Substituted tricyclic compound and use thereof

Abstract

A tricyclic compound as a VHL ligand, a preparation method therefor, and a use of the compound or a pharmaceutical composition thereof for preventing and / or treating a series of diseases, disorders, and conditions.

Description

Substituted tricyclic compounds and uses thereof Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and specifically relates to a tricyclic compound that serves as a VHL ligand and a method for preparing the same. The present invention also relates to the use of the compound or a pharmaceutical composition thereof for preventing and / or treating a range of diseases, disorders, and conditions. Background Art

[0002] The von Hippel-Lindau (vhl) gene was first discovered through positional cloning in 1993. The protein consists of 213 amino acid residues with a molecular weight of 24-30 kDa. It is associated with von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder caused by inactivating mutations in VHL that predisposes to various tumor types, such as retinal angiomas and hemangioblastomas. The VHL protein also exhibits E3 ligase activity, and its primary substrate in the human body is hypoxia-inducible factor (HIF-1α). Under hypoxic conditions, HIF-1α cannot be oxidatively hydroxylated, thus preventing its recognition by VHL and subsequent ubiquitination and degradation. This leads to the upregulation of downstream proteins such as vascular endothelial growth factor and platelet-derived growth factor in response to hypoxia. If a class of small molecules is identified that can compete with HIF-1α for binding to the VHL protein, it may have potential applications in diseases associated with this signaling pathway, such as cancer and chronic anemia.

[0003] In recent years, researchers have leveraged the ubiquitin-proteasome pathway's ability to specifically degrade protein substrates to construct proteolysis-targeting chimeras (PROTACs). PROTACs are compounds with two heterofunctional ligands connected by a linker: one ligand targets the protein of interest (POI), while the other specifically recruits an E3 ligase. When a PROTAC binds to the E3 ligase and the target protein, a ternary complex is formed. By hijacking the E3 ligase, the PROTAC positions the POI in a favorable spatial position to promote ubiquitination. The ubiquitinated target protein is then recognized and degraded by the proteasome, selectively reducing the target protein's intracellular levels. Compared to traditional small molecule inhibitor development methods, PROTAC technology offers the potential to target traditionally undruggable targets and overcome the "drug resistance" associated with small molecule inhibitors. Furthermore, PROTACs can catalyze multiple rounds of target protein degradation, and complete protein removal will result in more potent drug efficacy.

[0004] In summary, designing high-quality small molecule ligands with good binding affinity for E3 ligases not only has the potential for direct application in diseases such as cancer but also forms the foundation for the development of PROTAC technology. Currently, the VHL ligands developed on the market have not yet been commercialized. The lack of efficient E3 ligase ligands as a first step in developing PROTAC degraders has been a major challenge in the initial development of this field. Therefore, it is necessary to develop new VHL ligands to meet clinical needs. Summary of the Invention

[0005] In one aspect, the present invention relates to a compound represented by formula (I), or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof:

[0006] Wherein, R1 and R2 are each independently selected from H, hydroxyl, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2- 6-alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the C 1-6 Hydroxyalkyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2-6 Alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more Ra replace;

[0007] R3 is selected from H, hydroxyl, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6 alkoxy, C 1-6 Haloalkoxy or -C 0-3 Alkylene-N(R c )2, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or -C 0-3 Alkylene-N(R c ) 2 optionally further represented by one or more R a replace;

[0008] R4 is independently selected from H, hydroxy, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0009] R5 is selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -(CH2) n N(R9)2、-(CH2) n -CO-O R9 or -(CH2) n -CO-N(R9)2;

[0010] m and n are each independently selected from 0, 1, 2, 3 or 4;

[0011] Ring B is selected from C 6-10 Aryl or 5-18 membered heteroaryl, preferably 5-10 membered heteroaryl, more preferably 5-6 membered heteroaryl, the C 6-10 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a replace;

[0012] X1, X2, X3 are each independently selected from the group consisting of not present, C(R 10 )2, O or NR 10 , but X1, X2, and X3 are not simultaneously selected from non-existence;

[0013] The R9, R 10 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6Alkoxy or C 1-6 alkyl halide;

[0014] The R a are independently selected from the group consisting of absent, H, hydroxy, oxo, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-OR b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(O) 1-2 R b 、-C 0-3 Alkylene-S(R b )5、=C(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); the amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2- 6-alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace;

[0015] Each R b are independently H, halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 6 cycloalkyl, C 1-6 Haloalkoxy or C 1-6 haloalkyl; wherein said C 1-6 Alkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, C 1-6 Haloalkoxy or C 1-6 The haloalkyl group is optionally further substituted with one or more H, C 1-6 Alkoxy, -N(C 1- 3 alkyl) 2;

[0016] Each R c Each independently selected from H, hydroxy, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0017] In another aspect, the present invention relates to a compound represented by formula (IA):

[0018] Wherein, the definitions of R1, R2, R3, R4, R5, m, X1, X2, and X3 are the same as those in the general formula (I).

[0019] In another aspect, the present invention relates to a compound represented by formula (IA-1):

[0020] Wherein, the definitions of R1, R2, R3, R4, R5, m, X1, X2, and X3 are the same as those in the general formula (I).

[0021] In another aspect, the present invention relates to a compound represented by formula (IB):

[0022] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0023] In another aspect, the present invention relates to a compound represented by formula (IC):

[0024] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0025] In another aspect, the present invention relates to a compound represented by formula (ID):

[0026] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0027] In another aspect, the present invention relates to a compound represented by formula (IE):

[0028] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0029] In another aspect, the present invention relates to a compound represented by formula (IF):

[0030] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0031] On the other hand, the present invention relates to a compound represented by formula (IG):

[0032] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0033] On the other hand, the present invention relates to a compound represented by formula (IH):

[0034] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0035] In another aspect, the present invention relates to a compound represented by formula (IJ):

[0036] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0037] In another aspect, the present invention relates to a compound represented by formula (IK):

[0038] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0039] In another aspect, the present invention relates to a compound represented by formula (IL):

[0040] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0041] In another aspect, the present invention relates to a compound represented by formula (IM):

[0042] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0043] In another aspect, the present invention relates to a compound represented by formula (IN):

[0044] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0045] In another aspect, the present invention relates to compounds of formula (IP):

[0046] Wherein, the definitions of R1, R2, R3, R4, R5 and m are the same as those in the general formula (I).

[0047] In another aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds described herein, or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing compounds, and one or more pharmaceutically acceptable excipients.

[0048] In another aspect, the compound of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing compounds, is a VHL ligand that binds to VHL E3 ubiquitin ligase.

[0049] In another aspect, the compound of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing compounds, comprises a VHL binding moiety.

[0050] In another aspect, the present invention relates to a method of binding or inhibiting VHL using one or more compounds described herein, or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing compounds, or one or more pharmaceutical compositions described herein.

[0051] In another aspect, the present invention relates to a method for preparing one or more compounds of the present invention, or stereoisomers or tautomers thereof, or a pharmaceutically acceptable salt of any of the foregoing compounds, or one or more pharmaceutical compositions of the present invention.

[0052] In another aspect, the present invention relates to a bifunctional compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof,

[0053] The bifunctional compound comprises a W group, a linker L and a VHL ligand portion;

[0054] Wherein, the W group is a warhead, which is a protein targeting portion;

[0055] The L is a chemical linker used to connect the VHL ligand and the protein targeting portion, and the L is selected from the following groups: -A1-...-A q -, where A1 to A q is a bond or a chemical group coupled to at least one of the warhead, the VHL ligand, or a combination thereof, and q is an integer greater than or equal to 1;

[0056] Wherein, q is an integer from 1 to 20;

[0057] wherein each A is independently selected from absence, a bond, CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 , CO, CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , optionally 0-6 R L1 and / or R L2 C 3-14 Cycloalkyl, optionally substituted with 0-6 R L1 and / or R L2 3-14 membered heterocyclic group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 substituted aryl, optionally substituted with 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 Each independently can be linked to other A groups to form cycloalkyl and / or heterocyclyl moieties, which can be further substituted by 0-4 R L5 Group substituted; and wherein R L1 、R L2 、R L3 、R L4 and R L5 are independently H, halogen, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1- 6-alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, aryl, heteroaryl, 3-14 membered heterocyclic group, OC 1- 6-cycloalkyl, SC 1-6 Cycloalkyl, NHC 1-6 Cycloalkyl, N(C1-6 Cycloalkyl)2, N(C 1-6 Cycloalkyl)(C 1-6 alkyl), OH, NH2, SH, SO2C 1-6 Alkyl, P(O)(OC 1-6 Alkyl)(C 1-6 alkyl), P(O)(OC 1-6 Alkyl)2, CC-C 1-6 Alkyl, CCH, CH=CH(C 1-6 alkyl), C(C 1-6 alkyl)=CH(C 1-6 alkyl), C(C 1-6 alkyl)=C(C 1-6 alkyl)2、Si(OH)3、Si(C 1-6 Alkyl)3, Si(OH)(C 1-6 Alkyl)2, COC 1-6 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-6 Alkyl, SO2N(C 1-6 Alkyl)2, SONHC 1-6 Alkyl, SON(C 1-6 Alkyl)2, CONHC 1-6 Alkyl, CON(C 1-6 alkyl)2, N(C 1-6 alkyl)CONH(C 1-6 alkyl), N(C 1-6 alkyl)CON(C 1-6 alkyl)2、NHCONH(C 1-6 alkyl), NHCON(C 1-6 alkyl)2、NHCONH2、N(C 1-6 alkyl)SO2NH(C 1- 6 alkyl), N(C 1-6 alkyl)SO2N(C 1-6 Alkyl)2、NHSO2NH(C 1-6 alkyl), NHSO2N(C 1-6 Alkyl)2, NHSO2NH2.

[0058] The definitions of the ring B, R2, R3, R4, R5, m, X1, X2 and X3 are the same as those in the general formula (I).

[0059] In some embodiments of the present invention, the formula (II) is selected from the compound represented by formula (II-1):

[0060] Wherein, W, L, R2, R3, R4, R5, m, X1, X2, X3 and ring B are as defined in formula (II).

[0061] In some embodiments of the present invention, q is an integer of 1-10, preferably an integer of 2-8, and more preferably an integer of 2-6.

[0062] In some embodiments of the present invention, L is a group -A1-A2-A3-A4-A5-, wherein A1, A2, A3, A4, and A5 are each independently selected from the group consisting of absence, bond, O, S, SO, SO2, CO, CR L1 R L2 NR L3 , C≡C, optionally 0-6 R L1 and / or R L2 C 3-14 Cycloalkyl, optionally substituted with 0-6 R L1 and / or R L2 3-14 membered heterocyclic group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 substituted aryl, optionally substituted with 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group; wherein R L1 、R L2 and R L3 are each independently selected from H, halogen, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, aryl, heteroaryl, 3-14 membered heterocyclic group, OC 1-6 Cycloalkyl, SC 1-6 Cycloalkyl, NHC 1-6 Cycloalkyl, N(C 1-6 Cycloalkyl)2, N(C 1-6 Cycloalkyl)(C 1-6 alkyl), OH, NH2, SH, SO2C 1-6 Alkyl, COC 1-6 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, among which R L1 or R L2 Each independently can be linked to other A groups to form cycloalkyl and / or heterocyclyl moieties.

