Pyridine derivative and application thereof

Abstract

The invention relates to a pyridine derivative as shown in a formula (I) and application thereof. The pyridine derivative has a good anti-tumor effect. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a pyridine derivative and application thereof. Background Art

[0002] Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that regulates key cellular processes, including DNA damage repair, cell cycle regulation, transcriptional regulation, and RNA splicing, by catalyzing the symmetrical dimethylation of arginine in histones and other proteins. Studies have shown that overexpression of PRMT5 plays a key role in a variety of cancers (B and T cell lymphoma, metastatic melanoma, neuroblastoma, glioblastoma, germ cell tumor, ovarian cancer, breast cancer, etc.), so it is a drug target with good clinical potential.

[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, the researchers found that MTAP - / - The activity of tumor cells was significantly reduced after the expression of PRMT5 was inhibited. Further verification found that WT Knockout of MTAP in cells made the 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 reducing the toxic side effects caused by compounds, deserve further study. Summary of the invention

[0004] The purpose of the present invention is to provide a pyridine derivative capable of inhibiting the overexpression of PRMT5 and the application of the pyridine derivative in the preparation of anti-tumor drugs.

[0005] 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:

[0006]

[0007] Where: R 1 and each R 2 are independently selected from -CN, H, -D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl, heterocyclyl-alkyl, heteroaryl-alkyl, aryl-alkyl, cycloalkyl-alkyl, -OR m1 、-N(R m1 ) 2 、-C(=O)R m1 、-C(=O)OR m1 、-NR m1 C(=O)R m1 、-NR m1 C(=O)OR m1 、-C(=O)N(R m1 ) 2 、-OC(=O)N(R m1 ) 2 、-S(=O)R m1 、-S(=O) 2 R m1 、-SR m1 、-S(=O)(=NR m1 )R m1 、-NR m1 S(=O) 2 R m1 and -S(=O) 2 N(R m1 ) 2 ;

[0008] Or any two R 2 Together with the atoms to which they are attached, they form a 3-10 membered cycloalkyl or heterocycloalkyl group;

[0009] Among them, each R m1 are independently selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 1-C 6 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl, heterocyclyl-alkyl, heteroaryl-alkyl, aryl-alkyl, cycloalkyl-alkyl; each R m1 are independently optional to be substituted at any position;

[0010] n is a natural number from 0 to 8;

[0011] X and Y are independently selected from O, S or -CF 3 ;

[0012] Z is selected from C, N or O;

[0013] A is selected from a fused ring of 11 to 20 members;

[0014] B is selected from a 5-10 membered monocyclic or condensed ring;

[0015] Wherein, ring A can be optionally substituted by one or more selected from H, D, =O, halogen, CN, NO 2 、-L-OR m2 、-L-SR m2 、-LN(R m2 ) 2 、-SF 5 、-C(O)R m2 、-C(O)OR m2 、-C(O)N(R m2 ) 2 、-OC(O)R m2 、-NR m2 C(O)R m2 、-S(O)R m2 、-S(O) 2 R m2 、-S(O)OR m2 、-S(O) 2 OR m2 、-S(O)N(R m2 ) 2 、-S(O) 2 N(R m2 ) 2 、-P(O)(R m2 ) 2 、-P(O) 2 R m2 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6substituted by alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl and 5-10 membered aryl; L is a chemical bond, C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene or C 2 -C 6 Alkyne; each R m2 are independently selected from H, D, C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl; each R m2 are independently optional to be substituted at any position;

[0016] Wherein, ring B can be optionally substituted by one or more selected from -CN, H, -D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl, heterocyclyl-alkyl, heteroaryl-alkyl, aryl-alkyl, cycloalkyl-alkyl, -OR m3 、-N(R m3 ) 2 、-C(=O)R m3 、-C(=O)OR m3 、-NR m3 C(=O)R m3 、-NR m3 C(=O)OR m3 、-C(=O)N(R m3 ) 2 、-OC(=O)N(R m3 ) 2 、-S(=O)R m3 、-S(=O) 2 R m3 、-SR m3 、-S(=O)(=NR m3 )R m3 、-NR m3 S(=O) 2 R m3 and -S(=O)2 N(R m3 ) 2 ; Each R m3 are independently selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl, heterocyclyl-alkyl, heteroaryl-alkyl, aryl-alkyl, cycloalkyl-alkyl; each R m3 Each of the above groups is independently optional and may be substituted at any position.

[0017] Specifically, the present invention relates to a compound represented by formula (II), or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:

[0018]

[0019] in:

[0020] R 1 and R 2 are independently selected from -CN, H, D, halogen, C 1 -C 3 Alkyl or -C(=O)R 3 ;

[0021] R 3 Selected from C 1 -C 3 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;

[0022] X and Y are independently selected from O, S or -CF 3 ;

[0023] Z is selected from C, N or O;

[0024] A is selected from a fused ring of 11 to 20 members;

[0025] B is selected from a 5-10 membered fused ring.

[0026] Unless otherwise specified, Represents a single bond or a double bond.

[0027] One or more embodiments of the present application provide a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein B is selected from:

[0028]

[0029] One or more embodiments of the present application provide a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein B is further substituted with one or more of the following substituents: -NH 2 , =O, H, D and C 1 -C 6 alkyl.

[0030] One or more embodiments of the present application provide a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein A is selected from: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, and A15 are independently any suitable ring structure.

[0032] One or more embodiments of the present application provide a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15 are independently selected from a 3-8 membered heterocycle or carbocycle.

[0033] One or more embodiments of the present application provide a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein A1, A2, A3, A4, A5, A6, A7 and A8 each contain at least 2 heteroatoms, and A1, A2, A3, A4, A5, A6, A7, A8, A10 are each independently selected from a 5-6 membered heterocycle or a 5-8 membered spirocycle containing a heteroatom.

[0034] One or more embodiments of the present application provide a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein A is selected from:

[0035]

[0036] One or more embodiments of the present application provide a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein A is further substituted with one or more substituents selected from the following: C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, -CN, D, =O, halogen, and 3-8 membered heterocyclic ring; the 3-8 membered heterocyclic ring is optionally replaced by H, halogen or C1 -C 3 Alkyl substitution.

[0037] One or more embodiments of the present application provide a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the following structures:

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] One or more embodiments of the present application provide a pharmaceutical composition, the pharmaceutical composition comprising:

[0052] (1) The compounds of the present application or their stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals;

[0053] (2) optionally one or more other active ingredients; and

[0054] (3) Pharmaceutically acceptable carriers and / or excipients.

[0055] One or more embodiments of the present application provide the use of the pharmaceutical composition of the present application or the compound or its stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals in the preparation of anti-tumor drugs.

[0056] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0057] 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 carbon isotopes 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, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0058] "Alkyl" refers to a straight 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 further 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 the alkyl group is substituted, it may be optionally 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 the definition of "alkyl" described above.

[0059] "Heteroalkyl" refers to an alkyl group as defined herein that further contains one or more heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain. The heteroatoms are inserted between adjacent carbon atoms of the parent carbon chain and / or between a carbon atom and the parent molecule (i.e., at the point of attachment). For example, -CH 2 OH, -CH 2-O-CH3, -CH 2 NH 2 、-CH 2 NH(CH 3 ),-CH 2 N(CH 3 ) 2 、-CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 、-CH 2 CH 2 NH 2 、-CH 2 CH 2 NH(CH 3 ),-CH 2 CH 2 N(CH 3 ) 2 .

[0060] "Alkenyl" refers to a straight 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 vinyl, propene-2-yl, butene-2-yl, butene-2-yl, pentene-2-yl, pentene-4-yl, hexene-2-yl, hexene-3-yl, heptene-2-yl, heptene-3-yl, heptene-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.

[0061] "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 further 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, octyne-3-yl, nonyn-3-yl, decyn-4-yl, undecyne-3-yl, dodecyne-4-yl. The alkynyl may optionally be further substituted with one or more substituents.

[0062] "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, and non-limiting examples include phenyl and naphthyl. The aryl group can be optionally further substituted by one or more substituents.

[0063] "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 5-8 membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. Heteroaryl can be connected to a heteroatom or a carbon atom, and can be a bridged ring or a spiro ring, and non-limiting examples include cyclopyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridinyl, pyrrolopyridinyl. Heteroaryl is optionally further substituted by one or more substituents.

[0064] "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-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-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The "carbocyclic group" or "carbocycle" is optionally further substituted by one or more substituents.

[0065] "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 3-8 membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be connected 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, thiinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiinyl, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furan ... pyranyl, thiophene, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl oxazolyl, benzopyridyl, pyrrolopyridyl, 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]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted by one or more substituents.

[0066] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of 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, and the ring carbon atoms are preferably 3 to 10 carbon atoms, and 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, etc. When a cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

[0067] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which may 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 3-8 membered heterocyclic ring. 1, 2 or 3 N, S optionally substituted in the ring of "heterocycloalkyl" may be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or a carbon atom; "heterocycloalkyl" may be a bridged ring or a spiro ring. Non-limiting examples of “heterocycloalkyl” include oxirane, aziridine, 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.

[0068] 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 2-6 Alkynyl, -NR q4 Rq5 , =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, and 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 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; Rq2 , R q3 Select 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) 2 NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , where the C 1-6 The alkyl group is 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.

[0069] "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, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0070] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, 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.

[0071] "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.

[0072] "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.

[0073] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0074] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0075] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0076] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group. DETAILED DESCRIPTION

[0077] The following embodiments 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.

[0078] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;

[0079] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0080] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0081] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0082] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

[0083] 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 Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, and Jiangsu Aikon Biomedicine Research and Development.

[0084] Intermediate A1,3-dihydrofuro[3,4-c]pyridine-4,7-diamineIntermediate A1,3-dihydrofuro[3,4-c]pyridine-4,7-diamine

[0085]

[0086] first step

[0087] 2-((Prop-2-yn-1-yloxy)methyl)pyrazine I-2

[0088] 2-((prop-2-yn-1-yloxy)methyl)pyrazine

[0089] I-1 (purchased from Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd., 5.0 g, 45.5 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydride (1.6 g, 68.3 mmol) was added at 0°C for activation for 0.5 h, and then acetylene bromide (6.5 g, 54.6 mmol) was slowly added. The reaction was completed after 3 h, and water (200 mL) was added to quench the reaction. Ethyl acetate (50 mL*3) was used for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain I-2 (yellow liquid, 6.4 g, yield 95%).

[0090] LC-MS m / z(ESI)=149.06[M+1].

[0091] Step 2

[0092] 1,3-Dihydrofurano[3,4-c]pyridine I-3

[0093] 1,3-dihydrofuro[3,4-c]pyridine

[0094] I-2 (6.4 g, 43.2 mmol) was dissolved in trifluoroacetic acid (30 mL), refluxed at 75 ° C, poured into 200 ml of water and stirred after 2 h, and then adjusted to pH 8-9 with 25% NaOH aqueous solution, and then extracted with dichloromethane (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain I-3 (yellow liquid, 3.5 g, yield 68%).

[0095] LC-MS m / z(ESI)=122.05[M+1].

[0096] Step 3

[0097] 1,3-Dihydrofuro[3,4-c]pyridine-5-oxide I-4

[0098] 1,3-dihydrofuro[3,4-c]pyridine 5-oxide

[0099] I-3 (3.5 g, 28.9 mmol) was dissolved in dichloromethane (50 mL), and m-chloroperbenzoic acid (5.98 g, 34.68 mmol) was added at 0°C. After the addition was completed, the reaction was allowed to react at room temperature for 2 h. After the reaction was completed, the mixture was directly concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane: methanol = 30:1) to obtain I-4 (white solid, 2.1 g, yield 53%).

[0100] LC-MS m / z(ESI)=138.05[M+1].

[0101] Step 4

[0102] N-(4-methoxybenzyl)-1,3-dihydrofuro[3,4-c]pyridin-4-amine I-5

[0103] N-(4-methoxybenzyl)-1,3-dihydrofuro[3,4-c]pyridin-4-amine

[0104] I-4 (800 mg, 5.8 mmol) was dissolved in dichloromethane (20 mL), and p-methoxyaniline (1.03 g, 7.5 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (3.5 g, 7.5 mmol), and N,N-diisopropylethylamine (1.87 g, 14.5 mmol) were added at room temperature. The reaction was carried out for 3 h at room temperature. After the reaction was completed, it was directly concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain I-5 (white solid, 1.2 g, yield 81%).

[0105] LC-MS m / z(ESI)=257.12[M+1]

[0106] Step 5

[0107] 1,3-Dihydrofuro[3,4-c]pyridin-4-amine I-6

[0108] 1,3-dihydrofuro[3,4-c]pyridin-4-amine

[0109] I-5 (1.2 g, 4.7 mmol) was dissolved in trifluoroacetic acid (10 mL) and refluxed at 75 ° C for 3 h. After the reaction, the reaction solution was dropped into a saturated sodium bicarbonate aqueous solution (200 mL), extracted with ethyl acetate (30 mL*3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain I-6 (white solid, 0.6 g, yield 94%).

[0110] LC-MS m / z(ESI)=137.06[M+1]

[0111] Step 6

[0112] 7-Bromo-1,3-dihydrofuro[3,4-c]pyridin-4-amine I-7

[0113] 7-bromo-1,3-dihydrofuro[3,4-c]pyridin-4-amine

[0114] I-6 (0.60 g, 4.4 mmol) was dissolved in acetonitrile (20 mL), and N-bromosuccinimide (0.94 g, 5.3 mmol) was added at room temperature. The reaction was allowed to react for 2 h at room temperature. After the reaction was completed, the mixture was directly concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain I-7 (yellow solid, 0.73 g, yield 78%).

[0115] LC-MS m / z(ESI)=214.97[M+1]

[0116] Step 7

[0117] 7-((Benzhydryl)amino)-1,3-dihydrofuro[3,4-c]pyridin-4-amine I-8

[0118] 7-((diphenylmethylene)amino)-1,3-dihydrofuro[3,4-c]pyridin-4-amine

[0119] I-7 (0.73 g, 3.4 mmol), benzophenone imine (1.8 g, 10.2 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.1 g, 1.7 mmol), palladium acetate (381 mg, 1.7 mmol), cesium carbonate (5.5 g, 17.0 mmol) were dissolved in toluene (30 mL), ventilated with nitrogen, reacted at 75 ° C for 5 h, and after the reaction was completed, the crude product I-8 (yellow solid, 1.0 g, yield 99%) was directly filtered.

[0120] LC-MS m / z(ESI)=316.14[M+1]

[0121] Step 8

[0122] 1,3-Dihydrofurano[3,4-c]pyridine-4,7-diamine intermediate A

[0123] 1,3-dihydrofuro[3,4-c]pyridine-4,7-diamine

[0124] I-8 (1.0 g, 3.4 mmol) and hydroxylamine hydrochloride (1.4 g, 20.4 mmol) were dissolved in methanol (30 mL) and reacted at room temperature for 3 h. After the reaction, it was directly concentrated under reduced pressure and passed through a column (DCM:MeOH=20:1) to obtain intermediate A (yellow solid, 320 mg, yield 62%).

[0125] LC-MS m / z(ESI)=152.07[M+1]

[0126] Intermediate B tert-butyl 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0127]

[0128] first step

[0129] 5-Methyl-2-oxopiperidine-1-carboxylic acid tert-butyl ester II-2

[0130] tert-butyl 5-methyl-2-oxopiperidine-1-carboxylate

[0131] II-1 (25.0 g, 221.2 mmol) was dissolved in tetrahydrofuran (250 mL), (Bo c)2O (50.6 g, 232.3 mmol) and DMAP (2.7 g, 22.1 mmol) were added at 25 °C, and the reaction was completed after 16 h. The solvent was removed by rotary evaporation, ethyl acetate (600 ml) was added to dilute, and 10% KHSO 4 The organic phases were washed (50 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain II-2 (yellow liquid, 47 g, yield 99%).

[0132] LC-MS m / z(ESI)=214.14[M+1].

[0133] Step 2

[0134] 3-Methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester II-3

[0135] tert-butyl 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0136] II-2 (47 g, 220.6 mmol) was dissolved in THF (300 mL), and KHMDS (330 mL 1M in 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 NH 4 The reaction was quenched with Cl solution, the solvent was removed by rotary evaporation, EA (600 mL) was added for extraction, and then 10% NaOH solution (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%).

[0137] LC-MS m / z(ESI)=346.05[M+1].

[0138] Intermediate C3-ethylpyridine-2,5-diamine Intermediate C3-ethylpyridine-2,5-diamine

[0139]

[0140] first step

[0141] 5-Nitro-3-vinylpyridin-2-amine III-2

[0142] 5-nitro-3-vinylpyridin-2-amine

[0143] Compound III-1 (34.0 g, 137.0 mmol), potassium vinyl trifluoroborate (24.9 g, 165.2 mmol), Pd(DPPF)Cl 2 (11.3 g, 13.7 mmol) and potassium carbonate (106.9 g, 688.3 mmol) were dissolved in dioxane (500 mL) and water (120 mL) under nitrogen protection, and the temperature was raised to 80°C for reaction for 2 hours. The reaction progress was monitored by TLC.

[0144] The reaction was stopped, filtered, and the filtrate was obtained. It was then concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain III-2 (yellow solid, 17.7 g, yield 73%).

[0145] LC-MS m / z(ESI)=166.05[M+1].

[0146] Step 2

[0147] Tert-butyl (5-nitro-3-vinylpyridin-2-yl)carbamate III-3

[0148] tert-butyl(5-nitro-3-vinylpyridin-2-yl)carbamate

[0149] Compound III-2 (17.7 g, 104.0 mmol) was dissolved in DMF (400 mL), sodium hydride (4.2 g, 104 mmol) was added in batches at 0°C, stirred for 30 min, and then di-tert-butyl dicarbonate (23.9 g, 110.0 mmol) was added dropwise. The mixture was reacted at room temperature overnight and the reaction progress was monitored by TLC.

[0150] The reaction was stopped, quenched with water, extracted with EA, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain III-3 (yellow solid, 15.2 g, yield 53%).

[0151] LC-MS m / z(ESI)=266.11[M+1].

[0152] Step 3

[0153] Tert-butyl (5-amino-3-ethylpyridin-2-yl)carbamate III-4

[0154] tert-butyl(5-amino-3-ethylpyridin-2-yl)carbamate

[0155] Compound III-3 (15.2 g, 57.3 mmol) was dissolved in MeOH (300 mL), Pd / C (1.5 g) was added, hydrogen was introduced and the mixture was reacted at room temperature. The reaction progress was monitored by TLC.

[0156] Stop the reaction, filter and obtain the filtrate, and separate by column chromatography (DCM:MeOH=50:1) to obtain III-4 (yellow solid, 5.0 g, yield 23%).

[0157] LC-MS m / z(ESI)=238.15[M+1].

[0158] Step 4

[0159] 3-Ethylpyridine-2,5-diamine Intermediate C

[0160] 3-ethylpyridine-2,5-diamine

[0161] Compound III-4 (5 g, 21.0 mmol) was dissolved in a mixture of DCM and MeOH, and 2 mol / L hydrochloric acid ethyl acetate solution (60 ml) was added to react at room temperature. The reaction progress was monitored by TLC.

[0162] The reaction was stopped, filtered, the solid was collected and dried to obtain Intermediate C (yellow solid, 3.4 g, yield 99%).

[0163] LC-MS m / z(ESI)=138.10[M+1].

[0164] Intermediate D6-(((trifluoromethyl)sulfonyloxy)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0165] tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0166]

[0167] first step

[0168] 2-Oxopiperidine-1-carboxylic acid tert-butyl ester VI-2

[0169] tert-butyl 2-oxopiperidine-1-carboxylate

[0170] According to the method of compound II-2, compound VI-2 (reddish brown liquid, 16.7 g, yield 85%) was obtained.

[0171] LC-MS m / z(ESI)=200.12[M+1].

[0172] Step 2

[0173] tert-Butyl 6-(((Trifluoromethyl)sulfonyloxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0174] tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxyl ate

[0175] According to the method of compound intermediate B, intermediate D (reddish brown liquid, 26.2 g, yield 96%) was obtained.

[0176] LC-MS m / z(ESI)=332.07[M+1].

[0177] Intermediate E2-((6-amino-5-ethylpyridin-3-yl)amino)-2-oxoacetic acid Intermediate E2-((6-amino-5-ethylpyridin-3-yl)amino)-2-oxoacetic acid

[0178]

[0179] first step

[0180] Ethyl 2-((6-((tert-butoxycarbonyl)amino)-5-ethylpyridin-3-yl)amino)-2-oxoacetate V-1

[0181] ethyl 2-((6-((tert-butoxycarbonyl)amino)-5-ethylpyridin-3-yl)amino)-2-oxoaceta te

[0182] Compound III-4 (50.0 g, 210.0 mmol), potassium 2-ethoxy-2-oxoacetate (42 g, 270 mmol), triethylamine (53 g, 520 mmol) and DMF (300 mL) were placed in a nitrogen atmosphere, and HATU (102 g, 270 mmol) was added at 0 degrees. The mixture was stirred at room temperature for 30 min and the reaction progress was monitored by TLC.

[0183] The reaction was stopped, EA was added to dilute the reaction solution, and then washed with saturated sodium chloride aqueous solution and water. The solvent was removed by rotary evaporation to obtain V-1 (yellow solid, 75 g, yield 95%).

[0184] LC-MS m / z(ESI)=338.20[M+1].

[0185] Step 2

[0186] Ethyl 2-((6-amino-5-ethylpyridin-3-yl)amino)-2-oxoacetate V-2

[0187] ethyl 2-((6-amino-5-ethylpyridin-3-yl)amino)-2-oxoacetate

[0188] Compound V-1 (66 g, 190 mmol) was dissolved in DCM (150 mL), trifluoroacetic acid (200 mL) was added, and the mixture was stirred for 2 h. The reaction progress was monitored by LCMS.

[0189] The reaction solution was dried, a large amount of water was added, the pH value was adjusted to 7-8 with sodium bicarbonate, and then extracted with EA, and the solvent was removed by rotary evaporation to obtain V-2 (yellow solid, 40 g, yield 85%).

[0190] LC-MS m / z(ESI)=238.11[M+1].

