Prmt5-mta co-collaborative inhibitors, pharmaceutical compositions thereof and uses thereof

Abstract

The present application belongs to the field of pharmaceutical chemistry, and relates to a kind of PRMT5-MTA co-synergistic inhibitor, its pharmaceutical composition and its application in medicine.The specific application relates to a compound of formula (I), or stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound shown in formula (I).The compound and its pharmaceutical composition can be used for preparing medicine for preventing or treating PRMT5 related diseases, and can be used for preparing medicine for preventing or treating PRMT5 related cancer, especially.(I).

Description

Invention Field This invention belongs to the field of medicinal chemistry, specifically relating to a class of PRMT5-MTA co-synergistic inhibitors, their pharmaceutical compositions, and their applications in pharmaceuticals. Background Technology

[0001] PRMT5 (protein arginine methyltransferase 5) is a type II arginine methyltransferase that adds symmetrical dimethylation to the arginine residues of specific proteins in vivo. It is expressed to varying degrees in various tissues and organs of the human body and, as an important epigenetic regulator, participates in a series of transcriptional regulatory events, thereby regulating various important cellular functions. It plays a crucial role in maintaining tissue homeostasis and in the survival and self-renewal capacity of stem cells / progenitor cells in the nervous, muscular, reproductive, and hematopoietic systems. Studies have found that PRMT5 is highly expressed in many human tumors such as lung cancer, ovarian cancer, colorectal cancer, breast cancer, melanoma, leukemia, lymphoma, and malignant glioma, and its high expression is closely related to tumor development, progression, and poor prognosis.

[0002] MTAP (S-methyl-5'-thioadenosine phosphorylase) is produced by the methyladenosine phosphorylase gene located on chromosome 9. MTAP This gene encodes and catalyzes the reversible phosphorylation of methionine (MTA) to adenine and 5-methionine-1-phosphate. MTAP With tumor suppressor genes CDKN2A Adjacent to each other, and frequently co-deleted in human cancers, MTAP-deficient tumor cells have been found to accumulate large amounts of MTA compared to MTAP-normal cells. MTA is analogous to SAM (S-adenosyl methionine), a methyl donor that acts as a ligand for PRMT5, and can competitively bind to PRMT5, forming a PRMT5-MTA complex. In this complex, the growth and proliferation of MTAP-deficient tumor cells are significantly dependent on PRMT5 activity. Therefore, developing a PRMT5-MTA co-synergistic inhibitor could stabilize the PRMT5-MTA complex structure, inhibit SAM binding to PRMT5, suppress PRMT5 signaling, and thus selectively kill MTAP-deficient tumor cells without affecting MTAP-normal cells.

[0003] Although some PRMT5-MTA synergistic inhibitors have been shown to have significant anti-tumor effects in multiple tumor cell lines (MTAP-deficient) in vitro, the types are limited, and there are currently no PRMT5-MTA inhibitors on the market. There is still an urgent need to develop more new PRMT5-MTA synergistic inhibitors to prevent and treat MTAP-deficient cancers, and to provide more drug options for clinical applications. Summary of the Invention

[0004] This invention provides a PRMT5-MTA co-synergistic inhibitor that inhibits the binding of SAM to PRMT5, thereby selectively killing MTAP-deficient tumor cells for cancer treatment. This invention also provides pharmaceutical compositions comprising this class of compounds, and the use of this class of compounds and pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of cancer.

[0005] On the one hand, the present invention provides a compound, which is a compound of formula (I) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I). (I), Among them, R 1 for , , , , , or ; L is the key; "Can be a single bond or a double bond; X1 is -O-, -S-, -S(=O)-, -SO2-, -NR Xa -or-CR Xb R Xc - and R in X1 Xb and R Xc Not both H; X2 is -S-, -S(=O)-, -SO2-, -NR Xa -or-CR Xb R Xc -; R Xa R Xb R Xc Each is independently H, D, -CN, -SF5, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; or R Xb R Xc Together with the carbon atom it is attached to, they form C 3-6 Carbon rings or 3-10 membered heterocyclic rings; Each R 2 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -OR 2a -C(=O)R 2a -OC(=O)R 2a -OC(=O)NR 2a R 2b -C(=O)OR 2a -NR 2a R 2b -C(=O)NR 2a R 2b -NR 2a C(=O)R 2b -NR 2a C(=O)OR 2b -NR 2a S(=O)2R 2b -SR 2a -SF5, -S(=O) R 2a -S(=O)2R 2a -S(=O)(=NR) 2a )R 2b or -S(=O)2NR 2a R 2b Or two R atoms bonded to the same carbon atom 2 Together with the carbon atoms bonded to them, they form =O, =S, =CR a R b Or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 2c replace; The R mentioned 2a R 2b R 2c Each is independently H, D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Ring A is C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic ring; wherein, depending on the structure of ring A, the bonds shared by ring A and the five-membered ring containing X1 can be single or double bonds; Each R 3 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -O-(C 2-6 ynyl group), -C(=O)R 3a -OC(=O)R 3a -OC(=O)NR 3a R 3b -C(=O)OR 3a -NR 3a R 3b -C(=O)NR 3a R 3b -NR 3a C(=O)R 3b -NR 3a C(=O)OR 3b -NR 3a S(=O)2R 3b -SR 3a -SF5, -S(=O) R 3a -S(=O)2R 3a -S(=O)(=NR) 3a )R 3b or -S(=O)2NR 3a R 3b ; wherein, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 3c replace; Each R 3cEach can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic or C 6-10 Aryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic groups and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 3d Substitution; or two R atoms attached to the same carbon atom 3c Together with the carbon atoms bonded to them, they form =O, =S, or =CR. c R d ; Each R 3d Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic or C 6-10 Aryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic groups and C 6-10 Each aryl group is independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, halogen, -CN, -SF5, -OH, -NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; The R mentioned 3a R 3b R 3e R 3f Each is independently H, D, halogen, -CN, -SF5, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Alkoxy, C 1-6 Halogenated alkoxy groups; Or, two R atoms attached to the same carbon atom 3 Together with the carbon atoms bonded to them, they form =O, =S, =CR e R f C 3-6 Carbon rings or 3-10 membered heterocycles, wherein the C 3-6 The carbon ring and 3-10 membered heterocycles are each independently and optionally p R 8 Replaced; Alternatively, two R atoms connected to adjacent or non-adjacent ring atoms. 3 Together with the ring atoms attached to them, they form C 3-6 Carbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-10 quintile heterocyclic aromatic rings, wherein the C 3-6 Carbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-10 heterocyclic rings are each independently and optionally divided by p R 8 Replaced; Each R 8 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy group; or two R groups attached to the same carbon atom 8 Together with the carbon atom it is bonded to, it forms =O, =S, or =CR. g R h ; R 4 R 5 R 6 R 7 Each is independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or -NR i R j ; Y1 is N or CR Ya Y2 is N or CR Yb Y3 is N or CR Yc Y4 is N or CR Yd Y5 is N or CR Ye ;R Ya R Yb R Yc R Yd R Ye Each is independently H, D, -CN, halogen, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 1-6 alkylene-O-(C 1-6 Alkyl), -C(=O)NR n R m Or C 1-6 Halogenated alkoxy groups; Y6 is N, C, or CR Yf Y7 is N, C or CR Yg Ring B is C 3-6 Carbon rings, 5-membered heterocyclic rings, 5-10-membered heteroaromatic rings, or C 6-10 Aromatic rings, wherein each ring B is independently and optionally divided by q R 9 Replaced; R Yf R Yg Each is independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups; Each R 9 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkyl group; or two R atoms attached to adjacent or non-adjacent ring atoms. 9 Together with the ring atoms attached to them, they form C 3-6 Cycloalkyl or 3-10 membered heterocyclic groups; or two R groups attached to the same carbon atom 9 Together with the carbon atom it is bonded to, it forms =O or =S; The conditions are: (1) R 1 Not for , or Structure; or, when R 1 for or When the structure is defined, equation (I) is: , or ; (2) When equation (I) is , , , or And R 1 for , , or R Ya When R is H, Cl or F, 3 Not -CF3 or ; Z1 is N or CR Za Z2 is N or CR Zb Z3 is N or CR Zc ;R Za R Zb R Zc Each is independently H, D, -CN, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Hydroxyalkyl; Z4 is N, C, or CR. Zd Z5 is N, C or CR Ze ; Ring C is C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic rings, wherein each of the rings C is independently and optionally divided by s R 10 Replace; R Zd R Ze Each is independently H, D, halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups; Each R 10 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy group; or two R groups attached to the same carbon atom 10 Together with the carbon atom it is bonded to, it forms =O or =S; W1 is N or CR Wa W2 is N or CR Wb ; R Wa R Wb Each is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or R Wa R Wb Together with the ring atoms they are connected to, they form C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic ring, the C 3-6Carbon rings, 3-10 membered heterocycles, 5-10 membered heteroaromatic rings and C 6-10 The aromatic rings are each independently and arbitrarily assigned to t R. 11 Replaced; Each R 11 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy group; or two R groups attached to the same carbon atom 11 Together with the carbon atom it is bonded to, it forms =O or =S; Each R a R b R c R d R e R f R g R h R i R j R n and R m Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n, m, p, q, s, and t are each independently 0, 1, 2, 3, 4, 5, or 6.

[0006] In other implementations, Y1 is N or CR Ya Y2 is N or CR Yb Y3 is N or CR Yc Y4 is N or CR Yd Y5 is N or CR Ye ;R Ya R Yb R Yc R Yd R Ye Each is independently H, D, -CN, halogen, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -C 1-4 alkylene-O-(C 1-4 Alkyl), -C(=O)NR n R m Or C 1-4 Halogenated alkoxy groups; Y6 is N, C, or CR YfY7 is N, C or CR Yg Ring B is C 3-6 Carbon rings, 5-membered heterocycles, 5-6-membered heteroaromatic rings, or benzene, wherein each ring B is optionally and independently divided by q R. 9 Replaced; R Yf R Yg Each is independently H, D, halogen, -CN, C 1-4 Alkyl, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkyl groups; Each R 9 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Alkyl group; or two R atoms attached to adjacent or non-adjacent ring atoms. 9 Together with the ring atoms attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; or two R groups attached to the same carbon atom 9 Together with the carbon atom it is bonded to, it forms =O or =S; The conditions are: (1) R 1 Not for , or Structure; or, when R 1 for or When the structure is defined, equation (I) is: , or ; (2) When equation (I) is , , , or And R 1 for , , or R Ya When R is H, Cl or F, 3 Not -CF3 or ; Z1 is N or CR Za Z2 is N or CR Zb Z3 is N or CR Zc ;R Za R Zb R Zc Each is independently H, D, -CN, hydroxyl, halogen, C1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Hydroxyalkyl; Z4 is N, C, or CR. Zd Z5 is N, C or CR Ze ; Ring C is C 3-6 Carbocyclic rings, 3-6 membered heterocyclic rings, 5-6 membered heteroaromatic rings, or benzene, wherein each of the ring Cs is optionally and independently divided by s Rs. 10 Replace; R Zd R Ze Each is independently H, D, halogen, -CN, hydroxyl, C 1-4 Alkyl, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkyl groups; Each R 10 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 alkoxy group; or two R groups attached to the same carbon atom 10 Together with the carbon atom it is bonded to, it forms =O or =S; W1 is N or CR Wa W2 is N or CR Wb ; R Wa R Wb Each is independently H, D, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or R Wa R Wb Together with the ring atoms they are connected to, they form C 3-6 Carbocyclic rings, 3-6 membered heterocyclic rings, 5-6 membered heteroaromatic rings, or benzene, wherein the C 3-6 The carbon ring, 3-6 membered heterocycles, 5-6 membered heteroaromatic rings, and benzene are each independently and optionally divided by t R 11 Replaced; Each R 11 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 alkoxy group; or two R groups attached to the same carbon atom 11 Together with the carbon atom it is attached to, it forms =O or =S.

[0007] In some implementations, Y1 is N or CR YaY2 is N or CR Yb Y3 is N or CR Yc Y4 is N or CR Yd Y5 is N or CR Ye ;R Ya R Yb R Yc R Yd R Ye Each of the following is independently H, D, -CN, F, Cl, Br, I, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2 Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2, (CH2)4OH, -OCH3, -OCH2CH3, -OCH(CH3 )2, -OCH2F, -OCF3, -OCHF2, -CH2OCH3, -(CH2)2OCH3, -CH2OCH2CH3, -CH2O(CH2)2CH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3)2; Y6 is N, C, or CR Yf Y7 is N, C or CR Yg Cycle B is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiacyclopentane, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, 1,3,5-triazine, or benzene, wherein each of the cyclic B is optionally and independently divided by q R 9 Replaced; R Yf R YgEach can be independently H, D, F, Cl, Br, I, -CN, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2 or (CH2)4OH; Each R 9 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to adjacent or non-adjacent ring atoms. 9 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiaran; or two R atoms bonded to the same carbon atom. 9 Together with the carbon atom it is bonded to, it forms =O or =S; The conditions are: (1) R 1 Not for , or Structure; or, when R 1 for or When the structure is defined, equation (I) is: , or ; (2) When equation (I) is , , , or And R 1 for , , or R Ya When R is H, Cl or F, 3 Not -CF3 or ; Z1 is N or CR Za Z2 is N or CR Zb Z3 is N or CR Zc ;R Za R Zb R Zc Each can be independently H, D, -CN, hydroxyl, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2 or (CH2)4OH; Z4 is N, C, or CR. Zd Z5 is N, C or CR Ze The ring C is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxacyclobutane, thiohexacyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiohexacyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, thiazide, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, 1,3,5-triazine, or benzene, wherein each of the ring Cs is optionally and independently divided by s Rs. 10 Replace; R Zd R ZeEach can be independently H, D, F, Cl, Br, I, -CN, hydroxyl, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2 or (CH2)4OH; Each R 10 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to the same carbon atom. 10 Together with the carbon atom it is bonded to, it forms =O or =S; W1 is N or CR Wa W2 is N or CR Wb ; R Wa R Wb Each independently represents H, D, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br or -(CH2)2Cl; or R Wa R Wb Together with the ring atoms they are attached to, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H-Pyran, Tetrahydrothiaran, Piperidine, Morpholine, Thiomorpholine, Piperazine, Dioxane, Dithiaran, Thioxane, Furan, Imidazole, Isoxazole, Oxazole, Pyrrole, Pyridine, Pyrimidine, Pyridazine, Thiazole, Tetrazol, Triazole, Thiophene, Pyrazole, Isothiazole, 1,2,3-Oxadiazole, 1,2,5-Oxadiazole, 1,2,4-Oxadiazole, 1,2,3-Triazole, 1,2,3-Thiodiazole, 1,3,4-Thiodiazole, 1,2,5-Thiodiazole Pyrazine, 1,3,5-triazine, or benzene, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, thiazide, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazine, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, 1,3,5-triazine, or benzene are each independently and optionally t R 11 Replaced; Each R 11 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to the same carbon atom. 11 Together with the carbon atom it is attached to, it forms =O or =S.

[0008] In some preferred embodiments, R 1 Choose from any of the following structures: , , , , , , , , , , , , , , , , , , , , , or ; Among them, R 4 R 5 R 6 R 7 R 9 R 10 R 11 R Zc R Ya R Yc R Ye Each has the definition as described in this invention, R 9a With R 9 Same definition.

[0009] In some implementations, X1 is -O-, -S-, -S(=O)-, -SO2-, -NR Xa -or-CR Xb R Xc - and R in X1 Xb and R Xc X2 is not simultaneously H; it is -S-, -S(=O)-, -SO2-, -NR. Xa -or-CR Xb R Xc -; R Xa R Xb R Xc Each is independently H, D, -CN, -SF5, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; or R Xb R Xc Together with the carbon atom it is attached to, they form C 3-6 Carbon rings or 3-6 membered heterocycles; Each R 2 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl, -OR 2a -C(=O)R 2a -OC(=O)R 2a -OC(=O)NR 2a R 2b -C(=O)OR 2a -NR 2a R 2b -C(=O)NR 2a R 2b -NR 2a C(=O)R 2b -NR 2a C(=O)OR 2b -NR 2a S(=O)2R 2b -SR 2a -SF5, -S(=O) R 2a -S(=O)2R 2a -S(=O)(=NR) 2a )R 2b or -S(=O)2NR 2a R 2b Or two R atoms bonded to the same carbon atom 2 Together with the carbon atoms bonded to them, they form =O, =S, =CR a R b Or C 3-6 cycloalkyl; wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 2c replace; The R mentioned 2a R 2b R 2c Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy or C1-4 Halogenated alkoxy groups; Ring A is C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic ring; wherein, depending on the structure of ring A, the bonds shared by ring A and the five-membered ring containing X1 can be single or double bonds; Each R 3 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl, -O-(C 2-4 ynyl group), -C(=O)R 3a -OC(=O)R 3a -OC(=O)NR 3a R 3b -C(=O)OR 3a -NR 3a R 3b -C(=O)NR 3a R 3b -NR 3a C(=O)R 3b -NR 3a C(=O)OR 3b -NR 3a S(=O)2R 3b -SR 3a -SF5, -S(=O) R 3a -S(=O)2R 3a -S(=O)(=NR) 3a )R 3b or -S(=O)2NR 3a R 3b ; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each optionally surrounded by 1, 2, 3, or 4 R groups. 3c replace; Each R 3c Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or phenyl, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 The cycloalkyl group, the 3-6 membered heterocyclic group, and the phenyl group are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 3d Substitution; or two R atoms attached to the same carbon atom 3c Together with the carbon atoms bonded to them, they form =O, =S, or =CR. c R d ; Each R 3d Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or phenyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 The cycloalkyl group, the 3-6 membered heterocyclic group, and the phenyl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, halogen, -CN, -SF5, -OH, -NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituted with haloalkoxy groups; The R mentioned 3a R 3b R 3e R 3f Each is independently H, D, halogen, -CN, -SF5, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups; Or, two R atoms attached to the same carbon atom 3 Together with the carbon atoms bonded to them, they form =O, =S, =CR e R f C 3-6Carbon rings or 3-6 membered heterocycles, wherein the C 3-6 The carbon ring and the 3-6 membered heterocycles are each independently and optionally divided by p R 8 Replaced; Alternatively, two R atoms connected to adjacent or non-adjacent ring atoms. 3 Together with the ring atoms attached to them, they form C 3-6 Carbocyclic rings, 3-6 membered heterocyclic rings, benzene, or 5-6 membered heteroaromatic rings, wherein the C 3-6 The carbon ring, 3-6 membered heterocycles, benzene, and 5-6 membered heteroaromatic rings are each independently and optionally p-R 8 Replaced; Each R 8 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 alkoxy group; or two R groups attached to the same carbon atom 8 Together with the carbon atom it is bonded to, it forms =O, =S, or =CR. g R h .

[0010] In some embodiments, the compound of the present invention is a compound of formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II). (II) Among them, rings A, L, X1, X2, and R 1 R 2 R 3 , n, and m each have the definitions described in this invention.

[0011] In other embodiments, the compound of the present invention is a compound represented by formula (IV-1), (IV-2), (VI), (VI-1), or (VI-2), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound represented by formula (IV-1), (IV-2), (VI), (VI-1), or (VI-2). , , ... or ; Among them, ring A, ring B, ring C, X1, X2, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Z1, Z2, Z3, Z4, Z5, W1, W2, R1 R 2 R 3 R 4 R 5 R 6 R 7 , n, and m each have the definitions described in this invention. On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug; optionally, it further comprises a pharmaceutically acceptable carrier.

[0012] On the other hand, the present invention provides the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to protect against, treat, cure or alleviate cancer in a patient.

[0013] In some implementations, the cancer is MTAP deficiency-related cancer; optionally, the MTAP deficiency-related cancer is ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

[0014] On the other hand, the present invention provides compounds or pharmaceutical compositions described herein for the prevention, treatment or treatment of cancer.

[0015] On the other hand, the present invention provides a method for preventing, treating or treating cancer, comprising administering a patient a therapeutically effective amount of the compound or pharmaceutical composition described herein.

[0016] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formulas (I), (II), (IV-1), (IV-2), (VI), (VI-1) or (VI-2).

[0017] Unless otherwise indicated, all stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of this invention.

[0018] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically suitable in relation to the other components of the formulation and the mammal intended for treatment.

[0019] The salts of the compounds of the present invention also include salts of intermediates used for the preparation or purification of compounds of formula (I), (II), (IV-1), (IV-2), (VI), (VI-1) or (VI-2) or salts of enantiomers isolated from compounds of formula (I), (II), (IV-1), (IV-2), (VI), (VI-1) or (VI-2), but not necessarily pharmaceutically acceptable salts.

[0020] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0021] Detailed specifications Definitions and general terms Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to encompass all alternatives, modifications, and equivalents, all of which are included within its scope. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0022] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0023] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0024] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles concerning one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0025] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0026] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0027] "Stereoisomers" refer to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, trans-blocking isomers, and so on. Unless otherwise stated, all stereoisomers or mixtures of stereoisomers of the structural formulas described in this invention are within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.

[0028] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0029] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in racemic or enantiomerically enriched forms, for example ( R )-、( S )- or( R , S The configuration exists. In some implementations, the asymmetric atoms are in ( R )-or( S - In terms of configuration, it has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess.

[0030] Depending on the choice of starting materials and method, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active ( R )-or( S The )-isomer can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be... E orZ Configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans configuration.

[0031] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0032] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0033] The term "optional" or "optionally" means that an event or situation described below may, but is not guaranteed to, occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "optional key" means that the key may or may not be present, and the description includes single, double, or triple keys.

[0034] The term "substituted" indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. As described in this invention, the compounds of this invention may optionally be substituted by one or more substituents, such as the general formula compounds above, or as in the specific examples, subclasses, and classes of compounds included in this invention. The term "optionally substituted" may be used interchangeably with the term "unsubstituted or substituted," meaning that the structure is unsubstituted or substituted by one or more substituents as described in this invention.

[0035] Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at each position in the same or different manner.

[0036] The term "unsubstituted" means that the specified group does not have substituents.

[0037] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0038] In various parts of this specification, the substituents of the disclosed compounds are disclosed according to the type or range of groups. In particular, the invention includes every independent sub-combination of the members of these types and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0039] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0040] As used in this invention, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl group contains 1 to 12 carbon atoms, denoted as C1. 1-12 Alkyl group; in other embodiments, the alkyl group contains 1-6 carbon atoms, denoted as C1. 1-6 Alkyl group; in some further embodiments, the alkyl group contains 1-4 carbon atoms, denoted as C1. 1-4 Alkyl group; in some embodiments, the alkyl group contains 1-3 carbon atoms, denoted as C1. 1-3 Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (... n -Pr, -CH2CH2CH3), isopropyl ( i-Pr, -CH(CH3)2), n-butyl ( n -Bu、-CH2CH2CH2CH3), isobutyl ( i -Bu、-CH2CH(CH3)2), sec-butyl( s -Bu、-CH(CH3)CH2CH3), tert-butyl( t -Bu、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), n-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(- CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0041] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in others, it contains 1-4 carbon atoms; in still others, it contains 1-3 carbon atoms; and in still still others, it contains 1-2 carbon atoms. Examples of such groups include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and so on.

[0042] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group and the hydroxyl group have the definitions described herein. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1, 2, 3, or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C14-C ... 1-6 Hydroxyalkyl, i.e., C 1-6 Alkyl groups are substituted with one or more hydroxyl groups, preferably C 1-6 Hydroxyalkyl means a C that has been substituted with a hydroxyl group. 1-6 Alkyl. In some embodiments, hydroxyalkyl indicates C10. 1-4 Hydroxyalkyl. In some embodiments, hydroxyalkyl means C 1-3 Hydroxyalkyl groups. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OH, -CH2CH(OH)CH2CH2OH, -CH2CH(OH)CH2CH(CH3)OH, etc.

[0043] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group and the halogen atom have the definitions described herein. In some embodiments, the haloalkyl group is C10. 1-6 Haloalkyl, indicating C 1-6 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-4 Haloalkyl, indicating C 1-4 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-3 Haloalkyl, indicating C 1-3 The alkyl group is replaced by one or more halogen atoms. Examples of such groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and so on.

[0044] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, with at least one unsaturated site, i.e., one carbon-carbon sp. 2 A double bond, wherein the alkenyl group may optionally be replaced by one or more substituents described in this invention, including " cis "and" tans The positioning of "or" E "and" ZThe positioning of "". In one embodiment, the alkenyl group contains 2-8 carbon atoms, denoted as C 2-8 Alkenyl group; in another embodiment, the alkenyl group comprises 2-6 carbon atoms, denoted as C0 2-6 Alkenyl group; in another embodiment, the alkenyl group comprises 2-4 carbon atoms, denoted as C1 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (i.e., propenyl, -CH=CH-CH3), etc.

[0045] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkynyl group comprises 2-8 carbon atoms, denoted as C1. 2-8 Alkynyl group; in other embodiments, the alkynyl group comprises 2-6 carbon atoms, denoted as C0. 2-6 Alkynyl group; in some other embodiments, the alkynyl group comprises 2-4 carbon atoms, denoted as C0. 2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0046] The term "alkoxy" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; and in still other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy ( n -PrO、 n -propoxy, -OCH2CH2CH3), 2-propoxy ( i -PrO、 i -propoxy, -OCH(CH3)2), 1-butoxy n -BuO、 n -Butoxy, -OCH2CH2CH2CH3), 2-Methyl-1-propoxy ( i -BuO、 i-butoxy, -OCH2CH(CH3)2), 2-butoxy ( s -BuO、 s -Butoxy, -OCH(CH3)CH2CH3), 2-Methyl-2-propoxy t -BuO、 t -Butoxy, -OC(CH3)3), 1-Pentoxy ( n -Pentoxy, -OCH2CH2CH2CH2CH3), 2-Pentoxy (-OCH(CH3)CH2CH2CH3), 3-Pentoxy (-OCH(CH2CH3)2), 2-Methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-Methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-Methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-Methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0047] The term "haloalkoxy" means that an alkoxy group is replaced by one or more halogen atoms, wherein the alkoxy group and the halogen have the definitions as described in this invention.

[0048] The term "carbocyclic" or "carbocyclic" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 carbon atoms. Carbocyclic groups include spirobicyclic, fused, and bridged carbocyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Further examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and so on.

[0049] The term "cycloalkyl" refers to a monovalent or polyvalent non-aromatic monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms, wherein the -CH2- group in the carbide ring may optionally be replaced by -C(=O)- (or -(CO)-). In some embodiments, the cycloalkyl group comprises 3-12 carbon atoms, i.e., C 3-10 Cycloalkyl; in other embodiments, the cycloalkyl group comprises 3-8 carbon atoms, i.e., C64-C84-C6 ... 3-8 Cycloalkyl; in some further embodiments, the cycloalkyl group comprises 3-6 carbon atoms, i.e., C64-C ... 3-6 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-5 cyclic carbon atoms, i.e., C1 3-5Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of substitution of the -CH2- group in the carbide ring by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc. The cycloalkyl groups may optionally be substituted by one or more substituents described in this invention.