[0063] In some embodiments of the present invention, L is a group -A1-A2-A3-A4-, wherein A1, A2, A3, and A4 are each independently selected from the group consisting of absence, bond, O, S, SO, SO2, CO, CR L1 R L2 NR L3 , optionally 0-6 R L1 and / or R L2 C 3-14 Cycloalkyl, optionally substituted with 0-6 R L1 and / or R L2 3-14 membered heterocyclic group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 The aryl group substituted by the group, optionally substituted by 0-6 R L1 and / or R L2 a heteroaryl substituted with a group; wherein R L1 、R L2 and R L3 are each independently selected from H, halogen, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, aryl, heteroaryl, 3-14 membered heterocyclic group, OC 1-6 Cycloalkyl, SC 1-6 Cycloalkyl, NHC 1-6 Cycloalkyl, N(C 1-6 Cycloalkyl)2, N(C 1-6 Cycloalkyl)(C 1-6 alkyl), OH, NH2, SH, SO2C 1-6 Alkyl, COC 1-6 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, wherein the R L1 or R L2 Each independently can be linked to other A groups to form cycloalkyl and / or heterocyclyl moieties.

[0064] In a further embodiment of the present invention, the C 3-14 Cycloalkyl is selected from

[0065] The 3-14 membered heterocyclic group is selected from

[0066] The aryl group is

[0067] The heteroaryl 5-6 membered nitrogen-containing heteroaryl is selected from

[0068] In some embodiments of the present invention, L is a group -A1-A2-A3-A4-, wherein A4 is selected from optionally substituted by 0-6 R L1 and / or R L2 5-6 membered nitrogen-containing heteroaryl substituted by a group; said A1 is selected from optionally substituted by 0-6 R L1 and / or R L2 A3, A2, A3 are each independently selected from the group consisting of absence, bond, CR L1 R L2 、-O-、C≡C、NR L3 or a 3-7 membered N-containing heterocyclic group; wherein said R L1 、R L2 and R L3 are independently H, halo, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, aryl, heteroaryl, 3-14 membered heterocyclic group, OC 1-6 Cycloalkyl, SC 1-6 Cycloalkyl, NHC 1-6 Cycloalkyl, N(C 1-6 Cycloalkyl)2, N(C 1-6 Cycloalkyl)(C 1-6 alkyl), OH, NH2, SH, SO2C 1-6 Alkyl, COC 1-6 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, wherein the R L1 or R L2 Each independently can be linked to other A groups to form cycloalkyl and / or heterocyclyl moieties.

[0069] In a further embodiment of the present invention, the 5-6 membered nitrogen-containing heteroaryl group is selected from

[0070] The 3-14 membered heterocyclic group is preferably selected from

[0071] The 3-7 membered N-containing heterocyclic group is selected from

[0072] In some embodiments of the present invention, L is selected from the following groups:

[0073] In some embodiments of the present invention, the W group is a protein targeting moiety, wherein the target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins related to the integration function of the cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolic metabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction protein activity, structural molecule activity, binding activity Proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcriptional regulator activity, extracellular organization and biogenesis activity, and translational regulation activity).

[0074] In some embodiments of the invention, the W is a protein targeting moiety, wherein the target protein is selected from ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tryptase, serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and analogs, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinases (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus type 1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7), farnesyltransferase, geranyl eranyltransferase, TrkAa NGF receptor, β-amyloid protein, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, GABA-gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylate succinate synthetase, protoporphyrinogen oxidase, L-1 receptor-associated kinase 3 (IRAK-3 or IRAK-M), or enolpyruvyl-shikimate-phosphate synthase.

[0075] In some embodiments of the present invention, the W is a protein targeting moiety, wherein the target protein is selected from various types of mutant KRAS proteins and wild-type KRAS proteins.

[0076] In some embodiments of the present invention, the W is a KRAS protein binding fragment represented by formula (III);

[0077] The X is selected from -O- or C≡C,

[0078] described represents independently selected from a single bond or a double bond;

[0079] The X4 is CR 13 、C(R 13 )2, O, N or NR 13 ; R 13 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a1 replace;

[0080] Said X5 is selected from C, CH or N;

[0081] The X6 is selected from CR 12 、C(R 12 )2, O, N or NR 12 ; R 12 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a1 replace;

[0082] The R 11 Select from non-existent, C 3-14Cycloalkyl or 3-14 membered heterocyclic group; said C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a1 replace;

[0083] The R 14 Selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 Alkenyl, C 3-6 Cycloalkyl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl group is optionally further substituted with one or more R a1 replace;

[0084] The R 15 Selected from absent, -O- or -NR 11 -;R 11 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl;

[0085] The R 12 Selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a1 replace;

[0086] The K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic, condensed, spirocyclic or bridged ring, optionally further substituted by one or more R a1 replace;

[0087] or R 14 Together with K and the atoms to which it is attached, it forms a 3-14 membered heterocyclic group, wherein the 3-14 membered heterocyclic group may be further optionally substituted with one or more R a1 replaced by;

[0088] The m1 and n1 are each independently selected from 0, 1, 2, 3, 4 or 5;

[0089] The R a1 Each independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b1 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b1 、-C 0-3 Alkylene-N(R b1 )2. -C 0-3 Alkylene-S(=O)R b1 、-C 0-3 Alkylene-S(=O)2R b1 、-C 0-3 Alkylene-SR b1 、-C 0-3 Alkylene-S(R b1 )5. -C 0-3 Alkylene-C(=O)R b1 、-C 0-3 Alkylene-C(=O)OR b1 、-C 0-3 Alkylene-C(=O)N(R b1 )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b1 replace;

[0090] Each R b1 are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 substituted by a haloalkyl group; or two R b1 The atoms connected to them form C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Haloalkyl substitution.

[0091] In some embodiments of the present invention, W is a KRAS protein binding fragment represented by formula (III-1) or (III-2);

[0092] Among them, X4, X5, X6, m1, n1, R 11 , R 12 , R 14 , R 15 , K is as defined in formula (III).

[0093] In some embodiments of the present invention, in the general formula of W, K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic ring, and is optionally further substituted by one or more R a1 replace.

[0094] In some embodiments of the present invention, in the general formula of W, K is selected from

[0095] In some embodiments of the present invention, in the general formula of W, K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a spiro ring and is optionally further substituted by one or more R a1 replace.

[0096] In some embodiments of the present invention, in the general formula of W, K is selected from

[0097] In some embodiments of the present invention, in the general formula of W, K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a fused ring, and is optionally further substituted by one or more R a1 replace.

[0098] In some embodiments of the present invention, in the general formula of W, K is selected from

[0099] In some embodiments of the present invention, in the general formula of W, K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a bridged ring, and is optionally further substituted by one or more R a1 replace.

[0100] In some embodiments of the present invention, in the general formula of W, K is selected from

[0101] In some embodiments of the present invention, the K is selected from

[0102] In some embodiments of the present invention, in the general formula of W, the R 12 Selected from C 6-18 Aryl or 5-18 membered heteroaryl, the C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a1 Substitution; said R a1 Each independently selected from H, halogen, hydroxy, amino, cyano, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2- 6 olefins.

[0103] In some embodiments of the present invention, in the general formula of W, the R 12 Selected from described Optionally further comprised of one or more a1 Substitution; said R a1Each independently selected from H, halogen, hydroxy, amino, cyano, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Olefins.

[0104] In some embodiments of the present invention, in the general formula of W, the R 12 Selected from

[0105] In some embodiments of the present invention, the W is selected from

[0106] In some embodiments of the present invention, the W is selected from

[0107] In some embodiments of the present invention, the compound of formula (II) is selected from:

[0108] On the other hand, the present invention provides a pharmaceutical composition comprising any of the above-mentioned bifunctional compounds represented by general formula (II) of the present invention or its pharmaceutically acceptable salts, stereoisomers, tautomers, solvates or polymorphs, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0109] The present invention further provides the use of any of the above-mentioned bifunctional compounds represented by general formula (II) or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates or polymorphs thereof, or pharmaceutical compositions comprising the same, in the preparation of a drug for regulating protein ubiquitination and degradation in a subject.

[0110] The present invention further provides the use of any of the above-mentioned bifunctional compounds represented by general formula (II) or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates or polymorphs thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for regulating the ubiquitination and degradation of KRAS protein in a subject.

[0111] The present invention further provides use of any of the above-mentioned bifunctional compounds represented by general formula (II) or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates or polymorphs thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing KRAS-mediated or KRAS-dependent diseases, wherein the KRAS-mediated disease is preferably selected from tumors.

[0112] In certain embodiments, the disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatobiliary carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

[0113] Unless otherwise indicated, general chemical terms used in the structural formulae have their usual meanings.

[0114] For example, the term "halogen," as used herein, refers to fluorine, chlorine, bromine, or iodine, unless otherwise indicated.

[0115] The moiety used in the present invention that binds to an E3 ubiquitin ligase or a component thereof (eg, VHL) is referred to as a ubiquitin ligase binding moiety.

[0116] In the present invention, the connection order of the groups is not particularly limited and the groups can be connected from left to right or from right to left.

[0117] The term "protein targeting moiety" or W group is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and positions / presents the protein or polypeptide in proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, KRAS inhibitors, compounds targeting proteins containing the human BET Bromodomain, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among many others.

[0118] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 The "1-6" in "alkyl" refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in a straight chain or branched form.

[0119] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups, ie, -O-alkyl.

[0120] The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane with two C—H bonds replaced as the point of attachment of the alkylene to the rest of the compound. Similarly, C 1-3 The "C" in the alkylene 1-3 ” refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.

[0121] The term "haloalkyl" refers to an alkyl group in which one or more H groups have been replaced by a halogen atom.

[0122] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when attached to a heteroatom.

[0123] In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" refers to a polyunsaturated carbon ring or heterocycle with aromatic characteristics (having (4n+2) delocalized π electrons, where n is an integer).

[0124] The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or condensed ring aromatic group containing carbon ring atoms. 6-18 Aryl, more preferably C 6-10 A monocyclic or bicyclic aromatic ring group. Phenyl or naphthyl is preferred; naphthyl is most preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring connecting to the parent structure is an aryl ring. Non-limiting examples include, but are not limited to, benzocyclopentyl.

[0125] The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heteroatom, wherein the heteroatom is selected from N, O and / or S. The heterocyclyl may include a monocyclic or polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). The heterocyclyl may be connected to the other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably, a 3-14 membered heterocyclyl is used, and the "3-14 members" in the 3-14 membered heterocyclyl refers to a heterocyclyl composed of 3-14 C, N, O or S ring atoms; wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. Examples of these heterocyclyls include, but are not limited to Pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydrooxadiazolyl. The heterocyclic group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0126] The term "heteroaryl" as used herein, unless otherwise specified, refers to a monocyclic or polycyclic (e.g., 2, 3, or 4 fused, spiro, or bridged) aromatic heterocycle having at least one heteroatom, wherein the heteroatom is selected from N, O, and / or S, and wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. A 5- to 18-membered heteroaryl is preferred, wherein the "5- to 18-membered" in the 5- to 18-membered heteroaryl refers to a heteroaryl group consisting of 5 to 18 ring atoms of C, N, O, or S. A 5- to 10-membered heteroaryl is more preferred; a 5- to 6-membered heteroaryl is even more preferred. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolyl, or isoquinolyl. The heteroaryl group may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.