[0191] Step 3

[0192] 2-((6-amino-5-ethylpyridin-3-yl)amino)-2-oxoacetic acid intermediate E

[0193] 2-((6-amino-5-ethylpyridin-3-yl)amino)-2-oxoacetic acid

[0194] Compound V-2 (40 g, 160 mmol) was dissolved in MeOH / THF / H 2 O (400 mL) (1:4:5), stirred at room temperature for 30 min, and the reaction progress was monitored by LCMS.

[0195] After removing the organic solvent by rotary evaporation, the aqueous solution was freeze-dried, and the solid was slurried with DCM / THF, a small amount of water was added, and the pH value was adjusted to about 5 with HCl ethyl acetate solution. The solid was filtered, collected and dried to obtain intermediate E (yellow solid, 25 g, yield 71%).

[0196] LC-MS m / z(ESI)=210.10[M+1].

[0197] Example 1

[0198] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-2-oxospiro[indole-3,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide Compound 1

[0199] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-2-oxo spiro[indoline-3,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide

[0200]

[0201] first step

[0202] 5-Bromo-1'-methylspiro[indol-3,4'-piperidin]-2-one 1b

[0203] 5-bromo-1'-methylspiro[indoline-3,4'-piperidin]-2-one

[0204] 1a (1.27 g, 6.0 mmol) was dissolved in THF (30 mL) at -75 °C. Sodium bis(trimethylsilyl)amide (30 mL, 30 mmol) was slowly added dropwise under nitrogen protection. After stirring for 30 min, enbicin (1.15 g, 6 mmol) was slowly added dropwise. After stirring for 30 min, the mixture was reacted at room temperature for 2 d. The reaction progress was monitored by TLC.

[0205] The reaction was stopped, saturated aqueous ammonium chloride solution was added, extracted with DCM, the organic phases were combined and concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol=20:1) to obtain 1b (reddish brown solid, 895 mg, yield 51%).

[0206] LC-MS m / z(ESI)=295.04[M+1].

[0207] Step 2

[0208] 1'-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indole-3,4'-piperidinyl]-2-one 1c

[0209] 1'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-pipe ridin]-2-one

[0210] 1b (450 mg, 1.5 mmol), bis(pyrazolyl)boronic acid (427 mg, 1.6 mmol), potassium acetate (300 mg, 3.0 mmol), Pd(dppf)Cl 2 (112 mg, 0.15 mmol) was dissolved in 1,4-Dioxane (50 mL) and heated to 100°C under nitrogen protection. The reaction progress was monitored by TLC.

[0211] Stop the reaction, filter and use the filtrate directly in the next reaction.

[0212] LC-MS m / z(ESI)=343.21[M+1].

[0213] Step 3

[0214] 3-Methyl-6-(1'-methyl-2-oxospiro[indole-3,4'-piperidinyl]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1d

[0215] tert-butyl 3-methyl-6-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)-3,4-di hydropyridine-1(2H)-carboxylate

[0216] Intermediate B (792 mg, 2.29 mmol), anhydrous sodium carbonate (405 mg, 3.8 mmol), Pd(dpp f)Cl 2 (112 mg, 0.15 mmol) was dissolved in the filtrate obtained in the previous step, heated to 100°C under nitrogen protection, and the reaction progress was monitored by TLC.

[0217] The reaction was stopped and 1d (brown solid, 497 mg, yield 79%) was obtained by separation using silica gel column chromatography (DCM:MeOH=30:1).

[0218] LC-MS m / z(ESI)=412.25[M+1].

[0219] Step 4

[0220] 1'-Methyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[indole-3,4'-piperidin]-2-one 1e

[0221] 1'-methyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[indoline-3,4'-piperidi n]-2-one

[0222] 1d (497 mg, 1.2 mmol) was dissolved in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the trifluoroacetic acid was evaporated by concentration under reduced pressure. Saturated aqueous sodium bicarbonate solution (50 mL) was added to the residue, and extracted with dichloromethane (20*3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:Me OH=30:1) to obtain 1e (brown solid, 275 mg, yield 73%).

[0223] LC-MS m / z(ESI)=312.20[M+1].

[0224] Step 5

[0225] 1'-Methyl-5-(5-methylpiperidin-2-yl)spiro[indole-3,4'-piperidin]-2-one 1f

[0226] 1'-methyl-5-(5-methylpiperidin-2-yl)spiro[indoline-3,4'-piperidin]-2-one

[0227] 1e (275 mg, 0.88 mmol) was dissolved in anhydrous methanol (10 mL), sodium borohydride (40.1 mg, 1.06 mmol) was added at 0°C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the methanol was evaporated by concentration under reduced pressure, water (50 mL) was added to the residue, and dichloromethane (20*3 mL) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=20:1) to obtain 1f (brown solid, 217 mg, yield 78%).

[0228] LC-MS m / z(ESI)=314.22[M+1].

[0229] Step 6

[0230] 2-(5-methyl-2-(1'-methyl-2-oxospiro[indole-3,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetic acid methyl ester 1g

[0231] methyl 2-(5-methyl-2-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)piperi din-1-yl)-2-oxoacetate

[0232] 1f (217 mg, 0.69 mmol) and triethylamine (141 mg, 1.38 mmol) were dissolved in dichloromethane (20 mL), and methyl oxalyl chloride (101.9 mg, 0.83 mmol) was added at 0°C, and the mixture was reacted at room temperature for 1 h. After the reaction was complete, saturated sodium bicarbonate water (50 mL) was added, and the mixture was extracted with dichloromethane (20*3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=5:1) to obtain 1g (yellow liquid, 240 mg, yield 86%).

[0233] LC-MS m / z(ESI)=400.22[M+1].

[0234] Step 7

[0235] 2-(5-methyl-2-(1'-methyl-2-oxospiro[indole-3,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetic acid 1h

[0236] 2-(5-methyl-2-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetic acid

[0237] Dissolve 1g (240mg, 0.6mmol) in methanol: water = 2:1 (10mL: 5mL), add lithium hydroxide (63mg, 1.5mmol) at room temperature, and react for 2h at room temperature. After the reaction is complete, concentrate under reduced pressure to obtain the lithium salt of 1h (yellow solid, 300mg, yield 86%).

[0238] LC-MS m / z(ESI)=386.20[M+1].

[0239] Step 8

[0240] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-2-oxospiro[indole-3,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide Compound 1

[0241] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-2-oxo spiro[indoline-3,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide

[0242] 1h (124 mg, 0.32 mmol), intermediate A (60 mg, 0.32), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (122.4 mg, 0.32 mmol), and triethylamine (98.5 mg, 0.96 mmol) were dissolved in N,N-dimethylacetamide (5 mL). After reacting at room temperature for 4 h, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phases were combined and concentrated under reduced pressure. The compound 1 (yellow solid, 50 mg, yield 30%) was separated by column chromatography (dichloromethane: methanol = 10:1).

[0243] 1 H NMR (400MHz, DMSO-d6) δ10.58–10.44(m,2H),8.46-8.41(m,1H),8.28-8.24(m,1H),7.40-7.23(m,2H),6.05-5.93(m,2H),5.07–4.65(m,5H),3. 38-3.35(m,1H),3.27–3.22(m,1H),2.59–2.50(m,4H),2.40–1.94(m,4H ),1.87(s,3H),1.83-1.59(m,4H),1.38-1.30(m,1H),1.06-1.00(m,3H).

[0244] LC-MS m / z(ESI)=519.26[M+1].

[0245] Example 2

[0246] N-(4-amino-1,3-dihydrofurano[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)-2-oxoacetamide Compound 2

[0247] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-3H-sp iro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)-2-oxoacetamide

[0248]

[0249]

[0250] first step

[0251] 4-(4-Chloro-2-fluorobenzyl)-1-methylpiperidin-4-ol 2b

[0252] 4-(4-chloro-2-fluorobenzyl)-1-methylpiperidin-4-ol

[0253] Magnesium powder (1.2 g, 50.0 mmol) and a particle of iodine were dissolved in ether (20 mL). Under nitrogen protection, 2a (2.6 g, 12.0 mmol) in ether (30 mL, 30 mmol) was slowly added. When the yellow color of the reaction solution disappeared, 2a was continuously added dropwise. After reacting at 40 °C for 30 min, the temperature was lowered to 0 °C, N-methyl-4-piperidone (1.1 g, 10.0 mmol) was added dropwise, and the mixture was gradually allowed to react at room temperature. The reaction progress was monitored by TLC.

[0254] The reaction was stopped, saturated aqueous ammonium chloride solution was added, extracted with EA, the organic phases were combined and concentrated under reduced pressure, and separated by column chromatography (DCM:MeOH=10:1) to obtain 2b (yellow liquid, 660 mg, yield 51%).

[0255] LC-MS m / z(ESI)=258.10[M+1].

[0256] Step 2

[0257] 6-Chloro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]2c

[0258] 6-chloro-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]

[0259] 2b (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, stirred and reacted for 5 min, and DMF (3.7 mL) was added to continue the reaction. The reaction progress was monitored by TLC.

[0260] The reaction was stopped, water was added, extracted with EA, washed once with water, the organic phase was separated, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and then separated by column chromatography (DCM: MeOH = 30:1) to obtain 2c (yellow liquid, 406 mg, yield 72%).

[0261] LC-MS m / z(ESI)=238.09[M+1].

[0262] Step 3

[0263] 1'-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]2d

[0264] 1'-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[0265] 2d (356.0 mg, 1.5 mmol), bipyraclostrobin (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 the mixture was reacted at 130 °C in a microwave oven for 2.5 h. The reaction progress was monitored by TLC.

[0266] Stop the reaction, filter and obtain the filtrate with 2d, and directly proceed to the next step of reaction.

[0267] LC-MS m / z(ESI)=330.22[M+1].

[0268] Step 4

[0269] 3-Methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2e

[0270] tert-butyl 3-methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0271] According to the method of 1d, 2e was obtained (black solid, 177 mg, yield 29%).

[0272] LC-MS m / z(ESI)=399.26[M+1].

[0273] Step 5

[0274] 1'-Methyl-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]2f

[0275] 1'-methyl-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[0276] According to the method of 1e, 2f (brown liquid, 167 mg, yield 99%) was obtained.

[0277] LC-MS m / z(ESI)=299.20[M+1].

[0278] Step 6

[0279] 1'-Methyl-6-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]2g

[0280] 1'-methyl-6-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[0281] According to the method of 1f, 2g (brown liquid, 82 mg, yield 48%) was obtained.

[0282] LC-MS m / z(ESI)=299.20[M+1].

[0283] Step 7

[0284] 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)-2-oxoacetate 2h

[0285] methyl 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piper idin-1-yl)-2-oxoacetate

[0286] According to the method of 1g, 2h was obtained (yellow liquid, 33 mg, yield 31%).

[0287] LC-MS m / z(ESI)=387.22[M+1].

[0288] Step 8

[0289] 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)-2-oxoacetic acid 2i

[0290] 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)-2-oxoacetic acid

[0291] According to the method of 1h, 2i (yellow solid, 46 mg, yield 99%) was obtained.

[0292] LC-MS m / z(ESI)=373.20[M+1].

[0293] Step 9

[0294] N-(4-amino-1,3-dihydrofurano[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)-2-oxoacetamide Compound 2

[0295] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-3H-sp iro[benzofuran-2,4'-piperidin]-6-yl)piperidin-1-yl)-2-oxoacetamide

[0296] According to the method of compound 1, compound 2 (white solid, 30 mg, yield 48%) was obtained.

[0297] 1H NMR (400MHz, DMSO-d6) δ10.57-10.38(m,1H),7.90–7.77(m,1H),7.24-7.17(m,1H),6.84–6.61(m,2H),6.04-5.94(m,2H), 5.07–4.65(m,5H),3.29–3.21(m,2H),3.04(s,2H),3.00-2.83(m,3H),2.58(s,2H),2.21–1.62(m,9H),1.05-0.97(m,3H).

[0298] LC-MS m / z(ESI)=506.27[M+1].

[0299] Example 3

[0300] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetamide Compound 3

[0301] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetamide

[0302]

[0303] first step

[0304] 6-Bromo-2-(2-(tert-Butyloxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid methyl ester 3b

[0305] methyl 6-bromo-2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-indazole-3-carbox ylate

[0306] 3a (5.0 g, 19.6 mmol), N-(tert-butyloxycarbonyl)ethanolamine (3.9 g, 24.4 mmol), and triphenylphosphine (7.7 g, 29.3 mmol) were dissolved in THF (50 mL). DIAD (5.9 g, 29.3 mmol) was slowly added dropwise under nitrogen protection. The mixture was reacted at room temperature and the reaction progress was monitored by TLC.

[0307] The reaction was stopped, aqueous solution was added, and EA was extracted. The organic phases were combined and concentrated under reduced pressure. 3b (white solid, 12.5 g, yield 99%) was separated by column chromatography (EA:PE=10:1).

[0308] LC-MS m / z(ESI)=398.06[M+1].

[0309] Step 2

[0310] 2-(2-Aminoethyl)-6-bromo-2H-indazole-3-carboxylic acid methyl ester 3c

[0311] methyl 2-(2-aminoethyl)-6-bromo-2H-indazole-3-carboxylate

[0312] 3b (610.0 mg, 2.3 mmol) was dissolved in 4 M 1,4-dioxane hydrochloric acid solution (50 mL), and the reaction was stirred at room temperature. The reaction progress was monitored by TLC.

[0313] The reaction was stopped, the solid was collected by suction filtration and dried to obtain 3c (red solid, 6.2 g, yield 91%).

[0314] LC-MS m / z(ESI)=298.01[M+1].

[0315] Step 3

[0316] 8-Bromo-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 3d

[0317] 8-bromo-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0318] Compound 3c (6.2 g, 18.8 mmol) was dissolved in methanol (50 mL) and Cs 2 CO 3 (18.4 g, 56.4 mmol), react at room temperature, and monitor the reaction progress by TLC.

[0319] The reaction was stopped, filtered, the solid was collected and dried to obtain 3d (white solid, 4.3 g, yield 87%).

[0320] LC-MS m / z(ESI)=265.99[M+1].

[0321] Step 4

[0322] 8-Bromo-2-methyl-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 3e

[0323] 8-bromo-2-methyl-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0324] 3d (500.0 mg, 1.8 mmol) was dissolved in DMF (15 mL), and NaH (113.3 mg, 2.8 mmol) was added under stirring in an ice bath. After stirring for 15 min, CH 3 I (400.0 mg, 2.8 mmol), and reacted at room temperature. The reaction progress was monitored by TLC.

[0325] The reaction was stopped, water was added, and the mixture was extracted with EA. The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=50:1) to obtain 3e (white solid, 530 mg, yield 99%).

[0326] LC-MS m / z(ESI)=280.00[M+1].

[0327] Step 5

[0328] 2-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 3f

[0329] 2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0330] According to the method of 1c, the filtrate with 3f was directly used for the next reaction.

[0331] LC-MS m / z(ESI)=328.18[M+1].

[0332] Step 6

[0333] 3-Methyl-6-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 3g

[0334] tert-butyl 3-methyl-6-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0335] According to the method of 1d, 3g (yellow solid, 890 mg, yield 99%) was obtained.

[0336] LC-MS m / z(ESI)=397.22[M+1].

[0337] Step 7

[0338] 2-Methyl-8-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 3h

[0339] 2-methyl-8-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0340] According to the method of 1e, 3h was obtained (yellow liquid, 400 mg, yield 61%).

[0341] LC-MS m / z(ESI)=297.16[M+1].

[0342] Step 8

[0343] 2-Methyl-8-(5-methylpiperidin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 3i

[0344] 2-methyl-8-(5-methylpiperidin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0345] According to the method of 1f, 3i was obtained (yellow liquid, 140 mg, yield 35%).

[0346] LC-MS m / z(ESI)=299.18[M+1].

[0347] Step 9

[0348] 2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetate 3j

[0349] methyl 2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetate

[0350] According to the method of 1g, 3j was obtained (yellow liquid, 44 mg, yield 24%).

[0351] LC-MS m / z(ESI)=385.18[M+1].

[0352] Step 10

[0353] 2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetic acid 3k

[0354] 2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)pi peridin-1-yl)-2-oxoacetic acid

[0355] According to the method of 1h, 3k (yellow solid, 55 mg, yield 99%) was obtained.

[0356] LC-MS m / z(ESI)=371.16[M+1].

[0357] Step 11

[0358] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetamide Compound 3

[0359] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetamide

[0360] According to the method of compound 1, compound 3 (yellow solid, 40 mg, yield 55%) was obtained.

[0361] 1 H NMR (400MHz, DMSO-d6) δ10.75–10.57(m,1H),8.03–7.88(m,2H),7.71-7.63(m,1H),7.34-7.l6(m,1H),6.60(s,2H),4.99–4.81(m,3H),4.72– 4.67(m,2H),3.92-3.85(m,2H),3.46-3.39(m,3H),3.29-3.25(m,1H), 3.07(s,3H),2.24–1.61(m,4H),1.45-1.34(m,1H),1.08-1.00(m,3H).

[0362] LC-MS m / z(ESI)=504.23[M+1].

[0363] Example 4

[0364] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetamide Compound 4

[0365] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetami de

[0366]

[0367] first step

[0368] (R)-8-Nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 4b

[0369] tert-butyl(R)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0370] 4a (10 g, 46.2 mmol) and 3,4-difluoronitrobenzene (8.8 g, 55.5 mmol) were dissolved in DMSO (150 mL), reacted at room temperature for 16 h, and then heated to 80 ° C to continue the reaction for 4 h. After the reaction was complete, ethyl acetate (600 mL) was added for dilution, and saturated brine (150*4 mL) was used for washing. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 4b (yellow solid, 7.0 g, yield 46%).

[0371] LC-MS m / z(ESI)=336.19[M+1].

[0372] Step 2

[0373] (R)-8-Nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine 4c

[0374] (R)-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine

[0375] 4b (7 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), and TFA (20 mL) was added at room temperature. The reaction was continued for 1 h. After the reaction was complete, the solvent was removed by rotary evaporation, DCM (400 mL) was added, and the pH was adjusted to 8-9 with 1 M sodium carbonate, and then extracted. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 4c (red solid, 4 g, yield 81%).

[0376] LC-MS m / z(ESI)=236.20[M+1].

[0377] Step 3

[0378] (R)-3-Methyl-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine4d

[0379] (R)-3-methyl-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine

[0380] Compound 4c (4 g, 17.0 mmol) and aqueous formaldehyde solution (20 mL, 37%) were dissolved in methanol (100 mL). 2 The mixture was ventilated and stirred at room temperature for 30 min, and then sodium cyanoborohydride (2.6 g, 42.5 mmol) was added and reacted at room temperature for 16 h. After the reaction was complete, the mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 4d (yellow solid, 3 g, yield 70%).

[0381] LC-MS m / z(ESI)=250.10[M+1].

[0382] Step 4

[0383] (R)-3-Methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-amine 4e

[0384] (R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-amine

[0385] 4d (3 g, 12.0 mmol) was dissolved in methanol (40 mL), and Pd / C (300 mg, 10%) was added to replace the hydrogen. The reaction was carried out at room temperature for 6 h. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to obtain 4e (yellow solid, 2.2 g, yield 84%).

[0386] LC-MS m / z(ESI)=220.10[M+1].

[0387] Step 5

[0388] (R)-3-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine 4f

[0389] (R)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,4a,5-hexah ydrobenzo[b]pyrazino[1,2-d][1,4]oxazine

[0390] 4e (2.2 g, 10.0 mmol) was dissolved in methanol (30 mL), and HCl (10 mL, 3 M) and sodium nitrite (693 mg, 10.0 mmol) aqueous solution (5 mL) were added at 0 °C. The reaction was continued for 30 min, and then bis(pinacolato)diboron (7.6 g, 30.0 mmol) was added. After the reaction was continued for 2 h, NaHCO was added to the reaction solution. 3 The aqueous solution was used to quench the reaction and extracted with DCM (50 mL*2). The organic phase was washed with anhydrous Na 2 SO 4 The residue was dried and concentrated, and then purified by column chromatography (DCM:MeOH=20:1) to give 4f (yellow solid, 1 g, yield 30%).

[0391] LC-MS m / z(ESI)=331.10[M+1].

[0392] Step 6

[0393] 3-Methyl-6-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 4g

[0394] tert-butyl 3-methyl-6-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0395] According to the method of 1d, 4f was used to obtain 4g (yellow solid, 600 mg, yield 50%)

[0396] LC-MS m / z(ESI)=400.20[M+1].

[0397] Step 7

[0398] (4aR)-3-methyl-8-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine 4h

[0399] (4aR)-3-methyl-8-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-1,2,3,4,4a,5-hexahy drobenzo[b]pyrazino[1,2-d][1,4]oxazine

[0400] According to the method of 1e, 4h was obtained using 4g (yellow solid, 350 mg, yield 77%)

[0401] LC-MS m / z(ESI)=300.20[M+1].

[0402] Step 8

[0403] (4aR)-3-Methyl-8-(5-methylpiperidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine 4i

[0404] (4aR)-3-methyl-8-(5-methylpiperidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyraz ino[1,2-d][1,4]oxazine

[0405] According to the method of 1f, 4h was used to obtain 4i (yellow solid, 300 mg, yield 85%)

[0406] LC-MS m / z(ESI)=302.20[M+1].

[0407] Step 9

[0408] 2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetate 4j

[0409] methyl 2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetate

[0410] According to the method of 1g, 4j was obtained using 4i (yellow liquid, 160 mg, yield 41%)

[0411] LC-MS m / z(ESI)=388.22[M+1].

[0412] Step 10

[0413] 2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetic acid 4k

[0414] 2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetic acid

[0415] According to the method of 1h, 4k (yellow solid, 152 mg, yield 99%) was obtained using 4j.

[0416] LC-MS m / z(ESI)=374.05[M+1].

[0417] Step 11

[0418] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetamide Compound 4

[0419] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoac etamide

[0420] According to the method of compound 1, using 4k, compound 4 (yellow solid, 70 mg, yield 32%) was obtained

[0421] 1H NMR(400MHz,DMSO-d6)δ10.61–10.28(m,1H),7.96–7.65(m,1H),6.94–6.53(m,3H),6.1 2–5.86(m,2H),5.00–4.66(m,5H),4.26–4.17(m,1H),3.93–3.82(m,1H),3.74–3.64(m,1 H),3.32–3.29(m,2H),3.26–3.15(m,1H),3.08–3.00(m,1H),2.92–2.78(m,2H),2.70–2 .56(m,1H),2.28–2.19(m,3H),2.15–1.83(m,4H),1.77–1.64(m,2H),1.05–0.95(m,3H).

