Macrocyclic EGFR degrader compound and use thereof

Abstract

The present application relates to a degrader compound targeting EGFR, and specifically provides a compound as represented by formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof. The compound has the substituents and structural features described in the present application. The present application further provides a pharmaceutical composition comprising the compound as represented by formula (I) or the stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutical use of the compound or the stereoisomer or pharmaceutically acceptable salt thereof.

Description

Macrocyclic EGFR degrading agents and their applications

[0001] Cross-references to related applications

[0002] This application claims priority and benefits from the following patent applications, the entire contents of which are incorporated herein by reference:

[0003] Chinese Invention Patent Application No. 202410688893.7, filed with the State Intellectual Property Office of the People's Republic of China on May 30, 2024;

[0004] Chinese Invention Patent Application No. 202510057521.9, filed with the State Intellectual Property Office of the People's Republic of China on January 14, 2025; and

[0005] Chinese Invention Patent Application No. 202510567928.6 was filed with the State Intellectual Property Office of the People's Republic of China on April 30, 2025. Technical Field

[0006] This disclosure relates to macrocyclic compounds or their stereoisomers or pharmaceutically acceptable salts as EGFR degrading agents, methods for their preparation, pharmaceutical compositions containing the compound or its stereoisomers or pharmaceutically acceptable salts, and the use of said compound or its stereoisomers or pharmaceutically acceptable salts in the prevention or treatment of EGFR-mediated or EGFR-related diseases. Background Technology

[0007] Epidermal growth factor receptor (EGFR) is a transmembrane protein belonging to the tyrosine kinase family. EGFR plays a crucial role in physiological processes such as cell growth, proliferation, and differentiation. However, EGFR mutations or overexpression can lead to persistent activation of the EGFR signaling pathway, resulting in abnormal cell proliferation. Studies have shown that 30% of lung cancer patients are caused by EGFR mutations. EGFR-targeted therapy has made rapid progress in the past decade, but with the advancement of treatment, drug resistance has gradually emerged, thus necessitating the development of new treatment methods.

[0008] PROTAC (Proteolysis Targeting Chimera) is a heterobifunctional small molecule composed of three parts: a protein-binding ligand, a ligand that binds to the ubiquitin ligase E3, and a linker connecting the two. PROTAC brings the target protein to be degraded closer to the intracellular ubiquitin ligase E3, forming a target protein-PROTAC-E3 ternary complex. This makes the target protein more easily ubiquitinated by the E3 ubiquitin ligase. The ubiquitinated protein triggers the intracellular ubiquitination-proteasome system, specifically degrading the target protein, reducing its level, and thus inhibiting the protein-mediated signaling pathway. Compared to small molecule inhibitors, PROTAC has better selectivity, overcomes small molecule resistance, and can degrade some difficult-to-treat targets. Furthermore, unlike small molecule inhibitors which merely occupy the target site, PROTAC technology can degrade the target protein, providing more effective inhibition of EGFR-mediated signaling pathways. This has the potential to solve the problem of EGFR small molecule resistance in the current market and become an effective method for treating EGFR-mediated diseases. Summary of the Invention

[0009] This disclosure relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: TL-Linker-DIM

[0010] (I)

[0011] in:

[0012] The DIM is a ligand compound capable of binding to cereblon-type E3 ubiquitin ligases;

[0013] The Linker is a linker group that covalently binds at least one TL and at least one DIM;

[0014] The TL group is one of the following groups:

[0015] in:

[0016] Ring A is selected from C3-C6 cycloalkyl, 4-10 membered heterocyclic groups, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0017] Ring B is selected from phenylene or 5-10-membered heteroaryl groups;

[0018] L 1 L 3 They are selected independently from each other, C1-C 10 Alkylene, C2-C 10 alkenyl or C2-C 10 Imyynyl group, the C1-C 10Alkylene, C2-C 10 alkenyl or C2-C 10 The alkynyl group may be optionally replaced by one or more groups selected from OH, SH, NH2, halogen, CN, and C1-C4 alkoxy groups;

[0019] L 2 Selected from key, NR 4 C1-C 10 Alkylene, C2-C 10 alkenyl, C2-C 10 Ethyneyl, C3-C6 cycloalkylene, 4-8 heterocyclic alkylene, C6-C 10 arylene or 5-10 quinone heteroarylene, wherein C1-C 10 Alkylene, C2-C 10 alkenyl, C2-C 10 Ethyneyl, C3-C6 cycloalkylene, 4-8 heterocyclic alkylene, C6-C 10 arylene or 5-10 heteroarylene, optionally enclosed by one or more R t Replaced;

[0020] L 4 Selected from O, S, NR 5 CHR 5 or C(R) 5 )2;

[0021] R 4 R 5 They are selected independently from H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl, wherein C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 4a Replaced;

[0022] Each R 1 Independently selected from OH, halogen, CN, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 1a Replaced;

[0023] Each R 2 Independently selected from OH, halogen, CN, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 2a Replaced;

[0024] R 3 Selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic groups, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 3a Replaced;

[0025] Each R t The radical is independently selected from deuterium, OH, halogen, CN, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4-8-membered heterocyclic group or 5-10-membered heteroaryl group, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4-8-membered heterocyclic group or 5-10-membered heteroaryl group is optionally surrounded by one or more R. b Replaced;

[0026] Each R 1a R 2a R 3a R 4a The groups are independently selected from deuterium, halogens, CN, OH, NH2, =O, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, or 4-6-membered heterocyclic groups, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, or 4-6-membered heterocyclic group is optionally surrounded by one or more R groups. b Replaced;

[0027] R b Selected from deuterium, halogen, OH, NH2, =O, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or 4-6 membered heterocyclic groups;

[0028] r is selected from 0, 1, 2, 3, 4 or 5;

[0029] t is selected from 0, 1, 2, 3 or 4.

[0030] In some implementations, ring A is selected from 4-10 membered heterocyclic groups, C6-C 10 Aryl or 5-10 heteroaryl compounds.

[0031] In some embodiments, ring A is selected from phenyl or 5-6 heteroaryl groups.

[0032] In some embodiments, ring A is selected from phenyl, furanyl, thiophene, pyrrole, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, or tetrahydroisoquinolinyl.

[0033] In some implementations, ring A is a phenyl group.

[0034] In some embodiments, ring B is a phenylene or a 5-6 membered heteroaryl group.

[0035] In some implementations, ring B is a 5-6 member heteroaryl group.

[0036] In some embodiments, ring B is pyridinyl or pyrazolyl. In some embodiments, ring B is phenylene or pyrazolyl. In some embodiments, ring B is pyrazolyl.

[0037] In some implementation schemes, ring B is

[0038] In some implementation schemes, ring B is

[0039] In some implementation schemes, ring B is Where * represents L 4 The connection position.

[0040] In some implementation schemes, ring B is Where * represents L 4 The connection position.

[0041] In some implementation schemes, for Where * represents L 4 The connection position.

[0042] In some implementation schemes, for Where * represents L 4 The connection position.

[0043] In some implementations, L 1The group is selected from C1-C6 alkylene groups, wherein the C1-C6 alkylene groups are optionally substituted by one or more groups selected from OH, SH, NH2, halogen, CN or C1-C4 alkoxy groups.

[0044] In some implementations, L 1 Selected from key, The asterisk (*) represents L. 2 The connected positions.

[0045] In some implementations, L 2 Selected from key, NR 4 C1-C6 alkylene, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group, wherein the C1-C6 alkylene, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group is optionally surrounded by one or more R t What it replaced.

[0046] In some implementation schemes, R 4 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group is optionally surrounded by one or more R groups. 4a What it replaced.

[0047] In some implementation schemes, R 4 Selected from H, C1-C6 alkyl or 4-6 membered heterocyclic groups, wherein the C1-C6 alkyl or 4-6 membered heterocyclic group is optionally surrounded by one or more R groups. 4a What it replaced.

[0048] In some implementations, L 2 Selected from a bond, a C1-C6 alkylene group or a 4-8 membered heterocyclic group, wherein the C1-C6 alkylene group or the 4-8 membered heterocyclic group is optionally surrounded by one or more R groups. t What it replaced.

[0049] In some implementations, L 2 Selected from C1-C6 alkylene groups or 4-8 membered heterocyclic groups containing one or two N atoms as heteroatoms, wherein the C1-C6 alkylene group or the 4-8 membered heterocyclic group containing one or two N atoms as heteroatoms is optionally separated by one or more R t What it replaced.

[0050] In some implementation schemes, each R t The OH, NH2, or C1-C6 alkyl group is independently selected from deuterium, OH, halogen, CN, NH2, or C1-C6 alkyl group, wherein the OH, NH2, or C1-C6 alkyl group is optionally converted by one or more R b What it replaced.

[0051] In some implementation schemes, each R tIt is independently selected from deuterium, OH, halogen, CN, NH2 or C1-C6 alkyl.

[0052] In some implementations, L 2 Selected from key, Where * represents L 3 The connected positions.

[0053] In some implementations, L 3 The group is selected from C1-C6 alkylene groups, wherein the C1-C6 alkylene groups are optionally substituted by one or more groups selected from OH, SH, NH2, halogen, CN or C1-C4 alkoxy groups.

[0054] In some implementations, L 3 Selected from key, The asterisk (*) represents L. 4 The connected positions.

[0055] In some implementations, L 4 Selected from O, S or NR 5 .

[0056] In some implementations, L 4 Selected from O or NR 5 .

[0057] In some implementation schemes, R 5 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group is optionally surrounded by one or more R groups. 4a What it replaced.

[0058] In some implementations, L 4 Selected from O or NR 5 R 5 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group is optionally surrounded by one or more R groups. 4a What it replaced.

[0059] In some implementations, L 4 Selected from O or NH.

[0060] In some implementations, L 4 Selected from O.

[0061] In some implementations, -L 1 -L 2 -L 3 -L 4 -Selected from in This represents the bond connected to ring B.

[0062] In some implementation schemes, each R 1 Independently selected from OH, halogen, NH2, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, NH2, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally surrounded by one or more R 1a What it replaced.

[0063] In some implementation schemes, each R 1 Independently selected from OH, halogens, or NH2, wherein the OH or NH2 is optionally reacted with one or more R 1a What it replaced.

[0064] In some implementations, r is 0, 1, or 2.

[0065] In some implementations, r is 0.

[0066] In some implementation schemes, each R 2 Independently selected from halogens, C1-C6 alkyl groups, or C3-C6 cycloalkyl groups, wherein the C1-C6 alkyl group or C3-C6 cycloalkyl group is optionally converted by one or more R groups. 2a What it replaced.

[0067] In some implementation schemes, each R 2 It is independently selected from C1-C6 alkyl groups, such as methyl.

[0068] In some implementations, t is 0 or 1.

[0069] In some implementations, t is 1.

[0070] In some implementation schemes, (R 2 ) t Selected from methyl.

[0071] In some implementation schemes, R 3 Selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally converted by one or more R 3a What it replaced.

[0072] In some implementation schemes, R 3 Selected from one or more R 3a The substituted methyl group.

[0073] In some implementation schemes, each R 1a R 2a R 3a R 4aThe components are independently selected from deuterium, halogens, CN, OH, NH2, =O, or C1-C6 alkyl groups, wherein the OH, NH2, or C1-C6 alkyl group is optionally converted by one or more R groups. b What it replaced.

[0074] In some implementation schemes, each R 1a R 2a R 3a R 4a They are independently selected from deuterium, halogens, CN, OH, =O or C1-C6 alkyl groups.

[0075] In some implementation schemes, each R b It is independently selected from deuterium, halogen, OH, NH2, =O, C1-C3 alkyl or C1-C3 alkoxy.

[0076] In some implementation schemes, R 3a Selected from halogens, such as F.

[0077] In some implementation schemes, R 3 Selected from methyl, CH2F, CHF2 or CF3.

[0078] In some implementations, r = 1, and the TL is transmitted through R. 1 Connected to the Linker, i.e., the TL is:

[0079] In some implementations, r = 0, and the TL is directly connected to the Linker through ring A, i.e., the TL is:

[0080] In some implementations, the TL is selected from...

[0081] In some implementations, the TL is selected from...

[0082] In some implementations, the Linker is a linker group covalently bonded to a TL and a DIM.

[0083] In some implementations, the Linker is selected from -L A -、-L B -、-R 1L -、-R 2L -、-Q 1 -、-Q 2 -、

[0084] Where: -L A -、-L B - are selected independently of the following keys: -O-, -S-, -NR 3’ -、-CR 4’ R 5’ -、-CR 4’ R 5’ -NR 3’ -、-CR 4’ R 5’ -O-、-C(O)-、-CR 4’ R 5’ -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ -;

[0085] R 1L and R 2L The groups are independently selected from bonds, -C(O)-, alkylene, heteroalkylene, alkenyl or ynylene, wherein the alkylene, heteroalkylene, alkenyl or ynylene groups are optionally substituted by groups selected from the following: halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclic, aryl or heteroaryl.

[0086] Q 1 Q 2 Q 3 and Q 4 The groups are independently selected from cycloalkyl, heterocyclic, aryl, heteroaryl, or cycloalkenyl groups, wherein each of the cycloalkyl, heterocyclic, aryl, heteroaryl, or cycloalkenyl groups is optionally substituted by a group selected from the following groups: halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0087] R 3’ Selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0088] R 4’ and R 5’ Each is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0089] R 6’ It is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl.

[0090] In some implementations, the Linker is selected from...

[0091] In some implementation schemes, Q 1 Q 2 Q 3 The groups are independently selected from C3-C8 cycloalkyl or 4-10 heterocyclic groups, wherein the C3-C8 cycloalkyl or 4-10 heterocyclic groups are optionally substituted by groups selected from the following: halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, OH, C1-C3 hydroxyalkyl or NH2.

[0092] In some implementation schemes, Q 1 Q 2 Q 3 Each of the groups is a 4-10 membered heterocyclic group, which may be optionally substituted with the following groups: halogen, C1-C3 alkyl, =O.

[0093] In some implementations, -L A -、-L B - Selected independently from: key, -O-, -CR 4’ R 5’ -

[0094] In some implementation schemes, R 4’ and R 5’ Each is independently selected from H and halogens.

[0095] In some implementation schemes, R 1L and R 2L The groups are independently selected from: bonds, C1-C6 alkylene or C1-C6 ynynylene, wherein the C1-C6 alkylene or C1-C6 ynynylene is optionally substituted by groups selected from: halogen, OH.

[0096] In some implementations, the Linker is selected from the following structures: key,

[0097] In some implementations, the Linker is selected from the following structures:

[0098] In some implementations, the Linker is selected from the following structures:

[0099] In some embodiments, the DIM is selected from the structure shown in formula (DIM-1) or (DIM-2):

[0100] in:

[0101] Selected from

[0102] Y is the key, or Y is selected from Y. A , O, NH, NR E C(O)O, C(O)NR E '、NR E 'C(O), Y A -NH、Y A -NR E Y A -C(O), Y A -C(O)O、Y A -OC(O), Y A -C(O)NR E 'or Y A -NR E 'C(O), wherein Y A Selected from C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 ynylene;

[0103] X is selected from C(O) or C(R). A )2;X A -X B Selected from C(R) A ) = N or C(R) A )2-C(R A )2;

[0104] Each R A Independently selected from H or C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally divided by C6-C 10 Aryl or 5-10 heteroaryl substitutions;

[0105] Each R A 'Independently selected from C1-C3 alkyl groups;'

[0106] Each R B Independently selected from H or C1-C3 alkyl groups, or two R groups. B Together with the atoms attached to it, they form C(O), C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-6 membered heterocyclic groups;

[0107] R C Selected from H, halogens, or C1-C3 alkyl groups;

[0108] Each R DIt is independently selected from halogens, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy groups;

[0109] Each R E Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocyclic alkyl, wherein R E Optional substitution with groups selected from the following: halogen, N(R) a 2. NHC(O)R a ,NHC(O)OR a OR b C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl, C6-C 10 The aryl or 5-10 heteroaryl group may be further substituted with a group selected from the following: halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

[0110] R E 'Selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocyclic alkyl may optionally be substituted by a group selected from the following: halogen, N(R a 2. NHC(O)R a ,NHC(O)OR a OR b C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl, C6-C 10 The aryl or 5-10 heteroaryl group may be further substituted with a group selected from the following: halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

[0111] Each R a Independently selected from H or C1-C6 alkyl groups;

[0112] R b Selected from H or p-toluenesulfonyl;

[0113] t is selected from 0 or 1;

[0114] m is selected from 0, 1, 2, or 3;

[0115] p is selected from 0, 1, or 2.

[0116] In some embodiments, the DIM is further selected from the structure shown in formula (DIM-3) or (DIM-4):

[0117] Among them, the rings A, Y, R A R A '、R B R C R D m and p are as defined above.

[0118] In some embodiments, the DIM is further selected from the structure shown in formula (DIM-5), (DIM-6), (DIM-7), or (DIM-8):

[0119] Wherein, Y, X, X A -X B R A R A '、R B R C R D m and p are as defined above.

[0120] In some embodiments, the DIM is further selected from the structure shown in formula (DIM-9) or (DIM-10):

[0121] Wherein, Y, X, X A -X B R A R A '、R B R C R D m and p are as defined above.

[0122] In some implementations, the DIM is selected from the structure shown in formula (DIM-11):

[0123] in:

[0124] X C Selected from the following: -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R'-, -P(O)OR'-, -P(O)NR'2-, -C(O-), -C(S-) or X D Selected from C, N, or Si;

[0125] X E Selected from bond, -C(R')2-, -NR'-, -O-, -S- or -Si(R')2-;

[0126] R F Does not exist, or R F Selected from H, deuterium, halogen, CN, -OR'-, -SR'-, -S(O)R'-, -S(O)2R'-, -N(R')2-, -P(O)(OR')2, -P(O)(N(R')2)OR'-, -P(O)(N(R')2)2, -Si(OH)2R', -Si(OH)(R')2, -Si(R')3 or C1-C4 alkyl;

[0127] Each R G Independently selected from H, deuterium, and R H , Halogen, CN, -NO2, -OR', -SR', -N(R')2, -Si(R')3, -S(O)2R', -S(O)2N(R')2, -S(O)R', -C(O)R', -C(O)OR', -C(O) N(R')2, -C(O)N(R')OR', -C(R')2N(R')C(O)R', -C(R')2N(R')C(O)N(R')2, -OC(O)R', -OC(O)N(R')2, -OP(O) (R')2, -OP(O)(OR')2, -OP(O)(OR')N(R')2, -OP(O)(N(R')2)2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)N (R')2, -N(R')S(O)2R', -NP(O)(R')2, -N(R')P(O)(OR')2, -N(R')P(O)(OR')N(R')2 or -N(R')P(O)(N(R')2)2;

[0128] Each R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl;

[0129] Cycle E, cycle F, and cycle G are independently selected from phenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, 5-7 heterocyclic or 5-6 heteroaryl, wherein cycle E, cycle F and cycle G are each optionally further substituted with =O;

[0130] L 1Selected from bonds, C1-C3 alkylene, C2-C3 alkenyl or C2-C3 alkyne, wherein any one or two methylene groups in the C1-C3 alkylene, C2-C3 alkenyl or C2-C3 alkyne may optionally be replaced by the following groups: -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S- or -S(O)2-;

[0131] Each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, or two R's together with the atoms attached to them form a 4-7 membered heterocyclic or 5-6 membered heteroaryl;

[0132] q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0133] In some implementations, the DIM is selected from the structure shown in formula (DIM-11'):

[0134] Wherein X C R F R G , q, ring E, ring F and ring G are as defined in equation (DIM-11).