[0127] The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. 3-14 Cycloalkyl, where "C 3-14 " means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms. The cycloalkyl group may include monocyclic and polycyclic rings (e.g., having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, The cycloalkyl group can also be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0128] The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-6 Alkyl, C 3-12 Cycloalkyl, -OR 1 、-SR 1 , =O, =S, -C(O)R 1 、-C(S)R1 、=NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2 , cyano, nitro, -S(O)2R 1 、-OS(O2)OR 1 、-OS(O)2R 1 、-OP(O)(OR 1 )(OR 2 ); where R 1 and R 2 Independently selected from -H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formaldehyde, -COCH3, cyano, nitro, -CF3, amino, dimethylamino, sulfonyl, and acetyl.

[0129] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0130] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.

[0131] When the compound provided by the present invention is an acid, its corresponding salt can be easily prepared from pharmaceutically acceptable nontoxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0132] When compound provided by the invention is a base, it is possible to conveniently prepare its corresponding salt from pharmaceutically acceptable nontoxic acid, including inorganic and organic acids. Such acid includes, as, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, tamoxifen, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0133] Prodrugs of the compounds of the present invention are included within the scope of protection of the present invention. Generally, such prodrugs are functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, ester salt, or other derivative of the compounds of the present invention, which, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention or their pharmaceutically active metabolites or residues.

[0134] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0135] When the compound represented by formula (I) exists in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0136] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0137] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient composition can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0138] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0139] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0140] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0141] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and / or side effects caused by the disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0142] The term "effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0143] The room temperature mentioned in the present invention refers to the temperature of the indoor environment, which is generally 18-25°C. DETAILED DESCRIPTION

[0144] To make the above content clearer and more specific, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0145] Unless otherwise stated, all temperatures herein are in degrees Celsius.

[0146] The following abbreviations are used in the examples: DMF: N,N-dimethylformamide; NIS: N-iodosuccinimide; THF: tetrahydrofuran; EA: ethyl acetate; PE: petroleum ether; DCM: dichloromethane; MeOH: methanol; DPPA: diphenylphosphoryl azide; CDI: N,N'-carbonyldiimidazole; DIEA / DIPEA: N,N-diisopropylethylamine; POCl3: phosphorus oxychloride; DMSO: dimethyl sulfoxide; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; TFA: trifluoroacetic acid; DABCO: triethylenediamine; TBAF: tetrabutylammonium fluoride; TEA: triethylamine; TMSOI: trimethylsulfoxide iodide; ACN / MeCN: acetonitrile; Dioxane: 1,4-dioxane PdCl2(PPh3)2: bistriphenylphosphine palladium dichloride; Cs2CO3: cesium carbonate; DMP: Dess-Martin periodinane; CuI: cuprous iodide; K3PO4: potassium phosphate; ZnCl2: zinc chloride; CataCXium A Pd G3: [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate.

[0147] Synthesis of intermediate M1:

[0148] Step 1: Synthesis of compound M1-1

[0149] At room temperature, 2-chloro-3-fluoro-pyridine-4-carboxylic acid (54.00 g), toluene (390.00 mL), tert-butyl alcohol (390.00 mL), triethylamine (128.27 mL), powdered Molecular sieves (90.00 mL) (pre-activated), under nitrogen protection, reflux for half an hour (internal temperature 87°C). Then cool naturally to room temperature, then add DPPA (99.44 mL), heat to reflux, and keep warm for 5 hours. The reaction mixture is cooled to below 40°C, then diluted with EA 500 mL; continue to cool to room temperature, filter with diatomaceous earth to remove the added molecular sieves; rinse the filter residue with EA 1500 mL several times and drain; collect the filtrate, wash with water 700 mL and saturated brine 700 mL in sequence, and separate the liquids; dry the organic phase with anhydrous sodium sulfate; filter, remove the desiccant, and concentrate. The concentrate is separated and purified by column chromatography (PE / EA = 30:1 to 20:1), and the eluent is concentrated to finally obtain compound M1-1 (68.2 g, yield 89.88%).

[0150] ESI-MS m / z:247.1[M+H] + .

[0151] Step 2: Synthesis of Compound M1-2

[0152] At room temperature, compound M1-1 (65.00 g) was dissolved in CH3CN (82.00 mL), cooled in a water bath, and hydrochloric acid (4M / dioxane) (264 mL) was slowly added. The reaction was stirred at room temperature for about 16 hours, and a white solid precipitated in a suspended state. The reaction mixture was filtered, and the filter cake was rinsed with a small amount of acetonitrile, drained, and the filtrate discarded. The filter cake was collected and added to a mixture of 700 mL of saturated sodium bicarbonate aqueous solution and 700 mL of ethyl acetate, alkalized, extracted, and separated; the aqueous phase was further extracted with 350 mL of ethyl acetate and separated; the ethyl acetate phases were combined, washed with 300 mL of saturated sodium chloride aqueous solution, and separated; the organic phase was dried over anhydrous sodium sulfate, filtered, the desiccant was removed, and concentrated to obtain compound M1-2 (36.3 g, 94.0% yield).

[0153] ESI-MS m / z:147.1[M+H] + .

[0154] Step 3: Synthesis of Compound M1-3

[0155] Compound M1-2 (36.00 g) was dissolved in acetonitrile (180.00 mL) at room temperature, and NIS (66.32 g) and p-toluenesulfonic acid (2.12 g) were added. The mixture was heated to 70°C under nitrogen. The reaction mixture was cooled to 50°C, and 900 mL of water was added. A white solid precipitated and was slurried for half an hour. The mixture was filtered, and the filter cake was rinsed with water and dried. The filter cake was collected and completely dissolved in 1200 mL of ethyl acetate. The mixture was then washed twice with 350 mL of saturated sodium sulfite solution and then with 350 mL of saturated brine. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound M1-3 (63.2 g, 94.43% yield).

[0156] ESI-MS m / z:272.9[M+H] + .

[0157] Step 4: Synthesis of Compound M1-4

[0158] At room temperature, compound M1-3 (57.50 g) was dissolved in DMF (22.00 mL), zinc cyanide (32.22 g), tetrakistriphenylphosphine palladium (12.19 g) and powdered Molecular sieves (20.00 mL) were added, and the mixture was heated to 100°C under a nitrogen atmosphere for approximately 7 hours. The oil bath was removed, and the mixture was allowed to cool naturally to room temperature for post-processing. The reaction mixture was filtered using diatomaceous earth as a filter aid and drained. The filtrate was collected and concentrated at 60-70°C to obtain a pale yellow solid crude product. The filter residue was rinsed with 500 mL of ethyl acetate and drained. The rinse was collected and added to the crude product, and concentrated again until no liquid was distilled out. The concentrated crude solid product was dissolved in 700 mL of ethyl acetate, and then washed three times with 250 mL of saturated sodium chloride each time, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a pale yellow solid. 160 mL of a 3 / 1 PE / EA mixture was added, and the mixture was slurried for half an hour, filtered, and drained. The filter cake was collected, water bathed at 45°C, concentrated, and then pumped to constant weight with a high vacuum oil pump to obtain compound M1-4 (36.1 g, 99.7% yield).

[0159] ESI-MS m / z:172.0[M+H] + .

[0160] Step 5: Synthesis of Compound M1-5

[0161] At room temperature, concentrated sulfuric acid (61.37 mL) was added to a 500 mL single-necked flask, cooled to below 10°C in an ice-water bath, and compound M1-4 (39.30 g) was added in batches. After the addition, the mixture was stirred for 10 minutes. In a nitrogen atmosphere, the mixture was kept at 60°C in an oil bath and reacted for about 1 hour. The reaction solution was cooled to room temperature and then carefully added to 1100 mL of ice-water mixture, diluted and quenched, and a small amount of yellow solid precipitated. After stirring for 10 minutes, the mixture was filtered; the filter cake was collected and slurried with 50 mL of saturated sodium bicarbonate aqueous solution for 20 minutes, filtered again, and the two filtrates were collected and combined; then sodium carbonate solid was slowly added to adjust the pH to approximately 7, and a white solid powder precipitated. Stir for half an hour, filter, and drain; rinse the filter cake with 100 mL of water each time and drain, for a total of rinsing twice. The filter cake was collected and placed in a vacuum oven and dried at 55°C to constant weight to obtain compound M1-5 (33.6 g, yield 77.37%).

[0162] ESI-MS m / z:190.0[M+H] + .

[0163] Step 6: Synthesis of Compound M1-6

[0164] At room temperature, tetrahydrofuran (470.00 mL) was added. After nitrogen replacement, sodium hydride (10.00 g) was added under a slight nitrogen flow. The mixture was heated in an oil bath at 40-45°C and stirred for 15 minutes. Compound M1-5 (18.95 g) was then added in portions. After addition, the mixture was mechanically stirred for 20 minutes. CDI (24.31 g) was then carefully added in portions. After addition, the mixture was stirred for 15 minutes, and the mixture was heated in an oil bath and refluxed. The reaction mixture was cooled to below 10°C in an ice-water bath. 500 mL of saturated aqueous ammonium chloride was then added. A light yellow solid precipitated. 1000 mL of water was added. The mixture was then transferred to a 5 L beaker and 3000 mL of water was added. The mixture was stirred for 1 hour, filtered, and drained. The filter cake was collected and dried in a vacuum oven at 50-55°C to constant weight to obtain compound M1-6 (18.3 g, 84.93% yield).

[0165] ESI-MS m / z:216.0[M+H] + .

[0166] Step 7: Synthesis of Compound M1

[0167] Compound M1-6 (18.00 g) and DIEA (36.00 mL) were dissolved in POCl3 (180.00 mL) at room temperature and heated to 100°C under a nitrogen atmosphere for approximately 2.5 hours. The mixture was concentrated under reduced pressure to remove phosphorus oxychloride and rinsed twice with 100 mL of DCM. The residue was dissolved in 400 mL of dichloromethane and then added dropwise to 500 mL of saturated aqueous sodium bicarbonate solution, cooled with ice water. After stirring for 15 minutes, the mixture was separated. The aqueous phase was extracted with 300 mL of dichloromethane and separated. The combined dichloromethane phases were washed with 300 mL of saturated aqueous sodium chloride solution and separated. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified on a silica gel column (PE / EA = 90 / 10 to 75 / 25) to obtain compound M1 (10.95 g, 51.94% yield).

[0168] ESI-MS m / z:251.9[M+H] + .

[0169] Synthesis of intermediate M2

[0170] Step 1: Synthesis of compound M2-1

[0171] Compound TMSOI (8.5 g) was dissolved in DMSO (20 mL), cooled to 0°C, and NaH (1.6 g) was added. The N2 was replaced three times, and the reaction was stirred at room temperature for 1.0 h. A solution of compound 3-oxopiperidine-1-carboxylic acid benzyl ester (9.0 g) dissolved in DMSO (5 mL) was slowly added dropwise, and the reaction was stirred at room temperature overnight. After the reaction was complete, the mixture was extracted with EA and H2O, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, and purified by column chromatography to obtain compound M2-1 (3.2 g). ESI-MS m / z: 248.3 [M+H] + .

