Compound having protein tyrosine kinase BTK-degrading activity, and preparation method therefor and use thereof

Abstract

The present application relates to the field of pharmaceutical chemistry, and specifically to a Bruton's tyrosine kinase (BTK) as shown in formula (I) and a mutant degrader thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, and a use thereof in the preparation of a drug for treating diseases or disorders mediated by degradation of BTK.

Description

A compound with the activity of degrading tyrosine protein kinase BTK and its preparation method and use Technical Field

[0001] The present application relates to the field of medicinal chemistry, and specifically to a compound having the activity of degrading tyrosine protein kinase BTK, and its preparation method and use. Background Art

[0002] Bruton's tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases, plays a crucial role in signaling via antigen-dependent BCR (B cell receptor) and antigen-independent TLR (Toll-like receptor) (Rip et al., 2019). Upon antigen binding to the BCR, spleen tyrosine kinase (Syk) in the cytoplasm is activated, recruiting and activating BTK. This further initiates a kinase cascade, promoting the expression of transcription factors such as NF-κB, PI3K, and ERK (Ahn and Brown, 2021), thereby regulating B cell gene transcription, proliferation, differentiation, and maturation. Studies have shown that abnormal or persistent BTK activation is a key factor in the development and progression of B cell lymphomas and autoimmune diseases such as rheumatoid arthritis (Wang et al., 2022; Zhang et al., 2021). Therefore, targeted inhibition of BTK is one of the main methods for treating B cell lymphomas such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).

[0003] Currently, multiple covalent inhibitors based on the BTKC481 site have been approved by the FDA for the treatment of B-cell lymphoma, such as the first-generation covalent inhibitor ibrutinib, the second-generation covalent inhibitors acalabrutinib and zanubrutinib, and the third-generation non-covalent inhibitor pirtobrutinib. Although BTK inhibitors have achieved good results in clinical treatment (for example, the objective response rate (ORR) of pirtobrutinib in MCL patients reached 51%, and the complete response (CR) and partial response (PR) rates reached 25% and 26%, respectively), drug-induced mutations in the BTK kinase domain (such as C481S, L528W, T474I, V416L, etc.) can lead to resistance to BTK inhibitors in patients during long-term treatment (Nakhoda et al, 2023). Among them, C481S is the main mutation type for covalent inhibitors, accounting for approximately 70% of clinical mutations (Nakhoda et al, 2023), while for non-covalent inhibitors, L528W and T474I mutations account for approximately 50% and 20% of mutation types, respectively (Wang et al, 2022). In a clinical trial of zanubrutinib for the treatment of CLL, researchers (Blombery et al., 2022) found a significant enrichment of the BTK-L528W mutation in CLL patients treated with zanubrutinib compared with those treated with ibrutinib. With the widespread use of second- and third-generation BTK inhibitors, addressing the subsequent enrichment of more diverse resistance mutations has become an urgent clinical need in the future treatment of B-cell lymphomas.

[0004] Proteolysis targeting chimeras (protacs) are a recently emerging biotechnology that utilizes the ubiquitin-proteasome system to induce target protein degradation. Unlike traditional small molecule inhibitors that only inhibit target proteins by occupying their sites, protacs can be recycled to recruit and induce target protein degradation, enabling efficient degradation of disease-related targets with low-dose protacs (Moreau et al, 2020).

[0005] This application aims to develop a new small molecule degrader that can efficiently and specifically induce the degradation of BTK wild / mutant proteins, with excellent metabolic stability, while achieving efficient anti-tumor effects on B-cell lymphoma while reducing the safety risks caused by off-target toxic side effects. Summary of the Invention

[0006] One of the purposes of the present application is to provide a compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof or a mixture thereof:

[0007] in:

[0008] Ring A is selected from the group consisting of a substituted 5-12 membered heteroaryl or 5-12 membered heterocyclic group; preferably, ring A is selected from 1 or 2 R a a 5-6 membered heteroaryl or 5-6 membered heterocyclic group substituted by a substituent;

[0009] D is selected from a bond, -CR1R1'-, -S-, -O- or -NR2-(CH2) m -;

[0010] Ring B is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl or C3-C 12 Cycloalkyl;

[0011] W1 and W2 are each independently selected from C or N;

[0012] R a Selected from H, C1-C6 alkyl or C(=O)-NH2;

[0013] R b1 Selected from C1-C6 haloalkyl, C1-C6 alkyl or halogen;

[0014] R b2 is selected from 4-6 membered heterocyclyl, -C(=O)-R3, -NR4R5, -S(=O)2R3, -NR6-C(=O)-R7; the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R8;

[0015] R1, R1', R c , R2 are each independently selected from H, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy or C1-C6 alkyl;

[0016] R3 are each independently selected from C3-C 10 Cycloalkyl, 5-12 heterocyclic, C1-C6 alkyl, C1-C6 haloalkyl, -S(=O)2CH3 or NR4R5, the C3-C 10 Cycloalkyl, 5-12 heterocyclyl, C1-C6 alkyl, C1-C6 haloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy or C1-C6 haloalkyl;

[0017] R4, R5, R6 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3;

[0018] R7 is selected from a 5-6 membered heteroaryl or a benzene ring optionally substituted with 1-3 R9;

[0019] R8 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3;

[0020] R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl;

[0021] L is -X1-X2-X3-X4-X5-X6-;

[0022] X1 is selected from a bond, -C(=O)-, C1-C6 alkylene, C5-C8 monocycloalkyl, C7-C 12 Spiroalkyl, 7-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group or 3-8 membered monoheterocyclic group; the C5-C8 monocycloalkyl, C7-C 12 Spirocycloalkyl, 7-12 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl or 3-8 membered monoheterocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, -C(O)NH2, hydroxyl or halogen;

[0023] X2 is selected from a bond, -C(=O)- or C1-C6 alkylene;

[0024] X3, X4, X5, and X6 are each independently selected from a bond, a 3-12 membered heterocyclic group, a C1-C6 alkylene group, a C3-C 10 Cycloalkyl, -O-, -NR2- or -C(=O)-; X1, X2, X3, X4, X5, and X6 are not all bonds;

[0025] Y is selected from wherein W3 is selected from N or C;

[0026] Ring E1 is selected from R e is selected from halogen, methyl, methoxy or trifluoromethyl;

[0027] Ring E2 is selected from 5-10 membered heteroaryl; preferably 5-6 membered heteroaryl;

[0028] m, p, q are selected from 0, 1, 2 or 3;

[0029] s is selected from 0, 1 or 2.

[0030] One of the purposes of the present application is to provide a compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof or a mixture thereof:

[0031] in:

[0032] Ring A is selected from the group consisting of a substituted 5-12 membered heteroaryl or 5-12 membered heterocyclyl; preferably, ring A is selected from the group consisting of a a 5-6 membered heteroaryl or 5-6 membered heterocyclic group substituted by a substituent;

[0033] D is selected from a bond, -CR1R1'-, -S-, -O- or -NR2-(CH2) m -;

[0034] Ring B is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl or C3-C 12 Cycloalkyl;

[0035] W1 and W2 are each independently selected from C or N;

[0036] R a Selected from H, C1-C6 alkyl or C(=O)-NH2;

[0037] R b1 Selected from C1-C6 haloalkyl, C1-C6 alkyl or halogen;

[0038] R b2 is selected from 4-6 membered heterocyclyl, -C(=O)-R3, -NR4R5, -S(=O)2R3, -NR6-C(=O)-R7; the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R8;

[0039] R1, R1', R c , R2 are each independently selected from H, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy or C1-C6 alkyl;

[0040] R3 are each independently selected from C3-C 10 Cycloalkyl, 5-12 heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -S(=O)2CH3 or NR4R5, the C3-C 10 Cycloalkyl, 5-12 heterocyclyl, C1-C6 alkyl, C1-C6 haloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy or C1-C6 haloalkyl;

[0041] R4, R5, R6 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3;

[0042] R7 is selected from a 5-6 membered heteroaryl or a benzene ring optionally substituted with 1-3 R9;

[0043] R8 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3;

[0044] R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl;

[0045] L is -X1-X2-X3-X4-X5-X6-;

[0046] X1 is selected from a bond, -C(=O)-, C1-C6 alkylene, C5-C8 monocycloalkyl, C7-C 12 Spiroalkyl, 7-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group or 3-8 membered monoheterocyclic group; the C5-C8 monocyclic alkyl, C7-C 12 Spirocycloalkyl, 7-12 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl or 3-8 membered monoheterocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, -C(O)NH2, hydroxyl or halogen;

[0047] X2 is selected from a bond, -C(=O)- or C1-C6 alkylene;

[0048] X3, X4, X5, and X6 are each independently selected from a bond, a 3-12 membered heterocyclic group, a C1-C6 alkylene group, a C3-C 10 Cycloalkyl, -O-, -NR2- or -C(=O)-; X1, X2, X3, X4, X5, and X6 are not all bonds;

[0049] Y is selected from wherein W3 is selected from N or C;

[0050] Ring E1 is selected from R e is selected from halogen, methyl, methoxy or trifluoromethyl;

[0051] Ring E2 is selected from 5-10 membered heteroaryl; preferably 5-6 membered heteroaryl;

[0052] m, p, q are selected from 0, 1, 2 or 3;

[0053] s is selected from 0, 1 or 2.

[0054] In some preferred embodiments, Ring A is selected from * indicates the position of attachment to D; provided that: when ring A is selected from Y is

[0055] In some preferred embodiments, R ais selected from H, C1-C3 alkyl or C(=O)-NH2; more preferably, R a is selected from C1-C3 alkyl or C(=O)-NH2; further preferably, R a Selected from -CH3 or C(=O)-NH2.

[0056] In some embodiments, R b1 is selected from C1-C6 haloalkyl, C1-C6 alkyl or halogen, preferably selected from C1-C3 haloalkyl, C1-C3 alkyl or halogen, more preferably selected from C1-C3 alkyl or halogen, further preferably selected from -CH3 or F; R b2 Selected from -C(=O)-R3, -NR4R5 or -S(=O)2R3, or R b2 Selected from -C(=O)-R3, -NR4R5 or -S(=O)2R3; R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl, preferably C1-C3 alkyl or C1-C3 hydroxyalkyl; each R8 is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl or -S(=O)2CH3, preferably H or C1-C3 alkyl; t is selected from 0, 1 or 2; preferably, R b2 Selected from -NH2, -NH-S(=O)2CH3 or -S(=O)2CH3, or R b2 Selected from -C(=O)-R3 or -S(=O)2CH3; R3 are each independently selected from C3-C5 cycloalkyl, C1-C3 alkyl or C1-C3 alkoxy, and the C3-C5 cycloalkyl, C1-C3 alkyl or C1-C3 alkoxy may be optionally substituted by 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy or C1-C6 haloalkyl.

[0057] In a preferred embodiment, R b2 Selected from or -S(=O)2CH3, or selected from -C(=O)OCH3 or -S(=O)2CH3.

[0058] In some preferred embodiments, R3 is independently selected from C3-C5 cycloalkyl or C1-C3 alkyl, or is independently selected from C3-C5 cycloalkyl, C1-C3 alkoxy. c, R2 are each independently selected from H, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy or C1-C3 alkyl; preferably, they are each independently selected from H, C1-C3 alkoxy or C1-C3 alkyl.

[0059] In some preferred embodiments, Ring E1 is selected from Preferably More preferably, ring E1 is selected from * indicates the position where the sum is attached to L.

[0060] In some preferred embodiments, Ring E1 is selected from * indicates the position where the sum is attached to L.

[0061] In some preferred embodiments, ring E2 is selected from 5-6 membered heteroaryl, preferably pyridine.

[0062] In some preferred embodiments, Y is selected from: Preferably selected from

[0063] In some preferred embodiments, the compound of formula (I) has the structure shown in formula (II):

[0064] in,

[0065] W1, W2, W3 are each independently selected from C or N;

[0066] D is selected from a bond, -CR1R1'-, -S-, -O- or -NR2-(CH2) m -;

[0067] Ring B is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl or C3-C6 cycloalkyl;

[0068] R b2 is selected from 4-6 membered heterocyclyl, -C(=O)-R3, -NR4R5, -S(=O)2R3 or -NR6-C(=O)-R7; the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R8;

[0069] R1, R1', R c , R2 are each independently selected from H, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy or C1-C6 alkyl;

[0070] R3 are each independently selected from C3-C 10Cycloalkyl, 5-12 heterocyclic, C1-C6 alkyl, C1-C6 haloalkyl, -S(=O)2CH3 or NR4R5, the C3-C 10 Cycloalkyl, 5-12 heterocyclyl, C1-C6 alkyl, C1-C6 haloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl;

[0071] R4, R5, R6 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3;

[0072] R7 is selected from a 5-6 membered heteroaryl or a benzene ring optionally substituted with 1-3 R9;

[0073] R8 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3;

[0074] R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl;

[0075] L is -X1-X2-X3-X4-X5-X6-;

[0076] X1 is selected from a bond, -C(=O)-, C1-C6 alkylene, C5-C8 monocycloalkyl, C7-C 12 Spiroalkyl, 7-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group or 3-8 membered monoheterocyclic group; the C5-C8 monocycloalkyl, C7-C 12 Spirocycloalkyl, 7-12 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl or 3-8 membered monoheterocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, -C(O)NH2, hydroxyl or halogen;

[0077] X2 is selected from a bond, -C(=O)- or C1-C6 alkylene;

[0078] X3, X4, X5, X6 are each independently selected from a bond, a 3-12 membered heterocyclic group, a C1-C6 alkylene group, a C3-C 10 Cycloalkyl, -O-, -NR2- or -C(=O)-; X1, X2, X3, X4, X5, and X6 are not all bonds;

[0079] Ring E1 is selected from

[0080] R e is selected from halogen, methyl, methoxy or trifluoromethyl;

[0081] m, s, and p are selected from 0, 1, or 2.

[0082] In some preferred embodiments, the compound of formula (I) has the structure shown in formula (II):

[0083] in,

[0084] W1, W2, W3 are each independently selected from C or N;

[0085] D is selected from a bond, -CR1R1'-, -S-, -O- or -NR2-(CH2) m -;

[0086] Ring B is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl or C3-C6 cycloalkyl;

[0087] R b2 is selected from 4-6 membered heterocyclyl, -C(=O)-R3, -NR4R5, -S(=O)2R3 or -NR6-C(=O)-R7; the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R8;

[0088] R1, R1', R c , R2 are each independently selected from H, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy or C1-C6 alkyl;

[0089] R3 are each independently selected from C3-C 10 Cycloalkyl, 5-12 heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -S(=O)2CH3 or NR4R5, the C3-C 10 Cycloalkyl, 5-12 heterocyclyl, C1-C6 alkyl, C1-C6 haloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl;

[0090] R4, R5, R6 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3;

[0091] R7 is selected from a 5-6 membered heteroaryl or a benzene ring optionally substituted with 1-3 R9;

[0092] R8 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3;

[0093] R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl;

[0094] L is -X1-X2-X3-X4-X5-X6-;

[0095] X1 is selected from a bond, -C(=O)-, C1-C6 alkylene, C5-C8 monocycloalkyl, C7-C 12 Spiroalkyl, 7-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group or 3-8 membered monoheterocyclic group; the C5-C8 monocyclic alkyl, C7-C 12 Spirocycloalkyl, 7-12 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl or 3-8 membered monoheterocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, -C(O)NH2, hydroxyl or halogen;

[0096] X2 is selected from a bond, -C(=O)- or C1-C6 alkylene;

[0097] X3, X4, X5, X6 are each independently selected from a bond, a 3-12 membered heterocyclic group, a C1-C6 alkylene group, a C3-C 10 Cycloalkyl, -O-, -NR2- or -C(=O)-; X1, X2, X3, X4, X5, and X6 are not all bonds;

[0098] Ring E1 is selected from

[0099] R e is selected from halogen, methyl, methoxy or trifluoromethyl;

[0100] m, s, and p are selected from 0, 1, or 2.

[0101] In some preferred embodiments, in the compounds of formula (I) and formula (II), ring B is selected from a benzene ring, a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group or a C3-C6 cycloalkyl; preferably, ring B is selected from W3 is selected from C or N; further preferably, ring B is selected from More preferably, ring B is selected from Still further preferably, ring B is selected from *Indicates the location of attachment to D.

[0102] In some preferred embodiments, in the compounds of the above formula (I) and formula (II), D is selected from a bond, -NH-, -N(CH3)- or -NH-CH2-; preferably selected from a bond, -NH- or -N(CH3)-.

[0103] In some preferred embodiments, in the compound of formula (II), D is selected from a bond, and ring B is selected from Preferably *Indicates the location of attachment to D.

[0104] In some preferred embodiments, in the compound of formula (II), D is selected from -NR2-(CH2)m -; Ring B is selected from Preferably *Indicates the location of attachment to D.

[0105] In some preferred embodiments, in the compound of formula (II), R b2 Selected from -C(=O)-R3, -NR4R5 or -S(=O)2R3; further preferably, R b2 Selected from -NH2, -NH-S(=O)2CH3 or -S(=O)2CH3.

[0106] In some preferred embodiments, in the compound of formula (II), R b2 Selected from or -S(=O)2CH3; or selected from -C(=O)OCH3 or -S(=O)2CH3.

[0107] In some preferred embodiments, in the compound of formula (II) above, D is selected from a bond, -NH-, -N(CH3)- or -NH-CH2-, preferably selected from a bond, -NH- or -N(CH3)-;

[0108] W1, W2, W3 are each independently selected from C or N;

[0109] Ring B is selected from Preferably selected from * indicates the location of attachment to D;

[0110] R b2 Selected from or -S(=O)2CH3; or selected from -C(=O)OCH3 or -S(=O)2CH3;

[0111] Ring E1 is selected from

[0112] L is selected from * Indicates the location attached to Y.

[0113] In some preferred embodiments, in the compound of formula (II) above, D is selected from a bond, -NH-, -N(CH3)- or -NH-CH2-, preferably selected from a bond, -NH- or -N(CH3)-;

[0114] W1, W2, W3 are each independently selected from C or N;

[0115] Ring B is selected from Preferably selected from * indicates the location of attachment to D;

[0116] R b2 Selected from or -S(=O)2CH3; or selected from -C(=O)OCH3 or -S(=O)2CH3;

[0117] Ring E1 is selected from

[0118] L is selected from * Indicates the location attached to Y.