[0135] In some implementations, the DIM is selected from the structure shown in formula (DIM-12):

[0136] Wherein: cyclic H is selected from C5-C9 cycloalkyl, C5-C9 cycloalkenyl, or 5-9 membered heterocyclic groups, wherein the C5-C9 cycloalkyl, C5-C9 cycloalkenyl, or 5-9 membered heterocyclic group is optionally substituted with =O; k is selected from 0, 1, 2, 3, or 4; X C X D X E R F R G L 1 And ring E is as defined in equation (DIM-11).

[0137] In some implementations, the DIM is selected from the structure shown in (DIM-12'):

[0138] Wherein, X C R F R G , k, ring E and ring H are as defined in equation (DIM-12).

[0139] In some embodiments, the DIM is selected from the structure shown in formula (DIM-13):

[0140] Wherein, X C X D X E R F R G L 1 The ring E and k are defined as in equation (DIM-12).

[0141] In some embodiments, the DIM is selected from the structures shown in (DIM-1), (DIM-2), (DIM-3), (DIM-4), (DIM-5), (DIM-6), (DIM-7), (DIM-8), (DIM-9), or (DIM-10).

[0142] In some embodiments, the DIM is selected from the structure shown in formula (DIM-1), (DIM-2), (DIM-3), or (DIM-4). In some embodiments, the DIM is the structure shown in formula (DIM-1) or (DIM-3). In some embodiments, the DIM is the structure shown in formula (DIM-3).

[0143] In some implementations, the DIM is selected from the following structures:

[0144] In some implementations, the DIM is selected from the following structures:

[0145] In some implementations, the DIM is

[0146] In some embodiments, the compounds of this disclosure or their stereoisomers or pharmaceutically acceptable salts are selected from the following compounds or their stereoisomers or pharmaceutically acceptable salts:

[0147] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound represented by general formula (I) of this disclosure or a specific compound thereon or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0148] On the other hand, this disclosure provides a method for treating EGFR-mediated diseases in mammals, including administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of a compound of general formula (I) of this disclosure or a specific compound thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0149] On the other hand, this disclosure provides a method for treating tumors in mammals, comprising administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of a compound of general formula (I) or a specific compound thereof or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0150] On the other hand, this disclosure provides the use of compounds of general formula (I) or specific compounds described above, or their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of EGFR-mediated diseases.

[0151] On the other hand, this disclosure provides the use of compounds of general formula (I) or specific compounds described above, or their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of tumors.

[0152] On the other hand, this disclosure provides the use of compounds of general formula (I) or specific compounds described above, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of EGFR-mediated diseases.

[0153] On the other hand, this disclosure provides the use of compounds of general formula (I) or specific compounds described above, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of tumors.

[0154] On the other hand, this disclosure provides compounds of general formula (I) or specific compounds described above for the prevention or treatment of EGFR-mediated diseases, or their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof.

[0155] On the other hand, this disclosure provides compounds of general formula (I) or specific compounds described above for the prevention or treatment of tumors, or stereoisomers thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0156] In some implementations, EGFR-mediated diseases are selected from tumors.

[0157] In some implementations, the tumor is selected from cancer.

[0158] Terminology Definitions and Explanations

[0159] Unless otherwise stated, the terms used in this disclosure have the following meanings: the definitions of groups and terms recorded in this disclosure, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0160] In this article Indicates the connection site. For this article... of when When not attached to a fixed ring or atom, it indicates that it can be attached to any group within the brackets that contains a substituted hydrogen atom (including hydrogen atoms directly attached to the ring atom, hydrogen atoms on non-hydrogen substituents of the ring atom, and hydrogen atoms in further substituents of the substituent), after the loss of that hydrogen atom. For example... middle The connection locations include, but are not limited to, R 1 and its substituents, ring A, ring B, R 2 and its substituents, R 3 and its substituents, etc. middle The connection locations include R 1 and R 1 Substituent R 1a wait.

[0161] The term "capable of binding" refers to the ability to bind to a target in a measurable manner (e.g., the ligand of an E3 ubiquitin ligase can form a covalent bond with the cysteine ​​residue of the E3 ubiquitin ligase, etc.).

[0162] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins for targeted degradation. E3 ubiquitin ligases, alone or in combination with E2 ubiquitin ligases, are responsible for transferring ubiquitin to target proteins. Typically, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is linked to a first ubiquitin; a third ubiquitin to a second ubiquitin, and so on. Polyubiquitination labels the protein for degradation by the proteasome. However, there are also ubiquitination events limited to monoubiquitination, where the ubiquitin ligase adds only a single ubiquitin to the substrate molecule. Monoubiquitinated proteins do not target the proteasome for degradation but can instead alter their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Further complicating matters, E3 ubiquitin ligases can target different lysine residues on ubiquitin to create chains.

[0163] Unless otherwise specified, use wedge keys and virtual wedge keys. The absolute configuration of a solid center is represented by black solid bonds and imaginary bonds. It indicates the relative configuration of a stereocenter (such as the cis-trans configuration of alicyclic compounds).

[0164] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this disclosure can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0165] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0166] The compounds disclosed herein may have asymmetric atoms such as carbon, sulfur, nitrogen, and phosphorus atoms, or asymmetric double bonds. Therefore, the compounds disclosed herein may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E- and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof or other mixtures, such as mixtures enriched with enantiomers or diastereomers. All such isomers and mixtures thereof are within the scope of the definition of the compounds disclosed herein. Alkyl groups and other substituents may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms. All such isomers involved in all substituents and mixtures thereof are also included within the scope of the definition of the compounds disclosed herein. The compounds containing asymmetric atoms disclosed herein can be isolated in optically active pure form or in racemic form. The optically active pure form can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0167] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on the aromatic group.

[0168] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0169] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0170] The term "substituted" refers to the fact that a specific atom or group can be replaced with a specified other atom or group. For example, the CH2 in -CH2CH2CH2- can be replaced by O, S, or NH to obtain -CH2OCH2-, -OCH2CH2-, -CH2SCH2-, -SCH2CH2-, -CH2NHCH2-, or -NHCH2CH2-, etc.

[0171] When any variable (e.g., R) a R b When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is surrounded by two R... b Replaced, then each R b Each has its own independent options; for group N(C1-C6 alkyl)2, when C1-C6 alkyl is R b When substituted, the two C1-C6 alkyl groups have independent R groups. b Options.

[0172] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a bond.

[0173] When one of the variables is selected as a bond or does not exist, it means that the two groups it is connected to are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0174] Unless otherwise specified, the linking direction of the linking groups mentioned in this article is arbitrary.

[0175] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. R represents 1 Substitution can occur at any of the 1, 2, 3 or 4 positions on the benzene ring.

[0176] C in this article m -C n It refers to having an integer number of carbon atoms, either mn or in the range m to n. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Similarly, "m-membered" to "n-membered" indicates that the number of ring atoms is m to n. For example, 5-14-membered rings include 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, and 14-membered rings. It also includes any range from n to m. For example, 5-14-membered rings include 6-14-membered, 6-11-membered, 5-10-membered, 6-10-membered, and 6-8-membered rings.

[0177] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The hydrocarbon group is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. The term "C1-C" is used. 10"Alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1, 3-Dimethylbutyl or 1,2-Dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood as referring to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, specific examples including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C4 alkyl" can be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms. The "C1-C6 alkyl" 10 "alkyl" can include the range of "C1-C6 alkyl", "C1-C4 alkyl" or "C1-C3 alkyl", and "C1-C6 alkyl" can further include "C1-C4 alkyl" or "C1-C3 alkyl", and "C1-C4 alkyl" can further include "C1-C3 alkyl".

[0178] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- atoms are replaced by heteroatoms selected from NH, O and S, or where one or more -CH- atoms are replaced by N; wherein the alkyl group is as defined above.

[0179] The term "halogenated alkyl" refers to the group obtained by further substituting the alkyl group with a halogen, such as "C1-C6 haloalkyl" which refers to C1-C6 alkyl groups that have been further substituted with a halogen.

[0180] The term "hydroxyalkyl" refers to the group obtained by further substituting the alkyl group with OH.

[0181] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, that is, a residue derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably alkylene containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), and more preferably alkylene containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene, -CH(CH3)-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. The term "C1-C6 alkylene" can be understood to mean an alkylene having 1, 2, 3, 4, 5, or 6 carbon atoms. The term "C1-C3 alkylene" can be understood to mean an alkylene having 1, 2, or 3 carbon atoms. Preferably, “C1-C6 alkylene” may include “C1-C3 alkylene”.

[0182] The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- atoms are replaced by heteroatoms selected from N, O, and S; wherein the alkylene group is as defined above.

[0183] The term "alkoxy" refers to a monovalent group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols; it can be understood as "alkyloxy" or "alkyl-O-", where alkyl is defined as described above. The term "C1-C"... 10 "Alkoxy" can be understood as "C1-C" 10 "alkyloxy" or "C1-C" 10 Alkyl-O-”; the term “C1-C6 alkoxy” can be understood as “C1-C6 alkyloxy” or “C1-C6 alkyl-O-”. “C1-C3 alkoxy” can be understood as “C1-C3 alkyloxy” or “C1-C3 alkyl-O-”. The “C1-C” 10 "Alkoxy" can include the range of "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" can further include "C1-C3 alkoxy".

[0184] The term "haloalkoxy" refers to the group obtained by further substituting the alkoxy group with a halogen, such as "C1-C6 haloalkoxy" which refers to C1-C6 alkoxy groups that have been further substituted with a halogen.

[0185] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, either straight-chain or branched, and possessing at least one double bond. The term "C2-C" is also relevant. 10"Alkenyl" should be understood as referring to a straight-chain or branched unsaturated monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The term "C2-C6 alkenyl" should be understood as referring to a straight-chain or branched unsaturated monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms. 10 The term "alkenyl" is preferably "C2-C6 alkenyl" or "C2-C4 alkenyl," with "C2-C6 alkenyl" being more preferably "C2-C4 alkenyl," and even more preferably C2 or C3 alkenyl. It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, or (Z)-1-methylprop-1-enyl, etc.

[0186] The term "alkenyl" refers to a residue derived by further removing a hydrogen atom from an alkenyl group, wherein the definition of an alkenyl group is as described above. The term "C2-C6 alkenyl" should be understood as an alkenyl group having 2 to 6 carbon atoms. The term "C2-C3 alkenyl" should be understood as an alkenyl group having 2 or 3 carbon atoms. Preferably, "C2-C6 alkenyl" includes "C2-C3 alkenyl".

[0187] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, either straight-chain or branched, and possessing at least one triple bond. The term "C2-C" is also relevant. 10 "Alynyl" can be understood as representing a straight-chain or branched unsaturated monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The term "C2-C6 alkynyl" can be understood as representing a straight-chain or branched unsaturated monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms. Examples of "C2-C6 alkynyl" include, but are not limited to, ethynyl (-C≡CH) and propynyl (-C≡CCH). 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl. "C2-C 10 "Alynyl" can include "C2-C6 alkynyl" or "C2-C3 alkynyl", "C2-C6 alkynyl" can include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), propynyl-1-alkynyl (-C≡CCH3) or propynyl-2-alkynyl (propynyl).

[0188] The term "acetylenic" refers to a residue derived by further removing a hydrogen atom from an acetylenic group, where the definition of acetylenic is as shown above. The term "C2-C6 acetylenic" should be understood as an acetylenic group having 2 to 6 carbon atoms. The term "C2-C3 acetylenic" should be understood as an acetylenic group having 2 or 3 carbon atoms. Preferably, "C2-C6 acetylenic" includes "C2-C3 acetylenic".

[0189] The term "cycloalkyl" refers to a fully saturated carbon ring existing in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C" is also used. 10 "Cycloalkyl" should be understood as indicating a saturated monovalent monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The term "C3-C8 cycloalkyl" should be understood as indicating a saturated monovalent monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, 6, 7, or 8 carbon atoms. The term "C3-C6 cycloalkyl" should be understood as indicating a saturated monovalent monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, or 6 carbon atoms; specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term "C5-C9 cycloalkyl"... "Alkyl" should be understood as indicating a saturated monovalent monocyclic, fused, spirocyclic, or bridged ring having 5, 6, 7, 8, or 9 carbon atoms. The term "C5-C7 cycloalkyl" should be understood as indicating a saturated monovalent monocyclic, fused, spirocyclic, or bridged ring having 5, 6, or 7 carbon atoms. Specific examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. The term "C3-C7 cycloalkyl" should be understood as indicating a saturated monovalent monocyclic, fused, spirocyclic, or bridged ring having 5, 6, or 7 carbon atoms. 10 "Cycloalkyl" can include "C3-C8 cycloalkyl", "C3-C6 cycloalkyl", "C5-C9 cycloalkyl" or "C5-C7 cycloalkyl", the term "C3-C8 cycloalkyl" can include "C3-C6 cycloalkyl" or "C5-C7 cycloalkyl", and the term "C5-C9 cycloalkyl" can include "C5-C7 cycloalkyl".

[0190] The term "cycloalkylene" refers to a residue derived by further removing a hydrogen atom from a cycloalkyl group, as defined above. The term "C3-C6 cycloalkylene" should be understood as a cycloalkylene group having 3, 4, 5, or 6 carbon atoms.

[0191] The term "cycloalkenyl" refers to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring. Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. The term "C5-C" is also used. 10 "Cycloalkenyl" refers to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring, having 5, 6, 7, 8, 9, or 10 carbon atoms. The term "C5-C9 cycloalkenyl" refers to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring, having 5, 6, 7, 8, or 9 carbon atoms. The term "C5-C7 cycloalkenyl" refers to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring, having 5, 6, or 7 carbon atoms. The term "C3-C6 cycloalkenyl" refers to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring, having 3, 4, 5, or 6 carbon atoms. The term "C5-C..." 10 "Cycloalkenyl" can include "C5-C9 cycloalkenyl" or "C5-C7 cycloalkenyl", and the term "C5-C9 cycloalkenyl" can include "C5-C7 cycloalkenyl".

[0192] The term "heterocyclic group" or "heterocycle" refers to a fully saturated or partially saturated (not aromatic as a whole) monovalent monocyclic, fused, spirocyclic, or bridged ring group containing 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). These "heteratoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH-, or -NHC(=O)NH-, etc., which typically contain 3 to 20 ring atoms. The term "5-14 membered heterocyclic group" refers to a heterocyclic group with 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, and whose ring atoms contain 1 to 5 independent heteroatoms or heterogroups selected from those described above. "5-14 membered heterocyclic group" can include "6-14 membered heterocyclic group", "6-11 membered heterocyclic group", "6-10 membered heterocyclic group", "6-8 membered heterocyclic group", "5-10 membered heterocyclic group", "5-9 membered heterocyclic group", "5-8 membered heterocyclic group", or "5-7 membered heterocyclic group". The term "5-10 membered heterocyclic group" can include "5-9 membered heterocyclic group", "5-8 membered heterocyclic group", "5-7 membered heterocyclic group", "6-10 membered heterocyclic group", or "6-8 membered heterocyclic group". The term "4-10 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and whose ring atoms contain 1-5 independently selected heteroatoms or heteroatomic groups as described above. "4-10 membered heterocyclic group" includes "4-7 membered heterocyclic group", wherein specific examples of 4 membered heterocyclic groups include, but are not limited to, azacyclobutane or oxacyclobutane; specific examples of 5 membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic groups include, but are not limited to... Limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazineyl, trithiaalkyl, tetrahydropyridinyl, or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups include, but are not limited to, diazacycloheptyl. The heterocyclic group can also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopentano[c]pyrrolo-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazinolo-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group can be a benzofused cyclic group of the above-mentioned 4-7-membered heterocyclic groups, specific examples including, but not limited to, dihydroisoquinolinyl, etc."4-10 membered heterocyclic group" can include "5-10 membered heterocyclic group", "5-9 membered heterocyclic group", "5-8 membered heterocyclic group", "5-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-10 membered heterocyclic group", "6-8 membered heterocyclic group", "4-8 membered heterocyclic group", "4-7 membered heterocyclic group", "4-6 membered heterocyclic group", "4-10 membered heterocyclic alkyl group", "5-10 membered heterocyclic alkyl group", "4-7 membered heterocyclic alkyl group", "5-6 membered heterocyclic alkyl group", "6-8 membered heterocyclic alkyl group", etc. "4-7 membered heterocyclic group" can further include "4-6 membered heterocyclic group", "5-7 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocyclic alkyl group", "4-6 membered heterocyclic alkyl group", "5-7 membered heterocyclic alkyl group", "5-6 membered heterocyclic alkyl group", etc. Although some bicyclic heterocyclic groups in this disclosure contain a benzene ring or a heteroaromatic ring, the heterocyclic groups as a whole are still non-aromatic.

[0193] The term "subheterocyclic group" refers to a residue derived from a heterocyclic group by further removing a hydrogen atom, as defined above. The term "4-8 membered subheterocyclic group" should be understood as a subheterocyclic group with 4, 5, 6, 7, or 8 ring atoms.

[0194] The term "heterocyclic alkyl" refers to a fully saturated monovalent cyclic group that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring, etc., containing 1 to 5 heteroatoms or heteroatom groups (i.e., atomic groups containing heteroatoms) in the ring atoms. The "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH-, or -NHC(=O)NH-, etc., which typically contain 3 to 20 ring atoms. The term "3-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 independent heteroatoms or heterogroups selected from those described above. "3-10 membered heterocyclic alkyl" includes "3-8 membered heterocyclic alkyl", wherein specific examples of 4 membered heterocyclic alkyl include, but are not limited to, acridine, oxadiazolyl, or thiobutylcycloyl; specific examples of 5 membered heterocyclic alkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, or tetrahydropyrazolyl; specific examples of 6 membered heterocyclic alkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxalyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, or 1,4-dithiaalkyl; and specific examples of 7 membered heterocyclic alkyl include, but are not limited to, azirheptanyl, oxaheptanyl, or thioheptanyl.

[0195] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic cyclic group with a conjugated π-electron system. Aryl groups can have 6-20, 6-14, or 6-12 carbon atoms. The term "C6-C"... 20 "Aryl" should be understood as a monovalent aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 20 carbon atoms. In particular, it refers to a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or rings having 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups; or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. The term "C6-C" is used. 10"Aryl" should be understood as a monovalent aromatic monocyclic or bicyclic group with 6, 7, 8, 9, or 10 carbon atoms. Specifically, it refers to a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), for example, naphthyl.