[0172] Step 2: Synthesis of compound M2-2

[0173] Compound M2-1 (3.2 g), sodium cyanide (1.3 g), anhydrous ethanol (10 mL), and water (10 mL) were replaced with N2 three times and stirred at room temperature for 5 h. After the reaction was complete, the mixture was extracted with EA and H2O, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, and purified by column chromatography (PE:EA 43%) to obtain compound M2-2 (3.0 g). ESI-MS m / z: 275.3 [M+H] + .

[0174] Step 3: Synthesis of Compound M2-3

[0175] Compound M2-2 (1.5 g), palladium hydroxide (0.2 g), and anhydrous ethanol (10 mL) were replaced with hydrogen five times and stirred at room temperature for 1.5 h. After the reaction was complete, the mixture was filtered and the solvent was dried to obtain compound M2-3 (0.9 g), which was directly used for the next step. ESI-MS m / z: 141.3 [M+H] + .

[0176] Step 4: Synthesis of Compound M2

[0177] Compound M1 (1.6 g) and DIPEA (3.5 mL) were dissolved in DCM (15 mL), cooled to below -40°C, and stirred for 10 minutes. Compound M2-3 (0.9 g) was then added and stirred for 1 hour at the same temperature. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted with EA and H2O, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, and purified by column chromatography (EA:DCM 12%) to obtain compound M2 (1.2 g). ESI-MS m / z: 356.3 [M+H] + .

[0178] Synthesis of intermediate M3:

[0179] Step 1: Synthesis of Compound M3-1

[0180] ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.0 g) was added to a 50 mL single-necked flask, followed by 6 mL of DMF and cesium fluoride (5.9 g). The mixture was stirred at room temperature for 1 h. TLC confirmed the complete reaction of the starting material. The reaction solution was slowly added dropwise to water (20 mL), resulting in the precipitation of a white solid. The filter cake was collected by filtration and dried to obtain 0.65 g of a white solid, compound M3-1.

[0181] Step 2: Synthesis of Compound M3

[0182] Compound M3-1 (0.65 g) was added to a 50 mL single-necked vial, along with 6 mL of MeOH and Pd / C (600 mg, 10% purity). The mixture was reacted at room temperature under a hydrogen atmosphere for 20 min. After the reaction was complete, the filtrate was filtered, collected, and concentrated. The concentrate was purified by column chromatography to afford compound M3 (496 mg, 75.5% yield).

[0183] 1 H NMR (500MHz, Methanol-d4) δ7.56(dd,J=8.9,5.8Hz,1H),7.39(d,J=2.7Hz,1H),7.36(d,J=2.7Hz,1H),7.20( t,J=9.2Hz,1H),5.27(s,2H),3.50(s,3H),3.12(qd,J=7.5,2.5Hz,2H),1.44(s,12H),1.26(t,J=7.5Hz,3H).

[0184] Synthesis of intermediate M4:

[0185] Compound M3 (1.0 g) was added to a 50 mL single-necked bottle, followed by 10 mL of hydrochloric acid (4 M / Dioxane). After reacting at room temperature for half an hour, the reaction mixture was neutralized by adding saturated sodium bicarbonate solution and extracted twice with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (DCM:ammonia methanol = 10:1) to obtain compound M4 (0.82 g). 1 H NMR (500MHz, CDCl3) δ7.46 (dd, J=8.9, 5.8Hz, 1H), 7.27 (d, J=2.7Hz, 1H), 7.17 (dd, J=12. 5,5.9Hz,1H),7.12(d,J=2.7Hz,1H),3.17–3.07(m,2H),1.45(s,12H),1.29–1.25(m,3H).

[0186] Synthesis of intermediate M5:

[0187] Step 1: Synthesis of compound M5-1

[0188] N-tert-Butyloxycarbonyl-4-hydroxypiperidine (1.0 g) was added to a 25 mL single-necked flask and dissolved in THF (10 mL). NaH (300.0 mg) and 2,5-dibromopyrazine (1.18 g) were added and heated to 50°C for 5 h. The reaction solution was evaporated to dryness. Purification by column chromatography (PE:EA = 6:1) afforded 1.38 g of a pale yellow solid, compound M5-1.

[0189] Step 2: Synthesis of compound M5-2

[0190] Compound M5-1 (690.0 mg) was added to a 25 mL single-necked flask and dissolved in DMF (10 mL). Trimethylethynylsilane (283.7 mg), CuI (73.3 mg), PdCl2(PPh3)2 (135.2 mg), and DIPEA (0.95 mL) were added. Under nitrogen protection, the mixture was heated to 50°C for 3 h. Saturated brine (5 mL) was added to the reaction solution, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate and the product was isolated by column chromatography (PE:EA = 6:1) to obtain 522.2 mg of a light yellow solid, compound M5-2.

[0191] Step 3: Synthesis of Compound M5

[0192] Compound M5-2 (522.2 mg) was added to a 25 mL single-necked flask and dissolved in THF (10 mL). A 1 M solution of TBAF in tetrahydrofuran (2.2 mL) was added and allowed to react at room temperature for 2 h. The reaction solution was evaporated to dryness. Purification by column chromatography (PE:EA = 4:1) afforded 378.2 mg of a pale yellow solid, Compound M5.

[0193] Synthesis of intermediate M6:

[0194] Step 1: Synthesis of compound M6-1

[0195] 5-Chloropyrazine-2-carboxaldehyde (1.0 g) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1.59 g) were dissolved in methanol (10 mL). After reacting at room temperature for 1 hour, sodium cyanoborohydride was added in batches. After completion of the reaction, ethyl acetate and water were added, and the mixture was extracted three times. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography to obtain compound M6-1 (480 mg). ESI-MS m / z: 353.2 [M+H] + .

[0196] Step 2: Synthesis of Compound M6

[0197] Compound M6-1 (480 mg), bistriphenylphosphine palladium dichloride (85 mg), and cuprous iodide (46 mg) were dissolved in TEA (0.84 mL) under nitrogen protection. Trimethylsilyl acetylene (0.33 mL) was added and the mixture was allowed to react overnight at 60°C. LCMS monitored the reaction for completion. The reaction solution was directly concentrated, and EA (10 mL) was added to the reaction solution. The mixture was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound M6 (210 mg). ESI-MS m / z: 415.1 [M+H] + .

[0198] Synthesis of intermediate M7

[0199] Step 1: Synthesis of compound M7-1

[0200] Intermediate M1 (5.0 g) was dissolved in DCM (20 mL), cooled to approximately -40°C, and DIPEA (7.7 g) was added. The mixture was stirred at low temperature for 30 min, and (3R)-3-methylpiperidin-3-ol hydrochloride (4.2 g) was slowly added. The reaction was stirred for 1.0 h. After the reaction was complete, the mixture was diluted with water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by column chromatography (EA:DCM = 1:10) to obtain compound M7-1 (5.3 g).

[0201] ESI-MS m / z:331.3[M+H] + .

[0202] Step 2: Synthesis of compound M7-2

[0203] Compound M7-1 (5.3 g), cesium carbonate (10.4 g), DABCO (0.4 g), and 1,1-cyclopropane dimethanol (3.3 g) were dissolved in DMF (20 mL). The reaction was stirred at room temperature overnight. After the reaction was complete, the mixture was extracted with EA and H2O, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by column chromatography (EA:DCM 18%) to obtain compound M7-2 (5.0 g). ESI-MS m / z: 397.1 [M+H] + .

[0204] Step 3: Synthesis of Compound M7-3

[0205] Compound M7-2 (5.0 g), M3 (9.0 g), potassium carbonate (3.5 g), and Cataxium A Pd G3 (1.3 g) were dissolved in 1,4-dioxane (24 mL) and H2O (4 mL). The mixture was reacted at 90°C under nitrogen for 1 h. After the reaction was complete, the reaction solution was diluted with EA and H2O, extracted again with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain compound M7-3 (6.0 g, 85% purity), which was directly used in the next step. ESI-MS m / z: 595.2 [M+H] + .

[0206] Step 4: Synthesis of Compound M7

[0207] To a solution of compound M7-3 (6.0 g) in DCM (50 mL) was added DMP (6.4 g) portionwise and stirred at room temperature for 3.0 h. After the reaction was complete, the mixture was quenched with saturated sodium sulfite, diluted with water, and extracted with DCM. The aqueous phase was extracted twice more with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography (PE:EA 50%) to afford compound M7 (3.4 g).

[0208] ESI-MS m / z:593.4[M+H] + .

[0209] Synthesis of intermediate M8:

[0210] Step 1: Synthesis of compound M8-1

[0211] Compound M7-2 (16.5 g) was dissolved in DCM (200 mL), and DMP (18.4 g) was slowly added in batches at 0°C. The temperature was naturally raised to room temperature and the reaction was allowed to proceed for 2 hours. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with DCM. The organic phase was washed with saturated brine and purified by column chromatography to obtain compound M8-1 (9.5 g). ESI-MS m / z: 395.2 [M+H] + .

[0212] Step 2: Synthesis of Compound M8

[0213] Compound M8-1 (9.5 g), M4 (15.21 g), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (3.50 g), and potassium phosphate (15.3 g) were added to 1,4-dioxane (100.00 mL) and water (25 mL). The mixture was reacted at 90°C under nitrogen for 1.5 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and purified by column chromatography to obtain compound M8 (8.5 g). ESI-MS m / z: 549.1 [M+H] + .

[0214] Synthesis of intermediate M9:

[0215] Under N2 protection, (5-((triisopropylsilyl)ethynyl)pyrazin-2-yl)methyl methanesulfonate (231 mg) was added to a 25 mL three-necked flask, acetonitrile (5 mL) was added, and 3-Boc-7,7-difluoro-3,9-diazaspiro[5.5]undecane (200 mg) and potassium carbonate (173 mg) were added with stirring, and stirred at room temperature for 12 h. After the reaction was completed, saturated ammonium chloride was quenched, and ethyl acetate was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered to obtain the mother liquor, and the sample was wet loaded. The target point was flushed with PE:EA=3:1, and the compound M9 (222 mg) was obtained by spin drying.

[0216] Synthesis of intermediate M10:

[0217] Step 1: Synthesis of compound M10-1

[0218] To a 100 mL single-necked flask, (S)-6-methyl-1,4-oxazepan-6-ol (390 mg) and DIPEA (1.1 g) were added sequentially and dissolved in DCM (30 mL). The mixture was cooled to below -40°C and compound M1 (670 mg) was added portionwise. The mixture was stirred for 1.0 h. After the reaction was complete, the mixture was quenched with saturated ammonium chloride, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by column chromatography (PE:EA = 1:1) to afford a pale yellow solid, compound M10-1 (800 mg). ESI-MS m / z: 347.1 [M+H] + .

[0219] Step 2: Synthesis of compound M10-2

[0220] Compound M10-1 (400 mg), 1,1-cyclopropane dimethanol (240 mg), cesium carbonate (750 mg), and DABCO (30 mg) were added to a 50 mL single-necked flask in sequence and dissolved in DMF (15 mL). The mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by column chromatography (DCM:EA = 9:1) to afford a light yellow solid, compound M10-2 (250 mg). ESI-MS m / z: 413.2 [M+H] + .