[0119] In some preferred embodiments, in the compound of formula (II) above, D is selected from a bond, -NH- or -N(CH3)-;

[0120] W1 and W2 are C;

[0121] W3 is selected from C or N;

[0122] Ring B is selected from * indicates the location of attachment to D;

[0123] R b2 Selected from or -C(=O)OCH3;

[0124] Ring E1 is selected from Preferably selected from * indicates the location where and is attached to L;

[0125] L is selected from * Indicates the location attached to Y.

[0126] In some preferred embodiments, the present application provides compounds represented by the following formulae (I-1) to (I-4), pharmaceutically acceptable salts thereof, deuterated derivatives thereof, stereoisomers thereof, tautomers thereof, or mixtures thereof:

[0127] wherein W4 is selected from C or N;

[0128] W1, W2, W3, R c , R2, R b2 、R e 、R a , R7, Ring B, L, Y, Ring E1, m, p, q, and s are as defined in any one of the above items.

[0129] In some embodiments, in the compounds of formula (I), formula (II), and formula (I-1)-(I-4), L is -X1-X2-X3-X4-X5-X6- * ; * represents the location attached to Y; where

[0130] X1 is selected from a bond, -C(=O)-, C1-C6 alkylene, C5-C8 monocycloalkyl, C7-C 12 Spiroalkyl, 7-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group or 3-8 membered monoheterocyclic group; the C5-C8 monocyclic alkyl, C7-C 12 Spirocycloalkyl, 7-12 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl or 3-8 membered monoheterocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, -C(O)NH2, hydroxyl or halogen; preferably, X1 is selected from a bond, -C(=O)- or a 3-6 membered monoheterocyclyl;

[0131] X2 is selected from a bond, -C(=O) or C1-C3 alkylene; preferably, X2 is selected from a bond, -C(=O) or C1-C2 alkylene;

[0132] X3, X4, X5, and X6 are each independently selected from a bond, a 4-6 membered heterocyclic group, a C1-C3 alkylene group, a C3-C6 cycloalkyl group, -O-, -NH-, or -C(=O)-; not all of X1, X2, X3, X4, X5, and X6 are bonds.

[0133] In some preferred embodiments, in the compounds of formula (I), formula (II), and formula (I-1)-(I-4), L is selected from

[0134] In some more preferred embodiments, in the compounds of formula (I), formula (II), and formula (I-1)-(I-4), L is selected from Preferably selected from * Indicates the position of attachment to Y or loop E1.

[0135] In some preferred embodiments, in the compound of formula (I), ring A is selected from * indicates the position of attachment to D, provided that: when ring A is selected from Y is

[0136] R aSelected from C1-C3 alkyl or C(=O)-NH2, preferably selected from -CH3 or C(=O)-NH2;

[0137] D is selected from a bond, -NH-, -N(CH3)- or -NH-CH2-, preferably selected from a bond, -NH- or -N(CH3)-;

[0138] W1 and W2 are each independently selected from C or N;

[0139] Ring B is selected from * indicates the location of attachment to D;

[0140] R b1 Selected from C1-C3 alkyl or halogen, preferably selected from -CH3 or F;

[0141] R b2 Selected from or -S(=O)2CH3, or selected from -C(=O)OCH3 or -S(=O)2CH3;

[0142] q is selected from 0, 1 or 2;

[0143] Y is selected from

[0144] L is selected from * Indicates the location attached to Y.

[0145] In some preferred embodiments, for any of the above compounds, pharmaceutically acceptable salts, deuterated substances, stereoisomers, tautomers or mixtures thereof, the compound is selected from but not limited to:

[0146] Another object of the present application is to provide the use of any of the above-mentioned compounds, their pharmaceutically acceptable salts, deuterated substances, stereoisomers, tautomers, or mixtures thereof in the preparation of drugs for preventing and / or treating diseases or conditions mediated by the degradation of Bruton's tyrosine kinase (BTK).

[0147] Alternatively, another object of the present application is to provide a compound of any one of the above, a pharmaceutically acceptable salt thereof, a deuterated substance, a stereoisomer thereof, a tautomer thereof, or a mixture thereof for preventing and / or treating a disease or condition mediated by degradation of Bruton's tyrosine kinase (BTK). Alternatively, another object of the present application is to provide a method for preventing and / or treating a disease or condition mediated by degradation of Bruton's tyrosine kinase (BTK), comprising administering to a subject in need thereof a preventive and / or therapeutically effective amount of a compound of any one of the above, a pharmaceutically acceptable salt thereof, a deuterated substance, a stereoisomer thereof, a tautomer thereof, or a mixture thereof. In this article, the preventive and / or therapeutically effective amount refers to an amount sufficient to prevent, improve, inhibit, postpone, or slow the progression of a disease or condition mediated by degradation of Bruton's tyrosine kinase (BTK), which can be determined by a clinician based on the severity of the disease, the patient's physical condition, age, sex, weight, etc.

[0148] In this article, the disease or condition mediated by degradation of Bruton's tyrosine kinase (BTK) refers to a disease or condition or its related symptoms that can achieve clinically beneficial therapeutic effects such as alleviation, improvement, cessation of progression, alleviation or no longer worsening by degradation of Bruton's tyrosine kinase (BTK).

[0149] In some embodiments, the disease or disorder is cancer or an autoimmune disease.

[0150] In some preferred embodiments, the cancer is a hematological cancer selected from, but not limited to, B-cell lymphoma, myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hairy cell leukemia, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, or follicular lymphoma.

[0151] In some preferred embodiments, the cancer is B-cell lymphoma, chronic lymphocytic leukemia, a myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hairy cell leukemia, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, or follicular lymphoma.

[0152] In some more preferred embodiments, the cancer is B-cell lymphoma.

[0153] In some preferred embodiments, the autoimmune diseases include inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, Aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, immune thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvodynia, and chronic graft-versus-host disease.

[0154] It should be noted that any of the above implementation plans of this application can be freely combined to form a new technical solution. DETAILED DESCRIPTION

[0155] In order to make the present application easier to understand, the present application will be described in detail below with reference to embodiments. These embodiments are merely illustrative and do not limit the scope of application of the present application.

[0156] Terms and Definitions:

[0157] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this application belongs. As used herein, the following terms have the meanings ascribed to them below unless otherwise indicated.

[0158] The term "substituted" herein refers to the replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom with a selection from the indicated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. It should be understood that other atoms, such as hydrogen atoms or substituents as described herein, may be present as needed to satisfy the valence of the atoms.

[0159] The term "independently" or "each independently" means that when more than one substituent (such as R1, R2) is selected from many possible substituents, those substituents (such as R1, R2) may be the same or different, and when the same substituent (such as R3) appears multiple times at the same time, it means that the substituent (such as R3) can be independently selected from the same or different substituents each time it appears.

[0160] Whenever a group is described as "optionally" or "optionally" the group may be unsubstituted or substituted with one or more substituents as indicated. If no substituents are specified, it means that the group may be optionally substituted with one or more groups selected from, but not limited to, deuterium, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, nitro, amino, aminohydroxyl; preferably deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, F, Cl, Br, hydroxyl, C1-C6 alkoxy, cyano, amino, C6 ... 10 The alkyl group is substituted with an aryl group, a 3-6 membered heterocyclic group, a 5-10 membered heteroaryl group or a C1-C6 hydroxyalkyl group.

[0161] The term "alkyl" appearing alone or in combination in this application refers to a straight or branched saturated hydrocarbon group consisting solely of carbon atoms and hydrogen atoms (including deuterium atoms), including, but not limited to, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, and C1 alkyl (including deuterated C1-C6 alkyl, deuterated C1-C5 alkyl, deuterated C1-C4 alkyl, deuterated C1-C3 alkyl, deuterated C1-C2 alkyl, and deuterated C1 alkyl). As non-limiting examples of alkyl, the following straight or branched saturated hydrocarbon groups can be cited: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and its other seven isomers, n-hexyl and its other sixteen isomers. For example, "C1-C6 alkyl" includes methyl, C1-C3, ethyl, propyl, butyl, pentyl, hexyl and all isomers thereof. The C1-C6 alkyl may be substituted with an optional substituent.

[0162] The term "haloalkyl" in this application refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen substituent, such as F or Cl. For example, "C 1- Non-limiting examples of "C6 haloalkyl" include, but are not limited to, -CF3, -CHF2, -CHCF2, -CH2CH2F, -CH2CF3.

[0163] The term "alkoxy" appearing alone or in combination herein refers to an "-O-alkyl" group, including deuterated alkoxy. Alkoxy herein includes, but is not limited to, C1-C6 alkoxy, C1-C5 alkoxy, C1-C4 alkoxy, C1-C3 alkoxy, C1-C2 alkoxy, and C1 alkoxy (including deuterated C1-C6 alkoxy, deuterated C1-C5 alkoxy, deuterated C1-C4 alkoxy, deuterated C1-C3 alkoxy, deuterated C1-C2 alkoxy, and deuterated C1 alkoxy). For example, the term "C1-C3 alkoxy" represents a saturated, straight-chain or branched hydrocarbon moiety having at least 1 and up to 3 carbon atoms, bound by an oxygen linker atom. Specific exemplary embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy (including deuterated methoxy, deuterated ethoxy, deuterated n-propoxy, deuterated isopropoxy, deuterated n-butoxy, deuterated sec-butoxy, and deuterated tert-butoxy), etc. The "alkoxy" may be substituted with an optional substituent, for example, non-limiting examples of substitutions with F or Cl include -OCF3, -OCF2, etc.

[0164] The term "haloalkoxy" in this application refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen substituent, such as F or Cl. For example, "C 1- Non-limiting examples of "C6 haloalkoxy" include, but are not limited to, -OCF3, -OCHF2, -OCHCF2, -OCH2CH2F, -OCH2CF3.

[0165] The term "cycloalkyl" as used herein, alone or in combination, refers to a saturated monocyclic or polycyclic (such as spirocyclic, fused or bridged) hydrocarbon ring. For example, the term "C3-C 12 "Cycloalkyl" refers to a saturated monocyclic or polycyclic ring having 3 to 12 ring carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, which may be optionally substituted with one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl, etc. "Monocycloalkyl" and "spirocycloalkyl" appearing in this application are all cycloalkyl.

[0166] The term "heterocyclyl" as used herein, alone or in combination, refers to a monocyclic, bicyclic, or tricyclic group composed of carbon atoms and one or more heteroatoms, wherein the cyclic group may be saturated, partially unsaturated (non-aromatic), or fully unsaturated (aromatic), wherein the heteroatoms may be heteroatoms selected from N, S, or O as ring members, or one or two -CH2- groups in the ring may be substituted by one or two -C(=O)- or -C(=S)- groups. Specific non-limiting examples include: The heterocyclic group described herein includes a "spiro heterocyclic group", a "bridged heterocyclic group", a "fused heterocyclic group" and a "monoheterocyclic group".

[0167] The term "heteroaryl" as used herein, alone or in combination, refers to a monocyclic or fused polycyclic monovalent group having aromatic properties, wherein at least one (e.g., 1, 2, 3, or 4) ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are C. Specific non-limiting examples include, but are not limited to, The heteroaryl groups described herein include "spiroheteroaryl", "bridged heteroaryl", "fused heterocyclic group" and "monocyclic aryl".

[0168] As used herein, the term "aryl" alone or in combination refers to an aromatic hydrocarbon radical having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aromatic radicals having multiple carbon atoms. Additionally, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together, non-limiting examples of which include phenyl, naphthyl, or tetrahydronaphthyl.

[0169] The term "halogen" herein refers to F, Cl, Br or I.

[0170] The term "hydroxyl" herein refers to an -OH group.

[0171] The term "amino" in this application refers to a -NH2 group, which may be substituted or unsubstituted. When expressed as a substituted amino group, it is -N(R") n , wherein R" is an independently optional suitable substituent (such as any substituent defined above).

[0172] The term "cyano" as used herein refers to a -CN group.

[0173] The term "nitro" as used herein refers to a -NO2 group.

[0174] The term "hydroxyalkyl" herein refers to an alkyl group in which at least one hydrogen atom is replaced by a hydroxy group. For example, "C1-C6 hydroxyalkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms in which at least one hydrogen atom is replaced by -OH. Non-limiting examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, and -C(CH3)3OH.

[0175] The alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclic group, and carbocyclic group mentioned above in the present application may be optionally substituted by one or more substituents.

[0176] Unless otherwise indicated, "hetero" and "heteroatom" herein refer to atoms other than carbon or hydrogen, including, but not limited to, O, S, and N. In this document, heteroaryl and heterocyclic groups may contain one or more (e.g., 1-3, 1-2) heteroatoms.

[0177] The term "nitrogen protection" in this application means connecting the reaction bottle to a 1 L nitrogen balloon.

[0178] Unless otherwise specified in the present application, the solution mentioned in the reaction of the present application is an aqueous solution.

[0179] The term "room temperature" in this application refers to a temperature between 10°C and 25°C.

[0180] The intermediates involved in this application can be purchased from commercial sources or prepared according to known methods disclosed in the prior art.

[0181] When referring to a compound in this application, all isomeric forms of the structure are included, such as stereoisomers (including enantiomers and diastereomers), geometric isomers (or conformational isomers), and tautomeric forms. The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular asymmetry plane due to at least one chiral factor (including a chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane-polarized light; the term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. For example, proton tautomers (or prototropic tautomers) include (but are not limited to) interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and amide-iminoalcohol isomerization; the term "cis-trans isomer" refers to stereoisomers formed by the different positions of atoms (or groups) on either side of a double bond or ring system relative to a reference plane; in cis isomers, the atoms (or groups) are on the same side of the double bond or ring system, while in trans isomers, the atoms (or groups) are on opposite sides of the double bond or ring system.

[0182] In addition, the compounds of the present invention may also contain unnatural proportions of atomic isotopic forms at one or more atoms constituting these compounds, i.e., hydrogen isotopic forms of D or T, or isotopes of any atoms, such as all isotopic forms of C and N. Specifically, radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14C) Radiolabeled compounds. All isotopic variations of the compounds of the optional structures described herein, whether or not radioactive, are encompassed within the scope of protection of this application. In particular, this application includes deuterated forms of hydrogen at any position in the compounds of the general formula described herein, including hydrogen on substituent groups.

[0183] The words "comprise," "include," and "contain" and their equivalents are to be understood as open, non-exclusive, meaning "including but not limited to," meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be encompassed. Unless otherwise indicated, all numbers used herein to represent amounts of ingredients, measurements, or reaction conditions are to be understood as being modified in all cases by the term "about." When associated with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%. Unless the context clearly indicates otherwise, singular terms herein encompass plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" herein is intended to include "and."

[0184] All patents, patent applications, and other publications are expressly incorporated herein by reference for the purposes of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements regarding the dates of these documents or the representation of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents.

[0185] Example

[0186] The present invention is described in detail below by way of examples, but this does not necessarily limit the scope of protection of the present invention. It will be apparent to those skilled in the art that various changes and modifications will be made to the present invention without departing from the spirit and scope of the present invention. Unless otherwise indicated, the reagents, materials, etc. mentioned in the following examples are those commercially available in this area.

[0187] Example 1: N-(3-(5-((5-((2S)-4-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)-2-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide

[0188] The preparation scheme is shown in the figure below:

[0189] Step 1: Preparation of methyl 4-(chlorocarbonyl)-3-fluorobenzoate (Intermediate 2)

[0190] To a solution of 2-fluoro-4-(methoxycarbonyl)benzoic acid (1100 mg, 5.55 mmol) and thionyl chloride (6.5 mL) was added dropwise N,N-dimethylformamide (0.05 mL). The reaction mixture was warmed to 80°C and stirred for 2 h. The reaction solution was concentrated to dryness under reduced pressure to afford crude Intermediate 2 (1200 mg, colorless oil), which was used directly in the next reaction.

[0191] Step 2: Preparation of methyl 4-((3-bromo-5-fluoro-2-methylphenyl)carbamoyl)-3-fluorobenzoate (Intermediate 4)

[0192] To a solution of 3-bromo-5-fluoro-2-methylaniline (1360 mg, 6.66 mmol) in tetrahydrofuran (25 mL) were added N,N-diisopropylethylamine (3590 mg, 27.76 mmol) and Intermediate 2 (1200 mg, 5.54 mmol). The resulting mixture was stirred at 25°C for 1 h. The reaction mixture was spin-dried and purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 30-70%) to afford Intermediate 4 (1300 mg, white solid) in a yield of 60.9%.

[0193] LC-MS: m / z[M+H] + =385.8.

[0194] Step 3: Preparation of N-(3-bromo-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide (Intermediate 5)

[0195] To a solution of intermediate 4 (1300 mg, 3.38 mmol) in tetrahydrofuran (30 mL) was added methylmagnesium bromide (3.38 mL, 10.14 mmol, 3 M tetrahydrofuran solution) dropwise at 0°C. The mixture was stirred at 0°C for 0.5 h, then the reaction mixture was warmed to 60°C and stirred for 16 h. The mixture was poured into a saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 10-50%) to obtain intermediate 5 (1897 mg, yellow solid) in a yield of 73.81%.

[0196] LC-MS: m / z[M+H] + =385.8.

[0197] Step 4: Preparation of (S)-4-(6-((5-(5-(2-fluoro-4-(2-hydroxypropyl-2-yl)benzamido)-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-3-yl]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (Intermediate 6)

[0198] To a solution of Intermediate 5 (1200 mg, 3.12 mmol), Intermediate A (2460 mg, 4.68 mmol), and potassium carbonate (1290 mg, 9.37 mmol) in dioxane (60 mL) and water (12 mL) was added 1,1-bis(diphenylphosphino)diphenylferric palladium(II) chloride (228.6 mg, 0.31 mmol). The reaction system was flushed with nitrogen three times and stirred at 100°C under nitrogen for 3 h. The reaction solution was dried and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10-50%) to afford Intermediate 6 (1350 mg, purple solid) in a 61.5% yield.

[0199] LC-MS: m / z[M+H] + =703.2.

[0200] The preparation of intermediate A follows the method disclosed in patent WO2021091575.