[0196] The term "aryl" refers to a residue derived by further removing a hydrogen atom from an aryl group, as defined above. The term "C6-C"... 10 "Arylene" should be understood as an arylene with 6-10 carbon atoms.

[0197] The term "heteroaryl" or "heteroary ring" refers to an aromatic monocyclic or fused polycyclic system containing at least one, preferably 1, 2, 3, or 4 ring atoms selected from N, O, and S, with the remaining ring atoms being 5-14 membered aromatic cyclic groups of carbon. The heteroaryl group is preferably 5-10 membered, more preferably 5- or 6-membered heteroaryl. The term "5-10 membered heteroaryl" should be understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, particularly 5, 6, 9, or 10 ring atoms, and containing 1, 2, 3, 4, or 5, preferably 1, 2, or 3 heteroatoms independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl or isindolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and their benzo[derivatives], such as quinolinyl, quinazolinyl or isoquinolinyl; or acrylinyl, inazinyl, purinyl and their benzo[derivatives]; or cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylinyl, phenazinyl, phenothiazinyl or phenothiazinyl. The term "5-6-membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and comprising 1, 2, or 3, preferably 1 or 2, heteroatoms independently selected from N, O, and S. The term "6-membered heteroaryl" refers to an aromatic ring system having 6 ring atoms, and comprising 1, 2, or 3, preferably 1 or 2, heteroatoms independently selected from N, O, and S. The term "5-10-membered heteroaryl" can include either "5-6-membered heteroaryl" or "6-membered heteroaryl," and the term "5-6-membered heteroaryl" can include "6-membered heteroaryl."

[0198] The term "hybrid aryl" refers to a residue derived from a heteroaryl group by further removing a hydrogen atom, as defined above. The term "5-10 cyclic aryl" refers to a heteroaryl group having 5, 6, 7, 8, 9, or 10 ring atoms.

[0199] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0200] The term "hydroxyl group" refers to the -OH group.

[0201] The term "cyano" refers to the -CN group.

[0202] The term "amino" refers to the -NH2 group.

[0203] The term "nitro" refers to the -NO2 group.

[0204] The term “therapeutic effective amount” means the amount of a compound of this disclosure used to treat a particular disease, condition, or symptom; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or symptom; or (iii) to delay the onset of one or more symptoms of a particular disease, condition, or symptom described herein. The amount of a compound of this disclosure constituting a “therapeutic effective amount” varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and this disclosure.

[0205] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0206] The term “pharmaceutically acceptable salt” or “medicinal salt” refers to a pharmaceutically acceptable salt of an acid or base, including salts formed by a compound with an inorganic or organic acid, and salts formed by a compound with an inorganic or organic base.

[0207] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this disclosure or their stereoisomers or pharmaceutically acceptable salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this disclosure to an organism.

[0208] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0209] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0210] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0211] Compounds of this disclosure labeled with certain isotopes (e.g., using...) 3 H and 14 C-labeling can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0212] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds of this disclosure with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0213] Typical routes of administration of the compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof disclosed herein include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0214] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0215] In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0216] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

[0217] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0218] The dosage of compounds or compositions used in the treatments described in this disclosure will generally vary depending on the severity of the disease, the patient’s weight, and the relative efficacy of the compound. However, as a general guideline, a suitable daily dose of the compound of formula (I) described herein is from 0.01 mg / kg to 1000 mg / kg.

[0219] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this disclosure.

[0220] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required by this disclosure. To obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments. Detailed Implementation

[0221] The following detailed description of specific implementation schemes illustrates the contents of this disclosure, but does not imply any adverse limitation thereof. Various specific implementation schemes of this disclosure have been described in detail herein, and it will be apparent to those skilled in the art that various changes and modifications can be made to these specific implementation schemes without departing from the spirit and scope of this disclosure.

[0222] All reagents used in this disclosure are commercially available and can be used without further purification.

[0223] Unless otherwise stated, proportions expressed for mixed solvents are volume-based. Unless otherwise stated, % refers to wt%.

[0224] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., with tetramethylsilane (TMS) as the internal standard; "IC 50 "Half-inhibitory concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0225] The eluent described below may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0226] Abbreviations:

[0227] SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride; SEM: (trimethylsilyl)ethoxy)methyl; MeCN: acetonitrile; NIS: N-iodosuccinimide; MeI: iodomethane; MeOH: methanol; DCM: dichloromethane; DMF: N,N-dimethylformamide; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; Pd(dppf)Cl2·DCM: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride Palladium chloride dichloromethane complex; B2Pin2: bis-pinacol boronic acid ester; KOAc: potassium acetate; 1,4-dioxane: 1,4-dioxane; PPh3: triphenylphosphine; DIAD: diisopropyl azodicarboxylate; THF: tetrahydrofuran; EtOH: ethanol; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt; DIEA: N,N-diisopropylethylamine; Boc: tert-butyloxycarbonyl; Brett Phos Pd G3: (2-Dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); LiHMDS: Lithium bis(trimethylsilyl)amino; NaOAc: Sodium acetate; HOAc: Acetic acid; NaBH(OAc)3: Sodium borohydride acetate; rt: Room temperature; Pd-PEPPSI-I Hept-Cl: (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium; FA: formic acid; Bn: benzyl; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene; i PrOH: Isopropanol; t BuONa: Sodium tert-butoxide; DIEA: N,N-diisopropylethylamine; Raney-Ni: Raney nickel; BrCN: Cyanogen bromide; Ruphos: 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; DMA: N,N-dimethylacetamide; TFA: trifluoroacetic acid; RuPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium.

[0228] Example 1: Synthesis of Compound 1

[0229] Step 1: Synthesis of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazole-3-one (1b)

[0230] 1.0 g (10.19 mmol) of 2-methyl-1H-pyrazole-3(2H)-one 1a was dissolved in anhydrous acetonitrile (15 mL), potassium carbonate (3.52 g, 25.48 mmol) was added, and 2-(trimethylsilyl)ethoxymethyl chloride (2.55 g, 15.29 mmol) was slowly added under ice bath conditions. The reaction was then brought to room temperature for 3 hours, and the reaction was confirmed by LC-MS. The reaction solution was quenched with water (10 mL) at 0 °C, extracted with ethyl acetate (20 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was slurried with petroleum ether (50 mL) to give the title compound 1b (1.1 g). m / z (ESI): 229.1 [M+H] + .

[0231] Step 2: Synthesis of 4-iodo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazole-3-one (1c)

[0232] 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one 1b (1.1 g, 4.82 mmol) was dissolved in anhydrous acetonitrile (20 mL). N-iodosuccinimide (1.19 g, 5.30 mmol) was slowly added under ice bath conditions, and the reaction was carried out for 1 hour at the same temperature. The reaction was confirmed by LC-MS. The reaction solution was quenched at 0 °C with saturated sodium sulfite aqueous solution (10 mL), extracted with dichloromethane (10 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was slurried with petroleum ether (30 mL) to give the title compound 1c (1.75 g). m / z (ESI): 354.9 [M+H] + .

[0233] Step 3: Synthesis of methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1e)

[0234] Methyl 5-bromo-6-hydroxy-pyridine-3-carboxylate 1d (2.0 g, 8.62 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL). Sodium hydroxide (689.50 mg, 17.24 mmol, 60% purity) was added under ice bath conditions, and the reaction was carried out at 0 °C for 1 hour. Then, iodomethane (1.35 g, 9.48 mmol) was added, and the reaction was continued under the same conditions for another hour. The reaction was confirmed by LC-MS. The reaction was quenched with water (15 mL) under ice bath conditions, and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (petroleum ether:ethyl acetate = 2:1) to give the title compound 1e (940 mg). m / z (ESI): 245.9, 247.9 [M+H] + .

[0235] Step 4: Synthesis of (5-(methoxycarbonyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (1f)

[0236] 5-Bromo-1-methyl-6-oxo-pyridine-3-carboxylate 1e (200 mg, 812.82 μmol) was dissolved in dioxane (6 mL), followed by potassium acetate (239.31 mg, 2.44 mmol), bis-pinacolborate (309.61 mg, 1.22 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (66.38 mg, 81.28 μmol). The reaction mixture was incubated at 80 °C under a nitrogen atmosphere for 12 hours, and the reaction was monitored by LC-MS until completion. After cooling to room temperature, the insoluble matter was removed by filtration. The filtrate was concentrated, and the resulting crude product 1f could be used directly in the next step without further purification. m / z (ESI): 212.0 [M+H] + .

[0237] Step 5: Synthesis of methyl 1-methyl-5-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid ester (1 g)

[0238] The crude product 1f obtained in the previous step and 4-iodo-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one 1c (285.45 mg, 805.77 μmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). Potassium carbonate (334.09 mg, 2.42 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (58.96 mg, 80.58 μmol) were added. The reaction solution was reacted at 80 °C under a nitrogen atmosphere for 2 hours, and the reaction was detected by LCMS. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude product was purified by normal phase chromatography (petroleum ether:tetrahydrofuran = 1:1) to obtain 1 g (244 mg) of the title compound. m / z(ESI): 394.2 [M+H] + .

[0239] Step 6: Synthesis of methyl 5-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1 h)

[0240] 1 g (240 mg, 609.90 μmol) of methyl 1-methyl-5-[2-methyl-3-oxo-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-6-oxo-pyridine-3-carboxylate was dissolved in 3 mL of anhydrous dichloromethane, and dioxane hydrochloride (2 M, 3.05 mL) was added. The reaction mixture was reacted at 40 °C for 4 hours, and the reaction was completed by LC-MS. The reaction mixture was concentrated under reduced pressure to give the title compound 1 h (161 mg). MS m / z (ESI): 264.1 [M+H] + .

[0241] Step 7: Synthesis of (R)-5-((5-bromo-2-nitroanilino)-4-methylpentane-1-ol (1k)

[0242] 4-Bromo-2-fluoro-1-nitrobenzene 1j (2.97 g, 13.51 mmol) was dissolved in anhydrous acetonitrile (80 mL), and (4R)-5-amino-4-methyl-pentan-1-ol 1i (1.9 g, 16.21 mmol) and potassium carbonate (3.73 g, 27.02 mmol) were added. The reaction solution was reacted at 80 °C under a nitrogen atmosphere for 2 hours, and the reaction was detected by LCMS to indicate completion. The reaction was quenched with saturated sodium sulfite aqueous solution (20 mL) under ice bath conditions, extracted with dichloromethane (20 mL * 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was slurried with petroleum ether (50 mL) to give the title compound 1k (4.11 g). m / z (ESI): 317.0, 319.0 [M+H] + .

[0243] Step 8: Synthesis of (R)-5-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (1l)

[0244] 192.18 mg (730.0 μmol) of methyl 5-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate and 361.17 mg (1.38 mmol) of triphenylphosphine were dissolved in anhydrous tetrahydrofuran (6 mL). 145 mg (457.1 μmol) of (R)-5-(5-bromo-2-nitro-anilino)-4-methyl-pentan-1-ol and 222.76 mg (1.10 mmol) of diisopropyl azodicarbonate were added under a nitrogen atmosphere at 0 °C. The reaction mixture was allowed to react for 2 hours at 25 °C under a nitrogen atmosphere, and the reaction was completed by LCMS. The reaction solution was quenched with water (5 mL), extracted with dichloromethane (8 mL x 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (petroleum ether:tetrahydrofuran = 2:1) to give the title compound 1l (150 mg). m / z (ESI): 562.1 [M+H] + .

[0245] Step 9: Synthesis of (R)-5-(5-((5-(((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (1m)

[0246] 1 L (130 mg, 231.15 μmol) of methyl 5-[5-[(4R)-5-(5-bromo-2-nitro-anilino)-4-methyl-pentoxy]-1-methyl-pyrazole-4-yl]-1-methyl-6-oxo-pyridine-3-carboxylic acid was dissolved in ethanol (3 mL) and water (0.8 mL). Iron powder (103.27 mg, 1.85 mmol) and ammonium chloride (123.64 mg, 2.31 mmol) were added. The reaction mixture was reacted at 80 °C under a nitrogen atmosphere for 2 hours, and the reaction was confirmed by LC-MS. The reaction mixture was diluted with water (5 mL), filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate (8 mL * 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 1 M (129 mg). m / z (ESI): 532.1, 534.1 [M+H] + .

[0247] Step 10: Synthesis of (R)-5-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazole-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (1n)

[0248] Methyl 5-[5-[(4R)-5-(2-amino-5-bromo-aniline)-4-methyl-pentoxy]-1-methyl-pyrazol-4-yl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ester 1m (125 mg, 234.77 μmol) was dissolved in anhydrous dichloromethane (2 mL), and cyanogen bromide (51.63 mg, 486.79 μmol) was added. The reaction mixture was reacted at 25 °C for 2 hours, and the reaction was detected as complete by LCMS. The reaction mixture was quenched with saturated sodium carbonate aqueous solution (5 mL), stirred at room temperature for 0.5 hours, extracted with dichloromethane (8 mL * 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by normal phase chromatography (petroleum ether: tetrahydrofuran = 1:1) to obtain the title compound 1n (96 mg). m / z (ESI): 557.2, 559.2 [M+H] + .

[0249] Step 11: Synthesis of (R)-5-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (1o)

[0250] Methyl (R)-5-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazole-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ester 1n (96 mg, 172.22 μmol) was dissolved in tetrahydrofuran (1 mL) and water (0.5 mL), and lithium hydroxide monohydrate (14.5 mg, 344.43 μmol) was added. The reaction solution was reacted at 25 °C for 2 hours, and the reaction was completed as detected by LCMS. The pH of the reaction solution was adjusted to 5-6 with 1M hydrochloric acid, and the solution was concentrated under reduced pressure to give the title compound 1o (93 mg). m / z (ESI): 543.1, 545.1 [M+H] + .

[0251] Step 12: Synthesis of intermediate 1p

[0252] (R)-5-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazole-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid 1O (93 mg, 171.14 μmol) was dissolved in dioxane (2 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (96.85 mg, 256.71 μmol) and N,N-diisopropylethylamine (66.36 mg, 513.42 μmol, 89.43 μL) were added. The reaction solution was reacted at 60 °C for 3 hours, and the reaction was completed as detected by LCMS. The reaction solution was quenched with water (5 mL), extracted with dichloromethane (8 mL x 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (dichloromethane:methanol = 10:1) to give the title compound 1p (76.5 mg). m / z (ESI): 525.1, 527.1 [M+H] + .

[0253] Step 13: Synthesis of intermediate 1q

[0254] 1 p (66.5 mg, 126.57 μmol) and tert-butyl 4-(pyrrolidone-3-yl)piperazine-1-carboxylate (32.32 mg, 126.57 μmol) were dissolved in 1,4-dioxane (1 mL). Under a nitrogen atmosphere, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34.31 mg, 37.97 μmol) and a solution of bis(trimethylsilyl)aminolithium (1 M, 379.71 μL) were added. The reaction mixture was stirred at 60 °C for 2 hours. The reaction was monitored by LCMS until complete. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was subjected to normal-phase chromatography (dichloromethane / methanol = 0% to 5%) to give the title compound 1q (15 mg). m / z (ESI): 700.5 [M+H] + .

[0255] Step 14: Synthesis of 1r

[0256] 1q (15 mg, 21.43 μmol) was dissolved in methanol (0.5 mL), and dioxane hydrochloride solution (2 M, 107.17 μL) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound 1r (13 mg). m / z (ESI): 600.4 [M+H] + .

[0257] Step 15: Synthesis of Compound 1

[0258] 1r (13 mg, 21.68 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde 1s (12.01 mg, 32.51 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), followed by the addition of sodium acetate (17.78 mg, 216.77 μmol), acetic acid (1.30 mg, 21.68 μmol), and sodium borohydride acetate (9.19 mg, 43.35 μmol). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction was monitored by LCMS until complete. The reaction was quenched by adding 2 drops of water. Purification by high performance liquid chromatography (Phenomenex Gemini NX column, 5 μm silica, 30 mm diameter, 150 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile in decreasing polarity (acetonitrile ratio 29%-69%) as eluent) gave title compound 1 (3.9 mg). MS m / z (ESI): 953.4 [M+H] + .

[0259] 1 H NMR (400MHz, DMSO-d6) δ12.31-12.22(m,1H),11.11-11.03(m,1H),8.80(d,J=1.7Hz,1H),8.35(s,1H),8.25(d,J=1.8Hz,1H),7 .65(d,J=8.4Hz,1H),7.36-7.28(m,2H),7.26-7.20(m,1H),6.68-6.62(m,1H),6.49-6.42(m,1H),5.06(dd,J=5.3,12.7Hz,1H) ,4.41-4.30(m,1H),4.11-3.84(m,6H),3.71(s,3H),3.61(s,3H),3.47(s,3H),3.11-3.06(m,1H),3.01-2.74(m,7H),2.60(d,J =5.1Hz,2H),2.43-2.38(m,2H),2.24-2.09(m,5H),2.05-1.72(m,9H),1.49-1.39(m,1H),1.21-1.10(m,2H),0.84-0.78(m,3H).

[0260] Example 2: Synthesis of Compound 2

[0261] Step 1: Synthesis of intermediate 2b

[0262] Compound 1p (50 mg, 95 μmol) and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate 2a (51 mg, 190 μmol) were dissolved in anhydrous 1,4-dioxane (2 mL), followed by the addition of methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (26 mg, 29 μmol) and a solution of bis(trimethylsilyl)aminolithium (1 M, 285.50 μL). The mixture was then reacted at 60 °C for 1 hour. After the reaction solution cooled to room temperature, water (10 mL) was added to quench the reaction, followed by extraction with dichloromethane (10 mL x 3) three times. The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal-phase chromatography (silica, dichloromethane / methanol = 20 / 1) to give compound 2b (17.7 mg). m / z (ESI): 714.6 [M+H] + .

[0263] Step 2: Synthesis of intermediate 2c

[0264] Compound 2b (17.7 mg, 24.79 μmol) was dissolved in anhydrous methanol (1 mL), and dioxane hydrochloride solution (2 M, 123.97 μL) was added. The reaction mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give compound 2c (15.2 mg). m / z (ESI): 614.5 [M+H] + .

[0265] Step 3: Synthesis of Compound 2

[0266] Compound 2c (15.2 mg, 24.78 μmol) and compound 1s (9.15 mg, 24.78 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), and sodium acetate (10.16 mg, 123.9 μmol), acetic acid (1.49 mg, 24.78 μmol), and sodium borohydride acetate (7.88 mg, 37.17 μmol) were added. The reaction was carried out at room temperature for 30 minutes, and the reaction was quenched by adding water (2 drops). The solution was purified by high performance liquid chromatography (C18 column, 40 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (acetonitrile ratio 30%-60%) as eluent) to give compound 2 (6.5 mg).

[0267] MS m / z (ESI): 967.4 [M+H] + .

