KRAS pan-inhibitor and preparation method and application thereof

Abstract

The present application belongs to the field of medicinal chemistry, and particularly relates to KRAS pan-inhibitors represented by formula (I) and a preparation method and application thereof.

Description

Technical Field

[0001] This application belongs to the field of medicinal chemistry, specifically involving novel KRAS pan-inhibitors, their preparation methods, and applications. Background Technology

[0002] KRAS mutations are among the most common oncogenic drivers in solid tumors, with G12D mutations being prevalent in pancreatic cancer (39%), colorectal cancer (44%), and lung adenocarcinoma. Developing covalent inhibitors is extremely challenging due to the lack of traditional small molecule binding sites on the KRAS protein surface and the absence of active residues (such as cysteine ​​in G12C) in G12D mutants. Current technologies utilize KRAS G12C inhibitors (such as AMG510 and MRTX849) for targeting via covalent binding to cysteine, but they are ineffective against G12D. Non-covalent inhibitors (such as MRTX1133), while designed for G12D, suffer from insufficient affinity (higher IC50 values ​​for other mutants), poor selectivity (significant inhibition of wild-type KRAS), and drug resistance issues; recent clinical trials have abandoned them. Combination therapy strategies, such as combining KRAS inhibitors with MEK inhibitors or EGFR inhibitors, only partially alleviate drug resistance problems and have significant toxicity. KRAS pan-inhibitors are currently in a popular development stage, but there are still no reports of marketed drugs.

[0003] In summary, existing technologies for KRAS pan-inhibitors have the following drawbacks:

[0004] Limited efficacy: Monotherapy is insufficient to overcome compensatory activation of KRAS signaling pathways (such as the MEK / ERK pathway).

[0005] Drug resistance: Mutant cells escape inhibition through bypass signaling or microenvironmental remodeling. Preclinical studies have shown that bypass activation of the KRAS signaling pathway (such as the EGFR or PI3K pathway) may lead to resistance to monotherapy, requiring combination therapy to enhance efficacy.

[0006] Complex Synthesis: The preparation of some compounds (such as MRTX1133) involves cumbersome steps and low yields. For example, the pyrido[4,3-d]pyrimidine skeleton of MRTX1133 requires multiple substituent optimization steps (such as R2, R4, and R7 sites), making the synthetic route complex and potentially increasing production costs and the difficulty of impurity control.

[0007] Pharmacokinetic challenges exist: non-covalent binding mechanisms may lead to lower drug stability in vivo, shorter half-life, and the need for frequent dosing to maintain effective concentrations.

[0008] Limitations of clinical data: Currently, only preclinical research data (such as mouse xenograft models) are publicly available, and results from human clinical trials are lacking. Long-term toxicity, dose tolerability, and duration of efficacy are still unclear.

[0009] Therefore, there is a demand for pan-KRAS inhibitors. Summary of the Invention

[0010] The first aspect of this application provides a compound of formula (I), or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0011]

[0012] in,

[0013] Ring A and the fused pyrimidine ring together form the following bicyclic fused ring structure:

[0014]

[0015] X1 is selected from: N, CR1, where R1 is selected from H, C1-C6 alkyl, halogen;

[0016] Preferably, X1 is selected from: CH, CF;

[0017] X2 is selected from: CR2, where R2 is selected from:

[0018] H, C1-C6 alkyl,

[0019] Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl.

[0020] Among them, each R xb Whether the R values ​​are the same or different, each R value xb Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably H, hydroxyl, amino, halogen, C1-C6 haloalkyl, x2 is selected from integers from 1 to 5.

[0021] Y is selected from O, S, and HH, with O and HH being preferred, and each R xc Whether the R values ​​are the same or different, each R value xc Independently selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, preferably hydroxyl or amino, where x3 is an integer selected from 1 to 7.

[0022] Among them, each R xd Whether the R values ​​are the same or different, each R value xd Independently selected from amino, halogen, C1-C6 alkyl, cyano, and one or more R xd When present, it cannot be simultaneously a halogen or simultaneously a C1-C6 alkyl group, and x4 is selected from integers from 1 to 7;

[0023] Preferably, X2 is selected from CR2, where R2 is selected from H, C1-C6 alkyl.

[0024] Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, C1-C6 alkyl, and C2-C6 alkynyl groups.

[0025] Where R 4x R 5x R 6x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, preferably H, hydroxyl, amino, halogen, and C1-C6 haloalkyl.

[0026] Where Y is selected from O, S, and HH, with O and HH being preferred, and R... 7x Selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, with hydroxyl and amino being preferred.

[0027] Where R 8x R 9x R 10x R 11x R 12x R 13x Independently selected from H, amino, halogen, C1-C6 alkyl, cyano, and R 8x R 9x R 10x R 11x R 12x R 13x When not H, they cannot be halogens or C1-C6 alkyl groups simultaneously. Y1, Y2, and Y3 are independently selected from NH, S, O, N, and C.

[0028] More preferably, X2 is selected from: CR2, where R2 is selected from:

[0029]

[0030] X3 is selected from: N, CR3, where R3 is selected from H, C1-C6 alkyl;

[0031] Preferably, X3 is selected from: N, CH;

[0032] X4 is selected from: N, CR4, where R4 is selected from H, C1-C6 alkyl, halogen;

[0033] Preferably, X4 is selected from: N, CH;

[0034] X5 is selected from: O, =O, CR 51 R 52 Where R 51 R 52 Independently selected from H, C1-C6 alkyl groups;

[0035] Preferably, X5 is selected from: O, =O, CH2;

[0036] X6 is selected from: 1) NR6, where R6 is selected from:

[0037] Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, wherein R 1x R 2x R 3x The two elements in the formula cannot both be halogens. Among them, each R xe Whether the R values ​​are the same or different, each R value xe Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano, preferably H, amino, halogen, or cyano, x5 is selected from integers from 1 to 5.

[0038] Among them, each R xf Whether the R values ​​are the same or different, each R value xf Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, or C1-C6 alkoxy, where x6 is selected from integers from 1 to 7.

[0039] Among them, each R xg Whether the R values ​​are the same or different, each R value xgIndependently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, or C1-C6 alkoxy, x7 is selected from integers from 1 to 8.

[0040] 2) CR 61 R 62 , where R 61 R 62 Selected independently from:

[0041] H, C1-C6 alkyl,

[0042] Among them, each R xa Whether the R values ​​are the same or different, each R value xa Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, preferably H, hydroxyl, amino, halogen, C1-C6 alkyl, and C2-C6 alkynyl, where x1 is an integer selected from 1 to 7.

[0043] Among them, each R xe Whether the R values ​​are the same or different, each R value xe Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano, preferably H, amino, halogen, or cyano, x5 is selected from integers from 1 to 5.

[0044] Among them, each R xf Whether the R values ​​are the same or different, each R value xf Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, or C1-C6 alkoxy, where x6 is selected from integers from 1 to 7.

[0045] Among them, each R xg Whether the R values ​​are the same or different, each R value xg Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, C1-C6 alkoxy, and x7 is selected from integers from 1 to 8;

[0046] Preferably, X6 is selected from:

[0047] 1) NR6, where R6 is selected from:

[0048] Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, C2-C6 alkynyl groups, wherein R 1x R 2x R 3x The two elements in the formula cannot both be halogens.

[0049] Where R 14x R 15x R 16x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano, preferably H, amino, halogen, or cyano.

[0050] Where R 17x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, R 18x R 19x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, or R 18x R 19x Independently selected from C1-C6 alkyl groups, R 18x With R 19x And the carbon atoms connected to them are linked together to form a ring,

[0051] Where R 20x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, with hydroxyl, amino, and C1-C6 alkoxy being preferred.

[0052] Where R 21x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, with hydroxyl, amino, and C1-C6 alkoxy being preferred.

[0053] 2) CR 61 R 62 , where R 61 R 62 Selected independently from:

[0054] H, C1-C6 alkyl,

[0055] Where R 1x R 2x R 3xIndependently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, preferably H, hydroxyl, amino, halogen, C1-C6 alkyl, and C2-C6 alkynyl.

[0056] Where R 14x R 15x R 16x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano, preferably H, amino, halogen, or cyano.

[0057] Where R 17x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, R 18x R 19x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, or R 18x R 19x Independently selected from C1-C6 alkyl groups, R 18x With R 19x And the carbon atoms connected to them are linked together to form a ring,

[0058] Where R 20x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, with hydroxyl, amino, and C1-C6 alkoxy being preferred.

[0059] Where R 21x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, and C1-C6 alkoxy;

[0060] More preferably, X6 is selected from:

[0061] NR6, where R6 is selected from:

[0062] CR 61 R 62 Where R 61 R 62 Selected independently from: H,

[0063] X7 is selected from: C3-C6 cycloalkyl groups optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, or C1-C6 haloalkyl (e.g., cyclopropyl, cyclobutyl), O, CR 71 R 72 Where R 71 R 72 Independently selected from H, C1-C6 alkyl groups;

[0064] Preferably, X7 is selected from: cyclopropylene O, CH2;

[0065] X8 is selected from: C3-C6 cycloalkyl groups optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, or C1-C6 haloalkyl (e.g., cyclopropyl or cyclobutyl), =O, CR 81 R 82 Where R 81 R 82 Independently selected from H, C1-C6 alkyl groups;

[0066] Preferably, X8 is selected from: cyclopropylene =O, CH2;

[0067] R9 is selected from: aziridine, piperidinyl, aziridine-heptyl, oxaziridine-heptyl, diazabicyclo[2.2.2]octyl, cyclohexyl, cyclohexenyl, oxaziridine-heptenyl, methylamino:cyano, C1-C6 alkyl, hydroxyl, amino, halogen, C1-C6 alkoxy, fluorine-substituted cyclopropyl, piperazine-substituted by methyl or oxo, excluding: piperidinyl with only hydroxyl substituents, and aziridine-heptyl with only hydroxyl substituents;

[0068] More preferably, R9 is selected from:

[0069] W1 is selected from: direct bond, NH, O. Where R 1y R 2y Each is independently selected from H, C1-C6 alkyl groups. Where R 3y Selected from H, C1-C6 alkyl groups, with position 1 above connected to a pyrimidine ring, and position 2 above connected to R. 10 Connected;

[0070] Preferably, W1 is selected from: direct bonds, NH, O, Position 1 above is connected to the pyrimidine ring, and position 2 above is connected to R. 10 Connected;

[0071] R 10 Selected from:

[0072] 1) Where R s Selected from: 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S; 5-10 membered nitrogen-containing bridged ring heterocyclic groups; 5-10 membered nitrogen-containing fused ring heterocyclic groups; 5-10 membered nitrogen-containing spirocyclic heterocyclic groups; and amino groups. The 4-7 membered monocyclic heterocyclic group, 5-10 membered nitrogen-containing bridged ring heterocyclic group, 5-10 membered nitrogen-containing fused ring heterocyclic group, 5-10 membered nitrogen-containing spirocyclic heterocyclic group, and amino group are optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl, preferably C1-C6 alkyl, halogen, and C1-C6 haloalkyl.

[0073] 2) 5-10 member nitrogen-containing spirocyclic heterocyclic groups optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, preferably C1-C6 alkyl or halogen;

[0074] 3) 5-10 nitrogen-containing bridged ring heterocyclic groups optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, preferably C1-C6 alkyl or halogen;

[0075] 4) C3-C7 cycloalkyl groups optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, preferably C1-C6 alkyl or amino;

[0076] 5) A 4-7 membered monocyclic heterocyclic group comprising 1-2 heteroatoms selected from N, O, and S (e.g., azirrobutyl, thiocyclopentyl, azirropentyl, oxocyclohexyl, azirrohexyl, oxocyclohepyl, azirrohepyl, oxocyclohepyl, oxoazirrohepyl), wherein the 4-7 membered monocyclic heterocyclic group is optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxoyl, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, preferably C1-C6 alkyl, amino, oxoyl, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, halogen, C1-C6 alkoxy, aminoC1-C6 alkyl;

[0077] 6) Among them, R 1z R 2z R 3z R 4z R 5z Each of the following is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, C1-C6 alkylamino, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, S, optionally substituted C3-C7 cycloalkyl, preferably C1-C6 alkyl, amino, C1-C6 alkylamino, aminoC1-C6 alkyl, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, halogen, piperidinyl;

[0078] Or R 3z R 4z R 5z The two groups, together with their respective carbon atoms, form piperidinyl, halogen-substituted piperidinyl, azircyclic pentyl, halogen-substituted azircyclic pentyl, hydroxyl-substituted azircyclic pentyl, azircyclic butyl, halogen-substituted azircyclic butyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with azircyclic pentyl, optional 5-10 member nitrogen-containing spirocyclic heterocyclic group substituted with halogen, optional 5-10 member nitrogen-containing bridged ring heterocyclic group substituted with halogen or halogen alkenyl, and R 1z R 2z As defined above;

[0079] 7) Among them, R 6z R 7z R 8z R 9z R 10z R 11z R 12z Each of the following is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, C1-C6 alkylamino, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, S, optionally substituted C3-C7 cycloalkyl, preferably amino, halogen, or C3-C7 cycloalkyl;

[0080] 8) Among them, R 13z R 14z R 15zEach of the following groups is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, C1-C6 alkylamino, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, S, optionally substituted C3-C7 cycloalkyl, preferably C1-C6 alkylamino, and derived from R. 12z R 14z R 15z The two components together with their respective carbon atoms form a C3-C7 cycloalkyl group;

[0081] 9) Where m1, m2, and m3 are independently selected from 0, 1, and 2, and ring X is a 3-7 member monocyclic heterocyclic group or a 5-10 member nitrogen-containing bridged ring heterocyclic group. Where R 16z Selected from halogens and C1-C6 alkyl groups. Where R 17z Selected from H, C1-C6 alkyl groups;

[0082] Preferably, R 10 Selected from:

[0083]

[0084]

[0085]

[0086] and

[0087] Exclude the following structures:

[0088]

[0089] In some implementations, formula (I) is in,

[0090] X1 is selected from: N, CR1, where R1 is selected from H, C1-C6 alkyl, halogen;

[0091] Preferably, X1 is selected from: CH, CF;

[0092] X2 is selected from: CR2, where R2 is selected from:

[0093] H, C1-C6 alkyl,

[0094] Where R 1x R2x R 3x Independently selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl.

[0095] Among them, each R xb Whether the R values ​​are the same or different, each R value xb Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably H, hydroxyl, amino, halogen, C1-C6 haloalkyl, x2 is selected from integers from 1 to 5.

[0096] Y is selected from O, S, and HH, with O and HH being preferred, and each R xc Whether the R values ​​are the same or different, each R value xc Independently selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, preferably hydroxyl or amino, where x3 is an integer selected from 1 to 7.

[0097] Among them, each R xd Whether the R values ​​are the same or different, each R value xd Independently selected from amino, halogen, C1-C6 alkyl, cyano, and one or more R xd When present, it cannot be simultaneously a halogen or simultaneously a C1-C6 alkyl group, and x4 is selected from integers from 1 to 7.

[0098] Preferably, X2 is selected from CR2, where R2 is selected from H, C1-C6 alkyl.

[0099] Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, C1-C6 alkyl, and C2-C6 alkynyl groups.

[0100] Where R 4x R 5x R 6x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, preferably H, hydroxyl, amino, halogen, and C1-C6 haloalkyl.

[0101] Where Y is selected from O, S, and HH, with O and HH being preferred, and R... 7xSelected from hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, with hydroxyl and amino being preferred.

[0102] Where R 8x R 9x R 10x R 11x R 12x R 13x Independently selected from H, amino, halogen, C1-C6 alkyl, cyano, and R 8x R 9x R 10x R 11x R 12x R 13x When not H, they cannot be halogens or C1-C6 alkyl groups simultaneously. Y1, Y2, and Y3 are independently selected from NH, S, O, N, and C.

[0103] More preferably, X2 is selected from: CR2, where R2 is selected from:

[0104]

[0105] X3 is selected from: N, CR3, where R3 is selected from H, C1-C6 alkyl;

[0106] Preferably, X3 is selected from: N, CH;

[0107] X4 is selected from: N, CR4, where R4 is selected from H, C1-C6 alkyl, halogen;

[0108] Preferably, X4 is selected from: N, CH;

[0109] R 9a Selected from: aziridine, piperidinyl, aziridine-heptyl, oxaziridine-heptyl, diazabicyclo[2.2.2]octyl, cyclohexyl, cyclohexenyl, oxaziridine-heptenyl, methylamino:cyano, C1-C6 alkyl, hydroxyl, amino, C1-C6 alkoxy, fluorine-substituted cyclopropyl, piperazine-substituted by methyl or oxo, excluding: piperidinyl with only hydroxyl substituents, and aziridine-heptyl with only hydroxyl substituents;

[0110] Preferably, R 9a Selected from:

[0111] W 1a Selected from: direct bond, NH, O, Where R 1y R 2yEach is independently selected from H, C1-C6 alkyl groups. Where R 3y Selected from H, C1-C6 alkyl groups, with position 1 above connected to a pyrimidine ring, and position 2 above connected to R. 10a Connected;

[0112] Preferably, W 1a Selected from: direct bond, NH, O, Position 1 above is connected to the pyrimidine ring, and position 2 above is connected to R. 10a Connected;

[0113] R 10a Selected from:

[0114] 1) Where R s Selected from: 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S; 5-10 membered nitrogen-containing bridged ring heterocyclic groups; 5-10 membered nitrogen-containing fused ring heterocyclic groups; 5-10 membered nitrogen-containing spirocyclic heterocyclic groups; and amino groups. The 4-7 membered monocyclic heterocyclic group, 5-10 membered nitrogen-containing bridged ring heterocyclic group, 5-10 membered nitrogen-containing fused ring heterocyclic group, 5-10 membered nitrogen-containing spirocyclic heterocyclic group, and amino group are optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl, preferably C1-C6 alkyl, halogen, and C1-C6 haloalkyl.

[0115] 2) 5-10 member nitrogen-containing spirocyclic heterocyclic groups optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, preferably C1-C6 alkyl or halogen;

[0116] 3) 5-10 nitrogen-containing bridged ring heterocyclic groups optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, preferably C1-C6 alkyl or halogen;

[0117] 4) C3-C7 cycloalkyl groups optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, preferably C1-C6 alkyl or amino;

[0118] 5) A 4-7 membered monocyclic heterocyclic group comprising 1-2 heteroatoms selected from N, O, and S (e.g., azirrobutyl, thiocyclopentyl, azirropentyl, oxocyclohexyl, azirrohexyl, oxocyclohepyl, azirrohepyl, oxocyclohepyl, oxoazirrohepyl), wherein the 4-7 membered monocyclic heterocyclic group is optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxoyl, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, preferably C1-C6 alkyl, amino, oxoyl, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, halogen, C1-C6 alkoxy, aminoC1-C6 alkyl;

[0119] 6) Among them, R 1z R 2z R 3z R 4z R 5z Each of the following is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, C1-C6 alkylamino, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, S, optionally substituted C3-C7 cycloalkyl, preferably C1-C6 alkyl, amino, C1-C6 alkylamino, aminoC1-C6 alkyl, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, halogen, piperidinyl;

[0120] Or R 3z R 4z R 5z The two groups, together with their respective carbon atoms, form piperidinyl, halogen-substituted piperidinyl, azircyclic pentyl, halogen-substituted azircyclic pentyl, hydroxyl-substituted azircyclic pentyl, azircyclic butyl, halogen-substituted azircyclic butyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with azircyclic pentyl, optional 5-10 member nitrogen-containing spirocyclic heterocyclic group substituted with halogen, optional 5-10 member nitrogen-containing bridged ring heterocyclic group substituted with halogen or halogen alkenyl, and R 1z R 2z As defined above;

[0121] 7) Among them, R 6z R 7z R 8z R 9z R 10z R 11z R 12zEach of the following is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, C1-C6 alkylamino, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, S, optionally substituted C3-C7 cycloalkyl, preferably amino, halogen, or C3-C7 cycloalkyl;

[0122] 8) Among them, R 13z R 14z R 15z Each of the following groups is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, C1-C6 alkylamino, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, S, optionally substituted C3-C7 cycloalkyl, preferably C1-C6 alkylamino, and derived from R. 12z R 14z R 15z The two components together with their respective carbon atoms form a C3-C7 cycloalkyl group;

[0123] Preferably, R 10a Selected from:

[0124]

[0125]

[0126]

[0127] and

[0128] Exclude the following structures:

[0129]

[0130] In some embodiments, formula (I-1) is one of the following formulas: (I-1-1), (I-1-2), or (I-1-3):

[0131] The variables are defined as described above in equation (I-1).

[0132] In some implementations, formula (I) is Among them, X5 is selected from: O, =O, CR 51 R 52 Where R 51 R 52 Independently selected from H, C1-C6 alkyl groups;

[0133] Preferably, X5 is selected from: O, =O, CH2;

[0134] X6 is selected from: 1) NR6, where R6 is selected from:

[0135] Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, wherein R 1x R 2x R 3x The two elements in the formula cannot both be halogens.

[0136] Among them, each R xe Whether the R values ​​are the same or different, each R value xe Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano, preferably H, amino, halogen, or cyano, x5 is selected from integers from 1 to 5.

[0137] Among them, each R xf Whether the R values ​​are the same or different, each R value xf Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, or C1-C6 alkoxy, where x6 is selected from integers from 1 to 7.

[0138] Among them, each R xg Whether the R values ​​are the same or different, each R value xg Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, or C1-C6 alkoxy, x7 is selected from integers from 1 to 8.

[0139] 2) CR 61 R 62 , where R 61 R 62 Selected independently from:

[0140] H, C1-C6 alkyl,

[0141] Among them, each R xa Whether the R values ​​are the same or different, each R value xa Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, preferably H, hydroxyl, amino, halogen, C1-C6 alkyl, and C2-C6 alkynyl, where x1 is an integer selected from 1 to 7.

[0142] Among them, each R xe Whether the R values ​​are the same or different, each R value xe Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano, preferably H, amino, halogen, or cyano, x5 is selected from integers from 1 to 5.

[0143] Among them, each R xf Whether the R values ​​are the same or different, each R value xf Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, or C1-C6 alkoxy, where x6 is selected from integers from 1 to 7.

[0144] Among them, each R xg Whether the R values ​​are the same or different, each R value xg Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, C1-C6 alkoxy, and x7 is selected from integers from 1 to 8;

[0145] Preferably, X6 is selected from:

[0146] 1) NR6, where R6 is selected from:

[0147] Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, C2-C6 alkynyl groups, wherein R 1x R 2x R 3x The two elements in the formula cannot both be halogens.

[0148] Where R 14x R 15x R 16xIndependently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano, preferably H, amino, halogen, or cyano.

[0149] Where R 17x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, R 18x R 19x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, or R 18x R 19x Independently selected from C1-C6 alkyl groups, R 18x With R 19x And the carbon atoms connected to them are linked together to form a ring,

[0150] Where R 20x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, with hydroxyl, amino, and C1-C6 alkoxy being preferred.

[0151] Where R 21x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, with hydroxyl, amino, and C1-C6 alkoxy being preferred.

[0152] 2) CR 61 R 62 , where R 61 R 62 Selected independently from:

[0153] H, C1-C6 alkyl,

[0154] Where R 1x R 2x R 3x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, preferably H, hydroxyl, amino, halogen, C1-C6 alkyl, and C2-C6 alkynyl.