[0050] The terms "heterocycle" and "heterocyclic group" are used interchangeably herein to refer to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system comprising 3-14 ring atoms, wherein one or more atoms on the ring are independently replaced by heteroatoms, which have the meaning as described herein. The ring may be fully saturated or contain one or more degrees of unsaturation, but no aromatic rings are permitted. When a heterocycle is attached to other parts of a molecule via a linking site, the heterocycle is represented as a monovalent heterocyclic group. Unless otherwise stated, the heterocyclic group may be a carbonyl or heteroatomyl group, and the -CH2- group may optionally be replaced by -C(=O)-; the nitrogen atom of the ring may optionally be oxidized to... N -Oxides; the sulfur atoms in the ring can optionally be oxidized to S -Oxides (such as groups of SO, SO2). In some embodiments, the heterocycle or heterocyclic group consists of 3-10 atoms and is represented as a 3-10 membered heterocycle or a 3-10 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-9 atoms and is represented as a 3-9 membered heterocycle or a 3-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-9 atoms and is represented as a 5-9 membered heterocycle or a 5-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-6 atoms and is represented as a 3-6 membered heterocycle or a 3-6 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-6 atoms and is represented as a 5-6 membered heterocycle or a 5-6 membered heterocyclic group. The heterocyclic group is optionally substituted by one or more substituents described in this invention. Examples of heterocyclic groups include, but are not limited to, ethylene oxide, azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl,4 H-pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, dioxane, dithiaranyl, thiaranyl, homopiperazineyl, homopiperidinyl, oxetaneheptane, thioheptanyl, oxazolidinyl, diazadinyl, thioazolidinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, etc. Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridinyl, pyrimidinidone, etc. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, etc.

[0051] The term "aryl" may be used interchangeably with the term "aromatic ring" to refer to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more attachment sites connected to the remainder of the molecule. In some embodiments, the aryl group contains 6-12 ring atoms, denoted as C 6-12 Aryl or 6-12-membered aryl. In some embodiments, the aryl group contains 6-10 ring atoms, denoted as C. 6-10 Aryl or 6-10-membered aryl groups. Examples of aryl groups may include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthraceneyl. The aryl group may optionally be substituted by one or more substituents described in this invention.

[0052] The term "heteroaryl" may be used interchangeably with the terms "heteroary ring" or "heteroary compound" to refer to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system containing 5-14, 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is typically, but not necessarily, linked to the parent molecule via its aromatic ring. Unless otherwise stated, the heteroaryl group may be linked to the remainder of the molecule (e.g., the main structure in the general formula) at any reasonable site (which may be C or N). When a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-; the nitrogen atom of the ring may optionally be oxidized to... N -Oxides; the sulfur atoms in the ring can optionally be oxidized to S-Oxides (such as SO, SO2 groups). The heteroaryl group is optionally substituted with one or more substituents described in this invention. In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, denoted as a 5-12-membered heteroaryl; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, denoted as a 5-10-membered heteroaryl; in still other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, denoted as a 5-6-membered heteroaryl. The heteroaryl group is optionally substituted with one or more substituents described in this invention. Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also including, but not limited to, the following bicyclic compounds: benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo[1,2- a ]pyridyl, pyrazolo[1,5- a ]pyridyl, pyrazolo[1,5- a ]pyrimidinyl, imidazo[1,2- b [1,2,4]triazolo[4,3-]pyridazinyl,[1,2,4]triazolo[4,3-] b [1,2,4]triazolo[1,5-]pyridazinyl, [1,2,4]triazolo[1,5-] a [Pyrimidinyl, [1,2,4]triazolo[1,5-] a ]Pyridyl, etc.

[0053] The term "bicyclic or tricyclic" includes fused rings, bridged rings, and spirocyclic rings. The bicyclic or tricyclic ring may optionally be substituted with one or more substituents described in this invention. Examples of such substituents include, but are not limited to, bicyclic [2.2.1]heptyl, 2-methyl-diazabicyclic [2.2.1]heptyl, etc.

[0054] The terms "fused ring," "fused ring," and "fused ring group" are used interchangeably here to refer to a saturated or unsaturated ring system formed by two or more ring structures sharing two adjacent ring atoms, which may contain independent or conjugated unsaturated states. Examples of fused ring groups include, but are not limited to, 2,3,3a,4,7,7a-hexahydro-1 H -Indene, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene, 3-aza-fused[3.1.0]hexane, 3-aza-bicyclo[3.3.0]octane, hexahydro-furan[3,4- c ]pyrrole, hexahydrothiophene[3,4-c]pyrrole, 3,4,5,6-tetrahydrocyclopentane[ c Thiophene group, etc.

[0055] The terms "bridged ring" and "bridged ring group" are used interchangeably herein to refer to a saturated or unsaturated ring system formed by two or more cyclic structures sharing two non-directly connected ring atoms. Examples of such systems include, but are not limited to, bicyclic [2.2.1]heptyl, 2-oxo-5-azabicyclic [2.2.1]heptyl, 2-thio-5-azabicyclic [2.2.1]heptyl, 2-oxo-5-azabicyclic [2.2.1]heptyl, 2,5-diazabicyclic [2.2.1]heptyl, 2-methyl-2,5-diazabicyclic [2.2.1]heptyl, etc. The bridged ring group may optionally be substituted by one or more substituents described in this invention.

[0056] The terms "spirocyclic" and "spirocyclic group" are used interchangeably here to refer to a saturated or unsaturated ring system formed by two or more ring structures sharing a single ring atom. Each ring in a spirobicyclo group can be a carbocyclic or heterocyclic group, and examples include, but are not limited to, 1,4-dioxo-8-azaspiro[4,5]decane-8-yl, 2-oxo-8-azaspiro[4,5]decane-8-yl, 2,8-diazaspiro[4,5]decane-8-yl, 2,7-diazaspiro[4.4]nonane-2-yl, 7-oxo-2-azaspiro[4.5]decane-2-yl, 4-azaspiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, spiro[2.4]heptyl, spiro[4.4]nonyl, 7-hydroxy-5-azaspiro[2.4]heptane-5-yl, spiro[2.4]heptyl, spiro[4.4]nonyl, etc. The spirocyclic group may optionally be replaced by one or more substituents described in this invention.

[0057] The term "unsaturated" as used in this invention means that the group contains one or more degrees of unsaturation.

[0058] The term “heteroatom” refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrroleyl), or NR (like NR in N-substituted pyrroleyl).

[0059] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0060] The term "hydroxyl" is used alone or in combination with other terms (such as hydroxyalkyl) and signifies -OH.

[0061] The term "composed of jk atoms" or "jk element" indicates that the cyclic group is composed of jk ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k > j; "jk" includes j, k, and any natural number between them. For example, "composed of 3-8 atoms" or "3-8 element", "composed of 3-6 atoms" or "3-6 element", "composed of 5-10 atoms" or "5-10 element", or "composed of 5-6 atoms" or "5-6 element" indicates that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10), or 5-6 (i.e., 5 or 6) ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0062] As described in this invention, substituent (R) f A ring system formed by a single bond to a central ring represents f substituents R that can be substituted at any substituted or reasonable position on the ring. For example, formula a represents that ring G can be substituted by f Rs, where when f is greater than 1, each R can be independently selected from the same or different substituents.

[0063] Formula a As described in this invention, a substituent R formed by a single bond connecting to a central double ring (as shown in formula b) means that the substituent R can be substituted at any substituted or reasonable position on the ring it is connected to (as shown in the H ring in formula b). For example, formula b represents that any substituted position on the H ring can be substituted by R, as shown in formula b. 1~ b 5 As shown.

[0064]

[0065] As described in this invention, the group "-C(=O)NH-" has two connection sites that can be attached to the rest of the molecule, and the connection methods of the two connection sites can be interchanged. For example, formula c represents that the group -C(=O)NH- can be attached to the rest of the molecule through the E-terminus or the E'-terminus.

[0066]

[0067] The term "pharmaceuticalally acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar undesirable reactions, such as gastrointestinal upset, dizziness, etc. Preferably, as used herein, the term "pharmaceuticalally acceptable" means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0068] As used in this invention, "pharmaceutically acceptable salts" refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or these salts obtained by other methods described in the literature, such as ion exchange. This invention also contemplates the formation of quaternary ammonium salts from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained through quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates, and aromatic sulfonates.

[0069] The term "carrier" refers to a diluent, excipient, excipient, or matrix that is administered together with the compound. These drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Aqueous and aqueous solutions, saline solutions, and aqueous glucose and glycerol solutions are preferred as carriers, particularly for injectable solutions. Suitable drug carriers are described in EW Martin's "Remington's Pharmaceutical Sciences".

[0070] As used in this invention, the term "prodrug" refers to the conversion of a compound in vivo into a compound represented by formula (I), (II), (IV-1), (IV-2), or (VI). Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound containing a hydroxyl group can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound.

[0071] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0072] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0073] When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; and in yet another embodiment, a molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound.

[0074] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0075] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0076] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are included within the scope of this invention.

[0077] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0078] The nitrogen oxides of the compounds of this invention are also included within the scope of this invention. The nitrogen oxides of the compounds of this invention can be prepared by oxidizing the corresponding nitrogen-containing basic substances in the presence of an acid, such as acetic acid, using a common oxidizing agent (e.g., hydrogen peroxide) at elevated temperature, or by reacting with a peracid in a suitable solvent, such as with peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0079] The pharmaceutically acceptable salts of the present invention can be synthesized using conventional chemical methods from a parent compound, a basic or acidic moiety. Generally, these salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in suitable cases, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. Other suitable salts can be listed, for example, in “Remington’s Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0080] Furthermore, the compounds disclosed in this invention, including their salts, can also be obtained in their hydrated form or in the form containing their solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in this invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this invention is intended to include both solvated and unsolvated forms.

[0081] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125I. The isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotope-labeled reagents instead of the previously used unlabeled reagents, as described in the examples and preparation processes of the present invention.

[0082] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0083] Description of the compounds of the present invention This invention provides a PRMT5-MTA co-synergistic inhibitor that selectively inhibits the binding of SAM to PRMT5 for the treatment of related cancers. This invention also provides pharmaceutical compositions comprising this class of compounds, and the use of this class of compounds and pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of cancer.

[0084] The compounds of this invention exhibit excellent properties, such as good half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, and solubility, which can promote the reduction of side effects, the expansion of the therapeutic index, or the improvement of tolerability.

[0085] On the one hand, the present invention provides a compound, which is a compound of formula (I) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I). (I), Among them, rings A, L, X1, X2, and R 1 R 2 R 3 , n, and m each have the definitions described in this invention.

[0086] In some implementations, L stands for key.

[0087] In some implementation schemes, " indicates a single or double bond.

[0088] In some implementations, X1 is -O-, -S-, -S(=O)-, -SO2-, -NR Xa -or-CR Xb R Xc - and R in X1 Xb and R Xc X2 is not simultaneously H; it is -S-, -S(=O)-, -SO2-, -NR. Xa -or-CR Xb R Xc-, R Xa R Xb R Xc It has the meaning described in this invention.

[0089] In some implementation schemes, R Xa R Xb R Xc Each is independently H, D, -CN, -SF5, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; or R Xb R Xc Together with the carbon atom it is attached to, they form C 3-6 Carbon rings or 3-10 membered heterocycles.

[0090] In some implementation schemes, R Xa R Xb R Xc Each is independently H, D, -CN, -SF5, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; or R Xb R Xc Together with the carbon atom it is attached to, they form C 3-6 Carbon rings or 3-6 membered heterocycles.

[0091] In some implementation schemes, R Xa R Xb R Xc Each can be independently H, D, -CN, -SF5, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -OCH3, -OCH2CH3 or -OCH(CH3)2; or R Xb R Xc Together with the carbon atoms they are attached to, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiaran.

[0092] In some preferred embodiments, X1 is -O- and X2 is -CH2-.

[0093] In some implementations, each R 2 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -OR 2a -C(=O)R 2a -OC(=O)R 2a -OC(=O)NR 2a R 2b -C(=O)OR 2a -NR 2a R 2b -C(=O)NR 2a R 2b -NR 2a C(=O)R 2b -NR 2a C(=O)OR 2b -NR 2a S(=O)2R 2b -SR 2a -SF5, -S(=O) R 2a -S(=O)2R 2a -S(=O)(=NR) 2a )R 2b or -S(=O)2NR 2a R 2b Or two R atoms bonded to the same carbon atom 2 Together with the carbon atoms bonded to them, they form =O, =S, =CR a R b Or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 2c Replace; where R 2a R 2b R 2c R a R b It has the meaning described in this invention.

[0094] In some implementations, each R 2 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl, -OR 2a -C(=O)R 2a -OC(=O)R 2a -OC(=O)NR 2a R 2b -C(=O)OR 2a -NR 2a R 2b -C(=O)NR 2a R 2b -NR 2a C(=O)R 2b -NR 2a C(=O)OR 2b -NR 2a S(=O)2R 2b -SR 2a -SF5, -S(=O) R 2a -S(=O)2R 2a -S(=O)(=NR) 2a )R 2b or -S(=O)2NR 2a R 2b Or two R atoms bonded to the same carbon atom 2 Together with the carbon atoms bonded to them, they form =O, =S, =CR a R b Or C 3-6 cycloalkyl; wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 2c Replace; where R 2a R 2b R 2c R a R b It has the meaning described in this invention.

[0095] In some implementations, the R 2a R 2b R 2c Each is independently H, D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0096] In some implementations, the R 2a R 2b R 2c Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups.

[0097] In some implementations, the R 2a R 2b R 2c Each of the following can be independently H, D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2.

[0098] In some implementations, each R 2Each of the following is independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, -OCH(CH3)2, -SF5, -C(=O)CH3, -OC(=O) CH3, -OC(=O)NH2, -OC(=O)NHCH3, -NH2, -C(=O)NCH3, -S(=O)2CH3, -SCH3, -SCH2CH3, -SCH(CH3)2, -SCF3, -SCH2F, -SCHF2, -SCHCl2, -SCH2CF3, -SCH2CHCl2, -SCH2CHF2 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiocyclobutyl, pyrrolidine, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl or phenyl; or two R atoms attached to the same carbon atom. 2Together with the carbon atom attached to it, it forms =O, =S, =CH2, =CHCH3, =CHCH2F, =CHCHF2, =CH(CH2)2CH3, =CH(CH2)2CH2F, cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0099] In some implementations, ring A is C. 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic ring.

[0100] In some implementations, ring A is C. 3-6 Carbon rings, 3-6 membered heterocyclic rings, 5-6 membered heteroaromatic rings, or benzene.

[0101] In some embodiments, ring A is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, Tetrahydrothiaran, Piperidine, Morpholine, Thiomorpholine, Piperazine, Dioxane, Dithiaran, Thioxane, Furan, Imidazole, Isoxazole, Oxazole, Pyrrole, Pyridine, Pyrimidine, Pyridazine, Thiazole, Tetrazol, Triazole, Thiophene, Pyrazole, Isothiazine, 1,2,3-Oxadiazole, 1,2,5-Oxadiazole, 1,2,4-Oxadiazole, 1,2,3-Triazole, 1,2,3-Thiodiazole, 1,3,4-Thiodiazole, 1,2,5-Thiodiazole, Pyrazine, 1,3,5-Triazine, Benzene, Naphthyl ring, Benzopyridine, Benzopyrimidine, Benzoimidazol, Benzopyrrole, Benzopyrazole, Benzopyrrole, Piperidine, Benzothiazole, or Benzothiphene.

[0102] In some preferred embodiments, ring A is , , , , , , or That is, equation (I) can be specifically represented by the following structure: (III-1) (III-2) (III-3) (III-4) (III-5) (III-6) (III-7) or (III-8); Among them, R 1 R 2 R 3 L, X1, X2, n, and m have the meanings described in this invention.

[0103] In some implementations, each R 3 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -O-(C 2-6 ynyl group), -C(=O)R 3a -OC(=O)R 3a -OC(=O)NR 3a R 3b -C(=O)OR 3a -NR 3a R 3b -C(=O)NR 3a R 3b -NR 3a C(=O)R 3b -NR 3a C(=O)OR 3b -NR 3a S(=O)2R 3b -SR 3a -SF5, -S(=O) R 3a -S(=O)2R 3a -S(=O)(=NR) 3a )R 3b or -S(=O)2NR 3a R 3b ; wherein, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 3c Replace; where R 3a R 3b R 3c It has the meaning described in this invention.

[0104] In some implementations, each R 3 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl, -O-(C 2-4 ynyl group), -C(=O)R 3a -OC(=O)R 3a -OC(=O)NR 3a R 3b -C(=O)OR 3a -NR 3a R 3b -C(=O)NR 3a R 3b -NR 3a C(=O)R 3b -NR 3a C(=O)OR 3b -NR 3a S(=O)2R 3b -SR 3a -SF5, -S(=O) R 3a -S(=O)2R 3a -S(=O)(=NR) 3a )R 3b or -S(=O)2NR 3a R 3b ; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each optionally surrounded by 1, 2, 3, or 4 R groups. 3c Replace; where R 3a R 3b R 3c It has the meaning described in this invention.

[0105] In some implementations, each R 3c Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, C6-10 aryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic and C6-10 aryl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 3d Substitution; or two R atoms attached to the same carbon atom 3c Together with the carbon atoms bonded to them, they form =O, =S, or =CR. c R d Among them, R c R d R 3d It has the meaning described in this invention.

[0106] In some implementations, each R 3c Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 The cycloalkyl group, the 3-6 membered heterocyclic group, and the phenyl group are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 3d Substitution; or two R atoms attached to the same carbon atom 3c Together with the carbon atoms bonded to them, they form =O, =S, or =CR. c R d Among them, R c R d R 3d It has the meaning described in this invention.

[0107] In some implementations, each R 3cEach of the following can be independently identified as D, F, Cl, Br, I, -CN, -SF5, -OH, -NO2, -N(CH3)2, -NHCH3, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -C H2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, -OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl, 4-pyrazolyl) ), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl or phenyl; wherein -N(CH3)2, -NHCH3, -CH3, -CH2CH3, -(CH2)2 CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH= CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, - OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl, 4-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, and phenyl are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 3d Substitution; or two R atoms attached to the same carbon atom 3c Together with the carbon atoms attached to them, they form =O, =S, =CH2, =CHCH3, =CHCH2F, =CHCHF2, =CH(CH2)2CH3 or =CH(CH2)2CH2F.

[0108] In some implementations, each R 3d Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, C6-10 aryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic groups, and C6-10 aryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 D, halogen, -CN, -SF5, -OH, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted with haloalkoxy groups; wherein, R 3e R 3f It has the meaning described in this invention.

[0109] In some implementations, each R 3d Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6cycloalkyl, 3-6 membered heterocyclic group, phenyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 D, halogen, -CN, -SF5, -OH, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Substituted with haloalkoxy groups; wherein, R 3e R 3f It has the meaning described in this invention.

[0110] In some implementations, each R 3d Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -SF5, -OH, -NO2, -NR 3e R 3f -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, spiropentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, dihydrothiophene, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N-pyrrole, 2-pyrrole, 3-pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophene, 3-thiophene, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl or benzene The groups mentioned include -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, spiropentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexane, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, dihydrothiophene, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophene, 3-thiophene, pyrazole (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, and phenyl, each individually. The R can be optionally replaced by 1, 2, 3, or 4 D, F, Cl, Br, I, -CN, -SF5, -OH, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, or; wherein, R 3e R 3f It has the meaning described in this invention.

[0111] In some implementations, the R 3a R 3b R 3e R 3f Each is independently H, D, halogen, -CN, -SF5, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; In some implementations, the R 3a R 3b R 3e R 3f Each is independently H, D, halogen, -CN, -SF5, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups; In some implementations, the R3a R 3b R 3e R 3f Each of the following can be independently H, D, F, Cl, Br, I, -CN, -SF5, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2.

[0112] In some implementations, each R 3 Each independently is C 2-4 alkynyl group; wherein, the C 2-4 Each alkynyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. 3c Replace; where each R 3c Each is independently a 5-6 membered heteroaryl or a 3-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl and C 3-6 Each cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R's. 3d Replace; each R 3d Each independently is C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 halogens, -OH, C 1-4 Alkyl groups are substituted.

[0113] In some implementations, each R 3Each of these can be independently identified as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2 Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡ C(CH3), -OC≡CH, -OC≡C(CH3), -OC≡CCH2CH3, -O-CH2C≡CH, -O-CH2C≡C(CH3), -SF5, -C(=O) CH3, -OC(=O) CH3, -OC(=O)NH2, -OC(=O)NHCH3, -NH2, -C(=O)NCH3, -S(=O)2CH3, -SCH3, -SCH2CH3, -SCH(CH3)2, -SCF3, -SCH2F, -SCHF2, -SCHCl2, -SCH2CF3, -SCH2CHCl2, -SCH2CHF2 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiocyclobutyl, pyrrolidine, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl or phenyl; wherein, -CH3, -C H2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH =CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3) , -OC≡CH, -OC≡C(CH3), -OC≡CCH2CH3, -O-CH2C≡CH, -O-CH2C≡C(CH3), -C(=O) CH3, -OC(=O) CH3, -OC(=O)NH2, -OC(=O)NHCH3, -NH2, -C(=O)NCH3, -S(=O)2CH3, -SCH3, -SCH2CH3, -SCH(CH3)2, -SCH2F, -SCHF2, -SCHCl2, -SCH2CF3, -SCH2CHCl2, -SCH2CHF2 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiocyclobutyl, pyrrolidine, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophene, 3-thiophene, pyrazole (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, and phenyl are each independently and optionally surrounded by 1, 2, 3, or 4 R's. 3c Replace; where R 3c It has the meaning described in this invention.

[0114] In some implementations, each R 3 Each can be independently represented as F, -CF3, -CH3, -C≡CH, -O-CH2C≡CH. , , , , , , , , , , , , , , or .

[0115] In some preferred embodiments, each R 3 Each can be F, -CF3, or -C≡CH independently.

[0116] In some implementations, two R atoms attached to the same carbon atom 3 Together with the carbon atoms bonded to them, they form =O, =S, =CR e R f C 3-6 Carbon rings or 3-10 membered heterocycles, wherein the C 3-6 The carbon ring and 3-10 membered heterocycles are each independently and optionally p R 8 Replaced; where p and R 8 It has the meaning described in this invention.

[0117] In some implementations, two R atoms attached to the same carbon atom 3 Together with the carbon atoms bonded to them, they form =O, =S, =CRe R f C 3-6 Carbon rings or 3-6 membered heterocycles, wherein the C 3-6 The carbon ring and the 3-6 membered heterocycles are each independently and optionally divided by p R 8 Replaced; where p and R 8 It has the meaning described in this invention.

[0118] In some implementations, two R atoms attached to the same carbon atom 3 Together with the carbon atoms they are attached to, they form =O, =S, =CH2, =CHCH3, =CHCH2F, =CHCHF2, =CH(CH2)2CH 3、 =CH(CH2)2CH2F, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiaran; wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxaziridine, thioaziridine, pyrrolidine, pyrrolidine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally p-R 8 Replaced; where p and R 8 It has the meaning described in this invention.

[0119] In some implementations, two R atoms connected to adjacent or non-adjacent ring atoms 3 Together with the ring atoms attached to them, they form C 3-6 Carbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-10 quintile heterocyclic aromatic rings, wherein the C 3-6 Carbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-10 heterocyclic rings are each independently and optionally divided by p R 8 Replaced; where p and R 8 It has the meaning described in this invention.

[0120] In some implementations, two R atoms connected to adjacent or non-adjacent ring atoms 3 Together with the ring atoms attached to them, they form C 3-6 Carbocyclic rings, 3-6 membered heterocyclic rings, benzene, or 5-6 membered heteroaromatic rings, wherein the C 3-6 The carbon ring, 3-6 membered heterocycles, benzene, and 5-6 membered heteroaromatic rings are each independently and optionally p-R 8 Replaced; where p and R 8 It has the meaning described in this invention.

[0121] In some implementations, two R atoms connected to adjacent or non-adjacent ring atoms 3 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, Tetrahydrothiaran, Piperidine, Morpholine, Thiomorpholine, Piperazine, Dioxane, Dithiazide, Thioxane, Benzene, Furan, Imidazole, Isoxazole, Oxazole, Pyrrole, Pyridine, Pyrimidine, Pyridazine, Thiazole, Tetrazol, Triazole, Thiophene, Pyrazole, Isothiazole, 1,2,3-Oxadiazole, 1,2,5-Oxadiazole, 1,2,4-Oxadiazole, 1,2,3-Triazole, 1,2,3-Thiodiazole, 1,3,4-Thiodiazole, 1,2,5-Thiodiazole Azole, pyrazine, or 1,3,5-triazine; cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, thiazide, benzene, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazine, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, and 1,3,5-triazine are each independently and optionally pR 8 Replaced; where p and R 8 It has the meaning described in this invention.

[0122] In some implementations, two R atoms connected to adjacent or non-adjacent ring atoms 3 Formed together with ring A or .

[0123] In some implementations, each R 8 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy group; or two R groups attached to the same carbon atom 8 Together with the carbon atom it is bonded to, it forms =O, =S, or =CR. g R h Among them, R g R h It has the meaning described in this invention.

[0124] In some implementations, each R 8 Each is independently H, D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 alkoxy group; or two R groups attached to the same carbon atom 8 Together with the carbon atom it is bonded to, it forms =O, =S, or =CR. g R h Among them, R g R h It has the meaning described in this invention.

[0125] In some implementations, each R 8 Each of the following can be independently H, D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to the same carbon atom. 8Together with the carbon atom it is attached to, it forms =O, =S, =CHCH3, =CHCH2F, =CHCHF2, =CH(CH2)2CH3 or =CH(CH2)2CH2F.

[0126] In some implementation schemes, R 1 for , , , , , or .

[0127] In some implementation schemes, R 4 R 5 R 6 R 7 Each is independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or -NR i R j Among them, R i R j It has the meaning described in this invention.

[0128] In some implementation schemes, R 4 R 5 R 6 R 7 Each can be independently H, D, F, Cl, Br, I, -CN, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl or -NH2.

[0129] In some preferred embodiments, R 4 R 5 R 6 All are -NH2; R 7 For H.

[0130] In some implementations, Y1 is N or CR Ya Y2 is N or CR Yb Y3 is N or CR Yc Y4 is N or CR Yd Y5 is N or CR Ye ;R Ya RYb R Yc R Yd R Ye Each is independently H, D, -CN, halogen, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 1-6 alkylene-O-(C 1-6 Alkyl), -C(=O)NR n R m Or C 1-6 Halogenated alkoxy groups; Y6 is N, C, or CR Yf Y7 is N, C or CR Yg Ring B is C 3-6 Carbon rings, 6-membered heterocyclic rings, 5-10-membered heteroaromatic rings, or C 6-10 Aromatic rings, wherein each ring B is independently and optionally divided by q R 9 Replaced; R Yf R Yg Each is independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups; Each R 9 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkyl group; or two R atoms attached to adjacent or non-adjacent ring atoms. 9 Together with the ring atoms attached to them, they form C 3-6 Cycloalkyl or 3-10 membered heterocyclic groups; or two R groups attached to the same carbon atom 9 Together with the carbon atom it is bonded to, it forms =O or =S; The conditions are: (1) R 1 Not for , or Structure; or, when R 1 for or When the structure is defined, equation (I) is: , or ; (2) When equation (I) is , , , or And R 1 for , , or R Ya When R is H, Cl or F, 3 Not -CF3 or ; Z1 is N or CR Za Z2 is N or CR Zb Z3 is N or CR Zc ;R Za R Zb R Zc Each is independently H, D, -CN, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Hydroxyalkyl; Z4 is N, C, or CR. Zd Z5 is N, C or CR Ze ; Ring C is C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic rings, the C 3-6 Carbon rings, 3-10 membered heterocycles, 5-10 membered heteroaromatic rings and C 6-10 The aromatic rings are each independently and arbitrarily assigned to s R 10 Replace; R Zd R Ze Each is independently H, D, halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups; Each R 10 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy group; or two R groups attached to the same carbon atom 10 Together with the carbon atom it is bonded to, it forms =O or =S; W1 is N or CR Wa W2 is N or CR Wb ; R Wa R Wb Each is independently H, D, halogen, C 1-6 Alkyl or C 1-6Halogenated alkyl; or R Wa R Wb Together with the ring atoms they are connected to, they form C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic ring, the C 3-6 Carbon rings, 3-10 membered heterocycles, 5-10 membered heteroaromatic rings and C 6-10 The aromatic rings are each independently and arbitrarily assigned to t R. 11 Replaced; Each R 11 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy group; or two R groups attached to the same carbon atom 11 Together with the carbon atom it is bonded to, it forms =O or =S; where Y1 and R 1 R 2 R 3 R n R m , q, m, n, and L have the meanings described in this invention.