[0268] 1H NMR(400MHz,DMSO-d6)δ12.42-12.21(m,1H),11.12-11.02(m,1H),8.79(d ,J=2.0Hz,1H),8.34(s,1H),8.26(d,J=2.1Hz,1H),7.64(d,J=8.6Hz,1H),7 .34(d,J=8.7Hz,1H),7.29(s,1H),7.21(dd,J=1.7,8.7Hz,1H),7.14-7.06( m,1H),6.85(d,J=8.2Hz,1H),5.06(dd,J=5.4,12.9Hz,1H),4.40-4.29(m,1 H),4.14-3.99(m,3H),3.97-3.87(m,2H),3.75-3.64(m,5H),3.61(s,3H),3 .31(s,2H),2.99-2.86(m,3H),2.81-2.72(m,1H),2.71-2.53(m,6H),2.42- 2.24(m,5H),2.21-2.07(m,3H),2.06-1.97(m,1H),1.94-1.73(m,7H),1.62 -1.49(m,2H),1.48-1.37(m,1H),1.20-1.04(m,2H),0.80(d,J=6.5Hz,3H).

[0269] Example 3: Synthesis of Compound 3

[0270] Step 1: Synthesis of intermediate 3b

[0271] Compound 1p (65 mg, 123.71 μmol) and piperazine-1-carboxylic acid tert-butyl ester 3a (46.08 mg, 247.42 μmol) were dissolved in anhydrous 1,4-dioxane (2 mL), followed by the addition of methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (33.64 mg, 37.11 μmol) and a solution of bis(trimethylsilyl)aminolithium (1 M, 371.15 μL). The mixture was then reacted at 60 °C for 1 hour under nitrogen protection. After the reaction was cooled to room temperature, water (10 mL) was added to quench the reaction, followed by extraction three times with dichloromethane (10 mL * 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal-phase chromatography (silica, dichloromethane / methanol = 20 / 1) to give compound 3b (48 mg). m / z (ESI): 631.3 [M + H] +.

[0272] Step 2: Synthesis of intermediate 3c

[0273] Compound 3b (48 mg, 76.10 μmol) was dissolved in anhydrous methanol (1 mL), and dioxane hydrochloride solution (2 M, 380.51 μL) was added. The reaction mixture was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give compound 3c (46 mg). m / z (ESI): 531.2 [M+H] + .

[0274] Step 3: Synthesis of Compound 3

[0275] Compound 3c (46 mg, 86.69 μmol) and compound 1s (38.43 mg, 104.03 μmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL), and sodium acetate (35.56 mg, 433.46 μmol), acetic acid (5.21 mg, 86.69 μmol), and sodium borohydride acetate (22.05 mg, 104.03 μmol) were added. The reaction was allowed to proceed at room temperature for 30 minutes, and the reaction was quenched by adding 2 drops of water. The solution was purified by high performance liquid chromatography (C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile in decreasing polarity (acetonitrile ratio 0%-40%) as eluent) to give compound 3 (14.2 mg).

[0276] MS m / z (ESI): 884.6 [M+H] + .

[0277] 1H NMR (400MHz, DMSO-d6) δ12.46-12.22(m,1H),11.07(s,1H),8.79(d,J=2.1Hz,1H),8.34(s,1H),8.26(d,J=2.1Hz,1H),7.65(d,J=8.6Hz,1H),7.3 6(d,J=8.8Hz,1H),7.31(s,1H),7.23(dd,J=1.9,8.8Hz,1H),7.11(s,1H) ,6.90-6.82(m,1H),5.06(dd,J=5.4,12.9Hz,1H),4.40-4.29(m,1H),4.1 4-4.00(m,3H),3.97-3.87(m,2H),3.71(s,3H),3.61(s,3H),3.16(s,4H ),2.99(t,J=12.2Hz,2H),2.92-2.84(m,1H),2.82-2.74(m,1H),2.60(d, J=2.5Hz,1H),2.54(s,4H),2.26-2.14(m,3H),2.04-1.98(m,1H),1.97-1 .78(m,6H),1.47-1.38(m,1H),1.23-1.12(m,2H),0.80(d,J=6.4Hz,3H).

[0278] Example 4: Synthesis of Compound 4

[0279] Compound 2c (10 mg, 16.29 μmol) and compound 4a (7.30 mg, 19.55 μmol) were dissolved in N,N-dimethylformamide (1 mL), and sodium acetate (6.68 mg, 81.45 μmol), acetic acid (977 μg, 16.29 μmol), and sodium borohydride acetate (4.14 mg, 19.55 μmol) were added. The mixture was reacted at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water to the reaction solution. The reaction solution was directly purified by high performance liquid chromatography (C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile with decreasing polarity (acetonitrile ratio 0%-40%) as the eluent) to obtain compound 4 (7.0 mg).

[0280] m / z(ESI): 972.0 [M+H] + .

[0281] 1H NMR (400MHz, DMSO-d6) δ12.35(s,1H),10.86(s,1H),8.80(s,1H),8.42(d,J=6.8Hz,1H),8.34(s,1H),8.26( d, J=2.4Hz, 1H), 7.76 (d, J=8.8Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 7.12 (s, 1H), 6.86 (d, J=4.8Hz, 1H), 6.58 (d, J= 4.8Hz,1H),6.51(s,1H),4.72-4.66(m,1H),4.40-4.28(m,1H),4.09(d,J=10.8Hz,1H),3.94-3.85(m,7H),3 .72-3.68(m,5H),3.61(s,3H),2.84-2.65(m,7H),2.15-1.44(m,16H),1.32-1.15(m,9H),0.85-0.79(m,4H).

[0282] Example 5: Synthesis of Compound 5

[0283] Compound 2c (15 mg, 24.44 μmol) and compound 5a (11.30 mg, 29.33 μmol) were dissolved in N,N-dimethylformamide (1 mL), and sodium acetate (10.02 mg, 122.2 μmol), acetic acid (1.47 mg, 24.44 μmol), and sodium borohydride acetate (6.22 mg, 29.33 μmol) were added. The reaction was allowed to proceed at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water. The reaction solution was then purified directly by high performance liquid chromatography (C18 column, 30 mm diameter, 150 mm length; using a mixture of water (0.225% formic acid) and acetonitrile with decreasing polarity (acetonitrile ratio 0%-40%) as the eluent) to obtain compound 5 (7.0 mg).

[0284] m / z(ESI): 984.1 [M+H] + .

[0285] 1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),10.96(s,1H),8.80(s,1H),8.35(s,1H),8.26(s,1H),7.38-7.33(m,2H),7.11( s,1H),7.07(d,J=8.4Hz,1H),6.86(d,J=8.4Hz,1H),5.08-5.03(m,1H),4.43(d,J=16.8Hz,1H),4.35(brs,1H),4.26( d,J=16.8Hz,1H),3.96-3.90(m,2H),3.86(s,3H),3.75-3.65(m,5H),3.61(s,3H),3.57-3.51(m,2H),2.93-2.61(m,6 H),2.42-2.28(m,5H),2.18-2.16(m,3H),2.03-1.80(m,7H),1.66-1.44(m,3H),1.32-1.23(m,9H),0.85-0.79(m,4H).

[0286] Example 6: Synthesis of Compound 6

[0287] Compound 2c (15 mg, 24.44 μmol) and compound 6a (10.10 mg, 29.33 μmol) were dissolved in N,N-dimethylformamide (1 mL), and sodium acetate (10.02 mg, 122.2 μmol), acetic acid (1.47 mg, 24.44 μmol), and sodium borohydride acetate (6.22 mg, 29.33 μmol) were added. The mixture was reacted at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops). The reaction solution was then purified directly by high performance liquid chromatography (C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile in decreasing polarity (acetonitrile ratio 0%-40%) as the eluent) to obtain compound 6 (5.0 mg).

[0288] m / z (ESI): 942.7 [M+H] + .

[0289] 1H NMR (400MHz, DMSO-d6) δ12.35(s,1H),10.85(s,1H),8.79(d,J=2.4Hz,1H),8.69(d,J=8.4Hz,1H),8.35(s,1H),8.2 8(dd,J=13.2,2.0Hz,2H),7.84(d,J=8.8Hz,1H),7.39(d,J=8.0Hz,1H),7.39(d,J=8.8Hz,1H),7.11(s,1H),6.85(d d,J=8.8,1.6Hz,1H),4.77-4.71(m,1H),4.39-4.30(m,1H),4.10-4.04(m,5H),3.74-3.68(m,5H),3.61(s,3H),2.8 7-2.63(m,9H),2.43-2.14(m,11H),2.02-1.77(m,8H),1.57-1.43(m,3H),1.23-1.15(m,2H),0.80(d,J=6.4Hz,3H).

[0290] Example 7: Synthesis of Compound 7

[0291] Compound 2c (15 mg, 24.44 μmol) and compound 7a (14 mg, 36.32 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (10.02 mg, 122.20 μmol) and sodium borohydride acetate (25.90 mg, 122.20 μmol) were added. The reaction was allowed to proceed at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water. The reaction solution was then purified directly by high-performance liquid chromatography (C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile in decreasing polarity (acetonitrile ratio 0%-40%) as the eluent) to give compound 7 (6.3 mg, yield: 26%). m / z (ESI): 983.7 [M+H] + .

[0292] 1H NMR (400MHz, DMSO-d6) δ12.38(s,1H),11.01(s,1H),8.86(d,J=2.0Hz,1H),8.41(s,1H),8.32(d,J=2.0Hz,1H),7.40(d,J=8.8H z,1H),7.17(s,1H),6.92(d,J=8.8Hz,1H),6.82(d,J=10.8Hz,2H),5.12(dd,J=13.2,4.8Hz,1H),4.45-4.36(m,1H),4.32(d,J= 16.8Hz,1H),4.16(d,J=16.8Hz,2H),4.03-3.95(m,2H),3.92(s,3H),3.84-3.74(m,6H),3.67(s,3H),3.01-2.90(m,1H),2.90- 2.60(m,9H),2.48-2.32(m,5H),2.89-2.15(m,3H),2.09-1.92(m,6H),1.86-1.50(m,7H),1.40-1.20(m,1H),0.91-0.85(m,5H).

[0293] Example 8: Synthesis of Compound 8

[0294] Compound 3c (15 mg, 28.27 μmol) and compound 5a (16 mg, 41.51 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (11.59 mg, 141.34 μmol) and sodium borohydride acetate (29.96 mg, 141.34 μmol) were added. The reaction was allowed to proceed at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water. The reaction solution was then purified directly by high-performance liquid chromatography (C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile in decreasing polarity (acetonitrile ratio 0%-40%) as the eluent) to give compound 8 (6 mg, yield: 23%). m / z (ESI): 900.1 [M+H] + .

[0295] 1H NMR (400MHz, DMSO-d6) δ12.30(s,1H),10.90(s,1H),8.74(d,J=8.0Hz,1H),8.29(d,J=8.0Hz,1H),8.20 (d,J=8.0Hz,1H),7.35-7.31(m,2H),7.09-7.01(m,2H),6.84-6.76(m,1H),5.02-4.98(m,1H),4.41-4.1 7(m,4H),4.10-4.00(m,2H),3.92-3.84(m,2H),3.81(s,3H),3.65(s,3H),3.59-3.49(m,4H),3.20-3.08 (m.2H),2.90-2.50(m,6H),2.30-2.05(m,2H),1.96-1.83(m,6H),1.40-1.20(m,8H),0.81-0.73(m,4H).

[0296] Example 9: Synthesis of Compound 9

[0297] Compound 2c (15 mg, 24.44 μmol) and compound 9a (13 mg, 36.58 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (10.02 mg, 122.20 μmol) and sodium borohydride acetate (25.90 mg, 122.20 μmol) were added. The reaction was allowed to proceed at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water. The reaction solution was then purified directly by high-performance liquid chromatography (C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile in decreasing polarity (acetonitrile ratio 0%-40%) as the eluent) to give compound 9 (4 mg, yield: 17%). m / z (ESI): 953.7 [M+H] + .

[0298] 1H NMR (400MHz, DMSO-d6) δ12.28(s,1H),10.87(s,1H),8.73(d,J=2.4Hz,1H),8.28(s,1H),8.19(d,J=2.0Hz,1H),7 .43(d,J=8.8Hz,1H),7.28(d,J=8.8Hz,1H),7.04-6.95(m,3H),6.79(d,J=8.8Hz,1H),4.97(dd,J=13.2,4.8Hz,1H ),4.32-3.98(m,4H),3.90-3.75(m,3H),3.69-3.59(m,4H),3.54(s,3H),2.89-2.68(m,5H),2.63-2.42(m,6H),2 .38-2.25(m,5H),2.15-2.08(m,3H),1.96-1.78(m,6H),1.75-1.66(m,2H),1.55-1.08(m,6H),0.80-0.72(m,5H).

[0299] Example 10: Synthesis of Compound 10

[0300] Step 1: Synthesis of 3-(8-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-2-carbonyl-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidin-2,6-dione (10c)

[0301] Compounds 10a (350 mg, 901.56 μmol) and 10b (215 mg, 1.35 mmol) were dissolved in 1,4-dioxane (5 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (175.40 mg, 180.31 μmol) and cesium carbonate (587.49 mg, 1.80 mmol) were added. The mixture was purged with argon three times, and then reacted at 100 °C for 2 hours under argon protection. The mixture was filtered, the filtrate was concentrated, and the crude product was purified by normal-phase silica gel column chromatography (tetrahydrofuran:petroleum ether = 1:2) to give compound 10c (355 mg, yield 84%). m / z (ESI): 467.3 [M+H] + .

[0302] Step 2: Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-8-yl)piperidine-4-carboxaldehyde (10d)

[0303] Compound 10c (25 mg, 53.59 μmol) was dissolved in anhydrous dichloromethane (2 mL) at room temperature, followed by the addition of formic acid (3 mL). The reaction was allowed to proceed at room temperature for 2 hours, then concentrated under reduced pressure to obtain crude product 10d, which could be used directly in the next step without further purification. m / z (ESI): 421.2 [M+H] + .

[0304] Step 3: Synthesis of Compound 10

[0305] Compound 2c (15 mg, 24.44 μmol) and compound 10d (15 mg, 35.68 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (10.02 mg, 122.20 μmol) and sodium borohydride acetate (25.90 mg, 122.20 μmol) were added. The reaction was allowed to proceed at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water. The reaction solution was then purified directly by high-performance liquid chromatography (C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile in decreasing polarity (acetonitrile ratio 0%-40%) as the eluent) to give compound 10 (4 mg, yield: 15%). m / z (ESI): 1018.6 [M+H] + .

[0306] 1 H NMR (400MHz, DMSO-d6) δ12.35(s,1H),11.12(s,1H),8.80(d,J=2.0Hz,1H),8.35(s,1H),8.26(s,1H),7.77(d,J=8.8Hz,1H),7.56( s,1H),7.49(d,J=8.8Hz,1H),7.35(d,J=8.8Hz,1H),7.26(d,J=9.2Hz,1H),7.20(d,J=8.8Hz,1H),7.12(s,1H),6.86(d,J=8.8Hz,1H ),5.47(dd,J=12.4,5.2Hz,1H),4.40-4.30(m,1H),4.09(d,J=13.2Hz,1H),3.96-3.82(m,6H),3.75-3.65(m,4H),3.61(s,3H),2.9 5-2.85(m,1H),2.82-2.76(m,6H),2.72-2.56(m,6H),2.38-2.15(m,2H),2.07-1.83(m,10H),1.78-1.25(m,8H),0.85-0.79(m,5H).

[0307] Example 11: Synthesis of Compound 11

[0308] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (11c)

[0309] Compound 11a (637 mg, 2.0 mmol) and compound 11b (1.0 g, 2.4 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL), followed by the sequential addition of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (146 mg, 0.2 mmol) and potassium carbonate (828 mg, 6.0 mmol). The mixture was purged with argon three times, and then reacted at 70 °C for 3 hours under argon protection. After cooling to room temperature, water (5 mL) was added to the reaction system, followed by extraction with ethyl acetate (10 mL x 3) three times. The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 20:1-5:1) to give compound 11c (245 mg, yield: 25%). m / z (ESI): 482.1 [M+H] + .

[0310] Step 2: Synthesis of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (11e)

[0311] Compound 11c (2.1 g, 4.35 mmol) and compound 11d (623 mg, 4.35 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL), and then tris(dibenzylacetone)palladium (199 mg, 218 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (252 mg, 435 μmol) and cesium carbonate (4.26 g, 13.06 mmol) were added sequentially. The air was purged three times with argon, and the reaction was carried out at 80 °C for 12 hours under argon protection. After the reaction mixture cooled to room temperature, water (10 mL) was added to the reaction system, followed by extraction with ethyl acetate (50 mL x 3) three times. The organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 20:1-3:1) to give compound 11e (568 mg, yield: 24%). m / z (ESI): 545.2 [M+H] + .

[0312] Step 3: Synthesis of 3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione (11f)

[0313] Compound 11e (500 mg, 0.918 mmol) was dissolved in isopropanol / N,N-dimethylformamide (10 mL / 2 mL), and 10% palladium on carbon (0.25 g) was added. The mixture was then reacted at 45 °C for 16 hours under a hydrogen atmosphere (4 bar). The reaction solution was directly filtered, and the filtrate was concentrated. The crude product obtained could be used directly in the next reaction without purification. m / z (ESI): 367.2 [M+H] + .

[0314] Step 4: Synthesis of 3-(2,6-difluoro-4-(4-oxopiridin-1-yl)phenyl)piperidine-2,6-dione (11 g)

[0315] Compound 11f (100 mg, 272.96 μmol) was dissolved in concentrated hydrochloric acid (2 mL) and reacted at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18, 0.5% formic acid:acetonitrile = 20:1–1:20) to give compound 11 g (65 mg, yield 74%). m / z (ESI): 323.1 [M+H] + .

[0316] Step 5: Synthesis of Compound 11

[0317] Compound 3c (20 mg, 37.69 μmol) and compound 11 g (24 mg, 74.46 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (6.33 mg, 49.00 μmol) and sodium borohydride acetate (23.97 mg, 113.08 μmol) were added. The reaction solution was heated to 50 °C and reacted for 24 hours. The reaction was quenched by adding water (2 drops). The reaction solution was directly purified by high performance liquid chromatography (C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile with decreasing polarity (acetonitrile ratio 0%-40%) as eluent) to give compound 11 (1 mg, yield: 3%). m / z (ESI): 837.4 [M+H] + .

[0318] Example 12: Synthesis of Compound 12-A and Compound 12-B

[0319] Step 1: Synthesis of intermediates 12x-A and 12x-B

[0320] Compound 12x (770 mg, 1.30 mmol) was purified by supercritical fluid chromatography (column: DAICL CHIRALCEL OD column, length 250 mm, inner diameter 30 mm, particle size 10 μm; mobile phase A: ethanol (containing 0.1% ammonia), mobile phase B: supercritical carbon dioxide; gradient: mobile phase B from 40% to 40%; flow rate: 2.5 mL / min) to give compound 12x-A (229.2 mg, retention time: 3.59 min) (MS m / z (ESI): 594.0, 596.0 [M+H]). + .) and compound 12x-B (260.1 mg, retention time: 5.15 min) (MS m / z (ESI): 593.9, 595.9 [M+H]) + .).

