v is 0; in some embodiments, v is 1; and in some embodiments, v is 2.

[0180] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, wherein 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 1-6Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 0 For halogen or =O; in some implementations, R 0 It is a halogen.

[0181] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-6 Alkyl; Y is N or CH; W 2 For N or CH; B 1 B 3 and B 4 Whether the two are the same or different, and each is an independent CR 1 ;R 1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; Z 1 For O; Z 2 It is CH2 or CH2CH2; k1 and k2 are each independently 0 or 1; A 2 For CH or N; R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; a is 0 or 1; L is selected from E is q is 0, 1, 2, or 3; G 5 For N or CR 5 ;R 5 They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0182] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-6 Alkyl; Y is N; W 2 For N; B 1 B 3 and B 4 CH; Z 1 For O; Z 2 CH2; k1 and k2 are 1; A 2 N is N; a is 0; L is selected from N. *The terminal is connected to E; E is selected from...

[0183] In some embodiments of this disclosure, the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-6 Alkyl; W 2 For CH or N; B1 B 3 and B 4 Whether the two are the same or different, and each is an independent CR 1 ;R 1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; Z 1 =0; k1 and k2 are 1; A 2 For CH or N; n is 0, 1 or 2; X a For CH or N; X b For N or CH; b1 and b2 are each independently 0 or 1; G 1 G 2 and G 4 Whether the two are the same or different, and each is an independent CR 5 G 5 For N or CR 5 ;R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl.

[0184] In some embodiments of this disclosure, the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-6 Alkyl; W 2 For N; B 1 B 3 and B 4 CH; Z 1 =0; k1 and k2 are 1; A 2 For N; n is 0 or 1; X a For CH or N; X b For N or CH; b1 and b2 are each independently 0 or 1; G 1 G 2 and G 4 For CH; G 5 It can be N or CH.

[0185] Table A lists typical compounds disclosed herein, including but not limited to:

[0186]

[0187]

[0188] This disclosure provides a compound of general formula (IA) or a salt thereof.

[0189]

[0190] in:

[0191] Ring A 1 for *The end is connected to NH;

[0192] R w It is a hydrogen atom or an amino protecting group;

[0193] Rings B, D, W 1 W 2 W 3 B 1 B 2 B 3 B 4 Z 1 Z 2 A 1 k1, k2, R 2 And a is as defined in general formula (I).

[0194] This disclosure provides a compound of general formula (IIA) or a salt thereof.

[0195]

[0196] in:

[0197] Ring A 1 for *The terminal is connected to NH; R w It is a hydrogen atom or an amino protecting group;

[0198] R B Y, W 2 B 1 B 2 B 3 B 4 Z 1 Z 2 A 1 k1, k2, R 2 And a is as defined in general formula (II).

[0199] This disclosure provides a compound of general formula (IIIA) or a salt thereof.

[0200]

[0201] in:

[0202] R w It is a hydrogen atom or an amino protecting group;

[0203] R 4 Y, W 2 B 1 B 3 B 4 Z 1 Z 2 k1, k2, R 2And a is as defined in general formula (III).

[0204] This disclosure provides a compound of general formula (IVA) or a salt thereof.

[0205]

[0206] in:

[0207] R w It is a hydrogen atom or an amino protecting group;

[0208] R 4 Y, W 2 B 1 B 3 B 4 Z 1 Z 2 A 1 k1, k2, R 2 And a is as defined in general formula (IV).

[0209] This disclosure provides a compound of general formula (VA) or a salt thereof.

[0210]

[0211] in:

[0212] R w It is a hydrogen atom or an amino protecting group;

[0213] R 4 W 2 B 1 B 3 B 4 Z 1 k1 and k2 are defined as in general formula (V).

[0214] This disclosure provides a compound of general formula (VIA) or a salt thereof.

[0215]

[0216] in:

[0217] R w It is a hydrogen atom or an amino protecting group;

[0218] R 4 W 2 B 1 B 3 B 4 Z 1 A 1 k1 and k2 are as defined in general formula (VI).

[0219] In some embodiments of this disclosure, the compounds or salts of the general formulas (IA), (IIA), (IIIA), (IVA), (VA), or (VIA), wherein R w For hydrogen atoms; in some implementations, R w It is an amino protecting group; in some embodiments, R w For Boc; in some implementations, R w It is a hydrogen atom or Boc.

[0220] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0221]

[0222]

[0223] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V) or a pharmaceutically acceptable salt thereof, comprising:

[0224]

[0225] The compound represented by general formula (VA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (VB-1) or its salt to give the compound represented by general formula (V) or its pharmaceutically usable salt.