[0155] Where R 14x R 15x R 16xIndependently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano, preferably H, amino, halogen, or cyano.

[0156] Where R 17x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, R 18x R 19x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, or R 18x R 19x Independently selected from C1-C6 alkyl groups, R 18x With R 19x And the carbon atoms connected to them are linked together to form a ring,

[0157] Where R 20x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl, with hydroxyl, amino, and C1-C6 alkoxy being preferred.

[0158] Where R 21x Selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, preferably hydroxyl, amino, and C1-C6 alkoxy;

[0159] More preferably, X6 is selected from:

[0160] NR6, where R6 is selected from:

[0161] CR 61 R 62 Where R 61 R 62 Selected independently from: H,

[0162] X7 is selected from: C3-C6 cycloalkyl groups optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, or C1-C6 haloalkyl (e.g., cyclopropyl, cyclobutyl), O, CR 71 R 72 Where R 71 R 72 Independently selected from H, C1-C6 alkyl groups;

[0163] Preferably, X7 is selected from: cyclopropylene O, CH2;

[0164] X8 is selected from: C3-C6 cycloalkyl groups optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, or C1-C6 haloalkyl (e.g., cyclopropyl or cyclobutyl), =O, CR 81 R 82 Where R 81 R 82 Independently selected from H, C1-C6 alkyl groups;

[0165] Preferably, X8 is selected from: cyclopropylene =O, CH2;

[0166] R 9b Selected from: aziridine, piperidinyl, aziridine-heptyl, oxazadicycloheptanyl, diazabicyclo[2.2.2]octyl, cyclohexyl, cyclohexenyl, oxazadicycloheptenyl, methylamino:cyano, C1-C6 alkyl, hydroxyl, amino, C1-C6 alkoxy, fluorine-substituted cyclopropyl, piperazine-substituted with methyl or oxo, excluding: piperidinyl with only hydroxyl substituents, aziridine-heptyl with only hydroxyl substituents; or, a seven-membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N, O, S (e.g., N, O), a 5-10-membered nitrogen-bridged ring heterocyclic group; preferably oxazadicycloheptanyl, diazabicyclo[3.2.1]octyl:hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, oxydicycloheptanyl, oxazadi ...

[0167] Preferably, R 9b Selected from:

[0168] W 1b Selected from: NH, O, Where R 1y R 2y Each is independently selected from H, C1-C6 alkyl groups. Where R 3y Selected from H, C1-C6 alkyl groups, with position 1 above connected to a pyrimidine ring, and position 2 above connected to R. 10b Connected;

[0169] Preferably, W 1b Selected from: NH, O, Position 1 above is connected to the pyrimidine ring, and position 2 above is connected to R. 10b Connected;

[0170] R 10b Selected from: Where m1, m2, and m3 are independently selected from 0, 1, and 2, and ring X is a 3-7 member monocyclic heterocyclic group or a 5-10 member nitrogen-containing bridged ring heterocyclic group. Where R 16z Selected from halogens and C1-C6 alkyl groups. Where R 17z Selected from H, C1-C6 alkyl groups;

[0171] Preferably, R 10b Selected from: and

[0172] Exclude the following structures:

[0173] In some implementations, formula (I) is in,

[0174] X3 is selected from: N, CR3, where R3 is selected from H, C1-C6 alkyl;

[0175] Preferably, X3 is selected from: N;

[0176] X4 is selected from: N, CR4, where R4 is selected from H, C1-C6 alkyl;

[0177] Preferably, X4 is selected from: CH;

[0178] X5 is selected from: O, =O, CR 51 R 52 Where R 51 R 52 Independently selected from H, C1-C6 alkyl groups;

[0179] Preferably, X5 is selected from: =O;

[0180] X6 is selected from: NR6, where R6 is selected from:

[0181] Where R 1x R 2x R 3x It is independently selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl;

[0182] Preferably, X6 is selected from NR6, wherein R6 is selected from: Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, and C2-C6 alkynyl groups;

[0183] More preferably, X6 is selected from: NR6, where R6 is selected from:

[0184] R 9cSelected from: aziridine, piperidinyl, aziridine-heptyl, oxazonicycloheptyl, diazabicyclo[2.2.2]octyl, cyclohexyl, cyclohexenyl, oxazonicycloheptenyl, methylamino:cyano, C1-C6 alkyl, hydroxyl, amino, C1-C6 alkoxy, fluorine-substituted cyclopropyl, piperazine-substituted with methyl or oxo, excluding: piperidinyl with only hydroxyl substituent, aziridine-heptyl with only hydroxyl substituent; or, a seven-membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N, O, S (e.g., N, O); preferably oxazonicycloheptyl with substituted groups: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy;

[0185] Preferably, R 9c Selected from:

[0186] W 1c Selected from: NH, O, Where R 1y R 2y Each is independently selected from H, C1-C6 alkyl groups. Where R 3y Selected from H, C1-C6 alkyl groups, with position 1 above connected to a pyrimidine ring, and position 2 above connected to R. 10b Connected;

[0187] Preferably, W 1c Selected from: Position 1 above is connected to the pyrimidine ring, and position 2 above is connected to R. 10b Connected;

[0188] R 10c Selected from: Where R s Selected from: 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S; 5-10 membered nitrogen-containing bridged ring heterocyclic groups; 5-10 membered nitrogen-containing fused ring heterocyclic groups; 5-10 membered nitrogen-containing spirocyclic heterocyclic groups; and amino groups. The 4-7 membered monocyclic heterocyclic group, 5-10 membered nitrogen-containing bridged ring heterocyclic group, 5-10 membered nitrogen-containing fused ring heterocyclic group, 5-10 membered nitrogen-containing spirocyclic heterocyclic group, and amino group are optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl, preferably C1-C6 alkyl, halogen, and C1-C6 haloalkyl.

[0189] Preferably, R 10c Selected from:

[0190] In some embodiments, the compound is selected from:

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199] The second aspect of this application provides a pharmaceutical composition comprising at least one compound described in the first aspect of this application, or a stereoisomer thereof, a tautomer thereof, a solvate thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers and / or excipients.

[0200] The third aspect of this application provides a method for preparing the compound described in the first aspect of this application, or its stereoisomers, tautomers, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof.

[0201] The fourth aspect of this application provides the use of the compounds described in the first aspect of this application, or their stereoisomers, tautomers, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the second aspect of this application, in the preparation of a medicament for the treatment and / or prevention of various cancers caused by KRAS mutations.

[0202] In some implementations, the cancer is selected from pancreatic cancer, non-small cell lung cancer, colorectal cancer, ovarian cancer, and bile duct cancer.

[0203] The fifth aspect of this application provides the compounds described in the first aspect of this application, or their stereoisomers, tautomers, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the second aspect of this application, for the treatment and / or prevention of various cancers caused by KRAS mutations.

[0204] In some implementations, the cancer is selected from pancreatic cancer, non-small cell lung cancer, colorectal cancer, ovarian cancer, and bile duct cancer.

[0205] The sixth aspect of this application provides a method for treating and / or preventing cancers caused by various KRAS mutations, comprising administering to an individual in need an effective amount of the compound described in the first aspect of this application, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in the second aspect of this application.

[0206] In some implementations, the cancer is selected from pancreatic cancer, non-small cell lung cancer, colorectal cancer, ovarian cancer, and bile duct cancer.

[0207] The seventh aspect of this application provides a method for screening KRAS inhibitors. The corresponding KRAS-G12D protein sequence is shown in the sequence portion.

[0208] Terminology Definition

[0209] In this application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, to better understand this application, definitions and explanations of relevant terms are provided below.

[0210] In the event that the compound name used in this application is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0211] As used in this application, the term "stereoisomer" refers to an isomer formed by at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans).

[0212] Similarly, the compounds of this application may exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0213] Unless otherwise stated, the compounds of this application may exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of this application may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0214] The compounds of this application may exist in the form of solvates (such as hydrates), wherein the compounds of this application contain a solvent, such as water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the solvent may be stoichiometric or non-stoichiometric.

[0215] As used herein, the term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms of the same number but with a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in compounds of this application include, but are not limited to, hydrogen isotopes such as... 2 H, 3 H; carbon isotopes, for example 11 C, 13 C and 14 C; Chlorine isotopes, for example 36 Cl; fluorine isotopes, for example 18 F; Iodine isotopes, for example 123 I and 125 I; nitrogen isotopes, for example 13 N and 15 N; oxygen isotopes, for example 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0216] As used in this application, the term "pharmaceutically acceptable salt" refers to a salt of the compound of this application that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: salts formed by addition to inorganic acids or acids formed with organic acids, or salts containing acidic protons on the parent compound but surrounded by metal ions, or coordination compounds formed with organic bases.

[0217] Pharmaceutically acceptable salts of the compounds described in this application include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and similar salts.

[0218] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and similar salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using the relative ions of halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0219] Pharmaceutically acceptable salts are also intended to include hemisalts, wherein the ratio of compound to acid is 2:1. Exemplary hemisalts are those derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary hemisalts are those derived from diprotic mineral acids (e.g., sulfuric acid). Preferred exemplary hemisalts include (but are not limited to) hemi-maleic acid salts, hemi-fumaric acid salts, and hemi-succinic acid salts.

[0220] As used in this application, the term "optionally substituted" means that the group may be unsubstituted or substituted. For example, "C1-C6 alkyl optionally substituted with a halogen" means that the C1-C6 alkyl group may be unsubstituted or substituted with a halogen to obtain a haloalkyl group. It should be understood that when stating "R is selected from C1-C6 alkyl, -C1-C6 alkoxy, and -NH-C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with a halogen," it means that the C1-C6 alkyl group in C1-C6 alkyl, -C1-C6 alkoxy, and -NH-C1-C6 alkyl is optionally substituted with a halogen. It should be understood that -N-(C1-C6 alkyl)2 indicates that two C1-C6 alkyl groups are attached to the nitrogen atom, and these two alkyl groups may be the same or different.

[0221] As used herein, unless otherwise expressly indicated, the descriptive phrase “...each independently selected” used throughout may mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0222] As used in this application, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0223] As used in this application, the term "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group, such as C1-C6 alkyl, which refers to a group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of C1-C6 alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc., wherein the propyl group includes n-propyl and isopropyl, and the butyl group includes n-butyl, isobutyl, and neobutyl.

[0224] As used in this application, the term "halogenated" means that the modified group is substituted with one or more halogens, for example, substituted with 1, 2, 3, 4, 5 or 6 halogens. For example, "C1-C6 haloalkyl" means that a C1-C6 alkyl group as defined above is substituted with one or more halogens, examples of which include, but are not limited to, CF3, CHF2 or CF2CF3.

[0225] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon atoms. For example, C3-C7 cycloalkyl groups have 3 to 6 carbon atoms, such as 3, 4, 5, 6, or 7 carbon atoms. The cycloalkyl group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, cyclohexyl, cycloheptyl, and adamantyl.

[0226] As used in this application, the term "cycloalkylene" refers to a divalent cycloalkyl group formed by substituting one hydrogen atom of a cycloalkyl group. For example, C3-C6 cycloalkylene is a divalent cycloalkyl group formed by substituting one hydrogen atom of a C3-C6 cycloalkyl group, such as cyclopropylene, cyclobutylene, etc.

[0227] As used in this application, the term "alkoxy" refers to any of the above-described alkyl groups (e.g., C1-C6 alkyl groups) that are attached to the remainder of the molecule by an oxygen atom (-O-). For example, C1-C6 alkoxy groups.

[0228] As used in this application, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group with 2 to 6 carbon atoms, examples of which include vinyl, allyl, etc. A C2-6 alkenyl group must have at least one double bond.

[0229] As used in this application, the term "C2-C6 ynyl" refers to a straight or branched chain of 2-6 carbon atoms, such as ethynyl or propynyl. An ynyl group must have one triple bond and may optionally have one or more double bonds.

[0230] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic group composed of ring atoms, wherein one, two, three, or four ring atoms are heteroatoms, and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized. For example, a 5-10 membered heterocyclic group refers to a group composed of 5-10 ring atoms, including 5-7 membered heterocyclic groups, 4-7 membered heterocyclic groups, etc. The heterocyclic group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, oxo-heterobutyl, azirrobutyl, azirropentyl, piperidinyl, piperazinyl, or morpholinyl. The term "nitrogen-containing monocyclic heterocyclic group" means that at least one heteroatom in the heterocyclic group is a nitrogen atom, and the heterocyclic group is monocyclic; examples include, but are not limited to, piperidinyl. The term "nitrogen-bridged heterocyclic group" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom, and the heterocyclic group is a bridged ring. Examples include, but are not limited to, those containing nitrogen atoms. The term "nitrogen-containing fused heterocyclic group" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom, and the heterocyclic group is fused ring, examples of which include, but are not limited to, nitrogen-containing fused rings. The term "nitrogen-containing spirocyclic heterocyclic group" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom, and the heterocyclic group is a fused ring, examples of which include, but are not limited to, nitrogen-containing spirocyclic heterocyclic groups. wait.

[0231] As used in this application, the term "partially unsaturated" refers to a ring system that is neither saturated (i.e., does not contain double bonds) nor completely unsaturated (i.e., contains the maximum possible number of double bonds). In other words, a partially unsaturated ring system contains at least one double bond, but not the maximum possible number of double bonds.

[0232] As used herein, the term "pharmaceutical carrier and / or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, as is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutical carriers and / or excipients include, but are not limited to: pH adjusters, surfactants, ionic strength enhancers, diluents, agents for maintaining osmotic pressure, agents for delaying absorption, preservatives, and stabilizers. For example, pH adjusters include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. Agents for maintaining osmotic pressure include, but are not limited to, sugars, NaCl, and their analogues. Agents for delaying absorption include, but are not limited to, monostearates and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols, and polyols (such as glycerol). Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc. Stabilizers have the meaning commonly understood by those skilled in the art for stabilizing the desired activity of the active ingredient in a pharmaceutical product, including, but not limited to, monosodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin, or casein) or their degradation products (such as lactalbumin hydrolysate), etc.

[0233] As used in this application, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to a certain extent.

[0234] As used herein, the term "treatment" aims to alleviate, reduce, improve, or eliminate a targeted disease state or symptom. A subject is successfully "treated" if, in accordance with the methods described herein, a therapeutic amount of the antibody-drug conjugate or its racemic, enantiomer, diastereomer, pharmaceutically acceptable salt, or mixture of the foregoing forms is received, and one or more indications and symptoms exhibit an observable and / or detectable reduction or improvement. It should also be understood that treatment of the disease state or symptom includes not only complete treatment but also the achievement of some biological or medically relevant outcome without achieving complete treatment.

[0235] As used in this application, the term "prevention" aims to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms before the onset of the relevant drug. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, reducing the risk of a subject developing a specific disease or disease-related symptoms after the administration of the relevant drug, or lessening the severity of subsequently occurring related symptoms, can be considered as "prevention" of the onset or development of the disease. Detailed Implementation

[0236] The embodiments of this application will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this application. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available products or can be prepared by methods known to those skilled in the art.

[0237] The English words or abbreviations used below have the following meanings:

[0238]

[0239]

[0240] Example

[0241] Example 1: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-group)-2-amino-7-fluorobenzo[b]thiophene-3-nitrile (Compound 1)

[0242]

[0243] Step 1, Synthesis of tert-butyl 2,4-dichloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid (1-2): 1.22 g, 4 mmol, 1 eq of tert-butyl 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid was placed in a reaction flask, and EtOAc (20 mL), NaIO4 (2.57 g, 12 mmol, 3 eq) / H2O (20 mL) were added. After 5 min, RuCl3 (166 mg, 0.8 mmol, 0.2 eq) was added. After the addition was complete, the mixture was stirred overnight at room temperature. Extract with EtOAc (20 mL x 3) / H₂O (20 mL), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (PE:EtOAc = 100:10-100:20) to give pale yellow solid compounds 1-2 (900 mg, yield 70%). ESI-MS: 319.2 [M + H₂] +

[0244] Step 2, Synthesis of 2,4-dichloro-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one (1-3): Tert-butyl 2,4-dichloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid (900 mg, 2.83 mmol, 1 eq) was placed in a reaction flask, DCM (9 mL) was added, followed by HCl / dioxane (2 mL, 8 mmol, 2.8 eq). After the addition was complete, the mixture was stirred at room temperature for 2 h. The solution was concentrated to dryness to give a yellow solid compound 1-3 (700 mg, crude). ESI-MS: 219.2 [M+H] +

[0245] Step 3, Synthesis of (1R,5S)-3-(2-chloro-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1-4): 2,4-dichloro-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one (700 mg, crude) was placed in a reaction flask, and DCM (10 mL), DIEA (1.07 g, 8.26 mmol, 3 eq), and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (584 mg, 2.75 mmol, 1 eq) were added sequentially. After the addition was complete, the mixture was stirred overnight at room temperature. Extracted with DCM (20 mL x 3) / H₂O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (PE:EtOAc = 100:10-100:50) to give yellow solid compounds 1-4 (900 mg, yield 83%). ESI-MS: 394.2 [M + H₂] +

[0246] Step 4, Synthesis of (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1-5): ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) Methanol (400 mg, 2.51 mmol, 1 eq) was placed in a reaction flask, DMF (10 mL) was added, and the mixture was stirred at room temperature for 30 min. Then, (1R, 5S)-3-(2-chloro-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (900 mg, 2.29 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at room temperature for 2 h. The mixture was extracted with EtOAc (20 mL * 3) / H2O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 1-5 (600 mg, yield 51%). ESI-MS: 517.2 [M + H] +

[0247] Step 5, Synthesis of tert-butyl(1R,5S)-3-(7-(2-((tert-butyloxycarbonyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1-6): The tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyrido[ [3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (52 mg, 0.1 mmol, 1 eq), (4-bromo-3-cyano-7-fluorobenzothiophene-2-yl)carbamate tert-butyl ester (41 mg, 0.11 mmol, 1.1 eq), K3PO4 (64 mg, 0.3 mmol, 3 eq), N1,N2-dimethylethane-1,2-diamine (13 mg, 0.15 mmol, 1.5 eq), CuI (23 mg, 0.12 mmol, 1.2 eq) were placed in a reaction flask, and dioxane (3 mL) was added. The mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 1-6 (20 mg, yield 25%). ESI-MS: 808.1 [M+H] +

[0248] Step 6, Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)- group)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile (compound 1): tert-butyl(1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)- 3-Cyano-7-fluorobenzothiophene-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester was placed in a reaction flask, and CH3CN (2 mL) was added. HCl / dioxane (0.4 mL, 1 M) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 1 h. The solution was concentrated, and pre-HPLC was used to prepare a pale yellow solid compound 1 (5 mg, yield 33%). ESI-MS: 607.1 [M+H] +

[0249] Example 2: 9-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2,3-dihydro-1H-cyclopenta[a]naphthyl-7-ol (Compound 2)

[0250]

[0251] Step 1, Synthesis of 2,6-dibromo-4-methoxyaniline (2-2): 4-Methoxyaniline (4 g, 32.48 mmol, 1 eq) was placed in a reaction flask, and DCM (300 mL), MeOH (100 mL), benzyltrimethylammonium tribromide (12.67 g, 32.48 mmol, 1 eq), and CaCO3 (13.66 g, 97.44 mmol, 3 eq) were added. After addition, the mixture was stirred at ambient temperature for 2 h. The mixture was filtered, the filtrate was concentrated, and extracted with DCM (200 mL * 3) / H2O (200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Column chromatography (PE:EA = 100:0-100:30) was performed to give a yellow solid compound 2-2 (6.5 g, yield 71%). ESI-MS: 282.2 [M + H] +

[0252] Step 2, Synthesis of 2-bromo-4-methoxy-6-((trimethylsilyl)ethynyl)aniline (2-3): 2,6-Dibromo-4-methoxyaniline (6.5 g, 23.14 mmol, 1 eq), ethynyltrimethylsilane (2.27 g, 23.14 mmol, 1 eq), Pd(PPh3)2Cl2 (812 mg, 1.16 mmol, 0.05 eq), and CuI (440 mg, 2.31 mmol, 0.1 eq) were placed in a reaction flask, and THF (100 mL) and TEA (6.33 mL, 46.27 mmol, 2 eq) were added. The mixture was stirred at 70 °C for 5 h under argon protection. After cooling, filtration, concentration, and column chromatography (PE:EA = 100:0-100:30), a yellow oily compound 2-3 (4.5 g, yield 65%) was obtained. ESI-MS: 299.2 [M+H] +

[0253] Step 3, Synthesis of ((3-bromo-2-iodo-5-methoxyphenyl)ethynyl)trimethylsilane (2-4): 2-bromo-4-methoxy-6-((trimethylsilyl)ethynyl)aniline (4.5 g, 15.09 mmol, 1 eq) was placed in a reaction flask, and CH3CN (100 mL) and H2O (10 mL) were added. p-Toluenesulfonic acid (520 mg, 3 mmol, 0.2 eq) was added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 1 h. Then, NaNO2 (3.12 g, 45.26 mmol, 3 eq) and KI (7.51 g, 45.26 mmol, 3 eq) were added. After the addition was complete, the mixture was stirred overnight at ambient temperature. Extracted with EtOAc (100mL*3) / H2O (100mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (PE:EA=100:0-100:20) to give a yellow oily compound 2-4 (1.1g, yield 18%). 1 H NMR (600MHz, methanol-d4) δ6.99 (dd, J=2.7, 1.8Hz, 1H), 6.85 (dd, J=13.0, 2.8Hz, 1H), 3.78 (s, 3H).

[0254] Step 4, Synthesis of ((3-bromo-2-(cyclopent-1-en-1-yl)-5-methoxyphenyl)ethynyl)trimethylsilane (2-5): ((3-bromo-2-iodo-5-methoxyphenyl)ethynyl)trimethylsilane (1.1 g, 2.69 mmol, 1 eq), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (522 mg, 2.69 mmol, 1 eq), Na2CO3 (712 mg, 6.72 mmol, 2.5 eq), Pd(dppf)Cl2 (196 mg, 0.269 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (15 mL) and H2O (3 mL) were added. Under argon protection, the mixture was stirred overnight at 100 °C. Cool, filter, extract with EtOAc (40 mL * 3) / H2O (40 mL), combine organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (PE:EA = 100:0-100:10) to give a yellow oily compound 2-5 (0.3 g, yield 32%). 1¹H NMR (600MHz, chloroform-d) δ 7.09 (t, J = 2.1Hz, 1H), 6.94 (t, J = 2.1Hz, 1H), 5.68 (q, J = 2.1Hz, 1H), 3.77 (d, J = 1.4Hz, 3H), 2.62 (tt, J = 7.5, 2.0Hz, 2H), 2.51 (tt, J = 7.4, 2.2Hz, 2H), 2.02 (p, J = 7.4Hz, 2H), 0.20 (d, J = 1.5Hz, 9H).

