SOS1 protein degradation agent and application thereof

Abstract

The invention provides an SOS1 protein degradation agent and application thereof. Specifically, the invention provides S-L-E. In the formula (I), S-L-E. The compounds are as shown in the specification, and stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof. The compounds are represented by formula (I) S-L-E. The compound disclosed by the invention is novel in structure and has a good degradation effect on SOS1 protein.

Description

SOS1 protein degraders and their applications

[0001] This application claims priority to Chinese Patent Application No. 2022112964110 filed on October 21, 2022, priority to Chinese Patent Application No. 2023100911954 filed on January 20, 2023, and priority to Chinese Patent Application No. 2023108422053 filed on July 11, 2023. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medical technology, and specifically relates to an SOS1 protein degrader and applications thereof. Background Art

[0003] SOS1 (son of sevenless homolog 1) is a widely expressed regulatory protein in cells. As a key protein in signaling pathways, SOS1 plays an important role in regulating many intracellular signal transduction pathways, such as the Ras and Rac signaling pathways. SOS1 is composed of 1333 amino acids and contains a proline-rich domain (PxxP) at its C-terminus. This domain binds to growth factor receptor-bound protein 2 (Grb2), a protein in the Ras pathway, to form a Grb2-SOS1 complex, bringing SOS1 to the vicinity of Ras proteins on the cell membrane. SOS1 catalyzes the binding of Ras to GTP, promoting Ras activation and, in turn, activating multiple downstream signaling pathways, such as the Ras-Raf-Mek-Erk and Ras-PI3K-AKT-mTOR pathways. PxxP can also bind to the SH3 (Src homology 3) domain of proteins such as E3B1 in the Rac pathway to form an EPS8-E3B1-SOS1 complex. The EPS8-E3B1-SOS1 complex connects to actin filaments through EPS8, causing GTP conversion, thereby activating Rac and subsequently activating signaling pathways such as JNK and MAPK.

[0004] Ras mutations are considered major oncogenes with a high incidence in human cancers. Studies have shown that 20-30% of tumor patients harbor Ras mutations, with KRas mutations accounting for 85%, NRas and HRas mutations accounting for 12% and 3%, respectively. However, due to the picomolar affinity of GTP for its binding site and the smooth surface of the Ras protein lacking other suitable binding pockets, directly inhibiting Ras activity is considered extremely challenging.

[0005] Abnormal expression or mutation of SOS1 is also closely associated with the development of clinical diseases. Studies have shown that SOS1 mutations are present in patients with NS and CFC. HGF1 is a rare autosomal dominant genetic disease, the cause of which is also related to mutations in the PxxP domain of SOS1. In addition, abnormal expression or mutation of SOS1 is also associated with the development of cancer.

[0006] WO2018172250A1, WO2020173935A1, WO2019201848A1, WO2020180768A1, WO2020180770A1, WO2019122129A1 and EP3558979A1 disclose several types of SOS1 inhibitors, but so far, there have been no reports on SOS1 degraders. Proteolysis Targeting Chimeria (PROTAC) is a technology different from traditional small molecule inhibitors. Traditional small molecule inhibitors usually need to act on the active site of the target protein to inhibit its activity. PROTAC is a heterogeneous bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein through a connecting chain, and the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase. This bifunctional molecule recognizes the target protein and E3 ubiquitin ligase in vivo, brings the target protein and E3 ubiquitin ligase closer to form a ternary complex, ubiquitinates the target protein, and then degrades the target protein through the ubiquitin-proteasome pathway in vivo. Compared to traditional small molecule inhibitors, PROTAC only needs to bring the target protein closer to the E3 ubiquitin ligase to degrade the substrate. This mode of action allows this technology to be applied to some undruggable targets. On the other hand, since the target protein can be released after degradation and continue to participate in the degradation process of the next protein, this catalytic degradation effect allows a smaller PROTAC drug dose to achieve efficient degradation. On the other hand, traditional small molecule inhibitors are prone to drug resistance, which is often due to point mutations, causing the small molecule inhibitors to lose their inhibitory effect on the target. PROTAC can directly degrade the target protein, which can avoid the drug resistance caused by point mutations to a certain extent. Therefore, compared with traditional small molecule inhibitors, the use of PROTAC technology for the development of new drug small molecules has high advantages and feasibility.

[0007] Summary of the Invention

[0008] In order to solve the technical problem of the lack of SOS1 protein degraders in the prior art, the present invention provides a new SOS1 protein degrader and its application, which can effectively bind to or inhibit the SOS1 target protein, and further, can effectively and specifically degrade the SOS1 protein.

[0009] The present invention solves the above technical problems through the following methods.

[0010] The present invention provides a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and / or pharmaceutically acceptable salts thereof: SLE I

[0011] Where S is:

[0012] L is a connecting chain, which connects S and E through a covalent bond;

[0013] E is the E3 ubiquitin ligase ligand;

[0014] Among them, S:

[0015] is selected from a single bond or a double bond;

[0016] X is CH or N;

[0017] R1 is hydrogen, halogen, OH, mercapto, CN, NO2, NR a R b , C1-C6 alkyl, C1-C6 alkylthiol, C1-C6 heteroalkyl, C1-C6 alkoxy, -O(C1-C6 heteroalkyl), -S(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, -COOR c 、-NHS(O)(R d )、-NHS(O)2(R d )、-NHC(O)-(C1-C6 alkyl)、-NHC(O)-NR a R b 、-NH-(CH2) k -NH-C(O)-R aa 、-NH-(CH2) i -R f’ 、-O-(CH2) z -phenyl, -O-(CH2) z -(4-7 membered heterocycloalkyl), -O-(CH2) z -(5-10 membered heteroaryl), The superscript "*" indicates the same connect;

[0018] Or two adjacent R1 together with the carbon atoms to which they are attached form a C5-C7 cycloalkyl group or a 5-7 membered heterocycloalkyl group;

[0019] Each R a and R b are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl;

[0020] R c is hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl or C3-C8 cycloalkyl;

[0021] R d and R e’ are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0022] R aa is a C1-C6 alkyl, a 3-8 membered heterocycloalkyl or a C3-C8 cycloalkyl;

[0023] k is 1 or 2;

[0024] i is 0, 1, or 2;

[0025] R f’ is a 4-7 membered heterocycloalkyl group, a 5-10 membered heteroaryl group or a C1-C6 alkylsulfonyl group;

[0026] z is 0, 1, or 2;

[0027] wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl mentioned above are optionally replaced by 1, 2 or 3 groups selected from deuterium, halogen, OH, oxo, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylsulfonyl, phenyl, benzyl, 5-10 membered heteroaryl, -(CH2)-(5-8 membered heteroaryl), -NHC(O)(C1-C6 alkyl), phenoxy, 5-10 membered heteroaryloxy and -NR a R b The m is 1, 2 or 3;

[0028] A1 is C4-C 12 Cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, 1, 2, 3, 4 or 5 Rc” Substituted C4-C 12 Cycloalkyl, 1, 2, 3, 4 or 5 R d” substituted 3-8 membered heterocycloalkyl, substituted by 1, 2, 3, 4 or 5 R c’ Substituted C6-C 12 Aryl or 1, 2, 3, 4 or 5 R d’ substituted 5-10 membered heteroaryl,

[0029] Each R c’ 、R d’ 、R c” and R d” are independently hydrogen, OH, oxo, halogen, CN, C1-C6 alkyl, C1-C6 alkyl(SO2)-, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, halogenated 3-8 membered heterocycloalkyl, -O-CH2-4-7 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 alkylsulfonyl, -NR e R f 、-NHC(=O)-C1-C6 alkyl、C(O)NR c”’ R d”’ 、-C(O)OR g’ 、-(CH2)NR c”’ R d”’ , -S(O)2C1-C6 alkyl, -CH=CH-C3-C8 cycloalkyl, -L'-A2, 1, 2, 3, 4 or 5 R g Substituted C1-C6 alkyl, 1, 2, 3, 4 or 5 R h Substituted C6-C 10 Aryl, 1, 2, 3, 4 or 5 R i substituted 5-10 membered heteroaryl or 1, 2, 3, 4 or 5 R o’ substituted C3-C8 cycloalkyl;

[0030] Each R o’ 、R g 、R h and R i are independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R j or by one or more R l Substituted C1-C6 alkyl;

[0031] Each R e and R fare independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R j or by one or more R l Substituted C1-C6 alkyl;

[0032] Each R k and R j are independently hydrogen or C1-C6 alkyl;

[0033] Each R l are independently -NR m R n ,

[0034] R m and R n are independently deuterium, hydrogen or C1-C6 alkyl;

[0035] Each R c”’ and R d”’ are independently hydrogen, C1-C6 alkyl, 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl;

[0036] R g’ is hydrogen or C1-C6 alkyl;

[0037] L' is a bond, -(CH2) k’ -、-O(CH2) k’ -、-(CH2) k’ -O-, -O-(CH2) k’ -O- or -CH=CH-(CH2) n -, k' is 0, 1, 2 or 3, and n is 0, 1 or 2;

[0038] A2 is H, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 1, 2, 3, 4 or 5 R e” Substituted C4-C 12 Cycloalkyl, 1, 2, 3, 4 or 5 R f” substituted 3-10 membered heterocycloalkyl, substituted by 1, 2, 3, 4 or 5 R g” Substituted C6-C 10 Aryl or 1, 2, 3, 4 or 5 R h” substituted 5-8 membered heteroaryl;

[0039] Each R e” 、R f” 、R g” and R h”are independently hydrogen, halogen, OH, oxo, CN, NO2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkyl (NR z R za ),-C(O)R v 、-C(O)NR v R w 、-CH2C(O)NR v R w 、-C(O)OR v 、-NR z R za 、-NHC(O)R z 、-NHC(O)OR z 、-NHS(O)2R z 、-O(CH2) s -(C3-C8 cycloalkyl), -O(CH2) s -phenyl, -O(CH2) s -(3-10 membered heterocycloalkyl), -O(CH2) s -(5-10 membered heteroaryl), -S(O)2R z 、-S(O)2NH2、-S(O)2NR z R za , -CH2NHCH2C(O)-(5-10 membered heteroaryl), -CH2NHCH2C(O)-(3-10 membered heterocycloalkyl), -CH2NHC(O)-(5-10 membered heteroaryl), -CH2NHC(O)-(3-10 membered heterocycloalkyl), C1-C6 alkyl or C1-C6 alkoxy;

[0040] Each R v and R w are independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or -(CH2)2NR x R y , R x and R y are independently hydrogen, C1-C4 alkyl or -(CH2)2N(CH3)2;

[0041] Each R z and R za are independently hydrogen, C1-C4 alkyl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, hydroxy-substituted C1-C4 alkyl, methoxy-substituted C1-C4 alkyl, C1-C4 haloalkyl or phenyl;

[0042] Each s is independently 0, 1, 2 or 3;

[0043] Each R e” 、R f” 、R g” and R h” wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally substituted by 1, 2 or 3 selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl, 5-10 membered heteroaryl, -C(O)NR i’ R j’ 、-NR k’ R l’ and -NR s’ R t’ Substituents substituted;

[0044] R i’ and R j’ are independently hydrogen or C1-C6 alkyl;

[0045] R k’ and R l’ are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, phenyl, 5-10 membered heteroaryl, -CH2-C(O)-R m 、-C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are independently optionally substituted by 1, 2 or 3 groups selected from C1-C6 haloalkyl, OH, oxo, phenyl, CN, C1-C6 alkoxy and 5-10 membered heteroaryl, the heteroaryl being optionally substituted by methyl; R m is a 9-10 membered bicyclic heteroaryl, a C1-C6 alkoxy group or a -NR n R o , R n and R o is independently hydrogen, C1-C6 alkyl or phenyl, the alkyl group is optionally substituted with C1-C6 alkoxy or phenyl, or -NR n R o is a 4-7 membered azacycloalkyl group, which is connected to other parts of the molecule through a N atom and further contains one or more heteroatoms selected from N and O; R p is C1-C6 alkoxy, C1-C6 alkyl optionally substituted by 1, 2 or 3 -OH or C1-C6 alkoxy, 3-6 membered monocyclic or 9-10 membered bicyclic heteroaryl, 4-7 membered heterocycloalkyl or Rp -CH2-NR q R r , R q and R r are independently hydrogen, phenyl or C1-C6 alkyl optionally substituted by F;

[0046] -NR s’ R t’ R s’ and R t’ With the nitrogen atom to form a 4-7 membered monocyclic nitrogen heterocycloalkyl or a 6-10 membered spirocyclic nitrogen heterocycloalkyl, wherein the heterocycloalkyl further includes up to two heteroatoms selected from N and O, and the heterocycloalkyl is optionally substituted by 1, 2 or 3 groups selected from OH, oxo, C1-C6 alkyl, C1-C6 hydroxyalkyl and -C(O)OR z Substituents substituted, the R z C1-C6 alkyl, halogen, -N(C1-C6 alkyl)2, -CH2N(C1-C6 alkyl)2 or -C(O)NR s” R t” , R s” and R t” are independently hydrogen, C1-C6 alkyl, 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl;

[0047] R4 is hydrogen, oxo, C1-C6 alkyl, C1-C6 heteroalkyl, N(C1-C6 alkyl) 1-2 , C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, said alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocycloalkyl being optionally substituted with deuterium, CN, OH, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or halogen;

[0048] R5 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, N(C1-C6 alkyl) 1-2 , C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, said alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocycloalkyl being optionally substituted with deuterium, CN, OH, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or halogen;

[0049] Wherein, unless otherwise specified, the heteroaryl group mentioned above is a heteroatom or a heteroatom group selected from one or more of N, O, S and S(═O)2, and the number of heteroatoms is 1, 2 or 3 heteroaryl groups; the heterocycloalkyl group mentioned above is a heteroatom or a heteroatom group selected from one or more of N, O, S and S(═O)2, and the number of heteroatoms is 1, 2 or 3 heterocycloalkyl groups; the heteroalkyl group mentioned above is a heteroatom or a heteroatom group selected from one or more of N, O, S, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene and ethynylene, and the number of heteroatoms is 1, 2 or 3 heteroalkyl groups.

[0050] In one embodiment, the S is also

[0051] In one embodiment, R1 is hydrogen, -OCH3, -OCH2CH3, -CH2OH, -C(O)OH, -C(O)OCH3, -Br, -OCH(CH3)2, -O(CH2)2CH(CH3)2, -O(CH2)3CH3, -O(CH2)2OCH3, -O(CH2)-phenyl, -N=S(O)(CH3)2, -CH3, cyclopropyl, -N(CH3)2, -NHCH3, -NH2, -C(CH3)2-OH, -NH(CH2)-NH-C(O)CH3, -NH(CH2)-morpholine, -NH-C(O)CH3, -NH-C(O)NHCH3, -NH-C(O)-N(CH3)2, nitro, -NH-S(O)2CH3, -N=S(O)(CH3)2, hydroxyl, -O-(CH2)2-S(O)2CH3, -F, Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, azetidinyl, azelanyl, piperidinyl, piperazinyl, oxetane, oxolanyl, oxhexanyl, thietanyl, thiolanyl, thiolanyl, azetidinyloxy, azelanyloxy, piperidinyloxy, piperazinyloxy, oxetaneoxy, oxolanyloxy, oxhexanyloxy, thietanyloxy, thiolanyloxy, thiolanyloxy, thiolanyloxy, -OCH2CH2CH3, -OCH2CH2CH2N(CH3)2, -OCH2CH2CH2OH, -OCH2CH2NC(O)CH3, -OCH2CH2N(CH3)2, -OCH2CH2OH, -SCH3, -N(CH3)2, The symbol “*” indicates that the group is connected to other groups through the site marked with “*”.

[0052] In one embodiment, the R c’ 、R d’ 、R c” and R d” are independently hydrogen, OH, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(=CH2)CH3, -C(CH3)(=CH2)CH3, -CH=CH(CH2)2CH3, -CH=CHCH3, -CH=CH-cyclopropyl, -C(O)NH2, -C(O)OCH3, -S(O)2CH3, -OCH3, -CH2NH 2、 trifluoromethyl, methyl, trifluoromethoxy, or halogen (F, Cl, Br), -NH2, -NHC(O)CH3, -NHCH2CH3, -NHCH(CH3)2, or -L'-A2.

[0053] In one embodiment, the A1 is optionally substituted The substituents are hydroxyl, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(=CH2)CH3, -C(CH3)(=CH2)CH3, -CH=CH(CH2)2CH3, -CH=CHCH3, -CH=CH-cyclopropyl, -C(O)NH2, -C(O)OCH3, -S(O)2CH3, -OCH3, -CH2NH 2、 trifluoromethyl, difluoromethyl, methyl, trifluoromethoxy, halogen (F, Cl, Br), -NH2, -NHC(O)CH3, -NHCH2CH3, -NHCH(CH3)2 or -L'-A2; the number of the substituents is 1, 2 or 3.

[0054] In one embodiment, L' is a bond, -(CH2) k’ -、-O(CH2) k’ -or-CH=CH-(CH2) n -, k' is 1 or 2, and n is 0, 1 or 2.

[0055] In one embodiment, the R e” 、R f” 、R g” and R h” are independently -C(O)NH(CH2)2CH3, -C(O)N(CH3)2, -C(O)NH2, -C(O)NH(CH2)2N(CH3)2, -CH2C(O)NH2, hydrogen, -F, -Cl, -Br, cyano, -CF3, -CH3, -CH2CH3, -CH=CH2, -CH2CN, -CH(CH3)-NH2, -CH=CH-CN, -C(O)-OH, -C(O)OCH3, -C(O)CH3, -C(CH3)2-C(O)-OCH3, -C(CH3)2-CN, oxo, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, -NH2, -NH-C(O)CH3, -NH-S(O)2CH3, -NH-C(O)OC(CH3)3, -S(O)2CH3, -S(O)2NCH3, -S(O)2NH2, -OCH2CH3, -O(CH2)2CH3, -OCF3, -OCH2 cyclopropyl, -OCH3, -O(CH2)3CH3, -OCH2 phenyl, -O-phenyl, -(CH2)-OH, -(CH2)2-OH, -(CH2)-OCH3, -(CH2)-OCH2CH3, -CH(OH)-CH2-phenyl, -CH(OH)-CH2CH3, -CH(OH)-CH2CH2CH3, -CH(OH)-CH2CH2CH2CH3, -CH(OH)-CH(CH3)2, -CH(OH)-phenyl, -CH(OH)-CN, -CH(OH)-CH2-OH, -CH(OH)-CF3, -CH(OH)-(CH2)2-phenyl, *-CH(OH)-C≡CH, -CH(NH2)-CH2-C(O)OH, -CH2-NH-S(O)2-CH3, -CH2-NH-(CH2 )3CH3, -CH2-NH-CH3, -CH2-N(CH3)2, -CH2-NH-CH2CH3, -CH(CH3)-NH2, -CH2-NH2, -CH2CH2-NH2, -CH2NH-CH2-phenyl, -CH2N(CH2CH3)2, -CH2NH-cyclopropyl, -CH2NH-cyclobutyl, -CH2NH-cyclopentyl, -CH2NH-pyridyl, -CH2NH-phenyl, -CH2NH-(CH2)2-OH, -CH2N(CH3)-(CH2)2-OH, -CH2NH-CH2-CN, -CH2N(CH3)-CH2-CN, -CH2N(CH3)-CH2-CF3, -CH2N(CH3)-CH2-CF2H, -CH2NH-CH2-CF2H, -CH2NH-(CH2)2-OCH3, -CH2NH-C(O)-OC(CH3)3, -CH2CH2NH-C(O)-OC(CH3)3, -CH2NH-C(O)-CH2NOH, -CH2NH-C(O)-CH2OCH3, -CH(CH3)NH-C(O)-OC(CH3)3, -CH2NH-C(O)-CH3, -CH2NHCH2-C(O)-NH2, -CH2NHCH2-C(O)-(CH3)2, -CH2NHCH2-C(O)-OCH3, -CH2NHCH2-C(O)-NHCH3, -CH2NHCH2-C(O)-NH(CH2)2-OCH3, -CH2NHCH2-C(O)-NHCH2-phenyl, -CH2NHCH2-C(O)-NH-phenyl, -CH2NH-C(O)-CH2NH-phenyl, Or -CH2NH-C(O)-CH2NH-CH2CF3, wherein the "*" indicates connection with other parts in the molecule. Wherein, the "*" indicates connection with other groups through the site marked with "*".

[0056] In one embodiment, A2 is optionally substituted The substituents are -C(O)NH(CH2)2CH3, -C(O)N(CH3)2, -C(O)NH2, -C(O)NH(CH2)2N(CH3)2, -CH2C(O)NH2, hydrogen, -F, -Cl, -Br, cyano, -CF3, -CH3, -CH2CH3, -CH=CH2, -CH2CN, -CH(CH3)-NH2, -CH=CH-CN, -C(O)-OH, -C(O)OCH3, -C(O)CH3, -C(CH3)2-C(O)-OCH3, -C(CH3)2-CN, oxo, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, -NH2, -NH-C(O)CH3, -NH-S(O)2CH3, -NH-C(O)OC(CH3)3, -S(O)2CH3, -S(O)2NCH3, -S(O)2NH2, -OCH2CH3, -O(CH2)2CH3, -OCF3, -OCH2 cyclopropyl, -OCH3, -O(CH2)3CH3, -OCH2 phenyl, -O-phenyl, -(CH2)-OH, -(CH2)2-OH, -(CH2)-OCH3, -(CH2)-OCH2CH3, -CH(OH)-CH2-phenyl, -CH(OH)-CH2CH3, -CH(OH)-CH2CH2CH3, -CH(OH)-CH2CH2CH2CH3, -CH(OH)-CH(CH3)2, -CH(OH)-phenyl, -CH(OH)-CN, -CH(OH)-CH2-OH, -CH(OH)-CF3, -CH(OH)-(CH2)2-phenyl, *-CH(OH)-C≡CH, -CH(NH2)-CH2-C(O)OH, -CH2-NH-S(O)2-CH3, -CH2-NH-(CH2 )3CH3, -CH2-NH-CH3, -CH2-N(CH3)2, -CH2-NH-CH2CH3, -CH(CH3)-NH2, -CH2-NH2, -CH2CH2-NH2, -CH2NH-CH2-phenyl, -CH2N(CH2CH3)2, -CH2NH-cyclopropyl, -CH2NH-cyclobutyl, -CH2NH-cyclopentyl, -CH2NH-pyridyl, -CH2NH-phenyl, -CH2NH-(CH2)2-OH, -CH2N(CH3)-(CH2)2-OH, -CH2NH-CH2-CN, -CH2N(CH3)-CH2-CN, -CH2N(CH3)-CH2-CF3, -CH2N(CH3)-CH2-CF2H, -CH2NH-CH2-CF2H, -CH2NH-(CH2)2-OCH3, -CH2NH-C(O)-OC(CH3)3, -CH2CH2NH-C(O)-OC(CH3)3, -CH2NH-C(O)-CH2NOH, -CH2NH-C(O)-CH2OCH3, -CH(CH3)NH-C(O)-OC(CH3)3, -CH2NH-C(O)-CH3, -CH2NHCH2-C(O)-NH2, -CH2NHCH2-C(O)-(CH3)2, -CH2NHCH2-C(O)-OCH3, -CH2NHCH2-C(O)-NHCH3, -CH2NHCH2-C(O)-NH(CH2)2-OCH3, -CH2NHCH2-C(O)-NHCH2-phenyl, -CH2NHCH2-C(O)-NH-phenyl, -CH2NH-C(O)-CH2NH-phenyl, or -CH2NH-C(O)-CH2NH-CH2CF3, the number of the substituents is 1 or 2, wherein the mark "*" indicates that it is connected to other groups through the site marked with "*".

[0057] In one embodiment, in said S:

[0058] X is CH or N;

[0059] R1, R4 and R5 are independently hydrogen, CN, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 heteroalkyl, N(C1-C6 alkyl) 1-2 , C1-C6 alkoxy, one or more R a1 Substituted C1-C6 alkyl or one or more R a2 Substituted C1-C6 alkoxy;

[0060] R a1 and R a2 are independently deuterium or halogen;

[0061] m is 1, 2, or 3;

[0062] A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, 1, 2, 3 or 4 R c’ Substituted C6-C 12 Aryl or 1, 2, 3 or 4 R d’ substituted 5-10 membered heteroaryl;

[0063] Each R c’ and R d’ are independently CN, C1-C6 alkyl, -NR e R f , halogen, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 alkyl (SO2)-, 1, 2, 3, 4 or 5 R g Substituted C1-C6 alkyl, 1, 2, 3, 4 or 5 R h Substituted C6-C 10 Aryl or 1, 2, 3, 4 or 5 R i substituted 5-10 membered heteroaryl;

[0064] Each R e 、R f 、R g and R h are independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R jor by one or more R l Substituted C1-C6 alkyl; R k and R j are independently hydrogen or C1-C6 alkyl;

[0065] Each R l are independently -NR m R n , R m and R n are independently deuterium, hydrogen or C1-C6 alkyl;

[0066] Wherein, the heteroaryl group mentioned above is a heteroatom or heteroatom group selected from one or more of N, O, S and S(═O)2, and the number of heteroatoms is 1, 2 or 3 heteroaryl groups; the heteroalkyl group is a heteroatom or heteroatom group selected from one or more of N, O, S, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene and ethynylene, and the number of heteroatoms is 1, 2 or 3 heteroalkyl groups.

[0067] In one embodiment, among R1, R4 and R5, the C3-C8 cycloalkyl group may independently be a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0068] In one embodiment, among R1, R4 and R5, the C1-C6 alkyl, N(C1-C6 alkyl) 1-2 and one or more R a1 The C1-C6 alkyl group in the substituted C1-C6 alkyl group may independently be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0069] In one embodiment, in R1, R4 and R5, the C1-C6 heteroalkyl group may independently be a C1-C4 heteroalkyl group containing 1 or 2 heteroatoms selected from N, O, and S, such as CH3OCH2-, CH3CH2OCH2-, CH3OCH2CH2-, CH3NHCH2-, CH3CH2NHCH2-, CH3NHCH2CH2-, CH3SCH2-, CH3CH2SCH2-, CH3SCH2CH2- or CH3OCH2OCH2-.

[0070] In one embodiment, in R1, R4 and R5, the C1-C6 alkoxy group can independently be a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.

[0071] In one embodiment, Ra1 and R a2 wherein the halogen may independently be F, Cl, Br or I.

[0072] In one embodiment, in A1, the C6-C 12 Aryl or 1, 2, 3 or 4 R c’ Substituted C6-C 12 C6-C in aromatic groups 12 Aryl groups may independently be phenyl or naphthyl.

[0073] In one embodiment, in A1, the 5-10 membered heteroaryl group is replaced by 1, 2, 3 or 4 R d’ The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl can be independently furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, indolyl or

[0074] In one embodiment, each R c’ and R d’ wherein the C1-C6 alkyl, C1-C6 alkyl(SO2)- or C1-C6 alkyl(SO2)- is replaced by 1, 2, 3, 4 or 5 R g The C1-C6 alkyl group in the substituted C1-C6 alkyl group may independently be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0075] In one embodiment, each R c’ and R d’ In the C6-C 10 Aryl or 1, 2, 3, 4 or 5 R h Substituted C6-C 10 C6-C in aromatic groups 10 Aryl groups may independently be phenyl or naphthyl.

[0076] In one embodiment, each R c’ and R d’ wherein the halogen may independently be F, Cl, Br or I.

[0077] In one embodiment, each R c’ and R d’ wherein the 5-10 membered heteroaryl group is replaced by 1, 2, 3, 4 or 5 R i The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl can be independently furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, indolyl or

[0078] In one embodiment, each Re 、R f 、R g and R h wherein the halogen may independently be F, Cl, Br or I.

[0079] In one embodiment, each R e 、R f 、R g 、R h 、R k 、R j 、R m and R n wherein the C1-C6 alkyl group is replaced by one or more R l The C1-C6 alkyl group in the substituted C1-C6 alkyl group can independently be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. In one embodiment, in the S, each R1 is independently hydrogen, CN, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl or C1-C6 alkoxy, such as hydrogen, C1-C3 alkyl or C1-C3 alkoxy, further such as hydrogen, methyl or methoxy.

[0080] In one embodiment, in the S, R4 is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 1-2 , by one or more R a1 Substituted C1-C6 alkyl, R a1 are independently deuterium or halogen; for example, C1-C3 alkyl, C1-C3 alkyl substituted by 3 deuteriums, or C1-C3 alkyl substituted by 3 fluorines, and also for example, methyl, -CD3 or -CH2CF3.

[0081] In one embodiment, in said S, R5 is C1-C6 alkyl, such as C1-C3 alkyl, and also such as methyl.

[0082] In one embodiment, in said S, m is 1 or 2.

[0083] In one embodiment, in said S, A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, substituted by one or more R c’ Substituted C6-C 12 Aryl or one or more R d’ Substituted 5-10 membered heteroaryl, wherein the heteroaryl is a heteroatom or heteroatom group selected from one or more of N, O, S and S(=O)2, and the number of heteroatoms is 1, 2 or 3; the C6-C 12 Aryl or one or more R c’ Substituted C6-C12 C6-C in aromatic groups 12 Aryl, for example, phenyl; the 5-10 membered heteroaryl or one or more R d’ The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is for example thienyl or For example

[0084] In one embodiment, each R c’ Independently CN, amino, halogen, C1-C6 alkyl, C1-C6 alkyl(SO2)- or C1-C6 alkyl substituted by 1, 2, 3, 4 or 5 halogen; for example, CN, C1-C3 alkyl, C1-C3 alkyl substituted by 1, 2 or 3 fluorine; also for example, CN, methyl, -CHF2, -CF3 or amino.

[0085] In one embodiment, each R d’ Independently C6-C 12 Aryl (eg phenyl) or one or more R h Substituted C6-C 12 Aryl (eg, phenyl).

[0086] In one embodiment, each R h are independently hydrogen, halogen, l Substituted C1-C6 alkyl, such as hydrogen, halogen, substituted by one or more R l Substituted C1-C3 alkyl; also such as hydrogen, Cl or one or more R l Substituted methyl.

[0087] In one embodiment, each R l are independently -NR m R n , R m and R n Independently hydrogen or C1-C6 alkyl, preferably hydrogen or C1-C3 alkyl; for example -NHCH3 or -N(CH3)2.

[0088] In one embodiment, in said S, A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, substituted by one or more R c’ Substituted C6-C 12 Aryl or one or more R d’ A substituted 5-10 membered heteroaryl group, wherein the heteroaryl group is a heteroatom or a heteroatom group selected from one or more of N, O, S and S(=O)2, and the number of heteroatoms is 1, 2 or 3;

[0089] Each R c’are independently CN, amino, halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with 1, 2, 3, 4, or 5 halogens;

[0090] Each R d’ Independently C6-C 12 Aryl or one or more R h Substituted C6-C 12 aryl;

[0091] Each R h are independently hydrogen, halogen, l Substituted C1-C6 alkyl;

[0092] Each R l are independently -NR m R n , R m and R n are independently hydrogen or C1-C6 alkyl.

[0093] In one embodiment, in said S, X is CH or N;

[0094] Each R1 is independently hydrogen, C1-C6 alkyl or C1-C6 alkoxy;

[0095] m is 1 or 2;

[0096] R4 is hydrogen, C1-C6 alkyl or one or more R a1 Substituted C1-C6 alkyl, R a1 are independently deuterium or halogen;

[0097] R5 is hydrogen or C1-C6 alkyl;

[0098] A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, substituted by one or more R c’ Substituted C6-C 12 Aryl or one or more R d’ A substituted 5-10 membered heteroaryl group, wherein the heteroaryl group is a heteroatom or a heteroatom group selected from one or more of N, O, S and S(=O)2, and the number of heteroatoms is 1, 2 or 3;

[0099] Each R c’ are independently CN, amino, halogen, C1-C6 alkyl, C1-C6 alkyl(SO2)-, or C1-C6 alkyl substituted with 1, 2, 3, 4 or 5 halogens;

[0100] Each R d’ Independently C6-C 12 Aryl or one or more Rh Substituted C6-C 12 aryl;

[0101] Each R h are independently hydrogen, halogen or substituted by one or more R l Substituted C1-C6 alkyl;

[0102] Each R l are independently -NR m R n , R m and R n are independently hydrogen or C1-C6 alkyl.

[0103] In one embodiment, in said S, X is CH or N;

[0104] Each R1 is independently hydrogen, C1-C3 alkyl or C1-C3 alkoxy;

[0105] R4 is C1-C3 alkyl, C1-C3 alkyl substituted by 3 deuteriums, or C1-C3 alkyl substituted by 3 fluorines;

[0106] R5 is a C1-C3 alkyl group;

[0107] m is 1 or 2;

[0108] A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, substituted by one or more R c’ Substituted C6-C 12 Aryl or one or more R d’ Substituted 5-10 membered heteroaryl, wherein the heteroaryl is a heteroatom or heteroatom group selected from one or more of N, O, S and S(=O)2, and the number of heteroatoms is 1, 2 or 3; the C6-C 12 Aryl or one or more R c’ Substituted C6-C 12 C6-C in aromatic groups 12 Aryl is phenyl; the 5-10 membered heteroaryl may be replaced by one or more R d’ The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is thienyl or

[0109] Each R c’ independently CN, C1-C3 alkyl, C1-C3 alkyl(SO2)-, C1-C3 alkyl substituted with 1, 2 or 3 fluorines;

[0110] Each R d’ is independently phenyl or is replaced by one or more R h substituted phenyl;

[0111] Each R h are independently hydrogen, halogen, l Substituted C1-C3 alkyl;

[0112] Each R l are independently -NR m R n , R m and R n independently hydrogen or C1-C3 alkyl.

[0113] In one embodiment, in said S, X is CH or N;

[0114] Each R1 is independently hydrogen, methyl or methoxy;

[0115] R4 is methyl, -CD3 or -CH2CF3;

[0116] R5 is methyl;

[0117] m is 1 or 2;

[0118] A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, substituted by one or more R c’ Substituted C6-C 12 Aryl or one or more R d’ Substituted 5-10 membered heteroaryl; the C6-C 12 Aryl or one or more R c’ Substituted C6-C 12 C6-C in aromatic groups 12 Aryl is phenyl; the 5-10 membered heteroaryl may be replaced by one or more R d’ The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is

[0119] R c’ are independently CN, methyl, -CHF2, -CF3, CH3SO2- or amino;

[0120] R d’ is independently phenyl or is replaced by one or more R h substituted phenyl;

[0121] R h are independently hydrogen, Cl or substituted by one or more R l Substituted methyl; R l It is -NHCH3 or -N(CH3)2.

[0122] In one embodiment, the S is S':

[0123] Wherein, “*” indicates that the marked C atom is in R configuration, S configuration or a mixture thereof; X, R1, A1, R4, R5 and m are defined as described in the previous embodiment;

[0124] Preferably

[0125] In any embodiment of the present invention, unless otherwise specified, “*” indicates that the marked C atom is in R configuration, S configuration or a mixture thereof.

[0126] In one embodiment, the S' is S'-1:

[0127] X, R1, A1, R4, R5 and m are as defined in the previous embodiment.

[0128] In one embodiment, the S is S-1 or S-2:

[0129] In the above formulae, the definitions of the substituents are the same as those in the previous embodiment.

[0130] In one embodiment, the S-1 is S-1-1 or S-1-2:

[0131] In the above formulas, W and Y are independently 1, 2, 3, 4 or 5;

[0132] Preferably, the S-1 is

[0133] R1, R4, R5, R c’ and R h The definition of is as described in the previous scheme.

[0134] In one embodiment, the S-2 is S-2-1 or S-2-2:

[0135] In the above formulas, W and Y are independently 1, 2, 3, 4 or 5;

[0136] Preferably, the S-2 is

[0137] R1, R4, R5, R c’ and R h The definition of is as described in the previous scheme.

[0138] In one embodiment, S is:

[0139] In certain embodiments of the present invention, L is a bond.

[0140] In certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -One or more methylene groups are optionally selected from -NR 3’ -, -O-, -S-, -S(O)-, -S(O)NR 3’ -、-NR 3’ S(O)-, -S(O)2-, -S(O)2NR 3’ -、-NR 3’ S(O)2-、-NR 4’ S(O)2NR 3’ -、-CR 1’ R 2’ -, -C(O)-, -C(O)O-, -OC(O)-, -NR 3’ C(O)O-、-OC(O)NR 3’ -、-C(O)NR 3’ -、-NR 3’ C(O)-、-NR 4’ C(O)NR 3’ -、-P(O)-、-P(O)O-、-OP(O)-、-OP(O)O-、vinylene、ethynylene、C3-C 12 Cycloalkylene, 3-12 membered heterocycloalkylene containing one or more heteroatoms selected from N, O and S, 6-10 membered arylene and 5-10 membered heteroarylene groups are substituted, and the methylene, vinylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene are independently optionally substituted by one or more halogen, -OR 3’ 、-NR 3’ R 4’ , oxo, nitro, cyano, C1-C6 alkyl, -S(C1-C6 alkyl), C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -C(O)R 1’ 、-C(O)OR 3’ 、-OC(O)R 1’ 、-C(O)NR 3’ 、-NR 3’ C(O)R 1’ 、-S(O)R 1’ 、-S(O)NR 3’ 、-S(O)2R 1’ 、-S(O)2NR3’ 、-NR 3’ S(O)2R 1’ 、-NR 4’ S(O)2NR 3’ 、-OC(O)NR 3’ and -NR 4’ C(O)NR 3’ The alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are independently optionally substituted by one or more halogen, -OH, -NR 3’ R 4’ , oxo, nitro, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6- C 10 The substituents of aryl and 5-10 membered heteroaryl are substituted; R 1’ 、R 2’ Each is independently halogen, -OH, -NR 3’ , C1-C6 alkyl, chloro C1-C6 alkyl, hydroxy C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, C3-C 10 Cycloalkyl, -O(C3-C 10 Cycloalkyl), -NH(C3-C 10 cycloalkyl), 3-10 membered heterocycloalkyl, -O(3-10 membered heterocycloalkyl), -NH(3-10 membered heterocycloalkyl), C6-C 10 Aryl, -O(C6-C 10 Aryl), -NH(C6-C 10 aryl), 5-10 membered heteroaryl, -O(5-10 membered heteroaryl) or -NH(5-10 membered heteroaryl); or R 1’ 、R 2’ Together with the C atoms to which they are attached, they form a C3-C8 cycloalkyl group or a 3-8 membered heterocycloalkyl group; R 3’ 、R 4’ are independently hydrogen, deuterium, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl; j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25.