[0226] in:

[0227] n1 is 0, 1, 2 or 3;

[0228] n is 1, 2, 3 or 4 (n is n1+1);

[0229] A 2 Let N be the number of people in the group.

[0230] R w It is a hydrogen atom;

[0231] R 4 W 2 B 1 B 3 B 4 Z 1 k1, k2, b1, b2, X a X b G 1 G 2 G 4 and G 5 As defined in general formula (V);

[0232] or,

[0233]

[0234] The compound represented by general formula (VA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (VB-2) or its salt to give the compound represented by general formula (V) or its pharmaceutically usable salt.

[0235] in:

[0236] n is 0;

[0237] A 2 Let N be the number of people in the group.

[0238] X a For CH;

[0239] R w It is a hydrogen atom;

[0240] R 4 W 2 B 1 B 3 B 4 Z 1 k1, k2, b1, b2, X b G 1 G 2 G 4 and G 5 As defined in general formula (V).

[0241] Another aspect of this disclosure relates to a method for preparing a compound of general formula (VI) or a pharmaceutically acceptable salt thereof, comprising:

[0242]

[0243] The compound of general formula (VIA) or its salt undergoes a reductive amination reaction with the compound of general formula (VB-1) or its salt to give the compound of general formula (VI) or its pharmaceutically usable salt.

[0244] in:

[0245] n1 is 0, 1, 2 or 3;

[0246] n is 1, 2, 3 or 4 (n is n1+1);

[0247] A 2 Let N be the number of people in the group.

[0248] R w It is a hydrogen atom;

[0249] R 4 W 2 B 1 B 3 B 4 Z 1A 1 k1, k2, b1, b2, X a X b G 1 G 2 G 4 and G 5 As defined in general formula (VI);

[0250] or,

[0251]

[0252] The compound of general formula (VIA) or its salt undergoes a reductive amination reaction with the compound of general formula (VB-2) or its salt to give the compound of general formula (VI) or its pharmaceutically usable salt.

[0253] in:

[0254] n is 0;

[0255] A 2 Let N be the number of people in the group.

[0256] X a For CH;

[0257] R w It is a hydrogen atom;

[0258] R 4 W 2 B 1 B 3 B 4 Z 1 A 1 k1, k2, b1, b2, X b G 1 G 2 G 4 and G 5 As defined in general formula (VI).

[0259] In some embodiments of this disclosure, the preparation method of the compound represented by general formula (V) or (VI) or its pharmaceutically acceptable salt thereof, wherein n1 is 0 or 1; in some embodiments, n1 is 0.

[0260] In some embodiments of this disclosure, the method for preparing the compound of general formula (V) or (VI) or its pharmaceutically acceptable salt thereof, wherein n is 1 or 2; in some embodiments, n is 1.

[0261] In some embodiments of this disclosure, the method for preparing the compound of general formula (V) or (VI) or its pharmaceutically acceptable salt thereof, wherein n is n1+1; n1 is 0, 1, 2, or 3; in some embodiments, n1 is 0; n is 1; in some embodiments, n1 is 1; n is 2; in some embodiments, n1 is 2; n is 3; in some embodiments, n1 is 3; n is 4. In some embodiments of this disclosure, the method for preparing the compound of general formula (V) or (VI) or its pharmaceutically acceptable salt thereof, wherein the reductive amination reaction is carried out under alkaline conditions and in the presence of a reducing agent; wherein 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; wherein the reagent providing alkaline conditions includes, but is not limited to, triethylamine.

[0262] In some embodiments of this disclosure, the preparation method of the compound represented by general formula (V) or (VI) or its pharmaceutically acceptable salt, wherein the reductive amination reaction can also be carried out under acidic conditions and in the presence of a reducing agent; wherein 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 reagent providing the acidic conditions is glacial acetic acid; in some embodiments, the acidic conditions are provided by an acid produced in the reaction, for example, sodium acetate reacting with hydrochloride to produce acetic acid;

[0263] The reducing agents mentioned therein include, but are not limited to, sodium borohydride acetate, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, and sodium acetylborohydride.

[0264] In some embodiments of this disclosure, the preparation method of the compound represented by general formula (V) or (VI) or its pharmaceutically acceptable salt thereof, wherein the reductive amination reaction is carried out in a solvent, including but not limited to: 1,2-dichloroethane, 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.

[0265] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of the above general formula (I), (II), (III), (IV), (V) or (VI) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0266] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III), (IV), (V) or (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.