[0255] Step 5, Synthesis of 1-bromo-2-(cyclopent-1-en-1-yl)-3-ethynyl-5-methoxybenzene (2-6): ((3-bromo-2-(cyclopent-1-en-1-yl)-5-methoxyphenyl)ethynyl)trimethylsilane (300 mg, 0.86 mmol, 1 eq) was placed in a reaction flask, and MeOH (5 mL) and K₂CO₃ (237 mg, 1.72 mmol, 2 eq) were added. After addition, the mixture was stirred at ambient temperature for 2 h. The mixture was filtered and subjected to column chromatography (PE:EA = 100:0-100:10) to give a yellow oily compound 2-6 (200 mg, yield 84%). 1 H NMR (600MHz, chloroform-d) δ7.13(d,J=2.6Hz,1H),6.99(d,J=2.6Hz,1H),5.70(p,J=2.2Hz,1H),3.78(s,3 H),3.10(s,1H),2.62(ddt,J=9.8,7.4,2.3Hz,2H),2.53(tq,J=7.3,2.5Hz,2H),2.08-2.01(m,2H).

[0256] Step 6, Synthesis of 9-bromo-7-methoxy-2,3-dihydro-1H-cyclopentan[a]naphthalene (2-7): 1-bromo-2-(cyclopent-1-en-1-yl)-3-ethynyl-5-methoxybenzene (200 mg, 0.72 mmol, 1 eq) and platinum dichloride (38 mg, 0.14 mmol, 0.2 eq) were placed in a reaction flask, acetone (3 mL) was added, and the mixture was refluxed overnight. After cooling, the mixture was concentrated and subjected to column chromatography (PE:EA = 100:0-100:30) to give a yellow solid compound 2-7 (150 mg, 75% yield). 1H NMR (600MHz, chloroform-d) δ7.55(d,J=8.2Hz,1H),7.47(d,J=2.6Hz,1H),7.35(d,J=8.2Hz,1H),7.10( d,J=2.6Hz,1H),3.88(s,3H),3.82(t,J=7.4Hz,2H),3.00(t,J=7.7Hz,2H),2.17-2.10(m,2H).

[0257] Step 7, Synthesis of 9-bromo-2,3-dihydro-1H-cyclopenta[a]naphthyl-7-ol (2-8): 9-bromo-7-methoxy-2,3-dihydro-1H-cyclopenta[a]naphthyl (150 mg, 0.54 mmol, 1 eq) was placed in a reaction flask, and DCM (2 mL) was added. BBr3 / DCM (1.6 mL, 1.6 mmol, 3 eq, 1 M) was slowly added under ice bath conditions. After addition, the mixture was stirred at ambient temperature for 2 h. DCM (10 mL * 2) / H2O (10 mL) was added under ice bath conditions, followed by extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:20) to give a yellow solid compound 2-8 (110 mg, yield 77%). ESI-MS: 264.2 [M + H] +

[0258] Step 8, Synthesis of 9-bromo-7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (2-9): 9-bromo-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-ol (110 mg, 0.42 mmol, 1 eq) was placed in a reaction flask, and DCM (2 mL) and DIEA (162 mg, 0.62 mmol, 1.5 eq) were added. Bromomethyl ether (78 mg, 0.63 mmol, 1.5 eq) was added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 2 h. DCM (10 mL * 2) / H2O (10 mL) was added, and the mixture was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:10) to give a yellow solid compound 2-9 (120 mg, 93% yield). ESI-MS: 308.2 [M+H] +

[0259] Step 9, Synthesis of 4-((1R,5S)-8-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (2-11): 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (338 mg, 1 mmol, 1 eq) was placed in a reaction flask, and THF (5 mL) and DIEA (0.35 mL, 2 mmol, 2 eq) were added. The mixture was cooled to -20 °C, and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (212 mg, 1 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 30 min, and then stirred overnight at ambient temperature. Extracted with EtOAc (20 mL x 3) / H₂O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give a yellow solid compound 2-11 (500 mg, yield 97%). ESI-MS: 515.2 [M + H₂] +

[0260] Step 10, Synthesis of 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (2-12): 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (2-12) Benzyl (H)-carboxylic acid ester (500 mg, 0.97 mmol, 1 eq), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methanol (155 mg, 0.97 mmol, 1 eq), Cs₂CO₃ (634 mg, 1.95 mmol, 2 eq), Pd₂(dba)₃ (89 mg, 0.097 mmol, 0.1 eq), and RuPhos (89 mg, 0.19 mmol, 0.2 eq) were placed in a reaction flask, and toluene (10 mL) was added. The mixture was stirred overnight at 90 °C under argon protection. After cooling, the mixture was filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:20) to give a yellow solid compound 2-12 (600 mg, 97% yield). ESI-MS: 637.2 [M+H] +

[0261] Step 11, Synthesis of (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2-13): 4-((1R,5S)-8-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 600 mg (0.94 mmol, 1 eq) of benzyl octyl-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid was placed in a reaction flask, and MeOH (6 mL), ammonia (0.1 mL), and Pa / C (60 mg, 10%) were added. After addition, the mixture was stirred overnight under H2 protection at ambient temperature. The mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give a yellow solid compound 2-13 (300 mg, 64% yield). ESI-MS: 503.2 [M+H] +

[0262] Step 12, Synthesis of tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(7-(methoxy-methoxy)-2,3-dihydro-1H-cyclopentano[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (2-14): The tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[ [3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol, 1 eq), 9-bromo-7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (33 mg, 0.11 mmol, 1.1 eq), Cs₂CO₃ (81 mg, 0.25 mmol, 2.5 eq), Pd₂(dba)₃ (9 mg, 0.001 mmol, 0.1 eq), RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, toluene (2 mL) was added, and the mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give a yellow solid compound 2-14 (40 mg, yield 55%). ESI-MS: 730.2 [M+H] +

[0263] Step 13, Synthesis of 9-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2,3-dihydro-1H-cyclopenta[a]naphthyl-7-ol (compound 2): tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(7-(methoxy-methoxy)-2,3-dihydro-1H-cyclopentano[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (40 mg, 0.05 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The mixture was concentrated and pre-HPLC was used to prepare a pale yellow solid compound 2 (6 mg, yield 18%). ESI-MS: 585.2 [M+H] +

[0264] Example 3: 5-ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol (Compound 3)

[0265]

[0266] Step 1, Synthesis of (1-(pyrrolidine-1-yl)cyclopropyl)methanol (3-2): (1-aminocyclopropyl)methanol (200 mg, 2.3 mmol, 1 eq) was placed in a reaction flask, and CH3CN (10 mL), 1,4-dibromobutane (496 mg, 2.3 mmol, 1 eq), and K2CO3 (793 mg, 5.7 mmol, 2.5 eq) were added. After addition, the mixture was stirred overnight at 90 °C. The mixture was filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow oily compound 3-2 (260 mg, yield 80%). ESI-MS: 142.2 [M+H]+

[0267] Step 2, Synthesis of 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (3-4): 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin (252 mg, 1 mmol, 1 eq) was placed in a reaction flask, and DCM (5 mL) and DIEA (0.35 mL, 2 mmol, 2 eq) were added. 1,4-oxazacycloheptane (101 mg, 1 mmol, 1 eq) was added at -40 °C. After the addition was complete, the mixture was stirred at this temperature for 30 min. DCM (10 mL * 2) / H2O (10 mL) was added, and the mixture was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give a yellow solid compound 3-4 (280 mg, 88% yield). ESI-MS: 318.2 [M+H] +

[0268] Step 3, Synthesis of 4-(7-chloro-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (3-5): (1-(pyrrolidine-1-yl)cyclopropyl)methanol (150 mg, 1.06 mmol, 1.2 eq) was placed in a reaction flask, and THF (4 mL) was added. NaH (42 mg, 1.06 mmol, 1.2 eq) was added in portions under ice bath conditions. After the addition was complete, the mixture was stirred for 30 min at ambient temperature and then placed under ice bath conditions. Add 280 mg (1 eq) of 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane. After addition, stir at ambient temperature for 2 h, extract with EtOAc (20 mL x 3) / H2O (20 mL), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 3-5 (160 mg, yield 43%). ESI-MS: 423.2 [M+H] +

[0269] Step 4, Synthesis of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (3-6): 4-(7-chloro-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (160 mg, 0.38 mmol, 1 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (233 mg, 0.44 mmol, 1.2 eq), K3PO4 (201 mg, 0.94 mmol, 2.5 eq), Ad2nBuP-Pd-G3 (20 mg, 0.038 mmol, 0.1 eq), THF (4 mL), H2O (0.8 mL), after addition, under argon protection, stirred overnight at 60 °C. Cool, extract with EtOAc (20 mL x 3) / H₂O (20 mL), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 3-6 (120 mg, yield 41%). ESI-MS: 773.2 [M + H₂] +

[0270] Step 5, Synthesis of 4-[7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-([1-(pyrrolidine-1-yl)cyclopropyl]methoxy)pyrido[4,3-d]pyrimidin-4-yl]-1,4-oxazacycloheptane (3-7): 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) -1,4-oxazacycloheptanane (50 mg, 0.06 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (98 mg, 0.6 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at ambient temperature for 2 h. Extraction was performed using EtOAc (10 mL x 2) / H₂O (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 3-7 (30 mg, 75% yield). ESI-MS: 616.2 [M+H] +Step 6, Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (compound 3): 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxypyrido[ [4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (30 mg, 0.048 mmol, 1 eq) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and pre-HPLC was used to prepare a pale yellow solid compound 3 (5 mg, yield 18%). ESI-MS: 572.2 [M+H] +

[0271] Example 4: 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile (Compound 4)

[0272]

[0273] Step 1, Synthesis of (3-cyano-7-fluoro-4-vinylbenzothiophene-2-yl)carbamate tert-butyl ester (4-2): 1.6 g (4.31 mmol, 1 eq), potassium trifluoro(vinyl)borate (693 mg, 5.17 mmol, 1.2 eq), K3PO4 (2.29 g, 10.78 mmol, 2.5 eq), and Pd(dppf)Cl2 (315 mg, 0.431 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (20 mL) and H2O (4 mL) were added. The mixture was stirred at 100 °C for 5 h under argon protection. Cool, extract with EtOAc (100 mL x 3) / H₂O (100 mL), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (PE:EA = 100:10-100:50) to give a yellow solid compound 4-2 (900 mg, yield 66%). ESI-MS: 319.2 [M + H₂] +

[0274] Step 2, Synthesis of (3-cyano-7-fluoro-4-(4-oxo-2-thio-1,3,4,5,6,7-hexahydro-2H-pyrano[2,3-d]pyrimidin-7-yl)benzothiophene-2-yl)tert-butyl carbamate (4-3): tert-butyl carbamate (900 mg, 2.83 mmol, 1 eq), 4,6-dihydroxy-2-mercaptopyrimidine (815 mg, 5.65 mmol, 2 eq), and 37% formaldehyde aqueous solution (458 mg, 5.65 mmol, 2 eq) were placed in a reaction flask. CH3CN (12 mL) and H2O (6 mL) were added, and the mixture was stirred overnight at room temperature. The mixture was filtered, and the filter cake was dried to give a white solid compound 4-3 (600 mg, yield: 45%). ESI-MS: 475.2 [M+H] +

[0275] Step 3, Synthesis of tert-butyl carbamate (3-cyano-7-fluoro-4-(4-hydroxy-2-(methylthio)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-7-yl)benzothiophene-2-yl)carbamate (4-4): 600 mg, 1.26 mmol, 1 eq of tert-butyl carbamate and 349 mg, 2.53 mmol, 2 eq of K2CO3 were placed in a reaction flask. 10 mL of CH3CN and 179 mg, 1.26 mmol, 1 eq of CH3I were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extract with EtOAc (20 mL x 3) / H₂O (20 mL), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (PE:EA = 100:10-100:50) to give a white solid compound 4-4 (550 mg, yield 89%). ESI-MS: 489.2 [M + H₂] +

[0276] Step 4, Synthesis of (1R, 5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(methylthio)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4-5): (3-cyano-7-fluoro-4-(4-hydroxy-2-(methylthio)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-7-... (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (550 mg, 1.13 mmol, 1 eq) and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (239 mg, 1.13 mmol, 1 eq) were placed in a reaction flask, and DMF (8 mL), DIEA (291 mg, 2.26 mmol, 2 eq), and BOP (597 mg, 1.35 mmol, 1.2 eq) were added. After addition, the mixture was stirred at room temperature for 4 h. Extraction was performed by adding EtOAc (30 mL * 3) / H2O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:100) to give a white solid compound 4-5 (500 mg, yield 65%). ESI-MS: 683.2 [M + H] +

[0277] Step 5, Synthesis of (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(methanesulfonyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4-6): (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3- Cyano-7-fluorobenzothiophene-4-yl)-2-(methylthio)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500 mg, 0.73 mmol, 1 eq) was placed in a reaction flask, and DCM (8 mL) and m-CPBA (303 mg, 1.76 mmol, 2.4 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed by adding DCM (20 mL * 3) / H₂O (20 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:100) to give a white solid compound 4-6 (300 mg, yield 57%). ESI-MS: 715.2 [M + H] +

[0278] Step 6, Synthesis of tert-butyl(1R,5S)-3-(7-(2-((tert-butyloxycarbonyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (4-7): Methanol (24 mg, 0.15 mmol, 1.2 eq) was placed in a reaction flask, THF (3 mL) was added, and NaH (6 mg, 0.15 mmol, 1.2 eq) was added under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 3 minutes. At 0 min, (1R, 5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(methanesulfonyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.14 mmol, 1 eq) was added under ice bath. After addition, the mixture was stirred at room temperature for 2 h, quenched with ammonium chloride solution, and extracted with EtOAc (20 mL * 3) / H2O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a white solid compound 4-7 (60 mg, yield 54%). ESI-MS: 795.2 [M+H] +

[0279] Step 7, Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzothiophene-3-onitrile (4-8): tert-butyl(1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3- Cyano-7-fluorobenzothiophene-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (60 mg, 0.075 mmol, 1 eq) was placed in a reaction flask, and DCM (2 mL) and TFA (0.4 mL) were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. The mixture was concentrated, and the pale yellow solid compound 4-8 (30 mg, yield 67%) was prepared by prep-HPLC. ESI-MS: 594.2 [M+H] +

[0280] Step 8, Synthesis of 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile (compound 4): 4-( Chiral resolution of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzothiophene-3-onitrile (30 mg) yielded a white solid compound 4 (10 mg). ESI-MS: 594.2 [M+H] +

[0281] Example 5: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(7-hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthyl)-6,7-dihydropyrido[3,4-d]pyrimidine-8 (Compound 5)

[0282]

[0283] Step 1, Synthesis of tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(7-(methoxy-methoxy)-2,3-dihydro-1H-cyclopentano[a]naphthyl)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (5-2): The (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (52 mg, 0.1 mmol, 1 eq, synthesis as per Example 1), 9-bromo-7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (34 mg, 0.11 mmol, 1.1 eq, synthesis as per Example 2), K3PO4 (64 mg, 0.3 mmol, 3 eq), N1,N2-dimethylethane-1,2-diamine (13 mg, 0.15 mmol, 1.5 eq), CuI (23 mg, 0.12 mmol, 1.2 eq) were placed in a reaction flask, and dioxane (3 mL) was added. The mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 5-2 (15 mg, yield 20%). ESI-MS: 744.1 [M+H] +

[0284] Step 2, Synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(7-hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthyl)-6,7-dihydropyrido[3,4-d]pyrimidine-8 (compound 5): tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) H)-yl)methoxy)-7-(7-(methoxy-methoxy)-2,3-dihydro-1H-cyclopentano[a]naphthyl)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (15 mg, 0.02 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The mixture was concentrated and pre-HPLC was used to prepare a pale yellow solid compound 5 (3 mg, yield 25%). ESI-MS: 599.2 [M+H] +

[0285] Example 6: 1-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-group)dibenzo[b,d]furan-3-ol (Compound 6)

[0286]

[0287] Step 1, Synthesis of 2-bromo-1-chloro-3,5-dimethoxybenzene (6-2): 1-Chloro-3,5-dimethoxybenzene (1.5 g, 8.69 mmol, 1 eq) was placed in a reaction flask, and DCE (15 mL) and NBS (1.55 g, 8.69 mmol, 1 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed using DCM (30 mL x 3) / H2O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:20) to give a colorless oily compound 6-2 (2 g, yield 91%). ESI-MS: 252.2 [M+H] +

[0288] Step 2, Synthesis of 2'-chloro-4',6'-dimethoxy-[1,1'-biphenyl]-2-amine (6-3): 2-bromo-1-chloro-3,5-dimethoxybenzene (2 g, 7.95 mmol, 1 eq), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (1.92 g, 8.75 mmol, 1.1 eq), K2CO3 (2.75 g, 19.88 mmol, 2.5 eq), and Pd(PPh3)4 (459 mg, 0.397 mmol, 0.05 eq) were placed in a reaction flask, and dioxane (30 mL) and H2O (5 mL) were added. After the addition was complete, the mixture was stirred overnight at 100 °C under argon protection. Cool, extract with EtOAc (40 mL x 3) / H₂O (40 mL), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (PE:EA = 100:10-100:50) to give a yellow solid compound 6-3 (0.8 g, yield 38%). ESI-MS: 265.2 [M + H₂] +

[0289] Step 3, Synthesis of 1-chloro-3-methoxydibenzo[b,d]furan (6-4): 2'-chloro-4',6'-dimethoxy-[1,1'-biphenyl]-2-amine (800 mg, 3 mmol, 1 eq) was placed in a reaction flask, and THF (5 mL) and HOAc (5 mL) were added. The mixture was cooled to -10 °C, and tert-butyl nitrite (625 mg, 6 mmol, 2 eq) was slowly added. After the addition was complete, the mixture was stirred overnight at room temperature. Extraction was performed with EtOAc (20 mL * 3) / H2O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:10) to give a white solid compound 6-4 (200 mg, yield 28%). ESI-MS: 233.2 [M + H] +

[0290] Step 4, Synthesis of 1-chlorodibenzo[b,d]furan-3-ol (6-5): 1-Chloro-3-methoxydibenzo[b,d]furan (200 mg, 0.86 mmol, 1 eq) was placed in a reaction flask, and DCM (3 mL) was added. A DCM solution of BBr3 (1.72 mL, 1.72 mmol, 2 eq, 1 M) was added under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed by adding DCM (20 mL x 2) / H2O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:20) to give a white solid compound 6-5 (150 mg, 80% yield). ESI-MS: 219.2 [M+H] +

[0291] Step 5, Synthesis of 1-chloro-3-(methoxymethoxy)dibenzo[b,d]furan (6-6): 1-chlorodibenzo[b,d]furan-3-ol (150 mg, 0.68 mmol, 1 eq) was placed in a reaction flask, and DCM (2 mL) and DIEA (177 mg, 1.36 mmol, 2 eq) were added. Bromo(methoxy)methane (103 mg, 0.82 mmol, 1.2 eq) was added under ice bath conditions. After addition, the mixture was stirred at room temperature for 2 h. Extraction was performed using DCM (20 mL x 2) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:10) to give a white solid compound 6-6 (170 mg, 94% yield). ESI-MS: 263.2 [M+H] +

[0292] Step 6, Synthesis of 2-chloro-4-(1,4-oxazacycloheptan-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (6-8): 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (304 mg, 1 mmol, 1 eq) was placed in a reaction flask, and THF (5 mL) and DIEA (0.35 mL, 2 mmol, 2 eq) were added. The mixture was cooled to -20 °C, and 1,4-oxazacycloheptanane (101 mg, 1 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 30 min, and then stirred overnight at ambient temperature. Extracted with EtOAc (20 mL x 3) / H₂O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give a yellow solid compound 6-8 (280 mg, yield 76%). ESI-MS: 370.2 [M + H₂] +

[0293] Step 7, Synthesis of 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (6-9): 2-chloro-4-(1,4-oxazacycloheptane-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (280 mg, 0.76 mmol, 1e q), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methanol (130 mg, 0.83 mmol, 1.1 eq), Cs₂CO₃ (494 mg, 1.52 mmol, 2 eq), Pd₂(dba)₃ (70 mg, 0.076 mmol, 0.1 eq), RuPhos (70 mg, 0.15 mmol, 0.2 eq) were placed in a reaction flask, toluene (10 mL) was added, and the mixture was stirred overnight at 90 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give a yellow solid compound 6-9 (200 mg, yield 54%). ESI-MS: 492.2 [M+H] +

[0294] Step 8, Synthesis of 4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (6-10): 200 mg, 0.4 mmol, 1 eq of 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (CBE) was placed in a reaction flask, CH3CN (2 mL) was added, and dioxane / HCl (0.5 mL) was added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 1 h. Concentrate to dryness to give a yellow solid compound 6-10 (180 mg, crude product), ESI-MS: 392.2 [M+H]. + Proceed directly to the next step.

