Fused ring compounds, pharmaceutical compositions containing the same and applications

Abstract

The present invention belongs to the field of pharmaceutical technology and provides a fused ring compound, a pharmaceutical composition containing the same, and applications thereof. The compound has a structure represented by the following formula (I), or is in the form of its tautomer, meso form, racemate, enantiomeric form, diastereomeric form, or a mixture thereof, a metabolite, a metabolic precursor, an isotopically substituted form, a pharma- ceutically acceptable salt, a hydrate, a solvate, a crystalline polymorph, or a cocrystal. The compound provided by the present invention can be used to treat one or more types of cancer caused by KRAS mutations selected from cancer caused by KRAS G12C, KRAS G12V, KRAS G12A, and G12D mutations, and has a high inhibitory activity as a G12D inhibitor in particular. JPEG2025510705000172.jpg55170

Description

cross reference

[0001] This application claims priority from China Patent Application No. 202210383719.2, entitled "Fused ring compounds, pharmaceutical compositions containing the same, and applications thereof", filed on April 11, 2022 to the State Intellectual Property Office of the People's Republic of China, China Patent Application No. 202310039419.7, entitled "Fused ring compounds, pharmaceutical compositions containing the same, and applications thereof", filed on January 13, 2023 to the State Intellectual Property Office of the People's Republic of China, China Patent Application No. 202310270906.4, entitled "Fused ring compounds, pharmaceutical compositions containing the same, and applications thereof", filed on March 20, 2023 to the State Intellectual Property Office of the People's Republic of China, the entire contents of which are incorporated herein by reference. [Technical field]

[0002] The present invention relates to the field of pharmaceutical technology, in particular to fused ring compounds, pharmaceutical compositions containing the same and applications. [Background technology]

[0003] The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene belongs to the RAS family, which includes two other genes HRAS and NRAS, with a homology between each gene reaching 85%. Essentially, KRAS is a monomeric G protein with GTP enzyme activity located on both sides of the cell membrane, and the protein encoded thereby is a 21KD molecular weight protein consisting of 188-189 amino acids. KRAS acts as an important regulatory component in signal transduction pathways such as tumor cell growth and angiogenesis, and can control and regulate the pathway of cell growth in normal cases, while in abnormal cases, it allows cells to continue growing and prevents cells from self-destructing. When the KRAS gene is mutated, the gene is permanently activated and continuously stimulates cell growth, causing intracellular signal transduction to become confused, cell proliferation to become uncontrollable, and as a result, cancer.

[0004] KRAS is the most common cancer mutated gene in humans, and about 30% of all cancers, including 95% of pancreatic ductal adenocarcinoma (PDAC), 45% of colon and rectal cancer (CRC), and 35% of non-small cell lung cancer (NSCLC), are associated with KRAS mutation activation. Due to protein structure problems, KRAS has been considered an "undruggable" target in the field of oncology drug research and development. However, with more and more research, researchers have found that some specific mutant KRAS proteins form drug-interacting sites, and after binding with small molecule drugs, they can lock KRAS in an inactive KRAS protein-GDP state, suppressing the activation of the KRAS pathway and initiating anti-tumor effects. In recent years, several KRAS G12C drug candidates have entered clinical trials, among which Amgen's AMG 510 and Mirati Therapeutics' MRTX 849 have progressed the fastest. Although the former has been approved for marketing by the FDA, G12C is not the predominant KRAS mutation subtype. Summary of the Invention [Problem to be solved by the invention]

[0005] In view of the above circumstances, the present invention provides a fused ring compound, a pharmaceutical composition containing the same, and applications thereof. The compound provided by the present invention can be used to treat one or more cancers caused by KRAS mutations selected from cancers caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutations, and in particular, as a G12D inhibitor, it has high inhibitory activity and good utilization rate, and can be used to manufacture prophylactic and / or therapeutic drugs for KRAS G12D-mediated diseases, and has good prospects for application. [Means for solving the problem]

[0006] The present invention provides a compound represented by the following formula (I), its tautomer, meso isomer, racemate, enantiomer, diastereoisomer or a mixed form thereof, metabolite, metabolic precursor, isotopically substituted form, pharma- ceutically acceptable salt, hydrate, solvate, crystalline polymorph, or cocrystal:

[0007] [ka]

[0008] During the ceremony, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 are each independently CR 4 or N, R 1 is selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl group; R 2 is selected from substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups; R 3 is selected from substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups; A 1 , A 2 , A 3 , A 4 , A 5 , A 6 The substituent R in 4 are each selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroaryl groups, substituted or unsubstituted cycloalkyl or heterocycloalkyl groups, substituted or unsubstituted unsaturated ring or heterocyclyl groups, substituted or unsubstituted aryl or heteroaryl groups, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, thiol groups, amide groups, sulfonyl groups, phosphoryl groups, alkylphosphinoyl groups, alkylsulfonyl groups, and alkylsulfinyl groups; L 1 and L 2is absent or independently selected from the group consisting of -CH=CH-, -N(Ra)-, -N(Ra)-(CRaRb)n-, -O-(CRaRb)n-, and -(CRaRb)n-; Ra and Rb are each independently selected from the group consisting of hydrogen, deuterium, C1 to C6 alkyl groups, C1 to C6 heteroalkyl groups, and C3 to C6 cycloalkyl groups.

[0009] Preferably, the compound has the structure shown in formula (II):

[0010] [ka]

[0011] During the ceremony, R 1 is selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl group; R 2 is selected from substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups; R 3 is selected from substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups; L 1 is absent or -CH=CH-, -N(Ra)-, or -N(Ra)-(CRaRb)-, and L 2 is -O-(CRaRb)n-, -CH=CH-, or -(CRaRb)n-, Ra and Rb are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, and C3-C6 cycloalkyl groups. 1 is absent or -N(Ra)- or -N(Ra)-(CRaRb)n, L 2 is preferably -O-(CRaRb)n- or -(CRaRb)n-.

[0012] Preferably, the compound has a structure represented by formula (III) or a structure represented by formula (IV):

[0013] [ka]

[0014] During the ceremony, Ring A is a 4-12 membered heterocycle having heteroatoms N and / or O; Ring B is a 4- to 12-membered heterocycle having a N heteroatom; ring A and ring B are each independently selected from the group consisting of a saturated or partially saturated monocyclic ring, an ortho-fused ring, a bridged ring, and a spiro ring; Z is hydrogen or deuterium; R 1 is selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl group; R 5 , R 6 , R 7 are each independently selected from the group consisting of hydrogen, deuterium, a halogen, a substituted or unsubstituted alkyl or cycloalkyl group, a substituted or unsubstituted heteroalkyl or heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group, with the proviso that each of the substituted groups is independently selected from the group consisting of a halogen, an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group; m1 is selected from integers of 0 to 6; m2 is selected from integers of 0 to 6.

[0015] Preferably, the halogen is F. Preferably, Ring B is selected from the following structures:

[0016] [ka]

[0017] During the ceremony, X 1 , X 2 is independently selected from the group consisting of hydrogen, deuterium, and halogen; Y is hydrogen or deuterium; R 8 , R 20 , R 21 are each selected from the group consisting of a substituted or unsubstituted aryl or heteroaryl group, a substituted or unsubstituted alkyl or cycloalkyl group, and a substituted or unsubstituted heteroalkyl or heterocycloalkyl group; R 9 , R 10 , R 22 are each independently selected from the group consisting of a substituted or unsubstituted alkyl or cycloalkyl group, a substituted or unsubstituted heteroalkyl or heterocycloalkyl group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group, with the proviso that each of the substituent groups is independently selected from the group consisting of a halogen, an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group, R 11 is a substituted monocyclic heteroalkyl group having N and / or O heteroatoms.

[0018] Preferably, R 9 , R 10 teeth

[0019] [ka]

[0020] is selected from.

[0021] and ring A is selected from the following structures:

[0022] [ka]

[0023] Ring C is

[0024] [ka]

[0025] It is preferable that:

[0026] During the ceremony, X 3~ X 16 are each independently -NR 12 -, -O-, -CO-, and -CR 14 R 15 - selected from the group consisting of R 12 , R 14 , R 15 are each independently selected from the group consisting of hydrogen, deuterium, a halogen, a substituted or unsubstituted alkyl or cycloalkyl group, a substituted or unsubstituted heteroalkyl or heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group, with the proviso that each of the substituted groups is independently selected from the group consisting of a halogen, an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group; q is selected from an integer of 0 to 3, and when q=0, the chemical bond is absent.

[0027] Preferably, R 1 is selected from the following structures:

[0028] [ka]

[0029] In the formula, W 1 , W 3 , W 5 , W 8 , W 9 , W 11 , W 12 , W 13 , W 15 , W 16 , W 17 -NR 12 -, -O-, -CO-, -CR 17 R 18 - and -SO 2 - selected from the group consisting of W 2 , W 4 , W 6 , W 7 , W 10 , W 14 , W 18 , W 19 , W 20 , W 21 , W 22 , W 23 , W 24 , W 25 , W 26 , W 27 is an N atom or R 16 C atom substituted with W 23 and W 24 R 16 if it is a C atom substituted with , the two carbon atoms may be connected by a chemical bond to form a saturated or unsaturated 5- or 6-membered ring, R 12 , R 16 , R 17 , R 18are each independently selected from the group consisting of hydrogen, deuterium, a halogen, a substituted or unsubstituted alkyl group or cycloalkyl group, a substituted or unsubstituted heteroalkyl group or heterocycloalkyl group, a hydroxyl group, an alkynyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group (wherein each of the substituted groups is independently selected from the group consisting of a halogen, an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group).

[0030] Preferably, the compound has any one of the following structures: a structure represented by formula (V), a structure represented by formula (VI), and a structure represented by formula (VII).

[0031] [ka]

[0032] During the ceremony, X 1 , X 2 is independently selected from the group consisting of hydrogen, deuterium, and halogen, Y is hydrogen or deuterium, Z is hydrogen or deuterium; R 8 , R 20 , R 21 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted aryl or heteroaryl groups, substituted or unsubstituted alkyl or cycloalkyl groups, and substituted or unsubstituted heteroalkyl or heterocycloalkyl groups; R 22is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or cycloalkyl groups, substituted or unsubstituted heteroalkyl or heterocycloalkyl groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups, with the proviso that each of said substituent groups is independently selected from the group consisting of halogen, alkyl groups, cycloalkyl groups, heteroalkyl groups, heterocycloalkyl groups, hydroxyl groups, cyano groups, amino groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups; X 3 -NR 12 -, -O-, -CO-, and -CR 14 R 15 - selected from the group consisting of W 19 , W 20 , W 22 are independently N atoms, R 16 A C atom substituted with

[0033] Preferably, the compound has the structure shown in formula (V) above. Preferably, the compound has one of the following structures: a structure represented by formula (VIII), a structure represented by formula (IX), and a structure represented by formula (X).

[0034] [ka]

[0035] X 1 , X 2 is independently selected from the group consisting of hydrogen, deuterium, and halogen, Y is hydrogen or deuterium, and Z is hydrogen or deuterium; X 3 -NR 12 -, -O-, -CO-, and -CR 14 R 15 - selected from the group consisting of W 19 , W20 , W 22 are independently N atoms, R 16 C atoms substituted with R 19 -H, -OH, halogen, -NO 2 , -CN, -CF 3 , -C 2 F 5 , -OCF 3 , -OCHF 2 , -OCH 2 F, selected from the group consisting of substituted or unsubstituted alkyl or cycloalkyl groups, substituted or unsubstituted heteroalkyl or heterocycloalkyl groups, alkyloxy groups, alkynyl groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups, with the proviso that each of the substituted groups is independently selected from the group consisting of halogen, alkyl groups, cycloalkyl groups, heteroalkyl groups, heterocycloalkyl groups, hydroxyl groups, cyano groups, amino groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups; R 22 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or cycloalkyl groups, substituted or unsubstituted heteroalkyl or heterocycloalkyl groups, alkyloxy groups, alkynyl groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups, with the proviso that each of said substituent groups is independently selected from the group consisting of halogen, alkyl groups, cycloalkyl groups, heteroalkyl groups, heterocycloalkyl groups, hydroxyl groups, cyano groups, amino groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups; m3 is selected from integers of 0 to 5, and when m3 is 2 or more, R19 may be a 4- to 7-membered ring condensed with a benzene ring.

[0036] Preferably, the compound has the structure shown in formula (VIII) above. In a preferred embodiment of the present invention, the compound has a structure represented by formula (XI) or a structure represented by formula (XII):

[0037] [ka]

[0038] Y is hydrogen or deuterium and Z is hydrogen or deuterium.

[0039] In formula XI, R23 in general formula XI is independently selected from the group consisting of -H, -F, -Cl, -CN, -CF3, an alkenyl group, an alkynyl group, a C1-3 linear alkyl group, and a C3-6 cycloalkyl group; R24 is selected from the group consisting of -H, a C1-5 alkyl or heteroaryl group, and -COR55, and R55 is selected from the group consisting of -H, a C1-10 linear / branched alkyl group, a C1-10 linear / branched heteroalkyl group, a C3-6 cycloalkyl group, and a C3-6 heterocycloalkyl group; R 25 -H, -CO(C 0-10 alkyl group), -COO(C 0-10 alkyl group), -COO-CH 2 -OCO(C 0-10 alkyl group), -COO-CH(CH 3 )-OCO(C 0-10 alkyl groups), K is C or N, provided that when K is N, R corresponding to K is 29 is non-existent. 26 , R 27 , R 28 , R 29 , R 30 are independently -H, -OH, halogen, -NO 2 , -CN, -CF 3 , -C 2 F 5 , -OCF 3 , -OCHF2 , -OCH 2 F, phosphate group, monomethyl phosphate group, dimethyl phosphate group, C 1-5 Linear / branched alkyl groups, C 1-5 Alkyloxy group, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, -N(C 0-10 Alkyl group)(C 0-10 alkyl group), -S(C 0-10 alkyl group), -OCON(C 0-10 Alkyl group)(C 0-10 Alkyl group), C 5-6 aryl groups, 5-membered heteroaryl groups, and 6-membered heteroaryl groups; or R 27 , R 28 and R 27 and R 28 The carbon atoms between are saturated or unsaturated. 3-8 Cycloalkyl groups, saturated or unsaturated C 3-8 Heterocycloalkyl groups, saturated or unsaturated cyclic lactones, C 5-6 An aryl group, a bridged cycloalkyl group, or a spirocycloalkyl group, wherein H in said group is -D, -OH, -F, -NO 2 , -CN, -CF 3 , -C 2 F 5 , C 1-3 may be substituted with an alkyl group or an amide group, m4 is selected from integers of 0 to 4.

[0040] In formula XII, R in general formula XII 31 are independently -F, -Cl, -NH 2 , -CN, -CF 3 , -C 2 F 5 , -OCF 3 , alkenyl group, alkynyl group, C 1-3 Linear / branched alkyl groups, C 1-3 Linear / branched alkyloxy group, C 3-6 selected from the group consisting of cycloalkyl groups, aryl groups, and heteroaryl groups; R32 -H, C 1-5 Linear / branched alkyl groups, C 3-6 cycloalkyl groups, R 33 -H, -CO(C 0-10 alkyl group), -COO(C 0-10 alkyl group), -COO-CH 2 -OCO(C 0-10 alkyl group), -COO-CH(CH 3 )-OCO(C 0-10 alkyl groups), R 34 , R 35 , R 36 , R 37 , R 38 are independently -H, -OH, halogen, -NO 2 , -CN, -CF 3 , -C 2 F 5 , -OCF 3 , -OCHF 2 , -OCH 2 F, C 1-5 Linear / branched alkyl groups, C 1-5 Alkyloxy group, C 3-10 Cycloalkyl groups and C 3-10 heterocycloalkyl groups, or R 35 , R 36 and R 35 and R 36 The carbon atoms between are saturated or unsaturated. 3-8 Cycloalkyl groups, saturated or unsaturated C 3-8 forming a heterocycloalkyl group, where H in said group is -D, -OH, -F, -NO 2 , -CN, -CF 3 , -C 2 F 5 , C 1-3 (which may be substituted with an alkyl group or an amide group), m5 is selected from integers of 0 to 4.

[0041] More preferably, the compound has the structure:

[0042] [ka]

[0043] In formula XIII, R 39 , R 40 are independently -H, -F, -Cl, -CN, an alkynyl group, and C 1-3 R is selected from the group consisting of straight-chain alkyl groups; 41 , R 42 , R 43 , R 44 are independently -H, -OH, -F, -Cl, -CN, -CF 3 , -C 2 F 5 , -OCF 3 , monomethylphosphoryl group, dimethylphosphoryl group, C 1-5 Linear / branched alkyl groups, C 1-5 Alkyloxy group, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, -S(C 0-10 alkyl group), -OCON(C 0-10 Alkyl group)(C 0-10 Alkyl group), C 5-6 aryl groups, 5-membered heteroaryl groups, and 6-membered heteroaryl groups; or R 42 , R 43 and R 42 and R 43 The carbon atoms between are saturated or unsaturated. 3-8 Cycloalkyl groups, saturated or unsaturated C 3-8 Heterocycloalkyl groups, 5-membered lactones, C 5-6 aryl groups, bridged cycloalkyl groups, and spirocycloalkyl groups, where H in said groups is -D, -OH, -F, -NO 2 , -CN, -CF 3 , -C 2 F 5 , C 1-3 (which may be substituted with an alkyl group or an amide group).

[0044] In formula XIV, R45 and R 46 are independently -H, -F, -Cl, -NH 2 , -CN, -CF 3 , -C 2 F 5 , -OCF 3 , alkynyl group, C 1-3 Straight chain alkyl group, C 1-3 Alkoxy group, C 3-6 R is selected from the group consisting of a cycloalkyl group, an aryl group, and a heteroaryl group; 47 , R 48 , R 49 are independently -H, -F, -Cl, -CN, -CF 3 , and -C 2 F 5 or R 47 , R 48 giving R 47 and R 48 The carbon atoms between are saturated or unsaturated. 3-8 Cycloalkyl groups, saturated or unsaturated C 3-8 forming a heterocycloalkyl group, where H in said group is -D, -OH, -F, -CN, -CF 3 , C 1-3 may be substituted with an alkyl group.

[0045] In formula XIII, R on the benzene ring 42 , R 43 giving R 42 and R 43 The carbon atoms between the carbon atoms may be saturated or unsaturated, as exemplified below. 3-8 Cycloalkyl groups, saturated or unsaturated C 3-8 Heterocycloalkyl groups, 5-membered lactones, C 5-6 It forms aryl groups, bridged cycloalkyl groups, and spirocycloalkyl groups.

[0046] [ka]

[0047] Here, K 2 , K 3 , K4 is condensed with a benzene ring to form a saturated or unsaturated five-membered ring; 2 , K 3 , K 4 are each independently selected from the group consisting of C, N, O, and S; K 5 , K 6 , K 7 are each independently selected from the group consisting of C, N, O, and S; K 8 is independently selected from the group consisting of C, N, O, and S; R 50 , R 51 , R 52 , R 53 are independently -H, -D, -OH, -F, -NO 2 , -CN, -CF 3 , -C 2 F 5 , C 1-3 Alkyl group, C 1-3 Alkoxyl groups, and C 3-6 cycloalkyl groups, and m6, m7, m8, and m9 are selected from the group consisting of integers of 0 to 6.

[0048] In formula XIV, R on the benzene ring 47 , R 48 and R 47 and R 48 The carbon atoms between the carbon atoms may be saturated or unsaturated, as exemplified below. 3-8 Cycloalkyl groups, saturated or unsaturated C 3-8 It forms a heterocycloalkyl group.

[0049] [ka]

[0050] Here, K 9 , K 10 , K 11 is independently selected from the group consisting of C, N, and O; R 54 are independently -H, -F, -CN, -CF 3 , -C 2 F 5 , C 1-3 Alkyl group, C 1-3Alkoxyl groups, and C 3-6 cycloalkyl groups; m10 is selected from the group consisting of integers of 0 to 4.

[0051] Preferably, formula (I) has a structure selected from:

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] The present invention provides a pharmaceutical composition comprising, as an active compound, one or more selected from the above-mentioned compounds, their tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, and cocrystals.

[0062] Preferably, the pharmaceutical composition further comprises one or more pharma- ceutically acceptable additives selected from carriers, diluents, and excipients. Note that the present invention is not particularly limited to the formulation form of the pharmaceutical composition.

[0063] The present invention provides the use of the above-mentioned compounds, their tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms (e.g., where a hydrogen atom is replaced by a deuterium atom), pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or co-crystals in the manufacture of a medicament for a KRAS inhibitor.

[0064] Preferably, the above compounds, their tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or co-crystals are used to prepare pharmaceutical agents for KRAS G12D mutation.

[0065] The present invention also provides use of the above compound, its tautomer, meso form, racemate, enantiomer, diastereoisomer or mixed form thereof, metabolite, metabolic precursor, isotopically substituted form, pharma- ceutically acceptable salt, hydrate, solvate, crystalline polymorph, or co-crystal in the manufacture of a medicament for treating, ameliorating, or preventing a disease or condition associated with Noonan syndrome, LEOPARD syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal carcinoma, or colorectal cancer.

[0066] To further clarify the present invention, the terms used herein are defined as follows. In the present invention, "pharmacologically acceptable" refers to any substance that does not interfere with the effectiveness of the biological activity of the active ingredients and that is not toxic to the host to which it is administered.

[0067] The pharma- ceutically acceptable additives described in the present invention are a general term for all additional substances contained in a drug other than the main drug. The additives must have the following characteristics: (1) almost no toxicity or side effects to the human body; (2) stable chemical properties and not easily affected by temperature, pH, storage time, etc.; (3) no adverse effects on the blending with the main drug, and no effect on the efficacy or quality inspection of the main drug; and (4) no interaction with the packaging material. The additives in the present invention are not particularly limited, but include fillers (diluents), lubricants (lubricants or anti-adhesives), dispersants, wetting agents, binders, regulators, solubilizers, antioxidants, bacteriostatic agents, emulsifiers, disintegrants, etc. Binders include syrup, gum arabic, gelatin, sorbitol, tragacanth gum, cellulose and its derivatives (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, etc.), gelatin slurry, syrup, starch slurry, polyvinylpyrrolidone, etc. Examples of filler binders include lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (e.g., calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol, and glycine. Examples of lubricants include finely powdered silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, and polyethylene glycol. Examples of disintegrants include starch and its derivatives (e.g., sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone, and microcrystalline cellulose. Examples of wetting agents include sodium dodecyl sulfate, water, and alcohol. Examples of antioxidants include sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, and dibutyl benzoic acid. Examples of bacteriostatic agents include 0.5% phenol, 0.3% cresol, and 0.5% chlorobutanol. Adjusting agents include hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate, and buffers, including sodium dihydrogen phosphate and disodium hydrogen phosphate.Examples of emulsifiers include polysorbate-80, sorbitan monooleate, Pluronic F-68, lecithin, soy lecithin, etc. Examples of solubilizers include polysorbate 80, bile, glycerin, etc.

[0068] The method of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, but representative administration methods include, but are not limited to, oral administration, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0069] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional excipient (or carrier) such as sodium citrate or dicalcium phosphate, or at least one of the following ingredients: (a) fillers or compatibilizers such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerin; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding solvents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium dodecyl sulfate, and mixtures thereof. Capsule, tablet and pill dosage forms may contain buffering agents.

[0070] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coating or shell materials, such as casings or other materials known in the art. The dosage form can include opacifying agents, and the active compound or compounds in the composition may be released slowly in a part of the digestive tract. Examples of embedding components that can be used include polymeric substances and waxy substances. If necessary, the active compound may be formed into a microencapsulated form with one or more of the above-mentioned excipients.

[0071] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents, such as water or other solvents, solubilizers and emulsifiers commonly used in the art, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, or mixtures thereof).

[0072] Besides these inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0073] In addition to the active compounds, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0074] Compositions used for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders which upon dissolution provide sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyol, and suitable mixtures thereof.

[0075] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0076] The compound according to the present invention can also be used in injection preparations, among which the injection preparations are selected from liquid injection preparations (aqueous injection preparations), sterile powder for injection (powder injection preparations) or injectable tablets (injectable tablets are prepared by aseptically preparing a drug as a molded tablet or a machine-compressed tablet, and the tablet is dissolved in water for injection immediately before use, and then injected subcutaneously or intramuscularly).

[0077] In addition to containing the compound, the powder for injection further contains at least an excipient, which is an ingredient intentionally added to a drug and has no pharmacological properties in the amount used, but may contribute to the processing, dissolution or dissolution of the drug, drug delivery by a targeted administration route, or stability.

[0078] A "substitution" refers to the replacement of a hydrogen atom in a molecule with another, different atom or molecule. "Membered" refers to the number of skeletal atoms that constitute the ring. In the present invention, the term "one bond" should be understood to mean that there is only one chemical bond at the location, or that there is none. The term "alkyl group" refers to an aliphatic hydrocarbon group and a saturated hydrocarbon group. The alkyl group portion may be a straight-chain alkyl group or a branched alkyl group. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0079] C1-Cn used in the present invention includes C1-C2, C1-C3...C1-Cn (wherein n is an integer greater than 1), and indicates the minimum and maximum numbers of carbon atoms in the substituent as a prefix of the substituent. For example, a "C1-C6 alkyl group" refers to a linear or branched alkyl group containing 1 to 6 carbon atoms. "Heteroalkyl groups" refers to alkyl groups that contain heteroatoms and includes alkoxy groups. The term "alkenyl group" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group may be linear or branched.

[0080] The term "alkynyl group" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be linear or branched. An "amide group" is a chemical structure of the formula -C(O)NHR or -NHC(O)R, where R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like. A "sulfonyl group" is a group represented by the formula -S(=O) 2 The chemical structure represented by R, where R can be selected from an alkyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amino group, and the like, includes a sulfonamide group. A "phosphoryl group" is a chemical structure of the formula -P(=O)RR', where R, R' can each be independently selected from alkyl groups, heteroalkyl groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, hydroxyl groups, amino groups, and the like. An "ester group" is a chemical structure of the formula -COOR, where R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

[0081] An "acyl group" is a chemical structure of the formula -C(O)R, where R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like. "Cycloalkyl group" refers to a saturated or unsaturated cyclic hydrocarbon substituent. "Heterocycloalkyl group" refers to a cycloalkyl group that contains at least one heteroatom in the ring backbone. Heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.

[0082] "Ring" refers to any covalently closed structure, examples of which include carbocyclic rings (e.g., aryl or cycloalkyl groups), heterocyclic rings (e.g., heteroaryl or heterocycloalkyl groups), aromatic groups (e.g., aryl or heteroaryl groups), and non-aromatic groups (e.g., cycloalkyl or heterocycloalkyl groups). The "ring" according to the present invention may be a monocyclic ring, a polycyclic ring, or a fused ring, a spiro ring, or a bridged ring.

[0083] Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0084] [ka]

[0085] These include, but are not limited to, the following: Exemplary heterocycloalkyl groups include, but are not limited to, the following groups:

[0086] [ka]

[0087] An "aryl group" refers to a planar ring having a delocalized pi-electron system and containing 4n+2 pi-electrons, where n is an integer. The aryl ring may be composed of 5, 6, 7, 8, 9, or more than 9 atoms. Aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, indenyl, and the like. Exemplary heteroaryl groups include, but are not limited to, the following:

[0088] [ka]

[0089] A "halogen" or "halogen atom" is fluorine, chlorine, bromine, or iodine. "Heuterium" is an isotope of hydrogen (H), also known as deuterium, and has the symbol D or 2 It is usually written as H.

[0090] The alkyl group, heteroalkyl group, ring group, heterocyclyl group, amino group, ester group, carbonyl group, amido group, sulfonyl group, phosphoryl group, boric acid group, boric acid ester group, guanidino group, acylguanidine group, aryl group, heteroaryl group, imido group, and the like described in this specification may be an unsubstituted alkyl group, heteroalkyl group, ring group, heterocyclyl group, amino group, ester group, carbonyl group, amido group, sulfonyl group, phosphoryl group, boric acid group, boric acid ester group, guanidino group, acylguanidine group, aryl group, heteroaryl group, or imido group, or may be a substituted alkyl group, heteroalkyl group, ring group, heterocyclyl group, amino group, ester group, carbonyl group, amido group, sulfonyl group, phosphoryl group, boric acid group, boric acid ester group, guanidino group, acylguanidine group, aryl group, heteroaryl group, or imido group.

[0091] Unless otherwise stated, "substituted" as used above refers to the replacement of the referenced group with one or more additional groups, each of which is independently selected from alkyl, cycloalkyl, aryl, carboxyl, heteroaryl, heterocycloalkyl, hydroxyl, alkyloxy, alkylthio, aryloxy, O=, guanidino, cyano, nitro, acyl, halogen, haloalkyl, amino, and the like.

[0092] The term "pharmaceutical acceptable salt" refers to a compound of the present invention that is suitable for forming a pharmaceutical salt with an acid or base. The above acids and bases are common Lewis acids and Lewis bases. Acids suitable for forming salts include, but are not limited to, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.

[0093] "Optional" or "optionally" means that the event or circumstance described below may occur but does not necessarily occur, and the description includes cases where the event or circumstance occurs or does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may be present but does not necessarily exist, and the description includes cases where the heterocyclyl group is replaced with an alkyl group and cases where the heterocyclyl group is not replaced with an alkyl group.

[0094] Most KRAS missense mutations occur at codon 12, resulting in a change from glycine to another amino acid. The major KRAS missense mutations are KRAS G12D and KRAS G12V mutations, which are found in 90% of pancreatic cancers. KRAS G12D is found as the most common KRAS mutation in colon cancer. Unfortunately, there are no clinical or commercially available drugs for KRAS G12D and KRAS G12V, as the amino acid residues at the mutated sites are difficult to chemically bond.

[0095] The first KRAS G12D inhibitor compound, MRTX1133 (WO2021041671), was reported by Mirati Therapeutics and was able to selectively bind to KRAS G12D mutant proteins and inhibit downstream ERK phosphorylation with high activity, demonstrating sustained dose-dependent suppression of KRAS-dependent signals in animal models of pancreatic and colorectal cancer. However, the plan to start clinical trials for the compound this year has been postponed, and Mirati has decided to change the candidate drug, which was originally expected to be a conventional oral or intravenous formulation, to a long-acting formulation that requires injection of a small amount of MRTX1133. Therefore, MRTX1133 should still have undisclosed drawbacks such as toxicity and side effects. In addition, a compound with KRAS G12D inhibitory activity (WO 2021 / 106231) was disclosed by Taiho Pharmaceutical Co., Ltd., but is still in the early research stage.

[0096] There are several development strategies for KRAS inhibitors, including those that target upstream and downstream targets or those that indirectly target KRAS. However, these strategies may have problems, such as activating bypass pathways or inhibiting normal KRAS activity, and research into these has not progressed very far. Therefore, the investigation and development of novel and effective KRAS G12D mutation inhibitors is of great clinical value. Effect of the Invention

[0097] Compared with the prior art, the present application has the following technical advantages: The present invention provides a novel class of compounds targeting KRAS G12D that have unexpectedly superior activity and pharmacokinetic properties.

[0098] The compounds according to the present invention, their tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or cocrystals can be used in the manufacture of medicaments for treating, ameliorating, or preventing diseases or conditions associated with Noonan syndrome, LEOPARD syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal carcinoma, and colorectal cancer, and have great development value.