[0131] In some implementations, Y1 is N or CR Ya Y2 is N or CR Yb Y3 is N or CR Yc Y4 is N or CR Yd Y5 is N or CR Ye ;R Ya R Yb R Yc R Yd R Ye Each is independently H, D, -CN, halogen, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -C 1-4 alkylene-O-(C 1-4 Alkyl), -C(=O)NR n R m Or C 1-4 Halogenated alkoxy groups; Y6 is N, C, or CR Yf Y7 is N, C or CR Yg Ring B is C 3-6Carbon rings, 5-membered heterocycles, 5-6-membered heteroaromatic rings, or benzene, wherein each ring B is optionally and independently divided by q R. 9 Replaced; R Yf R Yg Each is independently H, D, halogen, -CN, C 1-4 Alkyl, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkyl groups; Each R 9 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Alkyl group; or two R atoms attached to adjacent or non-adjacent ring atoms. 9 Together with the ring atoms attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; or two R groups attached to the same carbon atom 9 Together with the carbon atom it is bonded to, it forms =O or =S; The conditions are: (1) R 1 Not for , or Structure; or, when R 1 for or When the structure is defined, equation (I) is: , or ;; (2) When equation (I) is , , , or And R 1 for , , or R Ya When R is H, Cl or F, 3 Not -CF3 or ; Z1 is N or CR Za Z2 is N or CR Zb Z3 is N or CR Zc ;R Za R Zb R Zc Each is independently H, D, -CN, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C1-4 Hydroxyalkyl; Z4 is N, C, or CR. Zd Z5 is N, C or CR Ze ; Ring C is C 3-6 Carbocyclic rings, 3-6 membered heterocyclic rings, 5-6 membered heteroaromatic rings, or benzene, wherein each of the ring Cs is optionally and independently divided by s Rs. 10 Replace; R Zd R Ze Each is independently H, D, halogen, -CN, hydroxyl, C 1-4 Alkyl, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkyl groups; Each R 10 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 alkoxy group; or two R groups attached to the same carbon atom 10 Together with the carbon atom it is bonded to, it forms =O or =S; W1 is N or CR Wa W2 is N or CR Wb ; R Wa R Wb Each is independently H, D, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or R Wa R Wb Together with the ring atoms they are connected to, they form C 3-6 Carbocyclic rings, 3-6 membered heterocyclic rings, 5-6 membered heteroaromatic rings, or benzene, wherein the C 3-6 The carbon ring, 3-6 membered heterocycles, 5-6 membered heteroaromatic rings, and benzene are each independently and optionally divided by t R 11 Replaced; Each R 11 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 alkoxy group; or two R groups attached to the same carbon atom 11 Together with the carbon atom it is bonded to, it forms =O or =S; where Y1 and R 1 R 2 R 3 R n R m, q, m, n, and L have the meanings described in this invention.

[0132] In some implementations, Y1 is N or CR Ya Y2 is N or CR Yb Y3 is N or CR Yc Y4 is N or CR Yd Y5 is N or CR Ye ;R Ya R Yb R Yc R Yd R Ye Each of the following is independently H, D, -CN, F, Cl, Br, I, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2, (CH2)4OH , -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2F, -OCF3, -OCHF2, -CH2OCH3, -(CH2)2OCH3, -CH2OCH2CH3, -CH2O(CH2)2CH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3)2; Y6 is N, C, or CR Yf Y7 is N, C or CR Yg Cycle B is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiacyclopentane, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, 1,3,5-triazine, or benzene, wherein each of the cyclic B is optionally and independently divided by q R 9 Replaced; R Yf RYg Each can be independently H, D, F, Cl, Br, I, -CN, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2 or (CH2)4OH; Each R 9 Each of the following is independently D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to adjacent or non-adjacent ring atoms. 9 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiaran; or two R atoms bonded to the same carbon atom. 9 Together with the carbon atom it is bonded to, it forms =O or =S; The conditions are: (1) R 1 Not for , or Structure; or, when R 1 for or When the structure is defined, equation (I) is: , or ; (2) When equation (I) is , , , or And R 1 for , , or R Ya When R is H, Cl or F, 3 Not -CF3 or ; Z1 is N or CR Za Z2 is N or CR Zb Z3 is N or CR Zc ;R Za R Zb R Zc Each can be independently H, D, -CN, hydroxyl, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2 or (CH2)4OH; Z4 is N, C, or CR. Zd Z5 is N, C or CR Ze The ring C is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxacyclobutane, thiohexacyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiohexacyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, thiazide, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, 1,3,5-triazine, or benzene, wherein each of the ring Cs is optionally and independently divided by s Rs. 10 Replace; R Zd R ZeEach can be independently H, D, F, Cl, Br, I, -CN, hydroxyl, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2 or (CH2)4OH; Each R 10 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to the same carbon atom. 10 Together with the carbon atom it is bonded to, it forms =O or =S; W1 is N or CR Wa W2 is N or CR Wb ; R Wa R Wb Each independently represents H, D, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br or -(CH2)2Cl; or R Wa R Wb Together with the ring atoms they are attached to, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H-Pyran, Tetrahydrothiaran, Piperidine, Morpholine, Thiomorpholine, Piperazine, Dioxane, Dithiaran, Thioxane, Furan, Imidazole, Isoxazole, Oxazole, Pyrrole, Pyridine, Pyrimidine, Pyridazine, Thiazole, Tetrazol, Triazole, Thiophene, Pyrazole, Isothiazole, 1,2,3-Oxadiazole, 1,2,5-Oxadiazole, 1,2,4-Oxadiazole, 1,2,3-Triazole, 1,2,3-Thiodiazole, 1,3,4-Thiodiazole, 1,2,5-Thiodiazole Pyrazine, 1,3,5-triazine, or benzene, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, thiazide, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazine, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, 1,3,5-triazine, or benzene are each independently and optionally t R 11 Replaced; Each R 11 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to the same carbon atom. 11 Together with the carbon atom it is bonded to, it forms =O or =S; where Y1 and R 1 R 2 R 3 R n R m , q, m, n, and L have the meanings described in this invention.

[0133] In some preferred embodiments, R1 Choose from any of the following structures: , , , , , , , , , , , , , , , , , , , , , , or Among them, R 4 R 5 R 6 R 7 R 9 R 10 R 11 R Zc R Ya R Yc R Ye Each has the definition as described in this invention, R 9a With R 9 Same definition.

[0134] In some embodiments, the compound of the present invention is a compound of formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II). (II) Among them, rings A, L, X1, X2, and R 1 R 2 R 3 , n, and m each have the definitions described in this invention.

[0135] In other embodiments, the compounds of the present invention are compounds represented by formula (IV-1), (IV-2), (VI), (VI-1), or (VI-2), or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of compounds represented by formula (IV-1), (IV-2), (VI), (VI-1), or (VI-2). , or

[0136] Among them, ring A, ring B, ring C, X1, X2, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Z1, Z2, Z3, Z4, Z5, W1, W2, R 1 R 2 R 3 R 4 R 5 R 6 R 7 , n, and m each have the definitions described in this invention.

[0137] In some embodiments, the compound of the present invention is a structure or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug that is one of the following: .

[0138] On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug; optionally, it further comprises a pharmaceutically acceptable carrier.

[0139] On the other hand, the present invention provides the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to protect against, treat, cure or alleviate cancer in a patient.

[0140] On the other hand, the present invention provides compounds or pharmaceutical compositions described herein for the prevention, treatment or treatment of cancer.

[0141] On the other hand, the present invention provides a method for preventing, treating or treating cancer, comprising administering a patient a therapeutically effective amount of the compound or pharmaceutical composition described herein.

[0142] In some embodiments, the cancers described in this invention are MTAP deficiency-related cancers; optionally, the MTAP deficiency-related cancers are ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

[0143] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formulas (I), (II), (IV-1), (IV-2), (VI), (VI-1) or (VI-2).

[0144] Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of this invention.

[0145] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically appropriate in relation to the other components of the formulation and the mammal intended for treatment.

[0146] The salts of the compounds of the present invention also include salts of intermediates used for the preparation or purification of compounds of formula (I), (II), (IV-1), (IV-2), (VI), (VI-1) or (VI-2) or salts of enantiomers isolated from compounds of formula (I), (II), (IV-1), (IV-2), (VI), (VI-1) or (VI-2), but are not necessarily pharmaceutically acceptable salts.

[0147] If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, etc. Alternatively, organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, and salicylic acid can be used; pyranonic acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, etc.

[0148] If the compounds of the present invention are acidic, the desired salts can be prepared by suitable methods, such as using inorganic or organic bases, such as ammonia (primary, secondary, and tertiary ammonia), alkali metal hydroxides, or alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine; ammonia, such as primary, secondary, and tertiary ammonia; and cyclic ammonia, such as piperidine, morpholine, and piperazine, etc.; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0149] Pharmaceutical compositions, formulations, administration and uses of the compounds of the present invention According to another aspect, the pharmaceutical compositions of the present invention are characterized by compounds represented by formulas (I), (II), (IV-1), (IV-2), (VI), (VI-1), or (VI-2), compounds listed in the present invention, or compounds of the embodiments, and pharmaceutically acceptable carriers. The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues. The amounts of compounds in the compositions of the present invention are effective in treating or alleviating cancer in patients.

[0150] As described in this invention, pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable carriers, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York, the contents of this literature indicate that various carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. The use of any conventional carrier media, except for those incompatible with the compounds of the present invention, such as any adverse biological effects or harmful interactions with any other component of the pharmaceutically acceptable composition, is also within the scope of this invention.

[0151] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0152] Preferably, the compound is mixed with a suitable drug diluent, excipient, or carrier (in this case, a drug carrier) selected according to the form of administration and conventional pharmaceutical practice, and the administration method may be oral tablets, capsules, elixirs, syrups, etc.

[0153] For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be conjugated with an orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical ingredient can be conjugated with any orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerin, water, etc. Furthermore, suitable binders, lubricants, dissolving agents, and colorants can be added to the mixture when needed or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, astragalus gum, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Decomposing agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0154] The compounds of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0155] The compounds of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0156] The compounds of this invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0157] The compounds of this invention are also coupled with soluble polymers that serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of this invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly(ε-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0158] The dosing regimen of the compounds of this invention will vary depending on various known factors, such as the pharmacokinetic characteristics and patterns of the specific agent and the route of administration; the recipient's race, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian can make a decision and prescribe an effective dose of the drug to prevent, counteract, or halt the development of cancer.

[0159] The compounds and compositions described herein can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents via the same or different routes of administration. The compounds of the present invention can be contained in a single formulation or in a separate formulation together with other therapeutic agents. The compounds and compositions described herein can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents via the same or different routes of administration. The compounds of the present invention can be contained in a single formulation or in a separate formulation together with other therapeutic agents.

[0160] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0161] The dosing regimen of the compounds of this invention will vary depending on various known factors, such as the pharmacokinetic characteristics and patterns of the specific agent and the route of administration; the recipient's race, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian can make a decision and prescribe an effective dose of the drug to prevent, counteract, or halt the development of cancer.

[0162] The compositions and methods provided by this invention are particularly considered for use in inhibiting PRMT5 activity in cells in vivo. In some embodiments, cells requiring inhibition of PRMT5 activity are contacted in vivo with a therapeutically effective amount of the compound of this invention or a pharmaceutically acceptable salt thereof to negatively modulate PRMT5 activity.

[0163] The compounds and compositions of this invention can be used to treat a variety of cancers, including but not limited to prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, lymphoma, glioblastoma, melanoma astrocytoma, colon cancer, rectal cancer, endometrial cancer, esophageal cancer, stomach cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, sarcoma, bladder cancer, pancreatic cancer, liver cancer, bile duct cancer, and glioblastoma.Specifically, these compounds can be used to treat the following diseases: Heart: sarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viperoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); [The text abruptly ends here, likely due to an incomplete translation or source material.] Urogenital tract: Kidneys (adenocarcinoma, nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminomatous cyst, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma); Liver: Hepatocellular carcinoma (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: Gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; Bone: Osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor, chordoma, osteochondral exostosis, benign soft tissue tumors. Osteoma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), Meninges (meningioma, meningeal sarcoma, glioma), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), Spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecological: Uterus (endometrial cancer), Cervix (cervical cancer, pretumoral cervical dysplasia), Ovary (ovarian cancer, granulosa cell tumor, Sertoli stromal tumor, etc.) Germ cell tumors, malignant teratomas), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma), fallopian tubes (cancer); hematologic diseases: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin diseases: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, hydatidiform mole, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal diseases: neuroblastoma.

[0164] In some implementations, the cancer is MTAP-related cancer.

[0165] In some implementations, the MTAP deficiency-related cancers are ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

[0166] General Synthesis Process Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0167] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as described herein. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0168] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0169] In the examples described below, unless otherwise specified, all temperatures are in degrees Celsius (°C). Room temperature in the examples refers to 15°C to 30°C; in some examples, room temperature is 20°C to 30°C. Unless otherwise specified, common reagents are commercially available, such as anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous acetonitrile, and anhydrous dichloromethane, as well as toluene, diethyl ether, ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide, etc.

[0170] The following reactions are generally carried out at room temperature and pressure, or under positive nitrogen pressure, or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0171] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0172] 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 ¹H NMR spectra with CDCl₃ and DMSO-d 6. CD3OD or acetone - d 6 represents the solvent (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constant. J It is represented by Hertz (Hz).

[0173] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 × 15 mm, 3.5 μm, 6 min, flow rate 0.6 mL / min; mobile phase: A phase (aqueous phase): water-acetonitrile-formic acid = 950:50:1, B phase (organic phase): acetonitrile:formic acid = 1000:1, gradient 0 min: A phase 100%, 2 min: A phase 0%, 3.5 min: A phase 0%), electrospray ionization (ESI) at 210 nm / 254 nm, detection by UV.

[0174] Pure compounds were detected using UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0175] The abbreviations in Table 1 below are used throughout this invention: Table 1. Comparison of Abbreviations

[0176] The following reaction scheme describes the steps for preparing the compounds disclosed in this invention.

[0177] The following synthetic scheme lists the general experimental steps for preparing the compounds disclosed in this invention. Those skilled in the art can make appropriate modifications to the method or adjustments to the raw materials according to the actual situation to prepare the compounds described in this invention.

[0178] Reaction Scheme 1

[0179] Compound X-1 and compound X-2 undergo a coupling reaction under anhydrous and oxygen-free conditions via an inorganic base (preferably potassium phosphate) and a palladium catalyst (preferably bis(tert-butylphosphine)palladium) to give compound X-3. Compound X-3 is then reduced with sodium borohydride to give compound X-4, or asymmetricly reduced with a chiral reducing agent such as RuCl(p-cymene)[(S,S)-Ts-DPEN] to give compound X-4. Compound X-4 undergoes cyclization under strong base (such as sodium tert-butoxide) or palladium catalyst (such as Pd2(dba)3, Xphos PdG2, etc.) to give compound X-5. Compound X-5 is then deprotected by acid hydrolysis (such as trifluoroacetic acid, hydrochloric acid, etc.) to give intermediate M. Intermediate M reacts with compound R... 1 -L-COOH is reacted with an alkaline catalyst (such as TEA or DIPEA) under the condition of a condensing agent (such as HATU) to give the compound (I-1) of the present invention.

[0180] Among them, rings A and R 1 R 2 R 3 X2, m, and n each have the definitions described in this invention; Hal 1 and Hal 1 Each is independently F, Cl, Br, or I, when Hal 1 When F or Cl is preferred, Hal 2 Preferably Br or I; when Hal 1 When Br is preferred, Hal 2 I is preferred.

[0181] Reaction Scheme 2

[0182] Intermediate M undergoes an acylation reaction with monoethyl oxaloyl chloride under organic base conditions (such as DIPEA or TEA) to give compound X-6. Compound X-6 is hydrolyzed under alkaline conditions (preferably lithium hydroxide) to give carboxyl compound X-7. Compound X-7 reacts with compound X-8 in the presence of a catalyst (such as TEA or DIPEA) and a condensing agent (preferably HATU) to give compound X-9. Compound X-9 is deprotected under acidic conditions (such as TFA or hydrochloric acid) to give compound (I-2) of the present invention.

[0183] Among them, rings A and R 2 R 3 X2, Z1, Z2 and Z3 each have the definitions described in this invention; PG is an amino protecting group, preferably Boc, PMB and DMB.

[0184] Additionally, the chiral separation method involved is: IC chiral column 65 (methanol: ethylenediamine = 1000:1) + 35% CO2.

[0185] Example Multiple batches can be synthesized under the same conditions for each reaction step to provide sufficient raw materials or intermediates for subsequent reactions.

[0186] The synthetic route for intermediate M-1 involved is as follows:

[0187] Step 1: Synthesis of tert-butyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-3-oxoperidin-1-carboxylate Add 7.32 g (30.11 mmol) of 4-bromo-3-fluorotrifluorotoluene to a 100 mL single-necked flask and N -tert-butyloxycarbonyl-3-piperidinone (5 g, 25.09 mmol) was dissolved in toluene (50 mL). Bis(tri-tert-butylphosphine)palladium (0.64 g, 1.25 mmol) and potassium phosphate (13.31 g, 62.73 mmol) were added to the reaction flask. Under nitrogen protection, the reaction mixture was stirred at 90 °C for 7 h. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by column chromatography (PE / EA (V / V) = 8 / 1) with the addition of an appropriate amount of silica gel powder, yielding 3.7 g of a yellow oily substance (40.81%). LC-MS (ESI, pos. ion) was then performed. m / z 306.3 [M+H-OC(CH3)3] + .

[0188] Step 2: Synthesis of (2S,3S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester At 0 °C under a nitrogen atmosphere, tert-butyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-3-oxopiperidin-1-carboxylate (3.7 g, 10.24 mmol) was added to a 100 mL two-necked flask and dissolved in anhydrous acetonitrile (50 mL). Then, triethylenediamine (13.78 g, 122.88 mmol) and formic acid (1414.04 mg, 30.72 mmol) were added, followed by (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (195.44 mg, 0.31 mmol). The reaction was stirred for 12 h. After the reaction was complete, the reaction solution was quenched with 100 mL of sodium bicarbonate aqueous solution, followed by extraction with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography was performed for purification (PE / EA (V / V) = 6 / 1), yielding 3.3 g of a yellow oily substance, with a yield of 88.69%. LC-MS (ESI, pos. ion) m / z 308.0 [M+H-OC(CH3)3] + .

[0189] Step 3: Synthesis of (4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridine-1 (2 H )-tert-butyl carboxylate (2S,3S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.1 g, 8.53 mmol) was added to a 100 mL single-necked flask, dissolved in anhydrous tetrahydrofuran (50 mL), followed by the addition of potassium tert-butoxide (1.44 g, 12.79 mmol). The reaction mixture was refluxed at 70 °C with stirring for 7 h. After the reaction was complete, a saturated ammonium chloride aqueous solution (100 mL) was added to quench the reaction, followed by extraction with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated brine, dried, concentrated, and purified by column chromatography (PE / EA (V / V) = 100 / 8) to obtain 1.55 g of a yellow oil, yield 52.91%. LC-MS (ESI, pos. ion) m / z 288.3 [M+H-OC(CH3)3] + .

[0190] Step 4: Synthesis of (4aS,9bS)-7-(trifluoromethyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2-b]pyridine (intermediate A) Add (4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridine-1 (2 H 1.55 g (4.51 mmol) of tert-butyl carboxylate was dissolved in 5 mL of 1,4-dioxane, and then 8 mL of 4.0 M hydrochloric acid aqueous solution was added. The reaction mixture was then stirred at room temperature for 3 h. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added to adjust the pH of the reaction system to 8. The aqueous phase was then extracted with dichloromethane (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure for column chromatography purification (DCM / MeOH (V / V) = 100 / 5) to give 0.9 g of white solid, yield 81.97%. LC-MS (ESI, pos. ion) m / z :244.2 [M+H] + .

[0191] 1 HNMR (400MHz, DMSO-) d 6) δ 9.78 (s, 1H), 7.85 (d, J =7.8Hz, 1H), 7.39(d, J =7.9Hz, 1H), 7.36(s, 1H), 4.82(d, J =9.7Hz,2H),3.10–2.99(m,1H),2.93–2.82(m,1H),2.21(d, J =13.9Hz, 1H), 2.07(ddd, J =16.7,11.6,6.1Hz,1H),1.78–1.65(m,2H). The intermediate involved, N-1 ( N 7 -(4-methoxybenzyl)-1-methyl-1 H The synthetic route for pyrazolo[3,4-c]pyridine-4,7-diamine is as follows:

[0192] Step 1: Synthesis of 4-bromo-7-chloro-1-methyl-1 H -Pyrazolo[3,4-c]pyridine 4-Bromo-7-chloro-1 HNaH (2.58 g, 64.53 mmol) was added to a tetrahydrofuran solution (200 ml) of pyrazolo[3,4-c]pyridine (10 g, 43.02 mmol), and the mixture was stirred at 0 °C for 30 min. Then, iodomethane (6.72 g, 47.32 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by adding saturated ammonium chloride solution (50 ml), followed by extraction with DCM. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (PE / EA(V / V) = 15 / 1) to give 3.28 g of white solid product, yield 30.93%.

[0193] 1 H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 8.07 (s, 1H), 4.46 (s, 3H).

[0194] Step 2: Synthesis of 4-bromo- N -(4-methoxybenzyl)-1-methyl-1 H -Pyrazolo[3,4-c]pyridine-7-amine 4-Bromo-7-chloro-1-methyl-1- H 4-Methoxybenzylamine (7.31 g, 53.3 mmol) and sodium carbonate (5.65 g, 53.3 mmol) were added to an NMP solution (50 mL) of pyrazolo[3,4-c]pyridine (6.57 g, 26.65 mmol). The reaction mixture was stirred overnight at 130 °C. After the reaction was complete, the reaction mixture was diluted with water (200 mL), followed by extraction with ethyl acetate (1 L). The mixture was washed thoroughly with saturated brine several times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (PE / EA(V / V) = 3:1) to give 7.93 g of white solid product, yield 85.69%. LC-MS (ESI, pos. ion) m / z 348.9 [M+H] + .

[0195] Step 3: Synthesis of (7-((4-methoxybenzyl)amino)-1-methyl-1 H -Pyrazolo[3,4-c]pyridin-4-yl)tert-butyl carbamate 4-Bromo-N-(4-methoxyphenyl)-1-methyl-1- HA solution of pyrazolo[3,4-c]pyridine-7-amine (1.96 g, 5.64 mmol), tert-butyl carbamate (3.30 g, 28.2 mmol), and 1,4-dioxane (40 mL) was prepared by adding cesium carbonate (4.59 g, 14.1 mmol), Xantphos (0.65 g, 1.13 mmol), and Pd2(dba)3 (0.52 g, 0.56 mmol) to a 1,4-dioxane solution. The reaction mixture was then stirred at 110 °C for 12 h. After the reaction was complete, the reaction solution was filtered through diatomaceous earth to remove insoluble matter. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (PE / EA(V / V) = 2 / 1) to give 586.5 mg of a white solid product, with a yield of 27.1%. LC-MS (ESI, pos. ion) m / z 384.1 [M+H] + .

[0196] Step 4: Synthesis N 7 -(4-Methoxybenzyl)-1-methyl-1 H -Pyrazolo[3,4-c]pyridine-4,7-diamine To (7-((4-methoxybenzyl)amino)-1-methyl-1 H TFA (2 ml, 26.93 mmol) was added to 0.5 g (1.3 mmol) of pyrazolo[3,4-c]pyridin-4-yl)carbamate tert-butyl ester, and the reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and then the pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (DCM / MeOH (V / V) = 20 / 1) to give 242.4 mg of a reddish-brown solid product, with a yield of 65.6%. LC-MS (ESI, pos. ion) m / z 284.1 [M+H] + .

[0197] 1 HNMR (400MHz, DMSO-) d 6)δ7.97(s,1H),7.37–7.30(m,2H),6.95(s,1H),6.90–6.84(m,2H),6.03(t, J =5.7Hz, 1H), 4.88(s, 2H), 4.45(d, J =5.6Hz,2H),4.28(s,3H),3.72(s,3H). The synthesis scheme of intermediate M-2 is as follows:

[0198] Step 1: 1-Cyclopropyl-4-((trimethylsilyl)ethynyl)-1 H Synthesis of pyrazole Add 1-cyclopropyl-4-iodine-1 to a 250 mL single-necked flask sequentially. H β-pyrazole (5.58 g, 23.84 mmol), tetrahydrofuran (60 mL), ethynyltrimethylsilane (4.68 g, 47.68 mmol), cuprous iodide (0.45 g, 2.38 mmol), bis(triphenylphosphine) palladium dichloride (1.67 g, 2.38 mmol), and triethylamine (6.03 g, 59.6 mmol) were reacted at room temperature under nitrogen protection. After the reaction was complete, the organic solvent was removed by concentration under reduced pressure, the system was diluted with water (200 mL), and then extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 1), and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the product was purified by column chromatography (PE / EA (v / v) = 10 / 1) to give 4.37 g of a colorless oily product, with a yield of 89.70%. LC-MS (ESI, pos. ion) m / z: 205.2 [M+H] + .

[0199] Step 2: 1-Cyclopropyl-4-ethynyl-1 H Synthesis of pyrazole To 1-cyclopropyl-4-(2-(trimethylsilyl)ethynyl)-1 at room temperature H Potassium carbonate (8.87 g, 64.17 mmol) was added to a methanol (30 mL) solution of pyrazole (4.37 g, 21.39 mmol) and the reaction continued. After the reactants had reacted completely, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA (v / v) = 15 / 1) to give 1.69 g of an orange liquid product, with a yield of 59.79%. LC-MS (ESI, pos. ion) m / z: 133.1 [M+H] + .

[0200] Step 3: 4-((4-bromo-3-fluorophenyl)ethynyl)-1-cyclopropyl-1 H Synthesis of pyrazole To 1-cyclopropyl-4-ethynyl-1 HA solution of pyrazole (1.65 g, 12.48 mmol) and 1-bromo-2-fluoro-4-iodobenzene (4.51 g, 14.98 mmol) in tetrahydrofuran (33 mL) was reacted with cuprous iodide (0.24 g, 1.25 mmol), palladium dichloride (0.88 g, 1.25 mmol), and triethylamine (3.16 g, 31.20 mmol) under nitrogen protection at room temperature. After the reaction was complete, the organic solvent was removed by concentration under reduced pressure, the mixture was diluted with water (200 mL), and then extracted with dichloromethane (30 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 15 / 1) to give 2.67 g of yellow solid product, yield 70.08%. LC-MS (ESI, pos. ion) m / z: 304.9 [M+H] + .