[0295] Step Nine, Synthesis of 4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxy-methoxy]dibenzo[b,d]furan-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (6-11): 4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (39 mg, 0.1 mmol, 1 eq), 1-chloro-3- (Methoxymethoxy)dibenzo[b,d]furan (29 mg, 0.11 mmol, 1.1 eq), Cs₂CO₃ (81 mg, 0.25 mmol, 2.5 eq), Pd₂(dba)₃ (9 mg, 0.001 mmol, 0.1 eq), and RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, and toluene (2 mL) was added. The mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 6-11 (30 mg, 48% yield). ESI-MS: 618.2 [M+H] +

[0296] Step 10, Synthesis of 1-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-group)dibenzo[b,d]furan-3-ol (compound 6): 4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxy-methoxy]dibenzo[b,d]furan-3-ol) [b,d]furan-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)1,4-oxazacycloheptane (30 mg, 0.049 mmol, 1 eq) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and pre-HPLC was used to prepare a pale yellow solid compound 6 (5 mg, yield 17%). ESI-MS: 574.2 [M+H] +

[0297] Example 7: 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-nitrile (Compound 7)

[0298]

[0299] Step 1, Synthesis of 2-(bis(4-methoxybenzyl)amino)-4-bromo-7-fluorobenzothiophene-3-onitrile (7-2): NaH (425 mg, 17.71 mmol, 2.4 eq) was placed in a reaction flask, DMF (20 mL) was added, and a solution of 2-amino-4-bromo-7-fluorobenzothiophene-3-onitrile (2 g, 7.38 mmol, 1 eq) / DMF (5 mL) was slowly added dropwise under ice bath. After the addition was complete, the mixture was stirred at this temperature for 30 min, and p-methoxybenzyl chloride (2.77 g, 17.71 mmol, 2.4 eq) was added. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction solution was slowly added to a 40 mL saturated ammonium chloride solution for quenching. Extraction was performed by adding EtOAc (40 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:20) to give a yellow solid compound 7-2 (3 g, yield 79%). ESI-MS: 512.2 [M+H] +

[0300] Step 2, Synthesis of 2-(bis(4-methoxybenzyl)amino)-7-fluoro-4-vinylbenzothiophene-3-onitrile (7-3): 2-(bis(4-methoxybenzyl)amino)-4-bromo-7-fluorobenzothiophene-3-onitrile (3 g, 5.87 mmol, 1 eq), potassium trifluoro(vinyl)borate (943 mg, 7.04 mmol, 1.2 eq), K3PO4 (3.11 g, 14.67 mmol, 2.5 eq), and Pd(dppf)Cl2 (429 mg, 0.587 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (30 mL) and H2O (5 mL) were added. Under argon protection, the mixture was stirred overnight at 100 °C. Cool, extract with EtOAc (100 mL x 3) / H₂O (100 mL), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (PE:EA = 100:10-100:50) to give a yellow solid compound 7-3 (2 g, yield 74%). ESI-MS: 459.2 [M + H₂] +

[0301] Step 3, Synthesis of 2-(bis(4-methoxybenzyl)amino)-7-fluoro-4-formylbenzothiophene-3-onitrile (7-4): 2-(bis(4-methoxybenzyl)amino)-7-fluoro-4-vinylbenzothiophene-3-onitrile (2 g, 4.36 mmol, 1 eq) was placed in a reaction flask, and DCM (20 mL) was added. The mixture was cooled to -78 °C under ozone protection and stirred for 10 min. The solution was purged with argon, and triphenylphosphine (3.43 g, 13.08 mmol, 3 eq) was added. After the addition was complete, the mixture was heated to room temperature and stirred for 1 h. The mixture was filtered to obtain the target product compound 7-4 (1.5 g, 75% yield). ESI-MS: 461.2 [M+H] +

[0302] Step 4, Synthesis of Methyl 5-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-5-hydroxy-3-oxovalerate (7-5): NaH (390 mg, 9.77 mmol, 3 eq) was placed in a reaction flask, and THF (20 mL) was added. Methyl 3-oxobutyrate (1.13 g, 9.77 mmol, 3 eq) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. Then, n-butyllithium solution (1.5 mL, 3.91 mmol, 1.2 eq, 2.5 M) was added dropwise. After 30 min, the temperature was lowered to -60℃, and 10 mL of THF was added dropwise to 2-(bis(4-methoxybenzyl)amino)-7-fluoro-4-carboxybenzothiophene-3-onitrile (1.5 g, 3.26 mmol, 1 eq). The mixture was stirred at this temperature for 30 min, and 50 mL of saturated ammonium chloride solution was added. The mixture was extracted with EtOAc (50 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (100:0–100:50) to give the target compound 7-5 (1 g, yield 53%). ESI-MS: 577.2 [M + H] +

[0303] Step 5, Synthesis of methyl 2-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-4-oxo-3,4-dihydro-2H-pyran-5-carboxylic acid (7-6): Methyl 5-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-5-hydroxy-3-oxovalerate (1 g, 1.73 mmol, 1 eq) was placed in a reaction flask, DCM (15 mL) was added, and N,N-dimethylformamide dimethyl acetal (248 mg, 2.08 mmol, 1.2 eq) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. Add boron trifluoride diethyl ether (295 mg, 2.08 mmol, 1.2 eq), stir at room temperature for 1 h, add saturated ammonium chloride solution (40 mL), extract with DCM (40 mL * 3), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (100:10–100:60) to give target compound 7-6 (0.7 g, yield 69%). ESI-MS: 587.2 [M + H] +

[0304] Step 6, Synthesis of methyl 6-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-4-hydroxy-5,6-dihydro-2H-pyran-3-carboxylic acid (7-7): Methyl 2-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-4-oxo-3,4-dihydro-2H-pyran-5-carboxylic acid (700 mg, 1.2 mmol, 1 eq) was placed in a reaction flask and THF was added. (10 mL), under argon protection, cooled to -60 °C, added tri-sec-butylborohydride (1.4 mL, 1.4 mmol, 1.2 eq, 1 M). After addition, stirred at this temperature for 30 min, added saturated ammonium chloride solution (20 mL), extracted with EtOAc (20 mL * 3), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and column chromatography (100:10-100:60) to give target compound 7-7 (0.6 g, yield 85%). ESI-MS: 589.2 [M + H] +

[0305] Step 7, Synthesis of 2-(bis(4-methoxybenzyl)amino)-7-fluoro-4-(4-hydroxy-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)benzothiophene-3-onitrile (7-8): Methyl 6-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-4-hydroxy-5,6-dihydro-2H-pyran-3-carboxylic acid (600 mg, 1 mmol, 1 eq) was placed in a reaction flask, and ethanol (5 mL), water (1 mL), NaHCO3 (856 mg, 10 mmol, 10 eq), and S-methyl isothiourea sulfate (2-Methyl-2-thiopseudourea sulfate) (1.92 g, 10 mmol, 10 eq) were added. The mixture was stirred at 50 °C for 4 h. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (100:10-100:100) to give target compounds 7-8 (0.5 g, yield 78%). ESI-MS: 629.2 [M+H] +

[0306] Step 8, Synthesis of 7-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (7-9): 2-(bis(4-methoxybenzyl)amino)-7-fluoro-4-(4-hydroxy-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)benzothiophene-3-onitrile (500 mg, 0.79 mmol, 1 eq) was placed in a reaction flask, and DCM (8 mL) and DIEA (205 mg, 1.59 mmol, 2 eq) were added. Trifluoromethanesulfonic anhydride (269 mg, 0.95 mmol, 1.2 eq) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. Add saturated ammonium chloride solution (20 mL), extract with DCM (20 mL * 3), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (100:10-0:1) to give target compounds 7-9 (0.45 g, yield 74%). ESI-MS: 762.2 [M+H] +

[0307] Step nine, synthesis of (1R, 5S)-3-(7-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7-10): 7-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yltrifluoro Synthesis of methanesulfonate: 2-(bis(4-methoxybenzyl)amino)-7-fluoro-4-(4-hydroxy-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)benzothiophene-3-onitrile (0.45 g, 0.59 mmol, 1 eq) was placed in a reaction flask, and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (125 mg, 0.59 mmol, 1 eq) and DIEA (152 mg, 1.18 mmol, 2 eq) were added. After the addition was complete, the mixture was stirred overnight at 50 °C. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (100:10-0:1) to give the target compound 7-10 (0.4 g, yield 82%). ESI-MS: 824.2 [M+H] +

[0308] Step 10, Synthesis of (1R,5S)-3-(7-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(methanesulfonyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7-11): (1R,5S)-3-(7-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(methanesulfonyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7-11) 400 mg (0.48 mmol, 1 eq) of tert-butyl octane-8-carboxylic acid (3.2.1) was placed in a reaction flask, and DCM (6 mL) and m-CPBA (201 mg, 1.17 mmol, 2.4 eq) were added. The mixture was stirred at room temperature for 2 h after the addition was complete. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (100:10 - 0:1) to give the target compound 7-11 (0.3 g, yield 72%). ESI-MS: 856.2 [M + H] +

[0309] Step 11, Synthesis of tert-butyl(1R,5S)-3-(7-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (7-12): ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (63 mg, 0.39 g) 1 mmol (1.1 eq) was placed in a reaction flask, THF (5 mL) was added, followed by sodium tert-butoxide (38 mg, 0.39 mmol, 1.1 eq). Under ice bath conditions, (1R, 5S)-3-(7-(2-(bis(4-methoxybenzyl)amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(methanesulfonyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 0.35 mmol, 1 eq) was added, and the mixture was stirred at this temperature for 1 h after the addition was complete. The solution was concentrated and column chromatography (DCM:MeOH = 100:0-100:10) was used to determine the target compound 7-12 (100 mg, 30% yield). ESI-MS: 935.2 [M+H] +

[0310] Step 12, Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzothiophene-3-onitrile (7-13): tert-butyl(1R,5S)-3-(7-(2-(bis(4-methoxybenzyl)) (Amino)-3-cyano-7-fluorobenzothiophene-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (100 mg, 0.1 mmol, 1 eq) was placed in a reaction flask, and DCM (3 mL) and TFA (1 mL) were added. The mixture was stirred at room temperature for 1 h. After concentration, the mixture was prepared by prep-HPLC to obtain a pale yellow solid compound 7-13 (20 mg, yield 31%). ESI-MS: 595.2 [M+H] +

[0311] Step 13, Synthesis of 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile (compound 7): 4 Chiral resolution of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzothiophene-3-onitrile (20 mg) yielded target compound 7 (5 mg). ESI-MS: 595.2 [M+H] +

[0312] Example 8: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-group)dibenzo[b,d]furan-3-ol (Compound 8)

[0313]

[0314] Step 1, Synthesis of tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxyformyl)dibenzo[b,d]furan-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (8-2): The tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol, 1 eq, see Example 2), 1-chloro-3-(methoxymethoxy)dibenzo[b,d]furan (29 mg, 0.11 mmol, 1.1 eq, see Example 6), Cs2CO3 (81 mg, 0.25 mmol, 2.5 eq), Pd2(dba)3 (9 mg, 0.001 mmol, 0.1 eq), and RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, toluene (2 mL) was added, and the mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give a yellow solid compound 8-2 (25 mg, yield 34%). ESI-MS: 730.2 [M+H] +

[0315] Step 2, Synthesis of 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-group)dibenzo[b,d]furan-3-ol (compound 8): tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin) -7a(5H)-yl)methoxy)-7-(3-(methoxyformyl)dibenzo[b,d]furan-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (25 mg, 0.034 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The mixture was concentrated and pre-HPLC was used to prepare a pale yellow solid compound 8 (5 mg, yield 25%). ESI-MS: 586.2 [M+H] +

[0316] Example 9: 5-ethynyl-6-fluoro-4-(8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (compound 9)

[0317]

[0318] Step 1, Synthesis of 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (9-2): 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin (252 mg, 1 mmol, 1 eq) was placed in a reaction flask, and DCM (5 mL) and DIEA (0.35 mL, 2 mmol, 2 eq) were added. 1,4-oxazacycloheptane (101 mg, 1 mmol, 1 eq) was added at -40 °C. After the addition was complete, the mixture was stirred at this temperature for 30 min. DCM (10 mL * 2) / H2O (10 mL) was added, and the mixture was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give a yellow solid compound 9-2 (280 mg, 88% yield). ESI-MS: 318.2 [M+H] +

[0319] Step 2, Synthesis of 4-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (9-3): Methanol (168 mg, 1.06 mmol, 1.2 eq) was placed in a reaction flask, THF (4 mL) was added, and NaH (42 mg, 1.06 mmol, 1.2 eq) was added in portions under ice bath conditions. The mixture was stirred at ambient temperature for 30 min, and then 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (280 mg, 0.88 mmol, 1 eq) was added under ice bath conditions. After the addition was complete, the mixture was stirred at ambient temperature for 2 h, extracted with EtOAc (20 mL * 3) / H2O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 9-3 (170 mg, yield 44%). ESI-MS: 441.2 [M + H] +

[0320] Step 3, Synthesis of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxypyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptanane (9-4): 4-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptanane Alkane (170 mg, 0.38 mmol, 1 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (233 mg, 0.44 mmol, 1.2 eq), K3PO4 (201 mg, 0.94 mmol, 2.5 eq), Ad2nBuP-Pd-G3 (20 mg, 0.038 mmol, 0.1 eq), THF (4 mL), H2O (0.8 mL), after addition, under argon protection, stirred overnight at 60 °C. Cool, extract with EtOAc (20 mL x 3) / H₂O (20 mL), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 9-4 (250 mg, yield 82%). ESI-MS: 791.2 [M + H₂] +

[0321] Step 4, Synthesis of 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxypyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptanane (9-5): 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxypyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptanane (9-5) Pyrimidin-4-yl)-1,4-oxazacycloheptane (250 mg, 0.32 mmol, 1 eq) was placed in a reaction flask, and DMF (4 mL) and CsF (480 mg, 3.2 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at ambient temperature for 2 h, extracted with EtOAc (20 mL * 3) / H2O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 9-5 (170 mg, yield 85%). ESI-MS: 634.2 [M + H] +

[0322] Step 5, Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (compound 9): 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8- Fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (170 mg, 0.27 mmol, 1 eq) was placed in a reaction flask, and CH3CN (4 mL) was added. HCl / dioxane (1 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and pre-HPLC was used to prepare a pale yellow solid compound 9 (100 mg, yield 63%). ESI-MS: 590.2 [M+H] +

[0323] Example 10: 10-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-ylpyrrolo[2,1-a]isoquinoline-8-ol (Compound 10)

[0324]

[0325] Step 1, Synthesis of 2-(2-bromo-4-methoxyphenyl)-1H-pyrrole-1-carboxylic acid tert-butyl ester (10-2): 2-bromo-1-iodo-4-methoxyphenyl (500 mg, 1.6 mmol, 1 eq), (1-(tert-butoxycarbonyl)-1H-pyrrole-2-yl)boronic acid (404 mg, 1.9 mmol, 1.2 eq), K2CO3 (552 mg, 3.9 mmol, 2.5 eq), Pd(dppf)Cl2 (117 mg, 0.16 mmol, 0.1 eq), dioxane (10 mL), H2O (2 mL), aerated, stirred overnight at 100 °C. Extraction was performed using EtOAc (30 mL x 3) / H₂O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:20) to give the target compound 10⁻² (500 mg, yield 89%). ESI-MS: 353.2 [M + H₂] +

[0326] Step 2, Synthesis of 2-(2-bromo-4-methoxyphenyl)-1H-pyrrole (10⁻³): 2-(2-bromo-4-methoxyphenyl)-1H-pyrrole-1-carboxylic acid tert-butyl ester (500 mg, 1.4 mmol, 1 eq) was placed in a reaction flask, and THF (4 mL), MeOH (4 mL), and NaOMe (383 mg, 7 mmol, 5 eq) were added. After addition, the mixture was stirred at room temperature for 2 h. Extraction was performed with EtOAc (20 mL * 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:30) to obtain the target compound 10⁻³ (300 mg, yield 83%). ESI-MS: 253.2 [M + H] +

[0327] Step 3, Synthesis of 2-(2-bromo-4-methoxyphenyl)-1-(2,2-dimethoxyethyl)-1H-pyrrole (10⁻⁴): 2-(2-bromo-4-methoxyphenyl)-1H-pyrrole (300 mg, 1.2 mmol, 1 eq) was placed in a reaction flask, and DMF (6 mL), 2-bromo-1,1-dimethoxyethane (1 g, 6 mmol, 5 eq), and Cs₂CO₃ (1.9 g, 6 mmol, 5 eq) were added. After addition, the mixture was stirred overnight at 90 °C. Extraction was performed with EtOAc (20 mL * 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:30) to obtain the target compound 10⁻⁴ (330 mg, yield 81%). ESI-MS: 341.2 [M + H⁺] +

[0328] Step 4, Synthesis of 10-bromo-8-methoxypyrrolo[2,1-a]isoquinoline (10⁻⁵): 2-(2-bromo-4-methoxyphenyl)-1-(2,2-dimethoxyethyl)-1H-pyrrole (330 mg, 0.97 mmol, 1 eq) was placed in a reaction flask, and DCM (6 mL) and TfOH (1.46 g, 9.7 mmol, 10 eq) were added. After addition, the mixture was stirred overnight at room temperature. Extraction was performed with EtOAc (20 mL * 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:20) to obtain the target compound 10⁻⁵ (150 mg, yield 56%). ESI-MS: 277.2 [M + H⁺] +

[0329] Step 5, Synthesis of 10-bromopyrrolo[2,1-a]isoquinoline-8-ol (10⁻⁶): 150 mg (0.54 mmol, 1 eq) of 10-bromo-8-methoxypyrrolo[2,1-a]isoquinoline was placed in a reaction flask, and DCM (4 mL) and BBr₃ (680 mg, 2.72 mmol, 5 eq) were added. After addition, the mixture was stirred at room temperature for 2 h. Extraction was performed using DCM (20 mL * 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:30) to obtain the target compound 10⁻⁶ (120 mg, yield 84%). ESI-MS: 263.2 [M + H⁺] +

[0330] Step 6, Synthesis of 10-bromo-8-(methoxymethoxy)pyrrolo[2,1-a]isoquinoline (10⁻⁷): 120 mg of 10-bromopyrrolo[2,1-a]isoquinoline-8-ol (120 mg, 0.45 mmol, 1 eq) was placed in a reaction flask, and DCM (3 mL), DIEA (118 mg, 0.9 mmol, 2 eq), and bromomethyl methyl ether (68 mg, 0.55 mmol, 1.2 eq) were added. After addition, the mixture was stirred at room temperature for 2 h. Extraction was performed using DCM (20 mL * 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:20) to obtain the target compound 10⁻⁷ (110 mg, yield 78%). ESI-MS: 307.2 [M + H⁺] +

[0331] Step 7, (1R, 5S)-3-(2-(((2S, 7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-(methoxymethoxy]pyrrolo[2,1-a]isoquinoline-10-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Synthesis of tert-butyl octane-8-carboxylate (10-8): (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (50 mg) 0.1 mmol, 1 eq (refer to Example 2), 10-bromo-8-(methoxymethoxy)pyrrolo[2,1-a]isoquinoline (34 mg, 0.11 mmol, 1.1 eq), Cs₂CO₃ (81 mg, 0.25 mmol, 2.5 eq), Pd₂(dba)₃ (9 mg, 0.001 mmol, 0.1 eq), and RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, toluene (2 mL) was added, and the mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 10⁻⁸ (40 mg, yield 55%). ESI-MS: 728.2 [M+H] +

[0332] Step 8, Synthesis of 10-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-ylpyrrolo[2,1-a]isoquinoline-8-ol (compound 10): 1R,5S)-3-(2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-(methoxymethoxy]pyrrolo [2,1-a]isoquinoline-10-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (40 mg, 0.05 mmol, 1 eq) was placed in a reaction flask, CH3CN (2 mL) was added, and HCl / dioxane (0.5 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated and pre-HPLC was used to prepare a pale yellow solid compound 10 (10 mg, yield 31%). ESI-MS: 584.2 [M+H] +

[0333] Example 11: 9-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)azacyclobutane-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2,3-dihydro-1H-cyclopenta[a]naphthyl-7-ol (Compound 11)

[0334]

[0335] Step 1, Synthesis of tert-butyl 3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)azacyclobutane-1-carboxylate (11-2): 3-Formylazacyclobutane-1-carboxylate (400 mg, 2.16 mmol, 1 eq), 3-azabicyclo[3.1.0]hexane hydrochloride (258 mg, 2.16 mmol, 1 eq), and HOAc (129 mg, 2.16 mmol, 1 eq) were placed in a reaction flask, and MeOH (6 mL) was added. The mixture was stirred at room temperature for 30 min, and then NaBH3CN (407 mg, 6.48 mmol, 3 eq) was added. After the addition was complete, the mixture was stirred at room temperature overnight. Extraction was performed using DCM (30 mL x 3) / H₂O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:20) to give the target compound 11-2 (300 mg, yield 55%). ESI-MS: 253.2 [M + H₂]+

[0336] Step 2, Synthesis of 3-(azacyclobutane-3-ylmethyl)-3-azabicyclo[3.1.0]hexane (11-3): 3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester (300 mg, 1.19 mmol, 1 eq) was placed in a reaction flask, and CH3CN (4 mL) was added. HCl / dioxane (1 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated to obtain the target compound 11-3 (230 mg, crude product). ESI-MS: 153.2 [M+H] +

[0337] Step 3, Synthesis of 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (11-5): Synthesis of 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester: 2,4- Dichloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid benzyl ester (338 mg, 1 mmol, 1 eq) was placed in a reaction flask, and THF (5 mL) and DIEA (0.35 mL, 2 mmol, 2 eq) were added. The mixture was cooled to -20 °C, and (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (212 mg, 1 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 30 min, and then stirred overnight at ambient temperature. The mixture was extracted with EtOAc (20 mL * 3) / H2O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give the target compound 11-5 (500 mg, yield 97%). ESI-MS: 515.2 [M + H] +

[0338] Step 4, Synthesis of 2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)azabicyclobutane-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid benzyl ester (11-6): 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[ 3.2.1] Oct-3-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid benzyl ester (500 mg, 0.97 mmol, 1 eq), 3-(azacyclobutan-3-ylmethyl)-3-azabicyclo[3.1.0]hexane (230 mg, crude) were placed in a reaction flask, DMF (6 mL) and DIEA (295 mg, 2.92 mmol, 3 eq) were added, and the mixture was stirred overnight at 130 °C. After cooling, EtOAc (30 mL * 3) / H2O (30 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:-100:10) to give the target compound 11-6 (200 mg, yield 32%). ESI-MS: 630.2 [M + H] +

[0339] Step 5, Synthesis of (1R, 5S)-3-(2-(3-(3-azabicyclo[3.1.0]hexane-3-yl)methyl)azacyclobutane-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (11-7): 2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)azacyclobutane-1 200 mg (0.32 mmol, 1 eq) of benzyl oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid was placed in a reaction flask, and MeOH (5 mL), ammonia (0.1 mL), and Pa / C (20 mg, 10%) were added. After addition, the mixture was stirred overnight under H2 protection at ambient temperature. The mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 11-7 (70 mg, 44% yield). ESI-MS: 496.2 [M+H] +

[0340] Step 6, Synthesis of (1R, 5S)-3-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)azacyclobutane-1-yl)-7-(7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (11-8): The (1R, 5S)-3-(2-(3-(3-azabicyclo[3.1.0]hexane-3-yl)methyl)azacyclobutane-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol, 1 eq), 9-bromo-7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (34 mg, 0.11 mmol, 1.1 eq, see synthesis in Example 2), Cs2CO3 (81 mg, 0.25 mmol, 2.5 eq), Pd2(dba)3 (9 mg, 0.001 mmol, 0.1 eq), RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, toluene (2 mL) was added, and the mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 11-8 (20 mg, yield 27%). ESI-MS: 723.2 [M+H] +

[0341] Step 7, Synthesis of 9-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)azacyclobutane-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2,3-dihydro-1H-cyclopenta[a]naphthyl-7-ol (compound 11): (1R,5S)-3-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl) 20 mg (0.03 mmol, 1 eq) of tert-butyl octane-8-carboxylic acid (20 mg, 0.03 mmol, 1 eq) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated and prepared by prep-HPLC to obtain a pale yellow solid compound 11 (5 mg, yield 31%). ESI-MS: 578.2 [M+H]+

[0342] Example 12: 1-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)dibenzo[b,d]furan-3-ol (Compound 12)

[0343]

[0344] Step 1, Synthesis of 2-(3-(methoxymethoxy)dibenzo[b,d]furan-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (12-2): 1-Chloro-3-(methoxymethoxy)dibenzo[b,d]furan (100 mg, 0.38 mmol, 1 eq, refer to the synthesis in Example 6), pinacol diboron (145 mg, 0.57 mmol, 1.5 eq), KOAc (112 mg, 1.14 mmol, 3 eq), and Pd(dppf)Cl2 (28 mg, 0.038 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (5 mL) was added. After the addition was complete, the mixture was stirred overnight at 100 °C under argon protection. After cooling, the mixture was filtered, and the filtrate was concentrated to dryness to obtain the target compound 12-2 (200 mg, crude product). ESI-MS: 355.2 [M+H] +

[0345] Step 2, Synthesis of 4-(8-fluoro-7-(3-(methoxymethoxy)dibenzo[b,d]furan-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (12-3): 2-(3-(methoxymethoxy)dibenzo[b,d]furan-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (100 mg, crude), 4-(7-chloro-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (42 mg, 0.1 mm) 1 ol (refer to the synthesis in Example 3), K3PO4 (53 mg, 0.25 mmol, 2.5 eq), Ad2nBuP-Pd-G3 (5 mg, 0.02 mmol, 0.2 eq), THF (3 mL), H2O (0.6 mL), added, under argon protection, stirred overnight at 60 °C. Cooled, extracted with EtOAc (20 mL * 3) / H2O (20 mL), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 12-3 (30 mg, yield 49%). ESI-MS: 614.2 [M + H] +