[0099] The compounds provided by the present invention can be used to treat cancer caused by KRAS mutations, which are one or more of cancer caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutations.

[0100] The compound provided by the present invention can effectively block the binding of KRAS G12D protein to SOS1. In addition, the compound according to the present invention has obvious improvements in KRAS G12D inhibitory activity, liver microsome stability, and pharmacokinetics in rats. Furthermore, the synthesis method of the compound according to the present invention is simple and has a high yield. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0101] In order to make the technical solution of the present invention more understandable to those skilled in the art, the present invention will be described in more detail below in conjunction with specific examples. The structures of the compounds of the present invention were determined by mass spectrometry (MS) and / or nuclear magnetic resonance (1H NMR) instruments. Chemical abbreviations are used with the following meanings. DMF: N,N-dimethylformamide THF: tetrahydrofuran DIPEA: N,N-diisopropylethylamine PE: Petroleum ether EA: Ethyl acetate DCM: dichloromethane HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DMSO: Dimethyl sulfoxide

[0102] Synthesis of intermediates Preparation of intermediate 1: (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate tert-butyl

[0103] [ka]

[0104] Step 1: Synthesis of 2-chloro-3-fluoro-5-iodopyridin-4-amine 2-Chloro-3-fluoro-4-aminopyridine (14.60 g, 100 mmol) was dissolved in 200 mL acetonitrile, and p-toluenesulfonic acid (0.86 g, 5 mmol) was added at room temperature, followed by batchwise addition of NIS (24.75 g, 110 mmol). After the addition was complete, the reaction was stirred at 70° C. overnight. The reaction was poured into 1000 mL water, extracted with ethyl acetate, and the organic phase was back-extracted twice with an aqueous solution of sodium dithionite and saturated brine. After drying and spin drying, FCC purification (PE / EA=3 / 1) was performed to obtain 25.00 g of a yellow solid in 92% yield.

[0105] Step 2: Synthesis of methyl 4-amino-6-chloro-5-nicotinate 2-Chloro-3-fluoro-5-iodopyridin-4-amine (25.00 g, 91.9 mmol), triethylamine (30.30 g, 300 mmol) and 300 mL of methanol were added to the flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (3.66 g, 5 mmol) was added. The reaction mixture was heated to 80° C. under carbon monoxide (2 atm) and stirred overnight. The reaction mixture was cooled to room temperature and poured into 1000 mL water, extracted with ethyl acetate, the organic phase was dried and spun dry, and then purified by silica gel column chromatography (PE / EA=3 / 1) to give 14.50 g of a yellow solid in 78% yield.

[0106] Step 3: Synthesis of methyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate Trichloroacetyl isocyanate (5.8 g, 30.9 mmol) was added to 100 mL of methyl 4-amino-6-chloro-5-nicotinate (6.3 g, 30.9 mmol) in THF at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction system was spin-dried to obtain a crude product, which was then slurried with methyl tert-butyl ether to obtain 12.5 g of a yellow solid in 100% yield.

[0107] Step 4: Synthesis of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol At room temperature, 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)methyl nicotinate (12.5 g, 31.8 mmol) was added to 100 mL of methanol solution in ammonia / methanol solution (7 m, 20 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction system was spin-dried, and the crude product obtained was purified by FCC (PE / EA=3 / 1), yielding 6.4 g of a yellow solid in 94% yield.

[0108] Step 5: Synthesis of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine 7-Chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (6.4 g, 29.8 mmol) was dissolved in 40 mL of phosphoryl chloride at room temperature, DIPEA (19.3 g, 150 mmol) was added, and the reaction solution was stirred at 100° C. for 1 hour. The reaction system was spin-dried to obtain a crude product, which was used as is in the next step.

[0109] Step 6: Synthesis of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (crude product obtained in the previous step), DIPEA (25.8 g, 200 mmol) and 100 mL of dichloromethane were added to a flask, and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (6.6 g, 31 mmol) was added at -40° C. After stirring for 1 hour at -40° C., the mixture was poured into 1000 mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by silica gel column chromatography (PE / EA=3 / 1) to give 8.1 g of a yellow solid in 64% yield.

[0110] Step 7: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-tert-butylcarbamate (500 mg, 1.2 mmol), DIPEA (313 mg, 2.5 mmol), (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (282 mg, 2.0 mmol) and 5 mL of dioxane were added to a flask, and the mixture was stirred overnight at 80° C. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give 250 mg of a yellow solid in 40% yield.

[0111] Preparation of intermediate 2: 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0112] [ka]

[0113] Step 1: Synthesis of 1-bromo-3-(methoxymethoxy)naphthalene At 0°C, chloromethyl methyl ether (3.6 g, 45.0 mmol) was added dropwise to a solution of 4-bromonaphthalen-2-ol (10.0 g, 44.8 mmol) and DIPEA (17.4 g, 134.5 mmol) in methylene chloride (100 mL), and the mixture was stirred at room temperature for 1 hour after the addition was complete. The reaction solution was poured into 500 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, and purified by silica gel column chromatography (PE / EA=20 / 1) to obtain 11.5 g of a yellow oily product in 96% yield.

[0114] Step 2: Synthesis of 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 1-Bromo-3-(methoxymethoxy)naphthalene (10.0 g, 37.5 mmol), bis(pinacolato)diboron (10.2 g, 40 mmol), potassium acetate (7.8 g, 80 mmol) and 100 mL of dioxane were added to the flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (1.5g, 2mmol) was added. The reaction mixture was heated to 80°C under nitrogen gas protection and stirred overnight. After cooling to room temperature, the reaction mixture was poured into 500mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and then purified by silica gel column chromatography (PE / EA=10 / 1) to give 10.5g of white solid in 89% yield.

[0115] Preparation of intermediate 3: triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane

[0116] [ka]

[0117] Step 1: Synthesis of 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol Resorcinol (10.0 g, 62.5 mmol), (bromoethynyl)triisopropylsilane (19.6 g, 75.0 mmol), potassium acetate (12.3 g, 125.0 mmol) and dioxane (100 mL) were added to the flask, and after nitrogen gas exchange, dichloro(p-cymene)ruthenium(II)(dimer) (3.8 g, 6.3 mmol) was added. The reaction mixture was heated to 100° C. under nitrogen gas protection and stirred overnight. After cooling the reaction system to room temperature, it was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by silica gel column chromatography (PE / EA=50 / 1) to obtain 11.5 g of a yellow oily product in 89% yield.

[0118] Step 2: Synthesis of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol At 0°C, chloromethyl methyl ether (2.7 g, 34.0 mmol) was added dropwise to 100 mL of a methylene chloride solution of 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (11.5 g, 34.0 mmol) and DIPEA (17.4 g, 134.5 mmol), and the mixture was stirred at room temperature for 1 hour after the addition was complete. The reaction solution was poured into 500 mL of water, extracted with dichloromethane, and the organic phase was dried and then spin-dried, and purified by silica gel column chromatography (PE / EA=50 / 1) to obtain 8.6 g of a yellow oily product in 66% yield.

[0119] Step 3: Synthesis of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate Trifluoromethanesulfonic anhydride (7.0 g, 24.8 mmol) was added dropwise to a solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (8.6 g, 22.4 mmol) and DIPEA (5.8 g, 45.0 mmol) in methylene chloride (100 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour after the addition was complete. The reaction solution was poured into 500 mL of water, extracted with dichloromethane, and the organic phase was dried and then spin-dried, and purified by silica gel column chromatography (PE / EA=50 / 1) to obtain 5.5 g of a yellow solid in 48% yield.

[0120] Step 4: Synthesis of triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphthalen-1-yl)ethynyl)silane 3-(Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (4.8 g, 9.3 mmol), bis(pinacolato)diboron (5.0 g, 19.7 mmol), potassium acetate (2.9 g, 29.6 mmol) and 50 mL of dioxane were added to a flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (0.7 g, 1 mmol) was added. The reaction mixture was heated to 100° C. under nitrogen gas protection and stirred overnight. After cooling to room temperature, the reaction mixture was poured into 200 mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by silica gel column chromatography (PE / EA=20 / 1) to obtain 2.1 g of a white solid in 46% yield.

[0121] Preparation of intermediate 4: ((2-fluoro-6-(methoxymethoxy)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0122] [ka]

[0123] Step 1: Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol 7-Fluoro-1,3-naphthalenediol (178 mg, 1.0 mmol), (bromoethynyl)triisopropylsilane (260 mg, 1.0 mmol), potassium acetate (196 mg, 2.0 mmol) and 5 mL of dioxane were added to a flask, and after nitrogen gas exchange, dichloro(p-cymene)ruthenium(II)(dimer) (60 mg, 0.1 mmol) was added. The reaction mixture was heated to 100° C. under nitrogen gas protection and stirred overnight. After cooling the reaction system to room temperature, it was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by silica gel column chromatography (PE / EA=10 / 1) to obtain 295 mg of a yellow oily product in 82% yield.

[0124] Step 2: Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol At 0°C, DIPEA (319 mg, 2.47 mmol) was added to a dichloromethane (5 mL) solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (295 mg, 0.84 mmol), and MOMCl (67 mg, 0.84 mmol) was added dropwise. After reacting at 0°C for 2 hours, the temperature was slowly raised to room temperature. After the reaction was completed, the reaction system was spin-dried and purified using a silica gel column (PE / EA=20 / 1), obtaining 210 mg of a light yellow solid in a yield of 62%.

[0125] Step 3: Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate At -78°C, DIPEA (194mg, 1.50mmol) was added to a dichloromethane solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (210mg, 0.52mmol), and trifluoromethanesulfonic anhydride (169mg, 0.60mmol) was slowly added dropwise. The temperature was maintained while stirring for 1 hour. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, and the combined organic phase was back-extracted with water and saturated saline, dried over anhydrous sodium sulfate, spin-dried, and purified by Prep-TLC (PE / EA=20 / 1), obtaining 255mg of a light yellow solid in 81% yield for two steps.

[0126] Step 4: Synthesis of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (225 mg, 0.42 mmol), bis(pinacolato)diboron (127 mg, 0.50 mmol), potassium acetate (98 mg, 1.00 mmol) and 5 mL of dioxane were added to the flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (15 mg, 0.02 mmol) was added. The reaction mixture was heated to 100° C. under nitrogen gas protection and stirred overnight. After cooling to room temperature, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and purified by Prep-TLC (PE / EA=20 / 1) to give 140 mg of a white solid in 65% yield.

[0127] Preparation of intermediate 5: 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0128] [ka]

[0129] Step 1: Synthesis of 4-methoxy-4-oxo-3-(triphenylphosphoranylidene)butyric acid Triphenylphosphine (52.46g, 200mmol) was dissolved in acetonitrile (800mL) and a solution of maleic anhydride (19.5g, 200mmol) in acetonitrile was added dropwise at room temperature. After the dropwise addition was completed over 30 minutes, the mixture was reacted at room temperature for 3 hours. The precipitated yellow solid was collected as a filter cake by filtration and spin-dried, and then 800mL of methanol was added and the mixture was reacted at room temperature for 16 hours with stirring. After the solid was completely dissolved and the mixture became clear, the reaction system was spin-dried to obtain 55g of a fluffy yellow solid in a yield of 84%.

[0130] Step 2: Synthesis of 4-(2-bromo-4,5-difluorophenyl)-3-(methoxycarbonyl)but-3-enoic acid 4-Methoxy-4-oxo-3-(triphenylphosphoranylidene)butyric acid (8.9 g, 22.73 mmol) was dissolved in a mixture of toluene (50 mL) and dichloromethane (10 mL), and a dichloromethane solution of 2-bromo-4,5-difluorobenzaldehyde (5 g, 22.73 mmol) was added dropwise thereto under nitrogen gas protection. The reaction was allowed to proceed for 16 hours at room temperature under nitrogen gas protection. After the reaction was completed, aqueous sodium hydroxide solution was slowly added to the reaction system, stirred for 5 minutes, and extracted three times with ethyl acetate. The aqueous phase was collected and extracted with ethyl acetate after adjusting the acidity. The combined organic phase was back-extracted with sodium hydroxide solution, and the aqueous phase was collected again and extracted after adjusting the acidity. The obtained organic phase was dried and then spin-dried to obtain 5.5 g of an off-white solid (72% yield).

[0131] Step 3: Synthesis of methyl 4-acetoxy-8-bromo-5,6-difluoro-2-naphthoate 4-(2-Bromo-4,5-difluorophenyl)-3-(methoxycarbonyl)but-3-enoic acid (12 g, 35.9 mmol), sodium acetate (3.54 g, 43.2 mmol), and acetic anhydride (120 mL) were added to a single-neck flask and reacted for 6 hours at 140° C. After the reaction was completed, the acetic anhydride in the reaction system was removed by spin drying at 70° C., and the flash column was rinsed with a mixed solvent of petroleum ether: ethyl acetate = 1:1 to obtain 13.96 g of a black crude product, which was used as it is in the next step.

[0132] Step 4: Synthesis of methyl 8-bromo-5,6-difluoro-4-hydroxy-2-naphthoate To a solution of the crude product obtained in the previous step in methanol (200 mL), potassium carbonate (10.9 g, 76.8 mmol) was added and reacted at room temperature with stirring for 1 hour. After completion of the reaction, the reaction system was spin-dried and the crude product was used as it was in the next step.

[0133] Step 5: Synthesis of methyl 4-(benzyloxy)-8-bromo-5,6-difluoro-2-naphthoate Benzyl bromide (8 g, 46.7 mmol) was slowly added dropwise to the DMF solution of the crude product obtained in the previous step. After the addition was completed, the mixture was reacted at room temperature for 0.5 hours while stirring. After the reaction was completed, water was added to the reaction system, which was then extracted multiple times with ethyl acetate. The combined organic phase was back-extracted with water and saturated saline, and dried over anhydrous sodium sulfate. The filtrate was spin-dried and purified by applying it to a silica gel column (PE / EA=50 / 1) to obtain 9.5 g of a yellow solid (65% yield for the three steps).

[0134] Step 6: Synthesis of (4-(benzyloxy)-5,6-difluoronaphthalen-2-yl)methanol At -78°C, lithium aluminum hydride (1.3g, 35.2mmol) was added to a solution of 4-(benzyloxy)-8-bromo-5,6-difluoro-2-naphthoic acid methyl ester (9.5g, 23.4mmol) in tetrahydrofuran (100mL) under nitrogen gas protection. After reacting at low temperature for 1 hour, the temperature was slowly raised to room temperature and reacted at room temperature overnight. After the reaction was completed, the temperature was lowered to 0°C, a tetrahydrofuran dilution system was added, water (2mL), 15% sodium hydroxide solution (2mL), and water (6mL) were added in sequence, and the temperature was raised to room temperature and stirred for 15 minutes. An appropriate amount of anhydrous sodium sulfate was added, and the mixture was stirred at room temperature for 15 minutes, followed by filtration through diatomaceous earth, and the filtrate was spin-dried to obtain 7.5g of a light yellow solid. The crude product was used as is in the next step.

[0135] Step 7: Synthesis of 4-(benzyloxy)-5,6-difluoro-2-naphthaldehyde Manganese dioxide (20 g, 141 mmol) was added to a dichloromethane solution of (4-(benzyloxy)-5,6-difluoronaphthalen-2-yl)methanol (7.5 g, 25 mmol), and the mixture was allowed to react overnight at room temperature. After the reaction was completed, the reaction system was filtered through diatomaceous earth, and the filtrate was spin-dried and purified through a silica gel column (PE / EA=20 / 1) to obtain 5.5 g of a white solid (yield 73%).

[0136] Step 8: Synthesis of 4-(benzyloxy)-5,6-difluoronaphthalen-2-ol Under nitrogen gas protection, metachloroperbenzoic acid (11 g, 70 mmol) was added to a solution of 4-(benzyloxy)-5,6-difluoro-2-naphthaldehyde (5.4 g, 18.1 mmol) in dichloromethane (54 mL), and the mixture was allowed to react overnight at room temperature. After the reaction was completed, the reaction system was directly filtered, the filter cake was washed with a small amount of dichloromethane, the filtrate was spin-dried, and the solution was redissolved in ethyl acetate and dropped into an aqueous sodium carbonate solution. After stirring for 1 hour, the mixture was extracted with ethyl acetate, and the combined organic phase was back-extracted with water and saturated saline, dried over anhydrous sodium sulfate, and then spin-dried. The crude product was used as it was in the next step.

[0137] Step 9: Synthesis of 8-(benzyloxy)-1,2-difluoro-6-(methoxymethoxy)naphthalene At 0°C, DIPEA (4.7 g, 36.4 mmol) was added to a solution of the crude product obtained in the previous step in dichloromethane (50 mL), and MOMCl (1.2 g, 14.8 mmol) was added dropwise. After reacting at 0°C for 2 hours, the temperature was slowly raised to room temperature. After the reaction was completed, the reaction system was spin-dried and purified on a silica gel column (PE / EA=20 / 1) to obtain 540 mg of a light yellow solid (yield of two steps: 9%).

[0138] Step 10: Synthesis of 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-ol Palladium on carbon (10%, 50 mg) was added to a methanol solution of 8-(benzyloxy)-1,2-difluoro-6-(methoxymethoxy)naphthalene (540 mg, 1.6 mmol), hydrogen gas was replaced, and the reaction was carried out under a hydrogen gas environment for 3 hours. After the reaction was completed, the reaction system was filtered through diatomaceous earth, the filter cake was rinsed with methanol, and the filtrate was spin-dried to obtain the crude product. No additional purification was performed.

[0139] Step 11: Synthesis of 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate At -78°C, DIPEA (645mg, 5mmol) was added to the dichloromethane solution of the crude product obtained in the previous step, and trifluoromethanesulfonic anhydride (517mg, 1.83mmol) was slowly added dropwise. The temperature was maintained while stirring for 1 hour. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, and the combined organic phase was back-extracted with water and saturated saline, dried over anhydrous sodium sulfate, spin-dried, and purified through a silica gel column (PE / EA=20 / 1) to obtain 420mg of a light yellow solid (69% yield for the two steps).

[0140] Step 12: Synthesis of 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 7,8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (372 mg, 1.0 mmol), bis(pinacolato)diboron (254 mg, 1.0 mmol), potassium acetate (196 mg, 2.0 mmol) and 5 mL of dioxane were added to the flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (37 mg, 0.05 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred overnight. After cooling to room temperature, the reaction mixture was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried, and then purified by silica gel column chromatography (PE / EA=20 / 1) to obtain 240 mg of a white solid (yield 69%).

[0141] Preparation of intermediate 6: (1R,5S)-3-(7-chloro-8-fluoro-2-(((2S,3aR)-2-fluorohexahydropentenyl-3a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate tert-butyl

[0142] [ka]

[0143] (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate tert-butyl (500 mg, 1.2 mmol), DIPEA (313 mg, 2.5 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (318 mg, 2.0 mmol) and 5 mL of dioxane were added to a flask, and the mixture was stirred overnight at 80° C. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, followed by purification by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 275 mg of a yellow solid (43% yield).

[0144] Preparation of intermediate 7: (1R,5S)-tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0145] [ka]

[0146] Step 1: Synthesis of 7-bromo-8-fluoroquinazoline-2,4-diol 2-Amino-4-bromo-3-fluorobenzoic acid (1.0 g, 4.27 mmol) and urea (3.0 g, 50.00 mmol) were added to the flask, and the reaction system was heated to 170° C. and reacted for 4 hours with stirring. The reaction system was cooled to room temperature, extracted three times with water and ethyl acetate, and the organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then purified through a chromatographic column (PE / EA=5 / 1) to obtain 675 mg of the desired product (yield 61%).

[0147] Step 2: Synthesis of 7-bromo-2,4-dichloro-8-fluoroquinazoline 7-Bromo-8-fluoroquinazoline-2,4-diol (300 mg, 1.16 mmol), phosphoryl chloride (1.5 g, 9.80 mmol), DIEA (650 mg, 5.04 mmol) were added to the flask, and the reaction was heated to 90° C. and stirred for 3 hours. The reaction was cooled to room temperature, and the filtrate was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0148] Step 3: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate The crude product obtained in the previous step, DIEA (650 mg, 5.04 mmol), (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (200 mg, 0.95 mmol) and 30 mL of anhydrous ethanol were added to a flask, and the reaction system was heated to 80° C. and reacted for 4 hours with stirring. The reaction system was cooled to room temperature, extracted three times with water and ethyl acetate, and the organic phases were combined and then washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA=8 / 1) to obtain 190 mg of the desired product (35% yield for the two steps).

[0149] Example 1 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(difluoro(phenyl)methyl)phenol

[0150] [ka]

[0151] Step 1: Synthesis of (3-bromo-5-methoxyphenyl)(phenyl)methanol At 0°C under nitrogen gas protection, a reaction mixture of 3-bromo-5-methoxybenzaldehyde (2.15 g, 10.0 mmol) in 20 mL THF solution and phenylmagnesium bromide (1 m, 11 mL, 11.0 mmol) was added dropwise, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into 100 mL of water, extracted with ethyl acetate, the organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA=10 / 1) to obtain 2.8 g of a light yellow solid (yield 96%).

[0152] Step 2: Synthesis of (3-bromo-5-methoxyphenyl)(phenyl)methanone Activated manganese dioxide (4.4 g, 50.6 mmol) was added to a solution of (3-bromo-5-methoxyphenyl)(phenyl)methanol (2.8 g, 9.6 mmol) in 50 mL of dichloromethane, and the reaction mixture was stirred overnight at room temperature. It was filtered under reduced pressure, and the filtrate was spin-dried and purified by silica gel column chromatography (PE / EA=50 / 1) to give 2.6 g of a pale yellow solid (yield 93%).

[0153] Step 3: Synthesis of (3-bromo-5-hydroxyphenyl)(phenyl)methanone (3-Bromo-5-methoxyphenyl)(phenyl)methanone (2.0 g, 6.9 mmol) was dissolved in 20 mL of dichloromethane and heated at 0 °C with BBr 3 (2.5 g, 10.0 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 100 mL water, extracted with ethyl acetate, the organic phase was dried, spun dry, and purified by silica gel column chromatography (PE / EA=10 / 1) to give 1.2 g of a yellow solid (63% yield).

[0154] Step 4: Synthesis of (3-bromo-5-((4-methoxybenzyl)oxy)phenyl)(phenyl)methanone At 0°C, p-methoxybenzyl bromide (241 mg, 1.2 mmol) was added dropwise to a solution of (3-bromo-5-hydroxyphenyl)(phenyl)methanone (277 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) in 50 mL of acetonitrile, and after the addition was complete, the mixture was stirred at room temperature for 5 hours. It was filtered under reduced pressure, and the filtrate was dried to give 370 mg of a yellow solid (yield 93%).

[0155] Step 5: Synthesis of 1-bromo-3-(difluoro(phenyl)methyl)-5-((4-methoxybenzyl)oxy)benzene (3-Bromo-5-((4-methoxybenzyl)oxy)phenyl)(phenyl)methanone (370 mg, 0.9 mmol) and 1 mL bis(2-methoxyethyl)aminosulfur trifluoride were added to the flask. The reaction mixture was stirred at 80° C. for 2 h. The reaction was poured into 10 mL ice water, extracted with ethyl acetate, and the organic phase was dried, spun dry, and purified by Prep-TLC (PE / EA=30 / 1) to give 80 mg of a light yellow solid (21% yield).

[0156] Step 6: Synthesis of 2-(3-(difluoro(phenyl)methyl)-5-((4-methoxybenzyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 1-Bromo-3-(difluoro(phenyl)methyl)-5-((4-methoxybenzyl)oxy)benzene (60 mg, 0.14 mmol), bis(pinacolato)diboron (38 mg, 0.15 mmol), potassium acetate (29 mg, 0.30 mmol) and 2 mL of dioxane were added to the flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 10mg of ethyl acetate was added. Under nitrogen gas protection, the reaction mixture was heated to 100℃ and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by Prep-TLC (PE / EA=20 / 1) to obtain 60mg of yellow solid (yield 90%).

[0157] Step 7: Synthesis of tert-butyl (1R,5S)-3-(7-(3-(difluoro(phenyl)methyl)-5-((4-methoxybenzyl)oxy)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a)(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate Into a flask, (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate tert-butyl (67 mg, 0.13 mmol), 2-(3-(difluoro(phenyl)methyl)-5-((4-methoxybenzyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (60 mg, 0.13 mmol), potassium carbonate (40 mg, 0.29 mmol) and dioxane / water (2 mL / 0.2 mL) were added, and nitrogen gas was exchanged. Then, Pd(dppf)Cl 2 5mg was added. Under nitrogen gas protection, the reaction mixture was heated to 100℃ and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and purified by Prep-TLC (DCM / MeOH=20 / 1) to give 17mg of a grey solid (16% yield).

[0158] Step 8: Synthesis of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(difluoro(phenyl)methyl)phenol (1R,5S)-3-(7-(3-(difluoro(phenyl)methyl)-5-((4-methoxybenzyl)oxy)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a) (5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate tert-butyl (17 mg, 0.02 mmol) was dissolved in 2 mL of ethyl acetate and stirred for 0.5 h after adding HCl / EA (4 m, 1 mL) at room temperature. The reaction was spun dry, 2 mL of aqueous sodium carbonate was added, extracted with ethyl acetate, the organic phase was dried and spun dry, and purified by Prep-TLC (DCM / MeOH=8 / 1) to give 4 mg of a grey solid (31% yield). LC / MS: m / z=617.3[M+H] + .

[0159] Example 2 5-Ethynyl-4-(8-fluoro-4-((1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octyl-4-yl)amino)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0160] [ka]

[0161] Step 1: Synthesis of triethyl 4-oxocyclohexane-1,1,3-tricarboxylate NaH (8.56g, 357mmol) was suspended in anhydrous THF (80mL), the temperature was raised to 40-45°C, and a THF solution of diethyl malonate (22.85g, 149mmol) was added dropwise, and after the dropwise addition, the mixture was reacted for 15 minutes while stirring at the same temperature. A THF solution of ethyl acrylate was added dropwise, and after the addition, the mixture was reacted for 15 minutes. The reaction solution was cooled to room temperature and then added to ice water, the pH was adjusted to 3 with concentrated HCl, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a colorless oily product (37.6g, 83%).

[0162] Step 2: Synthesis of triethyl 4-oxocyclohexane-1,1-dicarboxylate Triethyl 4-oxocyclohexane-1,1,3-tricarboxylate (37.6 g, 120 mmol), sodium chloride (20.97 g, 359 mmol) were added to DMSO (170 mL) and H2O (5 mL) and reacted at 160°C for 1.7 hours. The reaction solution was cooled and added to ice water, extracted with ethyl acetate, dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to obtain a colorless oily product (21.6 g, 75%).

[0163] Step 3: Synthesis of triethyl 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylate Triethyl 4-oxocyclohexane-1,1-dicarboxylate (21.6 g, 89.2 mmol), ethylene glycol (6.64 g, 107 mmol) and paratoluenesulfonic acid hydrate (169 mg, 0.89 mmol) were added to toluene (180 mL) and refluxed at 120° C. for 4 hours while separating water. The reaction solution was cooled and saturated NaHCO 3 The mixture was added to an aqueous solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a pale yellow liquid (23.7 g, 93%).

[0164] Step 4: Synthesis of (1,4-dioxaspiro[4.5]decane-8,8-diyl)dimethanol LAH (6.47g, 166mmol) was placed in a three-neck flask, anhydrous THF (150mL) was added, and the mixture was replaced with nitrogen gas. A solution of 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylate triethyl (23.7g, 82.8mmol) in THF (100mL) was added dropwise under ice-salt bath cooling. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was carried out for 5 hours. H was added to the reaction system in an ice-water bath. 2 O / THF (1:1, 30 mL) was slowly added dropwise, followed by 5N aqueous sodium hydroxide (8 mL) and stirred at room temperature overnight. The reaction was diluted with DCM / MeOH (5:1, 250 mL) and filtered, rinsing with DCM / MeOH (5:1). 50 g of silica gel was added to the filtrate, stirred for 15 minutes, filtered and rinsing. The filtrate was concentrated under reduced pressure to give the product (16.7 g, 99%).

[0165] Step 5: Synthesis of (1,4-dioxaspiro[4.5]decane-8,8-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (1,4-Dioxaspiro[4.5]decane-8,8-diyl)dimethanol (16.7 g, 82.6 mmol) was weighed into a flask, pyridine (100 mL) was added, and TsCl (34.6 g, 182 mmol) was added in an ice-water bath, followed by stirring overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with 10% aqueous citric acid and saturated sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was slurried with ethanol to obtain a white solid (35 g, 83%).

[0166] Step 6: Synthesis of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (1,4-Dioxaspiro[4.5]decane-8,8-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (35 g, 68.5 mmol) was weighed into a flask, 1N HCl solution (260 mL) and THF (300 mL) were added, and the mixture was reacted at 80° C. for 5 hours. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to obtain the desired product (26.2 g, 82%).

[0167] Step 7: Synthesis of ((4-(1,3-dithian-2-yl)-4-hydroxycyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) Compound 1,3-dithiane (2.1g, 17.4mmol) and anhydrous THF (40mL) were added to the flask, and after replacing with nitrogen gas, n-butyllithium (2.5M, 8.5mL) was added dropwise under cooling in a dry ice / ethanol bath. After the dropwise addition, the temperature was raised to 0°C and the reaction was allowed to proceed for 1 hour. After cooling in a dry ice / ethanol bath, a THF solution of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (6.5g, 13.9mmol) was added dropwise, and after the dropwise addition, the temperature was raised to room temperature and the reaction was allowed to proceed for 1 hour. The reaction solution was diluted with saturated NH 4 The mixture was quenched with Cl solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the desired product (6.77 g, 83%).

[0168] Step 8: Synthesis of (1-(1,3-dithian-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate ((4-(1,3-dithian-2-yl)-4-hydroxycyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (6.77 g, 11.5 mmol), NaOH (1.38 g, 34.6 mmol), and THF (170 mL) were added to a flask and refluxed at 70° C. overnight. The reaction mixture was cooled to room temperature, extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to obtain the desired product (3.7 g, 77%).

[0169] Step 9: Synthesis of ((1-formyl-2-oxabicyclo[2.2.2]octyl-4-yl)methyl 4-methylbenzenesulfonate (1-(1,3-dithiane-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (3.7 g, 8.92 mmol), acetonitrile (50 mL) and water (12.5 mL) were added to a flask, and NBS (5.56 g, 31.2 mmol) was added in an ice-water bath. After the addition, the temperature was returned to room temperature and the reaction was carried out for 3 hours. The reaction solution was then cooled to room temperature with saturated NaHCO 3 The solution was added and extracted with ethyl acetate, the organic phases were combined and then back extracted with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was not subjected to further purification.

[0170] Step 10: Synthesis of (1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octyl-4-yl)methyl 4-methylbenzenesulfonate The crude product obtained in the above step was dissolved in ethanol and cooled to 100°C with NaBH 4 (508 mg, 13.4 mmol) was added, and the mixture was allowed to warm to room temperature and react for 1 hour. The reaction solution was diluted with saturated NH 4 The mixture was quenched with Cl solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the desired product (2.66 g, 91% yield for two steps).