[0201] Step 5: Preparation of (S)-2-fluoro-N-(5-fluoro-2-methyl-3-(1-methyl-5-((5-(2-methylpiperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide (Intermediate C)

[0202] To a solution of Intermediate 6 (700 mg, 0.99 mmol) in dichloromethane (9 mL) was added trifluoroacetic acid (3 mL), and the resulting mixture was stirred at 25° C. for 1 h. The reaction solution was concentrated under reduced pressure to give a crude product of Intermediate C (600 mg, brown solid).

[0203] LC-MS: m / z[M+H] + =603.2.

[0204] Step 6: Preparation of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (Compound B-2)

[0205] To a solution of 5-bromo-1,3-difluoro-2-iodobenzene (4000 mg, 12.50 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5200 mg, 12.50 mmol), and potassium phosphate (5300 mg, 25.00 mmol) in dioxane (40 mL) and water (8 mL) was added 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (917 mg, 1.25 mmol). The mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 16 h. The reaction mixture was dried and purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 0-5%) to afford compound B-2 (3500 mg, colorless oil) in a yield of 58.1%.

[0206] LC-MS: m / z[M+H] + =483.8.

[0207] Step 7: Preparation of (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methanol (Compound B-3).

[0208] To a solution of compound D-2 (600 mg, 1.24 mmol) and azetidin-3-ylmethanol (185 mg, 1.49 mmol) in 1,4-dioxane (20 mL) were added cesium carbonate (1620 mg, 4.97 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (116 mg, 0.25 mmol), and tris(dibenzylideneacetone)dipalladium (114 mg, 0.12 mmol). The mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 16 h. The reaction mixture was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10%-50%) to obtain compound D-3 (475 mg, yellow solid) in a yield of 78.4%.

[0209] LC-MS: m / z[M+H] + =489.0.

[0210] Step 8 Preparation of 3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine-2,6-dione (Compound B-4)

[0211] To a solution of compound B-3 (475 mg, 0.97 mmol) in 1,4-dioxane (15 mL) were added 10% Pd / C (150 mg) and palladium hydroxide on carbon (150 mg). The resulting mixture was purged with hydrogen three times and then stirred at 50°C under hydrogen protection for 16 h. The reaction solution was filtered through a pad of celite, the filter cake was washed with methanol (20 mL x 3), and the filtrate was concentrated to dryness under reduced pressure to obtain compound B-4 (237 mg, blue solid) in a yield of 78.7%.

[0212] LC-MS: m / z[M+H] + =310.8.

[0213] Step 9: Preparation of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde (Intermediate B)

[0214] To a solution of compound B-4 (237 mg, 0.76 mmol) in dimethyl sulfoxide (100 mL) was added 2-iodoacetylbenzoic acid (428 mg, 1.53 mmol), and the reaction was stirred at 50°C for 1 h. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 10%-50%) to obtain intermediate B (160 mg, yellow solid) in a yield of 68.2%.

[0215] LC-MS: m / z[M+H] + =308.8.

[0216] Step 10: Preparation of N-(3-(5-((5-((2S)-4-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)-2-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2-yl)benzamide (Example 1)

[0217] To Intermediate C (60 mg, 0.08 mmol) in dichloromethane (1 mL) were added Intermediate B (39.7 mg, 0.13 mmol) and triethylamine (34.8 mg, 0.34 mmol), and the mixture was stirred at 25°C for 16 h. Sodium triacetoxyborohydride (45.6 mg, 0.21 mmol) was then added to the reaction system, and the mixture was stirred at 25°C for 1 h. The crude product was purified on a silica gel preparative plate (developing solvent: 100% ethyl acetate) to afford Example 1 (16.10 mg of a purple solid) in a 20.9% yield.

[0218] LC-MS: m / z[M+H] + =895.4.

[0219] 1 HNMR(400MHz, CDCl3)δ8.62-8.54(m,1H),8.47-8.48(m,1H),8.17-8.21(m,1H),8.04-8.08(m,1H),8.00(s,1H),7.93-7.94(m,1H), 7.83(s,1H),7.42(s,1H),7.40-7.36(m,1H),7.28-7.29(m,1H),6.83-6.86(m,1H),6.80-6.75(m,2H),5.94(d,J=10.4Hz,2H),4.01 -3.90(m,3H),3.68(s,3H),3.54(s,2H),3.46(s,1H),3.02-3.04(m,2H),2.99-2.92(m,1H),2.77-2.78(m,1H),2.69-2.58(m,5H),2 .52-2.53(m,1H),2.32-2.36(m,1H),2.27(s,3H),2.17-2.06(m,1H),1.92(s,1H),1.61(s,6H),1.25(s,1H),0.96(d,J=6.4Hz,3H).

[0220] Example 2: N-(3-(5-((5-(2S)-4-((1s,3R)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethoxy)cyclobutane-1-carbonyl)-2-methylpiperazin-1-yl)pyridin-2-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide

[0221] The preparation scheme is shown in the figure below:

[0222] To a solution of Intermediate C (86 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) at room temperature were added Intermediate D (59 mg, 0.14 mmol) and N,N-diisopropylethylamine (54 mg, 0.42 mmol), followed by 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80 mg, 0.21 mmol). The resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into water, and the precipitate was collected and dried to obtain the crude product. The crude product was purified by preparative thin layer chromatography (developing solvent: petroleum ether / EE (ethyl acetate / ethanol = 3:1) / methanol / dichloromethane = 38 / 12 / 45 / 5) to obtain Example 2 (29.14 mg, yellow solid) in a yield of 20.8%.

[0223] LC-MS: m / z[M+H] + =1000.4.

[0224] 1 HNMR(400MHz,DMSO-d6)δ11.12(s,1H),9.94(s,1H),8.66-8.35(m,2H),7.86(s,1H),7.73-7.6 2(m,1H),7.65-7.58(m,1H),7.45-7.42(m,4H),7.28-7.18(m,2H),7.16-7.10(m,1H),7.06-7.0 1(m,2H),6.62(s,1H),5.33(s,1H),5.10-5.08(m,1H),3.95(m,1H),3.62(s,4H),3.55-3.46(m, 5H),3.09-2.87(m,7H),2.36(s,3H),2.23(s,3H),2.11-2.04(m,3H),1.49(s,6H),0.82(m,4H).

[0225] The preparation of intermediate D follows the method disclosed in patent WO2021091575.

[0226] Example 3: 3-((4-(1-(2-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)acetyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0227] The preparation scheme is shown in the figure below:

[0228] To a solution of Intermediate E (59 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) were added N,N-diisopropylethylamine (64 mg, 0.50 mmol), PyBop (104 mg, 0.20 mmol), and Intermediate F (40 mg, 0.11 mmol), and the mixture was stirred at 25°C for 1 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel prep plate (developing solvent: methanol:dichloromethane = 1:10) to obtain Example 3 (21.77 mg as a white solid) in a yield of 26.6%.

[0229] LC-MS: m / z [M+H] + = 818.4.

[0230] 1 HNMR(400MHz,DMSO-d6)δ11.16-11.18(m,2H),7.79-7.77(m,3H),7.66(s,1H),7.51 -7.49(m,2H),7.32(s,1H),7.16-7.14(m,2H),5.21-5.06(m,1H),4.54-4.52(m,1H) ,4.32-4.30(m,2H),4.13(s,4H),3.78-3.49(m,3H),3.26-3.24(m,2H),3.15-2.81( m,5H),2.66-2.64(m,7H),2.07(s,1H),1.80(s,5H),1.51-1.49(m,4H),1.23(s,1H).

[0231] The preparation of intermediate E was carried out according to the method disclosed in WO2021113557.

[0232] The preparation of intermediate F was carried out according to the method published in J. Med. Chem. 2023, 66, 17, 12559-12585.

[0233] Example 4: 3-((4-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0234] The preparation scheme is shown in the figure below:

[0235] To a solution of Intermediate E (130 mg, 0.23 mmol) in dichloromethane (8 mL) were added Intermediate B (84 mg, 0.27 mmol) and triethylamine (92 mg, 0.91 mmol), and the reaction mixture was stirred at 25°C for 16 h. Sodium triacetoxyborohydride (121 mg, 0.57 mmol) was then added to the reaction system, and the mixture was stirred at 25°C for 1 h. The crude product was purified on a silica gel preparative plate (developing solvent: methanol:dichloromethane = 1:10) to afford Example 4 (11.16 mg, white solid) in a 6.3% yield.

[0236] LC-MS: m / z[M+H] + =771.4.

[0237] 1 HNMR(400MHz,DMSO-d6)δ11.19(s,1H),10.87(s,1H),7.77(s,1H),7.66(s,1H),7.49(d,J=8.4Hz,2H),7.3 4(s,1H),7.16(d,J=8.4Hz,2H),6.13-6.11(m,2H),4.33-4.30(m,2H),4.04-4.00(m,1H),3.96-3.92(m,2H) ,3.60(m,1H),3.51-3.46(m,3H),3.27(m,4H),3.08-3.00((m,1H),3.00-2.86(m,4H),2.76(m,1H),2.71(s, 3H),2.58(m,2H),2.40(m,1H),2.06-2.02(m,3H),1.98-1.89(m,1H),1.80-1.76(m,5H),1.61-1.57(m,3H).

[0238] Example 5: 4-((5-((2S)-4-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)-2-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-1H-pyrazole-3-carboxamide

[0239] The preparation scheme is shown in the figure below:

[0240] Step 1: Preparation of ethyl 2-[(1Z)-2-(3-bromo-5-fluoro-2-methylphenyl)diazolylidene]-2-chloroacetate (Compound 2)

[0241] To a solution of compound 1 (8300 mg, 40.68 mmol) and hydrochloric acid (33.90 mL, 203.39 mmol) in ethanol (90 mL) and water (10 mL) was added dropwise sodium nitrite (3367.67 mg, 48.81 mmol) in water (10 mL) at -5-5°C, and the reaction mixture was stirred at -5-5°C for 0.5 h. To a solution of ethyl 2-chloro-3-oxobutanoate (6695.24 mg, 40.68 mmol) and sodium acetate trihydrate (38748.52 mg, 284.75 mmol) in ethanol (90 mL) and water (10 mL) was added dropwise at -5-5°C, and the mixture was stirred at 25°C for 1.5 h. The reaction mixture was added to water (1000 mL) and filtered, and the filter cake was dried under reduced pressure to obtain compound 2 (12.25 g, red solid) in a yield of 89.21%.

[0242] LC-MS: m / z[M+H] + =337.

[0243] Step 2: Preparation of ethyl 1-(3-bromo-5-fluoro-2-methylphenyl)-4-nitropyrazole-3-carboxylate (Compound 3)

[0244] To a solution of compound 2 (12.25 g, 36.29 mmol) and triethylamine (10.06 mL, 72.58 mmol) in chloroform (70 mL) was added dimethyl[(1E)-2-nitrovinyl]amine (4.21 g, 36.29 mmol), the mixture was degassed and replaced with nitrogen 3 times, and stirred at 70 ° C under nitrogen protection for 18 h. The reaction mixture was added to water (300 mL) and extracted with dichloromethane (150 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude product. The mixture was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10: 1) to obtain compound 3 (2.65 g, orange solid) in a yield of 19.62%.

[0245] LC-MS: m / z[M+H] + =372.

[0246] Step 3: Preparation of ethyl 1-[5-fluoro-2-methyl-3-({[(2-methylprop-2-yl)oxy]carbonyl}amino)phenyl]-4-nitropyrazole-3-carboxylate (Compound 4)

[0247] To a solution of compound 3 (2500 mg, 6.72 mmol), tert-butyl carbamate (1023.08 mg, 8.73 mmol), and cesium carbonate (4377.54 mg, 13.44 mmol) in dioxane (30 mL) were added 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (480.38 mg, 1.01 mmol) and tris(dibenzylideneacetone)dipalladium (24.61 mg, 0.03 mmol) at room temperature. The reaction mixture was stirred at 100°C under nitrogen overnight to yield a black suspension. The reaction mixture was filtered and concentrated. The crude product was isolated and purified using a silica gel column (petroleum ether with 2-10% ethyl acetate) to afford compound 4 (2480 mg, yellow solid) in a yield of 90.5%.

[0248] LC-MS: m / z[M+Na] + =431.2

[0249] Step 4: Preparation of 1-(3-amino-5-fluoro-2-methylphenyl)-4-nitropyrazole-3-carboxylic acid ethyl ester (Compound 5)

[0250] To a solution of compound 4 (2480 mg, 6.07 mmol) in 1,4-dioxane (15 mL) was added 1,4-dioxane hydrochloride (15 ml), and the resulting mixture was stirred at 25°C for 2 h to obtain a yellow solution. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude compound 5 (1270 mg, yellow solid) in a yield of 67.84%.

[0251] LC-MS: m / z[M+H] + =309.2.

[0252] Step 5: Preparation of ethyl 1-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-4-nitro-1H-pyrazole-3-carboxylate (Compound 6)

[0253] To a solution of compound 5 (450 mg, 1.46 mmol) and intermediate G (318.24 mg, 1.61 mmol) in 1-butylphosphonic anhydride (8 mL) was added triethylamine (0.51 mL, 3.65 mmol) at room temperature. The reaction mixture was heated in a microwave oven at 80°C under nitrogen for 1 h to yield a yellow, clear liquid. The reaction mixture was diluted with ethyl acetate (60 mL) and washed sequentially with water (20 mL) and saturated sodium bicarbonate (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified using a silica gel column (petroleum ether with 20-50% ethyl acetate) to yield compound 6 (180 mg, yellow oil) in a yield of 25.24%.

[0254] LC-MS: m / z[M+Na] + =511.2.

[0255] The preparation of intermediate G follows the method published in J.Med.Chem.2020, 63, 5102-5118.

[0256] Step 6: Preparation of 1-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropyl-2-yl)benzamido)-2-methylphenyl)-4-nitro-1H-pyrazole-3-carboxamide (Compound 7)

[0257] Compound 6 (180 mg, 0.37 mmol) was dissolved in NH3-MeOH (7N, 4 mL) at room temperature. The reaction mixture was stirred at 60°C for 6 h to yield a yellow solution. The reaction mixture was concentrated to afford compound 7 (130 mg, white solid) in a yield of 76.79%. The crude product was used directly in the next step.

[0258] LC-MS: m / z[M+Na] + =482.2.

[0259] Step 7: Preparation of 4-amino-1-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-1H-pyrazole-3-carboxamide (Compound 8)

[0260] Iron powder (63.20 mg, 1.13 mmol) was added to a solution of compound 7 (130 mg, 0.28 mmol) and ammonium chloride (151.36 mg, 2.83 mmol) in ethanol (4 mL) and water (2 mL). The reaction was refluxed for 1 h to yield a black suspension. After completion of the reaction, the reaction solution was filtered and concentrated. The crude product was purified using a silica gel column (petroleum ether with 40-100% ethyl acetate) to afford compound 8 (100 mg, yellow solid) in a yield of 82.29%.

[0261] LC-MS: m / z[M+Na] + =452.2.

[0262] Step 8: Preparation of (S)-tert-butyl 4-(6-((3-carbamoyl-1-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropyl-2-yl)benzamido)-2-methylphenyl)-1H-pyrazol-4-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate (Compound 9)

[0263] To a solution of compound 8 (100 mg, 0.23 mmol), intermediate H (94.39 mg, 0.30 mmol) and cesium carbonate (151.75 mg, 0.47 mmol) in dioxane (4 mL) were added dicyclohexyl(3-ethylpropoxy-2',4',6'-triisopropyl-[1,1'-diphenyl]-2-yl)phosphine (24.91 mg, 0.05 mmol) and (methanesulfonic acid {dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-diphenyl]-2-yl)phosphine} The reaction mixture was refluxed overnight under nitrogen to yield a brown suspension containing 4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (42.78 mg, 0.05 mmol). The mixture was filtered and concentrated. The crude product was purified using a silica gel column (petroleum ether with 40-100% ethyl acetate) to afford compound 9 (90 mg, pale yellow solid) in a 54.84% yield.

[0264] LC-MS: m / z[M+H] + =705.0.

[0265] The preparation of intermediate H follows the method disclosed in patent WO2021091575.

[0266] Step 9: Preparation of (S)-1-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropyl-2-yl)benzamido)-2-methylphenyl)-4-((5-(2-methylpiperazin-1-yl)pyridin-2-yl)amino)-1H-pyrazole-3-carboxamide (Compound 10)

[0267] To a solution of compound 9 (100 mg, 0.14 mmol) in dioxane (4 mL) was added hydrochloric acid-dioxane (3 mL) at room temperature. The reaction mixture was stirred under nitrogen for 2 h to obtain a yellow suspension. After the reaction, the reaction mixture was concentrated to obtain crude compound 10 (90 mg, yellow solid).

[0268] LC-MS: m / z[M+H] + =605.4.

[0269] Step 10: Preparation of (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl methanesulfonate (Intermediate I)

[0270] To a solution of compound B-4 (80 mg, 0.16 mmol) and triethylamine (65.41 μL, 0.47 mmol) in tetrahydrofuran (5 mL) and dichloromethane (5 mL) at 0-25°C was added methanesulfonyl chloride (24.35 μL, 0.31 mmol) in portions. The reaction mixture was stirred at room temperature under nitrogen for 2 h to yield a white suspension. The reaction mixture was diluted with dichloromethane (100 mL), washed sequentially with saturated ammonium chloride solution (20 mL), then with brine (20 mL), dried over anhydrous sodium sulfate, and filtered and concentrated to yield Intermediate I (90 mg, white solid) in a yield of 97.53%. The crude product was used directly in the next step.

[0271] LC-MS: m / z[M+H] + =587.0

[0272] Step 11: Preparation of 3-((4-(1-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-thionemidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (Example 5)

[0273] To a solution of compound 10 (90 mg, 0.15 mmol), potassium iodide (74.12 mg, 0.45 mmol), and N,N-diisopropylethylamine (96.19 mg, 0.74 mmol) was added intermediate I (69.37 mg, 0.18 mmol) at room temperature. The reaction mixture was stirred at 80°C under nitrogen overnight to yield a yellow solution. After the reaction, the reaction mixture was filtered and the mother liquor was collected. The mother liquor was separated and purified using prep-HPLC to yield Example 5 (7 mg, white solid) in a yield of 5.24%.