[0201] Step 4: 2-(4-((1-cyclopropyl-1) H Synthesis of tert-butyl pyrazol-4-yl)ethynyl)-2-fluorophenyl)-3-oxoperidin-1-carboxylic acid To 4-(2-(4-bromo-3-fluorophenyl)ethynyl)-1-cyclopropyl-1 H 3-O-piperidin-1-carboxylic acid tert-butyl ester (2.01 g, 10.10 mmol), potassium phosphate (4.47 g, 21.05 mmol), and bis(tri-tert-butylphosphine)palladium (0.43 g, 0.84 mmol) were added to a toluene (50 mL) solution of pyrazole (2.57 g, 8.42 mmol). The reaction was carried out under nitrogen protection and heated to 90 °C. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and the resulting mixture was diluted with water (200 mL). The mixture was then extracted with dichloromethane (30 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA (v / v) = 3 / 1) to give 1.63 g of a pale yellow solid product, with a yield of 45.70%. LC-MS (ESI, pos. ion) m / z: 424.1 [M+H] + .

[0202] Step 5: (2S,3S)-2-(4-((1-cyclopropyl-1 H Synthesis of tert-butyl pyrazol-4-yl)ethynyl)-2-fluorophenyl)-3-hydroxypiperidine-1-carboxylate Add 2-(4-(2-(1-cyclopropyl-1-yl)-1-yl)-yl-1 ... H1.60 g (3.78 mmol) of tert-butyl pyrazol-4-yl)ethynyl)-2-fluorophenyl)-3-oxopiperidin-1-carboxylate (45 mL) and acetonitrile were added sequentially. The mixture was cooled to 0 °C, and then triethylenediamine (2.30 g, 20.49 mmol), formic acid (0.52 g, 11.34 mmol), and RuCl(p-cymene)[(S,S)-Ts-DPEN] (0.072 g, 0.11 mmol) were added. The reaction was continued at 0 °C. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure. The resulting mixture was then diluted with water (150 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA (v / v) = 3 / 1) to give 1.53 g of oily product, with a yield of 95.17%. LC-MS (ESI,pos. ion) m / z: 426.22 [M+H] + .

[0203] Step 6: (4aS,9bS)-7-((1-cyclopropyl-1 H -pyrazol-4-yl)ethynyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of tert-butyl carboxylate Add (2S,3S)-2-(4-(2-(1-cyclopropyl-1-yl ...(2-( H 1.38 g (3.24 mmol) of tert-butyl pyrazol-4-yl)ethynyl)-2-fluorophenyl)-3-hydroxypiperidin-1-carboxylate, 15 mL of dioxane, and 0.56 g (5.02 mmol) of potassium tert-butoxide were reacted at 90 °C. After the reaction was complete, the organic solvent was removed by concentration under reduced pressure, and the resulting mixture was diluted with water (100 mL). The mixture was then extracted with dichloromethane (20 mL × 3). The combined organic phases were dried under reduced pressure, and the residue was purified by column chromatography (PE / EA (v / v) = 6 / 1) to give 446.0 mg of a colorless oil, with a yield of 33.91%. LC-MS (ESI, pos. ion) m / z: 406.1 [M+H] + .

[0204] Step 7: (4aS,9bS)-7-((1-cyclopropyl-1 H Synthesis of pyrazol-4-yl)ethyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2-b]pyridine Add (4aS, 9bS)-7-((1-cyclopropyl-1 ... H-pyrazol-4-yl)ethynyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridine-1(2H)-carboxylic acid tert-butyl ester (446 mg, 1.10 mmol), dichloromethane (10 mL), and trifluoroacetic acid (1254.22 mg, 11 mmol) were reacted at room temperature. After the reaction was completed, the solvent and excess trifluoroacetic acid were removed by concentration under reduced pressure. The pH was adjusted to 8 with 1M potassium carbonate aqueous solution, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH (v / v) = 20 / 1) to give (4aS,9bS)-7-((1-cyclopropyl-1 H 3,2-pyrazole-4-yl)ethyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2-b]pyridine (M-2) was a white solid product, 310.0 mg, in yield of 92.30%. LC-MS (ESI, pos. ion) m / z: 306.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.64 (s, 1H), 7.32 (d, J = 7.6Hz, 1H), 7.06 (dd, J = 7.7, 1.4 Hz, 1H), 6.97 (s, 1H), 4.46 – 4.42 (m, 1H), 4.25 (d, J = 5.1 Hz, 1H), 3.65 – 3.59 (m, 1H), 2.97 (d, J = 13.5 Hz, 1H), 2.74 –2.67 (m, 1H), 2.00 – 1.96 (m, 2H), 1.66 – 1.60 (m, 2H), 1.16 – 1.13 (m, 2H),1.08 – 1.05 (m, 2H). The synthesis scheme for intermediate M-3 is as follows:

[0205] Step 1: 4-Iodo-1-methyl-1 H Synthesis of pyrazole Add 4-iodine-1 to a 100 mL single-necked flask at room temperature. HPotassium carbonate (3.21 g, 23.21 mmol) and methyl iodide (2.63 g, 18.56 mmol) were added to a 20 mL DMF solution of pyrazole (3 g, 15.47 mmol), and the mixture was stirred at room temperature for 3 h. The reaction was stopped, and a small amount of water was added to quench the reaction mixture. The solution was then extracted three times with ethyl acetate (30 mL each time). The combined organic phases were dried under reduced pressure and concentrated to give 3.1 g of a yellow solid, yield 96.36%. LC-MS (ESI, pos. ion) m / z: 208.9 [M+H] + .

[0206] Step: 4-Iodo-1-methyl-1H-pyrazole-1-methyl-4-((trimethylsilyl)ethynyl)-1 H Synthesis of pyrazole Under a nitrogen atmosphere, 4-iodo-1-methyl-1-diol was added to a 100 mL single-necked flask. H A solution of pyrazole (3 g, 14.42 mmol) and THF (10 mL) was added, followed by the addition of ethyltrimethylsilane (2.83 g, 28.84 mmol), cuprous iodide (274.63 mg, 1.44 mmol), triethylamine (4377.5 mg, 43.26 mmol), and PdCl2(PPh3)2 (1012.1 mg, 1.44 mmol). The reaction was carried out under nitrogen protection and stirred at room temperature for 6 h. After the reaction was completed, the system was purified by vacuum concentration column chromatography (PE / EA(V / V) = 20:1) to give 1.0 g of black oil, yield 38.88%. LC-MS (ESI, pos. ion) m / z: 179.1 [M+H] + .

[0207] Step 3): 4-ethynyl-1-methyl-1 H Synthesis of pyrazole At 0°C, under nitrogen protection, 4-iodo-1-methyl-1 H -pyrazole-1-methyl-4-((trimethylsilyl)ethynyl)-1 HTEMPO (145.47 mg, 0.93 mmol) and tetrabutylammonium fluoride (3.65 g, 13.96 mmol) were added to 20 mL of THF containing pyrazole (1.66 g, 9.31 mmol), and the mixture was stirred for 0.5 h. After the reaction was complete, 30 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (30 mL each time). The organic phases were combined, dried under reduced pressure, and concentrated. The solution was then purified by column chromatography (PE / EA (V / V) = 20:1) to give 455 mg of a reddish-brown oil, with a yield of 45.55%. LC-MS (ESI, pos. ion) m / z: 107.2 [M+H] + .

[0208] Step 4: 4-((4-bromo-3-fluorophenyl)ethynyl)-1-methyl-1 H Synthesis of pyrazole Under a nitrogen atmosphere, 1-bromo-2-fluoro-4-iodobenzene (1.1 g, 3.66 mmol) and 4-ethynyl-1-methyl-1 H The following were added to 15 mL of THF containing pyrazole (466.12 mg, 4.39 mmol), cuprous iodide (69.70 mg, 0.37 mmol), triethylamine (1111.07 mg, 10.98 mmol), and PdCl₂(PPh₃)₂ (256.90 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 3.5 h. After the reaction was complete, the reaction system was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 10 / 1) to give 0.63 g of a yellow solid, yield 61.40%. LC-MS (ESI, pos. ion) m / z: 280.9 [M+H] + .

[0209] Step 5: 2-(2-fluoro-4-((1-methyl-1-) H Synthesis of tert-butyl pyrazol-4-yl)ethynyl)phenyl)-3-oxopiperidin-1-carboxylate Under a nitrogen atmosphere, tert-butyl 3-oxopiperidin-1-carboxylate (450 mg, 2.26 mmol) and 4-((4-bromo-3-fluorophenyl)ethynyl)-1-methyl-1 H Pd was added to a toluene (10 mL) system containing pyrazole (630.79 mg, 2.26 mmol). t-Bu3P)2)(115.50 mg, 0.23 mmol) and potassium phosphate (959.46 mg, 4.52 mmol) were added, and the reaction solution was stirred at 90 °C for 18 h. After the reaction was completed, the system was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V)=3 / 1) to give 233 mg of yellow oil, with a yield of 25.96%. LC-MS (ESI, pos. ion) m / z: 398.3 [M+H]+.

[0210] Step 6: (2S,3S)-2-(2-fluoro-4-((1-methyl-1) H Synthesis of tert-butyl pyrazol-4-yl)ethynyl)phenyl)-3-hydroxypiperidine-1-carboxylate At 0 °C under a nitrogen atmosphere, tert-butyl 2-(2-fluoro-4-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-oxopiperidin-1-carboxylate (0.232 g, 0.58 mmol) was added to a 50 mL single-necked flask and dissolved in anhydrous MeCN (10 mL). Then, triethylenediamine (0.78 g, 6.96 mmol), formic acid (80.09 mg, 1.74 mmol), and RuCl(p-cymene)[(S,S)-Ts-DPEN] (1.07 mg, 0.017 mmol) were added, and the reaction was continued at 0 °C. After the reaction was completed, 30 mL of sodium bicarbonate aqueous solution was added to quench the reaction, followed by extraction with ethyl acetate (30 mL × 3 times). The organic layers were combined and concentrated under reduced pressure, then purified by column chromatography (PE / EA (V / V) = 6 / 1) to obtain 0.18 g of a yellow oil, yield 77.19%. LC-MS (ESI, pos. ion) m / z: 400.0 [M+H]+.

[0211] Step 7: (4aS,9bS)-7-((1-methyl-1 H -pyrazol-4-yl)ethynyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of tert-butyl carboxylate Add (2S,3S)-2-(2-fluoro-4-((1-methyl-1- ... H180 mg (0.45 mmol) of tert-butyl pyrazol-4-yl)ethynyl)phenyl)-3-hydroxypiperidin-1-carboxylate was dissolved in THF (5 mL), and potassium tert-butoxide (0.18 g, 1.61 mmol) was added. The reaction mixture was then refluxed at 70 °C and stirred for 3.5 h. After the reaction was completed, 30 mL of ammonium chloride aqueous solution was added to quench the reaction, followed by extraction with ethyl acetate (60 mL × 3 times). The organic phases were combined, dried under reduced pressure, and concentrated. The solution was then purified by column chromatography (PE / EA (V / V) = 3 / 1) to obtain 80 mg of a yellow oil, with a yield of 46.79%. LC-MS (ESI, pos. ion) m / z: 380.3 [M+H] + .

[0212] Step 8: (4aS,9bS)-7-((1-methyl-1 H -pyrazol-4-yl)ethyl)-1,2,3,4,4a,9b-hexahydrobenzofurano[3,2- b Synthesis of pyridine Add (4aS,9bS)-7-((1-methyl-1-ethylhexylene ... H -pyrazol-4-yl)ethynyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b 80 mg (0.21 mmol) of pyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in DCM (15 mL), and trifluoroacetic acid (1.20 g, 10.5 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. After adjusting the pH to 7 with saturated sodium bicarbonate solution, the mixture was extracted three times with dichloromethane (20 mL each time). The combined organic phases were dried and concentrated, and purified by column chromatography (DCM / MeOH (V / V) = 100 / 5) to obtain 20 mg of M-3 as a yellow oil, yield 33.96%. LC-MS (ESI, pos. ion) m / z: 280.1 [M+H] + .

[0213] The synthesis scheme of intermediate M-4 is as follows:

[0214] (4aS,9bS)-7-ethynyl-1,2,3,4,4a,9b hexahydrobenzofurano[3,2- b Synthesis of pyridine (M-4): Nitrogen protection, at 0°C, to (4aS,9bS)-7-((triisopropylsilyl)ethynyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2- bThe pyridine (synthesized from triisopropylsilylacetylene and 1-bromo-2-fluoro-4-iodobenzene, according to intermediate M-2, 3 g, 8.44 mmol) was slowly added dropwise to tetrabutylammonium fluoride (TBAF, 2.17 g, 10.55 mmol, 1.0 M) in tetrahydrofuran (60 mL). After the reaction was complete, the reaction solution was poured into ethyl acetate (300 mL), washed with saturated brine (50 mL × 5), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / EtOH (v / v) = 10 / 1) to give 1.2 g of a light pink solid, yield 71.4%. LC-MS (ESI, pos. ion) m / z: 200.1 [M+H] + .

[0215] 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 4.81 (d, J = 9.8 Hz, 2H), 3.11 (s,1H), 3.10 – 2.97 (m, 1H), 2.93 – 2.80 (m, 1H), 2.21 (Br, 1H), 2.11 – 2.05 (m,1H), 1.78 – 1.65 (m, 2H). Synthesis of intermediate M-5: (4aS,9bS)-7-(3-morpholinylprop-1-yn-1-yl)-1,2,3,4,4a,9b-hexahydrobenzofurano[3,2-b]pyridine:

[0216] Using 4-propynyl-1-morpholine and 1-bromo-2-fluoro-4-iodobenzene as starting materials, and following the synthetic method for intermediate M-2, intermediate M-5 was prepared as a pale yellow oil. LC-MS (ESI, pos. ion) m / z: 299.1 [M+H] + .

[0217] Synthesis of intermediate M-6: 3-((4aS,9bS)-1,2,3,4,4a,9b-hexahydrobenzofurano[3,2-b]pyridin-7-yl)-N,N-dimethylprop-2-yn-1-amine:

[0218] Using 1-dimethylamine-2-propyne and 1-bromo-2-fluoro-4-iodobenzene as starting materials, and following the synthesis method of intermediate M-2, intermediate M-6 was prepared as a light brown oily substance. LC-MS (ESI, pos. ion) m / z: 257.2 [M+H] + .

[0219] Example 1: N -(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of α-hydroxyacetamide (compound 1) The synthesis route is as follows:

[0220] Step 1: Synthesis of (3-bromo-5-nitropyridin-2-yl)(tert-butyloxycarbonyl)carbamate tert-butyl 3-Bromo-5-nitropyridine-2-amine (1 g, 4.59 mmol), 4-dimethylaminopyridine (0.56 g, 4.59 mmol), dichloromethane (10 mL), and di-tert-butyl dicarbonate (3.01 g, 13.77 mmol) were added sequentially to a 250 mL single-necked flask and reacted at room temperature under nitrogen. After the reaction was complete, the reaction solution was slowly added dropwise to water (100 mL) to quench the reaction, and then extracted with dichloromethane (100 mL × 2 times). The organic phases were combined, washed with saturated brine (60 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 10 / 1) to give 1.85 g of a pale yellow solid product, with a yield of 96.43%. LC-MS(ESI): 262.1 [M-100-56+H] + .

[0221] Step 2: Synthesis of (5-nitro-3-vinylpyridin-2-yl)(tert-butyloxycarbonyl)carbamate tert-butyl To a 100 mL single-necked flask, add (3-bromo-5-nitropyridin-2-yl)(tert-butyloxycarbonyl)carbamate tert-butyl ester (1 g, 2.4 mmol), vinylboronic acid pinacol ester (0.48 g, 3.1 mmol), potassium carbonate (0.83 g, 6.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.20 g, 0.24 mmol), 1,4-dioxane (16 mL), and water (4 mL), and react at 100 °C under nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane. Water (50 mL) was added, followed by extraction with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel column chromatography (PE / EA (V / V) = 5 / 1) to give 750 mg of a yellow solid product, with a yield of 85.6%. LC-MS (ESI): 210.2 [M-100-56+H] + Step 3: Synthesis of (5-amino-3-ethylpyridin-2-yl)(tert-butoxycarbonyl)carbamate tert-butyl ester To a 100 mL single-necked flask, tert-butyl (5-nitro-3-vinylpyridin-2-yl)(tert-butyloxycarbonyl)carbamate (1000 mg, 2.7 mmol), palladium on carbon (718.3 mg, 0.68 mmol, 10% purity) and methanol (20 mL) were added sequentially. The reaction was carried out at room temperature under a hydrogen atmosphere. After the reaction was complete, the filtrate was filtered, concentrated under reduced pressure to remove the organic solvent, diluted with water (50 mL), and extracted with dichloromethane (8 mL × 3). The organic phases were combined, washed with water (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 3 / 1) to give 900 mg of a pale yellow solid product, yield 98.0%. LC-MS (ESI): 338.3 [M+H] + . Step 4: Synthesis of ethyl 2-((6-((di-tert-butoxycarbonyl)amino)-5-ethylpyridin-3-yl)amino)-2-oxoethyl acetate At 0 °C, (5-amino-3-ethylpyridin-2-yl)(tert-butyl)carbamate tert-butyl ester (900 mg, 2.7 mmol), triethylamine (0.54 g, 0.54 mmol), ethyl acetate (35 mL), and oxaloyl chloride monoethyl ester (473 mg, 3.5 mmol) were added sequentially to a 10 mL single-necked flask. The mixture was slowly heated to room temperature. After the reaction was complete, the reaction solution was slowly added dropwise to water (50 mL) to quench the reaction. The mixture was then extracted with dichloromethane (8 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 3 / 1) to give 1.12 g of a white solid product, yield 96%. LC-MS (ESI): 438.3 [M+H] + .

[0222] Step 5: Synthesis of 2-((6-((di-tert-butoxycarbonyl)amino)-5-ethylpyridin-3-yl)amino)-2-oxoacetic acid Ethyl 2-((6-((di-tert-butoxycarbonyl)amino)-5-ethylpyridin-3-yl)amino)-2-oxoethyl acetate (1.12 g, 2.6 mmol), ethanol (15 mL), water (5 mL), and lithium hydroxide (0.12 g, 2.9 mmol) were added sequentially to a 10 mL single-necked flask, and the reaction was carried out at room temperature. After the reaction proceeded to completion as determined by TLC, the solvent was removed by concentration under reduced pressure. The product was dissolved in dichloromethane (200 mL) and methanol (3 mL), and the pH was adjusted to 3-4 with a 1,4-dioxane solution of hydrogen chloride (4.0 M). The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 5 / 1) to give 69.0 mg of a pale yellow solid product, with a yield of 65.83%. LC-MS (ESI): 254.1 [M-100-56+H] + .

[0223] Step 6: Synthesis of (tert-butyloxycarbonyl) (3-ethyl-5-(2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1 (2 H 2-yl)acetamido)pyridin-2-yl)tert-butyl carbamate 2-((6-((di-tert-butoxycarbonyl)amino)-5-ethylpyridin-3-yl)amino)-2-oxoacetic acid (0.22 g, 0.53 mmol) and HATU (202.66 mg, 0.53 mmol) were added to a 50 mL single-necked flask at room temperature. Anhydrous dichloromethane (10 mL) was added to dissolve the HATU, followed by the addition of DIPEA (105.98 mg, 0.82 mmol). The mixture was stirred at room temperature for 30 minutes. Then, intermediate A ((4aS,9bS)-7-(trifluoromethyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2-b]pyridine) (100 mg, 0.41 mmol) was added. The reaction was allowed to proceed overnight. The reaction mixture was concentrated under reduced pressure and subjected to column chromatography (DCM / MeOH(V / V) = 50 / 1) to give 120 mg of a white solid, yield 46%. LC-MS (ESI, pos.ion) m / z 635.0 [M+H] + .

[0224] Step 7: Synthesis N -(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-] b ]Pyridine-1 (2 H )-yl)acetamide At room temperature, (tert-butyloxycarbonyl) (3-ethyl-5-(2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Trifluoroacetic acid (45 mg) was added to a 10 mL solution of tert-butyl carbamate (120 mg, 0.19 mmol) in DCM and reacted for 4 h. The pH was then adjusted to 8 with saturated sodium bicarbonate solution, followed by extraction with dichloromethane (30 mL × 3). The organic layer was evaporated to dryness and subjected to column chromatography (DCM / MeOH (V / V) = 50 / 2) to give 45 mg of a white solid, yield 54.8%. LC-MS (ESI, pos.ion) was also performed. m / z 435.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 9.05 (s, 1H), 8.14 (dd, J =12.1, 2.5 Hz, 1H), 7.75 (dd, J= 12.4, 2.5 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.95(d, J = 9.0 Hz, 1H), 5.07 (q, J = 6.9, 5.8 Hz, 1H), 4.89 – 4.82 (m, 1H), 4.48 (d, J = 6.2 Hz, 2H), 4.29 (dd, J = 13.1, 7.9 Hz, 1H), 3.03 – 2.95 (m, 1H), 2.74 (dt, J = 13.9, 7.0 Hz, 1H), 2.54 – 2.46 (m, 2H), 1.30 (td, J = 7.6, 3.9 Hz, 3H).

[0225] Example 2: (4-Amino-7,9-difluoro-1-methyl-1) H -pyrazolo[4,3-c]quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of 2-methyl ketone (compound 2) Synthesis route:

[0226] Step 1: Synthesis of methyl 4-amino-3-bromo-2,6-difluorobenzoate N-bromosuccinimide (4.76 g, 26.72 mmol) was slowly added to a solution of methyl 4-amino-2,6-difluorobenzoate (5 g, 26.72 mmol) in acetonitrile (200 mL) at 0 °C. The system was stirred at 0 °C until the reaction proceeded completely. The reaction mixture was concentrated under reduced pressure to remove a large amount of solvent, then dissolved in ethyl acetate (200 mL), and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA(V / V) = 4 / 1) to give 6.20 g of a light brown solid product, with a yield of 87.23%.

[0227] 1 H NMR (400 MHz, CDCl3) δ 6.35 (dd, J = 11.7, 1.8 Hz, 1H), 4.74 (s, 2H), 3.91 (s, 3H). Step 2: 4-Amino-7,9-difluoro-1-methyl-1 H -pyrazolo[4,3- c Synthesis of methyl quinoline-8-carboxylic acid ester Under a nitrogen atmosphere, methyl 4-amino-3-bromo-2,6-difluorobenzoate (1 g, 3.76 mmol) and 4-cyano-1-methyl-1-difluorobenzoate were added to a 50 ml single-necked flask. H Pinacol 5-boronate (964 mg, 4.14 mmol), potassium carbonate (1.04 g, 7.52 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.44 g, 0.56 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL). The reaction mixture was then subjected to nitrogen protection and reacted at 100 °C for 18 h. After the reaction was completed, the resulting reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 25 / 1) to give 60 mg of a brown solid product, with a yield of 5.46%. LC-MS (ESI, pos. ion) m / z : 293.0 [M+H] + .

[0228] Step 3: Synthesis of 4-amino-7,9-difluoro-1-methyl-1 H -Pyrazolo[4,3-c]quinoline-8-carboxylic acid To 4-amino-7,9-difluoro-1-methyl-1 H Lithium hydroxide (42 mg, 1.0 mmol) was added to a mixed solution (10 mL / 3 mL) of methyl pyrazolo[4,3-c]quinoline-8-carboxylate (100 mg, 0.2 mmol) in ethanol and water. The reaction was then carried out at 50 °C. After the reaction was complete by TLC, HCl solution (1.0 M) was added to adjust the pH to 6, and the system was directly evaporated to dryness under reduced pressure. Column chromatography (DCM / MeOH (V / V) = 25 / 1) gave 72 mg of white solid, yield 74.1%. LC-MS (ESI, pos.ion) m / z 279.0 [M+H] + .

[0229] Step 4: Synthesis of (4-amino-7,9-difluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1 (2 H )-methyl ketone 4-Amino-7,9-difluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (70 mg, 0.25 mmol) and HATU (114 mg, 0.3 mmol) were added to a 50 mL single-necked flask at room temperature and dissolved in anhydrous dichloromethane (10 mL). DIPEA (60 mg, 0.46 mmol) was then added, and the mixture was stirred at room temperature for 30 minutes. Intermediate M-1 (55 mg, 0.23 mmol) was then added. After reacting for two days, the mixture was filtered, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (DCM / MeOH (V / V) = 25 / 1) to give 10 mg of the target compound as a white solid, in 8.8% yield. LC-MS (ESI, pos.ion) was also performed. m / z 504.0 [M+H] + .

[0230] 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 10.9 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.57 (d, J = 9.1 Hz, 1H), 5.16 (d, J = 9.6 Hz, 1H), 4.45 (t, J = 8.6 Hz, 3H), 3.22 – 3.12(m, 2H), 1.83 – 1.73 (m, 4H). Example 3: (4-amino-9-fluoroimidazolo[1,5-a]quinoxaline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1 (2 H Synthesis of (compound 3) of methyl ketone Synthesis route:

[0231] Step 1: 5 H 10 H Synthesis of -diimidazole[1,5-A:1', 5'-D]pyrazine-5,10-dione 1H-imidazolium-5-carboxylic acid (5 g, 44.61 mmol) was added to a 100 mL single-necked flask, dissolved in 15 mL of thionyl chloride, and stirred at 80 °C for 24 h. The reaction was then stopped, and the reaction solution was concentrated under reduced pressure to remove the solvent, yielding 8 g of a pale yellow solid, with a yield of 95.32%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.87 (s, 2H), 8.23 ​​(s, 2H).

[0232] Step 2: N -(4-bromo-2,3-difluorophenyl)-1 H Synthesis of 5-imidazolium-formamide At -10°C, 4-bromo-2,3-difluoroaniline (2.5 g, 12.02 mmol) was added to a 100 mL two-necked flask, dissolved in anhydrous THF (50 mL), and then NaHMDS (5.51 g, 30.05 mmol) was added. After stirring for 30 minutes, 5... H 10 H 2.94 g (15.63 mmol) of diimidazole [1,5-A:1', 5'-D]pyrazine-5,10-dione was added, and the reaction mixture was heated to room temperature and stirred for 6 h. After the reaction was complete, the resulting solution was poured into water (150 mL), and the crude product precipitated and filtered. The filter cake was dissolved in dichloromethane, and purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 2:3) with the addition of an appropriate amount of silica gel, yielding 2.5 g of a yellow solid, with a yield of 68.86%. LC-MS (ESI, pos. ion) m / z 302.2[M+H] + .

[0233] Step 3: 8-Bromo-9-Fluorimidozolo[1,5-a]quinoxaline-4(5 H Synthesis of )-ketones Under a nitrogen atmosphere, add to a 250 mL single-necked flask N -(4-bromo-2,3-difluorophenyl)-1 HImidazol-5-carboxamide (4.6 g, 15.23 mmol) was dissolved in DMAc (100 mL), and cesium carbonate (9.92 g, 30.46 mmol) was slowly added to the reaction solution. The reaction solution was then stirred at 150 °C for 5 h. The resulting reaction solution was poured into water (100 mL) and stirred for 10 min. The mixture was filtered, and the filter cake was dried to give 3.4 g of a pale yellow solid, yield 79.15%. LC-MS (ESI, pos.ion) m / z 283.2 [M+H] + .

[0234] Step 4: 8-Bromo- N Synthesis of -(2,4-dimethoxybenzyl)-9-fluoroimidazolo[1,5-a]quinoxaline-4-amine Under a nitrogen atmosphere and at 0°C, 8-bromo-9-fluoroimidazole[1,5-a]quinoxaline-4(5) was added to a 100 mL single-necked flask. H 2,4-Dimethoxyphenyl)methylamine (0.86 g, 5.15 mmol) and 2,4-dimethoxyphenyl)methylamine were dissolved in anhydrous DMF (20 mL), followed by the addition of DIPEA (0.53 g, 4.12 mmol). After stirring for 1 h, the reaction mixture was further stirred at 80 °C for 16 h. After the reaction was complete, water (30 mL) was added to quench the reaction, causing the solid to precipitate. The precipitate was filtered, dissolved in dichloromethane and methanol, and then dried and concentrated with silica gel powder. The solution was purified by column chromatography (DCM / MeOH(V / V) = 100 / 1) to obtain 0.5 g of a yellow solid, yield 27.48%. LC-MS (ESI, pos. ion) m / z 430.9 [M+H] + .