[0171] Step 11: Synthesis of (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octyl-4-yl)methyl 4-methylbenzenesulfonate (1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octyl-4-yl)methyl 4-methylbenzenesulfonate (2.56 g, 7.84 mmol), DMAP (287 mg, 2.35 mmol), imidazole (1.06 g, 15.7 mmol) and DMF (15 mL) were added to a flask, and TBDPSCl (2.59 g, 9.41 mmol) was added and reacted at room temperature for 0.5 hours. The reaction solution was added to water, extracted with ethyl acetate, and the organic phases were combined and back-extracted with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography to obtain the desired product (4.0 g, 90%).

[0172] Step 12: Synthesis of (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octyl-4-yl)methanol (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octyl-4-yl)methyl 4-methylbenzenesulfonate (4.0 g, 7.08 mmol) and methanol (120 mL) were added to a flask, and Mg (1.89 g, 77.9 mmol) was added while stirring at room temperature. After 30 minutes, the reaction was vigorously exothermic and the reaction was stirred overnight. The reaction solution was diluted with saturated NH 4 The mixture was added to a Cl solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the desired product (2.4 g, 83%).

[0173] Step 13: Synthesis of 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octane-4-carboxylic acid (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octyl-4-yl)methanol (2.4 g, 5.85 mmol) and DMF (30 mL) were added to a flask, and PDC (6.6 g, 17.6 mmol) was added under ice-water bath. After the addition, the mixture was returned to room temperature and reacted for 2 hours. Ethyl acetate was added to the flask to dilute the reaction solution, which was then extracted with water. The organic phases were combined and then back-extracted with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to obtain the desired product (1.99 g, 80%).

[0174] Step 14: Synthesis of 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octyl-4-amine 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octane-4-carboxylic acid (1.0 g, 2.35 mmol), DPPA (688 mg, 2.50 mmol), tert-butyl alcohol (2 mL) and toluene (10 mL) were added to the flask, and the reaction was stirred at 100° C. overnight. After cooling to room temperature, 0.5 mL of concentrated hydrochloric acid was added, followed by stirring for 10 minutes. The reaction was poured into 50 mL of water, the pH value was adjusted to alkaline with sodium carbonate, extracted with ethyl acetate, the organic phase was dried and spun dry, and then purified by silica gel column chromatography (PE / EA=2 / 1) to obtain 60 mg of yellow oily product in 6% yield.

[0175] Step 15: Synthesis of N-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]oct-4-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-amine 1-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octyl-4-amine (50 mg, 0.13 mmol), 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (33 mg, 0.13 mmol) and DIPEA (39 mg, 0.30 mmol) were dissolved in 2 mL of dichloromethane and stirred at room temperature for 6 h. The reaction was poured into 10 mL of water, extracted with dichloromethane, the organic phase was dried, spun dry and purified by Prep-TLC (DCM / MeOH=50 / 1) to give 60 mg of a yellow solid in 76% yield.

[0176] Step 16: Synthesis of N-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]oct-4-yl)-7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine At room temperature, NaH (60%, 8 mg, 0.20 mmol) was added to a solution of (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (21 mg, 0.15 mmol) in 2 mL of THF, and the resulting reaction solution was stirred at room temperature for 1 hour, after which N-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]oct-4-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-amine (60 mg, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried, spun dry, and purified by Prep-TLC (DCM / MeOH=20 / 1) to give 33 mg of a yellow solid in 46% yield.

[0177] Step 17: Synthesis of N-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octyl-4-yl)-8-fluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl))ethynyl)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine N-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]oct-4-yl)-7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine (33 mg, 0.046 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (25 mg, 0.051 mmol), potassium carbonate (14 mg, 0.100 mmol) and dioxane / water (2 mL / 0.2 mL) were added to a flask, and nitrogen gas was exchanged. Then, 5 mg of Pd(dppf)Cl was added. 2 The reaction mixture was heated to 100° C. under nitrogen gas protection and stirred for 6 h. The reaction was cooled to room temperature and poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and purified by Prep-TLC (DCM / MeOH=20 / 1) to give 17 mg of a grey solid in 35% yield.

[0178] Step 18: Synthesis of (4-((7-(8-ethynyl-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-2-oxabicyclo[2.2.2]octyl-1-yl)methanol N-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octyl-4-yl)-8-fluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl))ethynyl)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine (10 mg, 0.0095 mmol) was dissolved in 1 mL DMF and stirred overnight after adding CsF (10 mg) at room temperature. The reaction was poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and spun to dryness, and the resulting crude product was used as is in the next reaction.

[0179] Step 19: Synthesis of 5-ethynyl-4-(8-fluoro-4-((1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octyl-4-yl)amino)-2-((tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The crude product from the previous step was dissolved in 2 mL ethyl acetate, HCl / EA (4 m, 0.5 mL) was added and stirred for 10 min. The reaction was spun to dryness and purified by Prep-HPLC to give 1 mg of a grey solid (17% yield for both steps). LC / MS: m / z=610.3[M+H] + . 1 H NMR

[0180] Example 3 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-(difluoro(phenyl)methyl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0181] [ka]

[0182] Step 1: Synthesis of 1-bromo-4-(difluoro(phenyl)methyl)benzene (4-Bromophenyl)(phenyl)methanone (300 mg, 1.15 mmol) and BAST (3 mL) were added to the reaction tube, the reaction tube was sealed, and the tube was heated to 90° C. and reacted overnight. The reaction solution was cooled and poured into water, extracted twice with ethyl acetate, and the organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, evaporated in vacuum, and then purified on a silica gel preparative plate to obtain 270 mg of the product in 83% yield.

[0183] Step 2: Synthesis of 2-(4-(difluoro(phenyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 1-Bromo-4-(difluoro(phenyl)methyl)benzene (1.0 g, 3.5 mmol), bis(pinacolato)diboron (1.3 g, 5.1 mmol), potassium acetate (1.0 g, 10.2 mmol) and 15 mL of dioxane were added to the flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (146 mg, 0.2 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into 100 mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and then purified by silica gel column chromatography (PE / EA=20 / 1) to obtain 970 mg of a whitish solid in 75% yield.

[0184] Step 3: Synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-(difluoro(phenyl)methyl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine The target product was synthesized in the same manner as in Example 1 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=601.3[M+H] + .

[0185] Example 4 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-(difluoro(phenyl)methyl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0186] [ka]

[0187] Step 1: Synthesis of 3-bromo-4,5-difluoro-1H-indole NBS (356 mg, 2.0 mmol) was added to a solution of 4,5-difluoro-1H-indole (300 mg, 2.0 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 6 hours. The reaction solution was poured into 50 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried to obtain a crude product.

[0188] Step 2: Synthesis of 3-bromo-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole The product from the previous step was dissolved in 5 mL of THF, added with NaH (60%, 120 mg, 3.0 mmol) at 0° C., stirred at room temperature for 0.5 h, and then added with SEM-Cl (367 mg, 2.2 mmol). The reaction was stirred at room temperature for 3 h. The reaction was poured into 50 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry. Purification by column chromatography gave 400 mg of colorless oil (85% yield for both steps).

[0189] Step 3: Synthesis of 4,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole 3-Bromo-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (100 mg, 0.28 mmol), bis(pinacolato)diboron (102 mg, 0.40 mmol), potassium acetate (59 mg, 0.60 mmol) and 3 mL of dioxane were added to a flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (7 mg, 0.01 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and then purified by silica gel column chromatography (PE / EA=5 / 1) to obtain 20 mg (18% yield) of a gray solid.

[0190] Step 4: Synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4,5-difluoro-1H-indol-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine The target product was synthesized in the same manner as in Example 1 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=550.2[M+H] + .

[0191] Example 5 4-(4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol

[0192] [ka]

[0193] Step 1: Synthesis of (1R,5S)-3-benzyl-8,8-difluoro-3-azabicyclo[3.2.1]octane 3-Benzyl-3-azabicyclo[3.2.1]octan-8-one (250 mg, 1.2 mmol) was dissolved in 5 mL of dichloromethane, and DAST (300 mg, 1.8 mmol) was added dropwise at 0°C. After the addition was completed, the mixture was slowly warmed to room temperature and stirred for 5 hours. The reaction solution was added dropwise to a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, the organic phase was dried and concentrated, and purified by a wet column and silica gel column chromatography (PE / EA=20 / 1) to obtain 215 mg of the desired product (colorless oily liquid, 78% yield).

[0194] Step 2: Synthesis of (1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octane (1R,5S)-3-benzyl-8,8-difluoro-3-azabicyclo[3.2.1]octane (200 mg, 0.8 mmol) was dissolved in 5 mL of methanol, and PdOH / C (10%, 20 mg) and 1 mL of hydrochloric acid in methanol (4 M) were added. The mixture was then heated under 2 atm of H 2 The reaction mixture was stirred at room temperature under a gas atmosphere for 4 hours, filtered, and the filtrate was spin-dried to give 140 mg of crude product (84% yield).

[0195] Step 3: Synthesis of 4-(4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol The target product was synthesized in the same manner as in Example 2 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=600.3[M+H] + .

[0196] Example 6 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydro-5,8-methyl-bridged indolazin-8a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0197] [ka]

[0198] Step 1: Synthesis of 2-(tert-butyl) 3-methyl 2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate 2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (5000 mg, 20.7 mmol), potassium carbonate (5726 mg, 41.5 mmol) and 50 mL of DMF were added to a flask, and methyl iodide (3535 mg, 24.9 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 6 hours, and TLC showed the reaction was complete. The reaction was filtered, the filtrate was collected, extracted with 250 mL of water and ethyl acetate, the organic phase was back-extracted with saturated saline, the organic phase was dried and then spin-dried, and the product was purified by silica gel column chromatography (PE / EA=50 / 1-20 / 1) to obtain 5 g of the desired product (yield 94%).

[0199] Step 2: Synthesis of 2-(tert-butyl) 3-methyl 3-(3-bromopropyl)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate 2-(tert-butyl) 3-methyl 2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1000mg, 3.9mmol) and 10mL of THF were added to the flask, the reaction mixture was cooled to -70℃, LDA (2M, 2mL, 4.0mmol) was added dropwise at -70℃, and after the addition was completed, the mixture was stirred for 1 hour. 1,3-dibromopropane (1188mg, 5.9mmol) was added dropwise to the reaction system, and after the addition was completed, the reaction system was stirred for 10 minutes, and then the reaction system was returned to room temperature and reacted for 2 hours. The completion of the reaction was confirmed by TLC. The reaction system was poured into 50mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and then purified by silica gel column chromatography (PE / EA=20 / 1~5 / 1) to obtain 1.2g of the desired product (yield 82%).

[0200] Step 3: Synthesis of methyl 3-(3-bromopropyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate 2-(tert-butyl) 3-methyl 3-(3-bromopropyl)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1200 mg, 3.2 mmol) and hydrogen chloride in 1,4-dioxane (4 M, 12 mL) were added to the flask and the reaction mixture was stirred at room temperature for 2 hours. The reaction was complete as determined by TLC. The reaction was spun dry and the hydrochloride salt was used directly in the next reaction.

[0201] Step 4: Synthesis of methyl hexahydro-5,8-methyl-bridged indolazine-8a(1H)-carboxylate Methyl 3-(3-bromopropyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (product of step 3), potassium carbonate (1325 mg, 9.6 mmol) and 10 mL of acetonitrile were added to the flask, and the reaction mixture was stirred at room temperature for 4 hours. Completion of the reaction was confirmed by TLC. The reaction was filtered, and the filtrate was dried and spun dry, and then purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 611 mg of the desired product (total yield of the two steps of step 3 and step 4 is 98%).

[0202] Step 5: Synthesis of (hexahydro-5,8-methyl-bridged indolazin-8a(1H)-yl)methanol Hexahydro-5,8-methyl-bridged indolazine-8a(1H)-carboxylate methyl (611mg, 3.1mmol) was dissolved in 5mL of THF, the temperature of the reaction mixture was lowered to -40℃, and under nitrogen gas protection, lithium aluminum hydride (357mg, 9.4mmol) was added in several portions, and the mixture was stirred at -40℃ for 2 hours. The reaction system was diluted with 5mL of THF, and then 0.6mL of water was added and stirred for 5 minutes, 15% aqueous sodium hydroxide solution (0.6mL) was added and stirred for 10 minutes, then 1.8mL of water was added and stirred for 30 minutes, and then anhydrous sodium sulfate was added to dry the reaction system, the reaction system was filtered, and the filtrate was spin-dried and then purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 96mg of the desired product (yield 18%).

[0203] Step 6: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((hexahydro-5,8-methyl-bridged indolazin-8a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate At room temperature, NaH (60%, 40 mg, 1.0 mmol) was added to a solution of (hexahydro-5,8-methyl-bridged indolazin-8a(1H)-yl)methanol (84 mg, 0.50 mmol) in 2 mL of THF, and the resulting reaction solution was stirred at room temperature for 1 hour, after which (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate tert-butyl (214 mg, 0.50 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by Prep-TLC (DCM / MeOH=20 / 1) to give 70 mg of a yellow solid (yield 25%).

[0204] Step 7: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-((hexahydro-5,8-methyl-bridged indolazin-8a(1H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((hexahydro-5,8-methyl-bridged indolazine-8a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.13 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (40 mg, 0.13 mmol), potassium carbonate (40 mg, 0.29 mmol) and dioxane / water (2 mL / 0.2 mL) were added to a flask, and nitrogen gas was exchanged. Then, Pd(dppf)Cl 2 5mg was added. Under nitrogen gas protection, the reaction mixture was heated to 100℃ and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and then purified by Prep-TLC (DCM / MeOH=20 / 1) to give 35mg of a grey solid (39% yield).

[0205] Step 8: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydro-5,8-methyl-bridged indolazin-8a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol tert-Butyl (1R,5S)-3-(8-fluoro-2-((hexahydro-5,8-methyl-bridged indolazin-8a(1H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.05 mmol) was dissolved in 2 mL of ethyl acetate and stirred for 0.5 h after adding HCl / EA (4 m, 1 mL) at room temperature. The reaction was spun dry, 2 mL of aqueous sodium carbonate was added, extracted with ethyl acetate, the organic phase was dried and spun dry, and purified by Prep-TLC (DCM / MeOH=8 / 1) to give 16 mg of a grey solid (57% yield). LC / MS: m / z=567.3[M+H] + .

[0206] Example 7 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)isoquinolin-1-ol

[0207] [ka]

[0208] Step 1: Synthesis of 4-bromo-1-((4-methoxybenzyl)oxy)isoquinoline 4-Bromo-1-chloroisoquinoline (300 mg, 1.24 mmol), potassium tert-butoxide (279 mg, 2.48 mmol) and (4-methoxyphenyl)methanol (859 mg, 6.22 mmol) were added to the flask, and the reaction mixture was heated to 80° C. and stirred for 3 hours. The reaction was completed by TLC. The reaction was cooled to room temperature, poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by silica gel column chromatography (PE / EA=10 / 1) to obtain 400 mg of the desired product (yield 94%).

[0209] Step 2: Synthesis of 1-((4-methoxybenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)isoquinoline 4-Bromo-1-((4-methoxybenzyl)oxy)isoquinoline (400 mg, 1.17 mmol), bis(pinacolato)diboron (889 mg, 3.51 mmol), potassium acetate (343 mg, 3.51 mmol) and 5 mL of 1,4-dioxane were added to the flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (170 mg, 0.23 mmol) was added, and the reaction mixture was heated to 90° C. under nitrogen gas protection and stirred overnight. After cooling to room temperature, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried, and then purified by silica gel column chromatography (PE / EA=10 / 1) to obtain 290 mg of the desired product (yield 64%).

[0210] Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)isoquinolin-1-ol The target product was synthesized in the same manner as in Example 1 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=542.3[M+H] + .

[0211] Example 8 3-((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H))-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)isoquinolin-1-yl)oxy)propane-1,2-diol

[0212] [ka]

[0213] Step 1: Synthesis of 4-bromo-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)isoquinoline 4-Bromo-1-chloroisoquinoline (1000 mg, 4.15 mmol), potassium tert-butoxide (929 mg, 8.30 mmol) and acetone glycerol (2.74 g, 20.75 mmol) were added to the flask, and the reaction mixture was heated to 80° C. and stirred for 3 hours. The reaction was completed by TLC. The reaction was cooled to room temperature, poured into 50 mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and then purified by silica gel column chromatography (PE / EA=10 / 1) to obtain 700 mg of the desired product (yield 50%).

[0214] Step 2: Synthesis of 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)isoquinoline 4-Bromo-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)isoquinoline (200 mg, 0.59 mmol), bis(pinacolato)diboron (452 ​​mg, 1.78 mmol), potassium acetate (174 mg, 1.78 mmol) and 5 mL of 1,4-dioxane were added to a flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (87 mg, 0.12 mmol) was added. The reaction mixture was heated to 90° C. under nitrogen gas protection and stirred overnight. After cooling to room temperature, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by silica gel column chromatography (PE / EA=10 / 1) to obtain 180 mg of the desired product (yield 79%).

[0215] Step 3: Synthesis of 3-((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrozin-7a(5H))-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)isoquinolin-1-yl)oxy)propane-1,2-diol The target product was synthesized in the same manner as in Example 1 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=616.3[M+H] + .

[0216] Example 9 4-(8-Fluoro-4-(2-(hydroxymethyl)morpholine)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0217] [ka]

[0218] Step 1: Synthesis of (4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)methanol Morpholin-2-ylmethanol (59 mg, 0.50 mmol), DIPEA (155 mg, 1.20 mmol) and 5 mL of tetrahydrofuran were added to a flask, and a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (100 mg, 0.40 mmol) in 1.5 mL of tetrahydrofuran was added at −40° C., and the reaction mixture was stirred for 2 hours at −40° C. The reaction was poured into 15 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by Prep-TLC (DCM / MeOH=50 / 1) to give 80 mg of the desired product (60% yield).

[0219] Step 2: Synthesis of (4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ylmorpholin-2-yl)methanol At room temperature, NaH (60%, 40 mg, 1.0 mmol) was added to a solution of (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (71 mg, 0.50 mmol) in 2 mL of THF, and the resulting reaction solution was stirred at room temperature for 1 hour, after which (4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)methanol (80 mg, 0.24 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, and purified by Prep-TLC (DCM / MeOH=20 / 1) to obtain 63 mg of a yellow solid (60% yield).

[0220] Step 3: Synthesis of (4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)methanol (4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ylmorpholin-2-yl)methanol (44 mg, 0.10 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (31 mg, 0.10 mmol), potassium carbonate (28 mg, 0.20 mmol) and dioxane / water (2 mL / 0.2 mL) were added to a flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (7 mg, 0.01 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 6 h. After cooling to room temperature, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and purified by Prep-TLC (DCM / MeOH=20 / 1) to give 25 mg of a yellow solid (42% yield).

[0221] Step 4: Synthesis of 4-(8-fluoro-4-(2-(hydroxymethyl)morpholine)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)methanol (25 mg, 0.04 mmol) was dissolved in 2 mL of ethyl acetate, and HCl / EA (4 m, 1 mL) was added at room temperature and stirred for 0.5 hours. The reaction was spun dry, 2 mL of aqueous sodium carbonate was added, extracted with ethyl acetate, the organic phase was dried, spun dry, and purified by Prep-TLC (DCM / MeOH=8 / 1) to give 12 mg of a gray solid (52% yield). LC / MS: m / z=546.2[M+H] + .

[0222] Example 10 1-(8-Fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-4-ol

[0223] [ka]

[0224] Step 1: Synthesis of 6-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[2.5]octane Potassium tert-butoxide (13 mg, 0.12 mmol) was added to a DMSO 1 mL solution of trimethylsulfoxide iodide (22 mg, 0.10 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, 1-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (30 mg, 0.05 mmol, obtained by synthesis in the same manner as in Example 9) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction system was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, and purified by Prep-TLC (DCM / MeOH=20 / 1) to obtain 6 mg of the desired product (yield 20%).

[0225] Step 2: Synthesis of 1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-4-ol 6-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[2.5]octane (25 mg, 0.04 mmol) was dissolved in 1 mL of THF and 0.5 mL of water, and 0.2 mL of trifluoroacetic acid was added at room temperature. The reaction was stirred for 1 hour. The reaction was poured into 5 mL of aqueous sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and then spun dry, followed by purification by Prep-TLC (DCM / MeOH=8 / 1) to give 6 mg of a gray solid (25% yield). LC / MS: m / z=560.3[M+H] + .

[0226] Example 11 4-(Aminomethyl)-1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol

[0227] [ka]

[0228] Step 1: Synthesis of 4-(aminomethyl)-1-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol 6-(8-Fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[2.5]octane (25 mg, 0.04 mmol) was dissolved in NH 3 The reaction was stirred for 2 h at 40° C. The crude product was spin-dried and used in the next reaction.

[0229] Step 2: Synthesis of 4-(aminomethyl)-1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol The crude product from the previous step was dissolved in 2 mL of EA, and HCl / EA solution (4 m, 1 mL) was added at room temperature, and the reaction was stirred for 0.5 h. The spin-dried reaction was added with 2 mL of aqueous sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and spin-dried, and then purified by Prep-TLC (DCM / MeOH=8 / 1) to give 5 mg of a grey solid (21% yield for both steps). LC / MS: m / z=559.3[M+H] + .

[0230] Example 12 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2-(2-fluoroethyl)-2-azabicyclo[2.2).1]heptan-3-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0231] [ka]

[0232] Step 1: Synthesis of methyl 2-azabicyclo[2.2.1]heptane-3-carboxylate 2-(tert-Butyl) 3-methyl 2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1 g, 3.9 mmol) was added to 10 mL of 1.4-dioxane hydrogen chloride and the reaction mixture was stirred at room temperature for 2 hours. The reaction was complete as determined by TLC. The reaction was spun to dryness to give the hydrochloride salt of the product, which was used directly in the next reaction.

[0233] Step 2: Synthesis of methyl 2-(2-fluoroethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate 2-Azabicyclo[2.2.1]heptane-3-carboxylate methyl ester (product of step 2) was dissolved in 10 mL of acetonitrile, and potassium carbonate (1083 mg, 7.8 mmol) was added. After the addition was completed, the reaction mixture was stirred at 60° C. for 24 hours, filtered, and the filtrate was dried and then spin-dried. The product was purified by silica gel column chromatography (PE / EA=20 / 1) to obtain 407 mg of the desired product (total yield of two steps: 52%).

[0234] Step 3: Synthesis of (2-(2-fluoroethyl)-2-azabicyclo[2.2.1]heptan-3-yl)methanol 2-(2-fluoroethyl)-2-azabicyclo[2.2.1]heptane-3-methyl carboxylate (407 mg, 2.0 mmol) and 5 mL tetrahydrofuran were added to the flask, and the reaction mixture was stirred at -40°C under nitrogen gas protection, and lithium aluminum hydride (231 mg, 6.087 mmol) was added in several portions, followed by stirring for 2 hours. The completion of the reaction was confirmed by TLC. The temperature of the reaction system was returned to room temperature, and then a small amount of THF was added to dilute the mixture, and then 0.4 mL of water was added, and the mixture was stirred for 10 minutes, and then 15% aqueous sodium hydroxide solution (0.4 mL) was added, and then 10 minutes of stirring was added, and then 1.2 mL of water was added, and after stirring for 30 minutes, anhydrous sodium sulfate was added to dry the mixture, and then the mixture was filtered, and the filtrate was dried and then spin-dried, and then purified by silica gel column chromatography (PE / EA=5 / 1-2 / 1) to obtain 160 mg of the desired product (yield 46%).

[0235] Step 4: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2-(2-fluoroethyl)-2-azabicyclo[2.2).1]heptan-3-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The target product was synthesized in the same manner as in Example 6 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=573.3[M+H] + . 1 H NMR (400mHz, d 6-DMSO) δ 9.98 (1H, brs), 9.16 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.42-7.45 (1H, m), 7.22-7.29 (3H, m), 4.52-4.60 (1H, m), 4.43-4.46 (3H, m), 4.17-4.20 (1H, m), 3.93-3.98 (1H, m), 3.61 (1H, s), 3.58 (1H, s), 3.53 (2H, s), 3.25 (1H, s), 2.86-2.88 (1H, m), 2.78-2.82 (1H, m), 2.33-2.36 (1H, m), 2.26-2.27 (1H, m), 1.80-1.88 (1H, m), 1.55-1.70 (6H, m), 1.20-1.33 (4H, m).

[0236] Example 13 (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)dimethylphosphine oxide

[0237] [ka]

[0238] Step 1: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate tert-butyl (533 mg, 1.0 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (314 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol) and dioxane / water (8 mL / 0.8 mL) were added to a flask, and nitrogen gas was exchanged. Then, Pd(dppf)Cl 2 (73 mg, 0.1 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 6 h. The reaction mixture was cooled to room temperature, poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried, spun dry, and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give 220 mg of a grey solid (32% yield).

[0239] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (220 mg, 0.32 mmol) was dissolved in 5 mL of ethyl acetate, and HCl / EA (4 m, 2 mL) was added at room temperature and stirred for 0.5 hours. The reaction system was spin-dried and the resulting crude product was used as it was in the next reaction.

[0240] Step 3: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate The crude product obtained in the previous step and 0.5 mL of DIPEA were dissolved in 5 mL of DCM and mixed at room temperature to obtain (Boc) 2 O (109 mg, 0.5 mmol) was added and stirred for 2 h. The reaction was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and the crude product was used directly in the next reaction.

[0241] Step 4: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate The crude product from the previous step and 0.5 mL of DIPEA were dissolved in 5 mL of DCM, trifluoromethanesulfonic anhydride (141 mg, 0.5 mmol) was added at 0° C., and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried, spun dry, and purified by Prep-TLC (DCM / MeOH=20 / 1) to give 85 mg of a yellow solid (34% yield for the three steps).

[0242] Step 5: Synthesis of tert-butyl (1R,5S)-3-(7-(3-(dimethylphosphoryl)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (77 mg, 0.1 mmol), dimethylphosphine oxide (78 mg, 1 mmol), triethylamine (101 mg, 1 mmol), Xantphos (12 mg, 0.02 mmol) and 3 mL of dioxane were added to a flask, and after nitrogen gas exchange, Pd 2 (dba) 3 (9 mg, 0.01 mmol) was added, and the reaction mixture was heated to 110° C. under nitrogen gas protection and stirred for 6 h. The reaction mixture was cooled to room temperature, poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry, and then purified by Prep-TLC (DCM / MeOH=20 / 1) to give 17 mg of the desired product (yield 24%).

[0243] Step 6: Synthesis of (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)dimethylphosphine oxide (1R,5S)-3-(7-(3-(dimethylphosphoryl)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (17 mg, 0.024 mmol) was dissolved in 2 mL of ethyl acetate and stirred for 0.5 h after adding HCl / EA (4 m, 1 mL) at room temperature. The reaction was spun dry, 2 mL of aqueous sodium carbonate was added, extracted with ethyl acetate, the organic phase was dried and spun dry, and purified by Prep-TLC (DCM / MeOH=8 / 1) to give 8 mg of a grey solid (53% yield). LC / MS: m / z=601.3[M+H]+ .

[0244] Example 14 (1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

[0245] [ka]

[0246] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (54 mg, 0.1 mmol) and DIPEA (52 mg, 0.4 mmol) were dissolved in 2 mL of tetrahydrofuran, and CDI (16 mg, 0.1 mmol) was added at room temperature. The reaction system was stirred at room temperature for 1 hour, and then 2,2,2-trifluoroethylamine (50 mg, 0.5 mmol) was added and the mixture was stirred at 70° C. for 6 hours. The reaction was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun to dryness, then purified by TLC (DCM / MeOH=10 / 1) to give 14 mg of the desired product as an off-white solid (yield 21%).

[0247] LC / MS: m / z=666.3 [M+H] + . 1 H NMR (400mHz, d 6-DMSO) δ 9.98 (1H, s), 9.17 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.42-7.44 (2H, m), 7.21-7.29 (3H, m), 4.45-4.55 (4H, m), 4.08 (2H, s), 3.87-3.95 (4H, m), 3.63-3.66 (2H, m), 2.90-2.95 (2H, m), 1.75-1.90 (10H, m), 1.52-1.50 (2H, m).

[0248] Example 15 4-(8-Fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0249] [ka]

[0250] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (54 mg, 0.1 mmol), potassium carbonate (28 mg, 0.2 mmol) and 2 mL of acetonitrile were added to a flask, and bromotrifluoroethane (16 mg, 0.1 mmol) was added at room temperature. The reaction system was stirred overnight at room temperature, then filtered under reduced pressure. The filtrate was spin-dried and purified by TLC (DCM / MeOH=8 / 1) to give 5 mg of the desired product (off-white solid, 8% yield).

[0251] LC / MS: m / z=623.3[M+H] + . 1 H NMR (400mHz, d 6-DMSO) δ 9.99 (1H, s), 9.18 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.42-7.46 (1H, m), 7.21-7.29 (3H, m), 4.46-4.50 (2H, m), 4.15-4.17 (2H, m), 3.69-3.72 (2H, m), 3.46 (2H, s), 3.16-3.23 (2H, m), 2.96-3.11 (2H, m), 2.55-2.70 (2H, m), 1.78-2.00 (8H, m), 1.59-1.70 (4H, m).

[0252] Example 16 3-(8-Fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-one

[0253] [ka]

[0254] Step 1: Synthesis of tert-butyl bis(2-oxyethyl)carbamate PDC (27.5 g, 73.2 mmol) was added to a solution of tert-butyl bis(2-hydroxyethyl)carbamate (5.0 g, 24.4 mmol) in 100 mL of THF. The reaction mixture was stirred at room temperature for 6 hours. The reaction was poured into 1000 mL of water and extracted with methyl tert-butyl ether. The organic phase was back-extracted three times with saturated brine, dried, spun dry, and the crude product was used directly in the next reaction.

[0255] Step 2: Synthesis of tert-butyl 9-(4-methoxybenzyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate The product obtained in the previous step was dispersed in 50 mL of water, and 3-oxoglutaric acid (3.6 g, 24.8 mmol) and sodium acetate (2.1 g, 25.3 mmol) were added at room temperature, and the mixture was stirred for 0.5 hours. A solution of 4-methoxybenzylamine (3.4 g, 24.8 mmol) in dilute hydrochloric acid (3 m, 8 mL) was slowly added dropwise to the reaction system, and after the addition was completed, the reaction solution was stirred overnight at room temperature. The mixture was diluted with water, adjusted to alkaline with sodium carbonate, extracted with dichloromethane, and the organic phase was dried and spin-dried. The product was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain 3.0 g of the desired product (17% yield for both steps).

[0256] Step 3: Synthesis of tert-butyl 7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate To a 5 mL solution of tert-butyl 9-(4-methoxybenzyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate (300 mg, 0.83 mmol) in methanol, 50 mg of 20% palladium hydroxide on carbon was added. The reaction solution was stirred at 45° C. for 3 hours under a hydrogen gas environment. The reaction solution was filtered under reduced pressure, and the filtrate was spin-dried. The crude product was used as is in the next reaction.

[0257] Step 4: Synthesis of 9-benzyl 3-(tert-butyl) 7-oxo-3,9-diazabicyclo[3.3.1]nonane-3,9-dicarboxylate The crude product from the previous step and 0.5 mL of DIPEA were dissolved in 5 mL of DCM, and Cbz-Cl (170 mg, 0.83 mmol) was added at 0° C. and stirred overnight at room temperature. The reaction mixture was poured into 20 mL of water, extracted with dichloromethane, and the organic phase was dried and spun to dryness, and then purified by Prep-TLC (PE / EA=2 / 1) to give 200 mg of colorless oily product (64% yield for both steps).