[0221] Step 3: Synthesis of compound M10-3

[0222] To a solution of compound M10-2 (250 mg) in DCM (10 mL) was added DMP (379 mg) and stirred at room temperature for 30 min. After the reaction was complete, the mixture was diluted with water and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by spin chromatography (DCM:EA = 6:1) to afford a light yellow solid, compound M10-3 (210 mg). ESI-MS m / z: 410.2 [M+H] + .

[0223] Step 4: Synthesis of Compound M10

[0224] Compound M10-3 (210 mg), 2-(8-ethyl-7-fluoro-3-methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (310.7 mg), CataCXium A Pd G3 (70.5 mg), K3PO4 (208.1 mg), 1,4-dioxane (8 mL), and H2O (2 mL) were heated to 90°C and stirred for 1.0 h. After the reaction was complete, the mixture was cooled to room temperature and extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography (DCM:MeOH = 15:1) to afford a pale yellow solid, compound M10 (150 mg). ESI-MS m / z: 565.4 [M+H] + .

[0225] Example 1: Synthesis of (2S,4R)-N-(1-(4,5-dihydrobenzo[6,7]oxacyclo[4,5-d]thiazol-8-yl)ethyl)-1-((S)-2-(4-(5-(1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxypyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0226] Step 1: Synthesis of compound 1-1

[0227] Compound 4-thiazoleacetic acid (2.0 g) was dissolved in 20.0 mL of THF. Borane tetrahydrofuran solution (1 M, 41.9 mL) was added dropwise under N2 protection and reacted at 60°C for 1.0 h. The reaction solution was cooled to room temperature and quenched by MeOH dropwise. The reaction was continued at 60°C for 1.0 h. The solvent was evaporated under reduced pressure and purified by column chromatography to obtain 1.80 g of the product, compound 1-1.

[0228] Step 2: Synthesis of compound 1-2

[0229] Compound 1-1 (1.50 g), methyl 3-hydroxy-4-bromobenzoate (2.95 g), and triphenylphosphine (3.35 g) were dissolved in 20.0 mL of THF. The mixture was purged with nitrogen 2-3 times. Diethyl azodicarboxylate (2.12 g) was added under ice-cooling and allowed to react at room temperature for 1 h. The solvent was evaporated under reduced pressure and the reaction solution was purified by column chromatography to obtain 3.80 g of the product, compound 1-2.

[0230] Step 3: Synthesis of Compound 1-3

[0231] Compound 1-2 (4.0 g), palladium acetate (1.31 g), and potassium acetate (3.44 g) were dissolved in 80.0 mL of DMAc. The atmosphere was purged with nitrogen 2-3 times and the reaction was carried out at 140°C for 2.0 h. The reaction mixture was filtered to remove insoluble impurities. The solvent was evaporated from the filtrate under reduced pressure and then purified by column chromatography to obtain 0.95 g of the product, compound 1-3.

[0232] Step 4: Synthesis of Compounds 1-4

[0233] Compound 1-3 (0.95 g) was added to a 25 mL single-necked flask and dissolved in anhydrous methanol (10 mL) and water (3.0 mL). Lithium hydroxide (1.46 g) was added and reacted at 50°C for 1.0 h. 1 M aqueous hydrochloric acid (20 mL) was added to the reaction solution, and the mixture was extracted with DCM / MeOH = 10 / 1 (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 0.80 g of a light yellow solid, compound 1-4.

[0234] Step 5: Synthesis of Compound 1-5

[0235] Compound 1-4 (0.8 g) and dimethylhydroxylamine hydrochloride (0.31 g) were dissolved in 10.00 mL of DCM, and DIPEA (2.82 mL) and HATU (1.35 g) were added sequentially. The mixture was reacted at room temperature for 1.0 h. The solvent was evaporated under reduced pressure and purified by column chromatography to obtain 0.85 g of a yellow product, namely compound 1-5.

[0236] Step 6: Synthesis of Compounds 1-6

[0237] Compound 1-5 (0.85 g) was dissolved in 10.00 mL of THF under ice-cooling. Methylmagnesium bromide (1.95 mL, 3 M) was added under N2 protection and the mixture was allowed to react at 0°C for 1.0 h. The reaction solution was added to saturated ammonium chloride solution (20 mL) and extracted with DCM / MeOH = 10 / 1 (20 mL * 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and then purified by column chromatography to obtain 0.70 g of a yellow product, namely compound 1-6.

[0238] Step 7: Synthesis of Compounds 1-7

[0239] Compound 1-6 (0.70 g) and tert-butylsulfenamide (0.70 g) were dissolved in 10.00 mL of anhydrous tetrahydrofuran, and tetraisopropyl titanate (17.6 mL) was added. The mixture was reacted at 80°C for 3.0 h. The reaction solution was cooled to room temperature and quenched by dropwise addition of ice water. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product (0.60 g), compound 1-7, was purified by column chromatography.

[0240] Step 8: Synthesis of Compounds 1-8

[0241] Compound 1-7 (0.60 g) was dissolved in 10.00 mL of anhydrous tetrahydrofuran, and lithium tri-sec-butylborohydride (5.17 mL) was added. The mixture was allowed to react at room temperature for 2.0 h. The reaction solution was added dropwise to ice water to quench the mixture. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 0.60 g of crude product, which was used directly in the next step, namely compound 1-8.

[0242] Step 9: Synthesis of Compounds 1-9

[0243] Compound 1-8 (0.60 g) was dissolved in 5.00 mL of dioxane hydrochloride and reacted at room temperature for 2.0 h. The reaction solution was evaporated under reduced pressure to remove the solvent, and the mixture was slurried with EA and filtered to obtain 0.35 g of a yellow product, namely compound 1-9.

[0244] Step 10: Synthesis of Compound 1-10

[0245] Compound 1-9 (0.35 g), (2S,4R)-1-BOC-2-carbamoyl-4-hydroxypyrrolidine (0.32 g), and DIPEA (0.65 mL) were dissolved in 5.00 mL of DMF. HATU (0.52 g) was added and the mixture was allowed to react at room temperature for 1.0 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography to obtain 0.52 g of the product, compound 1-10.

[0246] Step 11: Synthesis of Compound 1-11

[0247] Compound 1-10 (0.52 g) was dissolved in 2.83 mL of dioxane hydrochloride and 5.0 mL of methanol and allowed to react at room temperature for 1.0 h. The solvent was evaporated under reduced pressure, and the mixture was slurried with EA and filtered to obtain 0.33 g of a yellow product, which was used directly in the next step to obtain compound 1-11.

[0248] Step 12: Synthesis of Compounds 1-12

[0249] Compound 1-11 (0.33 g), Boc-L-valine (0.21 g), and DIPEA (0.48 mL) were dissolved in 5.00 mL of DMF, and HATU (0.38 g) was added. The mixture was reacted at room temperature for 1.0 h. The solvent was evaporated under reduced pressure and the reaction solution was purified by column chromatography to obtain 0.32 g of the product, compound 1-12.

[0250] Step 13: Synthesis of Compounds 1-13

[0251] Compound 1-13 (0.32 g) was dissolved in 5.00 mL of dioxane hydrochloride and reacted at room temperature for 1.0 h. The solvent was evaporated under reduced pressure, and the mixture was slurried with EA and filtered to obtain 0.16 g of a yellow product, namely compound 1-13.

[0252] Step 14: Synthesis of Compound 1-14

[0253] Compound 1-13 (0.16 g) was dissolved in a mixed solvent of anhydrous acetonitrile (3.00 mL) and tetrahydrofuran (3.00 mL). Triethylamine (0.23 mL) was added, and 2-azido-1,3-dimethylimidazolium hexafluorophosphate (0.19 g) was added under ice-cooling. The mixture was allowed to react at room temperature for 1.5 h. The reaction solution was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography to obtain 0.15 g of the product, compound 1-14.

[0254] Step 15: Synthesis of Compound 1-15

[0255] 1-14 (150 mg), M5 (187 mg), sodium ascorbate (159 mg), and anhydrous copper sulfate (44 mg) were dissolved in a mixture of 2.00 mL of tert-butanol, 2.00 mL of tetrahydrofuran, and 2.00 mL of water at room temperature and allowed to react for 1 h. The reaction mixture was quenched by the addition of 50 mL of aqueous solution and extracted three times with a 10 / 1 DCM / MeOH mixture. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then purified by column chromatography (DCM / MeOH = 10 / 1) to afford 152 mg of a yellow solid, compound 1-15.

[0256] Step 16: Synthesis of Compound 1-16

[0257] Compound 1-15 (152 mg) was dissolved in 3.0 mL of methanol, and 4.00 mL of dioxane hydrochloride was added. The mixture was allowed to react at room temperature for 1.0 h. 4 M NaOH solution was added dropwise under an ice bath to adjust the pH to approximately 12. The mixture was then extracted three times with a 10 / 1 DCM / MeOH mixture. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 80 mg of the product, compound 1-16.

[0258] Step 17: Synthesis of Compound 1

[0259] M8 (80 mg) and compound 1-16 (80.0 mg) were dissolved in anhydrous methanol (2.00 mL) at room temperature, and zinc chloride (0.22 mL, 1.0 mol / L) was added. The mixture was reacted at 55°C for 1.0 h. Sodium cyanoborohydride (34.7 mg) was added and the mixture was reacted at 70°C for 3.0 h. An appropriate amount of saturated aqueous ammonium chloride was added to the reaction solution to quench the reaction. The mixture was then extracted with DCM / MeOH = 10 / 1 (20.0 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then sent for sample preparation and purification to obtain 16.1 mg of a white solid product, compound 1.

[0260] LCMS: 1 / 2 [M+2H] + =611.02

[0261] 1H NMR (500MHz, Methanol-d4) δ9.21(t,J=3.6Hz,1H),8.87(d,J=3.5Hz,1H),8.74(s,1H),8.54(d,J=3. 5Hz,1H),8.19(s,1H),7.67(s,1H),7.63–7.54(m,1H),7.30(d,J=2.7Hz,1H),7.27–7.21(m,1H),7.1 1–7.02(m,2H),7.00(d,J=3.5Hz,1H),5.48–5.31(m,2H),5.13(s,2H),4.53(d,J=11.2Hz,2H),4.47( s,2H),4.37–4.29(m,2H),4.25(d,J=14.6Hz,1H),3.91(d,J=3.7Hz,1H),3.86(d,J=11.4Hz,1H),3.6 7(d,J=13.3Hz,1H),3.60(d,J=13.4Hz,1H),3.42(s,1H),3.40(d,J=5.3Hz,1H),3.00(s,2H),2.60(s ,2H),2.47(s,2H),2.20(s,2H),2.11(s,2H),1.85(s,2H),1.80(d,J=11.8Hz,2H),1.61(s,1H),1.48 (dd,J=7.2,3.7Hz,2H),1.46(d,J=3.5Hz,1H),1.33(s,2H),1.32–1.27(m,4H),1.16(dd,J=6.9,3.5H z,2H),1.03(d,J=6.3Hz,1H),0.90(s,1H),0.82(d,J=6.4Hz,3H),0.78(d,J=9.5Hz,2H),0.57(s,2H).

