GPR52 agonist and pharmaceutical use thereof

Abstract

A GPR52 agonist and a pharmaceutical use thereof, specifically relating to a compound represented by general formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, an intermediate thereof, a preparation method therefor, and a use thereof in the preparation of a drug for treating mental disorders.

Description

GPR52 agonists and their use in medicine TECHNICAL FIELD

[0001] The present application relates to a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt thereof, and intermediates and processes for preparing the same, and use in the manufacture of a medicament for treating or alleviating a mental disorder. BACKGROUND

[0002] G protein-coupled receptor 52 (GPR52) is an orphan receptor expressed in the cerebral cortex, striatum, and nucleus accumbens. GPR52 can inhibit dopamine D2 receptor signaling and activate dopamine D1 / N-methyl-D-aspartate (NMDA) receptors, so GPR52 agonists are expected to be a new type of antipsychotic drug for treating diseases such as schizophrenia.

[0003] Currently, no GPR52 agonist has been approved for marketing, so it is necessary to develop new GPR52 agonists for treating mental disorders such as schizophrenia. SUMMARY

[0004] The purpose of the present application is to provide a class of GPR52 agonists that can effectively reduce side effects, have good GPR52 agonist effects, oral bioavailability, good brain entry ability, and can efficiently cross the blood-brain barrier, and have weak inhibition on CYP, hERG and SLC transporters.

[0005] The present application provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt thereof,

[0006] In some embodiments, the compound of general formula (I) is selected from a compound of general formula (Ia), (Ib), (Ic), (Id), (Ib-1), (Ib-2), (Ib-3), (Ih), (Ii), (Ij) or (Ik),

[0007] In some embodiments, the compound of general formula (I) is selected from a compound of general formula (Ia-1), (Ia-2), (Ie), (If), (Ig),

[0008] In some embodiments, the compound of general formula (I) is selected from a compound of general formula (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ih-5), (Ih-6), (Ih-7),

[0009] In some embodiments, T' is selected from N, CH, CR t or CR t6 ;

[0010] In some embodiments, V' is selected from N, CH, CR v or CR v6 ;

[0011] In some embodiments, T' is selected from N, CH, CR t ;

[0012] In some embodiments, V' is selected from N, CH, CR v ;

[0013] In some embodiments, R L1 ' is selected from R L1 or R L1 ' and R t6 or R v6 form a 4- to 6-membered carbocyclyl, which carbocyclyl is optionally substituted with 1 to 4 R k ; and when R L1 ' and R t6 form a 4- to 6-membered carbocyclyl, one of the three T is selected from N, and the other two T are selected from CH or CR t ;

[0014] In some embodiments, R L1 ' is selected from R L1 ;

[0015] In some embodiments, ring A is selected from ring Al or ring A2;

[0016] In some embodiments, ring Al is selected from

[0017] In some embodiments, ring Al is selected from

[0018] In some embodiments, ring A2 is selected from -8- to 10-membered heteroaryl-R a4 , -5-membered heteroaryl-R a4 , which 5-membered heteroaryl is connected to ring B through a carbon atom, which heteroaryl is optionally substituted with 1 to 4 R A ;

[0019] In some embodiments, when ring A2 is selected from , RA may form a C 3-8 carbocycle or 5- to 8-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 5 R k substituents;

[0020] In some embodiments, ring A2is selected from - benzothiophenyl-R a4 , pyridopyrrolyl-R a4 , pyrimidopyrrolyl-R a4 , - thiophenyl-R a4 , - furanyl-R a4 , the pyridopyrrolyl, pyrimidopyrrolyl, thiophenyl, furanyl is optionally substituted with 1 to 4 R A substituents;

[0021] In some embodiments, when ring A2is selected from , the R A on the two adjacent C atoms can form a C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl, which cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with 1 to 4 R k substituents;

[0022] In some embodiments, ring A2is selected from the is optionally substituted with 1 to 4 R A substituents;

[0023] In some embodiments, when ring A2is selected from , the R A on the two adjacent C atoms can form a C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, which cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with 1 to 4 R k substituents;

[0024] In some embodiments, ring A2is selected from the is optionally substituted with 1 to 4 R A substituents;

[0025] In some embodiments, when ring A2is selected from , the R A on the two adjacent C atoms can form a C 3-6cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 6-membered heteroaryl, said cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl being optionally substituted with 1 to 4 R k substituted;

[0026] In some embodiments, W is selected from -C 1-3 alkylene-, -NH-C 1-2 alkylene-, -C 1-2 alkylene-NH-, -C 1-2 alkylene-NH-C 1-2 alkylene-, -CH=N-, -N=CH-, said alkylene being optionally substituted with 1 to 5 R k substituted;

[0027] In some embodiments, W is selected from -CH2-CH2-, -C(O)NH-CH2-, -N=CH-, -CH2-, said W being optionally substituted with 1 to 4 R k substituted;

[0028] In some embodiments, R a1 is selected from -C(=O)NR aa1 R aa2 , -C(=O)R aa1 , -C(=S)NR aa1 R aa2 ;

[0029] In some embodiments, R a1 is selected from -C(=O)NH2, -C(=O)CH3, -C(=O)H, -C(=S)NH2;

[0030] In some embodiments, X is selected from CR x ;

[0031] In some embodiments, Y is selected from N or CR y ;

[0032] In some embodiments, Y is selected from N;

[0033] In some embodiments, X is selected from N, Y is selected from N;

[0034] In some embodiments, Z is selected from CR z ;

[0035] In some embodiments, R x is selected from C 1-6 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl, or heterocycloalkyl being optionally substituted with 1 to 5 Rk substituted;

[0036] In some embodiments, R x is selected from C 1-4 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl, or heterocycloalkyl optionally substituted with 1 to 4 R k substituted;

[0037] In some embodiments, R x is selected from R x is selected from C 1-4 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, said alkylene, alkyl optionally substituted with 1 to 4 R k substituted;

[0038] In some embodiments, R x is selected from methyl, ethyl, propyl, isopropyl, methoxymethyl, said methylene, methyl, ethyl, propyl, isopropyl, methoxymethyl optionally substituted with 1 to 4 R k substituted;

[0039] In some embodiments, R x is selected from

[0040] In some embodiments, R y is selected from H, halogen, CN, C 1-6 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl, or heterocycloalkyl optionally substituted with 1 to 5 R k substituted;

[0041] In some embodiments, R z is selected from -C 1-2 alkylene-C 3-7 cycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -NHC 2-6 alkenyl, -NHC 2-6 alkynyl, -C 1-2 alkylene-NH2, -C 1-2 alkylene-NH-C 1-6 alkyl, -C 1-2alkylene-NH-C(O)R aa1 , -C 1-2 alkylene-N(C 1-6 alkyl)2, -C 1-2 alkylene-NH-C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C=NR aa1 , said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 5 R k ;

[0042] In some embodiments, R z is selected from -C 1-2 alkylene-C 3-6 ycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 1-4 haloalkyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -NHC 2-4 alkenyl, -NHC 2-4 alkynyl, -C 1-2 alkylene-NH2, -C 1-2 alkylene-NH-C 1-4 alkyl, -C 1-2 alkylene-NH-C(O)R aa1 , -C 1-2 alkylene-N(C 1-4 alkyl)2, -C 1-2 alkylene-NH-C 3-6 ycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C=NR aa1 , said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 4 R k ;

[0043] In some embodiments, R z is selected from -C 1-2 alkylene-C 3-6 ycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 1-4 haloalkyl, -N(C 1-4 alkyl)2, -NHC 1-4 alkyl, -C 1-2 alkylene-NH2, -C 1-2 alkylene-NH-C 1-4 alkyl, -C 1-2 alkylene-NH-C(O)R aa1 , -C 1-2alkylene-N(C 1-4 alkyl)2, -C 1-2 alkylene-NH-C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C=NR aa1 , said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 4 R k ;

[0044] In some embodiments, R z is selected from -CH2F, -CHF2, -CF3, said R z is optionally substituted with 1 to 4 R k ;

[0045] In some embodiments, R z is selected from

[0046] In some embodiments, R AA is selected from -C 1-2 alkylene-C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, said alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 5 R k ;

[0047] In some embodiments, R AA is selected from -C 1-2 alkylene-C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, said alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 5 R k ;

[0048] In some embodiments, R AA is selected from said being optionally substituted with 1 to 4 R k ;

[0049] In some embodiments,

[0050] In some embodiments, R a3 is selected from -S(=O)2NR aa1 R aa2 , -S(=O)(=N)NR aa1R aa2 , -NR aa1 S(=O)2R aa2 , -NR aa1 C(=O)R aa2 , -S(=O)2R aa2 , -C(=O)NH-C(=NR aa3 )NR aa1 R aa2 , -C(=NR aa3 )NR aa1 R aa2 , -NR aa1 C(=O)NR aa1 R aa2 , -C(=S)NR aa1 R aa2 , -C(=O)NR aa1 -C 1-4 alkylene-C 3-7 cycloalkyl, -C(=O)NR aa1 -C 1-4 alkylene-4- to 7-membered heterocycloalkyl, -C(=O)NR aa1 -C 1-4 alkylene-O-C 3-7 cycloalkyl, -C(=O)NR aa1 -C 1-4 alkylene-O-4- to 7-membered heterocycloalkyl, said alkylene, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 3 R k ;

[0051] In some embodiments, R a3 is selected from -S(=O)2NR aa1 R aa2 -S(=O)(=N)NR aa1 R aa2 -NR aa1 S(=O)2R aa2 -NR aa1 C(=O)R aa2 -S(=O)2R aa2 -C(=O)NH-C(=NR aa3 )NR aa1 R aa2 -C(=NR aa3 )NR aa1 R aa2 -NR aa1 C(=O)NR aa1 R aa2 -C(=S)NRaa1 R aa2 -C(=O)NR aa1 -C 1-2 alkylene-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-4- to 7-membered heterocycloalkyl, said alkylene, cycloalkyl, heterocycloalkyl are optionally substituted with 1 to 3 R k substituents;

[0052] In some embodiments, R a3 is selected from -S(=O)2NR aa1 R aa2 , -NR aa1 S(=O)2R aa2 , -NR aa1 C(=O)R aa2 , -S(=O)2R aa2 , -C(=NR aa3 )NR aa1 R aa2 , -NR aa1 C(=O)NR aa1 R aa2 , -C(=S)NR aa1 R aa2 , -C(=O)NR aa1 -C 1-2 alkylene-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-4- to 7-membered heterocycloalkyl, said alkylene, cycloalkyl, heterocycloalkyl are optionally substituted with 1 to 2 R k substituents;

[0053] In some embodiments, R a3 is selected from -S(=O)2NH2, The Choose 1 to 2 Rs k replace;

[0054] In some implementation schemes, R a3 Selected from -S(=O)2NH2;

[0055] In some implementation schemes, R a4 Selected from -C(=O)NR aa1 R aa2 Or R a3 ;

[0056] In some implementation schemes, R a4 Selected from -C(=O)NH2;

[0057] In some implementation schemes, R aa1 R aa2 Each is independently selected from H and C. 1-6 Alkyl, C 1-2 Alkylene-OC 1-4 Alkyl, C 3-7 Cycloalkyl, 4- to 7-membered heterocyclic alkyl, wherein the alkyl, alkylene, carbocyclic, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 5 R... k replace;

[0058] In some implementation schemes, R aa1 R aa2 Each is independently selected from H and C. 1-4 Alkyl, C 1-2 Alkylene-OC 1-4 Alkyl, C 3-7 Cycloalkyl, 4- to 7-membered heterocyclic alkyl, wherein the alkyl, alkylene, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace;