[0258] Step 5: Synthesis of benzyl 7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate A solution of 9-benzyl 3-(tert-butyl) 7-oxo-3,9-diazabicyclo[3.3.1]nonane-3,9-dicarboxylate (200 mg, 0.53 mmol) in 2 mL of ethyl acetate was added to a solution of 2 mL of hydrogen chloride in ethyl acetate (4 M) and stirred at room temperature for 1 hour. The reaction system was spun dry and the crude product was used as is in the next reaction.

[0259] Step 6: Synthesis of benzyl 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate The target product was synthesized in the same manner as in Example 9 using the product obtained in the previous step and the corresponding intermediate as raw materials.

[0260] Step 7: Synthesis of 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-one 5 mg of 10% palladium on carbon was added to 5 mL of a methanol solution of 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (10 mg). The reaction solution was stirred for 4 hours at room temperature under a hydrogen gas environment. The mixture was filtered under reduced pressure, the filtrate was spin-dried, and the crude product was used as is in the next reaction.

[0261] Step 8: Synthesis of 3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-one The crude product from the previous step was dissolved in 2 mL of ethyl acetate, added with HCl / EA (4 m, 1 mL) at room temperature, and stirred for 0.5 h. The reaction was spun down, 2 mL of aqueous sodium carbonate was added, extracted with ethyl acetate, the organic phase was dried, spun down, and purified by Prep-TLC (DCM / MeOH=8 / 1) to give 3 mg of a grey solid (39% yield for both steps). LC / MS: m / z=569.3[M+H] + .

[0262] Example 17 3-(8-Fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-ol

[0263] [ka]

[0264] Step 1: Synthesis of benzyl 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-hydroxy-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate Sodium borohydride (1 mg) was added to 1 mL of 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate benzyl (5 mg, 0.0067 mmol) in THF solution. The reaction mixture was stirred at room temperature for 0.5 hours, then poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, then purified by Prep-TLC (DCM / MeOH=30 / 1) to obtain 4 mg of a grey solid (yield 80%).

[0265] Step 2: Synthesis of 3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-ol The target product was synthesized in the same manner as in Example 16 using the product obtained in the previous step as the raw material. LC / MS: m / z=571.3[M+H] + .

[0266] Example 18 8-(8-Fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one

[0267] [ka]

[0268] CDI (2 mg, 0.012 mmol) was added to 1 mL of a solution of 4-(aminomethyl)-1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol (5 mg, 0.009 mmol) in THF. The reaction mixture was stirred at room temperature for 0.5 hours, then heated to 60° C. and stirred for 2 hours. The reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, then purified by Prep-TLC (DCM / MeOH=20 / 1) to give 2 mg of a grey solid (38% yield). LC / MS: m / z=585.3[M+H] + .

[0269] Example 19 (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid

[0270] [ka]

[0271] Step 1: Synthesis of (4-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-)pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid tert-Butyl (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg, 0.13mmol), potassium acetate (38mg, 0.39mmol), bis(pinacolato)diboron (66mg, 0.26mmol) in 5mL of 1,4-dioxane solution was added with 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20mg, 0.027mmol). The reaction mixture was stirred for 2 hours under nitrogen gas protection at 90°C. The reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spun to dryness, followed by purification by column chromatography (DCM / MeOH=20 / 1) to give 6 mg of a yellow solid (yield 38%).

[0272] Step 2: Synthesis of (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid (4-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-)pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid (6 mg) was dissolved in 2 mL of ethyl acetate, and HCl / EA (4 m, 0.5 mL) was added and stirred for 1 h. The reaction system was poured into 10 mL of water, the pH value was adjusted to weakly alkaline with sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried and then spin-dried, and then purified by Prep-TLC (DCM / MeOH=5 / 1) to give 1 mg of a light yellow solid (22% yield for two steps). LC / MS: m / z=569.3[M+H] + .

[0273] Example 20 4-(8-Fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0274] [ka]

[0275] Step 1: Synthesis of tert-butyl 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (250 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol) and 10 mL of dichloromethane were added to a flask, and tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (216 mg, 1.0 mmol) was added at -40° C. After stirring for 1 hour at -40° C., the mixture was poured into 50 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried. The mixture was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain 234 mg of a yellow solid (yield 54%).

[0276] Step 2: Synthesis of tert-butyl 4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (Tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (85 mg, 0.60 mmol) and 2 mL of tetrahydrofuran were added to the flask, and NaH (60%, 28 mg, 0.70 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (216 mg, 0.50 mmol) was added, and the reaction was then stirred at room temperature for 2 hours. The reaction was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and purified by Prep-TLC (DCM / MeOH=20 / 1) to give 170 mg of a grey solid (63% yield).

[0277] Step 3: Synthesis of tert-butyl 4-(8-fluoro-7-(3-(methoxymethyl)naphthalen-1yl)-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate 4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (107 mg, 0.20 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (62 mg, 0.20 mmol), potassium carbonate (55 mg, 0.40 mmol) and dioxane / water (2 mL / 0.2 mL) were added to a flask, and nitrogen gas was exchanged. Then, Pd(dppf)Cl 2 (7 mg, 0.01 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 6 h. After cooling to room temperature, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by Prep-TLC (DCM / MeOH=20 / 1) to give 42 mg of a yellow solid (30% yield).

[0278] Step 4: Synthesis of 4-(8-fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 4-(8-fluoro-7-(3-(methoxymethyl)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (40 mg, 0.058 mmol) was dissolved in 2 mL of ethyl acetate, HCl / EA (4 m, 0.5 mL) was added, and the mixture was stirred for 10 min. The reaction was poured into 10 mL of water, the pH value was adjusted to slightly alkaline with sodium bicarbonate, extracted with ethyl acetate, the organic phase was dried, spin-dried, and purified by Prep-TLC (DCM / MeOH=5 / 1) to give 19 mg of a grey solid (59% yield). LC / MS: m / z=545.3[M+H] + .

[0279] Example 21 1-(8-Fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-hydroxypiperidine-4-carboxamide

[0280] [ka]

[0281] Trimethylsilyl cyanide (15 mg, 0.15 mmol) was added to a solution of 1-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (30 mg, 0.05 mmol) in 5 mL of DCM. The reaction mixture was stirred at room temperature under nitrogen gas protection for 3 hours. Then, HCl / EA solution (1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness at low temperature, and then 10 mL of water was added, the pH was adjusted to alkaline with sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was dried and then spin-dried, and the mixture was purified by pre-TLC (DCM / MeOH=12 / 1) to obtain 3 mg of a yellow solid (yield 10%).

[0282] LC / MS: m / z=573.3 [M+H] + . 1 H NMR (400mHz, CDCl 3) δ 9.00 (s, 1H), 7.61 (t, J = 7.8 Hz, 2H), 7.38-7.29 (m, 2H), 7.23-7.18 (m, 2H), 4.58-4.45 (m, 3H), 4.30 (dd, J = 3.5, 10.5 Hz, 1H), 4.08 (t, J = 10.1 Hz, 1H), 3.61 (brs, 4H), 3.36 (s, 1H), 2.94 (t, J = 5.0 Hz, 1H), 2.89-2.86 (m, 1H), 2.48-2.44 (m, 2H), 1.87-1.80 (m, 2H), 1.72-1.59 (m, 5H), 1.39-1.29 (m, 3H), 0.90-0.83 (m, 1H).

[0283] Example 22 4-(4-(3-amino-1-oxa-8-azaspiro[4.5]dec-8-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0284] [ka]

[0285] Step 1: Synthesis of tert-butyl 3-(((benzyloxy)carbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate Benzyl chloroformate (510 mg, 3.0 mmol) was added to a solution of tert-butyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (512 mg, 2.0 mmol), DIPEA (774 mg, 6.0 mmol) in 10 mL of THF in an ice bath. After the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 50 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun to dryness to give 700 mg of an off-white solid (90% yield).

[0286] Step 2: Synthesis of benzyl (1-oxa-8-azaspiro[4.5]dec-3-yl)carbamate 10 mL of HCl / EA solution was added to a one-neck flask containing tert-butyl 3-(((benzyloxy)carbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (700 mg, 1.79 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was spin-dried to give 590 mg of a white solid as a crude product (100% yield).

[0287] Step 3: Synthesis of 4-(4-(3-amino-1-oxa-8-azaspiro[4.5]dec-8-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The target product was synthesized in the same manner as in Example 16 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=585.3[M+H] + .

[0288] Example 23 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-phenoxyphenol

[0289] [ka]

[0290] Step 1: Synthesis of 3-bromo-4-phenoxybenzaldehyde 10 mL of an acetonitrile mixture of 3-bromo-4-fluorobenzaldehyde (203 mg, 1.0 mmol), phenol (113 mg, 1.2 mmol), and potassium carbonate (414 mg, 3.0 mmol) was stirred for 2 hours at 50° C. After completion of the reaction, the reaction solution was spin-dried and then purified by column chromatography (PE / EA=20 / 1) to obtain 210 mg of a light yellow solid (yield 76%).

[0291] Step 2: Synthesis of 3-bromo-4-phenoxyphenol Metachloroperbenzoic acid (262 mg, 1.52 mmol) was added to a solution of 3-bromo-4-phenoxybenzaldehyde (210 mg, 0.76 mmol) in 80 mL DCM, and the reaction mixture was stirred for 5 hours under nitrogen gas protection at room temperature. The reaction mixture was added with 30 mL water, extracted three times with DCM, and the organic phase was dried and concentrated to dryness, and purified by pre-TLC to give 70 mg of an off-white solid (35% yield).

[0292] Step 3: Synthesis of 4-phenoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.02 mmol) was added to a solution of 3-bromo-4-phenoxyphenol (70 mg, 0.26 mmol), potassium acetate (76 mg, 0.78 mmol), and bis(pinacolato)diboron (132 mg, 0.52 mmol) in 3 mL of 1,4-dioxane. The reaction mixture was stirred at 90° C. under nitrogen gas protection for 2 hours. The reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, followed by pre-TLC (PE / EA=5 / 1) purification to obtain 35 mg of a light yellow solid (43% yield).

[0293] Step 4: Synthesis of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-phenoxyphenol The target product was synthesized in the same manner as in Example 1 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=583.3[M+H] + .

[0294] Example 24 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-[1,1'-biphenyl]-4-ol

[0295] [ka]

[0296] Step 1: Synthesis of 2-bromo-4-methoxy-1,1'-biphenyl [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (125 mg, 0.17 mmol) was added to 10 mL of 1,4-dioxane / water solution of 2-bromo-1-iodo-4-methoxybenzene (626 mg, 2.0 mmol), phenylboronic acid (366 mg, 3.0 mmol), and potassium carbonate (828 mg, 6.0 mmol). After addition, the reaction mixture was heated to 80° C. under nitrogen gas protection and stirred for 2 hours. The reaction mixture was poured into 50 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, then purified by column chromatography (PE / EA=15 / 1) to give 350 mg of off-white solid (67% yield).

[0297] Step 2: Synthesis of 2-bromo-[1,1'-biphenyl]-4-ol 2-Bromo-4-methoxy-1,1'-biphenyl (350 mg, 1.33 mmol) was dissolved in 5 mL of HBr / acetic acid solution, and the reaction mixture was stirred overnight at 100° C. The reaction mixture was poured into 50 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, then purified by column chromatography (PE / EA=4 / 1) to give 200 mg of an off-white solid (60% yield).

[0298] Step 3: Synthesis of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-ol 2-Bromo-[1,1'-biphenyl]-4-ol (50 mg, 0.20 mmol), potassium acetate (49 mg, 0.50 mmol), bis(pinacolato)diboron (51 mg, 0.20 mmol) were added to 3 mL of 1,4-dioxane solution of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 0.01 mmol). The reaction mixture was stirred for 2 hours under nitrogen gas protection at 90°C. The reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by Prep-TLC (PE / EA=5 / 1) to obtain 40 mg of a light yellow solid (yield 68%).

[0299] Step 4: Synthesis of 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-[1,1'-biphenyl]-4-ol The target product was synthesized in the same manner as in Example 1 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=567.3[M+H] + .

[0300] Example 25 4-(4-(3,3-difluorooctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0301] [ka]

[0302] Step 1: Synthesis of 1-(tert-butyl) 3-ethyl 4-(benzylamino)-5,6-dihydropyridine-1,3(2H)-dicarboxylate 1-(tert-Butyl) 3-ethyl 4-oxopiperidine-1,3-dicarboxylate (1 g, 3.64 mmol) was dissolved in 10 mL of toluene and benzylamine (390 mg, 3.64 mmol) was added. The reaction was heated to reflux overnight. The reaction was spun to dryness and the crude product was used directly in the next reaction.

[0303] Step 2: Synthesis of 1-(tert-butyl) 3-ethyl 4-(benzylamino)benzylamino-1,3-dicarboxylate The crude product from the previous step was dissolved in 10 mL of methanol, Pd / C (10%, 20 mg) was added, and the reaction mixture was stirred under hydrogen gas at room temperature for 2 h. It was filtered under reduced pressure, and the filtrate was spun to dryness, and the crude product was used directly in the next reaction.

[0304] Step 3: Synthesis of 1-(tert-butyl) 3-ethyl 4-(benzyl(2-ethoxy-2-oxoethyl)amino)benzylamino-1,3-dicarboxylate The crude product from the previous step was dissolved in 5 mL of acetonitrile and potassium carbonate (138 mg, 1 mmol) and ethyl acetate (84 mg, 0.5 mmol) were added. After the addition was complete, the reaction was stirred overnight at room temperature. The reaction was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and spun to dryness, and then purified by column chromatography (PE / EA=1 / 1) to give 150 mg of a yellow solid (9% yield for the three steps).

[0305] Step 4: Synthesis of 5-(tert-butyl)3a-ethyl 1-benzyl-3-oxohexahydro-5H-pyrrolo[3,2-c]pyridine-3a,5(4H)-dicarboxylate 1-(tert-butyl) 3-ethyl 4-(benzyl(2-ethoxy-2-oxoethyl)amino)benzylamino-1,3-dicarboxylate (150 mg, 0.33 mmol) was dissolved in 5 mL of toluene, potassium tert-butoxide (98 mg, 1.00 mmol) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried. The mixture was then purified by Prep-TLC (PE / EA=2 / 1) to obtain 65 mg of a yellow solid (yield 48%).

[0306] Step 5: Synthesis of tert-butyl 1-benzyl-3-oxooctahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate 5-(tert-butyl)3a-ethyl 1-benzyl-3-oxohexahydro-5H-pyrrolo[3,2-c]pyridine-3a,5(4H)-dicarboxylate (65 mg, 0.16 mmol) was dissolved in 5 mL of dioxane, 1 mL of 5 M aqueous sodium hydroxide was added, and the reaction was stirred overnight under reflux. The reaction was poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun to give a crude product which was used as is in the next reaction.

[0307] Step 6: Synthesis of tert-butyl 1-benzyl-3,3-difluorooctahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate The crude product from the previous step was dissolved in 3 mL of dichloromethane and DAST (40 mg, 0.24 mmol) was added at -78°C. After the addition was complete, the reaction solution was stirred at room temperature for 1 h. The reaction was poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun to dryness, and then purified by Prep-TLC (PE / EA=1 / 1) to give 35 mg of a yellow solid (61% yield for the two steps).

[0308] Step 7: Synthesis of 1-benzyl-3,3-difluorooctahydro-1H-pyrrolo[3,2-c]pyridine 1-Benzyl-3,3-difluorooctahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate tert-butyl (35 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and 0.2 mL of trifluoroacetic acid was added. The reaction solution was stirred at room temperature for 1 hour. The reaction system was spin-dried to obtain a crude product, which was used as is in the next reaction.

[0309] Step 8: Synthesis of 4-(4-(3,3-difluorooctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The target product was synthesized in the same manner as in Example 16 using the product obtained in the above step and the corresponding intermediate as starting materials. LC / MS: m / z=591.3[M+H] + .

[0310] Example 26 4-(4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((3-fluoropyrrolidin-1)-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0311] [ka]

[0312] Step 1: Synthesis of 2,7-dichloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidine 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (250 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol) and 10 mL dichloromethane were added to a flask, and 8,8-difluoro-3-azabicyclo[3.2.1]octane hydrochloride (184 mg, 1.0 mmol) was added at -40° C. After stirring for 1 hour at -40° C., the mixture was poured into 50 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, followed by purification by silica gel column chromatography (PE / EA=1 / 1) to obtain 210 mg of a yellow solid (yield 58%).

[0313] Step 2: Synthesis of (1-(((7-chloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol Sodium hydride (100 mg, 2.5 mmol) was added to 5 mL of a THF solution of cyclopropane-1,1-diyldimethanol (102 mg, 1.0 mmol) under nitrogen gas protection in an ice bath. After the addition, the reaction mixture was stirred for 1 hour under nitrogen gas protection at room temperature, and then 2 mL of a THF solution of 2,7-dichloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidine (181 mg, 0.5 mmol) was added to the reaction system under an ice bath, and the reaction system was stirred for 2 hours at room temperature. The reaction solution was poured into 50 mL of an aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, and then purified by column chromatography (PE / EA=3 / 1) to obtain 100 mg of an off-white solid (47% yield).

[0314] Step 3: Synthesis of (1-(((7-chloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanesulfonate Methanesulfonyl chloride (53 mg, 0.46 mmol) was added to (1-(((7-chloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (100 mg, 0.23 mmol), triethylamine (100 mg, 0.92 mmol) in 5 mL of DCM, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 30 mL of water, extracted with DCM, and the organic phase was dried and then spun to dryness to give 90 mg of a pale yellow oily product (77% yield).

[0315] Step 4: Synthesis of 7-chloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine A mixture of (1-(((7-chloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanesulfonate (90 mg, 0.18 mmol), potassium carbonate (99 mg, 0.72 mmol), and 3-fluoropyrrole hydrochloride (45 mg, 0.36 mmol) in 4 mL of acetonitrile was heated to 70° C. and stirred for 5 hours. The reaction was poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun to dryness before being purified by pre-TLC (DCM / MeOH=30 / 1) to give 20 mg of an off-white solid (22% yield).

[0316] Step 5: Synthesis of 4-(4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((3-fluoropyrrolidin-1)-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The target product was synthesized in the same manner as in Example 1 using the product obtained in the previous step as the raw material.

[0317] LC / MS: m / z=608.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 8.94 (s, 1H), 7.66-7.61 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.24-7.17 (m, 3H), 4.61 (d, J = 13.0 Hz, 2H), 4.40 (dd, J = 10.9, 47.7 Hz, 2H), 3.74 (d, J = 13.1 Hz, 2H), 2.88-2.82 (m, 2H), 2.68 (d, J = 11.4 Hz, 1H), 2.554-2.48 (m, 2H), 2.39-2.32 (m, 2H), 2.08-1.97 (m, 2H), 1.89-1.84 (m, 2H), 1.68-1.58 (m, 2H), 1.16-1.01 (m, 2H), 0.69 (s, 2H), 0.51 (s, 2H).

[0318] Example 27 4-(4-((1R,5S,8s)-8-(3,3-difluoroazetidin-1-yl)-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0319] [ka]

[0320] Step 1: Synthesis of 4-((1R,5S,8s)-8-(3,3-difluoroazetidin-1-yl)-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine To a 2 mL solution of (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-one (30 mg, 0.05 mmol, synthesized in a similar manner to Example 9) in THF, 3,3-difluoroazetidine (9 mg, 0.10 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours, and then 10 mg of sodium triacetoxyborohydride was added to the reaction solution, followed by stirring at room temperature for 2 hours. 10 mL of water was added, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, and purified by pre-TLC (DCM / MeOH=10 / 1) to obtain 22 mg of a yellow solid (65% yield).

[0321] Step 2: Synthesis of 4-(4-((1R,5S,8s)-8-(3,3-difluoroazetidin-1-yl)-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 4-((1R,5S,8s)-8-(3,3-difluoroazetidin-1-yl)-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (20 mg, 0.030 mmol) was dissolved in 2 mL of ethyl acetate, HCl / EA (4 m, 0.5 mL) was added, and the mixture was stirred for 10 min. The reaction was poured into 10 mL of water, the pH value was adjusted to weakly alkaline with sodium bicarbonate, extracted with ethyl acetate, the organic phase was dried and then spun dry, and purified by Prep-TLC (DCM / MeOH=10 / 1) to give 8 mg of a grey solid (42% yield). LC / MS: m / z=631.3[M+H] + .

[0322] Example 28 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)phenanthren-2-ol

[0323] [ka]

[0324] Step 1: Synthesis of ((2'-bromo-4'-methoxy-[1,1'-diphenyl]-2-yl)ethynyl)trimethylsilane 2-Bromo-1-iodoanisole (311 mg, 1.0 mmol), sodium carbonate (216 mg, 2.0 mmol), ((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethynyl)trimethylsilane (300 mg, 1.0 mmol) in 5 mL dioxane / water (10 / 1) was added with 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol). The reaction mixture was stirred for 2 hours under nitrogen gas protection at 90° C. The reaction mixture was poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by Prep-TLC (PE / EA=100 / 1) to obtain 280 mg of a white solid (78% yield).

[0325] Step 2: Synthesis of 2-bromo-2'-ethynyl-4-methoxy-1,1'-biphenyl ((2'-Bromo-4'-methoxy-[1,1'-diphenyl]-2-yl)ethynyl)trimethylsilane (280 mg, 0.78 mmol) was dissolved in 5 mL of methanol, and 1 g of potassium carbonate was added. The reaction mixture was stirred at room temperature for 2 hours. After filtration and spin drying of the filtrate, 230 mg of a yellow solid was obtained (yield 100%).

[0326] Step 3: Synthesis of 4-bromo-2-methoxyphenanthrene 2-Bromo-2'-ethynyl-4-methoxy-1,1'-biphenyl (230 mg, 0.80 mmol) was dissolved in 5 mL of 1,2-dichloroethane, and 20 mg of platinum dichloride was added. The reaction mixture was stirred overnight at 90°C. The reaction mixture was spin-dried and then purified by Prep-TLC (PE / EA=100 / 1) to obtain 180 mg of a white solid (yield 78%).

[0327] Step 4: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)phenanthren-2-ol The target product was synthesized in the same manner as in Example 1 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=609.3[M+H] + .

[0328] Example 29 (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)(methyl)phosphite

[0329] [ka]

[0330] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-(3-(ethoxy(methyl)phosphite)naphthalen-1-yl) 8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A solution of tert-butyl (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.039 mmol), methyl diethyl phosphite (14 mg, 0.1 mmol), triethylamine (20 mg, 0.2 mmol) and 5 mg of Xantphos (dba) in 3 mL of dioxane. 3 5 mg was added. The reaction mixture was stirred for 3 hours under nitrogen gas protection at 100° C. The reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried, spin-dried, and purified by Prep-TLC (DCM / MeOH=20 / 1) to obtain 10 mg of a yellow solid (yield 36%).

[0331] Step 2: Synthesis of (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)(methyl)phosphite tert-Butyl (1R,5S)-3-(7-(3-(ethoxy(methyl)phosphite)naphthalen-1-yl) 8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol) was dissolved in 2 mL of dioxane, 0.5 mL of 1 M aqueous sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. 1 mL of 4 M HCl dioxane solution was added. The mixture was then stirred for 0.5 hours. The reaction mixture was poured into 10 mL of water, adjusted to a weak alkali with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, followed by purification by Prep-TLC (DCM / MeOH=10 / 1) to obtain 1 mg of a gray solid (12% yield). LC / MS: m / z=603.3[M+H] + .

[0332] Example 30 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

[0333] [ka]

[0334] Step 1: Synthesis of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid 2-Amino-4-bromo-3-fluorobenzoic acid (2.34 g, 10.0 mmol), Ag 2 SO 4 (3.08g, 10.0mmol) and 30mL anhydrous ethanol were added to the flask, and an ethanol solution of iodine (2.53g, 10.0mmol) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 4 hours. After filtration and concentration of the filtrate, it was extracted with water and ethyl acetate, and the organic phase was dried and spin-dried, and then purified by chromatography column (PE / EA=1 / 1) to obtain 1.96g of the desired product (yield 54%).

[0335] Step 2: Synthesis of 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol 2-Amino-4-bromo-3-fluoro-5-iodobenzoic acid (1.9 g, 5.28 mmol) and urea (3.5 g, 50.00 mmol) were added to the flask, and the reaction system was heated to 170° C. and then reacted for 4 hours with stirring. The reaction system was cooled to room temperature, extracted three times with water and ethyl acetate, and the organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then purified by chromatography (PE / EA=5 / 1) to obtain 1.2 g of the desired product (yield 60%).

[0336] Step 3: Synthesis of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline 7-Bromo-8-fluoro-6-iodoquinazoline-2,4-diol (1.2 g, 3.12 mmol), phosphoryl chloride (2.3 g, 15.00 mmol) were added to the flask, and the reaction was heated to 90° C. and stirred for 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step.

[0337] Step 4: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (crude product from previous step), DIEA (1.29g, 10.00mmol), (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (678mg, 3.20mmol) and 20mL absolute ethanol were added to a flask, and the reaction system was stirred at room temperature for 4 hours. Extracted three times with water and ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA=4 / 1) to obtain 410mg of the desired product (22% yield for two steps).

[0338] Step 5: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-6-iodoquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (120mg, 0.20mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (48mg, 0.30mmol), cesium carbonate (130mg, 0.40mmol) and 1,4-diazabicyclo[2.2.2]octane (22mg, 0.20mmol) were added to the flask, and anhydrous THF (1mL) and DMF (1mL) were added under nitrogen gas protection, and nitrogen exchange was performed again, and the reaction was carried out at 60 ° C. for 4 hours with stirring. The reaction was quenched by adding water, and then extracted with ethyl acetate. The organic phase was washed with saturated saline, dried, filtered and concentrated under reduced pressure. The crude product was separated and purified by Prep-TLC (PE / EA=1 / 1) to obtain 85 mg of a yellow solid (yield 59%).

[0339] Step 6: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-6-((trimethylsilyl)ethynyl)quinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-6-iodoquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (85 mg, 0.12 mmol), trimethylsilylacetylene (15 mg, 0.15 mmol), triethylamine (30 mg, 0.30 mmol), 5 mg of cuprous iodide, and 2 mL of DMF were added to a flask, and after nitrogen gas exchange, Pd(PPh 3 )Cl 2 5mg was added. The reaction system was heated to 80°C under nitrogen gas protection and reacted for 3 hours with stirring. The reaction system was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Prep-TLC (DCM / MeOH=20 / 1) to obtain 28mg of the desired product (yield 35%).

[0340] Step 7: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol The target product was synthesized in the same manner as in Example 2 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=618.3[M+H] + .

[0341] Example 31 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((5-(3-fluoropropyl)-2-oxa-5-azabicyclo[2.2.1]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0342] [ka]

[0343] Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)serine methyl ester (tert-Butoxycarbonyl)serine methyl ester (3.0 g, 13.7 mmol), imidazole (2.8 g, 0.41 mmol) and 30 mL of dichloromethane were added to a flask, and TBDPSCl (3.7 g, 13.7 mmol) was added, followed by reaction at room temperature for 3 hours with stirring. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA=10 / 1) to obtain 6.3 g of the desired product (yield 100%).

[0344] Step 2: Synthesis of tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-3-oxopropan-2-yl)carbamate N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)serine methyl ester (6.3 g, 13.7 mmol) was dissolved in 100 mL of toluene, and DIBALH (1 M, 14 mL, 14 mmol) was added dropwise at -78°C. The mixture was then stirred for 1 hour at -78°C. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.

[0345] Step 3: Synthesis of tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-3-hydroxyhex-5-en-2-yl)carbamate The crude product obtained in the previous step was dissolved in 100 mL of tetrahydrofuran, and allylmagnesium bromide (1M, 14 mL, 14 mmol) was added dropwise at -78°C. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA=5 / 1) to obtain 2.6 g of the desired product (40% yield for both steps).

[0346] Step 4: Synthesis of tert-butyl 2-((((tert-butyldiphenylsilyl)oxy)methyl)-3-hydroxy-5-(iodomethyl)pyrrolidine-1-carboxylate tert-Butyl (1-((tert-butyldiphenylsilyl)oxy)-3-hydroxyhex-5-en-2-yl)carbamate (1.5 g, 3.2 mmol), 10 mL of 1 M aqueous sodium bicarbonate solution, and 10 mL of ethyl acetate were added to a flask. After adding elemental iodine (0.8 g, 3.1 mmol), the reaction solution was stirred at room temperature for 6 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA=5 / 1) to obtain 2.0 g of the desired product (yield 53%).

[0347] Step 5: Synthesis of tert-butyl 6-((((tert-butyldiphenylsilyl)oxy)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate 2-((((tert-butyldiphenylsilyl)oxy)methyl)-3-hydroxy-5-(iodomethyl)pyrrolidine-1-carboxylate tert-butyl (1.0 g, 1.7 mmol) was dissolved in 10 mL of tetrahydrofuran, and potassium tert-butoxide (196 mg, 2.0 mmol) was added at 0°C. The reaction system was stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA=10 / 1) to obtain 350 mg of the desired product (yield 44%).

[0348] Step 6: Synthesis of (2-oxa-5-azabicyclo[2.2.1]hept-6-yl)methanol tert-Butyl 6-((((tert-butyldiphenylsilyl)oxy)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (350 mg, 0.75 mmol) was dissolved in 10 mL of tetrahydrofuran, 200 mg of TBAF was added, and the mixture was stirred at room temperature overnight. 0.5 mL of 6 M dilute hydrochloric acid was added to the reaction solution. The mixture was then stirred at room temperature for 0.5 hours, and the reaction system was spin-dried. A crude product was obtained.

[0349] Step 7: Synthesis of (5-(3-fluoropropyl)-2-oxa-5-azabicyclo[2.2.1]hept-6-yl)methanol The crude product obtained in the previous step was dissolved in 5 mL of acetonitrile, and 1-fluoro-3-iodopropane (150 mg, 0.8 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added. The mixture was stirred at 80° C. for 6 h. After filtration and concentration under reduced pressure, the filtrate was purified by column chromatography (DCM / MeOH=10 / 1) to give 25 mg of the desired product (18% yield for both steps).

[0350] Step 8: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((5-(3-fluoropropyl)-2-oxa-5-azabicyclo[2.2.1]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol The target product was synthesized in the same manner as in Example 6 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=625.3[M+H] + .

[0351] Example 32 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6,8-trifluoronaphthalen-2-ol

[0352] [ka]

[0353] Step 1: Synthesis of 4,4,5,5-tetramethyl-2-(5,7,8-trifluoro-3-(methoxymethoxy)naphthalen-1-yl)-1,3,2-dioxaborane It was obtained by synthesis in the same manner as in intermediate 5 using 2,4,5-trifluorobenzaldehyde and 4-methoxy-4-oxo-3-(triphenylphosphoranylidene)butyric acid as raw materials.

[0354] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6,8-trifluoronaphthalen-2-ol The target product was synthesized in the same manner as in Example 6 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=613.2[M+H] + .

