A compound targeting a kras protein modulator and uses thereof

Abstract

A compound of formula (I) or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals that target KRAS protein regulators, and their pharmaceutical applications.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a compound of formula (I) or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals that target KRAS protein regulators, and their pharmaceutical applications. Background Technology

[0002] Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules. One end of the molecule is linked to a ligand of the target protein, and the other end is linked to a ligand of an E3 ligase, connected by a suitable linker. PROTACs can recognize both the target protein and the E3 ubiquitin ligase, bringing them closer together. By inducing the recruitment of the E3 ubiquitin ligase to the target protein surface, they initiate ubiquitination and induce the degradation of the target protein. PROTAC molecules have advantages such as high target selectivity / safety, overcoming drug resistance, being used for the degradation of refractory target proteins, and maintaining catalytic degradation activity at low concentrations (X. Yang, H. Yin, RD Kim, JB Fleming, H. Xie, Targeted Oncology, 2021, 16, 1-16).

[0003] The RAS (rat sarcoma) gene is an important oncogene, with three main subtypes: HRAS, NRAS, and KRAS. Mutations in the KRAS (kirsten rat sarcoma viral oncogene) gene account for more than 85% of all RAS gene mutations (AT Baines, D. Xu, CJ Der, Future Med. Chem. 2011, 3, 1787-1808.). KRAS is the most common mutated gene in various human cancers, with a mutation rate of 96% in pancreatic cancer (Almoguera, C.; Shibata, D.; Forrester, K.; Martin, J.; Arnheim, N.; Perucho, M. Cell 1988, 53(4), 549-54), 54% in colorectal cancer (Bos, JL; Fearon, ER; Hamilton, SR; Verlaan-de Vries, M.; van Boom, JH; van der Eb, AJ; Vogelstein, B. Nature 1987, 327(6120), 293-7), and 39% in lung cancer (Rodenhuis, S.; van de Wetering, ML; Mooi, WJ; Evers, SG; van Zandwijk, N.; Bos, JL New Engl. J. Med. 1987, 317, 929-935). KRAS is also an important proto-oncogene, and its mutations are widespread in various cancer cells. KRAS proteins play a crucial role in tumorigenesis and development by regulating biological processes such as cell proliferation, survival, and invasion. Most KRAS mutations occur at codon 12, accounting for 83% of all KRAS mutations, with KRAS G12D mutations being one of the most common variants. KRAS G12D mutations are most prevalent in pancreatic and colorectal cancers, accounting for 47% and 44% respectively, followed by NSCLC at 17%. (The AACR Project GENIE Consortium, Cancer Discovery 2017, 7, 818-831).

[0004] However, due to the lack of a defined drug-binding pocket and highly dynamic structural features of the KRAS protein, traditional inhibitor development faces significant challenges. It has long been considered an untreatable target. Irreversible inhibitors targeting KRAS G12C, AMG510 and MRTX849, have only recently been approved for the treatment of advanced lung cancer. However, due to drug resistance, the duration of efficacy of single-agent therapy targeting G12C is short (N. Tanaka, JJ Lin, C. Li, MBZhang, J. Kiedrowski, et al., Cancer Discovery, 2021, 11, 1913). Compared to G12C inhibitors, the development of G12D inhibitors is even more difficult than that of G12C inhibitors because there are no covalently bondable groups. Currently, there are no therapeutic drugs targeting KRAS G12D. Although newer small molecule inhibitors such as Mirati's MRTX1133 (NCT05737706), Hengrui's HRS-4642 (CXHL2200313), and Revolution's RMC-9805 (NCT06040541) and RMC-6236 (NCT06625320) have entered early-stage clinical trials.

[0005] In recent years, protein degrading agents (PROTACs) have emerged as a novel therapeutic strategy, offering new possibilities for targeting "undruggable" proteins by inducing ubiquitination and proteasome-dependent degradation of target proteins. However, no highly efficient and selective PROTACs targeting KRAS G12D mutants have yet been developed and marketed. The G12D-targeting PROTAC molecules ASP3082 (NCT05382559) and ASP4396 (NCT06364696) are still in early clinical development. Currently, the field lacks sufficient G12D degrading agents / inhibitors to meet clinical needs, necessitating the development of novel, highly bioactive, and effective KRAS G12D PROTAC molecules. Furthermore, novel KRAS G12D PROTAC protein degrading agents hold promise for overcoming the drug resistance problems inherent in traditional small-molecule chemistry, demonstrating a very broad potential for clinical applications. Summary of the Invention

[0006] This invention provides a KRAS protein modulator, which has high protein degradation activity, AGS cell proliferation inhibition activity, GP2D cell proliferation inhibition and / or G12D mutant cell activity, and can be used for the treatment of tumors such as pancreatic cancer, colorectal cancer, and lung cancer; the compound of this invention has good pharmacokinetics and in vivo tumor inhibition effect.

[0007] Compounds:

[0008] This invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal, wherein the compound is selected from compounds represented by general formula (I).

[0009]

[0010] Where K is the KRAS protein binding fragment, selected from the binding fragments of formulas (K-1), (K-2), (K-3), (K-4), (K-5), and (K-6):

[0011] , , , , ,

[0012] M is G1, G2, and G3 are each independently selected from N, O, S, CH, and C(C 1-6 Alkyl), C(CN), C(OH), C(C 1-6 alkoxy), C (halogen), C (ethynyl), C-NH (C 1-6 Alkyl) and CN (C 1-6 Alkyl)2; the This indicates that the ring contains double bonds; f is 0 or 1;

[0013] D1 is selected from N, CH, C(C) 1-6 Alkyl), C(CN), C(OH), C(C 1-6 Alkyl groups and C (halogens);

[0014] Each R1, R2, R3, R4, and R5 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, alkynyl, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups;

[0015] Each m is independently 0, 1, 2, 3 or 4;

[0016] Each n is independently 0, 1, 2 or 3;

[0017] Each r is independently 0, 1, or 2;

[0018] A is a 5- to 10-membered heterocyclic alkyl group; preferably, A is... , , , , , , , , or ;

[0019] L is L1-L2-L3-L4-L5;

[0020] Where L1 is a bond or -(CH2) 1-3 -;

[0021] L2 is selected from the bond and -(CH2). p1 (CR b R c ) p2 (CH2) p3 -;

[0022] L3 is selected from the bond, -NR a - 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 8-11 membered spirocycloalkyl, 8-10 membered fused cycloalkyl, 8-11 membered azaspirocycloalkyl, and 8-10 membered azafused cycloalkyl, wherein the 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 8-10 membered spirocycloalkyl, 8-10 membered fused cycloalkyl, 8-11 membered azaspirocycloalkyl, and 8-10 membered azafused cycloalkyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2;

[0023] L4 is selected from bond, -O-, -C(=O-), -(CR b R c ) s1 O(CR b R c ) s2 -、-(CR d R e ) s3 -、-NR f (CR b R c )s4 -、-(CR b R c ) s4 NR f -、 -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocycloalkyl, -C(O)-8-11 membered spirocycloalkyl, -C(O)-8-10 membered fused cycloalkyl, -C(O)-8-11 membered azaspirocycloalkyl, -C(O)-8-10 membered azafused cycloalkyl, -(CR d R e ) s3 -3-6 membered cycloalkyl groups and -(CR d R e ) s3 -4-6-membered heterocyclic alkyl; wherein the -C(O)-3-6-membered heterocyclic alkyl, -C(O)-3-6-membered heterocyclic alkyl, -C(O)-8-11-membered spirocyclic alkyl, -C(O)-8-10-membered fused cyclic alkyl, -(CR d R e ) s3 -3-6 membered cycloalkyl groups, -(CR d R e ) s3 -4-6 membered heterocyclic alkyl groups, -C(O)-8-11 membered azaspirocyclic alkyl groups, and -C(O)-8-10 membered azafused cyclic groups can be substituted by the following substituents: halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2;

[0024] L5 is selected from the key, -(CR d R e ) s3 -、 phenyl, 6-membered heteroaryl, 3-6-membered cycloalkyl, 4-11-membered heterocycloalkyl and 4-11-membered heterocycloalkyl carbonyl; wherein the phenyl, 6-membered heteroaryl, 3-6-membered cycloalkyl and 4-11-membered heterocycloalkyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2;

[0025] p1, p2, p3, s1, s2, s3, and s4 are each independently selected from integers from 0 to 6;

[0026] R a Selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl groups and -(CH2) 1-2 S(O)2C 1-6 alkyl;

[0027] Each R b R c R d R e Each is independently selected from hydrogen, =CH, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, halogen, cyano, halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, =O, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl group, -(CH2) 1-2 S(O)2C 1-6 Alkyl, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl; as a choice R b and R c Together with the carbon atoms they are attached to, they constitute C. 3-6 4-6 membered heterocyclic alkyl or cyclocyclic alkyl, R d R e Together with the carbon atoms they are attached to, they constitute C. 3-6 Memberial cycloalkyl or 4-6 membered heterocycloalkyl;

[0028] Each Rf Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl group, -(CH2) 1-2 S(O)2C 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl;

[0029] E is selected from the VHL or CRBN combination fragments shown in E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, and E-13:

[0030] , , , , , , , , , , , or ;

[0031] This indicates that the ring contains double bonds;

[0032] Each X1 is independently selected from NH, N(C) 1-6 Alkyl), CH2, CH(C) 1-6 Alkyl), CH, C(C) 1-6 Alkyl groups and C(CN);

[0033] Each X2, X3, X4, X5, X6, X7, and X8 is independently selected from N, CH, and C(C). 1-6 Alkyl), C(CN), C(C) 1-6 alkoxy), C (halogen), C-NH (C 1-6 Alkyl) and CN (C 1-6 Alkyl)2;

[0034] X9, X 10 For N or C, X9, X 10 Not both N;

[0035] Each Y1 is independently selected from CH2, O, S, NH, NC 1-6 Alkyl groups, CHF, CF2, C(CH3)2, and CHCF3;

[0036] Each Y2 is independently selected from CH, N, CF, C(CH3) and CCF3;

[0037] Z1 and Z2 are each independently selected from CH2, O, S, NH and NC. 1-6 alkyl;

[0038] Each R6, R7, R8, R9, R 11 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkoxy, -C(O)NH2, Halogenated C 1-6 Alkoxy, -N(C) 1-6 Alkyl groups)2, -C(O)OH and -C(O)OC 1-6 alkyl;

[0039] R 10 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and hydroxyl-substituted C 1-6 alkyl;

[0040] R 12 Selected from hydrogen, halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2;

[0041] Each R 13 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy and -N(C) 1-6 Alkyl)2;

[0042] R 14 Selected from hydrogen, methyl, ethyl, and hydroxy-substituted methyl groups;

[0043] Each t is 0, 1, or 2;

[0044] Each v is 0, 1, or 2;

[0045] Each q is 0, 1, 2, 3, or 4;

[0046] B is selected from phenyl, 5-6-membered heteroaryl, wherein the phenyl, 5-6-membered heteroaryl is substituted by the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2、-C(O)NH2;

[0047] The condition is: when K is equal to (K-2), L1 does not exist and L2 is equal to... A is And E is not or .

[0048] In one embodiment, the present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal, wherein the compound is selected from compounds represented by general formula (I).

[0049]

[0050] Where K is the KRAS protein binding fragment, selected from the binding fragments of formula (K-1), formula (K-2), and formula (K-3):

[0051] , ,

[0052] M is G1, G2, and G3 are each independently selected from N, O, S, CH, and C(C 1-6 Alkyl), C(CN), C(OH), C(C 1-6alkoxy), C (halogen), C (ethynyl), C-NH (C 1-6 Alkyl) and CN (C 1-6 Alkyl)2; the This indicates that the ring contains double bonds; f is 0 or 1;

[0053] D1 is selected from N, CH, C(C) 1-6 Alkyl), C(CN), C(OH), C(C 1-6 Alkyl groups and C (halogens);

[0054] Each R1, R2, R3, R4, and R5 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, alkynyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups;

[0055] Each m is independently 0, 1, 2, 3 or 4;

[0056] Each n is independently 0, 1, 2 or 3;

[0057] Each r is independently 0, 1, or 2;

[0058] A is , , , , , , , , or ;

[0059] L is L1-L2-L3-L4-L5;

[0060] Where L1 is a bond or -(CH2) 1-3 -;

[0061] L2 is selected from the bond and -(CH2). p1 (CR b R c ) p2 (CH2) p3 -;

[0062] L3 is selected from the bond, -NR a- 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 8-11 membered spirocycloalkyl, 8-10 membered fused cycloalkyl, 8-11 membered azaspirocycloalkyl, and 8-10 membered azafused cycloalkyl, wherein the 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 8-10 membered spirocycloalkyl, 8-10 membered fused cycloalkyl, 8-11 membered azaspirocycloalkyl, and 8-10 membered azafused cycloalkyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2;

[0063] L4 is selected from bond, -O-, -C(=O-), -(CR b R c ) s1 O(CR b R c ) s2 -、-(CR d R e ) s3 -、-NR f (CR b R c ) s4 -、-(CR b R c ) s4 NR f -、 -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocycloalkyl, -C(O)-8-11 membered spirocycloalkyl, -C(O)-8-10 membered fused cycloalkyl, -C(O)-8-11 membered azaspirocycloalkyl, -C(O)-8-10 membered azafused cycloalkyl, -(CR d R e ) s3 -3-6 membered cycloalkyl groups and -(CR d R e ) s3 -4-6-membered heterocyclic alkyl; wherein the -C(O)-3-6-membered heterocyclic alkyl, -C(O)-3-6-membered heterocyclic alkyl, -C(O)-8-11-membered spirocyclic alkyl, -C(O)-8-10-membered bridged cyclic alkyl, -(CR d R e ) s3 -3-6 membered cycloalkyl groups, -(CRd R e ) s3 -4-6 membered heterocyclic alkyl groups, -C(O)-8-11 membered azaspirocyclic alkyl groups, and -C(O)-8-10 membered azafused cyclic groups can be substituted by the following substituents: halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2;

[0064] L5 is selected from the key, -(CR d R e ) s3 - Phenyl, 6-membered heteroaryl, 3-6-membered cycloalkyl, and 4-6-membered heterocycloalkyl; wherein the phenyl, 6-membered heteroaryl, 3-6-membered cycloalkyl, and 4-6-membered heterocycloalkyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2;

[0065] p1, p2, p3, s1, s2, s3, and s4 are each independently selected from integers from 0 to 6;

[0066] R a Selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl groups and -(CH2) 1-2 S(O)2C 1-6 alkyl;

[0067] Each R bR c R d R e Each is independently selected from hydrogen, =CH, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, halogen, cyano, halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, =O, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl group, -(CH2) 1-2 S(O)2C 1-6 Alkyl, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl; as a choice R b and R c Together with the carbon atoms they are attached to, they constitute C. 3-6 4-6 membered heterocyclic alkyl or cyclocyclic alkyl, R d R e Together with the carbon atoms they are attached to, they constitute C. 3-6 Memberial cycloalkyl or 4-6 membered heterocycloalkyl;

[0068] Each R f Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl group, -(CH2) 1-2 S(O)2C 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl;

[0069] E is selected from the VHL or CRBN combination fragments shown in E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, and E-10:

[0070] , , , , , , , , , ;

[0071] This indicates that the ring contains double bonds;

[0072] Each X1 is independently selected from NH, N(C) 1-6 Alkyl), CH2, CH(C) 1-6 Alkyl), CH, C(C) 1-6 Alkyl groups and C(CN);

[0073] Each X2, X3, X4, X5, X6, X7, and X8 is independently selected from N, CH, and C(C). 1-6 Alkyl), C(CN), C(C) 1-6 alkoxy), C (halogen), C-NH (C 1-6 Alkyl) and CN (C 1-6 Alkyl)2;

[0074] X9, X 10 For N or C, X9, X 10 Not both N;

[0075] Each Y1 is independently selected from CH2, O, S, NH, NC 1-6 Alkyl groups, CHF, CF2, C(CH3)2, and CHCF3;

[0076] Each Y2 is independently selected from CH, N, CF, C(CH3) and CCF3;

[0077] Z1 and Z2 are each independently selected from CH2, O, S, NH and NC. 1-6 alkyl;

[0078] Each R6, R7, R8, R9, R 11 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkoxy, -C(O)NH2, Halogenated C 1-6 Alkoxy, -N(C) 1-6 Alkyl groups)2, -C(O)OH and -C(O)OC 1-6 alkyl;

[0079] R 10 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl and hydroxyl-substituted C 1-6 alkyl;

[0080] R 12 Selected from hydrogen, halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2;

[0081] Each R 13 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2;

[0082] R 14 Selected from hydrogen, methyl, ethyl, and hydroxy-substituted methyl groups;

[0083] Each t is 0, 1, or 2;

[0084] Each v is 0, 1, or 2;

[0085] Each q is 0, 1, 2, 3, or 4;

[0086] B is selected from phenyl, 5-6-membered heteroaryl, wherein the phenyl, 5-6-membered heteroaryl is substituted by the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2、-C(O)NH2;

[0087] The condition is: when K is equal to (K-2), L1 does not exist and L2 is equal to... A is And E is not .

[0088] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or eutectic provided by the present invention, L2 is a bond, -CH2CH(CH3)CH2- or .

[0089] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic provided by the present invention has an L1 bond.

[0090] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, wherein R1 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 1-6 Alkyl group; preferably, R1 is independently selected from F, Cl, cyano, methyl, ethyl, amino, CF3, and hydroxyl.

[0091] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, wherein R2 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, and C. 1-6 Alkyl group; preferably, R2 is independently selected from F, Cl, cyano, methyl, ethyl and hydroxy; more preferably, R2 is F.

[0092] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, wherein R3 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, ethynyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl and -N(C) 1-6 (alkyl)2; preferably, R3 is independently selected from F, Cl, cyano, methyl, ethyl, hydroxy and alkynyl; more preferably, R3 is ethyl, ethynyl or fluorine.

[0093] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, wherein R4 and R5 are each independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, ethynyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl and -N(C) 1-6 (alkyl)2, r is 1; preferably, R4 and R5 are each independently selected from hydrogen, F, Cl, cyano, methyl, ethynyl, ethyl and hydroxyl, r is 1; more preferably, R4 is cyano, and R5 is independently selected from hydrogen, deuterium, F, cyano, methyl, ethyl, ethynyl and hydroxyl, r is 1.

[0094] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, wherein G1, G2, and G3 are each independently selected from N and CH, C(C 1-3 Alkyl), C(CN), C(halogen), C(ethynyl), C(OH); preferably, G1 is CH, and G2 and G3 are N, C(CN), C(F), C(ethynyl), C(ethyl), CH or C(OH); more preferably, G1 is CH, G2 is ethyl or ethynyl, and G3 is F.

[0095] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic provided by the present invention, wherein f is 1.

[0096] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or eutectic provided by the present invention, wherein M has the following structure: or .

[0097] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, wherein p1 is 0 or 1; p2 is 1 or 2; p3 is 0 or 1; s1 is 0, 1 or 2; s2 is 0, 1 or 2; s3 is 1 or 2; and s4 is 1 or 2.

[0098] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, wherein R a It is hydrogen or C 1-6 alkyl.

[0099] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, wherein each R b R c R d R e Each is independently selected from hydrogen, =CH, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, halogen, cyano, halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, =O, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 Alkyl; as a choice R b and R c Together with the carbon atoms they are attached to, they constitute C. 3-6 4-6 membered heterocyclic alkyl or cyclocyclic alkyl, R d R e Together with the carbon atoms they are attached to, they constitute C. 3-6 Memberally cycloalkyl or 4-6-membered heterocycloalkyl; preferably, each R b R c R d R e Each is independently selected from hydrogen, =CH, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, halogen, cyano, amino, halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, as a choice R b and R c Together with the carbon atoms they are attached to, they form cyclopropyl, cyclobutyl, oxocyclobutyl, and azircyclobutyl.

[0100] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, wherein each R f Independently hydrogen, C 1-6 alkyl.

[0101] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, wherein each X1 is independently NCH3, NH, or C-CH3; X2, X3, X4, X5, X6, X7, and X8 are each independently selected from N, CH, C(C)1-6 Alkyl), C(CN) and C(halogen); preferably X2, X3, X4, X5, X6, X7 and X8 are each independently selected from N, CH, CCH3 and CF.

[0102] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic provided by the present invention, wherein Y1 is independently CH2 or O, and Y2 is independently CH, N or CF; preferably, Y1 is independently CH2 and Y2 is independently CH.

[0103] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, Z1 and Z2 are each independently selected from CH2, O, S and -NC. 1-6 The alkyl group is preferably O, S, or CH2 for Z1; more preferably O; preferably O or CH2 for Z2; more preferably CH2 for Z2.

[0104] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, R 12 Selected from hydrogen, halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl and -NH-C 1-6 Alkyl group; R is preferred 12 Selected from hydrogen, methyl, and F.

[0105] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, each R 13 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2; preferably, each R 13 It is independently selected from hydrogen, F, cyano, hydroxyl, amino, and methyl.

[0106] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, wherein R6, R7, and R8 are each independently selected from hydrogen, halogen, cyano, -C(O)OH, -C(O)OC 1-6 Alkyl, hydroxyl, amino, C1-6 Alkyl, C 1-6 Alkoxy, -C(O)NH2, Halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl group 2; preferably, R6, R7, and R8 are each independently selected from cyano, -C(O)OH, and -C(O)OC. 1-6 Alkyl, hydrogen, F, methyl, ethyl, -C(O)NH2.

[0107] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, wherein R9 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl and C 1-6 Alkoxy; preferably R9 is hydrogen, F, methyl or ethyl.

[0108] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, each R 11 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl and C 1-6 Alkyl groups; as preferred R 11 It can be hydrogen, F, methyl, or ethyl.

[0109] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal provided by the present invention, R 10 It is methyl, ethyl, isopropyl or tert-butyl; more preferably isopropyl or tert-butyl.

[0110] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, wherein B is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, pyrroleyl, thiazolyl, imidazoleyl, and pyrazolyl, wherein the phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, pyrroleyl, thiazolyl, imidazoleyl, and pyrazolyl groups may be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C(O)NH2, Halogenated C 1-6 alkoxy or -N(C) 1-6Alkyl)2; preferably B is selected from phenyl, pyridyl, thiophene, thiazolyl, imidazole, pyrazolyl, pyrrolyl; the phenyl, pyridyl, thiophene, thiazolyl, imidazole, pyrazolyl, pyrrolyl can be substituted by the following substituents: F, Cl, methoxy, cyano, hydroxyl, amino, methyl, ethyl, isopropyl or -C(O)NH2.

[0111] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention has the general formula (I-1), (I-2), (I-3), (I-4), (I-5), or (I-6):

[0112] , , , , ,

[0113] Wherein R1, R2, R3, R4, R5, L3, L4, L5, E, m, n, r, and A are as defined above.

[0114] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention has the form of a compound represented by formula (II-1), (II-2), (II-3), or (II-4):

[0115] , , ,

[0116] R1, R2, R3, R5, L3, L4, L5, E, m, and n are as defined above.

[0117] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, wherein L3 is selected from bonds, -NR a - Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, aziridine, piperidinyl, piperazine, 9-11 spirocyclic alkyl, 8 fused cyclic alkyl, 9-11 aziridine, 8 aziridine; wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, aziridine, piperidinyl, piperazine, 9-11 spirocyclic alkyl, 8 fused cyclic alkyl, 9-11 aziridine, and 8 aziridine can be substituted with the following substituents: halogen, C 1-6Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2;

[0118] The preferred L3 is selected from the following groups, whether bonded, substituted, or unsubstituted: , , , , , The substituents thereon are halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NH-C 1-6 alkyl.

[0119] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic provided by the present invention, L4 is selected from bonds, -C(=O)-, -O-, -CH2O(CH2)-, -C(CH3)2-, -(CH2). 1-2 -, -NHCH2-, -N(CH3)CH2-, -CH2NH-, -CH2N(CH3)-, , and .

[0120] In one embodiment, the present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal, wherein L5 is a bond, -CH2-, phenyl, 6-membered azira-aryl, 5-6-membered cycloalkyl, 5-11-membered heterocycloalkyl or 5-11-membered heterocycloalkyl carbonyl; wherein the phenyl, 6-membered azira-aryl, 5-6-membered cycloalkyl, 5-11-membered heterocycloalkyl or 5-11-membered heterocycloalkyl carbonyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NH-C 1-6 alkyl;

[0121] Preferably, L5 is a bond, -CH2-, substituted or non-substituted. , , , , or The substituents are selected from halogens, C 1-6Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -NH-C 1-6 alkyl.

[0122] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, wherein E is selected from the following structures:

[0123] , ,

[0124] , , , , , , , , ,

[0125] , , , , , , , , , , , , , , , , , , , , , and .

[0126] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or eutectic provided by the present invention: wherein K is selected from the following structures:

[0127] , , ,

[0128] , , , , , , and .

[0129] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal provided by the present invention, wherein L is selected from the following structures:

[0130] , , , , , , , , ,

[0131] , , , , , , , , ,

[0132] , , , , , , , , , , , , , , , , , , , , , and .

[0133] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or eutectic provided by the present invention has the following structure (III-1):

[0134]

[0135] The definitions of L3, L4, and L5 are as described above, where R3 is ethynyl or ethyl, R 15 X1 is methyl or F, and X2 is N or CH.

[0136] In one embodiment, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or eutectic provided by the present invention has the following structure (IV-1):

[0137]

[0138] Wherein, R3 is ethyl or ethynyl; E is... , , , , , or .

[0139] In one embodiment, the compound, or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or eutectic provided by the present invention, has the following structure:

[0140] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、

[0141] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , ,

[0142] Pharmaceutical compositions or preparations

[0143] The present invention also provides a pharmaceutical composition comprising the above-described compound, or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts, eutectics, and pharmaceutically acceptable excipients.

[0144] In this invention, "pharmaceutically acceptable" means any substance that does not interfere with the bioactivity of the active ingredient and is non-toxic to the host to which it is given.

[0145] The pharmaceutically acceptable excipients described in this invention refer to all additional materials in a drug other than the active pharmaceutical ingredient (API). Excipients should possess the following properties: (1) non-toxic to the human body and with virtually no side effects; (2) chemically stable and not easily affected by temperature, pH, storage time, etc.; (3) without incompatibility with the API and without affecting the efficacy and quality control of the API; and (4) not interacting with packaging materials. The excipients in the pharmaceutical compositions of this invention include, but are not limited to, fillers (diluents), lubricants, dispersants, humectants, binders, regulators, solubilizers, antioxidants, antibacterial agents, emulsifiers, disintegrants, etc.

[0146] There are no particular limitations on the administration methods of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to) oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers.

[0147] Treatment methods and uses

[0148] The present invention also provides the use of the above-described compounds, or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or the above-described pharmaceutical compositions, in the preparation of a medicament for regulating KRAS protein ubiquitination and degradation in a subject.

[0149] Furthermore, the use of the above-mentioned compound, or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions, in the preparation of a medicament for treating and / or preventing diseases mediated or dependent on the KRAS protein, wherein diseases mediated by the KRAS protein are preferably tumors; in some embodiments, KRAS is a KRAS G12D mutant.

[0150] In some 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 tumors, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell carcinoma, squamous cell carcinoma of the lung, lichenification, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma; preferably, the disease is pancreatic cancer, colorectal cancer, or lung cancer.

[0151] The present invention also provides a method for treating diseases using the above-described compounds, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts or pharmaceutical compositions thereof, including but not limited to diseases associated with the KRAS protein, wherein, preferably, in some embodiments, KRAS is a KRAS G12D mutant.

[0152] In some embodiments, the present invention provides a method for degrading KRAS protein in cells, comprising administering to a patient a therapeutically effective amount of the aforementioned compound, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Preferably, in some embodiments, KRAS is a KRASG12D mutant.

[0153] In some embodiments, the present invention provides a method for inhibiting the KRAS G12D protein in cells, comprising administering to a patient a therapeutically effective amount of the compound described above, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In a subject requiring such treatment, the KRAS G12D protein in cells is inhibited.

[0154] In some embodiments, the present invention provides a method for treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of the aforementioned compound, or a tautomer, racemic mixture, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is KRAS-mediated, for example, a KRAS G12D mutation. The cancer 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 tumors, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell carcinoma, squamous cell carcinoma of the lung, lichen keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, and liposarcoma; preferably, the cancer is pancreatic cancer, colorectal cancer, or lung cancer.

[0155] Definitions and Terms

[0156] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0157] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0158] Unless otherwise stated, the connection direction of the linking groups involved in this invention is arbitrary if not specified. For example, when L in the linking group KLE in the compound is selected from a certain value, L can connect K and E in a direction from left to right or from right to left.

[0159] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl, preferably C14. 1-6 Alkyl, more preferably C 1-4 alkyl.

[0160] As used in this article, C 1-g Including C 1-2 C 1-3 ...C 1-g , g is an integer greater than one; prefixes used as substituents indicate the minimum and maximum number of carbon atoms in the substituent, for example, "C 1-6 "Alkyl" refers to a straight-chain or branched alkyl group containing one to six carbon atoms.

[0161] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight-chain or branched saturated hydrocarbon group, containing a specified number of carbon atoms. Examples of alkylene groups with 1 to 6 carbon atoms include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene ((-CH2-CH2-CH2- or -CH(CH3)CH2-), etc.; said alkylene group may optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

[0162] The term "halogenated alkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms. The terms "halogenated C1-6 alkyl" and "halogenated C1-6 alkyl" are also used. 1-4 "Alkyl" refers to haloalkyl groups having 1 to 6 carbon atoms or 1 to 4 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0163] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0164] "Ring" refers to any covalently closed structure, including, for example, carbocyclic rings (e.g., aryl or cycloalkyl), heterocyclic rings (e.g., heteroaryl or heterocycloalkyl), aromatic groups (e.g., aryl or heteroaryl), and non-aromatic groups (e.g., cycloalkyl or heterocycloalkyl). The "ring" described in this invention can be monocyclic or polycyclic, and can be fused, spirocyclic, or bridged.