[0346] Step 3, Synthesis of 1-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)dibenzo[b,d]furan-3-ol: 4-(8-fluoro-7-(3-(methoxymethoxy)dibenzo[b,d]furan-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy]pyrido[4,3-d] Pyrimidin-4-yl)-1,4-oxazacycloheptane (compound 12) (30 mg, 0.04 mmol, 1 eq) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and compound 12 (8 mg, 28% yield) was obtained as a pale yellow solid by prep-HPLC. ESI-MS: 570.2 [M+H] +

[0347] Example 13: 9-(2-(3-(1-(3-azabicyclo[3.1.0]hexane-3-yl)ethyl)azacyclobutane-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2,3-dihydro-1H-cyclopenta[a]naphthyl-7-ol (Compound 13)

[0348]

[0349] Step 1, Synthesis of tert-butyl 3-(1-(3-azabicyclo[3.1.0]hexane-3-yl)ethyl)azacyclobutane-1-carboxylate (13-2): 3-acetylazacyclobutane-1-carboxylate (430 mg, 2.16 mmol, 1 eq), 3-azabicyclo[3.1.0]hexane hydrochloride (258 mg, 2.16 mmol, 1 eq), and HOAc (129 mg, 2.16 mmol, 1 eq) were placed in a reaction flask, and MeOH (6 mL) was added. The mixture was stirred at room temperature for 30 min, and then NaBH3CN (407 mg, 6.48 mmol, 3 eq) was added. After the addition was complete, the mixture was stirred at room temperature overnight. Extraction was performed using DCM (30 mL x 3) / H₂O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:20) to give the target compound 13-2 (310 mg, yield 54%). ESI-MS: 267.2 [M + H₂] +

[0350] Step 2, Synthesis of 3-(1-(azacyclobutane-3-yl)ethyl)-3-azabicyclo[3.1.0]hexane (13-3): 310 mg (1.16 mmol, 1 eq) of tert-butyl 3-(1-(3-azabicyclo[3.1.0]hexane-3-yl)ethyl)azacyclobutane-1-carboxylic acid was placed in a reaction flask, and CH3CN (4 mL) was added. HCl / dioxane (1 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated to obtain the target compound 13-3 (250 mg, crude product). ESI-MS: 167.2 [M+H] +

[0351] Step 3, Synthesis of 2-(3-(1-(3-azabicyclo[3.1.0]hexane-3-yl)ethyl)azabicyclobutane-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (13-4): 3-(1-(azabicyclo[3.1.0]hexane-3-yl)ethyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (13-4) Butane-3-yl)ethyl)-3-azabicyclo[3.1.0]hexane (500 mg, 0.97 mmol, 1 eq) and 3-(azabicyclobutane-3-ylmethyl)-3-azabicyclo[3.1.0]hexane (250 mg, crude) were placed in a reaction flask, and DMF (6 mL) and DIEA (295 mg, 2.92 mmol, 3 eq) were added. The mixture was stirred overnight at 130 °C. After cooling, EtOAc (30 mL x 3) / H2O (30 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:-100:10) to give the target compound 13-4 (180 mg, yield 29%). ESI-MS: 645.2 [M+H] +

[0352] Step 4, Synthesis of (1R, 5S)-3-(2-(3-(1-(3-azabicyclo[3.1.0]hexane-3-yl)ethyl)azacyclobutane-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (13-5): 2-(3-(1-(3-azabicyclo[3.1.0]hexane-3-yl)ethyl)azacyclobutane Benzyl ester of oct-3-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid (180 mg, 0.28 mmol, 1 eq) was placed in a reaction flask, and MeOH (5 mL), ammonia (0.1 mL), and Pa / C (18 mg, 10%) were added. After the addition was complete, the mixture was stirred overnight under H2 protection at ambient temperature. The mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 13-5 (60 mg, 42% yield). ESI-MS: 510.2 [M+H] +

[0353] Step 5, Synthesis of tert-butyl(1R,5S)-3-(2-(3-(1-(3-azabicyclo[3.1.0]hexane-3-yl)ethyl)azacyclobutane-1-yl)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (13-6): The tert-butyl(1R,5S)-3-(2-(3-(1-(3-azabicyclo[3.1.0]hexane-3-yl)ethyl)azacyclobutane-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d] Pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (51 mg, 0.1 mmol, 1 eq), 9-bromo-7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (34 mg, 0.11 mmol, 1.1 eq, see synthesis in Example 2), Cs2CO3 (81 mg, 0.25 mmol, 2.5 eq), Pd2(dba)3 (9 mg, 0.001 mmol, 0.1 eq), RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, toluene (2 mL) was added, and the mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 13-6 (18 mg, yield 24%). ESI-MS: 737.2 [M+H] +

[0354] Step 6, Synthesis of 9-(2-(3-(1-(3-azabicyclo[3.1.0]hexane-3-yl)ethyl)azabicyclobutane-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2,3-dihydro-1H-cyclopenta[a]naphthyl-7-ol (compound 13): tert-butyl(1R,5S)-3-(2-(3-(1-(3-azabicyclo[3.1.0]hexane-3-yl) (-yl)ethyl)azacyclobutane-1-yl)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (18 mg, 0.024 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The mixture was concentrated and pre-HPLC was used to prepare a pale yellow solid compound 13 (5 mg, yield 34%). ESI-MS: 592.2 [M+H] +

[0355] Example 14: 9-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-methylazacycloheptane-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2,3-dihydro-1H-cyclopenta[a]naphthyl-7-ol (Compound 14)

[0356]

[0357] Step 1, Synthesis of tert-butyl 3-(hydroxymethyl)-3-methylazacyclobutane-1-carboxylate (14-2): 1-(tert-butoxycarbonyl)-3-methylazacyclobutane-3-carboxylic acid (800 mg, 3.72 mmol, 1 eq) was placed in a reaction flask, and THF (10 mL) was added. BMS (11.16 mL, 22.32 mmol, 6 eq) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 h. The mixture was quenched with methanol under ice bath conditions, concentrated, and subjected to column chromatography (PE:EA = 100:0-100:50) to obtain the target compound 14-2 (680 mg, 90%). ESI-MS: 202.2 [M+H] +

[0358] Step 2, Synthesis of tert-butyl 3-formyl-3-methylazacyclobutane-1-carboxylate (14-3): tert-butyl 3-(hydroxymethyl)-3-methylazacyclobutane-1-carboxylate (680 mg, 3.38 mmol, 1 eq) was placed in a reaction flask, and DCM (8 mL) was added. Dess-Martin periodinane (2.87 g, 6.76 mmol, 2 eq) was added under ice bath conditions. After addition, the mixture was stirred overnight at room temperature. Extraction was performed with EtOAc (20 mL * 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:40) to obtain the target compound 14-3 (310 mg, yield 46%). ESI-MS: 200.2 [M + H] +

[0359] Step 3, Synthesis of 3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-methylazabicyclobutane-1-carboxylic acid tert-butyl ester (14-4): 3-formyl-3-methylazabicyclobutane-1-carboxylic acid tert-butyl ester (310 mg, 1.56 mmol, 1 eq), 3-azabicyclo[3.1.0]hexane hydrochloride (186 mg, 1.56 mmol, 1 eq), and HOAc (93 mg, 1.56 mmol, 1 eq) were placed in a reaction flask, and MeOH (5 mL) was added. The mixture was stirred at room temperature for 30 min, and then NaBH3CN (293 mg, 4.67 mmol, 3 eq) was added. After the addition was complete, the mixture was stirred at room temperature overnight. Extraction was performed using DCM (20 mL x 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:50) to give the target compound 14-4 (200 mg, yield 48%). ESI-MS: 267.2 [M + H₂] +

[0360] Step 4, Synthesis of 3-((3-methylazacyclobutane-3-yl)methyl)-3-azabicyclo[3.1.0]hexane (14-5): 3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-methylazacyclobutane-1-carboxylic acid tert-butyl ester (200 mg, 0.75 mmol, 1 eq) was placed in a reaction flask, CH3CN (3 mL) was added, and HCl / dioxane (1 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The mixture was concentrated, and the pH was adjusted to 8 with saturated NaHCO3 solution. Extraction was performed using DCM (30 mL * 3) / H2O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to obtain the target compound 14-5 (110 mg, yield 88%). ESI-MS: 167.2 [M+H] +

[0361] Step 5, Synthesis of 2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-methylazabicyclobutane-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (14-6): 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H) Benzyl carboxylate (340 mg, 0.66 mmol, 1 eq, according to the synthesis in Example 13), 3-((3-methylazacyclobutane-3-yl)methyl)-3-azabicyclo[3.1.0]hexane (110 mg, 0.66 mmol, 1 eq), sodium tert-butoxide (127 mg, 1.32 mmol, 2 eq), Pd2(dba)3 (60 mg, 0.066 mmol, 0.1 eq), BINAP (82 mg, 0.132 mmol, 0.02 eq), toluene (8 mL), purged under argon protection, stirred overnight at 100 °C. Cooled, concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 14-6 (120 mg, yield 28%). ESI-MS: 645.2 [M+H] +

[0362] Step 6, Synthesis of (1R, 5S)-3-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-methylazabicyclobutane-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (14-7): 2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-methylazabicyclobutane-1-yl) Cyclobutane-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid benzyl ester (120 mg, 0.18 mmol, 1 eq) was placed in a reaction flask, and MeOH (4 mL), ammonia (0.1 mL), and Pa / C (12 mg, 10%) were added. After the addition was complete, the mixture was stirred overnight under H2 protection at ambient temperature. The mixture was filtered, the filtrate was concentrated, and column chromatography (DCM: step MeOH = 100:0-100:10) was performed to give the target compound 14-7 (60 mg, yield 63%). ESI-MS: 510.2 [M+H] +

[0363] Step 7, Synthesis of tert-butyl(1R,5S)-3-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-methylazabicyclo-1-yl)-7-(7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (14-8): The tert-butyl(1R,5S)-3-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-methylazabicyclobutane-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (14-8) was synthesized by... [d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (51 mg, 0.1 mmol, 1 eq), 9-bromo-7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (34 mg, 0.11 mmol, 1.1 eq, see synthesis in Example 2), Cs2CO3 (81 mg, 0.25 mmol, 2.5 eq), Pd2(dba)3 (9 mg, 0.001 mmol, 0.1 eq), RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, toluene (2 mL) was added, and the mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 14-8 (18 mg, yield 24%). ESI-MS: 737.2 [M+H] +

[0364] Step 8, Synthesis of 9-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-methylazabicycloheptane-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2,3-dihydro-1H-cyclopenta[a]naphthyl-7-ol (compound 14): tert-butyl(1R,5S)-3-(2-(3-((3-azabicyclo[3.1.0]hexane-3-yl) (18 mg, 0.024 mmol, 1 eq) of 3-methylazhecyclo-1-yl)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (18 mg, 0.024 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated and prepared by prep-HPLC to obtain a pale yellow solid compound 14 (5 mg, yield 34%). ESI-MS: 592.2 [M+H] +

[0365] Example 15: 4-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-9H-carbazole-2-ol (Compound 15)

[0366]

[0367] Step 1, Synthesis of 3-((2-bromophenyl)amino)-5-chlorophenol (15-2): 3-amino-5-chlorophenol (400 mg, 2.79 mmol, 1 eq), 1,2-dibromobenzene (657 mg, 2.79 mmol, 1 eq), sodium tert-butoxide (402 mg, 4.18 mmol, 1.5 eq), di(tri-tert-butylphosphine)palladium (143 mg, 0.279 mmol, 0.1 eq), toluene (8 mL), toluene, purged under argon protection, stirred overnight at 100 °C. Cooled, concentrated, and column chromatography (PE:EA = 100:0-100:50) yielded the target compound 15-2 (350 mg, yield 42%). ESI-MS: 299.2 [M+H] +

[0368] Step 2, Synthesis of 4-chloro-9H-carbazole-2-ol: 3-((2-bromophenyl)amino)-5-chlorophenol (15-3) (350 mg, 1.17 mmol, 1 eq), K₂CO₃ (324 mg, 2.34 mmol, 2 eq), and Pd(PPh₃)₄ (67 mg, 0.058 mmol, 0.05 eq) were placed in a reaction flask, and DMAc (5 mL) was added. After addition, the mixture was purged under argon protection and refluxed for 4 h. After cooling, EtOAc (20 mL * 3) / H₂O (20 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:30) to obtain the target compound 15-3 (100 mg, yield 39%). ESI-MS: 218.2 [M + H] +

[0369] Step 3, Synthesis of 4-chloro-2-(methoxymethoxy)-9H-carbazole (15-4): 4-chloro-9H-carbazole-2-ol (100 mg, 0.46 mmol, 1 eq) was placed in a reaction flask, and DCM (3 mL) and DIEA (118 mg, 0.92 mmol, 2 eq) were added. Bromomethoxymethyl ether (57 mg, 0.46 mmol, 1 eq) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed using DCM (20 mL x 2) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:20) to obtain the target compound 15-4 (90 mg, yield 74%). ESI-MS: 262.2 [M+H] +

[0370] Step 4, Synthesis of 2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-9H-carbazole (15-5): 4-chloro-2-(methoxymethoxy)-9H-carbazole (90 mg, 0.34 mmol, 1 eq), pinacol diboronate (130 mg, 0.51 mmol, 1.5 eq), KOAc (101 mg, 1 mmol, 3 eq), and Pd(dppf)Cl2 (25 mg, 0.031 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (3 mL) was added. The mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered and subjected to column chromatography (PE:EA = 100:0-100:40) to give the target compound 15-5 (60 mg, yield 49%). ESI-MS: 354.2 [M+H] +

[0371] Step 5, Synthesis of 4-(8-fluoro-7-(2-(methoxymethoxy)-9H-carbazole-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxypyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (15-6): 4-(7-chloro-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (60 mg, 0.14 mmol, 1 eq, see the synthesis in Example 3), 2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-9H-carbazole (6... 0 mg (0.17 mmol, 1.2 eq), K3PO4 (90 mg, 0.42 mmol, 3 eq), Ad2nBuP-Pd-G3 (9 mg, 0.014 mmol, 0.1 eq), THF (3 mL), H2O (0.5 mL) were added. The mixture was then stirred overnight at 60 °C under argon protection. After cooling, the mixture was extracted with EtOAc (20 mL x 3) / H2O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 15-6 (20 mg, yield 23%). ESI-MS: 613.2 [M+H] +

[0372] Step 6, Synthesis of 4-(8-fluoro-4-(1,4-oxazacycloheptan-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-9H-carbazole-2-ol (compound 15): 4-(8-fluoro-7-(2-(methoxymethoxy)-9H-carbazole-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxypyrido[4,3-) [d]Pyrimidin-4-yl)-1,4-oxazacycloheptane (20 mg, 0.03 mmol, 1 eq) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and pre-HPLC was used to prepare a pale yellow solid compound 15 (5 mg, yield 27%). ESI-MS: 569.2 [M+H] +

[0373] Example 16: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7-hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropane-1-carboxamide (Compound 16)

[0374]

[0375] Step 1, Synthesis of methyl 1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropane-1-carboxylate (16-2): methyl 1-formylcyclopropanecarboxylate (300 mg, 2.34 mmol, 1 eq), 3-azabicyclo[3.1.0]hexane hydrochloride (280 mg, 2.34 mmol, 1 eq), and HOAc (139 mg, 1.56 mmol, 1 eq) were placed in a reaction flask, and MeOH (6 mL) was added. The mixture was stirred at room temperature for 30 min, and then NaBH3CN (441 mg, 7 mmol, 3 eq) was added. After the addition was complete, the mixture was stirred at room temperature overnight. Extraction was performed using DCM (30 mL x 3) / H₂O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:50) to give the target compound 16-2 (240 mg, yield 52%). ESI-MS: 196.2 [M + H₂] +

[0376] Step 2, Synthesis of 1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropane-1-carboxylic acid (16-3): Methyl 1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropane-1-carboxylic acid (240 mg, 1.23 mmol, 1 eq) was placed in a reaction flask, and THF (3 mL), H2O (1 mL), and LiOH (147 mg, 6.15 mmol, 5 eq) were added. After the addition was complete, the mixture was stirred at 60 °C for 4 h. The mixture was cooled, concentrated, and the pH was adjusted to 6 with 1 M hydrochloric acid. A solid precipitated, was filtered, and the filter cake was dried to obtain the target compound 16-3 (180 mg, yield 80%). ESI-MS: 182.2 [M+H] +

[0377] Step 3, Synthesis of 1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropane-1-carbonyl chloride (16-4): 180 mg, 1 mmol, 1 eq of 1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropane-1-carboxylic acid (180 mg, 1 mmol, 1 eq) was placed in a reaction flask, and DCM (4 mL) and SOCl2 (1.2 g, 10 mmol, 10 eq) were added. After addition, the mixture was refluxed for 4 h. After cooling, the mixture was concentrated to dryness to obtain the target compound 16-4 (220 mg, crude product).

[0378] Step 4, Synthesis of 4-((1R,5S)-8-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (16-6): 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (338 mg, 1 mmol, 1 eq) was placed in a reaction flask, and THF (5 mL) and DIEA (0.35 mL, 2 mmol, 2 eq) were added. The mixture was cooled to -20 °C, and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (212 mg, 1 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 30 min, and then stirred overnight at ambient temperature. Extracted with EtOAc (20 mL x 3) / H₂O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give the target compound 16-6 (500 mg, yield 97%). ESI-MS: 515.2 [M + H₂] +

[0379] Step 5, Synthesis of 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((tert-butoxycarbonyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (16-7): 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (500 mg, 0 0.97 mmol (1 eq), tert-butyl carbamate (137 mg, 1.17 mmol, 1.2 eq), Cs₂CO₃ (792 mg, 2.43 mmol, 2.5 eq), Pd₂(dba)₃ (88 mg, 0.097 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (Xantphos) (112 mg, 0.194 mmol, 0.2 eq), dioxane (8 mL), purged under argon protection, stirred overnight at 100 °C. Cooled, filtered, concentrated, and column chromatography (PE:EA = 100:10-100:100) to give target compound 16-7 (340 mg, yield 58%). ESI-MS: 595.2 [M+H] +

[0380] Step 6, Synthesis of 2-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid benzyl ester (16-8): 4-((1R,5S)-8-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((tert-butyloxycarbonyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid benzyl ester (340 mg, 0.57 mmol, 1 eq) was placed in a reaction flask, and CH3CN (4 mL) was added. HCl / dioxane (1 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 1 h. The solution was concentrated to obtain the target compound 16-8 (300 mg, crude product). ESI-MS: 395.2 [M+H] +

[0381] Step 7, Synthesis of 2-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (16-9): 300 mg of crude 2-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester was placed in a reaction flask, DCM (6 mL) was added, followed by triethylamine (230 mg, 2.28 mmol, 3 eq), and (BOC)₂O (166 mg, 0.76 mmol, 1 eq) was added under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed using EtOAc (20 mL x 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:100) to give the target compound 16-9 (260 mg, yield 69%). ESI-MS: 495.2 [M + H₂] +

[0382] Step 8, Synthesis of 2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropane-1-carboxamido)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (16-10): 2-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1] 260 mg (0.52 mmol, 1 eq) of oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid benzyl ester was placed in a reaction flask, and DCM (5 mL) and TEA (159 mg, 1.58 mmol, 3 eq) were added. 1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropane-1-carbonyl chloride (126 mg, 0.63 mmol, 1.2 eq) was slowly added under ice bath conditions. After addition, the mixture was stirred at room temperature for 2 h. Extraction was performed using DCM (20 mL * 3) / H2O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 16-10 (170 mg, yield 49%). ESI-MS: 658.2 [M+H] +

[0383] Step nine, synthesis of (1R, 5S)-3-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropane-1-carboxamido)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (16-11): 2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropane-1- Benzyl ester of ((1R, 5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid (170 mg, 0.26 mmol, 1 eq) was placed in a reaction flask, and MeOH (4 mL), ammonia (0.1 mL), and Pa / C (26 mg, 10%) were added. After the addition was complete, the mixture was stirred overnight under H2 protection at ambient temperature. The mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 16-11 (70 mg, 51% yield). ESI-MS: 524.2 [M+H] +

[0384] Step 10, Synthesis of tert-butyl(1R,5S)-3-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropane-1-carboxamido)-7-(7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (16-12): The tert-butyl(1R,5S)-3-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropane-1-carboxamido)-5,6,7,8-tetrahydropyrido[3,4-d] Pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (52 mg, 0.1 mmol, 1 eq), 9-bromo-7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (34 mg, 0.11 mmol, 1.1 eq, see synthesis in Example 2), Cs2CO3 (81 mg, 0.25 mmol, 2.5 eq), Pd2(dba)3 (9 mg, 0.001 mmol, 0.1 eq), RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, toluene (2 mL) was added, and the mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 16-12 (20 mg, yield 27%). ESI-MS: 750.2 [M+H] +

[0385] Step 11, Synthesis of N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7-hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropane-1-carboxamide (compound 16): tert-butyl(1R,5S)-3-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropane-1-carboxamide (-yl)methyl)cyclopropane-1-carboxamido)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (20 mg, 0.026 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath. After the addition was complete, the mixture was stirred at this temperature for 30 min. The mixture was concentrated and pre-HPLC was used to prepare a pale yellow solid compound 16 (6 mg, yield 37%). ESI-MS: 606.2 [M+H] +

[0386] Example 17: 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-nitrile (Compound 17)

[0387]

[0388] Step 1, Synthesis of 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-onitrile (17-2): 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidinyl (100 mg, 0.39 mmol, 1 eq) was placed in a reaction flask, and DCM (3 mL) and DIEA (102 mg, 0.79 mmol, 2 eq) were added. 3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-onitrile (77 mg, 0.39 mmol, 1 eq) was added at -40 °C. After the addition was complete, the mixture was stirred at this temperature for 30 min. Extraction was performed using DCM (20 mL x 2) / H₂O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:100) to give the target compound 17-2 (140 mg, yield 86%). ESI-MS: 411.2 [M + H₂] +

[0389] Step 2, Synthesis of 1-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-onitrile (17-3): Methanol (60 mg, 0.37 mmol, 1.1 eq) was placed in a reaction flask, THF (3 mL) was added, and NaH (15 mg, 0.37 mmol, 1.1 eq) was added in portions under ice bath conditions. After stirring at ambient temperature for 30 min, 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-onitrile (140 mg, 0.34 mmol, 1 eq) was added under ice bath conditions. After addition, the mixture was stirred at ambient temperature for 2 h, extracted with EtOAc (20 mL * 2) / H2O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 17-3 (100 mg, yield 54%). ESI-MS: 533.2 [M + H] +

[0390] Step 3, Synthesis of 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-onitrile (17-4): 1-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3- 1,3-O-piperazine-1-yl)azacyclobutane-3-onitrile (100 mg, 0.18 mmol, 1 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (115 mg, 0.22 mmol, 1.2 eq), K3PO4 (99 mg, 0.47 mmol, 2.5 eq), Ad2nBuP-Pd-G3 (10 mg, 0.018 mmol, 0.1 eq), THF (3 mL), H2O (0.5 mL), after addition, under argon protection, stirred overnight at 60 °C. Cool, extract with EtOAc (20 mL x 2) / H₂O (20 mL), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 17-4 (70 mg, yield 42%). ESI-MS: 884.2 [M + H₂] +

[0391] Step 4, Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy]pyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-onitrile (17-5): 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-onitrile (17-5) Pyrimidin-4-yl)-3-(4-methyl-3-oxoperpiperazin-1-yl)azacyclobutane-3-onitrile (70 mg, 0.079 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (120 mg, 0.79 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at ambient temperature for 2 h, extracted with EtOAc (20 mL * 2) / H2O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 17-5 (30 mg, yield 52%). ESI-MS: 727.2 [M + H] +

[0392] Step 5, Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-nitrile (compound 17): 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8 30 mg (0.04 mmol, 1 eq) of fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy]pyrido[4,3-d]pyrimidin-4-yl)-3-(4-methyl-3-oxopiperazin-1-yl)azacyclobutane-3-onitrile (30 mg, 0.04 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The mixture was concentrated and pre-HPLC was used to prepare a pale yellow solid compound 17 (7 mg, 25% yield). ESI-MS: 683.2 [M+H] +

[0393] Example 18: 1-(4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)dibenzo[b,d]furan-3-ol (Compound 18)

[0394]

[0395] Step 1, Synthesis of 2-chloro-4-(1,4-oxazacycloheptan-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (18-2): 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (304 mg, 1 mmol, 1 eq) was placed in a reaction flask, and THF (5 mL) and DIEA (0.35 mL, 2 mmol, 2 eq) were added. The mixture was cooled to -20 °C, and 1,4-oxazacycloheptanane (101 mg, 1 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 30 min, and then stirred overnight at ambient temperature. Extracted with EtOAc (20 mL x 3) / H₂O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give the target compound 18-2 (280 mg, yield 76%). ESI-MS: 370.2 [M + H₂] +

[0396] Step 2, Synthesis of 4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (18-3): 2-chloro-4-(1,4-oxazacycloheptane-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (280 mg, 0.76 mmol, 1 (eq), (1-(pyrrolidone-1-yl)cyclopropyl)methanol (128 mg, 0.83 mmol, 1.1 eq), Cs₂CO₃ (494 mg, 1.52 mmol, 2 eq), Pd₂(dba)₃ (70 mg, 0.076 mmol, 0.1 eq), RuPhos (70 mg, 0.15 mmol, 0.2 eq) were placed in a reaction flask, toluene (10 mL) was added, and the mixture was stirred overnight at 90 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 18-3 (170 mg, yield 47%). ESI-MS: 474.2 [M+H] +

[0397] Step 3, Synthesis of 4-(2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (18-4): 4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (170 mg, 0.36 mmol, 1 eq) was placed in a reaction flask, and CH3CN (2 mL) was added. Dioxane / HCl (0.5 mL) was added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 1 h. The solution was concentrated to dryness to obtain the target compound 18-4 (150 mg, crude product). ESI-MS: 374.2 [M+H] + Proceed directly to the next step.