[0141] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -One or more methylene groups are optionally selected from -NR3’ -、-O-、-CR 1’ R 2’ -, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NR 3’ -、-NR 3’ C(O)-、-S(O)2NR 3’ -、-NR 3’ S(O)2-, vinylene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered saturated or partially unsaturated fused cycloalkylene, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene, 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, The methylene, vinylene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, spiroheterocycloalkylene, fused cycloalkylene, heteroarylene, and heteroarylene are independently optionally substituted by one or more groups selected from halogen, oxo, -NR 3’ R 4’ 、-OR 3’ , nitro, -CN, C1-C6 alkyl, C3-C 10 The alkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted by one or more substituents selected from halogen, -OH, -NH2, -CN, C1-C4 alkyl, and C3-C6 cycloalkyl groups. 1’ 、R 2’ Each is independently halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), C3-C6 heterocycloalkyl, -O(C3-C6 heterocycloalkyl), -NH(C3-C6 cycloalkyl); or R 1’ 、R 2’ Together with the C atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group; R3’ 、R 4’ are independently hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0142] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -One or more methylene groups are optionally selected from -NR 3’ -、-O-、-CR 1’ R 2’ -, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NR 3’ -、-NR 3’ C(O)-、-S(O)2NR 3’ -、-NR 3’ S(O)2-, vinylene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated monocyclic cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered saturated or partially unsaturated fused cycloalkylene, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene, 5-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen or oxygen, 5-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen or oxygen, atom, a 5-11 membered saturated or partially unsaturated fused heterocycloalkylene having 1-2 independently selected nitrogen or oxygen heteroatoms, a 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene having 1-2 independently selected nitrogen or oxygen heteroatoms, a 5-6 membered heteroarylene having 1-4 independently selected nitrogen or oxygen heteroatoms, or a 8-10 membered bicyclic heteroaryl having 1-5 selected nitrogen or oxygen heteroatoms, said methylene, vinylene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, fused cycloalkylene, spiroheterocycloalkylene, heteroarylene are independently optionally substituted by one or more groups selected from halogen, oxo, -NR 3’ R 4’ 、-OR 3’ , nitro, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl substituted, the alkyl, cycloalkyl, heterocycloalkyl optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, R 1’ 、R 2’Each is independently halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), C3-C6 heterocycloalkyl, -O(C3-C6 heterocycloalkyl), -NH(C3-C6 cycloalkyl); or R 1’ 、R 2’ Together with the C atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group; R 3’ 、R 4’ are independently hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0143] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -, 1, 2, 3, 4 or 5 methylene groups are optionally selected from -NH-, -NCH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, vinylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, Cyclohexylene, oxiranediylene, oxetanediylene, oxolanediylene, oxhexylene, aziridinediylene, aziridinediylene, piperidinylene, piperazinylene, morpholinylene, homomorpholinylene, phenylene, pyrrolylene, thienylene, furanylene, imidazolylene, pyrazolylene, triazolylene, tetrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, and the methylene or replacement group is optionally replaced by one or more halogen, oxo, -NR 3’ R 4’ 、-OR 3’ , C1-C4 alkyl substituents, wherein the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, -NH2, R 3’ 、R 4’ is hydrogen, deuterium, or C1-C4 alkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0144] Preferably, in certain embodiments of the present invention, L is -(CH2) j-, the -(CH2) j -, 1, 2, 3, 4 or 5 methylene groups are optionally selected from -NH-, -NCH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxirane, oxetane, oxolanyl, oxhexylene, aziridine, aziridine, aziridine, aziridine, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, The methylene or replacement group is optionally replaced by one or more groups selected from F, Cl, oxo, -NR 3’ R 4’ 、-OR 3’ , C1-C4 alkyl substituents, wherein the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, -NH2, R 3’ 、R 4’ are independently hydrogen, deuterium, methyl, ethyl, or propyl, and j is 3, 4, 5, 6, 7, 8, 9, or 10.

[0145] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -1, 2, 3, 4 or 5 methylene groups in the group are optionally selected from -O-, -NH-, -NCH3-, -C(O)-, -C(O)NH-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, cyclohexylene, aziridine, aziridinyl, aziridine, piperidinyl, piperazinyl, and j is 4, 5, 6, 7, 8, 9 or 10.

[0146] Preferably, in certain embodiments of the present invention, L is selected from -(CH2) j-1 -C(O)-, said -(CH2) j-1 The methylene group in -C(O)- is as defined in the above L, and is optionally substituted by one or more groups, and the j is as defined in the above L.

[0147] Preferably, in certain embodiments of the present invention, L is selected from

[0148] In certain embodiments of the present invention, L is any of the following structures:

[0149] Preferably, in certain embodiments of the present invention, said L is LA,

[0150] Among them, LA:

[0151] Ring A is a bond, C3-C 12 Cycloalkylene (e.g. wherein the a end is connected to S and the b end is connected to X') or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g. wherein a end is connected to S and b end is connected to X"'), the cycloalkylene and heterocycloalkylene are optionally substituted by a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0152] Ring B is a bond, C3-C 12 Cycloalkylene (e.g., wherein the c-terminal is connected to X' and the d-terminal is connected to L3) or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g. wherein the c-terminus is connected to X"' and the d-terminus is connected to L3), the cycloalkylene and heterocycloalkylene are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0153] Ring C is C3-C 12Cycloalkylene (e.g. wherein the e end is connected to L3 and the f end is connected to X″) or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g. wherein the e end is connected to L3 and the f end is connected to X″), the cycloalkylene and heterocycloalkylene are optionally substituted by a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0154] X" is a bond, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, or -C(O)CH2O-;

[0155] L3 is -(CH2) k , one or two methylene groups in L3 are optionally selected from -O-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)- or -N(C3-C8 cycloalkyl)-, and k is 0, 1, 2, 3, 4, 5, 6 or 7;

[0156] X'' is a bond, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -CH2NCH3-, -NHC(O)- or -NCH3C(O)-.

[0157] In some embodiments, in the LA:

[0158] Ring A is a bond, C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0159] Ring B is a bond, C3-C 12Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0160] Ring C is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0161] X" is a bond, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, or -NCH3C(O)-;

[0162] L3 is -(CH2) k , one or two methylene groups in L3 are optionally selected from -O-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C1-C6 hydroxyalkyl)- or -N(C3-C8 cycloalkyl)-, and k is 0, 1, 2, 3 or 4;

[0163] X'' is a bond, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)- or -NCH3C(O)-.

[0164] In certain embodiments of the present invention, in the LA, L3 is -(CH2) k , one or two methylene groups in L3 are optionally replaced by -O-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C1-C6 hydroxyalkyl)- or -N(C3-C8 cycloalkyl)-, and k is 0, 1, 2, 3, 4, 5, 6 or 7.

[0165] Preferably, in certain embodiments of the present invention, in LA, ring A is a bond.

[0166] Preferably, in certain embodiments of the present invention, in LA, ring A is a 3-7 membered saturated or partially unsaturated cycloalkylene group, a 4-11 membered saturated or partially unsaturated spirocycloalkylene group, a 4-11 membered saturated or partially unsaturated fused cycloalkylene group, an 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0167] Preferably, in certain embodiments of the present invention, in LA, ring A is a 3-6 membered saturated cycloalkylene group or a 4-7 membered saturated monocyclic heterocycloalkylene group having 1 or 2 heteroatoms independently selected from nitrogen atoms.

[0168] Preferably, in certain embodiments of the present invention, in LA, ring A is a cyclohexylene group (e.g., cyclohexane-1,4-diyl, e.g., trans-cyclohexane-1,4-diyl), a piperidinylene group (e.g., piperidinyl-1,4-diyl) or a piperazinylene group (e.g., piperazine-1,4-diyl).

[0169] In certain embodiments of the present invention, in the LA, ring A is The a end is connected to S, and the b end is connected to X''.

[0170] In certain embodiments of the present invention, in the LA, ring A is The a end is connected to S, and the b end is connected to X''.

[0171] In certain embodiments of the present invention, in the LA, ring A is The a end is connected to S, and the b end is connected to X''.

[0172] Preferably, in certain embodiments of the present invention, in LA, ring B is a bond.

[0173] Preferably, in certain embodiments of the present invention, in LA, ring B is a 3-7 membered saturated or partially unsaturated cycloalkylene group, a 4-11 membered saturated or partially unsaturated spirocycloalkylene group, a 4-11 membered saturated or partially unsaturated fused cycloalkylene group, an 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0174] Preferably, in certain embodiments of the present invention, in LA, ring B is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, or a condensed heterocycloalkylene group.

[0175] Preferably, in certain embodiments of the present invention, in LA, ring B is a piperidinylene group (eg, piperidine-1,4-diyl) or a piperazinylene group (eg, piperazine-1,4-diyl).

[0176] In certain embodiments of the present invention, in the LA, ring B is The c-terminal is connected to X', and the d-terminal is connected to L3.

[0177] Preferably, in certain embodiments of the present invention, ring B is The c-terminal is connected to X', and the d-terminal is connected to L3.

[0178] Preferably, in certain embodiments of the present invention, in LA, ring C is a 3-7 membered saturated or partially unsaturated cycloalkylene group, a 4-11 membered saturated or partially unsaturated spirocycloalkylene group, a 4-11 membered saturated or partially unsaturated fused cycloalkylene group, an 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0179] Preferably, in certain embodiments of the present invention, in LA, ring C is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, or a condensed heterocycloalkylene group.

[0180] Preferably, in certain embodiments of the present invention, in the LA, ring C is piperidinylene (e.g., piperidine-1,4-diyl), piperazinylene (e.g., piperazine-1,4-diyl), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example )or (For example ).

[0181] In certain embodiments of the present invention, in the LA, ring C is The e end is connected to L3, and the f end is connected to X".

[0182] In certain embodiments of the present invention, in the LA, ring C is The e end is connected to L3, and the f end is connected to X".

[0183] Preferably, in certain embodiments of the present invention, ring A in LA is a 3-6 membered saturated cycloalkylene group; ring B is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms; ring C is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, or a fused heterocycloalkylene group; X" is a bond or -C(O)-; L3 is -(CH2) k , k is 1, 2, 3, 4 or 5 (e.g., k is 1, 2, 3 or 4).

[0184] Preferably, in certain embodiments of the present invention, in LA, X" is a bond or -C(O)-.

[0185] Preferably, in certain embodiments of the present invention, in LA, X" is a bond.

[0186] Preferably, in certain embodiments of the present invention, in said LA, X" is -C(O)-.

[0187] Preferably, in certain embodiments of the present invention, in said LA, X" is -C(O)CH2O-.

[0188] Preferably, in certain embodiments of the present invention, in LA, X'' is a bond or -C(O)-.

[0189] Preferably, in certain embodiments of the present invention, in LA, X'' is a bond.

[0190] Preferably, in certain embodiments of the present invention, in LA, X'' is -C(O)-.

[0191] Preferably, in certain embodiments of the present invention, in said LA, k is 1, 2, 3, 4 or 5.

[0192] Preferably, in certain embodiments of the present invention, in said LA, L3 is -(CH2) k , k is 1, 2, 3, 4 or 5.

[0193] Preferably, in certain embodiments of the present invention, in said LA, L3 is -(CH2) k , one or two methylene groups in L3 are optionally replaced by -O-, -NH-, -C≡C- or -N(C1-C6 alkyl)- (e.g., -N(CH3)-), and k is 1, 2, 3, 4 or 5.

[0194] Preferably, in certain embodiments of the present invention, in said LA, k is 1, 2, 3 or 4. Preferably, in certain embodiments of the present invention, in said LA, L3 is -(CH2) k -, wherein one or two CH2 contained in said L3 are optionally replaced by -O-, -NH- or -N(C1-C6 alkyl)- (e.g. -N(CH3)-), or one -CH2CH2- contained in said L3 is optionally replaced by -C≡C-; k is 1, 2, 3 or 4.

[0195] Preferably, in certain embodiments of the present invention, in said LA, L3 is -(CH2) k -, one methylene group in L3 is optionally replaced by -O-, -NH- or -N(C1-C6 alkyl)- (e.g., -N(CH3)-); k is 1, 2, 3 or 4.

[0196] Preferably, in certain embodiments of the present invention, the LA is LA-1:

[0197] wherein Ring A, Ring B, Ring C, L3, and X" are as defined and described in LA.

[0198] In certain embodiments of the present invention, the LA is LA-2:

[0199] Among them, ring A is wherein the a end is connected to S, and the b end is connected to X"'; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally substituted by F;

[0200] X'' is -C(O)-;

[0201] Ring B is wherein the c-terminus is connected to X'', and the d-terminus is connected to L3; 1, 2, 3 or 4 hydrogen atoms in the ring B are optionally substituted by F;

[0202] L3 is -(CH2) k -, wherein one or two CH2 contained in said L3 are optionally replaced by -O-, -NH- or -N(C1-C6 alkyl)- (e.g., -N(CH3)-), or one -CH2CH2- contained in said L3 is optionally replaced by -C≡C-; k is 1, 2, 3 or 4;

[0203] Ring C is wherein the e end is connected to L3, and the f end is connected to X"; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally substituted by F;

[0204] X" is -C(O)-.

[0205] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, ring A is The a end is connected to S, and the b end is connected to X''.

[0206] Preferably, in certain embodiments of the present invention, ring B is The c-terminal is connected to X', and the d-terminal is connected to L3.

[0207] In certain embodiments of the present invention, in LA, LA-1 and LA-2, L3 is -(CH2) k -, wherein one or two CH2 contained in L3 are independently optionally replaced by -O-, -NH- or -N(CH3)-; k is 1, 2, 3 or 4.

[0208] In certain embodiments of the present invention, in LA, LA-1 and LA-2, L3 is -(CH2) k-, wherein one or two CH2 contained in L3 are independently optionally replaced by -O-; k is 1, 2, 3 or 4.

[0209] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, k is 3 or 4, preferably 4.

[0210] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, L3 is -(CH2) k -, wherein one CH2 contained in L3 is optionally replaced by -O-; k is 4.

[0211] In certain embodiments of the present invention, in LA, LA-1 and LA-2, L3 can be -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, The k" end is connected to ring B, and the k' end is connected to ring C.

[0212] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, L3 can be -(CH2)4-,

[0213] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, ring C is The e end is connected to L3, and the f end is connected to X".

[0214] In certain embodiments of the present invention, the LA-2 is any of the following structures:

[0215] Preferably, in certain embodiments of the present invention, the LA-2 is any of the following structures:

[0216] In certain embodiments of the present invention, the LA is LA-3:

[0217] Among them, ring A is wherein the a end is connected to S, and the b end is connected to X"'; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally substituted by F;

[0218] X'' is -C(O)-;

[0219] Ring B is wherein the c-terminus is connected to X'', and the d-terminus is connected to L3; 1, 2, 3 or 4 hydrogen atoms in the ring B are optionally substituted by F;

[0220] L3 is -(CH2) k -, wherein one CH2 contained in said L3 is optionally replaced by -O-, -NH- or -N(C1-C6 alkyl)- (e.g., -N(CH3)-); k is 1 or 2;

[0221] Ring C is wherein the e end is connected to L3, and the f end is connected to X"; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally substituted by F;

[0222] X" is -C(O)-.

[0223] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-3, ring A is Preferably The a end is connected to S, and the b end is connected to X''.

[0224] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-3, ring B is The c-terminal is connected to X', and the d-terminal is connected to L3.

[0225] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-3, L3 is -(CH2) k -, k is 1 or 2.

[0226] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-3, ring C is The c-terminal is connected to X', and the d-terminal is connected to L3.

[0227] In certain embodiments of the present invention, the LA-3 is any of the following structures:

[0228] Preferably, in certain embodiments of the present invention, the LA-3 is any of the following structures:

[0229] In certain embodiments of the present invention, the LA is LA-4:

[0230] Among them, ring A is wherein the a end is connected to S, and the b end is connected to X"'; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally substituted by F;

[0231] X'' is a bond, -C(O)NH- or -C(O)NCH3-;

[0232] Ring B is a bond;

[0233] L3 is -(CH2) k , one or two methylene groups in L3 are optionally replaced by -O-, -NH-, -C(O)-, -C≡C- or -N(C1-C6 alkyl)-, and k is 0, 1, 2, 3, 4, 5, 6 or 7;

[0234] Ring C is wherein the e end is connected to L3, and the f end is connected to X"; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally substituted by F;

[0235] X" is -C(O)-.

[0236] In certain embodiments of the present invention, in the LA-4, ring A is The a end is connected to S, and the b end is connected to X''.

[0237] In certain embodiments of the present invention, in the LA-4, L3 is -CH2-, The k" end is connected to ring B, and the k' end is connected to ring C.

[0238] In certain embodiments of the present invention, in the LA-4, ring C is The e end is connected to L3, and the f end is connected to X".

[0239] In certain embodiments of the present invention, the LA-4 is any of the following structures:

[0240] Preferably, in certain embodiments of the present invention, the LA-4 is any of the following structures:

[0241] In certain embodiments of the present invention, the LA is LA-5:

[0242] wherein Ring A, X'', Ring B, L3 and Ring C are as defined in LA-2 or LA-3;

[0243] X" is -C(O)CH2O-, and the -C(O)- in X" is connected to the ring C.

[0244] In certain embodiments of the present invention, in the LA-5, ring A is The a end is connected to S, and the b end is connected to X''.

[0245] In certain embodiments of the present invention, in the LA-5, ring B is The c-terminal is connected to X', and the d-terminal is connected to L3.

[0246] In certain embodiments of the present invention, in the LA-5, L3 is -(CH2) k , k is 1 or 2, preferably 1.

[0247] In certain embodiments of the present invention, in the LA-5, ring C is The e end is connected to L3, and the f end is connected to X".

[0248] Preferably, in certain embodiments of the present invention, the LA-5 is

[0249] Preferably, in certain embodiments of the present invention, the LA is

[0250] In one embodiment, L is LB:

[0251] In the LB: Ring A" is connected to S;

[0252] Ring A", Ring B" and Ring C" are independently a bond, C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenylene or 3-12 membered heterocycloalkylene, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or -O-(C1-C6 alkyl);

[0253] X' and X" are independently a bond, -O-(C1-C6 alkylene)-, -S-(C1-C6 alkylene)-, -NH-(C1-C6 alkylene)-, -NH-, -NCH3-, -O-, -CH2-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C( O) NCH3-, -CH2NCH3-, -NHC(O)-, -NCH3C(O)- or -C(O)CH2O-; the C1-C6 alkylene in the -O-(C1-C6 alkylene)-, -S-(C1-C6 alkylene)- or -NH-(C1-C6 alkylene)- may be substituted by one or more Rx', wherein the Rx' is a C1-C6 alkyl, or two Rx' located on the same carbon atom are connected to the carbon atom to form a C3-C8 cycloalkyl;

[0254] La" is -(CH2) k’- , one or two methylene groups in La" are optionally replaced by -O-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)-, or -N(C3-C8 cycloalkyl)-, and k' is 0, 1, 2, 3, 4, 5, 6 or 7;

[0255] The heterocycloalkylene group is a heterocycloalkylene group having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0256] In one embodiment, in LB, among the ring A", ring B" and ring C", the C3-C 12 The cycloalkylene group can be independently C3-C6 monocyclic cycloalkylene, C7-C 11 Bicyclic spirocycloalkylene, C7-C 11 Sub-bridged ring cycloalkyl or C7-C 11 cycloalkylene, for example cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, spiro[3.3]hexylene, spiro[3.4]heptylene, spiro[3.5]octylene, spiro[4.4]octylene, spiro[4.5]nonylene, spiro[5.5]decylene, bicyclo[3.3.0]octylene or hexahydroindanylene.

[0257] In one embodiment, in LB, among the ring A", ring B" and ring C", the C3-C 12 The cycloalkenylene group can be independently a C3-C6 monocyclic cycloalkenylene group, a C7-C 11 Bicyclic spirocycloalkenylene, C7-C 11Sub-bridged ring cycloalkenyl or C7-C 11 Cycloalkenylene, such as cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene,

[0258] In one embodiment, in LB, the 3-12 membered heterocycloalkylene in the ring A'', ring B'' and ring C'' can be independently C3-C6 monocyclic heterocycloalkylene, C7-C 11 Bicyclic spirocyclic heterocycloalkylene, C7-C 11 Sub-bridged heterocyclic alkyl or C7-C 11 The alkylene radicals are alkylene radicals, for example, azitidinylene, oxetanylene, tetrahydrofuranylene, tetrahydropyrrolylene, tetrahydropyranylene, piperidinylene, morpholinylene or piperazinylene, 2,7-diaza[3.5]nonanylene, 7-aza[3.5]nonanylene, 2-aza[3.5]nonanylene, 2,6-diaza[3,3]-hexylene, 2-aza[3,3]-hexylene, 3-aza[5,5]undecylene or 3,9-diaza[5,5]undecylene.

[0259] In one embodiment, in LB, the C1-C6 alkyl group in the ring A", ring B" and ring C" or the C1-C6 alkyl group in -O-(C1-C6 alkyl) can independently be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0260] In one embodiment, in LB, the halogen in the substituents in the ring A", ring B" and ring C" can independently be F, Cl, Br or I.

[0261] In one embodiment, in LB, the C1-C6 heteroalkyl group in the ring A", ring B" and ring C" may independently be a C1-C4 heteroalkyl group containing 1 or 2 heteroatoms selected from N, O, and S, such as CH3OCH2-, CH3CH2OCH2-, CH3OCH2CH2-, CH3NHCH2-, CH3CH2NHCH2-, CH3NHCH2CH2-, CH3SCH2-, CH3CH2SCH2-, CH3SCH2CH2- or CH3OCH2OCH2-.

[0262] In one embodiment, in LB, the C1-C6 haloalkyl in the ring A", ring B" and ring C" may independently be a C1-C4 haloalkyl, such as a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl substituted with 1, 2 or 3 halogens, and the halogen may be F, Cl, Br or I.

[0263] In a certain embodiment, in LB, the C1-C6 hydroxyalkyl group in the ring A", ring B" and ring C" can independently be a C1-C4 hydroxyalkyl group, such as a hydroxymethyl group, a hydroxyethyl group, a hydroxy-n-propyl group, a hydroxy-isopropyl group, a hydroxy-n-butyl group, a hydroxy-sec-butyl group, a hydroxy-isobutyl group or a hydroxy-tert-butyl group. In a certain embodiment, in LB, the C3-C8 cycloalkyl group in the ring A", ring B" and ring C" can independently be a C3-C6 cycloalkyl group, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0264] In one embodiment, in LB, in the ring A", ring B" and ring C", the 3-8 membered heterocycloalkyl group in the substituent may independently be a 4-6 membered heterocycloalkyl group, such as azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl.

[0265] In one embodiment, in LB, in X'' and X", the C1-C6 alkylene in -O-(C1-C6 alkylene), -S-(C1-C6 alkylene) or -NH-(C1-C6 alkylene) may independently be C1-C4 alkylene, such as methylene, ethylene, n-propylene, isopropylene, sec-butylene, n-butylene, isobutylene or tert-butylene.

[0266] In one embodiment, in LB, in the Rx', the C1-C6 alkyl group can independently be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0267] In one embodiment, in LB, in the La", the C1-C6 alkyl in the -N(C1-C6 alkyl)- in the substituted group may be a C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0268] In one embodiment, in LB, in the La", the C1-C6 haloalkyl in the -N(C1-C6 haloalkyl) in the substituted group may be a C1-C4 haloalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl substituted by 1, 2 or 3 halogens, and the halogens may independently be F, Cl, Br or I.

[0269] In one embodiment, in LB, in the La", the C1-C6 hydroxyalkyl in the -N(C1-C6 hydroxyalkyl)- group of the substituted group may be a C1-C4 hydroxyalkyl, such as a hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxyisobutyl or hydroxy-tert-butyl group.

[0270] In one embodiment, in LB, in the aforementioned La", the C3-C8 cycloalkyl group in the -N(C3-C8 cycloalkyl)- group of the aforementioned substituted group may be a C3-C6 cycloalkyl group, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0271] In one embodiment, in the LB, ring A" is C3-C 12 Cycloalkylene, C3-C 12 cycloalkenylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S.

[0272] In a certain embodiment, in the LB, ring A" is a C5-C6 monocyclic cycloalkylene, a C5-C6 monocyclic cycloalkenylene, a 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, or a 7-8 membered bridged heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S; preferably a C5-C6 monocyclic cycloalkylene, a C5-C6 monocyclic cycloalkenylene, or a 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S.

[0273] In one embodiment, in the LB, ring A" is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, such as C5-C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, more such as piperidinylene, piperazinylene, cyclohexylene or cyclohexenylene.

[0274] In one embodiment, in the LB, ring B" is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, such as C5-C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, more such as piperidinylene, cyclohexylene or piperazinylene.

[0275] In one embodiment, in the LB, ring C" is a 3-12-membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, for example, a 5-6-membered monocyclic heterocycloalkylene group or a 7-11-membered spirocyclic heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, more for example, a piperidinylene group, a piperazinylene group, a 2,7-diaza[3.5]nonylene group, a 7-aza[3.5]nonylene group, a 2-aza[3.5]nonylene group, a 2,6-diaza[3,3]-hexylene group, a 2-aza[3,3]-hexylene group, a 3-aza[5,5]undecylene group or a 3,9-diaza[5,5]undecylene group.

[0276] In one embodiment, in the LB, X"" is -C(O)-, -O-(C1-C6 alkylene), -S-(C1-C6 alkylene) or -NH-(C1-C6 alkylene), and the C1-C6 alkylene in the -O-(C1-C6 alkylene), -S-(C1-C6 alkylene) or -NH-(C1-C6 alkylene) may be substituted by one or more Rx', wherein the Rx' is a C1-C6 alkyl, or two Rx' located on the same carbon atom are connected to the carbon atom to form a C3-C8 cycloalkyl. For example

[0277] In one embodiment, in the LB, La" is -(CH2) k’- , one or two methylene groups in La" are optionally substituted by -O-, -NH, or -N(Me)-, and k' is 0, 1, 2, 3, 4, 5 or 6.

[0278] In one embodiment, in the LB, X'' is -C(O)-.

[0279] In one embodiment, in the LB, ring A" is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, such as C5-C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S; more preferably piperidinylene, piperazinylene, cyclohexylene or cyclohexenylene;

[0280] Ring B" is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, such as C5-C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S; more preferably piperidinylene, cyclohexylene or piperazinylene;

[0281] Ring C″ is a 3-12-membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, for example, a 5-6-membered monocyclic heterocycloalkylene group or a 7-11-membered spirocyclic heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S; more preferably, a piperidinylene group, a piperazinylene group, a 2,7-diaza[3.5]nonylene group, a 7-aza[3.5]nonylene group, a 2-aza[3.5]nonylene group, a 2,6-diaza[3,3]-hexylene group, a 2-aza[3,3]-hexylene group, a 3-aza[5,5]undecylene group or a 3,9-diaza[5,5]undecylene group;

[0282] X"" is -C(O)-, -O-(C1-C6 alkylene), -S-(C1-C6 alkylene) or -NH-(C1-C6 alkylene), wherein the C1-C6 alkylene in -O-(C1-C6 alkylene), -S-(C1-C6 alkylene) or -NH-(C1-C6 alkylene) may be substituted by one or more Rx', wherein Rx' is a C1-C6 alkyl, or two Rx' located on the same carbon atom are connected to the carbon atom to form a C3-C8 cycloalkyl group;

[0283] La" is -(CH2) k’ , one or two methylene groups in La" are optionally replaced by -O-, -NH or -N(Me)-, and k' is 0, 1, 2, 3, 4, 5 or 6;

[0284] X'' is -C(O)-.

[0285] In one embodiment, in the LB, ring C" is a 5-6 membered monocyclic heterocycloalkylene or a 7-11 membered spirocyclic heterocycloalkylene containing 1-2 N heteroatoms, wherein the N atom is connected to X"', and the definitions of ring A", ring B", La", X"" and X"' are as described in any scheme.

[0286] In one embodiment, in the LB, ring A" is a C5-C6 monocyclic cycloalkylene or a 5-6 membered monocyclic heterocycloalkylene containing 1-2 N atoms;

[0287] Ring B" is a C5-C6 monocyclic cycloalkylene group or a 5-6 membered monocyclic heterocycloalkylene group containing 1-2 N heteroatoms;

[0288] and at least one of ring A" or ring B" is connected to X"" through an N atom;

[0289] Rings C", La", X"" and X'" are as defined in any of the previous schemes.

[0290] In one embodiment, LB is LB-1:

[0291] Wherein, in the LB-1, the definitions of ring A", ring B", ring C", La" and X'" are as described in the previous embodiment.

[0292] In one embodiment, Ring A" is Preferably The a side is connected to X””.

[0293] In one embodiment, Ring B" is Preferably The b side is connected to X””.

[0294] In one embodiment, La" is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2OCH2- or -CH2OCH2CH2-, preferably *-CH2-, *-CH2CH2-, *-CH2CH2CH2-, *-CH2CH2CH2CH2-, *-CH2CH2OCH2- or *-CH2OCH2CH2-, wherein the * side is connected to ring B".

[0295] In one embodiment, ring C" is Preferably The d side is connected to X''.

[0296] In one embodiment, LB is

[0297] In one embodiment, the E is a small molecule ligand of E3 ubiquitin ligase CRBN, VHL, XAIP or MDM2.

[0298] In one embodiment, E is E1:

[0299] Among them, each R 1a are independently halogen, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted 3-12 membered heterocycloalkyl, optionally substituted C6-C 10 Aryl, optionally substituted 5-10 membered heteroaryl, -CN or -O(CH2) x R 1a1 ;

[0300] And at least one R 1a -O(CH2) x R 1a1 ;

[0301] R 1b is unsubstituted isopropyl, -(CH2)C(O)OMe, or -(CH2)2OH;

[0302] R 1c is a substituted C1-C6 alkyl group;

[0303] R 1d is hydrogen, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;

[0304] R 1a1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted 3-12 membered heterocycloalkyl, optionally substituted C6-C 10 Aryl, optionally substituted 5-10 membered heteroaryl, -OR 1a2 、-N(R 1a3 )2、or -SR 1a2 ;

[0305] Each R 1a2 are independently hydrogen, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, an oxygen protecting group or a sulfur protecting group;

[0306] Each R 1a3 are independently hydrogen, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;

[0307] n is 1, 2, 3 or 4; and

[0308] x is 0, 1, 2, 3, 4, 5, or 6, and when R 1b is isopropyl, R 1c is methyl, R 1c is hydrogen, when n is 1, R 1a Not methyl or hydroxymethyl.

[0309] In one embodiment, the E1 is E1a, E1b or E1c:

[0310] Wherein, R1 is defined as above.

[0311] In one embodiment, E is E2:

[0312] Among them, in the E2:

[0313] X 101 For bonds, -CH2-, -CHCF3-, -S(O)2-, -S(O)-, -P(O)R 100 -、-P(O)OR 100 -、-P(O)N(R 100 )2, -C(O)-, -C(S)-, or

[0314] X 201 C or Si;

[0315] X 301 -CH2-, -O-, -S-, -C(R 100 )2- or -Si(R 100 )2-;

[0316] R 101 Selected from hydrogen, deuterium, halogen, -CN, -OR 100 、-SR 100 、-S(O)R 100 、-S(O)2R 100 、-N(R 100 )2、-P(O)(OR 100 )2、-P(O)[N(R 100 )2](OR 100 )、-P(O)[N(R 100 )2]2, -Si(OH)2(R 100 )-、-Si(OH)(R 100 )2-、-Si(R 100 )3-, or optionally substituted C1-C4 alkyl;

[0317] R 201 Selected from hydrogen, -R 601 、Halogen、-CN、-NO2、-OR 100 、-SR 100 、-S(O)R 100 、-S(O)2R 100 、-N(R 100 )2、-S(O)2N(R 100 )2、-C(O)R 100 、-C(O)OR 100 、-C(O)N(R 100)2 、-OC(O)R 100 、-OC(O)N(R 100 )2、-NR 100 C(O)OR 100 、-NR100 C(O)R 100 、 -NR 100 C(O)N(R 100 )2、-OP(O)(R 100 )2、-OP(O)(OR 100 )2、-OP(O)(OR 100 )[N(R 100 )2]、-OP(O)[N(R 100 )2]、-NP(O)(R 100 )2、-NR 100 P(O)(OR 100 )2、-N(R 100 )P(O)(OR 100 )[N(R 100 )2]、-N(R 100 )P(O)[N(R 100 )2]2, or -NR 100 S(O)2R 100 ;

[0318] L 101 is a bond or a C1-C4 alkylene group, wherein one or two methylene groups in the C1-C4 alkylene group are optionally replaced by -O-, -C(O)-, -C(S)-, -C(R 100 )2-、-CH(R 100 )-、-C(F)2-、-N(R 100 )-, -S-, -S(O)2- or -CH=CH;

[0319] Any of the following structures:

[0320] Wherein, ring B is a 6-membered heteroaryl containing 1-2 N atoms, a phenyl group, a 5-7-membered saturated or partially unsaturated C3-C 12 Cycloalkyl, 5-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 atoms selected from N, O and S, or 5-membered heteroaryl containing 1-3 atoms selected from N, O and S;

[0321] R 301 Selected from hydrogen, halogen, -OR 100 、-SR 100 or -N(R 100 )2;

[0322] R 401 is hydrogen, -R 601, -halogen, -CN, nitro, -OR 100 、-SR 100 、-N(R 100 )2、-S(O)R 100 、-S(O)2R 100 、-N(R 100 )2、-S(O)2N(R 100 )2、-C(O)R 100 、-C(O)OR 100 、-C(O)N(R 100)2 、-OC(O)R 100 、-OC(O)N(R 100 )2、-NR 100 C(O)OR 100 、-NR 100 C(O)R 100 、-NR 100 C(O)N(R 100 )2 or -NR 100 S(O)2R 100 ;

[0323] R 501 is hydrogen, -CN or C1-C4 alkyl;

[0324] R 601 is an optionally substituted C1-C6 alkyl, phenyl, a 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

[0325] R 100 is selected from hydrogen, optionally substituted C1-C6 alkyl, phenyl, a saturated or partially unsaturated 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or two R attached to the same N atom 100 Together with the N atom to which it is attached, it forms a saturated or partially unsaturated 5-6 membered heteroaryl group containing 0-3 heteroatoms selected from N, O and S in addition to the N atom;

[0326] m” is 0, 1, 2, 3 or 4.

[0327] In one embodiment of the present invention, the E is E3:

[0328] in:

[0329] X 101’ For bonds, -CH2-, -CHCF3-, -S(O)2-, -S(O)-, -P(O)R100’ -、-P(O)OR 100’ -、-P(O)N(R 100’ )2, -C(O)-, -C(S)-, or

[0330] X 201’ C, N or Si;

[0331] X 301’ -CH2-, -O-, -S-, -C(R 100’ )2- or -Si(R 100’ )2-;

[0332] R 101’ For hydrogen, deuterium, halogen, -CN, -OR 100’ 、-SR 100’ 、-S(O)R 100’ 、-S(O)2R 100’ 、-N(R 100’ )2、-P(O)(OR 100’ )2、-P(O)[N(R 100’ )2](OR 100’ )、-P(O)[N(R 100’ )2]2, -Si(OH)2(R 100’ )、-Si(OH)(R 100’ )2、-Si(R 100’ )3, or optionally substituted C1-C4 alkyl;

[0333] L 101’ is a bond or C1-C4 alkylene, wherein one or two methylene groups in the C1-C4 alkylene are optionally selected from -O-, -C(O)-, -C(S)-, -C(R 100’ )2-、-CH(R 100’ )-、-C(F)2-、-N(R 100’ )-, -S-, -S(O)2- or -CH=CH;

[0334] Does not exist or has any of the following structures:

[0335] R 201’ Selected from hydrogen, -R 601’ 、Halogen、-CN、-NO2、-OR 100’ 、-SR 100’ 、-S(O)R 100’ 、-S(O)2R 100’ 、-N(R100’ )2、-S(O)2NR 100’ 、-C(O)R 100’ 、-C(O)OR 100’ 、-C(O)N(R 100’ )2、-OC(O)R 100’ 、-OC(O)N(R 100’ )2、-NR 100’ C(O)OR 100’ 、-NR 100’ C(O)R 100’ 、-NR 100’ C(O)N(R 100’ )2、-OP(O)(R 100’ )2、-OP(O)(OR 100’ )2、-OP(O)(OR 100’ )[N(R 100’ )2]、-OP(O)[N(R 100’ )2]、-NP(O)(R 100’ )2、-NR 100’ P(O)(OR 100’ )2、-N(R 100’ )P(O)(OR 100’ )[N(R 100’ )2]、-N(R 100’ )P(O)[N(R 100’ )2]2, or -NR 100’ S(O)2R 100’ ;

[0336] Ring B' is a 6-membered heteroaryl group containing 1-2 N atoms, a phenyl group, a saturated or partially unsaturated C5-C7 cycloalkyl group, a saturated or partially unsaturated 5-7-membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O and S, or a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S;

[0337] R 301’ and R 401’ are independently hydrogen, -R 601’ 、Halogen、-CN、-NO2、-OR 100’ 、-SR 100’ 、-S(O)R 100’ 、-S(O)2R 100’ 、-N(R 100’ )2、-S(O)2NR 100’ 、-C(O)R 100’ 、-C(O)OR 100’ 、-C(O)N(R 100’ )2、-OC(O)R 100’、-OC(O)N(R 100’ )2、-NR 100’ C(O)OR 100’ 、-NR 100’ C(O)R 100’ 、-NR 100’ C(O)N(R 100’ )2 or -NR 100’ S(O)2R 100’ ;

[0338] R 501’ is hydrogen, -CN or C1-C4 alkyl;

[0339] R 601’ is an optionally substituted C1-C6 alkyl, phenyl, a saturated or partially unsaturated 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;

[0340] R 100’ is selected from hydrogen, optionally substituted C1-C6 alkyl, phenyl, a saturated or partially unsaturated 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, or two R attached to the same N atom 100’ Together with the N atom to which it is attached, it forms a saturated or partially unsaturated 5-6 membered heteroaryl group containing 0-3 heteroatoms selected from N, O and S in addition to the N atom;

[0341] P” is 0 or 1;

[0342] m'' is 0, 1, or 2;

[0343] n'' is 0, 1, 2, 3 or 4.