[0422] LC-MS m / z(ESI)=507.05[M+1].

[0423] Example 5

[0424] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indol]-5'-yl)piperidin-1-yl)-2-oxoacetamide compound 5

[0425] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2'-oxospiro[cyclopro pane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[0426]

[0427] first step

[0428] 5'-Bromospiro[cyclopropane-1,3'-indolin]-2'-one 5b

[0429] 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one

[0430] 5a (5 g, 23.8 mmol) was dissolved in THF (150 mL), and n-butyl lithium (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 heated to room temperature and stirred for 16 h. After the reaction was complete, saturated ammonium chloride solution was added to quench, and ethyl acetate (300 mL) was added for extraction, and saturated brine (50*4 mL) was used for washing. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 5b (yellow solid, 1.1 g, yield 19%).

[0431] LC-MS m / z(ESI)=238.00[M+1].

[0432] Step 2

[0433] 5'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 5c

[0434] 5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0435] According to the method of 1c, 5b was used to obtain 5c (yellow solid, 1g,)

[0436] LC-MS m / z(ESI)=300.20[M+1].

[0437] Step 3

[0438] 3-Methyl-6-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 5d

[0439] tert-butyl 3-methyl-6-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3,4-dihydro pyridine-1(2H)-carboxylate

[0440] According to the method of 1d, 5c was used to obtain 5d (yellow solid, 600 mg, yield 36%)

[0441] LC-MS m / z(ESI)=355.20[M+1].

[0442] Step 4

[0443] 5'-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 5e

[0444] 5'-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0445] According to the method of 1e, 5e was obtained using 5d (yellow liquid, 300 mg, yield 69%)

[0446] LC-MS m / z(ESI)=255.20[M+1].

[0447] Step 5

[0448] 5'-(5-Methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 5f

[0449] 5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0450] According to the method of 1f, 5e was used to obtain 5f (yellow solid, 250 mg, yield 82%)

[0451] LC-MS m / z(ESI)=257.18[M+1].

[0452] Step 6

[0453] 2-(5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetic acid methyl ester 5g

[0454] methyl 2-(5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetate

[0455] According to the method of 1g, 5f was used to obtain 5g (yellow solid, 180 mg, yield 54%)

[0456] LC-MS m / z(ESI)=343.20[M+1].

[0457] Step 7

[0458] 2-(5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetic acid 5h

[0459] 2-(5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-ox oacetic acid

[0460] According to the method of 1h, 5g was used to obtain 5h (yellow solid, 170 mg, yield 99%)

[0461] LC-MS m / z(ESI)=329.50[M+1].

[0462] Step 8

[0463] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indol]-5'-yl)piperidin-1-yl)-2-oxoacetamide compound 5

[0464] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2'-oxospiro[cycl opropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[0465] According to the method of compound 1, compound 5 (yellow solid, 30 mg, yield 23%) was obtained after 5 h.

[0466] 1 H NMR (400MHz, DMSO-d6) δ10.61–10.37(m,2H),7.98–7.77(m,1H),7.14–6.99(m,1H),6.97–6.85(m,2H),6.29– 6.04(m,2H),5.05–4.55(m,6H),3.28–3.20(m,1H),2.25–1.78(m,4H),1.70–1.42(m,5H),1.05–0.98(m,3H).

[0467] LC-MS m / z(ESI)=462.30[M+1].

[0468] Example 6

[0469] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indol]-5'-yl)piperidin-1-yl)-2-oxoacetamide compound 6

[0470] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[0471]

[0472] first step

[0473] 2-(5-methyl-2-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetic acid 6a

[0474] 2-(5-methyl-2-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetic acid

[0475] 5g (90mg, 0.26mmol) was dissolved in DMF (5mL), and sodium hydride (10mg, 0.40mmol) was added at 0°C. After stirring for 1h, iodomethane (56mg, 0.40mmol) was added, and the mixture was heated to room temperature and stirred for 2h. After the reaction was complete, saturated ammonium chloride solution was added to quench, and ethyl acetate (100mL) was added for extraction, and saturated brine (50*3mL) was used for washing. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6a (yellow solid, 70mg, yield 77%).

[0476] LC-MS m / z(ESI)=343.20[M+1].

[0477] Step 2

[0478] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indol]-5'-yl)piperidin-1-yl)-2-oxoacetamide compound 6

[0479] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-2'-oxo spiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[0480] According to the method of compound 1, compound 6 (white solid, 60 mg, yield 62%) was obtained using 6a.

[0481] 1 H NMR (400MHz, DMSO-d6) δ10.57–10.40(m,1H),7.95–7.70(m,1H),7.28–6.91(m,3H),6.15–5.96(m,2H),5.06– 4.57(m,5H),3.33–3.24(m,2H),3.23–3.16(m,3H),2.31–1.81(m,3H),1.79–1.40(m,6H),1.06–0.96(m,3H).

[0482] LC-MS m / z(ESI)=476.20[M+1].

[0483] Example 7

[0484] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1-oxo-1,2,3,4-tetrahydropyrazin[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide Compound 7

[0485] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1-oxo-1,2,3,4-te trahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide

[0486]

[0487] first step

[0488] 5-Bromo-2-(2-(tert-Butyloxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid methyl ester 7b

[0489] Methyl 5-bromo-2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-indazole-3-carbox ylate

[0490] Dissolve 1a (2.0 g, 7.8 mmol), N-(tert-butyloxycarbonyl)ethanolamine (1.6 g, 9.8 mmol), and triphenylphosphine (3.0 g, 11.2 mmol) in tetrahydrofuran (20 mL), add diisopropyl azodicarboxylate (2.4 g, 11.4 mmol) dropwise under nitrogen protection, and react at room temperature for 5 h. After the reaction is complete, add saturated aqueous ammonium chloride solution (50 mL), extract with ethyl acetate (20 mL*3), dry with anhydrous sodium sulfate, combine the organic phases, concentrate under reduced pressure, and separate 1b by column chromatography (petroleum ether: ethyl acetate = 6:1). (white solid, 2.4 g, yield 78%).

[0491] LC-MS m / z(ESI)=398.06[M+1].

[0492] Step 2

[0493] 2-(2-Aminoethyl)-5-bromo-2H-indazole-3-carboxylic acid methyl ester 7c

[0494] methyl 2-(2-aminoethyl)-5-bromo-2H-indazole-3-carboxylate

[0495] 7b (2.3 g, 5.8 mmol) was dissolved in hydrochloric acid-1,4-dioxane solution (4 M, 20 mL), reacted at room temperature for 2 h, and the solid was collected by filtration and dried to obtain 7c (white solid, 1.5 g, yield 88%).

[0496] LC-MS m / z(ESI)=298.01[M+1].

[0497] Step 3

[0498] 9-Bromo-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 7d

[0499] 9-bromo-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0500] Dissolve 7c (1.5 g, 5.1 mmol) and cesium carbonate (5.0 g, 15.4 mmol) in methanol (20 mL) and react at room temperature for 3 h. After the reaction is complete, filter and collect the solid and dry to obtain 7d (white solid, 1.2 g, yield 91%).

[0501] LC-MS m / z(ESI)=265.99[M+1].

[0502] Step 4

[0503] 9-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 7e

[0504] 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[1,2-b]indaz ol-1(2H)-one

[0505] Referring to the synthesis method of 1c, 7e was obtained using 7d (yellow solid, 0.9 g, yield 83%).

[0506] LC-MS m / z(ESI)=314.16[M+1].

[0507] Step 5

[0508] tert-Butyl 3-methyl-6-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)-3,4-dihydropyridine-1(2H)-carboxylate 7f

[0509] tert-butyl 3-methyl-6-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0510] Referring to the synthetic method of 1d, 7f was obtained using 7e and intermediate B (yellow solid, 720 mg, yield 65%).

[0511] LC-MS m / z(ESI)=383.20[M+1].

[0512] Step 6

[0513] 9-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 7g

[0514] 9-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0515] Referring to the synthetic method of 1e, 7f was used to obtain 7g (yellow solid, 520 mg, yield 78%).

[0516] LC-MS m / z(ESI)=283.15[M+1].

[0517] Step 7

[0518] 9-(5-Methylpiperidin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 7h

[0519] 9-(5-methylpiperidin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0520] Referring to the synthesis method of 1f, 7g was used to obtain 7h (yellow solid, 460 mg, yield 81%).

[0521] LC-MS m / z(ESI)=285.16[M+1].

[0522] Step 8

[0523] 2-(5-methyl-2-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetate 7i

[0524] methyl 2-(5-methyl-2-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)pipe ridin-1-yl)-2-oxoacetate

[0525] Referring to the synthetic method of 1g, 7h was used to obtain 7i (yellow solid, 510 mg, yield 83%).

[0526] LC-MS m / z(ESI)=371.16[M+1].

[0527] Step 9

[0528] 2-(5-methyl-2-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetic acid 7j

[0529] 2-(5-methyl-2-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetic acid

[0530] Referring to the synthesis method of 1h, 7i was used to obtain the lithium salt of 7j (yellow solid, 630 mg, yield 88%).

[0531] LC-MS m / z(ESI)=357.15[M+1].

[0532] Step 10

[0533] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1-oxo-1,2,3,4-tetrahydropyrazin[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide Compound 7

[0534] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1-oxo-1,2,3,4-te trahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide

[0535] Referring to the synthetic method of 1, compound 7 was obtained using 7j and intermediate A (yellow solid, 45 mg, yield 73%).

[0536] 1 H NMR (400MHz, DMSO-d6) δ10.54(d,1H),8.32(s,1H),8.00–7.73(m,3H),7.45–7.18(m,1H),6.13(s,2H),4. 90–4.61(m,5H),3.74-3.71(m,2H),3.47-3.39(m,2H),3.29-3.22(m,2H),2.27–1.70(m,5H),1.05(d,3H).

[0537] LC-MS m / z(ESI)=490.21[M+1].

[0538] Example 8

[0539] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazin[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide Compound 8

[0540] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide

[0541]

[0542]

[0543] first step

[0544] 9-Bromo-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 8a

[0545] 9-bromo-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0546] 7d (1.0 g, 3.8 mmol) and sodium hydride (228 mg, 5.7 mmol) were dissolved in tetrahydrofuran (20 mL). After activation for 30 min, iodomethane (804 mg, 5.7 mmol) was added and the mixture was reacted at room temperature for 5 h. After the reaction was complete, water (50 mL) was added and the mixture was extracted with ethyl acetate (20 mL*3). The mixture was dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated under reduced pressure to obtain 8a (white solid, 848 mg, yield 80%).

[0547] LC-MS m / z(ESI)=280.00[M+1].

[0548] Step 2

[0549] 2-Methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 8b

[0550] 2-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0551] Referring to the synthetic method of 1c, 8a was used to obtain 8b (yellow solid, 630 mg, yield 77%).

[0552] LC-MS m / z(ESI)=328.18[M+1].

[0553] Step 3

[0554] 3-Methyl-6-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 8c

[0555] tert-butyl 3-methyl-6-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0556] Referring to the synthetic method of 1d, 8c was obtained using 8b and intermediate B (yellow solid, 650 mg, yield 79%).

[0557] LC-MS m / z(ESI)=397.22[M+1].

[0558] Step 4

[0559] 2-Methyl-9-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 8d

[0560] 2-methyl-9-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0561] Referring to the synthetic method of 1e, 8d was obtained using 8c (yellow solid, 550 mg, yield 83%).

[0562] LC-MS m / z(ESI)=297.16[M+1].

[0563] Step 5

[0564] 2-Methyl-9-(5-methylpiperidin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one 8e

[0565] 2-methyl-9-(5-methylpiperidin-2-yl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one

[0566] Referring to the synthetic method of 1f, 8e was obtained using 8d (yellow solid, 530 mg, yield 86%).

[0567] LC-MS m / z(ESI)=299.18[M+1].

[0568] Step 6

[0569] 2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetate 8f

[0570] methyl 2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetate

[0571] Referring to the synthetic method of 1g, 8f was obtained using 8e (yellow solid, 570 mg, yield 79%).

[0572] LC-MS m / z(ESI)=385.18[M+1].

[0573] Step 7

[0574] 2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazine[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetic acid 8g

[0575] 2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)pi peridin-1-yl)-2-oxoacetic acid

[0576] Referring to the synthesis method of 1h, 8f was used to obtain 8 g of lithium salt (yellow solid, 640 mg, yield 89%).

[0577] LC-MS m / z(ESI)=371.16[M+1].

[0578] Step 8

[0579] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazin[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide Compound 8

[0580] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide

[0581] Referring to the synthesis method of 1, 8 g and intermediate A were used to obtain compound 8 (yellow solid, 56 mg, yield 76%).

[0582] 1 H NMR(400MHz,DMSO-d6)δ10.54(d,1H),7.98–7.74(m,3H),7.42-7.24(m,1H),6.16(s,2H),4.89–4.66(m,5 H),3.90-3.87(m,2H),3.46-3.41(m,2H),3.27-3.23(m,2H),3.07(s,3H),2.36–1.70(m,5H),1.05(d,3H).

[0583] LC-MS m / z(ESI)=504.23[M+1].

[0584] Example 9

[0585] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide Compound 9

[0586] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide

[0587]

[0588]

[0589] first step

[0590] 9-Bromo-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 9a

[0591] 9-bromo-1,2,3,4-tetrahydropyrazino[1,2-b]indazole

[0592] 7d (1.0 g, 3.8 mmol) and borane tetrahydrofuran complex (1.6 g, 19.0 mmol) were dissolved in tetrahydrofuran (20 mL) and reacted at 70°C for 5 h. After the reaction was complete, water (50 mL) was added, and ethyl acetate (20 mL*3) was extracted, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated under reduced pressure to obtain 9a (white solid, 687 mg, yield 72%).

[0593] LC-MS m / z(ESI)=252.01[M+1].

[0594] Step 2

[0595] 9-Bromo-2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 9b

[0596] 9-bromo-2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazole

[0597] 9a (251 mg, 1.0 mmol), formaldehyde aqueous solution (40%, 113 mg, 1.5 mmol), sodium cyanoborohydride (82 mg, 1.3 mmol) were dissolved in methanol (10 mL) and reacted at room temperature for 8 h. After concentration under reduced pressure, water (30 mL) was added, and ethyl acetate (10 mL*3) was extracted, dried over anhydrous sodium sulfate, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 9b (white solid, 220 mg, yield 83%).

[0598] LC-MS m / z(ESI)=266.02[M+1].

[0599] Step 3

[0600] 2-Methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 9c

[0601] 2-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydropyra zino[1,2-b]indazole

[0602] Referring to the synthesis method of 1c, 9b was used to obtain 9c (yellow solid, 250 mg, yield 79%).

[0603] LC-MS m / z(ESI)=314.20[M+1].

[0604] Step 4

[0605] tert-Butyl 3-methyl-6-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)-3,4-dihydropyridine-1(2H)-carboxylate 9d

[0606] tert-butyl 3-methyl-6-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0607] Referring to the synthesis method of 1d, 9c and intermediate B were used to obtain 9d (yellow solid, 310 mg, yield 84%).

[0608] LC-MS m / z(ESI)=383.24[M+1].

[0609] Step 5

[0610] 2-Methyl-9-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 9e

[0611] 2-methyl-9-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole

[0612] Referring to the synthesis method of 1e, 9d was used to obtain 9e (yellow solid, 260 mg, yield 79%).

[0613] LC-MS m / z(ESI)=283.18[M+1].

[0614] Step 6

[0615] 2-Methyl-9-(5-methylpiperidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 9f

[0616] 2-methyl-9-(5-methylpiperidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole

[0617] Referring to the synthesis method of 1f, 9e was used to obtain 9f (yellow solid, 245 mg, yield 85%).

[0618] LC-MS m / z(ESI)=285.20[M+1].

[0619] Step 7

[0620] 2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetate 9g

[0621] methyl 2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetate

[0622] Referring to the synthesis method of 1g, 9f was used to obtain 9g (yellow solid, 311 mg, yield 84%).

[0623] LC-MS m / z(ESI)=371.20[M+1].

[0624] Step 8

[0625] 2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetic acid 9h

[0626] 2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetic acid

[0627] Referring to the synthesis method of 1h, 9g was used to obtain the lithium salt of compound 9h (yellow solid, 360 mg, yield 84%).

[0628] LC-MS m / z(ESI)=357.19[M+1].

[0629] Step 9

[0630] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide Compound 9

[0631] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide

[0632] Referring to the synthesis method of compound 1, compound 9 was obtained using 9h and intermediate A (yellow solid, 42 mg, yield 73%).

[0633] 1 H NMR(400MHz,DMSO-d6)δ10.48(d,1H),7.88-7.76(m,1H),7.64-7.53(m,2H),7.28-7.11(m,1H),6.06(s,2H),5.13–4.5 9(m,5H),4.42(d,2H),4.07-4.01(m,2H),3.27-3.23(m,2H),3.06(s,2H),2.54(s,3H),2.33–1.76(m,5H),1.04(d,3H).

[0634] LC-MS m / z(ESI)=490.25[M+1].

[0635] Example 10

[0636] N-(4-amino-1,3-dihydrofurano[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide Compound 10

[0637] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-3H-sp iro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide

[0638]

[0639] first step

[0640] 3H-Spiro[benzofuran-2,4'-piperidine]10b

[0641] 3H-spiro[benzofuran-2,4'-piperidine]

[0642] 10a (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.

[0643] The reaction was stopped, the solvent was removed by rotary evaporation, and 10b (white solid, 1.2 g, yield 89%) was obtained by column chromatography.

[0644] LC-MS m / z(ESI)=268.13[M+1].

[0645] Step 2

[0646] 5-Bromo-3H-spiro[benzofuran-2,4'-piperidine]10c

[0647] 5-bromo-3H-spiro[benzofuran-2,4'-piperidine]

[0648] 10b (1.2 g, 5.6 mmol) and formaldehyde (543.7 mg, 6.7 mmol) were dissolved in MeOH (20 mL). The reaction was stirred for 30 min and then NaBH 3 CN (880 mg, 14 mmol) was added, and the reaction was continued at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by rotary evaporation, and 10c (yellow oily liquid, 1.3 g, yield 82%) was obtained by column chromatography.

[0649] LC-MS m / z(ESI)=282.23[M+1].

[0650] Step 3

[0651] 1'-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]10d

[0652] 1'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[0653] According to the method of 1c, 10d was obtained, the reaction was stopped, filtered, and the filtrate was directly used in the next reaction.

[0654] LC-MS m / z(ESI)=330.31[M+1].

[0655] Step 4

[0656] 3-Methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 10e

[0657] tert-butyl-3-methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0658] According to the method of 1d, 10e was obtained (dark brown liquid, 1.2 g, yield 66.7%).

[0659] LC-MS m / z(ESI)=399.20[M+1].

[0660] Step 5

[0661] 1'-Methyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]10f

[0662] 1'-methyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[0663] According to the method for compound 1e, compound 10f (brown oily liquid, 400 mg, yield 30%) was obtained.

[0664] LC-MS m / z(ESI)=299.20[M+1].

[0665] Step 6

[0666] 1'-Methyl-5-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine] 10g

[0667] 1'-methyl-5-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[0668] According to the method of compound 1f, compound 10g (yellow liquid, 33 mg, yield 31%) was obtained.

[0669] LC-MS m / z(ESI)=301.22[M+1].

[0670] Step 7

[0671] 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetate 10h

[0672] Methyl-2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piper idin-1-yl)-2-oxoacetate

[0673] According to the method of 1g, 10h (yellow solid, 46 mg, yield 99%) was obtained.

[0674] LC-MS m / z(ESI)=387.20[M+1].

[0675] Step 8

[0676] 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetic acid 10i

[0677] 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetic acid

[0678] According to the method of 1h, 10i was obtained (white solid, 180 mg, yield 93%).

[0679] LC-MS m / z(ESI)=373.27[M+1].

[0680] Step 9

[0681] N-(4-amino-1,3-dihydrofurano[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide Compound 10

[0682] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(1'-methyl-3H-sp iro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide

[0683] According to the method for synthesizing compound 1, compound 10 (white solid, 30 mg, yield 13.8%) was obtained.

[0684] 1 H NMR (400MHz, DMSO) δ10.54–10.33(m,1H),7.94–7.73(m,1H),7.42–7.16(m,1H),7.14–6.98(m,1H),6.75(t,1H),5.99(d,2H),5. 04–4.62(m,5H),3.04(d,2H),2.93–2.73(m,3H),2.15(dd,1H),1.96–1.81(m,5H),1.77–1.67(m,1H),1.30(dt,8H),1.02(d,3H).

[0685] LC-MS m / z(ESI)=506.21[M+1].

[0686] Embodiment 11

[0687] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indol]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 11

[0688] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2'-oxospiro[cyclopro pane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[0689]

[0690] first step

[0691] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 11

[0692] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[0693] According to the method of compound 1, using 5h (100 mg, 0.3 mmol), compound 11 (white solid, 50 mg, yield 37%) was obtained.

[0694] 1 H NMR (400MHz, DMSO) δ10.60–10.49(m,2H),8.05(t,1H),7.57–7.38(m,1H),7.10(d d,1H),6.96–6.85(m,2H),5.80–5.61(m,2H),5.59–5.00(m,1H),3.71(dd,1H),3. 27–2.71(m,1H),2.39(dq,2H),2.20(t,1H),1.93–1.79(m,1H),1.77–1.63(m,1H) ,1.61–1.53(m,2H),1.46(dd,2H),1.24(dd,2H),1.16–1.06(m,3H),1.01(d,3H).

[0695] LC-MS m / z(ESI)=448.20[M+1].