[0165] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group. As stated in this article, "C..." 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3-8 carbon atoms.

[0166] "Cycloalkenyl" refers to a cyclic substituent that has at least one carbon-carbon double bond on its ring skeleton.

[0167] "Heteroatoms" refer to nitrogen (N), oxygen (O), or sulfur (S) atoms.

[0168] "Heterocyclic alkyl" refers to a saturated cyclic group containing heteroatoms in its cyclic skeleton. As described herein, "4-6 membered heterocyclic alkyl" refers to a saturated cyclic group containing 4-6 cyclic atoms. In this invention, the nitrogen, carbon, or sulfur atoms in the heterocyclic alkyl group may optionally be oxidized.

[0169] "Aryl" refers to a monocyclic or polycyclic group with aromaticity, whose planar ring has a delocalized π-electron system and contains 4n+2 π electrons, where n is an integer; typical aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indene.

[0170] "Heteroaryl" refers to a monocyclic or polycyclic group containing heteroatoms and having aromaticity, such as a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl has 5 to 10 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen or S.

[0171] Typical heteroaryl groups include, but are not limited to:

[0172]

[0173] The alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-heterocyclic alkyl, aryl, heteroaryl, etc. mentioned in this article can be non-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl, aliphatic-heterocyclic, heterocyclic alkyl, aryl, heteroaryl, etc., or substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl, aliphatic-heterocyclic, heterocyclic alkyl, aryl, heteroaryl, etc.

[0174] The term "spirocyclic alkyl" refers to a saturated ring system with a specific number of carbon atoms, consisting of carbon and hydrogen atoms sharing only one ring carbon atom. Preferably, it is 6 to 14-membered, more preferably 8 to 11-membered. Non-limiting examples of spirocyclic groups are spirocyclic groups with 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, and 5 / 6-membered rings, wherein the count of each ring includes a spiro atom.

[0175] The term refers to a 5-20 quinary polycyclic heterocyclic group in which one or more ring atoms share a single spiro atom (spiro atom), wherein one or more ring atoms are selected from heteroatoms of N, O, and S(O)e (where e is an integer from 0 to 2), and the remaining ring atoms are carbon. The spirocyclic group may contain one or more double bonds, preferably 6-14 quinary, more preferably 7-12 quinary. Spirocyclic groups containing one or more nitrogen atoms are abbreviated as "nitrogen-spirocyclic groups". Spirocyclic alkyl groups are classified into mono-spirocyclic, bi-spirocyclic, or poly-spirocyclic groups based on the number of shared spiro atoms between rings, preferably mono-spirocyclic or bi-spirocyclic groups. More preferably, they are 4-quinary, 4-quinary, 4-quinary / 6-quinary, 5-quinary / 5-quinary, 5-quinary / 6-quinary, or 6-quinary / 6-quinary mono-spirocyclic groups.

[0176] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group (PAH) in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is a 6- to 14-membered PAH, more preferably a 7- to 10-membered PAH (e.g., 7, 8, 9 or 10-membered PAH) (i.e., 7- to 10-membered PAH). Based on the number of rings, they can be divided into bicyclic and polycyclic (such as tricyclic, tetracyclic, etc.) fused cyclic alkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cyclic alkyl groups.

[0177] The term "heterocyclic fused ring group" refers to a 5-20 membered polycyclic heterocyclic group in which each ring shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, and the one or more ring atoms are selected from heteroatoms of N, O, or S(O)e (where e is an integer from 0 to 2), with the remaining ring atoms being carbon. Preferably, it is 6-14 membered, more preferably 7-12 membered. When a fused heterocyclic group contains one or more nitrogen atoms, it is simply called a "nitrogen-fused heterocyclic group." Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups.

[0178] "Alkoxy" refers to -O- (alkyl), where alkyl is defined as described above, for example, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkyl group. C 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy.

[0179] "Haloalkoxy" refers to an alkoxy group that is replaced by one or more halogens, where the alkoxy group is as defined above.

[0180] "Halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0181] "Cyano" refers to -CN.

[0182] "Amino" refers to -NH2.

[0183] "Hydroxy group" refers to -OH.

[0184] The This indicates that the ring contains double bonds and satisfies the requirements of a saturated ring.

[0185] "(O)" means =O, such as -C(O)R means The same applies to other similar cases.

[0186] The structural formula of pyridine is: .

[0187] The structural formula for "thiophene" is: .

[0188] The structural formula of "pyrrole" is .

[0189] The structural formula for "furan" is: .

[0190] The structural formula of "pyrazole" is: .

[0191] The structural formula of "imidazole" is: .

[0192] The structural formula of "thiazole" is: .

[0193] The structural formula of pyridine is: .

[0194] The structural formula of "pyrimidine" is: .

[0195] The structural formula of "pyridazine" is: .

[0196] "Optionally substituted by one or more..." means that it can be substituted by one or more specified substituents, or it can be unsubstituted; if "one or more" is not specified, the minimum value of "multiple" is 2, and the maximum value is the number of substituted sites of the substituted group.

[0197] If a substituent is described as "selected from" or "selected independently from" a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (or other) substituent.

[0198] "Substitution" refers to the replacement of hydrogen atoms in a molecule with other different groups.

[0199] “Element” refers to the number of skeleton atoms that make up the ring.

[0200] In this invention, the term "key" or "single key" refers to a single connecting key at that location, or it can be understood as "none".

[0201] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0202] As used herein, “individual” or “subject” includes human or non-human animal. Exemplary human individuals include human individuals with a disease (as described herein) (hereinafter referred to as patients) or normal individuals. “Non-human animal” includes all vertebrates, such as non-mammals and mammals, such as non-human primates, livestock and / or domesticated animals.

[0203] As described herein, "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the disease being treated to a certain extent. Dosing regimens may be adjusted to provide the optimal desired response.

[0204] As described in this article, "pharmaceutically acceptable" means any substance that does not interfere with the bioactivity of the active ingredient and is non-toxic to the host to which it is given.

[0205] The term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid or base that is suitable for use as a medicine, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0206] The term "prevention" includes suppressing and delaying the onset of disease, encompassing not only prevention before the disease develops but also prevention of recurrence after treatment.

[0207] The term "treatment" includes curing symptoms, improving symptoms, and suppressing the progression of symptoms.

[0208] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. Tautomers can exist in compounds with two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium; attempts to isolate a single tautomer usually yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant.

[0209] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0210] The term "solvent" refers to an association formed by one or more solvent molecules with the compound of the present invention, suitable for use as a pharmaceutical product. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, EA, THF, DMF, dimethyl sulfoxide, etc.

[0211] The term "metabolite" refers to a pharmaceutically acceptable metabolic derivative form of the compound (or its salt) of the present invention.

[0212] The term "cocrystal" refers to a molecular complex in which an ionized or nonionized (I) compound (or any other compound disclosed herein) and one or more nonionized cocrystal formations (such as pharmaceutically acceptable salts) are linked by non-covalent interactions.

[0213] The term "isotope labeling" refers to the substitution of one or more atoms in a molecule with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 35S, 18F, 36Cl, 123I, and 125I, respectively. Certain isotope-labeled compounds of the present invention can be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly suitable for this purpose due to their ease of incorporation and convenient detection methods. For example, the compounds of the present invention can be enriched with 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or 99% of the specified isotopes. Attached Figure Description

[0214] Figure 1 Results of molecular docking between CRBN ligand a) and the CRBN protein crystal structure (PDB 4CI3);

[0215] Figure 2 Results of molecular docking between CRBN ligand b) and the CRBN protein crystal structure (PDB 4CI3);

[0216] Figure 3 Results of molecular docking between CRBN ligand c) and the CRBN protein crystal structure (PDB 4CI3). Detailed Implementation

[0217] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0218] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR determinations were performed using an AVANCE NEO 400 MHz Bruker instrument with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents, and tetramethylsilane (TMS) as the internal standard. MS determinations were performed using an ISQ-EC Thermo Fisher LC-MS instrument. Preparative chromatography was performed using a GX-281 Gilson chromatograph. The preparative HPLC separation method was: Sun Fire Prep C18 OBD™ 5μm, 30 x 150 mm Column, 0.6% formic acid aqueous solution / acetonitrile;

[0219] The solvent used in this invention is commercially available.

[0220] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0221] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~30℃).

[0222] HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate;

[0223] DIPEA or DIEA refers to diisopropylethylamine;

[0224] DMSO refers to dimethyl sulfoxide;

[0225] Pd2(dba)3 refers to tris(dibenzylacetone)dipalladium;

[0226] DCE refers to 1,2-dichloroethane;

[0227] DCM refers to dichloromethane;

[0228] DMF stands for N,N-dimethylformamide;

[0229] NMP refers to N-methylpyrrolidone;

[0230] TFA refers to trifluoroacetic acid;

[0231] NBS refers to N-bromosuccinimide;

[0232] TfOH refers to trifluoromethanesulfonic acid;

[0233] DPPA refers to diphenyl azidophosphate;

[0234] DMA stands for N,N-dimethylacetamide;

[0235] ACN refers to acetonitrile;

[0236] EA refers to ethyl acetate;

[0237] PE refers to petroleum ether;

[0238] EtOH refers to ethanol;

[0239] 1,4-dioxane refers to 1,4-dioxane;

[0240] Pd(PPh3)4 refers to tetraphenylphosphine palladium;

[0241] TBAF refers to tetrabutylammonium fluoride;

[0242] CsF refers to cesium fluoride;

[0243] H2O refers to tap water;

[0244] Pd(dppf)Cl2 refers to [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;

[0245] (A-taPhos)2PdCl2 refers to dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II);

[0246] Pd / C refers to palladium on carbon containing water;

[0247] DABCO refers to triethylenediamine;

[0248] NIS refers to N-iodosuccinimide;

[0249] POCl3 refers to phosphorus oxychloride;

[0250] Cata CXium A Pd G3 is a sulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II).

[0251] Synthesis method of the embodiment:

[0252] Synthesis of Intermediate I: Tert-butyl 4-((5-ethynylpyrazin-2-yl)oxy)piperidine-1-carboxylate

[0253]

[0254] Step a) Synthesis of tert-butyl 4-(5-bromopyrazin-2-yl)oxy)piperidine-1-carboxylate

[0255] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (5.0 g, 24.87 mmol) was added to THF (50 mL), and NaH (1.2 g, 30 mmol) was added at 0 °C and stirred for 0.5 h. 2,5-Dibromopyrazine (6.2 g, 26.1 mmol) was added and stirred at 50 °C for 4 h. The mixture was quenched with saturated ammonium chloride and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography to give 4-(5-bromopyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester, yield 91.1%.

[0256] ESI-MS m / z = 358.1 [M+H] +

[0257] Step b) Synthesis of tert-butyl 4-((5-((triisopropylsilyl)ethynyl)pyrazin-2-yl)oxy)piperidine-1-carboxylate

[0258] 4-(5-bromopyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (8.0 g, 22 mmol), triisopropylsilylacetylene (12 g, 67 mmol), TEA (6.8 g, 67 mmol), CuI (0.4 g, 2.2 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.80 g, 1.12 mmol) were added to THF (50 mL) and stirred at room temperature for 18 h. The reaction mixture was concentrated with silica gel, and the residue was purified by silica gel chromatography to give 4-((5-((triisopropylsilyl)acetylene)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester, yield 97.4%.

[0259] ESI-MS m / z = 460.3 [M+H] +

[0260] Step c) Synthesis of tert-butyl 4-((5-ethynylpyrazin-2-yl)oxy)piperidine-1-carboxylate

[0261] 2.5 g (5.4 mmol) of 4-((5-((triisopropylsilyl)ethynyl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester and CsF (4.3 g, 27 mmol) were added to 15 mL of DMF and stirred at 40 °C for 20 h. The mixture was extracted with water and EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel chromatography after solvent removal to obtain tert-butyl 4-((5-ethynylpyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester in 90.9% yield.

[0262] ESI-MS m / z = 304.2 [M+H] +

[0263] Synthesis of Intermediate II 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thiopheno[2,3-d]pyrimidine

[0264]

[0265] Step a) Synthesis of methyl 2-chloro-3-fluoroisonicotinic acid

[0266] 2-Chloro-3-fluoroisonicotinic acid (25.0 g, 147 mmol) was dissolved in methanol (200 mL) at room temperature, and concentrated sulfuric acid (2.8 g, 28.7 mmol) was added. The reaction mixture was reacted at 75 °C for 16 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (500 mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain methyl 2-chloro-3-fluoroisonicotinic acid in 98.5% yield.

[0267] ESI-MS m / z = 190 [M+H] +

[0268] Step b) Synthesis of (2-chloro-3-fluoropyridin-4-yl)methanol

[0269] Methyl 2-chloro-3-fluoroisonicotinic acid (12.0 g, 63.49 mmol) was dissolved in methanol (200 mL), and sodium borohydride (2.9 g, 76.19 mmol) was slowly added at 0 °C. The mixture was stirred at 0 °C for 1 h, and then allowed to rise to room temperature for 16 h. The reaction mixture was extracted with DCM (3 × 500 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude (2-chloro-3-fluoropyridin-4-yl)methanol in 97.1% yield.

[0270] ESI-MS m / z = 162.0 [M+H] +

[0271] Step c) Synthesis of 4-(bromomethyl)-2-chloro-3-fluoropyridine

[0272] (2-chloro-3-fluoropyridin-4-yl)methanol (10 g, 62 mmol) was dissolved in 200 mL DCM, and phosphorus tribromide (20 g, 75 mmol) was slowly added at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then the temperature was increased to 25 °C for 5 h. The reaction mixture was poured into a saturated sodium bicarbonate solution, extracted with DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 4-(bromomethyl)-2-chloro-3-fluoropyridinium in 86.1% yield.

[0273] ESI-MS m / z = 223.9 [M+H] +

[0274] Step d) Synthesis of 2-(2-chloro-3-fluoropyridin-4-yl)acetonitrile

[0275] 4-(bromomethyl)-2-chloro-3-fluoropyridine (12.0 g, 54 mmol) was dissolved in acetonitrile (200 mL), and trimethylcyanosilane (26.5 g, 268 mmol) and lithium hydroxide (1.5 g, 64 mmol) were added at 0 °C. The reaction mixture was reacted at room temperature for 8 hours. The reaction solution was directly concentrated and purified by silica gel chromatography (eluent: PE / EA = 3 / 1) to give 2-(2-chloro-3-fluoropyridine-4-yl)acetonitrile, in 76.4% yield.

[0276] ESI-MS m / z = 171.0 [M+H] +

[0277] Step e) Synthesis of 2-amino-7-chlorothiopheno[2,3-c]pyridine-3-nitrile

[0278] 2-(2-chloro-3-fluoropyridin-4-yl)acetonitrile (7.0 g, 41 mmol) and potassium tert-butoxide (4.6 g, 45 mmol) were dissolved in DMSO (100 mL) at 25°C. 0 Stir at C for 30 minutes. Then add ethoxycarbonyl isothiocyanate (5.9 g, 45 mmol) and stir for 30 minutes. Heat the reaction solution to 100°C. 0 Stir at C for 1 hour. Add sodium hydroxide (8.2 g, 206 mmol) and water (50 mL), 100 o Stir for 12 hours at C. Cool the reaction solution to room temperature, pour it into water (300 mL), stir for 1 hour in an ice bath, filter, and dry the solid to give 2-amino-7-chlorothiophene[2,3-c]pyridine-3-nitrile, yield 57.9%.

[0279] ESI-MS m / z = 210 [M+H] +

[0280] Step f) Synthesis of 2-amino-7-chlorothiopheno[2,3-c]pyridine-3-carboxamide

[0281] 2-Amino-7-chlorothiophene[2,3-c]pyridine-3-onitrile (5.0 g, 24 mmol) was dissolved in 50 mL DMSO, and potassium carbonate (6.6 g, 47 mmol) and hydrogen peroxide (14.6 g, 429 mmol, 30%) were added. The solution was then heated at 25 °C. 0 The reaction was carried out at C for 6 h. The reaction was quenched with a saturated sodium sulfite aqueous solution, and the reaction mixture was poured into water (200 mL) and stirred in an ice bath for 1 h. The solid was filtered and dried to give 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide, with a yield of 64.2%.

[0282] ESI-MS m / z = 228.0 [M+H] +

[0283] Step g) Synthesis of 8-chloro-2-mercaptopyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol

[0284] Potassium hydroxide (2.6 g, 46 mmol) was dissolved in ethanol (200 mL) and stirred at 25 °C for 30 minutes until completely dissolved. Carbon disulfide (3.5 g, 46 mmol) was added at room temperature and reacted for 30 minutes. Subsequently, 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (3.5 g, 15 mmol) and water (200 mL) were added, and the mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the ethanol was removed by concentration, and ice water (100 mL) was added and stirred for 30 minutes. The mixture was filtered to obtain a solid, which was dried to give 8-chloro-2-mercaptopyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol in 72.3% yield.

[0285] ESI-MS m / z = 270 [M+H] +

[0286] Step h) Synthesis of 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol

[0287] 3.0 g, 11 mmol of 8-chloro-2-mercaptopyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (1.0 g, 50 mL) was dissolved in ethanol / water (1:1). 0Add potassium hydroxide (1.2 g, 22 mmol) to C and stir for 30 minutes. While maintaining the temperature, slowly add iodomethane (1.5 g, 11 mmol) and stir for 1 hour. Concentrate the reaction solution under vacuum to remove ethanol, and pour into water (100 mL). Adjust the pH to 3 with 1N hydrochloric acid, precipitate the solid, filter, and dry to give 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol, yield 63.3%.

[0288] ESI-MS m / z = 284.0 [M+H] +

[0289] Step i) Synthesis of 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thiopheno[2,3-d]pyrimidine

[0290] 8-Chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (2.0 g, 7.06 mmol) was dissolved in phosphorus oxychloride (25 mL) at 120 °C. 0 The reaction was carried out at C for 3 hours. The reaction solution was concentrated to remove phosphorus oxychloride, ethanol (100 mL) was added and stirred for 30 minutes, filtered, and dried to obtain 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidine, with a yield of 84.4%.

[0291] ESI-MS m / z = 301.9 [M+H] +

[0292] Synthesis of Intermediate III: tert-butyl(1R,5S)-3-(8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((1-((((methanesulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0293]

[0294] Step a) Synthesis of (1R,5S)-3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0295] 4,8-Dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidine (1.0 g, 3.3 mmol), potassium carbonate (1.4 g, 10 mmol), and (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (844 mg, 4.0 mmol) were dissolved in ethanol (20 mL), and the reaction solution was reacted at 80 °C for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel chromatography to give (1R,5S)-3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 44.2%.

[0296] ESI-MS m / z = 478.1 [M+H] +

[0297] Step b) Synthesis of (1R,5S)-3-(8-chloro-2-(methanesulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0298] (1R,5S)-3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (700 mg, 1.46 mmol) was dissolved in 20 mL DCM, and m-chloroperoxybenzoic acid (1.0 g, 5.8 mmol) was added. The reaction was carried out at room temperature for 6 h. Extracted with water and DCM, the organic phase was washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain (1R,5S)-3-(8-chloro-2-(methanesulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 75.2%.

[0299] ESI-MS m / z = 510.1 [M+H] +

[0300] Step c) Synthesis of (1R,5S)-3-(2-(1-((((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-8-chloropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0301] (1R,5S)-3-(8-chloro-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (560 mg, 1.09 mmol) and (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol (741.0 mg, 2.18 mmol) were dissolved in DMF (15 mL). LiHMDS (2.2 mL, 2.2 mmol) was added at -10 °C and stirred for 0.5 hours. The mixture was then heated to 25 °C and reacted for 5 hours. The reaction solution was poured into saturated ammonium chloride water, extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to obtain (1R,5S)-3-(2-(1-((((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-8-chloropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 59.1%.

[0302] ESI-MS m / z = 770.3 [M+H] +

[0303] Step d) Synthesis of tert-butyl(1R,5S)-3-(2-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-8-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0304] (1R,5S)-3-(2-(1-((((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-8-chloropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500 mg, 0.65 mmol), cesium carbonate (634 mg, 1.95 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (499 mg, 0.97 mmol) and cataCXium A Pd G3 (95 mg, 0.13 mmol) were dissolved in 1,4-dioxane (20 (mL) and water (2mL), in 100 mL oThe reaction was carried out at C for 15 h. The reaction solution was concentrated and purified by silica gel chromatography to give tert-butyl(1R,5S)-3-(2-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-8-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, in 54.9% yield.

[0305] ESI-MS m / z = 1120.5 [M+H] +

[0306] Step e) Synthesis of tert-butyl(1R,5S)-3-(8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0307] 400 mg, 0.35 mmol of tert-butyl(1R,5S)-3-(2-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-8-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (THF) was dissolved in 10 mL of THF, and TBAF THF solution (1.4 mL, 1.4 mmol, 1 M) was added. The solution was then incubated at 25°C. 0 Stirred at C for 2 h. Extracted with water and DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give tert-butyl(1R,5S)-3-(8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, yield 98.3%.

[0308] ESI-MS m / z = 726.3 [M+H] +

[0309] Step f) Synthesis of tert-butyl(1R,5S)-3-(8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((1-((((methanesulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0310] 100 mg, 0.14 mmol of tert-butyl(1R,5S)-3-(8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (DCM) was dissolved in 10 mL of DCM, and triethylamine (71 mg, 0.70 mmol) and methanesulfonic anhydride (73 mg, 0.42 mmol) were added. The mixture was reacted at room temperature for 0.5 h. The mixture was extracted with water and DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl(1R,5S)-3-(8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((1-((((methanesulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, which was used directly in the next step with a yield of 88.8%.

[0311] ESI-MS m / z = 804.3 [M+H] +

[0312] Synthesis of Intermediate IV 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazolin

[0313]

[0314] Step a) Synthesis of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid

[0315] 2-Amino-4-bromo-3-fluorobenzoic acid (10 g, 43 mmol) was dissolved in 100 mL of DMF, and NIS (14.4 g, 64 mmol) was added. The mixture was then heated under nitrogen at 70 °C. o The reaction was carried out at C for 3 h. After cooling to room temperature, the mixture was quenched in ice water (200 mL), extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was pulped with PE:EA = 2:1 to obtain 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid, with a yield of 86.6%.

[0316] ESI-MS m / z = 359.9 [M+H] +

[0317] Step b) Synthesis of 7-bromo-8-fluoro-6-iodoquinazolin-2,4(1H,3H)-dione

[0318] 13.3 g (37 mmol) of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid and 500 g (833 mmol) of urea were placed in a reaction flask and the temperature was raised to 180 °C. o React at C for 4 hours. Cool to 100°C. o After reaching approximately 100 mL of water, stir for 10 minutes and then cool to room temperature. Filter the mixture to obtain a solid. Wash the solid three times with water and dry it to obtain 7-bromo-8-fluoro-6-iodoquinazolin-2,4(1H,3H)-dione, which can be used directly in the next step.

[0319] ESI-MS m / z = 384.8 [M+H] +

[0320] Step c) Synthesis of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazolin

[0321] 7-Bromo-8-fluoro-6-iodoquinazolin-2,4(1H,3H)-dione (15.5 g, 40 mmol) was dissolved in toluene (150 mL), and phosphorus oxychloride (61.7 g, 40 mmol) and diisopropylethylamine (15.6 g, 121 mmol) were added. The mixture was then heated under nitrogen at 100 mL / min. o The reaction was carried out overnight at C. After cooling to room temperature, DIEA (5 mL) was added, the system was concentrated under vacuum, and the residue was purified by silica gel chromatography (eluent: PE / EA, 3 / 1) to give 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazolin.

[0322] ESI-MS m / z = 420.8 [M+H] +

[0323] Step d) Synthesis of tert-butyl octane-8-carboxylate (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0324] 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (12.4 g, 29.4 mmol) was dissolved in DCM (100 mL), and DIEA (13.6 mL, 88 mmol) was added. The solution was then heated to 0°C. oC. 6.2 g, 29 mmol of (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was added to the reaction system and reacted at room temperature for 5 h. Water and DCM were then added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography to obtain (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0325] ESI-MS m / z: 597.0 [M+H] +

[0326] Step e) Synthesis of (1R,5S)-3-(7-bromo-2-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0327] (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (13 g, 22 mmol) was dissolved in 200 mL ACN, and DABCO (2.5 g, 22 mmol) and cesium carbonate (14.5 g, 44 mmol) were added. Under nitrogen protection, (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol (4.5 g, 44 mmol) was added, and the solution was heated to 50 mL. o The reaction was carried out overnight at C. The reaction was quenched with water and extracted with EA. The organic phases were combined, washed once with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column chromatography to give 66.5% (1R,5S)-3-(7-bromo-2-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0328] ESI-MS m / z: 777.1 [M+H] +

[0329] Step f) Synthesis of (1R,5S)-3-(2-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-7-cyano-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0330] (1R,5S)-3-(7-bromo-2-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (10 g, 13 mmol) was dissolved in 100 mL DMF, and tetrakis(triphenylphosphine)palladium (2.5 g, 1.3 mmol) and zinc cyanide (1.5 g, 13 mmol) were added. Under nitrogen protection, the mixture was heated at 50 °C. o The reaction was carried out overnight at C. After cooling to room temperature, water and EA were added for extraction. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column chromatography to give 61.2% of (1R,5S)-3-(2-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-7-cyano-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0331] ESI-MS m / z: 724.2 [M+H] +

[0332] Synthesis of intermediate V 6-bromo-1,3-dichloro-5-fluorofuran[3,2-f]quinazolin

[0333]

[0334] Step a) Synthesis of 2-bromo-1,3-difluoro-4-nitrobenzene

[0335] In 0 o C added 45 g of 2-bromo-1,3-difluorobenzene (233 mmol) to concentrated sulfuric acid (300 mL), and then at 0... o C. Slowly add concentrated nitric acid (100 mL) and stir for 2 h. After the reaction is complete, slowly add the reaction solution to ice water (1.0 L), extract with EA, combine the organic phases and wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove solvent to obtain 2-bromo-1,3-difluoro-4-nitrobenzene (36.1 g, 151 mmol, yield 65.2%).

[0336] ESI-MS m / z = 237.9 [M+H] +

[0337] Step b) Synthesis of 2-bromo-3-fluoro-1-methoxy-4-nitrobenzene

[0338] In 0 o C dissolved 30 g of 2-bromo-1,3-difluoro-4-nitrobenzene (126 mmol) in 300 mL of methanol, and then... oSodium methoxide (10.2 g, 190 mmol) was slowly added to C and stirred for 2 h. After the reaction was complete, the mixture was extracted with water and EA, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to give 2-bromo-3-fluoro-1-methoxy-4-nitrobenzene (11.6 g, 46.4 mmol, yield 37.0%).

[0339] 1 H NMR (400 MHz, CDCl3) δ ppm: 8.13 (t, J = 8.8 Hz, 1H), 6.80 (t, J =9.2, 1.2 Hz, 1H), 4.03 (s, 3H).

[0340] ESI-MS m / z = 249.9 [M+H] +

[0341] Step c) Synthesis of 2-bromo-3-fluoro-4-nitrophenol

[0342] 11.5 g (46.2 mmol) of 2-bromo-3-fluoro-1-methoxy-4-nitrobenzene was added to 100 mL of a 2 M solution of boron tribromide in dichloromethane, and the mixture was heated to 40 °C. o The reaction was carried out at C for 16 hours. After the reaction was complete, the reaction solution was slowly added to 150 mL of ice water, extracted with dichloromethane, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain 2-bromo-3-fluoro-4-nitrophenol (9.4 g, 40 mmol, yield 97.3%).

[0343] ESI-MS m / z: 233.9 [MH] -

[0344] Step d) Synthesis of 2-bromo-3-fluoro-6-iodo-4-nitrophenol

[0345] 2-Bromo-3-fluoro-4-nitrophenol (9.4 g, 40 mmol) was dissolved in 100 mL of acetonitrile, and then NIS (13.5 g, 60 mmol) was added and the mixture was reacted at room temperature for 5 hours. The reaction was quenched with water (200 mL), and the mixture was extracted twice with EA. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography to give 2-bromo-3-fluoro-6-iodo-4-nitrophenol (4.9 g, 13.5 mmol, yield 34.2%).

[0346] ESI-MS m / z: 359.8 [MH] -

[0347] Step e) Synthesis of 2-bromo-3-fluoro-4-nitro-6-((triisopropylsilyl)ethynyl)phenol

[0348] 2-Bromo-3-fluoro-6-iodo-4-nitrophenol (4.9 g, 13.52 mmol), triisopropylsilylacetylene (4.9 g, 27 mmol), cuprous iodide (516 mg, 2.71 mmol), and palladium dichloride bis(triphenylphosphine) (840 mg, 1.22 mmol) were dissolved in 60 mL of DMSO and incubated at 50 °C under nitrogen protection. o The reaction mixture was heated at C for 2 hours. The reaction solution was quenched with water, extracted twice with EA, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to give 2-bromo-3-fluoro-4-nitro-6-((triisopropylsilyl)ethynyl)phenol (3.9 g, 9.52 mmol, yield 70.2%).

[0349] ESI-MS m / z: 414.1 [MH] -

[0350] Step f) Synthesis of 4-amino-2-bromo-3-fluoro-6-((triisopropylsilyl)ethynyl)phenol

[0351] Dissolve 3.9 g (9.5 mmol) of 2-bromo-3-fluoro-4-nitro-6-((triisopropylsilyl)ethynyl)phenol in 50 mL of ethanol, then add 25 mL of an aqueous solution of iron powder (5.6 g, 100 mmol) and ammonium chloride (5.4 g, 100 mmol), and heat at 80 °C. o The reaction was carried out at C for 5 h. After the reaction was complete, the solid was removed by filtration, extracted twice with EA, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain 4-amino-2-bromo-3-fluoro-6-((triisopropylsilyl)ethynyl)phenol (2.8 g, 7.31 mmol, yield 76.3%).

