Pyridine derivative and use thereof in medicine

Abstract

The present invention relates to a pyridine derivative and a use thereof in medicine, and in particular to a compound as represented by formula (I), or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or co-crystals thereof, a pharmaceutical composition containing same, and a use of the compound or composition of the present application in preparation of a drug for treating a tumor.

Description

A pyridine derivative and its application in medicine Technical Field

[0001] The present invention relates to a pyridine derivative and its application in medicine. Background Art

[0002] Protein arginine methyltransferase 5 (PRMT5), a type II arginine methyltransferase, regulates key cellular processes, including DNA damage repair, cell cycle regulation, transcriptional regulation, and RNA splicing, by catalyzing the symmetric dimethylation of arginine in histones and other proteins. Studies have shown that overexpression of PRMT5 plays a key role in various cancers, making it a promising drug target.

[0003] Methylthioadenosine phosphorylase (MTAP) is one of the key enzymes in the methionine salvage biosynthesis pathway. Since the MTAP gene is located close to the tumor suppressor gene CDKN2A on the chromosome, co-deletion often occurs in cancer. By screening 390 cancer cell models with shRNA, researchers found that MTAP - / - The activity of tumor cells was significantly reduced after the expression of PRMT5 was inhibited. WT Knockout of MTAP in cells makes cells more sensitive to PRMT5 inhibition; - / - Re-expression of MTAP in cells can improve the tolerance of cells to PRMT5 inhibitors. The loss of MTAP in cells will lead to the accumulation of the metabolite methylthioadenosine (MTA), and MTA can compete with SAM to bind to PRMT5 to form a complex, while exerting a certain inhibitory effect on PRMT5. PRMT5 plays an important role in normal tissues. Direct inhibition of PRMT5 can easily lead to off-target compounds and bring serious side effects. Targeting the PRMT5-MTA complex can improve the compound's ability to inhibit MTAP. - / - The selectivity and targeting of tumors, as well as the reduction of toxic side effects caused by compounds, deserve further study.

[0004] Summary of the Invention

[0005] The purpose of the present invention is to provide a pyridine derivative capable of inhibiting the overexpression of PRMT5 and the use of the pyridine derivative in the preparation of anti-tumor drugs.

[0006] Specifically, the present invention relates to a compound represented by formula (I), or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof:

[0007] Wherein: R3 is selected from -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 4-6 Heterocyclic group, -C 0-6 Alkyl-C 5-10 Heteroaryl, -C 0-6 Alkyl-O-R8 or C 1-6 Alkyl; R8 is selected from H, D, hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocyclic or C 5- 10 Heteroaryl; R3 may be further optionally substituted by one or more selected from D, halogen, hydroxy, carbonyl, cyano, C 1-6 Alkyl, -C 0-6 Alkyl-OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocyclic or C 5-10 substituted by a heteroaryl substituent;

[0008] R4 is C(R9)3, each R9 is independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 5-10 Heteroaryl; wherein at least one R9 is selected from C 6-10 Aryl or C 5-10 heteroaryl, and the C 6-10 Aryl or C 5-10 Heteroaryl fused to C 3-6 Cycloalkyl or C 5-12 Heterocyclyl; R9 is optionally further selected from one or more C 1- 6 alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 5-10 substituted by a heteroaryl substituent;

[0009] or R3 and R4 and the nitrogen atom to which they are directly connected together form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted by one or more radicals selected from D, hydroxyl, halogen, cyano, nitro, azido, carboxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, =O, =S, -C 0-6 Alkyl-11-20 membered polycyclic, -C0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-6 The substituent of the heterocyclic group is substituted; wherein the C 1-6 Alkyl, -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4- 6 heterocyclic group is optionally further substituted by one or more selected from D, hydroxy, halogen, cyano, nitro, azido, carboxyl, C 1-6 Alkyl, -C 0-6 Alkyl-OH, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, =O, =S, -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-8 Substitution of a heterocyclic group by a substituent;

[0010] X, Y, and Z are independently selected from N or CR 10 , R 10 Selected from H, D, halogen, cyano, nitro, azido, C 1- 6 alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-OS(O)2R 11 、-C 0-8 Alkyl-OR 12 、-C 0-8 Alkyl-C(O)OR 13 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 16 、-C 0-8 Alkyl-OC(O)R 17 、-C 0- 8-alkyl-P(O)(R18 )2. -C 0-8 Alkyl-NR 19 R 20 、-C 0-8 Alkyl-C(O)NR 21 R 22 , or -C 0-8 Alkyl-N(R 23 )-C(O)R 24 ; the CR 10 Optionally further substituted by one or more selected from D, halogen, cyano, nitro, azido, C 1-6 Alkyl, C 1- 6 alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 is substituted by a heteroaryl substituent; R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 and R 24 are independently selected from H, D, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3- 12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl or C 5-10 heteroaryl;

[0011] Ring B is selected from a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring or a 5-10 membered heteroaryl ring, and Ring B is optionally further substituted with one or more selected from D, halogen, cyano, nitro, azido, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C 0-8Alkyl-SF5, -C 0-8 Alkyl-OS(O)2R 11 、-C 0-8 Alkyl-OR 12 、-C 0-8 Alkyl-C(O)OR 13 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 16 、-C 0-8 Alkyl-OC(O)R 17 、-C 0-8 Alkyl-P(O)(R 18 )2. -C 0-8 Alkyl-NR 19 R 20 、-C 0-8 Alkyl-C(O)NR 21 R 22 , or -C 0-8 Alkyl-N(R 23 )-C(O)R 24 substituted by a substituent;

[0012] R6 and R7 are each independently selected from H, D, hydroxyl, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl or C 3-12 or R6 and R7 together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group.

[0013] In one or more embodiments of the present application, R3 and R4 together with the nitrogen atom to which they are directly connected form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted by one or more selected from -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-6 The substituent of the heterocyclic group is substituted; wherein the -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-6 The heterocyclic group is optionally further substituted by one or more radicals selected from D, hydroxy, halogen, cyano, carboxyl, C1-6 Alkyl, -C 0-6 Alkyl-OH, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, =O, =S, -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-8 The substituents of the heterocyclic group are substituted.

[0014] In one or more embodiments of the present application, R3 and R4 together with the nitrogen atom to which they are directly connected form a 4-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further substituted with one or more -C 0-6 Alkyl-11-20 membered polycyclic substitution; wherein said -C 0-6 Alkyl-11-20 membered polycyclic ring is optionally further substituted with one or more selected from D, hydroxy, halogen, cyano, carboxyl, C 1-6 Alkyl, -C 0-6 Alkyl-OH, deuterated C 1-6 Alkyl, =O, =S, -C 0- 6-alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-8 The substituents of the heterocyclic group are substituted.

[0015] In one or more embodiments of the present application, X, Y, and Z are independently selected from N or CR 10 , R 10 Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl, C 5-10 heteroaryl; said CR 10 Optionally further substituted by one or more selected from D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 substituted by a heteroaryl substituent;

[0016] Ring B is selected from 5-10 membered heterocyclic groups or 5-10 membered heteroaryl groups, and Ring B is optionally further substituted with one or more selected from D, halogen, cyano, nitro, azido, C 1-6 Alkyl, C 1-6 Alkoxy, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C 0-8 Alkyl-OR 12 、-C 0-8 Alkyl-C(O)OR 13 、-C 0- 8-alkyl-C(O)R 16 or -C 0-8 Alkyl-OC(O)R 17 、substituted by a substituent.

[0017] In one or more embodiments of the present application, the compound represented by the above formula (I), or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, has a specific structure as shown in formula (II):

[0018] in:

[0019] Ring A is selected from a polycyclic ring of 11-15 members; Ring A is optionally further substituted with one or more groups selected from D, hydroxyl, halogen, cyano, nitro, azido, carboxyl, C 1-6 Alkyl, -C 0-6 Alkyl-OH, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, =O, =S, -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 3-8 Substitution of the heterocycloalkyl group;

[0020] Ring B is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, and Ring B contains 1-2 heteroatoms selected from N, O or S;

[0021] X, Y, and Z are independently selected from N or CR 10 ; R 10 is selected from H, D, halogen or alkyl;

[0022] Q is optionally selected from C, N, O or S; Q is optionally further substituted with halogen or alkyl;

[0023] R1 and R2 are each independently selected from H, D, C1-C6 alkyl or halogen.

[0024] In one or more embodiments of the present application, the A ring is selected from The P ring is selected from a 5-6 membered aryl or heteroaryl group; the Q ring is selected from a 5-6 membered carbocyclic group or heterocyclic group; R m and R n Together with the same carbon atom, they form a 3-6 membered carbocyclic or heterocyclic ring.

[0025] In one or more embodiments of the present application, the 11-20 membered polycyclic ring (or A ring) is selected from:

[0026] The B ring is selected from or other 5-membered heterocyclic groups or 5-membered heteroaryl groups.

[0027] In one or more embodiments of the present application, R3 is selected from -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 4-6 Heterocyclic group, -C 0-6 Alkyl-C 5-10 Heteroaryl, -C 0-6 Alkyl-O-R8 or C 1-6 Alkyl; R8 is selected from H, D, hydroxyl or C 1-6 Alkyl; R3 may be further optionally selected from one or more of D, halogen, hydroxyl, C 1-6 Alkyl or -C 0-6 Alkyl-OC 1-6 substituted by an alkyl substituent;

[0028] R4 is C(R9)3, each R9 is independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; wherein at least one R9 is selected from C 6-10 Aryl, and the C 6-10 Aryl fused to C 5-12 Heterocyclyl; R9 is optionally further substituted by one or more C 1-6 substituted by an alkyl substituent.

[0029] In one or more embodiments of the present application, the above-mentioned compound or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal is selected from:

[0030] In one or more embodiments of the present application, a pharmaceutical composition is provided, comprising:

[0031] (1) The compound according to any one of claims 1 to 9, or a stereoisomer, solvate, prodrug, metabolite, deuterated form, pharmaceutically acceptable salt, or cocrystal thereof;

[0032] (2) optionally one or more other active ingredients; and

[0033] (3) Pharmaceutically acceptable carriers and / or excipients.

[0034] In one or more embodiments of the present application, there is provided a use of the above-mentioned compound or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition as a drug (i.e., for treatment).

[0035] In one or more embodiments of the present application, there is provided a use of the above-mentioned compound or its stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals, or the pharmaceutical composition in the preparation of anti-tumor drugs.

[0036] In one or more embodiments of the present application, there is provided a use of the above-mentioned compound or its stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals, or the pharmaceutical composition in the preparation of PRMT5 inhibitors and / or PRMT5·MTA complex inhibitors.

[0037] In one or more embodiments of the present application, a method for preventing and / or treating tumors is provided, comprising administering to a patient a therapeutically effective dose of the above-mentioned compound or its stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals, or the pharmaceutical composition.

[0038] In one or more embodiments of the present application, the tumor is a tumor mediated by PRMT5 and / or PRMT5·MTA complex.

[0039] In one or more embodiments of the present application, the tumor is a solid tumor.

[0040] In one or more embodiments of the present application, a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof is provided, wherein:

[0041] The substituted A ring is selected from

[0042] In one or more embodiments of the present application, a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof is provided, wherein:

[0043] The substituted B ring is selected from

[0044] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0045] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0046] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when an alkyl group is substituted, it may optionally be further substituted by one or more substituents. "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyl, cyclopropyloxy and cyclobutyloxy. The definition of alkyl is the same as that of "alkyl" described above.

[0047] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, preferably an alkenyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably an alkenyl group of 2 to 8 carbon atoms, and further preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include ethenyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may be optionally further substituted by one or more substituents.

[0048] "Alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, preferably an alkynyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably an alkynyl group of 2 to 8 carbon atoms, and even more preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyne-3-yl, dodecyne-4-yl. The alkynyl group may optionally be further substituted with one or more substituents.

[0049] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5-8 membered (e.g., 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring, non-limiting examples of which include phenyl and naphthyl. The aryl group can optionally be further substituted with one or more substituents.

[0050] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5- to 8-membered heteroaryl group, and the 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. The heteroaryl group may be attached to a heteroatom or a carbon atom, and may be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridinyl, and pyrrolopyridinyl. The heteroaryl group may be further substituted with one or more substituents.

[0051] "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl" above; when it is a non-aromatic ring, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The "carbocyclyl" or "carbocycle" may be further substituted by one or more substituents.

[0052] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the above "heteroaryl"; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, and is preferably a 3- to 8-membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be attached to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxirane, glycidyl, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thiophene, thiophene, oxetanyl, thiophene ... pyranyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl oxazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3 1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The “heterocyclyl” or “heterocycle” may be further substituted with one or more substituents.

[0053] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-20 membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 membered) polycyclic ring system (the polycyclic ring may, for example, contain a bridged ring or a spirocyclic ring), preferably having 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When a cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

[0054] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic ring. The 1, 2, or 3 N or S atoms optionally substituted in the "heterocycloalkyl" ring can be oxidized to various oxidation states; the "heterocycloalkyl" can be attached to a heteroatom or a carbon atom; the "heterocycloalkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of “heterocycloalkyl” include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptanyl.

[0055] When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it may be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, -NR q4 R q5 、=NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 、C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 Heteroaryl, -C(=O)OC 5- 10 Heteroaryl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3- 8-cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3- 8-cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by a substituent of an alkynyl group, wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3- 8 heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or substituted by a substituent of =O; R q1 Selected from C 1-6Alkyl, C 1- 6 alkoxy or C 6-10 Aryl; R q2 、R q3 Selected from H or C 1-6 Alkyl; wherein R q4 、R q5 Selected from H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O)2NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , wherein the C 1- 6 alkyl groups are optionally further substituted with one or more groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5 and the N atom form a 3- to 8-membered heterocyclic ring, which may contain one or more heteroatoms selected from N, O or S.

[0056] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0057] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0058] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0059] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0060] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0061] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0062] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0063] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl. DETAILED DESCRIPTION

[0064] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0065] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD), with tetramethylsilane (TMS) as the internal standard.

[0066] MS was measured using Agilent 6120B (ESI) and Agilent 6120B (APCI).

[0067] HPLC analysis was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM).

[0068] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0069] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0070] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, and Jiangsu Aikon Biopharmaceutical Research and Development.

[0071] Intermediate A

[0072] 4-Amino-2,3-dihydro-furo[3,2-c]quinoline-8-carboxylic acid 1e

[0073] 4-amino-2,3-dihydrofuro[3,2-c]quinoline-8-carboxylic acid

[0074] first step

[0075] Methyl 4-amino-3-(4-hydroxybut-1-ynyl)benzoate A2

[0076] methyl 4-amino-3-(4-hydroxybut-1-yn-1-yl)benzoate

[0077] Under N2 conditions, methyl 4-amino-3-iodobenzoate A1 (500 mg, 1.8 mmol), 3-butyn-1-ol (253 mg, 3.6 mmol), cuprous iodide (34 mg, 0.2 mmol), bistriphenylphosphine palladium dichloride (63 mg, 0.1 mmol) and triethylamine (10 mL) were added to a 50 mL reaction bottle and reacted at 25°C for 3 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were concentrated under reduced pressure and purified by column chromatography to obtain A2 (black solid, 359 mg, 91% yield).

[0078] LC-MS m / z (ESI) = 220.09 [M+1].

[0079] Step 2

[0080] 4-(tert-Butylamino)-2,3-dihydrofuro[3,2-c]quinoline-8-carboxylic acid methyl ester A3

[0081] methyl 4-(tert-butylamino)-2,3-dihydrofuro[3,2-c]quinoline-8-carboxylate

[0082] Compound A2 (430 mg, 2.0 mmol), tert-butyl isocyanide (245 mg, 2.95 mmol), tetrakis(triphenylphosphine)palladium (222 mg, 0.2 mmol), 1,3-bis(diphenylphosphine)propane (162 mg, 0.4 mmol), and copper acetate (783 mg, 4.0 mmol) were placed in a reaction flask. After nitrogen ventilation, acetonitrile / toluene (5 mL / 5 mL) was added and the mixture was reacted at 100°C for 9 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were concentrated under reduced pressure and purified by column chromatography to obtain A3 (white solid, 482 mg, yield 82%).

[0083] LC-MS m / z (ESI) = 301.14 [M+1].

[0084] Step 3

[0085] 4-Amino-2,3-dihydrofuro[3,2-c]quinoline-8-carboxylic acid methyl ester A4

[0086] methyl 4-amino-2,3-dihydrofuro[3,2-c]quinoline-8-carboxylate

[0087] Compound A3 (300 mg, 1.0 mmol) was dissolved in trifluoroacetic acid (10 mL) and refluxed at 100° C. for 8 hours. After completion of the reaction, the reaction solution was added dropwise to a saturated aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (5 mL×3), and the combined organic phases were concentrated under reduced pressure to obtain compound A4 (red solid, 244 mg, yield 74%).

[0088] LC-MS m / z (ESI) = 245.08 [M+1].

[0089] Step 4

[0090] 4-Amino-2,3-dihydrofuro[3,2-c]quinoline-8-carboxylic acid intermediate A

[0091] 4-amino-2,3-dihydrofuro[3,2-c]quinoline-8-carboxylic acid

[0092] Compound 1d (244 mg, 1.0 mmol) and lithium hydroxide (126 mg, 3.0 mmol) were dissolved in tetrahydrofuran / water / methanol (10 mL / 5 mL / 5 mL). The mixture was reacted at room temperature for 8 hours, and then the tetrahydrofuran and methanol were evaporated under reduced pressure. Water (10 mL) was added, and the pH was adjusted to 6.0 with 1.5N hydrochloric acid. The solid was filtered to obtain Intermediate A (white solid, 173 mg, 75% yield).

[0093] LC-MS m / z (ESI) = 231.07 [M+1].

[0094] Intermediate B

[0095] tert-Butyl 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0096] tert-butyl 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0097] first step

[0098] 5-Methyl-2-oxopiperidine-1-carboxylic acid tert-butyl ester II-2

[0099] tert-butyl 5-methyl-2-oxopiperidine-1-carboxylate

[0100] II-1 (25.0 g, 221.2 mmol) was dissolved in tetrahydrofuran (250 mL), and (Boc)2O (50.6 g, 232.3 mmol) and DMAP (2.7 g, 22.1 mmol) were added at 25 ° C. The reaction was completed after 16 h, and the solvent was removed by rotary evaporation. Ethyl acetate (600 ml) was added to dilute it, and 10% KHSO4 was added for washing (50 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain II-2 (yellow liquid, 47 g, yield 99%).

[0101] LC-MS m / z (ESI) = 214.14 [M+1].

[0102] Step 2

[0103] tert-Butyl 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate II-3

[0104] tert-butyl 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0105] II-2 (47 g, 220.6 mmol) was dissolved in THF (300 mL), and KHMDS (330 mL 1 Min THF) was added dropwise at -75 ° C. After stirring for 2 h, N-bis(trifluoromethanesulfonyl)aniline (98.4 g, 275.8 mmol) was added and the mixture was heated to room temperature and stirred for 16 h. After the reaction was completed, saturated NH4Cl solution was added to quench the reaction, and the solvent was removed by rotary evaporation. EA (600 mL) was added for extraction and then 10% NaOH (60 mL) was added for washing. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate B (yellow liquid, 61 g, yield 80%).

[0106] LC-MS m / z (ESI) = 346.05 [M+1].

[0107] Intermediate C

[0108] 4-Amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid

[0109] 4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid

[0110] first step

[0111] 5-Amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinecarbonitrile C2

[0112] 5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile

[0113] Under N2 conditions, 5-aminopyridinecarbonitrile C1 (3.9 g, 32.9 mmol) and THF (32 mL) were placed in a 250 mL three-necked flask, and pinacol borane (6.4 g, 50 mmol) was slowly added with stirring at 45 ° C. The mixture was stirred at 50 ° C for 1 h, and then cooled to room temperature and slowly added with [Ir(COD)(OMe)]2 (330 mg, 0.049 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (268 mg, 0.1 mmol), and B2Pin2 (4.19 g, 16.5 mmol). The mixture was stirred at 65 ° C for 3 h. After the reaction was completed, the mixture was cooled to 40 ° C and quenched by adding isopropanol solution (4 mL). After stirring at 40 ° C for 0.5 h, it was cooled to room temperature and directly put into the next step.

[0114] LC-MS m / z (ESI) = 119.09 [M+1].

[0115] Step 2

[0116] 4-Amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonitrile C3

[0117] 4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonitrile

[0118] Under N2 conditions, potassium phosphate (21.2 g, 100 mmol) in water (40 mL), Pd(XantPhos)Cl2 (1 g, 1.64 mmol), and D2 (8.7 g, 32.8 mmol) were added to C2 in the previous step, and the mixture was stirred at 65°C for 3 h. The temperature was cooled to room temperature, acetonitrile (20 mL) was added, and the mixture was filtered. The filter cake was washed with H2O (20 mL) and acetonitrile (20 mL) in sequence, and the solid was collected to obtain (white solid, 3.6 g, yield 52%).

[0119] LC-MS m / z (ESI) = 213.09 [M+1].

[0120] Step 3

[0121] 4-Amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid intermediate C

[0122] C3 was added to a 250 mL three-necked flask under N2 conditions, and H2O (50 mL) and NaOH 1M (6 mL) were added. The mixture was stirred at 85°C for 17 h. The reaction was completed after monitoring by LC-MS. The mixture was cooled to 55°C, concentrated hydrochloric acid (5.95 mL) was added, and stirred for 0.5 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with H2O (6 mL) and isopropanol (20 mL) in sequence, and the solid was collected to obtain intermediate C (white solid, 3.6 g, yield 92%).

[0123] LC-MS m / z (ESI) = 232.09 [M+1].

[0124] Intermediate D2

[0125] 4-Cyanotetrahydrofuran-3-yl-4-methylbenzenesulfonate

[0126] 4-cyanotrahydrofuran-3-yl-4-methylbenzenesulfonate

[0127] Under N2 conditions, D1 (5 g, 45 mmol) was added to a 500 mL single-necked flask, K2CO3 (13.8 g, 100 mmol) and THF (200 mL) were added, and the mixture was stirred for 5 minutes. TsCl (9.5 g, 100 mmol) was slowly added, and the mixture was stirred at room temperature for 3 h. After monitoring by TLC, the reaction was completed, filtered, and the filtrate was collected. The solvent was removed by rotary evaporation and purified by normal phase purification (PE:EA=10:1) to obtain intermediate D2 (yellow oil, 8.7 g, yield 75%).

[0128] LC-MS m / z (ESI) = 268.09 [M+1].

[0129] Intermediate E

[0130] tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0131] 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0132] first step

[0133] tert-Butyl 2-oxopiperidine-1-carboxylate V-2

[0134] tert-butyl 2-oxopiperidine-1-carboxylate

[0135] According to the method of compound II-2, compound V-2 (reddish brown liquid, 16.7 g, yield 85%) was obtained.

[0136] LC-MS m / z (ESI) = 200.12 [M+1].

[0137] Step 2

[0138] tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate Intermediate E

[0139] 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0140] According to the method of compound intermediate B, intermediate E (reddish brown liquid, 26.2 g, yield 96%) was obtained.

[0141] LC-MS m / z (ESI) = 332.07 [M+1].

[0142] Intermediate F

[0143] 4-Amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid

[0144] 4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid

[0145] first step

[0146] Methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-2-fluorobenzoate VI-2

[0147] methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-2-fluorobenzoate

[0148] Under nitrogen protection, VI-1 (4.9 g, 20 mmol) was dissolved in THF (80 mL) and NaHMDS (25 mL, 50 mmol) was added at 0°C. The mixture was stirred for 30 min, and then di-tert-butyl dicarbonate (4.6 g, 21 mmol) was added dropwise. The reaction was allowed to react at room temperature overnight. The reaction progress was monitored by TLC.

[0149] The reaction was stopped, quenched by adding 0.1 M dilute hydrochloric acid, extracted with EA, and eluted by column chromatography (PE:EA=100:1) to obtain compound VI-2 (white solid, 2.7 g, yield 40%).

[0150] LC-MS m / z (ESI) = 348.02 [M+1].