[0344] In one embodiment, E is E4:

[0345] Among them, E4:

[0346] X 101 For bonds, -CH2-, -CHCF3-, -S(O)2-, -S(O)-, -P(O)R 100 -、-P(O)OR 100 -、-P(O)N(R 100 )2, -C(O)-, -C(S)-, or

[0347] X 201 C, N or Si;

[0348] X301 -CH2-, -O-, -S-, -C(R 100 )2- or -Si(R 100 )2-;

[0349] R 101 Selected from hydrogen, deuterium, halogen, -CN, -OR 100 、-SR 100 、-S(O)R 100 、-S(O)2R 100 、-N(R 100 )2、-P(O)(OR 100 )2、-P(O)[N(R 100 )2](OR 100 )、-P(O)[N(R 100 )2]2, -Si(OH)2(R 100 )-、-Si(OH)(R 100 )2-、-Si(R 100 )3-, or optionally substituted C1-C4 alkyl;

[0350] L 101 is a bond or C1-C4 alkylene, wherein one or two methylene groups in the C1-C4 alkylene are optionally selected from -O-, -C(O)-, -C(S)-, -C(R 100 )2-、-CH(R 100 )-、-C(F)2-、-N(R 100 )-, -S-, -S(O)2- or -CH=CH;

[0351] R 201 Selected from hydrogen, -R 601 、Halogen、-CN、-NO2、-OR 100 、-SR 100 、-S(O)R 100 、-S(O)2R 100 、-N(R 100 )2、-S(O)2NR 100 、-C(O)R 100 、-C(O)OR 100 、-C(O)N(R 100)2 、-OC(O)R 100 、-OC(O)N(R 100 )2、-NR 100 C(O)OR 100 、-NR 100 C(O)R 100 、-NR 100 C(O)N(R 100)2、-OP(O)(R 100 )2、-OP(O)(OR 100 )2、-OP(O)(OR 100 )[N(R 100 )2]、-OP(O)[N(R 100 )2]、-NP(O)(R 100 )2、-NR 100 P(O)(OR 100 )2、-N(R 100 )P(O)(OR 100 )[N(R 100 )2]、-N(R 100 )P(O)[N(R 100 )2]2, or -NR 100 S(O)2R 100 ;

[0352] R 601 is an optionally substituted C1-C6 alkyl, phenyl, a 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

[0353] R 100 R is selected from hydrogen, optionally substituted C1-C6 alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or two R 100 Together with the nitrogen atom to which it is attached, it forms a group containing 0 to 3 heteroatoms selected from N, O or S in addition to the attached nitrogen atom;

[0354] Ring E, Ring F, and Ring G are independently a 6-membered heteroaryl group containing 1-2 N atoms, a phenyl group, a 5-7-membered saturated or partially unsaturated cycloalkyl group, a 5-7-membered saturated or partially unsaturated heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S, or a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S; wherein, among Ring E, Ring F, and Ring G, Ring E and Ring F may share one atom to form a spiro ring or share two or more atoms to form a fused ring or a bridged ring, and Ring F and Ring G may share one atom to form a spiro ring or share two or more atoms to form a fused ring or a bridged ring;

[0355] m" is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0356] In one embodiment, E is E5:

[0357] Among them, E5: for

[0358] Each X 101 、X 601 and X 701 are independently a bond, -CH2-, -CHCF3-, -S(O)2-, -S(O)-, -P(O)R 100 -、-P(O)OR 100 -、-P(O)N(R 100 )2, -C(O)-, -C(S)-, or

[0359] Each X 301 and X 501 are independently a bond, -C(R 100 )2-、-NR 100 -, -O-, -S-, or -Si(R 100 )2-;

[0360] X 401 Selected from

[0361] Each R 100 R is independently hydrogen, optionally substituted C1-C6 alkyl, phenyl, saturated or partially unsaturated 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, or two R attached to the same N atom 100 Together with the N atom to which it is attached, it forms a saturated or partially unsaturated 5-6 membered heteroaryl group containing 0-3 heteroatoms selected from N, O and S in addition to the N atom;

[0362] Each R 301a are independently hydrogen, deuterium, -R 601 、Halogen、-CN、-NO2、-OR 100 、-SR 100 、-N(R 100 )2、-Si(R 100 )3, -S(O)R 100 、-S(O)2R 100 、-S(O)2N(R 100 )2、-C(O)R 100 、-C(O)OR 100 、-C(O)N(R 100 )2、-C(O)N(R 100 )OR 100 、-C(R 100 )2N(R100 )C(O)R 100 、-C(R 100 )2N(R 100 )C(O)N(R 100 )2、-OC(O)R 100 、-OC(O)N(R 100 )2、-NR 100 C(O)OR 100 、-NR 100 C(O)R 100 、-NR 100 C(O)N(R 100 )2、-OP(O)(R 100 )2、-OP(O)(OR 100 )2、-OP(O)(OR 100 )[N(R 100 )2]、-OP(O)[N(R 100 )2]、-NP(O)(R 100 )2、-NR 100 P(O)(OR 100 )2、-N(R 100 )P(O)(OR 100 )[N(R 100 )2]、-N(R 100 )P(O)[N(R 100 )2]2, or -NR 100 S(O)2R 100 ;

[0363] Each R 601 Independently optionally substituted C1-C6 alkyl, phenyl, saturated or partially unsaturated 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

[0364] Each R 701 are independently hydrogen, deuterium, halogen, -CN, -OR 100 、-SR 100 、-S(O)R 100 、-S(O)2R 100 、-N(R 100 )2、-P(O)(OR 100 )2、-P(O)[N(R 100 )2](OR 100 )、-P(O)[N(R 100 )2]2, -Si(OH)2(R 100 )-、-Si(OH)(R 100 )2-、-Si(R100 )3-, or optionally substituted C1-C4 alkyl; or

[0365] R 701 and X 101 、R 701 and X 301 It can also form, together with the atoms to which it is attached, a saturated or partially unsaturated 5-7 membered carbon ring or a heterocycle containing 1-3 heteroatoms selected from boron, N, O, Si and S;

[0366] or two R on the same carbon 701 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclic ring or a 4-7 membered heterocyclic ring containing 1-2 heteroatoms selected from boron, N, O, Si and S;

[0367] or two R on adjacent carbons 701 Together with the atoms to which it is attached, it forms a saturated or partially unsaturated 3-7 membered carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from boron, N, O, Si and S, or a saturated or partially unsaturated 7-13 membered bridged heterocyclic ring or spiroheterocyclic ring containing 1-3 heteroatoms selected from boron, N, O, Si and S;

[0368] Ring D is independently a 6-membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, a phenyl group, a saturated or partially unsaturated 5-7-membered cycloalkyl group, a saturated or partially unsaturated 5-7-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O and S, or a 5-membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;

[0369] L 101 is a bond or a C1-C4 alkylene group, wherein one or two methylene groups in the C1-C4 alkylene group are optionally selected from -O-, -C(O)-, -C(S)-, -C(R 100 )2-、-CH(R 100 )-、-C(F)2-、-N(R 100 )2-, -S-, -S(O)2- and -CH=CH- group replacement;

[0370] n” is 0, 1, 2, 3, or 4;

[0371] q” is 0, 1, 2, 3, or 4.

[0372] In one embodiment of the present invention, E is E6, E6a, E6b, E6c, E6d, E6e, E6f, E6g, E6h or E6i:

[0373] wherein in E6, E6a, E6b, E6c, E6d, E6e, E6f, E6g, E6h or E6i:

[0374] for

[0375] Y is a bond, Y1, O, NH, NR2, C(O)O, C(O)NR2', Y1-O, Y1-NH, Y1-NR2, Y1-C(O), Y1-C(O)O, Y1-OC(O), Y1-C(O)NR2' or Y1-NR2'C(O), wherein Y1 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0376] X is C(O) or C(R3)2;

[0377] X1-X2 is C(R3)=N or C(R3)2-C(R3)2;

[0378] Each R1 is independently halogen, nitro, NH2, OH, C(O)OH, C1-C6 alkyl or C1-C6 alkoxy;

[0379] R2 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or C(O)-3-8 membered heterocycloalkyl, and R2 may be optionally substituted by one or more 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 Aryl or 5-10 membered heteroaryl may be optionally substituted with one or more halogen, NH2, CN, nitro, OH, C(O)OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0380] R2' is H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, and when R2' is not H, it may be optionally replaced by one or more 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 10The aryl or 5-10 membered heteroaryl group may be optionally substituted with another one or more halogen, NH2, CN, nitro, OH, C(O)OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0381] Each R3 is independently H or C1-C3 alkyl, said C1-C3 alkyl being optionally replaced by C6-C 10 substituted with aryl or 5-10 membered heteroaryl;

[0382] Each R3' is independently C1-C3 alkyl;

[0383] Each R4 is independently H or C1-C3 alkyl; or two R4 together with the carbon atom to which they are attached form C(O), C3-C6 cycloalkyl or a 4-membered, 5-membered or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O;

[0384] R5 is H, C1-C3 alkyl, F or Cl;

[0385] Each R a are independently H or C1-C6 alkyl;

[0386] R b is H or tosyl;

[0387] t is 0 or 1;

[0388] m is 0, 1, 2, or 3;

[0389] n is 0, 1, or 2.

[0390] Ring A, X, X1, X2, Y, R1, R3, R 3′ , R4, R5, t, m and n are as defined in WO2017 / 007612 and US2018 / 0134684, and are incorporated herein by reference in their entirety.

[0391] In a preferred embodiment of the compound of formula I of the present invention, or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts, E is E7, E7b, E7c, E7d or E7e:

[0392] Among E7, E7b, E7c, E7d and E7e:

[0393] W is CH2, CR a R b , C(S), C(O) or SO2;

[0394] X is H2, CH2, O or S; Y is NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocycloalkyl, O or S;

[0395] Z is CH2, O or S, and in E7c, Z cannot be CH2 at the same time;

[0396] G and G' are independently hydrogen, C1-C6 alkyl, OH, -CH2-heterocycloalkyl optionally substituted by R', or -CH2-phenyl optionally substituted by R';

[0397] Q1, Q2, Q3, and Q4 are independently carbon, nitrogen, or nitrogen oxides;

[0398] A is hydrogen, C1-C6 alkyl, cycloalkyl or halogen;

[0399] R, R a and R b are independently hydrogen, hydroxy, halogen, -NH2, -N(C1-C6 alkyl) 1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -CONR′R″, -OR′, -NR′R″, -SR′, -SO2R′, -SO2NR′R″, -CR′R″, -CR′NR′R″, aryl, heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR′)R″, -P(O)R′R″, -OP(O)(OR′)R″, -Cl, -F, -Br, -I, -CF3, -CN, -NR′SO2NR 'R'', -NR'C(O)NR'R'', -C(O)NR'C(O)R'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-N O2)NR′R″, -SO2NR′COR″, -NO2, -COR′, -C(C=N-OR′)R″, -CR′=CR′R″, -CCR′, -S(C=O)(C=NR′)R″, -SF5 or -OCF3;

[0400] R′ and R″ are independently a bond, hydrogen, C1-C6 alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl;

[0401] n″ is an integer from 1 to 4;

[0402] ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.

[0403] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is:

[0404] In a preferred embodiment of the compound of formula I of the present invention, or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts, E is E7a:

[0405] Among them, E7a:

[0406] W is CH2, CR a R b , C(S), C(O) or SO2;

[0407] X is H2, CH2, O or S;

[0408] Z is H2, CH2, O or S;

[0409] G is selected from hydrogen, C1-C6 alkyl, OH, -CH2-heterocycloalkyl optionally substituted by R', -CH2-phenyl optionally substituted by R';

[0410] Q1, Q2, Q3, and Q4 are each independently carbon, nitrogen, or nitrogen oxides;

[0411] A is hydrogen, C1-C6 alkyl, cycloalkyl or halogen;

[0412] R is independently selected from hydrogen, hydroxy, halogen, -NH2, -N(C1-C6 alkyl) 1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -CONR′R″, -OR′, -NR′R″, -SR′, -SO2R′, -SO2NR′R″, -CR′R″, -CR′NR′R″, aryl, heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR′)R″, -P(O)R′R″, -OP(O)(OR′)R″, -Cl, -F, -Br, -I, -CF3, -CN, -NR′SO2NR 'R'', -NR'C(O)NR'R'', -C(O)NR'C(O)R'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-N O2)NR′R″, -SO2NR′COR″, -NO2, -COR′, -C(C=N-OR′)R″, -CR′=CR′R″, -CCR′, -S(C=O)(C=NR′)R″, -SF5 or -OCF3;

[0413] R′ and R″ are each independently selected from a bond, hydrogen, C1-C6 alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl;

[0414] n″ is an integer from 1 to 4;

[0415] ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.

[0416] In certain embodiments of the present invention, in E7a, W is CH2 or C(O).

[0417] In certain embodiments of the present invention, in E7a, X is O or S.

[0418] In certain embodiments of the present invention, in E7a, X is O.

[0419] In certain embodiments of the present invention, in E7a, Z is O.

[0420] In certain embodiments of the present invention, in E7a, G is hydrogen.

[0421] In certain embodiments of the present invention, in E7a, Q1, Q2, Q3, and Q4 are each independently carbon or nitrogen.

[0422] In certain embodiments of the present invention, in E7a, Q1 is carbon.

[0423] In certain embodiments of the present invention, in E7a, Q2 is carbon.

[0424] In certain embodiments of the present invention, in E7a, Q3 is carbon.

[0425] In certain embodiments of the present invention, in E7a, Q4 is carbon.

[0426] In certain embodiments of the present invention, in E7a, Q1, Q2, Q3, and Q4 are carbon.

[0427] In certain embodiments of the present invention, in E7a, A is hydrogen.

[0428] In certain embodiments of the present invention, in E7a, R is hydrogen.

[0429] In certain embodiments of the present invention, said E is E7a';

[0430] In E7a', Q1, Q2, Q4, X, W, G, Z, R, n", A and ----- are as defined and described in E7a.

[0431] In certain embodiments of the present invention, said E is E7a";

[0432] In E7a", Q1, Q2, Q3, X, W, G, Z, R, n", A and ----- are as defined and described in E7a.

[0433] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E7a-1:

[0434] Wherein said E7a-1:

[0435] Q1, Q2, Q3 and Q4 are each independently carbon or nitrogen;

[0436] W is C(O) or CH2;

[0437] A is hydrogen, C1-C6 alkyl or halogen (for example, A is hydrogen);

[0438] R is selected from hydrogen, hydroxy, halogen, -NH2, -N(C1-C6 alkyl) 1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl;

[0439] n″ is 1, 2, 3 or 4;

[0440] ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.

[0441] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E7a-2:

[0442] Wherein said E7a-2:

[0443] W is CH2 or C(O);

[0444] A is hydrogen, methyl, Cl or F (for example, A is hydrogen);

[0445] R is each independently selected from hydrogen, hydroxy, NH2, C1-C6 alkyl or C1-C6 alkoxy;

[0446] n″ is 1, 2, 3 or 4;

[0447] ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.

[0448] In certain embodiments of the present invention, when the carbon atom to which the ----- bond is attached has chirality, it is in the R configuration, the S configuration, or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).

[0449] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is any of the following structures:

[0450] The carbon atoms marked with * are in R configuration, S configuration or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).

[0451] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is the following structure:

[0452] The carbon atoms marked with * are in R configuration, S configuration or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).

[0453] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is the following structure:

[0454] The carbon atoms marked with * are in R configuration, S configuration or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).

[0455] In a preferred embodiment of the compound of formula I of the present invention, or its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts, E is any of the following structures:

[0456] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E8, E8a, E8b, E8c, E8d, E8e, E8f, E8g, E8h, E8i, E8j, E8k, E8l, E8m, E8n, E8o, E8p, E8q, E8s, E8t, E8u, E8v, E8w, E8x, E8y, E8z, E8aa, E8bb or E8cc:

[0457] wherein in E8, E8a, E8b, E8c, E8d, E8e, E8f, E8g, E8h, E8i, E8j, E8k, E8l, E8m, E8n, E8o, E8p, E8q, E8s, E8t, E8u, E8v, E8w, E8x, E8y, E8z, E8aa, E8bb or E8cc:

[0458] W is independently selected from CH2, CHR, C(O) or SO2;

[0459] Q1, Q2, Q3, Q4, Q5 are independently carbon, N, or N substituted by R', or nitrogen oxide;

[0460] R 1 does not exist, or is hydrogen, hydroxy, cyano, C1-C3 alkyl or C(O);

[0461] R 2 does not exist, or is hydrogen, hydroxy, cyano, C1-C3 alkyl, CHF2, CF3, CHO or C(O)NH2;

[0462] R 3 is hydrogen, alkyl (e.g., C1-C6 alkyl or C1-C3 alkyl), optionally substituted alkyl (e.g., C1-C6 alkyl or C1-C3 alkyl), alkoxy (e.g., C1-C6 alkoxy or C1-C3 alkoxy), or optionally substituted alkoxy (e.g., C1-C6 alkoxy or C1-C3 alkoxy);

[0463] R 4 is selected from hydrogen, alkyl or optionally substituted alkyl;

[0464] R 5 or R 6 are independently hydrogen, halogen, C(O)R', cyano, hydroxy or CF3;

[0465] X is carbon, nitrogen or C(O);

[0466] X1 is carbon, nitrogen or C(O);

[0467] R' is hydrogen, halogen, amine, alkyl (eg, C1-C3 alkyl), optionally substituted alkyl (eg, C1-C3 alkyl), alkoxy (eg, C1-C3 alkoxy), optionally substituted alkoxy (eg, C1-C3 alkoxy), NR 2 R 3 、C(O)OR 2 or optionally substituted phenyl;

[0468] R is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy or halogenated lower alkyl;

[0469] n is 0, 1, 2, 3, or 4;

[0470] is a single bond or a double bond.

[0471] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E9a, E9b, E9c, E9d, E9e, E9f, E9g, E9h, E9i, E9j, E9k, E9l, E9m, E9n, E9o, E9p, E9q, E9r or E9s:

[0472] wherein in E9a, E9b, E9c, E9d, E9e, E9f, E9g, E9h, E9i, E9j, E9k, E9l, E9m, E9n, E9o, E9p, E9q, E9r or E9s:

[0473] W is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl;

[0474] R 1 Selected from H, CN, C1-C3 alkyl;

[0475] R 2 is H or C1-C3 alkyl;

[0476] R 4 is methyl or ethyl;

[0477] R 5 is H or halogen;

[0478] R 6 is H or halogen;

[0479] R is H;

[0480] R' is H;

[0481] Q1 and Q2 are independently CH, CH2, CH(C1-C3 alkyl), N, NH or N(C1-C3 alkyl);

[0482] Is a single bond or a double bond.

[0483] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E10, E10a or E10b:

[0484] wherein in E10, E10a or E10b: the X A C(O) or C(R 3A )2;

[0485] Z is NR 3A or C(R 3A )2;

[0486] Each R 1A are independently halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy;

[0487] Each R 3A are independently hydrogen or C1-C3 alkyl;

[0488] R 3’ are independently C1-C3 alkyl;

[0489] Each R 4A are independently hydrogen or C1-C3 alkyl, or two R 4A Together with the carbon atoms to which they are attached, they form C(O), C3-C6 cycloalkyl, or together they form a 3-membered, 4-membered, 5-membered or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O;

[0490] R 5A is selected from hydrogen, C1-C3 alkyl or halogen;

[0491] Each R 6A are independently hydrogen or C1-C3 alkyl, or two R 6A Together with the carbon atoms to which they are attached, they form C(O), C3-C6 cycloalkyl, or together they form a 3-membered, 4-membered, 5-membered or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O;

[0492] m is 0, 1, 2, or 3;

[0493] n is 0, 1, or 2;

[0494] a1 is 0 or 1.

[0495] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E11:

[0496] Wherein, in E11: -X1-X2- is -C(R 3A )=N-or-C(R 3A )2-C(R 3A )2-;

[0497] Each R 1A are independently halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy;

[0498] Each R 3A are independently hydrogen or C1-C3 alkyl;

[0499] R 3’ are independently C1-C3 alkyl;

[0500] R 4A is hydrogen, or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form C(O), C3-C6 cycloalkyl, or together they form a 4-membered, 5-membered or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O;

[0501] m is 0, 1, 2, or 3;

[0502] n is 0, 1, or 2;

[0503] a1 is 0 or 1.

[0504] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E12:

[0505] Among them, E12:

[0506] Each R 2’ are independently halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy;

[0507] Each R 4’ are independently halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy;

[0508] Each R 5’ are independently halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy;

[0509] n1 is 0, 1, 2, 3, 4, 5, or 6;

[0510] n2 is 0, 1, 2, 3, or 4;

[0511] n3 is 0, 1 or 2.

[0512] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E13:

[0513] Among them, E13:

[0514] R 3A is hydrogen or C1-C3 alkyl;

[0515] Each R 3’ is a C1-C3 alkyl group;

[0516] Each R 6’ are independently halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy;

[0517] n1 is 0, 1, 2, 3, 4 or 5;

[0518] m1 is 0, 1, 2, 3, 4 or 5.

[0519] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E14, E14a, E14b, E14c, E14d or E14e:

[0520] wherein among E14, E14a, E14b, E14c, E14d and E14e,

[0521] Ar is aryl, cycloalkyl, heterocycloalkyl or heteroaryl;

[0522] L is absent or is -SO2, -SO2R', SO2R'R", -SO2NR'R", -SO2NR'R"C(=O), -NR'SO2R", -R'SO2NR'R"', -C(=O);, -C(=O)R', -OC(=O)R', -C(=O)NR'R", -NR'C(=O)R", -NR'C(=O), R"C(=O), -OR', -NR'R", -SR', -N3-C(=O)OR', -O(CR'R") rC(=O)R'、-O(CR'R") r NR"C(=O)R'、-O(CR'R") r NR"SO2R', -OC(=O)NR'R', -NR'C(=O)OR" or any substituted C1-C6 alkyl;

[0523] R', R", and R'" are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted ether, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylated aryl, or substituted or unsubstituted amine; r is an integer from 1 to 6;

[0524] R 1 、R 2 、R 3 and independently H, halogen, hydroxy, azide, alkoxy, thiol, imino, amino, phosphonate, phosphate, carbonyl, carboxyl, cyano, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, substituted or unsubstituted amine, substituted or unsubstituted amide, nitro, ester, morpholino, dioxolane, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or a combination thereof;

[0525] or R 1 、R 2 Combined to form a 5-7 membered heterocyclic ring, and when R 1 、R 2 When combined to form a 5-7 membered heterocyclic ring, Ar and the 5-7 membered heterocyclic ring do not form a fused ring, but are substituents of the 5-7 membered heterocyclic ring;

[0526] R 4 、R 5 are independently hydrogen, halogen, hydroxy, azide, ether, alkoxy, thiol, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted enone, unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocyclyl, or a combination thereof;

[0527] R 8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, or a combination thereof;

[0528] is a single bond or a double bond;

[0529] x is 0, 1, or 2;

[0530] y is an integer from 1 to 6.

[0531] In some embodiments, in E14, E14a, E14b, E14c, E14d and E14e, Ar, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , A, L, x, y, and As defined and described in WO2017 / 161119 (the entirety of which is incorporated herein by reference).

[0532] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E15, E15a, E15b, E15c, E15d, E15e, E15f, E15g or E15h:

[0533] wherein among E15, E15a, E15b, E15c, E15d, E15e, E15f, E15g and E15h:

[0534] Ring B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

[0535] L 101 is a bond or a C1-C6 alkyl group;

[0536] A is C, S, substituted or unsubstituted C1-C8 alkyl, or a combination thereof;

[0537] G 100 is C, S, N, substituted or unsubstituted C1-C8 alkyl or a combination thereof;

[0538] R 101 、R 201 and R 301wherein R is hydrogen, halogen, hydroxy, azide, alkoxy, thiol, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, cyano, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, substituted or unsubstituted amine, substituted or unsubstituted amide, nitro, ester, morpholino, dioxolane, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl halide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl; substituted or unsubstituted heterocycloalkyl; substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylheteroaryl, and combinations thereof; or wherein R 101 and R 201 Combined to form a 5-7 membered heterocycloalkyl; wherein when R 101 and R 201 When combined to form a 5-7 membered heterocyclic ring, Ring B is optionally not fused to the 5-7 membered heterocyclic ring, but is a substituent of the 5-7 membered heterocyclic ring;

[0539] R 401 and R 501 are hydrogen, halogen, hydroxy, azide, ether, alkoxy, thiol, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl halide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, and combinations thereof;

[0540] R 601 and R 701 are independently oxo, hydrogen, C1-C8 alkyl, or R 601 and R 701 Combine together to form oxo;

[0541] R 801 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl halide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkaryl, and combinations thereof;

[0542] x″ and y″ are independently 0, 1 or 2;

[0543] is a single bond or a double bond;

[0544] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E16, E16a or E16b:

[0545] Among the E16, E16a and E16b:

[0546] W 101 CR 601 R 701 , C(O), C(S), C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH or P(O)NH2;

[0547] W 201 It's CR 801 R 901 , C(O), C(S), C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH or P(O)NH 2 ;

[0548] X 100 Independently selected from NH, NR 301 , CH2, CHR 301 、C(R 301 )2, O or S;

[0549] n” is 0, 1, 2, or 3;

[0550] is a single bond or a double bond; When it is a single bond, n" is 0, 1, 2 or 3; when When it is a double bond, n" is 0, 1 or 2;

[0551] R 101 Selected from:

[0552] or R 101* ;

[0553] R 201 is alkyl, hydrogen, heteroalkyl, aryl, heteroaryl or heterocycloalkyl;

[0554] or R 101 and R 201 Combined to form a 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl or heteroaryl, the heterocycloalkyl or heteroaryl being optionally substituted by one or more selected from R 501 and R 120Substituents substituted;

[0555] R 101* Selected from:

[0556] R 301 Selected from: alkyl, -C(O)H, C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heteroalkyl;

[0557] R 401 is selected from alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(alkyl), -N(alkyl), -NHS(O), -N(alkyl)SOalkyl, -NHSO(aryl, heteroaryl, or heterocycloalkyl), -N(alkyl)SO(aryl, heteroaryl, or heterocycloalkyl), -NHSO(alkenyl), -N(alkyl)SO(alkenyl), -NHSO(alkynyl), -N(alkyl)SO(alkynyl), or haloalkyl, aryl, heteroaryl, heteroalkyl, and cycloalkyl;

[0558] or two R 401 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered ring;

[0559] R 501 and R 140 independently selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(alkyl), -N(alkyl), -NHS(O), -N(alkyl)SO(alkyl), -NHSO(aryl, heteroaryl, or heterocycloalkyl), -N(alkyl)SO(aryl), heteroaryl, or heterocycloalkyl), -NHSO(alkenyl), -N(alkyl)SO(alkenyl), -NHSO(alkynyl), -N(alkyl)SO(alkynyl), or haloalkyl, aryl, heteroaryl, heteroalkyl, and cycloalkyl;

[0560] or R 501 independently selected from C(O)R 401 , cyano, aryl, aryloxy, heterocycloalkyl, heteroaryl, arylalkyl, alkoxy, hydroxy, O-aralkyl, or cycloalkyl;

[0561] R 601 、R 701 、R 801 、R 901 、R 1001 , or R 110 independently selected from hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, amine, -NH(alkyl), and -N(alkyl);

[0562] or R 601and R 701 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring, or a 4-, 5- or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

[0563] or R 801 and R 901 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring; or they form a 4-, 5- or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

[0564] or R 1001 and R 110 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring; or they form a 4-, 5- or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

[0565] or R 601 and R 801 Together they form one or two carbon bridged rings;

[0566] or R 601 and R 1001 Together they form 1 or 2 carbon bridged rings;

[0567] or R 801 and R 1001 Together they form 1 or 2 carbon bridged rings;

[0568] or R 601 and R 140 together to form 3, 4, 5 or 6 carbon-fused rings;

[0569] or R 140 and R 1001 together to form 3, 4, 5 or 6 carbon-fused rings;

[0570] or R 801 and R 140 Together they form 1 or 2 carbon bridged rings;

[0571] or R 401 and R 140 Together, they form a 3, 4, 5, or 6 carbon-fused ring, wherein the R 501 Located in R 140 α carbon, or together form 1, 2, 3 or 4 carbon bridge rings, wherein the R 501 Not located in R 140 On α carbon;

[0572] R 120 For L 100 ;

[0573] R 170 Selected from:

[0574] Y 100 Selected from N, CH or CR 101 ; 0, 1, 2 or 3 Y 100 is N;

[0575] R 101 and independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -C(O)Oalkyl, -C(O)OH, NO2, F, Cl, Br, I, CF3, NH2, NH(alkyl), N(alkyl), or heteroalkyl.

[0576] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E17, E17a, E17b or E17c:

[0577] Among the E17, E17a, E17b and E17c:

[0578] W1 is CR6R7, C=O, C=S, C=CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH or P(O)H2;

[0579] W2 is CR8R9, C=O, C=S, C=CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH or P(O)H2;

[0580] X, X1 are independently selected from NH, NR 3 , CH2, CHR 3 、C(R 3 )2, O or S;

[0581] n” is 0, 1, 2, or 3;

[0582] is a single bond or a double bond; and when When it is a single bond, n" is 0, 1, 2 or 3; When it is a double bond, n" is 0, 1 or 2;

[0583] R1 is or R 1* , wherein X is O or N, and when X is O, R2 does not exist;

[0584] Ring A is phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, wherein the phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl is optionally replaced by R 12 replace;

[0585] Ring B is absent, phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally replaced by R5 or R 12 replace;

[0586] R2 is alkyl, H, aliphatic, heteroaliphatic, aryl, heteroaryl or heterocycloalkyl;

[0587] R 1* is an optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylamino, alkoxy, ester, sulfonyl or acylamino group;

[0588] R3 is alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl or alkynyl;

[0589] R4 is alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, -NHalkyl, -N(alkyl)2, -NHSO2alkyl, -N(alkyl)SO2alkyl, -NHSO2aryl, -N(alkyl)SO2aryl, -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl or halogenated alkane;

[0590] or two R4 together with the C atom to which they are attached form a 3-membered, 4-membered, 5-membered or 6-membered ring;

[0591] R6, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, hydroxy, alkoxy, amine, -NH(aliphatic, including alkyl) and -N(aliphatic, including alkyl)2;

[0592] or R6, R7 together with the carbon atoms to which they are bound form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring, or a 4-, 5- or 6-membered spiroheterocyclic ring, wherein the heteroatoms are 1 or 2 N or O;

[0593] or R8, R9 together with the carbon atoms to which they are bound form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring, or a 4-, 5- or 6-membered spiroheterocyclic ring, wherein the heteroatoms are 1 or 2 N or O;

[0594] or R 10 、R 11 Together with the carbon atoms to which they are bound, they form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring, or a 4-, 5- or 6-membered spiroheterocyclic ring, wherein the heteroatoms are 1 or 2 N or O;

[0595] or R6 and R8 form one or two carbon bridged rings;

[0596] or R6, R 10 Forming 1 or 2 carbon bridged rings;

[0597] or R8, R 10 Forming 1 or 2 carbon bridged rings;

[0598] or R 14 , R6 forms a 3, 4, 5 or 6 carbon-fused ring;

[0599] or R 14 、R 10 forming 3, 4, 5 or 6 carbon-fused rings;

[0600] or R 14 , R8 forms 1 or 2 carbon bridged rings;

[0601] or R 14 , R4 form a 3, 4, 5 or 6 carbon fused ring, and R4 is connected to R 14 or form a 1, 2, 3 or 4 carbon bridged ring, and R4 is not connected to R 14 On the carbon α;

[0602] R 12 is the chain that connects the target ligand;

[0603] R5, R 14 are independently selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), C(O)R4, -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl and carbocycle;

[0604] wherein each R5 may be optionally replaced by one or more selected from alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azido, amino, -NHalkyl, -N(alkyl), aryl, heterocycloalkyl, heteroaryl, haloalkyl, and cycloalkyl;

[0605] R 16 for

[0606] In some embodiments, in E17, E17a, E17b and E17c, R1, R4, R 10 、R11 、R 14 、R 16 、W1、W2、X、 and n" are as defined in WO2018 / 237026, the entire contents of which are incorporated herein by reference.

[0607] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E18, E18a, E18b, E18c, E18d, E18e, E18f, E18g, E18h, E18i, E18g, E18k, E18l or E18m:

[0608] wherein among E18, E18a, E18b, E18c, E18d, E18e, E18f, E18g, E18h, E18i, E18g, E18k, E18l and E18m:

[0609] X 1 -C(R)2, -O-, -NR-, -CF2-, -C(O)-, -C(S)- or

[0610] X 2 and X 3 are independently -CH2-, -C(O)-, -C(S)-, -C(R)2C(O)- or

[0611] Z 1 and Z 2 are independently a carbon atom or a nitrogen atom;

[0612] Ring A x Selected from phenyl, 4-6 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;

[0613] L x is a bond or a C1-C3 alkylene group, wherein 1-2 methylene groups in the alkylene group are optionally replaced by a group selected from -O-, -S-, -C(O)-, -C(S)-, -C(R)2-, -CRF, -CF2-, -NR-, -S(O)2-, -CH=CH- or an alkynylene group;

[0614] R x For hydrogen, deuterium, -R z, Halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)R, -S(O)2R, -S(O)2N(R)2, -CF(R)2-, -CF2R-, -CF3-, -C(R)2(OR)-, -C(R)2[ N(R)2]-, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -OC(O)R, -OC(O)N(R)2, -C(S)NR2, -NRC(O)OR, -NRC(O)R, -N RC(O)N(R)2, -NRS(O)2R, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OP(O)(R)2, -OP(O)(OR)2, -OP(O)(OR)[N(R)2 ], -OP(O)[N(R)2], -NP(O)(R)2, -NRP(O)(OR)2, -N(R)P(O)(OR)[N(R)2], -N(R)P(O)[N(R)2]2, -Si(OR)R2, or -SiR3; or

[0615] Two R's x Together with the atoms to which it is attached, it forms an optionally substituted 5-8 membered partially unsaturated or aryl-fused heterocycloalkyl group containing 0-2 heteroatoms selected from N, O or S;

[0616] Each R is independently hydrogen, or optionally substituted C1-C6 alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, or 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O or S; or

[0617] Two R on the same carbon atom or the same nitrogen atom together with the atoms to which they are attached form an optionally substituted 4-7 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl, or a heteroaryl containing 1-4 heteroatoms selected from N, O and S;

[0618] R y For hydrogen or

[0619] Ring B x is phenyl, a 4-10 membered saturated or partially unsaturated monocyclic or bicyclic cycloalkyl, or a heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the ring B x further optionally substituted with 1-2 oxo groups;

[0620] Each R w are independently hydrogen, deuterated, R z, Halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)R, -S(O)2R, -S(O)2N(R)2, -CF(R)2-, -CF2R-, -CF3-, -C(R)2(OR)-, -C(R)2 [N(R)2]-, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -OC(O)R, -OC(O)N(R)2, -C(S)NR2, -NRC(O)OR, -NRC(O)R, - NRC(O)N(R)2, -NRS(O)2R, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OP(O)(R)2, -OP(O)(OR)2, -OP(O)(OR)[N(R) 2], -OP(O)[N(R)2], -NP(O)(R)2, -NRP(O)(OR)2, -N(R)P(O)(OR)[N(R)2], -N(R)P(O)[N(R)2]2, -Si(OR)R2 or -SiR3;

[0621] Each R z Independently C1-C6 alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O and S;

[0622] x is 0, 1, 2, 3, or 4;

[0623] y is 0, 1, or 2;

[0624] w is 0, 1, 2, 3, or 4.

[0625] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E19, E19a, E19b, E19c, E19d, E19e, E19f, E19g, E19h or E19i:

[0626] wherein among E19, E19a, E19b, E19c, E19d, E19e, E19f, E19g, E19h and E19i:

[0627] A 1 -C(R 16a )=or-N=;

[0628] A 2 -C(R 16b )=or-N=;

[0629] A 3 -C(R 16c )=or-N=;

[0630] G is -C(R 16d )=or-N=;

[0631] Z is -CH2 or -C(=O)-;

[0632] R 5 is H, methyl or F;

[0633] R 16a 、R 16b 、R 16c and R 16d are independently H, halogen or C1-C4 alkyl.

[0634] In some embodiments, among E19, E19a, E19b, E19c, E19d, E19e, E19f, E19g, E19h and E19i, A 1 、A 2 、A 3 , Z, G, and R 5 As defined and described in WO2017 / 176958 (the entirety of which is incorporated herein by reference).

[0635] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E20, E20a, E20b, E20c, E20d, E20e or E20f:

[0636] Among E20, E20a, E20b, E20c, E20d, E20e and E20f:

[0637] L 1 Selected from: key,

[0638] X 1 、X 2 、X 3 and X 4 Independently selected from nitrogen or CR 4 , and X 1 、X 2 、X 3 and X 4 At most two of them are simultaneously selected from nitrogen;

[0639] Z2 and Z 3 is selected from -CH2- or -C(O)- and Z 1 and Z 2 At least one of them is selected from -C(O)-;

[0640] o is selected from 0, 1, 2, 3 or 4;

[0641] Each R 4 are independently hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0642] Each R 5 are independently hydrogen, C1-C6 alkyl or -C(O)-alkyl;

[0643] Each R 8 are independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; or two R 8 Together with the atoms to which it is attached, it forms a cyclopropyl group.