[0059] In some implementation schemes, R aa1 R aa2 Each is independently selected from H and C. 1-4 Alkyl, C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl, or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace;

[0060] In some implementation schemes, R aa1 R aa2each independently selected from H, deuterium, halogen, CN, -C(=0)OH, NH2, -NHC(=0)Raa, -NHC(=0)ORaa, -NHS(=0)2Raa, -OC(=0)Raa, -OC(=0)NR11Rpp, -OC(=0)ORaa, -SRaa, -S(=0)Raa, -S(=0)2Raa, -S(=0)2NR11Rpp, -NR11Rpp, -NRbbORcc, -NRbbC(=0)Rcc, -NRbbC(=O)ORcc, -NRbbC(=0)NR11Rpp, -NRbbS(=0)2Rcc, -NRbbS(=0)2NR11Rpp, -NRbbP(=0)H2Rcc, -PRbbH2, -P(=0)H2, -P(=0)(OH)2, -P(=0)(ORaa)2, -P(=0)(NR11Rpp)2, -P(=0)(NRbbORcc)(ORcc), -P(=0)(NRbbORcc)(NR11Rpp), and -P(=0)(ORcc)(ORcc); or k substituted;

[0061] In some embodiments, R aa3 is selected from H, CN, OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl, or heterocycloalkyl optionally substituted with 1 to 4 R k substituted;

[0062] In some embodiments, R aa3 is selected from H, CN, OH, C 1-4 alkyl, -O-C 1-4 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl, or heterocycloalkyl optionally substituted with 1 to 4 R k substituted;

[0063] In some embodiments, R aa3 is selected from H, CN, OH, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, said methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl optionally substituted with 1 to 4 R k substituted

[0064] In some embodiments, R A each independently selected from H, deuterium, halogen, CN, -C(=0)OH, NH2, -NHC(=0)Raa, -NHC(=0)ORaa, -NHS(=0)2Raa, -OC(=0)Raa, -OC(=0)NR11Rpp, -OC(=0)ORaa, -SRaa, -S(=0)Raa, -S(=0)2Raa, -S(=0)2NR11Rpp, -NR11Rpp, -NRbbORcc, -NRbbC(=0)Rcc, -NRbbC(=O)ORcc, -NRbbC(=0)NR11Rpp, -NRbbS(=0)2Rcc, -NRbbS(=0)2NR11Rpp, -NRbbP(=0)H2Rcc, -PRbbH2, -P(=0)H2, -P(=0)(OH)2, -P(=0)(ORaa)2, -P(=0)(NR11Rpp)2, -P(=0)(NRbbORcc)(ORcc), -P(=0)(NRbbORcc)(NR11Rpp), and -P(=0)(ORcc)(ORcc); or 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-7 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl optionally substituted with 1 to 5 R k substituted;

[0065] In some embodiments, R A each independently selected from H, deuterium, halogen, CN, -C(=0)OH, NH2, -NHC1-4 alkyl, -N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl optionally substituted with 1 to 4 R k substituents;

[0066] In some embodiments, R A each is independently selected from H, deuterium, halogen, CN, -C(=O)OH, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -OC 1-4 alkyl, -C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, said alkyl optionally substituted with 1 to 4 R k substituents;

[0067] In some embodiments, R A each is independently selected from F, Cl, Br, I, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl optionally substituted with 1 to 4 R k substituents;

[0068] In some embodiments, R A each is independently selected from F, Cl, Br, I, CN, methyl, ethyl, -CH2F, -CHF2, -CF3, methoxy, cyclopropyl,

[0069] In some embodiments, ring B is selected from ring B1or ring B2;

[0070] In some embodiments, ring B1is selected from one end is connected to ring A, the other end is connected to L;

[0071] In some embodiments, T is selected from N or CR t ;

[0072] In some embodiments, ring B1is selected from one end is connected to ring A, the other end is connected to L;

[0073] In some embodiments, ring B1is selected from *is connected to ring A and the other end is connected to L;

[0074] In some embodiments, R t each independently is selected from H, deuterium, halogen, OH, CN, or C 1-6 alkyl optionally substituted with 1 to 6 F;

[0075] In some embodiments, R t each independently is selected from H, deuterium, halogen, OH, CN, or C 1-4 alkyl optionally substituted with 1 to 6 F;

[0076] In some embodiments, R t each independently is selected from H, deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl optionally substituted with 1 to 6 F; in some embodiments, ring B2is selected from 5-membered heteroaryl, *is connected to ring A and the other end is connected to L, ring B2is optionally substituted with 1 to 3 R b2 ;

[0077] R t1 and R t2 are directly connected to form a C 3-8 carbocycle or 5- to 8-membered heterocycle optionally substituted with 1 to 5 R k ;

[0078] R t3 and R L1 are directly connected to form a C 3-8 carbocycle or 5- to 8-membered heterocycle optionally substituted with 1 to 5 R k ;

[0079] R t4 and R x are directly connected to form a C 5-10 carbocycle or 5- to 10-membered heterocycle optionally substituted with 1 to 5 R k ;

[0080] R t5 and R L1 are directly connected to form a C 3-8 carbocycle or 5- to 8-membered heterocycle optionally substituted with 1 to 5 R k ;

[0081] In some embodiments, ring B2is selected from thienyl, thiazolyl, imidazolyl, pyrazolyl, *is connected to ring A and the other end is connected to L, ring B2is optionally substituted with 1 to 3 Rb2 substituted;

[0082] R t1 and R t2 directly connected to form a C 4-6 carbocycle or 5- to 6-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituted;

[0083] R t3 and R L1 directly connected to form a C 4-6 carbocycle or 5- to 6-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituted;

[0084] R t4 and R x directly connected to form a C 5-8 carbocycle or 5- to 8-membered heterocycle, which heterocycle is optionally substituted with 1 to 4 R k substituted;

[0085] R t5 and R L1 directly connected to form a C 4-6 carbocycle or 5- to 6-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituted;

[0086] In some embodiments, ring B2is selected from one end is connected to ring A and the other end is connected to L, which ring B2is optionally substituted with 1 to 3 R b2 substituted;

[0087] R t1 and R t2 directly connected to form a C 4-6 carbocycle, which carbocycle is optionally substituted with 1 to 4 R k substituted;

[0088] R t3 and R L1 directly connected to form a C 4-6 carbocycle, which carbocycle is optionally substituted with 1 to 4 R k substituted;

[0089] R t4 and R x directly connected to form a 5- to 8-membered heterocycle, which heterocycle is optionally substituted with 1 to 4 R k substituted;

[0090] R t5 and R L1 directly connected to form a C 4-6carbocycle, the carbocycle or heterocycle is optionally substituted with 1 to 5 R k substituted;

[0091] In some embodiments, ring B2 is selected from * end is connected to ring A, the other end is connected to L;

[0092] In some embodiments, is selected from ring E is optionally substituted with 1 to 4 R k * end is connected to ring A, the other end is connected to L;

[0093] In some embodiments, is selected from ring E is optionally substituted with 1 to 4 R k * end is connected to ring A, the other end is connected to ring C;

[0094] In some embodiments, is selected from ring E is optionally substituted with 1 to 4 R k * end is connected to ring A, the other end is connected to ring C;

[0095] In some embodiments, is selected from ring E is optionally substituted with 1 to 4 R k * end is connected to ring B;

[0096] In some embodiments, is selected from

[0097] In some embodiments, is selected from

[0098] In some embodiments, is selected from

[0099] In some embodiments, m is selected from 0, 1, 2, 3, or 4;

[0100] In some embodiments, m is selected from 0, 1, or 2;

[0101] In some embodiments, m is selected from 0 or 1;

[0102] In some embodiments, R b1 is selected from C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6alkyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-OH, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted with 1 to 5 R k substituents;

[0103] In some embodiments, R b1 is selected from C 2-4 alkyl, C 2-4 alkenyl, C 1-4 alkynyl, -OC 1-2 alkyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-OH, -C 1-4 alkylene-OC 1-2 alkyl, -C 3-6 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC k cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted with 1 to 4 R b1 substituents;

[0104] In some embodiments, R 2-4 is selected from C 2-4 alkyl, C 1-4 alkenyl, OC 1-2 alkyl, -C 1-2 alkylene-CN, -C 3-6 alkylene-OH, C 3-6 cycloalkyl, -OC k cycloalkyl, the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl groups being optionally substituted with 1 to 4 R b1 substituents;

[0105] In some embodiments, R k is selected from methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -Ocyclopropyl, -Ocyclobutyl, -Ocyclopentyl, -Ocyclohexyl, the methoxy, ethoxy, cyclopropyl, cyclobutyl groups being optionally substituted with 1 to 4 R b2 substituents;

[0106] In some embodiments, R 1-6 is each independently selected from C 2-6 alkyl, C 2-6 alkenyl, C 1-2alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 5 R k substituents;

[0107] In some embodiments, R b2 each independently is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-OC 1-4 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 4 R k substituents;

[0108] In some embodiments, R b2 each independently is selected from C 1-4 alkyl, -C 1-2 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkylene, alkyl, cycloalkyl being optionally substituted with 1 to 4 R k substituents;

[0109] In some embodiments, R b2 each independently is selected from methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl, isopropyl being optionally substituted with 1 to 4 R k substituents;

[0110] In some embodiments, L is selected from L1or L2;

[0111] In some embodiments, L1is selected from -CH2-, -CH(D)-, -CD2-;

[0112] In some embodiments, L2is selected from -O-, -NH-, S, -NR L1 -, -CHR L1 - or -C(R L1 )2-;

[0113] In some embodiments, L1is selected from -CH2-;

[0114] In some embodiments, L2is selected from -0-, -NH-, -S-, -NR L1 -CHR L1 - or -C(R L1 )2-;

[0115] In some embodiments, L2is selected from -0-, -NH-, -S-, -NR L1 -CHR L1 - or -C(R L1 )2-;

[0116] In some embodiments, L2is selected from -0-, -NH-, -S-, -NR In some embodiments, R L1 each independently is selected from CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 5 R k ;

[0117] In some embodiments, R L1 each independently is selected from CN, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 4 R k ;

[0118] In some embodiments, R L1 each independently is selected from CN, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, cycloalkyl being optionally substituted with 1 to 4 R k ;

[0119] In some embodiments, R L1each independently selected from the group consisting of CN, F, CI, Br, I, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl optionally substituted with 1 to 4 R k substituted;

[0120] In some embodiments, two R L1 together with the atoms to which they are attached form a C 3-8 carbocycle or 5- to 8-membered heterocycle, said carbocycle or heterocycle optionally substituted with 1 to 5 R k substituted;

[0121] In some embodiments, two R L1 together with the atoms to which they are attached form a C 3-8 carbocycle or 5- to 8-membered heterocycle, said carbocycle or heterocycle optionally substituted with 1 to 4 R k substituted;

[0122] In some embodiments, two R L1 together with the atoms to which they are attached form a C k carbocycle or 5- to 8-membered heterocycle, said carbocycle or heterocycle optionally substituted with 1 to 4 R v substituted;

[0123] In some embodiments, ring C is selected from ring C1or ring C2;

[0124] In some embodiments, ring C1is selected from

[0125] In some embodiments, V is selected from N or CR v ;

[0126] In some embodiments, ring C1is selected from

[0127] In some embodiments, R v each independently selected from the group consisting of H, deuterium, halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, said alkyl optionally substituted with 1 to 6 F;

[0128] In some embodiments, R v each independently selected from the group consisting of H, deuterium, halogen, CN, C 1-4 alkyl, -OC 1-4 alkyl, said alkyl optionally substituted with 1 to 6 F;