[0151] Step 2

[0152] Methyl 4-((tert-Butoxycarbonyl)amino)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate VI-3

[0153] methyl 4-((tert-butoxycarbonyl)amino)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0154] According to the method of compound 1c, compound VI-3 (yellow solid, 2.9 g, yield 98%) was obtained.

[0155] LC-MS m / z (ESI) = 396.19 [M+1].

[0156] Step 3

[0157] Methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate VI-4

[0158] Methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0159] According to the method of compound 1e, compound VI-4 (white solid, 1.3 g, yield 61%) was obtained.

[0160] LC-MS m / z (ESI) = 296.14 [M+1].

[0161] Step 4

[0162] 4-Amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid methyl ester VI-5

[0163] methyl 4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate

[0164] Compound VI-4 (1.3 g, 4.6 mmol) was dissolved in THF (32 mL), and a solution of potassium phosphate (2.9 g, 14.0 mmol) in water (40 mL) was added. Intermediate D (1.3 g, 5.1 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene palladium dichloride (176 mg, 0.23 mmol) were added. The mixture was protected by nitrogen and heated to 65 ° C for 3 h. The reaction progress was monitored by TLC.

[0165] The reaction was stopped and filtered to obtain a solid, which was washed with MeCN (20 mL) and water (20 mL) in sequence to obtain compound VI-5 (white solid, 1.0 g, yield 90%).

[0166] LC-MS m / z (ESI) = 263.08 [M+1].

[0167] Step 5

[0168] 4-Amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid intermediate F

[0169] 4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid

[0170] Compound VI-5 (1.0 g, 3.8 mmol) was dissolved in a mixture of THF (15 mL) and water (15 mL). LiOH·H2O (64.6 mg, 15.4 mmol) was added and the mixture was heated to 75°C for 3 h. The reaction progress was monitored by TLC.

[0171] The reaction was stopped, the solvent was concentrated, and the pH was adjusted to 6 with 1.5 M dilute hydrochloric acid solution to precipitate a solid, which was filtered and dried to obtain intermediate F (white solid, 680 mg, yield 73%).

[0172] LC-MS m / z (ESI) = 249.06 [M+1].

[0173] Intermediate G

[0174] 4-Amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0175] 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0176] first step

[0177] 4-Amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid methyl ester VII-1

[0178] methyl 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate

[0179] Compound VI-4 (1.0 g, 3.5 mmol) was dissolved in 1,4-dioxane (40 mL), and a solution of potassium carbonate (1.6 g, 11.9 mmol) in water (10 mL) was added. 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (445 mg, 2.3 mmol) and tetrakistriphenylphosphine palladium (276 mg, 0.23 mmol) were added. The mixture was protected by nitrogen and heated to 90 ° C for 6 h. The reaction progress was monitored by TLC.

[0180] The reaction was stopped, the solvent was removed by rotary evaporation, water was added, and the mixture was filtered. The mixture was washed twice with water and then with DCM. The solid was collected and dried to obtain compound VII-1 (white solid, 310 mg, yield 47%).

[0181] LC-MS m / z (ESI) = 275.09 [M+1].

[0182] Step 2

[0183] 4-Amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid intermediate G

[0184] 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0185] Compound VII-1 (310 mg, 1.1 mmol) was dissolved in a mixture of THF (5 mL), MeOH (5 mL) and water (5 mL). LiOH·H2O (95 mg, 2.2 mmol) was added and the mixture was heated to 50°C for 3 h. The reaction progress was monitored by TLC.

[0186] The reaction was stopped, the solvent was concentrated, and the pH was adjusted to 6 with 1.5 M dilute hydrochloric acid solution to precipitate a solid, which was filtered to obtain intermediate G (white solid, 440 mg, yield 99%).

[0187] LC-MS m / z (ESI) = 261.07 [M+1].

[0188] Intermediate H

[0189] 4-Amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0190] 4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid

[0191] Compound VI-6 was obtained by referring to the synthesis method of compound VI-4, and intermediate H was obtained by referring to the synthesis method of intermediate G.

[0192] LC-MS m / z (ESI) = 277.10 [M+1].

[0193] Intermediate I

[0194] 4-Amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid intermediate I

[0195] 4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid

[0196] first step

[0197] 4-Amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid methyl ester VII-3

[0198] methyl 4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate

[0199] Referring to the synthesis of V1-5, compound VII-3 (white solid, 310 mg, yield 56%) was obtained using V1-6.

[0200] LC-MS m / z (ESI) = 279.05 [M+1].

[0201] Step 2

[0202] 4-Amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid intermediate I

[0203] 4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid

[0204] According to the method of compound intermediate F, intermediate I (white solid, 272 g, yield 78%) was obtained.

[0205] LC-MS m / z (ESI) = 265.03 [M+1].

[0206] Example 1

[0207] 5'-((5S)-1-(4-amino-2,3-dihydro[3,2-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one compound 1

[0208] 5'-((5S)-1-(4-amino-2,3-dihydrofuro[3,2-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0209] first step

[0210] 5'-Bromospiro[cyclopropane-1,3'-indolin]-2'-one 1b

[0211] 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one

[0212] 1a (5 g, 23.8 mmol) was dissolved in THF (150 mL), and n-butyllithium (30 mL, 2.5 M in THF) was added at -30°C. After stirring for 30 min, 1,2-dibromoethane (13 g, 71.4 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 16 h. After completion, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (300 mL), washed with saturated brine (50 x 4 mL), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 1b (yellow solid, 1.1 g, 19% yield).

[0213] LC-MS m / z (ESI) = 238.00 [M+1].

[0214] Step 2

[0215] 5'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 1c

[0216] 5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0217] Dissolve 1b (1 g, 4.2 mmol), pinacol diboronate (1.2 g, 5.0 mmol), potassium acetate (1.2 g, 12.0 mmol), and Pd(dppf)Cl2 (309 mg, 0.42 mmol) in 1,4-Dioxane (50 mL). Heat to 100°C under nitrogen and monitor the reaction progress by TLC. Stop the reaction, filter, and use the filtrate directly in the next step.

[0218] LC-MS m / z (ESI) = 286.15 [M+1].

[0219] Step 3

[0220] tert-butyl 3-methyl-6-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0221] To a 100 mL round-bottom flask were added Intermediate A (5 g, 15 mmol), 1c (3.1 g, 12 mmol), Pd(dppf)Cl2 (1.09 g, 1.5 mmol), and sodium carbonate (3.97 g, 37.5 mmol). Dioxane:water (10:1) (55 mL) was then added, and the mixture was reacted at 100°C for 3 h under nitrogen. After completion of the reaction, the mixture was extracted with ethyl acetate (100 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate (10:1)) to afford 1d (yellow solid, 600 mg, 36% yield).

[0222] LC-MS m / z (ESI) = 355.20 [M+1].

[0223] Step 4

[0224] 5′-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 1e

[0225] 5'-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0226] To a 100 mL round-bottom flask was added 1d (4.5 g, 14 mmol), followed by trifluoroacetic acid (15 mL). The mixture was allowed to react at room temperature for 2 h. After completion, the reaction was neutralized with triethylamine and extracted with ethyl acetate (100 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and isolated by column chromatography (dichloromethane:methanol = 10:1) to afford compound 1e (yellow liquid, 300 mg, 69% yield).

[0227] LC-MS m / z (ESI) = 255.20 [M+1].

[0228] Step 5

[0229] 5'-(5-Methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 1f

[0230] 5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0231] To a 100 mL round-bottom flask was added 1e (1.75 g, 7.6 mmol), followed by dissolution in methanol (30 mL). Sodium borohydride (345 mg, 9.12 mmol) was added portionwise under an ice bath, and the reaction mixture was allowed to warm to room temperature for 2 h. After completion of the reaction, the mixture was extracted with water (5 mL) and ethyl acetate (50 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 10:1) to afford 1f (a yellow solid, 250 mg, 82% yield).

[0232] LC-MS m / z (ESI) = 257.18 [M+1].

[0233] Step 6

[0234] 5'-((5S)-1-(4-amino-2,3-dihydro[3,2-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one compound 1

[0235] 5'-((5S)-1-(4-amino-2,3-dihydrofuro[3,2-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3′-indolin]-2'-one

[0236] 1f (110 mg, 0.47 mmol), intermediate A (130 mg, 0.56 mmol), PyBoP (243.0 mg, 0.52 mmol), and triethylamine (143 mg, 1.42 mmol) were dissolved in N,N-dimethylacetamide (5 mL). After reacting at room temperature for 16 h, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were concentrated under reduced pressure, eluted by column chromatography (dichloromethane: methanol = 10:1), and separated by chiral SFC to obtain compound 1 (yellow solid, 70 mg, yield 38%).

[0237] 1 H NMR (400MHz, DMSO-d6) δ13.15(s,1H),10.54(s,1H),7.77–7.71(m,2H),7.13–7.07(m,1H),6.95–6.87(m,2H),5.07–4.99( m,2H),3.26–3.20(m,2H),2.20–2.02(m,2H),1.96–1.60(m,4H),1.60–1.42(m,5H),1.36–1.28(m,3H),1.01–0.93(m,3H).

[0238] LC-MS m / z (ESI) = 469.22 [M+1].

[0239] Example 2

[0240] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one compound 2

[0241] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0242] first step

[0243] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one compound 2

[0244] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0245] Following the method for compound 1, using 1f, compound 2 (white solid, 60 mg, yield 36%) was obtained after chiral SFC separation.

[0246] 1 H NMR (400MHz, DMSO-d6) δ10.74–10.35(m,1H),8.99–8.68(m,1H),7.83–7.59(m,1H),7.18–6.81(m,4H),5.45–5.20(m,2 H),5.08–4.96(m,2H),3.19–2.88(m,2H),2.38–2.00(m,2H),2.00–1.40(m,6H),1.38–0.95(m,4H),0.94–0.53(m,2H).

[0247] LC-MS m / z (ESI) = 470.30 [M+1].

[0248] Example 3

[0249] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one compound 3

[0250] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[0251] first step

[0252] 5'-Bromospiro[cyclobutane-1,3'-indolin]-2'-one 3b

[0253] 5'-bromospiro[cyclobutane-1,3'-indolin]-2'-one

[0254] 3a (5 g, 25.8 mmol) was dissolved in THF (150 mL), and n-butyllithium (30 mL, 2.5 min THF) was added at -30°C. After stirring for 30 min, 1,3-dibromopropane (13 g, 71.4 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 16 h. After completion, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (300 mL), washed with saturated brine (50 x 4 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 3b (yellow solid, 3.9 g, 60% yield).

[0255] LC-MS m / z (ESI) = 254.00 [M+1].

[0256] Step 2

[0257] 5'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one 3c

[0258] 5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[0259] According to the method of 1c, compound 3c was obtained (yellow solid, 3.8 mg, yield 82%).

[0260] LC-MS m / z (ESI) = 300.18 [M+1].

[0261] Step 3

[0262] tert-Butyl 3-methyl-6-(2'-oxospiro[cyclobutane-1,3'-indoline]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0263] tert-butyl 3-methyl-6-(2'-oxospiro[cyclobutane-1,3'-indolin]-5′-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0264] According to the method of 1d, 3d was obtained (yellow solid, 3.8 g, yield 76%).

[0265] LC-MS m / z (ESI) = 369.20 [M+1].

[0266] Step 4

[0267] 5′-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[0268] 5'-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[0269] According to the method of 1e, 3e was obtained (yellow solid, 600 g, yield 68%).

[0270] LC-MS m / z (ESI) = 269.18 [M+1].

[0271] Step 5

[0272] 5'-(5-methylpiperidin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[0273] According to the method of 1f, 3f was obtained (yellow solid, 550 g, yield 90%).

[0274] LC-MS m / z (ESI) = 271.18 [M+1].

[0275] Step 6

[0276] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one compound 3

[0277] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[0278] Following the method for compound 1, 3f was used to obtain compound 3 (white solid, 100 mg, yield 56%) after chiral SFC separation.

[0279] 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.01–8.58(m,1H),7.84–7.59(m,1H),7.58–7.43(m,1H),7.24–6.98(m,3H),6.85–6.74(m,1H), 5.45–5.20(m,2H),5.11–4.91(m,2H),3.23–2.78(m,2H),2.47–1.96(m,8H),1.96–1.45(m,2H),1.43–1.16(m,2H),1.10–0.59(m,3H).

[0280] LC-MS m / z (ESI) = 484.20 [M+1].

[0281] Example 4

[0282] 6'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one compound 4

[0283] 6'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0284] first step

[0285] 1-(4-Methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 4b

[0286] 1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0287] Dissolve 4a (5.0 g, 34.0 mmol) in N,N-dimethylacetamide (60 mL). Add sodium hydride (1.8 g, 44.2 mmol) at 0°C and allow to react for 1 hour. Then add 4-methoxybenzyl chloride (5.9 g, 37.4 mmol). Warm the mixture to room temperature and allow to react for 2 hours. After the reaction is complete, add water (200 mL) and extract with ethyl acetate (30 mL x 3). Dry with anhydrous sodium sulfate. The combined organic phases are concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to afford 4b as a white solid (8.0 g, 88% yield).

[0288] LC-MS m / z (ESI) = 268.13 [M+1].

[0289] Step 2

[0290] 3-(2-Chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 4c

[0291] 3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0292] 4b (8.0 g, 30.0 mmol) was dissolved in tetrahydrofuran (60 mL). Bromochloroethane (45 mL, 45.0 mmol) was added dropwise at -78°C and allowed to react at the same temperature for 1 h. Then, lithium bis(trimethylsilylamide) (12.9 g, 90.0 mmol) was added dropwise and the temperature was slowly raised to room temperature and allowed to react for 8 h. After concentration under reduced pressure, water (200 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate. The combined organic phases were concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to afford 4c (8.3 g, 84% yield) as a yellow solid.

[0293] LC-MS m / z (ESI) = 330.12 [M+1].

[0294] Step 3

[0295] 3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 4d

[0296] 3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0297] Compound 4c (4.0 g, 12.2 mmol) and sodium iodide (3.6 g, 24.3 mmol) were dissolved in acetone (60 mL) and reacted at 80°C for 8 h. The mixture was concentrated under reduced pressure, and water (200 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated under reduced pressure to afford 4d (a yellow solid, 5.1 g, 80% yield).

[0298] LC-MS m / z (ESI) = 422.05 [M+1].

[0299] Step 4

[0300] 1'-(4-methoxybenzyl)-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 4e

[0301] 1′-(4-methoxybenzyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0302] 4d (4.0 g, 9.5 mmol) was dissolved in tetrahydrofuran (30 mL). Lithium bis(trimethylsilylamide) (10 mL, 9.5 mmol) was added dropwise at -78°C and the temperature was slowly raised to room temperature. The reaction was allowed to proceed for 5 h. After concentration under reduced pressure, water (200 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate. The combined organic phases were concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to afford 4e (a yellow solid, 1.4 g, 83% yield).

[0303] LC-MS m / z (ESI) = 294.14 [M+1].

[0304] Step 5

[0305] 1′,4′-Dihydro-2′H-spiro[cyclopropane-1,3′-quinolinyl]-2′-one 4f

[0306] 1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0307] 4e (1.4 g, 4.8 mmol) was dissolved in trifluoroacetic acid (30 mL) and reacted at 60°C for 3 h. After concentration under reduced pressure, saturated aqueous sodium carbonate was added to adjust the pH to 9. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, and the combined organic phases were concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford 4f (yellow solid, 730 mg, 88% yield).

[0308] LC-MS m / z (ESI) = 174.08 [M+1].

[0309] Step 6

[0310] 6'-Bromo-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 4g

[0311] 6'-bromo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0312] Dissolve 4f (730 mg, 4.2 mmol) and N-bromosuccinimide (976 mg, 5.5 mmol) in anhydrous acetonitrile (20 mL) and react at room temperature for 3 h. The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to afford 4g (a yellow solid, 917 mg, 87% yield).

[0313] LC-MS m / z (ESI) = 251.99 [M+1].

[0314] Step 7

[0315] 6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 4h

[0316] 6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0317] Referring to the synthesis method of 1c, 4g was used to obtain 4h (yellow solid, 840 mg, yield 84%).

[0318] LC-MS m / z (ESI) = 300.17 [M+1].

[0319] Step 8

[0320] (S)-tert-Butyl 3-methyl-6-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylate 4i

[0321] tert-butyl(S)-3-methyl-6-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0322] Referring to the synthetic method of 1d, h and intermediate B were used to obtain 4i (yellow solid, 942 mg, yield 79%).

[0323] LC-MS m / z (ESI) = 369.21 [M+1].

[0324] Step 9

[0325] (S)-6'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 11j

[0326] (S)-6′-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3′-quinolin]-2'-one

[0327] Referring to the synthesis method of compound 1e, compound 4i was used to obtain compound 4j (yellow solid, 780 mg, yield 78%).

[0328] LC-MS m / z (ESI) = 269.16 [M+1].

[0329] Step 10

[0330] 6'-((5S)-5-methylpiperidin-2-yl)-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 11k

[0331] 6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0332] Referring to the synthetic method of 1f, 4k was obtained using 4j (yellow solid, 749 mg, yield 83%).

[0333] LC-MS m / z (ESI) = 271.17 [M+1].

[0334] Step 11

[0335] 6'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-2'-one compound 4

[0336] 6'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0337] According to the method of compound 1, 4k (50 mg, 0.22 mmol) was used to obtain compound 4 (white solid, 70 mg, yield 66%).

[0338] 1 H NMR (400MHz, DMSO) δ10.14(s,1H),8.86(s,1H),7.72(s,1H),7.11(d,4H),6.89(d,1H),5.41–5.27(m,2H),5.03(s,2H),3.16(s ,1H),2.83(s,2H),2.13(s,2H),1.76(ddd,2H),1.27(dd,3H),1.05(s,2H),1.00–0.89(m,2H),0.82(dt,1H),0.75–0.66(m,2H).

[0339] LC-MS m / z (ESI) = 484.25 [M+1].

[0340] Example 5

[0341] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one compound 5

[0342] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0343] first step

[0344] 7'-Fluorospiro[cyclopropane-1,3'-indolin]-2'-one 5b

[0345] 7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0346] 5a (25 g, 165 mmol) was dissolved in THF (200 mL), and lithium diisopropylamide (330 mL, 2 M in THF) was added at 0°C. After stirring for 30 min, 1,3-dibromopropane (93 g, 496 mmol) was added, and the mixture was heated to room temperature and stirred for 16 h. After completion, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (300 x 3 mL), washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to afford 5b (brown solid, 21 g, 71.9% yield).

[0347] LC-MS m / z (ESI) = 178.16 [M+1].

[0348] Step 2

[0349] 5'-Bromo-7'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one 5c

[0350] 5'-bromo-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0351] 5b (18.4 g, 104 mmol) was dissolved in TFA (120 mL), and N-bromosuccinimide (20.3 g, 114 mmol) was added at 0°C. The mixture was heated to room temperature and stirred for 3 h. After the reaction was complete, sodium sulfite was added to quench the reaction. Saturated sodium carbonate solution was then added to adjust the pH to alkaline. Ethyl acetate (300*3 mL) was added for extraction, and the mixture was washed with saturated brine (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give 5b (brown solid, 21 g, yield 79%).

[0352] LC-MS m / z (ESI) = 256.01 [M+1].

[0353] Step 3

[0354] 7'-Fluoro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 5d

[0355] 7'-fluoro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0356] According to the method of 1c, 5c (1.0 g, 2.6 mmol) was used to give 5d (white solid, 1 g, yield 91%).

[0357] LC-MS m / z (ESI) = 304.14 [M+1].

[0358] Step 4

[0359] tert-Butyl 6-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-dihydroindole]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 5e

[0360] tert-butyl-6-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[0361] According to the method of synthesizing 1d, compound 5e (yellow solid, 800 mg, yield 72.7%) was obtained.

[0362] LC-MS m / z (ESI) = 373.23 [M+1].

[0363] Step 5

[0364] 7'-Fluoro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 5f

[0365] 7'-fluoro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0366] According to the method of 1e, 5f (yellow solid, 650 mg, yield 92%) was obtained.

[0367] LC-MS m / z (ESI) = 273.23 [M+1].

[0368] Step 6

[0369] 7'-Fluoro-5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one 5g

[0370] 7'-fluoro-5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0371] According to the method of 1f, using 5f, 5g (yellow solid, 500 mg, yield 76%) was obtained.

[0372] LC-MS m / z (ESI) = 275.20 [M+1].

[0373] Step 7

[0374] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one compound 5

[0375] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0376] According to the method of compound 1, 5 g (240 mg, 0.61 mmol) was used to obtain compound 5 (white solid, 30 mg, yield 8.1%) after chiral SFC separation.

[0377] 1 H NMR (400MHz, DMSO) δ10.35(s,1H),8.79(s,1H),7.76(s,1H),7.63–7.11(d,3H),6.89(d,1H),5.46–5.31(m,2H),5.05(s,2H ),3.18(s,1H),2.17(s,2H),1.81(ddd,2H),1.29(dd,3H),1.09(s,2H),1.05–0.85(m,2H),0.83(dt,1H),0.77–0.68(m,2H).

[0378] LC-MS m / z (ESI) = 488.20 [M+1].

[0379] Example 6

[0380] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(spiro[benzo[d][1,3]dioxane-2,1′-cyclobutane]-5-yl)piperidin-1-yl)methanone compound 6

[0381] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)piperidin-1-yl)methanone

[0382] first step

[0383] 5-Bromospiro[benzo[d][1,3]dioxane-2,1'-cyclobutane] compound 6b

[0384] 5-bromospiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]

[0385] Compound 5a (3 g, 15.8 mmol), cyclobutanone (2.2 g, 31.7 mmol), and p-toluenesulfonic acid (273 mg, 1.58 mmol) were dissolved in toluene (50 mL). The mixture was equipped with a water separator and refluxed at 130°C with stirring for 16 h. The reaction solution was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 6b (anhydrous oil, 1.1 g, yield 28.9%).

[0386] Step 2

[0387] 4,4,5,5-Tetramethyl-2-(spiro[benzo[d][1,3]dioxane-2,1'-cyclobutane]-5-yl)-1,3,2-dioxaborolane 6c

[0388] 4,4,5,5-tetramethyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)-1,3,2-dioxaborolane

[0389] According to the method of compound 1c, compound 6b (1.1 g, 4.6 mmol) was used to obtain compound 6c (yellow oil, 1.2 g, yield 92%).

[0390] Step 3

[0391] tert-Butyl 3-methyl-6-(spiro[benzo[d][1,3]dioxo-2,1'-cyclobutane]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate 6d

[0392] tert-butyl3-methyl-6-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0393] According to the method of compound 1d, compound 6c (1.2 g, 4.1 mmol) was used to obtain compound 6d (white solid, 1 g, yield 67%).

[0394] LC-MS m / z (ESI) = 358.20 [M+1].

[0395] Step 4

[0396] 3-Methyl-6-(spiro[benzo[d][1,3]dioxo-2,1'-cyclobutane]-5-yl)-2,3,4,5-tetrahydropyridine 6e

[0397] 3-methyl-6-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)-2,3,4,5-tetrahydropyridine

[0398] According to the method of compound 1e, compound 6d (1 g, 2.8 mmol) was used to obtain compound 6e (white solid, 600 mg, yield 83%).

[0399] LC-MS m / z (ESI) = 258.14 [M+1].

[0400] Step 5

[0401] 5-Methyl-2-(spiro[benzo[d][1,3]dioxo-2,1'-cyclobutane]-5-yl)piperidine 6f

[0402] 4-methyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)piperidine

[0403] 5- According to the method of compound 1f, compound 6e (600 mg, 2.3 mmol) was used to obtain compound 6f (white solid, 600 mg, yield 82%).

[0404] LC-MS m / z (ESI) = 261.23 [M+1].

[0405] Step 6

[0406] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(spiro[benzo[d][1,3]dioxane-2,1′-cyclobutane]-5-yl)piperidin-1-yl)methanone compound 6

[0407] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)piperidin-1-yl)methanone

[0408] According to the method of compound 1, compound 6f (100 mg, 0.38 mmol) was used to obtain compound 6 (white solid, 100 mg, yield 52%).