[0644] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E21:

[0645] Among them, E21:

[0646] X” is C or N;

[0647] Y" is C, N, O or S;

[0648] Q1, Q2, Q3, Q4, Q5 are independently CR3" or N;

[0649] R3" is independently hydrogen, deuterium, hydroxy, amino, cyano, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl (e.g. morpholinyl, ), C6-C10 aryl, 5-10 membered heteroaryl, -O(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), N(C1-C6 alkyl) 1-2 , NH(C3-C8 cycloalkyl), NH(3-8 membered heterocycloalkyl), -O-(6-10 membered aryl), -O-(5-10 membered heteroaryl); the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are optionally substituted with 1-3 groups independently selected from hydroxy, halogen, cyano and amino groups;

[0650] m” is 1, 2, or 3;

[0651] R1" is independently hydrogen, deuterium, hydroxy, amino, cyano, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -O(C1-C6 alkyl), wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 groups independently selected from hydroxy, halogen, cyano and amino;

[0652] R2" is hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, and the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1-3 groups independently selected from hydroxy, halogen, cyano and amino.

[0653] In certain embodiments of the present invention, one or two of Q1, Q2, Q3, Q4, and Q5 in E21 are N, and the rest are independently CR3.

[0654] In certain embodiments of the present invention, Q1, Q2, Q3, Q4, and Q5 in E21 are independently CR3.

[0655] In certain embodiments of the present invention, X" in E21 is N.

[0656] In certain embodiments of the present invention, X" in E21 is C.

[0657] In certain embodiments of the present invention, Y" in E21 is N.

[0658] In certain embodiments of the present invention, R1" in E21 is independently hydrogen, deuterium, -F, -Cl, or C1-C6 alkyl, and the alkyl is optionally substituted by 1-3 halogens; preferably, R1" is hydrogen.

[0659] In certain embodiments of the present invention, R2" in E21 is hydrogen or C1-C6 alkyl, and the alkyl is optionally substituted by 1-3 halogens; preferably, R2" is hydrogen.

[0660] In certain embodiments of the present invention, R3" in E21 is independently hydrogen, deuterium, halogen, -O(C1-C6 alkyl), or C1-C6 alkyl, and the alkyl is optionally substituted by 1-3 halogens; preferably, R3" is independently hydrogen, deuterium, F, Cl, methyl, methoxy, ethoxy, trifluoromethoxy, 2-hydroxyprop-2-yl or trifluoromethyl.

[0661] In certain embodiments of the present invention, m in E21 is 2.

[0662] In certain embodiments of the present invention, the E21 has the following structure:

[0663] wherein Q1, Q2, Q3, Q4, Q5, R1", R2", and m" are as defined in E21 above.

[0664] In certain embodiments of the present invention, the E21 has the following structure:

[0665] wherein R1", R2", R3", and m" are as defined in E21 above.

[0666] In certain embodiments of the present invention, the E21 has the following structure:

[0667] wherein R1", R2", and R3" are as defined in E21 above.

[0668] In certain embodiments of the present invention, the E21 has the following structure:

[0669] wherein said R3" is as defined in E21 above.

[0670] In certain embodiments of the present invention, the E21 has the following structure:

[0671] wherein Q1, Q2, Q3, Q5, R1", R2" and m" are as defined in E21 above.

[0672] In certain embodiments of the present invention, the E21 has the following structure:

[0673] wherein R1", R2", R3", and m" are as defined in E21 above.

[0674] In certain embodiments of the present invention, the E21 has the following structure:

[0675] wherein R1", R2", and R3" are as defined in E21-1 above.

[0676] In certain embodiments of the present invention, the E21 has the following structure:

[0677] wherein said R3" is as defined in E21 above.

[0678] In certain embodiments of the present invention, the E21 has the following structure:

[0679] wherein said R3" is as defined in E21 above.

[0680] In certain embodiments of the present invention, the E21 has the following structure:

[0681] wherein said R3" is as defined in E21 above.

[0682] In certain embodiments of the present invention, in E21 and E21-1a to 1j, R3" is hydrogen, halogen (e.g., F or Cl), C1-C6 alkyl or -O(C1-C6 alkyl) (e.g., -OCH3), and the C1-C6 alkyl and -O(C1-C6 alkyl) are optionally substituted with 1-3 halogens (e.g., F).

[0683] In certain embodiments of the present invention, in E21 and E21-1a to 1j, R3" is hydrogen, F, Cl, CF3, -OCF3, or -OCH3.

[0684] In certain preferred embodiments of the present invention, E21-1h, R3" is halogen (such as F or Cl) or -O(C1-C6 alkyl) (such as -OCH3).

[0685] In certain embodiments of the present invention, the E21-1h is any of the following structures:

[0686] In certain preferred embodiments of the present invention, the E21-1h is any of the following structures:

[0687] In certain embodiments of the present invention, the E21-1i has the following structure:

[0688] In certain embodiments of the present invention, the E21-1j is any of the following structures:

[0689] In certain embodiments of the present invention, the E21 is any of the following structures:

[0690] In certain embodiments of the present invention, the E21 is selected from

[0691] In certain preferred embodiments of the present invention, the E21 has the following structure:

[0692] In certain preferred embodiments of the present invention, the E21 has the following structure:

[0693] In certain preferred embodiments of the present invention, the E21 has the following structure:

[0694] In certain preferred embodiments of the present invention, the E21 has the following structure:

[0695] In certain preferred embodiments of the present invention, the E21 has the following structure:

[0696] In certain embodiments of the present invention, the E21 has the following structure:

[0697] wherein Q1, Q2, Q3, Q4, Q5, R1", R2", and m" are as defined in E21 above.

[0698] In certain embodiments of the present invention, the E21 has the following structure:

[0699] wherein R1", R2", R3", and m" are as defined in E21 above.

[0700] In certain embodiments of the present invention, the E21 has the following structure:

[0701] wherein R1", R2", and R3" are as defined in E21 above.

[0702] In certain embodiments of the present invention, the E21 has the following structure:

[0703] wherein said R3" is as defined in E21 above.

[0704] In certain embodiments of the present invention, the E21 has the following structure:

[0705] wherein Q1, Q2, Q3, Q5, R1", R2", and m" are as defined in E21 above.

[0706] In certain embodiments of the present invention, the E21 has the following structure:

[0707] wherein R1", R2", R3", and m" are as defined in E21-1 above.

[0708] In certain embodiments of the present invention, the E21 has the following structure:

[0709] wherein R1", R2", and R3" are as defined in E21 above.

[0710] In certain embodiments of the present invention, the E21 has the following structure:

[0711] wherein said R3" is as defined in E21 above.

[0712] In certain embodiments of the present invention, the E21 is selected from

[0713] In certain embodiments of the present invention, the E21 is selected from

[0714] Preferably, in certain embodiments of the present invention, the E21 is any of the following structures:

[0715] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E22:

[0716] E22 Wherein:

[0717] R 1′ is an optionally substituted C1-C6 alkyl, an optionally substituted -(CH2) n OH, optionally substituted -(CH2) n SH, optionally substituted -(CH2) n -O-(C1-C6 alkyl), optionally substituted-(CH2) n -WC(O)CW-(C0-C6 alkyl), wherein each W is independently hydrogen or C1-C3 alkyl, optionally substituted -(CH2) n C(O)OH, optionally substituted -(CH2) n C(O)-(C1-C6 alkyl), optionally substituted-(CH2) n NHC(O)-R1, optionally substituted -(CH2) n C(O)-NR1R2, optionally substituted -(CH2) n OC(O)-NR1R2, -(CH2O) n H, optionally substituted -(CH2) n OC(O)-(C1-C6 alkyl), optionally substituted-(CH2O) n C(O)OH, optionally substituted -(OCH2) n O-(C1-C6 alkyl), optionally substituted-(CH2O) nC(O)-(C1-C6 alkyl), optionally substituted-(CH2O) n C(O)-NR1R2, -(CH2CH2O) n H, optionally substituted -(CH2CH2O) n COOH, optionally substituted -(OCH2CH2) n O-(C1-C6 alkyl), optionally substituted-(OCH2CH2) n C(O)-NR1R2, optionally substituted -S(O)2R s , optionally substituted S(O)R s , nitro, cyano, or halogen (such as F, Cl, Br or I, preferably F or Cl);

[0718] R1 and R2 are independently hydrogen or C1-C6 alkyl, which is optionally substituted by 1 or 2 hydroxyl groups or by 1, 2 or 3 halogen groups (preferably F);

[0719] R s is C1-C6 alkyl, optionally substituted aryl, heteroaryl, heterocycloalkyl or -(CH2) m NR1R2;

[0720] X and X' are independently C(O), C(S), S(O), S(O)2 (preferably X and X' are both C(O));

[0721] R 2’ is optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w alkyl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w NR 1N R 2N , optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted-(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted-(CH2) n -C(O) u (NR1) v (SO2) w-heterocycloalkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w NR1C(O)R 1N , optionally substituted -NR 1 -(CH2)nC(O) u (NR1) v (SO2) w -aryl, optionally substituted -NR 1 -(CH2) n -aryl-heteroaryl, optionally substituted-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heterocycloalkyl, optionally substituted -X R2’ -alkyl, optionally substituted-X R2’ -aryl, optionally substituted -X R2’ -heteroaryl, optionally substituted -X R2’ -heterocycloalkyl;

[0722] R 3’ is optionally substituted alkyl, optionally substituted -(CH2) n (O) u (NR1)v(SO2) w -alkyl, optionally substituted-(CH2) n C(O) u (NR1)v(SO2) w -NR 1N R 2N, optionally substituted -(CH2) n C(O) u (NR1) v (SO2) w -C(O)NR1R2, optionally substituted -(CH2) n C(O) u (NR1) v (SO2) w -aryl, optionally substituted-(CH2) n C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted-(CH2) n C(O) u (NR1) v (SO2) w -heterocyclic aryl, optionally substituted -NR 1 -(CH2)nC(O) u (NR1) v (SO2) w -alkyl, optionally substituted -NR 1 -(CH2)nC(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heterocycloalkyl, optionally substituted -O-(CH2) n -C(O)u (NR1) v (SO2) w -alkyl, optionally substituted-O-(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -O-(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -O-(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted -O-(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted-O-(CH2) n -C(O) u (NR1) v (SO2) w -heterocycloalkyl, -(CH2) n -(V) n’ -(CH2) n -(V) n’ -alkyl, optionally substituted-(CH2) n -(V) n’ -(CH2) n -(V) n’ -aryl, optionally substituted-(CH2) n -(V) n’ -(CH2) n -(V) n’ -heteroaryl, optionally substituted-(CH2) n -(V) n’ -(CH2) n -(V) n’ -heterocycloalkyl, optionally substituted -(CH2) n -N(R 1’ )[C(O)] m’ -(V) n’ -alkyl, optionally substituted-(CH2) n -N(R 1’ )[C(O)] m’ -(V)n’ -aryl, optionally substituted-(CH2) n -N(R 1’ )[C(O)] m’ -(V) n’ -heteroaryl, optionally substituted-(CH2) n -N(R 1’ )[C(O)] m’ -(V) n’ -heterocycloalkyl, optionally substituted -X R3’ -alkyl, optionally substituted-X R3’ -aryl, optionally substituted -X R3’ -heteroaryl, optionally substituted -X R3’ -heterocycloalkyl;

[0723] R 1N and R 2N are independently hydrogen, optionally substituted -(CH2) n -aryl, optionally substituted-(CH2) n -heteroaryl, optionally substituted-(CH2) n - heterocycloalkyl, C1-C6 alkyl, the C1-C6 alkyl is optionally substituted by 1 or 2 hydroxyl groups or is optionally substituted by 1, 2 or 3 halogen groups;

[0724] V is O, S or NR1;

[0725] R 1 and R 1’ are independently hydrogen or C1-C3 alkyl;

[0726] X R2’ or X R3’ are independently optionally substituted -(CH2) n -、-(CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2CH2O)- or C3-C6 cycloalkyl, said X v is hydrogen, halogen or optionally substituted C1-C3 alkyl;

[0727] m is independently 0, 1, 2, 3, 4, 5 or 6;

[0728] m' is independently 1 or;

[0729] n is independently 0, 1, 2, 3, 4, 5 or 6;

[0730] n' is independently 0 or 1;

[0731] u is independently 0 or 1;

[0732] v is independently 1 or 1;

[0733] w is independently 0 or 1.

[0734] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E23, E23a, E23b, E23c, E23d or E23e:

[0735] Among E23, E23a, E23b, E23c, E23d and E23e:

[0736] R 1' 、R 2' 、R 3' , X is defined as described in E22;

[0737] R5 and R6 are independently OH, SH or an alkyl group which is substituted; or R5 and R6 form C=O with the carbon atom to which they are attached;

[0738] R7 is H or optionally substituted alkyl;

[0739] E is a bond, C=O or C=S;

[0740] G is a bond, an arbitrarily substituted alkyl group, -COOH, or C=J;

[0741] J is O or N-R8;

[0742] R8 is H, CN, an optionally substituted alkyl group or an optionally substituted alkoxy group;

[0743] M is aryl, heteroaryl, heterocyclic or The aryl, heteroaryl and heterocyclic groups may be substituted arbitrarily;

[0744] R9, R 10 R9, R 10 Together with the carbon atoms to which they are attached, they form an optionally substituted cycloalkyl group;

[0745] R 11 is heterocycloalkyl, alkoxy, heteroaryl, aryl or The heterocycloalkyl, alkoxy, heteroaryl, and aryl groups may be substituted arbitrarily;

[0746] R 12 is H or an arbitrarily substituted alkyl group;

[0747] R 13 is H, alkyl, alkyl-C=O, (cycloalkyl)alkyl-C=O, aralkyl-C=O, aryl-C=O, (heterocycloalkyl)-C=O, aralkyl or alkoxy-C=O, and the alkyl, alkyl-C=O, (cycloalkyl)alkyl-C=O, aralkyl-C=O, aryl-C=O, (heterocycloalkyl)-C=O, aralkyl or alkoxy-C=O may be arbitrarily substituted;

[0748] R 14 is H, haloalkyl, cycloalkyl, alkyl or heterocycloalkyl, and the cycloalkyl, alkyl or heterocycloalkyl may be arbitrarily substituted;

[0749] R 15 is H, heteroaryl, haloalkyl, aryl, alkoxy or heterocycloalkyl, and the heteroaryl, haloalkyl, aryl, alkoxy or heterocycloalkyl may be arbitrarily substituted;

[0750] R 16 is halogen, alkyl, haloalkyl, CN or haloalkoxy, and the alkyl, haloalkyl or haloalkoxy may be arbitrarily substituted;

[0751] R 17 is H, halogen, cycloalkyl, alkyl, alkenyl or haloalkyl, and the cycloalkyl, alkyl and alkenyl groups may be arbitrarily substituted;

[0752] R 23 is H or OH;

[0753] R 25 is H or substituted alkyl; or 2 R 25 forming =O or substituted cycloalkyl;

[0754] Z1, Z2, Z3 and Z4 are independently selected from C or N;

[0755] X is O or S;

[0756] Y is H, methyl or ethyl;

[0757] o is 0, 1, 2, 3, or 4.

[0758] In some embodiments, in E23, E23a, E23b, E23c, E23d and E23e, R 1' 、R 2' 、R 3' , R5, R6, R7, R9, R 10 、R 11 、R 14 、R 15、R 16 、R 17 、R 23 、R 25 , E, M, o, X, Y, Z1, Z2, Z3 and Z4 are as defined and described in US 2016 / 0272639, the entire contents of which are incorporated herein by reference.

[0759] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E23a:

[0760] wherein said E23a:

[0761] R 1’ is hydroxyl group;

[0762] R 2’ is -NH-CH2-aryl-HET;

[0763] R 3’ is selected from optionally substituted alkyl, -(CH)R CR3’ -NH-C(O)-R 3p1 or -(CH)R CR3’ -R 3p2 ;

[0764] R CR3’ is an optionally substituted C1-C4 alkyl group;

[0765] R 3p1 is an optionally substituted C1-C6 alkyl, an optionally substituted oxetane, -(CH2) n OCH3, phenyl optionally substituted with -O(CH2CH3), or morpholinyl linked to a carbonyl group at the 2- or 3-position, wherein n is 1 or 2;

[0766] R 3p2 for or optionally substituted phenyl;

[0767] HET is selected from optionally substituted thiazole, oxazole, isoxazole or isothiazole;

[0768] R HET Selected from hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted aryl.

[0769] In a preferred embodiment of the compound of formula I of the present invention, and / or its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs and / or pharmaceutically acceptable salts thereof, E is E23c

[0770] Among them, E23c:

[0771] Each R5 and R6 is independently -OH, -SH or an optionally substituted alkyl group, or R5, R6 and the carbon atom to which they are attached form a carbonyl group;

[0772] R7 is H or optionally substituted alkyl;

[0773] E is a bond, C=O, or C=S;

[0774] G is a bond, optionally substituted alkyl, -COOH, or C=J;

[0775] J is O or N-R8;

[0776] R8 is H, CN, optionally substituted alkyl or optionally substituted alkoxy;

[0777] M is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl or

[0778] Each R9 and R 10 R is independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, or optionally substituted heteroaryl or haloalkyl; or R, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl group;

[0779] R 11 is optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl or

[0780] R 12 is H or optionally substituted alkyl;

[0781] R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocycloalkyl)carbonyl or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate,

[0782] Each R 14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;

[0783] R15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocycloalkyl;

[0784] Each R 16 is independently halogen, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;

[0785] Each R 25 are independently H or optionally substituted alkyl; or two R 25 The groups may together form oxo or optionally substituted cycloalkyl;

[0786] R 23 is H or OH;

[0787] Z1, Z2, Z3 and Z4 are independently C or N; and

[0788] o is 0, 1, 2, 3, or 4.

[0789] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E23d:

[0790] Wherein said E23d:

[0791] X is O or S;

[0792] Y is H, methyl or ethyl;

[0793] R 17 is H, methyl, ethyl, hydroxymethyl or cyclopropyl;

[0794] M is optionally substituted heteroaryl, optionally substituted aryl.

[0795] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E23d-1

[0796] Wherein said E23d-1:

[0797] Y is H, methyl or ethyl;

[0798] R9 is H;

[0799] R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl;

[0800] R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, or an optionally substituted heterocycle;

[0801] R 17 is H, methyl, ethyl, hydroxymethyl or cyclopropyl.

[0802] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is a specific compound of Examples 1 to 208 in CN108601764 (the entire text of which is incorporated herein by reference).

[0803] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E24:

[0804] Among them, E24:

[0805] X 1 、X 2 independently a bond, O, NR Y3 , CR Y3 R Y4 , C=O, C=S, SO or SO2;

[0806] R Y3 、R Y4 are independently hydrogen, C1-C6 alkyl optionally substituted by 1 or more halogens, or C1-C6 alkyl optionally substituted by 0-3 R p Substituted C1-C6 alkoxy;

[0807] R p is 0, 1, 2 or 3 selected from hydrogen, halogen, hydroxy, C1-C3 alkyl or C(=O);

[0808] W 3 is selected from optionally substituted T, optionally substituted -TN(R 1a R 1b )X 3 , optionally substituted -TN(R 1a R 1b ), optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-bicyclic heteroaryl, optionally substituted -T-heterocycloalkyl, optionally substituted -T-bicyclic heterocycloalkyl, optionally substituted -NR 1 -T-aryl, optionally substituted-NR 1-T-heteroaryl or optionally substituted-NR 1 -T-heterocycloalkyl;

[0809] X 3 C(O), R 1 、R 1a or R 1b ;

[0810] Each R 1 、R 1a or R 1b are independently selected from hydrogen, C1-C6 alkyl optionally substituted by one or more halogen or hydroxyl groups, R Y3 C(O), R Y3 C(S), R Y3 S(O), R Y3 S(O)2、N(R Y3 R Y4) C(O), N(R Y3 R Y4) C(S), N(R Y3 R Y4) S(O) or N(R Y3 R Y4) S(O)2;

[0811] T is selected from optionally substituted alkyl, -(CH2) n -, each methylene group is optionally selected from halogen, hydroxyl, an optionally substituted amino acid side chain, methyl, an optionally substituted alkoxy, a C1-C6 alkyl group optionally substituted with one or more halogens, -C(O)NR 1 R 1a or NR 1 R 1a Substituents substituted;

[0812] or R 1 and R 1a may optionally form an optionally substituted heterocycloalkyl;

[0813] n is 0, 1, 2, 3, 4, 5 or 6;

[0814] W 4 for

[0815] R 14a and R 14b are independently hydrogen, haloalkyl, or optionally substituted alkyl;

[0816] W 5 is optionally substituted phenyl or optionally substituted heteroaryl;

[0817] R 15is optionally substituted hydrogen, cyano, halogen, hydroxyl, nitro, NR 14a R 14b , OR 14a 、CONR 14a R 14b NR 14a CONR 14b、 SO2NR 14a R 14b NR 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

[0818] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E25 or E25a:

[0819] Among the E25 and E25a:

[0820] The W 3 is optionally substituted aryl, optionally substituted heteroaryl or

[0821] R9 and R 10 R9 and R1 are independently hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl or optionally substituted heteroaryl, or R9 and R1 are independently hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl or optionally substituted heteroaryl. 10 together with the carbon atom to which it is attached, form an optionally substituted cycloalkyl group;

[0822] R 11 is an optionally substituted heterocycloalkyl, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl,

[0823] R 12 is independently hydrogen or optionally substituted alkyl;

[0824] R 13 is independently hydrogen, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocycloalkyl)carbonyl, or optionally substituted aralkyl;

[0825] R 14a 、R 14b are independently hydrogen, haloalkyl, or optionally substituted alkyl;

[0826] W 5 is selected from optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl;

[0827] R 15 is optionally substituted hydrogen, cyano, halogen, hydroxyl, nitro, NR 14a R 14b , OR 14a 、CONR 14a R 14b NR 14a CONR 14b、 SO2NR 14a R 14b NR 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

[0828] Each R 16 are independently halogen, cyano, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy or optionally substituted haloalkyl;

[0829] o is 0, 1, 2, 3, or 4;

[0830] R 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl or haloalkoxy;

[0831] p is 0, 1, 2, 3 or 4.

[0832] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is 26, E26a or E26b,

[0833] Among the E26, E26a and E26b,

[0834] R1 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl;

[0835] R 14a is hydrogen, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;

[0836] X is CH2 or C(O);

[0837] R 15 is selected from hydrogen, halogen, CN, hydroxy, nitro, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0838] R3 is absent or is an optionally substituted 5-6 membered heteroaryl.

[0839] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E27, E27a, E27b, E27c, E27d, E27e, E27f and E27g:

[0840] wherein in E27, E27a, E27b, E27c, E27d, E27e, E27f and E27g, X is selected from carbon, oxygen, sulfur, sulfoxide, sulfone and NR a ;

[0841] R a are independently H or an alkyl group having a carbon number of 1 to 6;

[0842] Y and Z are independently carbon or nitrogen;

[0843] A, A' and A" are independently selected from C, N, O and S, and may also be one or two atoms forming a fused bicyclic, or 6,5 and 5,5-fused aromatic bicyclic group;

[0844] R1, R2 are independently aryl or heteroaryl, heteroaryl having one or two heteroatoms independently selected from sulfur and nitrogen, wherein the aryl or heteroaryl group can be monocyclic or bicyclic, or unsubstituted or substituted with one to three substituents independently selected from halogen, -CN, C1 to C6 alkyl, C3 to C6 cycloalkyl, -OH, alkoxy having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, sulfoxide having 1 to 6 carbons, sulfone having 1 to 6 carbons, ketone having 2 to 6 carbons, amide having 2 to 6 carbons, and dialkylamine having 2 to 6 carbons;

[0845] R3, R4 are independently selected from H, methyl and C1-C6 alkyl;

[0846] R5 is aryl or heteroaryl, heteroaryl having one or two heteroatoms independently selected from sulfur or nitrogen, wherein the aryl or heteroaryl group can be monocyclic or bicyclic, or unsubstituted or substituted with one to three substituents independently selected from halogen, -CN, C1 to C6 alkyl, C3 to C6 cycloalkyl, -OH, alkoxy having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, sulfoxide having 1 to 6 carbons, sulfone having 1 to 6 carbons, ketone having 2 to 6 carbons, amide having 2 to 6 carbons, N(C2-C6 alkyl)2, alkyl ether (C2 to C6), alkyl ketone (C3 to C6), morpholinyl, alkyl ester (C3 to C6) or alkyl cyanide (C3 to C6);

[0847] R6 is H or -C(=O)R b ,in:

[0848] R b Selected from alkyl, cycloalkyl, monosubstituted, disubstituted or trisubstituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazinyl), 1-piperidinyl, 4-NR c -morpholinyl, 4-R c -1-piperidinyl and 3-R c -1-piperidinyl, wherein:

[0849] R c is selected from alkyl, fluoro-substituted alkyl, cyanoalkyl, hydroxy-substituted alkyl, cycloalkyl, alkoxyalkyl, amidealkyl, alkylsulfone, alkylsulfoxide, alkylamide, aryl, heteroaryl, monosubstituted, disubstituted or trisubstituted aryl or heteroaryl, CH2CH2R d and CH2CH2CH2R d ,in:

[0850] R d Selected from alkoxy, alkylsulfone, alkylsulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO2-alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

[0851] R7 is selected from H, C1-C6 alkyl, cycloalkyl, fluoro-substituted alkyl, cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, and substituted 5- or 6-membered heteroaryl or aryl;

[0852] R8 is selected from –R e -C(O)-R f 、-R e -alkoxy, -R e -aryl, -R e -heteroaryl and -R e -C(O)-R f -C(O)-R g ,in:

[0853] R e is an alkylene group having 1 to 6 carbons or a bond;

[0854] R f is a substituted 4- to 7-membered heterocyclic ring;

[0855] R g is selected from aryl, heteroaryl, substituted aryl or heteroaryl, and 4 to 7 membered heterocyclic ring;

[0856] R9 is selected from mono-, di- or tri-substituted groups on the fused bicyclic aromatic ring, wherein the substituents are independently selected from halogen, alkene, alkyne, alkyl, unsubstituted or substituted Cl or F alkyl;

[0857] R 10 Selected from aryl and heteroaryl, wherein the heteroaryl may contain one or two heteroatoms such as sulfur or nitrogen, the aryl or heteroaryl may be monocyclic or bicyclic, and the aryl or heteroaryl may be unsubstituted or substituted with one to three substituents, the substituents including halogen, F, Cl, -CN, alkene, alkyne, C1-C6 alkyl, C1-C6 cycloalkyl, -OH, alkoxy having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms substituted with fluorine, sulfoxide having 1 to 6 carbon atoms, sulfone having 1 to 6 carbon atoms, or ketone having 2 to 6 carbon atoms;

[0858] R 11 -C(O)-N(R h )(R i ), where R h and R i is selected from the group consisting of H, C1 to C6 alkyl, alkoxy-substituted alkyl, sulfone-substituted alkyl, aryl, heteroaryl, mono-, di- or tri-substituted aryl or heteroaryl, alkylcarboxylic acid, heteroarylcarboxylic acid, alkylcarboxylic acid, fluoro-substituted alkylcarboxylic acid, aryl-substituted cycloalkyl and heteroaryl-substituted cycloalkyl; wherein R h and R i R is independently H, 4-hydroxycyclohexane, monohydroxy and dihydroxy substituted alkyl (e.g., C3 to C6 alkyl), 3-hydroxycyclobutane, phenyl-4-carboxylic acid or substituted phenyl-4-carboxylic acid; or, h and R i The atoms to which it is attached connect to form a ring;

[0859] R 12 and R 13 R is independently H, lower alkyl (e.g., C1 to C6 alkyl), lower alkenyl (e.g., C2 to C6 alkenyl), lower alkynyl (e.g., C2 to C6 alkynyl), cycloalkyl (e.g., 4-, 5-, and 6-membered cycloalkyl), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, or 5- and 6-membered aryl and heteroaryl groups,12 and R 13 Can be linked to form 5- and 6-membered rings with or without substitution on the ring;

[0860] R 14 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;

[0861] R 15 For CN;

[0862] R 16 C1-C6 alkyl, C1-C6 cycloalkyl, C2-C6 alkenyl, C1-C6 alkyl or C3-C6 cycloalkyl in which one or more hydrogens are replaced by fluorine, an alkyl or cycloalkyl in which one CH2 is replaced by S(=O), -S or -S(=O)2, wherein the terminal CH3 is replaced by S(=O)2N(alkyl)(alkyl), -C(=O)N(alkyl)(alkyl), -N(alkyl)S(=O)2(alkyl), -C(=O)2(alkyl), -O(alkyl)alkyl or cycloalkyl, wherein hydrogen is replaced by hydroxy a C1-C6 alkyl or alkyl-cycloalkyl radical, a 3- to 7-membered cycloalkyl or heterocycloalkyl radical optionally containing a -(C=O)- group, or a 5- to 6-membered aryl or heteroaryl radical, said heterocycloalkyl or heteroaryl radical may contain one to three heteroatoms independently selected from O, N or S, and said cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical may be unsubstituted or substituted with one to three substituents independently selected from halogen, C1-C6 alkyl, hydroxylated C1-C6 alkyl, C1-C6 alkyl radical containing a thioether, ether, sulfone, sulfoxide, fluorine-substituted ether and cyano;

[0863] R 17 Selected from (CH2) n C(O)NR k R l , where R k and R l independently selected from H, C1-C6 alkyl, hydroxylated C1-C6 alkyl, C1-C6 alkoxyalkyl, C1-C6 alkyl in which one or more hydrogens are replaced by fluorine, C1-C6 alkyl in which one carbon is replaced by S(O) or S(O)(O), C1-C6 alkoxyalkyl in which one or more hydrogens are replaced by fluorine, C1-C6 alkyl in which one or more hydrogens are replaced by cyano, 5- and 6-membered aryl or heteroaryl, C1-C6 alkylaryl, and C1-C6 alkylalkylheteroaryl, wherein the aryl or heteroaryl group may be further substituted; and n is an integer from 0 to 6;

[0864] R 18Selected from substituted aryl, heteroaryl, alkyl, cycloalkyl, wherein the substitution is preferably -N(C1-C4 alkyl)(cycloalkyl), -N(C1-C4 alkyl)alkyl-cycloalkyl, and -N(C1-C4 alkyl)[(alkyl)-(heterocyclic substituted)-cycloalkyl];

[0865] R 19 Selected from aryl, heteroaryl and bicyclic heteroaryl, and these aryl or heteroaryl groups may be substituted by halogen, C1-6 alkyl, C1-6 cycloalkyl, CF3, F, CN, alkyne, alkyl sulfone, and the halogen substitution may be monosubstituted or trisubstituted;

[0866] R 20 and R 21 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, hydroxylated C1-C6 alkoxy and fluorine-substituted C1-C6 alkoxy, wherein R 20 and R 21 They may also be linked to form 5-, 6-, and 7-membered carbocyclic or heterocyclic rings, which may be further substituted;

[0867] R 22 is selected from H, C1-C6 alkyl, C1-C6 cycloalkyl, carboxylic acid, carboxylic ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acylurea and nitrogen-containing 5-membered heterocyclic ring, wherein the 5-membered heterocyclic ring may be further substituted with C1-C6 alkyl, alkoxy, fluorine-substituted alkyl, CN and alkyl sulfone;

[0868] R 23 is selected from aryl, heteroaryl, -O-aryl, -O-heteroaryl, -O-alkyl, -O-alkyl-cycloalkyl, -NH-alkyl, -NH-alkyl-cycloalkyl, -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl, and -N(alkyl)-heteroaryl, wherein the aryl or heteroaryl may be substituted by halogen, C1-C6 alkyl, hydroxylated C1-C6 alkyl, cycloalkyl, fluorinated C1-C6 alkyl, CN, alkoxy, alkylsulfone, amide, and sulfonamide;

[0869] R 24 is selected from -CH2-(C1-C6 alkyl), -CH2-cycloalkyl, -CH2-aryl and CH2-heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl groups may be substituted by halogen, alkoxy, hydroxylated alkyl, cyano-substituted alkyl, cycloalkyl and substituted cycloalkyl groups;

[0870] R 25is selected from C1-C6 alkyl, C1-C6 alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5-, 6- and 7-membered nitrogen-containing saturated heterocyclic rings and 5,6-fused and 6,6-fused nitrogen-containing saturated heterocyclic rings, and these saturated heterocyclic rings may be C 1- C6 alkyl, fluorine-substituted C1-C6 alkyl, alkoxy, aryl and heteroaryl substitution;

[0871] R 26 Selected from C1-C6 alkyl and C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl may be substituted by -OH, alkoxy, fluorine-substituted alkoxy, fluorine-substituted alkyl, -NH2, -NH-alkyl, NH-C(O)alkyl, -NH-S(O)2-alkyl and -S(O)2-alkyl;

[0872] R 27 is selected from aryl, heteroaryl and bicyclic heteroaryl, wherein the aryl or heteroaryl may be substituted by C1-C6 alkyl, alkoxy, NH2, NH-alkyl, halogen or -CN, and the substitutions may independently be monosubstituted, disubstituted and trisubstituted;

[0873] R 28 is selected from aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl and saturated heterocycle (e.g., piperidine, piperidone, tetrahydropyran, N-acyl-piperidine), wherein the cycloalkyl, saturated heterocycle, aryl or heteroaryl may be further mono-, di- or tri-substituted by substituents selected from -OH, alkoxy, halogen, -CN, alkylsulfone and fluoro-substituted alkyl; and

[0874] R 1” is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl and alkoxy-substituted cycloalkyl.

[0875] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E28, E28a, E28b, E28c, E28d, E28e, E28f, E28g, E28h or E28i, (MDM2)

[0876] wherein E28, E28a, E28b, E28c, E28d, E28e, E28f, E28g, E28h and E28i: 1’ and R 2’ are independently F, Cl, Br, I, ethynyl, cyano, nitro or CF3;

[0877] R3’ Selected from -OCH3, -OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3 and -OCH(CH3)2;

[0878] R 4’ Selected from hydrogen, halogen, methyl, -CF3, -OCH3, -C(CH3)3, -CH(CH3)2, -cyclopropyl, cyano, -C(CH3)2OH, -C(CH3)2OCH2CH3, -C(CH3)2OCH2OH, -C(CH3)2CH2OCH2CH3, -C(CH3)2CH2OCH2CH2OH, -C(CH3)2CN, -C(CH3)2C(O)CH3, -C(CH3)2C(O)NHCH3, -C(CH3)2C(O)N(CH3)2, -SCH3, -SCH2CH3, -S(O)2CH3, -S(O)2CH2CH3, -NHC(CH3)3, -NC(CH3)2, pyrrolidinyl and morpholinyl;

[0879] R 5’ is selected from halogen, cyclopropyl, -S(O)2CH3, -S(O)2CH2CH3, pyrrolidinyl, -NH2, -N(CH3)2 and -NHC(CH3)3;

[0880] R 6’ Selected from hydrogen, where R 6’ The * is the connection point to L; or R 4’ Can also be connected to L;

[0881] R 7’ is halogen, R 7’ The number of can be one or more;

[0882] R 8’ is hydrogen, F, Cl, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, hydroxyl, other C1-C6 alkyl, other C1-C6 alkenyl or other C1-C6 alkynyl, R 8’ The number of can be one or more;

[0883] R 9’ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl;

[0884] Z is hydrogen, -OCH3, -OCH2CH3 or halogen;

[0885] R10’ and R11’ independently is hydrogen, (CH2) n -R’, (CH2) n -NR’R”, (CH2) n -NR’C(O)R”, (CH2) n -NR’S(O)2R”, (CH2) n -C(O)OH, (CH2) n -C(O)OR’, (CH2) n -C(O)NR’R”, (CH2) n -OR’, (CH2) n -SR’, (CH2) n -SOR’, (CH2) n -CH(OH)-R’, (CH2) n -C(O)R’, (CH2) n -S(O)2R’, (CH2) n -S(O)NR’R”, (CH2) n -S(O)2NR’R”, (CH2CH2O) m -(CH2) n -R’, (CH2CH2O) m -(CH2) n -OH, (CH2CH2O) m -(CH2) n -OR’, (CH2CH2O) m -(CH2) n -NR’R”, (CH2CH2O) m -(CH2) n -NR’C(O)R”, (CH2CH2O) m -(CH2) n -S(O)2NR’R”, (CH2CH2O) m -(CH2) n -C(O)OH, (CH2CH2O) m -(CH2) n -C(O)OR’, (CH2CH2O) m -(CH2) n -C(O)NR’R”, (CH2CH2O) m -(CH2) n -S(O)OR’, (CH2CH2O) m -(CH2) n -C(O)R’, (CH2CH2O) m -(CH2)n -S(O)NR’R”、(CH2CH2O) m -(CH2) n -S(O)2NR’R”、-(CH2) p -(CH2CH2O) m -(CH2) n R’、-(CH2) p -(CH2CH2O) m -(CH2) n -OH、-(CH2) p -(CH2CH2O) m -(CH2) n -OR’、-(CH2) p -(CH2CH2O) m -(CH2) n -NR’R”、-(CH2) p -(CH2CH2O) m -(CH2) n -NR’C(O)R”、-(CH2) p -(CH2CH2O) m -(CH2) n -NR’S(O)2R”、-(CH2) p -(CH2CH2O) m -(CH2) n -C(O)OH、-(CH2) p -(CH2CH2O) m -(CH2) n -C(O)OR’、-(CH2)<0001​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-C(O)OH or heteroaryl-alkyl-C(O)-alkyl-NR'R", wherein the alkyl group is optionally substituted with OR'; or R 10’ and R 11’ independently heteroaryl-(CH2)n-heterocycloalkyl, the heterocycloalkyl being optionally substituted by alkyl, hydroxy, C(O)OR' or C(O)R'; the R' and R" being independently hydrogen, halogen, hydroxy, NH2, NH(alkyl), NH(alkyl) 1-2 , oxo, carboxyl, cycloalkyl or heteroaryl;

[0886] m, n and p are independently 0, 1, 2, 3, 4, 5 or 6;

[0887] R 12’ are independently -O-alkyl, -O-alkyl-alkoxy, -C(O)-alkyl, -C(OH)-alkyl-alkoxy, -C(O)-NH-alkyl, -C(O)-N-(alkyl) 1-2 , -S(O)-alkyl, S(O)2-alkyl, -C(O)-cyclic amine, -O-aryl-alkyl or -O-aryl-alkoxy;

[0888] R 1” is hydrogen, an alkyl group optionally substituted by an aryl group or an alkoxy group, or a cycloalkyl group optionally substituted by an aryl group or an alkoxy group.