[0262] Example 3: Synthesis of (2S,4R)-N-((S)-1-(4,5-dihydrobenzo[6,7]oxepan[4,5-d]thiazol-8-yl)ethyl)-1-((S)-2-(4-(5-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxyhydroxypyrrolidine-2-carboxamide

[0263] Step 1: Synthesis of compound 3-1

[0264] 44-15 (100 mg), M5 (95 mg), sodium ascorbate (106 mg), anhydrous copper sulfate (30 mg), and cesium fluoride (157 mg) were dissolved in a mixture of 2.00 mL of methanol, 2.00 mL of tetrahydrofuran, and 1.00 mL of water at room temperature and allowed to react for 1 h. The reaction mixture was quenched by the addition of 50 mL of aqueous solution and extracted three times with a 10 / 1 DCM / MeOH mixture. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then purified by column chromatography (DCM / MeOH = 10 / 1) to afford 140 mg of a yellow solid, compound 3-1.

[0265] Step 2: Synthesis of compound 3-2

[0266] Compound 3-1 (140 mg) was dissolved in 2 mL of methanol, and 2 mL of dioxane hydrochloride was added. The mixture was allowed to react at room temperature for 1.0 h. The solvent was evaporated under reduced pressure, and the reaction solution was extracted with water and a 10 / 1 DCM / MeOH mixture. The aqueous phase was collected, solid sodium bicarbonate was added to the aqueous phase until the pH reached approximately 9, and the mixture was extracted three times with a 10 / 1 DCM / MeOH mixture. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 95 mg of the product, compound 3-2.

[0267] Step 3: Synthesis of compound 3

[0268] M8 (130 mg) and compound 3-2 (95 mg) were dissolved in anhydrous methanol (2.00 mL) at room temperature. Zinc chloride (0.23 mL, 1.0 mol / L in THF) and sodium cyanoborohydride (23.8 mg) were added sequentially, and the mixture was allowed to react at 80°C for 1.5 h. An appropriate amount of saturated aqueous sodium bicarbonate solution was added to the reaction solution to quench the reaction. DCM / MeOH = 10 / 1 (20.0 mL*3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then sent for sample preparation and purification to obtain 25.0 mg of compound 3. LCMS: 1 / 2 [M+2H] + =610.70

[0269] Example 44: Synthesis of (2S,4R)-N-((S)-1-(4,5-dihydrobenzo[6,7]oxepano[4,5-d]thiazol-8-yl)ethyl)-1-((S)-2-(4-(5-((9-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((S)-6-hydroxy-6-methyl-1,4-oxazolidin-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-1,1-difluoro-3,9-diazaspiro[5.5]undec-3-yl)methyl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0270] Step 1: Synthesis of compound 44-1

[0271] Compound 4-thiazoleacetic acid (2.5 g) was dissolved in 30.0 mL of THF. Borane tetrahydrofuran solution (1 M, 52.4 mL) was added dropwise under N2 protection and reacted at 60°C for 1.0 h. The reaction solution was cooled to room temperature and quenched by the addition of MeOH. The reaction was continued at 60°C for 1.0 h. The solvent was evaporated under reduced pressure and purified by column chromatography to obtain 1.95 g of the product, compound 44-1.

[0272] Step 2: Synthesis of compound 44-2

[0273] Compound 44-1 (1.95 g), methyl 3-hydroxy-4-bromobenzoate (4.19 g), and triphenylphosphine (4.36 g) were dissolved in 30.0 mL of THF. The mixture was purged with nitrogen 2-3 times. Diisopropyl azodicarboxylate (3.21 g) was added under ice-cooling and allowed to react at room temperature for 1 h. The solvent was evaporated under reduced pressure and the reaction solution was purified by column chromatography to obtain 3.50 g of the product, compound 44-2.

[0274] Step 3: Synthesis of compound 44-3

[0275] Compound 44-2 (3.5 g), palladium acetate (1.01 g), potassium acetate (2.71 g), and triphenylphosphine (2.40 g) were dissolved in 80.0 mL of DMAc. The atmosphere was purged with nitrogen three times and the reaction was carried out at 100°C for 3.0 h. The reaction mixture was filtered to remove insoluble impurities. The solvent was evaporated from the filtrate under reduced pressure and then purified by column chromatography to obtain 2.0 g of the product, compound 44-3.

[0276] Step 4: Synthesis of compound 44-4

[0277] Compound 44-3 (2.0 g) was added to a 25 mL single-necked flask and dissolved in anhydrous methanol (20 mL) and water (5.0 mL). Lithium hydroxide monohydrate (3.21 g) was added and reacted at 50°C for 1.0 h. 1 M aqueous hydrochloric acid (20 mL) was added to the reaction solution, and extraction was performed with DCM / MeOH = 10 / 1 (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.8 g of a light yellow solid, compound 44-4.

[0278] Step 5: Synthesis of compound 44-5

[0279] Compound 44-4 (1.8 g) and dimethylhydroxylamine hydrochloride (0.77 g) were dissolved in 20.00 mL of DMF, and DIPEA (6.34 mL) and HATU (3.04 g) were added sequentially. The mixture was reacted at room temperature for 1.0 h. The solvent was evaporated under reduced pressure and purified by column chromatography to obtain 2.0 g of a yellow product, compound 44-5.

[0280] Step 6: Synthesis of compound 44-6

[0281] Compound 44-5 (2.0 g) was dissolved in 10.00 mL of THF under ice-cooling. Methylmagnesium bromide (4.59 mL, 3 M) was added under N2 protection and the mixture was allowed to react at 0°C for 1.0 h. The reaction solution was added to saturated ammonium chloride solution (20 mL) and extracted with DCM / MeOH = 10 / 1 (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and then purified by column chromatography to obtain 1.3 g of a yellow product, compound 44-6.

[0282] Step 7: Synthesis of compound 44-7

[0283] Compound 44-6 (1.2 g) and s-tert-butylsulfenamide (1.2 g) were dissolved in 15.00 mL of anhydrous tetrahydrofuran, and tetraisopropyl titanate (5.13 mL) was added. The mixture was reacted at 80°C for 3.0 h. The reaction solution was cooled to room temperature and quenched by dropwise addition of ice water. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography to obtain 1.6 g of the product, compound 44-7.

[0284] Step 8: Synthesis of compound 44-8

[0285] Compound 44-7 (0.70 g) was dissolved in a mixture of 10.00 mL of anhydrous tetrahydrofuran and 0.2 mL of water. Sodium borohydride (228 mg) was added at -50°C and the mixture was allowed to warm to room temperature for 2 h. The reaction mixture was quenched by adding it dropwise to ice water. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and then purified by column chromatography to obtain 0.5 g of the product, compound 44-8.

[0286] Step 9: Synthesis of compound 44-9

[0287] 44-8 (500 mg) was sampled and separated using the following conditions: Welch Ultimate-XB-C18 column (20×250 mm, 10 μm); mobile phase: MeCN: 0.1% TFA in H2O = 50% to 75%; gradient time: 6.0 min; flow rate: 20 ml / min; sample retention time: target compound B: 6.22 min. Compound B was collected to yield 230 mg of product, compound 44-9.

[0288] Step 10: Synthesis of compound 44-10

[0289] Compound 44-9 (230 mg) was dissolved in a mixture of 2.00 mL of dioxane hydrochloride and 2.0 mL of methanol and allowed to react at room temperature for 2.0 h. The reaction solution was evaporated under reduced pressure to remove the solvent. After re-dissolving in methanol, the solvent was again evaporated under reduced pressure to obtain 160 mg of a yellow product, which was used directly in the next step, namely compound 44-10.

[0290] Step 11: Synthesis of compound 44-11

[0291] Compound 44-10 (0.16 g), (2S,4R)-1-BOC-2-carbamoyl-4-hydroxypyrrolidine (0.18 g), and DIPEA (0.57 mL) were dissolved in 2.00 mL of DMF. HATU (0.27 g) was added and the mixture was allowed to react at room temperature for 1.0 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography to obtain 0.29 g of the product, compound 44-11.

[0292] Step 12: Synthesis of compound 44-12

[0293] Compound 44-11 (0.29 g) was dissolved in 3.0 mL of dioxane hydrochloride and 3.0 mL of methanol and allowed to react at room temperature for 1.0 h. The reaction solution was evaporated under reduced pressure to remove the solvent. After re-dissolving in methanol, the solvent was again evaporated under reduced pressure to obtain 0.22 g of a yellow product, which was used directly in the next step, namely compound 44-12.

[0294] Step 13: Synthesis of compound 44-13

[0295] Compound 44-12 (0.22 g), Boc-L-valine (0.18 g), and DIPEA (0.58 mL) were dissolved in 3.00 mL of DMF, and HATU (0.28 g) was added. The mixture was reacted at room temperature for 1.0 h. The solvent was evaporated under reduced pressure and the reaction solution was purified by column chromatography to obtain 0.37 g of the product, compound 44-13.

[0296] Step 14: Synthesis of compound 44-14

[0297] Compound 44-13 (0.32 g) was dissolved in 3.0 mL of dioxane hydrochloride and 3.0 mL of methanol and allowed to react at room temperature for 1.0 h. The reaction solution was evaporated under reduced pressure to remove the solvent. After re-dissolving in methanol, the solvent was again evaporated under reduced pressure to obtain 0.30 g of a yellow product, which was used directly in the next step, namely compound 44-14.

[0298] Step 15: Synthesis of compound 44-15

[0299] Compound 44-14 (0.30 g) was dissolved in a mixture of anhydrous acetonitrile (3.00 mL) and tetrahydrofuran (3.00 mL). Triethylamine (0.91 mL) was added, followed by 2-azido-1,3-dimethylimidazolium hexafluorophosphate (0.38 g) under ice-cooling. The mixture was allowed to react at room temperature for 1.5 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography to yield 0.30 g of compound 44-15.

[0300] Step 16: Synthesis of compound 44-16

[0301] 44-15 (220 mg), M9 (256 mg), sodium ascorbate (234 mg), anhydrous copper sulfate (65 mg), and cesium fluoride (344 mg) were dissolved in a mixture of 2.00 mL of methanol, 2.00 mL of tetrahydrofuran, and 1.00 mL of water at room temperature and reacted at 55°C for 1 h. The reaction solution was quenched by the addition of 50 mL of aqueous solution and extracted three times with a 10 / 1 DCM / MeOH mixture. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography (DCM / MeOH = 10 / 1) to give 282 mg of a yellow solid, compound 44-16.

[0302] Step 17: Synthesis of compound 44-17

[0303] Compound 44-16 (280 mg) was dissolved in 3.0 mL of methanol, and 3.00 mL of dioxane hydrochloride was added. The mixture was allowed to react at room temperature for 1.0 h. The solvent was evaporated under reduced pressure, and the reaction solution was extracted with water and a 10 / 1 DCM / MeOH mixture. The aqueous phase was collected, and solid sodium bicarbonate was added to the aqueous phase until the pH was approximately 9. The mixture was then extracted three times with a 10 / 1 DCM / MeOH mixture. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 196 mg of the product, compound 44-17.

[0304] Step 18: Synthesis of compound 44

[0305] M10 (142 mg) and compound 44-17 (100.0 mg) were dissolved in anhydrous methanol (2.00 mL) at room temperature. Zinc chloride (0.25 mL, 1.0 mol / L / THF) and sodium cyanoborohydride (23.8 mg) were added sequentially, and the mixture was reacted at 80°C for 1.5 h. An appropriate amount of saturated aqueous sodium bicarbonate solution was added to the reaction solution to quench the reaction. DCM / MeOH = 10 / 1 (20.0 mL*3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then used for sample preparation and purification to obtain 22.8 mg of compound 44.