[0352] ESI-MS m / z: 384.1 [MH] +

[0353] Step g) Synthesis of 7-bromo-6-fluoro-2-(triisopropylsilyl)benzofuran-5-amine

[0354] 4-Amino-2-bromo-3-fluoro-6-((triisopropylsilyl)ethynyl)phenol (2.8 g, 7.31 mmol) and cuprous iodide (1.4 g, 7.31 mmol) were dissolved in ethanol (30 mL) under nitrogen protection. o The reaction was carried out at C for 5 hours. The solid was removed by filtration, and water and EA were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to give 7-bromo-6-fluoro-2-(triisopropylsilyl)benzofuran-5-amine (2.6 g, 6.63 mmol, yield 91.2%).

[0355] ESI-MS m / z: 386.1 [M+H] +

[0356] Step h) Synthesis of 7-bromo-6-fluoro-4-iodo-2-(triisopropylsilyl)benzofuran-5-amine

[0357] 7-Bromo-6-fluoro-2-(triisopropylsilyl)benzofuran-5-amine (2.6 g, 6.6 mmol) was dissolved in 30 mL of acetonitrile, and NIS (1.9 g, 8.6 mmol) was added. The reaction was carried out at room temperature for 2 h. The mixture was extracted with water and EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give 7-bromo-6-fluoro-4-iodo-2-(triisopropylsilyl)benzofuran-5-amine (2.5 g, 4.92 mmol, yield 74.0%).

[0358] ESI-MS m / z: 512.0 [M+H] +

[0359] Step i) Synthesis of 5-amino-7-bromo-6-fluoro-2-(triisopropylsilyl)benzofuran-4-nitrile

[0360] 7-Bromo-6-fluoro-4-iodo-2-(triisopropylsilyl)benzofuran-5-amine (2.5 g, 4.9 mmol) was dissolved in DMF (30 mL), then cuprous cyanide (0.90 g, 10 mmol) was added and the solution was heated to 140 °C. o The reaction was carried out at C for 10 hours. After the reaction was complete, the solid was removed by filtration, and the mixture was extracted twice with water and EA. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to give 5-amino-7-bromo-6-fluoro-2-(triisopropylsilyl)benzofuran-4-onitrile (1.9 g, 4.5 mmol, yield 92.3%).

[0361] ESI-MS m / z: 411.1 [M+H] +

[0362] Step j) Synthesis of 5-amino-7-bromo-6-fluorobenzofuran-4-nitrile

[0363] 5-Amino-7-bromo-6-fluoro-2-(triisopropylsilyl)benzofuran-4-onitrile (1.9 g, 4.5 mmol) was dissolved in DMF (30 mL), then cesium fluoride (3.0 g, 20 mmol) was added and the solution was heated to 50 mL. o The reaction proceeds for 2 hours. After the reaction is complete, the solid is removed by filtration, water and EA are added for extraction, the organic phases are combined and washed with saturated brine, then dried with anhydrous sodium sulfate, and the solvent is removed by concentration under reduced pressure to obtain the crude product, which is used directly in the next step.

[0364] ESI-MS m / z: 255.0 [M+H] +

[0365] Step k) Synthesis of 5-amino-7-bromo-6-fluorobenzofuran-4-carboxamide

[0366] Dissolve the crude product from the previous step in 10 mL of ethanol, add 5 mL of sodium hydroxide (720 mg, 18 mmol) aqueous solution, and then heat at 50 °C. o The reaction was carried out at C for 2 hours. Water and EA were added to the reaction system for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding 5-amino-7-bromo-6-fluorobenzofuran-4-carboxamide (858 mg, 3.36 mmol, two-step yield 74.5%).

[0367] ESI-MS m / z: 273.0 [M+H] +

[0368] Step 1) Synthesis of 6-bromo-5-fluorofuran[3,2-f]quinazoline-1,3-diol

[0369] 5-Amino-7-bromo-6-fluorobenzofuran-4-carboxamide (858 mg, 3.36 mmol) and triphosgene (1.2 g, 4.03 mmol) were added sequentially to THF (25 mL) at room temperature. The mixture was heated to 60 °C under N2 protection and stirred overnight. After quenching the reaction mixture with water, it was stirred at room temperature for 30 minutes, filtered, and the filter cake was dried under reduced pressure to give a white solid 6-bromo-5-fluorofuran[3,2-f]quinazoline-1,3-diol (622 mg, 2.08 mmol, yield 62.3%).

[0370] ESI-MS m / z: 298.9 [M+H]-

[0371] Step m) Synthesis of 6-bromo-1,3-dichloro-5-fluorofuran[3,2-f]quinazoline

[0372] 6-Bromo-5-fluorofuran[3,2-f]quinazoline-1,3-diol (80 mg, 0.27 mmol) was dissolved in toluene (3 mL), and POCl3 (206 mg, 1.34 mmol) and DIEA (140 μL, 0.80 mmol) were added at room temperature. The mixture was heated to 100 °C and stirred overnight under nitrogen protection. The reaction mixture was cooled to room temperature, concentrated under vacuum, and the residue was purified by silica gel chromatography to give 6-bromo-1,3-dichloro-5-fluorofuran[3,2-f]quinazoline (71.0 mg, 0.21 mmol, yield 79.3%).

[0373] ESI-MS m / z: 334.9 [M+H] +

[0374] Synthesis of intermediate VI (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphth-1-yl)-5-fluoro-3-((1-(iodomethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0375]

[0376] Step a) Synthesis of (1R,5S)-3-(6-bromo-3-chloro-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0377] Intermediate X (10 g, 29 mmol) was dissolved in 100 mL of DCM, and DIEA (13.6 mL, 88 mmol) was added. Then, (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.2 g, 29 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 5 h. The mixture was extracted with water and DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography to give (1R,5S)-3-(6-bromo-3-chloro-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, in 75.5% yield.

[0378] ESI-MS m / z: 511.1 [M+H] +

[0379] Step b) Synthesis of tert-butyl octane-8-carboxylic acid ((1R,5S)-3-(6-bromo-3-(1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid

[0380] (1R,5S)-3-(6-bromo-3-chloro-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (12.8 g, 22 mmol) was dissolved in 200 mL ACN, and DABCO (2.5 g, 22 mmol) and cesium carbonate (14.5 g, 44 mmol) were added. (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol (4.5 g, 44 mmol) was added, and the mixture was dissolved under nitrogen protection at 50 °C. o The reaction was carried out overnight at C. Then, water and EA were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography to give (1R,5S)-3-(6-bromo-3-(1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, in 66.5% yield.

[0381] ESI-MS m / z: 691.2 [M+H] +

[0382] Step c) Synthesis of tert-butyl(1R,5S)-3-(3-(1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-fluoro-6-(7-fluoro-3-(methoxymethoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0383] (1R,5S)-3-(6-bromo-3-(1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (14.7 g, 24 mmol) was dissolved in 1,4-dioxane (100 mL) and water (20 mL). Then, ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (12 g, 23.7 mmol), Cata CXium A Pd G3 (585 mg, 0.82 mmol), and cesium carbonate (9.6 g, 30 mmol) were added. mmol), heated to 100 under nitrogen protection o The reaction was carried out at C for 12 hours. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography to give tert-butyl(1R,5S)-3-(3-(1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-fluoro-6-(7-fluoro-3-(methoxymethoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, in 60% yield.

[0384] ESI-MS m / z: 997.5 [M+H] +

[0385] Step d) Synthesis of (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphth-1-yl)-5-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0386] 8.8 g (8.9 mmol) of tert-butyl(1R,5S)-3-(3-(1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-fluoro-6-(7-fluoro-3-(methoxymethoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 50 mL of THF, and then TBAF trihydrate (5.6 g, 18 mmol) was added to the solution. The reaction was carried out at room temperature for 2 h. Extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphth-1-yl)-5-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 88.0%.

[0387] ESI-MS m / z: 727.3 [M+H] +

[0388] Step e) Synthesis of (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphth-1-yl)-5-fluoro-3-((1-(iodomethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0389] (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthyl-1-yl)-5-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.7 g, 7.8 mmol), elemental iodine (1.5 g, 12 mmol), triphenylphosphine (4.1 g, 15.6 mmol), and imidazole (1.6 g, 23.5 mmol) were dissolved in 80 mL DCM and stirred at room temperature under nitrogen for 2 hours. h. Water and DCM were added for extraction, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography to give (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthyl-1-yl)-5-fluoro-3-((1-(iodomethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 73.8%.

[0390] ESI-MS m / z = 837.2 [M+H] +

[0391] Synthesis of intermediate VII: 3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluoro-3-((1-(iodomethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (refer to intermediate VI)

[0392]

[0393] Following the synthetic method of intermediate VI steps c to e, ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane was replaced with 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, with other operations performed in the same manner, to obtain intermediate VII.

[0394] ESI-MS m / z = 841.2 [M+H] +

[0395] Synthesis of intermediate VIII 3-(6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(iodomethyl)cyclopropyl)methoxyquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (refer to intermediate VI)

[0396]

[0397] Following the synthetic method of intermediate VI steps c to e, ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane and (1R,5S)-3-(6-bromo-3-(1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was replaced with 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane and intermediate IV, with other procedures remaining the same, to obtain intermediate VIII.

[0398] ESI-MS m / z = 826.2 [M+H] +

[0399] Synthesis of intermediate IX: 3-(6-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(iodomethyl)cyclopropyl)methoxy]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (refer to intermediate VI)

[0400]

[0401] Following the synthetic method of intermediate VI steps a to e, 6-bromo-1,3-dichloro-5-fluorofurano[3,2-f]quinazoline was replaced with 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline, with the other operations being the same, to obtain intermediate IX.

[0402] ESI-MS m / z = 822.2 [M+H] +

[0403] Synthesis of intermediate X 3-(6-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0404]

[0405] Step a) Synthesis of 6-bromo-4-fluoro-3-iodo-1H-indazole

[0406] Dissolve 6-bromo-4-fluoro-1H-indazole (5.0 g, 23 mmol) in DMF (50 mL), add NIS (6.3 g, 28 mmol) in an ice bath, and incubate at 80 °C. 0 The reaction was carried out at C for 120 minutes. The crude product was concentrated, and the residue was purified by silica gel chromatography to give 6-bromo-4-fluoro-3-iodo-1H-indazole, with a yield of 99.0%.

[0407] ESI-MS m / z = 340.9 [M+H] +

[0408] Step b) Synthesis of 6-bromo-4-fluoro-3-iodo-1-methyl-1H-indazole

[0409] 6-Bromo-4-fluoro-3-iodo-1H-indazole (4.0 g, 12 mmol) was dissolved in 60 mL of acetonitrile, and iodomethane (2.7 g, 19 mmol) and cesium carbonate (8.1 g, 25 mmol) were added. The mixture was stirred at room temperature for 1 h. After filtration, the filtrate was concentrated under vacuum and purified by column chromatography to obtain 6-bromo-4-fluoro-3-iodo-1-methyl-1H-indazole in 64.1% yield.

[0410] ESI-MS m / z = 354.9 [M+H] +

[0411] Step c) Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-4-fluoro-1-methyl-1H-indazole

[0412] 6-Bromo-4-fluoro-3-iodo-1-methyl-1H-indazole (2.5 g, 7.4 mmol) was dissolved in 1,4-dioxane (50 mL) and water (5 mL). 2,6-bis(benzyloxy)-3-(tetramethyl-1,3,2-dioxoboron-2-yl)pyridine (3.1 g, 7.42 mmol), cesium carbonate (4.7 g, 23 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (540 mg, 0.74 mmol) were added. The mixture was stirred at 100 °C for 17 hours under nitrogen protection. The reaction solution was cooled to room temperature and filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-4-fluoro-1-methyl-1H-indazole, in 64.2% yield.

[0413] ESI-MS m / z = 518.1 [M+H] +

[0414] Step d) Synthesis of tert-butyl piperazine-1-carboxylate

[0415] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-4-fluoro-1-methyl-1H-indazole (3.6 g, 6.9 mmol), piperazine tert-butyl 1-carboxylate (3.9 g, 21 mmol) were dissolved in 20 mL of 1,4-dioxane. Cesium carbonate (6.9 g, 20.82 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (400 mg, 0.69 mmol), and Pd2(dba)3 (640 mg, 0.69 mmol) were added, and the mixture was incubated at 110 °C under nitrogen protection. o The reaction was carried out at C for 16 h. The crude product was concentrated, and the residue was purified by silica gel chromatography to give tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperazine-1-carboxylate, with a yield of 96.2%.

[0416] ESI-MS m / z = 624.3 [M+H] +

[0417] Step e) Synthesis of tert-butyl piperazine-1-carboxylate

[0418] 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylic acid tert-butyl ester (4.0 g, 6.41 mmol) was dissolved in EA / EtOH = 1:1 (200 mL), and after hydrogen purging, the solution was 28 mL. o The reaction was carried out at C for 8 hours. After filtration and concentration, crude product 4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylic acid tert-butyl ester was obtained and used directly in the next step with a yield of 74.8%.

[0419] ESI-MS m / z = 446.2 [M+H] +

[0420] Step f) Synthesis of 3-(4-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0421] 4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperazin-1-carboxylic acid tert-butyl ester (707 mg, 1.59 mmol) was dissolved in 30% TFA / DCM (10 mL) and stirred at room temperature for 2 hours. The crude product 3-(4-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazole-3-yl)piperidin-2,6-dione was directly used in the next step with a yield of 98.3%.

[0422] ESI-MS m / z = 346.2 [M+H] +

[0423] Step g) 2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0424] 3-(4-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (548 mg, 1.59 mmol), tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (761 mg, 3.18 mmol) were dissolved in 20 mL of DMA, and 50 μL of acetic acid were added. oReact at C for 3 hours. Cool to room temperature, add sodium triacetoxyborohydride (1.01 g, 4.77 mmol), and continue the reaction for 3 hours. Extract with water and EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate to obtain crude product, and purify the residue by silica gel chromatography to obtain 2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, yield 90.3%.

[0425] ESI-MS m / z = 569.3 [M+H] + .

[0426] Step h) Synthesis of 3-(6-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0427] 2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (800 mg, 1.41 mmol) was dissolved in 30% TFA / DCM (6 mL), stirred at room temperature for 2 hours, and then concentrated to obtain crude 3-(6-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione, which was directly used in the next step with a yield of 94.2%.

[0428] ESI-MS m / z = 469.3 [M+H] + .

[0429] Synthesis of intermediate XI 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0430]

[0431] Step a) Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0432] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-4-fluoro-1-methyl-1H-indazole (2.9 g, 5.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.6 g, 8.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.40 g, 0.56 mmol) and cesium carbonate (5.5 g, 16.8 mmol) were dissolved in 1,4-dioxane (14 mL) and water (2 mL) and heated in nitrogen at 100 °C. o The reaction was carried out at C for 16 hours. The reaction system was concentrated, and the residue was purified by silica gel chromatography to give tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid, with a yield of 87.8%.

[0433] ESI-MS m / z = 621.3 [M+H] +

[0434] Step b) Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-carboxylic acid

[0435] 515 mg (0.83 mmol) of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid was dissolved in 10 mL of ethanol, and 10% Pd / C (100 mg) and 10% palladium hydroxide (20 mg) were added. The reaction mixture was reacted at room temperature in hydrogen atmosphere for 0.5 h. The reaction mixture was filtered, concentrated, and the residue was purified by silica gel chromatography to give tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperidin-1-carboxylic acid in 50.8% yield.

[0436] ESI-MS m / z = 445.2 [M+H] +

[0437] Step c) Synthesis of 3-(4-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione

[0438] 4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylic acid tert-butyl ester (260.0 mg, 0.58 mmol) was dissolved in DCM (5.0 mL), and TFA (1.0 mL) was added. The reaction was carried out at room temperature for 2 hours. The crude product was concentrated and used directly in the next step, with a yield of 97.8%.

[0439] ESI-MS m / z = 345.2 [M+H] +

[0440] Step d) Synthesis of 2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0441] 3-(4-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (31 mg, 0.09 mmol) and 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (66 mg, 0.28 mmol) were dissolved in 3 mL of DMA, and 50 μL of acetic acid was added. o React at C for 3 hours. Cool to room temperature, add sodium triacetoxyborohydride (19.5 mg, 0.09 mmol), and continue the reaction for 3 hours. Extract with water and EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel chromatography to give 2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, yield 57.8%.

[0442] ESI-MS m / z = 568.3 [M+H] +

[0443] Step e) Synthesis of 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0444] 40 mg (0.07 mmol) of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid was dissolved in DCM (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The reaction was carried out at room temperature for 2 hours. The crude product was concentrated and purified by reverse-phase column chromatography to give 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione, in 67.8% yield.

[0445] ESI-MS m / z = 468.3 [M+H] +

[0446] Intermediate XII: tert-butyl(1R,5S)-3-(8-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-(1-((((methanesulfonyl)oxy)methyl)cyclopropyl)methoxypyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (refer to Intermediate III)

[0447]

[0448] Following the synthetic method of steps d to f of intermediate III, ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane was replaced with 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, with other procedures remaining the same, to obtain intermediate XII.

[0449] Synthesis of intermediate XIII (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0450]

[0451] Step a) Synthesis of 3-methylthiophene-2-nitrile

[0452] 2-Bromo-3-methylthiophene (25 g, 141 mmol), zinc cyanide (33 g, 282 mmol), and tetrakis(triphenylphosphine)palladium (8.2 g, 7.1 mmol) were dissolved in 60 mL of N-methylpyrrolidone and dissolved at 190 °C under nitrogen protection.o The reaction was carried out at C for 20 h. After cooling to room temperature, water and EA were added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to obtain crude product, and purified by silica gel chromatography to obtain 3-methylthiophene-2-carboxynitrile, with a yield of 83.2%.

[0453] ESI-MS m / z = 124.0 [M+H] +

[0454] Step b) Synthesis of 4-bromo-3-methylthiophene-2-carboxynitrile

[0455] 3-Methylthiophene-2-carboxynitrile (6.5 g, 53 mmol) was dissolved in DMF (15 mL), and N-bromosuccinimide (9.4 g, 53 mmol) in DMF (15 mL) was added dropwise under ice bath conditions. The reaction was carried out at room temperature for 30 minutes. The reaction was quenched with water, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to obtain 4-bromo-3-methylthiophene-2-carboxynitrile, with a yield of 77.3%.

[0456] ESI-MS m / z = 201.9 [M+H] +

[0457] Step c) Synthesis of 5-bromo-4-methylthiophene-3-carboxamide

[0458] 4-Bromo-3-methylthiophene-2-carboxynitrile (8.0 g, 40 mmol) was dissolved in ethanol (5 mL), and sulfuric acid (22.1 g, 225 mmol) was added. The solution was then heated at 65 °C. o The reaction was carried out for 30 minutes. The reaction solution was cooled to room temperature, and a small amount of sodium bicarbonate aqueous solution was added dropwise under an ice bath. The reaction was stopped when solid precipitated. The mixture was stirred for 30 minutes, filtered, and the filter cake was washed twice with pure water and three times with PE. The solid was collected and concentrated under vacuum to give 5-bromo-4-methylthiophene-3-carboxamide, with a yield of 86.3%.

[0459] ESI-MS m / z = 219.9 [M+H] +

[0460] Step d) Synthesis of tert-butyl (R)-(1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamate

[0461] 5-Bromo-4-methylthiophene-3-carboxamide (1.0 g, 4.55 mmol), (R)-(2-hydroxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)phenyl)ethyl)carbamate tert-butyl ester (2.0 g, 5.4 mmol), Pd(dppf)Cl2 (329 mg, 0.45 mmol), and cesium carbonate (4.4 g, 13.50 mmol) were dissolved in 1,4-dioxane:H2O=5:1 (10 mL) under nitrogen protection for 100 o The reaction was carried out at C for 3 h. After cooling to room temperature, the crude product was concentrated, and the residue was purified by silica gel chromatography to give (R)-(1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamate tert-butyl ester, with a yield of 99.3%.

[0462] ESI-MS m / z = 377.2 [M+H] +

[0463] Step e) Synthesis of (R)-5-(4-(1-amino-2-hydroxyethyl)phenyl)-4-methylthiophene-3-carboxamide

[0464] (R)-(1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)tert-butyl carbamate (2.3 g, 6.16 mmol) was dissolved in 18 mL of 4 M HCl dioxane solution and reacted for 2 hours. The crude product was concentrated and used directly in the next step.

[0465] ESI-MS m / z = 277.1 [M+H] +

[0466] Step f) Synthesis of tert-butyl (2S,4R)-2-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid

[0467] The crude product from the previous step and (2S,4R)-1-(tert-butyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.6 g, 7.06 mmol) were dissolved in 40 mL of DMF, and DIEA (2.7 g, 21 mmol) was added. HATU (3.5 g, 9.2 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 1 h. The mixture was extracted with EA and water, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain (2S,4R)-2-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, with a two-step yield of 66.1%.

[0468] ESI-MS m / z = 490.2 [M+H] +

[0469] Step g) Synthesis of (2S,4R)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0470] (2S,4R)-2-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 6.0 mmol) was dissolved in 1,4-dioxane hydrochloride (20 mL, 4 M) and reacted for 2 hours. The crude product (2S,4R)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide was concentrated and used directly in the next step.

[0471] ESI-MS m / z = 390.1 [M+H] +

[0472] Synthesis of step h) ((S)-1-((2S,4R)-2-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)tert-butyl carbamate

[0473] The crude product from the previous step and (tert-butyloxycarbonyl)-L-valine (1.4 g, 6.6 mmol) were dissolved in DMF (30 mL), and DIEA (3.1 g, 24 mmol) were added. The mixture was stirred at room temperature for 5 minutes. HATU (3.0 g, 7.8 mmol) was added under ice bath conditions, and the reaction was continued at room temperature for 1 hour. The mixture was quenched with water, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain ((S)-1-((2S,4R)-2-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate tert-butyl ester, with a two-step yield of 57%.

[0474] ESI-MS m / z = 589.3 [M+H] +

[0475] Step i) Synthesis of (2S,4R)-1-(L-valine)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0476] ((S)-1-((2S,4R)-2-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)carbamate tert-butyl ester (2.5 g, 4.25 mmol) was dissolved in 4M HCl EA (60 mL) and stirred at room temperature for 2 hours. The crude product (2S,4R)-1-(L-valine)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide was directly used in the next step.

[0477] ESI-MS m / z = 489.2 [M+H] +

[0478] Step j) Synthesis of (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0479] (2S,4R)-1-(L-valine)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (3.5 g, 7.2 mmol), anhydrous copper sulfate (2.3 g, 14 mmol), and triethylamine (4.6 g, 43 mmol) were dissolved in 30 mL THF and 30 mL ACN. A solution of 2-azido-1,3-dimethylimidazoline hexafluorophosphate (6.1 g, 21 mmol) in ACN (15 mL) was added dropwise under an ice-salt bath. o React at C for 2 h. Extract with water and EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate to obtain crude product, and purify the residue by silica gel chromatography to obtain (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide, yield 93.2%.

[0480] ESI-MS m / z = 515.2 [M+H] +

[0481] Synthesis of intermediate XIV (2S,4R)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide

[0482]

[0483] Step a) Synthesis of tert-butyl 4-((5-(1-((S)-1-((2S,4R)-2-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid

[0484] (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (120 mg, 0.23 mmol), copper sulfate pentahydrate (86 mg, 0.35 mmol), and sodium ascorbate (137 mg, 0.69 mmol) were dissolved in tert-butanol / tetrahydrofuran / water = 1:1:1 (15 mL). 4-((5-ethynylpyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (91 mg, 0.30 mmol) was added under ice-salt bath, and the reaction was allowed to proceed for 2 h. Extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to give tert-butyl 4-((5-(1-((S)-1-((2S,4R)-2-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid, yield 84.3%.

[0485] ESI-MS m / z = 818.4 [M+H] +

[0486] Step b) Synthesis of (2S,4R)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide

[0487] 4-((5-(1-((S)-1-((2S,4R)-2-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.04 mmol) was dissolved in 30% TFA / DCM (3 mL) and stirred at room temperature for 2 hours. The concentrate yielded (2S,4R)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide, with a yield of 95.8%.

[0488] ESI-MS m / z = 718.3 [M+H] +

[0489] Intermediate XV (2R,4S)-1-((R)-2-azido-3-methylbutyryl)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (refer to intermediate XIII)

[0490]

[0491] Following the synthetic method of intermediate XIII steps d to j, (R)-(2-hydroxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)ethyl)carbamate tert-butyl ester was replaced with (S)-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)ethyl)carbamate tert-butyl ester, with other procedures remaining the same, to obtain intermediate XV.

[0492] ESI-MS m / z = 499.2 [M+H] +

[0493] Synthesis of intermediate XVI (2S,4R)-N-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide (refer to intermediate XIV)

[0494]

[0495] Based on the synthesis method of intermediate XIV from step a to step b, intermediate XIII is replaced with intermediate XV, and the other operations are the same, to obtain intermediate XVI.

[0496] ESI-MS m / z = 702.3 [M+H] +

[0497] Synthesis of intermediate XVII (2S,4R)-N-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide (refer to intermediate VI)

[0498]

[0499] Following the synthetic method of steps b to e of intermediate VI, (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol was replaced with 2-(((tert-butyldimethylsilyl)oxy)methyl)prop-2-en-1-ol, and the other operations were the same, to obtain intermediate XVII.

[0500] ESI-MS m / z = 499.2 [M+H] +

[0501] Synthesis of intermediate XVIII 3-(5-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinolin-2-yl)piperidin-2,6-dione trifluoroacetate

[0502]

[0503] Step a) Synthesis of 7-iodo-1H-indazole-6-ol

[0504] 1H-indazole-6-ol (5.0 g, 37 mmol) was added to THF (150 mL), and NIS (8.3 g, 37 mmol) was added at 0 °C and stirred for 0.5 h. The reaction mixture was extracted with water and EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography to obtain 7-iodo-1H-indazole-6-ol in 93.8% yield.

[0505] ESI-MS m / z = 261.03 [M+H] + .

[0506] Step b) Synthesis of 7-iodo-6-((4-methoxybenzyl)oxy)-1H-indazole

[0507] 7-Iodo-1H-indazole-6-ol (9.1 g, 35 mmol) was added to DMF (150 mL), and after heating to 0 °C, potassium carbonate (9.6 g, 70 mmol) and 4-methoxybenzyl chloride (6.5 g, 42 mmol) were added. The mixture was stirred at room temperature for 16 h. The mixture was extracted with water and EA, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography to give 7-iodo-6-((4-methoxybenzyl)oxy)-1H-indazole in 56.4% yield.

[0508] ESI-MS m / z = 381.1 [M+H] + .

[0509] Step c) Synthesis of 7-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole

[0510] 7-Iodo-6-((4-methoxybenzyl)oxy)-1H-indazole (7.5 g, 2.0 mmol), palladium dichloride bis(triphenylphosphine) chloride (1.4 g, 2.0 mmol), tert-butyldimethyl(2-propynoxy)silane (6.7 g, 39 mmol), triethylamine (19.9 g, 197 mmol), and cuprous iodide (374 mg, 2.0 mmol) were added to DMF (150 mL) and heated at 50 °C. o Stirred at C for 12 hours. Extracted with water and EA, the organic phases were combined, washed with saturated brine, concentrated and purified by silica gel column chromatography to give 7-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole, yield 37.1%.

[0511] ESI-MS m / z = 423.2 [M+H] +

[0512] Step d) Synthesis of 3-(6-((4-methoxybenzyl)oxy)-1H-indazol-7-yl)prop-1-ol

[0513] 7-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole (3.1 g, 7.3 mmol), palladium on carbon (1.5 g, 10%), and palladium hydroxide on carbon (1.5 g, 10%) were added to acetic acid (100 mL) and stirred at room temperature for 16 h under a hydrogen atmosphere. The reaction solution was filtered to remove the palladium on carbon, and the mother liquor was concentrated and purified by silica gel chromatography to obtain 3-(6-((4-methoxybenzyl)oxy)-1H-indazole-7-yl)prop-1-ol, in yield 78.4%.

[0514] ESI-MS m / z = 313.1 [M+H] + .

[0515] Step e) Synthesis of 7-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-((4-methoxybenzyl)oxy)-1H-indazole

[0516] 3-(6-((4-methoxybenzyl)oxy)-1H-indazole-7-yl)prop-1-ol (1.8 g, 5.76 mmol) and imidazole (1.8 g, 17 mmol) were added to DCM (50 mL), followed by tert-butyldimethylchlorosilane (1.03 g, 6.9 mmol). The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated and purified by silica gel chromatography to give 7-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-((4-methoxybenzyl)oxy)-1H-indazole in 93.5% yield.

[0517] ESI-MS m / z = 427.2 [M+H] + .

[0518] Step f) Synthesis of 7-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-iodo-6-((4-methoxybenzyl)oxy)-1H-indazole

[0519] 7-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-((4-methoxybenzyl)oxy)-1H-indazole (2.3 g, 5.4 mmol) was added to a reaction flask containing 50 mL of acetonitrile, and NIS (1.2 g, 5.4 mmol) was added. The reaction mixture was stirred at 60 °C for 1 h. After concentration, the reaction solution was purified by silica gel chromatography to obtain 7-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-iodo-6-((4-methoxybenzyl)oxy)-1H-indazole, with a yield of 87.1%.

[0520] ESI-MS m / z = 553.1 [M+H] + .

[0521] Step g) Synthesis of 3-(3-iodo-6-((4-methoxybenzyl)oxy)-1H-indazol-7-yl)prop-1-ol

[0522] 7-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-iodo-6-((4-methoxybenzyl)oxy)-1H-indazole (2.6 g, 4.71 mmol) was added to a reaction flask containing tetrahydrofuran (20 mL), followed by TBAF (1 MtHF solution) (24 mL, 24 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with water and extracted with EA. The organic phases were combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography to obtain 3-(3-iodo-6-((4-methoxybenzyl)oxy)-1H-indazole-7-yl)prop-1-ol in 82.1%.

[0523] ESI-MS m / z = 439.1 [M+H] + .