[0696] Example 12

[0697] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)-2-oxoacetamide Compound 12

[0698] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide

[0699]

[0700] first step

[0701] 1-(4-Methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 12b

[0702] 1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0703] 12a (5.0 g, 34.0 mmol) was dissolved in N,N-dimethylacetamide (60 mL), sodium hydride (1.8 g, 44.2 mmol) was added at 0°C, and 4-methoxybenzyl chloride (5.9 g, 37.4 mmol) was added after reacting at the same temperature for 1 h. After the addition, the mixture was heated to room temperature and reacted for 2 h. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with ethyl acetate (30 mL*3), dried over anhydrous sodium sulfate, and the organic phases were combined, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain 12b (white solid, 8.0 g, yield 88%).

[0704] LC-MS m / z(ESI)=268.13[M+1].

[0705] Step 2

[0706] 3-(2-Chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 12c

[0707] 3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0708] 12b (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 the mixture was reacted at the same temperature for 1 h. Then, lithium bis(trimethylsilyl)amide (12.9 g, 90.0 mmol) was added dropwise, and the mixture was slowly heated to room temperature for 8 h. After concentrating under reduced pressure, water (200 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*3), dried over anhydrous sodium sulfate, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain 12c (yellow solid, 8.3 g, yield 84%).

[0709] LC-MS m / z(ESI)=330.12[M+1].

[0710] Step 3

[0711] 3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 12d

[0712] 3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0713] 12c (4.0 g, 12.2 mmol) and sodium iodide (3.6 g, 24.3 mmol) were dissolved in acetone (60 mL), reacted at 80°C for 8 h, concentrated under reduced pressure, added with water (200 mL), extracted with ethyl acetate (20 mL*3), dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated under reduced pressure to obtain 12d (yellow solid, 5.1 g, yield 80%).

[0714] LC-MS m / z(ESI)=422.05[M+1].

[0715] Step 4

[0716] 1'-(4-methoxybenzyl)-1'-, 4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one 12e

[0717] 1'-(4-methoxybenzyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0718] Compound 12d (4.0 g, 9.5 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium bis(trimethylsilyl)amide (10 mL, 9.5 mmol) was added dropwise at -78°C, and the temperature was slowly raised to room temperature for reaction for 5 h. After concentration under reduced pressure, water (200 mL) was added, and ethyl acetate (20 mL*3) was extracted, dried over anhydrous sodium sulfate, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain 12e (yellow solid, 1.4 g, yield 83%).

[0719] LC-MS m / z(ESI)=294.14[M+1].

[0720] Step 5

[0721] 1',4'-Dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one 12f

[0722] 1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0723] 12e (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 sodium carbonate aqueous solution was added to adjust the pH to 9, extracted with ethyl acetate (20 mL*3), dried over anhydrous sodium sulfate, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 12f (yellow solid, 730 mg, yield 88%).

[0724] LC-MS m / z(ESI)=174.08[M+1].

[0725] Step 6

[0726] 6'-Bromo-1'-, 4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one 12g

[0727] 6'-bromo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0728] 12f (730 mg, 4.2 mmol) and N-bromosuccinimide (976 mg, 5.5 mmol) were dissolved in anhydrous acetonitrile (20 mL) and reacted at room temperature for 3 h. After concentration under reduced pressure, the product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 12g (yellow solid, 917 mg, yield 87%).

[0729] LC-MS m / z(ESI)=251.99[M+1].

[0730] Step 7

[0731] 6'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinolin]-2'-one 12h

[0732] 6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',4'-dihydro-2'H-spiro[cyclopro pane-1,3'-quinolin]-2'-one

[0733] Referring to the synthesis method of 1c, 12g was used to obtain 12h (yellow solid, 840 mg, yield 84%).

[0734] LC-MS m / z(ESI)=300.17[M+1].

[0735] Step 8

[0736] (S)-3-methyl-6-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 12i

[0737] tert-butyl(S)-3-methyl-6-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quin olin]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0738] Referring to the synthetic method of 1d, 12h and intermediate B were used to obtain 12i (yellow solid, 942 mg, yield 79%).

[0739] LC-MS m / z(ESI)=369.21[M+1].

[0740] Step 9

[0741] (S)-6'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinolin]-2'-one 12j

[0742] (S)-6'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopro pane-1,3'-quinolin]-2'-one

[0743] Referring to the synthesis method of 1e, 12i was used to obtain 12j (yellow solid, 780 mg, yield 78%).

[0744] LC-MS m / z(ESI)=269.16[M+1].

[0745] Step 10

[0746] 6'-((5S)-5-methylpiperidin-2-yl)-1'-, 4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one 11k

[0747] 6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0748] Referring to the synthetic method of 1f, 12k was obtained using 12j (yellow solid, 749 mg, yield 83%).

[0749] LC-MS m / z(ESI)=271.17[M+1].

[0750] Step 11

[0751] 2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)-2-oxoacetate 12l

[0752] methyl 2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-qu inolin]-6'-yl)piperidin-1-yl)-2-oxoacetate

[0753] Referring to the synthesis method of 1g, 12k was used to obtain 12l (yellow solid, 946 mg, yield 87%).

[0754] LC-MS m / z(ESI)=357.17[M+1].

[0755] Step 12

[0756] 2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)-2-oxoacetic acid 12m

[0757] 2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)-2-oxoacetic acid

[0758] Referring to the synthesis method of 1h, 12l was used to obtain the lithium salt of 12m (yellow solid, 1.1 g, yield 87%).

[0759] LC-MS m / z(ESI)=343.16[M+1].

[0760] Step 13

[0761] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)-2-oxoacetamide Compound 12

[0762] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide

[0763] Referring to the synthesis method of compound 1, compound 12 was obtained using 11m and intermediate A (white solid, 78 mg, yield 77%).

[0764] 1H NMR(400MHz,DMSO-d6)δ10.44(d,Hz,1H),10.14(s,1H),7.90-7.82(m,1H),7.15–6.99(m,2H),6.92-6.87(m,1H),6.09(s,2H),5.01–4.6 0(m,5H),3.39-3.34(m,1H),3.27-3.22(m,1H),2.85-2.83(m,2H),2.24–1.57(m,5H),1.11–1.05(m,2H),1.02(d,3H),0.75-0.71(m,2H).

[0765] LC-MS m / z(ESI)=476.22[M+1].

[0766] Example 13

[0767] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)piperidin-1-yl)-2-oxoacetamide Compound 13

[0768] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[be nzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)piperidin-1-yl)-2-oxoacetamide

[0769]

[0770]

[0771] first step

[0772] Ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate 13b

[0773] ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate

[0774] 13a (2.2 g, 10.0 mmol) was dissolved in tetrahydrofuran (60 mL), sodium hydride (0.6 g, 15.0 mmol) was added at 0°C, and 1-hydroxycyclopropanecarboxylic acid ethyl ester (1.6 g, 12.0 mmol) was added after the reaction was carried out at the same temperature for 1 h. After the addition, the mixture was heated to room temperature and reacted for 5 h. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with ethyl acetate (30 mL*3), dried over anhydrous sodium sulfate, and the organic phases were combined, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 13b (yellow solid, 3.0 g, yield 92%).

[0775] LC-MS m / z(ESI)=329.99[M+1].

[0776] Step 2

[0777] 7-Bromospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 13c

[0778] 7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0779] 13b (3.0 g, 9.1 mmol) was dissolved in glacial acetic acid (40 mL), iron powder (1.5 g, 27.3 mmol) was added at 0°C, and water (200 mL) was added after reacting at room temperature for 8 h. The mixture was filtered, washed (water, 10 mL*3), and the solid was collected and dried to obtain 13c (white solid, 1.7 g, yield 71%).

[0780] LC-MS m / z(ESI)=253.97[M+1].

[0781] Step 3

[0782] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 13d

[0783] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0784] Referring to the synthesis method of 1c, 13c was used to obtain 13d (yellow solid, 1.1 g, yield 82%).

[0785] LC-MS m / z(ESI)=302.15[M+1].

[0786] Step 4

[0787] (S)-3-Methyl-6-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 13e

[0788] tert-butyl(S)-3-methyl-6-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cy clopropan]-7-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0789] Referring to the synthetic method of 1d, 13e was obtained using 13d and intermediate B (yellow solid, 973 mg, yield 82%).

[0790] LC-MS m / z(ESI)=371.19[M+1].

[0791] Step 5

[0792] (S)-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 13f

[0793] (S)-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0794] Referring to the synthesis method of 1e, 13e was used to obtain 13f (yellow solid, 771 mg, yield 84%).

[0795] LC-MS m / z(ESI)=271.14[M+1].

[0796] Step 6

[0797] 7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 13g

[0798] 7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[0799] Referring to the synthesis method of 1f, 12f was used to obtain 12g (yellow solid, 758 mg, yield 87%).

[0800] LC-MS m / z(ESI)=273.15[M+1].

[0801] Step 7

[0802] 2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)piperidin-1-yl)-2-oxoacetate 13h

[0803] methyl 2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)piperidin-1-yl)-2-oxoacetate

[0804] Referring to the synthesis method of 1g, 13g was used to obtain 13h (yellow solid, 894 mg, yield 88%).

[0805] LC-MS m / z(ESI)=359.15[M+1].

[0806] Step 8

[0807] 2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)piperidin-1-yl)-2-oxoacetic acid 13i

[0808] 2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopro pan]-7-yl)piperidin-1-yl)-2-oxoacetic acid

[0809] Referring to the synthesis method of 1h, 13h was used to obtain the lithium salt of 13i (yellow solid, 970 mg, yield 85%).

[0810] LC-MS m / z(ESI)=345.14[M+1].

[0811] Step 9

[0812] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)piperidin-1-yl)-2-oxoacetamide Compound 13

[0813] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[be nzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)piperidin-1-yl)-2-oxoacetamide

[0814] Referring to the synthesis method of compound 1, compound 13 was obtained using 13i and intermediate c (white solid, 106 mg, yield 79%).

[0815] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),10.57(d,1H),8.14–8.00(m,1H),7 .59–7.43(m,1H),7.03–6.68(m,3H),5.85(s,2H),5.50-5.04(m,1H),3.44 -3.40(m,1H),3.25–3.05(m,1H),2.45-2.36(m,2H),2.22–1.61(m,5H),1. 27-1.22(m,2H),1.19-1.16(m,3H),1.13-1.08(m,3H),1.03-0.99(m,2H).

[0816] LC-MS m / z(ESI)=464.22[M+1].

[0817] Embodiment 14

[0818] N-(Imidazolo[1,2-a]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indol]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 14

[0819] N-(imidazo[1,2-a]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-in dolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[0820]

[0821] first step

[0822] O-(Imidazolo[1,2-a]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indol]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 14

[0823] N-(imidazo[1,2-a]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-in dolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[0824] Referring to the synthesis method of compound 1, compound 5h and intermediate F were used to obtain compound 14 (white solid, 60 mg, yield 42%).

[0825] 1 H NMR (400MHz, DMSO-d6) δ10.61–10.20(m,2H),7.82–7.52(m,2H),7.0–7.74(m,2H),7.24–6.99(m,3H),6.90– 6.80(m,1H),5.02–4.49(m,2H),3.29–3.21(m,3H),2.25–1.78(m,2H),1.75–1.42(m,5H),1.06–0.97(m,3H).

[0826] LC-MS m / z(ESI)=444.20[M+1].

[0827] Embodiment 15

[0828] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetamide

[0829]

[0830] first step

[0831] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetamide

[0832] Referring to the synthesis method of compound 1, compound 4k and intermediate C were used to obtain compound 15 (white solid, 66 mg, yield 62%).

[0833] 1 H NMR (400MHz, DMSO-d6) δ10.58–10.48(m,1H),8.11–8.01(m,1H),7.56–7.45(m,1H) ),6.93–6.82(m,1H),6.81–6.63(m,2H),5.74–5.44(m,3H),4.29–4.17(m,1H),4. 02–3.85(m,2H),3.83–3.71(m,1H),3.26–3.02(m,4H),2.95(s,1H),2.78–2.63(m ,2H),2.46–2.31(m,4H),2.17–1.48(m,7H),1.15–1.08(m,3H),1.05–0.97(m,3H).

[0834] LC-MS m / z(ESI)=492.30[M+1].

[0835] Example 16

[0836] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 16

[0837] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoli n]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[0838]

[0839]

[0840] first step

[0841] 7'-Fluorospiro[cyclopropane-1,3'-indolin]-2'-one compound 16b

[0842] 7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0843] Compound 16a (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 the reaction was complete, saturated ammonium chloride solution was added to quench, and ethyl acetate (300*3 mL) was added for extraction, and saturated brine (100 mL) was washed, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 16b (brown solid, 21 g, yield 71.9%).

[0844] LC-MS m / z(ESI)=178.16[M+1].

[0845] Step 2

[0846] 5'-Bromo-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one 16c

[0847] 5'-bromo-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0848] Compound 16b (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 completed, sodium sulfite was added to quench the reaction. Saturated sodium carbonate solution was added to adjust the pH value to alkaline, 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 separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 16c (brown solid, 21 g, yield 79%).

[0849] LC-MS m / z(ESI)=256.01[M+1].

[0850] Step 3

[0851] 5'-Bromo-7'-fluoro-1'-(4-methoxybenzyl)spiro[cyclopropane-1,3'-indolin]-2'-one 16d

[0852] 5'-bromo-7'-fluoro-1'-(4-methoxybenzyl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0853] Compound 16c (5.0 g, 19.6 mmol) was dissolved in THF (60 mL), sodium hydride (561 mg, 23.5 mmol) was added at 0°C, the mixture was heated to room temperature and stirred for 30 min, p-methoxybenzyl chloride (3.7 g, 23.5 mmol) was added at the same temperature and the mixture was heated to room temperature for reaction. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 16d (yellow solid, 1 g, yield 13.6%).

[0854] LC-MS m / z(ESI)=376.14[M+1].

[0855] Step 4

[0856] 7'-Fluoro-1'-(4-methoxybenzyl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 16e

[0857] 7'-fluoro-1'-(4-methoxybenzyl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0858] According to the method for synthesizing compound 1c, compound 16e (white solid, 1 g, yield 91%) was obtained.

[0859] LC-MS m / z(ESI)=424.23[M+1].

[0860] Step 5

[0861] 6-(7'-Fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 16f

[0862] tert-butyl-6-(7'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[cyclopropane-1,3'-indol in]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[0863] According to the method for compound 1d, compound 16e was reacted with intermediate B to give compound 16f (yellow solid, 800 mg, yield 72.7%).

[0864] LC-MS m / z(ESI)=493.26[M+1].

[0865] Step 6

[0866] 7'-Fluoro-1'-(4-methoxybenzyl)-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 16g

[0867] 7'-fluoro-1'-(4-methoxybenzyl)-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0868] According to the method for compound 1e, compound 16f was used to obtain compound 16g (yellow solid, 600 mg, yield 92%).

[0869] LC-MS m / z(ESI)=393.20[M+1].

[0870] Step 7

[0871] 7'-Fluoro-1'-(4-methoxybenzyl)-5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 16h

[0872] 7'-fluoro-1'-(4-methoxybenzyl)-5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0873] According to the method of compound 1f, compound 16g was used to obtain compound 16h (yellow solid, 500 mg, yield 76%).

[0874] LC-MS m / z(ESI)=395.21[M+1].

[0875] Step 8

[0876] 2-(2-(7'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetate 16i

[0877] methyl 2-(2-(7'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[cyclopropane-1,3'-indo lin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetate

[0878] According to the method for compound 1g, compound 16i (light yellow solid, 550 mg, yield 90%) was obtained using compound 16h.

[0879] LC-MS m / z(ESI)=481.23[M+1].

[0880] Step 9

[0881] 2-(2-(7'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid 16j

[0882] 3-(2-(7'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid

[0883] According to the method of compound 1h, compound 16h was used to obtain compound 16i (white solid, 270 mg, yield 50.4%).

[0884] LC-MS m / z(ESI)=467.18[M+1].

[0885] Step 10

[0886] 2-(2-(7'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid 16k

[0887] 4-(2-(7'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid

[0888] According to the method of compound 1, compound 16j was used to obtain compound 16k (white solid, 100 mg, yield 29.5%).

[0889] LC-MS m / z(ESI)=586.10[M+1].

[0890] Step 11

[0891] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide 16

[0892] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[0893] Compound 16k (5.0 g, 19.6 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and trifluoroacetic acid (5 mL), trifluoromethanesulfonic acid (231 mg, 1.54 mmol) was added at 0°C, and the mixture was heated to room temperature for reaction. After the reaction was complete, sodium bicarbonate was added to adjust the pH value to alkaline, and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 16 (white solid, 18 mg, yield 25.3%)

[0894] 1 HNMR(400MHz,DMSO)δ11.07(s,1H),10.60(d,1H),8.04(dd,1H),7.49(dd,1H),6.80(d,1H),5.68(d,2H),5.61–5.00(m, 1H),4.24–3.52(m,1H),2.41(tt,3H),1.91–1.77(m,1H),1.63(dd,3H),1.52(dd,2H),1.19–1.04(m,6H),0.83(ddd,4H).

[0895] LC-MS m / z(ESI)=466.24[M+1].

[0896] Embodiment 17

[0897] N-(6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetamide

[0898]

[0899]

[0900] first step

[0901] N-(6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-((R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-1-yl)-2-oxoacetamide

[0902] Referring to the synthesis method of compound 1, compound 4k and intermediate E were used to obtain compound 17 (white solid, 70 mg, yield 46%).

[0903] 1 H NMR(400MHz,DMSO-d6)δ10.58–10.50(m,1H),8.09–8.04(m,1H),7.50–7.42( m,1H),6.90–6.80(m,1H),6.80–6.59(m,2H),5.75–5.40(m,3H),4.29–4.20( m,1H),4.02–3.86(m,2H),3.85–3.7(m,1H),3.20–3.98(m,4H),2.95(s,1H), 2.75–2.60(m,2H),2.40–2.21(m,6H),2.15–1.50(m,7H),1.05–0.97(m,3H).

[0904] LC-MS m / z(ESI)=478.30[M+1].

[0905] Embodiment 18

[0906] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(spiro[benzo[d][1,3]dioxetane]-5-yl)piperidin-1-yl)-2-oxoacetamide Compound 18

[0907] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cycl obutan]-5-yl)piperidin-1-yl)-2-oxoacetamide

[0908]

[0909]

[0910] first step

[0911] 5-Bromospiro[benzo[d][1,3]dioxetane-2,1'-cyclobutane] compound 18b

[0912] 5-bromospiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]

[0913] Compound 18a (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 refluxed and stirred at 130 °C for 16 h using a water separator. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 10:1).

[0914] Compound 18b was isolated (anhydrous oil, 1.1 g, yield 28.9%).

[0915] Step 2

[0916] 4,4,5,5-Tetramethyl-2-(spiro[benzo[d][1,3]dioxetane-2,1'-cyclobutane]-5-yl)-1,3,2-dioxaborolane 18c

[0917] 4,4,5,5-tetramethyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)-1,3,2-di oxaborolane

[0918] According to the method of compound 1c, compound 18c (yellow oil, 1.2 g, yield 92%) was obtained using compound 18b (1.1 g, 4.6 mmol).

[0919] Step 3

[0920] tert-Butyl 3-methyl-6-(spiro[benzo[d][1,3]dioxo-2,1'-cyclobutane]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0921] tert-butyl3-methyl-6-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)-3,4-dihy dropyridine-1(2H)-carboxylate

[0922] According to the method of compound 1d, compound 18c (1.2 g, 4.1 mmol) was used to obtain compound 18d (white solid, 1 g, yield 67%).

[0923] LC-MS m / z(ESI)=358.20[M+1].

[0924] Step 4

[0925] 3-Methyl-6-(spiro[benzo[d][1,3]dioxo-2,1'-cyclobutane]-5-yl)-2,3,4,5-tetrahydropyridine 18e

[0926] 3-methyl-6-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)-2,3,4,5-tetrahydro pyridine

[0927] According to the method of compound 1e, compound 18e (white solid, 600 mg, yield 83%) was obtained using compound 18d (1 g, 2.8 mmol).

[0928] LC-MS m / z(ESI)=258.14[M+1].

[0929] Step 5

[0930] 5-Methyl-2-(spiro[benzo[d][1,3]dioxo-2,1'-cyclobutane]-5-yl)piperidine 6f

[0931] 3-methyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)piperidine

[0932] 4- According to the method of compound 1f, compound 18e (600 mg, 2.3 mmol) was used to obtain compound 18f (white solid, 600 mg, yield 82%).

[0933] LC-MS m / z(ESI)=261.23[M+1].

[0934] Step 6

[0935] 2-(5-methyl-2-(spiro[benzo[d][1,3]dioxo-2,1'-cyclobutane]-5-yl)piperidin-1-yl)-2-oxoacetate 18g

[0936] methyl 2-(5-methyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)piperidi n-1-yl)-2-oxoacetate

[0937] According to the method for compound 1g, compound 18g (yellow solid, 450 mg, yield 84%) was obtained using compound 18f.

[0938] LC-MS m / z(ESI)=346.1[M+1].

[0939] Step 7

[0940] 2-(5-methyl-2-(spiro[benzo[d][1,3]dioxo-2,1'-cyclobutane]-5-yl)piperidin-1-yl)-2-oxoacetic acid 18h

[0941] 2-(5-methyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)piperidin-1-yl)-2-oxoacetic acid

[0942] According to the method for compound 1h, compound 18 was used to obtain compound 18h ​​(white solid, 450 mg, yield 100%).

[0943] LC-MS m / z(ESI)=332.14[M+1].

[0944] Step 8

[0945] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(spiro[benzo[d][1,3]dioxetane]-5-yl)piperidin-1-yl)-2-oxoacetamide Compound 18

[0946] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl)piperidin-1-yl)-2-oxoacetamide

[0947] According to the method of compound 1, compound 18h ​​(100 mg, 0.3 mmol) and intermediate C were used to obtain compound 18 (white solid, 60 mg, yield 44%).

[0948] 1HNMR(400MHz,DMSO-d6)δ10.58–10.46(m,1H),8.11–8.00(m,1H),7.56–7. 45(m,1H),7.43–7.26(m,1H),6.89–6.74(m,2H),5.72–5.61(m,2H),3.55– 3.35(m,1H),3.27–3.14(m,1H),2.61–2.51(m,4H),2.45–2.31(m,2H),2.2 1–1.61(m,6H),1.42–1.24(m,2H),1.17–1.09(m,3H),1.04–0.97(m,3H)..

[0949] LC-MS m / z(ESI)=451.30[M+1].