[0235] Step 5: Synthesis of 4-(2,4-dimethoxybenzyl)amino)-9-fluoroimidozolo[1,5-a]quinoxaline-8-carboxylic acid In a nitrogen atmosphere, 8-bromo- N-(2,4-dimethoxybenzyl)-9-fluoroimidazolo[1,5-a]quinoxaline-4-amine (400 mg, 0.93 mmol), palladium acetate (41.76 mg, 0.19 mmol), Xantphos (53.81 mg, 0.093 mmol), DCC (191.89 mg, 0.93 mmol), and TEA (94.11 mg, 0.93 mmol) were dissolved in DMF (10 mL), followed by the addition of formic acid (599.31 mg, 13.02 mmol). The mixture was then stirred at 100 °C for 12 h under nitrogen protection. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth. The filter residue was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH(V / V) = 100 / 8) to obtain 160 mg of brown solid, 43.52%. LC-MS (ESI, pos. ion) m / z 397.2 [M+H] + .

[0236] Step 6: (4-(2,4-dimethoxybenzyl)amino)-9-fluoroimidazolo[1,5-a]quinoxalin-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of methyl ketone Under a nitrogen atmosphere, 4-(2,4-dimethoxybenzyl)amino)-9-fluoroimidazolo[1,5-a]quinoxaloline-8-carboxylic acid (75.31 mg, 0.19 mmol) and HATU (108.37 mg, 0.29 mmol) were added to a 50 mL single-necked flask, dissolved in anhydrous DCM (10 mL), followed by the addition of DIPEA (49.11 mg, 0.38 mmol). The mixture was stirred at room temperature for 4 h. Then, intermediate M-1 (45 mg, 0.19 mmol) was added, and the reaction was stirred at room temperature for 9.5 h. After the reaction was complete, the resulting reaction solution was concentrated under reduced pressure with silica gel and purified by column chromatography (DCM / MeOH (V / V) = 100 / 3) to obtain 100 mg of a yellow oil, yield 86.95%. LC-MS (ESI, pos. ion) m / z 622.0 [M+H] + .

[0237] Step 7: (4-amino-9-fluoroimidazolo[1,5-a]quinoxaline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of methyl ketone Add (4-(2,4-dimethoxybenzyl)amino)-9-fluoroimidazolo[1,5-a]quinoxalin-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2) to a 25 mL single-necked flask H 200 mg (0.32 mmol) of methyl ketone was dissolved in trifluoroacetic acid (8 mL) and then stirred at 90 °C for 16 h. After the reaction was complete, water (10 mL) was added to quench the reaction mixture, followed by the addition of saturated sodium carbonate aqueous solution to adjust the pH to 8. The mixture was then extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography (DCM / MeOH (V / V) = 100 / 5) to give 60 mg of white solid, yield 39.56%. LC-MS (ESI, pos. ion) m / z : 472.0 [M+H] + . 1 HNMR(400MHz, CDCl3)δ8.83(s,1H),7.76(s,1H),7.54(d, J =7.4Hz, 1H), 7.45(d, J =8.5Hz,1H),7.41–7.33(m,1H),7.10(s,1H),6.49(d, J =7.5Hz,1H),5.38(s,2H),5.18–5.07(m,1H),3.45(s,1H),3.02(s,1H),2.11(s,1H),2.03(s,1H),1.75(s,2H). Example 4: N -(7-amino-1-methyl-1- H -pyrazole[3,4-c]pyridin-4-yl)-2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of 4-(2-)acetamide Synthesis route:

[0238] Step 1: 2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridine-1 (2 H Synthesis of ethyl acetate (-yl) (4aS,9bS)-7-(trifluoromethyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2-b]pyridine (150 mg, 0.62 mmol) was added to a 50 mL single-necked flask and dissolved in DCM (10 mL). TEA (126.10 mg, 1.25 mmol) was then added, and the reaction mixture was stirred at 0 °C for 20 min. Oxaloyl chloride monoethyl ester (126.97 mg, 0.93 mmol) was then slowly added dropwise, and the reaction mixture was stirred at room temperature for 14 h. After the reaction was complete, water (30 mL) was added to quench the reaction and remove most of the organic solvent. The reaction mixture was then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 200 mg of a yellow oil (yield 94.46%). LC-MS (ESI, pos. ion) was used for analysis. m / z 344.2 [M+H] + .

[0239] Step 2: 2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridine-1 (2 H Synthesis of α-hydroxyacetic acid Lithium hydroxide (48.67 mg, 1.16 mmol) was added to 2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridine-1 (2 H The mixture of ethyl acetate (0.20 g, 0.58 mmol) and water (1 mL) and methanol (8 mL) was stirred at room temperature for 3 h. After the reaction was complete, the pH was adjusted to approximately 5 with a 4M solution of 1,4-dioxane hydrogen chloride, and water (10 mL) was added. The mixture was then extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, concentrated, and then subjected to column chromatography (DCM / MeOH (V / V) = 100 / 1) to give 170 mg of a yellow oil, with a yield of 92.57%. LC-MS (ESI, pos. ion) m / z 316.2 [M+H] + .

[0240] Step 3: 2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridine-1 (2 H Synthesis of α-ethyl acetyl chloride Add 2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridine-1 (2... H 0.20 g (0.63 mmol) of α-hydroxyacetic acid was dissolved in 10 mL of DCM, followed by the addition of 1.51 g (12.71 mmol) of thionyl chloride and 0.05 mL of DMF. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the resulting solution was concentrated under reduced pressure to give 0.15 g of a yellow oil, with a yield of 70.85%. LC-MS (ESI, pos. ion) m / z 330.2 [M-Cl+OCH3] + .

[0241] Step 4: N -(7-((4-methoxybenzyl)amino)-1-methyl-1H-pyrazole[3,4-c]pyridin-4-yl)-2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of α-hydroxyacetamide Add to a 50 mL single-necked bottle N 7 -[(4-methoxyphenyl)methyl]-1-methyl-1 H -Pyrazolo[3,4-c]pyridine-4,7-diamine (127.50 mg, 0.45 mmol, intermediate N-1), dissolved in DCM (10 mL), was followed by the addition of DIPEA (0.58 g, 4.5 mmol), and then 2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridine-1 (2 H 150 mg of acetyl chloride (0.45 mmol) was added to the reaction mixture, which was then stirred at room temperature for 4 h. An appropriate amount of silica gel powder was added to the reaction mixture, and the mixture was purified by column chromatography (DCM / MeOH(V / V) = 100 / 1) to give 165 mg of a yellow solid, yield 63.22%. LC-MS (ESI, pos. ion) m / z 581.2 [M+H] + .

[0242] Step 5: N -(7-amino-1-methyl-1- H -pyrazole[3,4-c]pyridin-4-yl)-2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of α-(2-)acetamide Add to a 50 mL single-necked bottle N -(7-((4-methoxybenzyl)amino)-1-methyl-1 H -pyrazole[3,4-c]pyridin-4-yl)-2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Trifluoroacetamide (0.164 g, 0.28 mmol) was dissolved in TFA (10 mL), and the reaction mixture was stirred at 75 °C for 2 h. After the reaction was complete, most of the trifluoroacetic acid solvent in the reaction mixture was evaporated, and saturated sodium bicarbonate solution was added to adjust the pH of the reaction mixture to 7-8. The mixture was then extracted with dichloromethane (30 mL × 3), dried, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH (V / V) = 100 / 1) to give 50 mg of white solid, yield 38.44%. LC-MS (ESI, pos. ion) m / z 461.2 [M+H] + . 1 HNMR (599MHz, DMSO-) d 6)δ10.50(s,1H),9.09(s,1H),7.94(s,1H),7.84(s,1H),7.76(d, J =7.9Hz, 1H), 7.69(s, 1H), 7.53(d, J =7.9Hz,1H),6.83(s,1H),6.25(s,2H),4.27(s,3H),2.88(t, J =7.0Hz,2H),2.00–1.93(m,2H),1.29–1.19(m,2H). Example 5: (4-amino-7-fluoro-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1 (2 H Synthesis of methyl ketone (compound 5) Synthesis route:

[0243] HATU (170 mg, 0.43 mmol) was added to an anhydrous dichloromethane (10 mL) solution of 4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthyl-8-carboxylic acid (87 mg, 0.38 mmol) and triethylamine (75 mg, 2.0 mmol) at room temperature. The reaction was allowed to proceed for 30 minutes, followed by the addition of intermediate A (70 mg, 0.29 mmol) and continued reaction at room temperature. After the reaction was complete as determined by TLC, the system was directly evaporated to dryness and purified by column chromatography (DCM / MeOH(V / V) = 100 / 1.5) to obtain 45 mg of white solid product, yield 34.26%. LC-MS (ESI, pos. ion) m / z: 457.0 [M+H] + .

[0244] HRMS: 457.1485 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.88 (s, 1H), 7.94 –7.49 (m, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 17.2 Hz, 1H), 7.08 (s, 2H),6.28 – 6.04 (m, 1H), 5.39 (s, 2H), 5.21 – 5.03 (m, 3H), 4.28– 3.76 (m, 1H),1.98 (d, J = 11.7 Hz, 2H), 1.66 – 1.54 (m, 3H). Example 6: (4-Amino-7-fluoro-1-methyl-1- H -pyrazolo[4,3-c]quinolin-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of methyl ketone (compound 6) Synthesis route:

[0245] Step 1: Synthesis of methyl 4-amino-5-bromo-2-fluorobenzoate 15 g (88.68 mmol) of methyl 4-amino-2-fluorobenzoate and 300 mL of acetonitrile were added to a 1000 mL single-necked flask. NBS (15.78 g, 88.68 mmol) was slowly added at 0 °C, and the mixture was slowly heated to room temperature. After the reaction was complete, the pH was adjusted to 7 with 1 M sodium bicarbonate aqueous solution to quench the reaction. The system was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent. The resulting mixture was diluted with 500 mL of water and extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with 300 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 3 / 1) to give 21.5 g of a white solid product, yield 97.74%. LC-MS (ESI, pos. ion) m / z: 247.9 [M+H] + . Step 2: Synthesis of methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate Methyl 4-amino-5-bromo-2-fluorobenzoate (12.22 g, 49.26 mmol), pinacol diboronate (15.01 g, 59.11 mmol), potassium acetate (9.77 g, 99.51 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (5.07 g, 6.21 mmol), and dioxane (106 mL) were added sequentially to a 500 mL single-necked flask. The reaction was carried out at 85 °C under nitrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 10 / 1) to give 3.92 g of white solid product, yield 26.96%. LC-MS (ESI, pos.ion) m / z: 296.0 [M+H] + .

[0246] Step 3: Synthesis of 4-amino-7-fluoro-1-methyl-1 H methyl pyrazolo[4,3-c]quinoline-8-carboxylate Add methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (1 g, 3.39 mmol) and 5-bromo-1-methyl-1-ylbenzoate sequentially to a 100 mL single-necked flask. H4-Pyrazole-4-onitrile (0.63 g, 3.39 mmol), potassium phosphate (1.80 g, 8.47 mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine(II) (0.24 g, 0.34 mmol), dioxane (32 mL), and water (8 mL) were reacted at 90 °C under nitrogen atmosphere. After the reaction was complete, the organic solvent was removed by concentration under reduced pressure, the resulting mixture was diluted with water (160 mL), and then extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with water (150 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (DCM / EA (V / V) = 1 / 1) to give 376.6 mg of white solid product, yield 40.52%. LC-MS (ESI, pos. ion) m / z: 275.0 [M+H] + .

[0247] Step 4: Synthesis of 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid Add 4-amino-7-fluoro-1-methyl-1-ethylhexane to a 100 mL single-necked flask. H β-pyrazolo[4,3-c]quinoline-8-carboxylic acid methyl ester (376.6 mg, 1.37 mmol), dioxane (12 mL), water (6 mL), methanol (12 mL), and lithium hydroxide (143.71 mg, 3.43 mmol) were reacted at 50 °C. After the reaction, the pH was adjusted to 6 with 1 M hydrochloric acid aqueous solution, and the organic solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluting agent: DCM / MeOH (V / V) = 1 / 1) to give 319.7 mg of white solid product, yield 89.47%. LC-MS (ESI, pos. ion) m / z: 261.0 [M+H] + .

[0248] Step 5: Synthesis of (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1 (2 H )-methyl ketone Add 4-amino-7-fluoro-1-methyl-1-ethylhexane to a 25 mL single-necked flask. H-Pyrazolo[4,3-c]quinoline-8-carboxylic acid (52.04 mg, 0.20 mmol), HATU (121.67 mg, 0.32 mmol), DMF (4 mL) and DIPEA (62.04 mg, 0.48 mmol), reacted at room temperature for 0.5 h, then (4a S, 9b S)-7-(trifluoromethyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2-b]pyridine (40 mg, 0.16 mmol) was added, and the reaction continued at room temperature. After the reaction was complete, the pH was adjusted to 7 with ammonium chloride aqueous solution (1M), the resulting mixture was diluted with water (100 mL), and then extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with water (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluting agent: 100% EA) to give 50.9 mg of white solid product, yield 63.76%. LC-MS (ESI, pos. ion) m / z: 486.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.26 (s, 2H), 7.64 – 7.12 (m, 6H), 6.39 (s, 1H), 5.20 (s, 1H), 4.39 (s, 3H), 3.56 – 3.34 (m, 2H), 2.10 – 1.46 (m,4H). Example 7: N -(6-amino-5-ethylpyridin-3-yl)-2-oxo-2-((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-] b ]Pyridine-1 (2 H Synthesis of α-hydroxyacetamide (compound 7)

[0249] Step 1: Synthesis of 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate 4-Oxylideneoxaburan-3-carboxynitrile (2.5 g, 22.5 mmol), dichloromethane (50 mL), and DIPEA (8.72 g, 67.5 mmol) were added sequentially to a 250 mL two-necked flask. The mixture was cooled to -78 °C under nitrogen protection, and then trifluoromethanesulfonic anhydride (12.7 g, 45 mmol) was slowly added dropwise. After reacting for 1 hour, the mixture was allowed to return to room temperature. After the reactants were fully reacted (TLC monitoring), the pH was adjusted to 7 with 1N ammonium chloride aqueous solution, and the mixture was diluted with 200 mL of water. The mixture was then extracted with dichloromethane (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 15 / 1) to give 2.75 g of a light brown oily product, with a yield of 50.26%.

[0250] 1 H NMR (400 MHz, CDCl3) δ4.91–4.83(m,4H). Step 2: Synthesis of methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate Methyl 4-amino-5-bromo-2-fluorobenzoate (12.22 g, 49.26 mmol), pinacol diborate (15.01 g, 59.11 mmol), potassium acetate (9.77 g, 99.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (5.07 g, 6.2 mmol) were added sequentially to a 500 mL single-necked flask. Dioxane (106 mL) was then added, and the reaction was carried out at 85 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 10 / 1) to give 3.92 g of a white solid product, yield 26.9%. LC-MS (ESI, pos. ion) m / z 296.0 [M+H] + .

[0251] Step 3: 4-Amino-7-fluoro-1,3-dihydro[3,4-] c Synthesis of methyl quinoline-8-carboxylic acid ester Methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (500 mg, 1.69 mmol), 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (616.41 mg, 2.54 mmol), potassium phosphate (896.84 mg, 4.22 mmol), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine(II) (119.66 mg, 0.17 mmol) were added sequentially to a 50 mL single-necked flask. Then, dioxane (12 mL) and water (3 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give 425.2 mg of a white solid product, with a yield of 95.7%. LC-MS (ESI, pos.ion) m / z 263.1 [M+H] + .

[0252] Step 4: 4-Amino-7-fluoro-1,3-dihydro[3,4-] c Synthesis of quinoline-8-carboxylic acid Add 4-amino-7-fluoro-1,3-dihydro[3,4-] to a 50 mL single-necked flask. c Quinoline-8-carboxylic acid methyl ester (425.2 mg, 1.62 mmol), dioxane (6 mL), methanol (6 mL), and water (3 mL) were added, followed by lithium hydroxide monohydrate (169.94 mg, 4.05 mmol). The reaction was heated to 50 °C. After the reaction was complete, the pH was adjusted to 6 with 1N hydrochloric acid aqueous solution, and the organic solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM / MeOH (V / V) = 2 / 1) to give 362.2 mg of white solid product, yield 90%. LC-MS (ESI, pos. ion) m / z 261.1 [M+H] + .

[0253] Step 5: (4-amino-7-fluoro-1,3-dihydrofurano[3,4-) c Quinoline-8-yl)((4aS, 9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of methyl ketone Add 4-amino-7-fluoro-1,3-dihydro[3,4-] to a 25 mL single-necked flask. cQuinoline-8-carboxylic acid (74.21 mg, 0.3 mmol), HATU (174.9 mg, 0.46 mmol), dichloromethane (8 mL), and DIPEA (148.63 mg, 1.15 mmol) were added, and the reaction was carried out at room temperature for 30 minutes. Then, intermediate M-1 (55 mg, 0.23 mmol) was added, and the reaction was continued at room temperature. After the reaction was complete, the pH was adjusted to 7 with 1N ammonium chloride aqueous solution, and the dichloromethane was removed by concentration under reduced pressure. The resulting mixture was diluted with water (100 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (100% EA) to give 66.3 mg of a white solid product, with a yield of 61.93%. LC-MS (ESI, pos. ion) m / z : 474.1 [M+H] + .

[0254] 1 H NMR (400 MHz, DMSO- d 6) δ 7.88 – 7.10 (m, 5H), 6.85 (s, 2H), 6.36 (s, 1H), 5.33 (s, 2H), 5.25 – 5.06 (m, 1H), 4.99 (s, 2H), 2.91 – 2.54 (m,2H), 2.03 – 1.46 (m, 4H). Example 8: (4-amino-7-chloro-1,3-dihydrofurano[3,4-) c Quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of methyl ketone (compound 8)

[0255] Step 1: Synthesis of methyl 4-amino-5-bromo-2-chlorobenzoate 10 g (53.9 mmol) of 4-amino-2-chlorobenzoate and 200 mL of acetonitrile were added sequentially to a 500 mL single-necked flask. NBS (9.59 g, 53.9 mmol) was slowly added at 0 °C, and the reaction was carried out at room temperature. After the reaction was complete, the pH was adjusted to 7 with 1 N sodium bicarbonate aqueous solution. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent. The resulting mixture was diluted with 500 mL of water and extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with 300 mL × 1, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 9 / 1) to give 13.66 g of a pale yellow solid product, with a yield of 95.86%. LC-MS (ESI, pos. ion) m / z 263.9 [M+H] + .

[0256] Step 2: Synthesis of methyl 4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate Methyl 4-amino-5-bromo-2-chlorobenzoate (8.66 g, 32.74 mmol), pinacol diborate (8.73 g, 34.38 mmol), potassium acetate (6.49 g, 66.13 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (3.37 g, 4.13 mmol) were added sequentially to a 250 mL single-necked flask. Dioxane (75 mL) was then added, and the reaction was carried out at 85 °C under nitrogen protection. After the reaction was complete, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 10 / 1) to give 3.65 g of a white solid product, with a yield of 35.78%. LC-MS (ESI, pos. ion) m / z 312.12 [M+H] + .

[0257] Step 3: 4-Amino-7-chloro-1,3-dihydrofurano[3,4- c Synthesis of methyl quinoline-8-carboxylic acid ester Methyl 4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (500 mg, 1.6 mmol), 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (583.6 mg, 2.4 mmol), potassium phosphate (849.1 mg, 4 mmol), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine(II) (113.29 mg, 0.16 mmol) were added sequentially to a 50 mL single-necked flask. Then, dioxane (12 mL) and water (3 mL) were added, and the reaction was carried out at 90 °C under nitrogen protection. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give 377.4 mg of a white solid product, with a yield of 84.4%. LC-MS (ESI, pos. ion) m / z :279.0 [M+H] + .

[0258] Step 4: 4-Amino-7-chloro-1,3-dihydrofurano[3,4- c Synthesis of quinoline-8-carboxylic acid Add 4-amino-7-chloro-1,3-dihydrofurano[3,4-] to a 50 mL single-necked flask. c Quinoline-8-carboxylic acid methyl ester (377.4 mg, 1.35 mmol), dioxane (5 mL), methanol (5 mL), and water (2.5 mL) were added, followed by lithium hydroxide monohydrate (141.3 mg, 3.38 mmol). The reaction was heated to 50 °C. After the reaction was complete, the pH was adjusted to 6 with 1N hydrochloric acid aqueous solution, and the organic solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 3 / 1) to give 280.0 mg of white solid product, yield 78.12%. LC-MS (ESI, pos. ion) m / z 265.0 [M+H] + .

[0259] Step 5: (4-amino-7-chloro-1,3-dihydrofurano[3,4-) c Quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1 (2 H Synthesis of methyl ketone Add 4-amino-7-chloro-1,3-dihydrofurano[3,4-] to a 25 mL single-necked flask. cQuinoline-8-carboxylic acid (72.3 mg, 0.27 mmol), HATU (159.7 mg, 0.42 mmol), dichloromethane (8 mL), and DIPEA (135.7 mg, 1.05 mmol) were reacted at room temperature for 0.5 hours. Then, intermediate M-1 (50 mg, 0.21 mmol) was added, and the reaction continued at room temperature. After the reaction was complete, the pH was adjusted to 7 with 1N ammonium chloride aqueous solution, and the dichloromethane was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (100% EA) to give 50.1 mg of a white solid product, with a yield of 49.75%. LC-MS (ESI, pos. ion) m / z :490.1 [M+H] + .

[0260] 1 H NMR (400 MHz, DMSO- d 6) δ 7.90 – 7.46 (m, 3H), 7.35 – 7.15 (m, 2H), 6.85 (br, 2H), 6.39 – 6.41 (m, 1H), 5.33 (s, 2H), 5.20 – 5.09 (m, 1H), 5.00(s, 2H), 2.91 – 2.54 (m, 2H), 2.03 – 1.46 (m, 4H). Example 9: (4-Amino-1-methyl-1- H -pyrazolo[4,3- c [1,7]Naphthid-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 14)

[0261] Step 1: Synthesis of methyl 5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridinecarboxylate At room temperature, methyl 6-amino-5-bromonicotinic acid (5 g, 21.46 mmol), potassium acetate (8.49 g, 86.56 mmol), pinacol diboronate (8.24 g, 32.46 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (2.65 g, 3.25 mmol) were added to a 250 mL round-bottom flask. Toluene (100 mL) was then added and stirred until dissolved. The mixture was heated to 100 °C under nitrogen protection and reacted for 9 h. After the reaction was complete, the reaction solution was directly evaporated to dryness, then 50 mL of dichloromethane was added and stirred to dilute it. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MEOH (v / v) = 17 / 3) to give 4 g of methyl 5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridinecarboxylate, yield 66.5%. LC-MS (ESI, pos. ion) m / z 297.2 [M+H] + .

[0262] Step 2: 4-Amino-1-methyl-1 H -pyrazolo[4,3- c Synthesis of [1,7]naphthyl-8-carboxylic acid methyl ester Add methyl 5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridinecarboxylate (1.25 g, 4.49 mmol) and 4-bromo-1-methyl-1-ylpyridinecarboxylate to a round-bottom flask in sequence. H 5-Pyrazole-5-carboxynitrile (1.00 g, 5.39 mmol), potassium phosphate (2.38 g, 11.23 mmol), were dissolved in tetrahydrofuran (40 mL) and water (5 mL), followed by the addition of Pd(aMphos)Cl2 (0.25 g, 0.35 mmol). The mixture was heated to 100 °C overnight under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain 258 mg of a gray-black solid, with a yield of 22.32%. LC-MS (ESI, pos. ion) m / z 258.09 [M+H] + .

[0263] Step 3: 4-Amino-1-methyl-1 H -pyrazolo[4,3- c Synthesis of [1,7]naphthyl-8-carboxylic acid 4-amino-1-methyl-1 H -pyrazolo[4,3-c [1,7] Naphthyl-8-carboxylic acid methyl ester (258 mg, 1.00 mmol) was added to a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL), followed by lithium hydroxide monohydrate (0.042 g, 1.00 mmol). The mixture was stirred at room temperature for 5 h. After the reaction was complete, the reaction solution was adjusted to pH 5 with 1.0 mol / L dilute hydrochloric acid solution. The organic solvent was removed by vacuum concentration, and water was added to the reaction system. The mixture was ultrasonically vibrated until all solid particles were uniformly dispersed in the aqueous phase. The mixture was filtered, and the filter cake was washed with water (5 mL × 3 times). The filter cake was collected and dried to obtain 80 mg of gray-black solid, with a yield of 32.8%. LC-MS (ESI, pos. ion) m / z : 244.1 [M+H] + .

[0264] Step 4: (4-Amino-3-methyl-3-) H -pyrazolo[3,4- c [1,7]Naphthid-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1 (2 H Synthesis of methyl ketone At room temperature, 4-amino-1-methyl-1 H -pyrazolo[4,3- c [1,7] Naphthyl-8-carboxylic acid (0.12 g, 0.49 mmol) was reacted with HATU (0.23 g, 0.61 mmol) and DIPEA (0.079 g, 0.61 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 1 h. Then, intermediate M-1 (0.1 g, 0.41 mmol) was added, and the reaction was continued at room temperature with stirring. After the reaction was complete, the system was concentrated under reduced pressure and separated by column chromatography (DCM / MeOH (v / v) = 50 / 1) to give 17.3 mg of a white solid product, yield 9%. LC-MS (ESI, pos. ion) was also performed. m / z 469.0 [M+H] + .

[0265] 1 H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.67–8.53 (m, 1H), 8.07 (s,1H), 7.75–7.61 (m, 1H), 7.22 (d, J1.94 (m, 2H). Example 10: (4-amino-7-fluoro-3-methyl-3-) H -pyrazolo[3,4- c Quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of 15-methyl ketone (compound 15)

[0266] Step 1: 4-Amino-1-methyl-1 H -pyrazolo[4,3- c Synthesis of methyl quinoline-8-carboxylic acid ester Add methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (500 mg, 1.8 mmol) and 5-bromo-1-methyl-1-ylbenzoate sequentially to a 50 mL single-necked flask. H The reaction mixture consisted of pyrazole-4-onitrile (418.5 mg, 2.25 mmol), potassium carbonate (622.0 mg, 4.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (147.0 mg, 0.18 mmol), followed by the addition of dioxane (12 mL) and water (3 mL). The reaction was carried out under nitrogen protection at 90 °C. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give 245.0 mg of a pale yellow solid product, yield 52.99%. LC-MS (ESI, pos.ion) m / z 257.1 [M+H] + .

[0267] Step 2: 4-Amino-1-methyl-1 H -pyrazolo[4,3- c Synthesis of quinoline-8-carboxylic acid Add 4-amino-1-methyl-1-ethylhexane to a 25 mL single-necked flask. H -pyrazolo[4,3- cQuinoline-8-carboxylic acid methyl ester (245 mg, 0.96 mmol), methanol (3.5 mL), dioxane (3.5 mL), water (1.75 mL), and lithium hydroxide monohydrate (100.7 mg, 2.4 mmol) were reacted at 50 °C. After the reaction, the pH was adjusted to 6 with 1 M hydrochloric acid aqueous solution, and the organic solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 3 / 1) to give 219.0 mg of white solid product, yield 94.6%. LC-MS (ESI, pos. ion) m / z 243.0 [M+H] + .