[0267] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III), (IV), (V) or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for regulating BTK protein ubiquitination and degradation in a subject.

[0268] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III), (IV), (V) or (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.

[0269] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III), (IV), (V) or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of 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), acute lymphoblastic leukemia, and other similar diseases. Use in medicines for hematologic disorders, myeloid leukemia (acute and chronic), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), lymphoblastic lymphoma, marginal zone lymphoma (MZL), Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), primary central nervous system lymphoma (PCNSL), mantle cell lymphoma (MCL), B-cell lymphoma, myelodysplastic syndromes, and multiple myeloma.

[0270] This disclosure also relates to a method for regulating the ubiquitination and degradation of BTK protein in a subject, comprising administering to a desired patient a compound of the above general formula (I), (II), (III), (IV), (V) or (VI) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0271] This disclosure also relates to a method of inhibiting or degrading BTK in a subject, comprising administering to a desired patient a compound of the above general formula (I), (II), (III), (IV), (V) or (VI) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0272] This disclosure also relates to a method of treating and / or preventing diseases or conditions mediated or dependent on BTK, comprising administering to a desired patient a compound of the above general formula (I), (II), (III), (IV), (V) or (VI) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0273] This disclosure also relates to a method of treating and / or preventing tumors or autoimmune diseases, comprising administering to a desired patient a compound of the above general formula (I), (II), (III), (IV), (V) or (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, for the treatment and / or prevention of leukemia or lymphoma, and in some embodiments, for the treatment and / or prevention of chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemia (acute and chronic), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), lymphoblastic lymphoma, marginal zone lymphoma (MZL), Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), primary central nervous system lymphoma (PCNSL), mantle cell lymphoma (MCL), B-cell lymphoma, myelodysplastic syndrome, and multiple myeloma.

[0274] This disclosure further relates to a compound of the above general formula (I), (II), (III), (IV), (V) or (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicine.

[0275] This disclosure further relates to a compound of the above general formula (I), (II), (III), (IV), (V) or (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.

[0276] This disclosure further relates to a compound of the above general formula (I), (II), (III), (IV), (V) or (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on BTK.

[0277] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IV), (V) or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for regulating BTK protein ubiquitination and degradation in a subject.

[0278] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IV), (V) or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for use in inhibiting or degrading BTK in a subject.

[0279] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IV), (V) or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on BTK.

[0280] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IV), (V) or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of tumors or autoimmune diseases; in some embodiments, for the treatment and / or prevention of leukemia or lymphoma; in some embodiments, for the treatment and / or prevention of chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemia (acute and chronic), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), lymphoblastic lymphoma, marginal zone lymphoma (MZL), Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), primary central nervous system lymphoma (PCNSL), mantle cell lymphoma (MCL), B-cell lymphoma, myelodysplastic syndromes, and multiple myeloma.

[0281] In some embodiments, the tumor described in this disclosure is cancer. In some embodiments, the tumor described in this disclosure is a hematologic malignancy.

[0282] In some embodiments, the autoimmune diseases described in this disclosure are selected from urticaria, graft-versus-host disease, pemphigus vulgaris, hysteria, Addison's disease, Adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune familial autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Balódisease, Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman's disease. Disease, CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), allergic granulomatous vasculitis (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, herpetic dermatitis, dermatomyositis, Devic's disease Diseases including neuromyelitis optica, discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, goodpasture's syndrome, granulomatous polyangiitis, Graves' disease, Guillain-Barré syndrome, and Hashimoto's thyroiditis. Thyroiditis, hemolytic anemia, Henoch-Schonleinpurpura (HSP), herpes gestationis or pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS) (acne paradox), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosis,Immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytic clotting vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), mooren's ulcer, Mucha-Habermann disease. Multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, perivenitis (peripheral uveitis), Parsonnage-Turner syndrome. Pemphigus syndrome, peripheral neuropathy, peripheral encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone-induced dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome Sjögren's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmune diseases, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's sarteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), painful ophthalmoplegia syndrome (Tolosa-Hunt syndrome, THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD).Uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatous polyangiitis (GPA)).

[0283] 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).

[0284] 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 leukemia or lymphoma; in some embodiments, the BTK-mediated or dependent diseases or conditions described in this disclosure are selected from chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, myeloid leukemia, etc. Blood disorders (acute and chronic), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), lymphoblastic lymphoma, marginal zone lymphoma (MZL), Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), primary central nervous system lymphoma (PCNSL), mantle cell lymphoma (MCL), B-cell lymphoma, myelodysplastic syndromes, and multiple myeloma; in some embodiments, the BTK-mediated or dependent diseases or conditions described in this disclosure are chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL).