[0409] 1 H NMR (400MHz, DMSO-d6) δ8.93–8.83(m,1H),7.74–7.68(m,1H),7.44–7.32(m,1H),7.04(s,2H),6.93–6.75(m,3H),5.40–5.3 1(m,2H),5.05–5.00(m,2H),3.03–2.98(m,2H),2.60–2.53(m,4H),2.15–2.04(m,2H),1.82–1.70(m,5H),1.27–1.19(m,3H).

[0410] LC-MS m / z (ESI) = 473.30 [M+1].

[0411] Example 7

[0412] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indol]-2'-one compound 7

[0413] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0414] first step

[0415] tert-Butyl 6-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate 7b

[0416] tert-butyl 6-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0417] According to the method of compound 1d, compound 5d (1.0 g, 3.3 mmol) was used to obtain compound 7b (yellow solid, 900 mg, yield 81%).

[0418] LC-MS m / z (ESI) = 359.14 [M+1].

[0419] Step 2

[0420] 7'-Fluoro-5'-(1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 7c

[0421] 7'-fluoro-5'-(1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0422] According to the method of compound 1e, compound 7b was used to obtain compound 7c (yellow solid, 300 mg, yield 46.3%).

[0423] LC-MS m / z (ESI) = 359.16 [M+1].

[0424] Step 3

[0425] 7'-Fluoro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 5d

[0426] 7'-fluoro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0427] According to the method of compound 1f, compound 7c was used to obtain compound 7d (white solid, 230 mg, yield 41%).

[0428] LC-MS m / z (ESI) = 261.20 [M+1].

[0429] Step 4

[0430] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indol]-2'-one compound 7

[0431] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0432] According to the method for synthesizing compound 1, compound 7d (70 mg, 0.27 mmol) was reacted with intermediate C to obtain compound 7 (white solid, 120 mg, yield 80%).

[0433] 1 H NMR(400MHz,DMSO)δ11.05(s,1H),7.78(s,1H),7.10–6.98(m,3H),5.36(s,2H),5.03(s,2H),4.11(d,1H),3.84 –3.63(m,1H),3.16(d,3H),2.42(s,1H),1.87–1.80(m,1H),1.61(d,3H),1.52(d,3H),1.43(s,1H),1.23(s,1H).

[0434] LC-MS m / z (ESI) = 474.20 [M+1].

[0435] Example 8

[0436] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)-7'-fluoro-1'-methylspiro[cyclopropane-1,3'-indol]-2'-one compound 8

[0437] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)-7'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0438] first step

[0439] 2-(7'-Fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)piperidine-1-carboxylic acid tert-butyl ester Compound 8b

[0440] tert-butyl-2-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidine-1-carboxylate

[0441] Compound 7d (136 mg, 0.52 mmol) was dissolved in THF (5 mL), and di-tert-butyl carbonic anhydride (136 mg, 0.62 mmol) and triethylamine (210 mg, 2.08 mmol) were added. The mixture was stirred at room temperature for 16 h. After completion, the reaction was quenched by adding two drops of water. The mixture was then concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 8b (white solid, 150 mg, 80% yield).

[0442] LC-MS m / z (ESI) = 361.14 [M+1].

[0443] Step 2

[0444] tert-Butyl 2-(7'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)piperidine-1-carboxylate 8c

[0445] tert-butyl-2-(7'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidine-1-carboxylate

[0446] Compound 8b (150 mg, 0.42 mmol) was dissolved in DMF (3 mL), and sodium hydride (25 mg, 0.62 mmol) was added at 0°C. The mixture was stirred at this temperature for 2 h, and then iodomethane (88 mg, 0.62 mmol) was added at 0°C. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 8c (yellow oily liquid, 150 mg, yield 95.5%).

[0447] LC-MS m / z (ESI) = 375.21 [M+1].

[0448] Step 3

[0449] 7'-Fluoro-1'-methyl-5'-(piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 8d

[0450] 7'-fluoro-1'-methyl-5'-(piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0451] According to the method of compound 1e, compound 8d (yellow oily liquid, 100 mg, yield 91%) was obtained using compound 8c.

[0452] LC-MS m / z (ESI) = 275.20 [M+1].

[0453] Step 4

[0454] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)-7'-fluoro-1'-methylspiro[cyclopropane-1,3'-indol]-2'-one compound 8

[0455] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)-7'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0456] According to the method for synthesizing compound 1, compound 8d was reacted with intermediate C to obtain compound 8 (white solid, 130 mg, yield 59%).

[0457] 1H NMR(400MHz,DMSO)δ7.79(s,1H),7.14–7.00(m,3H),5.36(s,2H),5.03(s,2H),4.55–3.62(m,1H),3.38(s,3H),3 .18–3.05(m,1H),2.97(ddd,1H),2.47–2.28(m,1H),1.83(dd,1H),1.70–1.37(m,8H),1.23(s,1H),1.17(t,1H).

[0458] LC-MS m / z (ESI) = 488.21 [M+1].

[0459] Example 9

[0460] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone Compound 9

[0461] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone

[0462] first step

[0463] 4-(4-Chloro-2-fluorobenzyl)-1-methylpiperidin-4-ol 9b

[0464] 4-(4-chloro-2-fluorobenzyl)-1-methylpiperidin-4-ol

[0465] Magnesium powder (1.2 g, 50.0 mmol) and a trace amount of iodine were dissolved in diethyl ether (20 mL). Under nitrogen protection, a solution of compound 9a (2.6 g, 12.0 mmol) in diethyl ether (30 mL, 30 mmol) was slowly added. After the yellow color of the reaction solution disappeared, compound 9a was continuously added dropwise. After reacting at 40°C for 30 min, the temperature was lowered to 0°C and N-methyl-4-piperidone (1.1 g, 10.0 mmol) was added dropwise. The reaction was gradually allowed to react at room temperature. The reaction progress was monitored by TLC.

[0466] The reaction was stopped, saturated aqueous ammonium chloride solution was added, extracted with EA, and the combined organic phases were concentrated under reduced pressure. Elution by column chromatography (DCM:MeOH=10:1) gave compound 9b (yellow liquid, 660 mg, yield 51%).

[0467] LC-MS m / z (ESI) = 258.10 [M+1].

[0468] Step 2

[0469] 6-Chloro-1′-methyl-3H-pyridinium[benzofuran-2,4′-piperidine]9c

[0470] 6-chloro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]

[0471] Compound 9b (610.0 mg, 2.3 mmol) and NaH (460.0 mg, 11.5 mmol) were dissolved in toluene (11 mL), heated to 110°C under nitrogen protection, and stirred for 5 min. DMF (3.7 mL) was then added and the reaction was continued. The reaction progress was monitored by TLC.

[0472] The reaction was stopped, water was added, and the mixture was extracted with EA. The organic phase was washed with water and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was separated by column chromatography (DCM:MeOH=30:1) to obtain compound 9c (yellow liquid, 406 mg, yield 72%).

[0473] LC-MS m / z (ESI) = 238.09 [M+1].

[0474] Step 3

[0475] 1'-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]9d

[0476] 1'-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[0477] Compound 9c (356.0 mg, 1.5 mmol), pinacol diboronate (495 mg, 1.9 mmol), potassium acetate (442 mg, 4.5 mmol), and XPhos Pd G4 (129 mg, 0.15 mmol) were dissolved in 1,4-Dioxane (15 mL) and reacted in a microwave oven at 130°C for 2.5 h. The reaction progress was monitored by TLC.

[0478] The reaction was stopped, and the filtrate containing compound 9d was filtered and directly used for the next reaction.

[0479] LC-MS m / z (ESI) = 330.22 [M+1].

[0480] Step 4

[0481] tert-Butyl 3-methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate 9e

[0482] tert-butyl 3-methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0483] According to the method for compound 1d, compound 9e was obtained (black solid, 177 mg, yield 29%).

[0484] LC-MS m / z (ESI) = 399.26 [M+1].

[0485] Step 5

[0486] 1'-Methyl-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]9f

[0487] 1'-methyl-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[0488] According to the method for compound 1e, compound 9f was obtained (brown liquid, 167 mg, yield 99%).

[0489] LC-MS m / z (ESI) = 299.20 [M+1].

[0490] Step 6

[0491] 1'-Methyl-6-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]9g

[0492] 1'-methyl-6-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4′-piperidine]

[0493] According to the method of compound 1f, compound 9g (brown liquid, 82 mg, yield 48%) was obtained.

[0494] LC-MS m / z (ESI) = 299.20 [M+1].

[0495] Step 7

[0496] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone Compound 9

[0497] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone

[0498] According to the method of compound 1, compound 9 was obtained (brown solid, 14 mg, yield 21%).

[0499] 1 H NMR(400MHz,DMSO-d6)δ9.05-8.78(,1H),7.69(s,1H),7.41–7.32(m,1H),6 .99-6.92(m,1H),6.68–6.60(m,1H),5.38–5.24(m,2H),5.07–4.95(m,1H), 4.14–3.69(m,4H),3.48-3.40(m,2H),3.25–3.21(m,2H),3.04(s,2H),2.74 –2.63(m,4H),2.17–2.03(m,3H),1.72–1.43(m,9H),0.92(d,J=6.6Hz,3H).

[0500] LC-MS m / z (ESI) = 514.27 [M+1].

[0501] Example 10

[0502] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)spiro[cyclopropane-1,3'-indol]-2'-one compound 10

[0503] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0504] first step

[0505] tert-Butyl 6-(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate 10a

[0506] tert-butyl 6-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0507] According to the method for compound 1d, compound 10a was obtained (yellow liquid, 2.3 g, yield 76%).

[0508] LC-MS m / z (ESI) = 341.18 [M+1].

[0509] Step 2

[0510] 5'-(1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 10b

[0511] 5'-(1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3′-indolin]-2'-one

[0512] According to the method for compound 1e, compound 10b was obtained (yellow liquid, 880 mg, yield 49%).

[0513] LC-MS m / z (ESI) = 241.13 [M+1].

[0514] Step 3

[0515] 5'-(Piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 10c

[0516] 5'-(piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2′-one

[0517] According to the method of compound 1f, compound 10c (yellow solid, 788 mg, yield 88%) was obtained.

[0518] LC-MS m / z (ESI) = 243.14 [M+1].

[0519] Step 4

[0520] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)spiro[cyclopropane-1,3'-indol]-2'-one compound 10

[0521] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0522] According to the method of compound 1, compound 10 was obtained (white solid, 100 mg, yield 48%).

[0523] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.90(s,1H),7.76(s,1H),7.22(s,1H),7.10-7.03(m,2H),6.97-6. 86(m,2H),5.86–4.94(m,5H),3.55–3.40(m,2H),1.91-1.78(m,1H),1.63–1.43(m,7H),1.30-1.23(m,2H).

[0524] LC-MS m / z (ESI) = 456.20 [M+1].

[0525] Example 11

[0526] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)piperidin-1-yl)methanone Compound 11

[0527] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)piperidin-1-yl)methanone

[0528] first step

[0529] 1-(5-Bromo-2-(hydroxymethyl)phenyl)cyclopropan-1-ol 11b

[0530] 1-(5-bromo-2-(hydroxymethyl)phenyl)cyclopropan-1-ol

[0531] According to the method of compound 25b, compound 11b (yellow solid, 3.2 g, yield 58%) was obtained.

[0532] LC-MS m / z (ESI) = 242.99 [M+1].

[0533] Step 2

[0534] 6'-Bromo-3'-spiro[cyclopropane-1,1'-isobenzofuran]11c

[0535] 6'-bromo-3'H-spiro[cyclopropane-1,1'-isobenzofuran]

[0536] According to the method of compound 25c, compound 11c (white solid, 2.1 g, yield 60%) was obtained.

[0537] LC-MS m / z (ESI) = 224.98 [M+1].

[0538] Step 3

[0539] 4,4,5,5-Tetramethyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)-1,3,2-dioxaborolane 11d

[0540] 4,4,5,5-tetramethyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)-1,3,2-dioxaborolane

[0541] According to the method for compound 1c, compound 11d was obtained (yellow liquid, 1.2 g, yield 84%).

[0542] LC-MS m / z (ESI) = 273.16 [M+1].

[0543] Step 4

[0544] tert-Butyl 3-methyl-6-(3'-H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylate 11e

[0545] tert-butyl 3-methyl-6-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0546] According to the method for compound 1d, compound 11e was obtained (yellow liquid, 920 mg, yield 60%).

[0547] LC-MS m / z (ESI) = 342.20 [M+1].

[0548] Step 5

[0549] 3-Methyl-6-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)-1,2,3,4-tetrahydropyridine 11f

[0550] 3-methyl-6-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)-1,2,3,4-tetrahydropyridine

[0551] According to the method for compound 1e, compound 11f (yellow liquid, 377 mg, yield 58%) was obtained.

[0552] LC-MS m / z (ESI) = 242.15 [M+1].

[0553] Step 6

[0554] 5-Methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)piperidine 11g

[0555] 5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)piperidine

[0556] According to the method for compound 1f, compound 11g (yellow liquid, 97 mg, yield 25%) was obtained.

[0557] LC-MS m / z (ESI) = 244.16 [M+1].

[0558] Step 7

[0559] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6'-yl)piperidin-1-yl)methanone Compound 11

[0560] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-6′-yl)piperidin-1-yl)methanone

[0561] According to the method of compound 1, compound 11 was obtained (white solid, 110 mg, yield 45%).

[0562] 1 H NMR(400MHz,DMSO-d6)δ8.97-8.75(m,1H),7.82-7.69(m,1H),7.43–7.19(m,3H), 7.17–7.03(m,2H),5.40–4.98(m,5H),4.79-4.31(m,2H),3.67–3.44(m,1H),3.22– 2.89(m,1H),2.40–1.54(m,5H),1.43–1.09(m,3H),1.04–0.87(m,3H),0.86–0.60(m,1H).

[0563] LC-MS m / z (ESI) = 457.22 [M+1].

[0564] Example 12

[0565] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 12

[0566] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0567] first step

[0568] Ethyl 1-(5-bromo-3-fluoro-2-nitrophenoxy)cyclopropane-1-carboxylate 12b

[0569] ethyl 1-(5-bromo-3-fluoro-2-nitrophenoxy)cyclopropane-1-carboxylate

[0570] At 0°C, ethyl 1-hydroxycyclopropane-1-carboxylate (2.1 g, 16.1 mmol) was dissolved in THF (40 mL). NaH (882 mg, 22.0 mmol) was added and stirred for 10 min. A THF mixture of 12a (3.5 g, 14.7 mmol) was then added dropwise. The mixture was reacted at room temperature and the reaction progress was monitored by TLC.

[0571] The reaction was stopped, water was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate and eluted with column chromatography (EA:PE=1:40) to obtain compound 12b (brown solid, 3.4 g, yield 62%).

[0572] LC-MS m / z (ESI) = 347.98 [M+1].

[0573] Step 2

[0574] 7-Bromo-5-fluorospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 12c

[0575] 7-bromo-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0576] Compound 12b (3.4 g, 10 mmol) was dissolved in acetic acid (30 mL), and iron powder (1.7 g, 30 mmol) was added to react at room temperature. The reaction progress was monitored by TLC.

[0577] The reaction was stopped, water was added, and the residue was filtered to obtain a solid, which was then eluted by column chromatography (EA:PE=1:50) to obtain compound 12c (white solid, 2.3 g, yield 87%).

[0578] LC-MS m / z (ESI) = 271.96 [M+1].

[0579] Step 3

[0580] 5-Fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 12d

[0581] 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1′-cyclopropan]-3(4H)-one

[0582] According to the method of compound 1c, compound 12d (brown solid, 3.6 g, yield 99%) was obtained.

[0583] LC-MS m / z (ESI) = 320.14 [M+1].

[0584] Step 4

[0585] (S)-tert-Butyl 6-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 12e

[0586] tert-butyl (S)-6-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[0587] According to the method for compound 1d, compound 12e (yellow solid, 2.8 g, yield 96%) was obtained.

[0588] LC-MS m / z (ESI) = 389.18 [M+1].

[0589] Step 5

[0590] (S)-5-Fluoro-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 12f

[0591] (S)-5-fluoro-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0592] According to the method of compound 1e, compound 12f (white solid, 1.7 g, yield 60%) was obtained.

[0593] LC-MS m / z (ESI) = 289.13 [M+1].

[0594] Step 6

[0595] 5-Fluoro-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 12g

[0596] 5-fluoro-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0597] According to the method of compound 1f, compound 12g (white solid, 1.6 g, yield 89%) was obtained.

[0598] LC-MS m / z (ESI) = 291.14 [M+1].

[0599] Step 7

[0600] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 12

[0601] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0602] According to the method of compound 1, compound 12 was obtained (white solid, 110 mg, yield 63%).

[0603] 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.95-8.74(m,1H),7.80-7.70(m,1H),7.11-7.00(m,2H),6.97-6.68(m,2H),5.80–4.9 4(m,5H),2.16–1.58(m,4H),1.35-1.29(m,1H),1.28-1.25(m,2H),1.24-1.17(m,3H),0.95–0.91(m,1H),0.86–0.81(m,1H).

[0604] LC-MS m / z (ESI) = 504.20 [M+1].

[0605] Example 13

[0606] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-5-fluoro-4-methylspiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 13

[0607] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluoro-4-methylspiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0608] first step

[0609] (5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-7-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester 13a

[0610] tert-butyl(5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidine-1-carboxylate

[0611] Compound 12g (356 mg, 1.2 mmol) and TEA (500 mg, 4.8 mmol) were dissolved in THF (30 mL), and di-tert-butyl dicarbonate (401 mg, 1.8 mmol) was added dropwise. The mixture was reacted at room temperature and the reaction progress was monitored by TLC.

[0612] The reaction was stopped, water was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate and eluted with column chromatography (DCM:MeOH=60:1) to obtain compound 13a (yellow liquid, 430 mg, yield 91%).

[0613] LC-MS m / z (ESI) = 391.20 [M+1].

[0614] Step 2

[0615] (5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-7-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester 13b

[0616] tert-butyl(5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1′-cyclopropan]-7-yl)-5-methylpiperidine-1-carboxylate

[0617] Compound 13a (430 mg, 1.1 mmol) was dissolved in DMF (20 mL), and NaH (66.0 mg, 1.65 mmol) was added at 0°C. After stirring for 1 h, iodomethane (234.8 mg, 1.65 mmol) was added dropwise. The mixture was reacted at room temperature for 1 d. The reaction progress was monitored by TLC.

[0618] The reaction was stopped and quenched with water. EA was added for extraction. The organic phase was washed with water and the solvent was removed by rotary evaporation. Compound 13b (yellow liquid, 490 mg, yield 99%) was separated by column chromatography (DCM:MeOH=50:1).

[0619] LC-MS m / z (ESI) = 405.21 [M+1].

[0620] Step 3

[0621] 5-Fluoro-4-methyl-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 13c

[0622] 5-fluoro-4-methyl-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1′-cyclopropan]-3(4H)-one

[0623] According to the method of compound 1e, compound 13c (yellow solid, 328 mg, yield 89%) was obtained.

[0624] LC-MS m / z (ESI) = 305.16 [M+1].

[0625] Step 4

[0626] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-5-fluoro-4-methylspiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 13

[0627] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluoro-4-methylspiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0628] According to the method of compound 1, compound 13 was obtained (white solid, 180 mg, yield 88%).

[0629] 1H NMR (400MHz, DMSO-d6) δ8.99-8.75(m,1H),7.82-7.73(m,1H),7.18-6.94(m,3H),6.88-6.73(m,1H),5.82-4.99(m,5H),3.41-3.39(m ,2H),3.34(s,3H),2.22–1.79(m,3H),1.66-1.57(m,1H),1.38-1.29(m,1H),1.28-1.25(m,2H),1.24-1.18(m,3H),0.95-0.84(m,2H).

[0630] LC-MS m / z (ESI) = 518.21 [M+1].

[0631] Example 14

[0632] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-5-chlorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 14

[0633] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-5-chlorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0634] first step

[0635] Ethyl 1-(5-bromo-3-chloro-2-nitrophenoxy)cyclopropane-1-carboxylate 14b

[0636] ethyl 1-(5-bromo-3-chloro-2-nitrophenoxy)cyclopropane-1-carboxylate

[0637] According to the method of compound 12b, compound 14a (5 g, 21.4 mmol) was used to obtain compound 14b (white solid, 6.0 g, yield 77.5%).

[0638] LC-MS m / z (ESI) = 364.01 [M+1].

[0639] Step 2

[0640] 7-Bromo-5-chlorospiro[benzo[b[[1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 14c

[0641] 7-bromo-5-chlorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0642] According to the method of compound 12c, compound 14b was obtained (white solid, 4.4 g, yield 85.7%).

[0643] LC-MS m / z (ESI) = 287.99 [M+1].

[0644] Step 3

[0645] 5-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 14d

[0646] 7-5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1′-cyclopropan]-3(4H)-one

[0647] Referring to the synthesis method of 1c, 14d was obtained using 14c (yellow solid, 4.1 g, yield 83.6%).

[0648] LC-MS m / z (ESI) = 336.15 [M+1].

[0649] Step 4

[0650] (S)-tert-Butyl 6-(5-chloro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 14e

[0651] tert-butyl-(S)-6-(5-chloro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[0652] Referring to the synthetic method of 1d, 14d (2.0 g, 5.9 mmol) and intermediate B (3.0 g, 8.9 mmol) were used to obtain 14e (yellow solid, 1.04 g, yield 45%).

[0653] LC-MS m / z (ESI) = 405.16 [M+1].

[0654] Step 5

[0655] (S)-5-Chloro-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 14f

[0656] (S)-5-chloro-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1′-cyclopropan]-3(4H)-one

[0657] Referring to the synthetic method of 1e, 14e was used to obtain 14f (off-white solid, 700 mg, 96% yield).

[0658] LC-MS m / z (ESI) = 305.14 [M+1].

[0659] Step 6

[0660] 5-Chloro-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 14g

[0661] 5-chloro-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0662] Referring to the synthetic method of 1f, 14f was used to obtain 14g (yellow solid, 550 mg, yield 78%).

[0663] LC-MS m / z (ESI) = 306.18 [M+1].

[0664] Step 7

[0665] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-5-chlorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 14

[0666] 7-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-5-chlorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0667] Referring to the synthesis method of compound 1, 14 g (100 mg, 0.33 mmol) was used to obtain 14 (white solid, 150 mg, yield 87%).

[0668] 1 H NMR (400MHz, DMSO) δ10.64(s,1H),8.88(d,1H),7.74(s,1H),7.09(s,3H),6.86(s,1H),5.43–5.29(m,2H),5.03(s ,2H),3.10(dt,1H),3.01(td,1H),2.07(dd,2H),1.75–1.70(m,1H),1.31–1.20(m,7H),1.17(t,1H),0.94(d,2H).

[0669] LC-MS m / z (ESI) = 520.20 [M+1].

[0670] Example 15

[0671] 6-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 15

[0672] 6-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0673] first step

[0674] Ethyl 1-(4-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate 15b

[0675] ethyl 1-(4-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate

[0676] Referring to the synthesis method of 12b, 15a was used to obtain 12b (white solid, 2.2 g, yield 89%).

[0677] LC-MS m / z (ESI) = 329.99 [M+1].

[0678] Step 2

[0679] 6-Bromospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 13c

[0680] 6-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0681] Referring to the synthesis method of 12c, 15b was used to obtain 15c (white solid, 1.7 g, yield 84%).

[0682] LC-MS m / z (ESI) = 253.97 [M+1].

[0683] Step 3

[0684] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 30d

[0685] 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1′-cyclopropan]-3(4H)-one

[0686] Referring to the synthesis method of 1c, 15d was obtained using 15c (yellow solid, 1.1 g, yield 85%).

[0687] LC-MS m / z (ESI) = 302.15 [M+1].

[0688] Step 4

[0689] (S)-tert-Butyl 3-methyl-6-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate 30e

[0690] tert-butyl(S)-3-methyl-6-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0691] Referring to the synthetic method of 1d, 15e was obtained using 15d and intermediate B (yellow solid, 954 mg, yield 77%).