[0274] LC-MS: m / z[M+H] + =897.3.

[0275] 1HNMR(400MHz,DMSO-d6)δ10.85(s,1H),10.10(d,J=2.0Hz,1H),8.90(s,1H),8.56(s,1H),7.88(d,J=2 .8Hz,1H),7.78(s,1H),7.71(m,1H),7.61(d,J=9.0Hz,1H),7.50(s,1H),7.46-7.33(m,4H),6.95(d,J= 9.0Hz,1H),6.16-6.07(m,2H),5.36-5.29(m,1H),4.04-4.01(m,1H),3.97-3.92(m,2H),3.51(s,4H), 3.04-2.57(m,7H),2.43-2.35(m,3H),2.08(s,3H),2.06-1.87(m,2H),1.45(s,6H),0.90-0.86(m,3H).

[0276] Example 6: (R)-3-((4-(1-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0277] The preparation scheme is shown in the figure below:

[0278] Intermediate E (180 mg, 0.25 mmol) was added to a mixture of Intermediate J (120 mg, 0.32 mmol), HATU (200 mg, 0.53 mmol), N,N-diisopropylethylamine (220 mg, 1.70 mmol), and N,N-dimethylformamide (3 mL) and allowed to react at 20°C for 2 h. The reaction mixture was filtered. Prep-HPLC (acetonitrile:water containing 0.1% formic acid) afforded Example 6 (65 mg, yellow solid) in a 30.71% yield.

[0279] LC-MS: m / z[M+H] + =831.4.

[0280] 1HNMR(400MHz,DMSO-d6)δ11.23(d,J=7.2Hz,1H),10.34(s,1H),7.77(s,1H),7.66(s,1H ),7.56-7.49(m,4H),7.34(s,1H),7.21-7.13(m,3H),6.97(d,J=7.4Hz,1H),6.44(d,J=2 .6Hz,1H),4.53(d,J=7.2Hz,2H),4.34-4.27(m,2H),4.10(s,1H),3.78(m,2H),3.64-3. 58(m,1H),3.32-2.85(m,11H),2.81-2.65(m,8H),2.29-1.97(m,4H),1.93-1.35(m,9H).

[0281] The preparation of intermediate J follows the method disclosed in patent WO2023180388.

[0282] Example 7: 3-((4-(1-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-thioneimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0283] The preparation scheme is shown in the figure below:

[0284] Step 1: Preparation of (R)-3-(3-methyl-2-thionemidazolidin-1-yl)piperidine-1-carboxylic acid benzyl ester (Compound 2)

[0285] At room temperature, benzyl (R)-3-((2-(methylamino)ethyl)amino)piperidine-1-carboxylate (2.5 g, 8.56 mmol) was dissolved in dichloromethane (30 mL), and triethylamine (8.47 g, 85.6 mmol) and N,N'-thiocarbonyldiimidazole (2.28 g, 12.86 mmol) were added. The reaction was stirred at 25 ° C for 2 h. After the reaction was complete, the reaction solution was added with water (50 ml) and dichloromethane (50 ml) and extracted three times, washed once with saturated brine, and the organic phase was collected, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 2 (1.8 g, yellow solid) in a yield of 63%.

[0286] LC-MS: m / z[M+H] + =334.

[0287] Step 2: Synthesis of (R)-1-methyl-3-(piperidin-3-yl)imidazolidine-2-thione (Compound 3)

[0288] Compound 2 (500 mg, 1.49 mmol) was dissolved in 33% hydrobromic acid / acetic acid solution (5 ml) at room temperature. The reaction solution was stirred at 25 degrees Celsius for 2 h. After the reaction was complete, the reaction solution was concentrated to obtain a crude product of compound 3 (300 mg, yellow oil).

[0289] LC-MS: m / z[M+H] + =200.

[0290] Step 3: Synthesis of (R)-tert-butyl 4-(4-((3-carbamoyl-6-(3-(3-methyl-2-thionemidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate (Compound 4)

[0291] Intermediate K (300 mg, 0.69 mmol) and compound 3 (151 mg, 0.76 mmol) were dissolved in dimethyl sulfoxide (5 ml), and N,N-diisopropylethylamine (196 mg, 1.52 mmol) was added. The mixture was stirred at 100°C overnight. After the reaction was complete, water (20 ml) and ethyl acetate (10 ml) were added, and the mixture was extracted three times. The mixture was washed twice with saturated sodium chloride solution. The organic phase was collected and concentrated to dryness. The crude product was separated and purified using a silica gel column (0-80% ethyl acetate in petroleum ether) to obtain compound 4 (250 mg, yellow solid) in a yield of 61%.

[0292] LC-MS: m / z[M+H] + =595.

[0293] The synthesis of intermediate K was carried out according to the method disclosed in WO2021113557.

[0294] Step 4: Synthesis of (R)-5-(3-(3-methyl-2-thionemidazolidin-1-yl)piperidin-1-yl)-3-((4-(piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide (Compound 5)

[0295] Compound 4 (250 mg, 0.42 mmol) was dissolved in a hydrogen chloride-dioxane solution (4 mol / L) (4 ml). The reaction was stirred at 25°C for 2 h. After the reaction was complete, the reaction solution was concentrated to obtain a crude compound 5 (120 mg, yellow oil), which was used directly in the next step.

[0296] LC-MS: m / z[M+H] + =495.

[0297] Step 5: Preparation of 3-((4-(1-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-thionemidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (Example 7)

[0298] Compound 5 (77 mg, 0.23 mmol) and intermediate L (120 mg, 0.21 mmol) were dissolved in a mixed solution of 1,2-dichloroethane (2 ml) and methanol (0.2 ml). After stirring for 30 minutes, sodium triacetylborohydride (74 mg, 0.35 mmol) was added and stirring was continued at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated and purified by prep-HPLC to obtain Example 7 (12 mg, yellow solid) in a yield of 6%.

[0299] LC-MS: m / z[M+H] + =823.

[0300] 1 HNMR(500MHz,DMSO-d6)δ11.20(s,1H),10.84(s,1H),8.69(d,J=8.0Hz,1H),8.31(d,J=3.0Hz,1H),7. 87-7.76(m,2H),7.70(s,1H),7.50(d,J=8.5Hz,2H),7.40(m,1H),7.33(s,1H),7.18(d,J=8.5Hz,2H), 4.80-4.68(m,1H),4.41-4.29(m,3H),3.97-3.91(m,2H),3.68-3.51(m,4H),3.07(s,3H),3.05-2.72( m,7H),2.21-2.15(m,3H),2.04-1.95(m,3H),1.94-1.71(m,9H),2.21-2.15(m,3H),1.27-1.14(m,2H).

[0301] The synthesis of intermediate L was carried out according to the method disclosed in WO2021113557.

[0302] Example 8: N-(3-(5-((5-(2S)-4-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)-2-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methylphenyl)-2,3-difluoro-4-(2-hydroxypropan-2-yl)benzamide

[0303] The preparation scheme is shown in the figure below:

[0304] Step 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Compound 5)

[0305] To a solution of 3-bromo-5-fluoro-2-methylaniline (1.00 g, 4.60 mmol) in 1,4-dioxane (20 mL) were added pinacol diboron (1.53 g, 6.00 mmol), potassium acetate (1.35 g, 13.80 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (336 mg, 0.46 mmol). After nitrogen substitution, the reaction mixture was heated to 100°C and stirred for 3 h. The reaction mixture was dried and mixed with silica gel. Purification by silica gel column chromatography (ethyl acetate:petroleum ether = 0-10%) afforded compound 5 (1.14 g, yellow solid) in a 99.00% yield.

[0306] LC-MS: m / z[M+H] + =251.9.

[0307] Step 2: Preparation of methyl 2,3-difluoro-4-methylbenzoate (Compound 2)

[0308] To a solution of 2,3-difluoro-4-methylbenzoic acid (5.00 g, 29.05 mmol) in methanol (50 mL) was added thionyl chloride (4.15 g, 34.86 mmol), and the reaction mixture was stirred at 25 ° C for 3 h. The reaction solution was spin-dried, and the mixture was added to water (100 mL) and extracted with methyl tert-butyl ether (100 mL x 3). The combined organic phase was washed with saturated aqueous sodium carbonate solution (50 mL x 2), then with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 2 (5.1 g, colorless oil) in a yield of 94.4%.

[0309] LC-MS: m / z[M+H] + =186.8.

[0310] Step 3: Preparation of 2-(2,3-difluoro-4-methylphenyl)propan-2-ol (Compound 3)

[0311] To a solution of compound 2 (2.50 g, 13.43 mmol) in tetrahydrofuran (25 mL) was added methylmagnesium bromide (40.29 mL, 40.29 mmol, 1 M in tetrahydrofuran) at 0 ° C. The reaction mixture was warmed to 25 ° C and stirred for 16 h. The mixture was poured into a saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product of compound 3 (2.50 g, colorless oil).

[0312] LC-MS: m / z [M-H2O+H] + =168.8.

[0313] Step 4: Preparation of 2,3-difluoro-4-(2-hydroxypropyl-2-yl)benzoic acid (Compound 4)

[0314] Potassium permanganate (7.98 g, 50.5 mmol) was added to a solution of compound 3 (2.70 g, 14.4 mmol) in water (33 mL). The reaction mixture was heated to 95°C and stirred for 3 h. The mixture was filtered, and the filtrate was washed with methyl tert-butyl ether (100 mL). The resulting aqueous phase was adjusted to a pH of 2-3 with 2N hydrochloric acid and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 4 (1.1 g, white solid) in a yield of 35.3%.

[0315] LC-MS: m / z[M+H] + =216.8.

[0316] Step 5: Preparation of 2,3-difluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide (Compound 8-6)

[0317] To a solution of compound 4 (794 mg, 3.67 mmol) / HATU (2090 mg, 5.51 mmol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (1420 mg, 11.01 mmol). The resulting mixture was stirred at 25°C for 1 h, followed by the addition of compound 5 (1110 mg, 1.20 mmol). The resulting mixture was stirred at 60°C for 16 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain compound 8-6 (340 mg, white solid) in a yield of 20.6%.

[0318] LC-MS: m / z[M+H] + =450.0.

[0319] Step 6: Preparation of (S)-4-(6-((5-(3-(2,3-difluoro-4-(2-hydroxypropyl-2-yl)benzamido)-5-fluoro-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-3-yl-3-methylpiperazine-1-carboxylic acid tert-butyl ester) (Compound 8)

[0320] To a solution of compound 8-6 (400 mg, 0.89 mmol), compound 7 (427 mg, 0.89 mmol), and potassium carbonate (369 mg, 2.67 mmol) in dioxane (10 mL) and water (2 mL) was added 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (66 mg, 0.09 mmol). The mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 3 h. The reaction mixture was dried and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0-50%) to obtain compound 8 (300 mg, white solid) in a yield of 41.6%.

[0321] LC-MS: m / z[M+H] + =721.4.

[0322] The preparation of compound 7 followed the method published in J. Med. Chem. 2020, 63, 5102-5118.

[0323] Step 7: Preparation of (S)-2,3-difluoro-N-(5-fluoro-2-methyl-3-(1-methyl-5-((5-(2-methylpiperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide (Compound 9)

[0324] To a solution of compound 8 (300 mg, 0.42 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), and the resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated to dryness under reduced pressure to give crude compound 9 (258 mg, green solid), which was used directly in the next reaction.

[0325] LC-MS: m / z[M+H] + =621.0.

[0326] Step 8: Preparation of N-(3-(5-((5-(2S)-4-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)-2-methylpiperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methylphenyl)-2,3-difluoro-4-(2-hydroxypropan-2-yl)benzamide (Example 8)

[0327] To compound 9 (60 mg, 0.14 mmol) in dichloromethane (8 mL) were added intermediate B (54 mg, 0.17 mmol) and triethylamine (72 mg, 0.72 mmol), and the mixture was stirred at 25°C for 16 h. Sodium triacetoxyborohydride (76 mg, 0.36 mmol) was then added to the reaction system, and the mixture was stirred at 25°C for 1 h. The crude product was purified on a silica gel preparative plate (developing solvent: methanol:dichloromethane = 1:10) to afford Example 8 (27.82 mg, pink solid) in a yield of 21.8%.

[0328] LC-MS: m / z[M+H] + =913.4.

[0329] 1HNMR(400MHz,DMSO-d6)δ10.84(s,1H),10.07(s,1H),8.50-8.48(m,1H),8.43(s,1H),7.83-7.81(m,1H),7.58-7.50(m,2H),7.47- 7.43(m,1H),7.38-7.34(m,1H),7.26-7.22(m,2H),7.05-7.03(m,1H),6.13-6.07(m,2H),5.56(s,1H),4.00-3.98(m,1H),3.95-3. 93(m,2H),3.63-3.59(m,4H),3.50-3.48(m,2H),3.03(s,1H),2.94-2.90(m,2H),2.77(s,1H),2.69-2.61(m,1H),2.58-2.56(m,2H ),2.45(s,2H),2.34-2.30(m,1H),2.20(s,3H),2.05(s,1H),1.97-1.87(m,1H),1.53(s,6H),1.26-1.22(m,1H),0.88-0.92(m,3H).

[0330] Example 9: (R)-3-((4-(1-(2-(4-(4-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-1-yl)pyrazine-2-carboxamide

[0331] The preparation scheme is shown in the figure below:

[0332] Step 1: Preparation of tert-butyl 4-(4-nitro-1H-indazol-1-yl)piperidine-1-carboxylate (Compound 3)

[0333] To a solution of 4-nitro-1H-indazole (1.5 g, 9.195 mmol) and tert-butyl 4-(methylsulfonyl)oxy)piperidine-1-carboxylate (5137 mg, 18.389 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (8987 mg, 27.584 mmol). The resulting reaction mixture was stirred at 80°C overnight. The reaction mixture was poured into water and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: 8%-20% ethyl acetate / petroleum ether) to afford compound 3 (2700 mg, yellow solid) in an 84.87% yield.

[0334] LC-MS: m / z[M-56+H] + =290.4.

[0335] Step 2: Preparation of 4-nitro-1-(piperidin-4-yl)-1H-indazole (Compound 4)

[0336] To a solution of compound 3 (3000 mg, 8.67 mmol) in dichloromethane (27 mL) was added trifluoroacetic acid (10 mL), and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to dryness to obtain crude compound 4 (2133 mg, yellow oil), which was used directly in the next reaction.

[0337] LC-MS: m / z [M+H] + = 246.8.

[0338] Step 3: Preparation of methyl 2-(4-(4-nitro-1H-indazol-1-yl)piperidin-1-yl)acetate (Compound 5)

[0339] To a solution of compound 4 (2133 mg, 8.66 mmol) and triethylamine (2632 mg, 26.01 mmol) in dichloromethane (20 mL) was added methyl 2-bromoacetate (1990 mg, 13.01 mmol) at 0°C, and the resulting reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 15%-75% ethyl acetate / petroleum ether) to afford compound 5 (2200 mg, brown oil) in a yield of 79.80%.

[0340] LC-MS: m / z[M+H] + =318.9

[0341] Step 4: Preparation of methyl 2-(4-(4-amino-1H-indazol-1-yl)piperidin-1-yl)acetate (Compound 6)

[0342] To a solution of compound 5 (700 mg, 2.201 mmol) in ethanol / water (8 mL / 2 mL) were added reduced iron powder (1233 mg, 22.013 mmol) and ammonium chloride (1178 mg, 22.013 mmol). The resulting reaction mixture was heated to 80°C and stirred for 1 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50%-85% ethyl acetate / petroleum ether) to afford compound 6 (340 mg, green solid) in a yield of 53.57%.

[0343] LC-MS: m / z[M+H] + =289.0

[0344] Step 5: Preparation of 3-((1-(1-(2-methoxy-2-oxoethyl)piperidin-4-yl)-1H-indazol-4-yl)amino)propionic acid (Compound 7)

[0345] Acrylic acid (255.21 mg, 3.542 mmol) was added to a toluene (6 mL) solution of compound 6 (340 mg, 1.18 mmol). The resulting reaction mixture was stirred at 110°C under nitrogen for 4 h. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude compound 7 (424.8 mg, yellow oil), which was used directly in the next step.

[0346] LC-MS: m / z[M+H] + =361.0

[0347] Step 6: Preparation of (4-(4-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)acetic acid (Compound 8)

[0348] To a solution of compound 7 (424.8 mg, 1.18 mmol) in glacial acetic acid (5 mL) was added urea (212.6 mg, 3.54 mmol). The resulting reaction mixture was stirred at 110°C under nitrogen overnight. Hydrochloric acid (4N, 2 mL) was then added to the reaction mixture, and stirring was continued at 100°C for 4 h. The reaction mixture was concentrated under reduced pressure to yield crude compound 8 (438.2 mg, yellow solid). This was used directly in the next reaction.

[0349] LC-MS: m / z[M+H] + =372.0

[0350] Step 7: Preparation of (R)-3-((4-(1-(2-(4-(4-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-1-yl)pyrazine-2-carboxamide (Example 9)

[0351] To a solution of compound 7 (64.68 mg, 0.1743 mmol) and intermediate E (100 mg, 0.2092 mmol) in N,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine (90.133 mg, 0.6974 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (99.43 mg, 0.2615 mmol), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into ice water (10 mL). The suspended mixture was filtered and the filter cake was washed with water (2 mL x 2). The solid was collected and purified by reverse phase preparative HPLC (acetonitrile:water = 10% to 40%) to give Example 9 (15.15 mg, yellow solid) in a yield of 10.45%.

[0352] LC-MS: m / z[M+H] + =832.4

[0353] 1 HNMR(400MHz,DMSO-d6)δ11.20(d,J=9.6Hz,1H),10.44(s,1H),8.01(s,1H),7.75(s,1H),7.66(s,2H),7.51(d, J=7.2Hz,2H),7.39(m,1H),7.32(s,1H),7.16(d,J=9.6Hz,2H),7.04(d,J=7.2Hz,1H),4.66-4.64(m,1H),4.52-4 .49(m,1H),4.28-4.23(m,3H),3.89-3.83(m,2H),3.59-3.57(m,2H),3.15-3.11(m,3H),3.01-2.92(m,5H),2.8 2-2.73(m,3H),2.72-2.68(m,4H),2.64-2.61(m,1H),2.35-2.28(m,2H),2.17-2.15(m,2H),1.93-1.44(m,11H).