[0524] Step h) Synthesis of 3-(3-iodo-6-((4-methoxybenzyl)oxy)-1H-indazol-7-yl)propyl methanesulfonate

[0525] 3-(3-iodo-6-((4-methoxybenzyl)oxy)-1H-indazole-7-yl)prop-1-ol (1.7 g, 3.9 mmol) was dissolved in 30 mL of DCM, and TEA (1.2 g, 12 mmol) and methanesulfonic anhydride (1.35 g, 7.8 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The solution was extracted with dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, 3-(3-iodo-6-((4-methoxybenzyl)oxy)-1H-indazole-7-yl)propyl methanesulfonate was obtained in 94.8% yield.

[0526] ESI-MS m / z = 517.0 [M+H] + .

[0527] Step i) Synthesis of 2-iodo-5-((4-methoxybenzyl)oxy)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline

[0528] 3-(3-iodo-6-((4-methoxybenzyl)oxy)-1H-indazol-7-yl)propyl methanesulfonate (1.9 g, 3.7 mmol) and sodium hydride (736 mg, 18.4 mmol, 60%) were added to tetrahydrofuran (80 mL) at 40 °C. oStirred at C for 16 h. Quenched in an ice bath with an aqueous solution of ammonium chloride, extracted with EA, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 2-iodo-5-((4-methoxybenzyl)oxy)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline, yield 97.0%.

[0529] ESI-MS m / z = 421.0 [M+H] + .

[0530] Step j) Synthesis of 2-iodo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-ol

[0531] 1.5 g (3.57 mmol) of 2-iodo-5-((4-methoxybenzyl)oxy)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline was dissolved in trifluoroacetic acid (20 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (eluent: PE / tetrahydrofuran = 2 / 1) to give 2-iodo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-ol in 78.4% yield.

[0532] ESI-MS m / z = 301.1 [M+H] + .

[0533] Step k) Synthesis of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-ol

[0534] 2-Iodo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-ol (840 mg, 2.8 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (1.75 g, 4.21 mmol), cesium carbonate (2.7 g, 8.43 mmol), and Pd(dppf)Cl2 (205 mg, 0.28 mmol) were added to 1,4-dioxane / H2O (10:1) (20 mL) and stirred at 90 °C for 4 hours under nitrogen protection. The reaction solution was directly concentrated, and the residue was purified by silica gel chromatography to give 2-(2,6-bis(benzyloxy)pyridin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-ol, with a yield of 75.2%.

[0535] ESI-MS m / z = 464.1 [M+H] + .

[0536] Step l) Synthesis of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl trifluoromethanesulfonate

[0537] 2-(2,6-bis(benzyloxy)pyridin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-ol (1.0 g, 2.2 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (921 mg, 2.6 mmol) were dissolved in 20 mL DMF, and potassium carbonate (593 mg, 4.3 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography to obtain 2-(2,6-bis(benzyloxy)pyridin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yltrifluoromethanesulfonate in 93.1% yield.

[0538] ESI-MS m / z = 596.1 [M+H] + .

[0539] Step m) Synthesis of tert-butyl 4-(2-(2,6-bis(benzyloxy)pyridin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl)-3,6-dihydropyridin-1(2H)-carboxylic acid

[0540] 2-(2,6-bis(benzyloxy)pyridin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl trifluoromethanesulfonate (1.2 g, 2.1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (807 mg, 2.61 mmol), cesium carbonate (1.9 g, 6.0 mmol), and Pd(dppf)Cl2 (146 mg, 0.20 mmol) were added to a reaction flask containing 1,4-dioxane / H2O (10:1) (20 mL) and stirred at 100 °C for 4 h under nitrogen protection. The residue was directly concentrated and purified by silica gel chromatography (eluent: PE / tetrahydrofuran = 2 / 1) to give 4-(2-(2,6-bis(benzyloxy)pyridin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl)-3,6-dihydropyridin-1(2H)-carboxylic acid tert-butyl ester, yield 87.1%.

[0541] ESI-MS m / z = 629.3 [M+H]+

[0542] Step n) Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl)piperidin-1-carboxylic acid

[0543] 1.1 g (1.75 mmol) of 4-(2-(2,6-bis(benzyloxy)pyridin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, palladium on carbon (500 mg, 10%), and palladium hydroxide (500 mg, 10%) were added to a reaction flask containing 500 mL of ethanol. 1 mL of acetic acid was added, and the reaction mixture was stirred at 35 °C under a hydrogen atmosphere for 16 hours. The palladium on carbon was removed by filtration, and the mother liquor was concentrated to obtain 4-(2-(2,6-dioxopiperidin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl)piperidin-1-carboxylic acid tert-butyl ester, with a yield of 88.5%.

[0544] ESI-MS m / z = 453.2 [M+H]+.

[0545] Step o) Synthesis of 3-(5-(piperidin-4-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-yl)piperidin-2,6-dione

[0546] 700 mg (1.54 mmol) of 4-(2-(2,6-dioxopiperidin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl)piperidin-1-carboxylic acid tert-butyl ester was added to a reaction flask containing 10 mL of dichloromethane, followed by 3 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give 3-(5-(piperidin-4-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-yl)piperidin-2,6-dione in 95.9% yield.

[0547] ESI-MS m / z = 353.2 [M+H]+.

[0548] Step p) Synthesis of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl)piperidin-1-yl)-7-azaspiro[3,5]nonane-7-carboxylic acid

[0549] 3-(5-(piperidin-4-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-yl)piperidin-2,6-dione (520 mg, 1.47 mmol) was added to DMA (20 mL), followed by tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (1.0 g, 4.41 mmol) and acetic acid (88 mg, 1.47 mmol). The mixture was stirred at 50 °C for 2 h. After cooling to room temperature, sodium triacetylborohydride (620 mg, 2.94 mmol) was added and the mixture was stirred for 16 h. After quenching with sodium bicarbonate aqueous solution, the mixture was extracted with dichloromethane, and the organic phase was concentrated and purified by silica gel chromatography to obtain tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid, with a yield of 88.5%.

[0550] ESI-MS m / z = 576.3 [M+H]+.

[0551] Step q) Synthesis of 3-(5-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-yl)piperidin-2,6-dione trifluoroacetate

[0552] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-5-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (750 mg, 1.3 mmol) was dissolved in 10 mL DCM and 3 mL TFA and stirred at room temperature for 1 h. After concentration, water was added and lyophilized to give 3-(5-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-yl)piperidin-2,6-dione trifluoroacetate in 95.5% yield.

[0553] ESI-MS m / z = 476.2 [M+H] + .

[0554] Synthesis of intermediate XIX tert-butyl(1R,5S)-3-(8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((1-((((methanesulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0555]

[0556] Following the synthetic method of step e in intermediate VI, (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphth-1-yl)-5-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was replaced with tert-butyl(1R,5S)-3-(8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, with the other procedures being the same, to obtain intermediate XIX.

[0557] ESI-MS m / z = Exact Mass: 836.2 [M+H] +

[0558] Synthesis of intermediate XX 3-(5-(1-((4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-yl)piperidin-2,6-dione trifluoroacetate

[0559]

[0560] Following the synthetic method of intermediate XVIII step p to q, 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester was replaced with 4-fluoro-4-formylpiperidin-1-carboxylic acid tert-butyl ester, and the other operations were the same, to obtain 3-(5-(1-((4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-yl)piperidin-2,6-dione trifluoroacetate.

[0561] ESI-MS m / z = 468.3 [M+H] +

[0562] Synthesis of intermediate XXI tert-butyl(1R,5S)-3-(8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((1-((((methanesulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0563]

[0564] Following the synthetic method of step e in intermediate VI, (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphth-1-yl)-5-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was replaced with tert-butyl(1R,5S)-3-(8-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, with the other procedures being the same, to obtain intermediate XXI.

[0565] ESI-MS m / z = 840.2 [M+H] +

[0566] Example 1 Synthesis of (2S,4R)-1-((2S)-2-(4-(5-((1-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0567]

[0568] Step a) Synthesis of tert-butyl 3-(3-((1-((5-(1-(S)-1-((2S,,4R)-2-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0569] Intermediate XVI (100 mg, 0.14 mmol) was dissolved in 12 mL of DMF, and TEA (37 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for 30 minutes. Intermediate VII (141 mg, 0.17 mmol) was then added, and the mixture was stirred at 36 °C. o C was reacted overnight. Then, the mixture was extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by column chromatography to give the product tert-butyl 3-(3-((1-((5-(1-(S)-1-((2S,4R)-2- ((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (80 mg, yield 48.1%)

[0570] ESI-MS m / z: 1414.6 [M+H] +

[0571] Step b) Preparation of (2S,4R)-1-((2S)-2-(4-(5-(1-(1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide formate

[0572] 80 mg, 0.06 mmol of tert-butyl 3-(3-((1-((5-(1-((S)-1-((2S,4R)-2-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (80 mg, 0.06 mmol) was dissolved in EA (1 mL), and 4 M HCl was added. EA solution (2 mL) was reacted at room temperature for 0.5 hours. The residue was concentrated and purified by Prep-HPLC to obtain the product (2S,4R)-1-((2S)-2-(4-(5-((1-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide carboxylate (yield 49.3%).

[0573] 1H NMR (400 MHz, DMSO-d6) δ 105 (d, J = 2.7 Hz, 1H), 8.78 (d, J = 6.6Hz, 1H), 8.56 (d, J = 12.3 Hz, 1H), 8.51 (d, J = 7.7 Hz, 1H), 8.42 (s, 1H),8.30 (s, 1H), 8.19 (d, J = 1.9 Hz, 1H), 8.12 (s, 1H),7.94 (s, 1H), 7.82 (dd,J = 9.1, 6.1 Hz, 1H), 7.71 (s, 1H), 7.45 - 7.32 (m, 7H), 7.18 (s, 2H), 7.11(d, J = 2.8 Hz, 1H),5.41 (d, J = 10.1 Hz, 1H), 5.23 - 5.09 (m, 1H), 4.94 (h,J = 7.3, 6.6 Hz, 2H), 4.39 (dd, J = 23.5, 10.8 Hz, 4H), 4.30 - 4.06 (m, 4H),3.87 (s, 2H), 3.80 - 3.67 (m, 2H), 2.84 (s, 2H), 2.33 (s, 6H), 2.17 - 1.87(m, 9H), 1.81 (ddd, J = 12.8, 8.5, 4.5 Hz, 2H), 1.73 - 1.49 (m, 2H), 1.39 (d,J = 6.9 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H), 0.73 (d, J = 6.5 Hz, 5H), 0.48 (t,J = 7.4 Hz, 5H)。

[0574] ESI-MS m / z: 1270.5 [M+H] +

[0575] Example 2 Synthesis of (2S,4R)-1-((2S)-2-(4-((1-((4-(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-cyano-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoroquinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (refer to Example 1)

[0576]

[0577] According to the synthesis method of steps a to b in Example 1, intermediate VII was replaced with intermediate IX, and the other operations were the same, to obtain (2S,4R)-1-((2S)-2-(4-((1-((4-(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-cyano-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoroquinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide.

[0578] 1H NMR (400 MHz, DMSO-d6) δppm 10.31(s, 1H), 8.63-8.62 (d, J = 4.4Hz, 1H), 8.54-8.52 (d, J = 7.6 Hz, 1H), 8.31-8.30 (d, J = 2.8 Hz, 1H), 8.22(s, 1H), 8.17 (s, 1H),8.04-8.01 (m,2H), 7.93-7.92(m,1H), 7.74-7.60 (m, 3H),7.53-7.29(m, 9H),7.25-7.19(m, 1H),5.37-5.33(m, 1H), 4.97-4.85(m,1H),4.44-4.28(m, 6H), 4.05-4.00 (m, 1H),3.81-3.64(s, 6H), 3.60-3.49 (m,5H),2.45-2.19 (m,8H),2.11-1.99(m, 4H), 1.40-1.38 (d, J = 7.2 Hz, 3H), 1.10-1.08 (d, J = 6.4Hz, 3H), 0.73-0.66 (m, 5H), 0.45 (s, 2H).

[0579] ESI-MS m / z = 1193.5 [M+H] +

[0580] Example 3 Synthesis of (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-cyano-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoroquinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0581]

[0582] Step a) Synthesis of 3-(6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(1-((4-((5-((triisopropylsilyl)ethynyl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0583] 3-(6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(iodomethyl)cyclopropyl)methoxyquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 0.36 mmol) and 2-(piperidin-4-yloxy)-5-((triisopropylsilyl)ethynyl)pyrazine (131 mg, 0.36 mmol) were dissolved in DMF (5 mL), followed by the addition of cesium carbonate (351.2 mg, 1.08 mmol) at 40 °C. o Stirred at C for 16 hours. The reaction system was cooled to room temperature, poured into water (20 mL), and extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and mixed with silica gel. The mixture was purified by silica gel chromatography to obtain 3-(6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-((1-((4-((5-(((triisopropylsilyl)ethynyl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (265 mg, 0.25 mmol), yield 69.7%.

[0584] ESI-MS m / z: 1057.6 [M+H] +

[0585] Step b) Synthesis of 3-(6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((1-((4-(((5-ethynylpyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0586] 3-(6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-((4-((5-(((triisopropylsilyl)ethynyl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (265 mg, 0.25 mmol) was added to DMF (3 mL), the reaction mixture was stirred, and then cesium fluoride (43 mg, 0.28 mmol) was added and stirred at 50 °C. oThe reaction was carried out at C for 2 hours. The solid was removed by filtration, and the reaction solution was poured into water. The mixture was extracted three times with EA, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-(6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((1-((4-(((5-ethynylpyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, which was used directly in the next step.

[0587] ESI-MS m / z: 901.4 [M+H] +

[0588] Step c) Synthesis of tert-butyl 3-(2-((1-((5-(1-(S)-1-((2S,4R)-2-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0589] The tert-butyl octane-8-carboxylic acid ester, sodium ascorbate (460 mg, 0.50 mmol), and copper sulfate pentahydrate (62 mg, 0.25 mmol) from the previous step were dissolved in a mixture of tetrahydrofuran (2 mL), tert-butanol (2 mL), and water (2 mL), and stirred at room temperature for 5 minutes. (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (126 mg, 0.25 mmol) was dissolved in THF (1 mL) and added dropwise to the system. The reaction was allowed to proceed at room temperature for 3 hours. The reaction was then quenched by adding water (5 mL). EA extraction, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by silica gel chromatography to give tert-butyl 3-(2-((1-((5-(1-(S)-1-((2S,4R)-2-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (259 mg, 0.19 mmol), two-step yield 74.1%.

[0590] ESI-MS m / z = 1399.6 [M+H] +

[0591] Step d) Synthesis of (2S,4R)-1-((2S)-2-(4-(5-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-cyano-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoroquinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0592] 259 mg, 0.19 mmol of tert-butyl 3-(2-((1-((5-(1-(S)-1-((2S,4R)-2-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-cyano-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 1 mL of EA, and HCl EA solution (1) was added. The mixture was stirred at room temperature for 1 h at 4 M (mL). The crude product obtained by concentration under reduced pressure was purified by Prep-HPLC to (2S,4R)-1-((2S)-2-(4-(5-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-cyano-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoroquinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide carboxylate (53 mg, 0.04 mmol, yield 22.1%).

[0593] 1H NMR (400 MHz, MeOD-d4) δ 8.76 (s, 1H), 8.56 (t, J = 8.6 Hz, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 7.83 (s, 1H), 7.75 - 7.66 (m, 2H), 7.41 (s, 2H),7.38-7.33 (m, 2H), 7.28 (t, J = 9.4 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.00(s, 1H), 5.42 (dd, J = 10.2, 5.2 Hz, 2H), 5.06 (q, J = 6.7 Hz,1H), 4.77 -4.64 (m, 3H), 4.55 - 4.47 (m, 6H), 4.17 (s, 2H), 3.99 - 3.84 (m, 4H), 3.66-3.52 (m, 2H), 3.48 (p, J = 1.6 Hz, 1H), 3.13 (p, J = 1.6 Hz, 1H), 2.88 (s,1H), 2.65(m,1H) 2.50 (m, 2H), 2.33 (d, J = 1.8 Hz, 1H), 2.21 (d, J = 9.7 Hz,3H), 2.11 (s, 4H), 2.06 - 1.94 (m, 2H), 1.83 (s, 1H), 1.68 (d, J = 7.0 Hz,1H), 1.54 (dd, J = 6.8, 1.9 Hz, 3H), 1.29 (m,1H), 1.17 (d, J = 6.4 Hz, 3H), 0.97 (s, 2H), 0.85-0.82 (m, 6H).

[0594] ESI-MS m / z = 1255.5 [M+H] + .

[0595] Example 4 Synthesis of 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((2-(4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-6-nitrile

[0596]

[0597] Step a) Synthesis of 4-bromo-7-chloroisoquinoline-1-ol

[0598] 7-Chloroisoquinoline-1-ol (3.0 g, 16.8 mmol) and NBS (4.5 g, 25 mmol) were dissolved in 30 mL of ACN under nitrogen protection and heated to reflux for 2 h. The mixture was then filtered at room temperature, and the filter cake was washed three times with acetonitrile. The filter cake was collected and concentrated under vacuum to give 4-bromo-7-chloroisoquinoline-1-ol in 80.3% yield.

[0599] 1 HNMR(400MHz, CDCl3) δ ppm 7.46(s, 1H), 7.81 (dd, J=8.4, 2.0 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.27(d, J=2.00 Hz, 1H).

[0600] ESI-MS m / z: 257.9 [M+H] +

[0601] Step b) Synthesis of 4-(2,6-bis(benzyloxy)pyridin-3-yl)-7-chloroisoquinoline-1-ol

[0602] 4-Bromo-7-chloroisoquinoline-1-ol (3.5 g, 13.6 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (6.8 g, 16 mmol), cesium carbonate (8.8 g, 27 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (586 mg, 0.81 mmol) were dissolved in 1,4-dioxane (15 mL), and water (3 mL) was added. The mixture was then microwaved under nitrogen protection for 100 minutes. o The reaction was carried out at C for 45 minutes. The mixture was cooled to room temperature, extracted with water and EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 4-(2,6-bis(benzyloxy)pyridin-3-yl)-7-chloroisoquinoline-1-ol in 55.5%.

[0603] ESI-MS m / z: 469.1 [M+H] +

[0604] Step c) Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-hydroxyisoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0605] 4-(2,6-bis(benzyloxy)pyridin-3-yl)-7-chloroisoquinoline-1-ol (3.5 g, 7.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.8 g, 9.0 mmol), cesium carbonate (4.9 g, 15 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (275 mg, 0.41 mmol) were dissolved in 1,4-dioxane (15 mL) and water (3 mL) and microwaved at 120 °C under nitrogen protection. o The reaction was carried out at C for 2 hours. Then, the mixture was extracted with EA and water, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-hydroxyisoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, yield 48.0%.

[0606] ESI-MS m / z: 616.3 [M+H] +

[0607] Step d) Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-(((trifluoromethyl)sulfonyl)oxy)isoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0608] 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-hydroxyisoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.0 g, 3.62 mmol) and triethylamine (1.2 g, 10.8 mmol) were dissolved in dichloromethane (20 mL), and trifluoromethanesulfonic anhydride (1.5 g, 5.41 mmol) was added under an ice-water bath. The mixture was stirred under an ice bath for 1 hour. Quenching with saturated sodium bicarbonate solution (30 mL), extraction with dichloromethane, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, purifying the residue by silica gel chromatography, and concentrating the eluent to give 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-(((trifluoromethyl)sulfonyl)oxy)isoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, yield 69.5%.

[0609] ESI-MS m / z: 748.2 [M+H] +

[0610] Step e) Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methylisoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0611] 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-(((trifluoromethyl)sulfonyl)oxy)isoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.9 g, 2.5 mmol), tetramethyltin (895 mg, 5.02 mmol), lithium chloride (1.1 g, 25 mmol), and Pd(PPh3)4 (350 mg, 0.32 mmol) were dissolved in 1,4-dioxane (15 mL) and microwaved for 100 °C under nitrogen protection. o React at C for 2 hours. Cool to room temperature, extract with water and EA, combine organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel chromatography to give 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methylisoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, yield 48.0%.

[0612] ESI-MS m / z: 614.3 [M+H] +

[0613] Step f) Synthesis of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidine-1-carboxylic acid

[0614] 737 mg (1.22 mmol) of 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methylisoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, in 10% palladium on carbon (70 mg), was suspended in EA (10 mL) and anhydrous ethanol (10 mL) and reacted in hydrogen at room temperature for 16 h. The reaction solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 22.0% (4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-carboxylic acid tert-butyl ester).

[0615] ESI-MS m / z = 438.2 [M+H] +

[0616] Step g) Synthesis of 3-(1-methyl-7-(piperidin-4-yl)isoquinoline-4-yl)piperidin-2,6-dione hydrochloride

[0617] 116 mg (0.26 mmol) of 4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-carboxylic acid tert-butyl ester was added to 2 mL of 4 M HCl EA solution and reacted at room temperature for 0.5 h. The solvent was then concentrated, and the crude product was used directly in the next step.

[0618] ESI-MS m / z: 338.2 [M+H] +

[0619] Step h) Synthesis of tert-butyl 2-(4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid

[0620] The crude product from the previous step, acetic acid (0.1 mL), and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (86 mg, 360 μmol) were dissolved in DMA (4 mL) and reacted at 50 °C for 4 hours. Sodium cyanoborohydride (45.2 mg, 720 μmol) was added under ice bath, and the reaction was carried out overnight at room temperature. The mixture was extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give tert-butyl 2-(4-(4-(2,6-dioxopiridin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid, with a two-step yield of 64.6%.

[0621] ESI-MS m / z: 561.3 [M+H] +

[0622] Step i) Synthesis of 3-(7-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methylisoquinoline-4-yl)piperidin-2,6-dione hydrochloride

[0623] 2-(4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (88.2 mg, 156 μmol) was added to 4M HCl EA solution (2 mL) and reacted at room temperature for 0.5 h. The solvent was concentrated to obtain 3-(7-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methylisoquinoline-4-yl)piperidin-2,6-dione hydrochloride, which was used directly in the next step.

[0624] ESI-MS m / z: 461.3 [M+H] +

[0625] Step j) Synthesis of 3-(6-cyano-2-((1-((2-(4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0626] 3-(7-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methylisoquinoline-4-yl)piperidin-2,6-dione hydrochloride (20 mg, 43 μmol) was dissolved in 2 mL of acetonitrile, and triethylamine (0.1 mL, 430 μmol) and intermediate IX (35 mg, 43 μmol) were added. The mixture was then incubated under nitrogen protection at 40 °C. o The reaction was carried out at C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 3-(6-cyano-2-((1-((2-(4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 44.9%.

[0627] ESI-MS m / z = 1154.6 [M+H] +

[0628] Step k) 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((2-(4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-6-nitrile carboxylate

[0629] 3-(6-cyano-2-((1-((2-(4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (22 mg, 24 μmol) was added to HCl EA solution (2 mL, 4 M) and reacted at room temperature for 0.5 h. The residue was concentrated under reduced pressure, and the residue was subjected to Prep-HPLC to give 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((2-(4-(4-(2,6-dioxopiperidin-3-yl)-1-methylisoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-6-nitrile carboxylate in 26.8% yield.

[0630] 1 HNMR(400MHz, Methanol-d4) δ ppm 8.37 (s, 1H), 8.25 (s, 2H), 8.20 (s,1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.79 (dd, J = 9.2, 5.6 Hz, 1H), 7.27 (d, J =10 Hz, 2H), 7.07 (s, 1H), 4.53 - 4.33 (m, 3H), 4.19 (s, 3H), 4.10 - 3.90 (m,3H), 3.82 - 3.71 (m, 3H), 3.61 - 3.50 (m, 8H), 3.49 - 3.43 (m, 2H), 3.41 -3.34 (m, 2H), 3.15 (s, 4H), 2.85 - 2.19 (m, 9H), 2.11 - 1.98 (m, 6H), 1.25 -1.10 (m, 2H), 1.05 -0.88 (m, 2H), 0.86 - 0.81 (m, 2H).

[0631] ESI-MS m / z = 10¹⁰.⁵ [M+H] +

[0632] Example 5 Synthesis of (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((S)-1-(4-(4-cyano-3-methylthiophene-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0633]

[0634] Step a) Synthesis of tert-butyl (S)-(1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamate

[0635] 5-Bromo-4-methylthiophene-3-onitrile (5.0 g, 25 mmol), (S)-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)ethyl)carbamate tert-butyl ester (10.4 g, 303 mmol), cesium carbonate (16.3 g, 506 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (540 mg, 0.82 mmol) were dissolved in 1,4-dioxane (50 mL) and water (10 mL) under nitrogen protection and reacted at 120 °C for 2 h. The mixture was extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give (S)-(1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamate tert-butyl ester, yield 78.0%.

[0636] ESI-MS m / z: 343.1 [M+H] +

[0637] Step b) Synthesis of (S)-5-(4-(1-aminoethyl)phenyl)-4-methylthiophene-3-nitrile hydrochloride

[0638] (S)-(1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamate tert-butyl ester (6.7 g, 19.52 mmol) was added to 20 mL of 4 M HCl EA solution and reacted at room temperature for 0.5 h. The solvent was then concentrated to obtain crude (S)-5-(4-(1-aminoethyl)phenyl)-4-methylthiophen-3-nitrile hydrochloride.

[0639] ESI-MS m / z: 243.1 [M+H] +

[0640] Step c) (2S,4R)-2-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0641] The crude product from the previous step and (2S,4R)-1-(tert-butyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.4 g, 23 mmol) were dissolved in DMF (100 mL), and HATU (5.1 g, 13 mmol) and DIEA (15 mL, 97 mmol) were added. The reaction was carried out for 30 minutes. The mixture was extracted with water and EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to obtain (2S,4R)-2-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, with a two-step yield of 64.0%.

[0642] ESI-MS m / z: 456.2 [M+H] +

[0643] Step d) Synthesis of (2S,4R)-N-(S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride

[0644] (2S,4R)-2-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (6.8 g, 15 mmol) was added to 20 mL of 4 M HCl EA solution and reacted at room temperature for 0.5 h. The solvent was concentrated to obtain crude (2S,4R)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride, which was used directly in the next step.

[0645] ESI-MS m / z: 356.1 [M+H] +

[0646] Step e) Synthesis of tert-butyl carbamate ((S)-1-((2S,4R)-2-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutyl-2-yl) ester

[0647] The crude product from the previous step and (tert-butyloxycarbonyl)-L-valine (3.9 g, 18 mmol) were dissolved in DMF (100 mL), and HATU (6.8 g, 18 mmol) and DIEA (15 mL, 98 mmol) were added. The reaction was carried out for 30 minutes. The mixture was extracted with water and EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to obtain tert-butyl carbamate ((S)-1-((2S,4R)-2-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutyl-2-yl) ester, with a two-step yield of 62.5%.

[0648] ESI-MS m / z: 555.3 [M+H] +

[0649] Step f) Synthesis of (2S,4R)-1-(L-valine)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride

[0650] Tert-butyl carbamate ((S)-1-((2S,4R)-2-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutyl-2-yl) ester (5.2 g, 9.43 mmol) was added to 20 mL of 4 M HCl EA solution and reacted at room temperature for 0.5 h. The solvent was concentrated to obtain (2S,4R)-1-(L-valine)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride, which was used directly in the next step.

[0651] ESI-MS m / z: 455.2 [M+H] +

[0652] Step g) Synthesis of (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0653] (2S,4R)-1-(L-valine)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (4.3 g, 9.4 mmol) was dissolved in THF (40 mL) and ACN (40 mL) under nitrogen protection at 0°C. o Add TEA (7.5 mL, 47 mmol) and anhydrous copper sulfate (225 mg, 0.92 mmol) to the reaction mixture. Add a solution of 2-azido-1,3-dimethylimidazolium hexafluorophosphate (3.9 g, 14 mmol) in ACN (40 mL) dropwise to the above reaction mixture over 30 minutes. o React at C for 2 hours. Extract with water and EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate to obtain crude product, and purify by silica gel chromatography to obtain (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide, yield 51.8%.

[0654] ESI-MS m / z: 481.2 [M+H] +

[0655] Step h) Synthesis of tert-butyl 4-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid

[0656] (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (2.3 g, 4.9 mmol) was dissolved in tetrahydrofuran (40 mL), tert-butanol (40 mL), and water (40 mL). Copper sulfate pentahydrate (125 mg, 0.51 mmol) and sodium ascorbate (1.9 g, 9.8 mmol) were added under nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. Then, tert-butyl 4-((5-ethynylpyrazin-2-yl)oxy)piperidine-1-carboxylate (1.5 g, 4.9 mmol) was added, and the mixture was reacted at room temperature for 2 h. Extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give tert-butyl 4-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)carbamoyl)-4-hydroxypyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylate, in 43.8% yield.

[0657] ESI-MS m / z: 784.4 [M+H] +

[0658] Step i) Synthesis of (2S,4R)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide hydrochloride

[0659] 1.7 g (2.1 mmol) of 4-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)carbamoyl)-4-hydroxypyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester was added to HCl EA solution (20 mL, 4 M) and reacted at room temperature for 0.5 h. The solvent was concentrated to obtain (2S,4R)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide hydrochloride, which can be used directly in the next step.

[0660] ESI-MS m / z: 684.3 [M+H] +

[0661] Step j) Synthesis of tert-butyl(1R,5S)-3-(3-(1-(4-(5-(1-(((S)-1-((2S,4R)-2-(((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0662] (2S,4R)-N-((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide hydrochloride (30 mg, 43 μmol), TEA (0.1 mL, 430 μmol), and intermediate VI (35 mg, 43 μmol) were dissolved in 4 mL of acetonitrile and dissolved under nitrogen protection at 40 °C. o The reaction was carried out at C for 16 h. The mixture was concentrated under reduced pressure and purified by silica gel chromatography to give tert-butyl(1R,5S)-3-(3-(1-(4-(5-(1-(((S)-1-((2S,4R)-2-(((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, in 45% yield.