[0129] In some embodiments, R v each independently selected from the group consisting of H, halogen, C 1-4 alkyl, -OC1-4 alkyl, said alkyl is optionally substituted with 1 to 6 F;

[0130] In some embodiments, R v each is independently selected from H, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, said methyl, ethyl, propyl is optionally substituted with 1 to 6 F;

[0131] In some embodiments, ring C1 is selected from ring C1 is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl, isopropyl is optionally substituted with 1 to 4 F;

[0132] In some embodiments, ring C1 is selected from

[0133] In some embodiments, ring C2 is selected from 5-membered heteroaryl, 8- to 10-membered fused heteroaryl, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, C 5-10 spirocycloalkyl, -phenyl-R c1 , -6-membered heteroaryl-R c1 , said ring C2 is optionally substituted with 1 to 4 R c2 ;

[0134] R v1 and R L1 are directly connected to form a C 3-8 carbocyclic or 5- to 8-membered heterocyclic ring, said carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R k ;

[0135] In some embodiments, ring C2 is selected from thienyl, furanyl, thiazolyl, 8- to 10-membered fused heteroaryl, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, C 5-8 spirocycloalkyl, -phenyl-R c1 , -6-membered heteroaryl-R c1 , said ring C2 is optionally substituted with 1 to 4 R c2 ;

[0136] R v1 and R L1 are directly connected to form a C 3-8 carbocyclic or 5- to 8-membered heterocyclic ring, said carbocyclic or heterocyclic ring is optionally substituted with 1 to 4 R k ; In some embodiments, ring C2 is selected from -phenyl-R c1 , said ring C2 is optionally substituted with 1 to 4 R c2 ;

[0137] In some embodiments, ring C2 is selected from

[0138] In some embodiments, R c1 is selected from -SF5, -CF(CF3)2, -C(=O)NHC 1-6 alkyl, -NHC(=O)C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, 3- to 7-membered heterocycle, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycle is optionally substituted with 1 to 5 R k ;

[0139] In some embodiments, R c1 is selected from -SF5, -CF(CF3)2, -C(=O)NHC 1-4 alkyl, -NHC(=O)C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, 3- to 7-membered heterocycle, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycle is optionally substituted with 1 to 4 R k ;

[0140] In some embodiments, R c1 is selected from -SF5, -CF(CF3)2, -C(=O)NHC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycle, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle is optionally substituted with 1 to 4 R k ;

[0141] In some embodiments, R c1 is selected from -SF5, -CF(CF3)2, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, azetanyl, azetanyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, said R c1 is optionally substituted with 1 to 4 R k substituents;

[0142] In some embodiments, R c2 each is independently selected from deuterium, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl optionally substituted with 1 to 4 R k substituents;

[0143] In some embodiments, R c2 each is independently selected from deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-OC 1-4 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl optionally substituted with 1 to 4 R k substituents;

[0144] In some embodiments, R c2 each is independently selected from halogen, CN, C 1-4 alkyl, -C 1-2 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl optionally substituted with 1 to 4 R k substituents;

[0145] In some embodiments, R c2 each is independently selected from F, Cl, Br, I, CN, methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl, isopropyl optionally substituted with 1 to 4 R k substituents;

[0146] In some embodiments, R k each independently is selected from the group consisting of deuterium, =0, halogen, CN, OH, -C(=0)OH, -C(=0)NH2, NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclic, -O-3- to 7-membered heterocyclic, -NH-C 3-6 carbocyclic, -NH-3- to 7-membered heterocyclic, -C 1-2 alkylene-C 3-6 carbocyclic, -C 1-2 alkylene-3- to 7-membered heterocyclic, C 3-6 carbocyclic, 3- to 7-membered heterocyclic, said alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic being optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy;

[0147] In some embodiments, R k each independently is selected from the group consisting of deuterium, =0, halogen, CN, OH, -C(=0)OH, -C(=0)NH2, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclic, -O-3- to 7-membered heterocyclic, C 3-6 carbocyclic, 3- to 7-membered heterocyclic, said alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic being optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy;

[0148] In some embodiments, R kEach of the following is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -O-oxacyclobutyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0149] In some implementation schemes, R k Each is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, -C(=O)OH, -C(=O)NH2, -CH2OH, methyl, ethyl, propyl, isopropyl, tert-butyl, CD3, OCD3, CH2F, CHF2, CF3, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -O-oxacyclobutyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl

[0150] In some implementations, 'a' is selected from 0, 1, 2, 3, or 4;

[0151] In some implementations, 'a' is selected from 0, 1, or 2;

[0152] In some implementations, 'a' is selected from 0 or 1;

[0153] In some implementations, n is selected from 0, 1, 2, 3, or 4;

[0154] In some implementations, n is selected from 0, 1, or 2;

[0155] In some implementations, n is selected from 0 or 1;

[0156] The condition is that when ring A is selected from ring A1, one of the following conditions must be satisfied:

[0157] 1) Ring B is selected from ring B2;

[0158] 2) L is selected from L2;

[0159] 3) Ring C is selected from ring C2.

[0160] As a first embodiment of the present application, the above-mentioned compound represented by the general formula (I) or a stereoisomer, a pharmaceutically acceptable salt thereof,

[0161] Ring A is selected from ring A1or ring A2;

[0162] Ring A1is selected from

[0163] Ring A2is selected from -8 to 10 membered heteroaryl-R a4 , -5 membered heteroaryl-R a4 , the 5 membered heteroaryl being attached to ring B through a carbon atom, the heteroaryl being optionally substituted with 1 to 4 R A ;

[0164] As an option, when ring A2is selected from , R A on the two adjacent C atoms can form a C 3-8 carbocyclic ring or a 5 to 8 membered heterocyclic ring, the carbocyclic ring or the heterocyclic ring being optionally substituted with 1 to 5 R k ;

[0165] W is selected from -C 1-3 alkylene-, -NH-C 1-2 alkylene-, -C 1-2 alkylene-NH-, -C 1-2 alkylene-NH-C 1-2 alkylene-, -CH=N-, -N=CH-, the alkylene being optionally substituted with 1 to 5 R k ;

[0166] a is selected from 0, 1, 2, 3 or 4;

[0167] R a1 is selected from -C(=O)NR aa1 R aa2 , -C(=O)R aa1 , -C(=S)NR aa1 R aa2 ;

[0168] X is selected from CR x ;

[0169] Y is selected from N or CR y ;

[0170] or X is selected from N and Y is selected from N;

[0171] Z is selected from CR z ;

[0172] R x selected from C 1-6 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl or heterocycloalkyl optionally substituted with 1 to 5 R k substituents;

[0173] R y selected from H, halogen, CN, C 1-6 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl or heterocycloalkyl optionally substituted with 1 to 5 R k substituents;

[0174] R z selected from -C 1-2 alkylene-C 3-7 cycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -NHC 2-6 alkenyl, -NHC 2-6 alkynyl, -C 1-2 alkylene-NH2, -C 1-2 alkylene-NH-C 1-6 alkyl, -C 1-2 alkylene-NH-C(O)R aa1 , -C 1-2 alkylene-N(C 1-6 alkyl)2, -C 1-2 alkylene-NH-C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C=NR aa1 , said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 5 R k substituents;

[0175] R AA selected from -C 1-2 alkylene-C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, said alkylene, alkenyl, alkynyl, cycloalkyl optionally substituted with 1 to 5 R k substituents;

[0176] R a3 selected from -S(=O)2NR aa1 R aa2 -S(=O)(=N)NR aa1 R aa2 -NR aa1 S(=O)2R aa2 -NR aa1 C(=O)R aa2 -S(=O)2R aa2 -C(=O)NH-C(=NR aa3 )NR aa1 R aa2 -C(=NR aa3 )NR aa1 R aa2 -NR aa1 C(=O)NR aa1 R aa2 -C(=S)NR aa1 R aa2 -C(=O)NR aa1 -C 1-4 alkylene-C 3-7 cycloalkyl, -C(=O)NR aa1 -C 1-4 alkylene-4- to 7-membered heterocycloalkyl, -C(=O)NR aa1 -C 1-4 alkylene-O-C 3-7 cycloalkyl, -C(=O)NR aa1 -C 1-4 alkylene-O-4- to 7-membered heterocycloalkyl, said alkylene, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 3 R k ;

[0177] R a4 selected from -C(=O)NR aa1 R aa2 or R a3 ;

[0178] R aa1 , R aa2 are each independently selected from H, C 1-6 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, carbocyclic ring, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 5 R k ;

[0179] Raa3 H, CN, OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl or heterocycloalkyl optionally being substituted with 1 to 5 R k substituents;

[0180] R A each independently selected from H, deuterium, halogen, CN, -C(=O)OH, NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-7 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally being substituted with 1 to 5 R k substituents;

[0181] Ring B is selected from Ring B1 or Ring B2;

[0182] Ring B1 is selected from one end is connected to Ring A and the other end is connected to L;

[0183] T is selected from N or CR t ;

[0184] R t each independently selected from H, deuterium, halogen, OH, CN or C 1-6 alkyl, said alkyl optionally being substituted with 1 to 6 F;

[0185] Ring B2 is selected from 5-membered heteroaryl, one end is connected to Ring A and the other end is connected to L, said Ring B2 optionally being substituted with 1 to 3 R b2 substituents;

[0186] R t1 and R t2 are directly connected to form a C 3-8 carbocyclic or 5- to 8-membered heterocyclic ring, said carbocyclic or heterocyclic ring optionally being substituted with 1 to 5 R k substituents;

[0187] R t3 and R L1 are directly connected to form a C 3-8 carbocyclic or 5- to 8-membered heterocyclic ring, said carbocyclic or heterocyclic ring optionally being substituted with 1 to 5 Rk substituted;

[0188] R t4 and R x directly connected to form a C 5-10 carbocycle or a 5- to 10-membered heterocycle, which is optionally substituted with 1 to 5 R k substituted;

[0189] R t5 and R L1 directly connected to form a C 3-8 carbocycle or a 5- to 8-membered heterocycle, which is optionally substituted with 1 to 5 R k substituted;

[0190] R b1 is selected from C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-OH, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, which alkyl, alkylene, alkenyl, alkynyl, cycloalkyl is optionally substituted with 1 to 5 R k substituted;

[0191] R b2 each independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, which alkyl, alkylene, alkenyl, alkynyl, cycloalkyl is optionally substituted with 1 to 5 R k substituted;

[0192] L is selected from L1or L2;

[0193] L1is selected from -CH2-, -CH(D)-, -CD2-;

[0194] L2is selected from -O-, -NH-, -S-, -NR L1 -, -CHR L1 or -C(R L1 )2-;

[0195] R L1 each independently selected from the group consisting of CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 5 R k substituents;

[0196] each R L1 , together with the atom to which they are attached, form a C 3-8 carbocyclic or 5- to 8-membered heterocyclic ring, said carbocyclic or heterocyclic ring being optionally substituted with 1 to 5 R k substituents;

[0197] ring C is selected from ring C1 or ring C2; ring C1 is selected from

[0198] V is selected from N or CR v ;

[0199] ring C2 is selected from 5-membered heteroaryl, 8- to 10-membered annulated heteroaryl, benzo 4-6 carbocyclic, benzo 4- to 6-membered heterocyclic, C 5-10 bridged cycloalkyl, -phenyl-R c1 , -6-membered heteroaryl-R c1 , said ring C2 is optionally substituted with 1 to 4 R c2 substituents;

[0200] R v1 , together with R L1 directly attached, form a C 3-8 carbocyclic or 5- to 8-membered heterocyclic ring, said carbocyclic or heterocyclic ring being optionally substituted with 1 to 5 R k substituents;

[0201] R v each independently selected from the group consisting of H, deuterium, halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, said alkyl being optionally substituted with 1 to 6 F;

[0202] R c1 is selected from -SF5, -CF(CF3)2, -C(=O)NHC 1-6 alkyl, -NHC(=O)C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, 3- to 7-membered heterocycle, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycle being optionally substituted with 1 to 5 R k substituents;

[0203] R c2 each independently selected from the group consisting of deuterium, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 5 R k substituents;

[0204] R k each independently selected from the group consisting of deuterium, =0, halogen, CN, OH, -C(=0)OH, -C(=0)NH2, NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3- to 7-membered heterocycle, C 3-6 carbocycle, 3- to 7-membered heterocycle, said alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle being optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy;

[0205] with the proviso that when ring A is selected from ring A1, one of the following conditions is met:

[0206] 1) ring B is selected from ring B2;

[0207] 2) L is selected from L2;

[0208] 3) ring C is selected from ring C2.