[0354] Example 10: (R)-3-((4-(1-(2-(4-(6-chloro-4-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-1-yl)pyrazine-2-carboxamide

[0355] The preparation scheme is shown in the figure below:

[0356] Step 1: Preparation of tert-butyl 4-(6-chloro-4-nitro-1H-indol-1-yl)piperidine-1-carboxylate (Compound 3)

[0357] To a solution of 6-chloro-4-nitro-1H-indole (1.00 g, 2.54 mmol) and tert-butyl 4-(methylsulfonyl)oxy)piperidine-1-carboxylate (1.42 g, 5.08 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (2.48 g, 7.63 mmol), and the resulting reaction mixture was stirred at 90 ° C for 16 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 0-33% ethyl acetate / petroleum ether) to obtain compound 3 (1.93 g, yellow oil) in a yield of 100%.

[0358] LC-MS: m / z [M-56+H]+ = 323.8.

[0359] Step 2: Preparation of 6-chloro-4-nitro-1-(piperidin-4-yl)-1H-indole (Compound 4)

[0360] Trifluoroacetic acid (7 mL) was added to a solution of compound 3 (1.93 g, 5.08 mmol) in dichloromethane (20 mL), and the resulting reaction solution was stirred at 25° C. for 0.5 h. The reaction solution was concentrated to dryness under reduced pressure to obtain crude compound 4 (1.42 g, yellow oil).

[0361] LC-MS: m / z[M+H] + =279.8.

[0362] Step 3: Preparation of methyl 2-(4-(6-chloro-4-nitro-1H-indol-1-yl)piperidin-1-yl)acetate (Compound 5)

[0363] To a solution of compound 4 (1.42 g, 5.09 mmol) and triethylamine (1.54 g, 15.26 mmol) in dichloromethane (20 mL) was added methyl 2-bromoacetate (1.16 g, 7.63 mmol), and the resulting mixture was stirred at 25°C for 16 h. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: 0-50% ethyl acetate / petroleum ether) to afford compound 5 (1.79 g, red oil) in a 100% yield.

[0364] LC-MS: m / z[M+H] + =351.8.

[0365] Step 4: Preparation of methyl 2-(4-(4-amino-6-chloro-1H-indol-1-yl)piperidin-1-yl)acetate (Compound 6)

[0366] Iron powder (2.81 g, 50.31 mmol) and ammonium chloride (2.69 g, 50.31 mmol) were added to a mixture of ethanol / water (16 mL / 4 mL) of compound 5 (1.77 g, 5.03 mmol), and the resulting reaction mixture was stirred at 80 ° C for 1 h under nitrogen protection. The suspension was filtered through diatomaceous earth and washed with ethanol (20 mL x 3). The ethanol was removed by concentration under reduced pressure, and the concentrate was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 0-50% ethyl acetate / petroleum ether) to obtain compound 6 (1.40 g, yellow oil) in a yield of 87%.

[0367] LC-MS: m / z[M+H] + =321.9.

[0368] Step 5: Preparation of 3-((6-chloro-1-(1-(2-methoxy-2-oxoethyl)piperidin-4-yl)-1H-indol-4-yl)amino)propionic acid (Compound 7)

[0369] Acrylic acid (116 mg, 1.61 mmol) was added to a toluene (5 mL) solution of compound 6 (400 mg, 1.24 mmol), and the resulting mixture was stirred at 110° C. for 8 h. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude compound 7 (489 mg, yellow oil), which was used directly in the next reaction.

[0370] LC-MS: m / z[M+H] + =394.0.

[0371] Step 6: Preparation of 2-(4-(6-chloro-4-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidin-1-yl)acetic acid (Compound 8)

[0372] To a solution of compound 7 (489 mg, 1.243 mmol) in acetic acid (5 mL) was added urea (224 mg, 3.72 mmol), and the resulting reaction mixture was stirred at 110°C for 16 h. Dilute hydrochloric acid (4N, 4 mL) was added to the reaction solution, and the resulting reaction mixture was further stirred at 100°C for 6 h. The reaction mixture was concentrated to dryness under reduced pressure, and water / ethyl acetate (15 mL / 10 mL) was added, stirred, and filtered. The filter cake was dried under reduced pressure to obtain compound 8 (210 mg, gray solid) in a yield of 42%.

[0373] LC-MS: m / z[M+H] + =405.0.

[0374] Step 7: Preparation of (R)-3-((4-(1-(2-(4-(6-chloro-4-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-1-yl)pyrazine-2-carboxamide (Example 10)

[0375] To a solution of compound 8 (60 mg, 0.14 mmol) in N,N-dimethylformamide (2 mL) were added intermediate E (79 mg, 0.13 mmol), N,N-diisopropylethylamine (51 mg, 0.44 mmol), and HATU (113 mg, 0.29 mmol). The resulting reaction mixture was stirred at 25°C for 1 h. The reaction solution was purified by preparative HPLC to afford Example 10 (45.78 mg, light yellow solid) in a 21% yield.

[0376] LC-MS: m / z[M+H] + =865.4.

[0377] 1HNMR(400MHz,DMSO-d6)δ11.22(d,J=7.2Hz,1H),10.40(s,1H),7.76(s,1H),7.72(s,1H),7.67(s,1H),7. 59(d,J=2.8Hz,1H),7.53(d,J=7.6Hz,2H),7.33(s,1H),7.19(d,J=8.4Hz,2H),7.06(d,J=1.6Hz,1H),6.4 7(d,J=3.2Hz,1H),4.55-4.23(m,5H),3.82-3.79(m,2H),3.62-3.61(m,1H),3.29-2.88(m,11H),2.78-2. 75(m,3H),2.73-2.59(m,4H),2.36-2.34(m,2H),2.07-1.70(m,9H),1.59-1.55(m,2H),1.50-1.36(m,1H).

[0378] Example 11: 3-((4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidin-1-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0379] The preparation scheme is shown in the figure below:

[0380] Step 1: Preparation of [1-(4-nitrophenyl)hexahydropyridin-4-yl]methanol (Compound 3)

[0381] To a solution of 4-fluoro-1-nitrobenzene (2000 mg, 14.17 mmol) and hexahydropyridin-4-ylmethanol (1959.12 mg, 17.01 mmol) in dimethyl sulfoxide (20 L) was added N,N-diisopropylethylamine (3.52 mL, 21.26 mmol), and the resulting mixture was stirred at 120° C. for 1 h. The mixture was poured into water (300 mL) and filtered, and the filter cake was washed with water (50 mL) and dried under reduced pressure to obtain compound 3 (3345 mg, yellow solid) in a yield of 99.88%.

[0382] LC-MS: m / z[M+H] + =237.2

[0383] Step 2: Preparation of [1-(4-aminophenyl)piperidin-4-yl]methanol (Compound 4)

[0384] To a suspension of compound 3 (2000 mg, 8.46 mmol) in methanol (30 mL) was added 10% Pd / C (540.5 mg, 5.08 mmol), the resulting mixture was degassed and replaced with hydrogen, and stirred at 25° C. under hydrogen for 2 h. The suspension was filtered through celite and washed with methanol (30 mL), and the filtrate was concentrated to dryness under reduced pressure to give compound 4 (1730 mg, gray solid) in a yield of 99.07%.

[0385] LC-MS: m / z[M+H] + =207.2

[0386] Step 3: Preparation of 5-chloro-3-({4-[4-(hydroxymethyl)hexahydropyridin-1-yl]phenyl}amino)pyrazine-2-carboxamide (Compound 6)

[0387] To a solution of 3,5-dichloropyrazine-2-carboxamide (1000 mg, 5.21 mmol) and compound 4 (1074.43 mg, 5.21 mmol) in dimethyl sulfoxide (20 mL) was added N,N-diisopropylethylamine (1.36 mL, 7.81 mmol). The mixture was degassed and replaced with nitrogen three times, and stirred at 130°C under nitrogen for 18 h. The mixture was poured into water (300 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. Compound 6 (531 mg, red solid) was obtained by silica gel column chromatography and purification in a yield of 28%.

[0388] LC-MS: m / z[M+H] + =362.2.

[0389] Step 4: Preparation of 3-({4-[4-(hydroxymethyl)hexahydropyridin-1-yl]phenyl}amino)-5-[(3R)-3-(3-methyl-2-oxotetrahydro-1H-imidazol-1-yl)hexahydropyrazine-2-carboxamide (Compound 8)

[0390] To a solution of compound 6 (531 mg, 0.77 mol) and compound 7 (141.00 mg, 0.77 mmol) in dimethyl sulfoxide (10 ml) was added N,N-diisopropylethylamine (0.32 mL, 1.55 mmol). The mixture was poured into water (80 mL) and filtered, and the filter cake was washed with water (20 mL) and dried under reduced pressure to obtain compound 8 (170 mg, yellow solid) in a yield of 27.10%.

[0391] LC-MS: m / z[M+H] + =509.

[0392] Compound 7 was prepared according to the method disclosed in WO2021113557.

[0393] Step 5: Preparation of 3-{[4-(4-formylpiperidin-1-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxotetrahydro-1H-imidazol-1-yl)piperidin-1-yl]pyrazine-2-carboxamide (Compound 9)

[0394] To a solution of compound 8 (80 mg, 0.16 mmol) and triethylamine (436.05 μL, 3.15 mmol) in dimethyl sulfoxide (3 mL) was added sulfur trioxide pyridine (250.34 mg, 1.57 mmol), and the reaction mixture was heated to 25 ° C and stirred for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give a crude product of compound 9 (79 mg, yellow solid), which was used directly in the next step of synthesis.

[0395] LC-MS: m / z[M+H] + =507.

[0396] Step 6: Preparation of 3-((4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidin-1-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (Example 11)

[0397] A mixture of compound 9 (58 mg, 0.11 mmol) and intermediate M (30.84 mg, 0.10 mmol) in 1,2-dichloroethane (5 mL) and MeOH (0.5 mL) was stirred at 25 ° C for 0.5 h, and then sodium triacetoxyborohydride (48.53 mg, 0.23 mmol) was added and stirred at 25 ° C for 2 h. Saturated sodium bicarbonate (30 mL) was added to the reaction mixture and extracted with dichloromethane: methanol = 10: 1 (50 mL x 3). The combined organic phase was washed with brine (20 mL) and dried over anhydrous sodium sulfate to give a crude product. The crude product was purified by preparative HPLC to give Example 11 (31.6 mg, yellow solid) in a yield of 34.94%.

[0398] LC-MS: m / z[M+H] + =790.5.

[0399] 1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),10.87-10.78(m,1H),7.80(s,2H),7.67(s,1H) ),7.56(s,1H),7.36(d,J=8.8Hz,2H),7.23(s,1H),6.48(d,J=8.8Hz,2H),5.13(m,1H ),4.42-4.18(m,2H),3.99(s,4H),3.60(s,1H),3.43(d,J=8.2Hz,1H),3.21(d,J=8.2 Hz,2H),3.04-2.83(m,5H),2.81-2.60(m,6H),2.22-1.94(m,5H),1.83-1.41(m,9H).

[0400] The preparation of intermediate M follows the method published in J. Med. Chem. 2023, 66, 17, 12559-12585.

[0401] Example 12: 3-((4-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0402] The preparation scheme is shown in the figure below:

[0403] Step 1: Preparation of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3-ol (Compound 2)

[0404] To a solution of compound B-2 (420 mg, 0.873 mmol) and azetidine-3-ol (143.4 mg, 1.31 mmol) in dioxane (10 mL) was added -(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (111.6 mg, 0.208 mmol), tris(dibenzylidene-acetone)dipalladium (79.8 mg, 0.087 mmol) and cesium carbonate (567.5 mg, 1.75 mmol). The resulting reaction mixture was replaced with nitrogen three times and stirred at 100 ° C under nitrogen protection for 16 h. The mixture was poured into an aqueous solution (20 mL) and extracted with ethyl acetate (30 mLx3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (eluent: 0-8% ethyl acetate / petroleum ether) to give compound 2 (230 mg, gray solid) in a yield of 55.5%.

[0405] LC-MS: m / z[M+1] + =475.0.

[0406] Step 2: Preparation of 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (Compound 3)

[0407] To a solution of compound 2 (200 mg, 0.422 mmol) in dioxane (5 mL) were added 10% Pd(OH)2 / C (70 mg) and 10% Pd / C (70 mg). The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to afford crude compound 3 (120 mg, gray solid), which was used directly in the next reaction.

[0408] LC-MS: m / z[M+H] + =296.8.

[0409] Step 3: Preparation of 3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione (Compound 4)

[0410] To a solution of compound 3 (120 mg, 0.405 mmol) in dimethyl sulfoxide (4 mL) was added 2-iodoacetylbenzoic acid (170 mg, 0.607 mmol), and the reaction mixture was stirred at 50 ° C for 2 h. The mixture was poured into an aqueous solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: 0-50%, ethyl acetate / petroleum ether) to obtain compound 3 (83 mg, brown oil) in a yield of 71.31%.

[0411] LC-MS: m / z[M+H] + =294.8.

[0412] Step 4: Preparation of 3-((4-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (Example 12)

[0413] To a solution of compound 3 (83 mg, 0.289 mmol) and intermediate E (133.3 mg, 0.289 mmol) in dichloromethane (1 mL) and methanol (3 mL) was added triethylamine (36.62 mg, 0.375 mmol) at 0°C and stirred for 5 minutes. Then sodium cyanoborohydride (35.1 mg, 0.578 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by reverse preparative HPLC to give Example 12 (7.01 mg, white solid) in a yield of 3.28%.

[0414] LC-MS: m / z[M+H] + =757.4.

[0415] 1HNMR(400MHz,DMSO-d6)δ11.19(s,1H),10.85(s,1H),7.75(s,1H),7.66(s,1H),7.49(d,J=8.8Hz,2H),7. 32(s,1H),7.16(d,J=8.4Hz,2H),6.13(d,J=11.2Hz,2H),4.43-4.20(m,2H),4.09-3.35(m,1H),3.98-3.88 (m,2H),3.65-3.55(m,3H),3.28-3.15(m,6H),3.09-2.94(m,2H),2.94-2.81(m,2H),2.79-2.67(m,1H),2. 70(s,3H),2.45-2.38(m,1H),2.14-2.02(m,1H),1.98-1.88(m,3H),1.79-1.45(m,5H),1.66-1.55(m,3H).

[0416] Example 13: N-(3-(5-(5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methylphenyl)-2,3-difluoro-4-(2-hydroxypropan-2-yl)benzamide

[0417] The preparation scheme is shown in the figure below:

[0418] Step 1: Preparation of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (Compound 3)

[0419] To a solution of 5-bromo-2-nitropyridine (1.00 g, 4.93 mmol) in dimethyl sulfoxide (10 mL) were added lithium chloride (0.21 g, 4.93 mmol), tert-butyl piperazine-1-carboxylate (1.38 g, 7.39 mmol), and triethylamine (0.75 g, 7.39 mmol). The resulting reaction mixture was stirred at 85°C for 16 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30%-50%, ethyl acetate / petroleum ether) to obtain compound 3 (1.39 g, yellow solid) in a yield of 91.5%.

[0420] LC-MS: m / z[M+H] + =309.0.

[0421] Step 2: Preparation of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Compound 4)

[0422] To a solution of compound 3 (1.39 g, 4.51 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added 10% Pd / C (139 mg). The resulting mixture was degassed and replaced with hydrogen three times, then stirred at 25° C. under hydrogen protection for 16 h. The suspension was filtered, the filter cake was washed with tetrahydrofuran (40 mL x 3), and the filtrate was concentrated to dryness under reduced pressure to obtain crude compound 4 (1.2 g, gray solid), which was used directly in the next reaction.

[0423] LC-MS: m / z[M+H] + =279.0.

[0424] Step 3: Preparation of tert-butyl 4-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-3-ylpiperazine-1-carboxylate (Compound 6)

[0425] To a solution of compound 4 (1.20 g, 4.31 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (1.15 g, 4.31 mmol) in 1,4-dioxane (40 mL) were added cesium carbonate (4.21 g, 12.93 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.50 g, 0.86 mmol), and tris(dibenzylideneacetone)dipalladium (0.40 g, 0.43 mmol). The resulting reaction mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 16 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: 50%-75% ethyl acetate / petroleum ether) to afford compound 6 (1.39 g, green solid) in a yield of 69.5%.

[0426] LC-MS: m / z[M+H] + =466.0.

[0427] Step 4: Preparation of tert-butyl 4-(6-((5-(3-(2,3-difluoro-4-(2-hydroxypropan-2-yl)benzamido)-5-fluoro-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-3-yl]piperazine-1-carboxylate (Compound 7)

[0428] To a suspension of compound 8-6 (230 mg, 0.51 mmol), compound 6 (183 mg, 0.39 mmol), potassium phosphate (167 mg, 0.79 mmol), and sodium acetate (65 mg, 0.79 mmol) in acetonitrile (8 mL) and water (2 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (29 mg, 0.04 mmol). The resulting reaction mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 3 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: 50%-80%, ethyl acetate / petroleum ether) to afford compound 7 (144 mg, brown solid) in a yield of 51.8%.

[0429] LC-MS: m / z[M+H] + =707.2.

[0430] Step 5: Preparation of 2,3-difluoro-N-(5-fluoro-2-methyl-3-(1-methyl-6-oxo-5-((5-(piperazin-1-yl)pyridin-2-yl)amino)-1,6-dihydropyridin-3-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide (Compound 8)

[0431] Trifluoroacetic acid (2 mL) was added to a solution of compound 7 (144 mg, 0.20 mmol) in dichloromethane (6 mL), and the resulting mixture was stirred at 25°C for 1 h. The reaction solution was concentrated under reduced pressure to dryness to obtain crude compound 8 (124 mg, green solid), which was used directly in the next reaction.

[0432] LC-MS: m / z[M+H] + =607.2.