[0692] LC-MS m / z (ESI) = 371.19 [M+1].

[0693] Step 5

[0694] (S)-6-(5-Methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 30f

[0695] (S)-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0696] Referring to the synthetic method of 1e, 15e was used to obtain 15f (yellow solid, 754 mg, yield 81%).

[0697] LC-MS m / z (ESI) = 271.14 [M+1].

[0698] Step 6

[0699] 6-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 30g

[0700] 6-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0701] Referring to the synthesis method of 1f, 15f was used to obtain 15g (yellow solid, 733 mg, yield 83%).

[0702] LC-MS m / z (ESI) = 273.15 [M+1].

[0703] Step 7

[0704] 6-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 15

[0705] 6-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0706] Referring to the synthesis method of compound 1, 15 g (100 mg, 0.33 mmol) was used to obtain 15 (white solid, 120 mg, yield 87%).

[0707] 1 H NMR (400MHz, DMSO-d6) δ10.84–10.62(m,1H),8.93–8.77(m,1H),7.77–7.69(m,1H),7.17–7.00(m,2H),6.98–6.84(m,3H),5.39– 5.28(m,2H),5.10–4.94(m,2H),3.21–3.10(m,1H),2.18–1.97(m,2H),1.95–1.61(m,3H),1.33–1.09(m,6H),1.08–0.85(m,3H).

[0708] LC-MS m / z (ESI) = 486.20 [M+1].

[0709] Example 16

[0710] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-1'-methyl-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-2'-one compound 16

[0711] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5- methylpiperidin-2-yl)-1'-methyl-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0712] first step

[0713] (5S)-tert-Butyl 5-methyl-2-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-6'-yl)piperidine-1-carboxylate 16a

[0714] tert-butyl(5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)piperidine-1-carboxylate

[0715] According to the method of compound 8b, compound 16a (yellow solid, 200 mg, yield 80%) was obtained using compound 4k.

[0716] LC-MS m / z (ESI) = 371.30 [M+1].

[0717] Step 2

[0718] (5S)-tert-Butyl 5-methyl-2-(1'-methyl-2'-oxo-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-6'-yl)piperidine-1-carboxylate 16b

[0719] tert-butyl(5S)-5-methyl-2-(1′-methyl-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3′-quinolin]-6′-yl)piperidine-1-carboxylate

[0720] According to the method of compound 8c, compound 16a was used to obtain compound 16b (yellow liquid, 200 mg, yield 90%).

[0721] LC-MS m / z (ESI) = 385.30 [M+1].

[0722] Step 3

[0723] 1'-Methyl-6'-((5S)-5-methylpiperidin-2-yl)-1'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 16c

[0724] 1'-methyl-6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0725] According to the method of compound 1e, compound 16c (yellow oily liquid, 150 mg, yield 82%) was obtained using compound 16b.

[0726] LC-MS m / z (ESI) = 285.20 [M+1].

[0727] Step 4

[0728] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-1'-methyl-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-2'-one compound 16

[0729] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-1'-methyl-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0730] According to the method for synthesizing compound 1, compound 16c was reacted with intermediate C to obtain compound 16 (white solid, 100 mg, yield 65%).

[0731] 1H NMR(400MHz, DMSO-d6)δ8.94–8.71(m,1H),7.76–7.68(m,1H),7.32–6.97(m,5H),5.42–5.26(m,2H),5.11–4.94(m,2H),3.27–3 .22(m,3H),2.89–2.79(m,2H),2.25–1.98(m,2H),1.97–1.58(m,3H),1.38–1.17(m,2H),1.11–0.87(m,5H),0.81–0.60(m,3H).

[0732] LC-MS m / z (ESI) = 516.30 [M+1].

[0733] Example 17

[0734] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-7'-chlorospiro[cyclopropane-1,3'-indol]-2'-one compound 17

[0735] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one

[0736] first step

[0737] 7'-Chlorospiro[cyclopropane-1,3'-indolin]-2'-one compound 17b

[0738] 7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one

[0739] Compound 17a (10 g, 59 mmol) was dissolved in THF (100 mL), and lithium diisopropylamide (119 mL, 2 M in THF) was added at 0°C. After stirring for 30 min, 1,3-dibromopropane (33 g, 179 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 16 h. After completion, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (150 x 3 mL), washed with saturated brine (100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 17b (brown solid, 9.8 g, 75% yield).

[0740] LC-MS m / z (ESI) = 194.10 [M+1].

[0741] Step 2

[0742] 5'-Bromo-7'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one 17c

[0743] 5'-bromo-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0744] Compound 17b (9.8 g, 50 mmol) was dissolved in ACN (120 mL), and N-bromosuccinimide (10 g, 56 mmol) was added at room temperature. The mixture was stirred for 16 h, and ethyl acetate (300*3 mL) was added for extraction. The mixture was washed with saturated brine (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 17b (brown solid, 13 g, yield 82%).

[0745] LC-MS m / z (ESI) = 274.20 [M+1].

[0746] Step 3

[0747] 7'-Chloro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indol]-2'-one 28d

[0748] 7'-chloro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0749] According to the method of compound 1c, compound 17c (1.0 g, 2.6 mmol) was used to obtain compound 17d (white solid, 1 g, yield 85%).

[0750] LC-MS m / z (ESI) = 320.14 [M+1].

[0751] Step 4

[0752] (S)-tert-Butyl 6-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 17e

[0753] tert-butyl (S)-6-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[0754] According to the method for synthesizing compound 1d, compound 17d was used to obtain compound 17e (yellow solid, 750 mg, yield 65%).

[0755] LC-MS m / z (ESI) = 389.23 [M+1].

[0756] Step 5

[0757] (S)-7'-Chloro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 17f

[0758] (S)-7'-chloro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0759] According to the method of compound 1e, compound 17e was used to obtain compound 17f (yellow solid, 400 mg, yield 71%).

[0760] LC-MS m / z (ESI) = 289.20 [M+1].

[0761] Step 6

[0762] 7'-Chloro-5'-((5S)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 17g

[0763] 7'-chloro-5'-((5S)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0764] According to the method of compound 1f, compound 17f was used to obtain compound 17g (yellow solid, 350 mg, yield 90%).

[0765] LC-MS m / z (ESI) = 291.20 [M+1].

[0766] Step 7

[0767] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-7'-chlorospiro[cyclopropane-1,3'-indol]-2'-one compound 17

[0768] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one

[0769] According to the method for synthesizing compound 1, compound 17g was reacted with intermediate C to obtain compound 17 (white solid, 60 mg, yield 60%).

[0770] 1 H NMR (400MHz, DMSO-d6) δ11.07–10.86(m,1H),8.92–8.67(m,1H),7.78–7.57(m,1H),7.20–6.86(m,4H),5.66– 5.19(m,3H),5.03–5.02(m,2H),2.21–2.00(m,2H),1.88–1.45(m,6H),1.36–1.07(m,3H),1.00–0.78(m,3H).

[0771] LC-MS m / z (ESI) = 504.20 [M+1].

[0772] Example 18

[0773] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-7'-chloro-1'-methylspiro[cyclopropane-1,3'-indol]-2'-one compound 18

[0774] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-chloro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0775] first step

[0776] tert-Butyl (5S)-2-(7′-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-5-methylpiperidine-1-carboxylate

[0777] tert-butyl(5S)-2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidine-1-carboxylate

[0778] According to the method of compound 8b, compound 18a (yellow solid, 250 mg, yield 80%) was obtained using compound 17g.

[0779] LC-MS m / z (ESI) = 391.20 [M+1].

[0780] Step 2

[0781] (5S)-tert-Butyl 2-(7'-chloro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-5-methylpiperidine-1-carboxylate 18b

[0782] tert-butyl(5S)-2-(7'-chloro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidine-1-carboxylate

[0783] According to the method of compound 8c, compound 18a was used to obtain compound 18b (yellow liquid, 220 mg, yield 87%).

[0784] LC-MS m / z (ESI) = 405.30 [M+1].

[0785] Step 3

[0786] 7′-Chloro-1′-methyl-5′-((5S)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3′-indolin]-2′-one 18c

[0787] 7'-chloro-1'-methyl-5'-((5S)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0788] According to the method of compound 1e, compound 16c (yellow oily liquid, 170 mg, yield 82%) was obtained using compound 16b.

[0789] LC-MS m / z (ESI) = 305.20 [M+1].

[0790] Step 4

[0791] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-7'-chloro-1'-methylspiro[cyclopropane-1,3'-indol]-2'-one compound 18

[0792] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-chloro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0793] According to the method for synthesizing compound 1, compound 18c was reacted with intermediate C to obtain compound 18 (white solid, 70 mg, yield 60%).

[0794] 1 H NMR (400MHz, DMSO-d6) δ8.96–8.70(m,1H),7.83–7.63(m,1H),7.23–6.91(m,4H),5.65–5.21(m,3H),5.13–4.92(m,2H ),3.56–3.45(m,3H),3.23–3.09(m,1H),2.27–1.96(m,2H),1.91–1.43(m,7H),1.39–1.17(m,2H),1.07–0.76(m,3H).

[0795] LC-MS m / z (ESI) = 518.20 [M+1].

[0796] Example 19

[0797] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-7'-fluoro-1'-methylspiro[cyclopropane-1,3'-indol]-2'-one compound 19

[0798] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0799] first step

[0800] (5S)-tert-Butyl 2-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-5-methylpiperidine-1-carboxylate 19a

[0801] tert-butyl (5S)-2-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidine-1-carboxylate

[0802] According to the method of compound 13a, compound 19a was obtained (yellow liquid, 400 mg, yield 99%).

[0803] LC-MS m / z (ESI) = 375.20 [M+1].

[0804] Step 3

[0805] 7'-Fluoro-1'-methyl-5'-((5S)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 19c

[0806] 7'-fluoro-1'-methyl-5'-((5S)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0807] According to the method of compound 13c, compound 19c (yellow liquid, 400 mg, yield 99%) was obtained.

[0808] LC-MS m / z (ESI) = 289.16 [M+1].

[0809] Step 4

[0810] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-7'-fluoro-1'-methylspiro[cyclopropane-1,3'-indol]-2'-one compound 19

[0811] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0812] According to the method of compound 1, compound 19 was obtained (white solid, 100 mg, yield 57%).

[0813] 1 H NMR (400MHz, DMSO-d6) δ8.99-8.74(m,1H),7.83-7.70(m,1H),7.11-7.05(m,2H),7.05–6.78(m,2H),5.87–4.95(m,5H ),3.43-3.35(m,4H),3.17-3.03(m,1H),2.18-1.62(m,5H),1.58-1.48(m,2H),1.34-1.20(m,2H),1.06-0.88(m,3H).

[0814] LC-MS m / z (ESI) = 502.22 [M+1].

[0815] Example 20

[0816] 7-((5S)-1-(4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Compound 20

[0817] 7-((5S)-1-(4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0818] first step

[0819] 7-((5S)-1-(4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Compound 20

[0820] 7-((5S)-1-(4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0821] According to the method of compound 1, compound 20 (white solid, 110 mg, yield 61%) was obtained.

[0822] 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.72–7.23(m,2H),6.99-6.52(m,4H),5.84–4.92(m,5H),3.30–3.0 5(m,2H),2.20–1.77(m,3H),1.68–1.55(m,1H),1.35–1.25(m,3H),1.24–1.17(m,3H),0.92-0.78(m,2H).

[0823] LC-MS m / z (ESI) = 521.19 [M+1].

[0824] Example 21

[0825] 5'-((5S)-1-(4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indol]-2'-one compound 21

[0826] 5'-((5S)-1-(4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0827] first step

[0828] 5'-((5S)-1-(4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indol]-2'-one compound 21

[0829] 5'-((5S)-1-(4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0830] According to the method of compound 1, compound 21 was obtained (white solid, 50 mg, yield 54%).

[0831] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),7.69–7.22(m,2H),7.07–6.58(m,4H),5.87–4.89(m,5H), 3.26–2.90(m,2H),2.25–1.93(m,2H),1.70–1.47(m,5H),1.32–1.21(m,2H),0.91–0.78(m,3H).

[0832] LC-MS m / z (ESI) = 505.20 [M+1].

[0833] Example 22

[0834] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)-7'-chlorospiro[cyclopropane-1,3'-indol]-2'-one compound 22

[0835] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)-7'-chlorospiro[cyclopropane-1,3′-indolin]-2'-one

[0836] first step

[0837] tert-Butyl 6-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate 22a

[0838] tert-butyl 6-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0839] According to the method for synthesizing compound 1d, compound 17d and intermediate E were used to obtain compound 22a (white solid, 700 mg, yield 68%).

[0840] LC-MS m / z (ESI) = 375.20 [M+1].

[0841] Step 2

[0842] 7′-Chloro-5′-(1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3′-indolin]-2′-one 22b

[0843] 7'-chloro-5'-(1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0844] According to the method of compound 1e, compound 22a was used to obtain compound 22b (yellow solid, 450 mg, yield 87%).

[0845] LC-MS m / z (ESI) = 275.10 [M+1].

[0846] Step 3

[0847] 7'-Chloro-5'-(piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 22c

[0848] 7'-chloro-5'-(piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0849] According to the method of compound 1f, compound 22c (yellow solid, 400 mg, yield 88%) was obtained using compound 22b.

[0850] LC-MS m / z (ESI) = 277.10 [M+1].

[0851] Step 4

[0852] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)-7'-chlorospiro[cyclopropane-1,3'-indol]-2'-one compound 22

[0853] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one

[0854] According to the method for synthesizing compound 1, compound 22c was reacted with intermediate C to obtain compound 22 (white solid, 70 mg, yield 39%).

[0855] 1 H NMR (400MHz, DMSO-d6) δ11.09–10.87(m,1H),8.98–8.63(m,1H),7.88–7.63(m,1H),7.21–6.86(m,4H),5.43– 5.24(m,2H),5.15–4.92(m,2H),2.46–2.21(m,1H),2.02–1.72(m,2H),1.69–1.31(m,8H),1.28–1.18(m,2H).

[0856] LC-MS m / z (ESI) = 490.20 [M+1].

[0857] Example 23

[0858] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)-7'-chloro-1'-methylspiro[cyclopropane-1,3'-indol]-2'-one compound 23

[0859] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)-7'-chloro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0860] first step

[0861] tert-Butyl 2-(7′-chloro-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-yl)piperidine-1-carboxylate 23a

[0862] 2-tert-butyl 2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidine-1-carboxylate

[0863] According to the method of compound 8b, compound 22c was used to obtain compound 23a (yellow solid, 200 mg, yield 75%).

[0864] LC-MS m / z (ESI) = 377.20 [M+1].

[0865] Step 2

[0866] tert-Butyl 2-(7′-chloro-1′-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-yl)piperidine-1-carboxylate 23b

[0867] tert-butyl 2-(7'-chloro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidine-1-carboxylate

[0868] According to the method of compound 8c, compound 23a was used to obtain compound 23b (yellow solid, 190 mg, yield 91%).

[0869] LC-MS m / z (ESI) = 391.20 [M+1].

[0870] Step 3

[0871] 7'-Chloro-1'-methyl-5'-(piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 23c

[0872] 7'-chloro-1'-methyl-5'-(piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0873] According to the method of compound 1e, compound 23b was used to obtain compound 23c (yellow oil, 120 mg, yield 85%).

[0874] LC-MS m / z (ESI) = 291.15 [M+1].

[0875] Step 4

[0876] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)piperidin-2-yl)-7'-chloro-1'-methylspiro[cyclopropane-1,3'-indol]-2'-one compound 23

[0877] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)piperidin-2-yl)-7'-chloro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0878] According to the method for synthesizing compound 1, compound 23c was reacted with intermediate C to obtain compound 23 (white solid, 70 mg, yield 60%).

[0879] 1 1H NMR(400MHz,DMSO-d6)δ9.06–8.63(m,1H),7.89–7.61(m,1H),7.20–6.85(m,3H),5.52–5.21(m,2H),5.12–4 .85(m,2H),3.67–3.40(m,3H),3.23–2.59(m,3H),2.49–2.28(m,2H),2.04–1.45(m,7H),1.44–1.18(m,2H).

[0880] LC-MS m / z (ESI) = 504.20 [M+1].

[0881] Example 24

[0882] 6'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one compound 24

[0883] 6'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0884] first step

[0885] tert-Butyl 6-(2'-oxo-1'-,4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylate 24a

[0886] tert-butyl 6-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0887] Referring to the synthesis method of compound 1d, compound 4h and intermediate E were used to obtain compound 24a (yellow solid, 1.1 g, yield 83%).

[0888] LC-MS m / z (ESI) = 355.19 [M+1].

[0889] Step 2

[0890] 6'-(1,4,5,6-tetrahydropyridin-2-yl)-1'-dihydro-2'-spiro[cyclopropane-1,3'-quinolin]-2'-one 24b

[0891] 6'-(1,4,5,6-tetrahydropyridin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0892] Referring to the synthesis method of compound 1e, compound 24a was used to obtain compound 24b (yellow solid, 920 mg, yield 81%).

[0893] LC-MS m / z (ESI) = 255.14 [M+1].

[0894] Step 3

[0895] 6'-(Piperidin-2-yl)-1'-, 4'-dihydro-2'-spiro[cyclopropane-1,3'-quinolin]-2'-one 24c

[0896] 6'-(piperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0897] Referring to the synthesis method of compound 1f, compound 24b was used to obtain compound 24c (yellow solid, 870 mg, yield 81%).

[0898] LC-MS m / z (ESI) = 257.16 [M+1].

[0899] Step 4

[0900] 6'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one compound 24

[0901] 6'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0902] According to the method of compound 1, compound 24c (100 mg, 0.39 mmol) was used to obtain compound 24 (white solid, 134 mg, yield 73%)

[0903] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.88(s,1H),7.89(s,1H),7.16–6.88(m,3H),5.96(s,2H),5.44–5.13(m,5 H),4.13–3.58(m,1H),3.19–2.91(m,1H),2.78(s,2H),1.83–1.44(m,6H).1.09-1.03(m,2H),0.78-0.73(m,2H).

[0904] LC-MS m / z (ESI) = 470.21 [M+1].

[0905] Example 25

[0906] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidin-1-yl)methanone Compound 25

[0907] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidin-1-yl)methanone

[0908] first step

[0909] 1-(4-Bromo-2-(hydroxymethyl)phenyl)cyclopropan-1-ol 25b

[0910] 1-(4-bromo-2-(hydroxymethyl)phenyl)cyclopropan-1-ol

[0911] Compound 34a (5.0 g, 23.5 mmol) and tetraisopropyl titanate (7.3 g, 25.8 mmol) were dissolved in tetrahydrofuran (80 mL). Ethylmagnesium bromide (28.2 mL, 56.7 mmol) was added dropwise at 0°C. The mixture was allowed to warm to room temperature and react for 3 h. After completion of the reaction, saturated aqueous ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 25b (yellow solid, 3.6 g, 64% yield).

[0912] LC-MS m / z (ESI) = 242.99 [M+1].

[0913] Step 2

[0914] 5'-Bromo-3'-spiro[cyclopropane-1,1'-isobenzofuran]25c

[0915] 5'-bromo-3'H-spiro[cyclopropane-1,1'-isobenzofuran]

[0916] Compound 25b (3.6 g, 14.9 mmol) and triphenylphosphine (11.7 g, 44.7 mmol) were dissolved in tetrahydrofuran (50 mL). Diisopropyl azodicarboxylate (7.5 g, 37.3 mmol) was added dropwise at 0°C. After reacting for 4 hours, the organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 30:1) to afford compound 25c (white solid, 2.0 g, 61% yield).

[0917] LC-MS m / z (ESI) = 224.98 [M+1].

[0918] Step 3

[0919] 4,4,5,5-Tetramethyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-1,3,2-dioxaborolane 25d

[0920] 4,4,5,5-tetramethyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-1,3,2-dioxaborolane

[0921] Referring to the synthesis method of compound 1c, 25d was obtained using 25c (yellow solid, 1.4 g, yield 81%).

[0922] LC-MS m / z (ESI) = 273.16 [M+1].

[0923] Step 4

[0924] tert-Butyl 3-methyl-6-(3'-H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate 25e

[0925] tert-butyl 3-methyl-6-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-3,4- dihydropyridine-1(2H)-carboxylate

[0926] Referring to the synthesis method of compound 1d, 25e was obtained using 25d and intermediate B (yellow solid, 1.2 g, yield 87%).

[0927] LC-MS m / z (ESI) = 342.12 [M+1].

[0928] Step 5

[0929] 3-Methyl-6-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-1,2,3,4-tetrahydropyridine 25f

[0930] 2-methyl-6-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-1,2,3,4-tetrahydropyridine

[0931] 3- Referring to the synthesis method of compound 1e, 25e was used to obtain 25f (yellow solid, 1.0 g, yield 80%).

[0932] LC-MS m / z (ESI) = 242.15 [M+1].

[0933] Step 6

[0934] 5-Methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidine 25g

[0935] 5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidine

[0936] Referring to the synthesis method of compound 1f, 25g was obtained using 25f (yellow solid, 920 mg, yield 87%).

[0937] LC-MS m / z (ESI) = 244.16 [M+1].

[0938] Step 7

[0939] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidin-1-yl)methanone Compound 25

[0940] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidin-1-yl)methanone

[0941] According to the method of compound 1, compound 25 (white solid, 110 mg, yield 66%) was obtained.

[0942] 1H NMR(400MHz,DMSO-d6)δ8.94-8.79(m,1H),7.81-7.70(m,1H),7.43–7.19(m,3H),7.15–7.06(m,2H),5.41–4.99(m,5H),4.77-4 .33(m,2H),3.68–3.45(m,1H),3.25–2.91(m,1H),2.43–1.58(m,5H),1.46–1.11(m,3H),1.01–0.89(m,3H),0.81–0.68(m,1H).

[0943] LC-MS m / z (ESI) = 457.22 [M+1].

[0944] Example 26

[0945] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-2'-one compound 26

[0946] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0947] first step

[0948] 8-Fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 26b

[0949] 8-fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0950] Referring to the synthesis method of compound 4b, compound 26a was used to obtain compound 26b (white solid, 1.4 g, yield 81%).

[0951] LC-MS m / z (ESI) = 286.12 [M+1].

[0952] Step 2

[0953] 3-(2-Chloroethyl)-8-fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 26c

[0954] 3-(2-chloroethyl)-8-fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0955] Referring to the synthesis method of compound 4c, compound 26b was used to obtain compound 26c (white solid, 1.7 g, yield 84%).

[0956] LC-MS m / z (ESI) = 348.11 [M+1].

[0957] Step 3

[0958] 8-Fluoro-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 26d

[0959] 8-fluoro-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0960] Referring to the synthesis method of compound 4d, compound 26c was used to obtain compound 26d (yellow solid, 2.1 g, yield 81%).

[0961] LC-MS m / z (ESI) = 440.04 [M+1].

[0962] Step 4

[0963] 8-Fluoro-1'-(4-methoxybenzyl)-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 26e

[0964] 8'-fluoro-1'-(4-methoxybenzyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0965] Referring to the synthesis method of compound 4e, compound 26d was used to obtain compound 26e (yellow solid, 1.6 g, yield 81%).

[0966] LC-MS m / z (ESI) = 312.13 [M+1].

[0967] Step 5

[0968] 8'-Fluoro-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-2'-one 26f

[0969] 8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0970] Referring to the synthesis method of compound 4f, compound 26e was used to obtain compound 26f (yellow solid, 1.3 g, yield 81%).

[0971] LC-MS m / z (ESI) = 192.07 [M+1].

[0972] Step 6

[0973] 6'-Bromo-8-fluoro-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 26g

[0974] 6'-bromo-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0975] Referring to the synthesis method of compound 4f, compound 26f was used to obtain compound 26g (yellow solid, 1.7 g, yield 83%).

[0976] LC-MS m / z (ESI) = 269.99 [M+1].

[0977] Step 7

[0978] 8-Fluoro-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 26h

[0979] 8'-fluoro-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0980] Referring to the synthesis method of compound 4c, compound 26g was used to obtain compound 26h (yellow solid, 2.1 g, yield 84%).

[0981] LC-MS m / z (ESI) = 318.16 [M+1].