[0950] Embodiment 19

[0951] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)-2-oxoacetamide Compound 19

[0952] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'H-sp iro[cyclopropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide

[0953]

[0954] first step

[0955] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)-2-oxoacetamide Compound 19

[0956] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2'-oxo-1',4'-dihydro-2'H-sp iro[cyclopropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide

[0957] Referring to the synthesis method of compound 1, compound 19 (white solid, 78 mg, yield 48%) was obtained.

[0958] 1 H NMR (400MHz, DMSO-d6) δ10.58-10.44(m,1H),10.15(s,1H),8.11–7.98(m,1H),7.54-7. 43(m,1H),7.16–6.99(m,2H),6.94–6.86(m,1H),5.72-5.68(m,2H),5.55-5.02(m,1H), 3.53-3.40(m,1H),3.27-3.17(m,1H),2.87–2.75(m,2H),2.44-2.34(m,2H),2.25–1.58 (m,5H),1.35–1.29(m,1H),1.13(t,J=7.5Hz,3H),1.03-0.99(m,2H),0.74-0.66(m,2H).

[0959] LC-MS m / z(ESI)=462.24[M+1].

[0960] Embodiment 20

[0961] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazin[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetamide Compound 20

[0962] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetamide

[0963]

[0964] first step

[0965] 8-Bromo-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 20a

[0966] 8-bromo-1,2,3,4-tetrahydropyrazino[1,2-b]indazole

[0967] Compound 3d (2.0 g, 7.5 mmol), BH 3 The THF solution (37.7 mL, 37.7 mmol) was dissolved in THF (50 mL), and the temperature was raised to 75 °C under nitrogen protection. The reaction progress was monitored by TLC.

[0968] The reaction was stopped and the compound 20a (white solid, 1.0 g, yield 57%) was separated by column chromatography (EA:PE=1:4).

[0969] LC-MS m / z(ESI)=252.01[M+1].

[0970] Step 2

[0971] 8-Bromo-2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 20b

[0972] 8-bromo-2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazole

[0973] Compound 20a (1.0 g, 3.9 mmol) and formaldehyde aqueous solution (2.0 g, 19.9 mmol) were dissolved in methanol (50 mL), and sodium cyanoborohydride (375 mg, 5.9 mmol) was added. The mixture was stirred at room temperature and the reaction progress was monitored by TLC.

[0974] The reaction was stopped and the compound 20b (yellow liquid, 940 mg, yield 89%) was obtained by separation through column chromatography (DCM:MeOH=20:1).

[0975] LC-MS m / z(ESI)=266.02[M+1].

[0976] Step 3

[0977] 2-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 20c

[0978] 2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydropyra zino[1,2-b]indazole

[0979] According to the method of compound 1c, the filtrate containing compound 20c was directly used for the next reaction.

[0980] LC-MS m / z(ESI)=314.20[M+1].

[0981] Step 4

[0982] 3-Methyl-6-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 20d

[0983] tert-butyl 3-methyl-6-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0984] According to the method for compound 1d, compound 20d (brown liquid, 1.9 g, yield 99%) was obtained.

[0985] LC-MS m / z(ESI)=383.24[M+1].

[0986] Step 5

[0987] 2-Methyl-8-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 20e

[0988] 2-methyl-8-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole

[0989] According to the method of compound 1e, compound 20e (yellow liquid, 1.2 g, yield 99%) was obtained.

[0990] LC-MS m / z(ESI)=283.18[M+1].

[0991] Step 6

[0992] 2-Methyl-8-(5-methylpiperidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole 20f

[0993] 2-methyl-8-(5-methylpiperidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-b]indazole According to the method of compound 1f, compound 20f (brown solid, 115 mg, yield 70%) was obtained.

[0994] LC-MS m / z(ESI)=285.20[M+1].

[0995] Step 7

[0996] 2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazine[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetate 20g

[0997] Methyl2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetate

[0998] According to the method of compound 1g, compound 20g (yellow liquid, 123 mg, yield 83%) was obtained.

[0999] LC-MS m / z(ESI)=371.20[M+1].

[1000] Step 8

[1001] 2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetic acid

[1002] According to the method of compound 1h, compound 20h (yellow solid, 128 mg, yield 99%) was obtained.

[1003] LC-MS m / z(ESI)=357.18[M+1].

[1004] Step 9

[1005] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazin[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetamide Compound 20

[1006] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-(5-methyl-2-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidin-1-yl)-2-oxoacetamide

[1007] According to the method of compound 1, compound 20 (white solid, 49 mg, yield 31%) was obtained.

[1008] 1 H NMR(400MHz,DMSO-d6)δ10.60-10.49(m,1H),7.93-7.79(m,1H),7.70-7.62(m,1 H),7.51-7.43(m,1H),7.09–6.92(m,1H),6.14(s,2H),5.22–4.63(m,5H),4.52-4 .42(m,2H),4.26-4.09(m,2H),3.44-3.41(m,1H),3.27-3.24(m,1H),3.22-3.15( m,2H),2.62(s,3H),2.22-1.65(m,4H),1.42–1.33(m,1H),1.04(d,J=6.9Hz,3H).

[1009] LC-MS m / z(ESI)=490.25[M+1].

[1010] Embodiment 21

[1011] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide Compound 21

[1012] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide

[1013]

[1014] first step

[1015] 6'-Bromospiro[cyclopropane-1,3'-indolin]-2'-one 21b

[1016] 6'-bromospiro[cyclopropane-1,3'-indolin]-2'-one

[1017] Compound 21a (5.0 g, 23.5 mmol) was dissolved in THF (50 mL) at 0°C. LDA (35.3 mL, 70.7 mmol) was slowly added dropwise under nitrogen protection. After stirring for 30 min, 1,2-dibromoethane (13.3 g, 70.7 mmol) was slowly added dropwise. The mixture was reacted at room temperature for 2 d. The reaction progress was monitored by TLC.

[1018] The reaction was stopped, saturated aqueous ammonium chloride solution was added, extracted with DCM, the organic phases were combined and concentrated under reduced pressure, and separated by column chromatography (EA:PE=10:1) to give compound 21b (red solid, 750 mg, yield 13%).

[1019] LC-MS m / z(ESI)=237.98[M+1].

[1020] Step 2

[1021] 6'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 21c

[1022] 6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[1023] According to the method of compound 1c, the filtrate containing compound 21c was directly used for the next reaction.

[1024] LC-MS m / z(ESI)=286.15[M+1].

[1025] Step 3

[1026] (S)-3-Methyl-6-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 21d

[1027] tert-butyl(S)-3-methyl-6-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)-3,4-dihy dropyridine-1(2H)-carboxylate

[1028] According to the method of compound 1d, compound 21d (yellow liquid, 1.6 g, yield 51%) was obtained.

[1029] LC-MS m / z(ESI)=355.19[M+1].

[1030] Step 4

[1031] (S)-6'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[1032] According to the method of compound 1e, compound 21e (yellow solid, 488 mg, yield 29%) was obtained.

[1033] LC-MS m / z(ESI)=255.14[M+1].

[1034] Step 5

[1035] 6'-((5S)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 21f

[1036] 6'-((5S)-5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[1037] According to the method of compound 1f, compound 21f (yellow solid, 384 mg, yield 80%) was obtained.

[1038] LC-MS m / z(ESI)=255.14[M+1].

[1039] Step 6

[1040] 2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperidin-1-yl)-2-oxoacetic acid methyl ester 21g

[1041] methyl 2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperid in-1-yl)-2-oxoacetate

[1042] According to the method of compound 1g, compound 21g (yellow solid, 224 mg, yield 92%) was obtained.

[1043] LC-MS m / z(ESI)=343.16[M+1].

[1044] Step 7

[1045] 2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperidin-1-yl)-2-oxoacetic acid 21h

[1046] 2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperidin-1-yl)-2-oxoacetic acid

[1047] According to the method of compound 1h, compound 21h (yellow solid, 246 mg, yield 99%) was obtained.

[1048] LC-MS m / z(ESI)=329.14[M+1].

[1049] Step 8

[1050] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide Compound 21

[1051] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide

[1052] According to the method of compound 1, compound 21 (yellow solid, 90 mg, yield 70%) was obtained.

[1053] 1H NMR(400MHz,DMSO-d6)δ10.58–10.40(m,2H),7.93-7.77(m,1H),7.02–6.77(m,3H),6.08(s,2H),5.13–4.60(m,5H),3.46-3.38 (m,1H),3.30-3.23(m,1H),2.22-1.68(m,4H),1.57-1.15(m,2H),1.47-1.41(m,2H),1.36-1.30(m,1H),1.03(d,J=7.0Hz,3H).

[1054] LC-MS m / z(ESI)=462.21[M+1].

[1055] Embodiment 22

[1056] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indol]-6'-yl)piperidin-1-yl)-2-oxoacetamide Compound 22

[1057] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide

[1058]

[1059] first step

[1060] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indol]-6'-yl)piperidin-1-yl)-2-oxoacetamide Compound 22

[1061] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide

[1062] According to the method of compound 1, compound 22 (yellow solid, 60 mg, yield 31%) was obtained.

[1063] 1H NMR(400MHz,DMSO-d6)δ10.60-10.48(m,2H),8.12–8.00(m,1H),7.54-7.45(m ,m1H),7.00–6.78(m,3H),5.72-5.61(m,2H),5.60-5.09(m,1H),3.64-3.41(m, 1H),3.31-3.20(m,1H),2.45-2.32(m,2H),2.18–1.65(m,4H),1.58-1.51(m,2H ),1.47-1.41(m,2H),1.37–1.29(m,1H),1.16–1.08(m,3H),1.06-0.99(m,3H).

[1064] LC-MS m / z(ESI)=448.23[M+1].

[1065] Embodiment 23

[1066] N-(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-(2-(2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)piperidin-1-yl)acetamide Compound 23

[1067] N-(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-(2-(2'-oxospiro[cyclopropane-1,3'-indo lin]-5'-yl)piperidin-1-yl)acetamide

[1068]

[1069] first step

[1070] 6-(2'-Oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 23a

[1071] tert-butyl 6-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1072] According to the method of compound 1d, compound 23a (yellow liquid, 2.3 g, yield 76%) was obtained.

[1073] LC-MS m / z(ESI)=341.18[M+1].

[1074] Step 2

[1075] 5'-(1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 23b

[1076] 5'-(1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[1077] According to the method of compound 1e, compound 23b (yellow liquid, 880 mg, yield 49%) was obtained.

[1078] LC-MS m / z(ESI)=241.13[M+1].

[1079] Step 3

[1080] 5'-(Piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 23c

[1081] 5'-(piperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[1082] According to the method of compound 1f, compound 23c (yellow solid, 788 mg, yield 88%) was obtained.

[1083] LC-MS m / z(ESI)=243.14[M+1].

[1084] Step 4

[1085] 2-Oxo-2-(2-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)acetate 23d

[1086] methyl 2-oxo-2-(2-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)acetate

[1087] According to the method of compound 1g, compound 23d (yellow liquid, 230 mg, yield 85%) was obtained.

[1088] LC-MS m / z(ESI)=329.14[M+1].

[1089] Step 5

[1090] 2-Oxo-2-(2-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)acetic acid 23e

[1091] 2-oxo-2-(2-(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)piperidin-1-yl)acetic ac id

[1092] According to the method of compound 1h, compound 23e (yellow solid, 330 mg, yield 99%) was obtained.

[1093] LC-MS m / z(ESI)=315.13[M+1].

[1094] Step 6

[1095] N-(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-(2-(2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)piperidin-1-yl)acetamide Compound 23

[1096] N-(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-(2-(2'-oxospiro[cyclopropane-1,3'-indo lin]-5'-yl)piperidin-1-yl)acetamide

[1097] According to the method of compound 1, compound 23 (white solid, 40 mg, yield 23%) was obtained.

[1098] 1 H NMR(400MHz,DMSO-d6)δ10.57(s,2H),8.13-7.95(m,1H),7.58-7.38(m,1H),7.17-7.03(m,1H),6.96-6.86(m,2H),5.76–5.63(m,2H), 5.62-5.04(m,1H),3.72-3.50(m,2H),2.44–2.35(m,2H),2.01–1.53(m,6H),1.49–1.43(m,3H),1.25-1.20(m,1H),1.15-1.05(m,3H).

[1099] LC-MS m / z(ESI)=434.21[M+1].

[1100] Embodiment 24

[1101] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 24

[1102] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[ben zo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1103]

[1104]

[1105] first step

[1106] 1-(5-Bromo-3-fluoro-2-nitrophenoxy)cyclopropane-1-carboxylic acid ethyl ester 24b

[1107] ethyl 1-(5-bromo-3-fluoro-2-nitrophenoxy)cyclopropane-1-carboxylate

[1108] At 0°C, ethyl 1-hydroxycyclopropane-1-carboxylate (2.1 g, 16.1 mmol) was dissolved in THF (40 mL), and NaH (882 mg, 22.0 mmol) was added. The mixture was stirred for 10 min, and then a THF mixture of 24a (3.5 g, 14.7 mmol) was added dropwise. The mixture was reacted at room temperature and the reaction progress was monitored by TLC.

[1109] The reaction was stopped, water was added, and the mixture was extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (EA:PE=1:40) to obtain compound 24b (brown solid, 3.4 g, yield 62%).

[1110] LC-MS m / z(ESI)=347.98[M+1].

[1111] Step 2

[1112] 7-Bromo-5-fluorospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 24c

[1113] 7-bromo-5-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1114] Compound 24b (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.

[1115] The reaction was stopped, water was added, and the residue was filtered to obtain a solid, which was separated by column chromatography (EA:PE=1:50) to obtain compound 24c (white solid, 2.3 g, yield 87%).

[1116] LC-MS m / z(ESI)=271.96[M+1].

[1117] Step 3

[1118] 5-Fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 24d

[1119] 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

[1120] According to the method of compound 1c, compound 24d (brown solid, 3.6 g, yield 99%) was obtained.

[1121] LC-MS m / z(ESI)=320.14[M+1].

[1122] Step 4

[1123] (S)-6-(5-fluoro-3-oxo-3,4-dihydropyrro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 24e

[1124] tert-butyl(S)-6-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cycl opropan]-7-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1125] According to the method for compound 1d, compound 24e (yellow solid, 2.8 g, yield 96%) was obtained.

[1126] LC-MS m / z(ESI)=389.18[M+1].

[1127] Step 5

[1128] (S)-5-Fluoro-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 24f

[1129] (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

[1130] According to the method of compound 1e, compound 24f (white solid, 1.7 g, yield 60%) was obtained.

[1131] LC-MS m / z(ESI)=289.13[M+1].

[1132] Step 6

[1133] 5-Fluoro-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 24g

[1134] 5-fluoro-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopr opan]-3(4H)-one

[1135] According to the method of compound 1f, compound 24g (white solid, 1.6 g, yield 89%) was obtained.

[1136] LC-MS m / z(ESI)=291.14[M+1].

[1137] Step 7

[1138] 2-((5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetate 24h

[1139] methyl 2-((5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cy clopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetate

[1140] According to the method of compound 1g, compound 24h (yellow solid, 413 mg, yield 77%) was obtained.

[1141] LC-MS m / z(ESI)=377.14[M+1].

[1142] Step 8

[1143] 2-((5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid 24i

[1144] 2-((5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cycloprop an]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid

[1145] According to the method of compound 1h, compound 24i (white solid, 145 mg, yield 99%) was obtained.

[1146] LC-MS m / z(ESI)=363.13[M+1].

[1147] Step 9

[1148] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 24

[1149] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-3-oxo-3,4-dihydrospiro[ben zo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1150] According to the method of compound 1, compound 24 (yellow solid, 86 mg, yield 44%) was obtained.

[1151] 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),10.64-10.52(m,1H),8.12-8.00(m,1H),7.56- 7.43(m,1H),6.98-6.86(m,1H),6.78-6.64(m,1H),5.76(s,2H),5.53-4.99(m,1H),3 .47-3.41(m,1H),3.26-3.14(m,1H),2.45-2.36(m,2H),2.17–1.59(m,4H),1.37–1.2 9(m,1H),1.25-1.17(m,3H),1.15-1.07(m,3H),1.04-0.96(m,3H),0.92-0.70(s,1H).

[1152] LC-MS m / z(ESI)=482.21[M+1].

[1153] Embodiment 25

[1154] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 25

[1155] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydr ospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoac etamide

[1156]

[1157] first step

[1158] 2-((5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid 25a

[1159] 2-((5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acide

[1160] Compound 24h (300 mg, 0.8 mmol) was dissolved in DMF (15 mL), and NaH (48 mg, 1.2 mmol) was added at 0°C. The mixture was stirred for 10 min, and then a mixture of iodomethane (169 mg, 1.2 mmol) in DMF was added dropwise. The mixture was reacted at room temperature and the reaction progress was monitored by TLC.

[1161] The reaction was stopped, water was added and stirred for 1 h, the pH was adjusted to acidic, extracted with EA, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM: MeOH = 1:20) to obtain compound 25b (yellow liquid, 282 mg, yield 94%).

[1162] LC-MS m / z(ESI)=377.14[M+1].

[1163] Step 2

[1164] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 25

[1165] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydr ospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoac etamide

[1166] According to the method of compound 1, compound 25 (yellow solid, 80 mg, yield 43%) was obtained.

[1167] 1H NMR(400MHz,DMSO-d6)δ10.64-10.54(m,1H),8.11-7.99(m,1H),7.54-7.44(m,1H) ,7.05-6.94(m,1H),6.84-6.73(m,1H),5.77-5.63(m,2H),5.55–5.03(m,1H),3.47- 3.36(m,4H),3.28-3.17(m,1H),2.46–2.34(m,2H),2.11–1.53(m,4H),1.37–1.28( m,1H),1.25-1.19(m,3H),1.15–1.07(m,3H),1.03–0.93(m,3H),0.87–0.80(m,1H).

[1168] LC-MS m / z(ESI)=496.23[M+1].

[1169] Embodiment 26

[1170] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-oxospiro[cyclobutane-1,3'-indole]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 26

[1171] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[1172]

[1173] first step

[1174] 5'-Bromospiro[cyclobutane-1,3'-indolin]-2'-one 26b

[1175] 5'-bromospiro[cyclobutane-1,3'-indolin]-2'-one

[1176] 26a (5 g, 25.8 mmol) was dissolved in THF (150 mL), and n-butyl lithium (30 mL, 2.5 M in 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 heated to room temperature and stirred for 16 h. After the reaction was complete, saturated ammonium chloride solution was added to quench, and ethyl acetate (300 mL) was added for extraction, and saturated brine (50*4 mL) was used for washing. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 26b (yellow solid, 3.9 g, yield 60%).

[1177] LC-MS m / z(ESI)=254.00[M+1].

[1178] Step 2

[1179] 5'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one 26c

[1180] 5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[1181] According to the method of 1c, compound 26c (yellow solid, 3.8 mg, yield 82%) was obtained.

[1182] LC-MS m / z(ESI)=300.18[M+1].

[1183] Step 3

[1184] 5-Methyl-6-(2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[1185] tert-butyl3-methyl-6-(2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-3,4-dihydropyr idine-1(2H)-carboxylate

[1186] According to the method of 1d, 26d (yellow solid, 3.8 g, yield 76%) was obtained.

[1187] LC-MS m / z(ESI)=369.20[M+1].

[1188] Step 4

[1189] 5'-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[1190] 5'-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[1191] According to the method of 1e, 26e was obtained (yellow solid, 600 mg, yield 68%).

[1192] LC-MS m / z(ESI)=269.18[M+1].

[1193] Step 5

[1194] 5'-(5-methylpiperidin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[1195] spiro[cyclobutane-1,3'-indolin]-2'-one

[1196] According to the method of 1f, 26f (yellow solid, 550 mg, yield 90%) was obtained.

[1197] LC-MS m / z(ESI)=271.18[M+1].

[1198] Step 6

[1199] 2-(5-methyl-2-(2'-oxospiro[cyclobutane-1,3'-indoline]-5'-yl)piperidin-1-yl)-2-oxoethyl

[1200] Methyl ester

[1201] Methyl 2-(5-methyl-2-(2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)piperidin-1-y

[1202] l)-2-oxoacetate

[1203] According to the method of 1g, 26g (yellow oil, 550mg, yield 80%) was obtained.

[1204] LC-MS m / z(ESI)=357.20[M+1].

[1205] Step 7

[1206] 2-(5-methyl-2-(2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetic acid

[1207] According to the method of 1h, 26h was obtained (yellow oil, 550 mg, yield 99%).

[1208] LC-MS m / z(ESI)=343.30[M+1].

[1209] Step 8

[1210] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-oxospiro[cyclobutane-1,3'-indole]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 26

[1211] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-oxospiro[cyclobutane-1,3'-in dolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[1212] According to the method of compound 1, compound 26 (white solid, 60 mg, yield 46%) was obtained.

[1213] 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),10.24(s,1H),8.10–8.01(m,1H),7.55–7.44(m,2H),7.19–7.06(m,1H),6.84–6.74(m,1H),5. 76–5.69(m,2H),3.50–3.40(m,1H),3.29–3.19(m,1H),2.45–2.18(m,10H),2.05–1.64(m,4H),1.25–1.21(m,3H),1.05–1.01(m,3H).

[1214] LC-MS m / z(ESI)=462.21[M+1].

[1215] Embodiment 27

[1216] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 27

[1217] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-fluoro-4-methyl-3-oxo-3,4-dihydr ospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoac etamide

[1218]

[1219] first step

[1220] 2-(5-methyl-2-(2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetic acid

[1221] 2-((5S)-5-methyl-2-(1'-methyl-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)-2-oxoacetic acid

[1222] According to the method of 25a, 27a was obtained (yellow oil, 90 mg, 90% yield).

[1223] LC-MS m / z(ESI)=357.30[M+1].

[1224] Step 2

[1225] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(1'-methyl-2'-oxo-1'-, 4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)-2-oxoacetamide Compound 27

[1226] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(1'-methyl-2'-oxo-1',4'-dihy dro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)-2-oxoacetamide

[1227] According to the method of compound 25, compound 27 (white solid, 60 mg, yield 52%) was obtained.