[0398] Step 4, Synthesis of 4-(7-(3-(methoxymethoxy)dibenzo[b,d]furan-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptanane (18-5): 4-(2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptanane (40 mg, 0.1 mmol, 1 eq), 1-chloro-3-(methoxymethoxy)dibenzo[b,d]furan (29 mg) g (0.11 mmol, 1.1 eq, according to the synthesis in Example 6), Cs2CO3 (81 mg, 0.25 mmol, 2.5 eq), Pd2(dba)3 (9 mg, 0.001 mmol, 0.1 eq), RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, toluene (2 mL) was added, and the mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 18-5 (20 mg, yield 31%). ESI-MS: 600.2 [M+H] +

[0399] Step 5, Synthesis of 1-(4-(1,4-oxazacycloheptan-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)dibenzo[b,d]furan-3-ol (compound 18): 4-(7-(3-(methoxymethoxy)dibenzo[b,d]furan-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy]-5,6 20 mg (0.03 mmol, 1 eq) of 7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazane (1 mL) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was then slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and the target compound 18 (5 mg, 27% yield) was obtained by prep-HPLC. ESI-MS: 556.2 [M+H] +

[0400] Example 19: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (Compound 19)

[0401]

[0402] Step 1, Synthesis of (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (19-2): 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidinyl (252 mg, 1 mmol, 1 eq) was placed in a reaction flask, and DCM (4 mL) and DIEA (258 mg, 2 mmol, 2 eq) were added. The mixture was cooled to -40 °C, and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (212 mg, 1 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 30 min. Extraction was performed using DCM (20 mL x 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give the target compound 19-2 (400 mg, yield 93%). ESI-MS: 429.2 [M + H₂] +

[0403] Step 2, Synthesis of (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (19-3): (1-(pyrrolidine-1-yl)cyclopropyl)methanol (145 mg, 1.03 mmol, 1.1 eq) was placed in a reaction flask, THF (5 mL) was added, and NaH (41 mg, 1.03 mmol, 1.1 eq) was added in portions under ice bath conditions. After the addition was complete, the mixture was stirred at ambient temperature for 30 min. (1R,5S)-3-(2,7-dichloro-8-fluoropyridano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400 mg, 0.93 mmol, 1 eq) was added under bath conditions. After addition, the mixture was stirred at ambient temperature for 2 h. The mixture was extracted with EtOAc (30 mL * 2) / H2O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 19-3 (200 mg, yield 40%). ESI-MS: 534.2 [M + H] +

[0404] Step 3, Synthesis of tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (19-4): 1R,5S)-3-(7-chloro-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester tert-butyl alkyl-8-carboxylate (100 mg, 0.18 mmol, 1 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (115 mg, 0.22 mmol, 1.2 eq), K3PO4 (99 mg, 0.47 mmol, 2.5 eq), Ad2nBuP-Pd-G3 (10 mg, 0.018 mmol, 0.1 eq), THF (3 mL), H2O (0.5 mL), after addition, under argon protection, stirred overnight at 60 °C. Cool, extract with EtOAc (20 mL x 2) / H₂O (20 mL), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 19-4 (90 mg, yield 54%). ESI-MS: 884.2 [M + H₂] +

[0405] Step 4, Synthesis of (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphth-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxypyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (19-5): tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy]pyrido[4,3-d]pyrimidin -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (90 mg, 0.1 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (151 mg, 1 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at ambient temperature for 2 h, extracted with EtOAc (20 mL * 2) / H2O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 19-5 (50 mg, yield 67%). ESI-MS: 727.2 [M + H] +

[0406] Step 5, Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (compound 19): (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthyl-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)methoxy[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol) Oxypyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.068 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and the target compound 19 (15 mg, yield 37%) was obtained by prep-HPLC. ESI-MS: 583.2 [M+H] +

[0407] Example 20: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(1,7-diazaspiro[4.4]non-7-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (Compound 20)

[0408]

[0409] Step 1, Synthesis of (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20-2): 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidinyl (252 mg, 1 mmol, 1 eq) was placed in a reaction flask, and DCM (4 mL) and DIEA (258 mg, 2 mmol, 2 eq) were added. The mixture was cooled to -40 °C, and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (212 mg, 1 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 30 min. Extraction was performed using DCM (20 mL x 3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give the target compound 20-2 (400 mg, yield 93%). ESI-MS: 429.2 [M + H₂] +

[0410] Step 2, Synthesis of 7-(4-((1R,5S)-8-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (20-3): (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400 mg, 0.93 mmol, 1 eq), 1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (211 mg, 0.93 mmol, 1 eq), and DIEA (362 mg, 2.8 mmol, 3 eq) were placed in a reaction flask, and DMF (8 mL) was added. After the addition was complete, the mixture was stirred overnight at room temperature. Extraction was performed by adding EtOAc (30 mL * 3) / H2O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:100) to give the target compound 20-3 (350 mg, yield 60%). ESI-MS: 4619.2 [M + H] +

[0411] Step 3, Synthesis of 7-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (20-4): 7-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (20-4) was synthesized. Azaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol, 1 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (99 mg, 0.19 mmol, 1.2 eq), K3PO4 (86 mg, 0.4 mmol, 2.5 eq), Ad2nBuP-Pd-G3 (10 mg, 0.016 mmol, 0.1 eq), THF (3 mL), H2O (0.5 mL), after addition, under argon protection, stirred overnight at 60 °C. Cool, extract with EtOAc (20 mL x 2) / H₂O (20 mL), combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 20-4 (90 mg, yield 57%). ESI-MS: 969.2 [M + H₂] +

[0412] Step 4, Synthesis of 7-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (20-5): 7-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8((triisopropylsilyl)ethynyl)naphthyl- 1-yl)pyrido[4,3-d]pyrimidin-2-yl)-1,7-diazaspiro[4,4]nonane-1-carboxylic acid tert-butyl ester (90 mg, 0.09 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (141 mg, 0.9 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at ambient temperature for 2 h, extracted with EtOAc (20 mL * 2) / H2O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 20-5 (40 mg, yield 53%). ESI-MS: 812.2 [M + H] +

[0413] Step 5, Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(1,7-diazabicyclo[4.4]non-7-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (compound 20): 7-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl) 40 mg (0.049 mmol, 1 eq) of tert-butyl 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)-1,7-diazaspiro[4,4]nonane-1-carboxylic acid was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and the target compound 20 (8 mg, yield 28%) was obtained by prep-HPLC. ESI-MS: 568.2 [M+H] +

[0414] Example 21: 4-(4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (Compound 21)

[0415]

[0416] Step 1, Synthesis of 4-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (21-2): 4-(2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (37 mg, 0.1 mg) 1 mol (refer to Example 18), 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yltrifluoromethanesulfonate (58 mg, 0.11 mmol, 1.1 eq), Cs₂CO₃ (81 mg, 0.25 mmol, 2.5 eq), Pd₂(dba)₃ (9 mg, 0.001 mmol, 0.1 eq), and RuPhos (9 mg, 0.002 mmol, 0.2 eq) were placed in a reaction flask, toluene (2 mL) was added, and the mixture was stirred overnight at 110 °C under argon protection. After cooling, the mixture was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give the target compound 21-2 (30 mg, yield 31%). ESI-MS: 759.2 [M+H] +

[0417] Step 2, Synthesis of 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (21-3): 4-[7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropyl) [30 mg, 0.04 mmol, 1 eq]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1,4-oxazolidine (30 mg, 0.04 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (60 mg, 0.4 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed by adding EtOAc (20 mL x 2) / H2O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 21-3 (15 mg, yield 63%). ESI-MS: 602.2 [M+H] +

[0418] Step 3, Synthesis of 4-(4-(1,4-oxazacycloheptane-4-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (compound 21): 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-((1-(pyrrolidine-1-yl)cyclopropyl)methoxy) (15 mg, 0.024 mmol, 1 eq) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After addition, the mixture was stirred at this temperature for 30 min. The mixture was concentrated, and the target compound 21 (6 mg, yield 43%) was obtained by prep-HPLC. ESI-MS: 558.2 [M+H] +

[0419] Example 22: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)-1-(methylamino)cyclopropane-1-carboxamide (Compound 22)

[0420]

[0421] Step 1, Synthesis of methyl 1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxylic acid (22-2): 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (1 g, 5 mmol, 1 eq) was placed in a reaction flask, and DMF (20 mL) was added. NaH (0.6 g, 15 mmol, 3 eq) and CH3I (0.62 mL, 10 mmol, 2 eq) were added at ambient temperature. After addition, the mixture was stirred overnight. Water (60 mL) was added, and the mixture was extracted with DCM (60 mL * 3). The organic phases were combined, dried over sodium sulfate, filtered, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 22-2 (200 mg, yield 9%). ESI-MS: 230.2 [M + H]. +

[0422] Step 2, Synthesis of 1-((tert-Butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxylic acid (22-3): Methyl 1-((tert-Butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxylic acid (100 mg, 0.4 mmol, 1 eq) and NaOH (174 mg, 4 mmol, 10 eq) were placed in a reaction flask, and MeOH (5 mL) and H₂O (2 mL) were added. The mixture was stirred at 70 °C for 2 h. After cooling, the pH was adjusted to 3 with dilute hydrochloric acid, and the mixture was extracted with DCM (20 mL * 3). The organic phases were combined, dried over sodium sulfate, filtered, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 22-3 (50 mg, yield 53%), ESI-MS: 216.2 [M+H]. +

[0423] Step 3, Synthesis of 4-amino-6-chloro-5-fluoronicotinic acid (22-5): Ethyl 4-amino-6-chloro-5-fluoronicotinic acid (1 g, 4.5 mmol, 1 eq) and NaOH (1.8 mg, 45 mmol, 10 eq) were placed in a reaction flask, and MeOH (20 mL) and H₂O (mL) were added. After the addition was complete, the mixture was stirred overnight at ambient temperature. The pH was adjusted to 3 with dilute hydrochloric acid, and the mixture was extracted with DCM (40 mL * 3). The organic phases were combined, dried over sodium sulfate, filtered, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 22-5 (600 mg, yield 69%). ESI-MS: [M+H] + 190.9.

[0424] Step 4, Synthesis of 4-amino-6-chloro-5-fluoronicotinic acid (22-6): 4-amino-6-chloro-5-fluoronicotinic acid (0.6 g, 3.1 mmol, 1 eq) was placed in a reaction flask, and POCl3 (10 mL) was added. After the addition was complete, the mixture was refluxed overnight. The mixture was cooled and concentrated to give a brown solid compound 22-6 (800 mg, crude product).

[0425] Step 5, Synthesis of 7-chloro-8-fluoro-2-thio-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (22-7): 4-amino-6-chloro-5-fluoronicotinamide chloride (0.8 g, crude) and ammonium thiocyanate (290 mg, 3.8 mmol, 2 eq) were placed in a reaction flask, and THF (20 mL) was added. The mixture was stirred overnight at ambient temperature. Extraction was performed using H₂O (30 mL) and DCM (30 mL x 3). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (PE:EA = 100:10-100:100) to give a pale yellow solid compound 22-7 (400 mg, yield 45%). ESI-MS: [M+H] + 231.9.

[0426] Step 6, Synthesis of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (22-8): 7-chloro-8-fluoro-2-thio-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (0.4 g, 1.7 mmol, 1 eq) and sodium methoxide (186 mg, 3.4 mmol, 2 eq) were placed in a reaction flask, and DMF (8 mL) and methyl iodoform (490 mg, 3.4 mmol, 2 eq) were added. After the addition was complete, the mixture was stirred overnight at ambient temperature. Extracted by DCM (30 mL x 3) / H₂O (30 mL), the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (PE:EA = 100:10-100:100) to give a pale yellow solid compound 22-8 (380 mg, yield 90%). ESI-MS: [M+H] + 245.9.

[0427] Step 7, Synthesis of 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (22-9): 380 mg, 1.5 mmol, 1 eq of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4(3H)-one was placed in a reaction flask, and 6 mL of POCl3 was added. After the addition was complete, the mixture was refluxed overnight. The solution was cooled and concentrated to give a brown solid compound 22-9 (500 mg, crude). ESI-MS: [M+H] + 264.9.

[0428] Step 8, Synthesis of (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (22-10): 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidinyl (500 mg, crude) and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (402 mg, 1.9 mmol, 1 eq) were placed in a reaction flask, and DMF (8 mL) and DIEA (734 mg, 5.7 mmol, 3 eq) were added. After the addition was complete, the mixture was stirred overnight at ambient temperature. Extracted with DCM (40 mL * 3) / H₂O (40 mL), the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (PE:EA = 100:10-100:100) to give a pale yellow solid compound 22-10 (400 mg, yield 48%). ESI-MS: [M + H₂] + 440.9.

[0429] Step nine, synthesis of (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (22-11): (400...) (mg, 0.9mmol, 1eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (466mg, 0.9mmol, 1eq), Cs2CO3 (888mg, 2.7mmol, 3eq), Pd(dppf)Cl2 (30mg, 0.09mmol, 0.1eq) were placed in a reaction flask, and THF (8mL) and H2O (2mL) were added. The mixture was stirred overnight at 70°C under argon protection. Cool, extract with DCM (30 mL x 3) / H₂O (30 mL), combine organic phases, dry with sodium sulfate, filter, concentrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 22-11 (500 mg, yield 69%). ESI-MS: [M+H] + 790.9.

[0430] Step 10, Synthesis of (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (22-12): The (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy) tert-butyl octane-8-carboxylic acid (500 mg, 0.6 mmol, 1 eq) and m-CPBA (164 mg, 0.9 mmol, 1.5 eq) were placed in a reaction flask, and DCM (10 mL) was added. After the addition was complete, the mixture was stirred at ambient temperature for 2 h. The mixture was then extracted with DCM (20 mL * 3) / H₂O (20 mL), and the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 22-12 (400 mg, yield 78%). ESI-MS: [M + H₂] + 806.9.

[0431] Step 11, Synthesis of (1R,5S)-3-(2-amino-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (22-13): (1R,5S)-3-(8-fluoro-7- (7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400 mg, 0.5 mmol, 1 eq) was placed in a reaction flask, and ammonia water (10 mL) was added. After the addition was complete, the mixture was refluxed overnight. Extraction was performed using DCM (30 mL * 3) / H2O (30 mL). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 22-13 (200 mg, yield 53%). ESI-MS: [M+H] + 759.9.

[0432] Step 12, the synthesis of (1R,5S)-3-(2-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxamido)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (22-14), using (1R,5S)-3-(2-amino-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth- 1-(1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, 0.26 mmol, 1 eq), 1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxylic acid (68 mg, 0.3 mmol, 1.1 eq), EDCI (60 mg, 0.3 mmol, 1.1 eq), and DMAP (38 mg, 0.3 mmol, 1.1 eq) were placed in a reaction flask, and DMF (5 mL) was added. After the addition was complete, the mixture was stirred overnight at ambient temperature. Extract with DCM (40 mL x 3) / H₂O (40 mL), combine organic phases, dry with sodium sulfate, filter, concentrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 22-14 (60 mg, yield 25%). ESI-MS: [M+H] + 956.9.

[0433] Step Thirteen, Synthesis of (1R,5S)-3-(2-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxamido)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (22-15): (1R,5S)-3-(2-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxamido) (Amino)cyclopropane-1-carboxamido)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (60 mg, 0.06 mmol, 1 eq), CsF (19 mg, 0.12 mmol, 2 eq) were placed in a reaction flask, DMF (5 mL) was added, and the mixture was stirred overnight at ambient temperature. Extraction was performed using DCM (20 mL * 3) / H2O (20 mL), the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give a yellow solid compound 22-15 (20 mg, yield 39%). ESI-MS: [M+H] + 800.9.

[0434] Step fourteen, Synthesis of N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)-1-(methylamino)cyclopropane-1-carboxamide (compound 22): (1R,5S)-3-(2-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxamide) 20 mg (0.02 mmol, 1 eq) of tert-butyl octane-8-carboxylic acid (alkyl-1-carboxamido)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid was placed in a reaction flask, and DCM (2 mL) and TFA (0.4 mL) were added. After the addition was complete, the mixture was stirred at ambient temperature for 2 h. The mixture was concentrated to dryness, and the pH was adjusted to 8 with sodium bicarbonate solution. The mixture was extracted with DCM (20 mL * 3) / H2O (20 mL). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to thin-layer chromatography (DCM:MeOH = 100:8) to give a pale yellow solid compound 22 (5 mg, yield 36%). 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.24(s,2H),7.96(t,J=7.4Hz,1H),7 .45(t,J=9.0Hz,1H),7.38(s,1H),7.17(s,1H),6.97(s,1H),4.40(d,J=12 .6Hz,1H),4.28(d,J=12.6Hz,1H),3.93(s,1H),3.76(s,2H),3.58(d,J=12 .6Hz,2H),1.99(s,3H),1.79(s,4H),1.23(d,J=4.9Hz,4H).ESI-MS:[M+H] + 556.2.

[0435] Example 23: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (Compound 23)

[0436]

[0437] Step 1, Synthesis of 2-(3-bromo-1H-pyrazol-1-yl)acetonitrile (23-2): 3-bromo-1H-pyrazole (2 g, 13.6 mmol, 1 eq) and 2-bromoacetonitrile (2.6 g, 13.6 mmol, 1 eq) were placed in a reaction flask, and CH3CN (20 mL) and Cs2CO3 (8.9 g, 27.2 mmol, 3 eq) were added. After addition, the mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate was concentrated, and column chromatography (PE:EA = 100:0-100:20) was performed to give the target compound 23-2 (2 g, yield 79%). ESI-MS: [M+H] + 187.2.

[0438] Step 2, Synthesis of 1-(3-bromo-1H-pyrazol-1-yl)cyclopropane-1-onitrile (23-3): NaH (1 g, 25.8 mmol, 2.4 eq) was placed in a reaction flask, DMF (30 mL) was added, and the mixture was stirred at room temperature for 10 min. Then, 2-(3-bromo-1H-pyrazol-1-yl)acetonitrile (2 g, 10.7 mmol, 1 eq) and 1,2-dibromoethane (2 g, 10.7 mmol, 1 eq) were added. After the addition was complete, the mixture was stirred overnight at room temperature. Extraction was performed with EtOAc (40 mL * 3) / H₂O (40 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:20) to obtain the target compound 23-3 (900 mg, yield 39%). ESI-MS: 213.2 [M + H] +

[0439] Step 3, Synthesis of (1-(3-bromo-1H-pyrazol-1-yl)cyclopropyl)methylamine (23-4): 1-(3-bromo-1H-pyrazol-1-yl)cyclopropane-1-onitrile (900 mg, 4.2 mmol, 1 eq) was placed in a reaction flask, and THF (6 mL), MeOH / NH3 (6 mL), and Raney Ni (90 mg, 10%) were added. The mixture was stirred overnight under H2 conditions at ambient temperature. The mixture was filtered, and the filtrate was concentrated to obtain the target compound 23-4 (1 g, crude product), which was directly used in the next reaction. ESI-MS: 217.2 [M+H] +

[0440] Step 4, Synthesis of 3-bromo-1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazole (23-5): 1 g of crude (1-(3-bromo-1H-pyrazole-1-yl)cyclopropyl)methylamine was placed in a reaction flask, and 10 mL of CH3CN, 909 mg (4.2 mmol, 1 eq), and 1.16 g (8.4 mmol, 2 eq) of 1,4-dibromobutane were added. After addition, the mixture was refluxed overnight. The mixture was cooled, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 23-5 (700 mg, yield 61%). ESI-MS: 271.2 [M+H] +

[0441] Step 5, Synthesis of 1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (23-6): 3-bromo-1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazole (700 mg, 2.59 mmol, 1 eq), pinacol diboronate (987 mg, 3.89 mmol, 1.5 eq), KOAc (762 mg, 7.77 mmol, 3 eq), and Pd(dppf)Cl2 (189 mg, 0.259 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (10 mL) was added. Under argon protection, the mixture was stirred overnight at 100 °C. The solution was cooled, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 23-6 (400 mg, yield 49%). ESI-MS: 318.2 [M+H] +

[0442] Step 6, Synthesis of 4-amino-6-chloro-5-fluoronicotinic acid (23-8): Ethyl 4-amino-6-chloro-5-fluoronicotinic acid (3.3 g, 15.1 mmol, 1 eq) was placed in a reaction flask, and THF (20 mL), H₂O (5 mL), and NaOH (3 g, 75.5 mmol, 5 eq) were added. After the addition was complete, the mixture was stirred overnight at 70 °C. The mixture was cooled, concentrated, and the pH was adjusted to 5 with dilute hydrochloric acid. A solid precipitated, which was filtered, and the filter cake was dried to give the target compound 23-8 (2.7 g, yield 93%). ESI-MS: 191.2 [M+H] +

[0443] Step 7, Synthesis of 4-amino-6-chloro-5-fluoronicotinic acid (23-9): 4-amino-6-chloro-5-fluoronicotinic acid (2.7 g, 14.2 mmol, 1 eq) was placed in a reaction flask, and POCl3 (30 mL) was added. After the addition was complete, the mixture was stirred at 90 °C for 6 h. After cooling and concentration, the target compound 23-9 (4 g, crude product) was obtained and used directly in the next reaction step.