[0982] Step 8

[0983] (S)-tert-Butyl 3-methyl-6-(8-fluoro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylate 26i

[0984] tert-butyl(S)-6-(8'-fluoro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[0985] Referring to the synthesis method of compound 4d, compound 26h and intermediate B were used to obtain compound 26i (yellow solid, 2.3 g, yield 81%).

[0986] LC-MS m / z (ESI) = 387.20 [M+1].

[0987] Step 9

[0988] (S)-8-Fluoro-6'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 26j

[0989] (S)-8'-fluoro-6'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0990] Referring to the synthesis method of compound 4e, compound 26i was used to obtain compound 26j (yellow solid, 1.7 g, yield 83%).

[0991] LC-MS m / z (ESI) = 287.15 [M+1].

[0992] Step 10

[0993] 8-Fluoro-6'-((5S)-5-methylpiperidin-2-yl)-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 26k

[0994] 8'-fluoro-6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0995] Referring to the synthesis method of compound 4f, compound 26j was used to obtain compound 26k (yellow solid, 1.5 g, yield 81%).

[0996] LC-MS m / z (ESI) = 289.16 [M+1].

[0997] Step 11

[0998] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-2'-one compound 26

[0999] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1000] According to the method of compound 1, compound 26 (white solid, 123 mg, yield 78%) was obtained.

[1001] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.87(s,1H),7.74(s,1H),7.06-6.94(m,4H),5.76-5.35(m,3H),5.03(s,2 H),3.83–3.49(m,1H),3.24–3.03(m,1H),2.90(s,2H),2.23–1.58(m,5H),1.08-0.91(m,5H),0.76-0.73(m,2H).

[1002] LC-MS m / z (ESI) = 502.22 [M+1].

[1003] Example 27

[1004] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-8'-fluoro-1'-methyl-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-2'-one compound 27

[1005] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1'-methyl-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1006] first step

[1007] (5S)-tert-Butyl 2-(8'-fluoro-2'-oxo-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-6'-yl)-5-methylpiperidine-1-carboxylate 27a

[1008] tert-butyl(5S)-2-(8'-fluoro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-5-methylpiperidine-1-carboxylate

[1009] According to the method of compound 8b, compound 26k was used to obtain compound 27a (yellow solid, 310 mg, yield 86%).

[1010] LC-MS m / z (ESI) = 389.22 [M+1].

[1011] Step 2

[1012] (5S)-tert-Butyl 2-(8'-fluoro-1'-methyl-2'-oxo-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-6'-yl)-5-methylpiperidine-1-carboxylate 27b

[1013] tert-butyl(5S)-2-(8'-fluoro-1'-methyl-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-5-methylpiperidine-1-carboxylate

[1014] According to the method of compound 8c, compound 27a was used to obtain compound 27b (yellow liquid, 330 mg, yield 90%).

[1015] LC-MS m / z (ESI) = 403.23 [M+1].

[1016] Step 3

[1017] 8'-Fluoro-1'-methyl-6'-((5S)-5-methylpiperidin-2-yl)-1'-, 4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 27c

[1018] 8'-fluoro-1'-methyl-6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1019] According to the method of compound 1e, compound 27b was used to obtain compound 27c (yellow oily liquid, 212 mg, yield 83%).

[1020] LC-MS m / z (ESI) = 303.18 [M+1].

[1021] Step 4

[1022] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-yl)-5-methylpiperidin-2-yl)-8'-fluoro-1'-methyl-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-2'-one compound 27

[1023] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1'-methyl-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1024] According to the method for synthesizing compound 1, compound 27c was reacted with intermediate C to obtain compound 27 (white solid, 233 mg, yield 75%).

[1025] 1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.75(s,1H),7.23–6.91(m,4H),5.84–5.23(m,3H),5.04(d,2H),3.88-3.6 4(m,1H),3.31(s,3H),3.21-3.03(m,1H),2.84(s,2H),2.23–1.51(m,5H),1.02–0.80(m,5H),0.76–0.64(m,2H).

[1026] LC-MS m / z (ESI) = 516.23 [M+1].

[1027] Example 28

[1028] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclobutane-1,3'-indolin]-2'-one compound 28

[1029] 5'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclobutane-1,3'-indolin]-2'-one

[1030] first step

[1031] 7'-Fluorospiro[cyclobutane-1,3'-indolin]-2'-one 28b

[1032] 7'-fluorospiro[cyclobutane-1,3'-indolin]-2'-one

[1033] Following the procedure of 5b, 28a (25 g, 165 mmol) was used to give 28b (brown solid, 17 g, 54.8% yield).

[1034] LC-MS m / z (ESI) = 192.16 [M+1].

[1035] Step 2

[1036] 7'-Fluorospiro[cyclobutane-1,3'-indolin]-2'-one 28c

[1037] 7'-fluorospiro[cyclobutane-1,3'-indolin]-2'-one

[1038] Following the procedure of 5c, 28b (17 g, 89 mmol) was used to give 28c (brown solid, 16.2 g, 67.5% yield).

[1039] LC-MS m / z (ESI) = 270.01 [M+1].

[1040] Step 3

[1041] 7'-Fluoro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one 5d

[1042] 7'-fluoro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[1043] According to the method of 1c, 28c (1.0 g, 2.6 mmol) was used to give 28d (white solid, 950 g, 90% yield).

[1044] LC-MS m / z (ESI) = 318.14 [M+1].

[1045] Step 4

[1046] tert-Butyl 6-(7'-fluoro-2'-oxospiro[cyclobutane-1,3'-dihydroindole]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 5e

[1047] tert-butyl 6-(7'-fluoro-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1048] According to the method of synthesizing 1d, compound 28e (yellow solid, 700 mg, yield 67.2%).

[1049] LC-MS m / z (ESI) = 387.20 [M+1].

[1050] Step 5

[1051] 7'-Fluoro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one 5f

[1052] 7'-fluoro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[1053] According to the method of 1e, 28f was obtained (yellow solid, 600 mg, 85% yield).

[1054] LC-MS m / z (ESI) = 287.23 [M+1].

[1055] Step 6

[1056] 7'-Fluoro-5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 5g

[1057] 7'-fluoro-5'-(5-methylpiperidin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[1058] According to the method of 1f, 28f was used to obtain 28g (yellow solid, 550 mg, 83% yield).

[1059] LC-MS m / z (ESI) = 289.20 [M+1].

[1060] Step 7

[1061] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclobutane-1,3'-indolin]-2'-one compound 28

[1062] 5'-(1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-7'-fluorospiro[cyclobutane-1,3′-indolin]-2'-one

[1063] According to the method of compound 1, 5 g (100 mg, 0.34 mmol) was used to obtain compound 28 (white solid, 80 mg, yield 46%) after chiral SFC separation.

[1064] 1 H NMR(400MHz,DMSO)δ10.34(s,1H),8.78(s,1H),7.77(s,1H),7.60–7.12(d,3H),6.87 (d,1H),5.44–5.30(m,2H),5.05(s,2H),3.18(s,1H),2.17(s,2H),1.90–1.60(m,4H), 1.32–1.22(m,3H),1.09(s,2H),1.05–0.85(m,2H),0.83–0.80(m,1H),0.77–0.68(m,2H).

[1065] LC-MS m / z (ESI) = 502.20 [M+1].

[1066] Example 29

[1067] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-8'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one Compound 29

[1068] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-8'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1069] first step

[1070] 8-Chloro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 29b

[1071] 8-chloro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[1072] Referring to the synthesis method of compound 26b, compound 29a was used to obtain compound 29b (white solid, 5.2 g, yield 81%).

[1073] LC-MS m / z (ESI) = 302.11 [M+1].

[1074] Step 2

[1075] 8-Chloro-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 29c

[1076] 8-chloro-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[1077] Referring to the synthesis method of compound 26c, compound 29b was used to obtain compound 29c (yellow solid, 1.16 g, yield 18.5%).

[1078] LC-MS m / z (ESI) = 364.16 [M+1].

[1079] Step 3

[1080] 8-Chloro-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 29d

[1081] 8-chloro-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[1082] Referring to the synthesis method of compound 26d, compound 29c was used to obtain compound 29d (yellow oily liquid, 1.27 g, yield 87%).

[1083] LC-MS m / z (ESI) = 456.11 [M+1].

[1084] Step 4

[1085] 8'-Chloro-1'-(4-methoxybenzyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 29e

[1086] 8'-chloro-1'-(4-methoxybenzyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1087] Referring to the synthesis method of compound 26e, compound 29d was used to obtain compound 29e (yellow oily liquid, 750 mg, yield 82%).

[1088] LC-MS m / z (ESI) = 328.18 [M+1].

[1089] Step 5

[1090] 8'-Chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 29f

[1091] 8'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1092] Referring to the synthesis method of compound 26f, compound 29e was used to obtain compound 29f (yellow oily liquid, 480 mg, yield 94%).

[1093] LC-MS m / z (ESI) = 208.16 [M+1].

[1094] Step 6

[1095] 6'-Bromo-8'-chloro-1', 4'-dihydro-2'H-spiro[cyclopropane-1, 3'-quinoline]-2'-one 29g

[1096] 6'-bromo-8'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1097] Referring to the synthesis method of compound 26f, compound 29f was used to obtain compound 29g (white solid, 500 mg, yield 77%).

[1098] LC-MS m / z (ESI) = 285.99 [M+1].

[1099] Step 7

[1100] 8'-Chloro-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 29h

[1101] 8'-chloro-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1102] Referring to the synthesis method of compound 26h, compound 29g was used to obtain compound 29h (white solid, 425 mg, yield 73%).

[1103] LC-MS m / z (ESI) = 334.19 [M+1].

[1104] Step 8

[1105] (S)-tert-Butyl 6-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 29i

[1106] tert-butyl(S)-6-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1107] Referring to the synthesis method of compound 26i, compound 29h and intermediate B were used to obtain compound 29i (yellow solid, 410 mg, yield 80%).

[1108] LC-MS m / z (ESI) = 403.21 [M+1].

[1109] Step 9

[1110] (S)-8'-Chloro-6'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 29j

[1111] (S)-8'-chloro-6'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1112] Referring to the synthesis method of compound 26j, compound 29i was used to obtain compound 29j (brown solid, 370 mg, yield 94%).

[1113] LC-MS m / z (ESI) = 303.21 [M+1].

[1114] Step 10

[1115] 8'-Chloro-6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 29k

[1116] 8'-chloro-6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1117] Referring to the synthesis method of compound 26k, compound 29j was used to obtain compound 29k (yellow solid, 262 mg, yield 71%).

[1118] LC-MS m / z (ESI) = 305.23 [M+1].

[1119] Step 11

[1120] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-8'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one Compound 29

[1121] 6'-((5S)-1-(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbonyl)-5-methylpiperidin-2-yl)-8'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1122] According to the method of compound 26, compound 29 was obtained (white solid, 140 mg, yield 82%).

[1123] 1 H NMR(400MHz,DMSO)δ9.53(s,1H),8.86(s,1H),7.73(s,1H),7.25(s,1H),7.07(d,3H),5.35(dt,2H),5.03(s,2H),3.15–3.05(m,1H ),2.91(s,2H),2.12(s,2H),1.87–1.61(m,2H),1.36–1.26(m,1H),1.26–1.14(m,2H),1.09(d,2H),0.93(d,3H),0.80–0.70(m,2H).

[1124] LC-MS m / z (ESI) = 518.27 [M+1].

[1125] Example 30

[1126] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Compound 30

[1127] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1128] first step

[1129] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1′-cyclopropane]-3(4H)-one Compound 30

[1130] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1131] According to the method of compound 2, compound 12g and intermediate H were used to obtain compound 30 (white solid, 40 mg, yield 52%).

[1132] 1 H NMR (400MHz, DMSO) δ11.01(d,1H),8.31–7.95(m,2H),7.67–7.52(m,1H),7.30(d,2H),7.14–6.59(m,2H),4.43–4. 31(m,2H),4.08(d,1H),3.25–3.11(m,1H),3.00(dd,1H),2.27–1.53(m,5H),1.30–1.20(m,6H),1.01–0.88(m,2H).

[1133] LC-MS m / z (ESI) = 549.27 [M+1].

[1134] Example 31

[1135] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Compound 31

[1136] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1137] first step

[1138] Ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate 31b

[1139] ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate

[1140] According to the method of compound 12b, compound 31a (2.2 g, 10.0 mmol) was used to obtain compound 31b (yellow solid, 3.0 g, yield 92%).

[1141] LC-MS m / z (ESI) = 329.99 [M+1].

[1142] Step 2

[1143] 7-Bromospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 31c

[1144] 7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1145] According to the method of compound 12c, compound 31b (2.2 g, 10.0 mmol) was used to obtain compound 31c (white solid, 1.7 g, yield 71%).

[1146] LC-MS m / z (ESI) = 253.97 [M+1].

[1147] Step 3

[1148] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 31d

[1149] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1′-cyclopropan]-3(4H)-one

[1150] According to the method of compound 12d, compound 31c was used to obtain compound 31d (yellow solid, 1.1 g, yield 82%).

[1151] LC-MS m / z (ESI) = 302.15 [M+1].

[1152] Step 4

[1153] (S)-tert-Butyl 3-methyl-6-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-3,4-dihydropyridine-1(2H)-carboxylate 31e

[1154] tert-butyl(S)-3-methyl-6-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1155] According to the method for compound 12e, compound 31d was used to obtain compound 31e (yellow solid, 973 mg, yield 82%).

[1156] LC-MS m / z (ESI) = 371.19 [M+1].

[1157] Step 5

[1158] (S)-7-(5-Methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 31f

[1159] (S)-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1160] According to the method of compound 12f, compound 31e was used to obtain compound 31f (yellow solid, 771 mg, yield 84%).

[1161] LC-MS m / z (ESI) = 271.14 [M+1].

[1162] Step 6

[1163] 7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 31g

[1164] 7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4

[1165] H)-one

[1166] According to the method for compound 12g, compound 31f was used to obtain compound 31g (yellow solid, 758 mg, yield 87%).

[1167] LC-MS m / z (ESI) = 273.15 [M+1].

[1168] Step 7

[1169] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Compound 31

[1170] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1171] Referring to the synthesis method of compound 12, compound 31 was obtained using 31 g and intermediate H (white solid, 40 mg, yield 20%).

[1172] 1 H NMR(400MHz,DMSO)δ10.78(d,1H),8.31–7.86(m,2H),7.62(s,1H),7.30(d,2H),7.14–6 .71(m,3H),4.59–3.94(m,4H),3.21–2.96(m,1H),2.20–1.53(m,4H),1.38–0.95(m,9H).

[1173] LC-MS m / z (ESI) = 531.29 [M+1].

[1174] Example 32

[1175] 6'-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-2'-one compound 32

[1176] 6'-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1177] first step

[1178] 6'-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-2'-one compound 32

[1179] 6'-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1180] According to the method of compound 26, compound 26k and intermediate H were used to obtain compound 32 (white solid, 60 mg, yield 37%).

[1181] 1 H NMR (400MHz, DMSO) δ10.17(d,1H),8.31–7.95(m,2H),7.65–7.53(m,1H),7.29(d,2H),7.22–6.92( m,2H),4.62–3.93(m,4H),3.10(dd,1H),2.97–2.78(m,2H),2.26–1.54(m,4H),1.44–0.50(m,9H).

[1182] LC-MS m / z (ESI) = 547.29 [M+1].

[1183] Example 33

[1184] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Compound 33

[1185] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1186] first step

[1187] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Compound 33

[1188] 7-((5S)-1-(4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1189] According to the method of compound 4, using 4k and intermediate H, compound 33 (white solid, 36 mg, yield 36%) was obtained.

[1190] 1 H NMR (400MHz, DMSO) δ10.28(d,1H),8.42–8.05(m,2H),7.85–7.63(m,2H),7.49(d,2H),7.32–7.03( m,2H),4.92–4.23(m,4H),3.50(dd,1H),3.30–2.98(m,2H),2.32–1.72(m,4H),1.54–0.70(m,9H).

[1191] LC-MS m / z (ESI) = 531.28 [M+1].

[1192] Example 34

[1193] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 34

[1194] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone

[1195] first step

[1196] 5-Bromo-3H-spiro[benzofuran-2,4'-piperidine]34b

[1197] 4-bromo-3H-spiro[benzofuran-2,4'-piperidine]

[1198] 5-34a (950 mg, 5 mmol) was dissolved in MeOH (15 mL), and the reaction solution was cooled to 0°C. NBS (890 mg, 5 mmol) was added at this temperature, and the reaction was carried out at room temperature for 3 h. The reaction progress was monitored by TLC.

[1199] The reaction was stopped, the solvent was removed by rotary evaporation, and the compound was separated by column chromatography (DCM:MeOH=30:1) to give 34b (white solid, 1.2 g, yield 89%).

[1200] LC-MS m / z (ESI) = 268.13 [M+1].

[1201] Step 2

[1202] 5-Bromo-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]34c

[1203] 5-bromo-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]

[1204] 34b (1.2 g, 5.6 mmol) and formaldehyde (543.7 mg, 6.7 mmol) were dissolved in MeOH (20 mL) and stirred for 30 minutes. NaBH3CN (880 mg, 14 mmol) was then added and allowed to react at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the solvent was removed by rotary evaporation, and the product was separated by column chromatography (DCM:MeOH = 20:1) to afford 34c as a yellow oil (1.3 g, 82% yield).

[1205] LC-MS m / z (ESI) = 282.23 [M+1].

[1206] Step 3

[1207] 1'-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]34d

[1208] 1'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1209] Following the procedure of 1c, 34d was obtained. The reaction was stopped, filtered, and the filtrate was directly used in the next reaction.

[1210] LC-MS m / z (ESI) = 330.31 [M+1].

[1211] Step 4

[1212] tert-Butyl 3-methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate 34e

[1213] tert-butyl-3-methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1214] According to the method of 1d, 34e was obtained (dark brown liquid, 1.2 g, yield 66.7%).

[1215] LC-MS m / z (ESI) = 399.20 [M+1].

[1216] Step 5

[1217] 1'-Methyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]34f

[1218] 1'-methyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1219] According to the method for compound 1e, compound 34f was obtained (brown oily liquid, 400 mg, yield 30%).

[1220] LC-MS m / z (ESI) = 299.20 [M+1].

[1221] Step 6

[1222] 1'-Methyl-5-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine] 34g

[1223] 1'-methyl-5-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1224] According to the method of compound 1f, compound 34g was obtained (yellow liquid, 33 mg, yield 31%).

[1225] LC-MS m / z (ESI) = 301.22 [M+1].

[1226] Step 7

[1227] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 34

[1228] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)piperidin-1-yl)methanone

[1229] According to the method for synthesizing compound 1, compound 34g and intermediate F were used to obtain compound 34 (white solid, 40 mg, yield 45%).

[1230] 1 H NMR (400MHz, DMSO) δ7.73–6.59(m,7H),5.43(dd,2H),5.09–4.10(m,3H),3.24–2.82(m,4H),2.42–1.97(m,7H),1.76(dd,6H),1.37–0.79(m,6H).

[1231] LC-MS m / z (ESI) = 530.37 [M+1].

[1232] Example 35

[1233] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 35

[1234] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)piperidin-1-yl)methanone

[1235] first step

[1236] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 35

[1237] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone

[1238] According to the method for synthesizing compound 1, compound 34g and intermediate G were used to obtain compound 35 (white solid, 50 mg, yield 55%).

[1239] 1H NMR(400MHz,DMSO-d6)δ8.32–8.11(m,2H),7.99-7.94(m,1H),7.40–7.29(m,2H),7.23–6.99(m,3H),6.85–6.60(m,2H),6.00–5 .68(m,1H),4.43–4.00(m,4H),3.04–2.90(m,3H),2.45–2.32(m,4H),2.22–2.17(m,4H),1.82–1.65(m,7H),1.34–1.26(m,2H).

[1240] LC-MS m / z (ESI) = 543.28 [M+1].

[1241] Example 36

[1242] 7-((5S)-1-(4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 36

[1243] 7-((5S)-1-(4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1244] first step

[1245] 7-((5S)-1-(4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 36

[1246] 7-((5S)-1-(4-amino-7-chloro-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1247] According to the method of compound 1, compound 36 (white solid, 58 mg, yield 59%) was obtained.

[1248] 1 H NMR(400MHz,DMSO-d6)δ11.04(s,1H),7.70–7.21(m,2H),6.91-6.51(m,4H),5.83–4.90(m,5H),3.32–3.0 9(m,2H),2.22–1.78(m,3H),1.65–1.58(m,1H),1.33–1.27(m,3H),1.21–1.19(m,3H),0.90-0.77(m,2H).

[1249] LC-MS m / z (ESI) = 537.17 [M+1].

[1250] Example 37

[1251] 7-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 37

[1252] 7-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1253] first step

[1254] 7-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one compound 37

[1255] 7-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1256] In a 100 mL single-necked bottle, 6 g (100 mg, 0.34 mmol), intermediate G (89.7 mg, 0.34 mmol), HATU (131 mg, 0.34 mmol), DIPEA (133 mg, 1.0 mmol), and DMF (4 mL) were added respectively. The reaction was carried out at room temperature and the reaction progress was monitored by TLC.

[1257] The reaction was stopped, water was added, and the mixture was extracted with EA. The organic phase was washed with water, and the solvent was removed by rotary evaporation. Compound 37 (white solid, 45 mg, yield 24%) was separated by column chromatography (DCM:MeOH=50:1).

[1258] 1 H NMR(400MHz,DMSO-d6)11.00(s,1H),8.29-7.96(m,2H),7.40-7.22(m,3H),7.02–6.61(m,2H),4.64-4.37(m,1H),4.33(s,3H),3.29–2.8 0(m,2H),2.09(s,2H),1.88–1.52(m,2H),1.34–1.29(m,1H),1.25-1.19(m,2H),1.13-1.05(m,1H),1.05-0.89(m,3H),0.89–0.78(m,1H).

[1259] LC-MS m / z (ESI) = 533.20 [M+1].

[1260] Example 38

[1261] 6′-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-8′-fluoro-1′-, 4′-dihydro-2′-pyrazolo[cyclopropane-1,3′-quinoline]-2′-one compound 38

[1262] 6'-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1263] first step

[1264] 6'-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1'-, 4'-dihydro-2'-pyrazolo[cyclopropane-1,3'-quinoline]-2'-one compound 38

[1265] 6'-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1266] According to the method of compound 37, compound 38 (white solid, 60 mg, yield 32%) was obtained.

[1267] 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.30-7.89(m,2H),7.39–7.23(m,3H),7.15–6.86(m,2H),4.73–3.86(m,4H),3.31–2.96(m,2 H),2.90(s,2H),2.27-2.01(m,2H),1.78-1.52(s,2H),1.40–1.27(m,1H),1.13-1.07(m,2H),1.04-0.89(m,3H),0.79-0.63(m,2H).

[1268] LC-MS m / z (ESI) = 531.22 [M+1].

[1269] Example 39

[1270] 7-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Compound 39

[1271] 7-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1272] first step

[1273] Ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate 39b

[1274] ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate

[1275] According to the method of compound 12b, compound 39b (yellow solid, 3.0 g, yield 92%) was obtained.

[1276] LC-MS m / z (ESI) = 329.99 [M+1].

[1277] Step 2

[1278] 7-Bromospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 39c

[1279] 7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1280] According to the method of compound 12c, compound 39c (white solid, 1.7 g, yield 71%) was obtained.

[1281] LC-MS m / z (ESI) = 253.97 [M+1].

[1282] Step 3

[1283] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 39d

[1284] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1285] According to the method of compound 12d, compound 39d (yellow solid, 1.1 g, yield 82%) was obtained.

[1286] LC-MS m / z (ESI) = 302.15 [M+1].

[1287] Step 4

[1288] (S)-tert-Butyl 3-methyl-6-(3-oxo-3,4-dihydropyrro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-3,4-dihydropyridine-1(2H)-carboxylate 39e

[1289] tert-butyl(S)-3-methyl-6-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1290] According to the method of compound 12e, compound 39e (yellow solid, 973 mg, yield 82%) was obtained.