[0355] Example 33 3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-yl)oxy)methyl)-N-(2,2,2-trifluoroethyl)-2-azabicyclo[2.2.1]heptane-2-carboxamide

[0356] [ka]

[0357] Step 1: Synthesis of methyl 2-azabicyclo[2.2.1]heptane-3-carboxylate Methyl 2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (255 mg, 1.0 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 0.5 hours. The mixture was spin-dried, and the crude product was used as it was in the next step.

[0358] Step 2: Synthesis of (2-azabicyclo[2.2.1]heptan-3-yl)-methanol Methyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (crude product) was dissolved in 5 mL of tetrahydrofuran, and lithium aluminum hydride (76 mg, 2.0 mmol) was added at 0° C. and stirred for 1 hour. 20 mL of water was added to the reaction system, which was then extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH=20 / 1) to obtain 40 mg of the desired product (31% yield for both steps).

[0359] Step 3: Synthesis of 3-(hydroxymethyl)-N-(2,2,2-trifluoroethyl)-2-azabicyclo[2.2.1]heptane-2-carboxamide 2,2,2-Trifluoroethylamine (50mg, 0.5mmol) and triethylamine (0.2mL) were dissolved in dichloromethane (2mL), p-nitrophenyl chloroformate (100mg, 0.5mmol) was added at 0℃, and the mixture was stirred at room temperature for 1 hour, after which (2-azabicyclo[2.2.1]heptan-3-yl)-methanol (40mg, 0.3mmol) was added. The reaction solution was heated to 60℃ and stirred overnight. 20mL of water was added to the reaction system, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH=20 / 1) to obtain 35mg of the desired product (yield 44%).

[0360] Step 4: Synthesis of 3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-yl)oxy)methyl)-N-(2,2,2-trifluoroethyl)-2-azabicyclo[2.2.1]heptane-2-carboxamide The target product was synthesized in the same manner as in Example 6 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=688.2[M+H] + .

[0361] Example 34 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0362] [ka]

[0363] Step 1: Synthesis of p-methoxyphenylmagnesium bromide Magnesium chips (4.8g, 200mmol) were weighed into a flask, methoxybromobenzene (1g, 5.3mmol), 0.2g elemental iodine and 5mL of tetrahydrofuran were added, and the mixture was heated to start the reaction. After that, a solution of methoxybromobenzene (17.7g, 94.7mmol) in 150mL of tetrahydrofuran was added dropwise, and the reaction system was maintained at reflux. After the addition was completed, the mixture was refluxed for 0.5 hours. The reaction system was used as it was in the next reaction.

[0364] Step 2: Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-5-(4-methoxyphenyl)-5-oxopentanoate 1-(tert-butyl)-2-methyl-5-oxopyrrolidine-1,2-dicarboxylate (24.3 g, 100 mmol) and 250 mL of tetrahydrofuran were added to the flask, and the reaction mixture was cooled to -70°C in a dry ice ethanol bath under nitrogen gas protection, and then p-methoxyphenylmagnesium bromide (the reaction solution obtained in the previous step) was added. The reaction was allowed to proceed at this temperature for 3 hours. Saturated ammonium chloride solution (500 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried and then spin-dried, and then purified by column chromatography (PE / EA=1 / 1) to obtain 18.0 g of the desired product (yield 51%).

[0365] Step 3: Synthesis of methyl 5-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate Methyl 2-((tert-butoxycarbonyl)amino)-5-(4-methoxyphenyl)-5-oxopentanoate (18 g, 51.3 mmol) was added to the flask and HCl / MeOH (4 m, 100 mL) was added at room temperature and stirred overnight at room temperature. The reaction was directly spun down to give the crude product. No further purification was performed.

[0366] Step 4: Synthesis of methyl 5-(4-methoxyphenyl)pyrrole-2-carboxylate The crude product obtained in the previous step was dissolved in 200 mL of methanol, and sodium borohydride (3.8 g, 100 mmol) was added at 0° C. and stirred for 1 h. The reaction was spun down, 5 mL of cold water was added, extracted with ethyl acetate, the organic phase was dried and spun down to give the crude product. No further purification was performed.

[0367] Step 5: Synthesis of methyl 1-(3-bromopropyl)-5-(4-methoxyphenyl)pyrrolidine-2-carboxylate The crude product from the previous step was dissolved in 200 mL of acetonitrile, and potassium carbonate (13.8 g, 100 mmol) and 1,3-dibromopropane (10.1 g, 50 mmol) were added. The reaction mixture was stirred at 60° C. for 6 h. It was filtered under reduced pressure, and the filtrate was spun dry and purified by column chromatography (DCM / MeOH=20 / 1) to give 7.9 g of the desired product (44% yield for the three steps).

[0368] Step 6: Synthesis of methyl 3-(4-methoxyphenyl)tetrahydro-1H-pyrrozine-7a(5H)-carboxylate 1-(3-bromopropyl)-5-(4-methoxyphenyl)pyrrolidine-2-methyl carboxylate (7.9 g, 22.2 mmol) was dissolved in 100 mL of tetrahydrofuran, and LDA (1 m, 25 mL, 25 mmol) was added dropwise at 0°C. After the addition was completed, the mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour. The reaction mixture was poured into 300 mL of water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH=20 / 1) to obtain 3.6 g of the desired product (yield 59%).

[0369] Step 7: Synthesis of (3-(4-methoxyphenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methanol 3-(4-Methoxyphenyl)tetrahydro-1H-pyrrozine-7a(5H)-methyl carboxylate (2.7 g, 10 mmol) was dissolved in 30 mL of tetrahydrofuran, lithium aluminum hydride (760 mg, 20 mmol) was added at 0° C., and the mixture was stirred for 1 hour. 100 mL of water was added to the reaction system, which was then extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then purified by column chromatography C (DCM / MeOH=20 / 1) to obtain 2.2 g of the desired product (yield 89%).

[0370] Step 8: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro)-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-(4-Methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methanol (130 mg, 0.53 mmol) and 5 mL of tetrahydrofuran were added to the flask, and NaH (60%, 64 mg, 1.6 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate tert-butyl (173 mg, 0.40 mmol) was added, and the reaction solution was subsequently stirred at room temperature for 2 hours. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by Prep-TLC (DCM / MeOH=15 / 1) to give 75 mg of a yellow solid (29% yield).

[0371] Step 9: Synthesis of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(7-chloro-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro)-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (50 mg, 0.078 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (27 mg, 0.078 mmol), potassium carbonate (21 mg, 0.15 mmol) and dioxane / water (2 mL / 0.2 mL) were added to a flask, and nitrogen gas was exchanged. Then, Pd(dppf)Cl 2 5mg was added. Under nitrogen gas protection, the reaction mixture was heated to 100℃ and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried, spun dry, and purified by Prep-TLC (DCM / MeOH=15 / 1) to give 38mg of a grey solid (yield 58%).

[0372] Step 10: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (38 mg, 0.046 mmol) was dissolved in 2 mL of ethyl acetate, HCl / EA (4 m, 0.5 mL) was added, and the mixture was stirred for 10 minutes. The reaction system was poured into 10 mL of water, adjusted to a weak alkali with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, followed by purification by Prep-TLC to obtain 22 mg of a gray solid (71% yield).

[0373] LC / MS: m / z=684.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 8.89 (s, 1H), 7.45-7.39 (m, 1H), 7.27-7.17 (m, 4H), 6.78-6.74 (m, 2H), 4.67-4.60 (m, 1H), 4.47-4.40 (m, 1H), 4.36-4.21 (m, 2H), 3.71-3.58 (m, 7H), 2.91-2.83 (m, 1H), 2.72-2.58 (m, 1H), 2.35-2.25 (m, 1H), 2.13-2.05 (m, 1H), 1.94-1.53 ​​(m, 8H).

[0374] Example 35 3-(4-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolin-3-yl)phenoxy)propane-1,2-diol

[0375] [ka]

[0376] Step 1: Synthesis of 4-(7a-(hydroxymethyl)hexahydro-1H-pyrrozin-3-yl)phenol (3-(4-Methoxyphenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methanol (247 mg, 1.0 mmol) was dissolved in 5 mL of dichloromethane, and 0.2 mL of boron tribromide was added at 0° C. After stirring at 0° C. for 1 hour, the reaction system was directly spin-dried to obtain a crude product, which was used as it was in the next reaction.

[0377] Step 2: Synthesis of (3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methanol The crude product obtained in the previous step was dissolved in 5 mL of acetonitrile, and potassium carbonate (276 mg, 2.0 mmol) and 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (195 mg, 1.0 mmol) were added. The mixture was stirred at 80° C. for 6 hours. The mixture was filtered under reduced pressure, the filtrate was spin-dried, and the crude product was purified by column chromatography to give 110 mg of the desired product (32% yield for the two steps).

[0378] Step 3: Synthesis of 3-(4-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolin-3-yl)phenoxy)propane-1,2-diol The target product was synthesized in the same manner as in Example 34 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=707.3[M+H] + .

[0379] Example 36 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((5-(4-fluorophenyl)-1-(3-fluoropropyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0380] [ka]

[0381] Step 1: Synthesis of methyl 5-(4-fluorophenyl)-1-(3-fluoropropyl)pyrrolidine-2-carboxylate Methyl 5-(4-fluorophenyl)pyrrolidine-2-carboxylate (223 mg, 1.0 mmol), 1-fluoro-3-iodopropane (188 mg, 1.0 mmol), potassium carbonate (414 mg, 3.0 mmol) and 5 mL of acetonitrile were added to a flask. The mixture was heated to 80° C. and stirred for 6 hours. The reaction was cooled to room temperature, filtered under reduced pressure, and the filtrate was spin-dried to obtain a crude product, which was used as is in the next reaction.

[0382] Step 2: Synthesis of (5-(4-fluorophenyl)-1-(3-fluoropropyl)pyrrolidin-2yl)-methanol 5-(4-fluorophenyl)-1-(3-fluoropropyl)pyrrolidine-2-carboxylate methyl ester (crude product) was dissolved in 5 mL of tetrahydrofuran, and lithium aluminum hydride (76 mg, 2.0 mmol) was added at 0° C. and stirred for 1 hour. 20 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Prep-TLC (DCM / MeOH=20 / 1) to obtain 95 mg of the desired product (37% yield for both steps).

[0383] Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((5-(4-fluorophenyl)-1-(3-fluoropropyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol The target product was synthesized in the same manner as in Example 34 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=691.3[M+H] + .

[0384] Example 37 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-8-cyclopropyl-5,6-difluoronaphthalen-2-ol

[0385] [ka]

[0386] Step 1: Synthesis of methyl 4-(benzyloxy)-8-cyclopropyl-5,6-difluoro-2-naphthoate Methyl 4-(benzyloxy)-8-bromo-5,6-difluoro-2-naphthoate (407 mg, 1.0 mmol), cyclopropylboronic acid (172 mg, 2.0 mmol), potassium carbonate (414 mg, 3.0 mmol) and dioxane / water (5 mL / 0.5 mL) were added to a flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (37 mg, 0.05 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 3 hours. After cooling to room temperature, the reaction mixture was poured into 30 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, and purified by Prep-TLC (PE / EA=10 / 1) to give 295 mg of an off-white solid (yield 80%).

[0387] Step 2: Synthesis of 2-(5-cyclopropyl-7,8-trifluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane It was synthesized in the same manner as intermediate 5 using the product obtained in the previous step as the raw material.

[0388] Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-8-cyclopropyl-5,6-difluoronaphthalen-1-ol The target product was synthesized in the same manner as in Example 6 using the product obtained in the previous step and the corresponding intermediate as raw materials. LC / MS: m / z=635.3[M+H] + .

[0389] Example 38 (1R,5S,Z)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-one O-methyloxime

[0390] [ka]

[0391] (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-one (30 mg, 0.05 mmol) was dissolved in 2 mL of ethanol, and 0.1 mL of pyridine and methoxyamine hydrochloride (9 mg, 0.10 mmol) were added. The reaction mixture was stirred overnight at room temperature, and the reaction solution was spin-dried and purified by pre-TLC (DCM / MeOH=10 / 1) to obtain 8 mg of a white solid (25% yield). LC / MS: m / z=637.3[M+H] + .

[0392] Example 39 N-(4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)methanesulfonamide

[0393] [ka]

[0394] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-(3-aminonaphthalen-1-yl) 8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Under nitrogen gas protection, a solution of tert-butyl (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.039 mmol), benzophenone imine (18 mg, 0.1 mmol), cesium carbonate (66 mg, 0.2 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos) (5 mg) in dioxane (3 mL) was added to Pd 2 (dba) 3 5mg was added. The reaction mixture was stirred at 100°C under nitrogen gas protection for 3 hours. The reaction mixture was poured into 10mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, and purified by Prep-TLC (DCM / MeOH=20 / 1). The obtained product was dissolved in 5mL of methanol, and 10mg of 10% Pd / C was added, followed by stirring overnight at room temperature under a hydrogen gas environment. Filtration was performed under reduced pressure, and the filtrate was spin-dried to obtain 15mg of a yellow solid (yield 60%).

[0395] Step 2: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methanesulfonamido)naphthalen-1-yl) 2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-(3-aminonaphthalen-1-yl) 8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15 mg, 0.023 mmol) and triethylamine (10 mg, 0.1 mmol) were dissolved in 2 mL of dichloromethane, and methanesulfonyl chloride (4 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 10 mL of water, extracted with dichloromethane, and the organic phase was dried and spun dry, then purified by Prep-TLC (DCM / MeOH=20 / 1) to give 10 mg of a yellow solid (59% yield).

[0396] Step 3: Synthesis of N-(4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)methanesulfonamide tert-Butyl (1R,5S)-3-(8-fluoro-7-(3-(methanesulfonamido)naphthalen-1-yl)2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol) was added to a flask and dissolved in EA (0.5 mL), then hydrochloric acid-ethyl acetate solution (1.5 mL) was added and reacted at room temperature for 1 hour. The reaction system was spin-dried, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure, and the resulting crude product was purified by thin-layer silicon plate (DCM / MeOH=7 / 1) to give 3 mg of a white solid as the title compound (yield 35%). LC / MS: m / z=618.3[M+H] + .

[0397] Example 40 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0398] [ka]

[0399] tert-Butyl (1R,5S)-3-(7-(3-aminonaphthalen-1-yl) 8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.016 mmol) was added to a flask and dissolved in EA (0.5 mL), then hydrochloric acid-ethyl acetate solution (1.5 mL) was added and reacted at room temperature for 1 hour. The reaction system was spin-dried, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate and anhydrous Na 2 SO 4 The crude product obtained by drying at 40° C., filtering and concentrating under reduced pressure was purified by thin-layer silicon plate (DCM / MeOH=5 / 1) to give 5 mg of the title compound as a gray solid (yield 59%). LC / MS: m / z=540.3[M+H] + .

[0400] Example 41 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinazolin-6-yl)propionitrile

[0401] [ka]

[0402] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-6-((E)-2-cyanovinyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-6-iodoquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (166 mg, 0.23 mmol), triethylamine (50 mg, 0.50 mmol), acrylonitrile (2.8 g, 20 mmol) and 5 mL of DMF were added to a flask. After nitrogen gas exchange, 5 mg of tris(o-methylphenyl)phosphorus and 5 mg of palladium acetate were added. Under nitrogen gas protection, the reaction system was heated to 80° C. and reacted overnight with stirring. The reaction system was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified by Prep-TLC (DCM / MeOH=20 / 1) to obtain 76 mg of the desired product (yield 51%).

[0403] Step 2: Synthesis of tert-butyl (1R,5S)-3-(6-((E)-2-cyanovinyl)-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-6-((E)-2-cyanovinyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (76 mg, 0.12 mmol), cesium carbonate (65 mg, 0.2 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (53 mg, 0.15 mmol) and 2 mL of dioxane / water (10 / 1) were added to the flask. After nitrogen gas exchange, Pd(dppf)Cl 2 5 mg was added. The reaction system was heated to 90°C under nitrogen gas protection and reacted for 2 hours with stirring. The reaction system was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified by Prep-TLC (DCM / MeOH=15 / 1) to obtain 17 mg of the desired product (yield 18%).

[0404] Step 3: Synthesis of tert-butyl (1R,5S)-3-(6-(2-cyanoethyl)-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate At 0°C, (1R,5S)-3-(6-((E)-2-cyanovinyl)-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (17mg, 0.021mmol) was added to a tetrahydrofuran solution of lithium triethylborohydride (1M dissolved in THF, 0.1mL). The mixture was stirred at 0°C for 10 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain a crude product.

[0405] Step 4: Synthesis of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinazolin-6-yl)propionitrile The crude product from the previous step was dissolved in 2 mL of ethyl acetate, HCl / EA (4 m, 0.5 mL) was added, and stirred for 10 min. The reaction was poured into 10 mL of water, adjusted to a weak alkali with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and spun to dryness, then purified by Prep-TLC to give 3 mg of a grey solid (21% yield for both steps). LC / MS: m / z=647.3[M+H] + .

[0406] Example 42 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-1,6-naphthyridin-7-yl)-5,6-difluoronaphthalen-2-ol

[0407] [ka]

[0408] Step 1: Synthesis of 3-(4-amino-6-chloro-5-fluoropyridin-3-yl)propanol methyl ester 2-Chloro-3-fluoro-5-iodopyridin-4-amine (272 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), methyl propionate (168 mg, 0.2 mmol), cuprous iodide (19 mg, 0.1 mmol), and 2 mL of tetrahydrofuran were added to the flask. After nitrogen gas exchange, Pd(PPh 3 )Cl 2(35 mg, 0.05 mmol) was added. The reaction system was heated to 70° C. under nitrogen gas protection and reacted for 4 hours with stirring. The reaction system was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified by Prep-TLC (DCM / MeOH=20 / 1) to obtain 40 mg of the desired product (yield 18%).

[0409] Step 2: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 3-(4-amino-6-chloro-5-fluoropyridin-3-yl)propanol methyl ester (40 mg, 0.18 mmol), 100 mg lithium chloride, (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (42 mg, 0.20 mmol) and 2 mL of tert-butyl alcohol were added to a flask. The mixture was heated to 120°C and reacted for 2 days with stirring. The reaction system was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified by Prep-TLC (DCM / MeOH=20 / 1) to obtain 20 mg of the desired product (yield 28%).

[0410] Step 3: Synthesis of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.049 mmol), cesium carbonate (33 mg, 0.2 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (18 mg, 0.05 mmol) and 2 mL of dioxane / water (10 / 1) were added to the flask. After nitrogen gas exchange, Pd(dppf)Cl 2 3mg was added. The reaction system was heated to 90℃ under nitrogen gas protection and reacted for 2 hours with stirring. The reaction system was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified by Prep-TLC (DCM / MeOH=15 / 1) to obtain 10mg of the desired product (yield 34%).

[0411] Step 4: Synthesis of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (10 mg, 0.017 mmol), silver carbonate (28 mg, 0.1 mmol), (2R,7aS)-7a-(chloromethyl)-2-fluorohexahydro-1H-pyrrozine (4 mg, 0.02 mmol) and 2 mL DMF were added to the flask. The reaction system was heated to 80° C. under nitrogen gas protection and reacted for 4 hours with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain a crude product.

[0412] Step 5: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-1,6-naphthyridin-7-yl)-5,6-difluoronaphthalen-2-ol The crude product from the previous step was dissolved in 2 mL of ethyl acetate, HCl / EA (4 m, 0.5 mL) was added, and stirred for 10 min. The reaction was poured into 10 mL of water, adjusted to a weak alkali with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and spun to dryness, then purified by Prep-TLC to give 0.5 mg of a grey solid (5% yield for both steps). LC / MS: m / z=594.2[M+H] + .

[0413] Example 43 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(1,3-dihydroisobenzofuran-5-yl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0414] [ka]

[0415] Step 1: Synthesis of 5-bromo-1,3-dihydroisobenzofuran-1-ol 5-Bromoisobenzofuran-1(3H)-one (213 mg, 1.0 mmol) was dissolved in 5 mL of tetrahydrofuran and DIBALH (1 M, 1 mL, 1 mmol) was added dropwise at -70° C. After the addition was complete, the mixture was stirred for 2 hours at -70° C. The reaction was poured into 10 mL of water, extracted with dichloromethane, the organic phase was dried and spun dry, and the crude product was used directly in the next reaction.

[0416] Step 2: Synthesis of 5-bromo-1,3-dihydroisobenzofuran The crude product obtained in the previous step was dissolved in 5 mL of dichloromethane, and 0.2 mL of trifluoroacetic acid and 0.2 mL of triethylsilane were added. The reaction mixture was stirred at room temperature overnight. After cooling to room temperature, the reaction mixture was poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, and purified by Prep-TLC (PE / EA=2 / 1) to obtain 110 mg of the desired product (55% yield for both steps).

[0417] Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(1,3-dihydroisobenzofuran-5-yl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The product obtained in the previous step and the corresponding intermediate were used as raw materials, and the product was synthesized in the same manner as in Example 34. LC / MS: m / z=659.3[M+H] + .

[0418] Example 44 4-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrozin-3-yl)benzonitrile

[0419] [ka]

[0420] Step 1: Synthesis of (3-(4-bromophenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methanol It was synthesized in the same manner as in Example 34 using p-bromoiodobenzene and the corresponding reagents as raw materials.

[0421] Step 2: Synthesis of 4-(7a-(hydroxymethyl)hexahydro-1H-pyrrozin-3-yl)-benzonitrile (3-(4-bromophenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methanol (295 mg, 1.0 mmol), cuprous cyanide (445 mg, 5.0 mmol), pyridine (0.5 mL) and DMSO (5 mL) were added to a flask, and the reaction mixture was heated to 130° C. under nitrogen gas protection and stirred for 1 h. The reaction mixture was cooled to room temperature and then poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by Prep-TLC (PE / EA=2 / 1) to give 160 mg of a white solid (66% yield).

[0422] Step 3: Synthesis of 4-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrozin-3-yl)benzonitrile The product obtained in the previous step and the corresponding intermediate were used as raw materials, and the product was synthesized in the same manner as in Example 34. LC / MS: m / z=642.3[M+H] + .

[0423] Example 45 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0424] Example 46 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0425] [ka]

[0426] Step 1: Synthesis of (3-(4-(3,6-dihydro-2H-pyran-4-yl)-phenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methanol (3-(4-bromophenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methanol (296 mg, 1.0 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (210 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol) and dioxane / water (5 mL / 0.5 mL) were added to a flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (36 mg, 0.05 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 6 h. The reaction mixture was cooled to room temperature, poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried, spun dry, and purified by Prep-TLC (DCM / MeOH=20 / 1) to give 230 mg of a yellow solid (77% yield).

[0427] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The product obtained in the previous step and the corresponding intermediate were used as raw materials, and the product was synthesized in the same manner as in Example 34.

[0428] LC / MS: m / z=699.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 8.92 (s, 1H), 7.64-7.58 (m, 1H), 7.48-7.42 (m, 1H), 7.25-7.04 (m, 8H), 5.95 (s, 1H), 4.55-4.42 (m, 2H), 4.30-4.12 (m, 4H), 3.81-3.56 (m, 5H), 3.22 (s, 2H), 2.86-2.76 (m, 1H), 2.65-2.54 (m, 1H), 2.37 (s, 2H), 2.28-2.21 (m, 1H), 2.21-2.04 (m, 1H), 1.96-1.54 (m, 10H).

[0429] Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (10 mg, 0.014 mmol) was dissolved in 3 mL of methanol, 5 mg of Pd / C (10%) was added, and the reaction system was stirred for 6 hours at room temperature under a hydrogen gas environment. The mixture was filtered under reduced pressure, and the filtrate was spin-dried to give 8 mg of a gray solid (yield 80%). LC / MS: m / z=701.3[M+H] + .

[0430] Example 47 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0431] [ka]

[0432] Step 1: Synthesis of (3-(4-methoxyphenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methan-d2-ol Methyl 3-(4-methoxyphenyl)tetrahydro-1H-pyrrozine-7a(5H)-carboxylate (138 mg, 0.5 mmol) was dissolved in 2 mL of tetrahydrofuran, and lithium aluminum deuteride (42 mg, 1.0 mmol) was added at 0° C. and stirred for 1 hour. 10 mL of water was added to the reaction system, which was then extracted three times with ethyl acetate. The organic phase was dried and then spin-dried, and then purified by column chromatography (PE / EA=5 / 1) to obtain 75 mg of the desired product (yield 60%).

[0433] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The target product was synthesized in the same manner as in Example 34 using the product obtained in the previous step and the corresponding intermediate as raw materials.

[0434] LC / MS: m / z=649.3 [M+H] + . 1 H NMR (400mHz, CDCl 3) δ 8.96 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.21-7.12 (m, 5H), 6.72 (d, J = 8.4 Hz, 2H), 4.54 (d, J = 12.0 Hz, 2H), 3.67-3.55 (m, 5H), 3.26 (s, 3H), 2.95-2.85 (m, 1H), 2.77-2.67 (m, 1H), 2.35-2.25 (m, 1H), 2.13-2.05 (m, 1H), 1.99-1.70 (m, 10H).

[0435] Example 48 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0436] [ka]

[0437] Step 1: Synthesis of 1-(tert-butyl) 2-methyl (4R)-2-(3-(tert-butoxy)-3-oxopropyl)-4-fluoropyrrolidine-1,2-dicarboxylate 1-(tert-butyl) 2-methyl (4R)-4-fluoropyrrolidine-1,2-dicarboxylate (3g, 12.15mmol), HMPA (2.8g, 15.80mmol) and 30mL of tetrahydrofuran were added to a flask, and the reaction mixture was cooled to -70°C in a dry ice ethanol bath under nitrogen gas protection, after which LiHMDS (1m, 15.8mL) was added and reacted at this temperature for 30 minutes, after which a tetrahydrofuran solution (3mL) of 3-tert-butyl bromopropionate (2.5g, 12.15mmol) was added and stirred for 4 hours while maintaining at -70°C. Saturated ammonium chloride solution (20mL) was added, extracted three times with ethyl acetate, the organic phase was dried and then spin-dried, and purified by column chromatography (PE / EA=5 / 1) to obtain 3.29g of the desired product (72% yield).

[0438] Step 2: Synthesis of 3-((4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-2-yl)propionic acid 1-(tert-butyl) 2-methyl(4R)-2-(3-(tert-butoxy)-3-oxopropyl)-4-fluoropyrrolidine-1,2-dicarboxylate (3.29 g, 8.75 mmol) and 25 mL of dichloromethane were added to a flask followed by trifluoroacetic acid (25 mL) and stirred at room temperature overnight. The reaction was directly spun down to give the crude product of the trifluoroacetate salt of 3-((4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-2-yl)propionic acid (4.05 g). No further purification was performed.

[0439] Step 3: Synthesis of 3-((4R)-1-(tert-butoxycarbonyl)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-2-yl)propionic acid The crude trifluoroacetate salt of 3-((4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-2-yl)propionic acid (4.05 g, 12.15 mmol), triethylamine (6.14 g, 60.75 mmol) and 40 mL of methanol were added to a flask, and when the pH value measured by pH paper exceeded 7, the (Boc)2 O (3.45 g, 15.80 mmol) was added and stirred at room temperature for 1 h. The reaction was directly spun to dryness to give the crude product (3.88 g) without further purification.

[0440] Step 4: Synthesis of 1-(tert-butyl) 2-methyl (4R)-4-fluoro-2-(3-(methoxy(methyl)amino)-3-oxopropyl)pyrrolidine-1,2-dicarboxylate 3-((4R)-1-(tert-butoxycarbonyl)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-2-yl)propionic acid crude product (3.88 g, 12.15 mmol), N,O-dimethylhydroxylamine hydrochloride, HATU (6 g, 15.80 mmol), triethylamine (6.14 g, 60.75 mmol) and 40 mL N,N-dimethylformamide were added to a flask and stirred overnight at room temperature. The reaction mixture was poured directly into 400 mL water, extracted three times with ethyl acetate, and the organic phase was dried and then spun dry, followed by purification by column chromatography (PE / EA=5 / 1) to obtain 291 mg of the desired product (total yield of four steps 6.6%).

[0441] Step 5: Synthesis of 1-(tert-butyl) 2-methyl (4R)-4-fluoro-2-(3-(4-methoxyphenyl)-3-oxopropyl)pyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-methyl(4R)-4-fluoro-2-(3-(methoxy(methyl)amino)-3-oxopropyl)pyrrolidine-1,2-dicarboxylate (291 mg, 0.8 mmol) and 4 mL of tetrahydrofuran were added to the flask, and the reaction mixture was cooled to -70°C in a dry ice ethanol bath under nitrogen gas protection, and then (4-methoxyphenyl)magnesium bromide (1 m, 1.6 mL) was added and reacted at this temperature for 3 hours. Saturated ammonium chloride solution (4 mL) was added, and the mixture was extracted three times with ethyl acetate, and the organic phase was dried and then spin-dried, and then purified by Prep-TLC (PE / EA=1 / 1) to obtain 235 mg of the desired product (72% yield).

[0442] Step 6: Synthesis of methyl (6R)-6-fluoro-3-(4-methoxyphenyl)-6,7-dihydro-1H-pyrrolidin-7a(5H)-carboxylate 1-(tert-butyl) 2-methyl (4R)-4-fluoro-2-(3-(4-methoxyphenyl)-3-oxopropyl)pyrrolidine-1,2-dicarboxylate (235 mg, 0.57 mmol) was added to the flask and HCl / MeOH (4M, 20 mL) was added at room temperature and stirred overnight at room temperature. The reaction was directly spun down to give the crude product (167 mg). No further purification was performed.

[0443] Step 7: Synthesis of methyl (2R)-2-fluoro-5-(4-methoxyphenyl)tetrahydro-1H-pyrrolidin-7a(5H)-carboxylate The crude product of methyl (6R)-6-fluoro-3-(4-methoxyphenyl)-6,7-dihydro-1H-pyrrolidine-7a(5H)-carboxylate (167 mg, 0.57 mmol) was dissolved in 5 mL of methanol, and sodium borohydride (32 mg, 0.86 mmol) was added at 0° C. and stirred for 1 hour. The reaction system was spin-dried, 5 mL of cold water was added, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by Prep-TLC (PE / EA=1 / 1) to obtain 120 mg of a white liquid (yield 72%).

[0444] Step 8: Synthesis of ((2R)-2-fluoro-5-(4-methoxyphenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methanol Methyl (2R)-2-fluoro-5-(4-methoxyphenyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (120 mg, 0.41 mmol) was dissolved in 1 mL of tetrahydrofuran, and lithium aluminum hydride (24 mg, 0.62 mmol) was added at 0° C. and stirred for 1 hour. 24 mg of water, 24 mg of 15% sodium hydroxide solution, and 72 mg of water were added to the reaction system, and a small amount of anhydrous sodium sulfate was added to dry, followed by filtration and spin drying to obtain approximately 110 mg of crude product as the desired product. No additional purification was performed.

[0445] Step 9: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The target product was synthesized in the same manner as in Example 34 using the product obtained in the previous step and the corresponding intermediate as raw materials.

[0446] LC / MS: m / z=665.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 9.07 (s, 1H), 7.72-7.59 (m, 2H), 7.42-7.28 (m, 6H), 6.82 (d, J = 8.2 Hz, 2H), 5.41 (d, J = 53.6 Hz, 1H), 4.66-4.52 (m, 2H), 4.45-4.33 (m, 2H), 3.77 (s, 3H), 3.74-3.58 (m, 4H), 3.39-3.31 (m, 1H), 2.94-2.80 (m, 1H), 2.70-2.61 (m, 1H), 2.45-2.39 (m, 1H), 2.26-2.20 (m, 1H), 2.04-1.51 (m, 8H).