[0444] Step 8, Synthesis of 7-chloro-8-fluoro-2-thio-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (23-10): 4-Amino-6-chloro-5-fluoronicotinamide chloride was placed in a reaction flask, and THF (40 mL) and ammonium thiocyanate (2.1 g, 27.7 mmol, 2 eq) were added. After addition, the mixture was stirred overnight at room temperature. Extraction was performed with EtOAc (40 mL * 3) / H₂O (40 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the target compound 23-10 (3 g, 93% yield). ESI-MS: 232.2 [M + H] +

[0445] Step 9, Synthesis of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (23-11): 7-chloro-8-fluoro-2-thio-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (3 g, 12.9 mmol, 1 eq) was placed in a reaction flask, and DMF (30 mL), NaOMe (1.4 g, 25.9 mmol, 2 eq), and CH3I (1.8 g, 12.9 mmol, 1 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed using EtOAc (40 mL * 3) / H2O (40 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound 23-11 (3 g, 94% yield). ESI-MS: 246.2 [M + H] +

[0446] Step 10, Synthesis of 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (23-12): 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4(3H)-one (3 g, 12.2 mmol, 1 eq) was placed in a reaction flask, and POCl3 (30 mL) and DIEA (4.74 g, 36.6 mmol, 3 eq) were added. After addition, the mixture was stirred at 90 °C for 6 h. The mixture was concentrated, extracted with EtOAc (40 mL * 3) / H2O (40 mL), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the target compound 23-12 (2.1 g, yield 65%). ESI-MS: 265.2 [M + H] +

[0447] Step 11, Synthesis of (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (23-13): 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidinyl (2.1 g, 7.95 mmol, 1 eq) was placed in a reaction flask, and DCM (30 mL) and DIEA (2 g, 15.9 mmol, 2 eq) were added. The mixture was cooled to -40 °C, and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.69 g, 7.95 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 1 h. Extraction was performed using DCM (30 mL x 3) / H₂O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:100) to give the target compound 23-13 (3 g, yield 85%). ESI-MS: 440.2 [M + H₂] +

[0448] Step 12, Synthesis of (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (23-14): (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1g, 2.2) 7 mmol (1 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (1.4 g, 2.73 mmol, 1.2 eq), Cs2CO3 (1.21 g, 5.68 mmol, 2.5 eq), Pd(dppf)Cl2 (165 mg, 0.227 mmol, 0.1 eq) were placed in a reaction flask, and THF (20 mL) and H2O (4 mL) were added. The mixture was stirred overnight at 100 °C under argon protection. Cool, extract with DCM (50 mL x 3) / H₂O (50 mL), combine organic phases, dry with sodium sulfate, filter, concentrate, and perform column chromatography (DCM:MeOH = 100:0-100:2) to give target compound 23-14 (1 g, yield 56%), ESI-MS: [M+H + 790.9.

[0449] Step Thirteen, Synthesis of (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (23-15): The (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (23-15) was synthesized by... (3,2,1)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1 g, 1.27 mmol, 1 eq), DCM (10 mL), m-CPBA (240 mg, 1.39 mmol, 1.1 eq) was added under ice bath. After addition, the mixture was stirred at ambient temperature for 2 h. DCM (30 mL * 3) / H2O (30 mL) was extracted, the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) was performed to give target compound 23-15 (800 mg, yield 78%). ESI-MS: [M+H] + 806.9.

[0450] Step Fourteen, Synthesis of (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-hydroxypyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (23-16): The (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-hydroxypyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (23-16) was synthesized by... Isopropylsilyl)ethynyl)naphth-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (800 mg, 0.99 mmol, 1 eq) was placed in a reaction flask, and dioxane (10 mL), H2O (2 mL), and NaOH (396 mg, 9.9 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 3 h. The pH was adjusted to 6 with dilute hydrochloric acid under ice bath conditions, and the mixture was extracted with EtOAc (30 mL * 3) / H2O (30 mL). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 23-16 (0.5 g, yield 66%). ESI-MS: [M+H] + 760.9.

[0451] Step 15, Synthesis of (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((trifluoromethyl)sulfonyl)oxy)pyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (23-17): The (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)...) 500 mg (0.65 mmol, 1 eq) of silyl(ethynyl)naphth-1-yl)-2-hydroxypyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was placed in a reaction flask, and DCM (10 mL) and DIEA (170 mg, 1.3 mmol, 2 eq) were added. The mixture was cooled to -40 °C, and trifluoromethanesulfonic anhydride (223 mg, 0.79 mmol, 1.2 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 2 h. DCM (20 mL * 3) / H2O (20 mL) was added, and the mixture was extracted. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 23-17 (400 mg, yield 68%). ESI-MS: [M+H] + 893.9.

[0452] Step sixteen, Synthesis of (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(1-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (23-18): The tert-butyl ester (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((trifluoromethyl)sulfonyl)oxy)pyrido[4,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.11 mmol, 1 eq), 1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (43 mg, 0.13 mmol, 1.2 eq), K3PO4 (71 mg, 0.33 mmol, 3 eq), Pd(dppf)Cl2 (8 mg, 0.011 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (3 mL) and H2O (0.5 mL) were added. After the addition was complete, the mixture was stirred overnight at 100 °C under argon protection. Cool, filter, concentrate the filtrate, extract with EtOAc (20 mL * 3) / H₂O (20 mL), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 23-18 (50 mg, yield 47%). ESI-MS: 934.2 [M + H₂] +

[0453] Step 17, Synthesis of (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (23-19): The (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8 -((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.05 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (81 mg, 0.5 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. EtOAc (20 mL * 3) / H2O (20 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 23-19 (30 mg, yield 72%). ESI-MS: 777.2 [M+H] +

[0454] Step 18, Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (compound 23): 1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1- 30 mg (0.038 mmol, 1 eq) of tert-butyl octane-8-carboxylic acid (3.2.1) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and the target compound 23 (8 mg, 32% yield) was obtained by prep-HPLC. ESI-MS: 633.2 [M+H] +

[0455] Example 24: 5-ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Compound 24)

[0456]

[0457] Step 1, Synthesis of 4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (24-2): 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidinyl (2.1 g, 7.95 mmol, 1 eq, referring to the synthesis in Example 23) was placed in a reaction flask, and DCM (30 mL) and DIEA (2 g, 15.9 mmol, 2 eq) were added. The mixture was cooled to -40 °C, and 1,4-oxazacycloheptane (804 mg, 7.95 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 1 h. Extraction was performed using DCM (30 mL x 3) / H₂O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:100) to give the target compound 24-2 (2.23 g, yield 85%). ESI-MS: 329.2 [M + H₂] +

[0458] Step 2, Synthesis of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (24-3): 4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (2.23 g, 6.78 mmol, 1 eq), ((2-fluoro-6-(methoxy)... Methoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (4.17 g, 8.14 mmol, 1.2 eq), Cs₂CO₃ (3.5 g, 16.47 mmol, 2.5 eq), and Pd(dppf)Cl₂ (478 mg, 0.677 mmol, 0.1 eq) were placed in a reaction flask, and THF (40 mL) and H₂O (8 mL) were added. Under argon protection, the mixture was stirred overnight at 100 °C. After cooling, the mixture was extracted with DCM (80 mL x 3) / H₂O (80 mL). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:2) to give the target compound 24-3 (3 g, 65% yield). ESI-MS: [M+H] + 680.2.

[0459] Step 3, Synthesis of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (24-4): 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (3 g, 4.42 mmol, 1 eq), DCM (30 mL), and m-CPBA (835 mg, 4.84 mmol, 1.1 eq) were added under ice bath conditions. After addition, the mixture was stirred at ambient temperature for 2 h. Extract with DCM (50 mL x 3) / H₂O (50 mL), combine organic phases, dry with sodium sulfate, filter, concentrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 24-4 (2.5 g, yield 81%). ESI-MS: [M+H] + 696.2.

[0460] Step 4, Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-ol (24-5): 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (2.5 g, 3.6 mmol, 1 eq) was placed in a reaction flask, and dioxane (25 mL), H2O (5 mL), and NaOH (1.44 g, 36 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 3 h. The pH was adjusted to 6 with dilute hydrochloric acid under ice bath conditions. Extraction was performed using EtOAc (100 mL x 3) / H₂O (100 mL). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 24-5 (1.7 g, yield 72%). ESI-MS: [M+H] + 649.2.

[0461] Step 5, Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl trifluoromethanesulfonate (24-6): 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)- 4-(1,4-oxazacycloheptan-4-yl)pyrido[4,3-d]pyrimidin-2-ol (1.7 g, 2.62 mmol, 1 eq) was placed in a reaction flask, and DCM (20 mL) and DIEA (1.02 g, 7.86 mmol, 3 eq) were added. The mixture was cooled to -40 °C, and trifluoromethanesulfonic anhydride (887 mg, 3.14 mmol, 1.2 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 2 h. DCM (50 mL * 3) / H2O (50 mL) was added, and the mixture was extracted. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 24-6 (1.5 g, 73% yield). ESI-MS: [M+H] + 781.2.

[0462] Step 6, Synthesis of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(1-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (24-7): 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl trifluoromethanesulfonate (150m g (0.192 mmol, 1 eq), 1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (73 mg, 0.231 mmol, 1.2 eq, see synthesis in Example 23), K3PO4 (100 mg, 0.48 mmol, 2.5 eq), Pd(dppf)Cl2 (14 mg, 0.019 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (2 mL) and H2O (0.5 mL) were added. After the addition was complete, the mixture was stirred overnight at 100 °C under argon protection. Cool, filter, concentrate the filtrate, extract with EtOAc (20 mL * 3) / H₂O (20 mL), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 24-7 (100 mg, yield 63%). ESI-MS: 823.2 [M + H₂] +

[0463] Step 7, Synthesis of 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(1-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (24-8): 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Alkyl)ethynyl)naphth-1-yl)-2-(1-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (100 mg, 0.122 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (185 mg, 1.22 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed by adding EtOAc (20 mL * 3) / H2O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 24-8 (70 mg, yield 86%). ESI-MS: 666.2 [M + H] +

[0464] Step 8, Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-(1-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (compound 24): 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8 -Fluoro-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (70 mg, 0.1 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The mixture was concentrated, and the target compound 24 (10 mg, 15% yield) was prepared by prep-HPLC. ESI-MS: 622.2 [M+H] +

[0465] Example 25: (3R, 5R)-5-((3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidine-3-ol (Compound 25)

[0466]

[0467] Step 1: Synthesis of (2R,4R)-2-((3-bromo-1H-pyrazole-1-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (25-2): 3-bromo-1H-pyrazole (73 mg, 0.05 mmol, 1 eq) and (2R,4R)-2-(bromomethyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (139 mg, 0.05 mmol, 1 eq) were placed in a reaction flask, and CH3CN (3 mL) and Cs2CO3 (485 mg, 1.5 mmol, 3 eq) were added. After addition, the mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate was concentrated, and column chromatography (PE:EA = 100:10-100:100) was performed to give the target compound 25-2 (130 mg, yield 75%). ESI-MS: [M+H] + 347.2.

[0468] Step 2, Synthesis of (2R,4R)-4-hydroxy-2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (25-3): (2R,4R)-2-((3-bromo-1H-pyrazol-1-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 0.37 mmol, 1 eq), pinacol diboronate (143 mg, 0.56 mmol, 1.5 eq), KOAc (110 mg, 1.1 mmol, 3 eq), Pd(dppf)Cl2 (27 mg, 0.037 mmol, 0.1 eq) were placed in a reaction flask, dioxane (2 mL) was added, and the mixture was stirred overnight at 100 °C under argon protection. The solution was cooled, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:100) to give the target compound 25-3 (80 mg, yield 54%). ESI-MS: 394.2 [M+H] +

[0469] Step 3, Synthesis of (2R,4R)-2-((3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (25-5): 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl trifluoromethanesulfonate (1 0.00 mg, 0.12 mmol, 1 eq (refer to the synthesis in Example 24), (2R,4R)-4-hydroxy-2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.15 mmol, 1.2 eq), K3PO4 (81 mg, 0.38 mmol, 3 eq), Pd(dppf)Cl2 (8 mg, 0.011 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (3 mL) and H2O (0.5 mL) were added. After the addition was complete, the mixture was stirred overnight at 100 °C under argon protection. Cool, filter, concentrate the filtrate, extract with EtOAc (20 mL * 3) / H₂O (20 mL), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 25-5 (60 mg, yield 52%). ESI-MS: 899.2 [M + H₂] +

[0470] Step 4, Synthesis of (2R,4R)-2-((3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (25-6): The (2R,4R)-2-((3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy) 60 mg (0.06 mmol, 1 eq) of tert-butyl pyrido[4,3-d]pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was placed in a reaction flask, and DMF (2 mL) and CsF (101 mg, 0.6 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed by adding EtOAc (20 mL * 3) / H2O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 25-6 (35 mg, 70% yield). ESI-MS: 742.2 [M+H] +

[0471] Step 5, (3R, 5R)-5-((3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidine-3-ol (compound 25): (2R, 4R)-2-((3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl) 35 mg (0.047 mmol, 1 eq) of tert-butyl pyrido[4,3-d]pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and the target compound 25 (9 mg, yield 31%) was obtained by prep-HPLC. ESI-MS: 598.2 [M+H] +

[0472] The synthesis of Examples 26-82 is based on the synthesis of Example 25:

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482] Example 83: 4-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)-1H-pyrazol-3-yl)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphth-2-ol (Compound 83)

[0483]

[0484] Step 1, Synthesis of (1-(3-bromo-1H-pyrazole-1-yl)cyclopropyl)methanol (83-2): (1-bromocyclopropyl)methanol (302 mg, 2 mmol, 1 eq) and 3-bromo-1H-pyrazole (294 mg, 2 mmol, 1 eq) were placed in a reaction flask, and CH3CN (8 mL) and Cs2CO3 (1.3 g, 4 mmol, 2 eq) were added. After addition, the mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate was concentrated, and column chromatography (PE:EA = 100:0-100:50) was performed to give the target compound 83-2 (300 mg, yield 69%). ESI-MS: 218.2 [M+H] +

[0485] Step 2, Synthesis of 3-bromo-1-(1-(chloromethyl)cyclopropyl)-1H-pyrazole (83-3): (1-(3-bromo-1H-pyrazole-1-yl)cyclopropyl)methanol (300 mg, 1.38 mmol, 1 eq) was placed in a reaction flask, and DCM (5 mL) and SOCl2 (1.64 g, 13.8 mmol, 10 eq) were added. After the addition was complete, the mixture was refluxed and stirred for 5 h. The solution was concentrated to dryness to obtain the target compound 83-3 (400 mg, crude product), which was directly added to the next step.

[0486] Step 3, Synthesis of 3-((1-(3-bromo-1H-pyrazole-1-yl)cyclopropyl)methyl)-3-azabicyclo[3.1.0]hexane (83-4): 3-bromo-1-(1-(chloromethyl)cyclopropyl)-1H-pyrazole (400 mg, crude) was placed in a reaction flask, and CH3CN (8 mL), K2CO3 (528 mg, 3.8 mmol, 3 eq), and 3-azabicyclo[3.1.0]hexane (106 mg, 1.27 mmol, 1 eq) were added. After addition, the mixture was refluxed overnight. The mixture was cooled, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:5) to obtain the target compound 83-4 (150 mg, yield 42%). ESI-MS: 283.2 [M+H] +

[0487] Step 4, Synthesis of 3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methyl)-3-azabicyclo[3.1.0]hexane (83-5): 3-((1-(3-bromo-1H-pyrazol-1-yl)cyclopropyl)methyl)-3-azabicyclo[3.1.0]hexane (150 mg, 0.53 mmol, 1 eq), pinacol diboronate (202 mg, 0.79 mmol, 1.5 eq), KOAc (156 mg, 1.59 mmol, 3 eq), and Pd(dppf)Cl2 (38 mg, 0.053 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (3 mL) was added. The mixture was stirred overnight at 100 °C under argon protection. The solution was cooled, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 83-5 (50 mg, yield 28%). ESI-MS: 330.2 [M+H] +

[0488] Step 5, Synthesis of 4-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)-1H-pyrazol-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (83-6): 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl trifluoromethanesulfonate ( 78 mg, 0.1 mmol, 1 eq (refer to the synthesis in Example 24), 3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methyl)-3-azabicyclo[3.1.0]hexane (40 mg, 0.12 mmol, 1.2 eq), K3PO4 (64 mg, 0.3 mmol, 3 eq), Pd(dppf)Cl2 (8 mg, 0.01 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (3 mL) and H2O (0.5 mL) were added. After the addition was complete, the mixture was stirred overnight at 100 °C under argon protection. Cool, filter, concentrate the filtrate, extract with EtOAc (20 mL * 3) / H₂O (20 mL), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 83-6 (50 mg, yield 60%). ESI-MS: 835.2 [M + H₂] +

[0489] Step 6, Synthesis of 4-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)-1H-pyrazol-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (83-7): 4-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl) Cyclopropyl)-1H-pyrazol-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (50 mg, 0.06 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (91 mg, 0.6 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 2 h. Extraction was performed by adding EtOAc (20 mL * 3) / H2O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 83-7 (30 mg, yield 73%). ESI-MS: 678.2 [M + H] +

[0490] Step 7, Synthesis of 4-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)-1H-pyrazol-3-yl)-8-fluoro-4-(1,4-oxazabicycloheptan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (compound 83): 4-(2-(1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl) 30 mg (0.044 mmol, 1 eq) of 1H-pyrazol-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (1 mL) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and the target compound 83 (8 mg, 28% yield) was obtained by prep-HPLC. ESI-MS: 634.2 [M+H] +

[0491] The synthesis of Examples 84-96 is based on the synthesis of Example 83.

[0492]

[0493]

[0494]

[0495] Example 97: 4-(4-(1,4-oxazacycloheptane-4-yl)-2-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphth-2-ol (Compound 97)

[0496]

[0497] Step 1, Synthesis of 2-chloro-4-(1,4-oxazacycloheptan-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (97-2): 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (304 mg, 1 mmol, 1 eq) was placed in a reaction flask, and THF (5 mL) and DIEA (0.35 mL, 2 mmol, 2 eq) were added. The mixture was cooled to -20 °C, and 1,4-oxazacycloheptanane (101 mg, 1 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 30 min, and then stirred overnight at ambient temperature. Extracted with EtOAc (20 mL x 3) / H₂O (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:10-100:50) to give a yellow solid compound 97-2 (280 mg, yield 76%). ESI-MS: 370.2 [M + H₂] +

[0498] Step 2, Synthesis of 4-(1,4-oxazacycloheptane-4-yl)-2-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (97-3): 2-chloro-4-(1,4-oxazacycloheptane-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (280 mg, 0.76 mmol, 1 eq), 1-(1-(pyrrolidine-1-yl)-2-(1-(1-(pyrrolidine-1-yl)cyclopropyl ... (Methyl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (288 mg, 0.91 mmol, 1.2 eq, see synthesis in Example 23), Na₂CO₃ (214 mg, 2.28 mmol, 3 eq), and Pd(PPh₃)₃ (87 mg, 0.076 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (5 mL) and H₂O (1 mL) were added. After the addition was complete, the atmosphere was purged, and the mixture was stirred overnight at 100 °C under argon protection. The mixture was concentrated to dryness and subjected to direct column chromatography (PE:EA = 100:10-0:100) to give the target compound 97-3 (200 mg, 50% yield). ESI-MS: 524.2 [M+H] +

[0499] Step 3, Synthesis of 4-(2-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (97-4): 200 mg, 0.38 mmol, 1 eq of 4-(1,4-oxazacycloheptane-4-yl)-2-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (CBE) was placed in a reaction flask, CH3CN (3 mL) was added, and HCl / dioxane (1 mL) was added under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 h. Concentrate, adjust pH to 8 with NaHCO3 solution, extract with DCM (40 mL * 3) / H2O (20 mL), combine organic phases, dry, filter, concentrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 97-4 (80 mg, yield 49%). ESI-MS: 424.2 [M + H2O] +

[0500] Step 4, Synthesis of 4-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazapyridine( ... Heterocyclic heptane (80 mg, 0.18 mmol, 1 eq), 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yltrifluoromethanesulfonate (111 mg, 0.2 mmol, 1.1 eq), Cs₂CO₃ (154 mg, 0.47 mmol, 2.5 eq), Pd₂(dba)₃ (16 mg, 0.018 mmol, 0.1 eq), RuPhos (16 mg, 0.036 mmol, 0.2 eq), toluene (3 mL), after addition, the atmosphere was purged, and the mixture was stirred overnight at 110 °C under argon protection. The mixture was cooled, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 97-5 (60 mg, yield 39%). ESI-MS: 809.2 [M+H] +

[0501] Step 5, Synthesis of 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (97-6): 4-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)) Ethynyl)naphth-1-yl)-2-(1-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (60 mg, 0.07 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (112 mg, 0.7 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 1 h. The mixture was extracted with EA (20 mL * 3) / H2O (20 mL), the organic phases were combined, dried, filtered, concentrated, and column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 97-6 (30 mg, yield 62%). ESI-MS: 652.2 [M + H] +

[0502] Step 6, Synthesis of 4-(4-(1,4-oxazacycloheptan-4-yl)-2-(1-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (compound 97): 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2- (1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (30 mg, 0.046 mmol, 1 eq) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and the target compound 97 (9 mg, 32% yield) was obtained by prep-HPLC. ESI-MS: 608.2 [M+H] +

[0503] The synthesis of Examples 98 and 99 is based on the synthesis of Example 97:

[0504]

[0505]

[0506] Example 100: 4-(4-(1,4-oxazacycloheptane-4-yl)-2-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (Compound 100)

[0507]

[0508] Step 1, Synthesis of 4-(2,7-dichloroquinazoline-4-yl)-1,4-oxazacycloheptane (100-2): 2,4,7-trichloroquinazoline (233 mg, 1 mmol, 1 eq) was placed in a reaction flask, and THF (5 mL), DIEA (258 mg, 2 mmol, 2 eq), and 1,4-oxazacycloheptane (101 mg, 1 mmol, 1 eq) were added. After addition, the mixture was stirred overnight at room temperature. Extraction was performed using DCM (20 mL * 3) / H₂O (20 mL). The organic phases were combined, dried, filtered, concentrated, and subjected to column chromatography (PE:EA = 100:10-100:50) to give the target compound 100-2 (240 mg, 80% yield). ESI-MS: 299.2 [M + H] +