[0285] In some embodiments, the BTK described in this disclosure also includes mutations within the BTK protein, such as C481S, C481Y, C481R, and C481F.

[0286] 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.

[0287] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0288] 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.

[0289] As a general guideline, the active compounds of this disclosure are presented in some embodiments in a unit dose manner, or in a manner that allows the patient 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.

[0290] 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.

[0291] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0292] 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.

[0293] 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.

[0294] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] Terminology Explanation

[0306] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0307] 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.

[0308] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). The alkylene is, in some embodiments, an alkylene having 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), in some embodiments having 1 to 8 carbon atoms (i.e., C164-C ... 1-8 Alkylenes), in some embodiments having 2 to 7 carbon atoms (i.e., C164-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0309] 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-).

[0310] 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.

[0311] 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.

[0312] 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.

[0313] 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 has 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl) or 4 to 12 ring atoms (i.e., 4 to 12 membered cycloalkyl), in some embodiments it has 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), in some embodiments it has 4 to 8 ring atoms (i.e., 4 to 8 membered cycloalkyl), in some embodiments it has 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl), and in some embodiments it has 6 ring atoms (i.e., 6 membered cycloalkyl).

[0314] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0315] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0316] 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:

[0317] Its connection point can be anywhere;

[0318] wait.

[0319] 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:

[0320] Its connection point can be anywhere;

[0321] wait.

[0322] 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:

[0323] Its connection point can be anywhere.

[0324] 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.

[0325] 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).

[0326] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0327] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0328] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). The spiroheterocyclic group has 6 to 14 ring atoms in some embodiments (i.e., 6 to 14-membered spiroheterocyclic groups), and 7 to 11 ring atoms in some embodiments (i.e., 7 to 11-membered spiroheterocyclic groups). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups), and in some embodiments is a monospirocyclic or bispirocyclic group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic group. Non-limiting examples include:

[0329] wait.

[0330] 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:

[0331] wait.

[0332] 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:

[0333] wait.

[0334] 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.

[0335] 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:

[0336] wait.

[0337] 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.

[0338] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ring atoms (i.e., 5 to 15-membered heteroaryl). In some embodiments, the heteroaryl has 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), and in some embodiments, it has 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0339] 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.

[0340] 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:

[0341] wait.

[0342] 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.

[0343] 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.

[0344] When a polycyclic system is formed by the fusion of a monocyclic heterocyclic group with a cycloalkyl or aryl group and is divalent, the polycyclic system is classified as a "fused heterocyclic group" as long as one of the linkage sites is on the monocyclic heterocyclic group.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0350] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0351] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0352] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0357] 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.

[0358] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0359] The term "hydroxyl group" refers to -OH.

[0360] The term "thiol" refers to -SH.

[0361] The term "amino" refers to -NH2.

[0362] The term "cyano" refers to -CN.

[0363] The term "nitro" refers to -NO2.

[0364] The term "oxo" or "oxo group" refers to "=O".

[0365] The term "carbonyl" refers to C=O.

[0366] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0367] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0368] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0369] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0370] 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.

[0371] 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.

[0372] In the chemical structure of the compounds described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and the E-type are included."

[0373] 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:

[0374]

[0375] 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:

[0376]

[0377] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0378] 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.

[0379] 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.

[0380] 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.

[0381] 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.

[0382] "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.

[0383] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, in some embodiments 1 to 6, in some embodiments 1 to 3, in some embodiments 1 or 2, and in some embodiments 1 hydrogen atom is 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 having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0384] "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.

[0385] "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.

[0386] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0387] 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.

[0388] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0389] 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

[0390] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0391] Example

[0392] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0393] 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: waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: waters ACQuity Qda Detector / waters SQ Detector); and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0394] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLCe2695-2489 HPLC system.

[0395] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0396] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0397] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0398] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0399] 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.

[0400] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0401] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0402] 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, AccelaChemBio Inc, and Darui Chemicals.

[0403] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0404] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0405] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0406] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0407] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0408] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0409] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0410] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0411] 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.