[0663] ESI-MS m / z = 1392.6 [M+H] +

[0664] Step k) Synthesis of (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((S)-1-(4-(4-cyano-3-methylthiophene-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide formate

[0665] 22.5 mg, 16.15 μmol of tert-butyl(1R,5S)-3-(3-(1-(4-(5-(1-(((S)-1-((2S,4R)-2-(((S)-1-(4-(4-cyano-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (22.5 mg, 16.15 μmol) was added to 4M HCl EA solution (2 The reaction was carried out in mL at room temperature for 0.5 h. The residue was concentrated under reduced pressure, and the residue was subjected to Prep-HPLC to give (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((S)-1-(4-(4-cyano-3-methylthiophene-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide carboxylate, in 30.8% yield.

[0666] 1H NMR (400 MHz, Methanol-d4) δ 8.71 (s, 1H), 8.58 (d, J = 7.4 Hz,1H), 8.48 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H),7.40 - 7.08 (m, 8H), 5.34 (d, J = 11.0 Hz, 1H), 5.02 - 4.91 (m, 1H), 4.2 -4.51 (m, 4H), 4.48 - 4.25 (m, 4H), 4.11 (d, J = 8.4 Hz, 2H), 3.92 - 3.62 (m,7H), 3.52 - 3.32 (m, 4H), 3.11 (s, 1H), 2.86 (s, 1H), 2.54 (s, 1H), 2.37 (s,1H), 2.25 - 1.79 (m, 8H), 1.44 (d, J = 7.0 Hz, 2H), 1.20 (s, 1H), 1.08 (d, J= 6.2 Hz, 3H), 0.94 (s, 2H), 0.89 - 0.70 (m, 6H).

[0667] ESI-MS m / z = 1248.5 [M+H] +

[0668] Example 6 Synthesis of (2S,4R)-1-((2S)-2-(4-(5-((1-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0669]

[0670] Step a) Synthesis of 3-(3-((1-((4-((5-(1-((S)-1-((2S,4R)-2-(((R)-1-(4-(4-carbamoyl-3-methylthiophene-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0671] Intermediate XIV (141 mg, 0.17 mmol) was dissolved in 12 mL of DMF, and TEA (37 mg, 0.36 mmol) and intermediate VII (100 mg, 0.14 mmol) were added. The mixture was then incubated at 36 °C. o C was reacted overnight. Extraction was performed with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by silica gel chromatography to give 3-(3-((1-((4-(((5-(1-((S)-1-((2S,4R)-2-(((R)-1-(4-(4-carbamoyl-3-methylthiophene-2-yl)phenyl)-2-hydroxyethyl)carbamoyl) -4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80 mg, yield 49.3%)

[0672] ESI-MS m / z: 1430.6 [M+H] +

[0673] Step b) (2S,4R)-1-((2S)-2-(4-(5-((1-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide carboxylate

[0674] 3-(3-((1-((4-((5-(1-((S)-1-((2S,4R)-2-(((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80 mg, 0.05 mmol) was dissolved in EA (1 Add 2 mL of 4M HClEA solution to the mixture and react at room temperature for 0.5 hours. The residue was concentrated and purified by Prep-HPLC to give the product (2S,4R)-1-((2S)-2-(4-(5-((1-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide carboxylate, in 42.3% yield.

[0675] 1H NMR (400 MHz, Methanol-d4) δ 8.79 (s, 1H), 8.61 (d, J = 10 Hz, 1H),8.43 (s, 1H),8.28 (s, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.85 (d, J = 3.0 Hz,1H), 7.73 (dd, J = 9.0, 5.9 Hz, 1H), 7.51 - 7.41 (m, 4H), 7.36 (d, J = 2.6Hz, 1H), 7.33 - 7.23 (m, 2H), 7.07 (d, J = 2.6 Hz, 1H), 5.46 (d, J = 10 Hz,2H), 5.17 - 4.98 (m, 1H), 4.62 (t, J = 8.3 Hz, 2H), 4.60 - 4.56 (m, 2H), 4.53(s, 2H), 4.42 (d, J = 14.8 Hz, 1H), 4.22 (d, J = 22.6 Hz, 2H), 4.03 (s, 1H),3.97 (dd, J = 11.0, 3.8 Hz, 2H), 3.93 (s, 1H), 3.87 (d, J = 6.1 Hz, 2H), 3.80(d, J = 12.7 Hz, 1H), 3.69 - 3.56 (m, 1H), 3.53 - 3.47 (m, 1H), 3.43 (d, J =5.6 Hz, 2H), 2.75 - 2.59 (m, 1H), 2.57 - 2.41 (m, 2H), 2.37 (d, J = 7.4 Hz,4H), 2.27 (dd, J = 13.0, 7.3 Hz, 3H), 2.23 - 2.10 (m, 4H), 2.05 (ddd, J =13.4, 9.1, 4.6 Hz, 1H), 1.19 (d, J = 6.5 Hz, 4H), 1.05 (s, 2H), 0.94 (s, 2H),0.86 (dd, J = 6.8, 2.5 Hz, 3H), 0.57 (t, J = 7.4 Hz, 3H)。

[0676] ESI-MS m / z: 1286.5 [M+H] +

[0677] Example 7 Synthesis of (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((R)-1-(4-(4-carbamoyl-3-methyl)thiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0678]

[0679] Step a) Synthesis of tert-butyl(1R,5S)-3-(3-(1-(4-(5-(1-(((S)-1-((2S,4R)-2-(((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0680] Intermediate XIV (63 mg, 0.08 mmol) was dissolved in 2 mL of DMF, and TEA (23 mg, 0.23 mmol) and intermediate VI (64 mg, 0.08 mmol) were added. The mixture was then incubated under nitrogen protection at 30 °C. o React at C overnight. Extract with water and EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by silica gel chromatography to give tert-butyl(1R,5S)-3-(3-(1-(4-(5-(1-(((S)-1-((2S,4R)-2-(((R)-1-(4-(4-carbamoyl-3-methylthiophene-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine- 1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (43 mg, 0.03 mmol), yield 40.9%.

[0681] ESI-MS m / z = 1426.6 [M+H] +

[0682] Step b) Synthesis of (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((R)-1-(4-(4-carbamoyl-3-methyl)thiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide formate

[0683] 43 mg, 0.03 mg of tert-butyl(1R,5S)-3-(3-(1-(4-(5-(1-(((S)-1-((2S,4R)-2-(((R)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester ( Dissolve 1 mmol) in acetonitrile (1 mL), add 4 M HCl EA solution (1 mL) under ice bath, and react at room temperature for 2 h. The crude product was concentrated under reduced pressure and purified by Prep-HPLC to obtain (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(((R)-1-(4-(4-carbamoyl-3-methyl)thiophen-2-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide formate (10 mg, 0.01 mmol), yield 26.6%.

[0684] 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.75 (d, J = 1.6 Hz, 1H),8.55 (s, 1H), 8.53 - 8.45 (m, 1H), 8.38 (s, 1H),8.28 (d, J = 1.6 Hz, 1H),8.07 (d, J = 1.6 Hz, 1H), 8.01 (dd, J = 9.2, 5.6 Hz, 1H), 7.93 (s, 1H), 7.70(s, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.45 - 7.39 (m, 3H), 7.37 (s, 4H), 7.24(d, J = 2.4 Hz, 1H), 7.17 (d, J = 13.6 Hz, 2H), 5.40 (d, J = 10 Hz, 1H), 5.16(s, 1H), 5.02 (s, 1H), 4.89 - 4.82 (m, 2H), 4.46 (t, J = 8.0 Hz, 1H), 4.33(s, 3H), 4.06 (dd, J = 44.0, 12.0 Hz, 2H), 3.82 - 3.74 (m, 1H), 3.69 (d, J =11.2 Hz, 1H), 3.61 (s, 3H), 3.47 (s, 1H), 2.83 (s, 2H), 2.67 (q, J = 1.6 Hz,2H), 2.38 (d, J = 6.4 Hz, 2H), 2.33 (s, 2H), 2.27 (s, 2H), 2.08 (t, J = 10.6Hz, 1H), 1.99 (s, 2H), 1.80 (t, J = 13.2 Hz, 2H), 1.67 (s, 4H), 1.08 (d, J =6.4 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H), 0.67 (s, 2H), 0.44 (s, 4H)。

[0685] ESI-MS m / z = 1282.5[M+H] +

[0686] Example 8 Synthesis of 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((2-(4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-6-nitrile

[0687]

[0688] Step a) Synthesis of tert-butyl 4-(3-chloroisoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0689] 7-Bromo-3-chloroisoquinoline (3.0 g, 12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (4.6 g, 15 mmol), cesium carbonate (8.1 g, 25 mmol), and Pd(dppf)Cl2 (878 mg, 1.23 mmol) were dissolved in 1,4-dioxane and water (15 mL / 3 mL), and the mixture was heated to 100°C under nitrogen protection using a microwave oven. o C, react for 2 hours. Extract with water and EA at room temperature, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel chromatography to give tert-butyl 4-(3-chloroisoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid, yield 58.0%.

[0690] ESI-MS m / z: 345.1 [M+H] +

[0691] Step b) Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)isoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0692] 4-(3-chloroisoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.5 g, 7.2 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (3.6 g, 8.6 mmol), cesium carbonate (4.7 g, 14 mmol), and Pd(dppf)Cl2 (586 mg, 0.81 mmol) were dissolved in 1,4-dioxane and water (15 mL / 3 mL), and the mixture was microwaved to 120°C under nitrogen protection. oThe reaction was carried out at C for 2 h. Water and EA were added at room temperature for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)isoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid, in 65.5% yield.

[0693] ESI-MS m / z: 600.3 [M+H] +

[0694] Step c) Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidine-1-carboxylic acid

[0695] 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)isoquinoline-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.8 g, 4.71 mmol) and 10% palladium on carbon (200 mg) were dispersed in EA (10 mL) and anhydrous ethanol (10 mL). After three hydrogen purgings, the reaction was carried out at room temperature for 16 h. The filtrate was concentrated after filtration, and the residue was purified by silica gel chromatography to give 4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-carboxylic acid tert-butyl ester, yield 28.0%.

[0696] ESI-MS m / z: 424.2 [M+H] +

[0697] Step d) Synthesis of 3-(7-(piperidin-4-yl)isoquinoline-3-yl)piperidin-2,6-dione hydrochloride

[0698] 4-(3-(2,6-dioxadiazin-3-yl)isoquinoline-7-yl)piperidine-1-carboxylic acid tert-butyl ester (558 mg, 1.31 mmol) was dissolved in 10 mL of 4 M HCl EA solution and reacted at room temperature for 0.5 h. The solution was then concentrated to obtain crude 3-(7-(piperidine-4-yl)isoquinoline-3-yl)piperidine-2,6-dione hydrochloride.

[0699] ESI-MS m / z: 324.2 [M+H] +

[0700] Step e) Synthesis of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid

[0701] The crude product from the previous step, 0.1 mL of acetic acid, and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (86 mg, 360 μmol) were dissolved in 4 mL of DMA and reacted at 50 °C for 4 hours. Sodium cyanoborohydride (45 mg, 720 μmol) was added under ice bath, and the reaction was carried out overnight at room temperature. The mixture was extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid, with a two-step yield of 62.2%.

[0702] ESI-MS m / z: 547.3 [M+H] +

[0703] Step f) Synthesis of 3-(7-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)isoquinoline-3-yl)piperidin-2,6-dione hydrochloride

[0704] 105 mg (192 μmol) of 2-(4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester was dissolved in 4 M HCl EA solution (4 mL) and reacted at room temperature for half an hour. The solution was concentrated to obtain 3-(7-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)isoquinoline-3-yl)piperidin-2,6-dione hydrochloride, which was used directly in the next step.

[0705] ESI-MS m / z: 447.3 [M+H] +

[0706] Step g) Synthesis of 3-(6-cyano-2-(1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxytert-butyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoroquinazolino-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0707] The crude product from the previous step was dissolved in 5 mL of acetonitrile, and TEA (0.1 mL, 671 μmol) and intermediate IX (55 mg, 67 μmol) were added. Under nitrogen protection, the solution was incubated at 40 °C. oThe reaction was carried out at C for 16 h. After concentration under reduced pressure, the product was purified by silica gel column chromatography to obtain 3-(6-cyano-2-(1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxytert-butyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, with a two-step yield of 38.5%.

[0708] ESI-MS m / z = 1140.5 [M+H] +

[0709] Step h) Synthesis of 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((2-(4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-6-nitrile carbamate

[0710] 3-(6-cyano-2-(1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxytert-butyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (26 mg, 23 μmol) was dissolved in 3 mL of 4 M HCl EA solution and reacted at room temperature for 0.5 h. After concentration under reduced pressure, the product was purified by Prep-HPLC to obtain 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((2-(4-(3-(2,6-dioxopiperidin-3-yl)isoquinoline-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-6-nitrile carboxylate in 22.5% yield.

[0711] 1H NMR (400 MHz, Methanol-d4) δ 9.57 (s, 1H), 8.31 - 8.16 (m, 3H), 8.20 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.79 (dd, J= 9.2, 5.6 Hz, 1H), 7.32 - 7.20 (m, 2H), 7.06 (d, J = 2.5 Hz, 1H), 4.59 (d, J= 7.2 Hz, 2H), 4.48 - 4.32 (m, 5H), 4.19 (d, J = 9.8 Hz, 2H), 3.95 (d, J =9.2 Hz, 1H), 3.82 (d, J = 6.8 Hz, 1H), 3.69 (s, 3H), 3.54 (s, 3H), 3.39 (s,1H), 3.12 - 2.84 (m, 5H), 2.75 (s, 2H), 2.46 (dt, J = 8.2, 6.4 Hz, 2H), 2.36-1.84 (m, 9H), 1.71-1.40 (m, 5H), 0.98-0.71 (m, 5H).

[0712] ESI-MS m / z = 996.5 [M+H] +

[0713] Example 9 Synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(1-((2-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-6-nitrile

[0714]

[0715] Step a) Synthesis of compound 4-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromoquinazoline

[0716] 7-Bromo-4-chloroquinazoline (3.0 g, 12.3 mmol) was dissolved in 1,4-dioxane / water (30 mL / 5 mL), and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (5.1 g, 12 mmol), cesium carbonate (5.2 g, 16 mmol), and Pd(dppf)Cl2 (901 mg, 1.23 mmol) were added. The reaction was carried out at 90 °C for 2 h under nitrogen protection. After cooling to room temperature, the product was concentrated and purified by silica gel column chromatography to obtain the product 4-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromoquinazoline, yield: 68.4%.

[0717] ESI-MS m / z: 498.1 [M+H] +

[0718] Step b) Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)quinazolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0719] 4-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromoquinazoline (3.2 g, 6.4 mmol) was dissolved in 1,4-dioxane (30 mL) and water (5 mL), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.4 g, 7.7 mmol), cesium carbonate (3.1 g, 9.6 mmol) and Pd(dppf)Cl2 (470 mg, 0.64 mmol) were added. The reaction was carried out at 90 °C for 2 h under nitrogen protection. The solvent was concentrated and purified by silica gel column chromatography to obtain the product 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)quinazolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, yield: 80.4%.

[0720] ESI-MS m / z: 601.3 [M+H] +

[0721] Step c) Synthesis of compound 4-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidine-1-carboxylic acid tert-butyl ester

[0722] 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)quinazolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.8 g, 4.7 mmol) was dissolved in 30 mL THF, and ammonium acetate (647 mg, 8.4 mmol) and palladium on carbon (496 mg, 10%) were added.o The reaction was carried out at C for 4 h. After cooling to room temperature, the product was filtered through palladium on carbon, concentrated, and purified by silica gel column chromatography to obtain tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidine-1-carboxylic acid. Yield: 40.4%.

[0723] ESI-MS m / z: 425.2 [M+H] +

[0724] Step d) Synthesis of 3-(7-(piperidin-4-yl)quinazolin-4-yl)piperidin-2,6-dione

[0725] 4-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (800 mg, 1.88 mmol) was dissolved in DCM (10 mL), and TFA (3 mL, 9.40 mmol) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was concentrated to obtain a solid product, which was used directly in the next step.

[0726] ESI-MS m / z: 325.2 [M+H] +

[0727] Step e) Synthesis of compound 2-(4-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0728] The crude product from the previous step was dissolved in 15 mL of DMF, and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid was added (481 mg, 2.0 mmol) and two drops of acetic acid. The mixture was stirred overnight at room temperature under nitrogen protection, and then sodium triacetoxyborohydride (598 mg, 2.8 mmol) was added. The reaction was carried out at room temperature for 2 h. The mixture was extracted with water and EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the product tert-butyl 2-(4-(4-(2,6-dioxopiridin-3-yl)quinazolin-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid. The two-step yield was 54.3%.

[0729] ESI-MS m / z: 548.3 [M+H] +

[0730] Step f) Synthesis of compound 3-(7-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)quinazolin-4-yl)piperidin-2,6-dione

[0731] 380 mg (0.69 mmol) of tert-butyl 2-(4-(4-(2,6-dioxadipinidin-3-yl)quinazolin-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid was dissolved in DCM (12 mL), and TFA (0.4 mL, 3.45 mmol) was added. The reaction was carried out at room temperature for 0.5 hours. The crude solid 3-(7-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)quinazolin-4-yl)piperidin-2,6-dione was obtained with a yield of 90.2%.

[0732] ESI-MS m / z: 448.3 [M+H] +

[0733] Step g) Synthesis of tert-butyl(1R,5S)-3-(6-cyano-2-(1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0734] 3-(7-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)quinazolin-4-yl)piperidin-2,6-dione (76 mg, 0.17 mmol) was dissolved in 12 mL of DMF, and intermediate IX (140 mg, 0.17 mmol) and TEA (52 mg, 0.51 mmol) were added. The solution was then heated at 35 °C. o The reaction was carried out overnight at C. Water and EA were added for extraction, followed by washing with saturated brine, drying with anhydrous sodium sulfate, filtration, concentration, and purification by silica gel column chromatography to give tert-butyl(1R,5S)-3-(6-cyano-2-(1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, yield 41.1%.

[0735] ESI-MS m / z: 1141.5 [M+H] +

[0736] Step h) Synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(1-((2-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-6-nitrile carbamate

[0737] 80 mg, 0.07 mmol of tert-butyl(1R,5S)-3-(6-cyano-2-(1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (80 mg, 0.07 mmol) was dissolved in 2 mL of EA, and 2 mL of HCl EA solution (4 M) was added. The reaction was carried out at room temperature for 0.5 h. The concentrated residue was purified by Prep-HPLC to obtain the product 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(1-((2-(4-(2,6-dioxopiperidin-3-yl)quinazolin-7-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-6-nitrile carboxylate, with a yield of 49.3%.

[0738] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.32 (s, 1H),9.18 (s, 1H),8.36 - 8.24 (m, 2H),8.18 - 8.15 (m, 1H), 8.10 (s, 1H),8.02 (dd, J = 9.2, 5.9Hz, 1H), 7.84 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.45 (d, J = 2.6 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 5.09 (dd, J = 9.8, 5.2Hz, 1H), 4.36 (d, J = 12.2 Hz, 2H), 4.32 - 4.22 (m, 2H), 4.00 (s, 1H), 3.64 (d, J = 17.5 Hz, 4H), 3.03 - 2.86 (m, 2H), 2.78 (d, J = 11.0 Hz, 1H), 2.75 -2.65 (m, 2H), 2.63 - 2.56 (m, 1H), 2.45 - 2.16 (m, 8H), 1.98 - 1.60 (m, 12H), 1.59 - 1.37 (m, 6H), 0.64 (s, 2H), 0.41 (s, 2H).

[0739] ESI-MS m / z: 997.5 [M+H] +

[0740] Example 10 Synthesis of 3-(6-(1-(7-[(1-{[(1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofuran[3,2-f]quinazolin-3-yl)oxy]methyl}cyclopropyl)methyl]-7-azaspiro[3.5]nonane-2-yl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione

[0741]

[0742] Step a) Synthesis of 6-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine

[0743] 6-Chloro-1H-pyrrolo[2,3-b]pyridine (2.0 g, 13 mmol) was dissolved in 12 mL DMF, and NIS (3.2 g, 14 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was extracted with water and EA, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography to obtain 6-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine in 49.3% yield.

[0744] ESI-MS m / z = 278.9 [M+H] +

[0745] Step b) Synthesis of 6-chloro-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0746] 1.7 g (6.1 mmol) of 6-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine was added to a reaction flask containing 15 mL of DMF. NaH (0.4 g, 9.15 mmol) was added in portions at 0 °C, and the mixture was stirred in an ice bath for 30 minutes. Iodomethane (1.3 g, 9.2 mmol) was added, and the reaction mixture was allowed to return to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated ammonium chloride, extracted with EA, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography to obtain 6-chloro-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine in 89.6% yield.

[0747] ESI-MS m / z = 292.9 [M+H] +

[0748] Step c) Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0749] 6-Chloro-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (1.5 g, 5.13 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (2.1 g, 5.13 mmol), Pd(dppf)Cl2 (0.2 g, 0.26 mmol), and cesium carbonate (3.3 g, 10 mmol) were added to a reaction flask containing 1,4-dioxane (15 mL) and water (3 mL). The reaction system was heated to 80°C. oStirred at C for 12 hours. The reaction system was concentrated, and the residue was purified by silica gel chromatography to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine, in 51.3% yield.

[0750] ESI-MS m / z = 456.1 [M+H] +

[0751] Step d) Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0752] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine (1.1 g, 2.4 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.90 g, 2.8 mmol), (A-taPhos)2PdCl2 (0.2 g, 0.24 mmol), and cesium carbonate (1.5 g, 4.7 mmol) were added to a reaction flask containing 1,4-dioxane (10 mL) and water (2 mL). The reaction system was heated to 90°C. o Stirred at C for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel chromatography to give tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid, in 84.1% yield.

[0753] ESI-MS m / z = 603.3 [M+H] +

[0754] Step e) Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidine-1-carboxylate

[0755] 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.2 g, 1.9 mmol), ammonium formate (3.6 g, 57.31 mmol), and palladium on carbon (813 mg, 10%) were added to ethanol (15 mL) and heated to 80°C. oStirred at C for 48 hours. Filter the reaction solution with diatomaceous earth, concentrate the filtrate with silica gel, and purify the residue by silica gel chromatography to obtain tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-carboxylate, yield 36.9%.

[0756] ESI-MS m / z = 427.2 [M+H] +

[0757] Step f) Synthesis of 3-(1-methyl-6-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione

[0758] 300 mg (0.70 mmol) of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-carboxylic acid was added to a reaction flask containing 3 mL of DCM. Trifluoroacetic acid (1 mL) was added under ice bath conditions, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give 3-(1-methyl-6-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione, in 78.4% yield.

[0759] ESI-MS m / z = 327.2 [M+H] +

[0760] Step g) Synthesis of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid

[0761] 3-(1-methyl-6-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione (180 mg, 0.55 mmol), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (0.3 g, 1.1 mmol), and acetic acid (21 mg, 0.35 mmol) were added to DMA (4 mL) and heated at 50 °C. o Stir at C for 2 hours. Then at 0... oSodium cyanoborohydride (63 mg, 1.0 mmol) was added to C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was extracted with water and EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography to obtain tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid, in 65.9% yield.

[0762] ESI-MS m / z = 550.3 [M+H] +

[0763] Step h) Synthesis of 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione

[0764] 80 mg (0.15 mmol) of 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester was added to a reaction flask containing DCM (3 mL), and trifluoroacetic acid (1 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 30 minutes. After concentration, 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione was obtained in 91.7% yield.

[0765] ESI-MS m / z = 450.3 [M+H] +

[0766] Step i) Synthesis of 3-(3-((1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolino-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0767] 3-(6-(1-(7-aza[3.5]nonane-2-yl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione (60 mg, 0.13 mmol), intermediate VII (0.1 g, 0.13 mmol), and TEA (39 mg, 0.39 mmol) were dissolved in DMF (3 mL). The reaction system was heated at 50 °C. o Stirred at C for 16 hours. Water and EA were added to the reaction mixture for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography to obtain 3-(3-((1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 58.0%.

[0768] ESI-MS m / z = 1162.6 [M+H] +

[0769] Step j) Synthesis of 3-(6-(1-(7-[(1-{[(1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofuran[3,2-f]quinazolin-3-yl)oxy]methyl}cyclopropyl)methyl]-7-azaspiro[3.5]nonane-2-yl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione carbamate

[0770] 3-(3-((1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolino-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80 mg, 0.07 mmol) was dissolved in EA (1 mL), and 4M HCl EA solution (1 mL) was added. The reaction system was stirred at room temperature for 30 minutes. After concentrating the reaction solution, it was purified by Prep-HPLC and then lyophilized to obtain 3-(6-(1-(7-[(1-{[(1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-3-yl)oxy]methyl}cyclopropyl)methyl]-7-azaspiro[3.5]nonane-2-yl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione carbamate, with a yield of 21.7%.

[0771] 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 101 (s, 1H), 8.21 - 8.15 (m, 2H), 8.12 (s, 1H), 7.81 (dd, J = 8.8, 5.3 Hz, 2H), 7.42 - 7.31 (m, 2H),7.28 (s, 1H), 7.21 (s, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 8.2 Hz,1H), 4.39 - 4.24 (m, 2H), 4.06 (dd, J = 10.8, 5.0 Hz, 3H), 3.76 (s, 3H), 3.58(s, 5H), 2.94 (s, 2H), 2.72 (s, 3H), 2.38 (s, 8H), 2.09 (s, 2H), 1.90 (s,8H), 1.84 (s, 4H), 1.67 (d, J = 17.6 Hz, 4H), 1.43 (s, 2H), 0.65 (s, 2H), 0.45 (dd, J = 9.2 Hz, 3H), 0.41 (s, 2H).

[0772] ESI-MS m / z = 1018.5 [M+H] +

[0773] Example 11 Synthesis of (2S,4R)-1-((2S)-2-(4-(5-(7a-(1-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-3-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methoxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0774]

[0775] Step a) Synthesis of 1-benzyl 2-methyl-2-(but-3-en-1-yl)pyrrolidine-1,2-dicarboxylic acid ester

[0776] 11 g (42 mmol) of 1-methyl(2S)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester was dissolved in 11 mL THF, and LiHMDS (8.4 g, 50 mmol) was added dropwise at -65 °C with stirring for 1 h. Subsequently, 11.3 g (84 mmol) of 4-bromobut-1-ene was added dropwise and the reaction was brought to room temperature for 12 h. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with EA, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel chromatography to give 1-methyl-2-(but-3-en-1-yl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester, in 55.0% yield.

[0777] ESI-MS m / z = 318.2 [M+H] +

[0778] Step b) Synthesis of 1-benzyl 2-methyl-2-(2-(ethylene oxide-2-yl)ethyl)pyrrolidine-1,2-dicarboxylic acid ester

[0779] 4.2 g (13 mmol) of 2-methyl-2-(but-3-en-1-yl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester was dissolved in DCM (12 mL). Under ice bath conditions, m-chloroperoxybenzoic acid (5.7 g, 33 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched dropwise with saturated sodium sulfite aqueous solution, followed by extraction with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel chromatography to obtain 2-methyl-2-(2-(ethylene oxide-2-yl)ethyl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester, with a yield of 77.0%.

[0780] ESI-MS m / z = 334.2 [M+H] +

[0781] Step c) Synthesis of methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolizidine-7a(5H)-carboxylic acid

[0782] 4.2 g (12.60 mmol) of 2-methyl-2-(2-(ethylene oxide-2-yl)ethyl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester was dissolved in methanol (8 mL), Pd / C (60 mg, 12.6 mmol) was added, and the mixture was purged with hydrogen and reacted at room temperature for 3 hours. The mixture was filtered and concentrated to give crude methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolizidine-7a(5H)-carboxylic acid, in 97.0% yield.

[0783] ESI-MS m / z = 200.1 [M+H] +

[0784] Step d) Synthesis of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-formate

[0785] Methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolizidine-7a(5H)-carboxylate (2.0 g, 104 mmol) and imidazole (6.8 g, 100 mmol) were dissolved in dichloromethane (15 mL), and tert-butyldimethylchlorosilane (7.6 g, 50 mmol) was added. The reaction was carried out at room temperature for 16 hours. The mixture was extracted with water and EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to give methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizidine-7a(5H)-carboxylate, in 76.0% yield.

[0786] ESI-MS m / z = 314.2 [M+H] +

[0787] Step e) Synthesis of (3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol

[0788] Methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-carboxylate (2.5 g, 8.0 mmol) was dissolved in 15 mL of THF, and lithium aluminum hydride (605 mg, 16 mmol) was added at -20 °C. The mixture was stirred at room temperature for 1 h. Water (0.5 mL), 15% sodium hydroxide aqueous solution (0.5 mL), and water (3.5 mL) were added sequentially to the reaction solution. The solid was washed with THF (50 mL), dispersed in THF (30 mL), stirred at 25 °C for 5 min, filtered, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give (3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol, yield 67.0%.

[0789] ESI-MS m / z = 286.2 [M+H] +

[0790] Step f) Synthesis of tert-butyl 3-(6-bromo-3-((3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0791] (3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (147 mg, 0.52 mmol) was dissolved in THF (6 mL), and sodium hydride (34 mg, 0.86 mmol) was added under ice bath conditions. The reaction was allowed to proceed for 1 h. Intermediate V (265 mg, 0.52 mmol) was then added, followed by 50 mL of THF. o The reaction was carried out at C for 16 hours. Water and EA were added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to give tert-butyl 3-(6-bromo-3-((3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, yield 27.0%.

[0792] ESI-MS m / z = 760.3 [M+H]+

[0793] Step g) Synthesis of tert-butyl 3-(3-((3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0794] The following were added: tert-butyl 3-(6-bromo-3-((3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (180.2 mg, 0.24 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (85 mg, 0.24 mmol), cesium carbonate (244 mg, 0.75 mmol), and methanesulfonic acid (dadamantyl-n-butylphosphine)-2'-amino-1,1'-biphenyl-2-ethyl)palladium(II) (18 mg, 0.03 mmol). The product (mmol) was dissolved in 1,4-dioxane:H2O=6:1 (6 mL), and reacted at 110℃ for 3 hours under nitrogen protection. The crude product was concentrated, and the residue was purified by silica gel chromatography to give tert-butyl3-(3-((3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, in 57.0% yield.