[0889] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E29:

[0890] R1 is independently H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl or C3-C 10 - cycloalkyl, which is unsubstituted or substituted;

[0891] R2 is independently H, C1-C4-alkenyl, C1-C4-alkenyl, C1-C4-alkynyl or C3-C 10 - cycloalkyl, which is unsubstituted or substituted;

[0892] R3 is independently H, -CF3, -C2H5, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, -CH2-Z, or any of R2 and R3 together form a heterocycle;

[0893] each Z is independently H, -OH, F, Cl, -CH3, -CF3, -CH2Cl, -CH2F or -CH2OH;

[0894] R4 is independently C1-C 16Straight or branched alkyl, C1-C 16 -alkenyl, C1-C 16 -alkynyl, C3-C 10 -cycloalkyl, -(CH2) 0-6 -Z1, -(CH2) 0-6 -aryl or -(CH2) 0-6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

[0895] R5 is independently H, C 1-10 -alkyl, aryl, phenyl, C 3-7 -cycloalkyl, -(CH2) 1-6 -C 3-7 -cycloalkyl, -C 1-10 -alkyl-aryl, -(CH2) 0-6 -C 3-7 -cycloalkyl-(CH2) 0-6 -phenyl, -(CH2) 0-4 -CH[(CH2) 1-4 -phenyl]2, indanyl, -C(O)-C 1-10 -alkyl, -C(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-(CH2) 0-6 -phenyl, -(CH2) 0-6 -C(O)-phenyl, -(CH2) 0-6 -het or -C(O)-(CH2) 1-6 -het, or R5 is selected from the residues of amino acids in which alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted;

[0896] Z1 is independently selected from -N(R 10 )-C(O)-C 1-10 -alkyl, -N(R 10 )-C(O)-(CH2) 0-6 -C 3-7 -cycloalkyl, -N(R 10 )-C(O)-(CH2) 0-6 -phenyl, -N(R 10 )-C(O)(CH2) 1-6 -het、-C(O)-N(R 11 )(R 12 )、-C(O)-OC 1-10 -alkyl, -C(O)-O-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-O-(CH2) 0-6-phenyl, -C(O)-O-(CH2) 1-6 -het、-OC(O)-C 1-10 -alkyl, -OC(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -OC(O)-(CH2) 0-6 -phenyl, -OC(O)-(CH2) 1-6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

[0897] het is independently a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system, including at least one 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S, said heterocyclic ring or fused ring system being unsubstituted or substituted on a carbon or nitrogen atom;

[0898] R 10 is H, -CH3, -CF3, -CH2OH or -CH2Cl;

[0899] R 11 and R 12 Independently H, C 1-4 -alkyl, C 3-7 -cycloalkyl, -(CH2) 1-6 -C 3-7 -cycloalkyl or (CH2) 0-6 -phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; or R 11 and R 12 Together with nitrogen, it forms het, and

[0900] U is independently:

[0901] in:

[0902] Each n is independently an integer from 0 to 5;

[0903] X is selected from -CH and N;

[0904] R a and R b Independently C 0-8 -alkyl, wherein one or more carbon atoms in the alkyl chain are optionally replaced by a heteroatom selected from O, S or N, and wherein each alkyl group is independently unsubstituted or substituted;

[0905] R d Selected from Re-Q-(R f ) p (R g ) q and Ar1-D-Ar2;

[0906] R c H or any R c and R d together form a cycloalkyl group or het; wherein if R c and R d forming a cycloalkyl or het, then R5 is attached to the formed ring at a C or N atom;

[0907] p and q are independently selected from 0 or 1;

[0908] R e Selected from C 1-8 -alkyl and alkylene, and each R e not replaced or replaced;

[0909] Q is selected from N, O, S, S(O) and S(O)2;

[0910] Ar1 and Ar2 are independently selected from substituted or unsubstituted aryl and het;

[0911] R f and R g Independently selected from H, -Cl- 10 -alkyl, C 1-10 -alkylaryl, -OH, -OC 1-10 -alkyl, -(CH2) 0-6 -C 3-7 -cycloalkyl, -O-(CH2) 0-6 -aryl, phenyl, aryl, phenyl-phenyl, -(CH2) 1-6 -het、-O-(CH2) 1-6 -het、-OR 13 、-C(0)-R 13 、-C(O)-N(R 13 )(R 14 )、-N(R 13 )(R 14 ),-SR 13 、-S(O)-R 13 、-S(O)2-R 13 、-S(O)2-NR 13 R 14 、-NR 13 -S(O)2-R 14 、-SC t-10 -alkyl, aryl-C 1-4 -alkyl, het-C 1-4 -alkyl, -SO2-C 1-2 -alkyl, -SO2-C 1-2 -alkylphenyl, -OC1-4 -alkyl or any R g and R f together forming a ring selected from het or aryl; wherein alkyl, cycloalkyl, het and aryl are unsubstituted or substituted;

[0912] D is -CO-, -C(O)-C 1-7 -alkylene or arylene, -CF2-, -O-, -S(O) r , 1,3-dioxolane or C 1-7 -alkyl-OH, wherein r is 0-2; wherein alkyl, alkylene or arylene is unsubstituted or substituted by one or more halogen, OH, -OC 1-6 -alkyl, -SC 1-6 - alkyl or -CF3 substituted; or each D is independently N(R h );

[0913] R h is H, unsubstituted or substituted C 1-7 -alkyl, aryl, unsubstituted or substituted-O-(C 1-7 -cycloalkyl), -C(O)-C 1-10 -alkyl, -C(O)-C 0-10 -alkyl-aryl, -COC 01-10 -alkyl, -COC 0-10 -alkyl-aryl, -SO2-C 1-10 -alkyl or -SO2-(C 0-10 -alkylaryl);

[0914] R6, R7, R8 and R9 are independently H, -C 1-10 -alkyl, -C 1-10 -alkoxy, aryl-C 1-10 -alkoxy, -OH, -OC 1-10 -alkyl, -(CH2) 0-6 -C 3-7 -cycloalkyl, -O-(CH2) 0-6 -aryl, phenyl, -(CH2) 1-6 -het、-O-(CH2) 1-6 -het、-OR 13 、-C(O)-R 13 、-C(O)-N(R 13 )(R 14 )、-N(R 13 )(R 14 ),-SR 13 、-S(O)-R 13 、-S(O)2-R 13、-S(O)2-NR 13 R 14 or -NR 13 -S(O)2-R 14 wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted; and any of R6, R7, R8 and R9 optionally together form a ring system;

[0915] R 13 and R 14 Independently H, C 1-10 -alkyl, -(CH2) 0-6 -C 3-7 -cycloalkyl, -(CH2) 0-6 -(CH) 0-1 -(aryl) 1-2 、-C(O)-C 1-10 -alkyl, -C(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-O-(CH2) 0-6 -Aryl, -C(O)-(CH2) 0-6 -O-fluorenyl, -C(O)-NH-(CH2) 0-6 -Aryl, -C(O)-(CH2) 0-6 -Aryl, -C(O)-(CH2) 0-6 -het、-C(S)-C 1-10 -alkyl, -C(S)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(S)-O-(CH2) 0-6 -Aryl, -C(S)-(CH2) 0-6 -O-fluorenyl, -C(S)-NH-(CH2) 0-6 -Aryl, -C(S)-(CH2) 0-6 -Aryl or -C(S)-(CH2) 1-6 -het, wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted; or any R 13 and R 14 Together with nitrogen atoms, it forms het;

[0916] R 13 and R 14 The alkyl group in the formula (I) is unsubstituted or substituted, and when substituted, is substituted by one or more substituents selected from C 1-10 -alkyl, halogen, OH, -OC 1-6 -alkyl, -SC 1-6 -alkyl and -CF3; and R 13 and R 14The substituted phenyl or aryl is substituted by one or more substituents selected from halogen, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, nitro, -CN, -OC(O)-C 1-4 -alkyl and -C(O)-OC 1-4 -aryl;

[0917] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E30, E30a, E30b, E30c or E30d:

[0918] Among E30, E30a, E30b, E30c and E30d:

[0919] R 1 is hydrogen or alkyl;

[0920] R 2 is hydrogen or alkyl;

[0921] R 3 is hydrogen, alkyl, cycloalkyl or heterocycloalkyl;

[0922] R 5 and R 6 are independently hydrogen, alkyl, cycloalkyl or heterocycloalkyl; or R 5 、R 6 Together with the atoms to which they are attached, they form a pyrrole or piperidine ring and are optionally fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, each of which is further optionally fused to another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;

[0923] or R 5 and R 3 Together with the atoms to which they are attached, they form a 5-8 membered ring and are optionally fused to one or two cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings;

[0924] R 4 is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl or bicyclic aryl, arylalkyl, heteroaryl or bicyclic heteroaryl or heteroarylalkyl, and is further optionally substituted with 1-3 alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl or bicyclic aryl, arylalkyl, heteroaryl or bicyclic heteroaryl, heteroarylalkyl substituents.

[0925] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E31

[0926] Among them, E31:

[0927] A1 and A2 are independently selected from optionally substituted monocyclic rings, fused rings, aryl groups and heteroaryl groups;

[0928] R is H or Me.

[0929] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E32,

[0930] Among them, E32:

[0931] R 1 is selected from alkyl, cycloalkyl and heterocycloalkyl, and most preferably selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl; R 2 Select from –OPh or H.

[0932] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E33,

[0933] Among them, in the E33:

[0934] R 1 is H, -CH2OH, -CH2CH2OH, -CH2NH2 or -CH2CH2NH2;

[0935] X is S or CH2;

[0936] n is 1, 2, or 3;

[0937] R 2 for:

[0938] R 3 and R 4 Independently selected from H or Me.

[0939] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E34,

[0940] Among them, E34:

[0941] R 1 selected from H or Me;

[0942] R 2 Select H or

[0943] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E35,

[0944] Among them, the E35:

[0945] R 1 Selected from:

[0946] R 2 Selected from:

[0947] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E36,

[0948] Among them, E36:

[0949] n is 0, 1 or 2, preferably 2;

[0950] Z does not exist or is O;

[0951] R 1 Selected from:

[0952] R in 10 is hydrogen, alkyl or aryl;

[0953] X is selected from CH2 and O; and

[0954] It is a nitrogen-containing heteroaryl group.

[0955] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E37,

[0956] Among them, E37:

[0957] Z does not exist or is O;

[0958] R 3 and R 4 independently selected from H or Me;

[0959] R 1 Selected from:

[0960] R in 10 is H, alkyl or aryl;

[0961] wherein X is CH2 or O; and

[0962] in It is a nitrogen-containing heteroaryl group.

[0963] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E38,

[0964] Among them, E38:

[0965] Z does not exist or is O;

[0966] R 1 Selected from:

[0967] R in 10 is H, alkyl or aryl;

[0968] wherein X is CH2 and O; and

[0969] in is a nitrogen-containing heteroaryl group; and

[0970] R 2 is H, alkyl or acyl.

[0971] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E39,

[0972] Among them, E39:

[0973] R 2is selected from alkyl, cycloalkyl and heterocycloalkyl; more preferably selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably selected from cyclohexyl;

[0974] is a 5- or 6-membered nitrogen-containing heteroaryl; more preferably a 5-membered nitrogen-containing heteroaryl and most preferably thiazole; and Ar is an aryl or heteroaryl group.

[0975] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E40,

[0976] Among them, the E40:

[0977] R 1 is selected from halogen (e.g., fluorine), cyano,

[0978] X is selected from O or CH2.

[0979] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E41,

[0980] Among them, in said E41:

[0981] R is alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or halogen (in variable substitution positions).

[0982] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E42,

[0983] Among them, E36 It is a 6-membered nitrogen-containing heteroaryl group.

[0984] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E43,

[0985] Wherein, in E43, X is selected from CH2, O, NH or S.

[0986] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E44, E44a or E44b,

[0987] Among the E44, E44a and E44b:

[0988] n is 1 or 2;

[0989] R 2 、R 3 and R 4 are independently H or methyl;

[0990] X is independently O or S;

[0991] And R 1 for:

[0992] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E45,

[0993] Among them, E45:

[0994] R 3 and R 4 are independently hydrogen or methyl;

[0995] is the following 5-membered heterocycle: or

[0996] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E46 or E46a,

[0997] in:

[0998] R 1 for

[0999] R 2 H or methyl

[1000] N is 0, 1 or 2.

[1001] In one embodiment, E is EA:

[1002] In the EA,

[1003] Ring D is connected to L;

[1004] Among them, ring D is

[1005] Q1, Q1', Q2, Q2', Q3, Q3', Q4, Q4', Q5, Q5', Q6 or Q6' are independently CH or N;

[1006] R B and R B’ are independently hydrogen, deuterium, hydroxyl, halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -O-(C1-C6 heteroalkyl), C2-C6 alkenyl, C2-C6 alkynyl, -CONR C R D 、-OR C 、-NR C R D 、-SR C 、-SO2R C 、-SO2NR C R D 、-CR C R D 、-CR C NR C R D 、C6-C 10 Aryl, C5-C 10 Heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR C )R D 、-P(O)R C R D 、-OP(O)(OR C )R D , -Cl, -F, -Br, -I, -CF3, -CN, -NR C SO2NR C R D 、-NR C C(O)NR C R D 、-C(O)NR C C(O)R D 、-NR C C(=N-CN)NR C R D 、-C(=N-CN)NR C R D 、-NR C C(=N-CN)R D 、-NR CC(=C-NO2)NR C R D 、-SO2NR C COR D 、-NO2、-COR C 、-C(C=N-OR C )R D 、-CR C =CR C R D 、-CCR C 、-S(C=O)(C=NR C )R D or -SF5;

[1007] R C and R D are independently a bond, hydrogen, deuterium, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C5-C 10 heteroaryl or 3-8 membered heterocycloalkyl;

[1008] n″ and n′″ are independently 1, 2, 3 or 4;

[1009] t is 0, 1, or 2;

[1010] P1 is CH2, O or S;

[1011] W is CR E R F , C(S), C(O) or SO2;

[1012] R E and R F are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl;

[1013] P and Q are independently CH2, O or S;

[1014] Z is CH or N;

[1015] R A is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, halogen or C3-C8 heterocycloalkyl;

[1016] The heteroaryl group is a heteroaryl group having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; the heterocycloalkyl group is a heterocycloalkyl group having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroalkyl group is a heteroatom or heteroatom group selected from N, O, S, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene and ethynylene, and the number of heteroatoms is 1, 2 or 3.

[1017] In one embodiment, the EA is

[1018] In one embodiment, in EA, R B 、R B’ 、R C and R D In the above, the C1-C6 haloalkyl group may independently be a C1-C4 haloalkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group substituted by 1, 2 or 3 halogens, and the halogens may independently be F, Cl, Br or I.

[1019] In one embodiment, in EA, R B 、R B’ 、R C 、R D 、R E 、R F and R A In one embodiment, the C1-C6 alkyl group may be independently a C1-C4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group. B 、R B’ and R A wherein the halogen may independently be F, Cl, Br or I.

[1020] In one embodiment, in EA, R B 、R B’ 、R C 、R D 、R E 、R F and R AIn the C1-C6 heteroalkyl group or the C1-C6 heteroalkyl group in -O-(C1-C6 heteroalkyl group), the C1-C6 heteroalkyl group may independently be a C1-C4 heteroalkyl group containing 1 or 2 heteroatoms selected from N, O, and S, such as CH3OCH2-, CH3CH2OCH2-, CH3OCH2CH2-, CH3NHCH2-, CH3CH2NHCH2-, CH3NHCH2CH2-, CH3SCH2-, CH3CH2SCH2-, CH3SCH2CH2- or CH3OCH2OCH2-.

[1021] In one embodiment, in EA, R B and R B’ In the above, the C2-C6 alkenyl group may independently be a C2-C4 alkenyl group, such as vinyl, propenyl or allyl.

[1022] In one embodiment, in EA, R B and R B’ In the above, the C2-C6 alkynyl group may independently be a C2-C4 alkynyl group, such as ethynyl, propynyl or propargyl.

[1023] In one embodiment, in EA, R B 、R B’ 、R C and R D C6-C 10 Aryl groups may independently be phenyl or naphthyl.

[1024] In one embodiment, in EA, R B 、R B’ 、R C and R D C5-C 10 Heteroaryl can independently be furanyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, or indolyl.

[1025] In one embodiment, in EA, R B 、R B’ 、R C 、R D 、R E 、R F and R A In the above, the C3-C8 cycloalkyl group may independently be a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[1026] In one embodiment, in EA, R B 、R B’ 、R C 、R D 、R E 、R F and RA In the above, the 3- to 8-membered heterocycloalkyl group may independently be a 4- to 6-membered heterocycloalkyl group, such as azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl.

[1027] In one embodiment, in EA, Q1, Q1', Q2, Q2', Q3, Q3', Q4, Q4', Q5, Q5', Q6 or Q6' is independently CH.

[1028] In one embodiment, in the EA, R B and R B’ are independently hydrogen, CN, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, -O-(C1-C6 heteroalkyl), C3-C8 cycloalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR C .

[1029] In one embodiment, in the EA, R C It is C1-C6 haloalkyl, C1-C6 alkyl or C3-C8 cycloalkyl.

[1030] In one embodiment, in the EA, R B and R B’ are independently hydrogen, CN, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, -O-(C1-C6 heteroalkyl), C3-C8 cycloalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR C ; R C It is C1-C6 haloalkyl, C1-C6 alkyl or C3-C8 cycloalkyl.

[1031] In one embodiment, in EA, n" and n'" are independently 1.

[1032] In one embodiment, in the EA, P1 is O.

[1033] In one embodiment, in EA, W is CH2 or C(O).

[1034] In one embodiment, in EA, P and Q are independently O.

[1035] In one embodiment, in EA, Z is CH or N.

[1036] In one embodiment, in the EA, R A For hydrogen.

[1037] In one embodiment, in the EA,

[1038] Ring D is connected to L;

[1039] Among them, ring D is

[1040] Q1, Q1', Q2, Q2', Q3, Q3', Q4, Q4', Q5, Q5', Q6 or Q6' are independently CH;

[1041] R B and R B’ are independently hydrogen, halogen, CN, C1-C6 alkyl, C1-C6 heteroalkyl, -O-(C1-C6 heteroalkyl), C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR C ; R C is C1-C6 haloalkyl, C1-C6 alkyl or C3-C8 cycloalkyl;

[1042] n″ and n″′ are 1;

[1043] P1 is O;

[1044] W is CH2 or C(O);

[1045] P and Q are independently O;

[1046] Z is CH or N;

[1047] R A For hydrogen.

[1048] In one embodiment, the EA is EA-1, EA-2, EA-3 or EA-4:

[1049] In the above formulae, the definitions of the remaining substituents are the same as those described in the previous embodiment.

[1050] In one embodiment, in the EA, the EA-1 is EA-1-1:

[1051] The EA-2 is EA-2-1:

[1052] The EA-3 is EA-3-1:

[1053] The EA-4 is EA-4-1:

[1054] In one embodiment, in EA, when Z is CH, the configuration of C is R, S or a mixture thereof.

[1055] In one embodiment, E is:

[1056] In one embodiment, the compound represented by formula I is any one of the following compounds:

[1057] The present invention also provides a use of a compound represented by formula S' or a salt thereof in the preparation of a targeted SOS1 protein degradation agent.

[1058] Among them, the R G is hydrogen, halogen or the above ring A; X, R1, m, A1, R2, w, A2, R3, Y, L', R4, R5 and The definitions of are as described in the previous scheme;

[1059] Preferably,

[1060] R5 is Me;

[1061] R4 is Me or CD3 or CH2CF3;

[1062] X is N or CH;

[1063] R1 is OMe, Me, OCH2CH2OCH3, CN, Cl, F or Br;

[1064] m is 0 or 1;

[1065] R G for

[1066] In one embodiment, in the application, the targeted SOS1 protein degrader is a compound as shown in Formula I, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts.

[1067] The present invention also provides a compound as shown in Formula P-1, P-2, P-3 or P-4:

[1068] Among them, X, R1, m, A1, R5 and The definitions of Ring A", Ring B", Ring C", X"', X"" and La" and the connection relationship between them are as described above;

[1069] Preferably, the compound represented by formula P-1 is a compound represented by formula P-1-1:

[1070] For example

[1071] Preferably, the compound represented by formula P-2 is a compound represented by formula P-2-1:

[1072] For example

[1073] Preferably, the compound represented by formula P-3 is a compound represented by formula P-3-1:

[1074] For example

[1075] Preferably, the compound represented by formula P-4 is a compound represented by formula P-4-1:

[1076] For example Preferably, the compound represented by formula P-5 is a compound represented by formula P-5-1: For example

[1077] The present invention also provides a pharmaceutical composition comprising G and a pharmaceutically acceptable carrier, diluent or excipient, wherein G is the compound shown in Formula I above, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof.

[1078] The present invention provides a method for degrading SOS1 protein, comprising contacting the above-mentioned compound, its stereoisomer, enantiomer, diastereomer, deuterated product, hydrate, solvate, metabolite, prodrug or pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition with SOS1 protein.

[1079] The present invention provides a compound, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts, or the pharmaceutical composition for use as a drug for treating or preventing SOS1-mediated diseases or conditions.

[1080] The present invention provides a use of the above-mentioned compound, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions as a drug for treating or preventing diseases or conditions (cancer) caused by the interaction between SOS1 and Ras (e.g., KRAS) or SOS1 and Rac (e.g., KRAS).

[1081] The present invention provides a use of the above-mentioned compound, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating or preventing SOS1-mediated diseases or conditions (e.g., cancer).

[1082] The present invention provides the use of the above-mentioned compound, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating or preventing diseases or conditions (such as cancer) caused by the interaction between SOS1 and Ras (such as KRAS) or SOS1 and Rac (such as KRAS).

[1083] The present invention provides a use of the above-mentioned compound, its stereoisomers, enantiomers, diastereomers, deuterated products, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating or preventing cancer.

[1084] In any embodiment of the present invention, the cancer can be pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer or sarcoma.

[1085] The present invention provides use of the above-mentioned compound, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for treating or preventing pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[1086] The present invention provides a use of the above-mentioned compound, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating or preventing neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-cutaneous syndrome (CFC), Leggs syndrome and hereditary gingival fibromatosis.

[1087] In any embodiment of the present invention, the SOS1-mediated disease or condition may be cancer, neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-cutaneous syndrome (CFC), Leggs syndrome or hereditary gingival fibromatosis; wherein the cancer may be the cancer described in any embodiment of the present invention.

[1088] The present invention provides a method for treating or preventing a disease or condition mediated by SOS1, comprising administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition.

[1089] The present invention provides a method for treating or preventing a disease or condition (such as cancer) regulated by the interaction between SOS1 and Ras (such as KRAS) or SOS1 and Rac (such as KRAS), comprising administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound, or its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, metabolites, prodrugs or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition.

[1090] In certain embodiments of the present invention, the cancer may be selected from:

[1091] Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma group;

[1092] Lung: bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, enchondroma, hamartoma, mesothelioma;

[1093] Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[1094] Genitourinary system: kidney (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

[1095] Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[1096] Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer;

[1097] Bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, enchondroma (osteochondral exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;

[1098] Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germinal cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);

[1099] Gynecology: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma);

[1100] Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[1101] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[1102] Adrenal gland: neuroblastoma.

[1103] In certain embodiments of the present invention, the cancer can be selected from pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[1104] The present invention also provides a use of the above-mentioned compound, and / or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and / or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions in the preparation of a medicament for treating and / or preventing KRAS-mediated diseases or conditions.

[1105] The present invention also provides a method for treating and / or preventing KRAS-mediated diseases or conditions, comprising administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound, and / or its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[1106] In certain embodiments of the present invention, the KRAS may be a mutant KRAS, preferably one or more of KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12V.

[1107] DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[1108] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched alkyl groups; C1-C8 alkyl refers to an alkyl group containing 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched chain isomers thereof; preferably C1-C6 alkyl; more preferably C1-C4 alkyl. The alkyl group may be substituted or unsubstituted. In some embodiments, the alkyl group is C1, C2, C3, C4, C5, C6, C7 or C8 alkyl.

[1109] "Heteroalkyl" refers to a saturated aliphatic hydrocarbon group in which the methylene (-CH2-) is replaced by a heteroatom (such as O, S, N), a heteroatom group (such as -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene or ethynylene, including straight-chain or branched heteroalkyl groups; C1-C8 heteroalkyl refers to an alkyl group containing 1 to 8 carbon atoms in which at least one of the methylene groups is replaced by a heteroatom or heteroatom. Atomic radical substitution, for example -C(O)-CH3, -CH2-O-CH3, -CH2-S-CH3, -CH2-S(O)-CH3, -CH2-S(O)2-CH3, -CH2-S-CH2-CH3, -CH2-O-CH2-CH3, -CH2-O-CH2-CH3, -CH2-S(O)-CH2-CH3, or various branched isomers thereof; preferably C1-C6 heteroalkyl; more preferably C1-C4 heteroalkyl. The heteroalkyl group may be substituted or unsubstituted. In some embodiments, the heteroalkyl group is C1, C2, C3, C4, C5, C6, C7 or C8 heteroalkyl.

[1110] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent; "C3-C 11 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 11 carbon atoms; "C3-C8 cycloalkyl" refers to a cycloalkyl group containing 3 to 8 carbon atoms; "C5-C 10 "Membered cycloalkyl" refers to a cycloalkyl group comprising 5 to 10 carbon atoms;

[1111] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C3-C8 membered cycloalkyl; more preferably C3-C6 membered cycloalkyl.

[1112] Polycyclic cycloalkyl includes cycloalkyl of spiro ring, fused ring and bridged ring. "Spiroalkyl" refers to a polycyclic group in which a carbon atom (called spiro atom) is shared between the monocyclic rings. They may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiroalkyl is divided into monospiroalkyl, bispiroalkyl or polyspiroalkyl according to the number of spiro atoms shared between the rings, preferably 7-12 membered bispiroalkyl. Non-limiting examples of spiroalkyl include:

[1113] "Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Depending on the number of constituent rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic. Non-limiting examples of fused cycloalkyl groups include:

[1114] "Bridged cycloalkyl" refers to a fully carbon-containing polycyclic group in which any two rings share two carbon atoms that are not directly connected. They may contain one or more double bonds, but no ring has a completely conjugated π electron system. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl groups include:

[1115] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl can be optionally substituted or unsubstituted.

[1116] In some embodiments, the cycloalkyl group is C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12Monocyclic or polycyclic (eg, spirocyclic, fused or bridged) cycloalkyl groups.

[1117] "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more (e.g., 2, 3, 4, or 5) ring atoms are selected from nitrogen, oxygen, or S(O) r (wherein r is an integer of 0, 1 or 2), but does not contain a ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. "3-11-membered heterocycloalkyl" refers to a ring group containing 3 to 11 ring atoms, "5-10-membered heterocycloalkyl" refers to a ring group containing 5 to 10 ring atoms, and "3-8-membered heterocycloalkyl" refers to a ring group containing 3 to 8 ring atoms, preferably a "3-11-membered heterocycloalkyl" containing 1-2 heteroatoms selected from N, O or S, and more preferably a 3-11-membered heterocycloalkyl containing 1 or 2 N atoms.

[1118] Monocyclic heterocycloalkyl is preferably a 3-8 membered monocyclic heterocycloalkyl containing 1-2 N heteroatoms; non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl and piperazinyl.

[1119] Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. "Spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which the single rings share an atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). r (wherein r is an integer 0, 1, 2), and the remaining ring atoms are carbon. They may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spirocycloalkyl groups are divided into monospiroheterocycloalkyl, bispiroheterocycloalkyl or polyspiroheterocycloalkyl groups according to the number of spiro atoms shared between the rings, preferably saturated "3-11 membered bispiroheterocycloalkyl groups" containing 1-2 heteroatoms selected from N, O or S; more preferably saturated "7-11 membered bispiroheterocycloalkyl groups" containing 1 or 2 N atoms. Non-limiting examples of spiroheterocycloalkyl groups include:

[1120] "Fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, and one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, fused heterocycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably "3-11-membered bicyclic fused heterocycloalkyl groups" containing 1-3 heteroatoms selected from N, O, or S; and more preferably "3-11-membered bicyclic fused heterocycloalkyl groups" containing 1 or 2 saturated N atoms. Non-limiting examples of fused heterocycloalkyl groups include:

[1121] "Bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two atoms that are not directly connected, they may contain one or more double bonds, but no ring has a completely conjugated π electron system, and one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged heterocycloalkyl groups include:

[1122] The heterocycloalkyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[1123] The heterocycloalkyl group may be optionally substituted or unsubstituted.

[1124] In some embodiments, the heterocycloalkyl group is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered monocyclic or polycyclic (e.g., spirocyclic, fused, or bridged) heterocycloalkyl group, wherein the number of heteroatoms can be 1, 2, 3, 4, or 5, each heteroatom being independently nitrogen, oxygen, or S(O). r (where r is an integer 0, 1, or 2).

[1125] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) polycyclic group having a conjugated π electron system, "C6-C 10 "Metaaryl" refers to an all-carbon aromatic group containing 6-10 carbon atoms, such as phenyl and naphthyl; preferably phenyl. The aromatic ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aromatic ring, non-limiting examples of which include:

[1126] The aryl group may be optionally substituted or unsubstituted. In some embodiments, the aryl group is a 6-10 membered aryl group.

[1127] "Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen or S(O) r(wherein r is an integer of 0, 1, or 2), a 5-6 membered heteroaryl group refers to a heteroaromatic system containing 5-6 ring atoms, and a 5-10 membered heteroaryl group refers to a heteroaromatic system containing 5-10 ring atoms, preferably a 5-6 membered heteroaryl group; more preferably a 5-6 membered heteroaryl group containing 1 or 2 N atoms; non-limiting examples include furanyl, thienyl, pyridinyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazole, imidazolyl, triazolyl, tetrazolyl, etc.; preferably pyridinyl. The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include:

[1128]

[1129] The heteroaryl group may be optionally substituted or unsubstituted. In some embodiments, the heteroaryl group is a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl group, wherein the number of heteroatoms may be 1, 2, 3, 4, or 5, each heteroatom being independently nitrogen, oxygen, or S.

[1130] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. "C2-8 alkenyl" refers to a straight or branched alkenyl group containing 2 to 8 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc., preferably "C2-6 alkenyl", more preferably "C2-4 alkenyl". The alkenyl group may be substituted or unsubstituted. In some embodiments, the alkenyl group is C2, C3, C4, C5, C6, C7, or C8 alkenyl.

[1131] "Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. "C2-8 alkynyl" refers to a straight or branched chain alkynyl group containing 2 to 8 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, preferably "C2-6 alkynyl", more preferably "C2-4 alkynyl". The alkynyl group may be substituted or unsubstituted. In some embodiments, the alkynyl group is C2, C3, C4, C5, C6, C7, or C8 alkynyl.

[1132] "Ylene" refers to a divalent group, such as alkylene refers to a divalent alkyl group, alkenylene refers to a divalent alkenyl group, alkynylene refers to a divalent alkynyl group, cycloalkylene refers to a divalent cycloalkyl group, heterocycloalkylene refers to a divalent heterocycloalkyl group, arylene refers to a divalent aryl group, and heteroarylene refers to a divalent heteroaryl group. The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are as defined above, and the alkylene group may be optionally substituted or unsubstituted.

[1133] "Haloalkyl" refers to an alkyl group optionally substituted with one or more (e.g., 1, 2, or 3) fluorine, chlorine, bromine, or iodine atoms, wherein the alkyl group is as defined above, and non-limiting examples include difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

[1134] "Hydroxyalkyl" refers to an alkyl group optionally substituted with one or more -OH groups, wherein alkyl is as defined above, non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl.

[1135] "Alkoxy" refers to an -O-alkyl group wherein alkyl is as defined above, non-limiting examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[1136] "Cycloalkoxy" refers to an -O-cycloalkyl group wherein the cycloalkyl group is as defined above. Non-limiting examples include cyclopropaneoxy, cyclobutaneoxy, cyclopentaneoxy, cyclohexaneoxy, and the like.

[1137] "Heterocycloalkoxy" refers to an -O-heterocycloalkyl group, wherein the heterocycloalkyl group is as defined above, non-limiting examples of which include azetidinyloxy, azeolanyloxy, piperidinyloxy, piperazinyloxy, oxolanyloxy, oxhexyloxy, and the like.

[1138] "-C(O)C1-C3 alkyl" refers to -C(O)-CH3, -C(O)-CH2CH3 and the like.

[1139] "Cyano" refers to -CN.

[1140] "Hydroxy" refers to -OH.

[1141] "Sulfonyl" refers to -S(O)2-.

[1142] "Carboxy" or "carboxylic acid" refers to -COOH.

[1143] "Oxo" refers to a =0 group.

[1144] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[1145] "Pd(PPh3)2Cl2" refers to (dichlorobis(triphenylphosphine)palladium).

[1146] "TEA" refers to triethylamine.

[1147] "EA or EtOAc" refers to ethyl acetate.

[1148] "THF" refers to tetrahydrofuran.

[1149] "NaBH4" refers to sodium borohydride.

[1150] "DCM" refers to dichloromethane.

[1151] "Tf2O" refers to trifluoromethanesulfonic anhydride.

[1152] "(Bpin)2" refers to bispinacol borate.

[1153] "Pd(dppf)2Cl2" refers to 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride.

[1154] "KOAc" refers to potassium acetate.

[1155] "DMF" refers to N,N-dimethylformamide.

[1156] "NBS" refers to N-bromosuccinimide.

[1157] "EtOH" refers to ethanol.

[1158] "MeOH" refers to methanol.

[1159] "Pd / C" refers to palladium / carbon.

[1160] "Pd(OH)2 / C" refers to palladium hydroxide on carbon.

[1161] "DMSO" refers to dimethyl sulfoxide.

[1162] "HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[1163] "TFA" refers to trifluoroacetic acid.

[1164] "NMP" refers to N-methylpyrrolidone.

[1165] "IBX" refers to 2-iodoacylbenzoic acid.

[1166] "DIEA" refers to N,N-diisopropylethylamine.

[1167] "STAB" refers to sodium triacetoxyborohydride.

[1168] "T3P" refers to 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide.

[1169] "NaOH" refers to sodium hydroxide.

[1170] "DMAP" refers to 4-dimethylaminopyridine.

[1171] "TPSC1" refers to 2,4,6-triisopropylbenzenesulfonyl chloride.

[1172] "DPBS" refers to Dulbecco's phosphate buffered saline.

[1173] "Dess-Martin" refers to Dess-Martin reagent.

[1174] "PBS" refers to phosphate buffered saline.

[1175] "SDS-PAGE" refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

[1176] "PVDF" refers to polyvinylidene fluoride.

[1177] "PE" refers to petroleum ether.

[1178] "NaHCO3" refers to sodium bicarbonate.

[1179] "Na2SO4" refers to sodium sulfate.

[1180] "NH4Cl" refers to ammonium chloride.

[1181] "AcOH" refers to acetic acid.

[1182] "HCl" refers to hydrochloric acid.

[1183] "DCC" refers to N,N'-dicyclohexylcarbodiimide.

[1184] "Ti(OEt)4" refers to tetraethyl titanate.

[1185] "L-Selectride" refers to lithium triisobutylborohydride.

[1186] "BOP" refers to benzotriazol-1-oxytris(dimethylamino)phosphine hexafluorophosphate

[1187] "DBU" refers to 1,8-diazacyclo[5,4,0]undecene-7-ene

[1188] "LiOH.H2O" refers to lithium hydroxide monohydrate

[1189] "EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1190] "NIS" N-iodosuccinimide.

[1191] "Ac2O" refers to acetic anhydride.

[1192] "HOAc" refers to acetic acid.

[1193] "Hantzsch-ester" refers to diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.

[1194] "DMA" refers to dimethylacetamide.

[1195] "NiBr2(dtbpy)" refers to 4,4-di-tert-butylbipyridinium nickel dibromide.

[1196] "K2CO3" refers to potassium carbonate.

[1197] "9-BBN" refers to 9-borabicyclo[3.3.1]nonane.

[1198] "MTBE" refers to methyl tert-butyl ether.

[1199] "LiOH" refers to lithium hydroxide.

[1200] "DCE" refers to dichloroethane.

[1201] "NaBH3CN" refers to sodium cyanoborohydride.

[1202] "CBr4" refers to carbon tetrabromide.

[1203] "PPh3" refers to triphenylphosphine.

[1204] "n-BuLi" refers to n-butyllithium.

[1205] "NaH" refers to sodium hydrogen.

[1206] "i-PrOH" refers to isopropyl alcohol.

[1207] "ACN" refers to acetonitrile.

[1208] "NH4HCO3" refers to ammonium bicarbonate.

[1209] "m-CPBA" refers to meta-chloroperbenzoic acid.

[1210] "KI" refers to potassium iodide.

[1211] "IPA" refers to isophthalic acid

[1212] "N2H4-H2O" refers to hydrazine hydrate.

[1213] "NMI" refers to N-methylimidazole.

[1214] "TCFH" refers to tetramethylchlorouronium hexafluorophosphonate

[1215] "Ruphos Pd G2" refers to chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II).

[1216] "K3PO4" refers to potassium phosphate.

[1217] "(Boc)2O" refers to di-tert-butyl dicarbonate.

[1218] "DAST" refers to diethylaminosulfur trifluoride.