[0412] Example 1

[0413] 3-((1'-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)aminocarbonyl)pyridin-3-yl)piperidin-4-yl)methyl)-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)amino)-5-((R)-3-(3-methyl-2-oxoimidazol-1-yl)piperidin-1-yl)pyrazine-2-carboxamide1

[0414]

[0415]

[0416] first step

[0417] 1-Benzyl-4-(4-bromo-2-fluorophenyl)piperidine-4-carboxylic acid methyl ester 1c

[0418] 2-(4-bromo-2-fluorophenyl)acetic acid methyl ester 1a (3 g, 12.14 mmol, Bioderm) was dissolved in N,N-dimethylformamide (15 mL). Sodium hydride (418 mg, 10.91 mmol, 60% purity, Sinopharm) was added at 0 °C, and the mixture was stirred at room temperature for 30 minutes. Sodium iodide (183 mg, 1.22 mmol, Adamas) and N-benzyl-N,N-bis(2-chloroethyl)amine hydrochloride 1b (3.92 g, 14.60 mmol, Shaoyuan) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to 30 mL of saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 2). 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 silica gel column chromatography using eluent system B to give the title compound 1c (1.3 g, yield: 26.4%).

[0419] MS m / z(ESI): 406.3 [M+1]

[0420] Step 2

[0421] 4-(4-bromo-2-fluorophenyl)piperidine-4-carboxylic acid methyl ester 1d

[0422] Compound 1c (1.2 g, 2.95 mmol) was dissolved in 1,2-dichloroethane (20 mL), and 1-chloroethyl chloroformate (4.23 g, 29.59 mmol, Bioderm) was added. The mixture was reacted at 60 °C for 12 hours. After returning to room temperature, the reaction solution was concentrated under reduced pressure, and methanol (20 mL, Sinopharm) was added. The mixture was refluxed for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 1d (380 mg, yield: 40.7%).

[0423] MS m / z(ESI): 316.2 [M+1]

[0424] Step 3

[0425] 1-(tert-butyl)4-methyl-4-(4-bromo-2-fluorophenyl)piperidine-1,4-dicarboxylic acid ester 1e

[0426] Compound 1d (380 mg, 1.20 mmol) was dissolved in dichloromethane (5 mL, Sinopharm), and triethylamine (365 mg, 3.61 mmol, Sinopharm) and di-tert-butyl dicarbonate (315 mg, 1.44 mmol, Adamas) were added. The mixture was stirred at room temperature for 2 hours. 10 mL of water was added to the reaction solution, 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 residue was purified by silica gel column chromatography using eluent system B to give the title compound 1e (300 mg, yield: 60.0%).

[0427] MS m / z(ESI): 316.2 [M-99]

[0428] Step 4

[0429] 4-(4-bromo-2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester 1f

[0430] Compound 1e (300 mg, 0.72 mmol) was dissolved in tetrahydrofuran (4 mL), and lithium aluminum hydride (1 M, 0.74 mL, 0.74 mmol, Adamas) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h. After returning to room temperature, sodium sulfate decahydrate was added for quenching, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound 1f (279 mg, yield: 99.7%). The product was directly used in the next reaction without purification.

[0431] MS m / z(ESI): 288.3 [M-99]

[0432] Step 5

[0433] 1g of 6-bromo-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester

[0434] Compound 1f (279 mg, 0.72 mmol) was dissolved in tetrahydrofuran (10 mL), and potassium tert-butoxide (186 mg, 1.65 mmol, Adamas) was added. The tube was sealed and reacted at 100 °C for 30 min. After returning to room temperature, the solution was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give 1 g (200 mg, yield: 75.6%) of the title compound.

[0435] MS m / z(ESI): 268.0 [M-99]

[0436] Step 6

[0437] 6-((diphenylmethyl)amino)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 1h

[0438] 1 g (1.00 g, 2.72 mmol) of the compound was dissolved in toluene (20 mL, Anegacier), and benzophenone imine (590 mg, 3.26 mmol, BIDE), sodium tert-butoxide (365 mg, 3.80 mmol, Shaoyuan), tris(dibenzylacetone)palladium (248 mg, 0.27 mmol, BIDE), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (507 mg, 0.81 mmol, Shaoyuan) were added. The mixture was purged with nitrogen three times and heated to 80 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated under reduced pressure to give crude compound 1 h (1.2 g, yield: 94.3%). The product was directly used for the next reaction without purification.

[0439] MS m / z(ESI): 469.5 [M+1]

[0440] Step 7

[0441] 6-Amino-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 1i

[0442] Compound 1h (1.2 g, 2.56 mol) was dissolved in methanol (10 L, Sinopharm), and hydroxylamine (507 mg, 50%, 7.67 mmol, Sinopharm) was added. The mixture was reacted at room temperature for 18 hours. The system was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 1i (750 mg, yield: 96.2%).