[0321] Step 2: Synthesis of intermediate 12y-A

[0322] Compound 12x-A (209 mg, 351.56 μmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide monohydrate (29.50 mg, 703.10 μmol) was added. The reaction was carried out at room temperature for 2 hours. The pH of the reaction solution was adjusted to 5-6 with 1 M hydrochloric acid, and then the reaction solution was directly concentrated to obtain compound 12y-A (204 mg). m / z (ESI): 581.8 [M+H] + .

[0323] Step 3: Synthesis of intermediate 12z-A

[0324] Compound 12y-A (204 mg, 351.48 μmol) was dissolved in 1,4-dioxane (2 mL) and anhydrous N,N-dimethylformamide (2 mL). O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (397.76 mg, 1.05 mmol) and N,N-diisopropylethylamine (272.52 mg, 2.11 mmol) were added, and the mixture was reacted at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal-phase silica gel column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 2 / 1) to give compound 12z-A (154 mg). m / z (ESI): 562.2, 564.1 [M+H] + .

[0325] Step 4: Synthesis of intermediate 12aa-A

[0326] Compound 12z-A (52 mg, 92.45 μmol) and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (29.89 mg, 110.94 μmol) were dissolved in 1,4-dioxane (989.33 μL), followed by the addition of methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (25.14 mg, 27.74 μmol) and a solution of bis(trimethylsilyl)aminolithium (1 M, 277.35 μL). The reaction was then carried out at 60 °C for 0.5 h under nitrogen protection. The reaction was quenched with water (5 mL) and then extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was purified by normal-phase chromatography (silica, dichloromethane / methanol = 20 / 1) to give compound 12aa-A (17 mg). m / z (ESI): 751.5 [M+H] + .

[0327] Step 5: Synthesis of intermediate 12ab-A

[0328] Compound 12aa-A (17 mg, 22.64 μmol) was dissolved in methanol (0.5 mL), and dioxane hydrochloride solution (2 M, 113.19 μL) was added. The reaction mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 12ab-A, which could be used directly in the next step without purification. m / z (ESI): 651.2 [M+H] + .

[0329] Step 6: Synthesis of Compound 12-A

[0330] Compound 12ab-A (20 mg, 30.73 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (12.49 mg, 33.80 μmol) were dissolved in N,N-dimethylformamide (0.25 mL), followed by the addition of sodium acetate (25.20 mg, 307.31 μmol), acetic acid (184.54 μg, 3.07 μmol), and sodium borohydride acetate (16.28 mg, 76.83 μmol). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction was quenched by adding 2 drops of water. Purified by high performance liquid chromatography (Phenomenex Gemini NX column, 5 μm, 30 mm diameter, 150 mm length); (using a mixture of water (containing 0.225% formic acid) and acetonitrile in decreasing polarity (acetonitrile ratio 11%-51%) as eluent) to give title compound 12-A (1.6 mg).

[0331] m / z (ESI): 1004.9 [M+H] + .

[0332] 1 H NMR (400MHz, DMSO-d6) δ12.80-12.55(m,1H),11.13-11.00(m,1H),8.42(s,1H),8.37(s,1H),7.69-7.61(m,1H),7.56(s,1H) ,7.46-7.38(m,1H),7.33-7.27(m,1H),7.26-7.18(m,2H),6.99-6.87(m,1H),5.06(dd,J=5.9,11.9Hz,1H),4.78-4.65(m,1H ),4.62-4.49(m,1H),4.11-3.96(m,2H),3.74(s,4H),3.67-3.53(m,3H),3.20(d,J=2.2Hz,2H),3.04-2.81(m,4H),2.78-2.6 3(m,5H),2.56-2.54(m,9H),2.40-2.25(m,6H),2.15-1.99(m,4H),1.89-1.74(m,6H),1.69-1.52(m,4H),1.24-1.06(m,2H).

[0333] Compound 12-B was prepared by replacing compound 12x-A with compound 12x-B using a similar method.

[0334] m / z (ESI): 1004.9 [M+H] + .

[0335] 1 H NMR (400MHz, DMSO-d6) δ12.84-12.62(m,1H),11.21-11.03(m,1H),8.55-8.38(m,1H),8.04-7. 91(m,1H),7.77-7.54(m,2H),7.51-7.39(m,1H),7.37-7.13(m,3H),7.05-6.87(m,1H),5.20-5. 00(m,1H),4.82-4.49(m,2H),4.15-3.97(m,2H),3.73(s,3H),3.60(s,6H),3.01-2.90(m,2H),2 .79-2.64(m,6H),2.47-2.28(m,6H),2.21-1.96(m,5H),1.94-1.51(m,16H),1.43-1.02(m,5H).

[0336] Example 13: Synthesis of Compound 13

[0337] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,6-difluorophenyl)pyridine (13a)

[0338] 11c (1.0 g, 2.07 mmol) and 10b (396.15 mg, 2.49 mmol) were dissolved in 1,4-dioxane (10 mL), followed by the addition of (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (201.68 mg, 207.33 μmol) and cesium carbonate (2.03 g, 6.22 mmol). The mixture was purged with nitrogen, and the reaction was carried out at 90 °C for 5 hours under nitrogen protection. The reaction was quenched by adding water (10 mL) to the reaction solution, and then extracted three times with ethyl acetate (30 mL * 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 13a (270 mg, yield 23%).

[0339] m / z(ESI): 561.3 [M+H] + .

[0340] Step 2: Synthesis of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione (13b)

[0341] Compound 13a (270 mg, 481.60 μmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and 10% palladium on carbon (0.25 g) was added. The mixture was then reacted at 45 °C for 5 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered, and the filtrate was concentrated. The crude product obtained could be used directly in the next reaction without purification.

[0342] m / z(ESI): 383.2 [M+H] + .

[0343] Step 3: Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-4-carboxaldehyde (13c)

[0344] Compound 13b (20 mg, 52.30 μmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was then reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product obtained could be used directly in the next reaction without purification.

[0345] m / z(ESI): 337.1 [M+H] + .

[0346] Step 4: Synthesis of Compound 13

[0347] Compounds 3c (10 mg, 18.85 μmol) and 13c (10 mg, 29.73 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (7.73 mg, 94.23 μmol) and sodium borohydride acetate (19.97 mg, 94.23 μmol) were added. The reaction was allowed to proceed at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water, and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 13 (10 mg, yield 62%). m / z (ESI): 851.5 [M+H] + .

[0348] 1 H NMR (400MHz, DMSO-d6) δ12.35(s,1H),10.86(s,1H),8.80(d,J=2.4Hz,1H),8.35(s,1H),8.26(d,J=2.4Hz ,1H),7.35(d,J=9.2Hz,1H),7.11(d,J=2.0Hz,1H),6.85(d,J=8.8Hz,1H),6.61(d,J=13.2Hz,2H),4.37-4 .31(m,1H),4.11-4.02(m,2H),3.94-3.88(m,2H),3.78-3.74(m,2H),3.71(s,3H),3.61(s,3H),3.16-3.1 4(m,4H),3.81-3.72(m,4H),2.52-2.48(m,2H),2.23-1.77(m,10H),1.23-1.14(m,5H),0.87-0.79(m,4H).

[0349] Example 14: Synthesis of Compound 14

[0350] Step 1: Synthesis of intermediate 14a

[0351] 1p (30 mg, 57.10 mmol) and 10b (13.64 mg, 85.65 μmol) were dissolved in anhydrous 1,4-dioxane (10 mL), followed by the addition of (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (11.11 mg, 11.42 μmol) and cesium carbonate (37.21 mg, 114.20 mmol). The mixture was purged with nitrogen, and the reaction was carried out at 100 °C for 2 hours under nitrogen protection. The reaction was quenched by adding water (5 mL), and then extracted three times with ethyl acetate (30 mL * 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 14a (25 mg, yield 72%).

[0352] m / z (ESI): 604.3 [M+H] + .

[0353] Step 2: Synthesis of intermediate 14b

[0354] Compound 14a (10 mg, 16.56 μmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was then reacted at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting crude product 14b could be used directly in the next reaction without purification.

[0355] m / z (ESI): 558.3 ​​[M+H] + .

[0356] Step 3: Synthesis of Compound 14

[0357] Compounds 14b (9 mg, 16.14 μmol) and 14c (7.95 mg, 24.21 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (6.62 mg, 80.70 μmol) and sodium borohydride acetate (17.10 mg, 80.70 μmol) were added. The reaction was allowed to proceed at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water, and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 14 (2.8 mg, yield 20%).

[0358] m / z (ESI): 870.2 [M+H] + .

[0359] 1H NMR (400MHz, DMSO-d6) δ12.33(s,1H),10.88(s,1H),9.90(s,1H),8.73(d,J=2.4Hz,1H),8.28(s,1H),8.20(d, J=2.4Hz,1H),7.54(d,J=8.4Hz,1H),7.33(d,J=8.0Hz,1H),7.12-7.08(m,3H),5.02-4.97(m,1H),4.32-4.28(m ,2H),4.18(d,J=16.8Hz,1H),4.07-4.03(m,1H),3.95-3.86(m,4H),3.68-3.54(m,8H),3.20-3.08(m,2H),2.8 4-2.54(m,6H),2.33-2.26(m,1H),2.12-1.86(m,6H),1.45-1.30(m,2H),1.28-1.15(m,6H),0.78-0.74(m,4H).

[0360] Example 15: Synthesis of Compound 15

[0361] Compounds 14b (9 mg, 16.14 μmol) and 15a (8.68 mg, 21.98 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (6.62 mg, 80.70 μmol) and sodium borohydride acetate (17.10 mg, 80.70 μmol) were added. The reaction was allowed to proceed at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water, and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 15 (4.35 mg, yield 30%).

[0362] m / z(ESI): 900.3 [M+H] + .

[0363] 1H NMR (400MHz, DMSO-d6) δ12.27(s,1H),10.88(s,1H),8.73(d,J=2.4Hz,1H),8.28(s,1H),8.19(d, J=2.4Hz,1H),7.28(d,J=8.4Hz,1H),7.05(s,1H),6.82-6.60(m,3H),5.02-4.98(m,1H),4.28-4.1 9(m,2H),4.08-4.02(m,2H),3.92-3.86(m,2H),3.81(s,3H),3.64-3.54(m,8H),3.18-3.14(m,2H ),2.86-2.54(m,8H),2.36-2.12(m,3H),1.92-1.83(m,4H),1.41-1.16(m,8H),0.78-0.74(m,4H).

[0364] Example 16: Synthesis of Compound 16

[0365] Step 1: Synthesis of intermediate 16a

[0366] Compound 1p (20 mg, 38.07 μmol) and (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (10.67 mg, 53.29 μmol) were dissolved in N,N-dimethylacetamide (2 mL), and tris(dibenzylacetone)dipalladium (6.97 mg, 7.61 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (7.11 mg, 15.23 μmol), and sodium tert-butoxide (10.97 mg, 114.20 μmol) were added. The air was purged with nitrogen, and the reaction was carried out at 95 °C for 1 hour under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 16a (10 mg, yield 41%).

[0367] m / z (ESI): 645.3 [M+H] +

[0368] Step 2: Synthesis of intermediate 16b

[0369] Compound 16a (10 mg, 15.51 μmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was then reacted at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting crude product 16b could be used directly in the next reaction without purification.

[0370] m / z (ESI): 545.3 [M+H] +

[0371] Step 3: Synthesis of Compound 16

[0372] Compounds 16b (8 mg, 14.69 μmol) and 5a (7.36 mg, 19.09 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (6.02 mg, 73.44 μmol) and sodium borohydride acetate (15.57 mg, 73.44 μmol) were added. The mixture was reacted at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops), and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 16 (5 mg, yield 37%).

[0373] m / z (ESI): 914.6 [M+H] + .

[0374] 1 H NMR(400MHz,DMSO-d6)δ12.56(s,1H),10.96(s,1H),9.91(s,1H),8.80(s,1H),8.35( s,1H),8.28(s,1H),7.49-7.24(m,3H),7.10(d,J=8.0Hz,1H),5.09-5.06(m,1H),4.4 8-4.26(m,5H),4.13-4.07(m,2H),4.00-3.93(m,2H),3.88(s,3H),3.71(s,3H),3,62 (s,3H),2.91-2.61(m,8H),2.19-1.92(m,8H),1.45-1.11(m,10H),0.87-0.80(m,4H).

[0375] Example 17: Synthesis of Compound 17

[0376] Compounds 2c (17 mg, 27.70 μmol) and 13c (13.97 mg, 41.55 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (11.36 mg, 138.49 μmol) and sodium borohydride acetate (29.35 mg, 138.49 μmol) were added. The mixture was reacted at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops), and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 17 (12 mg, yield 46%).

[0377] m / z (ESI): 934.8 [M+H] + .

[0378] 1 H NMR (400MHz, DMSO-d6) δ12.35(s,1H),10.86(s,1H),8.80(d,J=2.4Hz,1H),8.34(s,1H),8.26( d,J=2.4Hz,1H),7.35(d,J=8.8Hz,1H),7.13(s,1H),6.87(d,J=8.8Hz,1H),6.61(d,J=13.2Hz, 2H),4.40-4.30(m,1H),4.11-4.02(m,2H),3.96-3.90(m,2H),3.76-3.70(m,7H),3.61(s,3H), 2.82-2.65(m,8H),2.18-1.92(m,9H),1.76-1.44(m,8H),1.24-1.12(m,7H),0.87-0.79(m,4H).

[0379] Example 18: Synthesis of Compound 18

[0380] Step 1: Synthesis of intermediate 18b

[0381] Compound 1p (15 mg, 28.55 μmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester 18a (8.49 mg, 42.82 μmol) were dissolved in anhydrous N,N-dimethylacetamide (2 mL), and tris(dibenzylacetone)dipalladium (5.23 mg, 5.71 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (5.33 mg, 11.42 μmol), and sodium tert-butoxide (8.23 mg, 85.65 μmol) were added. The air was purged with nitrogen, and the reaction was carried out at 95 °C for 2 hours under nitrogen protection. The reaction solution was directly purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 18b (12 mg, yield 65%).

[0382] m / z (ESI): 643.3 [M+H] +

[0383] Step 2: Synthesis of intermediate 18c

[0384] Compound 18b (12 mg, 18.67 μmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was then reacted at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting crude product 18c could be used directly in the next reaction without purification.

[0385] m / z(ESI): 543.3 [M+H]+

[0386] Step 3: Synthesis of Compound 18

[0387] Compound 18c (10 mg, 18.43 μmol) and 5a (10.65 mg, 27.64 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (7.56 mg, 92.14 μmol) and sodium borohydride acetate (19.53 mg, 92.14 μmol) were added. The mixture was reacted at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops), and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 18 (5 mg, yield 30%).

[0388] m / z (ESI): 912.4 [M+H] + .

[0389] 1 H NMR (400MHz, DMSO-d6) δ12.34(s,1H),10.96(s,1H),8.79(d,J=2.4Hz,1H),8.35(s,1H),8.26(d,J=2.4Hz,1H ),7.41-7.34(m,2H),7.10(d,J=8.0Hz,1H),6.63(s,1H),6.36(d,J=8.0Hz,1H),5.09-5.04(m,1H),4.47-4.26 (m,4H),4.13-4.07(m,2H),3.96-3.93(m,2H),3.87(m,3H),3.71(s,3H),3,61(s,3H),3.60-3.50(m,1H),3.22 -3.18(m,1H),2.94-2.52(m,7H),2.22-2.18(m,1H),2.03-1.78(m,7H),1.45-1.16(m,8H),0.87-0.80(m,4H).

[0390] Example 19: Synthesis of Compound 19

[0391] Step 1: Synthesis of 4-(2-(tert-butoxycarbonylamino)ethylamino)piperidine-1-carboxylic acid benzyl ester (19c)

[0392] Compounds 19a (500 mg, 2.14 mmol) and 19b (343.42 mg, 2.14 mmol) were dissolved in 1,2-dichloroethane (3 mL). Sodium borohydride acetate (1.14 g, 5.36 mmol) and acetic acid (130 mg, 2.16 mmol) were added under ice bath conditions, and the reaction was then brought to room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 19c (800 mg, 99% yield).

[0393] m / z(ESI): 378.2 [M+H] + .

[0394] Step 2: Synthesis of 4-(2-(tert-butoxycarbonylamino)ethyl-(2-chloroacetyl)amino)piperidine-1-carboxylic acid benzyl ester (19d)

[0395] Compound 19c (800 mg, 2.12 mmol) and N,N-diisopropylethylamine (821.73 mg, 6.36 mmol) were dissolved in dichloromethane (3 mL). Chloroacetyl chloride (287.24 mg, 2.54 mmol) was added under ice bath conditions, and the reaction was then brought to room temperature for 30 minutes. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18, water:acetonitrile = 20:1 to 1:20) to give compound 19d (850 mg, yield 88%).

[0396] m / z (ESI): 454.2 [M+H] + .

[0397] Step 3: Synthesis of 4-(1-benzyloxycarbonyl-piperidin-4-yl)-3-oxoperpiperazine-1-carboxylic acid tert-butyl ester (19e)

[0398] Compound 19d (150 mg, 330.43 μmol) was dissolved in N,N-dimethylformamide (3 mL), and sodium hydride (60% oil, 25.32 mg, 660.85 μmol) was added under ice bath conditions. The reaction was then brought to room temperature for 2 hours. Under ice bath conditions, the reaction was quenched with ice water, concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18, water:acetonitrile = 20:1 to 1:20) to give compound 19e (100 mg, yield 72%).

[0399] m / z (ESI): 418.2 [M+H] +

[0400] Step 4: Synthesis of tert-butyl 3-oxo-4-(piperidin-4-yl)piperazine-1-carboxylic acid (19f)

[0401] Compound 19e (110 mg, 263.47 μmol) was dissolved in isopropanol (10 mL), and palladium on carbon (50 mg) was added. The mixture was then reacted at room temperature for 5 hours under a hydrogen atmosphere (15 psi). The reaction solution was directly filtered, and the filtrate was concentrated. The crude product 19f obtained could be used directly in the next reaction without purification.

[0402] m / z(ESI): 284.2 [M+H] + .

[0403] Step 5: Synthesis of 19g intermediate

[0404] Compounds 1p (15 mg, 28.55 μmol) and 19f (15 mg, 52.94 μmol) were dissolved in N,N-dimethylacetamide (2 mL), and tris(dibenzylacetone)dipalladium (5.23 mg, 5.71 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (5.33 mg, 11.42 μmol), and sodium tert-butoxide (8.23 mg, 85.65 μmol) were added. The air was purged with nitrogen, and the reaction was carried out at 80 °C for 30 minutes under nitrogen protection. The reaction solution was directly purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give 19 g of compound (10 mg, yield 48%).

[0405] m / z (ESI): 728.4 [M+H] + .