[1291] LC-MS m / z (ESI) = 371.19 [M+1].

[1292] Step 5

[1293] (S)-7-(5-Methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 39f

[1294] (S)-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1295] According to the method of compound 12f, compound 39f (yellow solid, 771 mg, yield 84%) was obtained.

[1296] LC-MS m / z (ESI) = 271.14 [M+1].

[1297] Step 6

[1298] 7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 39g

[1299] 7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1300] According to the method of compound 12g, compound 39g (yellow solid, 758 mg, yield 87%) was obtained.

[1301] LC-MS m / z (ESI) = 273.15 [M+1].

[1302] Step 7

[1303] 7-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Compound 39

[1304] 7-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1305] According to the method of compound 37, compound 39 was obtained (white solid, 40 mg, yield 42%).

[1306] 1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.35–7.92(m,2H),7.44–7.16(m,3H),7.06–6.75(m,3H),4.87–3.72(m,4H),3.28–2.9 3(m,2H),2.20–1.97(m,2H),1.79–1.56(m,2H),1.38-1.27(m,1H),1.25–1.22(m,2H),1.18-1.11(m,2H),1.05–0.90(m,3H).

[1307] LC-MS m / z (ESI) = 515.21 [M+1].

[1308] Example 40

[1309] 6′-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-1′-, 4′-dihydro-2′-spiro[cyclopropane-1,3′-quinoline]-2′-one compound 40

[1310] 6'-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1311] first step

[1312] 6'-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-1'-, 4'-dihydro-2'-spiro[cyclopropane-1,3'-quinoline]-2'-one compound 40

[1313] 6'-((5S)-1-(4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1314] According to the method of compound 37, compound 40 was obtained (white solid, 45 mg, yield 47%).

[1315] 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.65–8.08(m,2H),7.63(s,1H),7.27–7.06(m,3H),7.04–6.81(m,2H),4.73–3.93(m,4 H),3.27–3.00(m,2H),2.85(s,2H),2.19–1.96(m,2H),1.80–1.55(m,2H),1.36–1.22(m,2H),1.07(s,3H),0.76–0.62(m,2H).

[1316] LC-MS m / z (ESI) = 513.23 [M+1].

[1317] Example 41

[1318] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone Compound 41

[1319] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1320] first step

[1321] 4-(2,3-Difluorobenzyl)-1-methylpiperidin-4-ol 41b

[1322] 4-(2,3-difluorobenzyl)-1-methylpiperidin-4-ol

[1323] According to the method of compound 9b, compound 41b was obtained (yellow liquid, 1.9 g, yield 20%).

[1324] LC-MS m / z (ESI) = 242.13 [M+1].

[1325] Step 2

[1326] 7-Fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]41c

[1327] 7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]

[1328] According to the method of compound 9c, compound 41c was obtained (yellow liquid, 800 mg, yield 47%).

[1329] LC-MS m / z (ESI) = 222.12 [M+1].

[1330] Step 3

[1331] 5-Bromo-7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]41d

[1332] 5-bromo-7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]

[1333] In a 100 mL single-necked bottle, ACN (30 mL), 41c (678 mg, 3.0 mmol), NBS (1.08 g, 6.0 mmol), and TFA (1.4 g, 12.2 mmol) were added respectively. The reaction was carried out at room temperature and the reaction progress was monitored by TLC.

[1334] The reaction was stopped, water was added, and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with EA and separated by column chromatography (DCM:MeOH=30:1) to give compound 41d (brown liquid, 330 mg, yield 35%).

[1335] LC-MS m / z (ESI) = 300.03 [M+1].

[1336] Step 4

[1337] 7-Fluoro-1'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]41e

[1338] 7-fluoro-1'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1339] According to the method of compound 1c, compound 41e (brown solid, 450 mg, yield 99%) was obtained.

[1340] LC-MS m / z (ESI) = 348.21 [M+1].

[1341] Step 5

[1342] (S)-tert-Butyl 6-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 41f

[1343] tert-butyl(S)-6-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1344] According to the method for compound 1d, compound 41f (brown liquid, 570 mg, yield 99%) was obtained.

[1345] LC-MS m / z (ESI) = 417.25 [M+1].

[1346] Step 6

[1347] (S)-7-fluoro-1'-methyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1348] According to the method for compound 1e, compound 41g (brown liquid, 208 mg, yield 48%) was obtained.

[1349] LC-MS m / z (ESI) = 317.20 [M+1].

[1350] Step 7

[1351] 7-Fluoro-1′-methyl-5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4′-piperidine]41h

[1352] 7-fluoro-1'-methyl-5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1353] According to the method for compound 1f, compound 41h was obtained (brown liquid, 133 mg, yield 63%).

[1354] LC-MS m / z (ESI) = 319.21 [M+1].

[1355] Step 8

[1356] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-pyrazolo[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone Compound 41

[1357] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1358] According to the method of compound 37, compound 41 was obtained (yellow solid, 40 mg, yield 55%).

[1359] 1 H NMR(400MHz,DMSO-d6)δ8.29-8.00(m,H),7.39–7.23(m,3H),7.09-6.95(m,2H),4.65–3.89(m,4H),3.21–3.07(m,2H),3.06 –2.97(m,2H),2.46–2.31(m,4H),2.22(s,3H),1.95–1.74(m,7H),1.69–1.62(m,1H),1.34-1.28(m,1H),1.05–0.90(m,3H).

[1360] LC-MS m / z (ESI) = 561.27 [M+1].

[1361] Example 42

[1362] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone Compound 42

[1363] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1364] first step

[1365] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone Compound 42

[1366] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1367] According to the method of compound 37, compound 42 was obtained (white solid, 15 mg, yield 20%).

[1368] 1 H NMR(400MHz,DMSO-d6)δ7.66–7.45(m,1H),7.41-7.19(m,1H),7.09–6.92(m,2H),6.82(s,2H),5.87–4.91(m,5H),3.19–3.12(m,2H ),2.88(s,2H),2.60-2.51(m,4H),2.30–2.03(m,3H),2.02–1.88(m,5H),1.86-1.44(m,3H),1.33–1.28(m,1H),0.96-0.79(m,3H).

[1369] LC-MS m / z (ESI) = 549.26 [M+1].

[1370] Example 43

[1371] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone Compound 43

[1372] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone

[1373] first step

[1374] 4-(4-Chloro-2-fluorobenzyl)-1-methylpiperidin-4-ol 43b

[1375] 4-(4-chloro-2-fluorobenzyl)-1-methylpiperidin-4-ol

[1376] Referring to the synthesis of compound 9b, compound 43b was obtained (yellow liquid, 630 mg, yield 51%).

[1377] LC-MS m / z (ESI) = 258.10 [M+1].

[1378] Step 2

[1379] 6-Chloro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]43c

[1380] 6-chloro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]

[1381] Referring to the synthesis of compound 9c, compound 43c was obtained (yellow liquid, 230 mg, yield 73%).

[1382] LC-MS m / z (ESI) = 238.09 [M+1].

[1383] Step 3

[1384] 1'-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]43d

[1385] 1'-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1386] Referring to the synthesis of compound 9d, compound 43d (yellow liquid, 140 mg, yield 63%) was obtained.

[1387] LC-MS m / z (ESI) = 330.22 [M+1].

[1388] Step 4

[1389] (S)-tert-Butyl 3-methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate 43e

[1390] tert-butyl (S)-3-methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1391] According to the method of compound 9e, compound 43e was obtained (black solid, 174 mg, yield 79%).

[1392] LC-MS m / z (ESI) = 399.26 [M+1].

[1393] Step 5

[1394] (S)-1'-Methyl-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]43f

[1395] (S)-1'-methyl-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1396] According to the method of compound 9f, compound 43f was obtained (brown liquid, 137 mg, yield 79%).

[1397] LC-MS m / z (ESI) = 299.20 [M+1].

[1398] Step 6

[1399] 1'-Methyl-6-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]43g

[1400] 1'-methyl-6-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1401] According to the method of compound 9g, compound 43g (brown liquid, 62 mg, yield 58%) was obtained.

[1402] LC-MS m / z (ESI) = 301.22 [M+1].

[1403] Step 7

[1404] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone Compound 43

[1405] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone

[1406] According to the method of compound 1, compound 43 was obtained (white solid, 15 mg, yield 41%).

[1407] 1 H NMR(400MHz,DMSO-d6)δ8.24(d,1H),7.70–7.30(m,4H),6.82(s,2H),5.41(t,2H),5.09–4.9 0(m,3H),3.11-2.68(m,4H),2.36(s,3H),2.27–1.57(m,6H),1.55–1.24(m,6H),1.23(s,3H).

[1408] LC-MS m / z (ESI) = 531.27 [M+1].

[1409] Example 44

[1410] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone Compound 44

[1411] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone

[1412] first step

[1413] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone Compound 44

[1414] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)methanone

[1415] According to the method of compound 1, compound 44 was obtained (white solid, 30 mg, yield 65%).

[1416] 1 H NMR(400MHz, DMSO-d6)δ9.65–9.19(m,1H),8.36–7.84(m,2H),7.45–7.23(m,2H),7.11–6.69(m,2H),6.35–6.12(m,1H),5.14–3 .63(m,5H),3.24–2.71(m,2H),2.49–2.20(m,8H),2.18–1.90(m,3H),1.89–1.56(m,2H),1.50–1.19(m,3H),1.10–0.62(m,4H)..

[1417] LC-MS m / z (ESI) = 543.25 [M+1].

[1418] Example 45

[1419] 4-amino-7-fluoro-N-methyl-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 45

[1420] 4-amino-7-fluoro-N-methyl-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1421] first step

[1422] 1'-Methyl-3H-spiro[benzofuran-2,4'-piperidine]-5-carbaldehyde compound 45a

[1423] 1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]-5-carbaldehyde

[1424] In a 100 mL three-necked flask, 34c (900 mg, 3.1 mmol) and THF (10 mL) were added dropwise. n-Butyl lithium (2.5 M in THF) (1.9 mL, 4.7 mmol) was added dropwise at -78°C. The reaction was allowed to react for 30 min. DMF (578 mg, 7.9 mmol) was then added dropwise. The reaction was allowed to react at room temperature for 1 h. The reaction progress was monitored by LCMS.

[1425] The reaction was stopped, water was added, and the mixture was extracted with EA. The organic phase was washed with water, and the solvent was removed by rotary evaporation. Compound 45a (yellow oil, 650 mg, yield 88%) was separated by column chromatography (DCM:MeOH=30:1).

[1426] LC-MS m / z (ESI) = 232.27 [M+1].

[1427] Step 2

[1428] N-Methyl-1-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methanamine 45b

[1429] N-methyl-1-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methanamine

[1430] In a 50 mL single-necked bottle, MeOH (10 mL), 45a (150 mg, 0.62 mmol), and 40% aqueous methylamine solution (0.09 mL, 0.93 mmol) were added, respectively, and the mixture was reacted at room temperature for 16 h. Then, sodium borohydride (49 mg, 1.3 mmol) was added, and the mixture was reacted at room temperature for 1 h. The reaction progress was monitored by LCMS.

[1431] The reaction was stopped and quenched with water. The solvent was removed by rotary evaporation and the residue was separated by column chromatography (DCM:MeOH=10:1) to obtain compound 45b (colorless liquid, 80 mg, yield 56%).

[1432] LC-MS m / z (ESI) = 247.20 [M+1].

[1433] Step 3

[1434] 4-amino-7-fluoro-N-methyl-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 45

[1435] 4-amino-7-fluoro-N-methyl-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1436] 45b (70 mg, 0.28 mmol), intermediate F (77 mg, 0.31 mmol), EDCI (65 mg, 0.34 mmol), HoAt (46 mg, 0.34 mmol), and DIPEA (110 mg, 0.85 mmol) were dissolved in DMF (5 mL). The mixture was reacted at room temperature for 5 min, and then 45b (70 mg, 0.28 mmol) was added. The reaction was continued at room temperature for 16 h. The reaction progress was monitored by TLC.

[1437] Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were concentrated under reduced pressure and eluted by column chromatography (dichloromethane:methanol=10:1) to give compound 45 (white solid, 70 mg, yield 52%).

[1438] 1H NMR(400MHz,DMSO-d6)δ7.63–7.53(m,1H),7.34–7.26(m,1H),7.22–6.90(m,2H),6.84(d,2H),6.76–6.64(m,1H),5.3 9–5.18(m,2H),5.06–4.90(m,2H),4.45(d,2H),3.03–2.72(m,5H),2.48–2.25(m,4H),2.20(d,3H),1.87–1.64(m,4H).

[1439] LC-MS m / z (ESI) = 477.22 [M+1].

[1440] Example 46

[1441] 4-Amino-7-fluoro-N-methoxy-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 46

[1442] 4-amino-7-fluoro-N-methoxy-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1443] first step

[1444] O-Methyl-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin-5-yl)methyl)hydroxylamine 46a

[1445] O-methyl-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)hydroxylamine

[1446] In a 50 mL single-necked bottle, MeOH (10 mL), 45a (120 mg, 0.52 mmol), methoxyamine (44 mg, 0.52 mmol), and acetic acid (28 mg, 0.46 mmol) were added respectively, and the reaction was carried out at 0°C for 30 min. Then, sodium cyanoborohydride (49 mg, 0.78 mmol) was added, and the reaction was carried out at room temperature for 16 h. The reaction progress was monitored by LCMS.

[1447] The reaction was stopped and quenched with water. The solvent was removed by rotary evaporation and the residue was separated by column chromatography (DCM:MeOH=10:1) to obtain compound 46a (colorless liquid, 80 mg, yield 58%).

[1448] LC-MS m / z (ESI) = 263.20 [M+1].

[1449] Step 2

[1450] 4-Amino-7-fluoro-N-methoxy-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 46

[1451] 4-amino-7-fluoro-N-methoxy-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1452] According to the method of compound 45, compound 46a and intermediate F were used to obtain compound 46 (white solid, 60 mg, yield 53%).

[1453] 1 H NMR(400MHz,DMSO-d6)δ7.69–7.58(m,1H),7.27(d,1H),7.21–7.02(m,2H),6.90–6.67(m,3H),5.31(s,2H),5 .05–4.95(m,2H),4.81(s,2H),3.45(s,3H),2.98(s,2H),2.49–2.28(m,4H),2.21(s,3H),1.87–1.68(m,4H).

[1454] LC-MS m / z (ESI) = 493.25 [M+1].

[1455] Example 47

[1456] 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 47

[1457] 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1458] first step

[1459] N-((1'-Methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)bicyclo[1.1.1]pentan-1-amine 47a

[1460] N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)bicyclo[1.1.1]pentan-1-amine

[1461] According to the method of compound 46a, compound 47a was obtained (colorless liquid, 100 mg, yield 79%).

[1462] LC-MS m / z (ESI) = 299.21 [M+1].

[1463] Step 2

[1464] 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 47

[1465] 4-amino-N-(bicyclo[1.1.1]pentan-1-yl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1466] According to the method of compound 45, compound 47a and intermediate F were used to obtain compound 47 (white solid, 62 mg, yield 52%).

[1467] 1H NMR(400MHz,DMSO-d6)δ7.57–7.06(m,3H),7.05–6.54(m,4H),5.46–5.06(m,2H),5.05–4.68(m,2H),4.66–4 .27(m,2H),3.17–2.69(m,3H),2.49–2.26(m,4H),2.25–1.96(m,6H),1.87–1.67(m,4H),1.65–1.52(m,3H).

[1468] LC-MS m / z (ESI) = 529.25 [M+1].

[1469] Example 48

[1470] 4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-N-(oxetan-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 48

[1471] 4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(oxetan-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1472] first step

[1473] N-((1'-Methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)oxetan-3-amine 48a

[1474] N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)oxetan-3-amine

[1475] According to the method of compound 46a, compound 48a was obtained (colorless liquid, 100 mg, yield 79%).

[1476] LC-MS m / z (ESI) = 289.20 [M+1].

[1477] Step 2

[1478] 4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-N-(oxetan-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 48

[1479] 4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(oxetan-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1480] According to the method of compound 45, compound 48 (white solid, 70 mg, yield 59%) was obtained using compound 48a and intermediate F.

[1481] 1 H NMR(400MHz,DMSO-d6)δ7.63–7.01(m,3H),6.97–6.60(m,4H),5.38–5.17(m,2H),4.98(d,2H),4.65–4.1 9(m,4H),3.99–3.60(m,2H),3.23–2.79(m,3H),2.49–2.28(m,4H),2.27–2.14(m,3H),1.87–1.63(m,4H).

[1482] LC-MS m / z (ESI) = 519.25 [M+1].

[1483] Example 49

[1484] (S)-4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-N-(tetrahydrofuran-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 49

[1485] (S)-4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(tetrahydrofuran-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1486] first step

[1487] (S)-N-((1'-Methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)tetrahydrofuran-3-amine 49a

[1488] (S)-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)tetrahydrofuran-3-amine

[1489] According to the method of compound 46a, compound 49a (colorless liquid, 80 mg, yield 71%) was obtained.

[1490] LC-MS m / z (ESI) = 303.20 [M+1].

[1491] Step 2

[1492] (S)-4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-N-(tetrahydrofuran-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 49

[1493] (S)-4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(tetrahydrofuran-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1494] According to the method of compound 45, compound 49a and intermediate F were used to obtain compound 49 (white solid, 11 mg, yield 71%).

[1495] 1 H NMR (400MHz, DMSO-d6) δ7.65–7.14(m,3H),7.10–6.56(m,4H),5.47–5.07(m,2H),5.06–4.80(m,2H),4.71–4.26(m,2H ),3.95–3.55(m,3H),3.52–3.37(m,4H),3.16–2.60(m,3H),2.49–2.25(m,3H),2.24–2.15(m,3H),1.88–1.64(m,4H).

[1496] LC-MS m / z (ESI) = 533.25 [M+1].

[1497] Example 50

[1498] 4-amino-7-fluoro-N-(1-methyl-1H-pyrazol-4-yl)-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 50

[1499] 4-amino-7-fluoro-N-(1-methyl-1H-pyrazol-4-yl)-N-((1′-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1500] first step

[1501] 1-Methyl-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1H-pyrazol-4-amine 49a

[1502] 1-methyl-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1H-pyrazol-4-amine

[1503] According to the method of compound 46a, compound 50a and intermediate F were used to obtain compound 50a (colorless liquid, 60 mg, yield 73%).

[1504] LC-MS m / z (ESI) = 313.20 [M+1].

[1505] Step 2

[1506] 4-amino-7-fluoro-N-(1-methyl-1H-pyrazol-4-yl)-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 50

[1507] 4-amino-7-fluoro-N-(1-methyl-1H-pyrazol-4-yl)-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1508] According to the method of compound 45, compound 50 was obtained (white solid, 11 mg, yield 71%).

[1509] 1 H NMR(400MHz,DMSO-d6)δ7.65–7.14(m,4H),7.10–6.50(m,5H),5.40–5.15(m,2H),5.00–4.92 (m,2H),4.48(d,2H),3.02–2.75(m,5H),2.47–2.24(m,4H),2.19(d,3H),1.85–1.60(m,4H).

[1510] LC-MS m / z (ESI) = 543.25 [M+1].

[1511] Example 51

[1512] (4-amino-7-fluoro-1,3-dihydrofuro[4,3-c]quinolin-8-yl)[(5S)-2-(1'-cyclopropyl-1',2',3,3',5',6'-hexahydrospiro[1-benzofuran-2,4'-pyridine]-5-yl)-5-methylhexahydropyridin-1-yl]methanone Compound 51

[1513] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(1'-cyclopropyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1514] first step

[1515] 5-Bromo-1′-cyclopropyl-3H-spiro[benzofuran-2,4′-piperidine]51a

[1516] 5-bromo-1'-cyclopropyl-3H-spiro[benzofuran-2,4′-piperidine]

[1517] 34b (500 mg, 1.8 mmol), 1-ethoxy-1-trimethylsilyloxycyclopropane (489 mg, 2.8 mmol), and acetic acid (337 mg, 5.6 mmol) were dissolved in MeOH (10 mL) and stirred for 1 h. NaBH3CN (880 mg, 2.9 mmol) was then added and the reaction was allowed to proceed at 60°C for 6 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed by rotary evaporation, and 51a was separated by column chromatography (DCM:MeOH = 50:1) to afford 51a as a colorless oil (430 g, 75% yield).

[1518] LC-MS m / z (ESI) = 308.10 [M+1].

[1519] Step 2

[1520] 1'-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]51b

[1521] 1'-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1522] According to the method of compound 1c, compound 51b was obtained (yellow liquid, 580 mg, yield 87%).

[1523] LC-MS m / z (ESI) = 356.23 [M+1].

[1524] Step 3

[1525] (S)-tert-Butyl 6-(1'-cyclopropyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 51c

[1526] tert-butyl (S)-6-(1'-cyclopropyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1527] According to the method of 1d, 51c was obtained (yellow liquid, 180 mg, yield 40%).

[1528] LC-MS m / z (ESI) = 425.30 [M+1].

[1529] Step 4

[1530] (S)-1'-Cyclopropyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]51d

[1531] (S)-1'-cyclopropyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1532] According to the method for compound 1e, compound 51d was obtained (yellow oily liquid, 140 mg, yield 90%).

[1533] LC-MS m / z (ESI) = 325.22 [M+1].

[1534] Step 5

[1535] 1'-Cyclopropyl-5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]51e

[1536] 1'-cyclopropyl-5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4′-piperidine]

[1537] According to the method of compound 1f, compound 51e was obtained (yellow liquid, 100 mg, yield 46%).

[1538] LC-MS m / z (ESI) = 327.30 [M+1].

[1539] Step 6

[1540] (4-amino-7-fluoro-1,3-dihydrofuro[4,3-c]quinolin-8-yl)[(5S)-2-(1'-cyclopropyl-1',2',3,3',5',6'-hexahydrospiro[1-benzofuran-2,4'-pyridine]-5-yl)-5-methylhexahydropyridin-1-yl]methanone Compound 51

[1541] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(1'-cyclopropyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1542] According to the method for synthesizing compound 1, compound 51 (white solid, 60 mg, yield 32%) was obtained using compound 51e and intermediate F.

[1543] 1 H NMR (400MHz, DMSO) δ7.75–6.61(m,7H),5.47(dd,2H),5.13–4.12(m,3H),3.29–2. 80(m,4H),2.45–1.81(m,7H),1.74(dd,6H),1.37–0.92(m,4H),0.72–0.45(m,4H).

[1544] LC-MS m / z (ESI) = 557.35 [M+1].

[1545] Example 52

[1546] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-(methyl-d3)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 52

[1547] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-(methyl-d3)-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)piperidin-1-yl)methanone

[1548] first step

[1549] 5-Bromo-1'-(methyl-d3)-3H-spiro[benzofuran-2,4'-piperidine]52a

[1550] 5-bromo-1'-(methyl-d3)-3H-spiro[benzofuran-2,4′-piperidine]

[1551] 34b (500 mg, 1.8 mmol) and sodium hydride (60%) (90 mg, 2.2 mmol) were dissolved in DMF (10 mL) and stirred at 0°C for 1 hour. Deuterated iodomethane (270 mg, 14 mmol) was then added and the reaction was allowed to react at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction was quenched with water, extracted with EA, and the solvent was removed by rotary evaporation. The product was separated by column chromatography (DCM:MeOH = 10:1) to afford 52a (200 g, 41% yield) as a colorless oil.

[1552] LC-MS m / z (ESI) = 285.06 [M+1].

[1553] Step 2

[1554] 1'-(Methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]52b

[1555] 1′-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1556] According to the method of compound 1c, compound 52b was obtained (yellow liquid, 160 mg, yield 76%).

[1557] LC-MS m / z (ESI) = 333.25 [M+1].

[1558] Step 3

[1559] (S)-tert-Butyl 3-methyl-6-(1'-(methyl-d3)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate 52c

[1560] tert-butyl (S)-3-methyl-6-(1'-(methyl-d3)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1561] According to the method of 1d, 52c was obtained (yellow liquid, 170 mg, yield 87%).

[1562] LC-MS m / z (ESI) = 402.30 [M+1].