[0306] LCMS: 1 / 2 [M+2H] + =670.53

[0307] 1H NMR (500MHz, Methanol-d4) δ9.66(s,1H),9.25(s,1H),8.87(d,J=10.5Hz,1H),8.74(d,J=11.4Hz,1H),8.69( dd,J=13.4,6.4Hz,1H),7.68(dd,J=9.0,5.8Hz,1H),7.59–7.53(m,1H),7.31(t,J=2.8Hz,1H),7.26(t,J=9.3H z,1H),7.09–6.95(m,3H),5.47(d,J=10.0Hz,1H),4.98(q,J=7.2Hz,1H),4.59(d,J=14.8Hz,1H),4.53(d,J=8. 1Hz,1H),4.50(d,J=5.9Hz,2H),4.33(dt,J=11.7,5.8Hz,2H),4.21(d,J=27.0Hz,3H),4.06–3.96(m,2H),3.95 –3.88(m,2H),3.85(s,3H),3.74–3.65(m,2H),3.43–3.37(m,2H),3.24–3.17(m,2H),3.13(s,2H),3.11–3.03 (m,2H),2.63(dq,J=13.3,6.6Hz,2H),2.50–2.40(m,2H),2.28–2.17(m,3H),2.10(s,3H),1.97(ddd,J=13.2,9 .1,4.4Hz,1H),1.63(d,J=7.0Hz,1H),1.49(d,J=7.0Hz,3H),1.36(d,J=6.3Hz,1H),1.31(t,J=7.3Hz,2H),1.2 7(d,J=4.2Hz,3H),1.17(d,J=6.8Hz,3H),1.01(s,2H),0.87(s,2H),0.84(d,J=6.7Hz,2H),0.82–0.79(m,2H).

[0308] Biological experiments

[0309] Example 1: Cell proliferation assay

[0310] Table 1

[0311] Cells with different mutations were plated in low-adsorption transparent 96-well plates according to the plating density in Table 1 and cultured overnight in a cell culture incubator. After the cells adhered, the test compounds were added to the 96-well plates at final concentrations of 20,000, 5,000, 1,250, 312.5, 78.13, 19.53, 4.88, 1.22, 0.31, and 0 nM (DMSO final concentration was 0.25%). After 96 hours of culture at 37°C, 50 μL of Cell-titer Glo working solution was added to each well, shaken to mix, and incubated at room temperature for 10 minutes. Luminescence values ​​were read on a multifunctional microplate reader, and the luminescence value data was converted into inhibition percentage. The percentage of cell proliferation inhibition was calculated according to the following formula:

[0312] Inhibition percentage = (1-(measured value-Blank) / (maximum value-Blank))*100%

[0313] ("Maximum value" is from 0.25% DMSO control wells, "Blank" is from blank medium control wells, and "Measured value" is from compound-treated wells).

[0314] GraphPad Prism software was used for curve fitting and IC 50 (nM) values, the results are shown in Table 2.

[0315] Table 2

[0316] Example 2. In Cell Western Blotting Experiment

[0317] Reagents and instruments

[0318] Table 3

[0319] Cell culture plating

[0320] Table 4

[0321] 1) Microscopic observation showed that the cells were in good condition, in the logarithmic growth phase, and had a cell density of 80-90%.

[0322] 2) Digest the cells with trypsin for 1-2 minutes, terminate the digestion with 5 mL of fresh culture medium, gently pipette the cells to form a single cell suspension, and centrifuge at 1000 rpm for 3 minutes.

[0323] 3) Add fresh culture medium to resuspend the cells, aspirate 10 μL of cell suspension, stain with trypan blue, and count the cell density using a cell counter.

[0324] 4) Prepare cell suspension with fresh culture medium and adjust the cell density to 2.78×10 5 / mL(5×10 4 The cell solution was added to a 96-well black plate with a density of 180 μL / well and incubated overnight in a 37°C, 5% CO2 incubator.

[0325] Preparation of drug compounds: Take 20 μL of 10 mM compound stock solution, add 30 μL DMSO, dilute to 4 mM, and use this as the highest concentration. Then, dilute the solution fourfold to obtain 9 concentrations of compound. Then, transfer 5 μL to 195 μL culture medium and mix to obtain compound working solution. Then, transfer 20 μL of the working solution into the cells.

[0326] Experimental preparation: Place the frozen aliquots of 4% paraformaldehyde at room temperature to dissolve.

[0327] Cell fixation: discard the culture medium, gently add the prepared 4% paraformaldehyde into the plate along the well wall (150 μL / well), and fix at room temperature for 20 minutes.

[0328] During this period, 0.5% Triton X-100 punching solution and 0.5% Tween 20 washing solution were prepared with PBS, the fixative was discarded, and the cells were washed 4 times on a shaker for 5 minutes with PBS containing 0.5% Tween 20;

[0329] Punching: Fix with 150 μL / well of 0.5% Triton X-100 for 20 min;

[0330] Discard the punch solution and wash with PBS containing 0.5% Tween 20 on a shaker for 5 min / 4 times;

[0331] Blocking: 150 μL / well blocking solution at room temperature for 1.5 h;

[0332] Primary antibody: 50 μL / well, incubate at 4°C overnight or at room temperature for 2 hours (add blocking solution to the last column as background; KRAS G12D -1:200, GAPDH-1:400);

[0333] Discard the primary antibody and wash with PBS containing 0.5% Tween 20 on a shaker for 5 min / 4 times;

[0334] Secondary antibody: 50 μL / well, incubate at room temperature for 1.5 h (anti-Rb 800:1 / 500; anti-Ms 680:1 / 500);

[0335] Discard the secondary antibody, wash with PBS containing 0.5% Tween 20 on a shaker for 5 min / 4 times, centrifuge at 1000 rpm / 1 min, and dry at room temperature for 3 hours before loading;

[0336] The measured Relative ICW800 signal values ​​were imported into Prism software for fitting and calculation of DC 50 , the results are shown in Table 5.

[0337] Table 5 Degradation activity of compounds in AGS cell line In Cell Western Blotting

[0338] Although the present invention has been fully described through its embodiments, it is noteworthy that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims of the present invention.

Claims

1. A compound represented by general formula (I), or a stereoisomer, tautomer, deuterated form, or pharmaceutically acceptable salt thereof: in, R1, R2 are each independently selected from H, hydroxyl, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2- 6-alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the C 1-6 Hydroxyalkyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2-6 Alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R a replace; R3 is selected from H, hydroxyl, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6 alkoxy, C 1-6 Haloalkoxy or -C 0-3 Alkylene-N(R c )2, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or -C 0-3 Alkylene-N(R c ) 2 optionally further represented by one or more R a replace; R4 is independently selected from H, hydroxy, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R5 is selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -(CH2) n N(R9)2、-(CH2) n -CO-O R9 or -(CH2) n -CO-N(R9)2; m and n are each independently selected from 0, 1, 2, 3 or 4; Ring B is selected from C 6-10 Aryl or 5-18 membered heteroaryl, preferably 5-10 membered heteroaryl, more preferably 5-6 membered heteroaryl, the C 6-10 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a replace; X1, X2, X3 are each independently selected from the group consisting of not present, C(R 10 )2, O or NR 10 , but X1, X2, and X3 are not simultaneously selected from non-existence; The R9, R 10 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 alkyl halide; The R a are independently selected from the group consisting of absent, H, hydroxy, oxo, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-OR b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(O) 1-2 R b 、-C 0-3 Alkylene-S(R b )5、=C(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); the amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2- 6-alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace; Each R b are independently H, halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 6 cycloalkyl, C 1-6 Haloalkoxy or C 1-6 haloalkyl; wherein said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkoxy or C 1-6 The haloalkyl group is optionally further substituted with one or more H, C 1-6 Alkoxy, -N(C 1- 3 alkyl) 2; Each R c Each independently selected from H, hydroxy, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide; 2. The compound according to claim 1, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from the compounds represented by formula (IA): Wherein, the definitions of R1, R2, R3, R4, R5, m, X1, X2, and X3 are as defined in claim 1.

3. The compound according to claim 2, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (IA) is selected from the compounds represented by formula (IA-1): Wherein, the definitions of R1, R2, R3, R4, R5, m, X1, X2, and X3 are as defined in claim 1.

4. The compound according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Formula (I) is selected from the compounds represented by formula (IB): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

5. The compound according to claim 1, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from the compounds represented by formula (IC): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

6. The compound according to claim 1, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from the compounds represented by formula (ID): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

7. The compound according to claim 1, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from the compounds represented by formula (IE): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

8. The compound according to claim 1, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from the compounds represented by formula (IF): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

9. The compound according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Formula (I) is selected from the compounds represented by formula (IG): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

10. The compound according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Formula (I) is selected from the compounds represented by formula (IH): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

11. The compound according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Formula (I) is selected from the compounds represented by formula (IJ): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

12. The compound according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Formula (I) is selected from the compounds represented by formula (IK): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

13. The compound according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Formula (I) is selected from the compounds represented by formula (IL): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

14. The compound according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Formula (I) is selected from the compounds represented by formula (IM): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

15. The compound according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Formula (I) is selected from the compounds represented by formula (IN): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

16. The compound according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Formula (I) is selected from the compounds represented by formula (IP): Wherein, the definitions of R1, R2, R3, R4, R5 and m are as defined in claim 1.

17. A pharmaceutical composition, characterized in that The pharmaceutical composition contains a therapeutically effective amount of the compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof.

18. A bifunctional compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, The bifunctional compound comprises a W group, a linker L and a VHL ligand portion; in, The W group is a warhead, which is a protein targeting moiety; the L is a chemical linker used to connect the VHL ligand and the protein targeting moiety, and the L is selected from the following groups: -A1-…-A q -, where A1 to A q is a bond or a chemical group coupled to at least one of the warhead, the VHL ligand, or a combination thereof, and q is an integer greater than or equal to 1; Wherein, q is an integer from 1 to 20; wherein each A is independently selected from absence, a bond, CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 , CO, CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , optionally 0-6 R L1 and / or R L2 C 3-14 Cycloalkyl, optionally substituted with 0-6 R L1 and / or R L2 3-14 membered heterocyclic group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 substituted aryl, optionally substituted with 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 Each independently can be linked to other A groups to form cycloalkyl and / or heterocyclyl moieties, which can be further substituted by 0-4 R L5 group substituted; and wherein R L1 、R L2 、R L3 、R L4 and R L5 are independently H, halogen, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1- 6-alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, aryl, heteroaryl, 3-14 membered heterocyclic group, OC 1- 6-cycloalkyl, SC 1-6 Cycloalkyl, NHC 1-6 Cycloalkyl, N(C 1-6 Cycloalkyl)2, N(C 1-6 Cycloalkyl)(C 1-6 alkyl), OH, NH2, SH, SO2C 1-6 Alkyl, P(O)(OC 1-6 Alkyl)(C 1-6 alkyl), P(O)(OC 1-6 Alkyl)2, CC-C 1-6 Alkyl, CCH, CH=CH(C 1-6 alkyl), C(C 1-6 alkyl)=CH(C 1-6 alkyl), C(C 1-6 alkyl)=C(C 1-6 alkyl)2、Si(OH)3、Si(C 1-6 Alkyl)3, Si(OH)(C 1-6 Alkyl)2, COC 1-6 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-6 Alkyl, SO2N(C 1-6 Alkyl)2, SONHC 1-6 Alkyl, SON(C 1-6 Alkyl)2, CONHC 1-6 Alkyl, CON(C 1-6 alkyl)2, N(C 1-6 alkyl)CONH(C 1-6 alkyl), N(C 1-6 alkyl)CON(C 1-6 alkyl)2、NHCONH(C 1-6 Alkyl), NHCON(C 1-6 alkyl)2、NHCONH2、N(C 1-6 alkyl)SO2NH(C 1- 6 alkyl), N(C 1-6 alkyl)SO2N(C 1-6 Alkyl)2, NHSO2NH(C 1-6 alkyl), NHSO2N(C 1-6 Alkyl)2, NHSO2NH2; The definitions of the ring B, R2, R3, R4, R5, m, X1, X2, and X3 are as defined in claim 1.