[0406] Step 6: Synthesis of intermediates over 19 hours

[0407] 19 g (10 mg, 13.74 μmol) of the compound was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was then reacted at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure, and the crude product obtained was used directly in the next reaction without purification.

[0408] m / z (ESI): 628.3 [M+H] + .

[0409] Step 7: Synthesis of Compound 19

[0410] Compounds 19h (8.6 mg, 13.70 μmol) and 5a (6.86 mg, 17.81 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (5.62 mg, 68.50 μmol) and sodium borohydride acetate (14.52 mg, 68.50 μmol) were added. The reaction was carried out at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops), and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 19 (3 ​​mg, yield 22%).

[0411] m / z (ESI): 997.6 [M+H] + .

[0412] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),10.96(s,1H),8.80(d,J=2.4Hz,1H),8.35(s,1H),8.26(d,J=2.4Hz,1H),7.40-7 .35(m,2H),7.16(s,1H),7.09(d,J=8.0Hz,1H),6.89(d,J=8.0Hz,1H),5.09-5.04(m,1H),4.47-4.26(m,4H),4.12-4.09 (m,1H),3.98-3.90(m,2H),3.87(s,3H),3.82-3.78(m,2H),3.72(s,3H),3,62(s,3H),3.60-3.50(m,2H),3.22-3.00(m, 2H),2.91-2.61(m,8H),2.33-2.18(m,2H),1.99-1.87(m,8H),1.48-1.41(m,1H),1.45-1.24(m,8H),0.86-0.81(m,4H).

[0413] Example 20: Synthesis of Compound 20

[0414] Compound 2c (12 mg, 19.55 μmol) and 11 g (12 mg, 37.23 μmol) were dissolved in dichloroethane (3 mL), and sodium triacetoxyborohydride (16.58 mg, 78.21 μmol) was added. The mixture was then heated to 50 °C and reacted for 24 hours. The reaction solution was concentrated, and the crude product was purified by direct reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 20 (3.0 mg, yield 17%).

[0415] m / z (ESI): 920.8 [M+H] + .

[0416] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),10.88(s,1H),8.82(d,J=2.4Hz,1H),8.37(s,1H),8.28(d,J=2.4Hz,1H),7.37(d,J=8 .8Hz,1H),7.14(s,1H),6.88(d,J=8.0Hz,1H),6.67-6.64(m,2H),4.40-4.30(m,1H),4.13-4.04(m,2H),3.95-3.92(m,2H),3 .80-3.74(m,2H),3.73(s,3H),3,63(s,3H),3.60-3.56(m,1H),3.51-3.48(m,1H),3.30-3.25(m,2H),3.12-3.08(m,1H),2.8 0-2.66(m,8H),2.25-2.08(m,2H),1.99-1.92(m,7H),1.69-1.63(m,5H),1.49-1.44(m,2H),1.25(s,3H),0.88-0.82(m,4H).

[0417] Example 21: Synthesis of Compound 21

[0418] Compounds 18c (30 mg, 55.29 μmol) and 13c (24 mg, 71.36 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (24.0 mg, 292.56 μmol) and sodium borohydride acetate (60.0 mg, 283.10 μmol) were added. The reaction was carried out at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops), and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 21 (20 mg, yield 42%).

[0419] m / z (ESI): 863.8 [M+H] + .

[0420] 1H NMR (400MHz, DMSO-d6) δ12.34(s,1H),10.88(s,1H),8.81(d,J=2.4Hz,1H),8.37(s,1H),8.27(d,J =2.4Hz,1H),7.35(d,J=8.4Hz,2H),6.66-6.60(m,2H),6.34(dd,J=8.4,2.0Hz,1H),4.42-4.32(m, 1H),4.14-4.04(m,2H),3.94(s,3H),3.88-3.75(m,3H),3.73(s,3H),3,63(s,3H),2.84-2.67(m,6 H),2.25-2.08(m,2H),1.99-1.92(m,4H),1.78-1.46(m,6H),1.26-1.15(m,5H),0.88-0.81(m,4H).

[0421] Example 22: Synthesis of Compound 22

[0422] Step 1: Synthesis of intermediate 22b

[0423] Compound 1p (20 mg, 38.07 μmol) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate 22a (24.24 mg, 114.20 μmol) were dissolved in 1,4-dioxane (3 mL), and then palladium (3.45 mg, 3.81 μmol) of (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) (1 M, 119.30 μL) and bis(trimethylsilylamino)lithium (1 M, 119.30 μL) were added. The air was purged with nitrogen, and the reaction was carried out at 60 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 22b (22 mg, yield 88%).

[0424] m / z (ESI): 657.3 [M+H] + .

[0425] Step 2: Synthesis of intermediate 22c

[0426] Compound 22b (22 mg, 33.50 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added. The mixture was then reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting crude product 22c could be used directly in the next step of the reaction without purification.

[0427] m / z (ESI): 557.3 [M+H]+ .

[0428] Step 3: Synthesis of Compound 22

[0429] Compounds 22c (18 mg, 32.34 μmol) and 13c (16.31 mg, 48.50 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (13.26 mg, 161.7 μmol) and sodium borohydride acetate (34.27 mg, 161.7 μmol) were added. The reaction was carried out at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops), and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 22 (10.15 mg, yield 36%).

[0430] m / z (ESI): 877.5 [M+H] + .

[0431] 1 H NMR (400MHz, DMSO-d6) δ12.33 (s, 1H), 10.86 (s, 1H), 8.79 (d, J = 2.4Hz, 1H), 8.35 (s, 1H), 8.25(d,J=2.4Hz,1H),7.34(d,J=8.4Hz,1H),6.65-6.59(m,3H),6.34(d,J=8.0Hz,1H),4. 38-4.30(m,1H),4.12-4.02(m,2H),3.98-3.75(m,6H),3.71(s,3H),3.61(s,3H),3.20-3 .00(m,2H),2.83-2.67(m,4H),2.24-1.81(m,10H),1.43-1.18(m,9H),0.85-0.80(m,4H).

[0432] Example 23: Synthesis of Compound 23

[0433] Step 1: Synthesis of intermediate 23b

[0434] Compounds 1p (20 mg, 38.07 μmol) and 23a (7.62 mg, 38.07 μmol) were dissolved in N,N-dimethylacetamide (3 mL), and tris(dibenzylacetone)dipalladium (3.49 mg, 3.81 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (3.55 mg, 7.61 μmol), and sodium tert-butoxide (10.97 mg, 114.20 μmol) were added. The air was purged with nitrogen, and the reaction was carried out at 90 °C for 2 hours under nitrogen protection. The reaction solution was filtered to remove insoluble matter, and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 23b (20 mg, yield 81%).

[0435] m / z (ESI): 644.4 [M+H] + .

[0436] Step 2: Synthesis of intermediate 23c

[0437] Compound 23b (20 mg, 31.07 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was then reacted at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting crude product 23c could be used directly in the next reaction without purification.

[0438] m / z (ESI): 544.3 [M+H] + .

[0439] Step 3: Synthesis of Compound 23

[0440] Compounds 23c (16.0 mg, 29.38 μmol) and 13c (14.82 mg, 44.07 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (12.05 mg, 146.88 μmol) and sodium borohydride acetate (31.13 mg, 146.88 μmol) were added. The mixture was reacted at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops), and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 23 (5.65 mg, yield 22%).

[0441] m / z (ESI): 865.7 [M+H] + .

[0442] 1 H NMR (400MHz, DMSO-d6)δ 1H NMR (400MHz, DMSO-d6) δ12.35(s,1H),10.86(s,1H),8.80(d,J=2.4Hz,1H),8.35(s,1H),8.26(d,J=2.4Hz ,1H),7.37-7.35(m,1H),7.11(s,1H),6.85(d,J=8.8Hz,1H),6.63-6.60(m,2H),4.40-4.30(m,1H),4.12-4 .02(m,2H),3.98-3.88(m,2H),3.78-3.74(m,2H),3.71(s,3H),3.61(s,3H),3.46-3.38(m,2H),2.96-2.6 7(m,5H),2.22-1.86(m,10H),1.72-1.68(m,1H),1.45-1.43(m,1H),1.23-1.09(m,8H),0.85-0.80(m,4H).

[0443] Example 24: Synthesis of Compound 24

[0444] Step 1: Synthesis of intermediate 24a

[0445] Compounds 1p (20 mg, 38.07 μmol) and 24a (7.62 mg, 38.07 μmol) were dissolved in N,N-dimethylacetamide (3 mL), and tris(dibenzylacetone)dipalladium (3.49 mg, 3.81 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (3.55 mg, 7.61 μmol), and sodium tert-butoxide (10.97 mg, 114.20 μmol) were added. The air was purged with nitrogen, and the reaction was carried out at 90 °C for 2 hours under nitrogen protection. The reaction solution was filtered to remove insoluble matter, and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 24b (22 mg, 90% yield).

[0446] m / z (ESI): 644.4 [M+H] + .

[0447] Step 2: Synthesis of intermediate 24c

[0448] Compound 24b (22 mg, 34.12 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was then reacted at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting crude product 24c could be used directly in the next reaction without purification.

[0449] m / z (ESI): 544.3 [M+H]+ .

[0450] Step 3: Synthesis of Compound 24

[0451] Compounds 24c (18.0 mg, 33.05 μmol) and 13c (14.45 mg, 42.96 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (13.56 mg, 165.24 μmol) and sodium borohydride acetate (35.02 mg, 165.24 μmol) were added. The reaction was carried out at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops), and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 24 (5.96 mg, yield 21%).

[0452] m / z (ESI): 865.7 [M+H] + .

[0453] 1 H NMR (400MHz, DMSO-d6) δ12.35(s,1H),10.86(s,1H),8.80(d,J=2.4Hz,1H),8.35(s,1H),8.26(d,J=2.4Hz ,1H),7.37-7.35(m,1H),7.14(s,1H),6.86(d,J=8.8Hz,1H),6.63-6.60(m,2H),4.40-4.30(m,1H),4.12-4 .02(m,2H),3.98-3.88(m,2H),3.78-3.74(m,2H),3.71(s,3H),3.61(s,3H),3.46-3.38(m,1H),2.96-2.6 7(m,6H),2.33-1.86(m,10H),1.72-1.68(m,1H),1.45-1.43(m,1H),1.32-1.09(m,8H),0.85-0.80(m,4H).

[0454] Example 25: Synthesis of Compound 25

[0455] Step 1: Synthesis of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate (25a)

[0456] Compound 1k (430 mg, 1.35 mmol) was dissolved in anhydrous dichloromethane (5 mL), followed by the sequential addition of methanesulfonic anhydride (283.39 mg, 1.63 mmol) and triethylamine (164.42 mg, 1.63 mmol). The reaction was carried out at room temperature for 2 hours. The reaction solution was then concentrated, and the crude product was directly subjected to reversed-phase chromatography (C1000 ppm) on a C1000 ppm column. 18 The product 25a (310 mg, 96% yield) was obtained by purification using 0.05% ammonia water:acetonitrile (20:1 to 1:20). m / z (ESI): 395.1 [M+H] + .

[0457] Step 2: Synthesis of methyl 5-(2-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ester (25d)

[0458] Compounds 25b (150 mg, 609.61 μmol) and 25c (156.98 mg, 670.57 μmol) were dissolved in a mixed solution of 1,4-dioxane (5.0 mL) and water (0.5 mL). Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (44.61 mg, 60.96 μmol) and potassium carbonate (168.50 mg, 1.22 mmol) were added. The mixture was purged with nitrogen, and then reacted at 90 °C for 2 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and the crude product was directly subjected to reverse-phase chromatography (C1000- ... 18 The product was purified by 0.05% ammonia water:acetonitrile (ratio 20:1 to 1:20) to obtain 25d (150mg, yield 90%). m / z (ESI): 274.1 [M+H] + .

[0459] Step 3: Synthesis of methyl 5-(2-hydroxyphenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ester (25e)

[0460] Compound 25d (150 mg, 548.88 μmol) was dissolved in anhydrous dichloromethane (5 mL), followed by the slow addition of boron tribromide (687.54 mg, 2.74 mmol). The reaction was allowed to proceed at room temperature for 2 hours. The reaction was then quenched by adding methanol (1.0 mL). The solvent was removed by vacuum distillation. The crude product was directly analyzed by reversed-phase chromatography (C1000- ... 18 Purification with 0.05% ammonia water:acetonitrile (20:1 to 1:20) yielded product 25e (110 mg, 77% yield). m / z (ESI): 260.2 [M+H] + .

[0461] Step 4: Synthesis of (R)-5-(2-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (25f)

[0462] Compound 25a (130 mg, 328.89 μmol) and compound 25e (93.79 mg, 361.78 μmol) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of potassium carbonate (90.91 mg, 657.78 μmol). The mixture was then heated to 60 °C and reacted for 5 hours. The reaction was quenched by adding water (5 mL), followed by extraction three times with ethyl acetate (30 x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal-phase silica gel column chromatography (EA:PE = 0-100%) to obtain product 25f (150 mg, yield 82%). m / z (ESI): 558.3 ​​[M+H] + .

[0463] Step 5: Synthesis of (R)-5-(2-((5-((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (25g)

[0464] Compound 25f (150 mg, 268.62 μmol) was dissolved in methanol (3 mL) under ice bath conditions, followed by the sequential addition of Raney nickel (75.0 mg, 1.28 mmol) and hydrazine hydrate (1.0 mL), and the reaction was continued under these conditions for 30 minutes. Insoluble matter was removed by filtration, the filtrate was concentrated, and the crude product was subjected to reversed-phase chromatography (C1000- ... 18 Purification with 0.05% ammonia water:acetonitrile (ratio 20:1 to 1:20) yielded 25 g (141 mg, 99% yield). m / z (ESI): 528.2 [M+H] + .

[0465] Step 6: Synthesis of (R)-5-(2-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (25h)

[0466] 25 g (141 mg, 266.82 μmol) of the compound was dissolved in anhydrous methanol (5 mL), and cyanogen bromide (58.68 mg, 533.65 μmol) was added. The reaction mixture was reacted at room temperature for 5 hours. The reaction solution was quenched with saturated sodium carbonate aqueous solution (5 mL), stirred at room temperature for 0.5 hours, and extracted with dichloromethane (8 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal-phase chromatography (petroleum ether:tetrahydrofuran = 1:1) to give compound 25h (100 mg, yield 68%). m / z (ESI): 553.3 [M+H] + .

[0467] Step 7: Synthesis of (R)-5-(2-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (25i)

[0468] Compound 25h (100 mg, 180.69 μmol) was dissolved in a mixed solution of tetrahydrofuran (5.0 mL), water (1.0 mL), and methanol (1.0 mL). Lithium hydroxide monohydrate (37.91 mg, 903.43 μmol) was added, and the reaction mixture was heated to 45 °C for 3 hours. The pH of the reaction solution was adjusted to 5-6 with 1 M hydrochloric acid, and the solution was concentrated under reduced pressure to give compound 25i (70 mg, 72% yield). m / z (ESI): 539.3 [M+H] + .

[0469] Step 8: Synthesis of intermediate 25j

[0470] Compound 25i (70 mg, 129.77 μmol) was dissolved in 1,4-dioxane (3.2 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (74.01 mg, 194.65 μmol) and N,N-diisopropylethylamine (33.54 mg, 259.54 μmol, 45.33 μL) were added. The reaction solution was reacted at 45 °C for 3 hours. The reaction solution was quenched with water (2.0 mL), and the reaction solution was directly concentrated. The crude product was directly subjected to reversed-phase chromatography (C1000- ... 18 Purification with 0.05% ammonia water:acetonitrile (20:1 to 1:20) yielded 25j (62mg, 92% yield). m / z (ESI): 521.3 [M+H] + .

[0471] Step 9: Synthesis of intermediate 25k

[0472] Compound 25j (30 mg, 57.54 μmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester 18a (34.22 mg, 172.61 μmol) were dissolved in 1,4-dioxane (2.5 mL), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (5.22 mg, 5.75 μmol) and bis(trimethylsilylamino)lithium (1 M, 345.2 μL) were added. The air was purged with nitrogen, and the reaction was carried out at 60 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 25k (10 mg, yield 27%). m / z (ESI): 639.6 [M+H] + .

[0473] Step 10: Synthesis of intermediate 25L

[0474] Compound 25k (10 mg, 15.66 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added. The mixture was then reacted at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting crude product 25k could be used directly in the next reaction without purification. m / z (ESI): 539.4 [M+H] + .

[0475] Step 11: Synthesis of Compound 25

[0476] Compound 25l (8.0 mg, 14.85 μmol) and 13c (5.0 mg, 14.85 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (6.09 mg, 74.26 μmol) and sodium borohydride acetate (15.74 mg, 74.26 μmol) were added. The reaction was carried out at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops), and then purified directly by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 25 (3.25 mg, yield 25%).

[0477] m / z (ESI): 859.3 [M+H] + .

[0478] 1H NMR (400MHz, DMSO-d6) δ12.24(s,1H),10.86(s,1H),8.83(d,J=2.4Hz,1H),8.31(d,J=2.4Hz,1H),7.6 8(dd,J=8.0,2.0Hz,1H),7.32(d,J=8.4Hz,1H),7.26(t,J=8.0Hz,1H),7.11(d,J=8.4Hz,1H),6.94(t, J=8.0Hz,1H),6.64-6.51(m,3H),6.33(d,J=8.8Hz,1H),4.18-3.71(m,11H),3.60(s,3H),2.82-2.67( m,4H),2.33-2.28(m,2H),2.10-1.97(m,5H),1.74-1.63(m,2H),1.32-1.18(m,8H),0.93-0.81(m,4H).

[0479] Example 26: Synthesis of Compound 26

[0480] Compounds 3c (10.0 mg, 18.85 μmol) and 7a (10.90 mg, 28.27 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (7.73 mg, 94.23 μmol) and sodium borohydride acetate (19.97 mg, 94.23 μmol) were added. The reaction was carried out at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops). The reaction solution was directly purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 26 (6.2 mg, yield 37%).

[0481] m / z(ESI): 900.4 [M+H] + .

[0482] 1H NMR (400MHz, DMSO-d6) δ12.25(s,1H),10.96(s,1H),8.80(d,J=2.0Hz,1H),8.35(s,1H),8.27(d,J=2.0Hz,1H),7.36(d,J=8.4Hz,1H) ,7.13(d,J=2.4Hz,1H),6.87(dd,J=8.4,2.0Hz,1H),6.78(d,J=13.6Hz,2H),5.07(dd,J=13.6,4.8Hz,1H),4.38-4.32(m,1H),4.26(d ,J=16.8Hz,1H),4.12-4.08(m,2H),3.96-3.90(m,2H),3.87(s,3H),3.81-3.78(m,2H),3.71(s,3H),3.61(s,3H),3.18-3.12(m,4H), 2.95-2.67(m,5H),2.42-2.33(m,1H),2.26-2.19(m,3H),1.98-1.76(m,6H),1.44-1.42(m,1H),1.31-1.23(m,5H),0.85-0.80(m,4H).