[0433] Step 6: Preparation of N-(3-(5-(5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methylphenyl)-2,3-difluoro-4-(2-hydroxypropan-2-yl)benzamide (Example 13)

[0434] To compound 8 (124 mg, 0.20 mmol) in dichloromethane (10 mL) were added intermediate B (90 mg, 0.26 mmol) and triethylamine (113 mg, 1.12 mmol). The resulting reaction mixture was stirred at 25°C for 16 h. Sodium triacetoxyborohydride (149 mg, 0.71 mmol) was then added to the reaction system, and stirring continued for 1 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by preparative thin-layer plate (developing solvent: methanol / dichloromethane = 1:10) and then by reverse-phase preparative HPLC to obtain Example 13 (66.76 mg, white solid) in a yield of 37.2%.

[0435] LC-MS: m / z[M+H] + =899.4.

[0436] 1 HNMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 10.04 (s, 1H), 8.46 (d, J = 2.4Hz, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.81-7.80 (m, 1H), 7. 52-7.47(m,2H),7.41(d,J=8.0Hz,1H),7.35-7.32(m,1H),7.21-7.18(m,2H),7.02-6.99(m,1H),6.09-6.06(m,2H),5.53(s, 1H),4.01-3.96(m,1H),3.93-3.89(m,2H),3.56(s,3H),3.47-3.44(m,2H),3.00(m,4H),2.97-2.85(m,1H),2.80-2.68(m,1H ),2.63-2.59(m,2H),2.49-2.48(m,2H),2.46-2.44(m,2H),2.16(s,3H),2.05-2.01(m,1H),1.94-1.91(m,1H),1.50(s,6H).

[0437] Example 14: 5-(((R)-1-(cyclopropanecarbonyl)piperidin-3-yl)(methyl)amino)-3-((4-(1-((1-(4-(2,6-dioxymethylpiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide

[0438] The preparation scheme is shown in the figure below:

[0439] Step 1: Preparation of tert-butyl (R)-3-((6-chloro-5-cyanopyrazin-2-yl)(methyl)amino)piperidine-1-carboxylate (Compound 3)

[0440] To a solution of 3,5-dichloropyrazine-2-carbonitrile (300 mg, 1.72 mmol) and N,N-diisopropylethylamine (445 mg, 3.44 mmol) in N,N-dimethylformamide (3 mL) was added tert-butyl (R)-3-(methylamino)piperidine-1-carboxylate (407 mg, 1.90 mmol). The resulting reaction mixture was stirred at 25°C for 1 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 12%-50%, ethyl acetate / petroleum ether) to afford compound 3 (600 mg, brown oil).

[0441] LC-MS: m / z[M-56+H] + =295.8.

[0442] Step 2: Preparation of (R)-3-chloro-5-(methyl(piperidin-3-yl)amino)pyrazine-2-carbonitrile (Compound 14-4)

[0443] To a solution of compound 3 (600 mg, 1.70 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (4 mL), and the resulting reaction mixture was stirred at 25°C for 1 h. The reaction solution was concentrated to dryness under reduced pressure to obtain crude compound 14-4 (429 mg, brown oil), which was used directly in the next reaction.

[0444] LC-MS: m / z[M+H] + =251.8.

[0445] Step 3: Preparation of (R)-3-chloro-5-((1-(cyclopropanecarbonyl)piperidin-3-yl)(methyl)amino)pyrazine-2-carbonitrile (Compound 6)

[0446] To a solution of compound 14-4 (376 mg, 1.49 mmol) in N,N-dimethylformamide (5 mL) were added cyclopropylcarboxylic acid (154 mg, 1.79 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (836 mg, 2.98 mmol), and N-methylimidazole (367 mg, 4.47 mmol). The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: 25%-50%, ethyl acetate / petroleum ether) to obtain compound 6 (400 mg, colorless oil) in a yield of 83.9%.

[0447] LC-MS: m / z[M+H] + =320.0.

[0448] Step 4: Preparation of (R)-tert-butyl 4-(4-(3-cyano-6-((1-(cyclopropanecarbonyl)piperidin-3-yl)(methyl)amino)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate (Compound 8)

[0449] To a solution of compound 6 (200 mg, 0.63 mmol), compound 7 (190 mg, 0.69 mmol), and cesium carbonate (611 mg, 1.88 mmol) in 1,4-dioxane (10 ml) were added palladium acetate (14 mg, 0.06 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (78 mg, 0.13 mmol). The resulting reaction mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 16 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: 25%-80%, ethyl acetate / petroleum ether) to obtain compound 8 (200 mg, yellow solid) in a yield of 57.1%.

[0450] LC-MS: m / z[M-Boc+H] + =460.0.

[0451] Compound 7 was prepared according to the method disclosed in WO2021113557

[0452] Step 5: Preparation of (R)-tert-butyl 4-(4-(3-carbonyl-6-((1-(cyclopropanecarbonyl)piperidin-3-yl)(methyl)amino)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate (Compound 9)

[0453] To a solution of compound 8 (200 mg, 0.36 mmol) and cesium carbonate (116 mg, 0.36 mmol) in methanol (4 mL) was added hydrogen peroxide (243 mg, 7.14 mmol), and the resulting mixture was stirred at 25 ° C for half an hour. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product of compound 9 (190 mg, yellow solid), which was used directly in the next reaction.

[0454] LC-MS: m / z[M-boc+H] + =478.2.

[0455] Step 6: Preparation of (R)-5-((1-(cyclopropanecarbonyl)piperidin-3-yl)(methyl)amino)-3-((4-(piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide (Compound 10)

[0456] Trifluoroacetic acid (2 mL) was added to a solution of compound 9 (190 mg, 0.33 mmol) in dichloromethane (6 mL), and the resulting reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was concentrated under reduced pressure to dryness to obtain crude compound 10 (157 mg, brown oil), which was used directly in the next reaction.

[0457] LC-MS: m / z[M+H] + =478.2.

[0458] Step 7: Preparation of 5-(((R)-1-(cyclopropanecarbonyl)piperidin-3-yl)(methyl)amino)-3-((4-(1-((1-(4-(2,6-dioxymethylpiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide (Example 14)

[0459] To a solution of compound 10 (132 mg, 0.23 mmol) in dichloromethane (10 mL) were added intermediate B (90 mg, 0.29 mmol) and triethylamine (90 mg, 0.90 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. Sodium acetate borohydride (120 mg, 0.56 mmol) was then added to the reaction mixture, and stirring continued for 1 h. The reaction mixture was concentrated under reduced pressure to dryness to obtain a crude product, which was purified by reverse-phase HPLC to afford Example 14 (18.78 mg, white solid) in a yield of 10.7%.

[0460] LC-MS: m / z[M+H] + =770.4.

[0461] 1HNMR(400MHz,DMSO-d6)δ11.24(s,1H),10.85(s,1H),7.76(s,1H),7.53-7.49(m,3H),7.33(s,1H), 7.11(d,J=8.4Hz,2H),6.11(d,J=8.4Hz,2H),4.58-4.12(m,3H),4.05-4.00(m,1H),3.96-3.93(m,2H ),3.51-3.48(m,2H),3.05(s,3H),2.98-2.89(m,3H),2.85-2.70(m,2H),2.59-2.57(m,2H),2.42-2. 39(m,2H),2.14-1.99(m,4H),1.97-1.77(m,5H),1.74-1.71(m,2H),1.61(s,3H),0.77-0.62(m,4H).

[0462] Example 15: 5-((((R)-1-(cyclopropanecarbonyl)piperidin-3-yl)amino)-3-((4-((1-(4-(2,6-dioxopiperidin-3-alkyl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide

[0463] The preparation scheme is shown in the figure below:

[0464] Step 1: Preparation of tert-butyl (R)-3-((6-chloro-5-cyanopyrazin-2-yl)amino)piperidine-1-carboxylate (Compound 3)

[0465] To a solution of 3,5-dichloropyrazine-2-carbonitrile (1.00 g, 5.74 mmol) and N,N-diisopropylethylamine (1.32 g, 11.49 mmol) in N,N-dimethylformamide (10 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (1.38 g, 6.89 mmol). The resulting reaction mixture was stirred at 0°C for 1 h. After monitoring the reaction for completion, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 15%-33% ethyl acetate / petroleum ether) to afford compound 3 (1.94 g, yellow oil) in a 100% yield.

[0466] LC-MS: m / z[M-Boc+H] + =237.8.

[0467] Step 2: Preparation of (R)-3-chloro-5-(piperidin-3-ylamino)pyrazine-2-carbonitrile (Compound 4)

[0468] Trifluoroacetic acid (4 mL) was added to a solution of compound 3 (1.0 g, 2.96 mmol) in dichloromethane (10 mL), and the resulting reaction solution was stirred at 25°C for 1 h. The reaction solution was concentrated under reduced pressure to dryness to obtain crude compound 4 (704 mg, yellow oil), which was used directly in the next reaction.

[0469] LC-MS: m / z[M+H] + =237.8.

[0470] Step 3: Preparation of (R)-3-chloro-5-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrazine-2-carbonitrile (Compound 6)

[0471] To a solution of compound 4 (700 mg, 2.95 mmol) in dichloromethane (20 mL) were added cyclopropylcarboxylic acid (253 mg, 2.94 mmol), N,N-diisopropylethylamine (1.14 g, 8.83 mmol), EDCI (847 mg, 4.42 mmol) and HOBt (596 mg, 4.41 mmol), and the reaction mixture was stirred at 0 ° C for 0.5 h. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: 33%-50%, ethyl acetate / petroleum ether) to obtain compound 6 (940 mg, colorless oily oil) in a yield of 100%.

[0472] LC-MS: m / z[M+H] + =305.8.

[0473] Step 4: Preparation of (R)-tert-butyl 4-(4-(3-cyano-6-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrazin-2-yl)aminophenyl)piperidine-1-carboxylate (Compound 8)

[0474] To a mixture of compound 6 (420 mg, 1.37 mmol), compound 7 (418 mg, 1.51 mmol), and cesium carbonate (1.34 g, 4.12 mmol) in 1,4-dioxane (10 ml) were added palladium acetate (31 mg, 0.13 mmol) and BINAP (171 mg, 0.27 mmol). The reaction mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 2 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: 33%-100%, ethyl acetate / petroleum ether) to obtain compound 8 (441 mg, yellow oil) in a 59% yield.

[0475] LC-MS: m / z[M-boc+H] + =446.0.

[0476] Step 5: Preparation of (R)-tert-butyl 4-(4-(3-carbamoyl-6-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate (Compound 9)

[0477] To a solution of compound 8 (441 mg, 0.80 mmol) and cesium carbonate (263 mg, 0.80 mmol) in dimethyl sulfoxide and methanol (2 mL / 4 mL) was added hydrogen peroxide (0.3 mL), and the resulting reaction mixture was stirred at 25 ° C for half an hour. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product of compound 9 (455 mg, yellow oil), which was used directly in the next reaction.

[0478] LC-MS: m / z[M+H] + =564.2.

[0479] Step 6: Preparation of (R)-5-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)-3-((4-(piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide (Compound 10)

[0480] Trifluoroacetic acid (1.6 mL) was added to a solution of compound 9 (455 mg, 0.80 mmol) in dichloromethane (5 mL), and the resulting reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was concentrated under reduced pressure to dryness to obtain crude compound 10 (370 mg, yellow oil), which was used directly in the next reaction.

[0481] LC-MS: m / z[M+H] + =464.2.

[0482] Step 7: Preparation of 5-((((R)-1-(cyclopropanecarbonyl)piperidin-3-yl)amino)-3-((4-((1-(4-(2,6-dioxopiperidine-3-alkyl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide (Example 15)

[0483] To a solution of compound 10 (120 mg, 0.251 mmol) in dichloromethane (7 mL) were added intermediate B (100 mg, 0.325 mmol) and triethylamine (64 mg, 0.627 mmol). The resulting reaction mixture was stirred at room temperature under nitrogen for 16 h. Sodium acetate borohydride (80 mg, 0.373 mmol) was then added to the reaction solution, and stirring was continued at 25°C for 2 h. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by preparative HPLC to afford Example 15 (20 mg, white solid) in a 10% yield.

[0484] LC-MS: m / z[M+H] + =756.4.

[0485] 1 HNMR(400MHz,DMSO-d6)δ11.34(m,1H),10.86(s,1H),7.71-7.54(m,4H),7.39-7.33(m,1H),7.24( s,1H),7.14(s,2H),6.18-6.10(m,2H),4.28-4.14(m,1H),4.09-4.01(m,4H),3.97-3.86(m,1H),3 .75-3.48(m,6H),2.96-2.93(m,2H),2.84-2.69(m,2H),2.61-2.59(m,2H),2.43(s,2H),2.06-2.0 3(m,4H),1.99-1.91(m,1H),1.74-1.72(m,2H),1.66-1.45(m,4H),0.78-0.56(m,3H),0.39(m,1H).

[0486] Example 16: 3-((4-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-5-(methyl((R)-1-(methylsulfonyl)piperidin-3-ylamino)pyrazine-2-carboxamide

[0487] The preparation scheme is shown in the figure below:

[0488] Step 1: Preparation of (R)-3-chloro-5-(methyl(1-(methylsulfonyl)piperidin-3-yl)amino)pyrazine-2-carbonitrile (Compound 2)

[0489] To a solution of compound 14-4 (400 mg, 1.58 mmol) and methanesulfonic anhydride (359 mg, 2.06 mmol) in dichloromethane (10 mL) was added dropwise N,N-diisopropylethylamine (411 mg, 3.17 mmol) at 0°C, and the resulting reaction solution was stirred at 25°C for 1 h. The reaction solution was poured into water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (eluent: 20%-50%, ethyl acetate / petroleum ether) to obtain compound 2 (157 mg, yellow oil) in a yield of 28%.

[0490] LC-MS: m / z[M+H] + =347.8.

[0491] Step 2: Preparation of (R)-tert-butyl 4-(4-((3-carbamoyl-6-(methyl(1-(methylsulfonyl)piperidin-3-yl)amino)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate (Compound 4)

[0492] To a solution of compound 2 (157 mg, 0.45 mmol) and compound 3 (137 mg, 0.49 mmol) in 1,4-dioxane (10 mL) were added cesium carbonate (441 mg, 1.35 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (56 mg, 0.09 mmol), and palladium acetate (10 mg, 0.04 mmol). The reaction mixture was degassed and replaced with nitrogen three times, then stirred at 100°C under nitrogen for 2 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: 20%-50%, ethyl acetate / petroleum ether) to obtain compound 4 (124 mg, yellow oil) in a yield of 46%.

[0493] LC-MS: m / z[M-Boc+H] + =488.0.

[0494] Step 3: Preparation of (R)-5-(methyl(1-(methylsulfonyl)piperidin-3-yl)amino)-3-((4-(piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide (Compound 5)

[0495] Trifluoroacetic acid (1 mL) was added to a solution of compound 4 (124 mg, 0.21 mmol) in dichloromethane (3 mL), and the resulting mixture was stirred at 25°C for 1 h. The reaction solution was concentrated to dryness under reduced pressure to obtain crude compound 5 (102 mg, yellow oil), which was used directly in the next reaction.

[0496] LC-MS: m / z[M+H] + =488.0.

[0497] Step 4: Preparation of 3-((4-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-5-(methyl((R)-1-(methylsulfonyl)piperidin-3-ylamino)pyrazine-2-carboxamide (Example 16)

[0498] To a solution of compound 5 (85 mg, 0.14 mmol) and intermediate B (57 mg, 0.18 mmol) in dichloromethane (5 mL) was added triethylamine (36 mg, 0.35 mmol), and the resulting reaction mixture was stirred at 25°C for 12 h. Sodium acetate borohydride (45 mg, 0.21 mmol) was then added, and stirring was continued at 25°C for 1 h. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by preparative HPLC to afford Example 16 (32.58 mg, white solid) in a 29% yield.

[0499] LC-MS: m / z[M+H] + =780.3.

[0500] 1 HNMR(400MHz,DMSO-d6)δ10.86(s,1H),8.40(s,1H),8.99(s,1H),7.70(s,1H),7.41(d,J=8.4Hz,2H),7.07(d, J=8.4Hz,2H),6.23-5.96(m,2H),4.44(s,1H),4.32-4.17(m,1H),4.05-4.01(m,1H),3.97-3.93(m,2H),3.85-3 .83(m,1H),3.51-3.48(m,3H),3.25-3.07(m,2H),3.03-2.92(m,7H),2.83-2.73(m,2H),2.61-2.59(m,2H),2.4 1-2.28(m,2H),2.07-2.02(m,3H),1.99-1.92(m,3H),1.72-1.69(m,3H),1.60-1.57(m,3H),1.39-1.23(m,1H).

[0501] Example 17: Preparation of 3-{[4-(4-{4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indazol-1-yl]hexahydropyridin-1-yl}hexahydropyridin-1-yl)phenyl]amino}-5-{[(3R)-1-(cyclopropylcarbonyl)hexahydropyridin-3-yl]amino}pyrazine-2-carboxamide

[0502] The preparation scheme is shown in the figure below:

[0503] Step 1: Preparation of 1-(4-aminophenyl)hexahydropyridine-4-ol (Compound 2)

[0504] To a solution of 4-fluoro-1-nitrobenzene (2000 mg, 14.17 mmol) and hexahydropyridin-4-ol (1719.95 mg, 17.00 mmol) in dimethyl sulfoxide (20 mL) was added N,N-diisopropylethylamine (3.52 mL, 21.26 mmol), and the resulting mixture was stirred at 120° C. for 1 h. The mixture was poured into water (300 mL) and filtered, and the filter cake was washed with water (50 mL) and dried under reduced pressure to obtain compound 2 (3080 mg, yellow solid) in a yield of 97.80%.

[0505] LC-MS: m / z[M+H] + =223.2

[0506] Step 2: Preparation of 1-(4-aminophenyl)hexahydropyridine-4-ol (Compound 3)

[0507] To a suspension / mixture of compound 2 (1080 mg, 4.86 mmol) in methanol (30 mL) was added 10% Pd / C (310.30 mg, 2.92 mmol), and the resulting mixture was degassed and replaced with hydrogen three times, then stirred at 25 ° C. under hydrogen protection for 2 h. The suspension was filtered through celite and washed with methanol (30 mL), and the filtrate was concentrated to dryness under reduced pressure to give compound 3 (930 mg, gray solid) in a yield of 99.54%.