[0795] ESI-MS m / z = 914.5 [M+H] +

[0796] Step h) Synthesis of tert-butyl 3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluoro-3-((3-(hydroxymethyl)tetrahydro-1H-pyrrolazin-7a(5H)-)yl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0797] 130 mg, 0.14 mmol of tert-butyl 3-(3-((3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 mL) was dissolved in tetrahydrofuran, and TBAF (37 mg, 0.14 mmol) was added and reacted for 30 minutes. The product was quenched with water and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to obtain tert-butyl 3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluoro-3-((3-(hydroxymethyl)tetrahydro-1H-pyrrolazin-7a(5H)-)yl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, with a yield of 77.0%.

[0798] ESI-MS m / z = 800.4 [M+H] +

[0799] Step i) Synthesis of tert-butyl 3-(3-((3-((((5-bromopyrazin-2-yl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0800] tert-butyl 3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluoro-3-[(3-(hydroxymethyl)-hexahydro-1H-pyrrolazin-7a-yl)methoxy]furan[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (79 mg, 0.10 mmol) and 2,5-dibromopyrazine (47 mg, 0.20 mmol) were dissolved in THF (3 mL), and sodium hydride (4.8 mg, 0.20 mmol) was added under ice bath conditions. oThe reaction was carried out at C for 1 h. The reaction system was quenched with a small amount of saturated ammonium chloride aqueous solution, concentrated to obtain crude product, and the residue was purified by silica gel chromatography to obtain tert-butyl 3-(3-((3-((((5-bromopyrazin-2-yl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, with a yield of 70%.

[0801] ESI-MS m / z = 956.3 [M+H] +

[0802] Step j) Synthesis of tert-butyl 3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluoro-3-((3-(((5-((triisopropylsilyl)ethynyl)pyrazin-2)-yl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0803] tert-butyl 3-(3-((3-((((5-bromopyrazin-2-yl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.07 mmol), ethynyltris(prop-2-yl)silane (67 mg, 0.36 mmol), cuprous iodide (14 mg, 0.07 mmol), triethylamine (37 mg, 0.36 mmol), and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.02 mmol) were dissolved in 4 mL The reaction was carried out at 40°C for 16 h under nitrogen protection in THF. The crude product was concentrated and purified by silica gel chromatography to give tert-butyl 3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluoro-3-((3-(((5-((triisopropylsilyl)ethynyl)pyrazin-2)-yl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, in 67.0% yield.

[0804] ESI-MS m / z = 1058.5 [M+H] +

[0805] Step k) Synthesis of 3-(6-(3-ethoxy-8-ethyl-7-fluoronaphthyl-1-yl)-3-(3-(((5-ethynylpyrazin-2-yl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0806] tert-butyl 3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluoro-3-((3-(((5-((triisopropylsilyl)ethynyl)pyrazin-2)-yl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (58 mg, 0.06 mmol) was dissolved in 2 mL THF, and TBAF (58 mg, 0.22 mmol) was added. The reaction was carried out at room temperature for 2 h. Extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to obtain 3-(6-(3-ethoxy-8-ethyl-7-fluoronaphthyl-1-yl)-3-(3-(((5-ethynylpyrazin-2-yl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 90%.

[0807] ESI-MS m / z = 886.4 [M+H] +

[0808] Step l) Synthesis of tert-butyl 3-(3-((5-(1-((S)-1-((2S,4R)-2-((S,1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxyquinazoline-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0809] 3-(6-(3-ethoxy-8-ethyl-7-fluoronaphthyl-1-yl)-3-(3-(((5-ethynylpyrazin-2-yl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35 mg, 0.04 mmol), intermediate XV (29 mg, 0.06 mmol), copper(II) sulfate (10 mg, 0.04 mmol) and sodium ascorbate (23 mg, 0.12 mmol) were dissolved in THF / tBuOH / H2O = 1:1:1 (6 mL) and stirred at room temperature for 2 h. Quenching with water, extraction with EA, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating to obtain the crude product, and purifying by silica gel chromatography to obtain tert-butyl 3-(3-((5-(1-((S)-1-((2S,4R)-2-((S,1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxyquinazoline-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, yield 77.0%.

[0810] ESI-MS m / z = 1400.6 [M+H] +

[0811] Step m) Synthesis of (2S,4R)-1-((2S)-2-(4-(5-(7a-(1-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-3-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methoxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide formate

[0812] tert-butyl 3-(3-((5-(1-((S)-1-((2S,4R)-2-((S,1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxyquinazoline-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (50 mg, 0.04 mmol) was dissolved in 4M HCl EA solution (2 mL) The reaction was carried out at room temperature for 30 minutes. The crude product was concentrated and purified by Prep-HPLC to give (2S,4R)-1-((2S)-2-(4-(5-(7a-(1-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-3-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methoxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-carbamoyl-3-methylthiophen-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide carboxylate, in 17.0% yield.

[0813] 1H NMR (400 MHz, MeOD-d4) δppm 8.78 (s, 1H), 8.65 (s, 1H), 8.55 (d, J= 14.3 Hz, 1H), 8.48 (d, J = 10.8 Hz, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.82(d, J = 7.6 Hz, 4H), 7.79 - 7.67 (m, 2H), 7.48 - 7.32 (m, 1H), 7.26 (dd, J =19.8, 15.6 Hz, 1H), 7.10 (d, J = 26.8 Hz, 1H),5.44 (d, J = 9.8 Hz, 1H), 5.17- 4.98 (m, 1H), 4.82 (s, 2H), 4.77 (d, J = 10.2 Hz, 2H), 4.71 (d, J = 18.4Hz, 1H), 4.64 (d, J = 9.6 Hz, 1H), 4.61 - 4.55 (m, 3H), 4.09 (d, J = 7.4 Hz,1H),3.93 (d, J = 10.8 Hz, 2H), 3.69 (t, J = 31.8 Hz, 1H), 3.51 (d, J = 27.8Hz, 1H), 2.63 (s, 1H), 2.48 (dd, J = 24.4, 7.2 Hz, 1H), 2.35 (d, J = 5.6 Hz,1H), 2.33 - 2.19 (m, 4H), 2.12 (d, J = 5.6 Hz, 5H), 2.06 - 1.89 (m, 6H), 1.67(dd, J = 26.2, 19.8 Hz, 1H), 1.58 - 1.45 (m, 1H), 1.17 (d, J = 6.2 Hz, 3H),0.91 - 0.76 (m, 4H), 0.53 (dd, J = 17.8, 7.5 Hz, 4H), 0.53 (dd, J = 17.8, 7.6Hz, 4H)。

[0814] ESI-MS m / z = 1256.5 [M+H] +

[0815] Example 12a or Example 12b (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-(((S)-8-(4-methylthiazolyl-5-yl)-2,3 4,5-Tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide or (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-(((R)-8-(4-methylthiazolyl-5-yl)-2,3 4,5-Tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide

[0816]

[0817] Step a) Synthesis of 8-(4-methylthiazol-5-yl)-3,4-dihydrobenzo[b]oxetane-5(2H)-one

[0818] 8-Bromo-3,4-dihydrobenzo[b]oxetane-5(2H)-one (2.1 g, 8.7 mmol), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)thiazole (2.4 g, 10 mmol), potassium carbonate (2.6 g, 26 mmol), and Pd(dppf)Cl2 (0.60 g, 0.87 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). The mixture was placed under nitrogen protection and heated to 90°C. o The reaction was carried out at C for 12 h. Water and EA were added for extraction, the organic phases were combined, washed once with water, twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel chromatography to obtain 8-(4-methylthiazol-5-yl)-3,4-dihydrobenzo[b]oxetane-5(2H)-one (1.7 g, 6.65 mmol), yield 76.3%.

[0819] ESI-MS m / z = 260.1 [M+H]+

[0820] Step b) Synthesis of 8-(4-methylthiazo-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-amine

[0821] 8-(4-methylthiazolyl-5-yl)-3,4-dihydrobenzo[b]oxetane-5(2H)-one (1.7 g, 6.7 mmol) and ammonium acetate (10.2 g, 133 mmol) were dissolved in isopropanol (20 mL), and sodium cyanoborohydride (2.1 g, 33 mmol) was slowly added. The reaction system was heated to 80 °C. o The reaction was carried out at C for 16 hours. The reaction system was cooled to room temperature, quenched with 1N sodium hydroxide aqueous solution, extracted with DCM, the organic phases were combined, washed once with water, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, yielding 8-(4-methylthiazo-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-amine (1.7 g, 6.53 mmol). The crude product was used directly in the next step.

[0822] ESI-MS m / z = 261.1 [M+H] +

[0823] Step c) Synthesis of (2S,4R)-4-hydroxy-2-((8-(4-methylthiazolyl-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0824] 8-(4-methylthiazolyl-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-amine (1.7 g, 6.53 mmol) and Boc-L-hydroxyproline (1.5 g, 6.53 mmol) were dissolved in DMF (20 mL), and DIEA (4.3 mL, 26 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then HATU (2.5 g, 6.5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Extracted with water and EA, the organic phases were combined, washed once with water, twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to obtain (2S,4R)-4-hydroxy-2-((8-(4-methylthiazolyl-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.9 g, 3.62 mmol), yield 55.4%.

[0825] ESI-MS m / z = 474.2 [M+H] +

[0826] Step d) Synthesis of (2S,4R)-4-hydroxy-N-(8-(4-methylthiazolyl-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide

[0827] (2S,4R)-4-hydroxy-2-((8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.9 g, 4.0 mmol) was dissolved in 20 mL of 4 M HCl 1,4-dioxane solution and stirred at room temperature for 2 hours. The reaction system was concentrated under reduced pressure to obtain (2S,4R)-4-hydroxy-N-(8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide (1.6 g, 4.21 mmol), the crude product of which was used directly in the next step.

[0828] ESI-MS m / z = 374.2 [M+H] +

[0829] Step e): Synthesis of ((2S)-1-((2S,4R)-4-hydroxy-2-((8-(4-methylthiazo-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)tert-butyl carbamate

[0830] (2S,4R)-4-hydroxy-N-(8-(4-methylthiazolyl-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide (1.6 g, 4.21 mmol) was dissolved in DMF (15 mL). DIEA (4.2 mL, 25 mmol) and (tert-butoxycarbonyl)-L-valine (0.9 g, 4.21 mmol) were added under nitrogen protection. The reaction mixture was stirred in an ice bath for 10 minutes, followed by the addition of HATU (1.6 g, 4.2 mmol), and stirred at room temperature for 3 hours. Extracted with water and EA, the organic phases were combined, washed once with water, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain ((2S)-1-((2S,4R)-4-hydroxy-2-((8-(4-methylthiazo-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)tert-butyl carbamate (1.7 g, 3.03 mmol), yield 73.4%.

[0831] ESI-MS m / z = 573.3 [M+H] +

[0832] Step f) Synthesis of (2S,4R)-1-(L-valine)-4-hydroxy-N-(8-(4-methylthiazolyl-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide

[0833] ((2S)-1-((2S,4R)-4-hydroxy-2-((8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)tert-butyl carbamate (1.7 g, 2.97 mmol) was dissolved in 15 mL of 4 M HCl and reacted at room temperature for 2 hours. The solution was concentrated under vacuum to obtain (2S,4R)-1-(L-valine)-4-hydroxy-N-(8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide (1.4 g, 2.96 mmol), the crude product of which was used directly in the next step.

[0834] ESI-MS m / z = 473.2 [M+H] +

[0835] Step g): Synthesis of (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxy-N-((S)-8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide or (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxy-N-((R)-8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide

[0836] (2S,4R)-1-(L-valine)-4-hydroxy-N-(8-(4-methylthiazolyl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide (1.4 g, 3.0 mmol) was dissolved in a mixed solvent of THF (10 mL) and ACN (10 mL). The reaction system was cooled in an ice-salt bath under nitrogen protection, and triethylamine (2.5 mL, 18 mmol) and anhydrous copper sulfate (945 mg, 5.9 mmol) were added. The mixture was stirred for 2 minutes. 2-Azide-1,3-dimethylimidazolium hexafluorophosphate (1.7 g, 5.92 mmol) was dissolved in acetonitrile (5 mL) and slowly added to the reaction system, controlled to be completed dropwise over 30 minutes. The reaction was carried out for 2 hours. Quenching with water, EA extraction, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and concentrating, the product was purified by Prep-HPLC to obtain two isomers: ((2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxy-N-((S)-8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide or (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxy-N-((R)-8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide, with a yield of 51.8%.

[0837] ESI-MS m / z = 499.2 [M+H] +

[0838] Step h) 4-((5-(1-((S)-1-((2S,4R)-4-hydroxy-2-((S)8-(4-methylthiazolyl-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester or 4- Synthesis of tert-butyl piperidine-1-carboxylate

[0839] Dissolve (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxy-N-((S)-8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide or (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxy-N-((R)-8-(4-methylthiazol-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide (370 mg, 0.74 mmol) in a mixed solvent of tert-butanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL), then add copper sulfate pentahydrate (92 mg, 0.37 mmol) and sodium ascorbate (293 mg). 4-((5-ethynylpyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (337 mg, 1.11 mmol) was then added and stirred at room temperature. The mixture was then reacted overnight at room temperature. Water and EA were added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and the residue was purified by silica gel column chromatography to give 4-((5-(1-((S)-1-((2S,4R)-4-hydroxy-2-((S)8-(4-methylthiazo-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl) 4-((5-(1-((S)-1-((2S,4R)-4-hydroxy-2-((R)-8-(4-methylthiazo-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxo)piperidine-1-carboxylic acid tert-butyl ester, yield 88.2%.

[0840] ESI-MS m / z = 802.4 [M+H] +

[0841] Step i) (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)-N-((S)-8-(4-methylthiazolyl-5-yl)-2,3,4,5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide or ( Synthesis of 2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-(5-(piperidin-4-yloxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)-N-((R)-8-(4-methylthiazolyl-5-yl)-2,3,4,5-tetrahydrobenzo[b]oxetane-heptene-5-yl)pyrrolidine-2-carboxamide

[0842] 4-((5-(1-((S)-1-((2S,4R)-4-hydroxy-2-((S)8-(4-methylthiazo-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolid-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-tert-butyl ester or 4- (5-(1-((S)-1-((2S,4R)-4-hydroxy-2-((R)-8-(4-methylthiazo-5-yl)-2,3,4-5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (580 mg, 0.72 mmol) was dissolved in DCM (6 mL), and TFA (2 mL) was added in an ice bath. The mixture was stirred at room temperature for 2 hours. The crude product was concentrated under vacuum and used directly in the next step.)

[0843] ESI-MS m / z = 702.3 [M+H] +

[0844] Step j) tert-butyl(1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluoro-3-(1-(4-(5-(1-(S)-1-(2S,4R)-4-hydroxy-2-((S)-8-(4-methylthiazolyl-5-yl)-2,3,4,5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester or tert-butyl Synthesis of butyl(1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluoro-3-(1-(4-(5-(1-((S)-1-(2S,4R)-4-hydroxy-2-((R)-8-(4-methylthiazolyl-5-yl)-2,3,4,5-tetrahydrobenzo[b]oxacycloheptane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0845] Dissolve the crude product from the previous step in 6 mL of DMF, slowly add TEA (0.2 mL, 1.70 mmol), then add intermediate VI (477 mg, 0.57 mmol), purge with nitrogen, and incubate for 30 minutes. oReact at C overnight. Extract with water and EA, combine the organic phases, wash with brine, dry to anhydrous sodium sulfate, filter, concentrate under vacuum, and purify the residue by silica gel column chromatography to give tert-butyl(1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluoro-3-(1-(4-(5-(1-(S)-1-(2S,4R)-4-hydroxy-2-((S)-8-( 4-Methylthiazolyl-5-yl)-2,3,4,5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)furan[3,2-f]quinazolin-1-yl)-3,8-diazo Heterocyclic [3.2.1]octane-8-carboxylic acid ester or tert-butyl(1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluoro-3-(1-(4-(5-(1-((S)-1-(2S,4R)-4-hydroxy-2-((R)-8-(4-methylthiazolyl-5-yl)-2,3,4,5-tetrahydrobenzo[b] [Oxyheptan-5-yl)carbamoyl)pyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, yield 10.3%.

[0846] ESI-MS m / z = 1410.6 [M+H] +

[0847] Step k) (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-(((S)-8-(4-methylthiazolyl-5-yl)-2,3 4,5-Tetrahydrobenzo[b]oxacycloheptan-5-yl)pyrrolidine-2-carboxamide formate or (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-(((R)-8-(4-methylthiazolyl-5-yl)-2,3 Synthesis of 4,5-tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide formate

[0848] The tert-butyl(1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluoro-3-(1-(4-(5-(1-(S)-1-(2S,4R)-4-hydroxy-2-((S)-8-(4-methylthiazo-5-yl)-2,3,4,5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester or tert-butyl 1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluoro-3-(1-(4-(5-(1-((S)-1-(2S,4R)-4-hydroxy-2-((R)-8-(4-methylthiazolyl-5-yl)-2,3,4,5-tetrahydrobenzo[b]oxetane-5-yl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)furano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (53.2) Dissolve 0.04 mg (0.04 mmol) in acetonitrile (1 mL), add 4M HCl EA solution (1 mL) under ice bath, and stir at room temperature for 2 hours.The crude product was concentrated and then prepared by Prep-HPLC to obtain: (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-(((S)-8-(4-methylthiazolyl-5-yl)-2,3 4,5-Tetrahydrobenzo[b]oxacycloheptan-5-yl)pyrrolidine-2-carboxamide formate or (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-(((R)-8-(4-methylthiazolyl-5-yl)-2,3 4,5-Tetrahydrobenzo[b]oxacycloheptan-5-yl)pyrrolidine-2-carboxamide formate and (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-(((S)-8-(4-methylthiazolyl-5-yl)-2,3 4,5-Tetrahydrobenzo[b]oxacycloheptan-5-yl)pyrrolidine-2-carboxamide formate or (2S,4R)-1-((2S)-2-(4-(5-(1-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-(((R)-8-(4-methylthiazolyl-5-yl)-2,3 4,5-Tetrahydrobenzo[b]oxetane-5-yl)pyrrolidine-2-carboxamide carboxylate.

[0849] P1: HPLC retention time 11,700 min (Analytical method: Agilent InfinityLab Poroshell 120EC-C18 100mm*2.1mm 1.9μm; Mobile phase: A: 0.01% TFA in Water, B: 0.01% TFA in CAN. Gradient: B from 5% to 95% in 20 min and hold 95% for 10 min; Flow rate: 0.4 mL / min; Column temperature: 40℃)

[0850] 1 H NMR (400 MHz, MeOD-d4) δ 8.87 (d, J = 7.4 Hz, 1H), 8.73 (s, 1H), 8.58 (d, J = 6.0 Hz, 1H), 8.26 (s, 1H), 8.18 (d, J = 3.9 Hz, 1H), 7.94 (d, J =2.0 Hz, 1H), 7.86 (s, 1H), 7.37 (d, J = 2.7 Hz, 1H), 7.33 - 7.26 (m, 2H),7.20 (t, J = 10.2 Hz, 3H), 7.12 (d, J = 1.9 Hz, 1H),5.44 (d, J = 10 Hz, 1H),5.27 (s, 1H), 5.21 (s, 1H), 4.20 (d, J = 7.6 Hz, 3H), 4.54 (s, 1H), 4.49 -4.37 (m, 1H), 4.30 (d, J = 13.6 Hz, 1H), 4.22 - 4.15 (m, 1H), 3.99 (s, 2H),3.96 - 3.87 (m, 4H), 3.78 (d, J = 11.6 Hz, 1H), 3.07 (s, 3H), 2.89 (d, J =4.6 Hz, 2H), 2.64 (td, J = 12.0, 6.6 Hz, 1H), 2.47 (d, J = 2.6 Hz, 1H), 2.26(d, J = 8.3 Hz, 4H), 2.15 - 2.05 (m, 1H), 2.04 (s, 4H), 1.98 (s, 3H), 1.30 (s, 1H), 1.10 - 1.08 (m, 3H), 1.02 (m,8H), 0.82 (m, 4H).

[0851] ESI-MS m / z = 1266.5 [M+H] +

[0852] P2: HPLC retention time 13.271 min (Analytical method: Agilent InfinityLab Poroshell 120EC-C18 100mm*2.1mm 1.9μm; Mobile phase: A: 0.01% TFA in Water, B: 0.01% TFA in CAN. Gradient: B from 5% to 95% in 20 min and hold 95% for 10 min; Flow rate: 0.4 mL / min; Column temperature: 40℃)

[0853] 1H NMR (400 MHz, MeOD-d4) δ 8.87 (d, J = 7.2 Hz, 1H), 8.73 (s, 1H), 8.58 (d, J = 6.0 Hz, 1H), 8.28 (s, 1H), 8.18 (d, J = 3.6 Hz, 1H), 7.94 (d, J =2.0 Hz, 1H), 7.86 (s, 1H), 7.37 (d, J = 2.8 Hz, 1H), 7.33 - 7.26 (m, 2H),7.20 (t, J = 10.2 Hz, 3H), 7.12 (d, J = 1.6 Hz, 1H), 5.44 (d, J = 10 Hz, 1H),5.27 (s, 1H), 5.21 (s, 1H), 4.62 (d, J = 8.4 Hz, 3H), 4.54 (s, 1H), 4.49 -4.37 (m, 1H), 4.30 (d, J = 13.6 Hz, 1H), 4.22 - 4.15 (m, 1H), 3.99 (s, 2H),3.96 - 3.87 (m, 4H), 3.78 (d, J = 11.6 Hz, 1H), 3.07 (s, 3H), 2.89 (d, J =4.8 Hz, 2H), 2.64 (td, J = 12.0, 6.6 Hz, 1H), 2.47 (d, J = 2.8 Hz, 1H), 2.26(d, J = 8.4 Hz, 4H), 2.15 - 2.05 (m, 1H), 2.04 (s, 4H), 1.98 (s, 3H), 1.30 (s, 1H), 1.21 - 1.14 (m, 3H), 1.02 (m,8H), 0.82 (m, 4H).

[0854] ESI-MS m / z = 1266.5 [M+H] +

[0855] Example 13 Synthesis of 3-(6-(1-(7-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (refer to Example 10)

[0856]

[0857] According to the synthesis methods in steps i and j of Example 10, intermediates VII and 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione were replaced with intermediates VI and XI, respectively, with the other operations being the same, to obtain 3-(6-(1-(7-((1-((( 1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione.

[0858] 1 H NMR (400 MHz, Methanol-d4) δ 8.25 (s, 1H), 7.98 (s, 1H), 7.90 (dd,J = 9.0, 5.8 Hz, 1H), 7.39 (s, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.24 (s, 3H), 6.79 (d, J = 11.6 Hz, 1H), 4.61 (d, J = 11.6 Hz, 1H), 4.52 (d, J = 8.0 Hz, 1H), 4.44 (d, J = 11.6 Hz, 1H), 4.40 - 4.28 (m, 6H), 4.15 - 4.02 (m, 6H),3.83 (d, J = 13.6 Hz, 2H), 3.27 - 3.09 (m, 4H), 2.95 (s, 2H), 2.85 - 2.69 (m,2H), 2.62 - 2.38 (m, 3H), 2.29 - 2.14 (m, 4H), 2.12 - 1.88 (m, 13H), 0.98 (s,2H), 0.84 (s, 2H).

[0859] ESI-MS m / z = 1032.5 [M+H] +

[0860] Example 14 Preparation of 3-(6-(4-((7-((1-((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-2-fluoro-7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0861]

[0862] Step a) Preparation of tert-butyl 2-((4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-2-fluoro-7-azaspiro[3.5]nonane-7-carboxylic acid

[0863] 3-(4-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.29 mmol), acetic acid (0.1 mL), and 2-fluoro-2-formyl-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (118.0 mg, 0.44 mmol) were dissolved in DMA (4 mL) and reacted at 50 °C for 4 hours. Sodium cyanoborohydride (45 mg, 0.72 mmol) was added under ice bath, and the reaction was carried out overnight at room temperature. Extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 2-((4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-2-fluoro-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, yield 70.6%.

[0864] ESI-MS m / z: 601.3 [M+H] +

[0865] Step b) 3-(4-fluoro-6-(4-((2-fluoro-7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride

[0866] 122 mg (0.20 mmol) of tert-butyl 2-((4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-2-fluoro-7-azaspiro[3.5]nonane-7-carboxylic acid was dissolved in 2 mL of 4M hydrochloric acid EA solution and reacted at room temperature for 0.5 h. After concentration under reduced pressure, it was directly used in the next step.

[0867] ESI-MS m / z: 501.3 [M+H] +

[0868] Step c) Preparation of 3-(3-((1-((2-((4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-2-fluoro-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0869] The crude product from step 3 was dissolved in acetonitrile (10 mL), and triethylamine (0.9 mL, 0.61 mmol) and 3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluoro-3-((1-(iodomethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (170 mg, 0.20 mmol) were added. The mixture was then dissolved under nitrogen protection at 40 °C. o The reaction was carried out at C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 3-(3-((1-((2-((4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-2-fluoro-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, with a two-step yield of 42.9%.

[0870] ESI-MS m / z = 1209.6 [M+H] +

[0871] Step d) Preparation of 3-(6-(4-((7-((1-((((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-2-fluoro-7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione carbamate

[0872] 3-(3-((1-((2-((4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-2-fluoro-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (105.0 mg, 0.9 mmol) was added to 4M HCl EA solution (2 mL) and reacted at room temperature for 0.5 h. Concentrate under reduced pressure, and the residue was subjected to Prep-HPLC to give 3-(6-(4-((7-((1-((((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-2-fluoro-7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione carbamate in 18.7% yield.

[0873] 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.00 (s, 1H), 7.91 (s,1H), 7.40 (d, J = 2.2 Hz, 1H), 7.35 (t, J = 9.0 Hz, 1H), 7.24 (s, 2H), 6.67(d, J = 13.6 Hz, 1H), 6.62 (s, 1H), 4.75 - 4.53 (m, 6H), 4.46 - 4.14 (m, 5H), 4.01 (d, J = 8.2 Hz, 1H), 3.95 (d, J = 1.8 Hz, 3H), 3.89 (d, J = 14.0 Hz,1H), 3.74 (s, 2H), 3.64 - 3.01 (m, 4H), 2.86 - 2.70 (m, 8H), 2.49 - 1.86 (m,15H), 1.02 (s, 2H), 0.90 (d, J = 6.8 Hz, 2H).

[0874] ESI-MS m / z = 1065.5 [M+H] +

[0875] Example 15 Preparation of 3-(6-(1-(7-[(1-{[(1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy]methyl}cyclopropyl)methyl]-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1,4-dimethyl-1H-indazol-3-yl)piperidin-2,6-dione (refer to Example 10)

[0876]

[0877] According to the synthesis methods in steps a and j of Example 10, intermediate VII and 6-chloro-1H-pyrrolo[2,3-b]pyridine were respectively converted to 6-bromo-4-methylindazole and intermediate VI, and the other operations were the same to obtain 3-(6-(1-(7-[(1-{[(1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy]methyl}cyclopropyl)methyl]-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1,4-dimethyl-1H-indazole-3-yl)piperidin-2,6-dione.

[0878] 1 H NMR (400 MHz, DMSO-d6) δ11.36 (s, 1H),10.89 (s, 1H), 10.35 (s,1H),8.17 (s, 1H), 8.10 (s, 1H) , 8.01 (s, 1H) , 7.54 - 7.44 (m, 2H), 7.27 (s,2H) , 7.12 (s, 1H), 6.79 (s, 1H), 4.50 (dd, J = 9.8, 5.2 Hz, 1H), 4.37 (s,2H), 4.24 (s, 4H), 4.14 (d, J = 18.6 Hz, 5H), 3.95 (s, 1H), 3.61 (s, 5H),3.22 (s, 5H), 2.92 (s, 2H), 2.67 (s, 1H) 2.61 (s, 3H) 2.57 (s, 2H), 2.35 (s,2H), 2.12 (s, 2H), 2.04 (s, 5H), 1.92 (s, 8H), 0.83 (s, 4H)。

[0879] 1 H NMR (400 MHz, DMSO+D2O) δ8.17 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H) ,7.54 - 7.44 (m, 2H), 7.27 (s, 2H) , 7.12 (s, 1H), 6.79 (s, 1H), 4.50 (dd, J =9.8, 5.2 Hz, 1H), 4.37 (s, 2H), 4.24 (s, 4H), 4.14 (d, J = 18.6 Hz, 5H), 3.95(s, 1H), 3.61 (s, 5H), 3.22 (s, 5H), 2.92 (s, 2H), 2.67 (s, 1H) 2.61 (s, 3H)2.57 (s, 2H), 2.35 (s, 2H), 2.12 (s, 2H), 2.04 (s, 5H), 1.92 (s, 8H), 0.83(s, 4H)。

[0880] ESI-MS m / z = 1028.5 [M+H] +

[0881] Example 16 Synthesis of 3-(6-(4-(7-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0882]

[0883] According to the synthetic methods in steps i and j of Example 10, intermediates VII and 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione were replaced with intermediates VI and X, respectively, with the other operations being the same, to obtain 3-(6-(4-(7- ((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione carbamate.