[0483] Example 27: Synthesis of Compound 27

[0484] Compounds 3c (10.0 mg, 18.85 μmol) and 27a (10.90 mg, 28.27 μmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium acetate (7.73 mg, 94.23 μmol) and sodium borohydride acetate (19.97 mg, 94.23 μmol) were added. The reaction was carried out at room temperature for 30 minutes. The reaction was quenched by adding water (2 drops). The reaction solution was directly purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 27 (6.1 mg, yield 36%).

[0485] m / z(ESI): 900.4 [M+H] + .

[0486] 1H NMR (400MHz, DMSO-d6) δ12.31(s,1H),10.97(s,1H),8.80(d,J=2.0Hz,1H),8.35(s,1H),8.26(d,J=2.0Hz,1H),7.36(d,J=8.4Hz,1H) ,7.13(d,J=2.4Hz,1H),6.86(dd,J=8.4,2.0Hz,1H),6.78(d,J=13.6Hz,2H),5.07(dd,J=13.6,4.8Hz,1H),4.38-4.32(m,1H),4.26(d ,J=16.8Hz,1H),4.12-4.08(m,2H),3.95-3.90(m,2H),3.87(s,3H),3.81-3.78(m,2H),3.71(s,3H),3.61(s,3H),3.18-3.12(m,4H), 2.95-2.67(m,5H),2.43-2.33(m,1H),2.26-2.13(m,3H),1.99-1.76(m,6H),1.47-1.42(m,1H),1.31-1.23(m,5H),0.87-0.80(m,4H).

[0487] Example 28: Synthesis of Compound 28

[0488] Step 1: Synthesis of (R)-5-((4-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol (28b)

[0489] 220 mg (1.00 mmol) of 4-bromo-1-fluoro-2-nitrobenzene 28a was dissolved in anhydrous acetonitrile (5 mL), and (4R)-5-amino-4-methyl-pentan-1-ol 1i (123.05 mg, 1.05 mmol) and potassium carbonate (414.62 mg, 3.00 mmol) were added. The mixture was then reacted at 80 °C for 8 hours. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 28b (268 mg, yield 84%). m / z (ESI): 317.0, 319.0 [M+H] + .

[0490] Step 2: Synthesis of (R)-5-(5-((5-(((4-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (28c)

[0491] Under ice bath conditions, compound 1h (124.5 mg, 472.92 μmol) and triphenylphosphine (372.12 mg, 1.42 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). Compound 28b (150 mg, 472.92 μmol) and diisopropyl azodicarbonate (286.88 mg, 1.42 mmol) were added under nitrogen protection. The reaction was then continued at 0 °C for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 28c (202 mg, yield 80%). m / z (ESI): 562.1 [M+H] + 564.1 [M+H] + .

[0492] Step 3: Synthesis of methyl(R)-5-(5-((5-(((2-amino-4-bromophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ester (28d)

[0493] Compound 28c (202 mg, 359.17 μmol) was dissolved in methanol (10 mL) under ice bath conditions, followed by the addition of Raney nickel (42.16 mg, 718.33 μmol) and hydrazine hydrate (35.96 mg, 718.33 μmol). The reaction was continued under these conditions for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated. The crude product was directly purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 28d (168 mg, yield 88%). m / z (ESI): 532.1, 534.1 [M+H] + .

[0494] Step 4: Synthesis of (R)-5-(5-((5-(2-amino-5-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxo)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (28e)

[0495] Compound 28d (168 mg, 315.54 μmol) was dissolved in anhydrous dichloromethane (10 mL), followed by the addition of cyanogen bromide (173.47 mg, 1.58 mmol), and the reaction was carried out at room temperature for 24 hours. The reaction solution was directly concentrated, and the crude product was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 28e (128 mg, yield 73%). m / z (ESI): 557.2, 559.2 [M+H] + .

[0496] Step 5: Synthesis of (R)-5-(5-((5-(2-amino-5-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (28f)

[0497] Compound 28e (128 mg, 229.62 μmol) was dissolved in tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL). Lithium hydroxide monohydrate (48.18 mg, 1.15 mmol) was added, and the mixture was reacted at 50 °C for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 28f (112 mg, 90% yield). m / z (ESI): 543.1, 545.1 [M+H] + .

[0498] Step 6: Synthesis of 28g of intermediate

[0499] Compound 28f (112 mg, 206.11 μmol) was dissolved in anhydrous 1,4-dioxane (20 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (117.55 mg, 309.16 μmol) and N,N-diisopropylethylamine (79.91 mg, 618.32 μmol) were added. The mixture was then heated to 60 °C and reacted for 3 hours. The reaction solution was concentrated, and the crude product was directly subjected to reversed-phase chromatography (C1000- ... 18 Purification with 0.05% ammonia water:acetonitrile (20:1 to 1:20) yielded 28 g (68 mg, yield 63%) of product. m / z (ESI): 525.1, 527.1 [M+H] + .

[0500] Step 7: Synthesis of intermediates over 28 hours

[0501] Compound 28 g (30 mg, 57.10 μmol) and compound 3a (15.95 mg, 85.65 μmol) were dissolved in N,N-dimethylacetamide (3 mL), followed by the addition of tris(dibenzylacetone)dipalladium (5.23 mg, 5.71 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (5.33 mg, 11.42 μmol), and sodium tert-butoxide (16.46 mg, 171.30 μmol). The mixture was purged with nitrogen, and the reaction was carried out at 90 °C for 2 hours under nitrogen protection. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated. The crude product was directly purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 28h (22 mg, yield 61%). m / z(ESI): 631.3 [M+H] + .

[0502] Step 8: Synthesis of intermediate 28i

[0503] Compound 28h (22 mg, 34.88 μmol) was dissolved in anhydrous dichloromethane (5 mL), and then trifluoroacetic acid (1.0 mL) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was then concentrated directly, and the crude product 28i obtained could be used directly in the next step of the reaction without purification.

[0504] Compound 28 was prepared by replacing 3c with 28i using a method similar to that in Example 13.

[0505] m / z (ESI): 851.5 [M+H] + .

[0506] 1H NMR (400MHz, DMSO-d6) δ13.32(s,1H),10.87(s,1H),8.79(d,J=2.4Hz,1H),8.35(s,1H),8.28(d,J=2.0Hz,1H),7.40(d,J =8.8Hz,1H),7.11(d,J=2.0Hz,1H),6.93(dd,J=9.2Hz,2.0Hz,1H),6.62(d,J=12.8Hz,2H),4.38-4.28(m,1H),4.13(d,J= 13.6Hz,1H),4.04(dd,J=12.4,5.2Hz,1H),3.98-3.90(m,1H),3.82-3.75(m,2H),3.71(s,3H),3.61(s,3H),3.12-3.06(m ,4H),2.81-2.67(m,4H),2.23-1.89(m,8H),1.80-1.77(m,3H),1.45-1.39(m,1H),1.32-1.14(m,6H),0.87-0.79(m,4H).

[0507] Example 29: Synthesis of Compound 29

[0508] Step 1: Synthesis of 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylic acid tert-butyl ester (29b)

[0509] Compound 29a (50 mg, 146.57 μmol) and compound 3a (40.95 mg, 219.85 μmol) were dissolved in anhydrous 1,4-dioxane (5 mL), followed by the addition of chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (22.77 mg, 29.31 μmol) and cesium carbonate (47.76 mg, 146.57 μmol). The air was purged with nitrogen, and the mixture was reacted at 120 °C for 12 hours under nitrogen protection. After the reaction mixture cooled to room temperature, it was filtered, the filtrate was concentrated, and the crude product was purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 29b (25 mg, yield 38%). m / z (ESI): 447.5 [M+H] + .

[0510] Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (29c)

[0511] Compound 29b (13.39 mg, 30 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was then reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product 29c could be used directly in the next reaction without purification. m / z (ESI): 347.4 [M+H] + .

[0512] Step 3: Synthesis of Compound 29

[0513] Compounds 14b (8.31 mg, 14.90 μmol) and 29c (10.32 mg, 29.80 μmol) were dissolved in N,N-dimethylformamide (3 mL), and sodium acetate (6.11 mg, 74.51 μmol) and sodium borohydride acetate (15.79 mg, 74.51 μmol) were added. The mixture was reacted at room temperature for 30 minutes. The reaction was quenched by adding 2 drops of water. The reaction solution was directly purified by reversed-phase chromatography (C18, 0.5% ammonia:acetonitrile = 20:1 to 1:20) to give compound 29 (5.2 mg, yield 39%).

[0514] m / z (ESI): 888.3 [M+H] + .

[0515] 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=2.4Hz,1H),8.34(s,1H),8.22(s,1H),7.36(d,J=12.8Hz,1H),7.32 (d,J=8.4Hz,1H),7.10(d,J=6.8Hz,1H),7.04(s,1H),6.81(d,J=8.4Hz,1H),4.40-4.30(m,1H),4.12-4 .06(m,1H),3.95(s,3H),3.91-3.82(m,3H),3.71(s,3H),3.68-3.62(m,1H),3.60(s,3H),3.15-3.08(m ,4H),2.82-2.51(m,10H),2.33-2.13(m,4H),1.92-1.65(m,5H),1.44-1.23(m,4H),0.85-0.79(m,4H).

[0516] Test Example 1: Compound Inhibition Test on Tumor Cell Proliferation

[0517] Brief introduction to experimental principle: After co-incubating the compound with tumor cells for 72 hours, the cell viability was quantitatively detected using the Promega CTG kit, thereby reflecting the effect of the compound on tumor cell proliferation.

[0518] Experimental instruments: Perkin Elmer Envision microplate reader; Eppendorf 5810R centrifuge; Countstar automated cell counter; Labcyte Echo 650 ultrasonic liquid handling system.

[0519] Experimental materials:

[0520] Experimental Methods: Cultured cells were resuspended (adherent cells were washed with PBS and digested with 0.25% Trypsin-EDTA) and counted to obtain cell density and viability information. 600 H838 cells / well and 3000 Ba / F3-EGFR-T790M-C797S-L858R (Ba / F3-TCL) cells / well were diluted in RPMI Medium 1640 medium containing 10% FBS (Ba / F3-TCL cell medium supplemented with 0.5 μg / mL puromycin) and added to 384-well plates (40 μL / well). The plates were then incubated at 37°C in a 5% CO2 incubator for 24 hours. On the second day, compound treatment: A 10 mM DMSO solution of the compound was added to each well of a 384-well plate. Using the Echo 650 serial dilution program, the compound was added to the cell culture plates seeded on the first day at a gradient concentration (final concentration 10000 nM, 3-fold dilution, 10 concentration points), with a final DMSO concentration of 0.2%. The compound and cells were incubated at 37°C in a 5% CO2 incubator for 72 hours. 20 μL / well of CTG was added to measure the growth inhibition of the compound on tumor cells, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0521] Data Analysis:

[0522] Calculate the % compound inhibition and use XLfit software to fit the IC50 of the compound. 50 .

[0523] The experiment included blank wells and DMSO wells. Blank wells contained 40 μL of RPMI Medium 1640 medium with 10% FBS, cell-free, and were considered to have 100% inhibition of tumor cell growth. DMSO wells contained 0.2% DMSO, with no other compound added, and were considered to have 0% inhibition of tumor cell growth. The Luminescence signal values ​​for each well were read using a PerkinElmer Envision microplate reader, and the following calculations were performed:

[0524] Compound inhibition percentage = (100 * (DMSO well signal value - analyte well signal value) / (DMSO well signal value - blank well signal value))%

[0525] The inhibitory effect of the compound on tumor cell growth was determined by the above experiments, and the measured IC50 was... 50 The values ​​are shown in Table 1 below.

[0526] Table 1. IC50 of the compounds on the growth inhibition of Ba / F3-TCL and H838 cells. 50

[0527] Note: "-" indicates that it has not been tested.

[0528] Test Example 2: Compound's Inhibition of Tumor Cell Proliferation

[0529] Brief introduction to experimental principle: After co-incubating the compound with tumor cells for 120 hours, the CTG kit from VKEY-BIO was used. The Luminescent Cell Viability Detection Kit quantifies cell viability, thereby reflecting the effect of compounds on tumor cell proliferation.

[0530] Experimental instruments: Perkin Elmer Envision microplate reader; Eppendorf 5810R centrifuge; Countstar automated cell counter; Labcyte Echo 650 ultrasonic liquid handling system.

[0531] Experimental materials:

[0532] Experimental Methods: PC9 (EGFR-Del19 / T790M / C797S) (PC9-DTC) cells were cultured in complete medium: RPMI-1640 + 10% FBS + 0.5 μg / mL puromycin. PC9 (EGFR-Del19 / T790M / C797S) cells were placed in complete medium and cultured at 37°C and 5% CO2. On the first day of the experiment, cells were washed with PBS, digested with 0.25% Trypsin-EDTA, and counted to obtain cell density and viability information. PC9 (EGFR-Del19 / T790M / C797S) cells were seeded at 600 cells / well, 40 μL per well, in 384-well plates and cultured overnight at 37°C and 5% CO2. On the second day, compound treatment: 10 mM of the compound in DMSO solution was added to 384-well LDV plates. Using the Echo 650 serial dilution program, the compound was added to the cell culture plates seeded on the first day at a gradient concentration (final concentration 10000 nM, 3-fold dilution, 10 concentration points). After incubating the compound and cells at 37°C and 5% CO2 for 120 hours, 20 μL / well CTG was added to measure the growth inhibition of the compound on tumor cells, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0533] Data Analysis:

[0534] The compound inhibition rate was calculated, and the IC50 of the compound was obtained by fitting the data using XLfit software. 50 .

[0535] The experiment included blank wells and DMSO wells: blank wells contained 40 μL of complete culture medium, cell-free, and were considered to have 100% inhibition of tumor cell growth; DMSO wells contained 0.2% DMSO, with no other compounds added, and were considered to have 0% inhibition of tumor cell growth. The Luminescence signal values ​​for each well were read using a Perkin Elmer Envision microplate reader, and the following calculations were performed:

[0536] Compound inhibition percentage = (100 * (DMSO well signal value - analyte well signal value) / (DMSO well signal value - blank well signal value))%

[0537] The inhibitory effect of the compound on tumor cell growth was determined by the above experiments, and the measured IC50 was... 50 The values ​​are shown in Table 2 below.

[0538] Table 2 shows the IC50 values ​​of the compounds on the growth inhibition of PC9-DTC cells. 50

[0539] Test Example 3: Compound Inhibition Test on Tumor Cell Proliferation

[0540] Brief description of experimental principle: After co-incubating the compound with tumor cells (NCI-H1975-LT or A431) for 120 hours, cell viability was quantitatively detected using the Promega CTG kit to reflect the effect of the compound on tumor cell proliferation.

[0541] Experimental instruments: Perkin Elmer Envision microplate reader; Eppendorf 5810R centrifuge; Countstar automated cell counter; Labcyte Echo 650 ultrasonic liquid handling system.

[0542] Experimental materials:

[0543] Experimental Methods: Cultured cells were resuspended (adherent cells were washed with PBS and digested with 0.25% Trypsin-EDTA) and counted to obtain cell density and viability information. 200 NCI-H1975-LT cells / well were suspended in RPMI 1640 medium and added to 384-well plates (40 μL / well). 600 A431 cells / well were suspended in DMEM medium and added to 384-well plates (40 μL / well). Both were incubated overnight at 37°C with 5% CO2. The test compounds were added to the cell plates using an Echo 650 ultrasonic liquid handling system, starting at 10 μM and serially diluted 3-fold for a total of 10 concentration gradients, with a final DMSO concentration of 0.2%. The compound and cells were incubated at 37°C in a 5% CO2 incubator for 120 hours. 20 μL / well CTG was added to measure the growth inhibition of the compound on tumor cells, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0544] Data Analysis:

[0545] The compound inhibition rate was calculated, and the IC50 of the compound was obtained by fitting the data using Xlfit software. 50 .

[0546] The experiment included blank wells and DMSO wells. Blank wells contained 40 μL of RPMI Medium 1640 medium with 10% FBS, cell-free, and were considered to have 100% inhibition of tumor cell growth. DMSO wells contained 0.2% DMSO, with no other compound added, and were considered to have 0% inhibition of tumor cell growth. The Luminescence signal values ​​for each well were read using a PerkinElmer Envision microplate reader, and the following calculations were performed:

[0547] Compound inhibition percentage = (100 * (DMSO well signal value - analyte well signal value) / (DMSO well signal value - blank well signal value))%

[0548] The inhibitory effect of the compound on tumor cell growth was determined by the above experiments, and the measured IC50 was... 50 The values ​​are shown in Table 3 below.

[0549] Table 3. Growth-inhibiting activities of compounds on different cell types.

[0550] Note: "-" indicates that it has not been tested.

[0551] Test Example 4: Test of the effect of compounds on EGFR degradation levels in NCI-H1975-LT and NCI-H838-WT cells

[0552] Brief description of experimental principle: After co-incubating the compound with tumor cells for 24 hours, quantitative detection was performed using Revvity's EGFR AlphaLISA assay kit to reflect the degradation of EGFR in tumor cells by the compound.

[0553] Experimental instruments: Perkin Elmer Envision microplate reader; Eppendorf 5810R centrifuge; Countstar automated cell counter; Labcyte Echo 650 ultrasonic liquid handling system.

[0554] Experimental materials:

[0555] Experimental Methods: Cultured cells were resuspended (adherent cells were washed with PBS and digested with 0.25% Trypsin-EDTA) and counted to obtain cell density and viability information. For each cell type, 40,000 cells / well were prepared into a cell suspension using serum-free RPMI 1640 medium and added to 96-well plates (80 μL / well), and incubated overnight at 37°C in a 5% CO2 incubator. The test compound was added to empty 96-well cell culture plates using an Echo 650 ultrasonic liquid handling system, diluted with serum-free RPMI 1640 medium, and then added to the cell culture plates at 20 μL per well. The final concentration of the compound in the culture system started at 1 μM, with 4-fold serial dilutions for a total of 8 concentration gradients, and the final concentration of DMSO was 0.1%. The compound and cells were incubated for another 24 hours at 37°C in a 5% CO2 incubator. Before collecting cell samples, cells were stimulated with 100 ng / mL Recombinant Human EGF Protein and incubated at 37°C for 10 min. The cell culture medium was then discarded, and the cells were washed twice with deionized water. Cells were then lysed using the lysis buffer provided in the kit, and AlphaLISA assays were performed according to the kit instructions. Inhibition rate and half-maximal concentration (DC) were calculated. 50 ).

[0556] The degradation of EGFR in tumor cells by the disclosed compound was determined through the above experiments, and the measured DC... 50 and D max The values ​​are shown in Table 4 below.

[0557] Table 4. Degradation activity of the compounds disclosed herein against EGFR

[0558] As shown in the test examples above, the disclosed compound exhibits good activity against EGFR mutant cells (H1975-LT, Ba / F3-TCL, PC9-DTC) while also showing weak killing effect on EGFR wild-type cells (H838, A431). This demonstrates that this molecular form can avoid the toxicity caused by inhibiting EGFR wild-type cells.