[0443] MS m / z (ESI): 305.3 [M+1]

[0444] Step 8

[0445] (R)-6-((3-cyano-6-(3-(3-methyl-2-oxoimidazol-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-2H-spiro[benzofuran-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester 1k

[0446] Compound 1i (750 mg, 2.46 mmol) was dissolved in 1,4-dioxane (10 mL, Adamas), and (R)-3-chloro-5-(3-(3-methyl-2-oxoimidazol-1-yl)piperidin-1-yl)pyrazin-2-carboxynitrile 1j (790 mg, 2.46 mmol, prepared by the intermediate method of Example 1 on page 158 of the specification in patent application WO2020081450A1), palladium acetate (110 mg, 0.49 mmol, Bioderm), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (306 mg, 0.49 mmol, Shaoyuan) and cesium carbonate (1.60 g, 4.91 mmol, Shaoyuan) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 3 hours. After returning to room temperature, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1k (1.6 g, yield: 96.5%).

[0447] MS m / z(ESI): 589.6 [M+1]

[0448] Step 9

[0449] (R)-6-((3-aminocarbonyl-6-(3-(3-methyl-2-oxoimidazol-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-2H-spiro[benzofuran-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester 1l

[0450] Compound 1k (1.4 g, 2.38 mmol) and cesium carbonate (774 mg, 2.38 mmol, Shaoyuan) were dissolved in methanol (50 mL, Sinopharm) and dimethyl sulfoxide (2.7 mL, Anaiji). Hydrogen peroxide (30% aqueous solution, 13 mL, 166 mmol, Sinopharm) was added dropwise, and the mixture was reacted at room temperature for 30 minutes. The system was concentrated, dissolved in ethyl acetate (50 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 1l (1.4 g, yield: 97.0%).

[0451] MS m / z (ESI): 607.6 [M+1]

[0452] Step 10

[0453] (R)-3-((2H-spirofuran-3,4'-piperidin]-6-yl)amino)-5-(3-(3-methyl-2-oxoimidazol-1-yl)piperidin-1-yl)pyrazin-2-carboxamide 1m

[0454] Compound 1L (150 mg, 0.25 mmol) was dissolved in tetrahydrofuran (2 mL, Sinopharm), and dioxane hydrochloride (4 M, 2 mL, 8.00 mmol, Adamas) was added. The mixture was reacted at room temperature for 1 hour. The solution was concentrated under reduced pressure, and 3 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (3 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound 1M (120 mg, yield: 95.8%).

[0455] MS m / z (ESI): 507.6 [M+1]

[0456] Step 11

[0457] 3-((1'-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)aminocarbonyl)pyridin-3-yl)piperidin-4-yl)methyl)-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)amino)-5-((R)-3-(3-methyl-2-oxoimidazol-1-yl)piperidin-1-yl)pyrazine-2-carboxamide1

[0458] Compound 1m (120 mg, 0.24 mmol), (S)-N-(2,6-dioxopiperidin-3-yl)-5-(4-formylpiperidin-1-yl)pyridineamide 1n (82 mg, 0.24 mmol, prepared by the method disclosed in Example 3 on page 127 of patent application WO2021113557A1), and triethylamine (0.13 mL, 0.55 mmol, Sinopharm) were dissolved in 1,2-dichloroethane (2 mL, Anaiji) and stirred at room temperature for 10 minutes. Sodium borohydride acetate (100 mg, 0.47 mmol, Shaoyuan) was added and stirring continued at room temperature for 2 hours. Concentrate under reduced pressure, add 5 mL of water, extract with a mixed solvent of isopropanol and chloroform (V / V = 1:3) (10 mL × 3), combine the organic phases, wash with 5 mL of saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system A to give title compound 1 (31 mg, yield: 15.7%).

[0459] MS m / z(ESI): 836.0 [M+1]

[0460] 1H NMR(500MHz,DMSO-d6)δ11.33(s,1H),10.85(s,1H),8.75-8.67(m,1H),8.39-8.26(m,1H),7.93-7.83(m,1H),7.82-7.74(m,1H) ,7.68(s,1H),7.45-7.38(m,1H),7.38-7.31(m,1H),7.20(s,1H),7.16-7.07(m,1H),7.01-6.90(m,1H),4.81-4.69(m,1H),4.38 -4.24(m,3H),4.01-3.90(m,2H),3.62-3.51(m,2H),3.32-3.21(m,6H),3.16-3.08(m,1H),3.02-2.92(m,1H),2.91-2.76(m,4H) ,2.69(s,3H),2.56-2.53(m,1H),2.28-2.11(m,3H),2.08-1.93(m,3H),1.89-1.71(m,7H),1.68-1.50(m,3H),1.26-1.16(m,2H).