[0447] Example 49 8-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-ylmethoxy)quinazolin-7-yl)quinolin-6-ol

[0448] [ka]

[0449] Step 1: Synthesis of 8-bromo-6-methoxyquinoline Compound 6-methoxyquinolin-8-amine (5.0 g, 28.70 mmol) was added to the flask and dissolved in 40% HBr (50 mL), and the reaction system was cooled to 0 ° C. An aqueous solution (10 mL) of sodium nitrite (2.57 g, 37.31 mmol) was prepared and added dropwise to the reaction system, and the reaction was allowed to proceed at 0 ° C for 30 minutes. Cuprous bromide (4.94 g, 34.44 mmol) and 40% HBr (50 mL) were added to another flask, and the reaction solution prepared above was added dropwise to the flask, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction system was quenched by adding a saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate, and the organic phase was washed with saturated saline and anhydrous Na 2 SO 4 The crude product obtained by drying at 40° C., filtering and concentrating under reduced pressure was separated and purified by prep-TLC (PE / EA=7 / 1) to obtain 3.56 g of the title compound as a white solid (yield 52%).

[0450] Step 2: Synthesis of 8-bromoquinolin-6-ol The compound 8-bromo-6-methoxyquinoline (3.0 g, 12.60 mmol) was added to a three-neck flask, and the reaction system was cooled to -78°C under nitrogen gas protection, and then 2.0 M boron tribromide (25.2 ml, 50.4 mmol) was added dropwise, and the reaction was carried out at -78°C for 1 hour, and then the reaction was carried out at room temperature for 2 hours. The reaction system was quenched by adding a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. The organic phase was washed with saturated saline and then with anhydrous Na 2 SO 4 The crude product obtained by filtration and concentration under reduced pressure was separated and purified by prep-TLC (PE / EA=3 / 1) to obtain 2.40 g of the title compound as a white solid (yield 85%).

[0451] Step 3: Synthesis of 8-bromo-6-(methoxymethoxy)quinoline 8-Bromoquinolin-6-ol (2.25 g, 10.04 mmol) was added to a three-neck flask, and dry tetrahydrofuran (30 mL) was added under nitrogen gas protection. The reaction system was cooled in an ice-water bath, and then sodium hydride (803 mg, 20.08 mmol) was added in several portions and reacted for 30 minutes. Then, chloromethyl methyl ether (970 mg, 12.05 mmol) was added dropwise, and the mixture was allowed to react for 1 hour at room temperature. The reaction system was quenched by adding a saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate. The organic phase was washed with saturated saline and anhydrous Na 2 SO 4 The crude product obtained by drying at 40° C., filtering and concentrating under reduced pressure was separated and purified by prep-TLC (PE / EA=2 / 1) to obtain 2.15 g of the title compound as a white solid (yield 80%).

[0452] Step 4: Synthesis of 6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline In a three-neck flask, add 8-bromo-6-(methoxymethoxy)quinoline (300 mg, 1.12 mmol), bis(pinacolato)diboron (569 mg, 2.24 mmol), potassium acetate (220 mg, 2.24 mmol), and Pd(dppf)Cl. 2 (81 mg, 0.11 mmol) was added, and then 1,4-dioxane (3 mL) and water (0.3 mL) were added under nitrogen gas protection, and nitrogen exchange was performed again, and the reaction was carried out at 80° C. for 4 hours with stirring. Water was added to quench the reaction, and then the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated saline and anhydrous Na 2 SO 4 The crude product obtained by drying at 40° C., filtering and concentrating under reduced pressure was separated and purified by prep-TLC (PE / EA=1 / 1) to give 170 mg of the title compound as a white solid (48% yield).

[0453] Step 5: Synthesis of 3-bromo-2,4-difluoro-6-iodoaniline 3-Bromo-2,4-difluoroaniline (3.3 g, 15.87 mmol), Ag 2 SO4 (4.9g, 15.87mmol) and 30mL absolute ethanol were added to the flask, and an ethanol solution of iodine (4.03g, 15.87mmol) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 4 hours. After filtration and concentration of the filtrate, water was added, and the organic phase was dried and spin-dried, and then purified by chromatography column (PE / EA=50 / 1) to obtain 2.7g of the desired product (yield 52%).

[0454] Step 6: Synthesis of 2-amino-4-bromo-3,5-difluorobenzoic acid 3-Bromo-2,4-difluoro-6-iodoaniline (2.7 g, 8.08 mmol), K 2 CO 3 (2.8 g, 20 mmol), DMF (30 mL) and 30 mL of water were added to a flask and Pd(dppf)Cl 2 (293mg, 0.4mmol) was added, and the reaction system was heated to 90°C under carbon monoxide gas protection and reacted overnight with stirring. The reaction system was cooled to room temperature, the reaction solution was poured into water, extracted with ethyl acetate, the aqueous phase was collected, the pH was adjusted to weak acidic with dilute acid, and then extracted with ethyl acetate. The organic phase was collected, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified by chromatography (DCM / MeOH=20 / 1) to obtain 1.0g of the desired product (yield 49%).

[0455] Step 7: Synthesis of 7-bromo-6,8-difluoroquinazoline-2,4-diol 2-Amino-4-bromo-3,5-difluorobenzoic acid (1.0 g, 3.98 mmol) and urea (2.4 g, 39.84 mmol) were added to the flask, and the reaction system was heated to 170° C. and reacted for 4 hours while stirring. The reaction system was cooled to room temperature, and water and ethyl acetate were added for three extractions. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then purified by chromatography (PE / EA=5 / 1) to obtain 650 mg of the desired product (yield 59%).

[0456] Step 8: Synthesis of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline 7-Bromo-6,8-difluoroquinazoline-2,4-diol (300 mg, 1.09 mmol), phosphoryl chloride (1.67 g, 10.86 mmol), DIEA (630 mg, 4.91 mmol) were added to the flask, and the reaction was heated to 90° C. and stirred for 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0457] Step 9: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline (300 mg, 0.95 mmol), DIEA (630 mg, 4.91 mmol), (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (201 mg, 0.95 mmol) and 30 mL anhydrous ethanol were added to a flask, and the reaction system was heated to 80° C. and reacted for 4 hours with stirring. The reaction system was cooled to room temperature, and extracted three times with water and ethyl acetate. The organic phase was combined and then washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Prep-TLC (PE / EA=8 / 1) to obtain 35 mg of the desired product (6% yield for two steps).

[0458] Step 10: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrozin-7a(5H)-ylmethoxy)quinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50 mg, 0.10 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (24 mg, 0.15 mmol), cesium carbonate (65 mg, 0.20 mmol) and 1,4-diazabicyclo[2.2.2]octane (11 mg, 0.10 mmol) were added to a flask, and anhydrous THF (1 mL) and DMF (1 mL) were added under nitrogen gas protection, and nitrogen exchange was performed again, and the reaction was carried out at 60 ° C. for 4 hours with stirring. Water was added to quench the reaction, and then it was extracted with ethyl acetate, and the organic phase was washed with saturated saline and anhydrous Na 2 SO 4 The crude product obtained by filtration and concentration under reduced pressure was separated and purified by prep-TLC (PE / EA=2 / 1) to obtain 22 mg of the title compound as a yellow solid (yield 36%).

[0459] Step 11: Synthesis of tert-butyl (1R,5S)-3-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(6-(methoxymethoxy)quinolin-8-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)quinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (20 mg, 0.033 mmol), 6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (16 mg, 0.050 mmol), cesium carbonate (22 mg, 0.066 mmol), and Pd(dppf)Cl 2(3 mg, 0.0033 mmol) was added to the flask, and then 1,4-dioxane (1 mL) and water (0.1 mL) were added under nitrogen gas protection, nitrogen exchange was performed, and the reaction was carried out for 2 hours with stirring at a temperature of 100°C. Water was added to quench the reaction, and then the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated saline and anhydrous Na 2 SO 4 The crude product obtained by drying at 40° C., filtering and concentrating under reduced pressure was separated and purified by prep-TLC (PE / EA=1 / 1) to obtain 10 mg of the title compound as a yellow solid (yield 43%).

[0460] Step 12: Synthesis of 8-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-ylmethoxy)quinazolin-7-yl)quinolin-6-ol tert-Butyl (1R,5S)-3-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(6-(methoxymethoxy)quinolin-8-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol) was added to a flask and dissolved in EA (0.5 mL), then hydrochloric acid-ethyl acetate solution (1.5 mL) was added and reacted at room temperature for 1 hour. The reaction system was spin-dried, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate and anhydrous Na 2 SO 4 The crude product obtained by drying at 40° C., filtering and concentrating under reduced pressure was purified by thin-layer silicon plate (DCM / MeOH=10 / 1) to obtain 5 mg of a white solid as the title compound (yield 62%).

[0461] LC / MS: m / z=577.3[M+H] + . 1 H NMR (400mHz, CDCl 3) δ 8.62-8.59 (m, 1H), 7.99-7.95 (m, 1H), 7.55 (dd, J = 2.1, 43.2 Hz, 1H), 7.31-7.29 (m, 2H), 7.17-7.15 (m, 1H), 5.22 (dd, J = 20.4, 54.4 Hz, 1H), 4.50-4.41 (m, 1H), 4.24-4.15 (m, 3H), 3.59-3.53 (m, 3H), 3.41-2.93 (m, 5H), 2.44-1.63 (m, 10H).

[0462] Example 50 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrozin-7a(5H))-yl)methoxy)pyrido[2,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0463] [ka]

[0464] Step 1: Synthesis of 2,4,7-trichloropyrido[2,3-d]pyrimidine 7-Chloropyrido[2,3-d]pyrimidine-2,4-diol (200 mg, 1.01 mmol), DIPEA (774 mg, 6.00 mmol) and 3 mL of toluene were added to a flask, followed by phosphoryl chloride (459 mg, 3.00 mmol). After stirring at 110° C. for 4 hours and spin drying, the crude product was used directly in the next step.

[0465] Step 2: Synthesis of tert-butyl (1R,5S)-3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (106 mg, 0.50 mmol), DIPEA (774 mg, 6.00 mmol) and 5 mL of DCM were added to the flask. The crude product obtained in the previous step was added at 0° C. The mixture was stirred for 1 hour, poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried, spun dry and purified by Prep-TLC (EA / PE=2 / 1) to give 205 mg of a white solid (49% yield for the two steps).

[0466] Step 3: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (80 mg, 0.50 mmol) and 2 mL of tetrahydrofuran were added to a flask, and NaH (60%, 20 mg, 0.50 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. (1R,5S)-3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (200 mg, 0.49 mmol) was added, and the reaction solution was subsequently stirred at room temperature for 2 hours. The reaction solution was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by Prep-TLC (DCM / MeOH=20 / 1) to give 120 mg of a white solid (46% yield).

[0467] Step 4: Synthesis of tert-butyl (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (53 mg, 0.10 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (31 mg, 0.10 mmol), potassium carbonate (28 mg, 0.20 mmol) and dioxane / water (2 mL / 0.2 mL) were added to a flask, and nitrogen gas was exchanged. Then, Pd(dppf)Cl 2 (7 mg, 0.01 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried, spun dry, and purified by Prep-TLC (DCM / MeOH=20 / 1) to give 23 mg of a yellow solid (34% yield).

[0468] Step 5: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrozin-7a(5H))-yl)methoxy)pyrido[2,3-d]pyrimidin-7-yl)naphthalen-2-ol (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (23 mg, 0.034 mmol) was dissolved in 2 mL of ethyl acetate, HCl / EA (4 m, 0.5 mL) was added, and the mixture was stirred for 10 minutes. The reaction mixture was poured into 10 mL of water, adjusted to a weak alkali with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and then spin-dried. It was purified by Prep-TLC (DCM / MeOH=5 / 1) to give 13 mg of a light yellow solid (72% yield for both steps).

[0469] LC / MS: m / z=541.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 8.30 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.33-7.29 (m, 1H), 7.17-7.14 (m, 2H), 6.73 (d, J = 8.8 Hz, 1H), 5.16 (d, J = 53.9 Hz, 1H), 4.29-4.18 (m, 4H), 3.52-3.43 (m, 4H), 3.23-2.88 (m, 4H), 2.10-1.66 (m, 10H).

[0470] Example 51 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)isoquinoline-4-nitrile

[0471] [ka]

[0472] Step 1: Synthesis of tert-butyl (1R,5S)-3-(3,6-dichloroisoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 1,3,6-Trichloroisoquinoline (100 mg, 0.43 mmol), DIPEA (129 mg, 1.00 mmol), (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (106 mg, 0.50 mmol) and 3 mL of NMP were added to a flask. After stirring at 100° C. for 4 hours, the mixture was poured into 20 mL of water, and the precipitated solid was separated by vacuum filtration. The filter cake was spin-dried to obtain 150 mg of a white solid (yield 85%).

[0473] Step 2: Synthesis of tert-butyl (1R,5S)-3-(3-chloro-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-tert-butyl 3-(3,6-dichloroisoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.37 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (126 mg, 0.40 mmol), potassium carbonate (138 mg, 1.0 mmol) and dioxane / water (4 mL / 0.4 mL) were added to a flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (15 mg, 0.02 mmol) was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 6 h. After cooling to room temperature, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried, spun dry, and purified by Prep-TLC (DCM / MeOH=20 / 1) to give 135 mg of a white solid (66% yield).

[0474] Step 3: Synthesis of tert-butyl (1R,5S)-3-(3-chloro-4-iodo-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(3-chloro-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (112 mg, 0.2 mmol) was dissolved in 3 mL of acetonitrile, and NIS (54 mg, 0.24 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction solution was spin-dried and purified by Prep-TLC (PE / EA=2 / 1), yielding 130 mg of a white solid (yield 95%).

[0475] Step 4: Synthesis of tert-butyl (1R,5S)-3-(3-chloro-4-cyano-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(3-chloro-4-iodo-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (130 mg, 0.19 mmol), cuprous cyanide (43 mg, 0.48 mmol), 0.1 mL pyridine and 1 mL DMSO were added to a flask, and the reaction mixture was heated to 130° C. under nitrogen gas protection and stirred for 1 hour. After cooling to room temperature, the reaction mixture was poured into 10 mL water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by Prep-TLC (PE / EA=2 / 1) to give 77 mg of a white solid (69% yield).

[0476] Step 5: Synthesis of tert-butyl (1R,5S)-3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (13 mg, 0.082 mmol) and 2 mL of tetrahydrofuran were added to a flask, and NaH (60%, 4 mg, 0.10 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. (1R,5S)-3-(3-chloro-4-cyano-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (40 mg, 0.068 mmol) was added, and the reaction solution was subsequently stirred at room temperature for 2 hours. The reaction solution was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by Prep-TLC (DCM / MeOH=20 / 1) to give 18 mg of a white solid (37% yield).

[0477] Step 6: Synthesis of 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)isoquinoline-4-nitrile (1R,5S)-3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (18 mg, 0.025 mmol) was dissolved in 2 mL of ethyl acetate, HCl / EA (4 m, 0.5 mL) was added, and the mixture was stirred for 10 minutes. The reaction system was poured into 10 mL of water, adjusted to a weak alkali with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, followed by purification by Prep-TLC (DCM / MeOH=5 / 1) to obtain 12 mg of a gray solid (yield 84%).

[0478] LC / MS: m / z=564.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 7.87-7.83 (m, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.31-7.27 (m, 1H), 7.14-7.07 (m, 2H), 7.00 (s, 1H), 5.36 (d, J = 51.8 Hz, 1H), 4.44-4.31 (m, 2H), 4.22-4.15 (m, 2H), 3.78-3.31 (m, 6H), 3.22-3.05 (m, 2H), 2.53-1.92 (m, 10H).

[0479] Example 52 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0480] [ka]

[0481] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro)-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-(4-Methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methanol (130 mg, 0.53 mmol) and 5 mL of tetrahydrofuran were added to the flask, and NaH (60%, 64 mg, 1.6 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamate tert-butyl (173 mg, 0.40 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and spun dry, and then purified by Prep-TLC (DCM / MeOH=15 / 1) to give 75 mg of a yellow solid (29% yield).

[0482] Step 2: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(7-chloro-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro)-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (50 mg, 0.078 mmol), ((2-fluoro-6-(methoxymethoxy)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (40 mg, 0.078 mmol), potassium carbonate (21 mg, 0.15 mmol) and dioxane / water (2 mL / 0.2 mL) were added to a flask, and nitrogen gas was exchanged. Then, Pd(dppf)Cl 2 5mg was added. Under nitrogen gas protection, the reaction mixture was heated to 100℃ and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried, spun dry, and purified by Prep-TLC (DCM / MeOH=15 / 1) to give 31mg of a grey solid (40% yield).

[0483] Step 3: Synthesis of tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-(4-methoxyphenyl))tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (30 mg, 0.030 mmol) was dissolved in 1 mL of DMF, and CsF (10 mg) was added at room temperature and stirred overnight. The reaction was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and then spun dry, and the crude product was used as is in the next reaction.

[0484] Step 4: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol The crude product from the previous step was dissolved in 2 mL of ethyl acetate, HCl / EA (4 m, 0.5 mL) was added, and stirred for 10 min. The reaction was poured into 10 mL of water, adjusted to a weak alkali with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and spun to dryness, then purified by Prep-TLC to give 12 mg of a grey solid (38% yield for both steps). LC / MS: m / z=689.3 [M+H] + . 1 H NMR (400mHz, CDCl 3) δ 8.85 (s, 1H), 7.71-7.62 (m, 1H), 7.29-7.10 (m, 4H), 6.78-6.69 (m, 2H), 4.59-4.43 (m, 2H), 4.31-4.20 (m, 2H), 3.56-3.35 (m, 5H), 3.25 (s, 3H), 3.23-3.19 (m, 1H), 2.95-2.84 (m, 1H), 2.79-2.71 (m, 1H), 2.35-2.24 (m, 1H), 2.11-2.02 (m, 1H), 1.99-1.64 (m, 10H).

[0485] The compounds of the following Examples 53 to 140 were produced using the corresponding commercially available reagents as starting materials by the same procedures as those described in the above Examples.

[0486] [Table 1] JPEG2025510705000087.jpg239170JPEG2025510705000088.jpg245170JPEG2025510705000089.jpg251170JPEG20255107050 00090.jpg236170JPEG2025510705000091.jpg240170JPEG2025510705000092.jpg229170JPEG2025510705000093.jpg227170 JPEG2025510705000094.jpg222170JPEG2025510705000095.jpg243170JPEG2025510705000096.jpg226170JPEG20255107050 00097.jpg248170JPEG2025510705000098.jpg248170JPEG2025510705000099.jpg225170JPEG2025510705000100.jpg124170

[0487] Example 138 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((3S,7aR)-3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0488] [ka]

[0489] The starting materials depicted in the synthetic pathway (wherein "cis isomer" refers to the cis isomer and "trans isomer" refers to the trans isomer) were used as starting materials, and the desired isomers were separated, and the target product was synthesized in the same manner as in Example 34. LC / MS: m / z=671.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 8.92 (s, 1H), 7.34-7.28 (m, 3H), 7.21-7.16 (m, 2H), 7.06 (brs, 1H), 7.02-6.87 (m, 2H), 4.65-4.56 (m, 1H), 4.41-4.35 (m, 1H), 4.30-4.21 (m, 2H), 3.76-3.37 (m, 6H), 2.85-2.81 (m, 1H), 2.61-2.59 (m, 1H), 2.30-2.29 (m, 1H), 2.13-2.11 (m, 1H), 1.98-1.81 (m, 4H), 1.76-1.61 (m, 5H).

[0490] Example 139 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((3R,7aS)-3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0491] [ka]

[0492] The target product was synthesized in the same manner as in Example 34 using the starting materials depicted in the synthetic route. LC / MS: m / z=671.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 8.92 (s, 1H), 7.33-7.31 (m, 3H), 7.20-7.16 (m, 2H), 7.05 (brs, 1H), 6.95-6.87 (m, 2H), 4.39-4.08 (m, 5H), 3.66-3.52 (m, 5H), 2.90-2.82 (m, 1H), 2.62-2.54 (m, 1H), 2.34-2.29 (m, 1H), 2.17-2.11 (m, 1H), 1.93-1.81 (m, 4H), 1.75-1.56 (m, 5H).

[0493] Example 140 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol (Trans racemate)

[0494] [ka]

[0495] The desired intermediate was synthesized in the same manner as in Example 34 using the starting materials depicted in the synthesis pathways in Step 1 and Step 2.

[0496] Step 3: Synthesis of methyl 2-(3-chloropropyl)-5-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)-3,4-dihydro-2H-pyrrole-2-carboxylate 5-(2,2-Difluorobenzo[d][1,3]dioxy-5-yl)-3,4-dihydro-2H-pyrrole-2-methyl carboxylate (5.0 g, 17.66 mmol) and 1-bromo-3-chloropropane (5.56 g, 35.32 mmol) were dissolved in 10 mL of DMF and 40 mL of THF, and sodium hydride (1.06 g, 26.49 mmol) was added in several portions under ice bath, and the mixture was stirred at room temperature for 1 to 2 hours. The reaction system was poured into 100 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and the crude product was purified by column chromatography (PE:EA=8:1) to obtain 4.1 g of a whitish solid (yield 64.6%).

[0497] Step 4: Synthesis of methyl 3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrozine-7a(5H)-carboxylate (trans racemate) The product obtained in the previous step (4.1 g, 11.40 mmol) was dissolved in 40 mL of methanol, and acetic acid (1.03 g, 17.1 mL) was added. The solution was then cooled to 37° C. in an ice bath using NaBH 3 CN (1.07 g, 17.1 mL) was added in portions and stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness, water (100 mL) was added, sodium carbonate was added to make it weakly alkaline, and the mixture was extracted with ethyl acetate. The organic phase was dried and then spun to dryness to obtain a crude product, which was purified by column chromatography. The product was eluted with a mixed solvent (PE:EA=5:1) to obtain 1.8 g of a pale yellow oily product as the cis intermediate, and eluted with a mixed solvent (PE:EA=2:1) ​​to obtain 1.5 g of a whitish solid as the trans intermediate (total yield 88.9%).

[0498] The target product was synthesized in the same manner as in Example 34 using the above trans intermediate as a raw material. LC / MS: m / z=733.2 [M+H] +. 1 H NMR (400mHz, CDCl 3 ) δ 10.29 (brs, 1H), 9.12 (s, 1H), 7.76-7.73 (m, 1H), 7.61-7.54 (m, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.30 (d, 1H, J = 8.0 Hz), 7.25 (s, 1H), 7.17 (d, 1H, J = 8.4 Hz), 4.50-4.40 (m, 2H), 4.30-4.27 (m, 1H), 4.23-4.18 (m, 2H), 3.65-3.56 (m, 4H), 2.32-2.30 (m, 1H), 2.23-2.17 (m, 1H), 2.15-2.05 (m, 2H), 1.96-1.93 (m, 1H), 1.88-1.85 (m, 2H), 1.65-1.51 (m, 7H).

[0499] Example 141 (trans isomer 1), Example 142 (trans isomer 2) 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0500] [ka]

[0501] Step 1: Synthesis of (3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl (S)-2-phenylpropionate (3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (trans racemate, 297 mg, 1.0 mmol), (S)-2-phenylpropionic acid (180 mg, 1.2 mmol), DMAP (12 mg, 0.1 mmol) and 5 mL of dichloromethane were added to a flask, and EDCI (288 mg, 1.5 mmol) was added in portions at room temperature. The mixture was stirred overnight at room temperature. The reaction solution was poured into 20 mL of water, extracted with dichloromethane, the organic phase was dried and then spin-dried, and purified by column chromatography (DCM / MeOH=50 / 1) to obtain 120 mg of a pale yellow solid in the upper spot (TLC spot 1) and 130 mg of a pale yellow solid in the lower spot (TLC spot 2) (yield 58%).

[0502] Step 2: Synthesis of (3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl (S)-2-phenylpropionate (TLC spot 1, 120 mg, 0.28 mmol) was dissolved in MeOH / H 2 The mixture was stirred at room temperature for 1 h. The reaction was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was back-extracted once with 1 M aqueous NaOH, dried, and spun to dryness to give 85 mg of the desired product (Trans isomer 1) (100% yield).

[0503] Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol The product obtained in the previous step (Trans isomer 1) was used as a starting material to obtain the target product in the same manner as in Example 34 (i.e., Example 141, Trans isomer 1). LC / MS: m / z=733.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 10.29 (brs, 1H), 9.12 (s, 1H), 7.76-7.73 (m, 1H), 7.61-7.54 (m, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.30 (d, 1H, J = 8.0 Hz), 7.25 (s, 1H), 7.17 (d, 1H, J = 8.4 Hz), 4.50-4.40 (m, 2H), 4.30-4.27 (m, 1H), 4.23-4.18 (m, 2H), 3.65-3.56 (m, 4H), 2.32-2.30 (m, 1H), 2.23-2.17 (m, 1H), 2.15-2.05 (m, 2H), 1.96-1.93 (m, 1H), 1.88-1.85 (m, 2H), 1.65-1.51 (m, 7H).

[0504] The target product was obtained in a similar manner using the product obtained in step 1 (TLC spot 2) as a starting material (i.e., Example 142, Trans isomer 2). LC / MS: m / z=733.3 [M+H] + . 1 H NMR (400mHz, CDCl 3) δ 10.29 (brs, 1H), 9.12 (s, 1H), 7.76-7.73 (m, 1H), 7.61-7.54 (m, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.30 (d, 1H, J = 8.0 Hz), 7.25 (s, 1H), 7.17 (d, 1H, J = 8.4 Hz), 4.50-4.40 (m, 2H), 4.30-4.27 (m, 1H), 4.23-4.18 (m, 2H), 3.65-3.56 (m, 4H), 2.32-2.30 (m, 1H), 2.23-2.17 (m, 1H), 2.15-2.05 (m, 2H), 1.96-1.93 (m, 1H), 1.88-1.85 (m, 2H), 1.65-1.51 (m, 7H).

[0505] Example 143 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((5'-(4-(trifluoromethyl)oxy)dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy]pyrido[4,3d]pyrimidin-7-yl)naphthalen-2-ol

[0506] [ka]

[0507] The target product was synthesized in the same manner as in Example 34 using the starting materials depicted in the synthetic route as raw materials and 1,1-bis(bromomethyl)cyclopropane as a nitrogen alkylating agent in Step 4. LC / MS: m / z=727.3[M+H] + .

[0508] Example 144 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-fluoro-3-(4-(trifluoromethyl)oxy)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol

[0509] [ka]

[0510] Step 1: Synthesis of 1-(tert-butyl) 2-methyl 4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate 1-(tert-butyl) 2-methyl-4-hydroxy-5-oxopyrrolidine-1,2-dicarboxylate (2.59 g, 10.0 mmol) and 25 mL of dichloromethane were added to a flask, and DAST (2.4 g, 15.0 mmol) was added at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 100 mL of water, extracted with dichloromethane, the organic phase was dried and then spun dry, and the crude product was purified by column chromatography (PE:EA=5:1) to obtain 1.7 g of a colorless oily product (65% yield).

[0511] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-fluoro-3-(4-(trifluoromethyl)oxy)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol The target product was synthesized in the same manner as in Example 34 using the product obtained in the previous step as the raw material. LC / MS: m / z=719.3 [M+H] + . 1 H NMR (400mHz, CDCl 3) δ 9.01 (s, 1H), 7.65-7.55 (m, 2H), 7.47 (d, 2H, J = 8.4 Hz), 7.37-7.30 (m, 4H), 7.23-7.15 (m, 4H), 5.19 (s, 0.5H), 5.07 (s, 0.5H), 4.47-4.32 (m, 4H), 3.98 (s, 0.5H), 3.91 (s, 0.5H), 3.65-3.47 (m, 4H), 3.04-2.98 (m, 1H), 2.78-2.70 (m, 1H), 2.56-2.50 (m, 1H), 2.17-2.12 (m, 1H), 1.99-1.87 (m, 3H), 1.76-1.60 (m, 5H).

[0512] Example 145 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(4,4-difluorochroman-6-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0513] [ka]

[0514] Step 1: Synthesis of 7-bromo-1,1-difluorochroman 6-Bromo-4-chromanone (5.0 g, 22.03 mmol) and 20 mL of BAST were added to the flask, and the mixture was stirred overnight at 70° C. The reaction mixture was poured into 200 mL of ice water, extracted with ethyl acetate, and the organic phase was dried and then spun to obtain a crude product, which was purified by column chromatography (PE:EA=8:1) to give 2.1 g of a pale yellow oily product (yield 38.2%). The desired product was synthesized in the same manner as in Example 34 using the above intermediate as a raw material. LC / MS: m / z=745.3 [M+H] + .

[0515] Example 146 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0516] [ka]

[0517] Step 1: Synthesis of 2-(4-bromo-2-(hydroxymethyl)phenyl)propan-2-ol 5-Bromobenzofuran-1(3H)-one (6.4 g, 30.00 mmol) and 50 mL of tetrahydrofuran were added to a three-neck flask, and methylmagnesium bromide (60 mL, 120.00 mmol) was added at 0° C., and the mixture was reacted overnight under heating and reflux. The reaction solution was poured into 200 mL of saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried and then spin-dried to obtain a crude product, which was purified by column chromatography (PE:EA=2:1) ​​to obtain 2.5 g of a light yellow solid (yield 34%).

[0518] Step 2: Synthesis of 5-bromo-1,1-dimethyl-1,3-dihydroisobenzofuran 2-(4-Bromo-2-(hydroxymethyl)phenyl)propan-2-ol (2.5 g, 10.20 mmol) and 20 mL of toluene were added to a flask, phosphoric acid (1.5 g, 15.30 mmol) was added at room temperature, and the reaction system was heated to 80° C. and stirred for 2 hours. After cooling to room temperature, the reaction system was poured into 50 mL of water, extracted with ethyl acetate, the organic phase was dried, and the crude product obtained by spin drying was purified by column chromatography (PE:EA=10:1) to obtain 1.5 g of a whitish solid (yield 65.2%). The desired product was synthesized in the same manner as in Example 34 using the above intermediate as a raw material. LC / MS: m / z=723.3[M+H] + .

[0519] Example 147 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(4-(difluoro(tetrahydro-2H-pyran-4-yl)methyl)phenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0520] [ka]

[0521] Step 1: Synthesis of (4-bromophenyl)(tetrahydro-2H-pyran-4-yl)methanone 1,4-Dibromobenzene (5.0g, 21.2mmol) and 30mL of tetrahydrofuran were added to the flask, and n-BuLi (2.5M, 8.5mL, 21.2mmol) was added at -78°C and stirred for 1 hour at -78°C. N-Methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (4.41g, 25.44mmol) was added and stirred for 1 hour at -78°C. The reaction solution was poured into 100mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and then spin-dried to obtain a crude product, which was purified by column chromatography (PE:EA=3:1) to obtain 4.5g of a whitish solid (yield 79.8%).