[0509] Step 2, Synthesis of 4-(7-chloro-2-(1-(1-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)quinazolin-4-yl)-1,4-oxazacycloheptane (100-3): 4-(2,7-dichloroquinazolin-4-yl)-1,4-oxazacycloheptane (240 mg, 0.8 mmol, 1 eq), 1-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1 3,2-dioxane-2-yl)-1H-pyrazole (306 mg, 0.96 mmol, 1.2 eq, according to the synthesis in Example 23), K2CO3 (333 mg, 2.41 mmol, 3 eq), and Pd(dppf)Cl2 (58 mg, 0.08 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (5 mL) and H2O (1 mL) were added. After the addition was complete, the atmosphere was purged, and the mixture was stirred overnight at 85 °C under argon protection. The mixture was concentrated to dryness and subjected to direct column chromatography (DCM:MeOH = 100:0-0:10) to give the target compound 100-3 (200 mg, yield 54%). ESI-MS: 453.2 [M+H] +

[0510] Step 3, Synthesis of 4-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)quinazolin-4-yl)-1,4-oxazacycloheptane (100-4): 4-(7-chloro-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)quinazolin-4-yl)-1,4-oxazacycloheptane (200 mg, 0.44 mmol, 1 eq) (2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (271 mg, 0.53 mmol, 1.2 eq), K₂CO₃ (183 mg, 1.32 mmol, 3 eq), Pd(PPh₃)₄ (50 mg, 0.044 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (5 mL) and H₂O (1 mL) were added. After the addition was complete, the atmosphere was purged, and the mixture was stirred overnight at 110 °C under argon protection. The mixture was concentrated to dryness and then subjected to direct column chromatography (DCM:MeOH = 100:0-0:10) to give the target compound 100-4 (100 mg, yield 28%). ESI-MS: 804.2 [M+H] +

[0511] Step 4, Synthesis of 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)quinazolin-4-yl)-1,4-oxazacycloheptane (100-5): 4-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)) Ethynyl)naphth-1-yl)-2-(1-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)quinazolin-4-yl)-1,4-oxazacycloheptane (100 mg, 0.12 mmol, 1 eq) was placed in a reaction flask, and DMF (2 mL) and CsF (189 mg, 1.2 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 1 h. Extraction was performed using EA (20 mL * 3) / H₂O (20 mL). The organic phases were combined, dried, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 100-5 (40 mg, yield 49%). ESI-MS: 647.2 [M + H] +

[0512] Step 5, Synthesis of 4-(4-(1,4-oxazacycloheptane-4-yl)-2-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-ol (Compound 100): 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl)-2-(1-(1-(pyrrolidine-1-ylmethyl)cyclopropyl)-1H-pyrazole-3-yl)quinazolin-4-yl)-1,4-oxazacycloheptane (40 mg, 0.06 mmol, 1 eq) was placed in a reaction flask, CH3CN (1 mL) was added, and HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The target compound 100 (12 mg, yield 32%) was concentrated and prepared by prep-HPLC. ESI-MS: 603.2 [M+H] +

[0513] The synthesis of Examples 101-103 is based on the synthesis of Example 100:

[0514]

[0515] The synthesis of Examples 105-106 is based on the synthesis of Example 23:

[0516]

[0517]

[0518] Example 107: 5-Ethyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Compound 107)

[0519]

[0520] Step 1, Synthesis of 4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (107-2): 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidinyl (2.1 g, 7.95 mmol, 1 eq, referring to the synthesis in Example 23) was placed in a reaction flask, and DCM (30 mL) and DIEA (2 g, 15.9 mmol, 2 eq) were added. The mixture was cooled to -40 °C, and 1,4-oxazacycloheptane (804 mg, 7.95 mmol, 1 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 1 h. Extraction was performed using DCM (30 mL x 3) / H₂O (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (PE:EA = 100:0-100:100) to give the target compound 10⁷⁻² (2.23 g, yield 85%). ESI-MS: 329.2 [M + H₂] +

[0521] Step 2, Synthesis of 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptanane (107-3): 4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptanane (200 mg, 0.6 mmol, 1 eq), 2-(8-ethyl-7-fluoro- 3-(methoxymethoxy)naphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (263 mg, 0.72 mmol, 1.2 eq), K3PO4 (387 mg, 1.8 mmol, 3 eq), and Ad2nBuP-Pd-G3 (40 mg, 0.072 mmol, 0.1 eq) were placed in a reaction flask, and THF (5 mL) and H2O (1 mL) were added. Under argon protection, the mixture was stirred overnight at 100 °C. After cooling, the mixture was extracted with DCM (20 mL * 3) / H2O (20 mL). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (PE:EA = 100:10-100:100) to give the target compound 107-3 (240 mg, 75% yield). ESI-MS: [M+H] +527.2.

[0522] Step 3, Synthesis of 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazane (107-4): 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazane (240 mg, 0.45 mmol, 1 eq), DCM (3 mL), and m-CPBA (86 mg, 0.5 mmol, 1.1 eq) were added under ice bath conditions. After the addition was complete, the mixture was stirred at ambient temperature for 2 h. Extract with DCM (20 mL * 3) / H₂O (20 mL), combine organic phases, dry with sodium sulfate, filter, concentrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give target compound 107-4 (200 mg, yield 80%). ESI-MS: [M + H₂] + 543.2.

[0523] Step 4, Synthesis of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-ol (107-5): 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazaane (200 mg, 0.37 mmol, 1 eq) was placed in a reaction flask, and dioxane (3 mL), H2O (0.5 mL), and NaOH (147 mg, 3.7 mmol, 10 eq) were added. After the addition was complete, the mixture was stirred at room temperature for 3 h. The pH was adjusted to 6 with dilute hydrochloric acid in an ice bath. Extraction was performed using EtOAc (20 mL x 3) / H₂O (20 mL). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 107-5 (120 mg, yield 65%). ESI-MS: [M+H] + 497.2.

[0524] Step 5, Synthesis of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl trifluoromethanesulfonate (107-6): 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-ol (120 mg, 0.24 mmol, 1 eq) was placed in a reaction flask, and DCM (2 mL) and DIEA (94 mg, 0.72 mmol, 3 eq) were added. The mixture was cooled to -40 °C, and trifluoromethanesulfonic anhydride (82 mg, 0.29 mmol, 1.2 eq) was added. After the addition was complete, the mixture was stirred at this temperature for 2 h. Add DCM (20 mL * 3) / H₂O (20 mL), extract, combine organic phases, dry with sodium sulfate, filter, concentrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 107-6 (100 mg, yield 65%). ESI-MS: [M + H₂] + 629.2.

[0525] Step 6, Synthesis of 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(1-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (107-7): 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl trifluoromethanesulfonate (100 mg, 0.15 mmol, 1 eq), 1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (60 mg, 0.19 mmol, 1.2 eq, see synthesis in Example 23), K3PO4 (78 mg, 0.37 mmol, 2.5 eq), Pd(dppf)Cl2 (12 mg, 0.015 mmol, 0.1 eq) were placed in a reaction flask, and dioxane (2 mL) and H2O (0.5 mL) were added. After the addition was complete, the mixture was stirred overnight at 100 °C under argon protection. Cool, filter, concentrate the filtrate, extract with EtOAc (20 mL * 3) / H₂O (20 mL), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and perform column chromatography (DCM:MeOH = 100:0-100:10) to give the target compound 10⁷⁻⁷ (60 mg, yield 56%). ESI-MS: 670.2 [M + H₂] +

[0526] Step 7, Synthesis of 5-ethyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazacycloheptan-4-yl)-2-(1-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (compound 107): 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8- Fluoro-2-(1-(1-(pyrrolidone-1-ylmethyl)cyclopropyl)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (60 mg, 0.09 mmol, 1 eq) was placed in a reaction flask, and CH3CN (1 mL) was added. HCl / dioxane (0.2 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 30 min. The solution was concentrated, and the target compound 107 (10 mg, 18% yield) was obtained by prep-HPLC. ESI-MS: 626.2 [M+H] +

[0527] The synthesis of Examples 108-115 is based on the synthesis of Example 107:

[0528]

[0529]

[0530] Activity test example:

[0531] Test Example 1:

[0532] The affinity of the test compound was determined using micro-thermal surge (MST) technology. The specific method is as follows: MST dye (2.5 μM stock solution) was dissolved on ice and diluted to 10 nM (4x) with molecular sieve buffer (20 mM HEPES, pH 7.4, 150 mM NaCl); the protein was diluted to 320 nM (4x) using the molecular sieve buffer, and 10 μl of protein was mixed with 10 μl of... After mixing the dye, centrifuge and incubate at room temperature for 30 min. Dilute the test compound using a molecular sieve buffer to a maximum concentration of 100 μM (4x), and the DMSO concentration should not exceed 0.5%. Then dilute at a ratio of 1:2 for 16 spots, with the minimum concentration not being 0. Take 10 μl of the protein and dye mixture and place it in a new 96-well PCR tube. Add 10 μl of the test compound at different concentrations, mix well, centrifuge, and prepare the working solution. Continue incubating at room temperature for 20 min. Use a capillary tube to draw 10 μl of the working solution, ensuring there are no air bubbles, and place it on the capillary rack in order of concentration. Cover with a magnetic strip and read the plate on the MST instrument.

[0533] The results showed that compound 3 prepared in this application had an affinity of 37 nM for the mutant KRAS G12D, which was significantly better than that of the control compound MRTX1133 (with an affinity of 138 nM), and was more likely to bind to KRAS G12D.

[0534] Reference compound MRTX1133

[0535] Test Example 2:

[0536] Cell viability assays were used to assess the selectivity of the compounds: Ba / F3 modified KRAS-WT / G12C / G12D / G12V cell lines were purchased from Yuanjing Biotechnology. The cells were seeded in white 384-well plates with 1000 cells per well. The plates were incubated at 37°C and 5% CO2 for 4 hours. Serially diluted compounds were added to ensure that the final concentration of DMSO was less than 0.5%. Incubation continued for 3 days. After 3 days, 30 μl of Cell titer glo reagent (Beyotime, C0069XL) was added. The plates were read using a Biotech microplate reader, and the total fluorescence signal was used to reflect the degree of inhibition of cell viability by the test compounds.

[0537] The results showed that compound 3 of this application had an effect on the IC50 of Ba / F3-KRAS-G12D cells. 50 The concentration was 0.17 μM, and the IC50 concentration in Ba / F3-KRAS-G12V cells was [missing value]. 50 The concentration was 1.60 μM, and the IC50 concentration in Ba / F3-KRAS-G12C cells was [missing value]. 50 The IC50 concentration for Ba / F3-KRAS-wild type cells was 1.90 μM. 50 The value is 1.96 μM.

[0538] Test Example 3:

[0539] KRAS-RAF1 PPI assay for compound activity: The protocol was performed using a kit purchased from cisbio (63ADK000CB47PEH). First, the 500X tag1-KRAS-G12C / D / V / WT protein was slowly dissolved on ice and diluted to 5X with diluent buffer (50mM HEPES, pH 7.5, 5mM MgCl2, 0.005% Tween 20, 1mM DTT). The 500X tag2-RAF1 protein was also slowly dissolved on ice and diluted to 5X with diluent buffer. The 100X anti-tag1-Tb3+ protein was slowly dissolved on ice and diluted to 1X with detection buffer. The 100X anti-tag1-d2 protein was also slowly dissolved on ice and diluted to 1X with detection buffer (50mM HEPES, pH 7.5, 5mM MgCl2, 0.005% Tween 20, 1mM DTT). 115 structurally similar test compounds (MRTX1133 analogs) were detected by diluent buffer. The buffer was diluted to different concentrations to ensure that the DMSO content was consistent and less than 0.5%. 4 μl of tag1-KRAS-G12C / D / V, 4 μl of tag2-RAF1, and 2 μl of the test compound were added to a black 384-well plate and incubated at room temperature for 15 min. 5 μl of anti-tag1-Tb3+ and 5 μl of anti-tag1-d2 were added to the black 384-well plate and incubated at 4 °C for 2 h. The plate was read using a Biotech microplate reader, and the activity of the test compound was reflected by detecting the Em620 / Ex665 signal. The results are shown in Table 1.

[0540] Cy5 competition assay for compound activity: The protocol was performed using a probe synthesized by the applicant and a purified protein. The probe was an analog of MRTX1133 carrying a Cy5 tag, and the protein was a purified KRAS-G12D protein with a His tag at the N-terminus. First, dilute the compound: Dilute the 10 mM stock solution of the compound to 160 μM with DMSO, then perform a 1:4 serial dilution, diluting 8 wells, with the last well having a concentration that is not 0. Next, take 0.5 μL of the above compound and add it to 19.5 μL of assay buffer (25 mM Hepes 7.4, 200 mM NaCl, 1 mM DTT, 0.005% Tween-20, 5 mM MgCl2). After mixing, the highest concentration is 4 μM (4X). Dilute the KRAS-G12D protein with assay buffer to a concentration of 240 nM (4x). Add 5 μL of protein and 5 μL of the compound to a black 384-well plate and incubate at room temperature for 10 min. Dilute 3.2 μM anti-his-Tb with assay buffer to a concentration of 4 nM (4X). Dilute 100 μM anti-his-Tb with assay buffer. Cy5-tracer at a concentration of 240 nM (4X) was mixed with an equal volume of anti-his-Tb and Cy5-tracer. 10 μL of the mixture was added to a black 384-well plate and incubated at room temperature for 10 min. The plate was then read using a Biotech microplate reader. The activity of the test compound was reflected by detecting the Em620 / Ex665 signal. The results are shown in Table 1.

[0541] Table 1. Results of activity tests on the compounds

[0542]

[0543]

[0544]

[0545]

[0546]

[0547] Note: + indicates IC 50 Or Ki>1000nM

[0548] ++ indicates 100nM <IC 50 Or Ki < 1000 nM

[0549] +++ indicates 10nM <IC 50 Or Ki < 100 nM

[0550] ++++ represents 1nM <IC 50 Or Ki < 10 nM

[0551] +++++ indicates IC 50 Or Ki < 1nM

[0552] - Indicates that it has not been tested.

[0553] * indicates the Cy5 competitive test result.

[0554] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application and not to limit them; although this application has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of this application or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of this application, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in this application.

Claims

1. The compound of formula (I-1-1), or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, The formula (I-1-1) is Equation (I-1-1), where, CR1, wherein R1 is selected from H, C1-C6 alkyl groups, and halogens; CR2, where R2 is selected from: H, C1-C6 alkyl, Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl. Among them, each R xb Whether the R values ​​are the same or different, each R value xb Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, x2 is selected from integers from 1 to 5. Where Y is selected from O and S, and each R xc Whether the R values ​​are the same or different, each R value xc Independently selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, x3 is selected from integers from 1 to 7. Among them, each R xd Whether the R values ​​are the same or different, each R value xd Independently selected from amino, halogen, C1-C6 alkyl, cyano, and one or more R xd When present, it cannot be simultaneously a halogen or simultaneously a C1-C6 alkyl group, and x4 is selected from integers from 1 to 7. CR4, wherein R4 is selected from H, C1-C6 alkyl groups, and halogens; R 9a Selected from: aziridine, piperidinyl, aziridine-heptyl, oxaziridine-heptyl, diazabicyclo[2.2.2]octyl, cyclohexyl, cyclohexenyl, oxaziridine-heptenyl: cyano, C1-C6 alkyl, hydroxyl, amino, C1-C6 alkoxy, fluorine-substituted cyclopropyl, piperazine-substituted by methyl or oxo, excluding: piperidinyl with only hydroxyl substituents, and aziridine-heptyl with only hydroxyl substituents; W 1a Selected from: Where R 1y R 2y Each is independently selected from H and C1-C6 alkyl groups, with position 1 above connected to a pyrimidine ring and position 2 above connected to R. 10a Connected; R 10a Selected from: 1) , where R s Selected from: 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S; 5-10 membered nitrogen-containing bridged ring heterocyclic groups; 5-10 membered nitrogen-containing fused ring heterocyclic groups; 5-10 membered nitrogen-containing spirocyclic heterocyclic groups; and amino groups. The 4-7 membered monocyclic heterocyclic group, 5-10 membered nitrogen-containing bridged ring heterocyclic group, 5-10 membered nitrogen-containing fused ring heterocyclic group, 5-10 membered nitrogen-containing spirocyclic heterocyclic group, and amino group are optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl. 2) 5-10 nitrogen-containing spirocyclic heterocyclic groups optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl; 3) 5-10 nitrogen-containing bridged ring heterocyclic groups optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl. 4) C3-C7 cycloalkyl groups optionally substituted with the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl. 5) A 4-7 membered monocyclic heterocyclic group comprising 1-2 heteroatoms selected from N, O, and S, wherein the 4-7 membered monocyclic heterocyclic group comprising 1-2 heteroatoms selected from N, O, and S is selected from azirrobutyl, thiocyclopentyl, azirropentyl, oxocyclohexyl, azirrohexyl, oxocycloheptyl, azirroheptyl, and oxonitrohexyl, wherein the 4-7 membered monocyclic heterocyclic group is optionally substituted by the following groups: C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl; 6) Among them, R 1z R 2z R 3z R 4z R 5z Each is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, C1-C6 alkylamino, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S, and C3-C7 cycloalkyl; Or R 3z R 4z R 5z The two groups, together with their respective carbon atoms, form piperidinyl, halogen-substituted piperidinyl, azircyclic pentyl, halogen-substituted azircyclic pentyl, hydroxyl-substituted azircyclic pentyl, azircyclic butyl, halogen-substituted azircyclic butyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with azircyclic pentyl, optional 5-10 member nitrogen-containing spirocyclic heterocyclic group substituted with halogen, optional 5-10 member nitrogen-containing bridged ring heterocyclic group substituted with halogen or halogen alkenyl, and R 1z R 2z As defined above; 7) Among them, R 6z R 7z R 8z R 9z R 10z R 11z R 12z Each is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, C1-C6 alkylamino, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S, and C3-C7 cycloalkyl; 8) Among them, R 13z R 14z R 15z Each is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, hydroxyl, amino, oxo, aminoC1-C6 alkyl, C1-C6 alkylamino, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 4-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S, and C3-C7 cycloalkyl; or, from R 13z R 14z R 15z The two atoms together, along with the carbon atoms they occupy, form a C3-C7 cycloalkyl group.

2. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, CR1 is selected from: CH, CF.

3. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For option R2 , where each R xb Whether the R values ​​are the same or different, each R value xb The elements are independently selected from H, hydroxyl, amino, halogen, and C1-C6 haloalkyl, and x2 is selected from integers from 1 to 5.

4. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For option R2 Where Y is selected from O, and each R xc Whether the R values ​​are the same or different, each R value xc The number is independently selected from hydroxyl and amino groups, and x3 is selected from integers from 1 to 7.

5. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, CR2, where R2 is selected from: H, C1-C6 alkyl, Where R 1x R 2x R 3x Independently selected from hydroxyl, amino, halogen, C1-C6 alkyl, and C2-C6 alkynyl groups. Where R 4x R 5x R 6x Independently selected from H, hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl. Where Y is selected from O, S, R 7x Selected from hydroxyl, amino, halogen, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 haloalkyl. Where R 8x R 9x R 10x R 11x R 12x R 13x Independently selected from H, amino, halogen, C1-C6 alkyl, cyano, and R 8x R 9x R 10x R 11x R 12x R 13x When not H, they cannot be halogens or C1-C6 alkyl groups simultaneously. Y1, Y2, and Y3 are independently selected from NH, S, O, N, and C.

6. The compound of claim 5, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For option R2 , where R 4x R 5x R 6x It is independently selected from H, hydroxyl, amino, halogen, and C1-C6 haloalkyl.

7. The compound of claim 5, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For option R2 Where Y is selected from O, R 7x Selected from hydroxyl and amino groups.

8. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, CR2, where R2 is selected from: ， ， ， ， ， ， ， ， ， ， 。 9. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, CR4 is selected from: N, CH.

10. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R 9a Selected from: , , , , , , , , , .

11. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For R 10a Option 1) , where R s Selected from: 4-7 member monocyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, S, 5-10 member nitrogen-containing bridged ring heterocyclic groups, 5-10 member nitrogen-containing fused ring heterocyclic groups, 5-10 member nitrogen-containing spirocyclic heterocyclic groups, and amino groups, wherein the 4-7 member monocyclic heterocyclic group, 5-10 member nitrogen-containing bridged ring heterocyclic group, 5-10 member nitrogen-containing fused ring heterocyclic group, 5-10 member nitrogen-containing spirocyclic heterocyclic group, and amino group are optionally substituted by the following groups: C1-C6 alkyl, halogen, and C1-C6 haloalkyl.

12. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For R 10a Option 2) 5-10 member nitrogen-containing spirocyclic heterocyclic groups optionally substituted with the following groups: C1-C6 alkyl, halogen.

13. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For R 10a Option 3) 5-10 member nitrogen-containing bridged ring heterocyclic groups optionally substituted with the following groups: C1-C6 alkyl, halogen.

14. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For R 10a Option 4) C3-C7 cycloalkyl groups optionally substituted with the following groups: C1-C6 alkyl, amino.

15. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For R 10a Option 5) A 4-7 membered monocyclic heterocyclic group comprising 1-2 heteroatoms selected from N, O, and S, wherein the 4-7 membered monocyclic heterocyclic group comprising 1-2 heteroatoms selected from N, O, and S is selected from azirobutyl, thiocyclopentyl, aziropentyl, oxacyclohexyl, azirohexyl, oxacycloheptyl, aziroheptyl, oxacycloheptyl, and oxacycloheptyl, wherein the 4-7 membered monocyclic heterocyclic group is optionally substituted with the following groups: C1-C6 alkyl, amino, oxo, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, halogen, C1-C6 alkoxy, and aminoC1-C6 alkyl.

16. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For R 10a Option 6) , where R 1z R 2z R 3z R 4z R 5z Each is independently selected from C1-C6 alkyl, amino, C1-C6 alkylamino, aminoC1-C6 alkyl, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, halogen, piperidinyl; Or R 3z R 4z R 5z The two groups, together with their respective carbon atoms, form piperidinyl, halogen-substituted piperidinyl, azircyclic pentyl, halogen-substituted azircyclic pentyl, hydroxyl-substituted azircyclic pentyl, azircyclic butyl, halogen-substituted azircyclic butyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with azircyclic pentyl, optional 5-10 member nitrogen-containing spirocyclic heterocyclic group substituted with halogen, optional 5-10 member nitrogen-containing bridged ring heterocyclic group substituted with halogen or halogen alkenyl, and R 1z R 2z As defined above.

17. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For R 10a Option 7) , where R 6z R 7z R 8z R 9z R 10z R 11z R 12z Each is independently selected from amino, halogen, and C3-C7 cycloalkyl groups.

18. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, For R 10a Option 8) , where R 13z R 14z R 15z Each is independently selected from C1-C6 alkylamine groups.

19. The compound of claim 1, or its stereoisomer, its tautomer, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R 10a Selected from: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 20. A compound, or a stereoisomer thereof, or a tautomer thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

21. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 20, or a stereoisomer thereof, or a tautomer thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers and / or excipients.

22. Use of any compound of claims 1 to 20, or a stereoisomer thereof, or a tautomer thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21, in the preparation of a medicament for the treatment and / or prevention of various cancers caused by KRAS mutations.

23. The use as described in claim 22, wherein, The cancers mentioned are selected from pancreatic cancer, non-small cell lung cancer, colorectal cancer, ovarian cancer, and bile duct cancer.

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