[1228] 1 H NMR (400MHz, DMSO-d6) δ10.58–10.47(m,1H),8.10–7.97(m,1H),7.55–7.42(m,1H),7.29–7.18(m,1H),7.10(m,2H),5.72–5.60(m,2H),3.28– 3.21(m,4H),2.88–2.79(m,2H),2.39(m,3H),2.26–1.96(m,2H),1.95– 1.60(m,3H),1.43–1.20(m,3H),1.17–1.05(m,5H),1.04–1.00(m,3H).

[1229] LC-MS m / z(ESI)=476.30[M+1].

[1230] Embodiment 28

[1231] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 28

[1232] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoli n]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1233]

[1234] first step

[1235] 7'-Chlorospiro[cyclopropane-1,3'-indolin]-2'-one compound 28b

[1236] 7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one

[1237] Compound 28a (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 heated to room temperature and stirred for 16 h. After the reaction was complete, saturated ammonium chloride solution was added to quench, and ethyl acetate (150*3 mL) was added for extraction, and saturated brine (100 mL) was washed, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 28b (brown solid, 9.8 g, yield 75%).

[1238] LC-MS m / z(ESI)=194.10[M+1].

[1239] Step 2

[1240] 5'-Bromo-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one 5c

[1241] 5'-bromo-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one

[1242] Compound 5b (9.8 g, 50 mmol) was dissolved in ACN (120 mL), N-bromosuccinimide (10 g, 56 mmol) was added at room temperature, and the mixture was stirred for 16 h. 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 separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 28b (brown solid, 13 g, yield 82%).

[1243] LC-MS m / z(ESI)=274.20[M+1].

[1244] Step 3

[1245] 7'-Chloro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indol]-2'-one 28d

[1246] 7'-chloro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[1247] According to the method of compound 1c, compound 28c (1.0 g, 2.6 mmol) was used to obtain compound 28d (white solid, 1 g, yield 85%).

[1248] LC-MS m / z(ESI)=320.14[M+1].

[1249] Step 4

[1250] 6-(7'-Chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 28e

[1251] tert-butyl 6-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1252] According to the method for synthesizing compound 1d, compound 28d was used to obtain compound 28e (yellow solid, 750 mg, yield 65%).

[1253] LC-MS m / z(ESI)=389.23[M+1].

[1254] Step 5

[1255] 7'-Chloro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 28f

[1256] 7'-chloro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclopropane-1,3'-in dolin]-2'-one

[1257] According to the method of compound 1e, compound 28e was used to obtain compound 28f (yellow solid, 400 mg, yield 71%).

[1258] LC-MS m / z(ESI)=289.20[M+1].

[1259] Step 6

[1260] 7'-Chloro-5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 28g

[1261] 7'-chloro-5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[1262] According to the method of compound 1f, compound 28f was used to obtain compound 28g (yellow solid, 350 mg, yield 90%).

[1263] LC-MS m / z(ESI)=291.20[M+1].

[1264] Step 7

[1265] 2-(2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid methyl ester 28h

[1266] methyl 2-(2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpi peridin-1-yl)-2-oxoacetate

[1267] According to the method for compound 1g, compound 28g was used to obtain compound 28h (yellow oil, 420 mg, yield 93%).

[1268] LC-MS m / z(ESI)=377.20[M+1].

[1269] Step 8

[1270] 2-(2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid 28h

[1271] 2-(2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid

[1272] According to the method for compound 1h, compound 28h was used to obtain compound 28i (white solid, 420 mg, yield 99%).

[1273] LC-MS m / z(ESI)=363.20[M+1].

[1274] Step 9

[1275] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 28

[1276] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoli n]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1277] According to the method of compound 1, compound 28i (100 mg, 0.27 mmol) was used to obtain compound 28

[1278] (white solid, 60 mg, yield 47%).

[1279] 1 HNMR(400MHz,DMSO-d6)δ11.04–10.96(m,1H),10.61–10.50(m,1H),8.11– 7.92(m,1H),7.59–7.38(m,1H),7.21–7.01(m,1H),6.95–6.88(m,1H),5.7 1–5.60(m,2H),4.10–3.80(m,1H),3.53–3.36(m,1H),3.30–3.17(m,1H),2 .40(d,2H),2.28–1.84(m,3H),1.79–1.46(m,6H),1.17–1.06(m,3H),1.05–

[1280] 0.96(m,3H).

[1281] LC-MS m / z(ESI)=488.20[M+1].

[1282] Embodiment 29

[1283] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 29

[1284] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(1'-methyl-2'-oxospiro[cyclopro pane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[1285]

[1286] first step

[1287] 2-(2-(7'-chloro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid 29a

[1288] 2-(2-(7'-chloro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-5-meth ylpiperidin-1-yl)-2-oxoacetic acid

[1289] Following the procedure of 25a, 29a was obtained (yellow oil, 200 mg, 90% yield).

[1290] LC-MS m / z(ESI)=377.20[M+1].

[1291] Step 2

[1292] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 29

[1293] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(1'-methyl-2'-oxospiro[cyclopro pane-1,3'-indolin]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[1294] According to the method of compound 25, compound 29 (white solid, 80 mg, yield 72%) was obtained.

[1295] 1H NMR (400MHz, DMSO-d6) δ10.64–10.51(m,1H),8.12–7.93(m,1H),7.57–7. 39(m,1H),7.21–7.03(m,1H),6.99–6.91(m,1H),5.81–5.45(m,3H),3.57– 3.40(m,4H),3.30–3.20(m,1H),2.45–2.30(m,2H),2.20–1.81(m,3H),1. 70–1.51(m,5H),1.37–1.20(m,2H),1.16–1.05(m,3H),1.04–0.97(m,3H).

[1296] LC-MS m / z(ESI)=462.30[M+1].

[1297] Embodiment 30

[1298] N-(4-amino-1,3-dihydropyrrolo[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-yl)piperidin-1-yl)-2-oxoacetamide Compound 30

[1299] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-6-yl)piperidin-1-yl)-2-oxoaceta mide

[1300]

[1301] first step

[1302] 1-(4-Bromo-2-nitrophenoxy)cyclopropane-1-carboxylic acid ethyl ester 30b

[1303] ethyl 1-(4-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate

[1304] Referring to the synthesis method of 24b, 30a was used to obtain 30b (white solid, 2.2 g, yield 89%).

[1305] LC-MS m / z(ESI)=329.99[M+1].

[1306] Step 2

[1307] 6-Bromospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one 13c

[1308] 6-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1309] Referring to the synthesis method of 24c, 30c was obtained using 30b (white solid, 1.7 g, yield 84%).

[1310] LC-MS m / z(ESI)=253.97[M+1].

[1311] Step 3

[1312] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 30d

[1313] 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1314] Referring to the synthesis method of 24d, 30d was obtained using 30c (yellow solid, 1.1 g, yield 85%).

[1315] LC-MS m / z(ESI)=302.15[M+1].

[1316] Step 4

[1317] (S)-3-Methyl-6-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 30e

[1318] tert-butyl(S)-3-methyl-6-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cy clopropan]-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1319] Referring to the synthesis method of 24e, 30e was obtained using 30d and intermediate B (yellow solid, 954 mg, yield 77%).

[1320] LC-MS m / z(ESI)=371.19[M+1].

[1321] Step 5

[1322] (S)-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 30f

[1323] (S)-6-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1324] Referring to the synthesis method of 24f, 30e was used to obtain 30f (yellow solid, 754 mg, yield 81%).

[1325] LC-MS m / z(ESI)=271.14[M+1].

[1326] Step 6

[1327] 6-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 30g

[1328] 6-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1329] Referring to the synthesis method of 24g, 30f was used to obtain 30g (yellow solid, 733 mg, yield 83%).

[1330] LC-MS m / z(ESI)=273.15[M+1].

[1331] Step 7

[1332] 2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-yl)piperidin-1-yl)-2-oxoacetate 30h

[1333] methyl 2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-6-yl)piperidin-1-yl)-2-oxoacetate

[1334] Referring to the synthesis method of 24h, 30g was used to obtain 30h (yellow solid, 874 mg, yield 86%).

[1335] LC-MS m / z(ESI)=359.15[M+1].

[1336] Step 8

[1337] 2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-yl)piperidin-1-yl)-2-oxoacetic acid 30i

[1338] 2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopro pan]-6-yl)piperidin-1-yl)-2-oxoacetic acid

[1339] Referring to the synthesis method of 24i, 30h was used to obtain the lithium salt of 30i (yellow solid, 981 mg, yield 86%).

[1340] LC-MS m / z(ESI)=345.14[M+1].

[1341] Step 9

[1342] N-(4-amino-1,3-dihydrospiro[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-yl)piperidin-1-yl)-2-oxoacetamide Compound 30

[1343] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-6-yl)piperidin-1-yl)-2-oxoaceta mide

[1344] Referring to the synthesis method of compound 1, compound 30 was obtained using 30i and intermediate A (white solid, 101 mg, yield 77%).

[1345] 1 H NMR(400MHz,DMSO-d6)δ10.70(d,1H),10.42(d,1H),7.86-7.75(m,1H),6.96–6.81(m,3H),6.05(s,2H),5.5-5.31(m,1H),4.93–4.70(m,4 H),3.44-3.40(m,1H),3.30–3.19(m,1H),2.18–1.67(m,4H),1.42–1.32(m,1H),1.26-1.22(m,3H),1.18–1.15(m,2H),1.03-1.00(m,2H).

[1346] LC-MS m / z(ESI)=478.20[M+1].

[1347] Embodiment 31

[1348] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide Compound 31

[1349] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahy dropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide

[1350]

[1351] first step

[1352] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide Compound 31

[1353] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2-methyl-1-oxo-1,2,3,4-tetrahy dropyrazino[1,2-b]indazol-9-yl)piperidin-1-yl)-2-oxoacetamide

[1354] According to the method of compound 1, compound 9h and intermediate C were used to obtain compound 13 (white solid, 112 mg, yield 74%).

[1355] 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.15–7.93(m,2H),7.81-7.75(m,1H),7 .59–7.49(m,1H),7.45–7.22(m,1H),5.82(s,2H),5.76-5.29(m,1H),4.73-4.6 9(m,2H),3.90-3.87(m,2H),3.55-3.51(m,1H),3.27–3.16(m,1H),3.07(s,3H ),2.45.2.43(m,2H),2.30–1.67(m,5H),1.18–1.10(m,3H),1.05-1.02(m,3H).

[1356] LC-MS m / z(ESI)=490.25[M+1].

[1357] Embodiment 32

[1358] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-yl)piperidin-1-yl)-2-oxoacetamide Compound 32

[1359] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-6-yl)piperidin-1-yl)-2-oxoacetamide

[1360]

[1361] first step

[1362] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-yl)piperidin-1-yl)-2-oxoacetamide Compound 32

[1363] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-6-yl)piperidin-1-yl)-2-oxoacetamide

[1364] According to the method of compound 1, using compound 30i and intermediate C, compound 32 (white solid, 97 mg, yield 79%) was obtained.

[1365] 1 H NMR(400MHz,DMSO-d6)δ10.70(d,Hz,1H),10.60–10.48(m,1H),8.18–8.02(m,1H),7.56-7.52(m,1H),6.98–6.79(m,3H),5.8 8(s,2H),5.55–5.03(m,1H),3.52-3.49(m,1H),3.28–3.20(m,1H),2.46–2.32(m,2H),2.21–1.57(m,5H),1.19–0.95(m,10H).

[1366] LC-MS m / z(ESI)=464.22[M+1].

[1367] Embodiment 33

[1368] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-(1-methylpiperidin-4-yl)-3'-oxo-1',2',3',4'-tetrahydro-115-spiro[cyclopropane-1,5'-isoquinoline]-7'-yl)piperidin-1-yl)-2-oxoacetamide Compound 33

[1369] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-(1-methylpiperidin-4-yl)-3'-oxo-1',2',3',4'-tetrahydro-1l5-spiro[cyclopropane-1,5'-isoquinolin]-7'-yl)piperidin-1-yl)-2-oxoacetamide

[1370]

[1371] first step

[1372] 1-(4-Bromophenyl)-N-(1-methylpiperidin-4-yl)cyclopropane-1-carboxamide 33b

[1373] 1-(4-bromophenyl)-N-(1-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[1374] Compound 33a (2.0 g, 8.3 mmol), N1-methylcyclohexane-1,4-diamine (1.1 g, 9.9 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.8 g, 9.9 mmol), and triethylamine (1.7 g, 16.6 mmol) were dissolved in N,N-dimethylformamide (20 mL), reacted at room temperature for 3 h, added with saturated sodium chloride aqueous solution (200 mL), extracted with DCM (30 mL), and the organic phases were combined and concentrated under reduced pressure, and separated by column chromatography (dichloromethane: methanol = 50:1) to obtain compound 33b (yellow solid, 2.2 g, yield 79%).

[1375] LC-MS m / z(ESI)=337.08[M+1].

[1376] Step 2

[1377] 7'-Bromo-2'-(1-methylpiperidin-4-yl)-1'-,2'-dihydro-3'H-spiro[cyclopropane-1,4'-isoquinolin]-3'-one 33c

[1378] 7'-bromo-2'-(1-methylpiperidin-4-yl)-1',2'-dihydro-3'H-spiro[cyclopropane-1,4'-isoquinolin]-3'-one

[1379] Compound 33b (900 mg, 2.8 mmol) and paraformaldehyde (250 mg, 8.3 mmol) were dissolved in Eaton's reagent (10 mL), reacted at 80°C for 4 h, then ice water was added, 10% sodium hydroxide aqueous solution (30 mL) was used to adjust the pH to 10, and dichloromethane (10 mL*3) was used for extraction. The organic phases were combined and concentrated under reduced pressure, and compound 33c was isolated by column chromatography (dichloromethane: methanol = 50:1). (Yellow solid, 910 mg, yield 93%).

[1380] LC-MS m / z(ESI)=349.08[M+1].

[1381] Step 3

[1382] 2'-(1-methylpiperidin-4-yl)-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1'-,2'-dihydro-3'-spiro[cyclopropane-1,4'-isoquinoline]-3'-one 33d

[1383] 2'-(1-methylpiperidin-4-yl)-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',2'-dihydro-3'H-spiro[cyclopropane-1,4'-isoquinolin]-3'-one

[1384] Referring to the synthesis method of compound 1c, 33d was obtained using 33c (yellow solid, 782 mg, yield 84%).

[1385] LC-MS m / z(ESI)=397.26[M+1]

[1386] Step 4

[1387] 3-Methyl-6-(2'-(1-methylpiperidin-4-yl)-3'-oxo-2'-,3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 33e

[1388] tert-butyl 3-methyl-6-(2'-(1-methylpiperidin-4-yl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1389] Referring to the synthesis method of compound 1d, 33e was obtained using 33d and intermediate B (yellow solid, 813 mg, yield 84%).

[1390] LC-MS m / z(ESI)=466.30[M+1]

[1391] Step 5

[1392] 7'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-2'-(1-methylpiperidin-4-yl)-1'-,2'-dihydro-3'-spiro[cyclopropane-1,4'-isoquinoline]-3'-one 33f

[1393] 7'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-2'-(1-methylpiperidin-4-yl)-1',2'-dih ydro-3'H-spiro[cyclopropane-1,4'-isoquinolin]-3'-one

[1394] Referring to the synthesis method of compound 1e, 33e was used to obtain 33f (yellow solid, 727 mg, yield 81%).

[1395] LC-MS m / z(ESI)=366.25[M+1].

[1396] Step 6

[1397] 7'-(5-methylpiperidin-2-yl)-2'-(1-methylpiperidin-4-yl)-1'-dihydro-3'-H-spiro[cyclopropane-1,4'-isoquinoline]-3'-one 33g

[1398] 7'-(5-methylpiperidin-2-yl)-2'-(1-methylpiperidin-4-yl)-1',2'-dihydro-3'H-spiro[cyclopropane-1,4'-isoquinolin]-3'-one

[1399] Referring to the synthesis method of compound 1f, 33g was obtained using 33f (yellow solid, 703 mg, yield 85%).

[1400] LC-MS m / z(ESI)=368.26[M+1].

[1401] Step 7

[1402] 2-(5-methyl-2-(2'-(1-methylpiperidin-4-yl)-3'-oxo-2'-, 3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)piperidin-1-yl)-2-oxoacetate 33h

[1403] methyl 2-(5-methyl-2-(2'-(1-methylpiperidin-4-yl)-3'-oxo-2',3'-dihydro-1'H-spir o[cyclopropane-1,4'-isoquinolin]-7'-yl)piperidin-1-yl)-2-oxoacetate

[1404] Referring to the synthesis method of compound 1g, 33h was obtained using 33g (yellow solid, 751 mg, yield 88%).

[1405] LC-MS m / z(ESI)=454.26[M+1].

[1406] Step 8

[1407] 2-(5-methyl-2-(2'-(1-methylpiperidin-4-yl)-3'-oxo-2'-, 3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)piperidin-1-yl)-2-oxoacetic acid 33i

[1408] 2-(5-methyl-2-(2'-(1-methylpiperidin-4-yl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclop ropane-1,4'-isoquinolin]-7'-yl)piperidin-1-yl)-2-oxoacetic acid

[1409] Referring to the synthesis method of compound 1h, 33h was used to obtain the lithium salt of 33i (yellow solid, 772 mg, yield 86%).

[1410] LC-MS m / z(ESI)=440.25[M+1].

[1411] Step 9

[1412] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-(1-methylpiperidin-4-yl)-3'-oxo-1',2',3',4'-tetrahydro-115-spiro[cyclopropane-1,5'-isoquinoline]-7'-yl)piperidin-1-yl)-2-oxoacetamide Compound 33

[1413] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2'-(1-methylpiperidin-4-yl)-3'-oxo-1',2',3',4'-tetrahydro-1l5-spiro[cyclopropane-1,5'-isoquinolin]-7'-yl)piperidin-1-yl)-2-oxoacetamide

[1414] Referring to the synthesis method of compound 1h, 33i and intermediate C were used to obtain 33 (white solid, 116 mg, yield 83%).

[1415] 1 H NMR(400MHz,DMSO-d6)δ10.52(d,1H),8.13–7.95(m,1H),7.47(d,1H),7.35–7.08(m, 3H),5.66(d,2H),5.34-5.22(m,1H),4.56(d,2H),4.35-4.33(m,1H),3.49-3.45(m,1 H),3.27–3.12(m,1H),2.94–2.52(m,4H),2.44–2.34(m,2H),2.20(s,3H),2.03–1.68 (m,7H),1.57-1.49(m,4H),1.38–1.29(m,2H),1.14–1.07(m,3H),1.03-0.99(m,3H).

[1416] LC-MS m / z(ESI)=559.33[M+1].

[1417] Embodiment 34

[1418] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 34

[1419] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-iso benzofuran]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[1420]

[1421]

[1422] first step

[1423] 1-(4-Bromo-2-(hydroxymethyl)phenyl)cyclopropane-1-ol 34b

[1424] 1-(4-bromo-2-(hydroxymethyl)phenyl)cyclopropan-1-ol

[1425] Compound 34a (5.0 g, 23.5 mmol) and tetraisopropyl titanate (7.3 g, 25.8 mmol) were dissolved in tetrahydrofuran (80 mL), and ethyl magnesium bromide (28.2 mL, 56.7 mmol) was added dropwise at 0°C. After addition, the temperature was naturally raised to room temperature for 3 h. After TLC monitoring, saturated aqueous ammonium chloride solution (200 mL) was added, and ethyl acetate (30 mL*2) was used for extraction. The organic phases were combined and concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 34b (yellow solid, 3.6 g, yield 64%).

[1426] LC-MS m / z(ESI)=242.99[M+1].

[1427] Step 2

[1428] 5'-Bromo-3'-spiro[cyclopropane-1,1'-isobenzofuran]34c

[1429] 5'-bromo-3'H-spiro[cyclopropane-1,1'-isobenzofuran]

[1430] Compound 34b (3.6 g, 14.9 mmol) and triphenylphosphine (11.7 g, 44.7 mmol) were dissolved in tetrahydrofuran (50 mL), and diisopropyl azodicarboxylate (7.5 g, 37.3 mmol) was added dropwise at 0°C. After reacting for 4 h, the organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain compound 34c (white solid, 2.0 g, yield 61%).

[1431] LC-MS m / z(ESI)=224.98[M+1].

[1432] Step 3

[1433] 4,4,5,5-Tetramethyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-1,3,2-dioxaborolane 34d

[1434] 4,4,5,5-tetramethyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-1,3,2-di oxaborolane

[1435] Referring to the synthesis method of compound 1c, 34d was obtained using 34c (yellow solid, 1.4 g, yield 81%).

[1436] LC-MS m / z(ESI)=273.16[M+1]

[1437] Step 4

[1438] 3-Methyl-6-(3'-H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 34e

[1439] tert-butyl 3-methyl-6-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-3,4-dih ydropyridine-1(2H)-carboxylate

[1440] Referring to the synthesis method of compound 1d, 34e was obtained using 34d and intermediate B (yellow solid, 1.2 g, yield 87%).

[1441] LC-MS m / z(ESI)=342.12[M+1]

[1442] Step 5

[1443] 3-Methyl-6-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-1,2,3,4-tetrahydropyridine 34f

[1444] 3-methyl-6-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)-1,2,3,4-tetrahydr opyridine

[1445] 4- Referring to the synthesis method of compound 1e, 34e was used to obtain 34f (yellow solid, 1.0 g, yield 80%).

[1446] LC-MS m / z(ESI)=242.15[M+1].

[1447] Step 6

[1448] 5-Methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidine 34g

[1449] 5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidine

[1450] Referring to the synthesis method of compound 1f, 34f was used to obtain 34g (yellow solid, 920 mg, yield 87%).

[1451] LC-MS m / z(ESI)=244.16[M+1].

[1452] Step 7

[1453] 2-(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidin-1-yl)-2-oxoacetate 34h

[1454] methyl 2-(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperid in-1-yl)-2-oxoacetate

[1455] Referring to the synthesis method of compound 1g, 34g was used to obtain 34h (yellow solid, 1.1 g, yield 86%).

[1456] LC-MS m / z(ESI)=330.16[M+1].

[1457] Step 8

[1458] 2-(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidin-1-yl)-2-oxoacetic acid 34i

[1459] 2-(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidin-1-yl)-2-oxoacetic acid

[1460] Referring to the synthesis method of compound 1h, 34h was used to obtain the lithium salt of 34i (yellow solid, 1.2 g, yield 84%).