[0522] Step 2: Synthesis of 4-((4-bromophenyl)difluoromethyl)tetrahydro-2H-pyran (4-Bromophenyl)(tetrahydro-2H-pyran-4-yl)methanone (4.5 g, 16.72 mmol) and 20 mL of BAST were added to the flask, and the mixture was stirred overnight at 70° C. The reaction solution was poured into 200 mL of ice water, extracted with ethyl acetate, and the organic phase was dried and then spun to obtain a crude product, which was purified by column chromatography (PE:EA=8:1) to obtain 3.1 g of a pale yellow oily product (yield 63.7%). The desired product was synthesized in the same manner as in Example 34 using the above intermediate as a raw material. LC / MS: m / z=787.3[M+H] + .

[0523] Example 148 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(1,3-dihydroisobenzofuran-5-yl-1,1,3,3-d4)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)naphth-2-ol

[0524] [ka]

[0525] Step 1: Synthesis of (4-bromo-1,2-phenylene)bis(methane-d2-ol) Dimethyl 4-bromophthalate (5.0 g, 18.32 mmol) and 50 mL of tetrahydrofuran were added to a flask, and the mixture was cooled to 0°C and cooled to 0°C. 4 (1.04 g, 27.47 mmol) was added and the mixture was stirred at 0° C. for 1 hour. After the reaction was completed, 1 mL of water and 1 mL of 15% aqueous sodium hydroxide solution were added dropwise to the reaction system in an ice bath, and the reaction system was stirred for 5 minutes, after which 3 mL of water was added. An appropriate amount of anhydrous magnesium sulfate was added and the reaction system was stirred for 15 minutes at room temperature. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness to obtain 3.5 g of a whitish solid (yield 86%).

[0526] Step 2: Synthesis of 5-bromo-1,3-dihydroisobenzofuran-1,1,3,3-d4 (4-Bromo-1,2-phenylene)bis(methane-d2-ol) (3.5 g, 15.84 mmol) and 30 mL of toluene were added to the flask, and phosphoric acid (2.33 g, 23.76 mmol) was added at room temperature. The reaction system was heated to 80° C. and stirred for 2 hours. After cooling to room temperature, the reaction system was poured into 80 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried to obtain a crude product, which was purified by column chromatography (PE:EA=10:1) to obtain 2.3 g of a whitish solid (72% yield). The desired product was synthesized in the same manner as in Example 34 using the above intermediate as a raw material. LC / MS: m / z=663.3[M+H] + .

[0527] Example 149 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(1,1,3,3-tetramethyl-1,3-dihydroisobenzofuran-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)naphthalen-2-ol

[0528] [ka]

[0529] The target product was synthesized by the same method as in Example 34 and Example 146 using the starting materials depicted in the synthetic route. LC / MS: m / z=715.4 [M+H] + .

[0530] Example 150 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(2-methoxy-2,3-dihydro-1H-inden-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol

[0531] [ka]

[0532] Step 1: Synthesis of 5-bromo-2,3-dihydro-1H-inden-2-ol 5-Bromo-1,3-dihydro-2H-inden-2-one (5.0 g, 23.70 mmol) and 30 mL of methanol were added to a flask, and NaBH4 (1.08 g, 28.44 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to quench the reaction, and the reaction system was concentrated to remove methanol. Water was then added, and the mixture was extracted with ethyl acetate, and the organic phase was concentrated to dryness to obtain 4.6 g of a whitish solid (yield 92%).

[0533] Step 2: Synthesis of 5-bromo-2-methoxy-2,3-dihydro-1H-indene 5-Bromo-2,3-dihydro-1H-inden-2-ol (4.6 g, 21.60 mmol), potassium carbonate (8.94 g, 64.79 mmol) and DMF (50 mL) were added to a flask, and methyl iodide (6.13 g, 43.20 mmol) was added at room temperature. Under nitrogen gas protection, the reaction mixture was heated to 80° C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried to obtain a crude product, which was purified by column chromatography (PE:EA=5:1) to obtain 2.8 g of a colorless oily product (yield 57.1%). The desired product was synthesized in the same manner as in Example 34 using the above intermediate as a raw material. LC / MS: m / z=687.3[M+H] + .

[0534] Example 151 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(1,3-dihydroisobenzofuran-5-yl-1,1-d2)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0535] [ka]

[0536] The target product was synthesized by the same method as in Example 34 and Example 148 using the starting material depicted in the synthetic route. LC / MS: m / z=697.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 9.13 (s, 1H), 8.03 (s, 1H), 8.00-7.97 (m, 1H), 7.79-7.73 (m, 1H), 7.57 (d, 1H, J = 6.0 Hz), 7.35-7.32 (m, 2H), 7.05-6.97 (m, 2H), 4.44-4.4 (m, 2H), 4.32-4.18 (m, 2H), 3.76-3.45 (m, 12H), 2.76-2.74 (m, 1H), 2.17-2.11 (m, 2H), 1.88-1.57 (m, 6H).

[0537] Example 152 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(2-fluoro-2,3-dihydro-1H-inden-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol

[0538] [ka]

[0539] Step 1: Synthesis of 5-bromo-2-fluoro-2,3-dihydro-1H-indene 5-Bromo-2,3-dihydro-1H-inden-2-ol (3.0 g, 14.08 mmol) and 25 mL of dichloromethane were added to a flask, and DAST (3.4 g, 21.13 mmol) was added at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 100 mL of water, extracted with dichloromethane, and the organic phase was dried and then spun to obtain a crude product, which was purified by column chromatography (PE:EA=5:1) to obtain 1.2 g of a colorless oily product (yield 39.6%). The desired product was synthesized in the same manner as in Example 34 using the above intermediate as a raw material. LC / MS: m / z=675.3[M+H] + .

[0540] Example 153 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(1,2,3,4-tetrahydro-1,4-epoxynaphthalen-6-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0541] [ka]

[0542] Step 1: Synthesis of 6-bromo-1,4-dihydro-1,4-epoxynaphthalene 1,4-Dibromo-2-fluorobenzene (50g, 0.20mol) and furan (40g, 0.59mol) were dissolved in toluene (150mL), purged with nitrogen gas three times, cooled to -30℃, and then n-butyllithium (80mL, 2.5M) was slowly added dropwise. After the addition, the temperature was raised to room temperature and stirred for 0.5 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted twice with ethyl acetate, and the organic phases were combined, washed once with saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA=10:1) to obtain 30g of a colorless oily product (yield 68%).

[0543] Step 2: Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-5-(1,4-dihydro-1,4-epoxynaphthalen-6-yl)-5-oxopentanoate 6-Bromo-1,4-dihydro-1,4-epoxynaphthalene (30 g, 0.13 mol) was dissolved in tetrahydrofuran (150 mL), and the mixture was purged with nitrogen gas three times. The temperature was lowered to -78°C, and n-butyllithium (54 mL, 2.5 M) was slowly added dropwise. After the addition was completed, the mixture was stirred at -78°C for 0.5 hours. Compound Boc-L-methyl pyroglutamate (33g, 0.13mol) was dissolved in tetrahydrofuran (330mL), purged with nitrogen gas three times, cooled to -78℃, and slowly added the above reaction solution while controlling the temperature below -55℃. After completion of the dropwise addition, the mixture was stirred at -78℃ for 0.5 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted twice with ethyl acetate, and the organic phases were combined, washed once with saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain 60g of a pale yellow oily product as a crude product.

[0544] Step 3: Synthesis of methyl 5-(1,4-dihydro-1,4-epoxynaphthalen-6-yl)-3,4-dihydro-2H-pyrrole-2-carboxylate The crude product obtained in the previous step was dissolved in dichloromethane (60 mL), trifluoroacetic acid (60 mL) was slowly added in an ice-water bath, and the mixture was warmed to room temperature and stirred for 1 hour. The crude product obtained by concentrating under reduced pressure was adjusted to pH 7-8 with aqueous sodium bicarbonate, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA=3:1) to obtain 11 g of a light yellow oily product (30% yield for both steps).

[0545] Step 4: Synthesis of methyl 2-(3-chloropropyl)-5-(1,4-dihydro-1,4-epoxynaphthalen-6-yl)-3,4-dihydro-2H-pyrrole-2-carboxylate Methyl 5-(1,4-dihydro-1,4-epoxynaphthalen-6-yl)-3,4-dihydro-2H-pyrrole-2-carboxylate (4 g, 14.9 mmol) and 1-bromo-3-chloropropane (4 g, 22.3 mmol) were dissolved in THF / DMF (36 mL / 3.6 mL), purged with nitrogen gas three times, and sodium hydride (892 mg, 22.3 mmol) was slowly added and stirred at room temperature for 1 hour. The reaction system was poured into a saturated aqueous solution of ammonium chloride, extracted twice with ethyl acetate, and the organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and purified by column chromatography (PE / EA=5:1) to give 3.7 g of a colorless oily product (73% yield).

[0546] Step 5: Synthesis of methyl 3-(1,4-dihydro-1,4-epoxynaphthalen-6-yl)tetrahydro-1H-pyrrozine-7a(5H)-carboxylate 2-(3-chloropropyl)-5-(1,4-dihydro-1,4-epoxynaphthalen-6-yl)-3,4-dihydro-2H-pyrrole-2-methyl carboxylate (3.7 g, 10.7 mmol) was dissolved in methanol (37 mL), and glacial acetic acid (965 mg, 16.0 mmol) and sodium cyanoborate (1.0 g, 16.0 mmol) were added in sequence, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with aqueous sodium bicarbonate and concentrated under reduced pressure to remove most of the methanol. The crude product was extracted three times with water and ethyl acetate, and the organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and purified by column chromatography (PE / EA=1:1). The lower spot was collected to give 1.6 g of a colorless oily product (50% yield).

[0547] Step 6: Synthesis of methyl 3-(1,2,3,4-tetrahydro-1,4-epoxynaphthalen-6-yl)tetrahydro-1H-pyrrozine-7a(5H)-carboxylate 3-(1,4-dihydro-1,4-epoxynaphthalen-6-yl)tetrahydro-1H-pyrrozine-7a(5H)-carboxylate methyl (3.5 g, 11.2 mmol) was dissolved in glacial acetic acid (18 mL), purged with nitrogen gas three times, added palladium carbon 10% (1.0 g), purged with hydrogen gas three times, and stirred at room temperature for 1 hour using a hydrogen balloon. The reaction solution was filtered through diatomaceous earth, concentrated to dryness, adjusted to alkaline pH with aqueous sodium bicarbonate, extracted three times with ethyl acetate, and the organic phases were combined, washed once with saturated saline, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated to dryness, and separated by reverse phase to obtain 1.6 g of a pale yellow oily product (46% yield).

[0548] Step 7: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(1,2,3,4-tetrahydro-1,4-epoxynaphthalen-6-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol The target product was synthesized in the same manner as in Example 34 using the product obtained in the previous step as the raw material.

[0549] LC / MS: m / z=721.3[M+H]+. 1 H NMR (400mHz, CDCl 3 ) δ 10.27 (s, 1H), 9.13 (s, 1H), 7.77-7.73 (m, 1H), 7.61-7.55 (m, 1H), 7.40 (s, 1H), 7.28-7.21 (m, 2H), 7.11-7.04 (m, 2H), 5.32-5.22 (m, 2H), 4.45-4.18 (m, 5H), 3.74-3.71 (m, 1H), 3.65-3.56 (m, 4H), 2.77-2.74 (m, 1H), 2.18-2.08 (m, 2H), 1.91-1.66 (m, 14H).

[0550] Example 154 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(spiro[cyclopropane-1,4'-isochroman]-6'-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0551] [ka]

[0552] Step 1: Synthesis of (1-(3-bromophenyl)cyclopropyl)methanol 1-(3-Bromophenyl)cyclopropane-1-carboxylic acid (4.82 g, 20.00 mmol) and 20 mL of tetrahydrofuran were added to a flask and heated at 0°C with BH 3 -THF (1M, 30 mL) was added and the mixture was stirred at room temperature for 4 hours. Methanol was added to quench the reaction. The reaction solution was concentrated to dryness, and the obtained crude product was used as it was in the next reaction.

[0553] Step 2: Synthesis of 1-bromo-3-(1-((methoxymethoxy)methyl)cyclopropyl)benzene The above crude product was added to 30 mL of dichloromethane solution, and TEA (6.06 g, 60.00 mmol) was added at room temperature, and MOMOCl (2.42 g, 30.00 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 8 hours under nitrogen gas protection. After cooling to room temperature, the reaction system was poured into 100 mL of water, extracted with dichloromethane, and the organic phase was back-extracted twice with dilute hydrochloric acid, dried, and then spin-dried to obtain a crude product, which was used as it was in the next reaction.

[0554] Step 3: Synthesis of 6'-bromospiro[cyclopropane-1,4'-isochroman] The crude product obtained in step 2 was dissolved in 30 mL of DCM, and TMSOTf (13.33 g, 60.00 mmol) was added at 0° C. and stirred for 2 hours. The reaction solution was directly spin-dried to obtain a crude product, which was purified by column chromatography (PE:EA=5:1) to obtain 1.8 g of a pale yellow oily product (37.5% yield for the three steps). The desired product was synthesized in the same manner as in Example 34 using the above intermediate as a raw material. LC / MS: m / z=735.3[M+H] + .

[0555] Example 155 5-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridine[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrozin-3-yl)isobenzofuran-1(3H)-one

[0556] [ka]

[0557] Step 1: Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-5-oxo-5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)valerate 5-Bromobenzofuran-1(3H)-one (2.1g, 10.0mmol), 1-(tert-butyl)2-methyl 5-oxopyrrolidine-1,2-dicarboxylate (2.4g, 10.0mmol) and 20mL of thoroughly dried tetrahydrofuran were added to a flask, and n-butyllithium (2.5M, 4.0mL, 10.0mmol) was added dropwise at 0°C, followed by stirring at 0°C for 1 hour. The reaction solution was poured into 100mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried, spin-dried and purified by column chromatography (PE / EA=5 / 1) to obtain 160mg of a yellow solid (4% yield).

[0558] Step 2: Synthesis of 5-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridine[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrozin-3-yl)isobenzofuran-1(3H)-one The target product was synthesized in the same manner as in Example 34 using the product obtained in the previous step as the raw material. LC / MS: m / z=709.3[M+H] + .

[0559] Example 156 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(3,3-dimethyl-1,3-dihydroisobenzofuran-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0560] [ka]

[0561] The target product was synthesized by the same method as in Example 34, Example 146, and Example 154 using the starting material depicted in the synthetic route.

[0562] LC / MS: m / z=723.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 10.28 (brs, 1H), 9.12 (s, 1H), 7.77-7.73 (m, 1H), 7.61-7.55 (m, 1H), 7.30 (s, 1H), 7.25-7.21 (m, 2H), 7.16 (1H, d, J = 2.8 Hz), 7.07-7.04 (m, 1H), 4.88 (s, 2H), 4.49-4.31 (m, 3H), 4.25-4.18 (m, 1H), 3.79-3.74 (m, 1H), 3.65-3.55 (m, 4H), 2.78 (brs, 1H), 2.56-2.50 (m, 1H), 2.18-2.10 (m, 2H), 1.92-1.80 (m, 4H), 1.79-1.63 (m, 6H), 1.34 (s, 6H).

[0563] Example 157 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(1,3,4,5-tetrahydrobenzo[c]oxaheterocyclyl-7-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl]-5,6-difluoronaphthalen-2-ol

[0564] [ka]

[0565] The target product was synthesized by the same method as in Example 34 and Example 154 using the starting material depicted in the synthetic route. LC / MS: m / z=723.3[M+H] + .

[0566] Example 158 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl-3d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0567] [ka]

[0568] Step 1: Synthesis of methyl 5-(4-fluorophenyl)pyrrolidine-2-carboxylate-5-d Methyl 5-(4-fluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (2.21 g, 10.00 mmol) and 20 mL of methanol were added to a flask, and acetic acid (0.9 g, 15.00 mmol), NaBD 3 CN (0.99 g, 15.00 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 100 mL of water, the pH was adjusted to about 9 with sodium carbonate, extracted with ethyl acetate, the organic phase was dried and then spin-dried to obtain a crude product, which was used as it was in the next reaction. The desired product was synthesized in the same manner as in Example 34 using the above intermediate as a raw material. LC / MS: m / z=672.3[M+H] + .

[0569] Example 159 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4-fluorophenyl)-3-methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol (trans racemate)

[0570] [ka]

[0571] Step 1: Synthesis of ethyl (E)-3-(4-fluorophenyl)but-2-enoate Ethyl 2-(dimethoxyphosphoryl)acetate (14.7 g, 75.0 mmol) and 50 mL of tetrahydrofuran were added to the flask, and NaH (60%, 3.2 g, 80 mmol) was added in portions at 0° C., and the mixture was stirred at room temperature for 1 hour. 4-Fluoroacetophenone (7.0 g, 50.7 mmol) was added, and the reaction solution was subsequently stirred at room temperature for 16 hours. The reaction solution was poured into 200 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and then spin-dried to obtain a crude product, which was used as is in the next reaction.

[0572] Step 2: Synthesis of (E)-3-(4-fluorophenyl)but-2-en-1-ol The above crude product was dissolved in 50 mL of tetrahydrofuran and added to LiAlH 4 (1.91g, 50.0mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, 1.9mL of water and 1.9mL of 15% aqueous sodium hydroxide solution were added dropwise to the reaction system in an ice bath, and the reaction system was stirred for 5 minutes, and then 5.7mL of water was added. An appropriate amount of anhydrous magnesium sulfate was added, and the reaction system was stirred for 15 minutes at room temperature, and the system was filtered under reduced pressure. The filtrate was concentrated to dryness, and the obtained crude product was purified by column chromatography (PE:EA=2:1) ​​to obtain 3.5g of a whitish solid (yield of two steps: 42.2%).

[0573] Step 3: Synthesis of (E)-1-(4-bromobut-2-en-2-yl)-4-fluorobenzene E)-3-(4-fluorophenyl)but-2-en-1-ol (3.5 g, 21.06 mmol) was dissolved in 30 mL of diethyl ether, and phosphorus tribromide (6.84 g, 25.27 mmol) was added under nitrogen gas protection and ice bath, and the reaction system was reacted for 15 minutes with stirring at room temperature. The reaction system was added to 100 mL of ice water, extracted with petroleum ether, the organic phase was dried and then spin-dried, and the crude product was used as it was in the next reaction.

[0574] Step 4: Synthesis of 1-(tert-butyl) 2-methyl (E)-2-(3-(4-fluorophenyl)but-2-en-1-yl)pyrrolidine-1,2-dicarboxylate Boc-L-proline methyl (4.13 g, 18.00 mmol) was dissolved in 40 mL of dry tetrahydrofuran, and LDA (2 M, 13.5 mL, 27.00 mmol) was added dropwise under nitrogen gas protection at -78 ° C. and stirred for 30 minutes. The crude product obtained in step 3 was dissolved in 10 mL of tetrahydrofuran and then added dropwise to the reaction system at -78 ° C., and the reaction was allowed to react for 2 hours while stirring. The reaction system was poured directly into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated to dryness, and the crude product was used as it was in the next reaction.

[0575] Step 5: Synthesis of methyl (E)-2-(3-(4-fluorophenyl)but-2-en-1-yl)pyrrolidine-2-carboxylate The crude product obtained in step 4 was dissolved in 40mL of hydrochloric acid ethyl acetate solution and stirred at room temperature for 1 hour. The reaction system was directly concentrated to dryness, then water was added, the aqueous phase was extracted twice with ethyl acetate, the aqueous phase was adjusted to alkaline with sodium carbonate, then extracted with ethyl acetate, the organic phase was extracted after adjusting to alkaline, dried, and concentrated to dryness to obtain 1.5g of pure product (30% yield for both steps).

[0576] Step 6: Synthesis of methyl 3-(4-fluorophenyl)-2-iodo-3-methyltetrahydro-1H-pyrrozine-7a(5H)-carboxylate (E)-2-(3-(4-fluorophenyl)but-2-en-1-yl)pyrrolidine-2-carboxylate methyl (1.5 g, 5.41 mmol) was dissolved in 20 mL of ethyl acetate, and after adding elemental iodine (1.98 g, 8.11 mmol) at 0°C, the reaction was stirred at room temperature for 2 hours. The reaction system was poured directly into water, extracted with ethyl acetate, and the organic phase was washed twice with an appropriate amount of aqueous sodium hydrogen sulfite solution, and the crude product obtained by concentrating to dryness was used as it was in the next reaction.

[0577] Step 7: Synthesis of methyl 3-(4-fluorophenyl)-3-methyltetrahydro-1H-pyrrozine-7a(5H)-carboxylate The crude product obtained in step 6 was dissolved in 20 mL of toluene, and tributyltin hydride (3.15 g, 10.82 mmol) and AIBN (88 mg, 0.54 mmol) were added at room temperature, and the reaction was heated to 80 ° C. for 2 hours. The reaction was poured directly into water, extracted with ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography (PE:EA = 8:1) to obtain 0.6 g of a pale yellow oily product as the cis intermediate, and 0.5 g of a pale yellow solid product as the trans intermediate was obtained by eluting with a mixed solvent (PE:EA = 2:1) (total yield of two steps 73.3%). The target product was synthesized in the same manner as in Example 140 using the above trans intermediate as a raw material.

[0578] LC / MS: m / z=685.3 [M+H] + . 1 H NMR (400mHz, CDCl 3 ) δ 8.93 (s, 1H), 7.48-7.44 (m, 2H), 7.37-7.33 (m, 1H), 7.25-7.17 (m, 3H), 7.04-6.99 (m, 2H), 4.68-4.41 (m, 5H), 3.74-3.52 (m, 4H), 2.88-2.82 (m, 1H), 2.37-2.23 (m, 4H), 2.11-1.93 (m, 4H), 1.87-1.59 (m, 7H).

[0579] Example 160 4-((3R,7aR)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridine[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrozin-3-yl)phenyl dimethylcarbamate (trans racemate)

[0580] [ka]

[0581] Step 1: Synthesis of 4-((3R,7aR)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrozin-3-yl)phenol tert-Butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((3R,7aR)-3-(4-methoxyphenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.47 mmol) and 5 mL of dichloromethane were added to a flask, and the mixture was cooled to 0° C. with BBr 3 (1M, 1.5 mL, 1.5 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 20 mL of water, extracted with dichloromethane, the organic phase was dried and then spun to dryness to obtain the crude product, which was used directly in the next reaction.

[0582] Step 2: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((3R,7aR)-3-(4-hydroxyphenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate The crude product was dissolved in 5 mL of dichloromethane and mixed with TEA (152 mg, 1.5 mmol) and Boc at room temperature. 2 O (110 mg, 0.5 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction was concentrated to dryness and purified by Prep-TLC (DCM / MeOH=30 / 1) to give 120 mg of a grey solid (40.8% yield for two steps).

[0583] Step 3: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-2-(((3R,7aR)-3-(4-((dimethylcarbamoyl)oxy)phenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0584] tert-Butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(((3R, 7aR)-3-(4-hydroxyphenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.19 mmol) was dissolved in 3 mL of dichloromethane, and DIEA (74 mg, 0.57 mmol) and dimethylcarbamoyl chloride (41 mg, 0.38 mmol) were added at room temperature and stirred overnight. The reaction was directly concentrated to dryness and then purified by Prep-TLC (DCM / MeOH=40 / 1) to give 60 mg of a gray solid (45.1% yield). The desired product was synthesized in the same manner as in Example 34 using the above intermediate as a raw material. LC / MS: m / z=740.3[M+H]+ .

[0585] Example 161 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenylamine (trans racemate)

[0586] [ka]

[0587] Step 1: Synthesis of 1-bromo-3-chloro-2-iodo-5-nitrobenzene 2-Bromo-6-chloro-4-nitroaniline (10 g, 40.0 mmol), potassium iodide (13.3 g, 80.1 mmol), cuprous iodide (15.2 g, 80.0 mmol) and 100 mL of acetonitrile were added to a flask, and tert-butyl nitrite (5.5 g, 53.4 mmol) was added at room temperature, after which the mixture was stirred overnight at 80° C. The reaction solution was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried to obtain a crude product, which was used as is in the next reaction.

[0588] Step 2: Synthesis of 3-bromo-5-chloro-4-iodoaniline 1-Bromo-3-chloro-2-iodo-5-nitrobenzene (crude product obtained in the previous step), 10 mL concentrated hydrochloric acid, and 100 mL ethanol were added to a flask, and iron powder (6.7 g, 119.6 mmol) was added at room temperature, and the mixture was stirred for 2 hours at 80° C. The reaction solution was poured into 500 mL water, the pH value was adjusted to alkaline with sodium hydroxide, extracted with ethyl acetate, the organic phase was dried, and then spin-dried to obtain a crude product, which was used directly in the next reaction.

[0589] Step 3: Synthesis of tert-butyl (3-bromo-5-chloro-4-iodophenyl)carbamate 3-Bromo-5-chloro-4-iodoaniline (crude product obtained in the previous step), triethylamine (8.1 g, 80.2 mmol), DMAP (1.2 g, 9.8 mmol) and 100 mL of dichloromethane were added to a flask and cooled to room temperature to obtain Boc 2 After adding O (17.4 g, 80.0 mmol), the mixture was stirred overnight at 50° C. The reaction solution was poured into 500 mL of water, extracted with ethyl acetate, and the organic phase was dried, spun dry, and purified by column chromatography (DCM / MeOH=50 / 1) to give 3.5 g of a light yellow solid (20% yield for three steps).

[0590] Step 4: Synthesis of tert-butyl (3-bromo-5-chloro-4-(trifluoromethyl)phenyl)carbamate tert-Butyl (3-bromo-5-chloro-4-iodophenyl)carbamate (3.5g, 8.1mmoL), 2,2-difluoro-2-(fluorosulfonyl)methyl acetate (3.1g, 16.2mmoL), cuprous iodide (1g, 5.3mmoL) and 50mL of DMF were added to a flask, and the mixture was stirred for 4 hours under nitrogen gas protection at 90°C. The reaction solution was poured into 200mL of water, extracted with ethyl acetate, the organic phase was dried, then spun dry, and purified by column chromatography (DCM / MeOH=50 / 1) to obtain 1.6g of a light yellow solid (yield 53%).

[0591] Step 5: Synthesis of 3-bromo-5-chloro-4-(trifluoromethyl)phenylamine tert-Butyl (3-bromo-5-chloro-4-(trifluoromethyl)phenyl)carbamate (1.6 g, 4.3 mmol) and 20 mL of dichloromethane were added to a flask, and 2 mL of trifluoroacetic acid was added at room temperature, followed by reaction at room temperature for 4 hours. The reaction solution was poured into 10 mL of water, the pH value was adjusted to alkaline with sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic phase was dried and then spin-dried to obtain 1.2 g of a yellow solid (yield 100%).

[0592] Step 6: Synthesis of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-4-(trifluoromethyl)phenylamine 3-Bromo-5-chloro-4-(trifluoromethyl)phenylamine (1.2 g, 4.38 mmol), bis(pinacolato)diboron (1.3 g, 5.1 mmol), potassium acetate (1.0 g, 10.2 mmol) and 10 mL of dioxane were added to the flask, and after nitrogen gas exchange, Pd(dppf)Cl 2 (220 mg, 0.3 mmol) was added. The reaction mixture was heated to 80° C. under nitrogen gas protection and stirred overnight. After cooling to room temperature, the reaction mixture was poured into 50 mL of water, extracted with ethyl acetate, the organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA=10 / 1) to obtain 830 mg of a white solid (yield 59%).

[0593] Step 7: Synthesis of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenylamine (trans racemate) The target product was synthesized in the same manner as in Example 34 using the boric acid ester depicted in the synthetic route as a raw material. LC / MS: m / z=748.2[M+H] + .

[0594] Example 162 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)phenylamine (trans racemate)

[0595] [ka]

[0596] Step 1: Synthesis of 2-bromo-1-((1,1,1,3,3-hexafluoropropan-2-yl)oxy)-4-nitrobenzene 3-Bromo-4-fluoronitrobenzene (2.2 g, 10.0 mmol), hexafluoroisopropanol (2.52 g, 15.0 mmol) and 15 mL of tetrahydrofuran were added to a flask, potassium tert-butoxide (2.24 g, 20.0 mmol) was added at 0° C., and the mixture was heated to 50° C. and stirred for 6 hours. The reaction solution was poured into 50 mL of water, extracted with ethyl acetate, and the organic phase was dried and then spin-dried to obtain a crude product, which was used as it was in the next reaction.

[0597] Step 2: Synthesis of 3-bromo-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)phenylamine The above crude product was dissolved in 20 mL of ethanol, and 4 mL of water, iron powder (2.79 g, 50.0 mmol) and ammonium chloride (2.68 g, 50.0 mmol) were added at room temperature, and the reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was diluted with ethyl acetate, filtered under reduced pressure, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography (PE:EA=5:1) to obtain 300 mg of a gray solid (8.9% yield for two steps). The desired product was synthesized in the same manner as in Example 161 using the above intermediate as a raw material. LC / MS: m / z=812.3[M+H] + .

[0598] Example 163 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3d]pyrimidin-7-yl)-4-(trifluoromethoxy)(trans racemate)

[0599] [ka]

[0600] The target product was synthesized in the same manner as in Example 161 using the starting materials depicted in the synthetic route. LC / MS: m / z=730.3 [M+H] + . 1 H NMR (400mHz, CDCl 3) δ 9.02 (s, 1H), 7.24-7.15 (m, 3H), 7.03-7.00 (m, 1H), 6.88-6.86 (m, 1H), 6.78-6.75 (m, 1H), 4.62-4.31 (m, 5H), 3.81 (brs, 2H), 3.73-3.57 (s, 4H), 2.62-2.52 (m, 1H), 2.38-2.24 (m, 2H), 2.17-1.99 (m, 4H), 1.76-1.56 (m, 7H).

[0601] Example 164 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3d]pyrimidin-7-yl)-5-fluoro-4-(trifluoromethoxy)(trans racemate)

[0602] [ka]

[0603] Step 1: Synthesis of 2-bromo-6-fluoro-4-nitrophenol 2-Fluoro-4-nitrophenol (2.0 g, 12.74 mmol) and 20 mL of acetonitrile were added to a flask, and NBS (2.72 g, 15.29 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 80 mL of water, extracted with ethyl acetate, and the organic phase was washed twice with an appropriate amount of aqueous sodium hydrogen sulfite solution, dried, then spin-dried, and purified by flash column chromatography (PE / EA=5 / 1) to obtain 2.2 g of a yellow solid (73.3% yield).

[0604] Step 2: Synthesis of 1-bromo-3-fluoro-5-nitro-2-(trifluoromethoxy)benzene 2-Bromo-6-fluoro-4-nitrophenol (2.2 g, 7.33 mmol), silver trifluoromethanesulfonate (5.65 g, 21.99 mmol), N-fluorobenzenesulfonimide (6.93 g, 21.99 mmol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor, 7.79 g, 21.99 mmol), cesium fluoride (3.34 g, 21.99 mmol), 2,6-di-tert-butylphenol (6.05 g, 29.32 mmol), and 100mL of toluene was added to the flask, and 2-fluoropyridine (2.85g, 29.32mmol) and (trifluoromethyl)trimethylsilane (5.21g, 36.65mmol) were added while stirring at room temperature. The reaction mixture was heated to 70°C under nitrogen gas protection and stirred for 6 hours. After cooling to room temperature, the reaction system was directly filtered, the filtrate was poured into 200mL of water, extracted with ethyl acetate, the organic phase was dried, and the crude product obtained by spin drying was purified by column chromatography (PE / EA=50 / 1) to obtain 0.4g of yellow solid (yield 14.1%). The desired product was synthesized in the same manner as in Example 161 using the above intermediate as a raw material.