[0508] LC-MS: m / z[M+H] + =193.2

[0509] Step 3: Preparation of 5-chloro-3-{[4-(4-hydroxyhexahydropyridin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Compound 5)

[0510] To a solution of compound 4 (1800 mg, 9.38 mmol) and compound 3 (1802.44 g, 9.38 mmol) in dimethyl sulfoxide (20 mL) was added N,N-diisopropylethylamine (2.46 mL, 14.06 mmol). The mixture was degassed and replaced with nitrogen three times, and stirred at 130 ° C under nitrogen for 18 h. The mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phases were concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative purification to obtain compound 5 (650 mg, red solid) in a yield of 19.93%.

[0511] LC-MS: m / z[M+H] + =348.1

[0512] Step 4: Preparation of 3-{[4-(4-hydroxyhexahydropyridin-1-yl)phenyl]amino}-5-{[(3R)-1-(cyclopropylcarbonyl)hexahydropyridin-3-yl]amino}pyrazine-2-carboxamide (Compound 7)

[0513] To a solution of compound 5 (1.00 g, 2.88 mmol) and compound 6 in dimethyl sulfoxide (15 mL) was added N,N-diisopropylethylamine (3.01 mL, 17.25 mmol). The mixture was degassed and replaced with nitrogen three times, and stirred at 130°C under nitrogen for 18 h. The mixture was poured into water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative purification to obtain compound 7 (200 mg, yellow solid) in a yield of 14.50%.

[0514] LC-MS: m / z [M+H] + = 480.1.

[0515] Step 5: Preparation of 5-{[(3R)-1-(cyclopropylcarbonyl)hexahydropyridin-3-yl]amino}-3-{[4-(4-oxohexahydropyridin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Compound 8)

[0516] To compound 7 (200 mg, 0.42 mmol) in dimethyl sulfoxide (5 mL) were added triethylamine (1.16 mL, 8.34 mmol) and pyridine sulfur trioxide (663.75 mg, 4.17 mmol), and the reaction mixture was stirred at 25 ° C for 2 h. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 x 3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product of compound 8 (159 mg, yellow solid) in a yield of 79.84%.

[0517] LC-MS: m / z[M+H] + =478.2.

[0518] Step 6: Preparation of 3-{[4-(4-{4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indazol-1-yl]hexahydropyridin-1-yl}hexahydropyridin-1-yl)phenyl]amino}-5-{[(3R)-1-(cyclopropylcarbonyl)hexahydropyridin-3-yl]amino}pyrazine-2-carboxamide (Example 17)

[0519] To a solution of compound 8 (139 mg, 0.29 mmol) and compound 9 (91.21 mg, 0.29 mmol) in N,N-dimethylformamide (5 mL) was added tetraisopropyl titanate (165.45 mg, 0.58 mmol), and the mixture was stirred at 25°C for 2 h. Then, sodium triacetylborohydride (185.06 mg, 0.87 mmol) was added, and the mixture was stirred at 25°C for 1 h.

[0520] Water (50 mL) was added to the reaction mixture, followed by extraction with dichloromethane:methanol = 10:1 (50 mL x 3). The organic phases were combined and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative purification to obtain Example 17 (28 mg, yellow solid). Yield: 12.41%.

[0521] LC-MS: m / z[M+H] + =775.6.

[0522] 1 HNMR(400MHz,DMSO-d6)δ11.10(s,1H),10.44(s,1H),8.01(s,1H),7.68-7.54(m,3H),7.51- 7.23(m,4H),7.15(s,1H),7.04(d,J=7.2Hz,1H),6.91-6.83(m,2H),4.64-4.57(m,1H),4.43 -4.33(m,1H),4.12-4.05(m,1H),3.87(t,J=6.8Hz,2H),3.68-3.61(m,6H),3.07(m,2H),2.8 0-2.58(m,4H),2.47-2.39(m,3H),2.20-1.73(m,8H),1.67-1.34(m,4H),0.87-0.28(m,4H).

[0523] Example 18: (3R)-3-[(5-carbamoyl-6-{[4-(4-{4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indazol-1-yl]hexahydropyridin-1-yl}hexahydropyridin-1-yl)phenyl]amino}pyrazin-2-yl)amino]hexahydropyridine-1-carboxylic acid methyl ester

[0524] The preparation scheme is shown in the figure below:

[0525] Step 1: Preparation of (3R)-3-[(6-{[4-(8-aza-1,4-dioxaspiro[4.5]decane-8-yl)phenyl]amino}-5-carbamoylpyrazin-2-yl)amino]piperidine-1-carboxylic acid methyl ester (Compound 2)

[0526] To a solution of methanol (268 μL, 6.61 mmol) and triethylamine (1.52 mL, 11.0 mmol) in tetrahydrofuran (30 mL) was added dropwise a solution of triphosgene (654 mg, 2.20 mmol) in tetrahydrofuran (30 mL) at 0°C. The reaction system was stirred at 0°C for 1 h, followed by the addition of a solution of compound 1 (1.0 g, 2.20 mmol) in tetrahydrofuran (30 mL). The temperature was raised to 25°C and stirred for 2 h. The mixture was purified by silica gel column chromatography (ethyl acetate:dichloromethane = 1:1 to 4:1) to afford compound 2 (780 mg, yellow solid) in a yield of 69.1%.

[0527] LC-MS: m / z[M+H] + =512.2

[0528] Step 2: Preparation of methyl (3R)-3-[(5-carbamoyl-6-{[4-(4-oxopyridin-1-yl)phenyl]amino}pyrazin-2-yl)amino]pyridin-1-carboxylate (Compound 3)

[0529] To a mixture of compound 2 (730 mg, 1.43 mmol) in acetone (10 mL) and water (20 mL) was added 4-methylbenzenesulfonic acid (492 mg, 2.86 mmol), and the resulting mixture was stirred at 70 ° C for 18 h. The reaction mixture was concentrated under reduced pressure to remove acetone. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane: methanol = 10: 1 (50 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative method to obtain compound 3 (415 mg, yellow solid) in a yield of 62.2%.

[0530] LC-MS: m / z[M+H] + =468.7

[0531] Step 3: Preparation of (3R)-3-[(5-carbamoyl-6-{[4-(4-{4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indazol-1-yl]hexahydropyridin-1-yl}hexahydropyridin-1-yl)phenyl]amino}pyrazin-2-yl)amino]hexahydropyridine-1-carboxylic acid methyl ester (Example 18)

[0532] To a solution of compound 3 (150 mg, 0.32 mmol) and compound 4 (150 mg, 0.48 mmol) in DMF (2 mL) and tetrahydrofuran (10 mL) was added tetraisopropyl titanate (182 mg, 0.64 mmol). After stirring at 70°C for 2 h, sodium triacetoxyborohydride (203 mg, 0.96 mmol) was added, and the resulting mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, then poured into water (30 mL) and filtered. The filter cake was slurried with dichloromethane:methanol = 10:1 (100 mL), and the suspension was separated by filtration. The filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was subjected to preparative purification to obtain Example 18 (18.5 mg, brown solid) in a yield of 7.58%.

[0533] LC-MS: m / z[M+H] + =765.4

[0534] 1 HNMR(400MHz,DMSO-d6)δ11.18(s,1H),10.45(s,1H),8.02(s,1H),7.59-7.66(m,3H),7.48(m ,2H),7.38(d,J=8.0Hz,1H),7.30(s,1H),7.19(s,1H),7.04(d,J=7.2Hz,1H),6.87(d,J=8.4Hz ,2H),4.62(m,1H),3.81-3.89(m,4H),3.63-3.66(m,5H),3.04-3.07(m,5H),2.78(t,J=6.8Hz, 2H),2.63(m,2H),2.41-2.47(m,3H),2.07-2.15(m,2H),1.77-1.95(m,6H),1.48-1.65(m,4H).

[0535] Example 19: (R)-5-((1-(cyclopropylcarbonyl)piperidin-3-yl)(methyl)amino)-3-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)pyrazine-2-carboxamide

[0536] The preparation scheme is shown in the figure below:

[0537] Step 1: Preparation of (R)-3-chloro-5-((1-(cyclopropylcarbonyl)piperidin-3-yl)(methyl)amino)pyrazine-2-carbonitrile (Compound 2)

[0538] Compound 1 (1.2 g, 3.93 mmol) was dissolved in N,N-dimethylformamide (12 mL), and sodium hydride (452 ​​mg, 19.6 mmol) was added at 0°C. After stirring for 30 minutes, iodomethane (1.5 mL) was added and stirring was continued at room temperature for 1 hour. After the reaction was complete, water (30 mL) was added and extracted with ethyl acetate (60 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. It was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 2 (1.2 g, yellow solid) with a yield of 95.6%.

[0539] LC-MS: m / z[M+H] + =320.1

[0540] Step 2: Preparation of (R)-3-((4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)-5-((1-(cyclopropylcarbonyl)piperidin-3-yl)(methyl)amino)pyrazine-2-carbonitrile (Compound 4)

[0541] Compound 2 (1.2 g, 3.76 mmol), compound 3 (880 mg, 3.76 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (700 mg, 1.13 mmol) and cesium carbonate (2451 mg, 7.52 mmol) were dissolved in 1,4-dioxane (15 mL). Palladium acetate (86 mg, 0.38 mmol) was added to the above mixture, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 100°C overnight. After the reaction was complete, the reaction solution was filtered and concentrated to dryness under reduced pressure. The product was purified by silica gel column chromatography to obtain compound 4 (1200 mg, yellow solid) in a yield of 61.7%.

[0542] LC-MS: m / z[M+H] + =518.3

[0543] Step 3: Preparation of (R)-3-((4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)-5-((1-(cyclopropylcarbonyl)piperidin-3-yl)(methyl)amino)pyrazine-2-carboxamide (Compound 5)

[0544] To a solution of compound 4 (1200 mg, 2.32 mmol) and cesium carbonate (756 mg, 2.32 mmol) in dimethyl sulfoxide (2 mL) and methanol (10 mL) was added hydrogen peroxide (394 mg, 11.6 mmol), and the mixture was stirred at 25°C overnight. After the reaction was complete, water (30 mL) was added, and the mixture was filtered. The filter cake was collected, washed with water, and dried by distillation under reduced pressure to obtain crude compound 5 (980 mg, yellow solid) in a yield of 78.8%.

[0545] LC-MS: m / z[M+H] + =536.3

[0546] Step 4: Preparation of (R)-5-((1-(cyclopropylcarbonyl)piperidin-3-yl)(methyl)amino)-3-((4-(4-oxopiperidin-1-yl)phenyl)amino)pyrazine-2-carboxamide (Compound 6)

[0547] Compound 5 (980 mg, 1.83 mmol) was dissolved in a mixed solution of water (5 mL) and acetonitrile (5 mL). To the above solution was added p-toluenesulfonic acid (944 mg, 5.49 mmol), and the mixture was stirred at 70°C for 5 h. After the reaction was complete, the mixture was concentrated to dryness and purified by reverse phase chromatography to obtain compound 6 (500 mg, yellow solid) in a yield of 55.5%.

[0548] LC-MS: m / z [M+H] + = 492.2

[0549] Step 5: Preparation of (R)-5-((1-(cyclopropylcarbonyl)piperidin-3-yl)(methyl)amino)-3-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)pyrazine-2-carboxamide (Example 19)

[0550] Compound 6 (500 mg, 1.01 mmol) and compound 7 (1.01 mmol, 318 mg) were dissolved in a mixed solution of N,N-dimethylformamide (2 mL) and tetrahydrofuran (10 mL), and tetraisopropyl titanate (456 mg, 2.02 mmol) was added, and the mixture was stirred at 70 ° C for 1 h. Then, sodium triacetylborohydride (426 mg, 2.02 mmol) was added and the mixture was returned to room temperature and continued to stir for 1 h. After the reaction was complete, the reaction solution was poured into (20 mL) water and extracted three times with ethyl acetate (20 mL). The combined organic phases were added with anhydrous sodium sulfate and dried, filtered, and concentrated to dryness to obtain a crude product. The crude product was purified by preparative method to obtain Example 19 (26 mg, yellow solid) with a yield of 3.1%.

[0551] LC-MS: m / z[M+H] + =789.4

[0552] 1 HNMR(400MHz,DMSO-d6)δ11.03(s,1H),10.45(s,1H),8.02(s,1H),7.72(s,1H),7.66(d,J=8.4Hz ,1H),7.36-7.47(m,4H),7.28(s,1H),7.04(m,1H),6.85(d,J=8.4Hz,2H),4.62(s,1H),4.36(s,2H ),3.87(t,J=6.4Hz,3H),3.61-3.63(m,2H),3.03(m,5H),2.78(t,J=6.4Hz,3H),2.59-2.68(m,4H ),2.40-2.44(m,2H),2.10-2.13(m,3H),1.75-1.88(m,6H),1.45-1.63(m,4H),0.75-0.80(m,4H).

[0553] Example 20: 3-[(4-{1-[(1-{4-[(3S*)-2,6-dioxohexahydropyridin-3-yl]-3,5-difluorophenyl}azetidin-3-yl)methyl]hexahydropyridin-4-yl}phenyl)amino]-5-[(3R)-3-(3-methyl-2-oxotetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]pyrazine-2-carboxamide

[0554] Example 21: 3-[(4-{1-[(1-{4-[(3R*)-2,6-dioxohexahydridine-3-yl]-3,5-difluorophenyl}azetidin-3-yl)methyl]hexahydropyridin-4-yl}phenyl)amino]-5-[(3R)-3-(3-methyl-2-oxotetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]pyrazine-2-carboxamide

[0555] Example 4 (20 mg) was separated by SFC using a ChiralPak IE column, 250×30 mm ID, 10 μm, mobile phases A (methanol with 0.1% ammonia) and B (acetonitrile), flow rate: 120 mL / min, column temperature: room temperature, to yield two single-configuration compounds with different retention times. After lyophilization, they were respectively: Example 20 (9 mg, yellow solid, retention time: 4.6 min) and Example 21 (10 mg, yellow solid, retention time: 6.7 min).

[0556] Example 22: 3-((4-(1-((1-(4-((S*)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(2-oxooxazolidin-3-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0557] Example 23: 3-((4-(1-((1-(4-((R*)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(2-oxooxazolidin-3-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0558] Examples 22 and 23 were synthesized using the same method as Examples 4, 20, and 21. Finally, SFC separation was performed using a ChiralPak IE column, 250×30 mm ID, 10 μm column, mobile phases A (methanol with 0.1% ammonia) and B (acetonitrile), at a flow rate of 120 mL / min and room temperature. Two single-configuration compounds with different retention times were obtained. After lyophilization, the products were respectively: Example 22 (10 mg, yellow solid, retention time: 3.0 min) and Example 23 (8 mg, yellow solid, retention time: 4.2 min).

[0559] LC-MS: m / z[M+H] + =758.4

[0560] 1 HNMR(400MHz,DMSO-d6)δ11.24(s,1H),10.85(s,1H),8.31(s,2H),7.78(s,1H),7.67(s,1H),7.50(d,J=8.2Hz,2 H),7.34(s,1H),7.16(d,J=8.2Hz,2H),6.11(d,J=11.4Hz,2H),4.40(d,J=12.8Hz,1H),4.29(q,J=7.6Hz,3H),3. 98(m,4H),3.13(t,J=11.8Hz,2H),3.02(d,J=12.4Hz,1H),2.95(t,J=9.7Hz,4H),2.78(m,2H),2.60(d,J=7.4Hz, 2H),2.45-2.37(m,1H),2.10-2.00(m,3H),1.99-1.89(m,2H),1.87-1.78(m,2H),1.77-1.69(m,2H),1.61(m,3H).

[0561] Example 24: (R)-methyl 3-((5-carbamoyl-6-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)pyrazin-2-yl)(methyl)amino)piperidine-1-carboxylate

[0562] The synthesis of Example 24 was carried out by referring to Examples 18 and 19. Finally, Example 24 (44 mg, yellow solid) was obtained by reverse preparative column chromatography.

[0563] LC-MS: m / z [M+H] + = 779.4

[0564] 1HNMR(400MHz,DMSO-d6)δ11.04(s,1H),10.45(s,1H),8.21(s,1H),8.02(s,1H),7.72(s,1H),7.66(d,J=8.8Hz,1 H),7.48(s,1H),7.45-7.36(m,3H),7.29(s,1H),7.04(d,J=7.4Hz,1H),6.85(d,J=8.9Hz,2H),4.62(s,1H),4.48-4 .33(m,1H),3.99(s,2H),3.88(t,J=6.7Hz,3H),3.64(d,J=9.5Hz,2H),3.07(s,2H),3.02(s,3H),2.78(t,J=6.5Hz, 3H), 2.66 (d, J = 12.0Hz, 4H), 2.5 (s, 3H), 2.11 (d, J = 10.0Hz, 2H), 1.82 (m, 7H), 1.61 (d, J = 10.6Hz, 2H), 1.47 (s, 1H).

[0565] Example 25: 5-((R(-3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1-(4-((S*)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide

[0566] Example 26: 5-((R)-3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1-(4-(R*)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide

[0567] Examples 25 and 26 were synthesized using the same method as Examples 4, 20, and 21. Finally, SFC separation was performed using a ChiralPak IE column, 250×30 mm ID, 10 μm column, mobile phases A (methanol with 0.1% ammonia) and B (acetonitrile), at a flow rate of 120 mL / min and room temperature. Two single-configuration compounds with different retention times were obtained. After lyophilization, the products were respectively: Example 25 (68 mg, yellow solid, retention time: 4.57 min) and Example 26 (75 mg, yellow solid, retention time: 6.38 min).

[0568] LC-MS: m / z[M+H] + =797.4;

[0569] 1 HNMR(400MHz,DMSO-d6)δ11.22(s,1H),10.85(s,1H),7.75(s,1H),7.66(s,1H),7.50(d,J=8.4Hz,2H),7.33( s,1H),7.17(d,J=8.5Hz,2H),6.10(d,J=11.1Hz,2H),4.33(m,2H),4.02(dd,J=12.6,5.0Hz,1H),3.94(t,J=7 .6Hz,2H),3.66-3.57(m,1H),3.49(m,2H),3.28-3.22(m,5H),3.03-2.88(m,5H),2.83-2.72(m,1H),2.58(d, J=7.3Hz,2H),2.46-2.37(m,2H),2.13-1.91(m,4H),1.86-1.68(m,5H),1.68-1.51(m,3H),0.69-0.57(m,4H).