[0268] Step 3: (4-Amino-7-fluoro-3-methyl-3-) H -pyrazolo[3,4- c Quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1 (2 H Synthesis of methyl ketone Add 4-amino-1-methyl-1-ethylhexane to a 25 mL single-necked flask. H -pyrazolo[4,3- c Quinoline-8-carboxylic acid (78.7 mg, 0.33 mmol), HATU (190.1 mg, 0.5 mmol), DMF (4 mL), and DIPEA (161.6 mg, 1.25 mmol) were reacted at room temperature for 0.5 h. Then, intermediate M-1 (60 mg, 0.25 mmol) was added, and the reaction was heated to 50 °C. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give 16.3 mg of an orange oil, yield 14.1%. LC-MS (ESI, pos. ion) m / z 468.0 [M+H] + .

[0269] 1 H NMR (400 MHz, DMSO- d 6) δ 8.34 (s, 1H), 7.71 – 7.62 (m, 4H), 7.32(d, J= 7.6 Hz, 1H), 7.22 (s, 1H), 5.44 – 5.17 (m, 2H), 4.43 (s, 3H), 2.90 –2.66 (m, 2H), 2.03 – 1.74 (m, 4H). Example 11: (4-amino-7-fluoro-3-methyl-3-) H -pyrazolo[3,4- c Quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1 (2 H Synthesis of 17-methyl ketone (compound 17)

[0270] Step 1: 4-Amino-7-fluoro-3-methyl-3 H -pyrazolo[3,4- c Synthesis of methyl quinoline-8-carboxylic acid ester Add methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (500 mg, 1.69 mmol) and 4-bromo-1-methyl-1-ylbenzoate sequentially to a 50 mL single-necked flask. H 5-pyrazole-5-onitrile (314.36 mg, 1.7 mmol), potassium phosphate (896.84 mg, 4.22 mmol), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (119.66 mg, 0.17 mmol) were added, followed by dioxane (12 mL) and water (3 mL). The reaction was carried out under nitrogen protection and heated to 90 °C. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (80 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (100% EA) to give 273.3 mg of a pale yellow solid product, with a yield of 58.82%. LC-MS (ESI, pos. ion) m / z 275.1 [M+H] + .

[0271] Step 2: 4-Amino-7-fluoro-3-methyl-3 H -pyrazolo[3,4- c Synthesis of quinoline-8-carboxylic acid Add 4-amino-7-fluoro-3-methyl-3 ... H-pyrazolo[3,4- c Quinoline-8-carboxylic acid methyl ester (273.3 mg, 1.0 mmol), dioxane (4 mL), methanol (4 mL), water (2 mL), and lithium hydroxide monohydrate (104.90 mg, 2.5 mmol) were reacted at 50 °C. After the reaction, the pH was adjusted to 6 with 1 N hydrochloric acid aqueous solution, and the organic solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 1 / 1) to give 266 mg of a pale yellow solid product, with a yield of 100%. LC-MS (ESI, pos. ion) m / z 261.1 [M+H] + .

[0272] Step 3: (4-Amino-7-fluoro-3-methyl-3-) H -pyrazolo[3,4- c Quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of methyl ketone Add 4-amino-7-fluoro-3-methyl-3 ... H -pyrazolo[3,4- c Quinoline-8-carboxylic acid (50.74 mg, 0.20 mmol), HATU (114.07 mg, 0.30 mmol), dichloromethane (1.5 mL), DMF (5 mL), and DIPEA (77.54 mg, 0.60 mmol) were added and reacted at room temperature for 0.5 hours. Then, intermediate M-1 (36 mg, 0.15 mmol) was added, and the reaction was continued at room temperature. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (100% EA) to give 15.1 mg of a white solid product, in 21.02% yield. LC-MS (ESI, pos. ion) m / z 486.2 [M+H] + .

[0273] 1 H NMR (400 MHz, DMSO- d 6) δ 8.54 (s, 1H), 8.24 (s, 1H), 7.56 – 7.16 (m, 4H), 6.39 (s, 1H), 4.36 (s, 3H), 2.94 – 2.61 (m, 2H), 2.07 – 1.42 (m, 4H). Example 12: (4-amino-7-chloro-3-methyl-3-) H -pyrazolo[3,4- c Quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of 18-methyl ketone (compound 18)

[0274] Step 1: 4-Amino-7-chloro-3-methyl-3 H -pyrazolo[3,4- c Synthesis of methyl quinoline-8-carboxylic acid ester Add methyl 4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (500 mg, 1.6 mmol) and 4-bromo-1-methyl-1-ylbenzoate sequentially to a 100 mL single-necked flask. H 5-pyrazole-5-onitrile (372 mg, 2 mmol), potassium phosphate (849.1 mg, 4 mmol), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (113.29 mg, 0.16 mmol) were added, followed by dioxane (12 mL) and water (3 mL). The reaction was carried out under nitrogen protection at 90 °C. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give 238.4 mg of a pale yellow solid product, yield 51.10%. LC-MS (ESI, pos. ion) m / z : 291.0[M+H] + .

[0275] Step 2: 4-Amino-7-chloro-3-methyl-3 H -pyrazolo[3,4- c Synthesis of quinoline-8-carboxylic acid Add 4-amino-7-chloro-3-methyl-3 ... H -pyrazolo[3,4- cQuinoline-8-carboxylic acid methyl ester (238.4 mg, 0.82 mmol), dioxane (3.5 mL), methanol (3.5 mL), and water (1.75 mL) were added, followed by lithium hydroxide monohydrate (86.02 mg, 2.05 mmol). The system was heated to 50 °C for reaction. After the reaction was completed, the pH was adjusted to 6 with 1N hydrochloric acid aqueous solution, and the organic solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 3 / 1) to give 208.8 mg of pale yellow solid product, yield 92.03%. LC-MS (ESI, pos. ion) m / z :277.0 [M+H] + .

[0276] Step 3: (4-Amino-7-chloro-3-methyl-3-) H -pyrazolo[3,4- c Quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1 (2 H Synthesis of methyl ketone Add 4-amino-7-chloro-3-methyl-3 ... H -pyrazolo[3,4- c Quinoline-8-carboxylic acid (75.53 mg, 0.27 mmol), HATU (159.7 mg, 0.42 mmol), dichloromethane (6 mL), and DIPEA (135.7 mg, 1.05 mmol) were reacted at room temperature for 0.5 hours. Then, compound M-1 (50 mg, 0.21 mmol) was added, and the reaction continued at room temperature. After the reaction was complete, the mixture was washed with saturated brine (100 mL × 2). The organic layer was dried over anhydrous sodium sulfate, and the residue after concentration under reduced pressure was purified by silica gel column chromatography (100% EA) to give 58 mg of a white solid product, in 56% yield. LC-MS (ESI, pos. ion) m / z 501.9 [M+H] + .

[0277] 1 H NMR (400 MHz, DMSO- d6) δ 8.72 – 7.42 (m, 3H), 7.35 – 7.03 (m, 3H), 6.45 – 6.39 (m, 1H), 5.50 – 5.10 (m, 1H), 4.35 (s, 3H), 2.96 – 2.49 (m, 2H), 2.26 – 1.27 (m, 4H). Example 13: (4-Amino-3-methyl-3- H -pyrazolo[3,4- c Quinoline-8-yl)[(4aS,9bR)-7-trifluoromethyl-3,4,4a,9b-tetrahydrobenzofuran[3,2- b ]Pyridine-1(2 H Synthesis of ]-[-]methyl ketone (compound 19)

[0278] Step 1: 4-Amino-3-methyl-3 H -pyrazolo[3,4- c Synthesis of methyl quinoline-8-carboxylate Under a nitrogen atmosphere, methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoate (500 mg, 1.8 mmol) and 4-bromo-1-methyl-1-ylbenzoate were added to a 100 ml single-necked flask. H 5-pyrazole-5-carboxynitrile (0.4 g, 2.16 mmol), potassium phosphate (0.96 g, 4.5 mmol), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (0.13 g, 0.18 mmol) were dissolved in dioxane (20 mL) and water (4 mL). The reaction mixture was then subjected to nitrogen protection and reacted at 100 °C for 4 h. After the reaction was complete, the resulting reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 50 / 1) to give the target product as a pale yellow solid of 370 mg, with a yield of 80.02%. LC-MS (ESI, pos. ion) m / z 257.1 [M+H] + .

[0279] Step 2: 4-Amino-3-methyl-3 H -pyrazolo[3,4- c Synthesis of quinoline-8-carboxylic acid To 4-amino-3-methyl-3 H -pyrazolo[3,4-c Lithium hydroxide (0.12 mg, 2.88 mmol) was added to a mixed solution (10 mL / 3 mL) of methyl quinoline-8-carboxylate (370 mg, 1.44 mmol) in dioxane and water. The mixture was then heated to 50 °C for reaction. After the reaction was complete by TLC, HCl solution (1.0 M) was added to adjust the pH to 6, and the mixture was directly evaporated to dryness under reduced pressure. Column chromatography (DCM / MeOH (V / V) = 10 / 1) yielded 200 mg of a white solid, with a yield of 57.18%. LC-MS (ESI, pos.ion) m / z: 243.1 [M+H] + .

[0280] Step 3: (4-Amino-3-methyl-3- H -pyrazolo[3,4- c Quinoline-8-yl)[(4aS,9bR)-7-trifluoromethyl-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of ]-[-]methyl ketone Add 4-amino-3-methyl-3 ... H -pyrazolo[3,4- c Quinoline-8-carboxylic acid (200 mg, 0.83 mmol) and HATU (470 mg, 1.24 mmol) were dissolved in anhydrous dichloromethane (10 mL), followed by the addition of DIPEA (160 mg, 0.46 mmol). The mixture was stirred at room temperature for 30 minutes, and then intermediate M-1 (200 mg, 0.83 mmol) was added. After reacting for 10 h, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (DCM / MeOH (V / V) = 30 / 1) yielded 50 mg of the target compound as a white solid, with a yield of 12.96%. LC-MS (ESI, pos.ion) m / z: 468.1 [M+H] + .

[0281] 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(s, 1H), 8.08 (s, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.27 (d, J= 9.4 Hz, 1H), 7.10(s, 1H), 6.40 (br, 1H), 5.55 (br, 2H), 5.11 (s, 1H), 4.46 (s, 3H), 3.70 –3.56 (m, 1H), 2.96 – 2.89 (m, 1H), 1.85-1.75 (m, 4H). Example 14: (4-Amino-3-methyl-3- H -pyrazolo[3,4- c [1,7]Naphthid-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 20)

[0282] Step 1: 4-Amino-3-methyl-3 H -pyrazolo[3,4- c Synthesis of [1,7]naphthyl-8-carboxylic acid methyl ester Add methyl 5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridinecarboxylate (1.5 g, 5.39 mmol) and 4-bromo-1-methyl-1-ylpyridinecarboxylate sequentially to a 100 mL round-bottom flask. H 5-pyrazole-5-carboxynitrile (1.20 g, 6.47 mmol), potassium phosphate (2.86 g, 13.47 mmol), and Pd(aMphos)Cl2 (0.30 g, 0.42 mmol) were added, followed by tetrahydrofuran (40 mL) and water (5 mL). The system was heated to 100 °C for 24 h under nitrogen protection. After the reaction, the solvent was removed by direct concentration under reduced pressure. The residue was purified by column chromatography (DCM / MeOH (V / V) = 93 / 7) to give 0.51 g of grayish-brown solid, yield 36.8%. LC-MS (ESI, pos. ion) m / z 258.1 [M+H] + .

[0283] Step 2: 4-Amino-3-methyl-3 H -pyrazolo[3,4- c Synthesis of [1,7]naphthyl-8-carboxylic acid To 4-amino-3-methyl-3 H -pyrazolo[3,4- c[1,7] Naphthyl-8-carboxylic acid methyl ester (0.5 g, 1.94 mmol) was reacted with lithium hydroxide monohydrate (0.098 g, 2.33 mmol) in a mixed solvent of tetrahydrofuran (20 mL) and water (8 mL) for 20 h at room temperature. After the reaction was complete, the pH of the system was adjusted to 5 with 1N dilute hydrochloric acid, and then the organic solvent was removed by direct vacuum concentration. Water was then added to the reaction solution, and the mixture was sonicated until all solid particles were uniformly dispersed in the aqueous phase. The mixture was filtered, and the filter cake was collected and dried to obtain 0.21 g of gray-black solid, with a yield of 44.42%. LC-MS (ESI, pos. ion) m / z :244.1 [M+H] + .

[0284] Step 3: (4-Amino-3-methyl-3- H -pyrazolo[3,4- c [1,7]Naphthid-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone To 4-amino-3-methyl-3 H -pyrazolo[3,4- c [1,7] Naphthyl-8-carboxylic acid (120 mg, 0.49 mmol) was reacted with HATU (0.23 g, 0.61 mmol) and DIPEA (0.079 g, 0.61 mmol) in 10 mL of dichloromethane. The mixture was stirred at room temperature for 1 h, followed by the addition of intermediate M-1 (0.1 g, 0.41 mmol) and continued stirring at room temperature. After the reaction was complete, the system was concentrated under reduced pressure to remove the organic solvent. The residue was purified by column chromatography (DCM / MeOH (V / V) = 90 / 10) to give 56 mg of a white solid product, 29.08%. LC-MS (ESI, pos. ion) m / z 469.0 [M+H] + .

[0285] 1 H NMR (400 MHz, DMSO- d 6) δ 8.83 (s, 1H), 8.70 (s, 1H), 8.44 (d, J = 8.2Hz, 1H), 7.89 – 7.54 (m, 1H), 7.34 (d, J= 7.3 Hz, 1H), 7.27 – 7.23 (m, 3H), 6.29 – 6.05 (m, 1H), 5.20 – 5.04 (m, 1H), 4.40 (s, 3H), 4.30 – 3.80 (m, 1H), 2.85 – 2.56 (m, 2H), 1.97 (m, 2H), 1.84 - 1.58 (m, 2H). Example 15: (4-amino-1,3-dihydrofurano[3,4-) c [1,7]Naphthid-8-yl)((4aS,9bS)-7-((1-cyclopropyl-1) H -pyrazol-4-yl)ethynyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1 (2 H Synthesis of 140-methyl ketone (compound 140)

[0286] Under a nitrogen atmosphere, the 4-amino-1,3-dihydrofurano[3,4- C [1,7] Naphthyl-8-carboxylic acid (60 mg, 0.2 mmol) was reacted with HATU (110 mg, 0.3 mmol) and DIPEA (52 mg, 0.4 mmol) in DCM (10 mL) at room temperature for 0.5 h. Then, M-2 (60 mg, 0.2 mmol) was added to the reaction system, and the mixture was stirred overnight. After the reactants had reacted completely, the system was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH (V / V) = 100 / 3) to give 40 mg of a white solid, yield 39.3%. LC-MS (ESI, pos. ion) m / z: 519.2 [M+H] + .

[0287] 1 H NMR (400 MHz, DMSO- d 6) δ 8.89 (d, J = 10.8 Hz, 1H), 8.17 (s, 1H), 7.87 (d, J = 42.2 Hz, 1H), 7.32 – 7.68 (m, 2H), 7.09 – 7.06 (m, 3H), 6.93 (d, J =15.5 Hz, 1H), 6.20 – 5.91 (m, 1H), 5.39 (br, 2H), 5.12 – 4.94 (m, 3H), 3.76(t,J = 3.7 Hz, 1H), 2.80 (br, 1H), 1.95 – 1.75 (m, 4H), 1.65 – 1.55 (m, 1H), 1.07 – 1.06 (m, 2H), 0.99 – 0.97 (m, 2H). Example 16: (4-amino-7-fluoro-1,3-dihydrofurano[3,4-) c Quinoline-8-yl)((4aS,9bS)-7-((1-cyclopropyl-1) H -pyrazol-4-yl)ethyl)-3,4,4a,9b tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 142)

[0288] Add 4-amino-7-fluoro-1,3-dihydro[3,4-] to a 25 mL single-necked flask. c Quinoline-8-carboxylic acid (51.63 mg, 0.21 mmol), HATU (121.67 mg, 0.32 mmol), dichloromethane (5 mL), and DIPEA (103.39 mg, 0.80 mmol) were reacted at room temperature for 0.5 h. Compound M-2 (50 mg, 0.16 mmol) was then added, and the reaction was continued at 50 °C. After the reaction was complete, the resulting mixture was diluted with water (100 mL) and extracted with dichloromethane (15 mL × 3). The combined organic phases were dried under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH (v / v) = 40 / 1) to give 35.2 mg of a white solid product, with a yield of 40.14%. LC-MS (ESI, pos. ion) m / z: 536.0 [M+H] + .

[0289] 1 HNMR (400MHz, CDCl3) δ 7.63 (d, J =8.3Hz,2H),7.52(d, J =6.3Hz, 1H), 7.39(d, J =11.1Hz,2H),7.09(d, J=7.0Hz,1H),6.93–6.87(m,1H),6.42(s,1H),5.42(s,2H),5.13(s,2H),5.05(s,1H),4.96(s,2H) ,3.60–3.33(m,2H),3.06–2.76(m,1H),2.14–1.96(m,2H),1.79–1.54(m,2H),1.13–1.03(m,4H). Example 17: (4-amino-7-chloro-1,3-dihydrofurano[3,4-) c Quinoline-8-yl)((4aS,9bS)-7-((1-cyclopropyl-1) H -pyrazol-4-yl)ethynyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1 (2 H Synthesis of 143 (-yl) methyl ketone

[0290] Add 4-amino-7-chloro-1,3-dihydrofurano[3,4-] to a 25 mL single-necked flask. c Quinoline-8-carboxylic acid (55.05 mg, 0.21 mmol), HATU (121.67 mg, 0.32 mmol), dichloromethane (5 mL), and DIPEA (103.39 mg, 0.80 mmol) were reacted at room temperature for 0.5 h. Compound M-2 (50 mg, 0.16 mmol) was then added, and the reaction was continued at 50 °C. After the reaction was complete, the resulting mixture was diluted with water (100 mL) and extracted with dichloromethane (15 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH (v / v) = 40 / 1) to give 22.6 mg of white solid product, yield 25%. LC-MS (ESI, pos. ion) m / z: 552.0 [M+H] + .

[0291] 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 15.5 Hz, 1H), 7.63 (d, J= 8.4 Hz,2H), 7.57 – 7.30 (m, 2H), 7.11 – 6.98 (m, 1H), 6.93 – 6.86 (m, 1H), 6.54 –6.42 (m, 1H), 5.39 (s, 2H), 5.12 – 4.98 (m, 5H), 3.60 – 3.19 (m, 2H), 3.09 –2.84 (m, 1H), 2.11 – 1.94 (m, 2H), 1.77 – 1.50 (m, 2H), 1.18 – 1.06 (m, 4H). Example 18: (4-Amino-7-fluoro-1-methyl-1- H -pyrazolo[4,3- c Quinoline-8-yl)((4aS,9bS)-7-((1-cyclopropyl-1) H -pyrazol-4-yl)ethynyl)-3,4,4a,9btetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 146)

[0292] Add 4-amino-7-fluoro-1-methyl-1-ethylhexane to a 25 mL single-necked flask. H -pyrazolo[4,3- c Quinoline-8-carboxylic acid (54.13 mg, 0.21 mmol), HATU (121.67 mg, 0.32 mmol), dichloromethane (5 mL), and DIPEA (103.39 mg, 0.80 mmol) were added. The mixture was reacted at room temperature for 0.5 hours, followed by the addition of (4aS, 9bS)-7-((1-cyclopropyl-1H-pyrazol-4-yl)ethyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2-b]pyridine (compound M-2) (50 mg, 0.16 mmol). The reaction was continued at room temperature. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH (v / v) = 30 / 1) to give 22.6 mg of a white solid product, with a yield of 25.2%. LC-MS (ESI, pos. ion) m / z: 548.0 [M+H] + .

[0293] 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J = 7.5 Hz, 1H), 7.98 (s, 1H), 7.63(d,J = 8.2 Hz, 2H), 7.46 – 7.39 (m, 2H), 7.10 (d, J = 7.3 Hz, 1H), 6.94 (s, 1H),6.47 (s, 1H), 5.58 (s, 2H), 5.06 (s, 1H), 4.46 (s, 3H), 3.60 – 3.40 (m, 2H),3.03 – 2.87 (m, 1H), 2.12 – 1.99 (m, 2H), 1.75 – 1.60 (m, 2H), 1.13 – 1.03 (m, 4H). Example 19: (4-Amino-7-fluoro-1-methyl-1 H -pyrazolo[4,3- c Quinoline-8-yl)((4aS,9bS)-7-((1-methyl-1-yl) H -pyrazol-4-yl)ethynyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 158)

[0294] Under a nitrogen atmosphere, 4-amino-7-fluoro-1-methyl-1 H -pyrazolo[4,3- c HATU (50.8 mg, 0.13 mmol) and DIPEA (23 mg, 0.18 mmol) were added to DCM (10 mL) containing quinoline-8-carboxylic acid (39.6 mg, 0.15 mmol) and reacted at room temperature for 1.5 h. Then (4aS, 9bS)-7-((1-methyl-1 H -pyrazol-4-yl)ethyl)-1,2,3,4,4a,9b-hexahydrobenzofurano[3,2- b Pyridine (compound M-3) (25 mg, 0.09 mmol) was added and the reaction was stirred overnight. After the starting material had reacted completely, the system was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH (V / V) = 100 / 3) to give 20 mg of white solid, yield 42.85%. LC-MS (ESI, pos. ion) m / z: 522.2 [M+H] + .

[0295] 1 H NMR (400 MHz, CDCl3) δ 8.25 (t, J= 17.2 Hz, 1H), 7.96 (s, 1H), 7.64(s, 1H), 7.56 (s, 1H), 7.47 – 7.34 (m, 2H), 7.11 (d, J = 7.1 Hz, 1H), 6.95 (s, 1H), 6.47 (s, 1H), 5.49 (s, 2H), 5.07 (s, 1H), 4.45 (s, 3H), 3.91 (s, 3H), 3.40 (s, 1H), 3.04 (s, 1H), 2.02 (td, J = 15.0, 7.8 Hz, 4H). Example 20: (4-Amino-1-methyl-1- H -pyrazolo[4,3-c]quinoline-8-yl)((4aS,9bS)-7-((1-cyclopropyl-1 H -pyrazin-4-yl)ethynyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1 (2 H Synthesis of 145-methyl ketone (compound 145)

[0296] Under a nitrogen atmosphere, HATU (130 mg, 0.35 mmol) and DIPEA (60 mg, 0.46 mmol) were added to 10 mL of DCM containing 84 mg of 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (84 mg, 0.35 mmol), and the reaction was carried out at room temperature for 0.5 h. Then, intermediate M-2 (70 mg, 0.23 mmol) was added to the reaction system, and the mixture was stirred overnight. After the reactants had reacted completely, the system was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH (V / V) = 100 / 3) to give 20 mg of a white solid, yield 16.5%. LC-MS (ESI, pos. ion) m / z: 530.05 [M+H] + .

[0297] 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.06 (s, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.64 (s,1H), 7.40 (s, 1H), 7.31 (s, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.96 (s, 1H), 6.85– 6.79 (m, 1H), 5.07 – 5.03 (m, 1H), 4.50 (s, 3H), 3.63 – 3.60 (m, 1H), 3.03– 2.96 (m, 1H), 2.04 – 2.02 (m, 2H), 1.85 – 1.83 (m, 2H), 1.15 – 1.13 (m,2H), 1.09 – 1.05 (m, 2H). Example 21: Synthesis of (4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridin-1(2H)-yl) methyl ketone (compound 9)

[0298] Under a nitrogen atmosphere, HATU (470 mg, 0.82 mmol) and DIPEA (160 mg, 1.23 mmol) were added to 10 mL of DCM containing 4-amino-3-methyl-3H-pyrazolo[3,4-c][1,7]naphthyl-8-carboxylic acid (0.23 g, 1.98 mmol). The reaction was carried out at room temperature for 1 h. Then, intermediate M-1 (70 mg, 0.23 mmol) was added to the reaction system, and the reaction was stirred overnight. After the starting materials had reacted completely, the system was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH(V / V) = 100 / 3) to give 17 mg of white solid, yield 4.8%. LC-MS (ESI, pos. ion) m / z: 456.0 [M+H] + .

[0299] 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 1H), 7.62 (d, J= 12.3 Hz,2H), 7.54 (s, 1H), 7.23 (m, 1H), 7.08 (s, 1H), 6.31 (s, 2H), 5.46 (s, 2H),5.35 (m, 1H), 5.17 (s, 2H), 5.07 (m, 1H), 3.65 (m, 2H), 2.91 - 2.12 (m, 2H), 1.82 - 1.72 (m, 2H). Example 22: Synthesis of (4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridin-1(2H)-yl) methyl ketone (compound 13)

[0300] Under a nitrogen atmosphere, HATU (350 mg, 0.93 mmol) and DIPEA (240 mg, 1.86 mmol) were added to 25 mL of DCM containing 0.2 g (0.8 mmol) of 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (DCM). The mixture was reacted at room temperature for 2 h, and then intermediate M-1 (150 mg, 0.62 mmol) was added to the reaction system, followed by stirring overnight. After the reactants had reacted completely, the system was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH (V / V) = 100 / 3) to obtain 140 mg of a white solid. This white solid was chirally resolved to give two compounds, named 13-1 and 13-2. The NMR spectra of the two isomers are as follows: Compound 13-1: 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.6 Hz, 1H), 7.65 (s,1H), 7.62 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.25 (d, J= 8.1 Hz, 1H), 7.09 (s, 1H), 6.28 (s, 1H), 5.53 - 5.48 (m, 2H), 5.39 - 5.34 (m, 1H), 5.08 (br, 1H), 4.93 (s, 2H), 2.95 - 2.88 (m, 1H), 2.16 – 2.09 (m, 1H), 2.05 – 1.97 (m, 1H), 1.90 – 1.85 (m, 1H), 1.58 (d, J = 6.0 Hz, 3H), 1.36 – 1.30 (m, 2H); Compound 13-2: 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.6 Hz, 1H), 7.65 (s,1H), 7.62 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.09 (s,1H), 6.31 (s, 1H), 5.53 - 5.48 (m, 2H), 5.39 - 5.35 (m, 1H), 5.08 (br, 1H),4.90 (s, 2H), 2.97 - 2.87 (m, 1H), 2.17 – 2.09 (m, 1H), 2.05 – 1.97 (m, 1H), 1.90 – 1.80 (m, 1H), 1.59 (d, J = 8.2 Hz, 3H), 1.29 – 1.27 (m, 2H). Example 23: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((4aS,9bS)-7-ethynyl-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1 (2 H Synthesis of methyl ketone (compound 59)

[0301] Under a nitrogen atmosphere, HATU (130 mg, 0.35 mmol) and DIPEA (188 mg, 0.49 mmol) were added to 15 mL of DCM containing 100 mg of 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (100 mg, 0.41 mmol). The reaction was carried out at room temperature for 1 h. Then, intermediate M-4 (70 mg, 0.35 mmol) was added to the reaction system, and the reaction was stirred overnight. After the starting material had reacted completely, the system was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH (V / V) = 100 / 3) to give 119 mg of white solid, yield 68%. LC-MS (ESI, pos. ion) m / z: 424.2 [M+H] + .