[1563] Step 4

[1564] (S)-1'-(Methyl-d3)-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]52d

[1565] (S)-1'-(methyl-d3)-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4′-piperidine]

[1566] According to the method for compound 1e, compound 52d was obtained (yellow oily liquid, 140 mg, yield 92%).

[1567] LC-MS m / z (ESI) = 302.22 [M+1].

[1568] Step 5

[1569] 1'-(Methyl-d3)-5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]52e

[1570] 1′-(methyl-d3)-5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1571] According to the method of compound 1f, compound 52e was obtained (yellow liquid, 70 mg, yield 66%).

[1572] LC-MS m / z (ESI) = 304.25 [M+1].

[1573] Step 6

[1574] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-(methyl-d3)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 52

[1575] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-(methyl-d3)-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)piperidin-1-yl)methanone

[1576] According to the method for synthesizing compound 1, compound 52e and intermediate F were used to obtain compound 52 (white solid, 70 mg, yield 57%).

[1577] 1 H NMR (400MHz, DMSO) δ7.75–6.58(m,7H),5.45(dd,2H),5.10–4.15(m,3H),3.25–2.83(m,4H),2.40–1.98(m,4H),1.77(dd,6H),1.35–0.80(m,6H).

[1578] LC-MS m / z (ESI) = 534.30 [M+1].

[1579] Example 53

[1580] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone Compound 53

[1581] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1582] first step

[1583] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone Compound 53

[1584] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-2-(7-fluoro-1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1585] According to the method of compound 37, compound 53 was obtained (white solid, 13 mg, yield 28%).

[1586] 1 H NMR (400MHz, DMSO-d6) δ7.46–7.26(m,1H),7.19-7.1(m,1H),6.99–6.71(m,2H),6.59(s,2H),5.62–4.72(m,5H),3.01–2.98(m,2H ),2.66(s,2H),2.5-2.21(m,4H),2.10–1.95(m,3H),1.89–1.72(m,5H),1.74-1.33(m,3H),1.27–1.16(m,1H),0.90-0.65(m,3H).

[1587] LC-MS m / z (ESI) = 532.27 [M+1].

[1588] Example 54

[1589] 4-amino-N-(cyclopropylmethyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 54

[1590] 4-amino-N-(cyclopropylmethyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1591] first step

[1592] N-Methyl-1-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methanamine 54a

[1593] 1-cyclopropyl-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)methanamine

[1594] According to the method of compound 46a, compound 54a was obtained (yellow oily liquid, 130 mg, yield 52%).

[1595] LC-MS m / z (ESI) = 287.10 [M+1].

[1596] Step 2

[1597] 4-amino-N-(cyclopropylmethyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 54

[1598] 4-amino-N-(cyclopropylmethyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1599] According to the method of compound 45, compound 54 was obtained (white solid, 62 mg, yield 52%)

[1600] 1 H NMR(400MHz,DMSO)δ7.96–7.82(m,1H),7.75(dd,10.3Hz,1H),7.26–6.86(m ,2H),6.79–6.65(m,1H),5.39(d,2H),5.09(s,2H),3.56(s,2H),3.38(s,2H ),3.16(t,2H),3.04(d,2H),2.93(d,1H),2.77(d,3H),2.14(dd,2H),2.01( dd,2H),1.35–1.20(m,3H),0.83(dd,1H),0.43(dd,2H),0.27–-0.12(m,2H).

[1601] LC-MS m / z (ESI) = 517.25 [M+1].

[1602] Example 55

[1603] 4-amino-N-cyclopropyl-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 55

[1604] 4-amino-N-cyclopropyl-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1605] first step

[1606] N-((1′-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)methyl)cyclopropylamine 55a

[1607] N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)cyclopropanamine

[1608] According to the method of compound 46a, compound 55a was obtained (yellow solid, 100 mg, yield 42.5%).

[1609] LC-MS m / z (ESI) = 273.19 [M+1].

[1610] Step 2

[1611] 4-amino-N-cyclopropyl-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 55

[1612] 4-amino-N-cyclopropyl-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1613] According to the method of compound 45, compound 55 (white solid, 90 mg, yield 49%) was obtained

[1614] 1H NMR (400MHz, DMSO) δ7.54(d,1H),7.27(d,1H),7.18(s,1H),7.08(d,1H),6.79(s,2H),6.72(d,1H),5.32(s,2H),4.99(s,2H),4.61 (s,2H),2.98(d,2H),2.64–2.52(m,3H),2.47–2.41(m,1H),2.26(s,3H),1.89–1.73(m,4H),1.36–1.15(m,1H),0.57–0.26(m,4H).

[1615] LC-MS m / z (ESI) = 503.25 [M+1].

[1616] Example 56

[1617] 4-amino-N-(3,3-difluorocyclobutyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 56

[1618] 4-amino-N-(3,3-difluorocyclobutyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1619] first step

[1620] 3,3-Difluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)cyclobutan-1-amine 56a

[1621] 3,3-difluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)cyclobutan-1-amine

[1622] According to the method of compound 46a, compound 56a (white solid, 200 mg, yield 79%) was obtained.

[1623] LC-MS m / z (ESI) = 323.19 [M+1].

[1624] Step 2

[1625] 4-amino-N-(3,3-difluorocyclobutyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 56

[1626] 4-amino-N-(3,3-difluorocyclobutyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1627] According to the method of compound 45, compound 56 (white solid, 75 mg, yield 22%) was obtained.

[1628] 1 H NMR (400MHz, DMSO) δ7.55(s,1H),7.42–7.23(m,1H),7.09(dd,1H),6.87(d,3H),6.65(dd,1H),5.26(d,2H),4.98(s, 2H),4.33(dd,2H),3.05–2.75(m,5H),2.42(d,3H),2.21(s,3H),1.75(d,4H),1.36–1.20(m,2H),0.95–0.73(m,1H).

[1629] LC-MS m / z (ESI) = 553.24 [M+1].

[1630] Example 57

[1631] 4-amino-N-cyclobutyl-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 57

[1632] 4-amino-N-cyclobutyl-7-fluoro-N-((1′-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1633] first step

[1634] N-((1′-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)methyl)cyclobutanamine 57a

[1635] N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)cyclobutanamine

[1636] According to the method of compound 46a, compound 57a (yellow oily liquid, 68 mg, yield 55%) was obtained.

[1637] LC-MS m / z (ESI) = 287.20 [M+1].

[1638] Step 2

[1639] 4-amino-N-cyclobutyl-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 57

[1640] 4-amino-N-cyclobutyl-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1641] According to the method of compound 45, compound 57 (white solid, 50 mg, yield 41%) was obtained.

[1642] 1 H NMR (400MHz, DMSO) δ7.53(d,1H),7.33(d,1H),7.15(s,1H),7.03(d,1H),6.84(s,2H),6.71(d,1H),5.33(s,2H),5.00(s, 2H),4.67(d,2H),4.20–4.03(m,1H),3.01(s,2H),2.31(s,3H),2.21–2.01(m,4H),1.93–1.68(m,8H),1.48–1.26(m,2H).

[1643] LC-MS m / z (ESI) = 517.25 [M+1].

[1644] Example 58

[1645] (S)-4-amino-7-fluoro-N-(1-methoxyprop-2-yl)-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 58

[1646] (S)-4-amino-7-fluoro-N-(1-methoxypropan-2-yl)-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1647] first step

[1648] (S)-1-Methoxy-N-((1′-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)methyl)propan-2-amine 58a

[1649] (S)-1-methoxy-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)propan-2-amine

[1650] According to the method of compound 46a, compound 58a (transparent solid, 59 mg, yield 45%) was obtained.

[1651] LC-MS m / z (ESI) = 305.23 [M+1].

[1652] Step 2

[1653] (S)-4-amino-7-fluoro-N-(1-methoxyprop-2-yl)-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 58

[1654] (S)-4-amino-7-fluoro-N-(1-methoxypropan-2-yl)-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1655] According to the method of compound 45, compound 58 (white solid, 70 mg, yield 67.6%) was obtained.

[1656] 1 H NMR (400MHz, DMSO) δ7.53(d,1H),7.31(d,1H),7.21(s,1H),6.79(d,3H),6.68(d,1H),5.30(d,2H),5.00(s,2H),4.70–4.43(m ,2H),3.89(dd,1H),3.54(dd,1H),3.10(dd,1H),3.02(s,3H),2.21(s,3H),1.87–1.57(m,7H),1.23–1.15(m,3H),1.01(s,3H).

[1657] LC-MS m / z (ESI) = 535.27 [M+1].

[1658] Example 59

[1659] 4-amino-7-fluoro-N-[(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl]-N-(oxacyclo-3-ylmethyl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide Compound 59

[1660] 4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(oxetan-3-ylmethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1661] first step

[1662] 1-(1'-Methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-N-(oxacyclan-3-ylmethyl)methanamine 59a

[1663] 1-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-N-(oxetan-3-ylmethyl)methanamine

[1664] According to the method of compound 46a, compound 59a (white solid, 60 mg, yield 48%) was obtained.

[1665] LC-MS m / z (ESI) = 303.18 [M+1].

[1666] Step 2

[1667] 4-amino-7-fluoro-N-[(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl]-N-(oxacyclo-3-ylmethyl)-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide Compound 59

[1668] 4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(oxetan-3-ylmethyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1669] According to the method of compound 45, compound 59 was obtained (white solid, 19 mg, yield 17.7%).

[1670] 1 H NMR(400MHz,DMSO)δ7.56(d,1H),7.29(dd,1H),7.19–6.60(m,5H),5.27(d,2H),5.07–4.81(m,4H),4.70( d,1H),4.58(d,2H),4.42(d,2H),2.90(t,2H),2.30(d,2H),2.19(s,3H),1.86–1.59(m,4H),1.25(dd,2H).

[1671] LC-MS m / z (ESI) = 533.23 [M+1].

[1672] Example 60

[1673] 4-amino-N-(1,3-dimethoxypropan-2-yl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 60

[1674] 4-amino-N-(1,3-dimethoxypropan-2-yl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1675] first step

[1676] 1,3-Dimethoxy-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)propan-2-amine 60a

[1677] 1,3-dimethoxy-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)propan-2-amine

[1678] According to the method of compound 46a, compound 60a (transparent solid, 50 mg, yield 34.7%) was obtained.

[1679] LC-MS m / z (ESI) = 335.23 [M+1].

[1680] Step 2

[1681] 4-amino-N-(1,3-dimethoxypropan-2-yl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 60

[1682] 4-amino-N-(1,3-dimethoxypropan-2-yl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1683] According to the method of compound 45, compound 60 was obtained (white solid, 30 mg, yield 36%).

[1684] 1H NMR (400MHz, DMSO) δ7.55(d,1H),7.30(d,1H),7.22(s,1H),7.11(d,1H),6.83(s,2H),6.68(d,1H),5.30(d,2H),5. 00(s,2H),4.59(s,2H),4.00(s,1H),3.65–3.57(m,2H),3.08(s,3H),2.27(d,5H),1.79(dt,7H),1.31–1.19(m,6H).

[1685] LC-MS m / z (ESI) = 565.28 [M+1].

[1686] Example 61

[1687] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(1'-(2-hydroxy-2-methylpropyl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone Compound 61

[1688] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(1'-(2-hydroxy-2-methylpropyl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1689] first step

[1690] 1-(5-Bromo-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-2-methylpropan-2-ol 61a

[1691] 1-(5-bromo-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-2-methylpropan-2-ol

[1692] 34b (500 mg, 1.8 mmol), methyl oxirane (675 mg, 9.36 mmol), and potassium carbonate (528 mg, 3.74 mmol) were dissolved in MeOH (10 mL). The reaction mixture was heated in a microwave at 120°C for 0.5 h, and the reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed by rotary evaporation, and the product was separated by column chromatography (DCM:MeOH = 30:1) to afford 61a as a yellow oil (768 mg, 92% yield).

[1693] LC-MS m / z (ESI) = 340.10 [M+1].

[1694] Step 2

[1695] 2-Methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)propan-2-ol 61b

[1696] 2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)propan-2-ol

[1697] According to the method for compound 1c, compound 61b (reddish brown solid, 940 mg, yield 95%) was obtained.

[1698] LC-MS m / z (ESI) = 388.27 [M+1].

[1699] Step 3

[1700] (S)-tert-Butyl 6-(1'-(2-hydroxy-2-methylpropyl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 61c

[1701] tert-butyl (S)-6-(1'-(2-hydroxy-2-methylpropyl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1702] According to the method of 1d, 61c was obtained (dark brown oily liquid, 1.2 g, yield 95%).

[1703] LC-MS m / z (ESI) = 457.31 [M+1].

[1704] Step 4

[1705] (S)-2-Methyl-1-(5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)propan-2-ol 61d

[1706] (S)-2-methyl-1-(5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)propan-2-ol

[1707] According to the method of compound 1e, compound 61d (brown solid, 500 mg, yield 54%) was obtained.

[1708] LC-MS m / z (ESI) = 357.25 [M+1].

[1709] Step 5

[1710] 2-Methyl-1-(5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)propan-2-ol 61e

[1711] 3-methyl-1-(5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-1'-yl)propan-2-ol

[1712] According to the method of compound 1f, compound 61e (brown solid, 340 mg, yield 68%) was obtained.

[1713] LC-MS m / z (ESI) = 359.30 [M+1].

[1714] Step 6

[1715] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(1'-(2-hydroxy-2-methylpropyl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone Compound 61

[1716] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(1'-(2-hydroxy-2-methylpropyl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1717] According to the method for synthesizing compound 1, compound 61e (70.0 mg) and intermediate F were used to obtain compound 61 (white solid, 80 mg, yield 70%).

[1718] 1 H NMR (400MHz, DMSO) δ7.68–6.64(m,7H),5.54(dd,2H),4.98(s,2H),4.08(s,1H),2.99(s, 3H),2.60(d,3H),2.34–1.54(m,10H),1.37–1.19(m,3H),1.12(d,7H),0.96–0.73(m,3H).

[1719] LC-MS m / z (ESI) = 589.31 [M+1].

[1720] Example 62

[1721] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 62

[1722] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone

[1723] first step

[1724] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 62

[1725] (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone

[1726] According to the method of compound 1, compound 62 (white solid, 98 mg, yield 75%) was obtained.

[1727] 1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.69(s,1H),7.15-7.02(m,4H),6.73(d,1H),5.75(d,1H),5.43–5.25(m,2H),5.03(d,2H) ),2.99(s,2H),2.62–2.51(m,2H),2.44(s,2H),2.26(s,3H),2.11(s,2H),1.85-1.71(m,7H),1.35–1.19(m,2H),0.89(s,3H).

[1728] LC-MS m / z (ESI) = 514.28 [M+1].

[1729] Example 63

[1730] (4-amino-7-fluoro-1,3-dihydrofuro[4,3-c]quinolin-8-yl)[(5S)-2-(3-hydroxy-1'-methyl-1',2',3,3',5',6'-hexahydrospiro[1-benzofuran-2,4'-pyridine]-5-yl)-5-methylhexahydropyridin-1-yl]methanone Compound 65

[1731] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(3-hydroxy-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1732] first step

[1733] (S)-1'-Methyl-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-one Compound 65b

[1734] (S)-1'-methyl-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-one

[1735] According to the method of compound 1e, compound 65b was obtained (yellow solid, 220 mg, yield 78%).

[1736] LC-MS m / z (ESI) = 313.18 [M+1].

[1737] Step 2

[1738] 1'-Methyl-5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-one 65c

[1739] 1'-methyl-5-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-one

[1740] According to the method for compound 1f, compound 41h was obtained (yellow solid, 158 mg, yield 71%).

[1741] LC-MS m / z (ESI) = 317.22 [M+1].

[1742] Step 3

[1743] (4-amino-7-fluoro-1,3-dihydrofuro[4,3-c]quinolin-8-yl)[(5S)-2-(3-hydroxy-1'-methyl-1',2',3,3',5',6'-hexahydrospiro[1-benzofuran-2,4'-pyridine]-5-yl)-5-methylhexahydropyridin-1-yl]methanone Compound 65

[1744] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-2-(3-hydroxy-1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)-5-methylpiperidin-1-yl)methanone

[1745] According to the method of compound 1, compound 65 (white solid, 66 mg, yield 68%) was obtained.

[1746] 1 H NMR (400MHz, DMSO) δ7.71–6.56(m,8H),5.21(d,1H),5.21–4.13(m,3H),3. 31–2.85(m,4H),2.44–1.95(m,7H),1.79-1.65(m,6H),1.41–0.82(m,6H).

[1747] LC-MS m / z (ESI) = 547.26 [M+1].

[1748] Example 64

[1749] 4-amino-N-(2,2-difluoroethyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 64

[1750] 4-amino-N-(2,2-difluoroethyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1751] first step

[1752] 2,2-Difluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)ethan-1-amine 64b

[1753] 2,2-difluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)ethan-1-amine

[1754] According to the method of compound 46a, compound 64b (colorless liquid, 120 mg, yield 81%) was obtained.

[1755] LC-MS m / z (ESI) = 297.17 [M+1].

[1756] Step 2

[1757] 4-amino-N-(2,2-difluoroethyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidinyl]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 64

[1758] 4-amino-N-(2,2-difluoroethyl)-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1759] According to the method of compound 45, compound 64 (white solid, 68 mg, yield 62%) was obtained.

[1760] 1 H NMR(400MHz,DMSO-d6)δ7.55-7.50(m,1H),7.36–7.09(m,2H),6.88–6.63(m,4H),6.41–5.93(m,1H),5.32–5.20(m,2H) ),4.98(s,2H),4.57(d,2H),3.85-3.55(m,2H),3.04-2.90(m,2H),2.71-2.58(m,4H),2.32(s,3H),1.88-1.75(m,4H).

[1761] LC-MS m / z (ESI) = 527.22 [M+1].

[1762] Example 65

[1763] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-2-(4-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-5-methylpiperidin-1-yl)methanone Compound 65

[1764] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-2-(4-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-5-methylpiperidin-1-yl)methanone

[1765] first step

[1766] 4-(4-Bromo-2,6-difluorobenzyl)-1-methylpiperidin-4-ol 65b

[1767] 4-(4-bromo-2,6-difluorobenzyl)-1-methylpiperidin-4-ol

[1768] According to the method of compound 9b, compound 65b was obtained (yellow liquid, 800 mg, yield 7%).

[1769] LC-MS m / z (ESI) = 320.04 [M+1].

[1770] Step 2

[1771] 6-Bromo-4-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]65c

[1772] 6-bromo-4-fluoro-1'-methyl-3H-spiro[benzofuran-2,4′-piperidine]

[1773] According to the method of compound 9c, compound 65c was obtained (yellow liquid, 220 mg, yield 31%).

[1774] LC-MS m / z (ESI) = 300.03 [M+1].

[1775] Step 3

[1776] 4-Fluoro-1'-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]65d

[1777] 4-fluoro-1'-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1778] According to the method of compound 1c, compound 65d (brown liquid, 150 mg, yield 58%) was obtained.

[1779] LC-MS m / z (ESI) = 348.21 [M+1].

[1780] Step 4

[1781] (S)-tert-Butyl 6-(4-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 65e

[1782] tert-butyl(S)-6-(4-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1783] According to the method for compound 1d, compound 65e was obtained (yellow liquid, 149 mg, yield 83%).

[1784] LC-MS m / z (ESI) = 417.25 [M+1].

[1785] Step 5

[1786] (S)-4-Fluoro-1'-methyl-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]65f

[1787] (S)-4-fluoro-1'-methyl-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1788] According to the method of compound 1e, compound 65f was obtained (yellow liquid, 47 mg, yield 41%).

[1789] LC-MS m / z (ESI) = 317.20 [M+1].

[1790] Step 6

[1791] 4-Fluoro-1'-methyl-6-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine] 65g

[1792] 4-fluoro-1'-methyl-6-((5S)-5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4′-piperidine]

[1793] According to the method of compound 1f, compound 65g (yellow liquid, 29 mg, yield 61%) was obtained.

[1794] LC-MS m / z (ESI) = 319.21 [M+1].

[1795] Step 7

[1796] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-2-(4-fluoro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-5-methylpiperidin-1-yl)methanone Compound 65

[1797] (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((5S)-2-(4-fluoro-1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-6-yl)-5-methylpiperidin-1-yl)methanone

[1798] According to the method of compound 37, compound 65 (brown solid, 6 mg, yield 11%) was obtained.

[1799] 1 H NMR(400MHz,DMSO-d6)δ8.39-8.04(m,2H),7.43–7.26(m,3H),6.74–6.51(m,2H),4.46–3.93(m,4H),3.1 0–2.82(m,4H),2.47–2.35(m,4H),2.21(s,3H),1.89-1.59(m,8H),1.37-1.32(m,1H),1.42-0.90(m,3H).

[1800] LC-MS m / z (ESI) = 561.27 [M+1].

[1801] Example 66

[1802] (R)-4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(tetrahydrofuran-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 66

[1803] (R)-4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(tetrahydrofuran-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1804] first step

[1805] (R)-N-((1'-Methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)tetrahydrofuran-3-amine 66a

[1806] (R)-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)tetrahydrofuran-3-amine

[1807] According to the method of compound 46a, compound 66a (colorless liquid, 72 mg, yield 50%) was obtained.

[1808] LC-MS m / z (ESI) = 303.20 [M+1].

[1809] Step 2

[1810] (R)-4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(tetrahydrofuran-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Compound 66

[1811] (R)-4-amino-7-fluoro-N-((1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)methyl)-N-(tetrahydrofuran-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide

[1812] According to the method of compound 45, compound 66 (white solid, 90 mg, yield 71%) was obtained.

[1813] 1H NMR (400MHz, DMSO-d6) δ7.63–7.31(m,2H),7.23–7.01(m,2H),6.85–6.71(m,3H),5.38–4.91(m ,5H),4.68–4.29(m,3H),3.91–3.77(m,2H),3.04(s,2H),2.47–2.33(m,4H),2.19–1.71(m,9H).

[1814] LC-MS m / z (ESI) = 533.25 [M+1].

[1815] Example 67

[1816] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-(oxetane-3-yl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 67

[1817] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-(oxetan-3-yl)-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)piperidin-1-yl)methanone

[1818] first step

[1819] 5-Bromo-1'-(3-oxyethyl)-3H-spiro[benzofuran-2,4'-piperidine]67a

[1820] 5-bromo-1'-(oxetan-3-yl)-3H-spiro[benzofuran-2,4′-piperidine]

[1821] According to the method of compound 51a, compound 67a (white solid, 400 mg, yield 66%) was obtained.

[1822] LC-MS m / z (ESI) = 324.05 [M+1].

[1823] Step 2

[1824] 1'-(Oxetane-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]67b

[1825] 1′-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1826] According to the method of 1c, compound 67d was obtained (yellow solid, 334 mg, yield 74%).

[1827] LC-MS m / z (ESI) = 372.23 [M+1].

[1828] Step 3

[1829] (S)-tert-Butyl 3-methyl-6-(1'-(oxetan-3-yl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate 67c

[1830] tert-butyl (S)-3-methyl-6-(1'-(oxetan-3-yl)-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1831] According to the method of 1d, compound 67c (brown liquid, 428 mg, yield 99%).

[1832] LC-MS m / z (ESI) = 441.27 [M+1].

[1833] Step 4

[1834] (S)-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1'-(oxetane-3-yl)-3H-spiro[benzofuran-2,4'-piperidine]67d

[1835] (S)-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1'-(oxetan-3-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1836] (T) According to the method for compound 1e, compound 67d (brown liquid, 256 mg, yield 77%) was obtained.

[1837] LC-MS m / z (ESI) = 341.22 [M+1].

[1838] Step 5

[1839] 5-((5S)-5-methylpiperidin-2-yl)-1'-(oxetane-3-yl)-3H-spiro[benzofuran-2,4'-piperidine]67e

[1840] 5-((5S)-5-methylpiperidin-2-yl)-1'-(oxetan-3-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1841] According to the method of compound 1f, compound 67e (yellow solid, 160 mg, yield 62%) was obtained.

[1842] LC-MS m / z (ESI) = 343.23 [M+1].