[1219] "KF" refers to potassium fluoride.

[1220] "CH3CN" refers to acetonitrile.

[1221] "POCl3" refers to phosphorus oxychloride.

[1222] "Na2CO3" refers to sodium carbonate.

[1223] "PCC" refers to pyridinium chlorochromate.

[1224] "DCC" refers to dicyclohexylcarbodiimide.

[1225] "NiBr2" refers to nickel bromide.

[1226] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[1227] "Pd(OAc)2" refers to palladium acetate.

[1228] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[1229] "i-Pr2NH" refers to diisopropylamine.

[1230] "CbzCl" refers to benzyloxycarbonyl chloride.

[1231] "Prep-HPLC or Pre-HPLC" refers to preparative high performance liquid chromatography.

[1232] "Sat." refers to a saturated solution.

[1233] "aq" refers to aqueous solution.

[1234] In the chemical structures herein, "-" as a connecting bond represents a single bond, and "=" represents a double bond (which may be trans or cis if the configuration is not limited).

[1235] "Optional" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

[1236] "Substituted" means that one or more hydrogen atoms, preferably up to five, and more preferably one to three, in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g., olefinic) bonds.

[1237] As used herein, the term "optionally substituted" may be unsubstituted or substituted unless otherwise indicated; when substituted, the substituents may be one or more (e.g., 2, 3, 4, 5, or 6) independently selected from alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl optionally substituted with one or more (e.g., 2, 3, 4, 5, or 6) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl optionally substituted with one or more groups selected from alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, oxo.

[1238] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert its biological activity.

[1239] The present invention also provides pharmaceutically acceptable salts of compounds of formula (I). The term "pharmaceutically acceptable salt" refers to acid addition salts or base addition salts of relatively nontoxic compounds of the present invention. The acid addition salts are salts formed between compounds of formula (I) of the present invention and suitable inorganic or organic acids. These salts can be prepared during the final separation and purification of the compound, or can be prepared by reacting the purified compound of formula (I) in its free base form with a suitable organic or inorganic acid. Representative acid addition salts include hydrobromide, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactobionate, and laurylsulfonate. The base addition salt is a salt formed by the compound of formula (I) with a suitable inorganic base or organic base, including, for example, salts formed with alkali metals, alkaline earth metals, and quaternary ammonium cations, such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, tetramethylammonium salts, tetraethylammonium salts, etc.; amine salts include salts formed with ammonia (NH3), primary amines, secondary amines or tertiary amines, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, etc.

[1240] The compounds of the present invention or their pharmaceutically acceptable salts can be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (powders, ointments or drops), or intratumorally.

[1241] The compound of the present invention can be administered at a dosage of approximately 0.05-300 mg / kg body weight / day, preferably 10-300 mg / kg body weight / day, more preferably 10-200 mg / kg body weight / day.

[1242] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including but not limited to capsules, tablets, pills, powders, granules and the like. In these solid dosage forms, the compound of formula (I) of the present invention is mixed as an active ingredient with at least one conventional inert excipient (or carrier), for example, sodium citrate or dicalcium phosphate, or with the following ingredients: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (2) binders, such as hydroxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (5) solubilizers, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) adsorbents, such as kaolin; and (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. Capsules, tablets and pills may also contain buffering agents.

[1243] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be coated or microencapsulated with coatings and shell materials such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be microencapsulated with one or more of the above-mentioned excipients.

[1244] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into liquid dosage forms for oral administration, including but not limited to pharmaceutically acceptable emulsions, solutions, suspensions, syrups and tinctures. In addition to the active ingredient, the compound of formula (I) or its pharmaceutically acceptable salt, the liquid dosage form may contain inert diluents such as water and other solvents, solubilizers and emulsifiers conventionally used in the art, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures of these substances. In addition to these inert diluents, the liquid dosage form of the present invention may also contain conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices.

[1245] The suspending agent includes ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol, microcrystalline cellulose, aluminum methylate and agar or a mixture of these substances.

[1246] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into dosage forms for parenteral injection, including but not limited to physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[1247] The compounds of the present invention or their pharmaceutically acceptable salts can also be formulated into dosage forms for topical administration including ointments, powders, suppositories, drops, sprays and inhalants, etc. The active ingredient, the compound of formula (I) of the present invention or its pharmaceutically acceptable salt is mixed under sterile conditions with a physiologically acceptable carrier and optional preservatives, buffers, or propellants that may be required if necessary.

[1248] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient, or diluent. When preparing the pharmaceutical composition, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof is typically mixed with a pharmaceutically acceptable carrier, excipient, or diluent.

[1249] The composition of the present invention can be formulated into conventional pharmaceutical preparations according to conventional preparation methods, such as tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, sprays, etc.

[1250] The compounds of the present invention or their pharmaceutically acceptable salts can be administered alone or, if necessary, in combination with other pharmaceutically acceptable therapeutic agents, such as other anti-tumor drugs. The components to be combined can be administered simultaneously or sequentially, in the form of a single formulation or in the form of different formulations. The combination can include not only a combination of a compound of the present invention and one other active agent, but also a combination of a compound of the present invention and two or more other active agents.

[1251] In the present invention, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrader compound of formula (I) may be: EGFR and / or its mutant inhibitors, ErbB2 (Her2) and / or its mutant inhibitors, ALK and / or its mutant inhibitors, MEK and / or its mutant inhibitors, Kras and / or its mutant inhibitors, BCR-ABL and / or its mutant inhibitors, FGFR1 / FGFR2 / FGFR3 and / or its mutant inhibitors, ROS1 and / or its mutant inhibitors, c-MET and / or its mutant inhibitors, AXL and / or its mutant inhibitors, NTRK1 and / or its mutant inhibitors, RET and / or its mutant inhibitors, taxanes, platinum-containing compounds, antimetabolites, mitotic kinase inhibitors, immunotherapeutic agents, anti-angiogenic drugs, topoisomerase inhibitors, A-Raf / B-Raf / C-RAf and / or its mutant inhibitors, ERK and / or its mutant inhibitors, apoptosis inhibitors, mTOR inhibitors, epigenetic regulators, IGF1 / 2 and / or IGF1-R inhibitors, Ras GEF and / or its mutant inhibitors, PI3K and / or its mutant inhibitors.

[1252] In the present invention, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrading agent compound of formula (I) can be: afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, EGF-816, trastuzumab, pertuzumab, crizotinib, alectinib, entrectinib, brigatinib ( brigatinib), trametinib, cobimetinib, binimetinib, selumetinib, refametinib, imatinib, dasatinib, nilotinib, nintedanib, crizotinib, lorlatinib, ceritinib, merestinib, paclitaxel, nab-Paclitaxel, docetaxel, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, a combination of trifluridine and tipiracil (TAS102), palbociclib, ribociclib, abemaciclib, ipilimumab, nivolumab, pembrolizumab Pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (spartalizumab), bevacizumab, irinotecan, liposomal irinotecan, topotecan, ulixertinib, rapamycin, temsirolimus, everolimus, ridaforolimus, JQ-1, GSK 525762, OTX 015 (=MK8628), CPI 0610, TEN-010 (=RO6870810), xentuzumab (antibody 60833 in WO 2010 / 066868), or MEDI-573 (=dusigitumab).

[1253] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[1254] The reagents and raw materials used in the present invention are commercially available.

[1255] The positive progress of the present invention is that the SOS1 protein degrader described in the present invention has a novel structure, can effectively bind to the SOS1 target protein or produce an inhibitory effect, and further, can effectively and specifically degrade the SOS1 protein. DETAILED DESCRIPTION

[1256] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[1257] Ⅰ Compound Preparation Examples

[1258] Intermediate 1: (R)-2-methyl-3-(1-((4-methyl-7-(4-(piperidine-4-carbonyl)piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzylcyanide

[1259] Step 1: Preparation of tert-butyl (R)-4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate

[1260] tert-Butyl 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate (80 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (8 mL), and (R)-3-(1-aminoethyl)-2-methylbenzylcyanide (43 mg, 0.22 mmol) and potassium fluoride (127 mg, 2.2 mmol) were added. The mixture was heated to 130°C and stirred for 68 hours. The reaction mixture was cooled to room temperature, and water (100 mL) was added. The mixture was filtered, and the filter cake was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to obtain tert-butyl (R)-4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate.

[1261] LC-MS:(ESI,m / z):[M+H] + =488.2.

[1262] Step 2: Preparation of (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile

[1263] (R)-tert-Butyl 4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate (60 mg, 0.12 mmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, which was used directly in the next reaction without purification.

[1264] LC-MS:(ESI,m / z):[M+H] + =388.1.

[1265] Step 3: Preparation of (R)-tert-butyl 4-(4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidine-1-carboxylate

[1266] (R)-2-Methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (160 mg, 0.41 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (122 mg, 0.53 mmol) were dissolved in DMF (10 mL), and HATU (202 mg, 0.53 mmol) and N,N-diisopropylethylamine (158 mg, 1.23 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 1:9) to give (R)-tert-butyl 4-(4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidine-1-carboxylate.

[1267] LC-MS:(ESI,m / z):[M+H] + =599.4.

[1268] Step 4: Preparation of (R)-2-methyl-3-(1-((4-methyl-7-(4-(piperidine-4-carbonyl)piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzyl nitrile

[1269] (R)-tert-Butyl 4-(4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (100 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to give (R)-2-methyl-3-(1-((4-methyl-7-(4-(piperidine-4-carbonyl)piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzyl cyanide, which was used directly in the next reaction without purification.

[1270] LC-MS:(ESI,m / z):[M+H] + =499.2.

[1271] Intermediate 2: (R)-3-(1-((7-(4-(1-((3-azaspiro[5.5]undec-9-yl)methyl)piperidine-4-carbonyl)piperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzylcyanide

[1272] Step 1: Preparation of (R)-tert-butyl 9-((4-(4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[1273] (R)-2-Methyl-3-(1-((4-methyl-7-(4-(piperidine-4-carbonyl)piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (100 mg, 0.16 mmol, TFA salt) and tert-butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (53 mg, 0.19 mmol) were dissolved in tetrahydrofuran (10 mL), sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added, and the mixture was heated to 50°C and stirred overnight. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to give (R)-9-((4-(4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester.

[1274] LC-MS:(ESI,m / z):[M+H] + =764.4.

[1275] Step 2: Preparation of (R)-3-(1-((7-(4-(1-((3-azaspiro[5.5]undec-9-yl)methyl)piperidine-4-carbonyl)piperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzylcyanide

[1276] (R)-tert-Butyl 9-((4-(4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (70 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to give (R)-3-(1-((7-(4-(1-((3-azaspiro[5.5]undec-9-yl)methyl)piperidin-4-carbonyl)piperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzyl cyanide, which was used directly in the next reaction without purification.

[1277] LC-MS:(ESI,m / z):[M+H] + =664.4.

[1278] Intermediate 3: 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1279] Step 1: Preparation of tert-butyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate

[1280] Tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (100 mg, 0.31 mmol) and pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (160 mg, 0.36 mmol) were dissolved in dimethyl sulfoxide (5 mL), and DIEA (119 mg, 0.93 mmol) was added under stirring and stirred at room temperature for 2 hours. The mixture was diluted with water (50 mL) and washed with ethyl acetate (50 mL x 4 ). 3) extraction, the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 1:9) to give tert-butyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate.

[1281] LC-MS:(ESI,m / z):[M+H-100] + =477.2.

[1282] Step 2: Preparation of 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1283] Tert-butyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate (90 mg, 0.16 mmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 8-9 with saturated aqueous sodium bicarbonate solution, water (40 mL) was added, and the mixture was extracted with methanol / dichloromethane (1 / 9, 50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione, which was used directly in the next reaction without purification.

[1284] LC-MS:(ESI,m / z):[M+H] + =477.2.

[1285] Intermediate 4: Preparation of methyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexene-3-ene-1-carboxylate

[1286] 7-Chloro-4-methylpyrido[3,4-d]pyridazin-1-ol (1.8 g, 9.23 mmol) was dissolved in 1,4-dioxane (100 mL) and water (25 mL), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexene-3-ene-1-carboxylic acid methyl ester (2.95 g, 11.07 mmol), potassium phosphate (3.9 g, 18.46 mmol) and Pd(dppf)2Cl2 (1.35 g, 1.2 mmol) were added. The reaction solution was replaced with nitrogen three times, and then heated to 100 ° C and stirred for 3 hours. The mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 4:1) to give methyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexene-3-ene-1-carboxylate.

[1287] LC-MS:(ESI,m / z):[M+H] + =300.1.

[1288] Intermediate 5: (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethylamine

[1289] Step 1: Preparation of 3-bromo-2-methylbenzaldehyde

[1290] Dissolve 1,3-dibromo-2-toluene (35 g, 140.04 mmol) in anhydrous tetrahydrofuran (350 mL) and cool the reaction mixture to -78°C. Then, add n-butyllithium (2.5 M, 61.62 mL) dropwise to the reaction mixture at -78°C. After the addition is complete, stir the reaction mixture at -78°C for 1 hour. DMF (12.28 g, 168.05 mmol) is then added dropwise to the reaction mixture at -78°C. The temperature is raised from -78°C to 0°C and stirred at 0°C for 2 hours. Saturated ammonium chloride solution is added to quench the reaction at 0°C. The mixture is separated, and the aqueous phase is extracted with ethyl acetate (100 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (petroleum ether) to yield 3-bromo-2-methylbenzaldehyde.

[1291] Step 2: Preparation of 1-bromo-3-(difluoromethyl)-2-toluene

[1292] Dissolve 3-bromo-2-methylbenzaldehyde (47 g, 236.13 mmol) in anhydrous dichloromethane (500 mL) and cool the system to 0°C. Then, add DAST (1 M, 354.19 mL) dropwise to the reaction system at 0°C. After the addition is complete, stir the reaction solution at 15°C for 16 hours. Cool the reaction system to 0°C and quench the reaction by adding saturated sodium bicarbonate solution. Separate the layers, extract the aqueous phase with dichloromethane (150 mL x 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting crude product is purified by silica gel column chromatography (petroleum ether) to yield 1-bromo-3-(difluoromethyl)-2-toluene.

[1293] 1 H NMR (400MHz, CDCl3) δ7.66 (dd, J = 8.0, 2.4Hz, 1H), 7.46 (d, J = 8.2Hz, 1H), 7.13 (t, J = 8.2Hz, 1H), 6.75 (t, J = 56Hz, 1H), 2.48 (s, 3H).

[1294] Step 3: Preparation of 1-(3-(difluoromethyl)-2-methylphenyl)ethanone

[1295] 1-Bromo-3-(difluoromethyl)-2-toluene (30 g, 135.72 mmol), tributyl(1-ethoxyvinyl)stannane (53.92 g, 149.29 mmol), and Pd(PPh3)2Cl2 (4.76 g, 6.79 mmol) were dissolved in anhydrous dioxane (300 mL). The temperature of the system was raised to 100°C and the reaction was carried out under nitrogen for 16 hours. The reaction system was cooled to 15°C and quenched by adding 1N hydrochloric acid solution and potassium fluoride solution and stirring for 10 minutes. The reaction solution was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 1-(3-(difluoromethyl)-2-methylphenyl)ethanone.

[1296] LC-MS:(ESI,m / z):[M+H] + =185.0

[1297] Step 4: Preparation of (R,E)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfonamide

[1298] 1-(3-(Difluoromethyl)-2-methylphenyl)ethanone (14 g, 76.01 mmol), (R)-2-methylpropane-2-sulfonamide (11.06 g, 91.21 mmol), diethylene glycol dimethyl ether (10.20 g, 76.01 mmol) and tetraethyl titanate (86.69 g, 380.06 mmol) were dissolved in anhydrous tetrahydrofuran (140 mL), the system temperature was raised to 80 ° C, and the reaction was carried out under nitrogen protection for 16 hours. The reaction system was cooled to 25°C and quenched by adding water. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain (R,E)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfonamide.

[1299] LC-MS:(ESI,m / z):[M+H] + =288.1.

[1300] Step 5: Preparation of (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonamide

[1301] Dissolve (R,E)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfonamide (19 g, 66.12 mmol) in anhydrous tetrahydrofuran (190 mL) and cool the system to 0°C. Then, add 9-BBN (0.5 M, 158.68 mL) dropwise to the reaction system at 0°C. After the addition is complete, stir the reaction mixture at 0°C for 3 h. The reaction system was heated to 15°C, quenched with methanol (25 mL) and stirred for 30 min, then water (200 mL) was added, the liquids were separated, the aqueous phase was extracted with dichloromethane (150 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonamide.

[1302] LC-MS:(ESI,m / z):[M+H] + =290.0.

[1303] Step 6: Preparation of (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethanamine

[1304] (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonamide (10 g, 34.56 mmol) was dissolved in anhydrous dichloromethane (150 mL). A 4M solution of dioxane hydrochloride (50 mL) was then added dropwise to the reaction system at 25°C. After the addition was complete, the reaction mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was added to dichloromethane (200 mL) with stirring, filtered, and the filter cake dried to yield (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethylamine.

[1305] LC-MS:(ESI,m / z):[M-NH2] + =169.0

[1306] 1 H NMR(400MHz, DMSO-d6)δ8.58(br,3H),7.79(d,J=8.0Hz,1H),7.54(d,J=8.0Hz,1H),7.46-7 .42(m,1H),7.24(t,J=54.8Hz,1H),4.68-4.58(m,1H),2.39(s,3H),1.49(d,J=6.8Hz,3H).

[1307] Intermediate 6: (R)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]piperazin-1-amine

[1308] Step 1: Preparation of tert-butyl (R)-4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate

[1309] Tert-butyl 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate (400 mg, 1.1 mmol) and (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethanamine hydrochloride (244 mg, 1.1 mmol) were dissolved in DMSO (15 mL), and potassium fluoride (1.2 g, 22 mmol) was added, and the temperature was raised to 130°C and stirred for 65 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM=3:97) to give (R)-tert-butyl 4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate.

[1310] LC-MS:(ESI,m / z):[M+H] + =513.2.

[1311] Step 2: Preparation of (R)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]piperazin-1-amine

[1312] (R)-tert-Butyl 4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate (130 mg, 0.25 mmol) was dissolved in a hydrogen chloride-1,4-dioxane solution (4 M, 10 mL) and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to give (R)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]piperazin-1-amine, which was used directly in the next reaction without purification.

[1313] LC-MS:(ESI,m / z):[M+H] + =413.1.

[1314] Intermediate 10: 7-chloro-4-methylpyrrolo[3,4-d]pyridazin-1-ol

[1315] Step 1: Preparation of methyl 5-bromo-2-chloroisonicotinate

[1316] 5-Bromo-2-chloroisonicotinic acid (10 g, 42.5 mmol) was dissolved in anhydrous methanol (100 mL). SOCl2 (6.1 mL, 51 mmol) was slowly added dropwise at 0°C. The reaction mixture was heated to 75°C and stirred for 8 hours. The mixture was concentrated under reduced pressure, and ethyl acetate (100 mL) was added. Saturated NaHCO3 solution was slowly added until the pH reached approximately 8. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield methyl 5-bromo-2-chloroisonicotinate.

[1317] LC-MS:(ESI,m / z):[M+H] + =250.0.

[1318] Step 2: Preparation of methyl 2-chloro-5-(1-ethoxyvinyl)isonicotinate

[1319] Methyl 5-bromo-2-chloroisonicotinate (10 g, 39.9 mmol) was dissolved in 1,4-dioxane (110 mL), and tributyl(1-ethoxyvinyl)silane (14.6 g, 40.2 mmol) and Pd(PPh3)2Cl2 (1.2 g, 1.608 mmol) were added. The reaction system was purged with nitrogen three times, then heated to 80°C and stirred overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature, KF was added, and stirred for 2 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude methyl 2-chloro-5-(1-ethoxyvinyl)isonicotinate.

[1320] LC-MS:(ESI,m / z):[M+H] + =242.0.

[1321] Step 3: Preparation of methyl 5-acetyl-2-chloroisonicotinate

[1322] Methyl 2-chloro-5-(1-ethoxyvinyl)isonicotinate (20 g, crude product, 39.9 mmol) was dissolved in THF (100 mL), concentrated HCl (70 mL) was added, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate was slowly added until the pH was approximately 8, followed by extraction with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:9) to obtain methyl 5-acetyl-2-chloroisonicotinate.

[1323] LC-MS:(ESI,m / z):[M+H] +=214.1.

[1324] Step 4: Preparation of 7-chloro-4-methylpyrrolo[3,4-d]pyridazin-1-ol

[1325] Methyl 5-acetyl-2-chloroisonicotinate (1 g, 4.69 mmol) was dissolved in anhydrous ethanol (15 mL), and hydrazine hydrate (703 mg, 14.08 mmol) was added. The reaction mixture was heated to 95°C and stirred for 0.5 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol:dichloromethane = 3:97) to obtain 7-chloro-4-methylpyrrolo[3,4-d]pyridazin-1-ol.

[1326] LC-MS:(ESI,m / z):[M+H] + =196.1.

[1327] Intermediate 11: (R)-2-methyl-3-(1-((4-methyl-7-(1-(piperidine-4-carbonyl)piperidin-4-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzylcyanide

[1328] Step 1: Preparation of tert-butyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1329] 7-Chloro-4-methylpyrido[3,4-d]pyridazin-1-ol (790 mg, 4.0 mmol) was dissolved in 1,4-dioxane / water (60 mL / 15 mL), and then 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid methyl ester (1.5 g, 4.9 mmol), potassium phosphate (1.7 g, 8.0 mmol) and Pd(dppf)2Cl2 (585 mg, 0.8 mmol) were added. The reaction solution was replaced with nitrogen three times, and then heated to 100°C and stirred for 3 hours. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (80 mL x 3), and the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate) to give tert-butyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

[1330] LC-MS:(ESI,m / z):[M-55] + =287.2.

[1331] Step 2: Preparation of tert-butyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate

[1332] tert-Butyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g, 3.5 mmol) was dissolved in methanol (80 mL) and tetrahydrofuran (80 mL). Palladium on carbon (10%, 600 mg) was added, and the resulting mixture was replaced with hydrogen three times and stirred at room temperature for 3 hours. The reaction solution was filtered through celite, and the filtrate was directly concentrated under reduced pressure to obtain tert-butyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate, which was used directly in the next reaction without purification.

[1333] LC-MS:(ESI,m / z):[M-55] + =289.1.

[1334] Step 3: Preparation of 1-chloro-4-methyl-7-(piperidin-4-yl)pyrido[3,4-d]pyridazine

[1335] Dissolve tert-butyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate (500 mg, 1.45 mmol) in CHCN (9 mL), add POCl (3 mL) and TEA (146 mg, 1.45 mmol), and heat to 100°C under nitrogen with stirring for 1 hour. Cool to room temperature, and adjust the pH of the reaction solution to 8 with aqueous NaCO in an ice bath. Use the solution directly in the next reaction without purification.

[1336] LC-MS:(ESI,m / z):[M+H] + =263.2.

[1337] Step 4: Preparation of tert-butyl 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate

[1338] To an aqueous solution of 1-chloro-4-methyl-7-(piperidin-4-yl)pyrido[3,4-d]pyridazine was added 1,4-dioxane (5 mL), NaCO (307 mg, 2.90 mmol), and (Boc)O (302 mg, 1.45 mmol). The reaction mixture was stirred at room temperature for 1 hour. Extraction was then performed with ethyl acetate (80 mL x 3). The organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate.

[1339] LC-MS:(ESI,m / z):[M+H] + =363.1.

[1340] Step 5: Preparation of tert-butyl (R)-4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate

[1341] Tert-butyl 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate (310 mg, 0.85 mmol) was dissolved in DMSO (30 mL), and (R)-3-(1-aminoethyl)-2-methylbenzonitrile (168 mg, 0.85 mmol) and KF (986 mg, 17.0 mmol) were added. The reaction solution was purged with nitrogen three times and heated to 130°C with stirring for 16 hours. The mixture was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate) to give tert-butyl (R)-4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate.

[1342] LC-MS:(ESI,m / z):[M+H] + =487.0.

[1343] Step 6: Preparation of (R)-2-methyl-3-(1-((4-methyl-7-(piperidin-4-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile

[1344] (R)-tert-Butyl 4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate (140 mg, 0.29 mmol) was dissolved in HCl / 1,4-dioxane solution (4 M, 5 mL) and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to give (R)-2-methyl-3-(1-((4-methyl-7-(piperidin-4-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, which was used directly in the next reaction without purification.

[1345] LC-MS:(ESI,m / z):[M+H] + =387.3.

[1346] Step 7: Preparation of (R)-tert-butyl 4-(4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carbonyl)piperidine-1-carboxylate

[1347] (R)-2-Methyl-3-(1-((4-methyl-7-(piperidin-4-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (150 mg, 0.31 mmol), 1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid (71 mg, 0.31 mmol), and HATU (141 mg, 0.37 mmol) were dissolved in DMF (5 mL). DIEA (120 mg, 0.93 mmol) was then added and stirred at room temperature for 1 hour. The reaction solution was diluted with water (20 mL), and a precipitate was formed. The precipitate was filtered and the filter cake was dried under vacuum to provide tert-butyl (R)-4-(4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carbonyl)piperidine-1-carboxylate.

[1348] LC-MS:(ESI,m / z):[M+H] + =597.9.

[1349] Step 8: Preparation of (R)-2-methyl-3-(1-((4-methyl-7-(1-(piperidine-4-carbonyl)piperidin-4-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzylcyanide

[1350] (R)-tert-Butyl 4-(4-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-1-carbonyl)piperidine-1-carboxylate (153 mg, 0.26 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to give (R)-2-methyl-3-(1-((4-methyl-7-(1-(piperidine-4-carbonyl)piperidin-4-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzyl cyanide (crude, trifluoroacetate) which was used directly in the next reaction without purification.

[1351] LC-MS:(ESI,m / z):[M+H] + =498.3.

[1352] Intermediate 12: 1-chloro-4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazine

[1353] Step 1: Preparation of tert-butyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate

[1354] 7-Chloro-4-methylpyrido[3,4-d]pyridazin-1-ol (1.0 g, 5.13 mmol) was dissolved in DMSO (15 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (1.14 g, 6.15 mmol) and potassium fluoride (2.98 g, 51.3 mmol). The reaction mixture was heated to 130°C and stirred overnight. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA) to yield tert-butyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate.

[1355] LC-MS:(ESI,m / z):[M+H] + =346.1.

[1356] Step 2: Preparation of 1-chloro-4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazine

[1357] Tert-butyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate (1.2 g, 3.48 mmol) was dissolved in acetonitrile (21 mL), POCl3 (7 mL) was added, and the mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL). The pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with MeOH / DCM (1 / 9, 100 mL x 5). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-chloro-4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazine.

[1358] LC-MS:(ESI,m / z):[M+H] + =264.2.

[1359] Intermediate 13: 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylic acid methyl ester

[1360] Step 1: Preparation of methyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylate

[1361] Methyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexene-3-ene-1-carboxylate (900 mg, 3.0 mmol) was dissolved in methanol (80 mL), and 10% palladium on carbon (300 mg) was added. The resulting mixture was heated to 60°C under a hydrogen atmosphere and stirred for 24 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was directly concentrated under reduced pressure to obtain methyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylate (crude product, 41.12% trans configuration, 49.90% cis configuration), which was used directly in the next reaction without purification.

[1362] LC-MS:(ESI,m / z):[M+H] + =302.1.

[1363] Step 4: Preparation of (1R,4R)-4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylic acid

[1364] Methyl 4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylate (720 mg, 2.38 mmol) was dissolved in methanol (100 mL). A 30% methanol solution of sodium methoxide (4.3 g, 23.88 mmol) was added. The reaction mixture was heated to 70°C and stirred overnight. After cooling to room temperature, the pH of the reaction mixture was adjusted to 3 with aqueous hydrochloric acid. The mixture was filtered and the resulting solid was dried to afford (1R,4R)-4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylic acid (crude product, trans configuration: 92.17%, cis configuration: none), which was used directly in the next reaction without purification.

[1365] LC-MS:(ESI,m / z):[M+H] + =288.1.

[1366] Step 5: Preparation of methyl (1R,4R)-4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylate

[1367] (1R,4R)-4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylic acid (700 mg, 2.38 mmol) was dissolved in methanol (30 mL). Concentrated sulfuric acid (5 drops) was added, and the mixture was heated to 80°C and stirred for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1R,4R)-4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylic acid methyl ester (trans configuration: 94.47%, cis configuration: none).

[1368] LC-MS:(ESI,m / z):[M+H] + =302.1.

[1369] 1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),9.24(s,1H),7.91(s,1H),2.97-2.87( m,1H),2.57(s,3H),2.47-2.36(m,1H),2.11-1.91(m,4H),1.71-1.45(m,4H).

[1370] Step 6: Preparation of methyl 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylate

[1371] Methyl (1R,4R)-4-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylate (100 mg, 0.33 mmol) was dissolved in acetonitrile (10 mL), and phosphorus oxychloride (10 mL) was added. The mixture was heated to 70°C under nitrogen and stirred for 60 hours. The reaction mixture was concentrated under reduced pressure, and the resulting oil was dissolved in dichloromethane (10 mL). Water (20 mL) was added, and the pH of the mixture was adjusted to 8 with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate) to obtain methyl 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carboxylate (trans configuration: 61.85%, cis configuration: 13.43%).

[1372] LC-MS:(ESI,m / z):[M+H] + =320.0.

[1373] Intermediate 14: 1-(2-chloro-5-(4-(4-hydroxybutyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1374] Step 1: Preparation of 4-(piperidin-4-yl)butan-1-ol

[1375] Dissolve tert-butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate (227 mg, 0.88 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.2 mL), and stir the reaction mixture at room temperature for 1 hour. Concentrate under reduced pressure to obtain 4-(piperidin-4-yl)butan-1-ol (TFA salt).

[1376] LC-MS:(ESI,m / z):[M+H] + =158.1.

[1377] Step 2: Preparation of 1-(2-chloro-5-(4-(4-hydroxybutyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1378] 4-(Piperidin-4-yl)butan-1-ol (340 mg, 0.88 mmol) and pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (382 mg, 0.88 mmol) were dissolved in DMSO (5 mL). DIEA (340 mg, 2.64 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:30) to obtain 1-(2-chloro-5-(4-(4-hydroxybutyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1379] LC-MS:(ESI,m / z):[M+H] + =408.2.

[1380] Intermediate 15: 3-((R)-1-((7-((1R,4R)-4-(4-((3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzylcyanide

[1381] Step 1: Preparation of tert-butyl 4-((1R,4R)-4-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carbonyl)piperazine-1-carboxylate

[1382] (1R,4R)-4-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1- Carboxylic acid (100 mg, 0.23 mmol) and tert-butyl piperazine-1-carboxylate (46 mg, 0.25 mmol) were dissolved in DMF (10 mL), and HATU (131 mg, 0.34 mmol) and N,N-diisopropylethylamine (90 mg, 0.70 mmol) were added with stirring. The reaction solution was stirred at room temperature overnight, diluted with water (100 mL), and filtered. The filter cake was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to give tert-butyl 4-((1R,4R)-4-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carbonyl)piperazine-1-carboxylate.

[1383] LC-MS:(ESI,m / z):[M+H] +=598.8.

[1384] Step 2: Preparation of 2-methyl-3-((R)-1-((4-methyl-7-((1R,4R)-4-(piperazine-1-carbonyl)cyclohexyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile

[1385] Tert-butyl 4-((1R,4R)-4-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carbonyl)piperazine-1-carboxylate (110 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to give 2-methyl-3-((R)-1-((4-methyl-7-((1R,4R)-4-(piperazine-1-carbonyl)cyclohexyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, which was used directly in the next reaction without purification.

[1386] LC-MS:(ESI,m / z):[M+H] + =498.2.

[1387] Step 3: Preparation of tert-butyl 9-((4-((1R,4R)-4-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[1388] 2-Methyl-3-((R)-1-((4-methyl-7-((1R,4R)-4-(piperazine-1-carbonyl)cyclohexyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (110 mg, 0.18 mmol, trifluoroacetate) and tert-butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (60 mg, 0.21 mmol) were dissolved in tetrahydrofuran (10 mL), and then sodium triacetoxyborohydride (191 mg, 0.90 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with water (100 mL), extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to give tert-butyl 9-((4-((1R,4R)-4-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[1389] LC-MS:(ESI,m / z):[M+H] + =763.5.

[1390] Step 4: Preparation of 3-((R)-1-((7-((1R,4R)-4-(4-((3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[1391] tert-Butyl 9-((4-((1R,4R)-4-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (100 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL) and then added. Trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain 3-((R)-1-((7-((1R,4R)-4-(4-((3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, which was used directly in the next reaction without purification.

[1392] LC-MS:(ESI,m / z):[M+H] + =663.4.

[1393] Intermediate 16: (R)-(1-((3-Azaspiro[5.5]undec-9-yl)methyl)piperidin-4-yl)(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazin-1-yl)methanone

[1394] Step 1: Preparation of (R)-tert-butyl 4-(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidine-1-carboxylate

[1395] (R)-N-(1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)-4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]piperazin-1-amine (130 mg, 0.26 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (60 mg, 0.26 mmol) were dissolved in DMF (3 mL), DIEA (100 mg, 0.79 mmol) and HATU (200 mg, 0.52 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM=1:24) to give (R)-tert-butyl 4-(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidine-1-carboxylate.

[1396] LC-MS:(ESI,m / z):[M+H] + =624.2.

[1397] Step 2: Preparation of (R)-(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazin-1-yl)(piperidin-4-yl)methanone

[1398] (R)-tert-Butyl 4-(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (110 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain (R)-(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazin-1-yl)(piperidin-4-yl)methanone, which was used directly in the next reaction without purification.

[1399] LC-MS:(ESI,m / z):[M+H] + =524.3.

[1400] Step 3: Preparation of (R)-tert-butyl 9-((4-(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[1401] (R)-(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazin-1-yl)(piperidin-4-yl)methanone (110 mg, 0.21 mmol) and tert-butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (55 mg, 0.23 mmol) were dissolved in THF (3 mL), NaBH(OAc)3 (164 mg, 1.05 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM=7:93) to give (R)-9-((4-(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester.

[1402] LC-MS:(ESI,m / z):[M+H] + =789.5.

[1403] Step 4: Preparation of (R)-(1-((3-azaspiro[5.5]undec-9-yl)methyl)piperidin-4-yl)(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazin-1-yl)methanone

[1404] (R)-tert-Butyl 9-((4-(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (120 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (2 mL) and stirring at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to afford (R)-(1-((3-azaspiro[5.5]undec-9-yl)methyl)piperidin-4-yl)(4-(1-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperazin-1-yl)methanone, which was used directly in the next reaction without purification.

[1405] LC-MS:(ESI,m / z):[M+H] + =689.4.

[1406] Intermediate 17: 4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)butyraldehyde

[1407] 1-(2-chloro-5-(4-(4-hydroxybutyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (400 mg, 0.98 mmol) was dissolved in dichloromethane (10 mL). PCC (425 mg, 1.96 mmol) was added with stirring, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (methanol:dichloromethane = 6:94) to obtain 4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)butanal.

[1408] LC-MS:(ESI,m / z):[M+H] + =406.1.

[1409] Intermediate 18: (R)-2-methyl-3-(1-((4-methyl-7-(4-(piperidine-4-carbonyl)piperidin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzylcyanide

[1410] Step 1: Preparation of 1-(tert-butyl)4-(1,3-dioxoisoindolin-2-yl)piperidine-1,4-dicarboxylate

[1411] 1-(tert-Butyloxycarbonyl)piperidine-4-carboxylic acid (6.0 g, 26.2 mmol) and 2-hydroxyisoindolin-1,3-dione (3.9 g, 24.01 mmol) were dissolved in tetrahydrofuran (40 mL), followed by the addition of DCC (5.4 g, 26.2 mmol) and DMAP (270 mg, 2.18 mmol) and stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue, followed by extraction with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 2:3) to obtain 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl)piperidine-1,4-dicarboxylate.

[1412] LC-MS:(ESI,m / z):[M+Na] + =397.1.

[1413] Step 2: Preparation of benzyl 4-((pyridin-2-ylthio)carbonyl)piperidine-1-carboxylate

[1414] 1-((Benzyloxy)carbonyl)piperidine-4-carboxylic acid (5.0 g, 19.01 mmol) and 1,2-di(pyridin-2-yl) disulfide (4.6 g, 20.90 mmol) were dissolved in acetonitrile (50 mL), followed by the addition of triphenylphosphine (5.5 g, 20.90 mmol) and stirring at room temperature overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain benzyl 4-((pyridin-2-ylthio)carbonyl)piperidine-1-carboxylate.

[1415] LC-MS:(ESI,m / z):[M+H] + =357.2.

[1416] Step 3: Preparation of benzyl 4-(1-(tert-butyloxycarbonyl)piperidine-4-carbonyl)piperidine-1-carboxylate

[1417] 1-(tert-Butyl) 4-(1,3-dioxoisoindolin-2-yl) piperidine-1,4-dicarboxylate (6.0 g, 16.04 mmol) and benzyl 4-((pyridin-2-ylthio)carbonyl) piperidine-1-carboxylate (5.7 g, 16.04 mmol) were dissolved in DMA / THF (30 / 30 mL), and methyl 2,2'-bipyridine-4,4'-dicarboxylate (90 mg, 0.32 mmol), NiBr2 (100 mg, 0.32 mmol), zinc powder (2.1 g, 32.08 mmol) and zinc chloride (440 mg, 3.21 mmol) were added with stirring. The reaction solution was stirred at room temperature overnight under nitrogen protection. The reaction solution was filtered and concentrated under reduced pressure. The residue was diluted with water (400 mL) and then extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=3:7) to give benzyl 4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperidine-1-carboxylate.

[1418] LC-MS:(ESI,m / z):[M+Na] + =453.1.