[0570] Control Example 1: Control Example 1 was synthesized according to the synthesis method of compound 195 of patent WO2021113557A1.

[0571] Experimental Example 1: Mino and TMD8 cell proliferation assay

[0572] Mino or TMD8 cells were cultured in RPMI1640 medium containing 10% fetal bovine serum (Gibco). When the cells grew to the logarithmic growth phase, the cells were collected and counted, and the cells were plated into 96-well cell culture plates (2000 cells / well). After overnight culture, the cells were added with the final concentrations of 1 μM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM, 0.01 The compound was diluted to 28nM, 0.00256nM, and 0.00051nM, with a final DMSO concentration of 0.2%. 0.2% DMSO and RPMI1640 medium (without cells and compound) were set as the solvent and negative control, respectively. Two replicates were set for each concentration. After the test compound was mixed, the 96-well plate was placed in a 37°C, 5% CO2 incubator and cultured (Mino cells were incubated for 96 hours, REC-1 and TMD8 cells were incubated for 72 hours). After treatment, the culture plate was placed at room temperature, 50μL CTG reagent was added, and the mixture was shaken for 2 minutes and incubated at room temperature for 10 minutes. The luminescence signal (RLU) of each well was measured using a microplate reader, and the inhibition rate of cell growth in each well was calculated. The dose-effect curve was fitted and the half-inhibitory concentration (IC50) was calculated.

[0573] Table 1 IC values ​​of exemplary compounds of this application on TMD8 / Mino cells 50 - indicates that the activity was not determined.

[0574] The exemplary compounds of the present application all exhibit excellent proliferation inhibition ability on relevant tumor cells.

[0575] Test Example 2: BTK mutant cell activity inhibition test

[0576] REC-1-BTK-L528W cells or Baf3-BTK-T474I cells in the logarithmic growth phase were plated into 96-well plates at 3 × 10 cells per well. 3 Cells were prepared by adding compound solutions of varying concentrations (starting at 2 μM and followed by five-fold serial dilutions), gently tapping to mix, and incubating in a cell culture incubator for 72 hours. 50 μL of CellTiter-Glo reagent was added, vortexed for 2 minutes, and incubated at room temperature for 10 minutes. The luminescence signal (RLU) of each well was measured using a microplate reader, and the inhibition rate of cell growth in each well was calculated. A dose-effect curve was then fitted to calculate the half-inhibitory concentration (IC50).

[0577] Table 2 IC of exemplary compounds of the present application against BTK-L528W / T474I mutant cells 50

[0578] - indicates that the activity was not determined.

[0579] The exemplary compounds of the present application all exhibit excellent proliferation inhibition ability against cells carrying BTK mutations.

[0580] Test Example 3: Single oral administration test in mice

[0581] Mice were administered a single oral dose of 10 mg / kg. On the day of administration, the compound was dissolved in 10% DMSO + 40% PEG 400 + 5% Tween 80 + 45% Saline and vortexed until a clear, transparent solution was obtained. Whole blood samples were collected 6 and 24 hours after oral administration, as well as a spleen sample collected 24 hours after oral administration, and BTK protein levels were analyzed by Western blotting.

[0582] Whole blood samples were pretreated using a whole blood protein extraction kit. According to the instructions, 100× PMSF was added to the protein extract and vortexed to mix thoroughly. An equal volume of the protein extract was added to the whole blood sample, mixed thoroughly, and then shaken on ice for 20 minutes. A cannula was inserted into the inner column of the spin column, and the extract was aspirated into the spin column. Centrifuge at 4°C, 10,000×g for 3–5 minutes. The liquid in the cannula was collected to obtain the total blood protein.

[0583] Mince the mouse spleen sample and add 150 μL of RIPA lysis buffer containing PMSF. Grind the tissue using a homogenizer on ice and continue lysing on ice for 10-20 minutes. Centrifuge at 4°C, 13,000 × g for 30 minutes. Transfer the supernatant to a fresh centrifuge tube to obtain total spleen protein.

[0584] Protein concentration was determined by the BCA assay. After heat denaturation, the proteins were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to a PVDF membrane. The membranes were incubated with blocking buffer for 1 hour at room temperature. BTK and GAPDH primary antibodies (both diluted 1:1000) were incubated overnight at 4°C. After three washes with TBST, HRP-conjugated rabbit anti-goat secondary antibodies (diluted 1:10,000) were added and incubated for 1 hour at room temperature. The membranes were then washed three times with TBST. After addition of ECL chemiluminescent solution, the gels were imaged using a gel imaging system. The grayscale values ​​of the target protein bands were calculated using Image-Pro Plus 6.0 software. The relative levels of BTK protein were compared with those in the vehicle group, and the degradation rate (Deg%) was calculated.

[0585] Table 3 BTK degradation rate in whole blood / spleen of mice after single administration of exemplary compounds of the present application A: >80%, B: 60-80%, C: <60%, - indicates not determined.

[0586] The data in Table 3 show that the exemplary compounds of the present application all exhibit strong degradation ability for BTK in mice.

[0587] For the purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications become part of the common general knowledge in the art in any country.

[0588] The embodiments described above are merely descriptions of preferred implementation methods of the present application and do not limit the scope of the present application. Without departing from the design spirit of the present application, various modifications and improvements made to the technical solutions of the present application by ordinary technicians in this field should fall within the scope of protection determined by the claims of the present application.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof: in, Ring A is selected from the group consisting of a substituted 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclic group; D is selected from a bond, -CR1R1'-, -S-, -O- or -NR2-(CH2) m -; Ring B is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl or C3-C 12 Cycloalkyl; W1 and W2 are each independently selected from C or N; R a Selected from H, C1-C6 alkyl or -C(=O)-NH2; R b1 Selected from C1-C6 haloalkyl, C1-C6 alkyl or halogen; R b2 is selected from 4-6 membered heterocyclyl, -C(=O)-R3, -NR4R5, -S(=O)2R3 or -NR6-C(=O)-R7; the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R8; R1, R1', R c , R2 are each independently selected from H, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy or C1-C6 alkyl; R3 are each independently selected from C3-C 10 Cycloalkyl, 5-12 heterocyclic, C1-C6 alkyl, C1-C6 haloalkyl, -S(=O)2CH3 or NR4R5, the C3-C 10 Cycloalkyl, 5-12 heterocyclyl, C1-C6 alkyl, C1-C6 haloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy or C1-C6 haloalkyl; R4, R5, R6 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3; R7 is selected from a 5-6 membered heteroaryl or a benzene ring optionally substituted with 1-3 R9; R8 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3; R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl; L is -X1-X2-X3-X4-X5-X6-; X1 is selected from a bond, -C(=O)-, C1-C6 alkylene, C5-C8 monocycloalkyl, C7-C 12 Spiroalkyl, 7-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group or 3-8 membered monoheterocyclic group; the C5-C8 monocycloalkyl, C7-C 12 Spirocycloalkyl, 7-12 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl or 3-8 membered monoheterocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, -C(O)NH2, hydroxyl or halogen; X2 is selected from a bond, -C(=O)- or C1-C6 alkylene; X3, X4, X5, and X6 are each independently selected from a bond, a 3-12 membered heterocyclic group, a C1-C6 alkylene group, a C3-C 10 Cycloalkyl, -O-, -NR2- or -C(=O)-; X1, X2, X3, X4, X5, and X6 are not all bonds; Y is selected from wherein W3 is selected from N or C; Ring E1 is selected from R e is selected from halogen, methyl, methoxy or trifluoromethyl; Ring E2 is selected from 5-10 membered heteroaryl; m, p, q are selected from 0, 1, 2 or 3; s is selected from 0, 1 or 2.

2. A compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated form thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof: in, Ring A is selected from the group consisting of a substituted 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclic group; D is selected from a bond, -CR1R1'-, -S-, -O- or -NR2-(CH2) m -; Ring B is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl or C3-C 12 Cycloalkyl; W1 and W2 are each independently selected from C or N; R a Selected from H, C1-C6 alkyl or -C(=O)-NH2; R b1 Selected from C1-C6 haloalkyl, C1-C6 alkyl or halogen; R b2 is selected from 4-6 membered heterocyclyl, -C(=O)-R3, -NR4R5, -S(=O)2R3 or -NR6-C(=O)-R7; the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R8; R1, R1', R c , R2 are each independently selected from H, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy or C1-C6 alkyl; R3 are each independently selected from C3-C 10 Cycloalkyl, 5-12 heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -S(=O)2CH3 or NR4R5, the C3-C 10 Cycloalkyl, 5-12 heterocyclyl, C1-C6 alkyl, C1-C6 haloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy or C1-C6 haloalkyl; R4, R5, R6 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3; R7 is selected from a 5-6 membered heteroaryl or a benzene ring optionally substituted with 1-3 R9; R8 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3; R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl; L is -X1-X2-X3-X4-X5-X6-; X1 is selected from a bond, -C(=O)-, C1-C6 alkylene, C5-C8 monocycloalkyl, C7-C 12 Spiroalkyl, 7-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group or 3-8 membered monoheterocyclic group; the C5-C8 monocycloalkyl, C7-C 12 Spirocycloalkyl, 7-12 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl or 3-8 membered monoheterocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, -C(O)NH2, hydroxyl or halogen; X2 is selected from a bond, -C(=O)- or C1-C6 alkylene; X3, X4, X5, and X6 are each independently selected from a bond, a 3-12 membered heterocyclic group, a C1-C6 alkylene group, a C3-C 10 Cycloalkyl, -O-, -NR2- or -C(=O)-; X1, X2, X3, X4, X5, and X6 are not all bonds; Y is selected from wherein W3 is selected from N or C; Ring E1 is selected from R e is selected from halogen, methyl, methoxy or trifluoromethyl; Ring E2 is selected from 5-10 membered heteroaryl; m, p, q are selected from 0, 1, 2 or 3; s is selected from 0, 1 or 2.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: Ring A is selected from * indicates the position of attachment to D; provided that: when ring A is selected from Y is R a Selected from H, C1-C3 alkyl or C(=O)-NH2, preferably selected from C1-C3 alkyl or C(=O)-NH2, more preferably selected from -CH3 or C(=O)-NH2; R b1 Selected from C1-C6 haloalkyl, C1-C6 alkyl or halogen, preferably selected from C1-C3 haloalkyl, C1-C3 alkyl or halogen, more preferably selected from C1-C3 alkyl or halogen.

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: R b2 Selected from -C(=O)-R3, -NR4R5 or -S(=O)2R3; R3 is each independently selected from C3-C5 cycloalkyl, C1-C3 alkyl or C1-C3 alkoxy, and the C3-C5 cycloalkyl, C1-C3 alkyl or C1-C3 alkoxy may be optionally substituted with 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy or C1-C6 haloalkyl; R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl, preferably selected from C1-C3 alkyl or C1-C3 hydroxyalkyl; Each R8 is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl or -S(=O)2CH3, preferably selected from H or C1-C3 alkyl; t is selected from 0, 1 or 2.

5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: Y is selected from: Preferably selected from 6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: It has the structure shown in formula (II): in, W1, W2, W3 are each independently selected from C or N; D is selected from a bond, -CR1R1'-, -S-, -O- or -NR2-(CH2) m -; Ring B is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl or C3-C6 cycloalkyl; R b2 is selected from 4-6 membered heterocyclyl, -C(=O)-R3, -NR4R5, -S(=O)2R3 or -NR6-C(=O)-R7; the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R8; R1, R1', R c , R2 are each independently selected from H, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy or C1-C6 alkyl; R3 are each independently selected from C3-C 10 Cycloalkyl, 5-12 heterocyclic, C1-C6 alkyl, C1-C6 haloalkyl, -S(=O)2CH3 or NR4R5, the C3-C 10 Cycloalkyl, 5-12 heterocyclyl, C1-C6 alkyl, C1-C6 haloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl; R4, R5, R6 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3; R7 is selected from a 5-6 membered heteroaryl or a benzene ring optionally substituted with 1-3 R9; R8 are each independently H, C1-C6 alkyl or -S(=O)2CH3; R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl; Ring E1 is selected from R e is selected from halogen, methyl, methoxy or trifluoromethyl; m, s, and p are selected from 0, 1, or 2.

7. The compound according to any one of claims 2 to 5, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: It has the structure shown in formula (II): in, W1, W2, W3 are each independently selected from C or N; D is selected from a bond, -CR1R1'-, -S-, -O- or -NR2-(CH2) m -; Ring B is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl or C3-C6 cycloalkyl; R b2 is selected from 4-6 membered heterocyclyl, -C(=O)-R3, -NR4R5, -S(=O)2R3 or -NR6-C(=O)-R7; the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R8; R1, R1', R c , R2 are each independently selected from H, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy or C1-C6 alkyl; R3 are each independently selected from C3-C 10 Cycloalkyl, 5-12 heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -S(=O)2CH3 or NR4R5, the C3-C 10 Cycloalkyl, 5-12 heterocyclyl, C1-C6 alkyl, C1-C6 haloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, cyano, -SF5, C1-C6 alkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl; R4, R5, R6 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3; R7 is selected from a 5-6 membered heteroaryl or a benzene ring optionally substituted with 1-3 R9; R8 are each independently selected from H, C1-C6 alkyl or -S(=O)2CH3; R9 is selected from halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl; L is -X1-X2-X3-X4-X5-X6-; X1 is selected from a bond, -C(=O)-, C1-C6 alkylene, C5-C8 monocycloalkyl, C7-C 12 Spiroalkyl, 7-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group or 3-8 membered monoheterocyclic group; the C5-C8 monocycloalkyl, C7-C 12 Spirocycloalkyl, 7-12 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl or 3-8 membered monoheterocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, -C(O)NH2, hydroxyl or halogen; X2 is selected from a bond, -C(=O)- or C1-C6 alkylene; X3, X4, X5, and X6 are each independently selected from a bond, a 3-12 membered heterocyclic group, a C1-C6 alkylene group, a C3-C 10 Cycloalkyl, -O-, -NR2- or -C(=O)-; X1, X2, X3, X4, X5, and X6 are not all bonds; Ring E1 is selected from R e is selected from halogen, methyl, methoxy or trifluoromethyl; m, s, and p are selected from 0, 1, or 2.

8. The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its deuterated substance, its stereoisomer, its tautomer or a mixture thereof, wherein: Ring E1 is selected from Preferably, ring E1 is selected from * indicates the location where and is attached to L; Preferably, ring B is selected from a benzene ring, a 5-6 membered heteroaryl, a 5-6 membered heterocyclyl or a C3-C6 cycloalkyl; preferably, ring B is selected from W3 is selected from C or N; further preferably, ring B is selected from *Indicates the location of attachment to D.

9. The compound according to any one of claims 2 to 5 or 8, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: Ring A is selected from * indicates the position of attachment to D, provided that: when ring A is selected from Y is R a Selected from C1-C3 alkyl or C(=O)-NH2, preferably selected from -CH3 or C(=O)-NH2; D is selected from a bond, -NH-, -N(CH3)- or -NH-CH2-, preferably selected from a bond, -NH- or -N(CH3)-; W1 and W2 are each independently selected from C or N; Ring B is selected from * indicates the location of attachment to D; R b1 is selected from C1-C3 alkyl or halogen, preferably selected from -CH3 or F; R b2 Selected from or -S(=O)2CH3, Or choose -C(=O)OCH3 or -S(=O)2CH3; q is selected from 0, 1 or 2; Y is selected from L is selected from * Indicates the location attached to Y.

10. The compound according to any one of claims 6 to 8, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: D is selected from a bond, -NH-, -N(CH3)- or -NH-CH2-, preferably selected from a bond, -NH- or -N(CH3)-; W1, W2, W3 are each independently selected from C or N; Ring B is selected from Preferably selected from * indicates the location of attachment to D; R b2 Selected from or -S(=O)2CH3; or selected from -C(=O)OCH3 or -S(=O)2CH3; Ring E1 is selected from L is selected from * Indicates the location attached to Y.

11. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, characterized in that: The compounds have structures shown in formulas (I-1) to (I-4): in, W4 is selected from C or N; W1, W2, W3, R c , R2, R b2 、R e 、R a , R7, Ring B, L, Y, Ring E1, m, p, q, s are as defined in any one of claims 1-5.

12. The compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, characterized in that: L is -X1-X2-X3-X4-X5-X6- * ; * Indicates the location attached to Y; X1 is selected from a bond, -C(=O)-, C1-C6 alkylene, C5-C8 monocycloalkyl, C7-C 12 Spiroalkyl, 7-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group or 3-8 membered monoheterocyclic group; the C5-C8 monocycloalkyl, C7-C 12 Spirocycloalkyl, 7-12 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl or 3-8 membered monoheterocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, -C(O)NH2, hydroxyl or halogen; X2 is selected from a bond or -C(=O)-; X3, X4, X5, and X6 are each independently selected from a bond, a 4-6 membered heterocyclyl, a C1-C3 alkylene group, a C3-C6 cycloalkyl group, -O-, -NH-, or -C(=O)-; not all of X1, X2, X3, X4, X5, and X6 are bonds; Preferably, L is selected from 13. The compound of formula (I) according to any one of claims 1 to 12, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, characterized in that: The compound is selected from:

14. The compound according to any one of claims 1 to 13, its pharmaceutically acceptable salt, its deuterated substance, its stereoisomer, its tautomer or a mixture thereof for use in preventing and / or treating a disease or condition mediated by degradation of Bruton's tyrosine kinase (BTK).

15. The compound for use according to claim 14, its pharmaceutically acceptable salt, its deuterated substance, its stereoisomer, its tautomer or a mixture thereof, wherein the disease or condition is cancer or an autoimmune disease; preferably, the cancer includes hematological cancers such as myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hairy cell leukemia, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma and follicular lymphoma; the autoimmune disease includes inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, St. Petersburg, cerebral ischemia, leukemia, leukemia, spondylosis ... Teal's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, immune thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvodynia, and chronic graft-versus-host disease.