[1843] Step 6

[1844] ((4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-(oxetane-3-yl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone Compound 67

[1845] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)((5S)-5-methyl-2-(1'-(oxetan-3-yl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)methanone

[1846] According to the method for synthesizing compound 45, compound 67 (white solid, 120 mg, yield 65%) was obtained.

[1847] 1 H NMR (400MHz, DMSO) δ7.64–7.41(m,1H),7.37–7.25(m,1H),7.22–6.88(m,2H),6.88–6.57(m,3H),5.95–4.88(m,5H),4.67-4.40(m,4H),4.38- 3.79(m,1H),3.52-3.40(m,1H),3.26-3.11(m,1H),3.00(s,2H),2.46– 2.18(m,4H),2.16–1.55(m,8H),1.34-1.27(m,1H),1.10–0.76(m,3H).

[1848] LC-MS m / z (ESI) = 573.28 [M+1].

[1849] Example 68

[1850] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)morpholino)methanone Compound 68

[1851] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)morpholino)methanone

[1852] first step

[1853] 2-((tributyltinyl)methoxy)ethan-1-ol 68b

[1854] 2-((tributylstannyl)methoxy)ethan-1-ol

[1855] Sodium hydride (556 mg, 13.9 mmol) was dissolved in a mixture of DMSO:THF = 10:1 (22 mL). 68a (2.1 g, 34.8 mmol) was added dropwise at 0°C under nitrogen protection. After the addition was complete, the temperature was raised to 25°C and the reaction was allowed to proceed for 1 h. A mixture of tributyl(iodomethyl)stannane (5.0 g, 11.6 mmol) in THF (11 mL) was added dropwise at 0°C. After the addition was complete, the temperature was raised to 55°C and the reaction progress was monitored by TLC.

[1856] The reaction was stopped, water was added, and the mixture was extracted with EA. The combined organic phases were concentrated under reduced pressure and eluted with column chromatography (EA:PE=1:10) to give compound 68b (colorless liquid, 2.46 g, yield 58%).

[1857] LC-MS m / z (ESI) = 367.16 [M+1].

[1858] Step 2

[1859] 2-((tributyltinyl)methoxy)ethyl methanesulfonate 68c

[1860] 2-((tributylstannyl)methoxy)ethyl methanesulfonate

[1861] 68b (2.46 g, 6.7 mmol) and triethylamine (1.37 g, 13.2 mmol) were dissolved in diethyl ether (30 mL), and methanesulfonic anhydride (1.3 g, 7.3 mmol) was added. The mixture was reacted at room temperature and the reaction progress was monitored by TLC.

[1862] The reaction was stopped, water was added, and the mixture was extracted with EA. The combined organic phases were concentrated under reduced pressure and eluted with column chromatography (EA:PE=1:10) to give compound 6c (yellow liquid, 3.1 g, yield 99%).

[1863] LC-MS m / z (ESI) = 445.14 [M+1].

[1864] Step 3

[1865] 2-(2-((tributyltinyl)methoxy)ethyl)isoindoline-1,3-dione 68d

[1866] 2-(2-((tributylstannyl)methoxy)ethyl)isoindoline-1,3-dione

[1867] 68c (3.1 g, 6.9 mmol) was dissolved in DMF (70 mL), and potassium phthalimide (1.9 g, 10.4 mmol) was added. The mixture was heated to 100°C for 3 h, and the reaction progress was monitored by TLC.

[1868] The reaction was stopped, water was added, and the mixture was extracted with EA. The combined organic phases were concentrated under reduced pressure and eluted with column chromatography (EA:PE=1:10) to give compound 68d (colorless liquid, 2.5 g, yield 73%).

[1869] LC-MS m / z (ESI) = 496.18 [M+1].

[1870] Step 4

[1871] 2-((tributyltinyl)methoxy)ethan-1-amine 68e

[1872] 2-((tributylstannyl)methoxy)ethan-1-amine

[1873] Compound 68d (2.5 g, 5.1 mmol) was dissolved in ethanol (40 mL), and hydrazine hydrate (2.5 mL, 51.0 mmol) was added. The mixture was heated under reflux for 30 min, and the reaction progress was monitored by TLC.

[1874] The reaction was stopped, the solvent was removed by rotary evaporation, DCM was added, and the mixture was filtered to obtain a filtrate, which was then evaporated to remove the solvent to obtain compound 68e (yellow liquid, 1.9 g, yield 99%).

[1875] LC-MS m / z (ESI) = 366.17 [M+1].

[1876] Step 5

[1877] (E)-1-(1'-Methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-N-(2-((tributyltinyl)methoxy)ethyl)methanimine 68f

[1878] (E)-1-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-N-(2-((tributylstannyl)methoxy)ethyl)methanimine

[1879] 68e (1.0 g, 3.0 mmol), 45a (700 mg, 3.0 mmol) and anhydrous magnesium sulfate (2.2 g) were reacted at room temperature and the reaction progress was monitored by TLC.

[1880] The reaction was stopped, filtered, and the filtrate was evaporated to remove the solvent to obtain compound 68f (yellow liquid, 1.3 g, yield 80%).

[1881] Step 6

[1882] 1'-Methyl-5-(morpholin-3-yl)-3H-spiro[benzofuran-2,4'-piperidine] 68g

[1883] 1'-methyl-5-(morpholin-3-yl)-3H-spiro[benzofuran-2,4′-piperidine]

[1884] Copper trifluoromethanesulfonate (191 mg, 0.5 mmol), (S,S)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (88.8 mg, 0.26 mmol), and (+)-2,2'-isopropylidenebis[(4R)-4-phenyl-2-oxazoline] (88.8 mg, 0.26 mmol) were dissolved in hexafluoroisopropanol (30 mL) and reacted at room temperature under nitrogen for 7 h. Then, 68f (1.3 g, 2.6 mmol) was added and reacted at room temperature for 16 h. The reaction progress was monitored by TLC.

[1885] The reaction was stopped, and DCM was added for dilution. Ammonia:saturated sodium chloride = 1:1 (20 ml) was added, and the mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with DCM. The organic phase was eluted by column chromatography (DCM:MeOH = 50:1) to obtain compound 68 g (yellow liquid, 400 mg, yield 68%).

[1886] LC-MS m / z (ESI) = 289.20 [M+1].

[1887] Step 7

[1888] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)morpholino)methanone Compound 68

[1889] (4-amino-7-fluoro-1,3-dihydrofuro[3,4-c]quinolin-8-yl)(3-(1'-methyl-3H-spiro[benzofuran-2,4′-piperidin]-5-yl)morpholino)methanone

[1890] According to the method of compound 45, compound 68 (white solid, 110 mg, yield 45%) was obtained.

[1891] 1 H NMR (400MHz, DMSO) δ7.71–6.61(m,7H),5.45(dd,2H),5.11–4.13(m,4H),3.26–2.80(m,4H),2.40–1.95(m,7H),1.75(dd,4H),1.35–1.15(m,3H).

[1892] LC-MS m / z (ESI) = 519.25 [M+1].

[1893] Biological experiments

[1894] Cell proliferation efficacy studies

[1895] HCT-116 and HCT-116MTAP- / - cells were cultured in McCoy's 5A complete medium (containing 10% FBS and 1% PS) at 37°C in a 5% CO2 incubator. Cells in the logarithmic growth phase were harvested, digested, and counted. 500 cells were plated per well in a 96-well plate and incubated overnight at 37°C in a 5% CO2 incubator. Test compounds were added to each well at varying concentrations (starting at 10 μM, diluted 1:3, for 9 concentrations). Quality control and blank controls were also established. Cultures were continued at 37°C in 5% CO2 for 5 days. The supernatant was discarded, and after trypsinization, 1 / 20 of the cells from each well were transferred to a new 96-well plate. Fresh culture medium was added to each well, along with varying concentrations of the test compounds (consistent with the concentrations before transfer). Cultures were continued at 37°C in 5% CO2 for 5 days. 80 μL of CellTiter-Glo detection reagent was added to each well, gently shaken for 2 min, incubated at room temperature for 10 min, and the chemiluminescence signal (RLU) was detected using a microplate reader (Thermo, VarioSkan LUX).

[1896] After data processing, GraphPad 8.0 was used to analyze the IC 50 Fitting and calculation of the compound's selectivity (Ratio) for HCT-116WT and HCT-116MTAP- / - cells: Ratio = IC 50 (HCT116 WT) / IC 50 (HCT116 MTAP- / -). The results are shown in Table 1 below:

[1897] Table 1 Cell proliferation efficacy

[1898] Among them, "A" represents IC 50 ≤0.1μM, “B” means 0.1μM <IC 50 <1μM, "C" indicates 1μM ≤ IC 50 <10 μM, “D” indicates IC 50 ≥10μM.

[1899] The results showed that the compounds of the present invention exhibited strong anti-proliferation activity against human colon cancer HCT-116MTAP- / - cells and showed good selectivity compared to human colon cancer HCT-116WT cells. It is expected that the compounds of the present invention will have therapeutic effects on MTAP-deficient tumors, while also having good selectivity and low side effects.

[1900] PRMT5 / MEP50 methyltransferase activity assay

[1901] In this experiment, MTase_GloTM Methyltransferase Assay (Promega, V7602) was used to determine the inhibitory effect of the compounds on PRMT5 activity. The specific procedure is as follows:

[1902] (1) Determine the inhibitory ability of the compound on PRMT5 / MEP50 activity in the absence of MTA. The compound was prepared into a 10 mM stock solution with DMSO, and the stock solution was serially diluted using 1× reaction buffer (starting concentration 1 μM, 1:4 dilution, 10 gradients). 20 nL of each diluted compound was transferred to a 384-well plate (Greiner, 784075); 2 μL of diluted PRMT5 / MEP50 complex (Reaction Biology, HMT-22-148) was added to each well; after mixing, centrifuged for 1 min (1000 rpm, RT) and allowed to stand at room temperature for 5 min; 2 μL of substrate reaction solution (containing 2.5 μM SAM, 1 μM Bio-H4 (1-21)) was added to each well; after mixing, centrifuged for 1 min (1000 rpm, RT) and allowed to stand at room temperature for 3 h; 1 μL of 5X MTase-Glo was added to each well. TM Reagent; after mixing, centrifuge for 1 min (1000 rpm, RT) and let stand at room temperature for 30 min; add 5 μL MTase-Glo to each well TM Detection Solution; after mixing, centrifuge for 1 min (1000 rpm, RT) and let stand at room temperature for 30 min; read the values ​​of each well with a microplate reader, perform curve fitting using GraphPad Prism, and perform IC 50 Value calculation.

[1903] (2) Determine the inhibitory ability of the compound on PRMT5 / MEP50 activity in the presence of MTA. The compound was prepared into a 10 mM stock solution with DMSO, and the stock solution was serially diluted using 1× reaction buffer (starting concentration 1 μM, 1:4 dilution, 10 gradients). 20 nL of each diluted compound was transferred to a 384-well plate (Greiner, 784075); 2 μL of diluted PRMT5 / MEP50 complex (Reaction Biology, HMT-22-148) was added to each well; after mixing, centrifuged for 1 min (1000 rpm, RT) and allowed to stand at room temperature for 5 min; 2 μL of substrate reaction solution (containing 2.5 μM SAM, 1 μM Bio-H4 (1-21), 1 μM MTA) was added to each well; after mixing, centrifuged for 1 min (1000 rpm, RT) and allowed to stand at room temperature for 3 h; 1 μL of 5X MTase-Glo was added to each well. TMReagent; after mixing, centrifuge for 1 min (1000 rpm, RT) and let stand at room temperature for 30 min; add 5 μL MTase-Glo to each well TM Detection Solution; after mixing, centrifuge for 1 min (1000 rpm, RT) and let stand at room temperature for 30 min; read the values ​​of each well with a microplate reader, perform curve fitting using GraphPad Prism, and perform IC 50 Value calculation.

[1904] (3) Calculate the selectivity of the compound for the PRMT5 / MTA complex. The calculation formula is: Fold = IC 50(PRMT5) / IC 50(PRMT5-MTA) .

[1905] Conclusion: The compounds of the present invention have significant inhibitory effects on the activity of PRMT5·MTA complex.

[1906] hERG experiments

[1907] This study used an automated patch clamp method to examine the effects of various test compound concentrations (0.3, 1, 3, 10, and 30 μM), a negative control (containing 0.3% DMSO), and a positive control (3, 10, 30, 100, and 300 nM cisapride) on hERG potassium channel currents in human embryonic kidney (HEK293) cells (Creacell, Catalog No. A-0320) expressing the hERG potassium channel. Two cells were tested for each negative and positive control and test compound concentration. The results showed that the compounds of the present invention had no significant inhibitory effect on hERG potassium channel currents within the tested concentration range, demonstrating a favorable safety profile.

[1908] Pharmacokinetic study in mice

[1909] An appropriate amount of the test substance was weighed and prepared into a 0.1 mg / mL solution using 5% DMSO + 5% HS-15 + 90% Saline for intravenous administration. The test substance was prepared into a 1 mg / mL formulation using 0.5% MC for oral administration. Healthy adult ICR mice were given the test substance (1 mg / kg) intravenously and blood was collected by microsampling at 5 min, 15 min, 0.5, 1, 2, 4, 8, and 24 h. Blood was collected by microsampling at 15 min, 0.5, 1, 2, 4, 8, and 24 h after oral administration of the test substance (10 mg / kg). Blood samples were centrifuged at 6000 g for 5 min at 4°C to separate plasma, and all samples were stored at -70°C until testing. The test substance concentration in plasma was determined by LC-MS / MS, and the main pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartmental model.

[1910] Conclusion: The compounds of the present invention have good oral bioavailability and exposure.

[1911] Mouse brain PK experiment

[1912] An appropriate amount of test substance was weighed and formulated into a 1 mg / mL formulation using 0.5% MC. Healthy adult ICR mice were fasted overnight and then gavaged with the test substance (5 mg / kg) or blank vehicle. Blood was collected via the jugular vein at 0.5, 1, 2, 4, 8, and 24 hours after administration. The mice were then sacrificed, and cerebrospinal fluid and brain tissue were collected. Blood samples were centrifuged at 6000 g for 5 minutes at 4°C to separate plasma. The brain tissue was rinsed with saline for residual blood and dried with absorbent paper. All samples were stored at -70°C until testing. LC-MS / MS was used to determine the test substance concentrations in plasma, cerebrospinal fluid, and brain tissue. Key pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartmental model.

[1913] Conclusion: The compounds of the present invention have certain brain penetrability in mice.

[1914] Pharmacokinetic study in dogs

[1915] Weigh an appropriate amount of the test substance, use 5% DMSO + 5% HS-15 + 90% Saline to prepare the test substance into a 0.5 mg / mL transparent clear solution for intravenous administration. Use 0.5% MC to prepare the test substance into a 0.6 mg / mL uniform suspension solution for oral administration. Take 6 healthy male beagle dogs (Chengdu Dashuo, SPF grade), with 3 animals in the intravenous and oral administration groups respectively, 3 animals at each time point, and blood is collected through the forelimb vein. Blood is collected at 5min, 15min, 0.5, 1, 2, 4, 8, 12h, and 24h after intravenous administration of the test substance (1 mg / kg). Blood is collected at 15min, 0.5, 1, 2, 4, 8, 12h, and 24h after oral administration of the test substance (3 mg / kg). Blood samples were anticoagulated with EDTA-K2 and centrifuged at 2000g for 10 minutes at 4°C to separate plasma. All plasma samples were stored at -80°C until testing. Plasma concentrations of the test substance (with gliclazide as the internal standard) were determined by LC-MS / MS, and key pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartmental model.

[1916] Conclusion: The compounds of the present invention have good oral bioavailability and exposure.

[1917] Drug efficacy test in Lu99 tumor-bearing model

[1918] Human large cell lung cancer Lu99 cells (Kebai, Cat. No. CBFB24041506P4) were cultured in RPMI medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin. When the cells reached the exponential growth phase, they were trypsinized, harvested, counted, and inoculated into the axilla of female BALB / c nude mice at a cell density of 5.0 × 10 6 / mouse, the inoculation volume is 200 μL (with Matrigel at a volume ratio of 1:1). 3 Around 24 hours after the experiment, the mice were randomly divided into groups according to the size of the tumor, with 8 mice in each group. The test compound was prepared using DMSO + 0.5% MC (5:95) and administered orally at a dosage of 10 mL / kg, twice a day (6 hours between doses). During the administration period, the tumor volume was measured twice a week and a tumor growth curve was drawn. The mouse body weight was measured twice a week and a weight change curve was drawn. At the end of the experiment, blood samples were collected from the orbital venous plexus of the mice at 0, 1, 2, 4, 7 (1 hour after the second dose), and 24 hours. Tumors were collected at 4 and 24 hours for plasma and tumor drug concentration detection.

[1919] The results showed that the compound of the present invention had a significant inhibitory effect on tumor growth in vivo and had no significant adverse effect on the body weight of mice. The results of the detection of drug concentrations in plasma and tumor tissue showed that the compound of the present invention could effectively accumulate in tumor tissue in mice.

[1920] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound represented by formula (I), or any stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: in: R3 is selected from -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 4-6 Heterocyclic group, -C 0-6 Alkyl-C 5-10 Heteroaryl, -C 0-6 Alkyl-O-R8 or C 1-6 Alkyl; R8 is selected from H, D, hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocyclic or C 5- 10 Heteroaryl; R3 may be further optionally substituted by one or more selected from D, halogen, hydroxy, carbonyl, cyano, C 1-6 Alkyl, -C 0-6 Alkyl-OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocyclic or C 5-10 substituted by a heteroaryl substituent; R4 is C(R9)3, each R9 is independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 5-10 Heteroaryl; wherein at least one R9 is selected from C 6-10 Aryl or C 5-10 heteroaryl, and the C 6-10 Aryl or C 5-10 Heteroaryl fused to C 3-6 Cycloalkyl or C 5-12 Heterocyclyl; R9 is optionally further selected from one or more C 1- 6 alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 5-10 substituted by a heteroaryl substituent; or R3 and R4 and the nitrogen atom directly connected thereto together form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted by one or more selected from D, hydroxyl, halogen, cyano, nitro, azido, carboxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, =O, =S, -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-6 The substituent of the heterocyclic group is substituted; wherein the C 1-6 Alkyl, -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4- The heterocyclic group is optionally further substituted by one or more selected from D, hydroxy, halogen, cyano, nitro, azido, carboxyl, C 1-6 Alkyl, -C 0-6 Alkyl-OH, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, =O, =S, -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-8 Substitution of heterocyclic groups by substituents; X, Y, and Z are independently selected from N or CR 10 , R 10 Selected from H, D, halogen, cyano, nitro, azido, C 1- 6 alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-OS(O)2R 11 , -C 0-8 Alkyl-OR 12 , -C 0-8 Alkyl-C(O)OR 13 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 16 , -C 0-8 Alkyl-OC(O)R 17 , -C 0- 8-Alkyl-P(O)(R 18 2. -C 0-8 Alkyl-NR 19 R 20 , -C 0-8 Alkyl-C(O)NR 21 R 22 , or -C 0-8 Alkyl-N(R 23 )-C(O)R 24 ; the CR 10 Optionally further substituted by one or more selected from D, halogen, cyano, nitro, azido, C 1-6 Alkyl, C 1- 6 alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 is substituted by a substituent of a heteroaryl group; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are independently selected from H, D, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3- 12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl or C 5-10 heteroaryl; Ring B is selected from a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring or a 5-10 membered heteroaryl ring, and Ring B is optionally further substituted with one or more selected from D, halogen, cyano, nitro, azido, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-OS(O)2R 11 , -C 0-8 Alkyl-OR 12 , -C 0-8 Alkyl-C(O)OR 13 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 16 , -C 0-8 Alkyl-OC(O)R 17 , -C 0-8 Alkyl-P(O)(R 18 2. -C 0-8 Alkyl-NR 19 R 20 , -C 0-8 Alkyl-C(O)NR 21 R 22 , or -C 0-8 Alkyl-N(R 23 )-C(O)R 24 substituted by a substituent; R6 and R7 are each independently selected from H, D, hydroxyl, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl or C 3-12 or R6 and R7 together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group.

2. The compound according to claim 1, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: R3 and R4 together with the nitrogen atom to which they are directly connected form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted with one or more selected from -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-6 The substituent of the heterocyclic group is substituted; wherein, The-C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-6 The heterocyclic group is optionally further substituted by one or more selected from D, hydroxy, halogen, cyano, carboxyl, C 1-6 Alkyl, -C 0-6 Alkyl-OH, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, =O, =S, -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-8 The substituents of the heterocyclic group are substituted.

3. The compound according to claim 2, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: R3 and R4 together with the nitrogen atom to which they are directly connected form a 4-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further substituted with one or more -C 0-6 Alkyl-11-20 membered polycyclic substituted; wherein, The-C 0-6 The alkyl-11-20 membered polycyclic ring is optionally further substituted with one or more selected from D, hydroxy, halogen, cyano, carboxyl, C 1-6 Alkyl, -C 0-6 Alkyl-OH, deuterated C 1-6 Alkyl, =O, =S, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 4-8 The substituents of the heterocyclic group are substituted.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: X, Y, and Z are independently selected from N or CR 10 , R 10 Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl, C 5-10 heteroaryl; said CR 10 Optionally further substituted by one or more selected from D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 substituted by a heteroaryl substituent; Ring B is selected from a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, and Ring B is optionally further substituted with one or more selected from D, Halogen, cyano, nitro, azido, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C 0-8 Alkyl-OR 12 , -C 0-8 Alkyl-C(O)OR 13 , -C 0- 8-Alkyl-C(O)R 16 or -C 0-8 Alkyl-OC(O)R 17 , is substituted by a substituent.

5. The compound according to claim 3, or any stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, whose structure is shown in formula (II): in: Ring A is selected from a polycyclic ring of 11-15 members; Ring A is optionally further substituted by one or more selected from D, hydroxyl, halogen, cyano, nitro, azido, carboxyl, C 1-6 Alkyl, -C 0-6 Alkyl-OH, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, =O, =S, -C 0-6 Alkyl-11-20 membered polycyclic, -C 0-6 Alkyl-C 3-6 Cycloalkyl or -C 0-6 Alkyl-C 3-8 Substitution of heterocycloalkyl groups; Ring B is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, and Ring B contains 1-2 heteroatoms selected from N, O or S; X, Y, and Z are independently selected from N or CR 10 ; R 10 is selected from H, D, halogen or alkyl; Q is optionally selected from C, N, O or S; Q is optionally further substituted by halogen or alkyl; R1 and R2 are each independently selected from H, D, C1-C6 alkyl or halogen.

6. The compound according to claim 5, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: The A ring is selected from The P ring is selected from a 5-6 membered aryl or heteroaryl group; the Q ring is selected from a 5-6 membered carbocyclic group or heterocyclic group; R m and R n Together with the same carbon atom they form a 3-6 membered carbocyclic or heterocyclic ring.

7. The compound according to claim 5, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: The A ring is selected from: The B ring is selected from or other 5-membered heterocyclic groups or 5-membered heteroaryl groups.

8. The compound according to claim 1, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: R3 is selected from -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 4-6 Heterocyclic group, -C 0-6 Alkyl-C 5-10 Heteroaryl, -C 0-6 Alkyl-O-R8 or C 1-6 Alkyl; R8 is selected from H, D, hydroxyl or C 1-6 Alkyl; R3 may be further selected from one or more of D, halogen, hydroxyl, C 1-6 Alkyl or -C 0-6 Alkyl-OC 1-6 substituted by an alkyl substituent; R4 is C(R9)3, each R9 is independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; wherein At least one R9 is selected from C 6-10 Aryl, and the C 6-10 Aryl fused to C 5-12 Heterocyclic group; R9 is optionally further substituted by one or more C 1-6 The alkyl group is substituted with an alkyl substituent.

9. The compound according to any one of claims 1 to 8, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: in, The compound is selected from:

10. A pharmaceutical composition, comprising: (1) The compound according to any one of claims 1 to 9, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof; (2) one or more other active ingredients; as well as (3) Pharmaceutically acceptable carriers and / or excipients.

11. Use of the compound according to any one of claims 1 to 9 or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 10 in the preparation of an anti-tumor drug.

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