[1419] Step 4: Preparation of tert-butyl 4-(piperidine-4-carbonyl)piperidine-1-carboxylate

[1420] Benzyl 4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperidine-1-carboxylate (1.0 g, 2.32 mmol) was dissolved in ethyl acetate (20 mL), and palladium hydroxide (300 mg) was added with stirring. The reaction solution was replaced with hydrogen three times, heated to 70°C and stirred for one hour, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(piperidine-4-carbonyl)piperidine-1-carboxylate.

[1421] LC-MS:(ESI,m / z):[M+H] + =297.3.

[1422] Step 5: Preparation of tert-butyl 4-(1-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-4-carbonyl)piperidine-1-carboxylate

[1423] Tert-butyl 4-(piperidine-4-carbonyl)piperidine-1-carboxylate (650 mg, 2.19 mmol) and 7-chloro-4-methylpyrido[3,4-d]pyridazin-1-ol (428 mg, 2.19 mmol) were dissolved in dimethyl sulfoxide (30 mL), and then potassium fluoride (1.27 g, 21.90 mmol) was added and replaced with nitrogen three times. The reaction solution was heated to 130 ° C under nitrogen protection and stirred for 48 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 6:94) to give tert-butyl 4-(1-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-4-carbonyl)piperidine-1-carboxylate.

[1424] LC-MS:(ESI,m / z):[M+H] + =456.3.

[1425] Step 6: Preparation of (1-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)(piperidin-4-yl)methanone

[1426] tert-Butyl 4-(1-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-4-carbonyl)piperidine-1-carboxylate (600 mg, 1.32 mmol) was dissolved in acetonitrile (40 mL), followed by the addition of phosphorus oxychloride (10 mL). The reaction mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, adjusted to a weak base with saturated sodium bicarbonate solution, concentrated under reduced pressure, and extracted with methanol / dichloromethane (1 / 9, 100 mL x 5). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (1-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)(piperidin-4-yl)methanone, which was used directly in the next reaction without purification.

[1427] LC-MS:(ESI,m / z):[M+H] + =374.2.

[1428] Step 7: Preparation of tert-butyl 4-(1-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-4-carbonyl)piperidine-1-carboxylate

[1429] (1-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)(piperidin-4-yl)methanone (500 mg, 1.34 mmol) was dissolved in dichloromethane (40 mL). Boc2O (300 mg, 1.74 mmol) and triethylamine (300 mg, 1.74 mmol) were added with stirring. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol:dichloromethane = 4:96) to obtain tert-butyl 4-(1-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-4-carbonyl)piperidine-1-carboxylate.

[1430] LC-MS:(ESI,m / z):[M+H] + =474.3.

[1431] Step 8: Preparation of (R)-tert-butyl 4-(1-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-4-carbonyl)piperidine-1-carboxylate

[1432] Tert-butyl 4-(1-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-4-carbonyl)piperidine-1-carboxylate (300 mg, 0.67 mmol) and (R)-3-(1-aminoethyl)-2-methylbenzonitrile (133 mg, 0.67 mmol) were dissolved in dimethyl sulfoxide (30 mL). Potassium fluoride (390 mg, 6.76 mmol) was added with stirring. The reaction solution was purged with nitrogen three times, heated to 130°C and stirred for 48 hours. The reaction solution was diluted with water (100 mL) and extracted with methanol / dichloromethane (1 / 9, 100 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer TLC (methanol:dichloromethane = 1:9) to give (R)-tert-butyl 4-(1-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-4-carbonyl)piperidine-1-carboxylate.

[1433] LC-MS:(ESI,m / z):[M+H] + =598.4.

[1434] Step 9: Preparation of (R)-2-methyl-3-(1-((4-methyl-7-(4-(piperidine-4-carbonyl)piperidin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzyl nitrile

[1435] (R)-tert-Butyl 4-(1-(1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)piperidine-4-carbonyl)piperidine-1-carboxylate (80 mg, 0.13 mmol) was dissolved in dichloromethane (2.5 mL), followed by the addition of trifluoroacetic acid (0.5 mL) and stirring at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to afford (R)-2-methyl-3-(1-((4-methyl-7-(4-(piperidine-4-carbonyl)piperidin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzyl cyanide, which was used directly in the next reaction without purification.

[1436] LC-MS:(ESI,m / z):[M+H] + =498.2.

[1437] Intermediate 19: 2-Methyl-3-((1R)-1-((4-methyl-7-(8-(piperidine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzylcyanide

[1438] Step 1: Preparation of tert-butyl 3-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1439] Dissolve 7-chloro-4-methylpyrido[3,4-d]pyridazin-1-ol (1.0 g, 5.12 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.1 g, 5.12 mmol) in dimethyl sulfoxide (30 mL). Add potassium fluoride (3.0 g, 51.28 mmol) with stirring. Heat the reaction mixture to 130 °C under nitrogen protection and stir for 48 hours. The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 6:94) to give tert-butyl 3-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1440] LC-MS:(ESI,m / z):[M+H] + =372.1.

[1441] Step 2: Preparation of 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1-chloro-4-methylpyrido[3,4-d]pyridazine

[1442] Dissolve tert-butyl 3-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 4.04 mmol) in acetonitrile (40 mL). Add phosphorus oxychloride (9 mL) with stirring. The reaction mixture is heated to 80°C and stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure to afford 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1-chloro-4-methylpyrido[3,4-d]pyridazine, which is used directly in the next reaction without purification.

[1443] LC-MS:(ESI,m / z):[M+H] + =290.2.

[1444] Step 3: Preparation of tert-butyl 3-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1445] 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1-chloro-4-methylpyrido[3,4-d]pyridazine (1.2 g, 4.15 mmol) was dissolved in 1,4-dioxane / water (20 / 20 mL). Boc2O (1.13 g, 4.98 mmol) and sodium bicarbonate (1.1 g, 12.45 mmol) were added with stirring, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 5:95) to give tert-butyl 3-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1446] LC-MS:(ESI,m / z):[M+H] + =390.5.

[1447] Step 4: Preparation of tert-butyl 3-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1448] Tert-butyl 3-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.64 mmol) and (R)-3-(1-aminoethyl)-2-methylbenzidine hydrochloride (125 mg, 0.64 mmol) were dissolved in dimethyl sulfoxide (10 mL). Potassium fluoride (370 mg, 6.40 mmol) was added with stirring. The reaction mixture was heated to 130°C under nitrogen protection and stirred for 48 hours. The reaction solution was diluted with water (100 mL) and extracted with dichloromethane / methanol (1 / 9, 100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 7:93) to give tert-butyl 3-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1449] LC-MS:(ESI,m / z):[M+H] + =514.2.

[1450] Step 5: Preparation of 3-((1R)-1-((7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzyl nitrile

[1451] Tert-butyl 3-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.58 mmol) was dissolved in a hydrogen chloride-1,4-dioxane solution (4 M, 1 mL) and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to give 3-((1R)-1-((7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzyl cyanide, which was used directly in the next reaction without purification.

[1452] LC-MS:(ESI,m / z):[M+H] + =414.2.

[1453] Step 6: Preparation of tert-butyl 4-(3-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)piperidine-1-carboxylate

[1454] 3-((1R)-1-((7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (240 mg, 0.58 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (140 mg, 0.58 mmol) were dissolved in DMF (10 mL), and HATU (260 mg, 0.70 mmol) and DIEA (230 mg, 1.74 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (100 mL) and extracted with methanol / dichloromethane (1 / 9, 100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 5:95) to give tert-butyl 4-(3-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)piperidine-1-carboxylate.

[1455] LC-MS:(ESI,m / z):[M+H] + =625.4.

[1456] Step 7: Preparation of 2-methyl-3-((1R)-1-((4-methyl-7-(8-(piperidine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzyl nitrile

[1457] tert-Butyl 4-(3-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)piperidine-1-carboxylate (100 mg, 0.16 mmol) was dissolved in dichloromethane (2.5 mL), followed by the addition of trifluoroacetic acid (0.5 mL) and stirring at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to afford 2-methyl-3-((1R)-1-((4-methyl-7-(8-(piperidine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzyl cyanide, which was used directly in the next reaction without purification.

[1458] LC-MS:(ESI,m / z):[M+H] + =525.6.

[1459] Intermediate 20: 2-Methyl-3-((1R)-1-((4-methyl-7-(6-(piperidine-4-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzylcyanide

[1460] Step 1: Preparation of tert-butyl 3-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[1461] Dissolve 7-chloro-4-methylpyrido[3,4-d]pyridazin-1-ol (1.0 g, 0.51 mmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.0 g, 0.51 mmol) in dimethyl sulfoxide (30 mL). Add potassium fluoride (3.0 g, 5.10 mmol) with stirring. Heat the reaction mixture to 130 °C under nitrogen protection and stir for 48 hours. The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 6:94) to give tert-butyl 3-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate.

[1462] LC-MS:(ESI,m / z):[M+H] + =358.1.

[1463] Step 2: Preparation of 3-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane

[1464] Dissolve tert-butyl 3-(1-hydroxy-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.6 g, 4.47 mmol) in acetonitrile (50 mL). Add phosphorus oxychloride (10 mL) with stirring. The reaction mixture is heated to 80°C and stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure to afford 3-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane, which is used directly in the next reaction without purification.

[1465] LC-MS:(ESI,m / z):[M+H] + =276.1.

[1466] Step 3: Preparation of tert-butyl 3-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[1467] 3-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane (1.3 g, 4.71 mmol) was dissolved in 1,4-dioxane / water (20 / 20 mL). Boc2O (1.3 g, 5.65 mmol) and sodium bicarbonate (1.2 g, 14.13 mmol) were added with stirring, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 5:95) to give tert-butyl 3-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate.

[1468] LC-MS:(ESI,m / z):[M+H] + =376.2.

[1469] Step 4: Preparation of tert-butyl 3-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[1470] Tert-butyl 3-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (200 mg, 0.53 mmol) and (R)-3-(1-aminoethyl)-2-methylbenzidine hydrochloride (104 mg, 0.53 mmol) were dissolved in dimethyl sulfoxide (10 mL). Potassium fluoride (310 mg, 5.33 mmol) was added with stirring. The reaction mixture was heated to 130°C under nitrogen protection and stirred for 48 hours. The reaction solution was diluted with water (100 mL) and extracted with methanol / dichloromethane (1 / 9, 100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 7:93) to give tert-butyl 3-(1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate.

[1471] LC-MS:(ESI,m / z):[M+H] + =500.4.

[1472] Step 5: Preparation of 3-((1R)-1-((7-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-4-methylpyrido[3...

Claims

1. A compound of formula I, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts: SLE I in, S is: L is a connecting chain, which connects S and E through a covalent bond; E is the E3 ubiquitin ligase ligand; Among them, S: is selected from a single bond or a double bond; X is CH or N; R1 is hydrogen, halogen, OH, mercapto, CN, NO2, NR a R b , C1-C6 alkyl, C1-C6 alkylthiol, C1-C6 heteroalkyl, C1-C6 alkoxy, -O(C1-C6 heteroalkyl), -S(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, -COOR c 、-NHS(O)(R d )、-NHS(O)2(R d )、-NHC(O)-(C1-C6 alkyl)、-NHC(O)-NR a R b 、-NH-(CH2) k -NH-C(O)-R aa 、-NH-(CH2) i -R f’ 、-O-(CH2) z -phenyl, -O-(CH2) z -(4-7 membered heterocycloalkyl), -O-(CH2) z -(5-10 membered heteroaryl), or The superscript "*" indicates the same connect; Or two adjacent R1 together with the carbon atom to which they are attached form a C5-C7 cycloalkyl group or a 5-7 membered heterocycloalkyl group; R a and R b are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl; R c is hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl or C3-C8 cycloalkyl; R d and R e’ are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; R aa is a C1-C6 alkyl, a 3-8 membered heterocycloalkyl or a C3-C8 cycloalkyl; k is 1 or 2; i is 0, 1, or 2; R f’ is a 4-7 membered heterocycloalkyl group, a 5-10 membered heteroaryl group or a C1-C6 alkylsulfonyl group; z is 0, 1, or 2; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by one, two or three groups selected from deuterium, halogen, OH, oxo, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylsulfonyl, phenyl, benzyl, 5-10 membered heteroaryl, -(CH2)-(5-8 membered heteroaryl), -NHC(O)(C1-C6 alkyl), phenoxy, 5-10 membered heteroaryloxy and -NR a R b m is 1, 2 or 3; A1 is C4-C 12 Cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, 1, 2, 3, 4 or 5 R c” Substituted C4-C 12 Cycloalkyl, 1, 2, 3, 4 or 5 R d” substituted 3-8 membered heterocycloalkyl, substituted by 1, 2, 3, 4 or 5 R c’ Substituted C6-C 12 Aryl or 1, 2, 3, 4 or 5 R d’ substituted 5-10 membered heteroaryl, Each R c’ 、R d’ 、R c” and R d” are independently hydrogen, OH, oxo, halogen, CN, C1-C6 alkyl, C1-C6 alkyl(SO2)-, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, halogenated 3-8 membered heterocycloalkyl, -O-CH2-4-7 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 alkylsulfonyl, -NR e R f 、-NHC(=O)-C1-C6 alkyl、C(O)NR c”’ R d”’ 、-C(O)OR g’ 、-(CH2)NR c”’ R d”’ , -S(O)2C1-C6 alkyl, -CH=CH-C3-C8 cycloalkyl, -L'-A2, 1, 2, 3, 4 or 5 R g Substituted C1-C6 alkyl, 1, 2, 3, 4 or 5 R h Substituted C6-C 10 Aryl, 1, 2, 3, 4 or 5 R i substituted 5-10 membered heteroaryl or 1, 2, 3, 4 or 5 R o’ substituted C3-C8 cycloalkyl; Each R o’ 、R g 、R h and R i are independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R j or by one or more R l Substituted C1-C6 alkyl; each R e and R f are independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R j or by one or more R l Substituted C1-C6 alkyl; Each R e and R f are independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R j or by one or more R l Substituted C1-C6 alkyl; Each R k and R j are independently hydrogen or C1-C6 alkyl; Each R l are independently -NR m R n , Each R m and R n are independently deuterium, hydrogen or C1-C6 alkyl; Each R c”’ and R d”’ are independently hydrogen, C1-C6 alkyl, 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl; R g’ is hydrogen or C1-C6 alkyl; L' is a bond, -(CH2) k’ -、-O(CH2) k’ -、-(CH2) k’ -O-, -O-(CH2) k’ -O- or -CH=CH-(CH2) n -, k' is 0, 1, 2 or 3, and n is 0, 1 or 2; A2 is H, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 1, 2, 3, 4 or 5 R e” Substituted C4-C 12 Cycloalkyl, 1, 2, 3, 4 or 5 R f” substituted 3-10 membered heterocycloalkyl, substituted by 1, 2, 3, 4 or 5 R g” Substituted C6-C 10 Aryl or 1, 2, 3, 4 or 5 R h” substituted 5-8 membered heteroaryl; Each R e” 、R f” 、R g” and R h” are independently hydrogen, halogen, OH, oxo, CN, NO2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkyl (NR z R za ),-C(O)R v 、-C(O)NR v R w 、-CH2C(O)NR v R w 、-C(O)OR v 、-NR z R za 、-NHC(O)R z 、-NHC(O)OR z 、-NHS(O)2R z 、-O(CH2) s -(C3-C8 cycloalkyl), -O(CH2) s -phenyl, -O(CH2) s -(3-10 membered heterocycloalkyl), -O(CH2) s -(5-10 membered heteroaryl), -S(O)2R z 、-S(O)2NH2、-S(O)2NR z R za , -CH2NHCH2C(O)-(5-10 membered heteroaryl), -CH2NHCH2C(O)-(3-10 membered heterocycloalkyl), -CH2NHC(O)-(5-10 membered heteroaryl), -CH2NHC(O)-(3-10 membered heterocycloalkyl), C1-C6 alkyl or C1-C6 alkoxy; Each R v and R w are independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or -(CH2)2NR x R y , the R x and R y are independently hydrogen, C1-C4 alkyl or -(CH2)2N(CH3)2; Each R z and R za are independently hydrogen, C1-C4 alkyl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, hydroxy substituted C1-C4 alkyl, methoxy substituted C1-C4 alkyl, C1-C4 haloalkyl or phenyl; Each s is independently 0, 1, 2 or 3; Each R e” 、R f” 、R g” and R h” wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally substituted by 1, 2 or 3 selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl, 5-10 membered heteroaryl, -C(O)NR i’ R j’ 、-NR k’ R l’ and -NR s’ R t’ Substituents substituted; R i’ and R j’ are independently hydrogen or C1-C6 alkyl; R k’ and R l’ are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, benzene yl, 5-10 membered heteroaryl, -CH2-C(O)-R m 、-C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are independently optionally substituted by 1, 2 or 3 groups selected from C1-C6 haloalkyl, OH, oxo, phenyl, CN, C1-C6 alkoxy and 5-10 membered heteroaryl, the heteroaryl being optionally substituted by methyl; R m is a 9-10 membered bicyclic heteroaryl, a C1-C6 alkoxy group or a -NR n R o , R n and R o is independently hydrogen, C1-C6 alkyl or phenyl, the alkyl group is optionally substituted with C1-C6 alkoxy or phenyl, or -NR n R o is a 4-7 membered azacycloalkyl group, which is connected to other parts of the molecule through a N atom and further contains one or more heteroatoms selected from N and O; R p is C1-C6 alkoxy, C1-C6 alkyl optionally substituted by 1, 2 or 3 groups selected from -OH and C1-C6 alkoxy, 3-6 membered monocyclic or 9-10 membered bicyclic heteroaryl, 4-7 membered heterocycloalkyl or R p -CH2-NR q R r , R q and R r are independently hydrogen, phenyl or C1-C6 alkyl optionally substituted by F; -NR s’ R t’ R s’ and R t’ With the nitrogen atom to form a 4-7 membered monocyclic nitrogen heterocycloalkyl or a 6-10 membered spirocyclic nitrogen heterocycloalkyl, wherein the heterocycloalkyl further includes up to two heteroatoms selected from N and O, and the heterocycloalkyl is optionally substituted by 1, 2 or 3 groups selected from OH, oxo, C1-C6 alkyl, C1-C6 hydroxyalkyl and -C(O)OR z Substituents substituted, the R z C1-C6 alkyl, halogen, -N(C1-C6 alkyl)2, -CH2N(C1-C6 alkyl)2 or -C(O)NR s” R t” , R s” and R t” are independently hydrogen, C1-C6 alkyl, 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl; R4 is hydrogen, oxo, C1-C6 alkyl, C1-C6 heteroalkyl, N(C1-C6 alkyl) 1-2 , C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, said alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocycloalkyl being optionally substituted with deuterium, CN, OH, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or halogen; R5 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, N(C1-C6 alkyl) 1-2 , C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, said alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocycloalkyl being optionally substituted with deuterium, CN, OH, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or halogen; Wherein, unless otherwise specified, the heteroaryl group mentioned above is a heteroatom or a heteroatom group selected from one or more of N, O, S and S(═O)2, and the number of heteroatoms is 1, 2 or 3 heteroaryl groups; the heterocycloalkyl group mentioned above is a heteroatom or a heteroatom group selected from one or more of N, O, S and S(═O)2, and the number of heteroatoms is 1, 2 or 3 heterocycloalkyl groups; the heteroalkyl group mentioned above is a heteroatom or a heteroatom group selected from one or more of N, O, S, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene and ethynylene, and the number of heteroatoms is 1, 2 or 3 heteroalkyl groups.

2. A compound of formula I, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts: SLE I in, S is: L is a connecting chain, which connects S and E through a covalent bond; E is the E3 ubiquitin ligase ligand; Among them, S: is selected from a single bond or a double bond; X is CH or N; R1 is hydrogen, halogen, OH, mercapto, CN, NO2, NR a R b , C1-C6 alkyl, C1-C6 alkylthiol, C1-C6 heteroalkyl, C1-C6 alkoxy, -O(C1-C6 heteroalkyl), -S(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, -COOR c 、-NHS(O)(R d )、-NHS(O)2(R d )、-NHC(O)-(C1-C6 alkyl)、-NHC(O)-NR a R b 、-NH-(CH2) k -NH-C(O)-R aa 、-NH-(CH2) i -R f’ 、-O-(CH2) z -phenyl, -O-(CH2) z -(4-7 membered heterocycloalkyl), -O-(CH2) z -(5-10 membered heteroaryl), or The superscript "*" indicates the same connect; Or two adjacent R1 together with the carbon atoms to which they are attached form a C5-C7 cycloalkyl group or a 5-7 membered heterocycloalkyl group; R a and R b are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl; R c is hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl or C3-C8 cycloalkyl; R d and R e’ are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; R aa is a C1-C6 alkyl, a 3-8 membered heterocycloalkyl or a C3-C8 cycloalkyl; k is 1 or 2; i is 0, 1, or 2; R f’ is a 4-7 membered heterocycloalkyl group, a 5-10 membered heteroaryl group or a C1-C6 alkylsulfonyl group; z is 0, 1, or 2; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by one, two or three groups selected from deuterium, halogen, OH, oxo, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylsulfonyl, phenyl, benzyl, 5-10 membered heteroaryl, -(CH2)-(5-8 membered heteroaryl), -NHC(O)(C1-C6 alkyl), phenoxy, 5-10 membered heteroaryloxy and -NR a R b m is 1, 2 or 3; A1 is C4-C 12 Cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, 1, 2, 3, 4 or 5 R c” Substituted C4-C 12 Cycloalkyl, 1, 2, 3, 4 or 5 R d” substituted 3-8 membered heterocycloalkyl, substituted by 1, 2, 3, 4 or 5 R c’ Substituted C6-C 12 Aryl or 1, 2, 3, 4 or 5 R d’ substituted 5-10 membered heteroaryl, Each R c’ 、R d’ 、R c” and R d” are independently hydrogen, OH, oxo, halogen, CN, C1-C6 alkyl, C1-C6 alkyl(SO2)-, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, halogenated 3-8 membered heterocycloalkyl, -O-CH2-4-7 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 alkylsulfonyl, -NR e R f 、-NHC(=O)-C1-C6 alkyl、C(O)NR c”’ R d”’ 、-C(O)OR g’ 、-(CH2)NR c”’ R d”’ , -S(O)2C1-C6 alkyl, -CH=CH-C3-C8 cycloalkyl, -L'-A2, 1, 2, 3, 4 or 5 R g Substituted C1-C6 alkyl, 1, 2, 3, 4 or 5 R h Substituted C6-C 10 Aryl, 1, 2, 3, 4 or 5 R i substituted 5-10 membered heteroaryl or 1, 2, 3, 4 or 5 R o’ substituted C3-C8 cycloalkyl; Each R o’ 、R g 、R h and R i are independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R j or by one or more R l Substituted C1-C6 alkyl; each R e and R f are independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R j or by one or more R l Substituted C1-C6 alkyl; Each R e and R f are independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R j or by one or more R l Substituted C1-C6 alkyl; Each R k and R j are independently hydrogen or C1-C6 alkyl; Each R l are independently -NR m R n , Each R m and R n are independently deuterium, hydrogen or C1-C6 alkyl; Each R c”’ and R d”’ are independently hydrogen, C1-C6 alkyl, 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl; R g’ is hydrogen or C1-C6 alkyl; L' is a bond, -(CH2) k’ -、-O(CH2) k’ -、-(CH2) k’ -O-, -O-(CH2) k’ -O- or -CH=CH-(CH2) n -, k' is 0, 1, 2 or 3, and n is 0, 1 or 2; A2 is H, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 1, 2, 3, 4 or 5 R e” Substituted C4-C 12 Cycloalkyl, 1, 2, 3, 4 or 5 R f” substituted 3-10 membered heterocycloalkyl, substituted by 1, 2, 3, 4 or 5 R g” Substituted C6-C 10 Aryl or 1, 2, 3, 4 or 5 R h” substituted 5-8 membered heteroaryl; Each R e” 、R f” 、R g” and R h” are independently hydrogen, halogen, OH, oxo, CN, NO2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -C1-C6 alkyl (NR z R za ),-C(O)R v 、-C(O)NR v R w 、-CH2C(O)NR v R w 、-C(O)OR v 、-NR z R za 、-NHC(O)R z 、-NHC(O)OR z 、-NHS(O)2R z 、-O(CH2) s -(C3-C8 cycloalkyl), -O(CH2) s -phenyl, -O(CH2) s -(3-10 membered heterocycloalkyl), -O(CH2) s -(5-10 membered heteroaryl), -S(O)2R z 、-S(O)2NH2、-S(O)2NR z R za , -CH2NHCH2C(O)-(5-10 membered heteroaryl), -CH2NHCH2C(O)-(3-10 membered heterocycloalkyl), -CH2NHC(O)-(5-10 membered heteroaryl), -CH2NHC(O)-(3-10 membered heterocycloalkyl), C1-C6 alkyl or C1-C6 alkoxy; Each R v and R w are independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or -(CH2)2NR x R y , the R x and R y are independently hydrogen, C1-C4 alkyl or -(CH2)2N(CH3)2; Each R z and R za are independently hydrogen, C1-C4 alkyl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, hydroxy substituted C1-C4 alkyl, methoxy substituted C1-C4 alkyl, C1-C4 haloalkyl or phenyl; Each s is independently 0, 1, 2 or 3; Each R e” 、R f” 、R g” and R h” wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally substituted by 1, 2 or 3 selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl, 5-10 membered heteroaryl, -C(O)NR i’ R j’ 、-NR k’ R l’ and -NR s’ R t’ Substituents substituted; R i’ and R j’ are independently hydrogen or C1-C6 alkyl; R k’ and R l’ are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, phenyl, 5-10 membered heteroaryl, -CH2-C(O)-R m 、-C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are independently optionally substituted by 1, 2 or 3 groups selected from C1-C6 haloalkyl, OH, oxo, phenyl, CN, C1-C6 alkoxy and 5-10 membered heteroaryl, the heteroaryl being optionally substituted by methyl; R m is a 9-10 membered bicyclic heteroaryl, a C1-C6 alkoxy group or a -NR n R o , R n and R o is independently hydrogen, C1-C6 alkyl or phenyl, the alkyl group is optionally substituted with C1-C6 alkoxy or phenyl, or -NR n R o is a 4-7 membered azacycloalkyl group, which is connected to other parts of the molecule through a N atom and further contains one or more heteroatoms selected from N and O; R p is C1-C6 alkoxy, C1-C6 alkyl optionally substituted by 1, 2 or 3 groups selected from -OH and C1-C6 alkoxy, 3-6 membered monocyclic or 9-10 membered bicyclic heteroaryl, 4-7 membered heterocycloalkyl or R p -CH2-NR q R r , R q and R r are independently hydrogen, phenyl or C1-C6 alkyl optionally substituted by F; -NR s’ R t’ R s’ and R t’ Together with the nitrogen atom, it forms a 4-7-membered monocyclic nitrogen heterocyclic alkyl group or a 6-10-membered spirocyclic nitrogen heterocyclic alkyl group. The alkyl group further includes up to two heteroatoms selected from N and O, and the heterocycloalkyl group is optionally substituted by 1, 2 or 3 groups selected from OH, oxo, C1-C6 alkyl, C1-C6 hydroxyalkyl and -C(O)OR z Substituents substituted, the R z C1-C6 alkyl, halogen, -N(C1-C6 alkyl)2, -CH2N(C1-C6 alkyl)2 or -C(O)NR s” R t” , R s” and R t” are independently hydrogen, C1-C6 alkyl, 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl; R4 is hydrogen, oxo, C1-C6 alkyl, C1-C6 heteroalkyl, N(C1-C6 alkyl) 1-2 , C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, said alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocycloalkyl being optionally substituted with deuterium, CN, OH, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or halogen; R5 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, N(C1-C6 alkyl) 1-2 , C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, said alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocycloalkyl being optionally substituted with deuterium, CN, OH, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or halogen; Wherein, unless otherwise specified, the heteroaryl group mentioned above is a heteroatom or a heteroatom group selected from one or more of N, O, S and S(═O)2, and the number of heteroatoms is 1, 2 or 3 heteroaryl groups; the heterocycloalkyl group mentioned above is a heteroatom or a heteroatom group selected from one or more of N, O, S and S(═O)2, and the number of heteroatoms is 1, 2 or 3 heterocycloalkyl groups; the heteroalkyl group mentioned above is a heteroatom or a heteroatom group selected from one or more of N, O, S, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene and ethynylene, and the number of heteroatoms is 1, 2 or 3 heteroalkyl groups.

3. The compound of formula I according to claim 1 or 2, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: It meets one or more of the following conditions: (1) R c’ 、R d’ 、R c” and R d” are independently hydrogen, OH, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(═CH2)CH3, -C(CH3)(═CH2)CH3, -CH═CH(CH2)2CH3, -CH═CHCH3, -CH═CH-cyclopropyl, -C(O)NH2, -C(O)OCH3, -S(O)2CH3, -OCH3, -CH2NH2, trifluoromethyl, difluoromethyl, methyl, trifluoromethoxy, or halogen (F, Cl, Br), -NH2, -NHC(O)CH3, -NHCH2CH3, -NHCH(CH3)2, or -L'-A2; (2) L' is a bond, -(CH2) k’ -、-O(CH2) k’ -or-CH=CH-(CH2) n -, k' is 1 or 2, and n is 0, 1 or 2; (3) The R e” 、R f” 、R g” and R h” are independently -C(O)NH(CH2)2CH3, -C(O)N(CH3)2, -C(O)NH2, -C(O)NH(CH2)2N(CH3)2, -CH2C(O)NH2, hydrogen, -F, -Cl, -Br, cyano, -CF3, -CH3, -CH2CH3, -CH=CH2, -CH2CN, -CH(CH3)-NH2, -CH=CH-CN, -C(O)-OH, -C(O)OCH3, -C(O)CH3, -C(CH3)2-C(O)-OCH3, -C(CH3)2-CN, oxo, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, -NH2, -NH-C(O)CH3, -NH-S(O)2CH3, -NH-C(O)OC(CH3)3, -S(O)2CH3、-S(O)2NCH3、-S(O)2NH2、-OCH2CH3、-O(CH2)2CH3、-OCF3、 -OCH2 cyclopropyl, -OCH3, -O(CH2)3CH3, -OCH2 phenyl, -O-phenyl, -(CH2)-OH, -(CH2)2-OH, -(CH2)-OCH3, -(CH2)-OCH2CH3, -CH(OH)-CH2-phenyl, -CH(OH)-CH2CH3, -CH(OH)-CH2CH2CH3, -CH(OH)-CH2CH2CH2CH3, -CH(OH)-CH(CH3)2, -CH(OH)-phenyl, -CH(OH)-CN, -CH(OH)-CH2-OH, -CH(OH)-CF3, -CH(OH)-(CH2)2-phenyl, ＊ -CH(OH)-C≡CH、-CH(NH2)-CH2-C(O)OH、-CH2-NH-S(O)2-CH3、-CH2-NH-(CH2)3CH3、-CH2-NH-CH3、-CH2-N(CH3)2、-CH2-NH-CH2CH3、-CH(CH3)-NH2、-CH2-NH2、-CH2CH2-NH2、-CH2NH-CH2-phenyl、-CH2N(CH2CH3)2、-CH2NH-cyclopropyl、-C H2NH-cyclobutyl, -CH2NH-cyclopentyl, -CH2NH-pyridyl, -CH2NH-phenyl, -CH2NH-(CH2)2-OH, -CH2N(CH3)-(CH2)2-OH, -CH2NH-CH2-CN, -CH2N(CH3)-CH2-CN, -CH2N(CH3)-CH2-CF3, -CH2N(CH3)-CH2-CF2H, -CH2NH-CH2-CF2H, -CH2NH-(CH2)2-OCH3, -CH2NH-C(O)-OC(CH3)3、-CH2CH2NH-C(O)-OC(CH3)3、-CH2NH-C(O)-CH2NOH、-CH2NH-C(O)-CH2OCH3、-CH(CH3)NH-C(O)-OC(CH3)3、-CH2NH-C(O)-CH3、 -CH2NHCH2-C(O)-NH2, -CH2NHCH2-C(O)-(CH3)2, -CH2NHCH2-C(O)-OCH3, -CH2NHCH2-C(O)-NHCH3, -CH2NHCH2-C(O)-NH(CH2)2-OCH3, -CH2NHCH2-C(O)-NHCH2-phenyl, -CH2NHCH2-C(O)-NH-phenyl, -CH2NH-C(O)-CH2NH-phenyl, or -CH2NH-C(O)-C H2NH-CH2CF3, wherein the "*" indicates that the site marked with "*" is connected to other groups; (4) R1 is hydrogen, -OCH3, -OCH2CH3, -CH2OH, -C(O)OH, -C(O)OCH3, -Br, -OCH(CH3)2, -O(CH2)2CH(CH3)2, -O(CH2)3CH3, -O(CH2)2OCH3, -O(CH2)-phenyl, -N=S(O)(CH3)2, -CH3, cyclopropyl, -N(CH3)2, -NHCH3, -NH2, -C(CH3)2-OH、 -NH(CH2)-NH-C(O)CH3, -NH(CH2)-morpholine, -NH-C(O)CH3, -NH-C(O)NHCH3, -NH-C(O)-N(CH3)2, nitro, -NH-S(O)2CH3, -N=S(O)(CH3)2, hydroxyl, -O-(CH2)2-S(O)2CH3, -F, Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, azetidinyl, azelanyl, piperidinyl, piperazinyl, oxetane, oxolanyl, oxhexanyl, thietanyl, thiolanyl, thiolanyl, azetidinyloxy, azelanyloxy, piperidinyloxy, piperazinyloxy, oxetaneoxy, oxolanyloxy, oxhexanyloxy, thietanyloxy, thiolanyloxy, thiolanyloxy, thiolanyloxy, <h2 style=";text-align:left;direction:ltr">-OCH2CH2CH3、-OCH2CH2CH2N(CH3)2、-OCH2CH2CH2OH、<h2 style=";text-align:left;direction:ltr"> -OCH2CH2NC(O)CH3、-OCH2CH2N(CH3)2、-OCH2CH2OH、 -SCH3, -N(CH3)2, Among them, the mark "*" indicates that it is connected to other groups through the site marked with "*"; (5) A1 is optionally substituted The substituents are hydroxy, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(=CH2)CH3, -C(CH3)(=CH2)CH3, -CH=CH(CH2)2CH3, -CH=CHCH3, -CH=CH-cyclopropyl, -C(O)NH2, -C(O)OCH3, -S(O)2CH3, -OCH3, -CH2NH 2、 trifluoromethyl, Difluoromethyl, methyl, trifluoromethoxy, halogen (F, Cl, Br), -NH2, -NHC(O)CH3, -NHCH2CH3, -NHCH(CH3)2 or -L'-A2; the number of the substituents is 1, 2 or 3; (6) A2 is optionally substituted The substituents are -C(O)NH(CH2)2CH3, -C(O)N(CH3)2, -C(O)NH2, -C(O)NH(CH2)2N(CH3)2, -CH2C(O)NH2, hydrogen, -F, -Cl, -Br, cyano, -CF3, -CH3, -CH2CH3, -CH=CH2, -CH2CN, -CH(CH3)-NH2, -CH=CH-CN, -C(O)-OH, -C(O)OCH3, -C(O)CH3, -C(CH3)2-C(O)-OCH3, -C(CH3)2-CN, oxo, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, -NH2, -NH-C(O)CH3, -NH-S(O)2CH3, -NH-C(O)OC(CH3)3, -S(O)2CH3、-S(O)2NCH3、-S(O)2NH2、-OCH2CH3、-O(CH2)2CH3、-OCF3、 -OCH2 cyclopropyl, -OCH3, -O(CH2)3CH3, -OCH2 phenyl, -O-phenyl, -(CH2)-OH, -(CH2)2-OH, -(CH2)-OCH3, -(CH2)-OCH2CH3, -CH(OH)-CH2-phenyl, -CH(OH)-CH2CH3, -CH(OH)-CH2CH2CH3, -CH(OH)-CH2CH2CH2CH3, -CH(OH)-CH(CH3)2, -CH(OH)-phenyl, -CH(OH)-CN, -CH(OH)-CH2-OH, -CH(OH)-CF3, -CH(OH)-(CH2)2-phenyl, ＊ -CH(OH)-C≡CH、-CH(NH2)-CH2-C(O)OH、-CH2-NH-S(O)2-CH3、-CH2-NH-(CH2)3CH3、-CH2-NH-CH3、-CH2-N(CH3)2、-CH2-NH-CH2CH3、-CH(CH3)-NH2、-CH2-NH2、-CH2CH2-NH2、-CH2NH-CH2-phenyl、-CH2N(CH2CH3)2、-CH2NH-cyclopropyl、-C H2NH-cyclobutyl, -CH2NH-cyclopentyl, -CH2NH-pyridyl, -CH2NH-phenyl, -CH2NH-(CH2)2-OH, -CH2N(CH3)-(CH2)2-OH, -CH2NH-CH2-CN, -CH2N(CH3)-CH2-CN, -CH2N(CH3)-CH2-CF3, -CH2N(CH3)-CH2-CF2H, -CH2NH-CH2-CF2H, -CH2NH-(CH2)2-OCH3, -CH2NH-C(O)-OC(CH3)3、-CH2CH2NH-C(O)-OC(CH3)3、-CH2NH-C(O)-CH2NOH、-CH2NH-C(O)-CH2OCH3、-CH(CH3)NH-C(O)-OC(CH3)3、-CH2NH-C(O)-CH3、 -CH2NHCH2-C(O)-NH2, -CH2NHCH2-C(O)-(CH3)2, -CH2NHCH2-C(O)-OCH3, -CH2NHCH2-C(O)-NHCH3, -CH2NHCH2-C(O)-NH(CH2)2-OCH3, -CH2NHCH2-C(O)-NHCH2-phenyl, -CH2NHCH2-C(O)-NH-phenyl, -CH2NH-C(O)-CH2NH-phenyl, or -CH2NH-C(O)-CH2NH-CH2CF3, the number of the substituents is 1 or 2, wherein the mark "*" indicates connection with other parts in the molecule.