[0209] As a second embodiment of the present application, the compound of general formula (I) is selected from the group consisting of compounds of general formula (la), (lb), (lc), (Id), (lb-1), (lb-2), (lb-3), (Ih), (Ii), (Ij) or (Ik),

[0210] ring E is selected from C 4-8 carbocycle or 5- to 8-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituents;

[0211] ring EE is selected from 5- to 8-membered heterocycle, which heterocycle is optionally substituted with 1 to 4 R k substituents;

[0212] Y is selected from N;

[0213] ring B1 is selected from * end is connected to ring A, other end is connected to L;

[0214] ring C1 is selected from

[0215] R x is selected from C 1-4 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, which alkyl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k substituents;

[0216] R z is selected from -C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 1-4 haloalkyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -NHC 2-4 alkenyl, -NHC 2-4 alkynyl, -C 1-2 alkylene-NH2, -C 1-2 alkylene-NH-C 1-4 alkyl, -C 1-2 alkylene-NH-C(O)R aa1 , -C 1-2 alkylene-N(C 1-4 alkyl)2, -C 1-2alkylene-NH-C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C=NR aa1 , said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 4 R k ;

[0217] R AA is selected from -C 1-2 alkylene-C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, said alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 5 R k ;

[0218] R a3 is selected from -S(=O)2NR aa1 R aa2 , -S(=O)(=N)NR aa1 R aa2 , -NR aa1 S(=O)2R aa2 , -NR aa1 C(=O)R aa2 , -S(=O)2R aa2 , -C(=O)NH-C(=NR aa3 )NR aa1 R aa2 , -C(=NR aa3 )NR aa1 R aa2 , -NR aa1 C(=O)NR aa1 R aa2 , -C(=S)NR aa1 R aa2 , -C(=O)NR aa1 -C 1-2 alkylene-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-4- to 7-membered heterocycloalkyl, said alkylene, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 3 R k ;

[0219] R a4 selected from -C(=O)NR aa1 R aa2 or R a3 ;

[0220] R aa1 , R aa2 each independently selected from H, C 1-4 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl or heterocycloalkyl optionally substituted with 1 to 4 R k ;

[0221] R aa3 selected from H, CN, OH, C 1-4 alkyl, -O-C 1-4 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl or heterocycloalkyl optionally substituted with 1 to 4 R k ;

[0222] R A each independently selected from H, deuterium, halogen, CN, -C(=O)OH, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl optionally substituted with 1 to 4 R k ;

[0223] R t each independently selected from H, deuterium, halogen, OH, CN or C 1-4 alkyl, said alkyl optionally substituted with 1 to 6 F;

[0224] R b1 selected from C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-OH, -C 1-2 alkylene-OC 1-4 alkyl, -C 1-2 alkylene-C3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted with 1 to 4 R k substituents;

[0225] R b2 each independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-OC 1-4 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted with 1 to 4 R k substituents;

[0226] R L1 each independently selected from the group consisting of CN, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted with 1 to 4 R k substituents;

[0227] R v each independently selected from the group consisting of H, deuterium, halogen, CN, C 1-4 alkyl, -OC 1-4 alkyl, the alkyl groups being optionally substituted with 1 to 6 F;

[0228] R c1 selected from the group consisting of -SF5, -CF(CF3)2, -C(=0)NHC 1-4 alkyl, -NHC(=0)C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, 3- to 7-membered heterocyclic ring, the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic ring groups being optionally substituted with 1 to 4 Rk substituted;

[0229] R c2 each independently selected from the group consisting of deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-OC 1-4 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 4 R k substituted;

[0230] R k each independently selected from the group consisting of deuterium, =0, halogen, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclic, -O-3 to 7 membered heterocyclic, C 3-6 carbocyclic, 3 to 7 membered heterocyclic, said alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic being optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy;

[0231] n is selected from 0, 1, 2, 3 or 4;

[0232] the remaining groups are defined as in the first embodiment of the invention.

[0233] As a third embodiment of the present application, the above-mentioned compounds represented by the general formula (I), (Ia), (Ib), (Ic), (Id), (Ib-1), (Ib-2), (Ib-3), (Ih), (Ii), (Ij) or (Ik), or a stereoisomer, a pharmaceutically acceptable salt thereof,

[0234] Ring A2 is selected from - benzopyrrolyl-R a4 , pyridopyrrolyl-R a4 , pyrimidopyrrolyl-R a4 , - thienyl-R a4, -furanyl-R a4 , said pyridinopyrrolyl, pyrimidinopyrrolyl, thienyl, furanyl is optionally substituted with 1 to 4 R A ;

[0235] Alternatively, when ring A2 is selected from , R A on the two adjacent C atoms can form a C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl, said cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with 1 to 4 R k ;

[0236] R x is selected from C 1-4 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, said alkylene, alkyl is optionally substituted with 1 to 4 R k ;

[0237] R z is selected from -C 1-2 alkylene-C 3-6 ycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 1-4 haloalkyl, -N(C 1-4 alkyl)2, -NHC 1-4 alkyl, -C 1-2 alkylene-NH2, -C 1-2 alkylene-NH-C 1-4 alkyl, -C 1-2 alkylene-NH-C(O)R aa1 , -C 1-2 alkylene-N(C 1-4 alkyl)2, -C 1-2 alkylene-NH-C 3-6 ycloalkyl, C 2-4 lenyl, C 2-4 kynyl, -C=NR aa1 , said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 4 R k ;

[0238] R a3 is selected from -S(=O)2NR aa1 R aa2 , -NR aa1 S(=O)2R aa2 , -NR aa1 C(=O)R aa2 , -S(=O)2R aa2, -C(=NR aa3 )NR aa1 R aa2 , -NR aa1 C(=O)NR aa1 R aa2 , -C(=S)NR aa1 R aa2 , -C(=O)NR aa1 -C 1-2 alkylene-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-4- to 7-membered heterocycloalkyl, which alkylene, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 2 R k ;

[0239] R aa1 , R aa2 are each independently selected from the group consisting of H, C 1-4 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, which alkyl, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 4 R k ;

[0240] R A are each independently selected from the group consisting of H, deuterium, halogen, CN, -C(=O)OH, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -OC 1-4 alkyl, -C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, which alkyl is optionally substituted with 1 to 4 R k ;

[0241] Ring B2is selected from the group consisting of thienyl, thiazolyl, imidazolyl, pyrazolyl, one end is attached to Ring A and the other end is attached to L, which Ring B2is optionally substituted with 1 to 3 R b2 ;

[0242] R t1 and Rt2 Direct connection forms C 4-6 Carbon rings or 5- to 6-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0243] R t3 With R L1 Direct connection forms C 4-6 Carbon rings or 5- to 6-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0244] R t4 With R x Direct connection forms C 5-8 Carbon rings or 5- to 8-membered heterocycles, wherein the heterocycle is optionally surrounded by 1 to 4 R... k replace;

[0245] R t5 With R L1 Direct connection forms C 4-6 Carbon rings or 5- to 6-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0246] R b1 Selected from C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, -C 1-2 Alkylene-CN, -C 1-2 alkylene-OH, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, or cycloalkyl group is optionally prefixed with 1 to 4 R groups. k replace;

[0247] R b2 Each independently selected from C 1-4 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0248] L1 is selected from -CH2-;

[0249] L2 is selected from -O-, -NH-, -S-, and -NR. L1 -、-CHR L1 -or-C(R) L1 )2-;

[0250] R L1each independently selected from the group consisting of CN, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, cycloalkyl being optionally substituted with 1 to 4 R k substituents;

[0251] R L1 together with the atom to which they are attached form a C 3-8 carbocyclic or 5- to 8-membered heterocyclic ring, said carbocyclic or heterocyclic ring being optionally substituted with 1 to 4 R k substituents;

[0252] Ring C1 is selected from the group consisting of

[0253] Ring C2 is selected from the group consisting of thienyl, furanyl, thiazolyl, 8- to 10-membered annulated heteroaryl, benzo C 4-6 carbocyclic, benzo 4- to 6-membered heterocyclic, C 5-8 bridged cycloalkyl, -phenyl-R c1 , -6-membered heteroaryl-R c1 , said Ring C2 being optionally substituted with 1 to 4 R c2 substituents;

[0254] R v1 and R L1 are directly attached to form a C 3-8 carbocyclic or 5- to 8-membered heterocyclic ring, said carbocyclic or heterocyclic ring being optionally substituted with 1 to 4 R k substituents;

[0255] R v each independently selected from the group consisting of H, halogen, C 1-4 alkyl, -OC 1-4 alkyl, said alkyl being optionally substituted with 1 to 6 F;

[0256] R c1 is selected from the group consisting of -SF5, -CF(CF3)2, -C(=O)NHC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic ring, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic ring being optionally substituted with 1 to 4 R k substituents;

[0257] R c2 each independently selected from the group consisting of halogen, CN, C 1-4 alkyl, -C 1-2 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl, -OC3-6 alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl being optionally substituted with 1 to 4 R k substituents;

[0258] R k each independently selected from the group consisting of deuterium, =0, F, Cl, Br, I, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -O-oxetanyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with 1 to 4 R 1-4 substituents; 1-4 substituents;

[0259] the remaining groups being defined as in the first or second embodiment of the application.