[0461] Biological evaluation

[0462] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0463] Test Example 1: Degradation activity of the disclosed compound against BTK expressed in TMD-8 cells.

[0464] 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.

[0465] TMD8 cells were cultured in RPMI 1640 complete medium containing 10% FBS. On day 1 of the experiment, all suspension cells were transferred to 15 mL centrifuge tubes, centrifuged at 1000 rpm for 3 min, the medium was removed, and the cells were resuspended in 5-10 mL of fresh cell culture medium and counted. The cell density was adjusted to 5 × 10⁶ cells / mL using phenol-free red blood cell medium. 5Cells / mL: 40.5 μL of cell suspension was added to each well of a 96-well cell culture plate. The plate was incubated for 24 hours (37°C, 5% CO2). The next day, the compound was serially diluted 4-fold with DMSO, then 20-fold with phenol red-free medium, and 4.5 μL was added to each well of the cell culture plate. Wells treated with DMSO were positive controls, and wells without cells 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.

[0466] 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 degrees Celsius overnight and then read the fluorescence value.

[0467] The DC was calculated using Graphpad Prism 10 software to perform curve fitting between the logarithm of each concentration of the test compound and the corresponding degradation rate. 50 Values. Using the log(inhibitor) vs. response--Variable slope(four parameters) equation in Nonlinear Regression of GraphPad Prism 10, the DC of the compound was calculated based on the logarithm of the compound concentration and the degradation rate. 50 Value. Degradation rate (%) = (RLU positive control - RLU compound concentration) / (RLU positive control - RLU negative control) × 100%

[0468] Table 1. Degradation activity of the compounds disclosed herein against BTK expressed in TMD-8 cells.

[0469] compound <![CDATA[DC 50 / nM]]> <![CDATA[D max％(Mean) ]]> 1 0.7 98.27

[0470] Conclusion: The compound disclosed herein exhibits degradation activity against BTK expressed in TMD-8 cells.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: Ring A is *The end is connected to NH; B 1 B 2 B 3 and B 4 One of them is a carbon atom bonded to NH, and the other three are the same or different, and each is independently either N or CR. 1 ; R 1 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 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 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; Z 1 is (CR a R b ) q1 M; Z 2 is (CR a R b ) q2 ; M is selected from bond, O, S(O). v C(O), C(O)O, OC(O), NR c C(O)NR c and NR c C(O); R a and R b They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl; R c Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; q1 and q2 are each independently 0, 1, 2, 3 or 4; k1 and k2 are each independently 0, 1, 2, 3 or 4; A 1 For N or CR A1 ; A 2 For N or CR A2 ; R A1 and R A2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, hydroxyalkyl groups, haloalkyl groups, hydroxyl groups, cyano groups, alkoxy groups, alkoxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups; a can be 0, 1, 2, 3, 4, or 5; R 2 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, oxo, -OR 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 =CR 17 R 18 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; W 1 For N or CR 3a ; W 2 For N or CR 3b ; W 3 For N or CR 3c ; R 3a R 3b and R 3c 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 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 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; D is selected from bonds, O, and NH; Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently optionally influenced by one or more R groups. B Replaced; R B Selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, oxo, -OR 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 =CR 17 R 18 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 4 replace; R 4 Selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, oxo, -OR 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 =CR 17 R 18 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; L is -L 1 -L 2 -L 3 -L 4 -L 5 -;L 5 Connected to E; L 1 L 2 L 3 L 4 and L 5 They may be the same or different, and each is independently selected from the bond, O, and S(O). v NR d C(O), C(O)NR d NR d C(O), C(O)O, OC(O), alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected by one or more R L replace; R d Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; R L The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, oxo, -OR 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 =CR 17 R 18 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; E is selected from G 1 G 2 G 3 G 4 and G 5 One of them is a carbon atom bonded to L, and the other four are the same or different, and each is independently either N or C. 5 ; Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom bonded to L, and the other three are the same or different, and each is independently either N or C. 5 ; R 5 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 14 -NR 15 R 16 -C(O)R 14 -C(O)OR 14 -C(O)NR 15 R 16 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; X 1 For N or CR 6 ; R 6 Selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino and hydroxyl; L a Selected from key, (CR) 7 R 8 ) m O, S, C(O), NR 9 C(O)NR 9 and NR 9 C(O); m can be 0, 1, 2, or 3; R 7 and R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups; or, R 7 and R 8 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; R 9 Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, and cycloalkylalkyl; Z is CR 10 R 11 Or C(O); R 10 and R 11 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups; or, R 10 and R 11 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; R 12 and R 13 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and cycloalkylalkyl; R 14 R 15 and R 16 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 15 and R 16 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally surrounded by one or more R atoms. 0 replace; R 17 and R 18 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or R 17 and R 18 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; R 0 They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; v can be 0, 1, or 2.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 1 Z 1 Z 2 k1, k2, A 1 A 2 R 1 R 2 and a as defined in claim 1; preferably, ring A is The * end is connected to NH.

3. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (III) is a pharmaceutically acceptable salt thereof: in: Y is either N or CH; B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 1 ; R 4 W 2 Z 1 Z 2 k1, k2, A 2 R 1 R 2 a, L, and E are as defined in claim 1.

4. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L is -L 1 -L 2 -;L 2 Connected to E; L 1 Selected from key, C 1-6 Alkylene, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; L 2 It is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups is independently optionally converted by one or more R L Replace; R L C 1-6 Alkyl; preferably, L is selected from alkyl groups. More preferably, L is And / or E is q is 0, 1, 2, or 3; G 5 For N or CR 5 ;R 5 As defined in claim 1; preferably, E is selected from...

5. The compound of general formula (I) according to any one of claims 1 to 4, wherein it is the compound of general formula (V) or a pharmaceutically acceptable salt thereof. in: n is 0, 1, 2, 3 or 4; X a For N or CR B1 ; X b For N or CR B2 ; R B1 and R B2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and hydroxyl groups; b1 is 0, 1, or 2; b2 is 0, 1, or 2; B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 1 ; G 1 G 2 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 5 ; R 4 W 2 Z 1 k1, k2, A 2 R 1 and R 5 As defined in claim 1.

6. The compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-6 Alkyl; preferably, R 4 Selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl; more preferably, R 4 It is methyl; and / or W 2 Let N be the number of people in the group. and / or B 1 B 3 and B 4 CH; and / or Z 1 =0; and / or k1 and k2 are 1; and / or A 2 Let N be the number of people in the group. and / or n is 0 or 1; preferably, n is 1; and / or X a For CH; X b For N; and / or for b1 and b2 to be 1; and / or G 1 G 2 and G 4 For CH; G 5 It is N or CH; preferably, G 1 G 2 and G 4 For CH; G 5 Let N be the number of elements in the array.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

8. A compound of general formula (IIIA) or a salt thereof, in: R w It is a hydrogen atom or an amino protecting group; R 4 Y, W 2 B 1 B 3 B 4 Z 1 Z 2 k1, k2, R 2 and a as defined in claim 3.

9. A compound or a salt thereof, selected from the following compounds:

10. A method for preparing a compound of formula (V) according to claim 5 or a pharmaceutically acceptable salt thereof, comprising: The compound represented by general formula (VA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (VB-1) or its salt to give the compound represented by general formula (V) or its pharmaceutically usable salt. in: n1 is 0, 1, 2 or 3; n is 1, 2, 3 or 4; A 2 Let N be the number of people in the group. R w It is a hydrogen atom; R 4 W 2 B 1 B 3 B 4 Z 1 k1, k2, b1, b2, X a X b G 1 G 2 G 4 and G 5 As defined in claim 5; or, The compound represented by general formula (VA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (VB-2) or its salt to give the compound represented by general formula (V) or its pharmaceutically usable salt. in: n is 0; A 2 Let N be the number of people in the group. X a For CH; R w It is a hydrogen atom; R 4 W 2 B 1 B 3 B 4 Z 1 k1, k2, b1, b2, X b G 1 G 2 G 4 and G 5 As defined in claim 5.

11. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and one or more pharmaceutically acceptable carriers, diluents or excipients.

12. Use of the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 11 in the preparation of a medicament for inhibiting or degrading BTK.

13. Use of the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 11 in the preparation of a medicament for the treatment and / or prevention of diseases or conditions mediated or dependent on BTK.

14. Use of the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 11 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), acute lymphoblastic leukemia, myeloid leukemia, small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), lymphoblastic lymphoma, marginal zone lymphoma (MZL), Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), primary central nervous system lymphoma (PCNSL), mantle cell lymphoma (MCL), B-cell lymphoma, myelodysplastic syndrome, and multiple myeloma.

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