4. The compound of formula I according to claim 1 or 2, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: Among the S: X is C or N; R1, R4 and R5 are independently hydrogen, CN, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 heteroalkyl, N(C1-C6 alkyl) 1-2 , C1-C6 alkoxy, one or more R a1 Substituted C1-C6 alkyl or one or more R a2 Substituted C1-C6 alkoxy; Each R a1 and R a2 are independently deuterium or halogen; m is 1, 2, or 3; A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, 1, 2, 3 or 4 R c’ Substituted C6-C 12 Aryl or 1, 2, 3 or 4 R d’ substituted 5-10 membered heteroaryl; Each R c’ and R d’ are independently CN, C1-C6 alkyl, -NR e R f , halogen, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 alkyl (SO2)-, 1, 2, 3, 4 or 5 R g Substituted C1-C6 alkyl, 1, 2, 3, 4 or 5 R h Substituted C6-C 10 Aryl or 1, 2, 3, 4 or 5 R i substituted 5-10 membered heteroaryl; Each R e 、R f 、R g and R h are independently hydrogen, deuterium, halogen, C1-C6 alkyl, -NR k R j or by one or more R l Substituted C1-C6 alkyl; R k and R j are independently hydrogen or C1-C6 alkyl; Each R l are independently -NR m R n , R m and R n are independently deuterium, hydrogen or C1-C6 alkyl; Wherein, the heteroaryl group mentioned above is a heteroatom or heteroatom group selected from one or more of N, O, S and S(═O)2, and the number of heteroatoms is 1, 2 or 3 heteroaryl groups; the heteroalkyl group is a heteroatom or heteroatom group selected from one or more of N, O, S, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene and ethynylene, and the number of heteroatoms is 1, 2 or 3 heteroalkyl groups.

5. The compound of formula I according to claim 4, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: It meets one or more of the following conditions: (1) In R1, R4 and R5, the C3-C8 cycloalkyl group is independently a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (2) In R1, R4 and R5, the C1-C6 alkyl, N(C1-C6 alkyl) 1-2 and one or more R a1 The C1-C6 alkyl group in the substituted C1-C6 alkyl group is independently a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (3) In R1, R4 and R5, the C1-C6 heteroalkyl group is independently a C1-C4 heteroalkyl group containing one or two heteroatoms selected from N, O and S, such as CH3OCH2-, CH3CH2OCH2-, CH3OCH2CH2-, CH3NHCH2-, CH3CH2NHCH2-, CH3NHCH2CH2-, CH3SCH2-, CH3CH2SCH2-, CH3SCH2CH2- or CH3OCH2OCH2-; (4) In R1, R4 and R5, the C1-C6 alkoxy group is independently a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy; (5)R a1 and R a2 wherein the halogen is independently F, Cl, Br or I; (6) In A1, the C6-C 12 Aryl or 1, 2, 3 or 4 R c’ Substituted C6-C 12 C6-C in aromatic groups 12 Aryl can independently be phenyl or naphthyl; (7) In A1, the 5-10 membered heteroaryl group is replaced by 1, 2, 3 or 4 R d’ The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is independently furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, indolyl or (8) Each R c’ and R d’ wherein the C1-C6 alkyl, C1-C6 alkyl(SO2)- or C1-C6 alkyl(SO2)- is replaced by 1, 2, 3, 4 or 5 R g The C1-C6 alkyl group in the substituted C1-C6 alkyl group is independently a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (9) Each R c’ and R d’ In the C6-C 10 Aryl or 1, 2, 3, 4 or 5 R h Substituted C6-C 10 C6-C in aromatic groups 10 Aryl is independently phenyl or naphthyl; (10) Each R c’ and R d’ wherein the halogen is independently F, Cl, Br or I; (11) Each R c’ and R d’ wherein the 5-10 membered heteroaryl group is replaced by 1, 2, 3, 4 or 5 R i The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is independently furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, indolyl or (12) Each R e 、R f 、R g and R h wherein the halogen is independently F, Cl, Br or I; (13) Each R e 、R f 、R g 、R h 、R k 、R j 、R m and R n wherein the C1-C6 alkyl group is replaced by one or more R l The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are independently C1-C4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

6. The compound of formula I according to claim 4, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, wherein: It meets one or more of the following conditions: (1) In the aforementioned S, each R1 is independently hydrogen, CN, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl or C1-C6 alkoxy, such as hydrogen, C1-C3 alkyl or C1-C3 alkoxy, and also such as hydrogen, methyl or methoxy; (2) In the aforementioned S, R4 is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 1-2 , by one or more R a1 Substituted C1-C6 alkyl, R a1 are independently deuterium or halogen; for example, C1-C3 alkyl, C1-C3 alkyl substituted by 3 deuteriums, or C1-C3 alkyl substituted by 3 fluorines, and also for example, methyl, -CD3 or -CH2CF3; (3) In the aforementioned S, R5 is a C1-C6 alkyl group, such as a C1-C3 alkyl group, or a methyl group; (4) In the aforementioned S, m is 1 or 2; (5) In the aforementioned S, A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, substituted by one or more R c’ Substituted C6-C 12 Aryl or one or more R d’ Substituted 5-10 membered heteroaryl, wherein the heteroaryl is a heteroatom or heteroatom group selected from one or more of N, O, S and S(=O)2, and the number of heteroatoms is 1, 2 or 3; the C6-C 12 Aryl or one or more R c’ Substituted C6-C 12 C6-C in aromatic groups 12 Aryl, for example, phenyl; the 5-10 membered heteroaryl or one or more R d’ The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is for example thienyl or For example (6) In the above S, each R c’ Independently CN, amino, halogen, C1-C6 alkyl, C1-C6 alkyl(SO2)-, or C1-C6 alkyl substituted by 1, 2, 3, 4 or 5 halogens; for example, CN, C1-C3 alkyl, C1-C3 alkyl(SO2)-, or C1-C3 alkyl substituted by 1, 2 or 3 fluorines; for example, CN, methyl, -CHF2, -CF3 or amino; (7) In the above S, each R d’ Independently C6-C 12 Aryl (eg phenyl) or one or more R h Substituted C6-C 12 Aryl (e.g., phenyl); (8) In the above S, each R h are independently hydrogen, halogen, l Substituted C1-C6 alkyl, such as hydrogen, Cl or one or more R l substituted methyl groups; (9) In the above S, each R l are independently -NR m R n , R m and R n are independently hydrogen or C1-C6 alkyl, such as -NHCH3 or -N(CH3)2; (10) In the above S: X is CH or N; Each R1 is independently hydrogen, C1-C6 alkyl or C1-C6 alkoxy; m is 1 or 2; R4 is hydrogen, C1-C6 alkyl or one or more R a1 Substituted C1-C6 alkyl, R a1 are independently deuterium or halogen; R5 is hydrogen or C1-C6 alkyl; A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, substituted by one or more R c’ Substituted C6-C 12 Aryl or one or more R d’ A substituted 5-10 membered heteroaryl group, wherein the heteroaryl group is a heteroatom or a heteroatom group selected from one or more of N, O, S and S(=O)2, and the number of heteroatoms is 1, 2 or 3; Each R c’ are independently CN, amino, halogen, C1-C6 alkyl, C1-C6 alkyl(SO2)-, or C1-C6 alkyl substituted with 1, 2, 3, 4 or 5 halogens; Each R d’ Independently C6-C 12 Aryl or one or more R h Substituted C6-C 12 aryl; Each R h are independently hydrogen, halogen or substituted by one or more R l Substituted C1-C6 alkyl; Each R l are independently -NR m R n , R m and R n are independently hydrogen or C1-C6 alkyl; Preferably, in said S: X is CH or N; Each R1 is independently hydrogen, C1-C3 alkyl or C1-C3 alkoxy; R4 is C1-C3 alkyl, C1-C3 alkyl substituted by 3 deuteriums, or C1-C3 alkyl substituted by 3 fluorines; R5 is a C1-C3 alkyl group; m is 1 or 2; A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, substituted by one or more R c’ Substituted C6-C 12 Aryl or one or more R d’ Substituted 5-10 membered heteroaryl, wherein the heteroaryl is a heteroatom or heteroatom group selected from one or more of N, O, S and S(=O)2, and the number of heteroatoms is 1, 2 or 3; the C6-C 12 Aryl or one or more R c’ Substituted C6-C 12 C6-C in aromatic groups 12 Aryl is phenyl; the 5-10 membered heteroaryl may be replaced by one or more R d’ 5-10 membered substituted 5-10 membered heteroaryl Heteroaryl is thienyl or Each R c’ independently CN, C1-C3 alkyl, C1-C3 alkyl(SO2)-, C1-C3 alkyl substituted with 1, 2 or 3 fluorines; Each R d’ is independently phenyl or is replaced by one or more R h substituted phenyl; Each R h are independently hydrogen, halogen, l Substituted C1-C3 alkyl; Each R l are independently -NR m R n , R m and R n independently hydrogen or C1-C3 alkyl; Preferably, in said S: X is CH or N; Each R1 is independently hydrogen, methyl or methoxy; R4 is methyl, -CD3 or -CH2CF3; R5 is methyl; m is 1 or 2; A1 is C6-C 12 Aryl, 5-10 membered heteroaryl, substituted by one or more R c’ Substituted C6-C 12 Aryl or one or more R d’ Substituted 5-10 membered heteroaryl; the C6-C 12 Aryl or one or more R c’ Substituted C6-C 12 C6-C in aromatic groups 12 Aryl is phenyl; the 5-10 membered heteroaryl may be replaced by one or more R d’ The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is Each R c’ are independently CN, methyl, -CHF2, -CF3, CH3SO2- or amino; Each R d’ is independently phenyl or is replaced by one or more R h substituted phenyl; Each R h are independently hydrogen, Cl or substituted by one or more R l substituted methyl groups; Each R l are independently -NHCH3 or -N(CH3)2; (11) The S is S': Preferably S": Wherein, "*" indicates that the marked C atom is in R configuration, S configuration or a mixture thereof; X, R1, A1, R4, R5 and m are defined as in claim 3; (12) The S is S'-1: Wherein, "*" indicates that the marked C atom is in R configuration, S configuration or a mixture thereof; X, R1, A1, R4, R5 and m are defined as in claim 3; (13) The S is S-1 or S-2: The S-1 is preferably S-1-1 or S-1-2: The S-1 is more preferably S-1-1', S-1-1", S-1-2' or S-1-2": The S-2 is preferably S-2-1 or S-2-2: The S-2 is more preferably S-2-1', S-2-1", S-2-2' or S-2-2": Wherein, in the S-1, S-2, S-1-1, S-1-2, S-1-1', S-1-1", S-1-2', S-1-2", S-2-1, S-2-2, S-2-1', S-2-1", S-2-2' or S-2-2", "*" indicates that the marked C atom is R configuration, S configuration or a mixture thereof; R1, A1, R4, R5, R c’ and R h The definition of claim 3; W and Y are independently 1, 2, 3, 4 or 5.

7. The compound of formula I according to any one of claims 1 to 6, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that: The S is any one of the following structures:

8. The compound of formula I according to claim 1 or 2, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: The L is any one of the following: (1) L is a bond; (2) L is -(CH2) j -, the -(CH2) j -One or more methylene groups are optionally selected from -NR 3’ -, -O-, -S-, -S(O)-, -S(O)NR 3’ -、-NR 3’ S(O)-, -S(O)2-, -S(O)2NR 3’ -、-NR 3’ S(O)2-、-NR 4’ S(O)2NR 3’ -、-CR 1’ R 2’ -, -C(O)-, -C(O)O-, -OC(O)-, -NR 3’ C(O)O-、-OC(O)NR 3’ -、-C(O)NR 3’ -、-NR 3’ C(O)-、-NR 4’ C(O)NR 3’ -、-P(O)-、-P(O)O-、-OP(O)-、-OP(O)O-、vinylene、ethynylene、C3-C 12 Cycloalkylene, containing one or more heteroatoms selected from N, O and S The 3-12 membered heterocycloalkylene, 6-10 membered arylene and 5-10 membered heteroarylene groups are replaced, wherein the methylene, vinylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene are independently optionally substituted by one or more selected from halogen, -OR 3’ 、-NR 3’ R 4’ , oxo, nitro, cyano, C1-C6 alkyl, -S(C1-C6 alkyl), C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -C(O)R 1’ 、-C(O)OR 3’ 、-OC(O)R 1’ 、-C(O)NR 3’ 、-NR 3’ C(O)R 1’ 、-S(O)R 1’ 、-S(O)NR 3’ 、-S(O)2R 1’ 、-S(O)2NR 3’ 、-NR 3’ S(O)2R 1’ 、-NR 4’ S(O)2NR 3’ 、-OC(O)NR 3’ and -NR 4’ C(O)NR 3’ The alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are independently optionally substituted by one or more halogen, -OH, -NR 3’ R 4’ , oxo, nitro, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 The substituents of aryl and 5-10 membered heteroaryl are substituted; R 1’ 、R 2’ Each is independently halogen, -OH, -NR 3’ R 4’ , C1-C6 alkyl, chloro C1-C6 alkyl, hydroxy C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, C3-C 10 Cycloalkyl, -O(C3-C 10 Cycloalkyl), -NH(C3-C 10 cycloalkyl), 3-10 membered heterocycloalkyl, -O(3-10 membered heterocycloalkyl), -NH(3-10 membered heterocycloalkyl), C6-C 10 Aryl, -O(C6-C 10 Aryl), -NH(C6-C 10 aryl), 5-10 membered heteroaryl, -O(5-10 membered heteroaryl) or -NH(5-10 membered heteroaryl); or R 1’ 、R 2’ Together with the C atoms to which they are attached, they form a C3-C8 cycloalkyl group or a 3-8 membered heterocycloalkyl group; R 3’ 、R 4’ are independently hydrogen, deuterium, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl; j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25; Preferably, L is -(CH2) j -, the -(CH2) j -One or more methylene groups are optionally selected from -NR 3’ -、-O-、-CR 1’ R 2’ -, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NR 3’ -、-NR 3’ C(O)-、-S(O)2NR 3’ -、-NR 3’ S(O)2-, vinylene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered saturated or partially unsaturated fused cycloalkylene, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene, 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, The methylene, vinylene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, spiroheterocycloalkylene, fused cycloalkylene, heteroarylene, and heteroarylene are independently optionally substituted by one or more groups selected from halogen, oxo, -NR 3’ R 4’ 、-OR 3’ , nitro, -CN, C1-C6 alkyl, C3-C 10 The alkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted by one or more substituents selected from halogen, -OH, -NH2, -CN, C1-C4 alkyl, and C3-C6 cycloalkyl groups. 1’ 、R 2’ Each is independently halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), C3-C6 heterocycloalkyl, -O(C3-C6 heterocycloalkyl), -NH(C3-C6 cycloalkyl); R 3’ 、R 4’ are independently hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; Preferably, L is -(CH2) j -, the -(CH2) j -One or more methylene groups are optionally selected from -NR 3’ -、-O-、-CR 1’ R 2’ -, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NR 3’ -、-NR 3’ C(O)-、-S(O)2NR 3’ -、-NR 3’ S(O)2-, vinylene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated monocyclic cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered saturated or partially unsaturated fused cycloalkylene, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene, 5-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 independently selected nitrogen or oxygen heteroatoms, 5-11 membered saturated or partially unsaturated spirocycloalkylene having 1-2 independently selected nitrogen or oxygen heteroatoms, 5-11 membered saturated or partially unsaturated fused heterocycloalkylene having 1-2 independently selected nitrogen or oxygen heteroatoms, substituted by 2 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene groups independently selected from nitrogen or oxygen heteroatoms, 5-6 membered heteroarylene groups having 1-4 independently selected from nitrogen or oxygen heteroatoms, or 8-10 membered bicyclic heteroaryl groups having 1-5 independently selected from nitrogen or oxygen heteroatoms, said methylene, vinylene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, fused cycloalkylene, spiroheterocycloalkylene, heteroarylene groups are independently optionally substituted by 1 or more groups selected from halogen, oxo, -NR 3’ R 4’ 、-OR 3’ , nitro, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl substituted, the alkyl, cycloalkyl, heterocycloalkyl optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, R 1’ 、R 2’ Each is independently halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), C3-C6 heterocycloalkyl, -O(C3-C6 heterocycloalkyl), -NH(C3-C6 cycloalkyl); R 3’ 、R 4’ are independently hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9 or 10; Preferably, L is -(CH2) j -, the -(CH2) j -, 1, 2, 3, 4 or 5 methylene groups are optionally selected from -NH-, -NCH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, vinylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, Cyclohexylene, oxiranediylene, oxetanediylene, oxolanediylene, oxhexylene, aziridinediylene, aziridinediylene, piperidinylene, piperazinylene, morpholinylene, homomorpholinylene, phenylene, pyrrolylene, thienylene, furanylene, imidazolylene, pyrazolylene, triazolylene, tetrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, and the methylene or replacement group is optionally replaced by one or more halogen, oxo, -NR 3’ R 4’ 、-OR 3’ , C1-C4 alkyl substituents, wherein the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, -NH2, R 3’ 、R 4’ are independently hydrogen, deuterium, C1-C4 alkyl, j is 2, 3, 4, 5, 6, 7, 8, 9 or 10; Preferably, L is -(CH2) j -, the -(CH2) j -, 1, 2, 3, 4 or 5 methylene groups are optionally selected from -NH-, -NCH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxirane, oxetane, oxolanyl, oxhexylene, aziridine, aziridine, aziridine, piperidinyl ... Azinyl, morpholinyl, homomorpholinyl, The methylene or replacement group is optionally replaced by one or more groups selected from F, Cl, oxo, -NR 3’ R 4’ 、-OR 3’ , C1-C4 alkyl substituents, wherein the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, -NH2, R 3’ 、R 4’ are independently hydrogen, deuterium, methyl, ethyl, or propyl, and j is 3, 4, 5, 6, 7, 8, 9, or 10; Preferably, L is -(CH2) j -, the -(CH2) j -1, 2, 3, 4 or 5 methylene groups in the group are optionally selected from -O-, -NH-, -NCH3-, -C(O)-, -C(O)NH-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, cyclohexylene, aziridine, aziridinyl, aziridine, piperidinyl, piperazinyl, and j is 4, 5, 6, 7, 8, 9 or 10.

9. The compound of formula I according to claim 8, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, wherein: L is -(CH2) j-1 -C(O)-, said -(CH2) j-1 The methylene group in -C(O)- is as defined in claim 8 and is optionally substituted by one or more groups, and said j is as defined in claim 8.

10. The compound of formula I according to claim 8 or 9, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that: L is any of the following structures:

11. The compound of formula I according to claim 1 or 2, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: The L is LB: In the LB: Ring A" is connected to S; Ring A", Ring B" and Ring C" are independently a bond, C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenylene, 3-12 membered heterocycloalkylene, wherein the cycloalkenylene, cycloalkylene and heterocycloalkylene are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or -O-(C1-C6 alkyl); X' and X" are independently a bond, -O-(C1-C6 alkylene)-, -S-(C1-C6 alkylene)-, -NH-(C1-C6 alkylene)-, -NH-, -NCH3-, -O-, -CH2-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C( O) NCH3-, -CH2NCH3-, -NHC(O)-, -NCH3C(O)- or -C(O)CH2O-; the C1-C6 alkylene in the -O-(C1-C6 alkylene)-, -S-(C1-C6 alkylene)- or -NH-(C1-C6 alkylene)- may be substituted by one or more Rx', wherein the Rx' is a C1-C6 alkyl, or two Rx' located on the same carbon atom are connected to the carbon atom to form a C3-C8 cycloalkyl; La" is -(CH2) k’ -, one or two methylene groups in said La" are optionally replaced by -O-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)- or -N(C3-C8 cycloalkyl)-, and k' is 0, 1, 2, 3, 4, 5, 6 or 7; The heterocycloalkylene group is a heterocycloalkylene group having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; Preferably, in the LB, ring A" is C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, such as C5-C6 monocyclic cycloalkylene, C5-C6 monocyclic cycloalkenylene, containing 1-2 heteroatoms selected from N, O and S heteroatoms, or 7-8 membered bridged heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S (preferably C5-C6 monocyclic cycloalkylene, C5-C6 monocyclic cycloalkenylene, or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S); more preferably piperidinylene, piperazinylene, cyclohexylene or cyclohexenylene; Ring B" is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, such as C5-C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S; more preferably piperidinylene, cyclohexylene or piperazinylene; Ring C″ is a 3-12-membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, for example, a 5-6-membered monocyclic heterocycloalkylene group or a 7-11-membered spirocyclic heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S; more preferably, a piperidinylene group, a piperazinylene group, a 2,7-diaza[3.5]nonylene group, a 7-aza[3.5]nonylene group, a 2-aza[3.5]nonylene group, a 2,6-diaza[3,3]-hexylene group, a 2-aza[3,3]-hexylene group, a 3-aza[5.5]undecylene group or a 3,9-diaza[5.5]undecylene group; X"" is -C(O)-, -O-(C1-C6 alkylene)-, -S-(C1-C6 alkylene)- or -NH-(C1-C6 alkylene)-, wherein the C1-C6 alkylene in -O-(C1-C6 alkylene)-, -S-(C1-C6 alkylene)- or -NH-(C1-C6 alkylene)- may be substituted by one or more Rx', wherein Rx' is a C1-C6 alkyl, or two Rx' located on the same carbon atom are connected to the carbon atom to form a C3-C8 cycloalkyl group; La" is -(CH2) k’ -, one or two methylene groups in said La" are optionally replaced by -O-, -NH or -N(Me)-, and k' is 0, 1, 2, 3, 4, 5 or 6; X'' is -C(O)-.

12. The compound of formula I according to claim 11, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, wherein: It meets one or more of the following conditions: (1) In LB, among the ring A", ring B" and ring C", the C3-C 12 The cycloalkylene groups are independently C3-C6 monocyclic cycloalkylene groups, C7-C 11 Bicyclic spirocycloalkylene, C7-C 11 Sub-bridged ring cycloalkyl or C7-C 11 cycloalkylene, for example cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, spiro[3.3]hexylene, spiro[3.4]heptylene, spiro[3.5]octylene, spiro[4.4]octylene, spiro[4.5]nonylene, spiro[5.5]decylene, bicyclo[3.3.0]octylene or hexahydroindanylene; (2) In LB, the C3-C 12 The cycloalkenylene groups are independently C3-C6 monocyclic cycloalkenylene, C7-C 11 Bicyclic spirocycloalkenylene, C7-C 11 Sub-bridged ring cycloalkenyl or C7-C 11 Cycloalkenylene, such as cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, (3) In LB, the 3-12 membered heterocycloalkylene in the ring A', ring B' and ring C' are independently C3-C6 monocyclic heterocycloalkylene, C7-C 11 Bicyclic spirocyclic heterocycloalkylene, C7-C 11 Sub-bridged heterocyclic alkyl or C7-C 11 The cycloheterocycloalkylene group, for example azetidinylene, oxetanylene, tetrahydrofuranylene, tetrahydropyrrolylene, tetrahydropyranylene, piperidinylene, morpholinylene or piperazinylene, 2,7-diaza[3.5]nonylene, 7-aza[3.5]nonylene, 2-aza[3.5]nonylene, 2,6-diaza[3,3]-hexylene, 2-aza[3,3]-hexylene, 3-aza[5,5]undecylene or 3,9-diaza[5,5]undecylene; (4) In LB, the C1-C6 alkyl group in the substituents of ring A″, ring B″ and ring C″ or the C1-C6 alkyl group in —O-(C1-C6 alkyl) is independently a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (5) In LB, the halogen in the substituents of Ring A'', Ring B'' and Ring C'' is independently F, Cl, Br or I; (6) In LB, in the ring A″, ring B″ and ring C″, the C1-C6 heteroalkyl group in the substituent is independently a C1-C4 heteroalkyl group containing one or two heteroatoms selected from N, O, and S, such as CH3OCH2-, CH3CH2OCH2-, CH3OCH2CH2-, CH3NHCH2-, CH3CH2NHCH2-, CH3NHCH2CH2-, CH3SCH2-, CH3CH2SCH2-, CH3SCH2CH2- or CH3OCH2OCH2-; (7) In LB, in the ring A″, ring B″ and ring C″, the C1-C6 haloalkyl in the substituent is independently a C1-C4 haloalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl substituted with 1, 2 or 3 halogens, wherein the halogen is F, Cl, Br or I; (8) In LB, the C1-C6 hydroxyalkyl groups in the substituents of Ring A″, Ring B″ and Ring C″ are independently C1-C4 hydroxyalkyl groups, such as hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxyisobutyl or hydroxy-t-butyl; (9) In LB, in the ring A", ring B" and ring C", the 3- to 8-membered heterocycloalkyl group in the substituent is independently a 4- to 6-membered heterocycloalkyl group, such as azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl; (10) In LB, in X'' and X'', the C1-C6 alkylene in -O-(C1-C6 alkylene), -S-(C1-C6 alkylene) or -NH-(C1-C6 alkylene) is independently C1-C4 alkylene, such as methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene or tert-butylene; (11) In LB, in the Rx', the C1-C6 alkyl group is independently a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (12) In LB, in the aforementioned La", the C1-C6 alkyl group in the -N(C1-C6 alkyl)- group in the aforementioned substituted group is a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (13) In LB, in the aforementioned La", the C1-C6 haloalkyl group in the -N(C1-C6 haloalkyl) group in the aforementioned substituted group is a C1-C4 haloalkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group substituted with 1, 2 or 3 halogens, wherein the halogens are independently F, Cl, Br or I; (14) In LB, in the aforementioned La", the C1-C6 hydroxyalkyl group in the -N(C1-C6 hydroxyalkyl)- group in the aforementioned substituted group is a C1-C4 hydroxyalkyl group, such as a hydroxymethyl group, a hydroxyethyl group, a hydroxy-n-propyl group, a hydroxy-isopropyl group, a hydroxy-n-butyl group, a hydroxy-sec-butyl group, a hydroxy-isobutyl group or a hydroxy-tert-butyl group; (15) In LB, in the aforementioned La", the C3-C8 cycloalkyl group in the -N(C3-C8 cycloalkyl)- group of the aforementioned substituted group is a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (16) In LB, in the ring A'', ring B'' and ring C'', the C3-C8 cycloalkyl in the substituent is independently a C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

13. The compound of formula I according to claim 11, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: It meets one or more of the following conditions: (1) In the LB described above, ring A" is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, such as C5-C6 monocyclic cycloalkylene, C5-C6 monocyclic cycloalkenylene, 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, or 7-8 membered bridged heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S (preferably C5-C6 monocyclic cycloalkylene, or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S), more such as piperidinylene, piperazinylene, cyclohexylene or cyclohexenylene, further such as Preferably Wherein side a is connected to X””; (2) In the LB described above, ring B" is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, such as C5-C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, more such as piperidinylene, cyclohexylene or piperazinylene, further such as Preferably Wherein side b is connected to X””; (3) In the LB described above, ring C″ is a 3-12-membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, for example, a 5-6-membered monocyclic heterocycloalkylene group or a 7-11-membered spirocyclic heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, more preferably a piperidinylene group, a piperazinylene group, a 2,7-diaza[3.5]nonylene group, a 7-aza[3.5]nonylene group, a 2-aza[3.5]nonylene group, a 2,6-diaza[3,3]-hexylene group, a 2-aza[3,3]-hexylene group, a 3-aza[5,5]undecylene group or a 3,9-diaza[5,5]undecylene group, further preferably Preferably The d side is connected to X'' (4) In the LB, X'' is -C(O)-, -O-(C1-C6 alkylene), -S-(C1-C6 alkylene) or -NH-(C1-C6 alkylene), and the C1-C6 alkylene in -O-(C1-C6 alkylene), -S-(C1-C6 alkylene) or -NH-(C1-C6 alkylene) may be substituted by one or more Rx', wherein Rx' is C1-C6 alkyl, or two Rx' located on the same carbon atom are connected to the carbon atom to form a C3 -C8 cycloalkyl; for example -C(O)-, -O-(C1-C3 alkylene), -S-(C1-C3 alkylene) or -NH-(C1-C3 alkylene), wherein the C1-C3 alkylene in -O-(C1-C3 alkylene), -S-(C1-C3 alkylene) or -NH-(C1-C3 alkylene) may be substituted by one or more Rx', wherein Rx' is C1-C6 alkyl, or two Rx' located on the same carbon atom are connected to the carbon atom to form a cyclopropyl group; for example (5) In the above LB, La" is -(CH2) k’ , one or two methylene groups in the La" are optionally substituted by -O- or -N(Me)-, and k' is 0, 1, 2, 3, 4, 5 or 6; the La" is, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2OCH2-, -CH2OCH2CH2-, -CH2CH2N(CH3)CH2-, -CH2N(CH3)CH2CH2-, preferably *-CH2-, *-CH2CH2-, *-CH2CH2CH2-, *-CH2CH2CH2CH2-, *-CH2CH2OCH2- or *-CH2OCH2CH2-, wherein the * side is connected to ring B"; (6) In the LB, X'' is -C(O)-; (7) In the LB described above, ring C″ is a 5-6 membered monocyclic heterocycloalkylene or a 7-11 membered spirocyclic heterocycloalkylene containing 1-2 N heteroatoms, wherein the N atom is connected to X″′; (8) In the LB described above, ring A″ is a C5-C6 monocyclic cycloalkylene or a 5-6 membered monocyclic heterocycloalkylene containing 1-2 N atoms; Ring B" is a C5-C6 monocyclic cycloalkylene group or a 5-6 membered monocyclic heterocycloalkylene group containing 1-2 N heteroatoms; and at least one of ring A" or ring B" is connected to X"" through an N atom; (9) The LB described is LB-1:

14. The compound of formula I according to any one of claims 11 to 13, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that: The LB is any one of the following structures:

15. The compound of formula I according to claim 1 or 2, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: The E mentioned above is EA: In the EA, Ring D is connected to L; Among them, ring D is Q1, Q1', Q2, Q2', Q3, Q3', Q4, Q4', Q5' or Q6' are independently CH or N; R B and R B’ are independently hydrogen, deuterium, hydroxyl, halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -O-(C1-C6 heteroalkyl), C2-C6 alkenyl, C2-C6 alkynyl, -CONR C R D 、-OR C 、-NR C R D 、-SR C 、-SO2R C 、-SO2NR C R D 、-CR C R D 、-CR C NR C R D 、C6-C 10 Aryl, C5-C 10 Heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR C )R D 、-P(O)R C R D 、-OP(O)(OR C )R D 、-CF3、-NR C SO2NR C R D 、-NR C C(O)NR C R D 、-C(O)NR C C(O)R D 、-NR C C(=N-CN)NR C R D 、-C(=N-CN)NR C R D 、-NR C C(=N-CN)R D 、-NR C C(=C-NO2)NR C R D 、-SO2NR C COR D 、-NO2、-COR C 、-C(C=N-OR C )R D 、-CR C =CR C R D 、-CCR C 、-S(C=O)(C=NR C )R D or -SF5; R C and R D are independently a bond, hydrogen, deuterium, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C5-C 10 heteroaryl or 3-8 membered heterocycloalkyl; n″ and n′″ are independently 1, 2, 3 or 4; t is 0, 1, or 2; P1 is CH2, O or S; W is CR E R F , C(S), C(O) or SO2; R E and R F are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl; P and Q are independently CH2, O or S; Z is CH or N; R A is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, halogen or C3-C8 heterocycloalkyl; The heteroaryl group is a heteroaryl group having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; the heterocycloalkyl group is a heterocycloalkyl group having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroalkyl group is a heteroatom or heteroatom group selected from one or more heteroatoms selected from N, O, S, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene and ethynylene, and the number of heteroatoms is 1, 2 or 3.

16. The compound of formula I according to claim 15, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: It meets one or more of the following conditions: (1) In EA, R B 、R B’ 、R C and R D wherein the C1-C6 haloalkyl group is independently a C1-C4 haloalkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group substituted with 1, 2 or 3 halogens, and the halogens are independently F, Cl, Br or I; (2) In EA, R B 、R B’ 、R C 、R D 、R E 、R F and R A wherein the C1-C6 alkyl group is independently a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (3) In EA, R B 、R B’ 、R C 、R D 、R E 、R F and R A wherein the C1-C6 heteroalkyl group or the C1-C6 heteroalkyl group in -O-(C1-C6 heteroalkyl group) is independently a C1-C4 heteroalkyl group containing 1 or 2 heteroatoms selected from N, O, and S, such as CH3OCH2-, CH3CH2OCH2-, CH3OCH2CH2-, CH3NHCH2-, CH3CH2NHCH2-, CH3NHCH2CH2-, CH3SCH2-, CH3CH2SCH2-, CH3SCH2CH2- or CH3OCH2OCH2-; (4) In EA, R B and R B’ In the above, the C2-C6 alkenyl group is independently a C2-C4 alkenyl group, such as vinyl, propenyl or allyl; (5) In EA, R B and R B’ In the above, the C2-C6 alkynyl group is independently a C2-C4 alkynyl group, such as ethynyl, propynyl or propargyl; (6) In EA, R B 、R B’ 、R C and R D C6-C 10 Aryl is independently phenyl or naphthyl; (7) In EA, R B 、R B’ 、R C and R D C5-C 10 Heteroaryl is independently furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl or indolyl; (8) In EA, R B 、R B’ 、R C 、R D 、R E 、R F and R A wherein the C3-C8 cycloalkyl group is independently a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (9) In EA, R B 、R B’ 、R C 、R D 、R E 、R F and R A wherein the 3-8 membered heterocycloalkyl group is independently a 4-6 membered heterocycloalkyl group, such as azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl; (10) In EA, R B 、R B’ and R A wherein the halogen is independently F, Cl, Br or I; (11) The EA described is 17. The compound of formula I according to claim 15, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: It meets one or more of the following conditions: (1) In the EA, Q1, Q1', Q2, Q2', Q3, Q3', Q4, Q4', Q5' or Q6' is independently CH; (2) In the EA described above, R B and R B’ are independently hydrogen, CN, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, -O-(C1-C6 heteroalkyl), C3-C8 cycloalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR C ; (3)R C is C1-C6 haloalkyl, C1-C6 alkyl or C3-C8 cycloalkyl; (4) In the EA, n″ and n′″ are independently 1; (5) In the EA, P1 is O; (6) In the EA, W is CH2 or C(O); (7) In the EA, P and Q are independently O; (8) In the EA, Z is CH or N; (9) In the EA described above, R A is hydrogen; (10) In the EA described above, ring D is connected to L; Among them, ring D is Q1, Q1', Q2, Q2', Q3, Q3', Q4, Q4', Q5' or Q6' are independently CH; R B and R B’ are independently hydrogen, halogen, CN, C1-C6 alkyl, C1-C6 heteroalkyl, -O-(C1-C6 heteroalkyl), C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR C ; R C is C1-C6 haloalkyl, C1-C6 alkyl or C3-C8 cycloalkyl; n″ and n″′ are 1; P1 is O; W is CH2 or C(O); P and Q are independently O; Z is CH or N; R A is hydrogen; (11) The EA is EA-1, EA-2, EA-3 or EA-4: Among them, Q1, Q1', Q2, Q2', Q3, Q3', Q4, Q4', Q6', R B 、R B’ , n″, n″′, P1, W, P, Q, Z and R A The definition of as claimed in claim 12; Preferably, the EA-1 is EA-1-1: Preferably, the EA-2 is EA-2-1: Preferably, the EA-3 is EA-3-1: Preferably, the EA-4 is EA-4-1: (12) In the EA described above, when the Z is CH, the configuration of the C is R configuration, S configuration or a mixture thereof.

18. The compound of formula I according to any one of claims 15 to 17, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that: The E is:

19. The compound of formula I according to claim 1, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that: The compound represented by formula I is any one of the following compounds:

20. Use of a compound represented by formula S' or a salt thereof in the preparation of a targeted SOS1 protein degradation agent, in, R G is hydrogen, halogen or the ring A" as described in any one of claims 11 to 14; X, R1, m, A1, R5 and The definitions are as described in any one of claims 1 to 7; Preferably, R5 is Me; R4 is Me or CD3 or CH2CF3; X is N or CH; R1 is OMe, Me, OCH2CH2OCH3, CN, Cl, F or Br; m is 0 or 1; R G for Preferably, the targeted SOS1 protein degrader is a compound of formula I according to any one of claims 1 to 19, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition comprising G and a pharmaceutically acceptable carrier, diluent or excipient, wherein G is a compound of formula I according to any one of claims 1 to 19, a stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, prodrug, or pharmaceutically acceptable salt thereof.

22. Use of a compound of formula I according to any one of claims 1 to 19, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by SOS1, or a disease or condition caused by the interaction of SOS1 with Ras or SOS1 with Rac, or cancer.

23. The use according to claim 22, wherein the cancer is selected from: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, liposarcoma tumor and teratoma group; Lung: bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, enchondroma, hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary system: kidney (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, enchondroma (osteochondral exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germinal cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecology: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Adrenal gland: neuroblastoma.

24. The use as claimed in claim 22, wherein: The cancer is pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer or sarcoma.

25. Use of a compound according to any one of claims 1 to 19, a stereoisomer, enantiomer, diastereomer, deuterate, hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21 in the preparation of a medicament for treating and / or preventing neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-cutaneous syndrome (CFC), Leggs syndrome, and hereditary gingival fibromatosis.

26. Use of the compound of any one of claims 1 to 19, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 21 in the preparation of a medicament for treating and / or preventing a KRAS-mediated disease or condition, wherein the KRAS is preferably a mutant KRAS, and the mutant KRAS is preferably one or more of KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12V.

27. A compound of formula P-1, P-2, P-3 or P-4: in, X, R1, m, A1, R5 and The definitions of ring A", ring B", ring C", X"', X"" and La" and the connection relationship therebetween are as described in any one of claims 11 to 14; Preferably, the compound represented by formula P-1 is a compound represented by formula P-1-1: For example Preferably, the compound represented by formula P-2 is a compound represented by formula P-2-1: For example Preferably, the compound represented by formula P-3 is a compound represented by formula P-3-1: For example Preferably, the compound represented by formula P-4 is a compound represented by formula P-4-1: For example Preferably, the compound represented by formula P-5 is a compound represented by formula P-5-1: For example