[0884] 1H NMR (400 MHz, MeOD-d4) δppm 8.47 (s, 1H), 7.98 (s, 1H), 7.96 -7.86 (m, 1H), 7.41 (s, 1H), 7.36 (t, J = 8.9 Hz, 1H), 7.24 (d, J = 5.7 Hz,2H), 6.75 - 6.60 (m, 2H), 4.67 (d, J = 11.6 Hz, 1H), 4.52 (d, J = 12.1 Hz,1H), 4.40 (d, J = 12.0 Hz, 1H), 4.36 - 4.25 (m, 2H), 4.03 (s, 1H), 4.01 -3.87 (m, 6H), 3.81 (d, J = 14.4 Hz, 1H), 3.44 (d, J = 46.6 Hz, 2H), 3.21 (dd,J = 30.8, 17.2 Hz, 7H), 2.94 (s, 1H), 2.92 - 2.82 (m, 1H), 2.75 (dt, J =22.1, 11.5 Hz, 2H), 2.56 (s, 4H), 2.41 (d, J = 8.4 Hz, 2H), 2.34 - 2.24 (m,1H), 2.18 (s, 2H), 1.99 (s, 5H), 1.91 (s, 2H), 1.78 (d, J = 9.5 Hz, 2H), 1.00(s, 2H), 0.88 (s, 2H).

[0885] ESI-MS m / z = 1033.5 [M+H] +

[0886] Example 17 Preparation of 3-(6-(4-((7-((1-((((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0887]

[0888] Step a) Synthesis of tert-butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylic acid

[0889] (Methoxymethyl)triphenylphosphine chloride (4.3 g, 13 mmol) and potassium tert-butoxide (1.4 g, 13 mmol) were dissolved in THF (20 mL) and reacted at room temperature for 1 hour. Then, 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.5 g, 6.27 mmol) was added, and the reaction was carried out at 25 °C for 2 hours. The crude product was concentrated, and the residue was purified by silica gel chromatography to give 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, in 89.5% yield.

[0890] ESI-MS m / z = 268.2 [M+H] +

[0891] Step b) Synthesis of tert-butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylic acid

[0892] 1.5 g (5.59 mmol) of 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester was dissolved in a mixture of acetonitrile (10 mL) and water (5 mL), and trifluoroacetic acid (0.2 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water, extracted with DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 2-formyl-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, with a yield of 84.1%.

[0893] ESI-MS m / z = 254.2 [M+H] +

[0894] Step c) Synthesis of 2-((4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0895] 3-(4-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (100 mg, 0.29 mmol) and 2-formyl-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (88 mg, 0.35 mmol) were dissolved in 5 mL of DMA, one drop of acetic acid was added, and the mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (128 mg, 0.58 mmol) was added, and the mixture was stirred overnight at room temperature. Quenching with sodium bicarbonate solution (40 mL), extraction with EA (2 × 20 mL), combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain the crude product. The crude product was purified by silica gel chromatography to obtain 2-((4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, yield 47.3%.

[0896] ESI-MS m / z = 583.3 [M+H] +

[0897] Step d) Synthesis of 3-(6-(4-((7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0898] 2-((4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added. 0 The reaction was carried out at C for 1.5 hours. The reaction solution was concentrated to obtain crude 3-(6-(4-((7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione, with a yield of 88.5%.

[0899] ESI-MS m / z = 482.3 [M+H] +

[0900] Step e) Synthesis of tert-butyl 3-(3-(1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-yl)methyl]cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0901] Intermediate VI (50 mg, 0.06 mmol), 3-(6-(4-((7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (43 mg, 0.09 mmol), potassium carbonate (41 mg, 0.32 mmol), and potassium iodide (50 mg, 0.32 mmol) were dissolved in 4 mL of DMF and heated at 30 °C. o The reaction was carried out at C for 16 h. Water and EA were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give tert-butyl 3-(3-(1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-yl)methyl]cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, yield 46.6%.

[0902] ESI-MS m / z = 1191.6 [M+H] +

[0903] Step f) Synthesis of 3-(6-(4-((7-((1-((((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0904] 50 mg, 0.4 mmol of tert-butyl 3-(3-(1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-yl)methyl]cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (4 mL) was dissolved in acetonitrile (4 mL), and 1 mL of 4M HCl EA solution was added dropwise in an ice bath. The reaction was carried out in an ice bath for 1 hour. The reaction solution was concentrated at 0℃ to obtain a crude product. The crude product was sent to Prep-HPLC to prepare 3-(6-(4-((7-((1-((((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)methyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione carbamate, with a yield of 59.6%.

[0905] 1 H NMR (400 MHz, MeOD-d4) δ 8.39 (s, 1H), 7.99 (s, 1H), 7.95 - 7.87(m, 1H), 7.40 (s, 1H), 7.37-7.33(m, 1H),7.24 (s, 2H), 6.71-6.68 (m, 2H), 4.66-4.56 (m, 2H), 4.45-4.42 (m, 1H), 4.36 - 4.25 (m, 2H), 4.19-4.12 (m, 2H), 4.03- 3.86 (m, 5H), 3.52-3.37 (m, 5H), 3.36-3.34 (m, 1H), 3.32-3.25 (m, 2H), 3.03- 2.63 (m, 11H), 2.47 - 2.18 (m, 4H), 2.17-1.83 (m, 9H), 1.76-1.58 (m, 2H), 1.01 (s, 2H),0.91-0.86(m,2H).

[0906] ESI-MS m / z = 1047.5 [M+H] +

[0907] Example 18 Synthesis of 3-(6-(4-(2-(1-((1-((((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0908]

[0909] Step a) Synthesis of compound tert-butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)piperidin-1-carboxylic acid

[0910] 3-(4-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (400 mg, 1.16 mmol), 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (421.8 mg, 1.86 mmol), and two drops of acetic acid were added to a reaction flask containing DMA (8 mL), and the mixture was stirred at 50 °C for 1.5 h. Sodium triacetoxyborohydride (639.2 mg, 3.02 mmol) was then added, and the mixture was stirred at room temperature for 16 h. The product was quenched with water, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to obtain 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)piperidin-1-carboxylic acid tert-butyl ester (448 mg, yield 69.5%).

[0911] ESI-MS m / z: 557.3 [M+H] +

[0912] Step b) Synthesis of compound 3-(4-fluoro-1-methyl-6-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione

[0913] 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperazin-1-yl)ethyl)piperidin-1-carboxylic acid tert-butyl ester (210 mg, 0.38 mmol) was dissolved in DCM (10 mL), and TFA (160 mg, 1.44 mmol) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by concentration to obtain a solid crude product 3-(4-fluoro-1-methyl-6-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)-1H-indazole-3-yl)piperidin-2,6-dione (150 mg, yield 92.5%), which was directly used in the next step of the reaction.

[0914] ESI-MS m / z: 457.3 [M+H] +

[0915] Step c) Synthesis of compound 3-(3-((1-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0916] 3-(4-fluoro-1-methyl-6-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione (80 mg, 0.17 mmol) was dissolved in DMF (12 mL), and TEA (52.0 mg, 0.51 mmol) and 3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluoro-3-((1-(iodomethyl)cyclopropyl)methoxyfurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (143.0 mg, 0.17 mmol) were added. oThe reaction was carried out overnight at C. The reaction was quenched with water, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the product 3-(3-((1-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (120 mg, yield 59.2%).

[0917] ESI-MS m / z: 1165.5 [M+H] +

[0918] Step d) Synthesis of 3-(6-(4-(2-(1-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione carbamate

[0919] 3-(3-((1-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80 mg, 0.7 mmol) was dissolved in EA (1 mL), and 4M HCl EA solution (2 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was concentrated and purified by Prep-HPLC to obtain the product 3-(6-(4-(2-(1-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione carbamate (40 mg, yield 57.0%).

[0920] 1H NMR (400 MHz, Methanol-d4) δ 8.39 (d, J = 1.7 Hz, 1H), 7.99 (s,1H), 7.88 (dd, J = 8.8, 6.2 Hz, 1H), 7.43 - 7.30 (m, 2H), 7.24 (s, 2H), 6.74- 6.59 (m, 2H), 4.83 (s, 2H), 4.63 (dd, J = 23.8, 12.6 Hz, 2H), 4.46 (d, J =11.8 Hz, 1H), 4.38 - 4.24 (m, 2H), 4.13 (d, J = 29.7 Hz, 2H), 4.02 (s, 1H), 3.97 (d, J = 1.8 Hz, 3H), 3.87 (d, J = 13.7 Hz, 3H), 3.25 (d, J = 14.2 Hz, 3H), 2.99 (s, 3H), 2.77 (dq, J = 10.3, 5.7, 5.3 Hz, 6H), 2.61 (s, 2H), 2.42(p, J = 10.3, 9.5 Hz, 1H), 2.28 (q, J = 6.4 Hz, 2H), 2.03 (d, J = 17.2 Hz,5H), 1.63 (d, J = 53.2 Hz, 6H), 1.01 (s, 2H), 0.88 (d, J = 6.5 Hz, 2H).

[0921] ESI-MS m / z: 1021.5 [M+H] +

[0922] Example 19 Preparation of 3-(6-(1-(7-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)pyridino[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0923]

[0924] Step a) Synthesis of tert-butyl(1R,5S)-3-(2-((1-((2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0925] Intermediate III (50 mg, 0.6 mmol), intermediate XI (42 mg, 0.9 mmol), potassium carbonate (41 mg, 0.32 mmol), and potassium iodide (50 mg, 0.32 mmol) were dissolved in DMF (4 mL). o The reaction was carried out at C for 16 hours. Water and EA were added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to give tert-butyl(1R,5S)-3-(2-((1-((2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, yield 70.1%.

[0926] ESI-MS m / z = 1175.5 [M+H] +

[0927] Step b) Synthesis of 3-(6-(1-(7-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)pyridino[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione carbamate

[0928] 50 mg, 0.4 mmol of tert-butyl(1R,5S)-3-(2-((1-((2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (4 mL) was dissolved in acetonitrile (4 mL), and 4 M HCl EA solution (1 mL) was added dropwise under ice bath. The reaction was carried out under ice bath for 1 hour. The reaction solution was concentrated at 0℃ to obtain a crude product. The crude product was sent to Prep-HPLC to prepare 3-(6-(1-(7-((1-(((4-(((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione carbamate, with a yield of 59.1%.

[0929] 1 H NMR (400 MHz, MeOD-d4) δ 8.66 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 7.92-7.86 (m, 2H), 7.42 (s, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.28 (s, 2H), 6.82(d, J = 11.2 Hz, 1H), 4.57 (d, J = 13.2 Hz, 1H), 4.50 - 4.41 (m, 2H), 4.39 -4.30 (m, 2H), 4.21-4.14 (m, 2H), 4.04-3.99 (m, 4H), 3.88 (d, J = 13.6 Hz,1H), 3.71-3.61 (m, 1H), 3.54-3.46 (m, 3H), 3.24 - 2.97 (m, 6H), 2.89 - 2.70 (m, 4H), 2.50 - 2.34 (m, 3H), 2.34 - 1.97 (m, 16H), 0.96 (s, 2H), 0.84 (s, 2H).

[0930] ESI-MS m / z = 1031.5 [M+H]+

[0931] Example 20 Preparation of 3-(6-(4-((4-((1-((((1-(((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0932]

[0933] Step a) Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazole

[0934] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-4-fluoro-1-methyl-1H-indazole (308 mg, 0.60 mmol), 4-(dimethoxymethyl)piperidine (191 mg, 1.2 mmol), Pd2(dba)3 (89 mg, 97 μmol), cesium carbonate (630 mg, 1.9 mmol), and xantphos (111 mg, 193 μmol) were dissolved in 1,4-dioxane (15 mL), and the mixture was microwaved to 100°C under nitrogen protection. o C, react for 12 hours. Concentrate under reduced pressure, and purify the residue by silica gel chromatography to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazole, yield 54.0%.

[0935] ESI-MS m / z: 597.3 [M+H] +

[0936] Step b) Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0937] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazole (613.0 mg, 1.01 mmol) and 10% palladium on carbon (100 mg) were added to EA (10 mL) and anhydrous ethanol (10 mL), and reacted at room temperature in hydrogen atmosphere for 16 h. The mixture was filtered, the filtrate was concentrated, and purified by silica gel chromatography to give 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione, in 48.0% yield.

[0938] ESI-MS m / z: 419.2 [M+H] +

[0939] Step c) Preparation of 1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-carboxaldehyde trifluoroacetate

[0940] 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (106 mg, 0.25 mmol) was added to dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and reacted at room temperature for 0.5 h. After concentrating to remove the solvent, the crude product was obtained and used directly in the next step.

[0941] ESI-MS m / z: 373.2 [M+H] +

[0942] Step d) Preparation of tert-butyl 4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid

[0943] The crude product from the previous step, along with acetic acid (0.1 mL) and piperazine-1-carboxylic acid tert-butyl ester (89.0 mg, 480 μmol), was dissolved in DMA (4 mL) and reacted at 50 °C for 4 hours. Sodium cyanoborohydride (50 mg, 750 μmol) was added under ice bath, and the reaction was continued overnight at room temperature. The mixture was extracted with water and EA, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester, with a two-step yield of 57.6%.

[0944] ESI-MS m / z: 543.3 [M+H] +

[0945] Step e) Preparation of 3-(4-fluoro-1-methyl-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride

[0946] 150 mg (276.1 μmol) of 4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester was added to 2 mL of 4 M HCl EA solution and reacted at room temperature for 0.5 h. The solvent was concentrated to obtain 3-(4-fluoro-1-methyl-6-(4-(piperazine-1-ylmethyl)piperidin-1-yl)-1H-indazole-3-yl)piperidin-2,6-dione hydrochloride, which was used directly in the next step.

[0947] ESI-MS m / z: 443.3 [M+H] +

[0948] Step f) Preparation of tert-butyl(1R,5S)-3-(3-((1-((4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0949] 3-(4-fluoro-1-methyl-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride (122 mg, 276 μmol) was dissolved in 10 mL of acetonitrile, and TEA (0.9 mL, 609 μmol) and intermediate VI (231 mg, 276 μmol) were added. The mixture was then heated under nitrogen protection at 40 °C. o The reaction was carried out at C for 16 h. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography to give tert-butyl(1R,5S)-3-(3-((1-((4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, in 39.5% yield.

[0950] ESI-MS m / z = 1151.5 [M+H]+

[0951] Step g) Preparation of 3-(6-(4-((4-((1-((((1-(((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione carbamate

[0952] 125 mg, 109 μmol of tert-butyl(1R,5S)-3-(3-((1-((4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (125 mg, 109 μmol) was added to 4 M HCl EA solution (2 mL) and reacted at room temperature for 0.5 h. Concentrate under reduced pressure, and the residue was subjected to Prep-HPLC to give 3-(6-(4-((4-((1-((((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione carbamate in 17.2% yield.

[0953] 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.00 (d, J = 1.8 Hz,1H), 7.92 - 7.83 (m, 1H), 7.38 (t, J = 2.0Hz, 1H), 7.32 (t, J = 8.8 Hz, 1H),7.23 (d, J = 6.2 Hz, 2H), 6.68 - 6.56 (m, 2H), 4.63 (dd, J = 8.4, 12.4 Hz,2H), 4.50 (d, J = 11.4 Hz, 1H), 4.39 - 4.22 (m, 4H), 4.02 (d, J = 10.2 Hz,1H), 3.94 (d, J = 1.6 Hz, 3H), 3.86 (d, J = 4.0 Hz, 1H), 3.76 (t, J = 8.2 Hz,2H), 3.62 - 3.00 (m, 9H), 2.85 - 2.57 (m, 7H), 2.47 - 2.24 (m, 3H), 2.18 -1.97 (m, 3H), 1.83 (s, 3H), 1.35 (d, J = 7.8 Hz, 3H), 0.93 (d, J = 7.0 Hz, 2H), 0.76 (d, J = 11.0 Hz, 2H).

[0954] ESI-MS m / z = 1007.5 [M+H] +

[0955] Example 21 Preparation of 3-(6-(4-(7-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Refer to Example 19)

[0956]

[0957] According to the synthesis method of Example 19, intermediate XI was replaced with intermediate X, and other operations were the same, to obtain 3-(6-(4-(7-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione.

[0958] 1 H NMR (400 MHz, MeOD-d4) δ 8.67 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 7.97 - 7.84 (m, 2H), 7.43 (s, 1H), 7.36 (t, J = 8.8 Hz, 1H), 7.29 (s, 1H), 6.75-6.71 (m, 2H), 4.59 (d, J = 13.2 Hz, 1H), 4.51 - 4.20 (m, 6H), 4.06 (d, J= 13.6 Hz, 1H), 4.01 - 3.89 (m, 4H), 3.87 - 3.47 (m,7H), 3.30 - 2.89 (m,8H), 2.79-2.69 (m, 2H), 2.61 - 1.93 (m, 15H), 0.99 (s, 2H), 0.90 (s, 2H).

[0959] ESI-MS m / z = 1032.4 [M+H] +

[0960] Example 22 Synthesis of 3-(6-(4-(7-(1-((1-((1-((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0961]

[0962] Step a) Synthesis of compound tert-butyl 4-(2-(4-(3-(2,6-dioxoperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)piperidine-1-carboxylic acid

[0963] 3-(6-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione (100 mg, 0.21 mmol), 1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid (53.2 mg, 0.21 mmol), and DIEA (0.1 mL, 0.63 mmol) were added to DMF (2 mL), and HATU (122.2 mg, 0.32 mmol) was added. The mixture was reacted at room temperature for 2 hours. The mixture was diluted with water, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by silica gel chromatography to obtain tert-butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)piperidin-1-carboxylic acid, with a yield of 95.2%.

[0964] ESI-MS m / z = 680.4 [M+H] +

[0965] Step b) Synthesis of compound 3-(4-fluoro-1-methyl-6-(4-(7-(piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione

[0966] 70 mg (0.10 mmol) of 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)piperidin-1-carboxylic acid tert-butyl ester was added to DCM (2 mL), followed by the addition of TFA (1 mL), and the mixture was reacted at room temperature for 0.5 h. The crude product was obtained after concentration under reduced pressure and used directly in the next step.

[0967] ESI-MS m / z = 580.3 [M+H] +

[0968] Step c) Synthesis of compound 3-(3-((1-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0969] The crude product from the previous step, intermediate VI (50 mg, 0.06 mmol), potassium iodide (20 mg, 0.12 mmol), and potassium carbonate (42 mg, 0.30 mmol) were added to DMF (2 mL) and 30 mL was added. o The reaction was carried out at C for 16 hours. The mixture was diluted with water, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by silica gel column chromatography to give compound 3-(3-((1-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 57.1%.

[0970] ESI-MS m / z = 1288.6 [M+H] +

[0971] Step d) Synthesis of compound 3-(6-(4-(7-(1-(1-(((1-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofuran[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)spiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione carbamate

[0972] 3-(3-((1-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (44 mg, 0.03 mmol) was dissolved in 4 mL ACN, and 4 M HCl EA solution (1 mL) was added. The mixture was stirred in an ice bath for 1 h. The compound was concentrated at low temperature and purified by Prep-HPLC to give 3-(6-(4-(7-(1-(1-(((1-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofuran[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)spiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione carbamate (21.7 mg, yield 63.3%).

[0973] 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 7.96 (s, 1H), 7.93 -7.87 (m, 1H), 7.42 - 7.37 (m, 1H), 7.37 - 7.30 (m, 1H), 7.27 - 7.18 (m, 2H),6.74 - 6.66 (m, 1H), 6.65 (s, 1H), 4.64 - 4.57 (m, 1H), 4.55 - 4.47 (m, 1H),4.46 - 4.39 (m, 1H), 4.37 - 4.30 (m, 1H), 4.29 - 4.24 (m, 1H), 4.18 - 4.03(m, 2H), 3.97 - 3.90 (m, 4H), 3.88 - 3.71 (m, 3H), 3.59 - 3.44 (m, 4H), 3.37(s, 3H), 3.22 (s, 2H), 3.12 - 2.94 (m, 4H), 2.90 (s, 1H), 2.78 - 2.62 (m,6H), 2.46 - 1.93 (m, 13H), 1.86 - 1.77 (m, 2H), 1.69 - 1.52 (m, 4H), 0.98 (s,2H), 0.84 (s, 2H).

[0974] ESI-MS m / z = 1144.5 [M+H] +

[0975] Example 23 Preparation of 3-(6-(4-(1-(1-((((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0976]

[0977] Step a) Synthesis of tert-butyl ((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)carbamate

[0978] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-4-fluoro-1-methyl-1H-indazole (1.5 g, 2.90 mmol), tert-butyl(piperidin-4-ylmethyl)carbamate (744 mg, 3.48 mmol), sodium tert-butoxide (836 mg, 8.71 mmol), and RuPhos-Pd-G3 (485 mg, 0.58 mmol) were dissolved in 1,4-dioxane (20 mL) and reacted at 110 °C for 2 hours. The reaction solution was concentrated and purified by silica gel chromatography to give tert-butyl((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperidin-4-yl)methyl)carbamate, in 95.1% yield.

[0979] ESI-MS m / z = 652.3 [M+H] +

[0980] Step b) Synthesis of tert-butyl((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)carbamate

[0981] 500 mg (0.76 mmol) of tert-butyl((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperidin-4-yl)methyl)carbamate was dissolved in 15 mL of DMF. Sodium hydride (61 mg, 1.5 mmol) was added in an ice bath, and the reaction was carried out at 25 °C for 0.5 h. Iodomethane (161 mg, 1.14 mmol) was then added, and the mixture was stirred at 25 °C for 4 h. The reaction solution was quenched with saturated ammonium chloride, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give tert-butyl((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperidin-4-yl)methyl)(methyl)carbamate in 88.8% yield.

[0982] ESI-MS m / z = 666.3 [M+H] +

[0983] Step c) Synthesis of tert-butyl((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)carbamate

[0984] tert-butyl((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperidin-4-yl)methyl)(methyl)carbamate (450 mg, 0.67 mmol) and palladium on carbon (10%) (200 mg) were dispersed in 20 mL of ethanol and stirred at 40 °C for 24 hours in hydrogen atmosphere. After the reaction was complete, dichloromethane and methanol (10:1) (40 mL) were added and stirred for 10 minutes. The mixture was then filtered, and the filtrate was concentrated to give tert-butyl((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazole-6-yl)piperidin-4-yl)methyl)(methyl)carbamate, in a yield of 61.1%.

[0985] ESI-MS m / z = 488.3 [M+H] +

[0986] Step d) Synthesis of 3-(4-fluoro-1-methyl-6-(4-(((methylamino)methyl)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione

[0987] 200 mg (0.41 mmol) of tert-butyl((1-(3-(2,6-dioxoperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)carbamate was dissolved in 5 mL of DCM and 2 mL of trifluoroacetic acid at 25 °C. 0 The reaction was carried out at C for 1.5 h. The reaction solution was concentrated to give crude 3-(4-fluoro-1-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione, with a yield of 94.2%.

[0988] ESI-MS m / z = 388.2 [M+H] +

[0989] Step e) Synthesis of tert-butyl 4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)amino)piperidin-1-carboxylic acid

[0990] Dissolve 3-(4-fluoro-1-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione (150 mg, 0.38 mmol) and tert-butyl 4-oxopiperidin-1-carboxylic acid (227 mg, 1.14 mmol) in 5 mL of DMA, add one drop of acetic acid, and stir at 50 mL of DMA. 0The reaction was carried out at C for 8 hours. After cooling to room temperature, sodium cyanoborohydride (47 mg, 0.76 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with water and EA, washed with saturated brine of the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product, and purified by silica gel chromatography to give tert-butyl 4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)amino)piperidin-1-carboxylic acid, 55.4% yield.

[0991] ESI-MS m / z = 571.3 [M+H] +

[0992] Step f) Synthesis of 3-(4-fluoro-1-methyl-6-(4-((methyl(piperidin-4-yl)amino)methyl)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate

[0993] 4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)amino)piperidin-1-carboxylic acid tert-butyl ester (120 mg, 0.21 mmol) was dissolved in 5 mL of DCM, and 2 mL of TFA was added. The reaction mixture was reacted for 1 hour. The reaction solution was concentrated to give 3-(4-fluoro-1-methyl-6-(4-(((methyl(piperidin-4-yl)amino)methyl)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate in 95.6% yield.

[0994] ESI-MS m / z = 471.3 [M+H] +

[0995] Step g) Synthesis of 3-(3-((1-((4-(((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)amino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolino-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0996] Intermediate VI (50 mg, 0.06 mmol), 3-(4-fluoro-1-methyl-6-(4-(((methyl(piperidin-4-yl)amino)methyl)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (43 mg, 0.09 mmol), potassium carbonate (41 mg, 0.32 mmol), and potassium iodide (50 mg, 0.32 mmol) were dissolved in 4 mL of DMF and dissolved at 30 °C. o The reaction was carried out at C for 16 h. Water and EA were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to obtain 3-(3-((1-((4-(((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)amino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, yield 70.7%.

[0997] ESI-MS m / z = 1179.6 [M+H] +

[0998] Step h) Synthesis of 3-(6-(4-(((1-((1-(((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0999] 3-(3-((1-((4-(((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)amino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.04 mmol) was dissolved in 4 mL of acetonitrile, and 4M HCl EA solution (1 mL) was added dropwise under ice bath. The reaction was allowed to proceed for 1 hour. The reaction solution was concentrated at 0℃ to obtain a crude product. The crude product was sent to Prep-HPLC to prepare 3-(6-(4-(((1-((1-(((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione carbamate, with a yield of 58.6%.

[1000] 1 H NMR (400 MHz, MeOD-d4) δ 8.33 (s, 1H), 7.97 (s, 1H), 7.86 - 7.77(m, 1H), 7.40 - 7.26 (m, 2H), 7.23 (s, 2H), 6.60-6.55 (m, 2H), 4.64-4.58 (m,2H), 4.45-4.42 (m, 1H), 4.37 - 4.25 (m, 2H), 4.20-4.12 (m, 2H), 4.01-3.98 (m,1H), 3.93 (s, 3H), 3.88-3.85 (m, 1H), 3.73-3.70 (m, 3H), 3.63-3.58 (m, 1H),3.10-2.98 (m, 3H), 2.92-2.88 (m, 1H), 2.83 - 2.59 (m, 8H), 2.53 (s, 3H),2.42-2.25 (m, 3H), 2.17 - 1.71 (m, 10H), 1.31-1.23 (m, 2H), 0.92 (s, 2H), 0.75-0.73 (m, 2H).

[1001] ESI-MS m / z = 1035.5 [M+H] +

[1002] Example 24 Synthesis of 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-6-nitrile (refer to Example 10)

[1003]

[1004] According to the synthesis methods in steps i and j of Example 10, intermediates VII and 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-2,6-dione were replaced with intermediates VIII and X, respectively, with the other operations being the same, to obtain 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-6-nitrile).

[1005] 1H NMR (400 MHz, Methanol-d4) δ 8.30 - 8.18 (m, 2H), 7.85 (s, 1H), 7.47 - 7.32 (m, 2H), 7.18 (s, 1H), 6.69 (d, J = 17.5 Hz, 2H), 4.76 (d, J =8.0 Hz, 1H), 4.64 (t, J = 7.8 Hz, 2H), 4.42 (d, J = 11.2 Hz, 1H), 4.29 (dd, J= 11.0, 5.0 Hz, 1H), 4.17 (d, J = 10.8 Hz, 2H), 3.96 (d, J = 1.8 Hz, 4H),3.87 (d, J = 14.0 Hz, 1H), 2.33 - 3.31 (m, 9H), 3.22 (d, J = 8.6 Hz, 2H), 3.02 (s, 1H), 2.88 - 2.59 (m, 6H), 2.41 (d, J = 11.0 Hz, 1H), 2.28 (dd, J =13.6, 5.6 Hz, 1H), 2.23 - 1.78 (m, 12H), 1.00 (s, 2H), 0.88 (d, J = 6.4 Hz, 2H).

[1006] ESI-MS m / z = 1018.5 [M+H] +

[1007] Example 25 Synthesis of 3-(6-(1-(7-((1-((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indol-3-yl)piperidin-2,6-dione (refer to Example 10)

[1008]

[1009] According to the synthesis method in steps a to j of Example 10, 6-chloro-1H-pyrrolo[2,3-b]pyridine and intermediate VII were replaced with 6-bromo-4-fluoro-1H-indole and intermediate VI, respectively, and the other operations were the same, to obtain 3-(6-(1-(7-((1-((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)piperidin-4-yl)-4-fluoro-1-methyl-1H-indole-3-yl)piperidin-2,6-dione.

[1010] 1 H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 7.96 (s, 1H), 7.92 -7.84 (m, 1H), 7.37 (s, 1H), 7.36 - 7.29 (m, 1H), 7.26 - 7.17 (m, 2H), 7.10(s, 1H), 7.07 (s, 1H), 6.66 (d, J = 12.0 Hz, 1H), 4.63 - 4.40 (m, 3H), 4.36 -4.26 (m, 1H), 4.14 - 4.08 (m, 1H), 4.08 - 3.96 (m, 2H), 3.95 - 3.87 (m, 1H), 3.86 - 3.79 (m, 1H), 3.78 (s, 3H), 3.51 - 3.33 (m, 4H), 3.28 - 3.05 (m, 5H), 2.93 (s, 1H), 2.91 - 2.84 (m, 1H), 2.82 - 2.72 (m, 1H), 2.71 - 2.54 (m, 3H), 2.40 - 2.15 (m, 5H), 2.11 - 1.86 (m, 13H), 0.95 (s, 2H), 0.81 (s, 2H).

[1011] ESI-MS m / z = 1031.5 [M+H] +

[1012] Example 26 Preparation of 3-(6-(4-(7-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Refer to Example 19)

[1013]

[1014] According to the synthesis methods of steps a and b in Example 19, intermediates III and X were replaced with intermediates XII and XI, respectively, and the other operations were the same, to obtain 3-(6-(4-(7-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-4-fluoro-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione.