[0302] 1 H NMR (600MHz, DMSO- d 6) δ 8.31 (s, 1H), 8.26 (s, 1H), 7.63 (s, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.17 (s, 2H), 7.10 – 7.07 (m, 1H), 6.96 (s, 1H), 6.09(s, 2H), 4.42 (s, 3H), 4.19 (s, 1H), 2.03 – 1.98 (m, 2H), 1.92 – 1.79 (m,3H), 1.61 – 1.56 (m, 1H). Example 24: (4-Amino-1-methyl ... H -pyrazolo[4,3-c]quinoline-8-yl)((4aS,9bS)-7-((1-methyl-1 H -pyrazin-4-yl)ethynyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1 (2 H Synthesis of 157 (-yl)-methyl ketone

[0303] With 4-amino-1-methyl-1 H Using pyrazolo[4,3-c]quinoline-8-carboxylic acid and intermediate M-3 as starting materials, and following the synthesis protocol of Example 23, 40 mg of a white solid was obtained in 44.5% yield. LC-MS (ESI, pos. ion) m / z: 504.2 [M+H] + .

[0304] 1H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 8.05 (s, 1H), 7.80 (d, J = 8.5Hz, 1H), 7.67 (s, 2H), 7.58 (s, 1H), 7.42 (s, 1H), 7.13 (dd, J = 7.6, 1.4 Hz,1H), 6.97 (s, 1H), 5.37 (t, J = 5.0 Hz, 1H), 5.32 (s, 1H), 4.51 (s, 3H), 3.94(s, 3H), 2.98 (s, 1H), 2.24 (t, J = 7.7 Hz, 1H), 2.05 – 2.01 (m, 4H). Example 25: (4-amino-1,3-dihydrofurano[3,4-) c Quinoline-8-yl)((4aS,9bS)-7-ethynyl-3,4,4a,9b-tetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 57)

[0305] Using 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid and intermediate M-4 as starting materials, 20 mg of a white solid was obtained according to the synthetic scheme of Example 23, with a yield of 34.5%. LC-MS (ESI, pos. ion) m / z: 412.2 [M+H] + .

[0306] 1 H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 8.6 Hz, 1H), 7.64 – 7.62 (m, 2H), 7.40 (s, 1H), 7.14 (dd, J = 7.6, 1.3 Hz, 1H), 6.97 (s, 1H), 5.48 – 5.46 (m,3H), 5.19 – 5.17 (m, 3H), 4.88 (s, 2H), 3.09 (s, 1H), 2.15 – 1.96 (m, 2H),1.83 – 1.72 (m, 4H). Example 26: (4-amino-1,3-dihydrofurano[3,4-) c[1,7]Naphthid-8-yl)((4aS,9bS)-7-ethynyl-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 58)

[0307] Using 4-amino-1,3-dihydrofurano[3,4-c][1,7]naphthidine-8-carboxylic acid and intermediate M-4 as starting materials, 60 mg of a white solid was obtained according to the synthesis scheme of Example 23, with a yield of 43.6%. LC-MS (ESI, pos. ion) m / z: 413.0 [M+H] + .

[0308] 1 H NMR (400 MHz, DMSO- d 6) δ 8.86 (s, 1H), 7.85 (d, J = 42.3 Hz, 1H),7.63 – 7.30 (m, 1H), 7.08 – 7.06 (m, 3H), 6.94 (d, J = 16.0 Hz, 1H), 6.18 –5.89 (m, 1H), 5.37 (s, 2H), 5.09 – 4.93 (m, 3H), 4.17 (s, 1H), 3.71 (s, 1H),2.76 (s, 1H), 1.92 – 1.56 (m, 4H). Example 27: (4-amino-1,3-dihydrofurano[3,4-) c Quinoline-8-yl)((4aS,9bS)-7-((1-methyl-1-yl) H -pyrazol-4-yl)ethynyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 153)

[0309] With 4-amino-3-methyl-3 H -pyrazolo[3,4- c Using naphthidine-8-carboxylic acid and intermediate M-3 as starting materials, 48 ​​mg of a white solid was obtained according to the synthesis scheme of Example 23, with a yield of 54.6%. LC-MS (ESI, pos. ion) m / z: 492.2 [M+H] + .

[0310] 1 H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.63 –7.56 (m, 2H), 7.55 (s, 1H), 7.37 (s, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.93 (s,1H), 6.29 (s, 1H), 5.43 (s, 2H), 5.14 (s, 2H), 5.11 (s, 2H), 5.00 (s, 1H),3.91 (s, 3H), 3.17 – 2.64 (m, 2H), 2.03 – 1.63 (m, 4H). Example 28: (4-Amino-7-chloro-3-methyl-3- H -pyrazolo[3,4- c Quinoline-8-yl)[(4aS,9bS)-7-ethynyl-3,4,4a,9b-tetrahydrobenzofuran[3,2- b ]Pyridine-1(2 H Synthesis of ]-[-]methyl ketone (compound 62)

[0311] With 4-amino-7-chloro-3-methyl-3 H -pyrazolo[3,4- c Using quinoline-8-yl and intermediate M-4 as starting materials, and following the synthesis protocol of Example 23, 45 mg of a white solid was obtained, with a yield of 67%. LC-MS (ESI, pos. ion) m / z: 458.1 [M+H] + .

[0312] 1 H NMR (600 MHz, CDCl3) δ 8.12 (t, J = 18.5 Hz, 1H), 7.79 (d, J = 68.6 Hz,1H), 7.58 – 7.52 (m, 1H), 7.45 (dd, J = 10.8, 7.6 Hz, 1H), 7.19 – 7.15 (m, 1H), 7.02 – 6.98 (m, 1H), 6.52 (dd, J= 55.4, 8.9 Hz, 1H), 5.73 (s, 1H), 5.59 (s,1H), 5.12 – 5.07 (m, 1H), 4.44 (t, J = 6.8 Hz, 3H), 3.23 – 3.16 (m, 1H), 3.06 (s, 1H), 2.88 – 2.82 (m, 1H), 2.04 – 1.94 (m, 2H), 1.91 – 1.84 (m, 2H). Example 29: ( S )-4-amino-3-methyl-1,3-dihydrofurano[3,4- c Quinolin-8-yl-((4aS,9bS)-7-((1-methyl-1) H -pyrazol-4-yl)ethynyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 171)

[0313] by( S Using 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid and intermediate M-3 as starting materials, a racemic compound was obtained according to the synthetic scheme of Example 23. After chiral resolution, the target product was obtained as a pale yellow solid (33 mg, yield 45.58%). LC-MS (ESI, pos. ion) m / z: 506.2 [M+H] + .

[0314] 1 H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.5 Hz, 1H), 7.63 (s, 2H), 7.55(s, 1H), 7.36 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.92 (s, 1H), 6.27 (s, 1H), 5.48 (t, J = 8.1 Hz, 2H), 5.35 (d, J = 11.9 Hz, 1H), 5.08 (s, 2H), 3.90 (s, 3H), 2.91 (s, 1H), 2.17 – 2.00 (m, 5H), 1.56 (d, J = 6.1 Hz, 3H). Example 30: ( S )-4-amino-3-methyl-1,3-dihydrofurano[3,4- c Quinoline-8-yl((4aS,9bS)-7-ethynyl-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 182)

[0315] by( S Using 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid and intermediate M-4 as starting materials, a racemic compound was obtained according to the synthetic scheme of Example 23. After chiral resolution, the target product was obtained as a white solid (17 mg, yield 55.4%). LC-MS (ESI, pos. ion) m / z: 426.2 [M+H] + .

[0316] 1 H NMR 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.5 Hz, 1H), 7.61 (d, J =13.7 Hz, 2H), 7.37 (s, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.95 (s, 1H), 6.29 (s,2H), 5.48 (d, J = 12.8 Hz, 1H), 5.35 (d, J = 12.3 Hz, 1H), 5.15 (s, 2H), 5.00 (s,1H), 3.59 (d, J = 64.2 Hz, 1H), 3.07 (s, 1H), 2.91 (s, 1H), 1.96 (s, 1H), 1.82– 1.70 (m, 2H), 1.57 (d, J = 6.0 Hz, 3H). Example 31: (4-Amino-3-methyl-3- H -pyrazolo[3,4- c Quinoline-8-yl)[(4aS,9bS)-7-ethynyl-3,4,4a,9b-tetrahydrobenzofuran[3,2- b ]Pyridine-1(2 HSynthesis of ]-[-]methyl ketone (compound 63)

[0317] With 4-amino-3-methyl-3 H -pyrazolo[3,4- c Using quinoline-8-carboxylic acid and intermediate M-4 as starting materials, and following the synthesis protocol of Example 23, 22 mg of a white solid was obtained, with a yield of 37.8%. LC-MS (ESI, pos. ion) m / z: 423.2 [M+H] + .

[0318] 1 H NMR (600 MHz, CDCl3) δ 8.27 (s, 1H), 8.14 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 12.5 Hz, 1H), 7.15 (d, J = 7.7 Hz,1H), 6.98 (s, 1H), 6.41 (s, 1H), 5.28 (s, 2H), 5.06 (s, 1H), 4.47 (s, 3H), 3.09 (s, 1H), 2.04 – 1.97 (m, 2H), 1.85 – 1.81 (m, 2H), 1.79 – 1.74 (m, 2H). Example 32: (4-Amino-7-chloro-3-methyl-3- H -pyrazolo[3,4- c Quinoline-8-yl)-[(4aS,9bS)-7-((1-methyl-1) H -pyrazol-4-yl)ethynyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of ]-[-]methyl ketone (compound 163)

[0319] With 4-amino-7-chloro-3-methyl-3 H -pyrazolo[3,4- c Using quinoline-8-carboxylic acid and intermediate M-3 as starting materials, and following the synthesis protocol of Example 23, 37 mg of a white solid was obtained in 42% yield. LC-MS (ESI, pos. ion) m / z: 538.1 [M+H] + .

[0320] 1 H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.91 – 7.33 (m, 5H), 7.14 –6.84 (m, 2H), 6.50 (d, J = 52.9 Hz, 1H), 5.64 (s, 2H), 5.08 – 5.00 (m, 1H), 4.42 (s, 3H), 3.92 (s, 3H), 3.26 – 2.76 (m, 2H), 1.86 – 1.55 (m, 4H). Example 33: (4-Amino-3-methyl-3- H -pyrazolo[3,4- c Quinoline-8-yl)((4aS,9bS)-7-((1-methyl-1-yl) H -pyrazol-4-yl)ethynyl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 161)

[0321] With 4-amino-3-methyl-3 H -pyrazolo[3,4- c Using quinoline-8-carboxylic acid and intermediate M-3 as starting materials, and following the synthesis protocol of Example 23, 15 mg of a white solid was obtained in 12% yield. LC-MS (ESI, pos. ion) m / z: 504.2 [M+H] + .

[0322] 1 H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.13 (s, 1H), 7.74 (d, J = 8.5Hz, 1H), 7.64 (s, 1H), 7.54 (d, J = 15.4 Hz, 2H), 7.40 (s, 1H), 7.11 (d, J = 7.9Hz, 1H), 6.93 (s, 1H), 6.36 (s, 1H), 5.27 (s, 2H), 5.04 (s, 1H), 4.45 (s,3H), 3.91 (s, 3H), 2.95 (s, 2H), 1.77 (d, J= 24.2 Hz, 4H). Example 34: Synthesis of (4-amino-7-chloro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-yl)((4aS,9bS)-7-trifluoromethyl-3,4,4a,9b-tetrahydrobenzofurano[3,2-b]pyridin-1(2H)-yl) methyl ketone (compound 16)

[0323] With 4-amino-7-chloro-3-methyl-3 H -pyrazolo[3,4- c Using quinoline-8-carboxylic acid and intermediate M-1 as starting materials, and following the synthesis protocol of Example 23, 30 mg of a white solid was obtained, with a yield of 20.7%. LC-MS (ESI, pos. ion) m / z: 502.1 [M+H] + .

[0324] Example 35: (4-amino-1-methyl-1) H -pyrazolo[4,3-c]quinoline-8-yl)((4aS, 9bS)-7-(3-morpholinoprop-1-yn-1-yl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of compound 165 (-yl) methyl ketone

[0325] With 4-amino-1-methyl-1 H -pyrazolo[4,3- c Using quinoline-8-carboxylic acid and intermediate M-5 as starting materials, and following the synthesis protocol of Example 23, 8 mg of a white solid was obtained in 15% yield. LC-MS (ESI, pos. ion) m / z: 523.2 [M+H] + .

[0326] 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.00 (s, 1H), 7.80 (d, J = 8.5Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.39 (s, 1H), 7.09 (dd, J = 7.7, 1.3 Hz, 1H), 6.93 (s, 1H), 5.43 (br, 1H), 5.04 (br, 1H), 4.50 (s, 3H), 3.79 (t, J= 4.7 Hz,4H), 3.53 (s, 2H), 2.97 (br, 1H), 2.66 (t, J = 4.6 Hz, 4H), 2.11 (br, 1H), 2.02– 1.98 (m, 2H), 1.86 – 1.83 (m, 2H). Example 36: (4-amino-7-fluoro-1,3-dihydrofurano[3,4-) c Quinolino-8-yl)-[(4aS,9bS)-7-(3-morpholinoprop-1-yn-1-yl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of ]-[-]methyl ketone (compound 187)

[0327] With 4-amino-7-fluoro-1,3-dihydro[3,4- c Using quinoline-8-carboxylic acid and intermediate M-5 as starting materials, and following the synthesis protocol of Example 23, 10 mg of a white solid was obtained, with a yield of 22.6%. LC-MS (ESI, pos. ion) m / z: 529.1 [M+H] + .

[0328] 1 H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 7.1 Hz, 1H), 7.48 – 7.32 (m, 2H), 7.08 (d, J = 7.7 Hz, 1H), 6.93 (s, 1H), 5.45 (m, J = 9.3 Hz, 2H), 5.16 (t, J = 3.5Hz, 2H), 5.09 – 4.94 (m, 3H), 3.87 – 3.65 (m, 4H), 3.52 (d, J = 12.2 Hz, 2H), 3.40 – 3.31 (m, 1H), 2.71 – 2.60 (m, 4H), 2.02 – 1.86 (m, 4H). Example 37: (4-amino-1,3-dihydrofurano[3,4-) c [1,7]Naphthid-8-yl)((4aS,9bS)-7-(3-dimethylaminoprop-1-yn-1-yl)-3,4,4a,9b-tetrahydrobenzofurano[3,2-b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 169)

[0329] With 4-amino-1,3-dihydrofurano[3,4- C Using [1,7]naphthyl-8-carboxylic acid and intermediate M-6 as starting materials, 25 mg of a white solid was obtained according to the synthesis scheme of Example 23, with a yield of 31.5%. LC-MS (ESI, pos. ion) m / z: 470.2 [M+H] + .

[0330] Example 38: (4-amino-1,3-dihydrofurano[3,4-) c [1,7]Naphthid-8-yl)((4aS,9bS)-7-(3-dimethylaminoprop-1-yn-1-yl)-3,4,4a,9b-tetrahydrobenzofurano[3,2- b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone (compound 178)

[0331] With 4-amino-1-methyl-1 H -pyrazolo[4,3- c Using quinoline-8-carboxylic acid and intermediate M-6 as starting materials, and following the synthesis protocol of Example 23, 20 mg of a white solid was obtained in 27% yield. LC-MS (ESI, pos. ion) m / z: 481.2 [M+H] + .

[0332] 1 H NMR (400 MHz, DMSO- d 6) δ 8.70 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 7.67 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.94 (s, 1H), 5.09 (s, 1H), 4.42 (s, 2H), 4.09 (s, 1H), 3.17 (s, 6H), 2.46 (s, 5H), 2.01 –1.58 (m, 4H). Example 39: (4-Amino-1-methyl-1- H -pyrazolo[4,3- c[1,8]Naphthid-8-yl)((4aS,9bS)-7-((1-cyclopropyl-1 H -pyrazol-4-yl)ethynyl)-3,4,4a,9b-tetrahydrobenzofuran[3,2-] b ]Pyridine-1(2 H Synthesis of )-yl)methyl ketone

[0333] Step 1: 4-Amino-1-methyl-1 H -pyrazolo[4,3- c Synthesis of methyl [1,8]naphthyl-8-carboxylate Under a nitrogen atmosphere, methyl 6-amino-5-bromopyridin-3-carboxylate (1 g, 4.33 mmol) and 1-methyl-5-(tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-methylpropionate were added to a 50 mL single-necked flask. H pyrazole-4-carboxynitrile (1.51 g, 6.50 mmol), potassium phosphate (1.84 g, 8.66 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.10 g, 1.30 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL). The reaction mixture was stirred at 100 °C. After the reaction was complete, 20 mL of water was added to the reaction mixture, and a solid precipitated. After filtration, the filter cake was washed with 30 mL of dichloromethane to give a yellow solid (0.55 g, yield 49.40%). LC-MS (ESI, pos. ion) m / z 258.2 [M+H] + .

[0334] Step 2: 4-Amino-1-methyl-1 H -pyrazolo[4,3- c Synthesis of [1,8]naphthyl-8-carboxylic acid Add 4-amino-1-methyl-1 ... H -pyrazolo[4,3- cMethyl naphthidine-8-carboxylate (555 mg, 2.16 mmol) and lithium hydroxide (180.03 mg, 7.52 mmol) were dissolved in a mixed solvent of water (2 mL), methanol (20 mL), and tetrahydrofuran (2 mL). The reaction mixture was then stirred at 90 °C for 3 h. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH of the reaction mixture to 4-5. Most of the solvent was then evaporated, and 20 mL of water was added. The mixture was shaken thoroughly, filtered, and dried. The filter cake was dried to give a gray solid (434 mg, yield 82.71%). LC-MS (ESI, pos. ion) m / z :244.2 [M+H] + .

[0335] Step 3: (4-Amino-1-methyl-1) H -pyrazolo[4,3- c [1,8]Naphthid-8-yl)((4a S ,9b S )-7-((1-Cyclopropyl-1 H -pyrazol-4-yl)ethynyl)-3,4,4a,9b-tetrahydrobenzofuran[3,2-b]pyridine-1(2 H Synthesis of )-yl)methyl ketone Add 4-amino-1-methyl-1 ... H -pyrazolo[4,3- c [1,8] Naphthyl-8-carboxylic acid (77.83 mg, 0.32 mmol) and HATU (91.26 mg, 0.24 mmol) were dissolved in DCM (5 mL) and DMF (1 mL), and then DIPEA (192.52 mg, 1.49 mmol) was added. The mixture was stirred at room temperature for 2 h. (4a) was added to the reaction system. S ,9b S )-7-((1-Cyclopropyl-1 H -pyrazol-4-yl)ethynyl)-1,2,3,4,4 a 9 b -hexahydrobenzofurano[3,2- b Pyridine (M-2, 50 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 22 h. After the reaction was complete, saturated sodium bicarbonate was added to quench the reaction mixture, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 5) to give a white solid (43 mg, yield 49.50%). LC-MS (ESI, pos. ion) m / z 531.2 [M+H] + ;HRMS(ESI) m / z: calcd for 530.2179,:531.2255, Found: 531.2255[M+H] + .

[0336] 1 H NMR (400 MHz, DMSO- d 6) δ 8.83 (s, 1H), 8.68 (s, 1H), 8.38 (s, 1H), 8.17 (s, 1H), 7.91 (s, 2H), 7.67 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.07 (d, J =7.4 Hz, 1H), 6.94 (s, 1H), 5.14 – 5.08 (m, 1H), 4.43 (s, 3H), 3.76 (ddd, J =11.2, 7.4, 3.9 Hz, 2H), 3.52 (s, 1H), 2.12 – 2.04 (m, 2H), 1.92 – 1.84 (m,2H), 1.65 – 1.58 (m, 1H), 1.10 – 1.04 (m, 2H), 1.02 – 0.96 (m, 2H). Example 40: (4-Amino-1-methyl-1- H -pyrazolo[4,3-c][1,8]naphthid-8-yl)((4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9btetrahydrobenzofurano[3,2-b]pyridine-1(2 H Synthesis of methyl ketone 190 Referring to the synthesis scheme of Example 39, 4-amino-1-methyl-1 H The product was obtained by condensation reaction of pyrazolo[4,3-c][1,8]naphthyl-8-carboxylic acid and (4aS,9bS)-7-(trifluoromethyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2-b]pyridine (synthetic method according to WO2025096589 A1, Example Ca-1) as starting materials. LC-MS (ESI, pos. ion) m / z 469.2 [M+H] + .

[0337] Example 41: (4-Amino-1-methyl-1- H -pyrazolo[4,3-c][1,8]naphthid-8-yl)((4aS,9bS)-7-((1-(oxecyclobutane-3-yl)-1) H Synthesis of pyrazin-4-yl)ethynyl)-3,4,4a,9b tetrahydrobenzofurano[3,2-b]pyridin-1(2H)-yl) methyl ketone 191 Referring to the synthesis scheme of Example 39, 4-amino-1-methyl-1 H The product was obtained by condensation reaction of pyrazolo[4,3-c][1,8]naphthyl-8-carboxylic acid and (4aS, 9bS)-7-((1-(oxecyclobutan-3-yl)-1H-pyrazol-4-yl)ethynyl)-1,2,3,4,4a,9b hexahydrobenzofurano[3,2-b]pyridine (synthetic method see M-1). LC-MS (ESI, pos. ion) m / z 547.2 [M+H] + .

[0338] Biological activity test cases Test Example 1: Inhibition of Cell Proliferation 1-1, Experiment A 1.1 Experimental Materials HCT116-WT cells were purchased from the ATCC Biostandard Resource Center in the United States.

[0339] HCT116-MTAP(- / -) cells are MTAP knockout HCT116 cells, independently constructed by Kanglong Pharmaceutical (Beijing) New Drug Technology Co., Ltd. based on HCT116-WT cells.

[0340] The MCCOYS 5A culture medium is from Gibco.

[0341] 1.2 Experimental Procedure 1) Cell resuscitation and culture: HCT116-WT cells and HCT116-MTAP(- / -) cells were resuscitated and cultured in MCCOYS 5A medium containing a mixture of 10% FBS and 1% penicillin and streptomycin in a saturated humidity incubator at 37°C and 5% CO2.

[0342] 2) Cell plating: After passage 2-3 times after resuscitation, when the cells enter the exponential growth phase with good growth status, collect the cells (the cell viability should be above 90%) and add 150 cells / 40 μL to each well of a 384-well plate.

[0343] 3) Compound preparation and sample loading: Dissolve the compound in DMSO to a stock solution with a concentration of 10 mM, and prepare the corresponding drug dilution: start at a total concentration of 10 μM, serially dilute 3-fold, setting 10 concentration points; additionally, set up culture medium wells and control wells containing 0.1% DMSO solvent. Transfer 40 nl of the prepared drug dilution to the above-mentioned 384-well plate containing cells, with 2 replicates, and incubate in a 37℃, 5% CO2 saturated humidity incubator for 10 days.

[0344] 4) Plate reading test: Add 40 nl of CTG (CellTiter-Glo® luminescence assay kit) to each well, incubate in the dark for 30 min, and detect the luminescence signal value on a plate reader.

[0345] 1.3 Data Processing Inhibition rate % = 100 - (Emission signal value of drug delivery wells – Average emission signal value of culture medium wells) / (Average emission signal value of solvent control wells – Average emission signal value of culture medium wells) * 100 IC 50 Value calculation method: IC is obtained by nonlinear fitting formula using Graph Pad Prism 8.0 software. 50 The value is calculated using the following formula: Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X) ×HillSlope)) Y: Inhibition rate; X: Log value of compound concentration; IC50 50 : Half-maximal inhibitory concentration.

[0346] 1.4 Experimental Results Table 2-A shows the inhibitory activity of compound A on the proliferation of HCT116 MTAP(- / -) cells and HCT116wt cells.

[0347] It is evident that the compounds of this invention exhibit good inhibitory activity against the proliferation of HCT116 MTAP(- / -) cells.

[0348] 1-2, Experiment B 1.1 Experimental Materials HCT116-WT cells were purchased from the ATCC Biostandard Resource Center in the United States.

[0349] HCT116-MTAP(- / -) cells are MTAP-knockout HCT116 cells purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0350] The RPMI1640 culture medium was sourced from Hyclone.

[0351] 1.2 Experimental Procedure 1) Cell resuscitation and culture: HCT116-WT cells and HCT116-MTAP(- / -) cells were resuscitated and cultured in RPMI1640 medium containing a mixture of 10% FBS and 1% penicillin and streptomycin in a saturated humidity incubator at 37°C and 5% CO2.

[0352] 2) Cell plating: After passage 2-3 times, when the cells enter the exponential growth phase with good growth, collect the cells (the cell viability should be above 90%) and add 200 cells / 90μL to each well of a 96-well plate.

[0353] 3) Compound preparation and sample loading: Dissolve the compound in DMSO to a stock solution with a concentration of 10 mM, and prepare the corresponding drug dilution: start at a total concentration of 10 μM, serially dilute 3-fold, setting 10 concentration points; additionally, set up culture medium wells and control wells containing 0.1% DMSO solvent. Transfer 10 μL of the prepared drug dilution to the above-mentioned 96-well plate containing cells, with 2 replicates, and incubate in a 37℃, 5% CO2 saturated humidity incubator for 10 days.

[0354] 4) Plate reading and detection: Add 100 μL of CTG (CellTiter-Glo® luminescence assay kit) to each well, incubate in the dark for 30 min, and detect the luminescence signal value on a plate reader.

[0355] 1.3 Data Processing Inhibition rate % = 100 - (Emission signal value of drug delivery wells – Average emission signal value of culture medium wells) / (Average emission signal value of solvent control wells – Average emission signal value of culture medium wells) * 100 IC 50 Value calculation method: IC is obtained by nonlinear fitting formula using Graph Pad Prism 8.0 software. 50 The value is calculated using the following formula: Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X) ×HillSlope)) Y: Inhibition rate; X: Log value of compound concentration; IC50 50 : Half-maximal inhibitory concentration.

[0356] Table 2-B shows the inhibitory activity of compounds on the proliferation of HCT116 MTAP(- / -) cells and HCT116wt cells.

[0357] It is evident that the compounds of this invention exhibit good inhibitory activity against the proliferation of HCT116 MTAP(- / -) cells.

[0358] Test Example 2: Stability in Human and Mouse Liver Microsomes 2.1 Test Instruments and Parameters 1) The LC / MS / MS system used for analysis included a Shimadzu LC~40BXR series vacuum degassing valve, a binary injection pump, an autosampler, a column oven, and an AB QTRAP5500+ mass spectrometer with an electrospray ionization (ESI) source. Quantitative analysis was performed in MRM mode, and the mass spectrometry parameters are shown in Table 3.

[0359] Table 3 Mass Spectrometry Parameters

[0360] 2) An Agilent Polaris 5 C18-A 30*2.0mm column was used for analysis. The analytical conditions were: H2O + 2 mM ammonium formate + 0.1% FA (mobile phase A) and MeOH + 2 mM ammonium formate + 0.1% FA (mobile phase B). The flow rate was 0.500 mL / min. The mobile phase gradient is shown in Table 4.

[0361] Table 4. Mobile phase gradient

[0362] 2.2 Preparation of Reagents and Solutions Microsomes were purchased from Genest (human liver microsomes NE240116000050, mouse liver microsomes: NE240116000215).

[0363] Verapamil was purchased from Aladdin. PRO was propranolol, and compound a was Ritapiram, prepared according to WO2016037591A1, with the following structure: .

[0364] 1) PRO & compound a stock solution (500 μg / mL): Take 250 μL of propranolol (4 mg / mL) and 500 μL of compound a (2 mg / mL) as internal standard stock solution, add them to 1250 μL of DMSO and mix well.