[0260] As a fourth embodiment of the application, the above-mentioned compounds of general formula (I), (Ia), (Ib), (Ic), (Id), (Ib-1), (Ib-2), (Ib-3), (Ih), (Ii), (Ij) or (Ik) or a stereoisomer, a pharmaceutically acceptable salt thereof,

[0261] ring A2is selected from said optionally substituted with 1 to 4 R A substituents;

[0262] As an alternative, when ring A2is selected from R A may form a C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl being optionally substituted with 1 to 4 R k substituents;

[0263] R x selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxymethyl, said methylene, methyl, ethyl, propyl, isopropyl, methoxymethyl being optionally substituted with 1 to 4 R k substituents;

[0264] R z is selected from -CH2F, -CHF2, -CF3, said R z is optionally substituted with 1 to 4 R k ;

[0265] R a3 is selected from - S(=0)2NH2, said R k is optionally substituted with 1 to 2 R

[0266] R aa1 , R aa2 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl being optionally substituted with 1 to 4 R k ;

[0267] R aa3 is selected from H, CN, OH, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, said methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl being optionally substituted with 1 to 4 R k ;

[0268] R A are each independently selected from F, Cl, Br, I, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl being optionally substituted with 1 to 4 R k ;

[0269] R AA is selected from said R k is optionally substituted with 1 to 4 R

[0270] Ring B1 is selected from * end is connected to ring A, the other end is connected to L;

[0271] Ring B2 is selected from * end is connected to ring A, the other end is connected to L, said ring B2 is optionally substituted with 1 to 3 R b2 ;

[0272] R t1 With R t2 Direct connection forms C 4-6 Carbon ring, wherein the carbon ring is optionally divided by 1 to 4 R k replace;

[0273] R t3 With R L1 Direct connection forms C 4-6 Carbon ring, wherein the carbon ring is optionally divided by 1 to 4 R k replace;

[0274] R t4 With R x Direct connection forms a 5- to 8-membered heterocycle, wherein the heterocycle is optionally bounded by 1 to 4 R... k Replace; R t5 With R L1 Direct connection forms C 4-6 Carbon rings, wherein the carbon rings or heterocycles are optionally bounded by 1 to 4 R... k replace;

[0275] R b1 The derivatives are selected from methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, and -O-cyclohexyl, wherein the methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0276] R b2 Each is independently selected from methyl, ethyl, propyl, and isopropyl, wherein the methyl, ethyl, propyl, and isopropyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0277] L1 is selected from -CH2-;

[0278] L2 is selected from -O-, -NH-, -S-, and -NR. L1 -、-CHR L1 -or-C(R) L1 )2-;

[0279] R L1 Each is independently selected from CN, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. k replace;

[0280] As an option, two R L1together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetanyl group, which is optionally substituted with 1 to 4 R k substituted;

[0281] Ring C1is selected from Ring C1is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, which are optionally substituted with 1 to 4 F;

[0282] Ring C2is selected from phenyl-R c1 , which is optionally substituted with 1 to 4 R c2 substituted;

[0283] R c1 is selected from -SF5, -CF(CF3)2, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, azetanyl, azetanyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, which is optionally substituted with 1 to 4 R c1 substituted; k substituted;

[0284] R c2 are each independently selected from F, Cl, Br, I, CN, methyl, ethyl, propyl, isopropyl, which are optionally substituted with 1 to 4 R k substituted;

[0285] R k are each independently selected from deuterium, =0, F, Cl, Br, I, CN, OH, -C(=0)OH, -C(=0)NH2, -CH2OH, methyl, ethyl, propyl, isopropyl, tert-butyl, CD3, OCD3, CH2F, CHF2, CF3, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -O-oxetanyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0286] the remaining group definitions are the same as in the first, second or third embodiment of the invention.

[0287] As a fifth embodiment of the present application, the above-mentioned compound represented by the general formula (I), (Ia), (Ib), (Ic), (Id), (Ib-1), (Ib-2), (Ib-3), (Ih), (Ii), (Ij) or (Ik), or a stereoisomer, a pharmaceutically acceptable salt thereof,

[0288] Ring A2is selected from The optionally substituted by 1 to 4 R A ;

[0289] As an option, when ring A2is selected from , R A on the adjacent two C atoms can form a C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl, said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl being optionally substituted by 1 to 4 R k ;

[0290] W is selected from -CH2-CH2-, -C(O)NH-CH2-, -N=CH-, -CH2-, said W being optionally substituted by 1 to 4 R k ;

[0291] is selected from Ring E is optionally substituted by 1 to 4 R k , the * end being attached to ring A and the other end being attached to L;

[0292] is selected from Ring E is optionally substituted by 1 to 4 R k , the * end being attached to ring A and the other end being attached to ring C;

[0293] is selected from Ring E is optionally substituted by 1 to 4 R k , the * end being attached to ring A and the other end being attached to ring C;

[0294] is selected from Ring E is optionally substituted by 1 to 4 R k , the * end being attached to ring B;

[0295] is selected from

[0296] is selected from

[0297] selected from the group consisting of

[0298] m is selected from 0, 1, 2, 3 or 4;

[0299] R a1 selected from the group consisting of -C(=0)NH2, -C(=0)CH3, -C(=0)H, -C(=S)NH2;

[0300] R x selected from the group consisting of

[0301] R z selected from the group consisting of

[0302] R AA selected from the group consisting of

[0303] R a3 selected from the group consisting of -S(=0)2NH2;

[0304] R a4 selected from the group consisting of -C(=0)NH2;

[0305] R A each independently selected from the group consisting of F, CI, Br, I, CN, methyl, ethyl, -CH2F, -CHF2, -CF3, methoxy, cyclopropyl,

[0306] Ring B2is selected from the group consisting of * end is connected to Ring A and the other end is connected to L;

[0307] L2is selected from the group consisting of -0-, -NH-, -S-,

[0308] Ring C1is selected from the group consisting of

[0309] Ring C2is selected from the group consisting of

[0310] the remaining groups are defined as in the first, second, third or fourth embodiment of the present invention.

[0311] As a sixth embodiment of the present application, the above-mentioned compounds represented by the general formula (Ih-3) or a stereoisomer, a pharmaceutically acceptable salt thereof,

[0312] X is selected from CR x ;

[0313] R x is selected from

[0314] Y is selected from N;

[0315] R A each independently is selected from H, deuterium, halogen, CN, -C(=O)OH, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -OC 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, said alkyl, cycloalkyl being optionally substituted with 1 to 4 R k ;

[0316] Preferably, R A each independently is selected from F, Cl, Br, I, CN, methyl, ethyl, -CH2F, -CHF2, -CF3, methoxy, cyclopropyl,

[0317] R L1 is selected from R L1 ;

[0318] R L1 each independently is selected from CN, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, cycloalkyl being optionally substituted with 1 to 4 R k ;

[0319] Preferably, R L1 each independently is selected from CN, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl being optionally substituted with 1 to 4 R k ;

[0320] T' is selected from N, CH, CR t ;

[0321] V' is selected from N, CH, CR v ;

[0322] T is selected from N or CR t ;

[0323] R t each independently selected from H, deuterium, halogen, OH, CN or C 1-4 alkyl, said alkyl being optionally substituted with 1 to 6 F;

[0324] preferably, R t each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl, said methyl, ethyl, propyl being optionally substituted with 1 to 6 F;

[0325] V is selected from N or CR v ;

[0326] R v each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, -OC 1-4 alkyl, said alkyl being optionally substituted with 1 to 6 F;

[0327] preferably, R v each independently selected from H, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, said methyl, ethyl, propyl being optionally substituted with 1 to 6 F;

[0328] the remaining group definitions are the same as in the first, second, third, fourth or fifth embodiment of the invention.

[0329] The present invention relates to a compound as shown below or a stereoisomer, a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures shown below in Table E.

[0330] Table E

[0331] The present application relates to a pharmaceutical composition comprising any of the above-mentioned compounds or stereoisomers thereof, pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0332] The present application relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compounds of the present application or stereoisomers thereof, pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0333] The present application relates to a method for treating or alleviating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of the above-mentioned compounds or stereoisomers thereof, pharmaceutically acceptable salts, preferably 1-1500 mg, and the disease is preferably a mental disorder.

[0334] In some embodiments, the pharmaceutical composition of the present application can be in the form of a unit dosage formulation (the amount of the main drug in the unit dosage formulation is also referred to as "formulation specification").

[0335] "Therapeutically effective amount" refers to an amount of a compound disclosed herein that, when administered to a subject for treatment of a disease or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will be dependent on the severity of the disease, the stage of the disease, the general health of the subject, age, weight, and response of the subject to the treatment, and the judgment of the treating physician.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-500 mg, 6-500 mg, 10-500 mg, 20-500 mg, 25-500 mg, 30-500 mg, 40-500 mg, 50-500 mg, 60-500 mg, 70-500 mg, 75-500 mg, 80-500 mg, 90-500 mg, 100-500 mg, 125-500 mg, 150-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 400-500 mg, 5-400 mg, 10-400 mg, 20-400 mg, 25-400 mg, 30-400 mg, 40-400 mg, 50-400 mg, 60-400 mg, 70-400 mg, 75-400 mg, 80-400 mg, 90-400 mg, 100-400 mg, 125-400 mg, 150-400 mg, 200-400 mg, 250-400 mg, 300-400 mg, 1-300 mg, 2-300 mg, 5-300 mg, 10-300 mg, 20-300 mg, 25-300 mg, 30-300 mg, 40-300 mg, 50-300 mg, 60-300 mg, 70-300 mg, 75-300 mg, 80-300 mg, 90-300 mg, 100-300 mg, 125-300 mg, 150-300 mg, 200-300 mg, 250-300 mg, 1-200 mg, 2-200 mg, 5-200 mg, 10-200 mg, 20-200 mg, 25-200 mg, 30-200 mg, 40-200 mg, 50-200 mg, 60-200 mg, 70-200 mg, 75-200 mg, 80-200 mg, 90-200 mg, 100-200 mg, 125-200 mg, 150-200 mg, 80-1000 mg, 80-800 mg.

[0336] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present application or a stereoisomer, pharmaceutically acceptable salt thereof.

[0337] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound of the present application or a stereoisomer, pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably 1-1500 mg, the disease preferably a psychiatric disorder.

[0338] A method for treating or ameliorating a disease in a mammal, the method comprising administering to the subject a compound of the present application or a stereoisomer, pharmaceutically acceptable salt thereof in a daily dose of 1-1000 mg / day, the daily dose can be in a single dose or divided doses, in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, the daily dose includes, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0339] The present application relates to a kit, which can include a single dose or multiple dose forms of a composition, the kit comprising a compound of the present application or a stereoisomer, pharmaceutically acceptable salt thereof, the amount of the compound of the present application or a stereoisomer, pharmaceutically acceptable salt thereof in the kit is the same as described above in the pharmaceutical composition.

[0340] The present application relates to the use of any of the above-mentioned compounds or stereoisomers, pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or / and alleviation of a mental disorder.

[0341] The present application relates to the use of the above-mentioned pharmaceutical composition for the manufacture of a medicament for the treatment or / and alleviation of a mental disorder.

[0342] The amount of the present application compound or stereoisomers, pharmaceutically acceptable salts thereof is in each case calculated as the free base.

[0343] General synthetic method of formula (A):

[0344] First step: S1 (synthesized according to WO2021181122) is oxidized by Dess-Martin oxidant (CAS: 87413-09-0) to obtain S2;

[0345] Second step: S2 is reacted with an appropriate nucleophile (such as 1-propynyl magnesium bromide or vinyl magnesium bromide) to obtain formula II.

[0346] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0347] The carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, I involved in the groups and compounds described in the present application include their isotopic cases, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present application are optionally replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br.

[0348] "Halogen" refers to F, Cl, Br or I.

[0349] "Halogen substituted" means F, Cl, Br or I substitution, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 substituents selected from F, Cl, Br or I, 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

[0350] "Alkyl" means a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neopentyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; alkyl groups appearing herein are defined as above. Alkyl groups can be monovalent, divalent, trivalent or tetravalent.

[0351] "Alkylene" means a substituted or unsubstituted straight chain and branched chain divalent saturated hydrocarbon group, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene groups include but are not limited to methylene, ethylene, propylene and butylene.

[0352] "Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl groups appearing herein are defined as above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.

[0353] "Heterocycloalkyl" means a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl group can be oxidized to various oxidation states. Heterocycloalkyl groups can be attached at a heteroatom or carbon atom, heterocycloalkyl groups can be attached to aromatic or non-aromatic rings, heterocycloalkyl groups can be attached with bridged or spirocyclic rings, non-limiting examples include oxetanyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups can be monovalent, divalent, trivalent or tetravalent

[0354] "Alkenyl" refers to substituted or unsubstituted straight and branched chain unsaturated hydrocarbon groups having at least one, usually one, two, or three carbon-carbon double bonds, including but not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms in the main chain, examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, and the like; alkenyl groups as they occur herein are defined in accordance with this definition. Alkenyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0355] "Alkynyl" refers to substituted or unsubstituted straight and branched chain unsaturated hydrocarbon groups having at least one, usually one, two, or three carbon-carbon triple bonds, including but not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonylnyl, 3-nonylnyl, 1-decynyl, 4-decynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0356] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy.