[1015] 1 H NMR (400 MHz, MeOD-d4) δ 8.70 (d, J = 5.2 Hz, 1H), 8.41 (s, 1H), 7.85 (d, J = 5.2 Hz, 1H), 7.76 - 7.64 (m, 1H), 7.36 (s, 1H), 7.28 (t, J = 9.2Hz, 1H), 7.13 (s, 1H), 6.68-6.64 (m, 2H), 4.61-4.52 (m, 1H), 4.42 (s, 2H),4.37 - 4.23 (m, 2H), 4.14-4.08 (m, 2H), 4.02 - 3.83 (m, 5H), 3.48-3.35 (m,7H), 3.23 - 2.98 (m, 4H), 2.83 - 2.63 (m, 6H), 2.44 - 2.12 (m, 6H), 2.11 -1.81 (m, 10H), 0.94 (s, 2H),0.83(s, 2H),0.68 (t, J = 7.2 Hz, 3H).

[1016] ESI-MS m / z = 1036.5 [M+H] +

[1017] Example 27 Synthesis of 3-(6-(4-(((1-((1-(((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)amino)methyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (Refer to Example 23)

[1018]

[1019] According to the synthesis method in steps c to h of Example 23, 4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)(methyl)amino)piperidin-1-carboxylic acid tert-butyl ester was replaced with tert-butyl((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)carbamate, and other operations were performed. Using the same method, 3-(6-(4-(((1-((1-(((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)amino)methyl)piperidin-1-yl)-4-fluoro-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione was obtained.

[1020] 1H NMR (400 MHz, MeOD-d4)δppm 8.40 (s, 1H), 8.08 (s, 1H), 7.92 - 7.82(m, 1H), 7.39 (s, 1H), 7.32 (t, J = 8.6 Hz, 1H), 7.26 (d, J = 7.0 Hz, 2H),7.00 (s, 1H), 6.83 (d, J = 12.4 Hz, 1H),4.80 (s, 1H), 4.64 - 4.38 (m, 1H),4.38 - 4.14 (m, 1H), 3.98 (d, J = 16.0 Hz, 6H), 3.82 (d, J = 12.0 Hz, 2H),3.56 (s, 2H), 3.50 - 3.35 (m, 2H), 3.23 (s, 5H), 3.20 - 3.02 (m, 5H), 2.87 -2.62 (m, 3H), 2.35 (dd, J = 34.8, 20 Hz, 7H), 2.20 - 1.89 (m, 6H), 1.61 (d, J= 11.0 Hz, 2H), 1.07 (d, J= 19.0 Hz, 2H), 0.97 (s, 2H).

[1021] ESI-MS m / z = 1021.5 [M+H] +

[1022] Example 28 Synthesis of 3-(6-(1-(7-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)piperidin-2,6-dione (Refer to Example 10)

[1023]

[1024] According to the synthesis method in steps a to j of Example 10, 6-chloro-1H-pyrrolo[2,3-b]pyridine was replaced with 6-bromo-1H-pyrazolo[4,3-B]pyridine and intermediate VI, respectively, and the other operations were the same, to obtain 3-(6-(1-(7-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)piperidin-2,6-dione.

[1025] 1 H NMR (400 MHz, Methanol-d4)δppm 8.44 (d, J = 10.8 Hz, 1H), 8.41 (s,1H), 7.96 (d, J = 18.0 Hz, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.30- 7.20 (m, 2H), 7.05 (s, 1H), 4.57 - 4.41 (m, 4H), 4.37 (d, J = 12.8 Hz, 1H), 4.08 (s, 3H), 4.00 (d, J = 17.3 Hz, 2H), 3.88 (d, J = 18.8 Hz, 2H), 3.48 (s,1H), 3.13 (s, 3H), 3.01 (s, 2H), 2.75 (d, J = 7.3 Hz, 2H), 2.59 (s, 2H), 2.53- 2.23 (m, 6H), 2.04 (d, J = 31.8 Hz, 16H), 1.46 - 1.22 (m, 2H), 0.96 (s,2H), 0.82 (s, 2H), 0.56 (t, J = 7.6 Hz, 3H).

[1026] ESI-MS m / z: 1019.5 [M+H] +

[1027] Example 29 Synthesis of 3-(6-(1-(7-((1-(((1-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-3-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methylimidazo[1,5-a]pyridin-1-yl)piperidin-2,6-dione

[1028]

[1029] Step a) Synthesis of N-((5-bromopyridin-2-yl)methyl)acetamide

[1030] (5-Bromopyridin-2-yl)methylamine (2.5 g, 13 mmol) was dissolved in 60 mL of DCM. Triethylamine (2.7 g, 26.7 mmol) and acetic anhydride (2.7 g, 26.7 mmol) were added under ice bath conditions, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography to give N-((5-bromopyridin-2-yl)methyl)acetamide, in 65.8% yield.

[1031] ESI-MS m / z = 229.0 [M+H] +

[1032] Step b) Synthesis of 6-bromo-3-methylimidazo[1,5-a]pyridine

[1033] Phosphorus oxychloride (1.7 g, 11.4 mmol) was slowly added dropwise to a solution of N-((5-bromopyridin-2-yl)methyl)acetamide (1.3 g, 5.7 mmol) in toluene (30 mL). The solution was heated at 110 °C. o Stirred at C for 16 h. After removing toluene by vacuum concentration, the mixture was extracted with saturated NaHCO3 aqueous solution and DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to obtain 6-bromo-3-methylimidazo[1,5-a]pyridine, with a yield of 87.8%.

[1034] ESI-MS m / z = 211.0 [M+H] +

[1035] 1H NMR (400 MHz, DMSO-d6) δppm 8.41 (s, 1H), 8.41 (s, 1H), 7.49 (d, J = 9.5 Hz, 1H), 7.31 (s, 1H), 6.77 (d, J = 9.5 Hz, 1H), 2.57 (s, 3H).

[1036] Step c) Synthesis of 6-bromo-1-iodo-3-methylimidazo[1,5-a]pyridine

[1037] 6-Bromo-3-methylimidazo[1,5-a]pyridine (1.1 g, 5.2 mmol) was dissolved in ACN (10 mL), and a solution of NIS (1.2 g, 5.2 mmol) in ACN (10 mL) was added dropwise under ice bath conditions. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (to obtain 6-bromo-1-iodo-3-methylimidazo[1,5-a]pyridine, yield 89.8%).

[1038] ESI-MS m / z = 336.9 [M+H] +

[1039] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (s, 1H), 7.22 (d, J = 9.6 Hz, 1H), 6.88 (d, J = 9.6 Hz, 1H), 2.58 (s, 3H).

[1040] Step d) Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-3-methylimidazo[1,5-a]pyridine

[1041] 6-Bromo-1-iodo-3-methylimidazo[1,5-a]pyridine (1.5 g, 4.45 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (1.9 g, 4.45 mmol), cesium carbonate (3.8 g, 17.82 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (651.2 mg, 0.89 mmol) were dissolved in 1,4-dioxane (14 mL) and water (2 mL), and reacted under nitrogen at 80 °C for 16 h. The reaction system was concentrated, and the residue was purified by silica gel chromatography to give 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-3-methylimidazo[1,5-a]pyridine in 90% yield.

[1042] ESI-MS m / z = 500.1 [M+H] +

[1043] Step e) Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidine-1-carboxylic acid

[1044] 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-3-methylimidazo[1,5-a]pyridine (2.8 g, 5.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.6 g, 8.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.4 g, 0.56 mmol) and cesium carbonate (5.5 g, 17 mmol) were dissolved in 1,4-dioxane (14 mL) and water (2 mL) and heated in nitrogen at 100 °C. o The reaction was carried out at C for 16 h. The reaction system was concentrated, and the residue was purified by silica gel chromatography to give tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidine-1-carboxylic acid, with a yield of 87.8%.

[1045] ESI-MS m / z = 603.3 [M+H] +

[1046] Step f) Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidine-1-carboxylic acid

[1047] 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 0.83 mmol) was dissolved in 10 mL of ethanol, and Pd / C (100 mg) and Pd(OH)2 / C (20 mg) were added. The reaction was carried out at room temperature in hydrogen atmosphere for 0.5 h. The mixture was then filtered, concentrated, and the residue was purified by silica gel column chromatography to give 4-(1-(2,6-dioxopiperidine-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidine-1-carboxylic acid tert-butyl ester, in 10.8% yield.

[1048] ESI-MS m / z = 427.2 [M+H] +

[1049] Step g) Synthesis of 3-(3-methyl-6-(piperidin-4-yl)imidazo[1,5-a]pyridin-1-yl)piperidin-2,6-dione

[1050] 4-(1-(2,6-dioxopiperidin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.09 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added. The mixture was reacted at room temperature for 2 hours. The crude product was concentrated and used directly in the next step.

[1051] ESI-MS m / z = 327.2 [M+H] +

[1052] Step h) Synthesis of tert-butyl 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3,5]nonane-7-carboxylic acid

[1053] The crude product from the previous step, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (66 mg, 0.28 mmol), was dissolved in 3 mL of DMA, and 50 μL of acetic acid was added. The solution was then heated to 50 mL of DMA. o The reaction was carried out at C for 3 h. Then, sodium triacetoxyborohydride (20 mg, 0.09 mmol) was added in an ice bath, and the reaction was carried out at room temperature for 3 h. The mixture was extracted with water and EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by silica gel column chromatography to give tert-butyl 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3,5]nonane-7-carboxylic acid, with a two-step yield of 57.8%.

[1054] ESI-MS m / z = 550.3 [M+H] +

[1055] Step i) Synthesis of 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methylimidazo[1,5-a]pyridin-1-yl)piperidin-2,6-dione

[1056] 70 mg (0.13 mmol) of tert-butyl 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3,5]nonane-7-carboxylic acid was dissolved in 5 mL of DCM and 1 mL of trifluoroacetic acid and reacted at room temperature for 2 h. The crude product was concentrated and used directly in the next step.

[1057] ESI-MS m / z = 450.3 [M+H] +

[1058] Step j) Synthesis of 3-(3-((1-((2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-5-fluorofurano[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1059] The crude product from the previous step, intermediate VII (70 mg, 0.08 mmol), and triethylamine (168 mg, 1.66 mmol) were dissolved in 1.5 mL of ACN and reacted at room temperature for 16 h. Extracted with water and EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give 3-(3-((1-((2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)...

Claims

1. A compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein, The compounds are selected from those represented by general formula (I). Where K is the KRAS protein binding fragment, selected from the binding fragments of formulas (K-1), (K-2), (K-3), (K-4), (K-5), and (K-6): 、 、 、 、 、 M is G1, G2, and G3 are each independently selected from N, O, S, CH, and C(C 1-6 Alkyl), C(CN), C(OH), C(C 1-6 alkoxy), C (halogen), C (ethynyl), C-NH (C 1-6 Alkyl) and CN (C 1-6 Alkyl)2; the This indicates that the ring contains double bonds; f is 0 or 1; D1 is selected from N, CH, C(C) 1-6 Alkyl), C(CN), C(OH), C(C 1-6 Alkyl groups and C (halogens); Each R1, R2, R3, R4, and R5 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, alkynyl, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups; Each m is independently 0, 1, 2, 3 or 4; Each n is independently 0, 1, 2 or 3; Each r is independently 0, 1, or 2; A is a 5- to 10-membered heterocyclic alkyl group; preferably, A is... , , , , , , , , or ; L is L1-L2-L3-L4-L5; Where L1 is a bond or -(CH2) 1-3 -; L2 is selected from the bond and -(CH2). p1 (CR b R c ) p2 (CH2) p3 -; L3 is selected from the bond, -NR a - 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 8-11 membered spirocycloalkyl, 8-10 membered fused cycloalkyl, 8-11 membered azaspirocycloalkyl, and 8-10 membered azafused cycloalkyl, wherein the 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 8-10 membered spirocycloalkyl, 8-10 membered fused cycloalkyl, 8-11 membered azaspirocycloalkyl, and 8-10 membered azafused cycloalkyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2; L4 is selected from bond, -O-, -C(=O-), -(CR b R c ) s1 O(CR b R c ) s2 -、-(CR d R e ) s3 -、-NR f (CR b R c ) s4 -、-(CR b R c ) s4 NR f -、 -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocycloalkyl, -C(O)-8-11 membered spirocycloalkyl, -C(O)-8-10 membered fused cycloalkyl, -C(O)-8-11 membered azaspirocycloalkyl, -C(O)-8-10 membered azafused cycloalkyl, -(CR d R e ) s3 -3-6 membered cycloalkyl groups and -(CR d R e ) s3 -4-6-membered heterocyclic alkyl; wherein the -C(O)-3-6-membered heterocyclic alkyl, -C(O)-3-6-membered heterocyclic alkyl, -C(O)-8-11-membered spirocyclic alkyl, -C(O)-8-10-membered fused cyclic alkyl, -(CR d R e ) s3 -3-6 membered cycloalkyl groups, -(CR d R e ) s3 -4-6 membered heterocyclic alkyl groups, -C(O)-8-11 membered azaspirocyclic alkyl groups, and -C(O)-8-10 membered azafused cyclic groups can be substituted by the following substituents: halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2; L5 is selected from the key, -(CR d R e ) s3 -、 phenyl, 6-membered heteroaryl, 3-6-membered cycloalkyl, 4-11-membered heterocycloalkyl and 4-11-membered heterocycloalkyl carbonyl; wherein the phenyl, 6-membered heteroaryl, 3-6-membered cycloalkyl and 4-11-membered heterocycloalkyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2; p1, p2, p3, s1, s2, s3, and s4 are each independently selected from integers from 0 to 6; R a Selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl groups and -(CH2) 1-2 S(O)2C 1-6 alkyl; Each R b R c R d R e Each is independently selected from hydrogen, =CH, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, halogen, cyano, halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, =O, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl group, -(CH2) 1-2 S(O)2C 1-6 Alkyl, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl; as a choice R b and R c Together with the carbon atoms they are attached to, they constitute C. 3-6 4-6 membered heterocyclic alkyl or cyclocyclic alkyl, R d R e Together with the carbon atoms they are attached to, they constitute C. 3-6 Memberial cycloalkyl or 4-6 membered heterocycloalkyl; Each R f Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl group, -(CH2) 1-2 S(O)2C 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl; E is selected from the VHL or CRBN combination fragments shown in E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, and E-13: , , , , , , , , , , , or ; This indicates that the ring contains double bonds; Each X1 is independently selected from NH, N(C) 1-6 Alkyl), CH2, CH(C) 1-6 Alkyl), CH, C(C) 1-6 Alkyl groups and C(CN); Each X2, X3, X4, X5, X6, X7, and X8 is independently selected from N, CH, and C(C). 1-6 Alkyl), C(CN), C(C) 1-6 alkoxy), C (halogen), C-NH (C 1-6 Alkyl) and CN (C 1-6 Alkyl)2; X9, X 10 For N or C, X9, X 10 Not both N; Each Y1 is independently selected from CH2, O, S, NH, NC 1-6 Alkyl groups, CHF, CF2, C(CH3)2, and CHCF3; Each Y2 is independently selected from CH, N, CF, C(CH3) and CCF3; Z1 and Z2 are each independently selected from CH2, O, S, NH and NC. 1-6 alkyl; Each R6, R7, R8, R9, R 11 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkoxy, -C(O)NH2, Halogenated C 1-6 Alkoxy, -N(C) 1-6 Alkyl groups)2, -C(O)OH and -C(O)OC 1-6 alkyl; R 10 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and hydroxyl-substituted C 1-6 alkyl; R 12 Selected from hydrogen, halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2; Each R 13 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2; R 14 Selected from hydrogen, methyl, ethyl, and hydroxy-substituted methyl groups; Each t is 0, 1, or 2; Each v is 0, 1, or 2; Each q is 0, 1, 2, 3, or 4; B is selected from phenyl, 5-6-membered heteroaryl, wherein the phenyl, 5-6-membered heteroaryl is substituted by the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2、-C(O)NH2; The condition is: when K is equal to (K-2), L1 does not exist and L2 is equal to... A is And E is not or .

2. A compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein, The compounds are selected from those represented by general formula (I). Where K is the KRAS protein binding fragment, selected from the binding fragments of formula (K-1), formula (K-2), and formula (K-3): 、 、 M is G1, G2, and G3 are each independently selected from N, O, S, CH, and C(C 1-6 Alkyl), C(CN), C(OH), C(C 1-6 alkoxy), C (halogen), C (ethynyl), C-NH (C 1-6 Alkyl) and CN (C 1-6 Alkyl)2; the This indicates that the ring contains double bonds; f is 0 or 1; D1 is selected from N, CH, C(C) 1-6 Alkyl), C(CN), C(OH), C(C 1-6 Alkyl groups and C (halogens); Each R1, R2, R3, R4, and R5 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, alkynyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups; Each m is independently 0, 1, 2, 3 or 4; Each n is independently 0, 1, 2 or 3; Each r is independently 0, 1, or 2; A is , , , , , , , , or ; L is L1-L2-L3-L4-L5; Where L1 is a bond or -(CH2) 1-3 -; L2 is selected from the bond and -(CH2). p1 (CR b R c ) p2 (CH2) p3 -; L3 is selected from the bond, -NR a - 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 8-11 membered spirocycloalkyl, 8-10 membered fused cycloalkyl, 8-11 membered azaspirocycloalkyl, and 8-10 membered azafused cycloalkyl, wherein the 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 8-10 membered spirocycloalkyl, 8-10 membered fused cycloalkyl, 8-11 membered azaspirocycloalkyl, and 8-10 membered azafused cycloalkyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2; L4 is selected from bond, -O-, -C(=O-), -(CR b R c ) s1 O(CR b R c ) s2 -、-(CR d R e ) s3 -、-NR f (CR b R c ) s4 -、-(CR b R c ) s4 NR f -、 -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocycloalkyl, -C(O)-8-11 membered spirocycloalkyl, -C(O)-8-10 membered fused cycloalkyl, -C(O)-8-11 membered azaspirocycloalkyl, -C(O)-8-10 membered azafused cycloalkyl, -(CR d R e ) s3 -3-6 membered cycloalkyl groups and -(CR d R e ) s3 -4-6-membered heterocyclic alkyl; wherein the -C(O)-3-6-membered heterocyclic alkyl, -C(O)-3-6-membered heterocyclic alkyl, -C(O)-8-11-membered spirocyclic alkyl, -C(O)-8-10-membered bridged cyclic alkyl, -(CR d R e ) s3 -3-6 membered cycloalkyl groups, -(CR d R e ) s3 -4-6 membered heterocyclic alkyl groups, -C(O)-8-11 membered azaspirocyclic alkyl groups, and -C(O)-8-10 membered azafused cyclic groups can be substituted by the following substituents: halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2; L5 is selected from the key, -(CR d R e ) s3 - Phenyl, 6-membered heteroaryl, 3-6-membered cycloalkyl, and 4-6-membered heterocycloalkyl; wherein the phenyl, 6-membered heteroaryl, 3-6-membered cycloalkyl, and 4-6-membered heterocycloalkyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2; p1, p2, p3, s1, s2, s3, and s4 are each independently selected from integers from 0 to 6; R a Selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl groups and -(CH2) 1-2 S(O)2C 1-6 alkyl; Each R b R c R d R e Each is independently selected from hydrogen, =CH, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, halogen, cyano, halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, =O, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl group, -(CH2) 1-2 S(O)2C 1-6 Alkyl, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl; as a choice R b and R c Together with the carbon atoms they are attached to, they constitute C. 3-6 4-6 membered heterocyclic alkyl or cyclocyclic alkyl, R d R e Together with the carbon atoms they are attached to, they constitute C. 3-6 Memberial cycloalkyl or 4-6 membered heterocycloalkyl; Each R f Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -S(O)2C 1-6 Alkyl group, -(CH2) 1-2 S(O)2C 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl; E is selected from the VHL or CRBN combination fragments shown in E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, and E-10: 、 、 、 、 、 、 、 、 、 ； This indicates that the ring contains double bonds; Each X1 is independently selected from NH, N(C) 1-6 Alkyl), CH2, CH(C) 1-6 Alkyl), CH, C(C) 1-6 Alkyl groups and C(CN); Each X2, X3, X4, X5, X6, X7, and X8 is independently selected from N, CH, and C(C). 1-6 Alkyl), C(CN), C(C) 1-6 alkoxy), C (halogen), C-NH (C 1-6 Alkyl) and CN (C 1-6 Alkyl)2; X9, X 10 For N or C, X9, X 10 Not both N; Each Y1 is independently selected from CH2, O, S, NH, NC 1-6 Alkyl groups, CHF, CF2, C(CH3)2, and CHCF3; Each Y2 is independently selected from CH, N, CF, C(CH3) and CCF3; Z1 and Z2 are each independently selected from CH2, O, S, NH and NC. 1-6 alkyl; Each R6, R7, R8, R9, R 11 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkoxy, -C(O)NH2, Halogenated C 1-6 Alkoxy, -N(C) 1-6 Alkyl groups)2, -C(O)OH and -C(O)OC 1-6 alkyl; R 10 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and hydroxyl-substituted C 1-6 alkyl; R 12 Selected from hydrogen, halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2; Each R 13 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered heterocyclic alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2; R 14 Selected from hydrogen, methyl, ethyl, and hydroxy-substituted methyl groups; Each t is 0, 1, or 2; Each v is 0, 1, or 2; Each q is 0, 1, 2, 3, or 4; B is selected from phenyl, 5-6-membered heteroaryl, wherein the phenyl, 5-6-membered heteroaryl is substituted by the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclic alkyloxy, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2、-C(O)NH2; The condition is: when K is equal to (K-2), L1 does not exist and L2 is equal to... A is And E is not .

3. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or eutectics, wherein L2 is a bond, -CH2CH(CH3)CH2- or .

4. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectics according to claim 1 or 2, wherein L1 is a bond.

5. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein R1 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 1-6 Alkyl group; preferably, R1 is independently selected from F, Cl, cyano, methyl, ethyl, amino, CF3 and hydroxyl.

6. The compound of claim 1 or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein R2 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, and C. 1-6 Alkyl group; preferably, R2 is independently selected from F, Cl, cyano, methyl, ethyl and hydroxy; more preferably, R2 is F.

7. The compound of claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein R3 is independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, ethynyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl and -N(C) 1-6 (alkyl)2; preferably, R3 is independently selected from F, Cl, cyano, methyl, ethyl, hydroxy and alkynyl; more preferably, R3 is ethyl, ethynyl or fluorine.

8. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein R4 and R5 are each independently selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, ethynyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl and -N(C) 1-6 (alkyl)2, r is 1; preferably, R4 and R5 are each independently selected from hydrogen, F, Cl, cyano, methyl, ethynyl, ethyl and hydroxyl, r is 1; more preferably, R4 is cyano, and R5 is independently selected from hydrogen, deuterium, F, cyano, methyl, ethyl, ethynyl and hydroxyl, r is 1.

9. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein G1, G2, and G3 are each independently selected from N and CH, C(C 1-3 Alkyl), C(CN), C(halogen), C(ethynyl), C(OH); preferably, G1 is CH, and G2 and G3 are N, C(CN), C(F), C(ethynyl), C(ethyl), CH or C(OH); more preferably, G1 is CH, G2 is ethyl or ethynyl, and G3 is F.

10. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectics according to claim 1, wherein f is 1.

11. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein M has the following structure: or .

12. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectics according to claim 1 or 2, wherein p1 is 0 or 1; p2 is 1 or 2; p3 is 0 or 1; s1 is 0, 1 or 2; s2 is 0, 1 or 2; s3 is 1 or 2; and s4 is 1 or 2.

13. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein the R a It is hydrogen or C 1-6 alkyl.

14. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein each R b R c R d R e Each is independently selected from hydrogen, =CH, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, halogen, cyano, halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, =O, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 Alkyl; as a choice R b and R c Together with the carbon atoms they are attached to, they constitute C. 3-6 4-6 membered heterocyclic alkyl or cyclocyclic alkyl, R d R e Together with the carbon atoms they are attached to, they constitute C. 3-6 Memberally cycloalkyl or 4-6-membered heterocycloalkyl; preferably, each R b R c R d R e Each is independently selected from hydrogen, =CH, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, halogen, cyano, amino, halogenated C 1-6 Alkyl, hydroxyl-substituted C 1-6 Alkyl, as a choice R b and R c Together with the carbon atoms they are attached to, they form cyclopropyl, cyclobutyl, oxocyclobutyl, and azircyclobutyl.

15. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein each R f Independently hydrogen, C 1-6 alkyl.

16. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein each X1 is independently NCH3, NH, or C-CH3; X2, X3, X4, X5, X6, X7, and X8 are each independently selected from N, CH, C(C) 1-6 Alkyl), C(CN) and C(halogen); preferably X2, X3, X4, X5, X6, X7 and X8 are each independently selected from N, CH, CCH3 and CF.

17. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectics according to claim 1 or 2, wherein each of Y1 is independently CH2 or O, and each of Y2 is independently CH, N or CF; preferably, each of Y1 is independently CH2 and each of Y2 is independently CH.

18. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein Z1 and Z2 are each independently selected from CH2, O, S, and -NC. 1-6 The alkyl group is preferably O, S, or CH2 for Z1; more preferably O; preferably O or CH2 for Z2; more preferably CH2 for Z2.

19. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals according to claim 1 or 2, R 12 Selected from hydrogen, halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl and -NH-C 1-6 Alkyl group; R is preferred 12 Selected from hydrogen, methyl, and F.

20. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, each R 13 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl)2; preferably, each R 13 It is independently selected from hydrogen, F, cyano, hydroxyl, amino, and methyl.

21. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein R6, R7, and R8 are each independently selected from hydrogen, halogen, cyano, -C(O)OH, -C(O)OC. 1-6 Alkyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)NH2, Halogenated C 1-6 Alkoxy and -N(C) 1-6 Alkyl group 2; preferably, R6, R7, and R8 are each independently selected from cyano, -C(O)OH, and -C(O)OC. 1-6 Alkyl, hydrogen, F, methyl, ethyl, -C(O)NH2.

22. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein R9 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl and C 1-6 Alkoxy; preferably R9 is hydrogen, F, methyl or ethyl.

23. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, each R 11 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl and C 1-6 Alkyl groups; as preferred R 11 It can be hydrogen, F, methyl, or ethyl.

24. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, R 10 It is methyl, ethyl, isopropyl or tert-butyl; more preferably isopropyl or tert-butyl.

25. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein B is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, pyrroleyl, thiazolyl, imidazoleyl, and pyrazolyl, wherein the phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, pyrroleyl, thiazolyl, imidazoleyl, and pyrazolyl groups may be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C(O)NH2, Halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2; preferably B is selected from phenyl, pyridyl, thiophene, thiazolyl, imidazole, pyrazolyl, pyrrolyl; the phenyl, pyridyl, thiophene, thiazolyl, imidazole, pyrazolyl, pyrrolyl can be substituted by the following substituents: F, Cl, methoxy, cyano, hydroxyl, amino, methyl, ethyl, isopropyl or -C(O)NH2.

26. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, having the general formula (I-1), (I-2), (I-3), (I-4), (I-5), or (I-6): 、 、 、 、 、 R1, R2, R3, R4, R5, L3, L4, L5, E, m, n, r, and A are as defined in claims 1-25.

27. The compound according to claim 1 or 2, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, having the form of formula (II-1), (II-2), (II-3), or (II-4): 、 、 、 Wherein R1, R2, R3, R5, L3, L4, L5, E, m, and n are as defined in claims 1-25.

28. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals according to claims 1-27, wherein L3 is selected from bonds, -NR a - Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, aziridine, piperidinyl, piperazine, 9-11 spirocyclic alkyl, 8 fused cyclic alkyl, 9-11 aziridine, 8 aziridine; wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, aziridine, piperidinyl, piperazine, 9-11 spirocyclic alkyl, 8 fused cyclic alkyl, 9-11 aziridine, and 8 aziridine can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 alkoxy or -N(C) 1-6 Alkyl)2; The preferred L3 is selected from the following groups, whether bonded, substituted, or unsubstituted: , , , , , The substituents thereon are halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NH-C 1-6 alkyl.

29. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectics according to claims 1-28, wherein L4 is selected from bonds, -C(=O)-, -O-, -CH2O(CH2)-, -C(CH3)2-, -(CH2). 1-2 -, -NHCH2-, -N(CH3)CH2-, -CH2NH-, -CH2N(CH3)-, , and .

30. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectics according to claims 1-29, wherein L5 is a bond, -CH2-, phenyl, 6-membered azira-aryl, 5-6-membered cycloalkyl, 5-11-membered heterocycloalkyl or 5-11-membered heterocycloalkyl carbonyl; wherein the phenyl, 6-membered azira-aryl, 5-6-membered cycloalkyl, 5-11-membered heterocycloalkyl or 5-11-membered heterocycloalkyl carbonyl can be substituted with the following substituents: halogen, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NH-C 1-6 alkyl; Preferably, L5 is a bond, -CH2-, substituted or non-substituted. , , , , , or The substituents are selected from halogens, C 1-6 Alkoxy, cyano, hydroxy, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -NH-C 1-6 alkyl.

31. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals according to claims 1-30, wherein E is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , or .

32. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or eutectics according to claims 1-31, wherein K is selected from the following structures: 、 、 、 , , , , , , and .

33. The compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals according to claims 1-32, wherein L is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , and .

34. The compound according to claim 1, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, having the structure of formula (III-1): Wherein L3, L4, and L5 are defined as described in claims 1-33, R3 is ethynyl or ethyl, R 15 X1 is methyl or F, and X2 is N or CH.

35. The compound according to claim 1, or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, having the structure of formula (IV-1): in, R3 is ethyl or ethynyl; E is... , , , , , or .

36. A compound or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals having the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 37. A pharmaceutical composition comprising the compound of any one of claims 1-36, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

38. Use of a compound according to any one of claims 1-36, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37, in the preparation of a medicament for regulating KRAS protein ubiquitination and degradation in a subject.

39. Use of any compound of claims 1-36, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 37, in the preparation of a medicament for treating and / or preventing diseases mediated or dependent on the KRAS protein, wherein the disease mediated by the KRAS protein is preferably a tumor.

40. The use according to claim 39, characterized in that, The diseases are 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 tumors, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell carcinoma, squamous cell carcinoma of the lung, lichenification, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma; preferably, the diseases are pancreatic cancer, colorectal cancer, or lung cancer.

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