[0559] Test Example 5: Detection of Pharmacokinetic Properties in Rats

[0560] I. Experimental Materials

[0561] Male SD rats aged 6 to 8 weeks (purchased from Vital Rivers)

[0562] II. Test Methods

[0563] Male SD rats aged 6 to 8 weeks were selected. The intravenous and oral doses of the compound were 2 mg / kg and 10 mg / kg, respectively. Rats were fasted for at least 12 hours before administration, and food was resumed 4 hours after administration. Animals had free access to water throughout the experiment. On the day of the experiment, the intravenous administration group received a solution prepared with 5% NMP + 95% (20% HP-β-CD) at a volume of 5 mL / kg; while the gavage group received a solution prepared with 5% NMP + 15% PEG400% + 80% (20% HP-β-CD) at a volume of 10 mL / kg. Animal weight was measured before administration, and the volume of administration was calculated based on animal weight. Samples were collected from the intravenous group at the following times: 0 h (before administration), 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. Samples were collected at the following times for the oral administration group: 0 h (before administration), 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. All animals were euthanized under CO2 anesthesia after plasma samples were collected at the last time point. Plasma concentrations and corresponding pharmacokinetic parameters were calculated using a non-compartmental model of Phoenix WinNonlin (version 8.3.4) pharmacokinetic software.

[0564] III. Test Results

[0565] The results of the pharmacokinetic studies in rats are shown in Table 5.

[0566] Table 5. Pharmacokinetic parameters of the compound after a single oral gavage administration to rats.

[0567] Test Example 6: Detection of Pharmacokinetic Properties in Mice

[0568] I. Experimental Materials

[0569] Female Balbc mice aged 6 to 8 weeks (purchased from Vital Rivers).

[0570] II. Test Methods

[0571] Balbc female mice aged 6 to 8 weeks were selected. The intravenous and oral doses of the compound were 2 mg / kg and 10 mg / kg, respectively. Mice were fasted for at least 12 hours before administration and were given food 4 hours after administration. Animals had free access to water throughout the experiment. On the day of the experiment, both the intravenous and gavage groups were given a solution prepared with 5% NMP + 95% (20% HP-β-CD), followed by the corresponding dose of the compound. The intravenous administration volume was 5 mL / kg, and the gavage volume was 10 mL / kg. Animal weight was measured before administration, and the administration volume was calculated based on animal weight. Samples were collected at the following times for the intravenous group: 0 h (before administration), 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. Samples were collected at the following times for the oral group: 0 h (before administration), 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. All animals were euthanized under CO2 anesthesia after plasma samples were collected at the last time point. Plasma concentrations and corresponding pharmacokinetic parameters were calculated using a non-compartmental model of Phoenix WinNonlin (version 8.3.4) pharmacokinetic software.

[0572] III. Test Results

[0573] The results of the in vivo pharmacokinetic studies in mice are shown in Table 6.

[0574] Table 6. Pharmacokinetic parameters of the compound after a single oral gavage administration to mice.

[0575] Unless expressly excluded or otherwise limited, every reference cited herein, including any cross-referenced patent or patent application, and any patent or patent claiming priority to which this application asserts, is incorporated herein by reference in its entirety. Furthermore, where any meaning or definition of a term herein contradicts any meaning or definition of the same term in an incorporated reference, the meaning or definition given to that term herein shall prevail.

[0576] Although specific embodiments of this disclosure have been illustrated and described, those skilled in the art will recognize that, where feasible, the technical features described in one embodiment may be applied to another embodiment or combined with the technical features described in another embodiment. Therefore, those skilled in the art can make various changes and modifications to the embodiments of this disclosure without departing from the spirit and scope of this disclosure.

Claims

1. A compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, TL-Linker-DIM (I) wherein: the DIM is a ligand compound capable of binding to a cereblon-type E3 ubiquitin ligase; the Linker is a linker covalently bound to at least one TL and at least one DIM; wherein: ring B is selected from phenylene or 5-10 membered heteroarylene; r is selected from 0, 1, 2, 3, 4, or 5; t is selected from 0, 1, 2, 3, or 4. ring B is phenylene or 5-6 membered heteroarylene; ring B is 5-6 membered heteroarylene; or, ring B is pyridinylene or pyrazolylene; or, ring B is phenylene or pyrazolylene; or, ring B is pyrazolylene. wherein: t is selected from 0 or 1; m is selected from 0, 1, 2, or 3; p is selected from 0, 1, or 2. wherein: ring E, ring F, ring G are independently of each other selected from phenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each of ring E, ring F, and ring G is optionally further substituted by =0; each R’ is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, or two R’ together with the atom to which they are attached form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl; q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. The TL is a group represented by the following formula:

24. A pharmaceutical composition comprising a compound of any one of claims 1-23 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Ring A is selected from C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl; 10 aryl or 5-10 membered heteroaryl; the individual is a mammal, preferably a human. L 1 , L 3 are independently from each other selected from a bond, C1-C 10 alkylene, C2-C 10 alkenylene or C2-C 10 alkynylene, said C1-C 10 alkylene, C2-C 10 alkenylene or C2-C 10 alkynylene are optionally substituted by one or more groups selected from OH, SH, NH2, halogen, CN, C1-C4alkoxy; L 2 is selected from a bond, NR 4 , C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C6cycloalkylene, 4-8 membered heterocyclyl ene, C6-C 10 arylene, or 5-10 membered heteroarylene, said C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C6cycloalkylene, 4-8 membered heterocyclyl ene, C6-C 10 arylene, or 5-10 membered heteroarylene is optionally substituted with one or more R t ; L 4 selected from O, S, NR 5 , CHR 5 or C(R 5 )2; R 4 , R 5 are independently of each other selected from H, Ci-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocyclyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, said Ci-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocyclyl, C6-C 10 aryl or 5- to 10-membered heteroaryl are optionally substituted by one or more R 4a ; Each R 1 Independently selected from OH, halogen, CN, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 1a Replaced; Each R 2 Independently selected from OH, halogen, CN, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 2a Replaced; R 3 Selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic groups, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 3a Replaced; Each R t The radical is independently selected from deuterium, OH, halogen, CN, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4-8-membered heterocyclic group or 5-10-membered heteroaryl group, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4-8-membered heterocyclic group or 5-10-membered heteroaryl group is optionally surrounded by one or more R. b Replaced; Each R 1a R 2a R 3a R 4a The groups are independently selected from deuterium, halogens, CN, OH, NH2, =O, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, or 4-6-membered heterocyclic groups, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, or 4-6-membered heterocyclic group is optionally surrounded by one or more R b Replaced; R b selected from deuterium, halogen, OH, NH2, =0, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl; the individual is a mammal, preferably a human. ​ 2. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from 4-10 membered heterocyclic groups, C6-C 10 Aryl or 5-10-membered heteroaryl; or, ring A is selected from phenyl or 5-6-membered heteroaryl; or, ring A is selected from phenyl, furanyl, thiophene, pyrrole, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, or tetrahydroisoquinolinyl.

3. The compound of formula (I) according to claim 1 or 2, wherein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. ​ 4. The compound of formula (I) according to any one of claims 1 to 3, wherein L 1 Selected from C1-C6 alkylene groups, wherein the C1-C6 alkylene groups are optionally substituted by one or more groups selected from OH, SH, NH2, halogen, CN, or C1-C4 alkoxy groups; or, L 1 Selected from key, The asterisk (*) represents L. 2 The connected positions.

5. The compound of formula (I) according to any one of claims 1 to 4, wherein L 2 is selected from a bond, NR 4 , C1-C6alkylene, C3-C6cycloalkyl, or 4-8 membered heterocyclyl, said C1-C6alkylene, C3-C6cycloalkyl, or 4-8 membered heterocyclyl optionally substituted with one or more R t ; or, L 2 is selected from a bond, C1-C6alkylene, or 4-8 membered heterocyclyl containing 1 or 2 N atoms as heteroatoms, said C1-C6alkylene, or 4-8 membered heterocyclyl containing 1 or 2 N atoms as heteroatoms optionally substituted with one or more R t ; or, L 2 is selected from a bond, wherein * represents the position of attachment to L 3 .

6. The compound of formula (I) according to claim 5, wherein each R is independently selected from deuterium, OH, halogen, CN, NH2, or Ci-C6alkyl optionally substituted with one or more R t independently selected from deuterium, OH, halogen, CN, NH2, or Ci-C6alkyl optionally substituted with one or more R b independently selected from deuterium, OH, halogen, CN, NH2, or Ci-C6alkyl optionally substituted with one or more R t independently selected from deuterium, OH, halogen, CN, NH2, or Ci-C6alkyl.

7. The compound of formula (I) according to any one of claims 1 to 6, wherein L 3 is selected from a bond or C1-C6alkylene, which C1-C6alkylene is optionally substituted with one or more groups selected from OH, SH, NH2, halogen, CN, or C1-C4alkoxy; or, L 3 is selected from a bond, represents the position of attachment to L 4 .

8. The compound of formula (I) according to any one of claims 1 to 7, wherein L 4 selected from O, S or NR 5 ; or, L 4 is selected from O or NR 5 ; or, L 4 is selected from O or NR 5 , R 5 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclyl, said C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclyl optionally substituted with one or more R 4a ; or, L 4 is selected from O or NH.

9. The compound of formula (I) according to any one of claims 1 to 8, wherein -L 1 -L 2 -L 3 -L 4 - is selected from wherein represents a bond to ring B.

10. The compound of formula (I) according to any one of claims 1 to 9, wherein each R is independently selected from OH, halogen, NH2, C3-C6cycloalkyl, or 4-8 membered heterocyclyl, said OH, NH2, C3-C6cycloalkyl, or 4-8 membered heterocyclyl optionally substituted with one or more R 1 independently selected from OH, halogen, or NH2, said OH or NH2 optionally substituted with one or more R 1a independently selected from OH, halogen, or NH2, said OH or NH2 optionally substituted with one or more R 1 independently selected from OH, halogen, or NH2, said OH or NH2 optionally substituted with one or more R 1a independently selected from OH, halogen, or NH2, said OH or NH2 optionally substituted with one or more R 11. The compound of formula (I) according to any one of claims 1 to 10, wherein each R is independently selected from halogen, C1-C6alkyl or C3-C6cycloalkyl, said C1-C6alkyl or C3-C6cycloalkyl being optionally substituted with one or more R 2 independently selected from halogen, C1-C6alkyl or C3-C6cycloalkyl, said C1-C6alkyl or C3-C6cycloalkyl being optionally substituted with one or more R 2a each R is independently selected from halogen, C1-C6alkyl or C3-C6cycloalkyl, said C1-C6alkyl or C3-C6cycloalkyl being optionally substituted with one or more R 2 each R is independently selected from halogen, C1-C6alkyl or C3-C6cyc 12. The compound of formula (I) according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 3 selected from C1-C6alkyl or C3-C6cycloalkyl, said C1-C6alkyl or C3-C6cycloalkyl optionally substituted with one or more R 3a ; or, R 3 is selected from methyl, CH2F, CHF2, or CF3. 3a ; or, R 3 is selected from methyl, CH2F, CHF2, or CF3.

13. The compound of formula (I) according to any one of claims 1 to 12, wherein each R 1a , R 2a , R 3a , R 4a is independently from each other selected from deuterium, halogen, CN, OH, NH2, =0 or Ci-C6-alkyl, said OH, NH2 or Ci-C6-alkyl is optionally substituted with one or more R b ; or, each R 1a , R 2a , R 3a , R 4a is independently from each other selected from deuterium, halogen, CN, OH, =0 or Ci-C6-alkyl; or, R 3a is selected from halogen, e.g. F.

14. The compound of formula (I) according to any one of claims 1 to 13, wherein r = 1, the TL is linked to the Linker via R 1 with the Linker, i.e. the TL is or, r = 0, the TL is directly linked to the Linker via the ring A, i.e. the TL is 15. The compound of formula (I) according to any one of claims 1 to 14, wherein The TL is selected from Alternatively, the TL is selected from 16. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein, The Linker is a linker covalently bonding one TL and one DIM; or, the Linker is selected from -L A -, -L B -, -R 1L -, -R 2L -, -Q 1 -, -Q 2 -, wherein: -L A - and -L B - are independently of each other selected from a bond, -O-, -S-, -NR 3’ -, -CR 4’ R 5’ -, -CR 4’ R 5’ -, -NR 3’ -, -CR 4’ R 5’ -, -O-, -C(O)-, -CR 4’ R 5’ -, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ - ; R 1L and R 2L are independently of each other selected from a bond, -C(O)-, alkylene, heteroalkylene, alkenylene or alkynylene, wherein said alkylene, heteroalkylene, alkenylene or alkynylene is optionally substituted with a group selected from halogen, alkyl, alkoxy, halogenalkyl, OH, hydroxyalkyl, CN, NH2, =0, cycloalkyl, heterocyclyl, aryl or heteroaryl; Q 1 , Q 2 , Q 3 and Q 4 are each independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl, wherein each of said cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl is independently optionally substituted with a group selected from halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =0, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 3’ selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 4’ and R 5’ each independently is selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =0, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

17. The compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 16, wherein, said Linker is selected from 18. The compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 16 or 17, wherein, Q 1 , Q 2 , Q 3 are independently of each other selected from C3-C8-cycloalkyl or 4-10 membered heterocyclyl, said C3-C8-cycloalkyl or 4-10 membered heterocyclyl being optionally substituted with a group selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, OH, C1-C3-hydroxyalkyl or NH2; or, Q 1 , Q 2 , Q 3 are independently of each other 4-10 membered heterocyclyl, said 4-10 membered heterocyclyl being optionally substituted with a group selected from halogen, C1-C3-alkyl, =0; or, -L A -, -L B - are independently of each other selected from: a bond, -O-, -CR 4’ R 5’ -; or, R 4’ and R 5’ are each independently selected from H, halogen; or, R 1L and R 2L are independently of each other selected from: a bond, C1-C6-alkylene or C1-C6-alkynylene, said C1-C6-alkylene or C1-C6-alkynylene being optionally substituted with a group selected from halogen, OH.

19. The compound of formula (I) according to any one of claims 1-18, wherein The DIM is selected from the group consisting of structures shown in formula (DIM-1) or (DIM-2): ​ selected from the group consisting of Y is a chemical bond or Y is selected from Y A , O, NH, NR E , C(O)O, C(O)NR E , NR E 'C(O), Y A -NH, Y A -NR E , Y A -C(O), Y A -C(O)O, Y A -OC(O), Y A -C(O)NR E , or Y A -NR E 'C(O), wherein said Y A is selected from C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene; X is selected from C(O) or C(R A )2; X A -X B is selected from C(R A )=N or C(R A )2-C(R A )2; Each R A Independently selected from H or C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally divided by C6-C 10 Aryl or 5-10 heteroaryl substitutions; Each R A 'Independently selected from C1-C3 alkyl groups;' each R is independently selected from H, C1-C3alkyl, or two R B is independently selected from H or C1-C3alkyl, or two R B together with the atom to which they are attached form C(O), C3-C6cycloalkyl, C3-C6cycloalkenyl, or 4-6 membered heterocyclyl; R C selected from H, halogen or C1-C3 alkyl; Each R D It is independently selected from halogens, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy groups; Each R E Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocyclic alkyl, wherein R E Optional substitution with groups selected from the following: halogen, N(R) a 2. NHC(O)R a ,NHC(O)OR a OR b C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl, C6-C 10 The aryl or 5-10 heteroaryl group may be further substituted with a group selected from the following: halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. R E is selected from H, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, or 3-8 membered heterocycloalkyl, optionally substituted with a group selected from halogen, N(R a )2, NHC(O)R a , NHC(O)OR a , OR b , C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein said C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally further substituted with a group selected from halogen, NH2, CN, NO2, OH, COOH, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; each R is independently selected from H or C1-C6alkyl; a is independently selected from H or C1-C6alkyl; R b selected from H or p-toluenesulfonyl; ​ ​ ​ 20. The compound of formula (I) according to any one of claims 1-18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The DIM is selected from the group consisting of structures represented by formula (DIM-11): ​ X C is selected from a chemical bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R’-, -P(O)OR’-, -P(O)NR’2-, -C(O)-, -C(S)- or X D Selected from C, N, or Si; X E is selected from a chemical bond, -C(R')2-, -NR'-, -0-, -S-, or -Si(R')2-; R F is absent, or R F is selected from H, deuterium, halogen, CN, -OR'-, -SR'-, -S(O)R'-, -S(O)2R'-, -N(R')2-, -P(O)(OR')2, -P(O)(N(R')2)OR'-, -P(O)(N(R')2)2, -Si(OH)2R', -Si(OH)(R')2, -Si(R')3, or C1-C4 alkyl; each R is independently selected from H, deuterium, R G halo, CN, -N02, -OR', -SR', -N(R')2, -Si(R')3, -S(0)2R', -S(0)2N(R')2, -S(0)R', -C(0)R', -C(0)OR', -C(0)N(R')2, -C(0)N(R')OR', -C(R')2N(R')C(0)R', -C(R')2N(R')C(0)N(R')2, -OC(0)R', -OC(0)N(R')2, -OP(0)(R')2, -OP(0)(OR')2, -OP(0)(OR')N(R')2, -OP(0)(N(R')2)2, -N(R')C(0)OR', -N(R')C(0)R', -N(R')C(0)N(R')2, -N(R')S(0)2R', -NP(0)(R')2, -N(R')P(0)(OR')2, -N(R')P(0)(OR')N(R')2, or -N(R')P(0)(N(R')2)2; H each R' is independently selected from H, deuterium, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, phenyl, or 5-6 membered heteroaryl; Each R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl; ​ L 1 is selected from a chemical bond, C1-C3alkylene, C2-C3alkenylene, or C2-C3alkynylene, wherein any 1 or 2 methylene groups of said C1-C3alkylene, C2-C3alkenylene, or C2-C3alkynylene are optionally replaced with -O-, -C(O)-, -C(S)-, -C(R’)2-, -CH(R’)-, -C(F)2-, -N(R’)-, -S-, or -S(O)2-; ​ ​ 21. The compound of formula (I) according to any one of claims 1-18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The DIM is selected from the group consisting of structures represented by formula (DIM-12): wherein: ring H is selected from C5-C9cycloalkyl, C5-C9cycloalkenyl, or 5-9 membered heterocyclyl, said C5-C9cycloalkyl, C5-C9cycloalkenyl, or 5-9 membered heterocyclyl optionally substituted with =0; k is selected from 0, 1, 2, 3, or 4; X C , X D , X E , R F , R G , L 1 and ring E is as defined in claim 20.

22. The compound of formula (I) according to any one of claims 1-18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The DIM is selected from the group consisting of structures represented by formula (DIM-13): wherein X C , X D , X E , R F , R G , L 1 , ring E and k are as defined in claim 21.

23. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound has a structure selected from one of the following: ​ 25. A method of treating a disease mediated by EGFR, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of claims 1-23, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 24, wherein the disease mediated by EGFR is preferably a tumor, optionally wherein, ​

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