[0357] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, which may be a monocyclic, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0358] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. Heterocyclic groups can be attached to heteroatoms or carbon atoms, and can be attached to aromatic or non-aromatic rings. They can be connected to bridged or spirocyclic rings. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithial, dihydrofuranyl, dihydropyranyl, dithiapentylcycloalkyl, tetrahydro Furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl,

[0359] "Heterocyclic group" or "heterocyclic" can be monovalent, divalent, trivalent or tetravalent.

[0360] "Heteroaryl" or "heteroaromatic" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, or S(=O)n, n is 0, 1, 2) and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples include

[0361] As used herein, heteroaryl is defined as above. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the point of attachment is to the heteroaryl ring.

[0362] "Substituted" or "substitution" means substituted with one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, thiol, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged cyclyl, spirocyclyl, annelated cyclyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, carboxylate, -(CH2) m -C(=O)-R a , -O-(CH2) m -C(=O)-R a , -(CH2) m -C(=O)-NR b R c , -(CH2) m S(=O) n R a , -(CH2) m -alkenyl-R a , OR d , or -(CH2) m -alkynyl-R a (where m, n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c , etc., where R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethylsulfonyl, and, optionally, R b and R c may form a five or six membered cycloalkyl or heterocyclyl ring, R aR d each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.

[0363] "1 to X substituents selected from" means 1, 2, 3,... X substituents selected from. X is selected from any integer between 1 and 10. For example, "1 to 4 R k substituents" means 1, 2, 3, or 4 R k substituents. For example, "1 to 5 substituents selected from" means 1, 2, 3, 4, or 5 substituents selected from. For example, "hetero-bridged ring is optionally substituted with 1 to 4 substituents selected from D or F" means hetero-bridged ring is optionally substituted with 1, 2, 3, or 4 substituents selected from D or F.

[0364] A ring of X-Y members (X is an integer, and 3≤X

[0365] C x-y A carbocyclic ring (including aryl, cycloalkyl, monocyclic carbocyclic ring, spiro carbocyclic ring, fused carbocyclic ring, or bridged carbocyclic ring) includes a ring of C x , C x+1 , C x+2 , C x+3 , C x+4 ... C y members (x is an integer, and 3≤x 3-6 Cycloalkyl" means C3, C4, C5, or C6 cycloalkyl;

[0366] When a group has one or more available sites for connection, any one or more sites of the group can be connected to other groups through a chemical bond. When the connection mode of the chemical bond is not fixed, and there is a hydrogen atom in the available site, the number of H atoms in the site will be reduced to the corresponding valence number of groups corresponding to the number of connected chemical bonds. For example represents that any available site on the piperidinyl group can be connected to other groups through 1 chemical bond, at least including the 4 connection modes, even if the H atoms are drawn on the -N-, also include For example R group on the piperidinyl group can be on the C, can be on the N, at least including

[0367] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus such phrases include instances where the event or circumstance occurs and instances where it does not. For example, "an alkyl group optionally substituted with F" means that the alkyl group can or can not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0368] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof means a salt of a compound of the present application that retains the biological effectiveness and properties of the free acids or free bases, and which is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0369] "Pharmaceutical composition" means a mixture of one or more compounds of the present application, or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, and other chemical components, wherein the other chemical components are pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic or prophylactic agents.

[0370] "Carrier" means a material that does not itself induce the production of antibodies to it, and it does not have a significant stimulating effect on the biological activity and properties of the given compound.

[0371] "Dosage form" means the weight of the principal drug contained in each bottle, tablet, or other unit of preparation. "Prodrug" means a compound that can be converted under metabolic conditions, such as in vivo, to a biologically or pharmaceutically active compound of the present application. Prodrugs of the present application are prepared by modifying the amino or carboxyl groups of the compounds of the present application, which modifications are readily achieved by techniques known in the art, or in vivo. When a prodrug of the present application is administered to a mammalian subject, the prodrug is cleaved to form the free amino or carboxyl groups.

[0372] "Animal" means a mammal, such as a human, companion animal, zoo animal, and farm animal, preferably a human, horse, or dog.

[0373] "Stereoisomer" means isomers that have the same molecular formula but different structures resulting from the spatial arrangement of atoms. Stereoisomers include enantiomers and diastereomers.

[0374] "Tautomer" means isomers that differ only in the arrangement of atoms in a molecule, such as keto-enol isomers and amide-imidol isomers. DETAILED DESCRIPTION

[0375] The following examples illustrate the technical solutions of the present application, but the scope of protection of the present application includes but is not limited to this.

[0376] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured by a nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300) with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the determination solvent, and tetramethylsilane (TMS) as the internal standard;

[0377] MS was measured by (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0378] HPLC was measured by using Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100x4.6mm, 3.5μM);

[0379] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography is 0.15mm-0.20mm, and the specification of the product used in thin layer chromatography separation and purification is 0.4mm-0.5mm;

[0380] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0381] In order to achieve the purpose of the present application, the compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aldrin Biochemical Technology Co., Ltd., Shanghai McLean Biotechnology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anjieji Chemical, Shanghai Titan Science and Technology Co., Ltd., Kelong Chemical, Bailingwei Technology Co., Ltd., etc.

[0382] THF: tetrahydrofuran; DCM: dichloromethane; HATU: CAS 148893-10-1; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; NBS: N-bromosuccinimide; DBU: CAS 6674-22-2; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; MNH3: methanolic ammonia solution (7.0 mol / L).

[0383] Example 1: Preparation of compound 1

[0384] First Step: Preparation of 1B

[0385] 1A (0.1 g, 0.24 mmol) (synthesis method refer to patent WO2023041909A1), Dess-Martin Oxidizing Agent (0.15 g, 0.35 mmol) were added into dichloromethane (5 mL) and reacted at room temperature for 1 h. Saturated sodium thiosulfate (3 mL) was added and stirred at room temperature for 10 min, then water (5 mL) was added to dilute, extracted with dichloromethane (5 mL x 2), the organic phase was concentrated under reduced pressure to obtain 1B (0.11 g) as a crude product.

[0386] LCMS m / z = 407.1 [M+H] +

[0387] Second Step: Preparation of trifluoroacetate salt of compound 1

[0388] 1B (0.11 g) as a crude product, 1C (0.053 g, 0.54 mmol), NaBH(OAc)3 (0.086 g, 0.41 mmol), acetic acid (0.016 g, 0.27 mmol) were added into dichloromethane (5 mL) and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and further purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18(30mm x 150mm); mobile phase composition: acetonitrile / water containing 0.1% trifluoroacetic acid) and freeze-dried to obtain trifluoroacetate salt of compound 1 (40 mg).

[0389] LCMS m / z = 490.1 [M+H] +

[0390] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, 1H), 7.83 (s, 1H), 7.73-7.45 (m, 5H), 7.39 (1H, dd), 4.37 (s, 2H), 4.24 (s, 2H), 3.55 (s, 2H), 2.39 (s, 3H).

[0391] Example 2: Preparation of compound 2

[0392] First Step: Preparation of compound 2B

[0393] To a solution of 2A (5.0 g, 24.39 mmol), tert-butyldimethylsilyl chloride (4.04 g, 26.8 mmol) and imidazole (2.49 g, 36.57 mmol) in THF (100 mL) was added and stirred at room temperature for 4 h. After the reaction was completed, water (100 mL) was added and extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: petroleum ether) to give 2B (6.59 g, yield 85%).

[0394] 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.14-7.09 (m, 1H), 7.03-6.98 (m, 1H), 4.70 (s, 2H), 0.96 (s, 9H), 0.12 (s, 6H).

[0395] Second Step: Preparation of compound 2D

[0396] To a solution of 2B (4.0 g, 12.53 mmol), 2C (1.18 g, 13.74 mmol) and potassium carbonate (10.39 g, 75.18 mmol) in a mixture solvent of 1,4-dioxane (80 mL) and water (20 mL) was added and stirred at 100 °C for 12 h after three times of N2 replacement and addition of 1,1’-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.92 g, 1.13 mmol). After the reaction was completed, water (100 mL) was added and extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: petroleum ether) to give 2D (2.2 g, yield 63%).

[0397] 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.14-7.09 (m, 1H), 7.03-6.98 (m, 1H), 4.70 (s, 2H), 0.96 (s, 9H), 0.12 (s, 6H).

[0398] Third Step: Preparation of compound 2E

[0399] Compound 2D (2.2 g, 7.84 mmol), tetrabutylammonium fluoride (8.6 mL, 8.62 mmol, 1 M in THF) were added to THF (10 mL) and reacted at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and then purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 0-50%) to obtain 2E (1.2 g, yield 92%).

[0400] 1 H NMR (400 MHz, CDC13) δ 6.88-6.81 (m, 2H), 6.68-6.62 (m, 1H), 4.63 (s, 2H), 1.92-1.84 (m, 1H), 1.02-0.95 (m, 2H), 0.73-0.66 (m, 2H).

[0401] Fourth step: Preparation of compound 2G

[0402] Compound 2E (1.2 g, 7.22 mmol) and triphenylphosphine (2.27 g, 8.65 mmol) were added to DCM, then 2F (2.87 g, 8.65 mmol) was added and reacted at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure and then purified by column chromatography (mobile phase: petroleum ether) to obtain compound 2G (1.4 g, yield 85%).

[0403] 1 H NMR (400 MHz, CDC13) δ 6.92-6.86 (m, 2H), 6.69-6.64 (m, 1H), 4.41 (s, 2H), 1.93-1.84 (m, 1H), 1.03-0.97 (m, 2H), 0.74-0.68 (m, 2H).

[0404] Fifth step: Preparation of compound 2I

[0405] Compound 2G (1.3 g, 5.67 mmol), 2H (1.04 g, 7.38 mmol) and potassium carbonate (2.35 g, 17 mmol) were added to a mixed solvent of 1,4-dioxane (40 mL) and water (10 mL), 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex (0.23 g, 0.28 mmol) was added after replacing N2 three times, and heated to 100°C for 12 h after replacing N2 three times again. After the reaction was completed, water (100 mL) was added and extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, and then the organic phase was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 0-50%) to obtain 2I (0.64 g, yield 46%).

[0406] LCMS m / z = 246.1 [M+1] +

[0407] Step 6: Preparation of compound 2K

[0408] Compound 21 (0.64 g, 2.61 mmol) was added to hydrazine hydrate (2J) (9.1 mL) and ethanol (9.1 mL) and reacted at 90 °C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure to precipitate a solid, the filter cake was collected by suction filtration, and the filter cake was washed with ethanol (5 mL x 3) to obtain crude compound 2K (0.63 g).

[0409] LCMS m / z = 258.1 [M+1] +

[0410] Step 7: Preparation of compound 2M

[0411] Compound 2K (0.63 g, 2.45 mmol) and 2L (0.45 g, 2.64 mmol) were added to ethanol (10.0 mL), and then acetic acid (15 mg, 0.25 mmol) was added, and the mixture was reacted at 80 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to precipitate a solid, the filter cake was collected by suction filtration, and the filter cake was washed with ethanol (5 mL x 3) to obtain crude compound 2M (0.85 g).

[0412] LCMS m / z = 410.2 [M+1] +

[0413] Step 8: Preparation of compound 2N

[0414] Compound 2M (0.85 g, 2.08 mmol) and lithium hydroxide monohydrate (0.44 g, 10.5 mmol) were added to a mixed solvent of THF (5.0 mL), MeOH (5.0 mL), and water (2.5 mL), and the mixture was reacted at room temperature for 4 h. After the reaction was completed, the pH was adjusted to 2 with 2M HC1, and then the filter cake was collected by suction filtration, washed with water (2 mL x 3), and dried to obtain crude compound 2N (0.63 g).