19. The bifunctional compound of formula (II) according to claim 18, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: Formula (II) is selected from the compounds represented by formula (II-1): wherein W, L, R2, R3, R4, R5, m, X1, X2, X3, and ring B are as defined in claim 18.

20. The bifunctional compound of formula (II) according to claim 18 or 19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: Said q is an integer of 1-10, preferably an integer of 2-8, and more preferably an integer of 2-6.

21. The bifunctional compound of formula (II) according to any one of claims 18 to 20, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The L is a group -A1-A2-A3-A4-A5-, wherein A1, A2, A3, A4, A5 are each independently selected from the group consisting of absence, bond, O, S, SO, SO2, CO, CR L1 R L2 NR L3 , C≡C, optionally 0-6 R L1 and / or R L2 C 3-14 Cycloalkyl, optionally substituted with 0-6 R L1 and / or R L2 3-14 membered heterocyclic group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 substituted aryl, optionally substituted with 0-6 R L1 and / or R L2 wherein R L1 、R L2 and R L3 are each independently selected from H, halogen, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, aryl, heteroaryl, 3-14 membered heterocyclic group, OC 1-6 Cycloalkyl, SC 1-6 Cycloalkyl, NHC 1-6 Cycloalkyl, N(C 1-6 Cycloalkyl)2, N(C 1-6 Cycloalkyl)(C 1-6 alkyl), OH, NH2, SH, SO2C 1- 6-alkyl, COC 1-6 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, among which R L1 or R L2 Each independently can be linked to other A groups to form cycloalkyl and / or heterocyclyl moieties.

22. The bifunctional compound of formula (II) according to any one of claims 18 to 21, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The L is a group -A1-A2-A3-A4-, wherein A1, A2, A3, and A4 are each independently selected from the group consisting of absence, bond, O, S, SO, SO2, CO, CR L1 R L2 NR L3 , optionally 0-6 R L1 and / or R L2 C 3-14 Cycloalkyl, optionally substituted with 0-6 R L1 and / or R L2 3-14 membered heterocyclic group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 substituted aryl, optionally substituted with 0-6 R L1 and / or R L2 a heteroaryl substituted with a group; wherein R L1 、R L2 and R L3 are each independently selected from H, halogen, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 3- 14 Cycloalkyl, aryl, heteroaryl, 3-14 membered heterocyclic group, OC 1-6 Cycloalkyl, SC 1-6 Cycloalkyl, NHC 1-6 Cycloalkyl, N(C 1-6 Cycloalkyl)2, N(C 1-6 Cycloalkyl)(C 1-6 alkyl), OH, NH2, SH, SO2C 1-6 Alkyl, COC 1-6 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, among which R L1 or R L2 Each independently can be linked to other A groups to form cycloalkyl and / or heterocyclyl moieties.

23. The bifunctional compound of formula (II) according to any one of claims 18 to 22, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The C 3-14 Cycloalkyl is selected from The 3-14 membered heterocyclic group is selected from The aryl group is The heteroaryl 5-6 membered nitrogen-containing heteroaryl is selected from 24. The bifunctional compound of formula (II) according to any one of claims 18 to 23, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The L is a group -A1-A2-A3-A4-, wherein the A4 is selected from optionally 0-6 R L1 and / or R L2 5-6 membered nitrogen-containing heteroaryl substituted by a group; said A1 is selected from optionally substituted by 0-6 R L1 and / or R L2 A3, A2, A3 are each independently selected from the group consisting of absence, bond, CR L1 R L2 、-O-、C≡C、NR L3 or a 3-7 membered N-containing heterocyclic group; wherein said R L1 、R L2 and R L3 are independently H, halogen, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, aryl, heteroaryl, 3-14 membered heterocyclic group, OC 1-6 Cycloalkyl, SC 1-6 Cycloalkyl, NHC 1-6 Cycloalkyl, N(C 1-6 Cycloalkyl)2, N(C 1-6 Cycloalkyl)(C 1-6 alkyl), OH, NH2, SH, SO2C 1-6 Alkyl, COC 1-6 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, wherein the R L1 or R L2 Each independently can be linked to other A groups to form cycloalkyl and / or heterocyclyl moieties.

25. The bifunctional compound of formula (II) according to claim 24 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The 5-6 membered nitrogen-containing heteroaryl group is selected from The 3-14 membered heterocyclic group is preferably selected from The 3-7 membered N-containing heterocyclic group is selected from 26. The bifunctional compound of formula (II) according to claim 24 or 25, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The L is selected from the following groups:

27. The bifunctional compound of formula (II) according to any one of claims 18 to 26, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The W group is a protein targeting moiety, wherein the target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins involved in the integral functions of the cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolic metabolism), antioxidant activity, proteolysis, biosynthesis, proteins having kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction protein activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, proteins responsive to stimuli, action proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcriptional regulator activity, extracellular organization and biogenesis activity, and translational regulatory activity.

28. The bifunctional compound of formula (II) according to any one of claims 18 to 27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: Said W is a protein targeting moiety, wherein said target protein is selected from ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e. Gq, histamine receptor, 5-lipoxygenase, tryptase, serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and the like, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinases (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Ca 2+ Channels, VCAM, VLA-4 integrins, selectins, CD40 / CD40L, neokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus type 1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptors, norepinephrine reuptake receptors, endothelin receptors, neuropeptide Y and receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7), farnesyltransferase, geranyl eranyltransferase, TrkA a NGF receptor, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, GABA-gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylate succinate synthetase, protoporphyrinogen oxidase, L-1 receptor-associated kinase 3 (IRAK-3 or IRAK-M), or enolpyruvyl-shikimate-phosphate synthase.

29. The bifunctional compound of formula (II) according to any one of claims 18 to 28, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The W is a protein targeting moiety, wherein the target protein is selected from various types of mutant KRAS proteins and wild-type KRAS proteins.

30. The bifunctional compound of formula (II) according to any one of claims 18 to 29, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: Said W is a KRAS protein binding fragment represented by general formula (III); The X is selected from -O- or C≡C, described represents independently selected from a single bond or a double bond; The X4 is CR 13 、C(R 13 )2, O, N or NR 13 ; R 13 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a1 replace; Said X5 is selected from C, CH or N; The X6 is selected from CR 12 、C(R 12 )2, O, N or NR 12 ; R 12 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a1 replace; The R 11 Select from non-existent, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; said C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a1 replace; The R 14 Selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 Alkenyl, C 3-6 Cycloalkyl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl group is optionally further substituted with one or more R a1 replace; The R 15 Selected from absent, -O- or -NR 11 -;R 11 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl; The R 12 Selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a1 replace; The K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic, condensed, spirocyclic or bridged ring, optionally further substituted by one or more R a1 replace; or R 14 Together with K and the atoms to which it is attached, it forms a 3-14 membered heterocyclic group, wherein the 3-14 membered heterocyclic group may be further optionally substituted with one or more R a1 replaced by; The m1 and n1 are each independently selected from 0, 1, 2, 3, 4 or 5; The R a1 Each independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b1 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b1 、-C 0-3 Alkylene-N(R b1 )2. -C 0-3 Alkylene-S(=O)R b1 、-C 0-3 Alkylene-S(=O)2R b1 、-C 0-3 Alkylene-SR b1 、-C 0-3 Alkylene-S(R b1 )5. -C 0-3 Alkylene-C(=O)R b1 、-C 0-3 Alkylene-C(=O)OR b1 、-C 0-3 Alkylene-C(=O)N(R b1 )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b1 replace; Each R b1 are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 substituted by a haloalkyl group; or two R b1 The atoms connected to them form C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Haloalkyl substitution.

31. The bifunctional compound of formula (II) according to claim 30, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: W is a KRAS protein binding fragment represented by formula (III-1) or (III-2); Among them, X4, X5, X6, m1, n1, R 11 , R 12 , R 14 , R 15 , K is defined as in claim 30.

32. The bifunctional compound of formula (II) according to claim 30 or 31, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The K is selected from C 3- 14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic ring, and is optionally further substituted by one or more R a1 replace.

33. The bifunctional compound of formula (II) according to claim 32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The K is selected from 34. The bifunctional compound of formula (II) according to claim 30 or 31, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a spiro ring and is optionally further substituted by one or more R a1 replace.

35. The bifunctional compound of formula (II) according to claim 34, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The K is selected from 36. The bifunctional compound of formula (II) according to claim 30 or 31, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a fused ring, and is optionally further substituted by one or more R a1 replace.

37. The bifunctional compound of formula (II) according to claim 36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The K is selected from 38. The bifunctional compound of formula (II) according to claim 30 or 31, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a bridged ring, and is optionally further substituted by one or more R a1 replace.

39. The bifunctional compound of formula (II) according to claim 38, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The K is selected from 40. The bifunctional compound of formula (II) according to any one of claims 30 to 39, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The K is selected from 41. The bifunctional compound of formula (II) according to any one of claims 30 to 40, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The R 12 Selected from C 6-18 Aryl or 5-18 membered heteroaryl, the C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a1 Substitution; said R a1 Each independently selected from H, halogen, hydroxy, amino, cyano, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Olefins.

42. The bifunctional compound of formula (II) according to any one of claims 30 to 41, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The R 12 Selected from described Optionally further comprised of one or more a1 Substitution; said R a1 Each independently selected from H, halogen, hydroxy, amino, cyano, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2- 6 olefins.

43. The bifunctional compound of formula (II) according to any one of claims 30 to 41, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The R 12 Selected from 44. The bifunctional compound of formula (II) according to any one of claims 18 to 43, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: W is selected from 45. The bifunctional compound of formula (II) according to any one of claims 18 to 44, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, characterized in that: The compound of formula (II) is selected from:

46. A pharmaceutical composition comprising the bifunctional compound of formula (II) according to any one of claims 18 to 45 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

47. Use of the bifunctional compound of formula (II) according to any one of claims 18 to 45 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, or the pharmaceutical composition according to claim 43 in the preparation of a medicament for regulating KRAS protein ubiquitination and degradation in a subject.

48. Use of the bifunctional compound of formula (II) according to any one of claims 18 to 45 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or polymorph thereof, or the pharmaceutical composition according to claim 43 in the preparation of a medicament for treating and / or preventing a KRAS-mediated or dependent disorder, wherein the KRAS-mediated disease is preferably selected from tumors.

49. The use according to claim 48, characterized in that The disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

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