[0365] 2) Preparation of stock solutions: Weigh a certain amount of the test compound and verapamil and prepare a stock solution with a concentration of 10 mM using DMSO, and store it in a -20°C refrigerator; prepare a stock solution of deuterated internal standard with a concentration of 1 mg / mL using DMSO, store it in a -20°C refrigerator for later use, and then dilute it with acetonitrile to a certain concentration before analysis.

[0366] 3) Preparation of 0.1 M potassium dihydrogen phosphate buffer solution (pH=7.4): Weigh a certain amount of potassium dihydrogen phosphate and dissolve it in ultrapure water by sonication to a concentration of 0.1 M; weigh a certain amount of dipotassium hydrogen phosphate and dissolve it in ultrapure water by sonication to a concentration of 0.1 M; slowly add the 0.1 M potassium dihydrogen phosphate solution to the 0.1 M dipotassium hydrogen phosphate solution, and stop when the pH reaches 7.4.

[0367] 4) Preparation of the compound and verapamil working solution: 100 μM drug delivery solution: Add 5 μL of 10 mM stock solution to 495 μL of acetonitrile:water (1:1); 30 μM drug delivery solution: Add 60 μL of 100 μM drug delivery solution to 140 μL of 0.1 M potassium phosphate buffer.

[0368] 1.5 μM Dosage Solution: Add 30 µL of 30 µM dosage solution and 23.00 µL (20 mg / mL) of liver microsomes to 547.00 µL of 0.1 M potassium phosphate buffer, one solution per species.

[0369] 5) Preparation of NADPH solution: Weigh a certain amount of NADPH test sample (purchased from Bangtai Biotechnology (Shenzhen) Co., Ltd., batch number: BT04T122M003) and prepare a 6 mM NADPH solution with buffer solution.

[0370] 6) Preparation of internal standard working solution: Take 180 µL of PRO & compound a stock solution (500 μg / mL) and 0.5 L of ACN, add 0.5 L of MeOH solution, and mix well.

[0371] 2.3 Experimental Procedure 1) Preparation of working solutions: Working solution 01: Take 5 μL of the test compound or verapamil stock solution (10 mM) and add it to 495 µL of 50% ACN / H2O; Working solution 02: Take 60 µL of the test compound or verapamil working solution (100 μM) and add it to 140 µL of 0.1M potassium phosphate buffer (hereinafter referred to as buffer).

[0372] 2) Take a 96-well plate, name it according to the required testing time, and divide the plate positions accordingly; 3) Take 18.8 μL of liver microsomes (20 mg / mL) and add it to 456.2 μL of buffer. Pre-incubate the liver microsome solution and working solution O2 at 37°C for about 10 min. 4) Add 25 μL of the test compound or verapamil working solution O2 to the liver microsome solution, mix well, take out 30 μL of the mixed solution, add 150 μL of MeOH:ACN (1:1) stop solution containing internal standard, and then add 15 μL of NADPH solution (6mM) and mix well to obtain the T0 sample. 5) Take another 30 μL of the above mixed solution and transfer it to the wells of the 96-well plate at the corresponding time points. Add 15 μL of buffer to the NCF90 well and add 15 μL of NADPH solution (6 mM) to the other time points. The final reaction system contains 0.5 mg / mL liver microsomal protein and 2 mM NADPH. 6) Incubate for time and add 150 μL of MeOH:ACN (1:1) stop solution containing internal standard at 15 min, 30 min, 60 min and 90 min respectively; 7) Pretreatment: After centrifugation at 4000 rpm for 5 min, take 75+75 μL of the supernatant and add it to 100 μL of ultrapure water. Mix well and perform LC-MS / MS analysis. Some compounds were analyzed using a cassette.

[0373] 2.4 Data Processing Peak areas were determined based on the extracted ion chromatograms. The slope value k was determined through linear regression of the natural logarithm of the remaining percentage of parent drug against the incubation time curve. The in vitro half-life (in vitro t) was determined based on the slope value. 1 / 2 ):

[0374] The following equation (average value of duplicate well measurements) was used to calculate the in vitro t 1 / 2 (min) converted to in vitro intrinsic clearance rate (in vitro CLint, unit µL / min / mg protein):

[0375] Calculate CLint (mL / min / kg), predict liver CLHep (mL / min / kg), and liver extraction rate (ER) using equations: (ref.: Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.) Drug Metabolism and Disposition 2001, 29: 1316-1324.

[0376] 2.5 Experimental Results Table 5. Experimental results on the stability of the compounds of the present invention in various liver microparticles.

[0377] As shown in the table, the compounds of this invention are metabolized at a moderate level in the liver microparticles of both humans and mice.

[0378] Test Example 3: Pharmacokinetic Evaluation 3.1 Experimental Materials Male Balb / c Mouse mice were purchased from Hunan Slack.

[0379] Preparation of compound solutions: The test compound was prepared into a solution using 10% dimethyl sulfoxide (purchased from Beijing Innocare Technology Co., Ltd.), 10% Kolliphor HS15 (a powerful nonionic solubilizer and emulsifier, purchased from BASFSE) and 80% physiological saline for oral or intravenous administration.

[0380] 3.2 Experimental Procedure Male Balb / c mice weighing 25-30 g were randomly divided into two groups. One group was given the test compound intravenously at a dose of 2.0 mg / kg, and the other group was given the test compound orally at a dose of 5 mg / kg. Blood samples were collected at time points of 0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours after administration.

[0381] Establish a standard curve within an appropriate range based on the sample concentration, using AB SCIEX Q TRAP 5500. + A novel LC-MS / MS model was used to determine the concentration of the analyte in plasma samples in MRM mode. Pharmacokinetic parameters were calculated using a non-compartmental model.

[0382] 3.3 Experimental Results Table 6. Pharmacokinetics of the compounds of the present invention in mice.

[0383] The compounds of this invention exhibit good pharmacokinetic effects.

[0384] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0385] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound that is a compound of formula (I) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I). (I)， in, R 1 for , , , , , or ; L is the key; "Can be a single bond or a double bond; X1 is -O-, -S-, -S(=O)-, -SO2-, -NR Xa -or-CR Xb R Xc - and R in X1 Xb and R Xc Not both H; X2 is -S-, -S(=O)-, -SO2-, -NR Xa -or-CR Xb R Xc -; R Xa R Xb R Xc Each is independently H, D, -CN, -SF5, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; or R Xb R Xc Together with the carbon atom it is attached to, they form C 3-6 Carbon rings or 3-10 membered heterocyclic rings; Each R 2 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -OR 2a -C(=O)R 2a -OC(=O)R 2a -OC(=O)NR 2a R 2b -C(=O)OR 2a -NR 2a R 2b -C(=O)NR 2a R 2b -NR 2a C(=O)R 2b -NR 2a C(=O)OR 2b -NR 2a S(=O)2R 2b -SR 2a -SF5, -S(=O) R 2a -S(=O)2R 2a -S(=O)(=NR) 2a )R 2b or -S(=O)2NR 2a R 2b Or two R atoms bonded to the same carbon atom 2 Together with the carbon atoms bonded to them, they form =O, =S, =CR a R b Or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 2c replace; The R mentioned 2a R 2b R 2c Each is independently H, D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Ring A is C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic rings; Each R 3 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -O-(C 2-6 ynyl group), -C(=O)R 3a -OC(=O)R 3a -OC(=O)NR 3a R 3b -C(=O)OR 3a -NR 3a R 3b -C(=O)NR 3a R 3b -NR 3a C(=O)R 3b -NR 3a C(=O)OR 3b -NR 3a S(=O)2R 3b -SR 3a -SF5, -S(=O) R 3a -S(=O)2R 3a -S(=O)(=NR) 3a )R 3b or -S(=O)2NR 3a R 3b ; wherein, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 3c replace; Each R 3c Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic or C 6-10 Aryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic groups and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 3d Substitution; or two R atoms attached to the same carbon atom 3c Together with the carbon atoms bonded to them, they form =O, =S, or =CR. c R d ; Each R 3d Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic or C 6-10 Aryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic groups and C 6-10 Each aryl group is independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, halogen, -CN, -SF5, -OH, -NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; The R mentioned 3a R 3b R 3e R 3f Each is independently H, D, halogen, -CN, -SF5, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Or, two R atoms attached to the same carbon atom 3 Together with the carbon atoms bonded to them, they form =O, =S, =CR e R f C 3-6 Carbon rings or 3-10 membered heterocycles, wherein the C 3-6 The carbon ring and 3-10 membered heterocycles are each independently and optionally p R 8 Replaced; Alternatively, two R atoms connected to adjacent or non-adjacent ring atoms. 3 Together with the ring atoms attached to them, they form C 3-6 Carbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-10 quintile heterocyclic aromatic rings, wherein the C 3-6 Carbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-10 heterocyclic rings are each independently and optionally divided by p R 8 Replaced; Each R 8 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy group; or two R groups attached to the same carbon atom 8 Together with the carbon atom it is bonded to, it forms =O, =S, or =CR. g R h ; R 4 R 5 R 6 R 7 Each is independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or -NR i R j ; Y1 is N or CR Ya Y2 is N or CR Yb Y3 is N or CR Yc Y4 is N or CR Yd Y5 is N or CR Ye ;R Ya R Yb R Yc R Yd R Ye Each is independently H, D, -CN, halogen, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 1-6 alkylene-O-(C 1-6 Alkyl), -C(=O)NR n R m Or C 1-6 Halogenated alkoxy groups; Y6 is N, C, or CR Yf Y7 is N, C or CR Yg Ring B is C 3-6 Carbon rings, 5-membered heterocyclic rings, 5-10-membered heteroaromatic rings, or C 6-10 Aromatic rings, wherein each ring B is independently and optionally divided by q R 9 Replaced; R Yf R Yg Each is independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups; Each R 9 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkyl group; or two R atoms attached to adjacent or non-adjacent ring atoms. 9 Together with the ring atoms attached to them, they form C 3-6 Cycloalkyl or 3-10 membered heterocyclic groups; or two R groups attached to the same carbon atom 9 Together with the carbon atom it is bonded to, it forms =O or =S; The conditions are: (1) R 1 Not for , or Structure; or, when R 1 for or When the structure is defined, equation (I) is: , or ; (2) When equation (I) is , , , or And R 1 for , , or R Ya When R is H, Cl or F, 3 Not -CF3 or ; Z1 is N or CR Za Z2 is N or CR Zb Z3 is N or CR Zc ;R Za R Zb R Zc Each is independently H, D, -CN, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Hydroxyalkyl; Z4 is N, C, or CR. Zd Z5 is N, C or CR Ze ; Ring C is C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic rings, wherein each of the rings C is independently and optionally divided by s R 10 Replace; R Zd R Ze Each is independently H, D, halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups; Each R 10 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy group; or two R groups attached to the same carbon atom 10 Together with the carbon atom it is bonded to, it forms =O or =S; W1 is N or CR Wa W2 is N or CR Wb ; R Wa R Wb Each is independently H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or R Wa R Wb Together with the ring atoms they are connected to, they form C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic ring, the C 3-6 Carbon rings, 3-10 membered heterocycles, 5-10 membered heteroaromatic rings and C 6-10 The aromatic rings are each independently and arbitrarily assigned to t R. 11 Replaced; Each R 11 Each is independently D, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy group; or two R groups attached to the same carbon atom 11 Together with the carbon atom it is bonded to, it forms =O or =S; Each R a R b R c R d R e R f R g R h R i R j R n and R m Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n, m, p, q, s, and t are each independently 0, 1, 2, 3, 4, 5, or 6.

2. The compound according to claim 1, wherein, Y1 is N or CR Ya Y2 is N or CR Yb Y3 is N or CR Yc Y4 is N or CR Yd Y5 is N or CR Ye ;R Ya R Yb R Yc R Yd R Ye Each is independently H, D, -CN, halogen, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -C 1-4 alkylene-O-(C 1-4 Alkyl), -C(=O)NR n R m Or C 1-4 Halogenated alkoxy groups; Y6 is N, C, or CR Yf Y7 is N, C or CR Yg Ring B is C 3-6 Carbon rings, 5-membered heterocycles, 5-6-membered heteroaromatic rings, or benzene rings, wherein each ring B is optionally and independently divided by q R. 9 Replaced; R Yf R Yg Each is independently H, D, halogen, -CN, C 1-4 Alkyl, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkyl groups; Each R 9 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Alkyl group; or two R atoms attached to adjacent or non-adjacent ring atoms. 9 Together with the ring atoms attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; or two R groups attached to the same carbon atom 9 Together with the carbon atom it is bonded to, it forms =O or =S; The conditions are: (1) R 1 Not for , or Structure; or, when R 1 for or When the structure is defined, equation (I) is: , or ; (2) When equation (I) is , , , or And R 1 for , , or R Ya When R is H, Cl or F, 3 Not -CF3 or ; Z1 is N or CR Za Z2 is N or CR Zb Z3 is N or CR Zc ;R Za R Zb R Zc Each is independently H, D, -CN, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Hydroxyalkyl; Z4 is N, C, or CR. Zd Z5 is N, C or CR Ze ; Ring C is C 3-6 Carbon rings, 3-6 membered heterocycles, 5-6 membered heteroaromatic rings, or benzene rings, wherein each of the ring Cs is optionally and independently divided by s Rs. 10 Replace; R Zd R Ze Each is independently H, D, halogen, -CN, hydroxyl, C 1-4 Alkyl, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkyl groups; Each R 10 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 alkoxy group; or two R groups attached to the same carbon atom 10 Together with the carbon atom it is bonded to, it forms =O or =S; W1 is N or CR Wa W2 is N or CR Wb ; R Wa R Wb Each is independently H, D, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or R Wa R Wb Together with the ring atoms they are connected to, they form C 3-6 Carbocyclic rings, 3-6 membered heterocyclic rings, 5-6 membered heteroaromatic rings, or benzene rings, wherein the C 3-6 The carbon ring, 3-6 membered heterocycles, 5-6 membered heteroaromatic rings, and benzene ring are each independently and optionally divided by t R 11 Replaced; Each R 11 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 alkoxy group; or two R groups attached to the same carbon atom 11 Together with the carbon atom it is attached to, it forms =O or =S.

3. The compound according to claim 1 or 2, wherein, Y1 is N or CR Ya Y2 is N or CR Yb Y3 is N or CR Yc Y4 is N or CR Yd Y5 is N or CR Ye ;R Ya R Yb R Yc R Yd R Ye Each of the following is independently H, D, -CN, F, Cl, Br, I, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2, (CH2)4OH , -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2F, -OCF3, -OCHF2, -CH2OCH3, -(CH2)2OCH3, -CH2OCH2CH3, -CH2O(CH2)2CH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3)2; Y6 is N, C, or CR Yf Y7 is N, C or CR Yg Cycle B is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiacyclopentane, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, 1,3,5-triazine, or benzene, wherein each of the cyclic B is optionally and independently divided by q R 9 Replaced; R Yf R Yg Each can be independently H, D, F, Cl, Br, I, -CN, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2 or (CH2)4OH; Each R 9 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to adjacent or non-adjacent ring atoms. 9 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiaran; or two R atoms bonded to the same carbon atom. 9 Together with the carbon atom it is bonded to, it forms =O or =S; The conditions are: (1) R 1 Not for , or Structure; or, when R 1 for or When the structure is defined, equation (I) is: , or ; (2) When equation (I) is , or , or And R 1 for , , or R Ya When R is H, Cl or F, 3 Not -CF3 or ; Z1 is N or CR Za Z2 is N or CR Zb Z3 is N or CR Zc ;R Za R Zb R Zc Each can be independently H, D, -CN, hydroxyl, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2 or (CH2)4OH; Z4 is N, C, or CR. Zd Z5 is N, C or CR Ze ; Cyclic C atoms include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, and 2... H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, thiazide, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, 1,3,5-triazine, or benzene, wherein each of the ring Cs is optionally and independently divided by s Rs. 10 Replace; R Zd R Ze Each can be independently H, D, F, Cl, Br, I, -CN, hydroxyl, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH(OH)CH3, -C(OH)(CH3)2 or (CH2)4OH; Each R 10 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to the same carbon atom. 10 Together with the carbon atom it is bonded to, it forms =O or =S; W1 is N or CR Wa W2 is N or CR Wb ; R Wa R Wb Each independently represents H, D, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br or -(CH2)2Cl; or R Wa R Wb Together with the ring atoms they are attached to, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, Tetrahydrothiaran, Piperidine, Morpholine, Thiomorpholine, Piperazine, Dioxane, Dithiaran, Thioxane, Furan, Imidazole, Isoxazole, Oxazole, Pyrrole, Pyridine, Pyrimidine, Pyridazine, Thiazole, Tetrazol, Triazole, Thiophene, Pyrazole, Isothiazole, 1,2,3-Oxadiazole, 1,2,5-Oxadiazole, 1,2,4-Oxadiazole, 1,2,3-Triazole, 1,2,3-Thiodiazole, 1,3,4-Thiodiazole, 1,2,5-Thiodiazole Pyrazine, 1,3,5-triazine, or benzene, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, thiazide, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazine, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, 1,3,5-triazine, or benzene are each independently and optionally t R 11 Replaced; Each R 11 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, or -OCH(CH3)2; or two R atoms attached to the same carbon atom. 11 Together with the carbon atom it is attached to, it forms =O or =S.

4. The compound according to any one of claims 1-3, wherein, R 1 Choose from any of the following structures: , , , , , , , , , , , , , , , , , , , , , , or ; Among them, R 4 R 5 R 6 R 7 R 9 R 10 R 11 R Zc R Ya R Yc R Ye Each has the definition as described in any one of claims 1-3 above, R 9a With R 9 Same definition.

5. The compound according to any one of claims 1-4, wherein, X1 is -O-, -S-, -S(=O)-, -SO2-, -NR Xa -or-CR Xb R Xc - and R in X1 Xb and R Xc Not both H; X2 is -S-, -S(=O)-, -SO2-, -NR Xa -or-CR Xb R Xc -; R Xa R Xb R Xc Each is independently H, D, -CN, -SF5, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; or R Xb R Xc Together with the carbon atom it is attached to, they form C 3-6 Carbon rings or 3-6 membered heterocycles; Each R 2 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl, -OR 2a -C(=O)R 2a -OC(=O)R 2a -OC(=O)NR 2a R 2b -C(=O)OR 2a -NR 2a R 2b -C(=O)NR 2a R 2b -NR 2a C(=O)R 2b -NR 2a C(=O)OR 2b -NR 2a S(=O)2R 2b -SR 2a -SF5, -S(=O) R 2a -S(=O)2R 2a -S(=O)(=NR) 2a )R 2b or -S(=O)2NR 2a R 2b Or two R atoms bonded to the same carbon atom 2 Together with the carbon atoms bonded to them, they form =O, =S, =CR a R b Or C 3-6 cycloalkyl; wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, and benzenecycloyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 2c replace; The R mentioned 2a R 2b R 2c Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; Ring A is C 3-6 Carbocyclic rings, 3-10 membered heterocyclic rings, 5-10 membered heteroaromatic rings, or C 6-10 Aromatic rings; Each R 3 Each is independently D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl, -O-(C 2-4 ynyl group), -C(=O)R 3a -OC(=O)R 3a -OC(=O)NR 3a R 3b -C(=O)OR 3a -NR 3a R 3b -C(=O)NR 3a R 3b -NR 3a C(=O)R 3b -NR 3a C(=O)OR 3b -NR 3a S(=O)2R 3b -SR 3a -SF5, -S(=O) R 3a -S(=O)2R 3a -S(=O)(=NR) 3a )R 3b or -S(=O)2NR 3a R 3b ; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each optionally surrounded by 1, 2, 3, or 4 R groups. 3c replace; Each R 3c Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or phenyl, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 The cycloalkyl group, the 3-6 membered heterocyclic group, and the phenyl group are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 3d Substitution; or two R atoms attached to the same carbon atom 3c Together with the carbon atoms bonded to them, they form =O, =S, or =CR. c R d ; Each R 3d Each can be independently represented as D, halogen, -CN, -SF5, -OH, -NO2, or -NR. 3e R 3f C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or phenyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, C 3-6 The cycloalkyl group, the 3-6 membered heterocyclic group, and the phenyl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, halogen, -CN, -SF5, -OH, -NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; The R mentioned 3a R 3b R 3e R 3f Each is independently H, D, halogen, -CN, -SF5, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups; Or, two R atoms attached to the same carbon atom 3 Together with the carbon atoms bonded to them, they form =O, =S, =CR e R f C 3-6 Carbon rings or 3-6 membered heterocycles, wherein the C 3-6 The carbon ring and the 3-6 membered heterocycles are each independently and optionally divided by p R 8 Replaced; Alternatively, two R atoms connected to adjacent or non-adjacent ring atoms. 3 Together with the ring atoms attached to them, they form C 3-6 Carbocyclic rings, 3-6 membered heterocyclic rings, benzene, or 5-6 membered heteroaromatic rings, wherein the C 3-6 The carbon ring, 3-6 membered heterocycles, benzene, and 5-6 membered heteroaromatic rings are each independently and optionally p-R 8 Replaced; Each R 8 Each is independently H, D, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 alkoxy group; or two R groups attached to the same carbon atom 8 Together with the carbon atom it is bonded to, it forms =O, =S, or =CR. g R h .

6. The compound according to any one of claims 1-5, wherein, Ring A is , , , , , , or That is, equation (I) can be specifically represented by the following structure: (III-1) (III-2) (III-3) (III-4) (III-5) (III-6) (III-7) or (III-8); Each R 3 Each of these can be independently represented as D, F, Cl, Br, I, -CN, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2) 2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C ≡C(CH3), -OC≡CH, -OC≡C(CH3), -OC≡CCH2CH3, -O-CH2C≡CH, -O-CH2C≡C(CH3), SF5, -C(=O) CH3, -OC(=O) CH3, -OC(=O)NH2, -OC(=O)NHCH3, -NH2, -C(=O)NCH3, -S(=O)2CH3, -SCH3, -SCH2CH3, -SCH(CH3)2, -SCF3, -SCH2F, -SCHF2, -SCHCl2, -SCH2CF3, -SCH2CHCl2, -SCH2CHF2 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiocyclobutyl, pyrrolidine, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N -pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl or phenyl; wherein, the -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH =CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OC≡CH, - OC≡C(CH3), -OC≡CCH2CH3, -O-CH2C≡CH, -O-CH2C≡C(CH3), -C(=O)CH3, -OC(=O) CH3, -OC(=O)NH2, -OC(=O)NHCH3, -NH2, -C(=O)NCH3, -S(=O)2CH3, -SCH3, -SCH2CH3, -SCH(CH3)2, -SCH2F, -SCHF2, -SCHCl2, -SCH2CF3, -SCH2CHCl2, -SCH2CHF2 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiocyclobutyl, pyrrolidine, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophene, 3-thiophene, pyrazole (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, and phenyl are each independently and optionally surrounded by 1, 2, 3, or 4 R's. 3c replace; Each R 3c Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -SF5, -OH, -NO2, -NR 3e R 3f , -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, -OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N -pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl, 4-pyridyl), 4-pyridyl, ... -pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl or phenyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, -OCH( CH3)2, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Ethylene oxide, Azacyclobutyl, Oxacyclobutyl, Thiocyclobutyl, Pyrrolyl, 2-Pyrrololinyl, 3-Pyrrololinyl, Pyrazolinyl, Pyrazolyl, Imidazolinyl, Imidazolyl, Tetrahydrofuranyl, Dihydrofuranyl, Tetrahydrothiophenyl, Dihydrothiophenyl, 1,3-Dioxocyclopentyl, Dithiocyclopentyl, Tetrahydropyranyl, Dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N -pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl, 4-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, and phenyl are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 3d Substitution; or two R atoms attached to the same carbon atom 3c Together with the carbon atoms attached to them, they form =O, =S, =CH2, =CHCH3, =CHCH2F, =CHCHF2, =CH(CH2)2CH3 or =CH(CH2)2CH2F; Each R 3d Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -SF5, -OH, -NO2, -NR 3e R 3f -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, spiropentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, dihydrothiophene, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N -pyrrole, 2-pyrrole, 3-pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophene, 3-thiophene, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl or benzene The groups mentioned include -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, spiropentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexane, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, dihydrothiophene, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, 2-furanyl, 3-furanyl N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, and phenyl The self can be independently and optionally replaced by 1, 2, 3 or 4 D, F, Cl, Br, I, -CN, -SF5, -OH, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2 or the other two. The R mentioned 3a R 3b R 3e R 3f Each can be independently H, D, halogen, -CN, -SF5, -NO2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C≡C(CH3), -C≡CCH2CH3, -CH2C≡CH, -CH2C≡C(CH3), -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F or -OCH2CHF2; Or two R atoms attached to the same carbon atom 3 Together with the carbon atoms they are attached to, they form =O, =S, =CH2, =CHCH3, =CHCH2F, =CHCHF2, =CH(CH2)2CH 3、 =CH(CH2)2CH2F, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiaran; wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxaziridine, thioaziridine, pyrrolidine, pyrrolidine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally p-R 8 Replaced; Or two R atoms connected to adjacent or non-adjacent ring atoms 3 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, azacyclobutane, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, Tetrahydrothiaran, Piperidine, Morpholine, Thiomorpholine, Piperazine, Dioxane, Dithiazide, Thioxane, Benzene, Furan, Imidazole, Isoxazole, Oxazole, Pyrrole, Pyridine, Pyrimidine, Pyridazine, Thiazole, Tetrazol, Triazole, Thiophene, Pyrazole, Isothiazole, 1,2,3-Oxadiazole, 1,2,5-Oxadiazole, 1,2,4-Oxadiazole, 1,2,3-Triazole, 1,2,3-Thiodiazole, 1,3,4-Thiodiazole, 1,2,5-Thiodiazole Azole, pyrazine, or 1,3,5-triazine; cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrolidine, pyrrololine, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxacyclopentane, 1,2-dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, thiazide, benzene, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazine, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,3-thiodiazole, 1,3,4-thiodiazole, 1,2,5-thiodiazole, pyrazine, and 1,3,5-triazine are each independently and optionally pR 8 Replaced; Optionally, two R atoms connected to adjacent or non-adjacent ring atoms 3 Formed together with ring A or .

7. The compound according to any one of claims 1-6, R 4 R 5 R 6 R 7 Each is independently H, D, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or -NH2; preferably, R 4 R 5 R 6 R 7 Each can be independently H, D, F, Cl, Br, I, -CN, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl or -NH2.

8. The compound according to any one of claims 1-7, wherein it is a compound of formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound of formula (II). (II) in, Ring A, L, X1, X2, R 1 R 2 R 3 , n, and m each have the definition as described in any one of claims 1-7 above.

9. The compound according to any one of claims 1-8, wherein it is a compound represented by formula (IV-1), (IV-2), (VI), (VI-1), or (VI-2), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound represented by formula (IV-1), (IV-2), (VI), (VI-1), or (VI-2). , , , or ; in, Ring A, Ring B, Ring C, X1, X2, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Z1, Z2, Z3, Z4, Z5, W1, W2, R 1 R 2 R 3 R 4 R 5 R 6 R 7 , n, and m each have the definition as described in any one of claims 1-8 above.

10. The compound according to any one of claims 1-9, comprising a structure or stereoisomer thereof, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug, which are any of the following: 。 11. A pharmaceutical composition comprising the compound of any one of claims 1-10 or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug; optionally, further comprising a pharmaceutically acceptable carrier.

12. Use of the compound according to any one of claims 1-10 or the pharmaceutical composition according to claim 11 in the preparation of a medicament, wherein, The aforementioned medicine is used to protect against, treat, cure, or alleviate cancer in patients.

13. The use according to claim 12, wherein, The cancers mentioned are MTAP deficiency-related cancers; optionally, the MTAP deficiency-related cancers are ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

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