[0415] LCMS m / z = 382.1 [M+1] +

[0416] Step 9: Preparation of compound 2

[0417] Compound 2N (0.63 g, 1.65 mmol), 2O (264.8 mg, 4.95 mmol) and HATU (1.25 g, 3.29 mmol) were added into DMF (10 mL), then N,N- diisopropylethylamine (0.85 g, 6.58 mmol) was added and the reaction was allowed to proceed at room temperature overnight. The reaction was concentrated under reduced pressure, the concentrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; column: XBridge® Prep C18 (19 mm x 250 mm); mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile) and lyophilized to give compound 2 (129 mg, yield 21%).

[0418] LCMS m / z = 381.1 [M+1] +

[0419] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, 1H), 7.71 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.31 (dd, 1H), 6.96-6.87 (m, 2H), 6.72 (d, 1H), 5.66 (t, 1H), 4.91 (d, 2H), 4.05 (s, 2H), 2.37 (s, 3H), 1.90 (tt, 1H), 0.99-0.90 (m, 2H), 0.72-0.64 (m, 2H).

[0420] Example 3: Preparation of compound 3

[0421] First step: Preparation of 3C

[0422] 3A (5000 mg, 32.44 mmol), 3B (3214 mg, 32.44 mmol), HATU (13.6 g, 35.77 mmol) and DIPEA (16 mL) were added into dichloromethane (100 mL) and the reaction was allowed to proceed at room temperature for 3 h. The reaction was concentrated under reduced pressure, the concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-60%) to give 3C (11 g) as a crude product.

[0423] LCMS m / z = 236.0 [M+H] +

[0424] Second step: Preparation of 3D

[0425] The crude 3C (11 g), NBS (9.99 g, 56.13 mmol) and azobisisobutyronitrile (1.54 g, 9.37 mmol) were added to acetonitrile (300 mL) and heated to 80 °C for 3 hours. Cooled to room temperature, the reaction was concentrated under reduced pressure, the concentrate was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-50%) to obtain 3D (12.1 g)

[0426] LCMS m / z = 314.0 and 316.0 [M+H] +

[0427] Third step: Preparation of 3E

[0428] The synthesis method of reference example 2 step 5 was referred to, to obtain 3E (2.83 g).

[0429] LCMS m / z = 331.1 [M+H] +

[0430] Fourth step: Preparation of 3F

[0431] The synthesis method of reference example 2 step 6 was referred to, to obtain 3F (2.2 g).

[0432] LCMS m / z = 343.2 [M+H] +

[0433] Fifth step: Preparation of 3G

[0434] The synthesis method of reference example 2 step 7 was referred to, to obtain 3G (1005 mg).

[0435] LCMS m / z = 495.1 [M+H] +

[0436] Sixth step: Preparation of 3H

[0437] The synthesis method of reference example 2 step 8 was referred to, to obtain 3H (400 mg).

[0438] LCMS m / z = 467.2 [M+H] +

[0439] Seventh step: Preparation of compound 3

[0440] To a solution of 3H (400 mg, 0.86 mmol), ammonium chloride (138 mg, 2.58 mmol), HATU (654 mg, 1.72 mmol) and DIPEA (0.57 mL) in DMF (10 mL) was added and stirred at room temperature overnight. Water (50 mL) was added and extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and further purified by prep-HPLC (Instrument: waters 2767 prep liquid; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) and lyophilized to give compound 3 (201 mg, yield: 50%).

[0441] LCMS m / z = 466.2 [M+H] +

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 9.18 - 9.10 (m, 1H), 8.43 (d, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.62 - 7.55 (m, 1H), 7.55 - 7.32 (m, 4H), 4.91 (s, 2H), 4.19 (s, 2H), 4.11 - 4.06 (m, 2H), 2.36 (s, 3H).

[0443] Example 4: Preparation of compound 4

[0444] First step: Preparation of 4C

[0445] To a solution of 4A (1.10 g, 9.56 mmol), 4B (1.72 g, 9.55 mmol), potassium carbonate (2.64 g, 19.10 mmol) in DMF (30 mL) was added and stirred at 80 °C for 4 h. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL), and the organic phase was concentrated under reduced pressure to give 4C (2.60 g) as a crude product.

[0446] LCMS m / z = 276.1 [M+H] +

[0447] Second to fifth steps refer to the synthetic method of the sixth to ninth steps of Example 2 to compound 4 (50 mg)

[0448] LCMS m / z = 411.0 [M+H] +

[0449] 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, 1H), 7.72-7.63 (m, 2H), 7.59 (s, 1H), 7.54-7.38 (m, 2H), 7.38-7.35 (m, 1H), 7.13-7.08 (m, 1H), 5.61 (t, 1H), 4.93 (d, 2H), 2.33 (s, 3H).

[0450] Example 5: Preparation of compound 5

[0451] First step: Preparation of 5C

[0452] 5A (2000 mg, 9.05 mmol), 5B (3489 mg, 13.57 mmol), cesium carbonate (5897 mg, 18.10 mmol) and potassium iodide (150 mg, 0.90 mmol) were added into acetonitrile (100 mL) and reacted at 80 °C overnight under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-50%) to obtain 5C (3.16 g, yield 88%).

[0453] LCMS m / z = 397.9 [M+H] +

[0454] Second step: Preparation of 5F

[0455] 5C (3.16 g, 7.96 mmol), 5D (1.05 g, 7.94 mmol), cesium carbonate (5.19 g, 15.93 mmol), cuprous iodide (76 mg, 0.40 mmol) and 1,10-phenanthroline (0.11 g, 0.61 mmol) were added into N,N-dimethylformamide (40 mL) and reacted at 80 °C overnight under nitrogen atmosphere. After cooling to room temperature, water (50 mL) was added and extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (V / V = 0-11%)). The purified intermediate was added to 1,4-dioxane (5 mL) and hydrogen chloride solution in 1,4-dioxane (20 mL, 4 mol / L) and reacted at room temperature overnight. It was concentrated under reduced pressure again to obtain the crude hydrochloride salt of 5F (3.3 g), which was directly used in the next step.

[0456] LCMS m / z = 302.1 [M+1] +

[0457] Third step: Preparation of 5G

[0458] The crude hydrochloride of 5F (3.3 g), 2L (1.83 g, 10.75 mmol), glacial acetic acid (59 mg, 0.98 mmol) obtained in the previous step were added into ethanol (50 mL) and reacted at 80 °C overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V = 0-5%) to obtain 5G (2.5 g).

[0459] LCMS m / z = 454.2 [M+H] +

[0460] Fourth step: preparation of 5H

[0461] 5G (2.5 g, 5.51 mmol) and lithium hydroxide monohydrate (1.16 g, 27.64 mmol) were added to a mixed solvent of THF (10 mL), MeOH (10 mL) and water (5 mL) and reacted at room temperature for 4 h. After the reaction was completed, the pH was adjusted to 2 with 2M HCl, extracted with dichloromethane (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of 5H (1.5 g).

[0462] LCMS m / z = 426.1 [M+H] +

[0463] Fifth step: preparation of compound 5

[0464] The crude product of 5H (1.5 g), ammonium chloride (0.57 g, 10.66 mmol), HATU (2.68 g, 7.05 mmol) and DIPEA (2.34 mL) were added to DMF (20 mL) and reacted at room temperature overnight. Water (50 mL) was added and extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(19 mm x 250 mm); mobile phase composition: acetonitrile / water containing 5 mmol ammonium bicarbonate) and lyophilized to obtain compound 5 (0.2 g).

[0465] LCMS m / z = 425.1 [M+H] +

[0466] 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1H), 7.69-7.59 (m, 3H), 7.57-7.48 (m, 1H), 7.37-7.25 (m, 2H), 6.56 (d, 1H), 5.77 (t, 1H), 5.22 (s, 2H), 4.52 (d, 2H), 2.33 (s, 3H).

[0467] Example 6: Preparation of compound 6

[0468] First step: Preparation of 6B

[0469] Reference to the synthesis method of example 2, step 5, 6B (300 mg) was obtained.

[0470] LCMS m / z = 334.0 [M+H] +

[0471] Second step: Preparation of 6D

[0472] 6B (300 mg, 0.90 mmol), 6C (775 mg, 9.00 mmol), potassium carbonate (373 mg, 2.70 mmol), palladium acetate (4 mg, 0.018 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (21 mg, 0.036 mmol) were added into 1,4-dioxane (10 mL) and reacted at 90 °C for 4 h under nitrogen atmosphere. The concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-50%) to obtain 6D (250 mg, yield 82%).

[0473] LCMS m / z = 340.1 [M+1] +

[0474] Third step: Preparation of compound 6

[0475] 6D (100 mg, 0.29 mmol) was added into dichloromethane (5 mL), 6E (57 mg, 0.40 mmol) was added at -78 °C, and the reaction was carried out at room temperature for 1 h. The concentrate was concentrated under reduced pressure, hydrochloric acid solution (6N, 4 mL) was added to the concentrate, and the reaction was carried out at 100 °C for 30 min. The reaction solution was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(19 mm x 250 mm); mobile phase composition: acetonitrile / water (containing 5 mmol ammonium bicarbonate)) and freeze-dried to obtain compound 6 (25 mg, yield 22%).

[0476] LCMS m / z = 383.1 [M+H] +

[0477] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, 1H), 8.03 (s, 1H), 7.58-7.42 (m, 4H), 7.31-7.20 (m, 1H), 7.07-7.03 (m, 1H), 4.14 (s, 2H), 4.00-3.92 (m, 2H), 3.81-3.72 (m, 2H).

[0478] Example 7: Preparation of compound 7

[0479] First step: Preparation of compound 7C

[0480] 7A (1.0 g, 7.03 mmol) and NaH (60%, 309.3 mg, 7.73 mmol) were added to DMF (23 mL), 7B (1.25 g, 7.72 mmol) was added dropwise slowly under stirring at 0 °C, after the addition was completed, it was restored to room temperature and reacted for 24 h. After the reaction was completed, the reaction system was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 20-50%) to obtain 7C (1.56 g, yield 83%).

[0481] LCMS m / z = 268.1 [M+H] +

[0482] Second step: Preparation of compound 7D

[0483] 7C (1.56 g, 5.83 mmol) was added to ethanol (20.0 mL) and hydrazine hydrate (30.0 mL), and stirred at 110 °C for 24 h. After the reaction was completed, the reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure to precipitate a solid, the filter cake was collected by suction filtration, the filter cake was washed with ethanol (5 mL x 3), and dried to obtain crude 7D (1.04 g).

[0484] LCMS m / z = 264.2 [M+H] +

[0485] Third step: Preparation of compound 7E

[0486] Compound 7D (1.04 g, 3.95 mmol) and 2L (0.74 g, 4.35 mmol) were added to ethanol (20.0 mL), and then acetic acid (24.0 mg, 0.40 mmol) was added. The reaction was carried out at 80 °C overnight. After the reaction was completed, the reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure until a solid was precipitated. The filter cake was collected by suction filtration, washed with ethanol (2 mL x 3), and dried to obtain the crude product 7E (0.87 g).

[0487] LCMS m / z = 416.1 [M+H] +

[0488] Fourth step: Preparation of compound 7F

[0489] Compound 7E (0.87 g, 2.09 mmol) and lithium hydroxide monohydrate (438.5 mg, 10.5 mmol) were added to a mixed solvent of THF (5.0 mL), MeOH (5.0 mL), and water (2.5 mL), and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the pH was adjusted to 2 with 2M HCl, and then the filter cake was collected by suction filtration, washed with water (2 mL x 3), and dried to obtain the crude product compound 7F (0.39 g).