[0605] LC / MS: m / z=748.2 [M+H] + . 1 H NMR (400mHz, d 6 -DMSO) δ 9.11 (s, 1H), 7.35-7.33 (m, 2H), 7.18-7.16 (m, 1H), 6.66-6.57 (m, 2H), 5.88 (brs, 2H), 4.41-4.38 (m, 2H), 4.29-4.17 (m, 3H), 3.61-3.55 (m, 4H), 2.30-2.10 (m, 4H), 1.96-1.85 (m, 3H), 1.61-1.53 ​​(m, 7H).

[0606] Example 165 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)-[1,1'-biphenyl]-3-amine (trans racemate)

[0607] [ka]

[0608] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-(5-amino-2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (trans racemate) tert-Butyl (1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (intermediate of Example 161, trans racemic, 85 mg, 0.1 mmol), phenylboronic acid (24 mg, 0.2 mmol), potassium carbonate (41 mg, 0.3 mmol) and dioxane / water (2 mL / 0.2 mL) were added to a flask, and nitrogen gas was exchanged, followed by addition of Pd(dppf)Cl 21 mg was added. Under nitrogen gas protection, the reaction mixture was heated to 100° C. and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into 5 mL of water, extracted with ethyl acetate, the organic phase was dried, spun dry, and purified by Prep-TLC (DCM / MeOH=10 / 1) to give 60 mg of a grey solid (67% yield).

[0609] Step 2: Synthesis of 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)-[1,1'-biphenyl]-3-amine (trans racemate) tert-Butyl (1R,5S)-3-(7-(5-amino-2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.067 mmol) was dissolved in 2 mL of ethyl acetate, HCl / EA (4 m, 0.5 mL) was added, and the mixture was stirred for 10 minutes. The reaction was poured into 10 mL of water, adjusted to a weak alkali with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, followed by purification by Prep-TLC to give 45 mg of a gray solid (85% yield). LC / MS: m / z=790.3[M+H] + .

[0610] Example 166 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxy-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3d]pyrimidin-7-yl)-4-ethynylaniline (trans racemate)

[0611] [ka]

[0612] Step 1: Synthesis of 3-bromo-4-((triisopropylsilyl)ethynyl)benzenamine 3-Bromo-4-iodoaniline (1.0 g, 3.36 mmol) and 10 mL of DMF were added to a flask, and triisopropylsilylacetylene (1.23 g, 6.72 mmol), TEA (1.36 g, 13.44 mmol), cuprous iodide (65 mg, 0.34 mmol), and Pd(PPh) were added at room temperature. 3 ) 2 Cl 2 (239 mg, 0.34 mmol) was added and the mixture was stirred at 70° C. for 4 h. The reaction mixture was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and then spun to dryness, and the crude product was purified by column chromatography (PE / EA=10 / 1) to give 0.6 g of a light yellow solid (yield 50.9%).

[0613] Step 2: Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-4-((triisopropylsilyl)ethynyl)benzenamine 3-Bromo-4-((triisopropylsilyl)ethynyl)benzeneamine (0.6 g, 1.70 mmol), bis(pinacolato)diboron (0.5 g, 1.97 mmol), potassium acetate (0.4 g, 4.08 mmol) and 50 mL of dioxane were added to the flask, and after nitrogen gas exchange, Pd(dppf)Cl 2(73 mg, 0.1 mmol) was added. The reaction mixture was heated to 80° C. under nitrogen gas protection and stirred overnight. After cooling to room temperature, the reaction mixture was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and then spin-dried, and purified by silica gel column chromatography (PE / EA=20 / 1) to obtain 445 mg of a white solid (yield 65.4%). The desired product was synthesized in the same manner as in Example 52 using the above intermediate as a raw material. LC / MS: m / z=670.3[M+H] + .

[0614] Example 167 (Isobutyryloxy)methyl (1R,5S)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0615] [ka]

[0616] Step 1: Synthesis of (isobutyryloxy)methyl (1R,5S)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol (150mg, 0.22mmol), TEA (89mg, 0.88mmol) and 5mL of dichloromethane were added to a flask, and ((chlorocarbonyl)oxy)methyl isobutyrate (43mg, 0.24mmol) was added at 0℃, and the mixture was stirred at room temperature for 1 hour. The reaction system was directly spin-dried and then purified by Prep-TLC (DCM / MeOH=35 / 1) to obtain 105mg of a whitish solid (yield 58.7%). LC / MS: m / z=815.3[M+H] + .

[0617] Example 168 (Isobutyryloxy)methyl (1R,5S)-3-(7-(3-acetoxy-7,8-difluoronaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0618] [ka]

[0619] Step 1: Synthesis of ((isobutyryloxy)methyl (1R,5S)-3-(7-(3-acetoxy-7,8-difluoronaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ((isobutyryloxy)methyl (1R,5S)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50mg, 0.06mmol), TEA (31mg, 0.36mmol) and 5mL of dichloromethane were added to a flask, and acetyl chloride (14mg, 0.18mmol) was added at 0℃, and the mixture was stirred at room temperature for 1 hour. The reaction system was directly spin-dried and then purified by Prep-TLC (DCM / MeOH=50 / 1) to obtain 35mg of a white solid (yield 66.1%). LC / MS: m / z=857.3[M+H] + .

[0620] Example 169 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-yl dimethylcarbamate

[0621] [ka]

[0622] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol (670 mg, 1.0 mmol), triethylamine (303 mg, 3.0 mmol) and 5 mL of dichloromethane were added to a flask, and the mixture was cooled to 0° C. and cooled to 3° C. with 5 mL of Boc. 2 O (218 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was used in the next reaction as it was.

[0623] Step 2: Synthesis of tert-butyl (1R,5S)-3-(7-(3-((dimethylcarbamoyl)oxy)-7,8-difluoronaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Dimethylcarbamoyl chloride (107 mg, 1.0 mmol) was added to the reaction solution obtained in the previous step at 0° C. and stirred overnight. The reaction solution was concentrated to dryness and then purified by column chromatography (DCM / MeOH=40 / 1) to give 230 mg of a gray solid (27% yield for both steps).

[0624] Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-yl dimethylcarbamate tert-Butyl (1R,5S)-3-(7-(3-((dimethylcarbamoyl)oxy)-7,8-difluoronaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.27 mmol) was dissolved in 5 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added at room temperature, and the mixture was stirred at room temperature for 0.5 hours. The reaction system was poured into 10 mL of water, adjusted to a weak alkali with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and then spin-dried, followed by purification by Prep-TLC to obtain 150 mg of a gray solid (74% yield).

[0625] LC / MS: m / z=742.3[M+H] + . The compounds of the following Examples 170 to 246 were synthesized using the corresponding commercially available reagents as starting materials by the same procedures as those described in the above Examples.

[0626] [Table 2] JPEG2025510705000133.jpg232170JPEG2025510705000134.jpg230170JPEG2025510705000135.jpg247170 JPEG2025510705000136.jpg231170JPEG2025510705000137.jpg222170JPEG2025510705000138.jpg236170 JPEG2025510705000139.jpg251170JPEG2025510705000140.jpg239170JPEG2025510705000141.jpg249170 JPEG2025510705000142.jpg220170JPEG2025510705000143.jpg250170JPEG2025510705000144.jpg201170

[0627] Note: "trans isomer" refers to the trans isomer and "trans racemate" refers to the trans racemate.

[0628] Drug efficacy test Test Example 1: KRAS G12D GTP::SOS1 homogeneous time-resolved fluorescence binding experiment 1. Test method: Protein-protein interactions were measured by homogeneous time-resolved fluorescence techniques. 0.1 μl of compound was added to a 384 reaction plate (Corning, CLS4514), and after centrifugation, 5 μl of a mixture of Tag2-KRAS G12D (Cisbio, 63ADK000CB17PEG) protein and GTP (SIGMA, V900868) to a final concentration of 10 μM was added. 5 μl of Tag1-SOS1 (Cisbio, 63ADK000CB17PEG) protein solution was added and reacted at room temperature for 15 minutes. All protein interactions occurred in Diluent (Cisbio, 62DLBDDF) buffer. 10 μl of a detection solution of 100X Anti-Tag1-Tb and 25X Anti-Tag2-XL665 that had been premixed was added and reacted at 4°C for 180 minutes. The detection reagent was generated in Detection Buffer (Cisbio, 62DB2FDG). The reaction signals were detected by a multifunction microplate reader, and the data were analyzed using GraphPad Prism data analysis software.

[0629] 2. Table 3 shows the inhibitory activity of the compounds according to the present invention against KRAS G12D GTP::SOS1 binding.

[0630] [Table 3]

[0631] Conclusion: The above data show that some compounds of the present invention are effective in blocking the binding of KRAS G12D protein and SOS1, and can be used to treat pancreatic ductal carcinoma, colon cancer, rectal cancer, non-small cell lung cancer, etc., and have the prospects for broad application.

[0632] Test Example 2: Measurement of the inhibitory activity of compounds against KRas Gl2D-mediated ERK phosphorylation 1. Test method: Day 1: Seed AGS cells into 384-well cell culture plates and incubate at 37 °C, 5% CO 2 The cells were cultured overnight in an incubator. Day 2: Add compounds to plates using Echo550 and incubate at 37°C, 5% CO 2 The cells were incubated in an incubator for 3 hours, then paraformaldehyde was added for fixation, permeabilization was performed with methanol, and the cells were blocked with blocking solution, after which a mixture of primary antibodies (rabbit anti-pERK, mouse anti-GAPDH) was added and incubated overnight at 4°C. Day 3: The primary antibody was discarded and the secondary antibody mixture (goat anti-rabbit 800CW, goat anti-mouse 680RD) was added and incubated at room temperature in the dark. After washing with PBST, the cell culture plate was inverted and centrifuged for 1 minute. The fluorescence signal value was read using an Odyssey CLx.

[0633] ERK phosphorylation was calculated according to the following formula: Relative expression level = (fluorescence signal ratio of compound - average positive control value) / (average negative control value - average positive control value) Negative control: DMSO Positive control: Reference 10 μM IC50 values ​​were calculated according to parametric equation fitting by XLFit 5.0. Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)×HillSlope)) X: log value of compound concentration Y: Mean relative expression of p-ERK among duplicate wells

[0634] 2. The inhibitory activity of the compounds according to the present invention against ERK phosphorylation is shown in Table 4.

[0635] [Table 4] JPEG2025510705000147.jpg199170

[0636] [Table 5]

[0637] Conclusion: The above data indicate that the compounds of the present invention are effective in inhibiting the phosphorylation of ERK, a downstream target of the KRAS pathway, and some of the compounds have activity equivalent to that of MRTX1133, while some of the compounds have activity superior to that of MRTX1133, and have the prospects for broad application.

[0638] Test Example 3: Measurement of the inhibition of 3D cell proliferation by compounds Add diluted test compounds to 384-well low-adherence cell culture plates using a nanoliter liquid dispensing system (LABCYTE, P-0200), and plate cells at 37°C and 5% CO. 2 After incubation in a 200-well incubator for 7 days, CellTiter-Glo® 2D reagent was added and the luminescence value was read on an Envision multifunctional microplate reader (the light signal is proportional to the amount of ATP in the system, and the ATP content represents the number of viable cells in the system). Finally, the IC50 (half maximal inhibitory concentration) of the compound was determined by a nonlinear fitting equation using XLFIT software.

[0639] 1. Experimental Method a) Diluted test compounds were added to 384-well low-binding capacity cell culture plates using a nanoliter liquid dispensing system. b) The cells were seeded in the 384-well culture plate of a) and centrifuged at room temperature at 1000 rpm for 1 minute, and the final DMSO concentration of the compound was adjusted to 0.5%, and the plate was incubated at 37°C and 5% CO 2 The plate was placed in a constant temperature incubator and incubated for 7 days. c) CellTiter-Glo(R) 3D was added to the 384-well cell culture plate in b) and incubated at room temperature with shaking, protected from light. d) Luminescence values ​​were read on an Envision multifunction microplate reader.

[0640] 2. Data Analysis Using XLFIT software, the IC50 (half maximal inhibitory concentration) of the compound was determined by the following nonlinear fitting equation: Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)×HillSlope)) X: log value of compound concentration Y: Inhibition rate (%) Inhibition rate (%) = 100 x (mean negative control value - compound reading) / (mean negative control value - mean positive control value) Negative control: DMSO Positive control: Medium only

[0641] 3. The data of the inhibitory activity of some compounds of the present invention on 3D cell proliferation are shown in Table 6.

[0642] [Table 6]

[0643] Conclusion: The above data indicate that some compounds of the present invention are effective in inhibiting the proliferation of KRAS G12D mutant cells, with activity comparable to that of MRTX1133.

[0644] Test E...

Claims

1. A compound represented by the following formula (I), its tautomer, meso isomer, racemate, enantiomer, diastereoisomer or mixed form thereof, metabolite, metabolic precursor, isotopically substituted form, salt, pharma- ceutically acceptable salt, hydrate, solvate, crystalline polymorph, or cocrystal. 【Chemistry 1】 (In the formula, A １ , A ２ , A ３ , A ４ , A ５ , A ６ are each independently C-R ４ or N, R １ is selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group; R ２ is selected from substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups; R ３ is selected from substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups; A １ , A ２ , A ３ , A ４ , A ５ , A ６ The substituent R in ４ are each selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroaryl groups, substituted or unsubstituted cycloalkyl or heterocycloalkyl groups, substituted or unsubstituted unsaturated ring or heterocyclyl groups, substituted or unsubstituted aryl or heteroaryl groups, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, thiol groups, amide groups, sulfonyl groups, phosphoryl groups, alkylphosphinoyl groups, alkylsulfonyl groups, and alkylsulfinyl groups; L １ and L ２ is absent or independently selected from the group consisting of -CH=CH-, -N(Ra)-, -N(Ra)-(CRaRb)n-, -O-(CRaRb)n-, and -(CRaRb)n-; Ra and Rb are each independently selected from the group consisting of hydrogen, deuterium, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, and a C3-C6 cycloalkyl group.

2. The compound according to claim 1, characterized in that the compound has the structure shown in the following formula (II), its tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or co-crystals. 【Chemistry 2】 (In the formula, R １ is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted aryl groups; R ２ is selected from substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups; R ３ is selected from substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups; L １ is absent or is -N(Ra)- or -N(Ra)-(CRaRb)-; L ２ is -O-(CRaRb)n-, -CH=CH-, or -(CRaRb)n-, where Ra and Rb are each independently selected from the group consisting of hydrogen, deuterium, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, and a C3-C6 cycloalkyl group.

3. The compound according to claim 2, characterized in that the compound has a structure represented by the following formula (III) or a structure represented by the following formula (IV), or a tautomer, meso isomer, racemate, enantiomeric isomer, diastereomeric isomer or a mixed form thereof, metabolite, metabolic precursor, isotopically substituted form, pharma- ceutically acceptable salt, hydrate, solvate, crystalline polymorph, or cocrystal thereof. 【Chemistry 3】 (In the formula, Ring A is a 4-12 membered heterocycle having heteroatoms N and / or O; Ring B is a 4- to 12-membered heterocycle having a heteroatom N; ring A and ring B are each independently selected from the group consisting of saturated or partially saturated monocyclic, ortho-fused, bridged, and spiro rings; Z is hydrogen or deuterium; R １ is selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl group; R ５ , R ６ , R ７ are each independently selected from the group consisting of hydrogen, deuterium, a halogen, a substituted or unsubstituted alkyl or cycloalkyl group, a substituted or unsubstituted heteroalkyl or heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group, with the proviso that the substituted groups are each independently selected from the group consisting of a halogen, an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group; m1 is selected from integers from 0 to 6; m2 is selected from integers of 0 to 6.

4. The compound according to claim 3, characterized in that Ring B is selected from the following: its tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or co-crystals. 【Chemistry 4】 (however, X １ , X ２ is independently selected from the group consisting of hydrogen, deuterium, and halogen; Y is hydrogen or deuterium; R ８ , R ２０ , R ２１ are each selected from the group consisting of a substituted or unsubstituted aryl or heteroaryl group, a substituted or unsubstituted alkyl or cycloalkyl group, and a substituted or unsubstituted heteroalkyl or heterocycloalkyl group; R ９ , R １０ , R ２２ are each independently selected from the group consisting of a substituted or unsubstituted alkyl group or cycloalkyl group, a substituted or unsubstituted heteroalkyl group or heterocycloalkyl group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group (wherein each of the substituted groups is independently selected from the group consisting of a halogen, an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group); R １１ is a substituted monocyclic heteroalkyl group having heteroatoms N and / or O.

5. Ring A is selected from the following: 【Chemistry 5】 Ring C 【Chemistry 6】 (where X ３ ~X １６ are each independently -NR １２ -, -O-, -CO-, and -CR １４ R １５ - is selected from the group consisting of; R １２ , R １４ , R １５ are each independently selected from the group consisting of hydrogen, deuterium, a halogen, a substituted or unsubstituted alkyl or cycloalkyl group, a substituted or unsubstituted heteroalkyl or heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group, wherein the substituted groups are each independently selected from the group consisting of a halogen, an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group; q is selected from the integers 0 to 3, and when q=0, the chemical bond is absent.

4. The compound according to claim 3, its tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or co-crystals, characterized in that:

6. R １ The compound according to claim 3, characterized in that: is selected from the following: its tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or co-crystals. 【Chemistry 7】 (However, １ , W ３ , W ５ , W ８ , W ９ , W １１ , W １２ , W １３ , W １５ , W １６ , W １７ is -NR １２ -, -O-, -CO-, -CR １７ R １８ - and -SO ２ - selected from the group consisting of W ２ , W ４ , W ６ , W ７ , W １０ , W １４ , W １８ , W １９ , W ２０ , W ２１ , W ２２ , W ２３ , W ２４ , W ２５ , W ２６ , W ２７ is a N atom or R １６ and a C atom substituted with W ２３ And W ２４ R １６ In the case where the C atom is a C atom substituted with, the two carbon atoms are linked by a chemical bond to form a saturated or unsaturated 5- or 6-membered ring, R １２ , R １６ , R １７ , R １８ are each independently selected from the group consisting of hydrogen, deuterium, a halogen, a substituted or unsubstituted alkyl group or cycloalkyl group, a substituted or unsubstituted heteroalkyl group or heterocycloalkyl group, a hydroxyl group, an alkynyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group (wherein each of the substituted groups is independently selected from the group consisting of a halogen, an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group).

7. The compound according to claim 3, characterized in that the compound has any one of the following structures: Formula (V), Formula (VI), and Formula (VII), or its tautomer, meso form, racemate, enantiomeric form, diastereomeric form, or mixed form thereof, metabolite, metabolic precursor, isotopically substituted form, pharma- ceutically acceptable salt, hydrate, solvate, crystalline polymorph, or cocrystal. 【Chemistry 8】 (In the formula, X １ , X ２ is independently selected from the group consisting of hydrogen, deuterium, and halogen, Y is hydrogen or deuterium, Z is hydrogen or deuterium; R ８ , R ２０ , R ２１ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted aryl or heteroaryl groups, substituted or unsubstituted alkyl or cycloalkyl groups, and substituted or unsubstituted heteroalkyl or heterocycloalkyl groups; R ２２ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or cycloalkyl groups, substituted or unsubstituted heteroalkyl or heterocycloalkyl groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups, with the proviso that each of the substituted groups is independently selected from the group consisting of halogen, alkyl groups, cycloalkyl groups, heteroalkyl groups, heterocycloalkyl groups, hydroxyl groups, cyano groups, amino groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups; X ３ is -NR １２ -, -O-, -CO-, and -CR １４ R １５ - selected from the group consisting of W １９ , W ２０ , W ２２ are independently a N atom, R １６ C atoms substituted with

8. The compound according to claim 7, characterized in that the compound has one of the following structures: Formula (VIII), Formula (IX), and Formula (X), its tautomer, meso form, racemate, enantiomeric form, diastereomeric form, or mixed form thereof, metabolite, metabolic precursor, isotopically substituted form, pharma- ceutically acceptable salt, hydrate, solvate, crystalline polymorph, or cocrystal. 【Chemistry 9】 (X １ , X ２ is independently selected from the group consisting of hydrogen, deuterium, and halogen, Y is hydrogen or deuterium, Z is hydrogen or deuterium; X ３ is -NR １２ -, -O-, -CO-, and -CR １４ R １５ - selected from the group consisting of W １９ , W ２０ , W ２２ each independently represents an N atom, R １６ C atoms substituted with R １９ is -H, -OH, halogen, -NO ２ , -CN, -CF ３ , -C ２ F ５ , -OCF ３ , -OCHF ２ , -OCH ２ F, a substituted or unsubstituted alkyl or cycloalkyl group, a substituted or unsubstituted heteroalkyl or heterocycloalkyl group, an alkyloxy group, an alkynyl group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group, wherein the substituted groups are each independently selected from the group consisting of a halogen, an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, a hydroxyl group, a cyano group, an amino group, an ester group, an amide group, an aryl group, a heteroaryl group, an acylguanidine group, a sulfonyl group, a phosphoryl group, a sulfone group, and a phosphate group; R ２２ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or cycloalkyl groups, substituted or unsubstituted heteroalkyl or heterocycloalkyl groups, alkyloxy groups, alkynyl groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups, with the proviso that each of the substituted groups is independently selected from the group consisting of halogen, alkyl groups, cycloalkyl groups, heteroalkyl groups, heterocycloalkyl groups, hydroxyl groups, cyano groups, amino groups, ester groups, amide groups, aryl groups, heteroaryl groups, acylguanidine groups, sulfonyl groups, phosphoryl groups, sulfone groups, and phosphate groups; m3 is selected from integers from 0 to 5, and when m3 is 2 or more, R １９ is a 4- to 7-membered ring optionally condensed with a benzene ring.

9. The compound according to claim 3, characterized in that the compound has a structure represented by the following formula (XI) or a structure represented by the following formula (XII), its tautomer, meso form, racemate, enantiomeric form, diastereomeric form or mixed form thereof, metabolite, metabolic precursor, isotopically substituted form, pharma- ceutically acceptable salt, hydrate, solvate, crystalline polymorph, or cocrystal. 【Chemistry 10】 wherein Y is hydrogen or deuterium, Z is hydrogen or deuterium, R in General Formula XI ２３ are independently -H, -F, -Cl, -CN, -CF ３ , alkenyl group, alkynyl group, C １－３ Linear alkyl groups, and C ３－６ cycloalkyl groups, R ２４ is -H, C １－５ an alkyl group or a heteroaryl group, and -COR ５５ (Here, R ５５ is -H, C １－１０ Linear / branched alkyl group, C １－１０ Linear / branched heteroalkyl groups, C ３－６ Cycloalkyl groups, and C ３－６ heterocycloalkyl groups; R ２５ is -H, -CO(C ０－１０ alkyl group), -COO(C ０－１０ alkyl group), —COO—CH ２ -OCO(C ０－１０ alkyl group), and -COO-CH(CH ３ )-OCO(C ０－１０ alkyl groups), K is C or N, and when K is N, R corresponding to K is ２９ is non-existent, The R ２６ , R ２７ , R ２８ , R ２９ , R ３０ are independently -H, -OH, halogen, or -NO ２ , -CN, -CF ３ , -C ２ F ５ , -OCF ３ , -OCHF ２ , -OCH ２ F, phosphate group, monomethyl phosphate group, dimethyl phosphate group, C １－５ Linear / branched alkyl group, C １－５ Alkyloxy group, C ３－１０ Cycloalkyl group, C ３－１０ Heterocycloalkyl groups, -N(C ０－１０ Alkyl group) (C ０－１０ alkyl group), -S(C ０－１０ alkyl group), -OCON(C ０－１０ Alkyl group) (C ０－１０ Alkyl group), C ５－６ aryl groups, 5-membered heteroaryl groups, and 6-membered heteroaryl groups; or R ２７ , R ２８ and R ２７ and R ２８ The carbon atom between is saturated or unsaturated C ３－８ Cycloalkyl groups, saturated or unsaturated C ３－８ Heterocycloalkyl groups, saturated or unsaturated cyclic lactones, C ５－６ Aryl groups, bridged cycloalkyl groups, spirocycloalkyl groups, where H in said groups is optionally -D, -OH, -F, -NO ２ , -CN, -CF ３ , -C ２ F ５ , C １－３ substituted with an alkyl group or an amide group); m4 is selected from integers from 0 to 4; Here, R in general formula XII ３１ are independently -F, -Cl, -NH ２ , -CN, -CF ３ , -C ２ F ５ , -OCF ３ , alkenyl group, alkynyl group, C １－３ Linear / branched alkyl group, C １－３ Linear / branched alkyloxy group, C ３－６ selected from the group consisting of cycloalkyl groups, aryl groups, and heteroaryl groups; R ３２ is -H, C １－５ Linear / branched alkyl groups, and C ３－６ cycloalkyl groups, R ３３ is -H, -CO(C ０－１０ alkyl group), -COO(C ０－１０ alkyl group), and —COO—CH ２ -OCO(C ０－１０ alkyl group), and -COO-CH(CH ３ )-OCO(C ０－１０ alkyl groups), The R ３４ , R ３５ , R ３６ , R ３７ , R ３８ are independently -H, -OH, halogen, or -NO ２ , -CN, -CF ３ , -C ２ F ５ , -OCF ３ , -OCHF ２ , -OCH ２ F.C. １－５ Linear / branched alkyl group, C １－５ Alkyloxy group, C ３－１０ Cycloalkyl groups, and C ３－１０ heterocycloalkyl groups, or R ３５ , R ３６ and R ３５ and R ３６ The carbon atom between is saturated or unsaturated C ３－８ Cycloalkyl groups, saturated or unsaturated C ３－８ forming a heterocycloalkyl group, wherein H in said group is optionally -D, -OH, -F, -NO ２ , -CN, -CF ３ , -C ２ F ５ , C １－３ substituted with an alkyl group or an amide group); m ５ is selected from integers of 0 to 4.

10. The compound of claim 9, characterized in that the compound has the following structure: its tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or co-crystals. 【Chemistry 11】 (In the formula, R ３９ , R ４０ are independently -H, -F, -Cl, -CN, an alkynyl group, and C １－３ linear alkyl groups; R ４１ , R ４２ , R ４３ , R ４４ are independently -H, -OH, -F, -Cl, -CN, or -CF ３ , -C ２ F ５ , -OCF ３ , monomethylphosphoryl group, dimethylphosphoryl group, C １－５ Linear / branched alkyl group, C １－５ Alkyloxy group, C ３－１０ Cycloalkyl group, C ３－１０ Heterocycloalkyl groups, -S(C ０－１０ alkyl group), -OCON(C ０－１０ Alkyl group) (C ０－１０ Alkyl group), C ５－６ aryl groups, 5-membered heteroaryl groups, 6-membered heteroaryl groups, or R ４２ , R ４３ and R ４２ and R ４３ The carbon atom between is saturated or unsaturated C ３－８ Cycloalkyl groups, saturated or unsaturated C ３－８ Heterocycloalkyl group, 5-membered lactone, C ５－６ Aryl groups, bridged cycloalkyl groups, and spirocycloalkyl groups, in which H is optionally -D, -OH, -F, -NO ２ , -CN, -CF ３ , -C ２ F ５ , C １－３ substituted with alkyl, amide groups); R ４５ and R ４６ are independently -H, -F, -Cl, -NH ２ , -CN, -CF ３ , -C ２ F ５ , -OCF ３ , an alkynyl group, C １－３ Straight chain alkyl group, C １－３ Alkoxyl group, C ３－６ selected from the group consisting of cycloalkyl groups, aryl groups, and heteroaryl groups; R ４７ , R ４８ , R ４９ are independently -H, -F, -Cl, -CN, -CF ３ , and -C ２ F ５ or R ４７ , R ４８ YR ４７ and R ４８ The carbon atom between is saturated or unsaturated C ３－８ Cycloalkyl groups, saturated or unsaturated C ３－８ forming a heterocycloalkyl group, where H in said group is optionally -D, -OH, -F, -CN, -CF ３ , C １－３ substituted with an alkyl group).

11. R on the benzene ring in formula XIII ４２ , R ４３ and R ４２ and R ４３ The carbon atoms between are saturated or unsaturated C ３－８ Cycloalkyl groups, saturated or unsaturated C ３－８ Heterocycloalkyl group, 5-membered lactone, C ５－６ forming an aryl group, a bridged cycloalkyl group, or a spirocycloalkyl group; 【Chemistry 12】 (In the formula, K ２ , K ３ , K ４ is condensed with a benzene ring to form a saturated or unsaturated five-membered ring; K ２ , K ３ , K ４ are each independently selected from the group consisting of C, N, O, and S; K ５ , K ６ , K ７ are each independently selected from the group consisting of C, N, O, and S; K ８ is independently selected from the group consisting of C, N, O, and S; R ５０ , R ５１ , R ５２ , R ５３ are independently -H, -D, -OH, -F, -NO ２ , -CN, -CF ３ , -C ２ F ５ , C １－３ Alkyl group, C １－３ Alkoxyl group, and C ３－６ cycloalkyl groups; m6, m7, m8, and m9 are selected from the group consisting of integers of 0 to 6); R on the benzene ring in formula XIV ４７ , R ４８ and R ４７ and R ４８ The carbon atoms between 【Chemistry 13】 (However, K ９ , K １０ , K １１ is independently selected from the group consisting of C, N, and O; R ５４ are independently -H, -F, -CN, -CF ３ , -C ２ F ５ , C １－３ Alkyl group, C １－３ Alkoxyl group, and C ３－６ cycloalkyl groups; m10 is selected from the group consisting of an integer of 0 to 4; ３－８ Cycloalkyl groups, saturated or unsaturated C ３－８ The compound according to claim 10, characterized in that it forms a heterocycloalkyl group, its tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or cocrystals.

12. The compound according to claim 1, characterized in that formula (I) is a structure selected from the following: its tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms, pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs, or co-crystals. 【Chemistry 14】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

13. A pharmaceutical composition comprising, as an active compound, one or more selected from the compound according to any one of claims 1 to 12, its tautomer, meso form, racemate, enantiomer, diastereoisomer or a mixed form thereof, metabolite, metabolic precursor, isotopically substituted form, pharma- ceutically acceptable salt, hydrate, solvate, crystalline polymorph, and cocrystal.

14. 13. Use of a compound according to any one of claims 1 to 12, its tautomers, meso isomers, racemates, enantiomers, diastereoisomers or mixed forms thereof, metabolites, metabolic precursors, isotopically substituted forms (e.g. where a hydrogen atom is replaced by a deuterium atom), pharma- ceutically acceptable salts, hydrates, solvates, crystalline polymorphs or co-crystals in the manufacture of a medicament for a KRAS inhibitor, preferably for the manufacture of a medicament for a KRAS G12D mutation.

15. 13. Use of a compound according to any one of claims 1 to 12, its tautomer, meso form, racemate, enantiomer, diastereoisomer or mixed form thereof, metabolite, metabolic precursor, isotopically substituted form, pharma- ceutically acceptable salt, hydrate, solvate, crystalline polymorph, or co-crystal, in the manufacture of a medicament for the treatment, amelioration, or prevention of a disease or condition associated with Noonan syndrome, LEOPARD syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal carcinoma, or colorectal cancer.

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