[1461] LC-MS m / z(ESI)=316.15[M+1].

[1462] Step 9

[1463] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)piperidin-1-yl)-2-oxoacetamide Compound 34

[1464] N-(6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(3'H-spiro[cyclopropane-1,1'-iso benzofuran]-5'-yl)piperidin-1-yl)-2-oxoacetamide

[1465] Referring to the synthesis method of compound 1h, 34i and intermediate C were used to obtain 34 (white solid, 121 mg, yield 79%).

[1466] 1 H NMR(400MHz,DMSO-d6)δ10.62(d,1H),8.18–8.00(m,1H),7.57-7.51(m,1H),7.32–6.91(m,3H),6.01(s,2H),5.19–5.01(m,2H),4.568-4.37(m,1 H),3.49-3.45(m,1H),3.27-3.22(m,1H),2.41(dt,2H),2.29–1.60(m,5H ),1.15-1.12(m,3H),1.13–1.08(m,2H),1.02(d,3H),0.95-0.93(m,2H).

[1467] LC-MS m / z(ESI)=435.23[M+1].

[1468] Embodiment 35

[1469] N-(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-(2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)acetamide Compound 35

[1470] N-(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-(2-(2'-oxo-1',4'-dihydro-2'H-spiro[cycl opropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)acetamide

[1471]

[1472] first step

[1473] 6-(2'-Oxo-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 35a

[1474] ttert-butyl 6-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1475] Referring to the synthesis method of compound 1d, compound 11h and intermediate D were used to obtain compound 35a (yellow solid, 1.2 g, yield 79%).

[1476] LC-MS m / z(ESI)=355.20[M+1].

[1477] Step 2

[1478] 6'-(1,4,5,6-tetrahydropyridin-2-yl)-1'-dihydro-2'-spiro[cyclopropane-1,3'-quinoline]-2'-one 35b

[1479] 6'-(1,4,5,6-tetrahydropyridin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-qui nolin]-2'-one

[1480] Referring to the synthesis method of compound 1e, compound 35a was used to obtain compound 35b (yellow solid, 1.0 g, yield 81%).

[1481] LC-MS m / z(ESI)=255.14[M+1].

[1482] Step 3

[1483] 6'-(Piperidin-2-yl)-1'-,4'-dihydro-2'-spiro[cyclopropane-1,3'-quinolinyl]-2'-one 35c

[1484] 6'-(piperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1485] Referring to the synthesis method of compound 1f, compound 35c was obtained using compound 35b. (yellow solid, 94

[1486] 1 mg, yield 87%).

[1487] LC-MS m / z(ESI)=257.16[M+1].

[1488] Step 4

[1489] 2-Oxo-2-(2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)acetate 35d

[1490] mmethyl 2-oxo-2-(2-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)acetate

[1491] Referring to the synthesis method of compound 1g, compound 35c was used to obtain compound 35d (yellow solid, 1.1 g, yield 89%).

[1492] LC-MS m / z(ESI)=343.16[M+1].

[1493] Step 12

[1494] 2-Oxo-2-(2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)acetic acid 35e

[1495] 2-oxo-2-(2-(2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)pip eridin-1-yl)acetic acid

[1496] Referring to the synthesis method of compound 1h, compound 35d was used to obtain the lithium salt of compound 35e (yellow solid, 1.3 g, yield 86%).

[1497] LC-MS m / z(ESI)=329.14[M+1].

[1498] Step 13

[1499] N-(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-(2-(2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)acetamide Compound 35

[1500] N-(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-(2-(2'-oxo-1',4'-dihydro-2'H-spiro[cycl opropane-1,3'-quinolin]-6'-yl)piperidin-1-yl)acetamide

[1501] Referring to the synthesis method of compound 1, compound 35e and intermediate C were used to obtain compound 35 (white solid, 73 mg, yield 79%).

[1502] 1 H NMR(400MHz,DMSO-d6)δ10.63(d,1H),10.16(s,1H),8.09(dd,1H),7.54(dd,1H),7.14–6.86(m,3H),5.98(s,2H),5.65–5.06(m,1H),4.35–3 .56(m,1H),3.22–2.93(m,1H),2.84(d,2H),2.50-2.49(m,2H),1.94– 1.38(m,6H),1.17–1.09(m,3H),1.08-1.05(m,2H),0.74-0.70(m,2H).

[1503] LC-MS m / z(ESI)=448.23[M+1].

[1504] Embodiment 36

[1505] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-((5S)-2-(8'-fluoro-2'-oxo-1'-, 4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 36

[1506] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-((5S)-2-(8'-fluoro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoac etamide

[1507]

[1508] first step

[1509] 8-Fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 36b

[1510] 8-fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[1511] Referring to the synthesis method of compound 11b, compound 36a was used to obtain compound 36b (white solid, 1.4 g, yield 81%).

[1512] LC-MS m / z(ESI)=286.12[M+1].

[1513] Step 2

[1514] 3-(2-Chloroethyl)-8-fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 36c

[1515] 3-(2-chloroethyl)-8-fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[1516] Referring to the synthesis method of compound 11c, compound 36b was used to obtain compound 36c (white solid, 1.7 g, yield 84%).

[1517] LC-MS m / z(ESI)=348.11[M+1].

[1518] Step 3

[1519] 8-Fluoro-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 36d

[1520] 8-fluoro-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[1521] Referring to the synthesis method of compound 11d, compound 36c was used to obtain compound 36d (yellow solid, 2.1 g, yield 81%).

[1522] LC-MS m / z(ESI)=440.04[M+1].

[1523] Step 4

[1524] 8-Fluoro-1'-(4-methoxybenzyl)-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinolin]-2'-one 36e

[1525] 8'-fluoro-1'-(4-methoxybenzyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoli n]-2'-one

[1526] Referring to the synthesis method of compound 11e, compound 36d was used to obtain compound 36e (yellow solid, 1.6 g, yield 81%).

[1527] LC-MS m / z(ESI)=312.13[M+1].

[1528] Step 5

[1529] 8'-Fluoro-1'-, 4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one 36f

[1530] 8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1531] Referring to the synthesis method of compound 11f, compound 36e was used to obtain compound 36f (yellow solid, 1.3 g, yield 81%).

[1532] LC-MS m / z(ESI)=192.07[M+1].

[1533] Step 6

[1534] 6'-Bromo-8-fluoro-1'-, 4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one 36g

[1535] 6'-bromo-8'-fluoro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1536] Referring to the synthesis method of compound 11f, compound 36f was used to obtain compound 36g (yellow solid, 1.7 g, yield 83%).

[1537] LC-MS m / z(ESI)=269.99[M+1].

[1538] Step 7

[1539] 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 36h

[1540] 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

[1541] Referring to the synthesis method of compound 1c, compound 36g was used to obtain compound 36h (yellow solid, 2.1 g, yield 84%).

[1542] LC-MS m / z(ESI)=318.16[M+1].

[1543] Step 8

[1544] (S)-3-methyl-6-(8-fluoro-2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 36i

[1545] tert-butyl(S)-6-(8'-fluoro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quin olin]-6'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1546] Referring to the synthesis method of compound 1d, compound 36i was obtained using compound 36h and intermediate B (yellow solid, 2.3 g, yield 81%).

[1547] LC-MS m / z(ESI)=387.20[M+1].

[1548] Step 9

[1549] (S)-8-Fluoro-6'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-1'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinolin]-2'-one 36j

[1550] (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

[1551] Referring to the synthesis method of compound 1e, compound 36i was used to obtain compound 36j (yellow solid, 1.7 g, yield 83%).

[1552] LC-MS m / z(ESI)=287.15[M+1].

[1553] Step 10

[1554] 8-Fluoro-6'-((5S)-5-methylpiperidin-2-yl)-1'-, 4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one 36k

[1555] 8'-fluoro-6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,

[1556] 3'-quinolin]-2'-one

[1557] Referring to the synthesis method of compound 1f, compound 36j was used to obtain compound 36k. (yellow solid, 1.

[1558] 5g, yield 81%).

[1559] LC-MS m / z(ESI)=289.16[M+1].

[1560] Step 11

[1561] 2-((5S)-5-methyl-2-(8-fluoro-2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)-2-oxoacetate 361

[1562] methyl 2-((5S)-2-(8'-fluoro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-qui nolin]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetate

[1563] Referring to the synthesis method of compound 1g, compound 36k was used to obtain compound 361 (yellow solid, 1.6 g, yield 74%).

[1564] LC-MS m / z(ESI)=375.16[M+1].

[1565] Step 12

[1566] 2-((5S)-5-methyl-2-(8-fluoro-2'-oxo-1',4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)piperidin-1-yl)-2-oxoacetic acid 36m

[1567] 2-((5S)-2-(8'-fluoro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetic acid

[1568] Referring to the synthesis method of compound 1h, compound 361 was used to obtain the lithium salt of compound 36m (yellow solid, 1.8 g, yield 88%).

[1569] LC-MS m / z(ESI)=361.15[M+1].

[1570] Step 13

[1571] N-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-2-((5S)-2-(8'-fluoro-2'-oxo-1'-, 4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 36

[1572] N-(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-2-((5S)-2-(8'-fluoro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoac etamide

[1573] Referring to the synthesis method of compound 1, compound 36 was obtained using compound 36m and intermediate C (white solid, 118 mg, yield 79%).

[1574] 1 H NMR (400MHz, DMSO-d6) δ10.54(d,1H),10.17(s,1H),8.04(d,1H),7.48(d,1H),7.16–6.82(m,2H),5.67(d,2H),5.52-5.07(m, 1H),4.11–3.52(m,1H),3.27-2.23(m,1H),2.85(s,2H),2.43-2.40(m,2H),2.17–1.59(m,5H),1.17-1.00(m,8H),0.74(s,2H).

[1575] LC-MS m / z(ESI)=480.23[M+1].

[1576] Embodiment 37

[1577] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-chloro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropyl]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 37

[1578] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-chloro-3-oxo-3,4-dihydrospiro[be nzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1579]

[1580] first step

[1581] 1-(5-Bromo-3-chloro-2-nitrophenoxy)cyclopropane-1-carboxylic acid ethyl ester 37b

[1582] ethyl 1-(5-bromo-3-chloro-2-nitrophenoxy)cyclopropane-1-carboxylate

[1583] At 0°C, ethyl 1-hydroxycyclopropane-1-carboxylate (3.0 g, 23.5 mmol) was dissolved in THF (50 mL), and NaH (1.28 g, 32.1 mmol) was added. The mixture was stirred for 30 min, and then a THF mixture of 37a (5 g, 21.4 mmol) was added dropwise. The reaction was allowed to react at room temperature, and the reaction progress was monitored by TLC.

[1584] The reaction was stopped, water was added, and the mixture was extracted with EA. The organic phase was taken and dried over anhydrous sodium sulfate, and then purified by column chromatography (EA:PE=1:7) to obtain compound 37b (white solid, 6 g, yield 77.5%).

[1585] LC-MS m / z(ESI)=363.99[M+1].

[1586] Step 2

[1587] 7-Bromo-5-chlorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 37c

[1588] 7-bromo-5-chlorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one

[1589] Compound 37b (6 g, 16.5 mmol) was dissolved in acetic acid (30 mL), and iron powder (2.8 g, 49.6 mmol) was added to react at room temperature. The reaction progress was monitored by TLC.

[1590] The reaction was stopped, water was added, and the mixture was filtered off. The solid was collected and separated by column chromatography (EA:PE=1:5) to obtain compound 37c (white solid, 4.4 g, yield 85.7%).

[1591] LC-MS m / z(ESI)=287.99[M+1].

[1592] Step 3

[1593] 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 37d

[1594] 5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]oxaz ine-2,1'-cyclopropan]-3(4H)-one

[1595] According to the method of compound 1c, compound 37d (yellow solid, 4.1 g, yield 83.6%) was obtained.

[1596] LC-MS m / z(ESI)=336.12[M+1].

[1597] Step 4

[1598] (S)-6-(5-chloro-3-oxo-3,4-dihydrospirobenzo[b[[1,4[oxazine-2,1'-cyclopropyl]-7-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 37e

[1599] tert-butyl-(S)-6-(5-chloro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cycl opropan]-7-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1600] According to the method of compound 1d, compound 37e (yellow solid, 1.04 g, yield 45%) was obtained using compound 38d (2 g, 5.9 mmol).

[1601] LC-MS m / z(ESI)=405.16[M+1].

[1602] Step 5

[1603] (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 37f

[1604] (S)-5-chloro-7-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[benzo[b][1,4]oxaz ine-2,1'-cyclopropan]-3(4H)-one

[1605] According to the method of compound 1e, compound 37f (white solid, 700 mg, yield 96%) was obtained.

[1606] LC-MS m / z(ESI)=305.17[M+1].

[1607] Step 6

[1608] 5-Chloro-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 37 g

[1609] 5-chloro-7-((5S)-5-methylpiperidin-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopr opan]-3(4H)-one

[1610] According to the method of compound 1f, compound 37g (white solid, 1.6 g, yield 89%) was obtained.

[1611] LC-MS m / z(ESI)=306.14[M+1].

[1612] Step 7

[1613] tert-butyl-(5-(2-((5S)-2-(5-chloro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamido)-3-ethylpyridin-2-yl)carbamate

[1614] Compound 37g (100 mg, 0.33 mmol), intermediate D (130 mg, 0.42 mmol), HA TU (159 mg, 0.42 mmol), DIPEA (128 mg, 0.99 mmol) were dissolved in a mixed solvent of N,N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL). After reacting at room temperature for 12 h, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were concentrated under reduced pressure and purified by column chromatography (PE:EA=1:1) to obtain compound 37h (light yellow solid, 150 mg, yield 76%).

[1615] LC-MS m / z(ESI)=598.26[M+1].

[1616] Step 8

[1617] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-chloro-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropyl]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 37

[1618] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(5-chloro-3-oxo-3,4-dihydrospiro[be nzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1619] According to the method of compound 37f, compound 37 (white solid, 70 mg, yield 56%) was obtained.

[1620] 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.84-9.62(m,1H),8.32-8.20(m,1H),7.76-7 .63(m,1H),7.08-6.98(m,1H),6.88-6.74(m,1H),5.96(s,2H),5.83-5.22(m,1H),3. 87-3.81(m,1H),3.56-3.44(m,1H),2.85-2.66(m,2H),2.37–1.79(m,4H),1.57–1.49 (m,1H),1.39-1.25(m,3H),1.19-1.11(m,3H),1.07-1.02(m,3H),0.98-0.83(s,1H).

[1621] LC-MS m / z(ESI)=498.27[M+1].

[1622] Embodiment 38

[1623] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 38

[1624] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-sp iro[cyclopropane-1,3'-quinolin]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1625]

[1626] first step

[1627] 8-Chloro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 38b

[1628] 8-chloro-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[1629] Referring to the synthesis method of compound 12b, compound 38a was used to obtain compound 38b (white solid, 5.2 g, yield 81%).

[1630] LC-MS m / z(ESI)=302.11[M+1].

[1631] Step 2

[1632] 8-Chloro-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 38c

[1633] 8-chloro-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[1634] Referring to the synthesis method of compound 12c, compound 38b was used to obtain compound 38c (yellow solid, 1.16 g, yield 18.5%).

[1635] LC-MS m / z(ESI)=364.16[M+1].

[1636] Step 3

[1637] 8-Chloro-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 38d

[1638] 8-chloro-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[1639] Referring to the synthesis method of compound 12d, compound 38c was used to obtain compound 38d (yellow oily liquid, 1.27 g, yield 87%).

[1640] LC-MS m / z(ESI)=456.11[M+1].

[1641] Step 4

[1642] 8'-Chloro-1'-(4-methoxybenzyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one 38e

[1643] 8'-chloro-1'-(4-methoxybenzyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinol in]-2'-one

[1644] Referring to the synthesis method of compound 12e, compound 38d was used to obtain compound 38e (yellow oily liquid, 750 mg, yield 82%).

[1645] LC-MS m / z(ESI)=328.18[M+1].

[1646] Step 5

[1647] 8'-Chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolinyl]-2'-one 38f

[1648] 8'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1649] Referring to the synthesis method of compound 12f, compound 38e was used to obtain compound 38f (yellow oily liquid, 480 mg, yield 94%).

[1650] LC-MS m / z(ESI)=208.16[M+1].

[1651] Step 6

[1652] 6'-Bromo-8'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-2'-one 38g

[1653] 6'-bromo-8'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1654] Referring to the synthesis method of compound 12f, compound 38f was used to obtain compound 38g (white solid, 500 mg, yield 77%).

[1655] LC-MS m / z(ESI)=285.99[M+1].

[1656] Step 7

[1657] 8'-Chloro-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-2'-one 38h

[1658] 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

[1659] Referring to the synthesis method of compound 12h, compound 38g was used to obtain compound 38h (white solid, 425 mg, yield 73%).

[1660] LC-MS m / z(ESI)=334.19[M+1].

[1661] Step 8

[1662] (S)-6-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 38i

[1663] tert-butyl(S)-6-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quin olin]-6'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1664] Referring to the synthesis method of compound 12i, compound 38h and intermediate B were used to obtain compound 38i (yellow solid, 410 mg, yield 80%).

[1665] LC-MS m / z(ESI)=403.21[M+1].

[1666] Step 9

[1667] (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 38j

[1668] (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

[1669] Referring to the synthesis method of compound 12j, compound 38i was used to obtain compound 38j (brown solid, 370 mg, yield 94%).

[1670] LC-MS m / z(ESI)=303.21[M+1].

[1671] Step 10

[1672] 8'-Chloro-6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-2'-one 38k

[1673] 8'-chloro-6'-((5S)-5-methylpiperidin-2-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[1674] Referring to the synthesis method of compound 12k, compound 38j was used to obtain compound 38k. (yellow solid, 2

[1675] 62 mg, 71% yield).

[1676] LC-MS m / z(ESI)=305.23[M+1].

[1677] Step 11

[1678] (5-((5S)-2-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetylcarbamate tert-butyl ester Compound 381

[1679] tert-butyl(5-(2-((5S)-2-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamido)-3-ethylpyridin-2-yl)carba mate

[1680] According to the method of compound 37h, compound 38k and intermediate D were used to obtain compound 381 (yellow solid, 177 mg, yield 74%).

[1681] LC-MS m / z(ESI)=596.36[M+1].

[1682] Step 12

[1683] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 38

[1684] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(8'-chloro-2'-oxo-1',4'-dihydro-2'H-sp iro[cyclopropane-1,3'-quinolin]-6'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1685] According to the method of compound 37, compound 38 (white solid, 80 mg, yield 54%) was obtained.

[1686] 1H NMR(400MHz,DMSO)δ10.56(d,1H),9.56(d,1H),8.04(d,1H),7.48(d,1H),7.23(d,1H),7.07(d,1H),5.68(d,2H),5.30(d,1H), 3.74(dd,1H),3.28–2.75(m,3H),2.39(dq,2H),2.20–1.63(m,4H),1.32(dd,1H),1.12(dd,5H),1.01(d,3H),0.79–0.72(m,2H).

[1687] LC-MS m / z(ESI)=496.36[M+1].

[1688] Embodiment 39

[1689] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-fluoro-2'-oxospiro[cyclobutane-1,3'-indole]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 39

[1690] N-(6-amino-5-ethylpyridin-3-yl)-2-(2-(7'-fluoro-2'-oxospiro[cyclobutane-1,3'-ind olin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1691]

[1692] first step

[1693] 7'-Fluorospiro[cyclobutane-1,3'-indolin]-2'-one 39b

[1694] 7'-fluorospiro[cyclobutane-1,3'-indolin]-2'-one

[1695] According to the method of 5b, 39a (25 g, 165 mmol) was used to give 39b (brown solid, 17 g, 54.8% yield).

[1696] LC-MS m / z(ESI)=192.16[M+1].

[1697] Step 2

[1698] 7'-Fluorospiro[cyclobutane-1,3'-indolin]-2'-one 39c

[1699] 7'-fluorospiro[cyclobutane-1,3'-indolin]-2'-one

[1700] According to the method of 28c, 39b (17 g, 89 mmol) was used to give 39c (brown solid, 16.2 g, 67.5% yield).

[1701] LC-MS m / z(ESI)=270.01[M+1].

[1702] Step 3

[1703] 7'-Fluoro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one 39d

[1704] 7'-fluoro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[1705] According to the method of 1c, 39c (1.0 g, 2.6 mmol) was used to give 39d (white solid, 950 g, yield 90%).

[1706] LC-MS m / z(ESI)=318.14[M+1].

[1707] Step 4

[1708] 6-(7'-Fluoro-2'-oxospiro[cyclobutane-1,3'-dihydroindole]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 39e

[1709] tert-butyl 6-(7'-fluoro-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[1710] According to the method of synthesizing 1d, compound 39e (yellow solid, 700 mg, yield 67.2%).

[1711] LC-MS m / z(ESI)=387.20[M+1].

[1712] Step 5

[1713] 7'-Fluoro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one 39f

[1714] 7'-fluoro-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)spiro[cyclobutane-1,3'-indo lin]-2'-one

[1715] According to the method of 1e, 39f was obtained (yellow solid, 600 mg, yield 85%).

[1716] LC-MS m / z(ESI)=287.23[M+1].

[1717] Step 6

[1718] 7'-Fluoro-5'-(5-methylpiperidin-2-yl)spiro[cyclopropane-1,3'-indolin]-2'-one 5g

[1719] 7'-fluoro-5'-(5-methylpiperidin-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[1720] According to the method of 1f, 39f was used to obtain 39g (yellow solid, 550 mg, yield 83%).

[1721] LC-MS m / z(ESI)=289.20[M+1].

[1722] Step 7

[1723] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(7'-fluoro-2'-oxospiro[cyclobutane-1,3'-indole]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide Compound 39

[1724] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-2-(7'-fluoro-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

[1725] According to the method of compound 1, 39g (100 mg, 0.34 mmol) was used to obtain compound 39 (white solid, 80 mg, yield 48%).

[1726] 1 HNMR(400MHz,DMSO-d6)δ10.58(s,1H),10.24(s,1H),8.10–8.01(m,1H),7.55–7.50(m,1H),7.16–7.07(m,1H),6.85–6.70(m,1H),5 .78–5.70(m,2H),3.48–3.36(m,1H),3.30–3.17(m,1H),2.48–2.15(m,10H),2.08–1.65(m,4H),1.23–1.19(m,3H),1.08–1.0(m,3H).

[1727] LC-MS m / z(ESI)=480.20[M+1].

[1728] Embodiment 40

[1729] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(1-methyl-3"H-spiro[azetidine-3,1'-cyclobutane-3',2"-benzofuran]-5"-yl)piperidin-1-yl)-2-oxoacetamide Compound 40

[1730] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(1-methyl-3”H-disspiro[azeti dine-3,1'-cyclobutane-3',2”-benzofuran]-5”-yl)piperidin-1-yl)-2-oxoacetamide

[1731]

[1732] first step

[1733] 6-(5-Bromo-2-fluorobenzyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 40b

[1734] tert-butyl 6-(5-bromo-2-fluorobenzyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carb oxylate

[1735] According to the method of 2b, 40b was obtained (yellow liquid, 6.3 g, yield 42%).

[1736] LC-MS m / z(ESI)=400.08[M+1].

[1737] Step 2

[1738] 2ctert-butyl 5"-bromo-3"H-dispiro[azetidine-3,1'-cyclobutane-3',2"-benzofuran]-1-carboxylate

[1739] According to the method of 2c, 40c was obtained (yellow liquid, 450.0 mg, yield 7%).

[1740] LC-MS m / z(ESI)=380.08[M+1].

[1741] Step 3

[1742] 5"-Bromo-3"-H-spiro[azetidine-3,1'-cyclobutane-3'-,2"-benzofuran]40d

[1743] 5”-bromo-3”H-disspiro[azetidine-3,1’-cyclobutane-3’,2”-benzofuran]

[1744] According to the method of 1e, 40d was obtained (black liquid, 331.0 mg, yield 99%).

[1745] LC-MS m / z(ESI)=280.03[M+1].

[1746] Step 4

[1747] 5"-Bromo-1-methyl-3"-H-dispiro[azetidine-3,1'-cyclobutane-3'-,2"-benzofuran]40e

[1748] 5”-bromo-1-methyl-3”H-disspiro[azetidine-3,1’-cyclobutane-3’,2”-benzofuran]

[1749] Compound 40d (331 mg, 1.1 mmol) and formaldehyde aqueous solution (494 mg, 5.9 mmol) were dissolved in methanol (20 mL) and stirred for 30 min. Sodium cyanoborohydride (111.9 mg, 1.8 mmol) was added and reacted at room temperature. The reaction progress was monitored by TLC.

[1750] The reaction was stopped and quenched with water. The solvent was removed by rotary evaporation and 4e (yellow solid, 224 mg, yield 63%) was separated by column chromatography (dichloromethane:methanol=10:1).

[1751] LC-MS m / z(ESI)=294.04[M+1].

[1752] Step 5

[1753] 1-Methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3"-H-spiro[azetidine-3,1'-cyclobutane-3'-,2'-benzofuran]40f

[1754] 1-methyl-5”-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3”H-disspiro[azetidine-3,1’-cyclobutane-3’,2”-benzofuran]

[1755] According to the method of 1c, 40f (brown solid, 73 mg, yield 28%) was obtained.

[1756] LC-MS m / z(ESI)=342.22[M+1].

[1757] Step 6

[1758] (S)-3-methyl-6-(1-methyl-3"-H-spiro[azetidine-3,1'-cyclobutane-3'-,2"-benzofuran]-5"-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 40g

[1759] tert-butyl(S)-3-methyl-6-(1-methyl-3”H-disspiro[azetidine-3,1'-cyclobutane-3',2”-benzofuran]-5”-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1760] According to the method of 1d, 40 g (brown liquid, 51 mg, yield 58%) was obtained.

[1761] LC-MS m / z(ESI)=411.26[M+1].

[1762] Step 7

[1763] (S)-1-methyl-5'-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3'-H-dipyridine-3,1'-cyclobutane-3'-,2"-benzofuran] 40h

[1764] (S)-1-methyl-5”-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3”H-disspiro[azetidine-3,1’-cyclobutane-3’,2”-benzofuran]

[1765] According to the method of 1e, 40h was obtained (brown liquid, 23 mg, yield 60%).

[1766] LC-MS m / z(ESI)=311.20[M+1].

[1767] Step 8

[1768] 1-Methyl-5'-((5S)-5-methylpiperidin-2-yl)-3"-H-spiro[azetidine-3,1'-cyclobutane-3'-,2"-benzofuran]40i

[1769] 1-methyl-5”-((5S)-5-methylpiperidin-2-yl)-3”H-disspiro[azetidine-3,1’-cyclobutan e-3’,2”-benzofuran]

[1770] According to the method of 1f, 40i was obtained (yellow liquid, 20 mg, yield 83%).

[1771] LC-MS m / z(ESI)=313.22[M+1].

[1772] Step 9

[1773] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(1-methyl-3"H-spiro[azetidine-3,1'-cyclobutane-3',2"-benzofuran]-5"-yl)piperidin-1-yl)-2-oxoacetamide Compound 40

[1774] N-(6-amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(1-methyl-3”H-disspiro[azeti dine-3,1'-cyclobutane-3',2”-benzofuran]-5”-yl)piperidin-1-yl)-2-oxoacetamide

[1775] According to the method of compound 39, compound 40 (yellow solid, 5 mg, yield 13%) was obtained.

[1776] 1 H NMR (400MHz, DMSO) δ10.93–10.68(m,1H),8.28–8.10(m,1H),7.72–7.60(m,1H),7.24(s,1H),7.11(s,1H),6.99-6.97(m,1H),6.87–6.66(m ,2H),5.55–5.05(m,1H),3.27–3.03(m,6H),2.81-2.69(m,4H),2.69- 1.98(m,3H),1.95-1.29(m,9H),1.06-1.00(m,3H),0.89–0.73(m,3H).

[1777] LC-MS m / z(ESI)=504.29[M+1].

[1778] Embodiment 41

[1779] N-(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide Compound 41

[1780] N-(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide

[1781]

[1782] first step

[1783] 3H-Spiro[benzofuran-2,4'-piperidine]41b

[1784] 3H-spiro[benzofuran-2,4'-piperidine]

[1785] Compound 10a (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.

[1786] The reaction was stopped, the solvent was removed by rotary evaporation, and the product was separated and purified by column chromatography to obtain compound 41b (white solid, 1.2 g, yield 89%).

[1787] LC-MS m / z(ESI)=268.13[M+1].

[1788] Step 2

[1789] 5-Bromo-3H-spiro[benzofuran-2,4'-piperidine]41c

[1790] 5-bromo-3H-spiro[benzofuran-2,4'-piperidine]

[1791] Compound 41b (1.2 g, 5.6 mmol) and formaldehyde (543.7 mg, 6.7 mmol) were dissolved in MeOH (20 mL). The reaction was stirred for 30 min and then NaBH 3 CN (880 mg, 14 mmol) was added, and the reaction was continued at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by rotary evaporation, and compound 41c (yellow oily liquid, 1.3 g, yield 82%) was obtained by column chromatography.

[1792] LC-MS m / z(ESI)=282.23[M+1].

[1793] Step 3

[1794] 1'-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]41d

[1795] 1'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1796] Compound 41d was obtained according to the method for compound 1c. The reaction was stopped and filtered. The filtrate was directly used for the next step.

[1797] LC-MS m / z(ESI)=330.31[M+1].

[1798] Step 4

[1799] 3-Methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 41e

[1800] tert-butyl-3-methyl-6-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[1801] According to the method for compound 1d, compound 41e was obtained (dark brown liquid, 1.2 g, yield 66.7%).

[1802] LC-MS m / z(ESI)=399.20[M+1].

[1803] Step 5

[1804] 1'-Methyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]41f

[1805] 1'-methyl-5-(5-methyl-1,4,5,6-tetrahydropyridin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1806] According to the method of compound 1e, compound 41f (brown oily liquid, 400 mg, yield 30%) was obtained.

[1807] LC-MS m / z(ESI)=299.20[M+1].

[1808] Step 6

[1809] 1'-Methyl-5-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]41g

[1810] 1'-methyl-5-(5-methylpiperidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]

[1811] According to the method of compound 1f, compound 41g (yellow liquid, 33 mg, yield 31%) was obtained.

[1812] LC-MS m / z(ESI)=301.22[M+1].

[1813] Step 7

[1814] 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetate 41h

[1815] Methyl-2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piper idin-1-yl)-2-oxoacetate

[1816] According to the method for compound 1g, compound 41h (yellow solid, 46 mg, yield 99%) was obtained.

[1817] LC-MS m / z(ESI)=387.20[M+1].

[1818] Step 8

[1819] 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetic acid 41i

[1820] 2-(5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetic acid

[1821] According to the method of compound 1h, compound 41i (white solid, 180 mg, yield 93%) was obtained.

[1822] LC-MS m / z(ESI)=373.27[M+1].

[1823] Step 9

[1824] N-(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide Compound 41

[1825] N-(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-((5S)-5-methyl-2-(1'-methyl-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-1-yl)-2-oxoacetamide

[1826] According to the method for synthesizing compound 1, compound 41 (white solid, 30 mg, yield 23%) was obtained.

[1827] 1 H NMR (400MHz, DMSO) δ10.80-10.59(m,1H),7.98–7.76(m,2H),7.26–7.03(m,2H),6.79-6.70(m,1H),6.27–6.20(m,2H),5.58-4.95(m,1H),4.30- 4.21(m,3H),3.29-3.23(m,2H),3.04-2.96(m,2H),2.70-2.52(m,4H),2 .32(s,3H),1.98–1.63(m,8H),1.35-1.30(s,1H),1.05(d,J=7.0Hz,3H).

[1828] LC-MS m / z(ESI)=518.28[M+1].

[1829] Biological experiments

[1830] Cell proliferation efficacy studies

[1831] HCT-116 and HCT-116MTAP- / - cells were placed in McCoy's 5A complete medium (containing 10% FBS, 1% PS) and cultured in a 37°C, 5% CO2 incubator. Cells in the logarithmic growth phase were taken, digested and counted; 500 cells / well of each cell were added to a 96-well plate; cultured overnight in a 37°C, 5% CO2 incubator. Different concentrations of the test compound were added to each well (starting at 10μM, 1:3 dilution, 9 concentrations), and a quality control group and a blank control group were set up. Culture was continued at 37°C, 5% CO2 for 5 days. The supernatant of each well was discarded, and after trypsin digestion, 1 / 20 of the number of cells in each well was transferred to a new 96-well plate. New culture medium was added to each well, and different concentrations of the test compound were added in sequence (consistent with the concentration before transfer); culture was continued at 37°C, 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 chemiluminescent signal (RLU) was detected using a microplate reader (Thermo, VarioSkan LUX).

[1832] After data processing, GraphPad 8.0 was used to analyze the IC 50 Fitting. And calculate the selectivity (Ratio) of the compound for HCT-116WT and HCT-116MTAP- / - cells: Ratio = IC 50 (HCT116WT) / IC 50 (HCT116MTAP- / -). The results are shown in Table 1 below:

[1833] Table 1 Cell proliferation efficacy

[1834]

[1835]

[1836] Among them, "A" represents IC 50 ≤0.1μM, "B" means 0.1μM <IC 50 <1μM, "C" means 1μM ≤ IC 50 <10 μM.

[1837] The results showed that the compounds of the present invention exhibited strong proliferation inhibition activity against human colon cancer HCT-116MTAP- / - cells, and showed good selectivity compared to human colon cancer HCT-116WT cells. It can be expected that the compounds of the present invention have a therapeutic effect on MTAP-deficient tumors, and have good selectivity and low side effects.

[1838] hERG experiments

[1839] This experiment used the automatic patch clamp method to detect the effects of different concentrations of test substances (0.3, 1, 3, 10 and 30 μM), negative controls (containing 0.3% DMSO) and positive controls (3, 10, 30, 100 and 300 nM cisapride) on hERG potassium currents in human embryonic kidney cells (HEK293) (Creacell, catalog number: A-0320) expressing hERG potassium channels. Two cells were tested for each concentration of negative, positive controls and test substances. The results showed that the compounds of the present invention had no significant inhibitory effect on hERG potassium channel currents within the test concentration range, reflecting good safety. The experimental results are shown in Table 2 below.

[1840] Table 2 Effect of hERG potassium current

[1841] Compound No. <![CDATA[hERGIC 50 (μM)]]> Compound 13 >30 Compound 19 >30

[1842] PRMT5 / MEP50 enzyme activity assay

[1843] Weigh an appropriate amount of the test substance and use DMSO to prepare the test substance into a 10mM stock solution. Use 1× buffer to dilute the stock solution 3 times (starting concentration 1μM, 10 gradients), and transfer 20nL of the gradient diluted test substance to a 384-well plate (Greiner, 784075). Add 2μL of PRMT5 / MEP50 complex (active motif, 31921, final concentration of 2nM) to the well plate and place it at room temperature for 5min. Then add 2μL of substrate reaction solution (final concentration: 5μM SAM, 1μM Bio-H4(1-21)) or 2μL of substrate reaction solution containing MTA (final concentration: 5μM SAM, 1μM Bio-H4(1-21), 1μM MTA) and place it at room temperature for 3h. After the reaction is completed, add 1μL 5×MTase-Glo to the well plate. TM Reagent (Promega, V7602) and place at room temperature for 30 min. Then add 5 μL MTase-Glo TM Detection Solution (Promega, V7602) was placed at room temperature for 30 min. The values ​​of each well were read using an ELISA reader, and the IC was calculated by curve fitting using GraphPad Prism. 50 value, and use the formula [Fold = IC 50 (PRMT5) / IC 50 (PRMT5+MTA)] to calculate the selectivity of the test substance for the PRMT5+MTA complex.

[1844] Conclusion: The compounds of the present invention can effectively inhibit the formation of PRMT5+MTA complex and are selective for PRMT5 without MTA.

[1845] In vivo pharmacokinetic study in mice

[1846] Weigh an appropriate amount of the test substance, use 5% DMSO + 5% HS-15 + 90% Saline to prepare the test substance into a 0.1 mg / mL solution for intravenous administration. Use 0.5% MC to prepare the test substance into a 1 mg / mL preparation for oral administration. Healthy adult ICR mice were intravenously administered with the test substance (1 mg / kg) and blood was collected by micro-blood sampling at 5min, 15min, 0.5, 1, 2, 4, 8, and 24h. Blood was collected by micro-blood sampling at 15min, 0.5, 1, 2, 4, 8, and 24h after oral administration of the test substance (10 mg / kg). The blood samples were centrifuged at 4℃ 6000g for 5min to separate plasma, and all samples were stored at -70℃ for testing. The drug concentration of the test substance in plasma was determined by LC-MS / MS, and the Winnolin 8.3 non-compartmental model was used to calculate the main pharmacokinetic parameters.

[1847] Conclusion: The compounds of the present invention have good oral bioavailability and exposure.

[1848] Rat brain PK experiment

[1849] Weigh an appropriate amount of the test substance and use 0.5% MC to prepare the test substance into a 1 mg / mL preparation. After fasting overnight, healthy adult male SD rats were gavaged with the test substance (5 mg / kg) or blank solvent. Blood was collected from the jugular vein at six time points: 0.5, 1, 2, 4, 8, and 24 h after administration. The animals were then killed to collect cerebrospinal fluid and brain tissue. The blood samples were centrifuged at 4°C 6000g for 5 min to separate plasma. The brain tissue was rinsed with saline for residual blood, and the water was dried with absorbent paper. All samples were stored at -70°C for testing. The drug concentrations of the test substance in plasma, cerebrospinal fluid, and brain tissue were determined by LC-MS / MS, and the main pharmacokinetic parameters were calculated by Winnolin 8.3 non-compartmental model.

[1850] Conclusion: The compounds of the present invention have certain brain penetration in rats.

[1851] Pharmacokinetic study in rats

[1852] Weigh an appropriate amount of the test substance, use 5% DMA + 5% HS-15 + 90% Saline to prepare the test substance into a 0.5 mg / mL transparent clear solution for intravenous administration; use 5% DMA + 5% HS-15 + 90% Saline to prepare the test substance into a 2 mg / mL uniform suspension for oral administration. Take 6 healthy male SD rats (Viton River, SPF grade), 3 animals in the intravenous and oral administration groups, 3 animals at each time point, and collect blood through the jugular vein. Blood was collected at 5min, 15min, 0.5, 1, 2, 4, 8, and 24h after intravenous administration of the test substance (1 mg / kg), and blood was collected at 15min, 0.5, 1, 2, 4, 6, 8, and 24h after oral administration of the test substance (10 mg / kg). After anticoagulation with EDTA-K2, the blood samples were centrifuged at 4°C, 6000g for 5 min to separate the plasma, and all plasma samples were stored at -70°C for testing. The plasma concentration of the test substance (internal standard: gliclazide) was determined by LC-MS / MS, and the main pharmacokinetic parameters were calculated by Winnolin 8.3 non-compartmental model.

[1853] Conclusion: The compounds of the present invention have good oral bioavailability and exposure.

[1854] Pharmacokinetic study in dogs

[1855] 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, 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 (1mg / kg), and blood is collected at 15min, 0.5, 1, 2, 4, 8, 12h, and 24h after oral administration of the test substance (3mg / kg). After anticoagulation with EDTA-K2, the blood samples were centrifuged at 4°C, 2000g for 10 min to separate the plasma, and all plasma samples were stored at -80°C for testing. The plasma concentration of the test substance (internal standard: gliclazide) was determined by LC-MS / MS, and the main pharmacokinetic parameters were calculated by Winnolin8.3 non-compartmental model.

[1856] Conclusion: The compounds of the present invention have good oral bioavailability and exposure.

[1857] 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 principle 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: R1 and each R2 are independently selected from -CN, H, -D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl, heterocyclyl-alkyl, heteroaryl-alkyl, aryl-alkyl, cycloalkyl-alkyl, -OR m1 、-N(R m1 )2, -C(=O)R m1 、-C(=O)OR m1 、-NR m1 C(=O)R m1 、-NR m1 C(=O)OR m1 、-C(=O)N(R m1 )2, -OC(=O)N(R m1 )2, -S(=O)R m1 、-S(=O)2R m1 、-SR m1 、-S(=O)(=NR m1 )R m1 、-NR m1 S(=O)2R m1 and -S(=O)2N(R m1 )2; Or any two R 2 Together with the atoms to which they are attached, they form a 3-10 membered cycloalkyl or heterocycloalkyl group; Among them, each R m1 are independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl, heterocyclyl-alkyl, heteroaryl-alkyl, aryl-alkyl, cycloalkyl-alkyl; each R m1 are independently optional to be substituted at any position; n is a natural number from 0 to 8; X and Y are independently selected from O, S or -CF3; Z is selected from C, N or O; A is selected from a fused ring of 11 to 20 members; B is selected from a 5-20-membered monocyclic or condensed ring; Wherein, ring A can be optionally substituted by one or more selected from H, D, =O, halogen, CN, NO2, -L-OR m2 、-L-SR m2 、-LN(R m2 )2, -SF5, -C(O)R m2 、-C(O)OR m2 、-C(O)N(R m2 )2. -OC(O)R m2 、-NR m2 C(O)R m2 、-S(O)R m2 、-S(O)2R m2 、-S(O)OR m2 、-S(O)2OR m2 、-S(O)N(R m2 )2、-S(O)2N(R m2 )2、-P(O)(R m2 )2, -P(O)2R m2 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl and 5-10 membered aryl; L is a chemical bond, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene; each R m2 are independently selected from H, D, C1-C6 alkyl or C1-C6 haloalkyl; each R m2 are independently optional to be substituted at any position; Wherein, the B ring can be optionally replaced by one or more selected from -CN, H, -D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl, heterocyclyl-alkyl, heteroaryl-alkyl, aryl-alkyl, cycloalkyl-alkyl, -OR m3 、-N(R m3 )2, -C(=O)R m3 、-C(=O)OR m3 、-NR m3 C(=O)R m3 、-NR m3 C(=O)OR m3 、-C(=O)N(R m3 )2, -OC(=O)N(R m3 )2, -S(=O)R m3 、-S(=O)2R m3 、-SR m3 、-S(=O)(=NR m3 )R m3 、-NR m3 S(=O)2R m3 and -S(=O)2N(R m3 )2; Each R m3 are independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl, heterocyclyl-alkyl, heteroaryl-alkyl, aryl-alkyl, cycloalkyl-alkyl; each R m3 Each of the above groups is independently optional and may be substituted at any position.

2. A compound represented by formula (II), or any stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: in: R1 and R2 are independently selected from -CN, H, -D, halogen, C1-C3 alkyl or -C(=O)R3; R3 is selected from C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; X and Y are independently selected from O, S or -CF3; Z is selected from C, N or O; A is selected from a fused ring of 11 to 20 members; B is selected from a 5- to 10-membered monocyclic or condensed ring.

3. The compound according to claim 2, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein: B is selected from:

4. The compound according to claim 3, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein: B is further substituted with one or more of the following substituents: -NH2, =O, H, -D and C1-C6 alkyl.

5. The compound according to claim 2, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein: A is selected from: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, and A15 are independently any suitable ring structure.

6. The compound according to claim 5, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15 are all independently selected from a 3-8 membered heterocyclic ring or a carbocyclic ring.

7. The compound according to claim 6, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein: A1, A2, A3, A4, A5, A6, A7 and A8 all contain at least 2 heteroatoms, and A1, A2, A3, A4, A5, A6, A7, A8 or A10 are all independently selected from a 5-6 membered heterocycle or a 5-8 membered spirocycle containing a heteroatom.

8. The compound according to any one of claims 2 to 7, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein: A is selected from:

9. The compound according to any one of claims 2 to 8, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein: A is further substituted by one or more substituents selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, -CN, D, =O, halogen, and 3-8 membered heterocyclic rings; the 3-8 membered heterocyclic ring is optionally substituted by H, halogen, or C1-C3 alkyl.

10. The compound according to claim 9, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from:

11. A pharmaceutical composition, comprising: (1) The compound according to any one of claims 1 to 10, or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal; (2) one or more other active ingredients; as well as (3) Pharmaceutically acceptable carriers and / or excipients.

12. Use of the compound according to any one of claims 1 to 10 or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 11 in the preparation of an anti-tumor drug.

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