[0490] LCMS m / z = 388.0 [M+1] +

[0491] Fifth step: Preparation of compound 7

[0492] Compound 7F (0.39 g, 1.01 mmol), 2O (162.1 mg, 3.03 mmol), and HATU (768.1 mg, 2.02 mmol) were added to DMF (5.0 mL), and then N,N-diisopropylethylamine (522.1 mg, 4.04 mmol) was added. The reaction was carried out at room temperature overnight. The concentrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatograph; column: XBridge® Prep C18 (19 mm x 250 mm); mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile) and lyophilized to obtain compound 7 (24.2 mg, yield: 6%).

[0493] LCMS m / z = 387.2 [M+1] +

[0494] 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, 1H), 7.88 (m, 2H), 7.65 (s, 1H), 7.58 (m, 1H), 7.50 (m, 1H), 7.39 (s, 1H), 7.29 (t, 1H), 7.04 (m, 1H), 6.73 (d, 1H), 5.73 (s, 2H), 5.58-5.52 (m, 1H), 4.89 (d, 2H), 2.34 (m, 3H).

[0495] Example 8: Preparation of compound 8

[0496] First step: Preparation of compound 8B

[0497] 8A (1.0 g, 5.29 mmol) and selenium dioxide (5.87 g, 52.9 mmol) were added to 1,4-dioxane (30 mL) and reacted at 110 °C for 48 h. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 3) to obtain 8B (450 mg, yield 42%).

[0498] LCMS m / z = 204.1 [M+H] +

[0499] Second step: Preparation of compound 8C

[0500] 8B (350 mg, 1.72 mmol), 6B (575 mg, 1.72 mmol), cuprous iodide (33 mg, 0.17 mmol), potassium phosphate (730 mg, 3.44 mmol), and N,N'-dimethylethylenediamine (455 mg, 5.16 mmol) were added to toluene (5 mL) and reacted at 110 °C for 17 h. After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution (20 mL), HCl (20 mL, 0.1 M aqueous solution), and saturated brine (20 mL) in turn, then dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 5) to obtain 8C (150 mg, yield 19%).

[0501] LCMS m / z = 457.0 [M+H] +

[0502] Third step: Preparation of compound 8D

[0503] Compound 8D (135 mg, 0.29 mmol) and lithium hydroxide monohydrate (61 mg, 1.45 mmol) were added into the mixture solvent of THF (3 mL), MeOH (3 mL) and water (1.5 mL), and the reaction was carried out at room temperature overnight. After the reaction was completed, the pH was adjusted to 2 with 2M HC1, and the compound 8E was obtained as a crude product (130 mg) after concentration.

[0504] LCMS m / z = 459.1 [M+H] +

[0505] Fourth step: Preparation of compound 8E

[0506] Compound 8D (135 mg, 0.29 mmol) and lithium hydroxide monohydrate (61 mg, 1.45 mmol) were added into the mixture solvent of THF (3 mL), MeOH (3 mL) and water (1.5 mL), and the reaction was carried out at room temperature overnight. After the reaction was completed, the pH was adjusted to 2 with 2M HC1, and the compound 8E was obtained as a crude product (130 mg) after concentration.

[0507] LCMS m / z = 445.1 [M+1] +

[0508] Fifth step: Preparation of compound 8

[0509] Compound 8E (130 mg), 2O (47 mg, 0.88 mmol) and HATU (221 mg, 0.58 mmol) were added into DMF (5 mL), and then N,N-diisopropylethylamine (187 mg, 1.45 mmol) was added, and the reaction was carried out at room temperature overnight. After concentration under reduced pressure, the residue was purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) and freeze-dried to obtain compound 8 (20 mg).

[0510] LCMS m / z = 444.2 [M+1] +

[0511] 1 H NMR (400 MHz, MeOH-d4) δ 8.59 (d, 1H), 8.05-7.99 (m, 1H), 7.56-7.53 (m, 1H), 7.52 (s, 1H), 7.45-7.42 (m, 1H), 7.41-7.33 (m, 2H), 7.28-7.18 (m, 3H), 4.82 (s, 2H), 4.28 (s, 2H).

[0512] Example 9: Preparation of compound 9

[0513] First Step: Preparation of compound 9B

[0514] Sodium hydride (0.74 g, 18.5 mmol, 60%) was suspended in N,N- dimethylformamide (60 mL). 9A (3.5 g, 15.26 mmol) (synthesized according to Archiv der Pharmazie, 1983, vol. 316, #8, p. 719-723) was added, followed by 5B (4.71 g, 18.32 mmol). The mixture was stirred at room temperature overnight, then diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 1) to give 9B (3 g, yield 48%).

[0515] LCMS m / z = 406.2 [M+H] +

[0516] Second Step: Preparation of compound 9C

[0517] 9B (2.5 g, 6.17 mmol) was added to THF (100 mL), tetrabutylammonium fluoride (12.3 mL, 1M in THF) was added, and the reaction was carried out at room temperature for 2 h. Saturated ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (mobile phase: ethyl acetate) to give 9C (1.4 g, yield 78%).

[0518] LCMS m / z = 292.1 [M+H] +

[0519] Third Step: Preparation of compound 9D

[0520] 9C (1.7 g, 5.84 mmol) was added to DCM (50 mL), and Dess-Martin oxidizing agent (3.72 g, 8.76 mmol) was added. The reaction was carried out at room temperature for 3 h. After the reaction was completed, saturated sodium bicarbonate solution (20 mL) and saturated sodium thiosulfate solution (20 mL) were added, and the mixture was extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 1) to give 9D (1 g, yield 59%).

[0521] LCMS m / z = 290.1 [M+H] +

[0522] Fourth Step: Preparation of compound 9E

[0523] To a solution of 9D (1 g, 3.46 mmol), 5D (0.91 g, 6.89 mmol), acetic acid (0.42 g, 6.99 mmol) in 1,2-dichloroethane (30 mL) was added, stirred at room temperature for 30 min, sodium cyanoborohydride (0.43 g, 6.84 mmol) was added, stirred at room temperature for 3 h, concentrated, the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 2 / 1) to give 9E (1 g, yield 71%).

[0524] LCMS m / z = 350.1 [M-55] +

[0525] Fifth step: Preparation of compound 9F

[0526] To a solution of 9E (1000 mg, 2.47 mmol) in hydrogen chloride-dioxane solution (30 mL, 4 mol / L) was added, stirred at room temperature for 5 h, concentrated, ethanol (20 mL), diisopropylethylamine (638 mg, 4.94 mmol) and 2L (462 mg, 2.72 mmol) were added, stirred at room temperature overnight, concentrated, the residue was purified by column chromatography (mobile phase: methanol / dichloromethane = 1 / 20) to give 9F (800 mg, yield 71%).

[0527] LCMS m / z = 458.1 [M+1] +

[0528] Sixth step: Preparation of compound 9G

[0529] Reference to the synthesis method of example 8 fourth step, to give 9G crude product (375 mg).

[0530] LCMS m / z = 430.2 [M+H] +

[0531] Seventh step: Preparation of compound 9

[0532] To a solution of compound 9G crude product (375 mg), 2O (140 mg, 2.62 mmol) and HATU (662 mg, 1.74 mmol) in DMF (10 mL) was added, then N,N-diisopropylethylamine (562 mg, 4.35 mmol) was added, stirred at room temperature overnight. Concentrated under reduced pressure, the concentrate was purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; column: SUNFIRE® Prep C18 (19 mm x 250 mm); mobile phase composition: acetonitrile / water (containing 0.05% ammonium acetate)) and lyophilized to give compound 9 (70 mg).

[0533] LCMS m / z = 429.2 [M+1]+

[0534] 1 H NMR (400 MHz, MeOH-d4) δ 7.47 (s, 1H), 7.45-7.40 (m, 1H), 7.38-7.32 (m, 1H), 4.99-4.92 (m, 1H), 4.92-4.85 (m, 1H), 4.76 (d, 2H), 4.54-4.46 (m, 1H), 3.81-3.62 (m, 2H), 2.75-2.54 (m, 2H), 2.48-2.36 (m, 1H), 2.34 (s, 3H), 2.27-2.15 (m, 1H).

[0535] Example 10: Preparation of compound 10

[0536] First step: Preparation of 10B

[0537] Compound 10A (2.0 g, 13.49 mmol) was added to THF (50.0 mL) at 0 °C, then NBS (3.60 g, 20.23 mmol) was added, and the reaction was stirred for 30 min and then returned to room temperature, and reacted for 48 h. After the reaction was completed, it was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (mobile phase: petroleum ether) to obtain crude 10B (3.1 g).

[0538] 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.89 (d, 1H), 7.56-7.53 (m, 1H), 7.28-7.24 (m, 1H), 2.44 (s, 3H).

[0539] Second step: Preparation of 10C

[0540] The crude compound 10B (3.1 g), sodium trifluoroacetate (4.8 g, 35.29 mmol), and cuprous iodide (3.0 g, 15.75 mmol) were added to N-methyl pyrrolidone (30.0 mL), and the reaction was stirred at 160 °C for 1 h, then the temperature was raised to 180 °C and reacted for another 1 h. After the reaction was completed, the reaction liquid was cooled to room temperature, and poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (mobile phase: petroleum ether) to obtain crude 10C (2.15 g).

[0541] Third step: Preparation of 10D

[0542] The crude compound 10C (1.5 g), NBS (1.36 g, 7.64 mmol) and azobisisobutyronitrile (0.23 g, 1.4 mmol) were added to carbon tetrachloride (20.0 mL) and reacted at 70 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (mobile phase: petroleum ether) to obtain 10D (0.67 g).

[0543] The fourth step to the eighth step was according to the synthetic method of the fifth step to the ninth step of Example 2 to obtain compound 10 (8.5 mg)

[0544] LCMS m / z = 447.1 [M+H] +

[0545] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.42 (d, 1H), 8.11 (d, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 5.63 (t, 1H), 4.90 (d, 2H), 4.30 (s, 2H), 2.34 (s, 3H).

[0546] Example 11: Preparation of compound 10

[0547] First step: Preparation of 11B

[0548] Compound 11A (2.0 g, 24.07 mmol) and sodium ethoxide (2.46 g, 36.15 mmol) were added to toluene (15.0 mL) at 0 °C, and the reaction was restored to room temperature for 1 h. Then acetonitrile (6.0 mL) and chloroacetyl chloride (1.36 g, 12.04 mmol) were added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, 3 mol / L sulfuric acid (20.0 mL) was added, and ethyl acetate (30 mL x 3) was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 20-50%) to obtain 11B (541 mg, 36%).

[0549] LCMS m / z = 124.1 [M+H] +

[0550] The second step to the third step was according to the synthetic method of the fifth step to the sixth step of Example 2 to obtain crude compound 11E (1.54 g)

[0551] LCMS m / z = 286.1 [M+H] +

[0552] Step 4: Preparation of compound 11F

[0553] The crude compound 11E (1.14 g), 11B (541 mg, 4.39 mmol) was added to ethanol (20.0 mL), then acetic acid (24 mg, 0.40 mmol) was added, and the mixture was reacted at 80 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure until solid was precipitated, the filter cake was collected by suction filtration, and the filter cake was washed with ethanol (1 mL x 3) to obtain the crude compound 11F (0.75 g).

[0554] LCMS m / z = 391.1 [M+1] +

[0555] Step 5: Preparation of compound 11

[0556] Ethanol (6.0 mL), the crude compound 11F (0.6 g), methoxyamine hydrochloride (0.39 g, 4.67 mmol), triethylamine (0.31 g, 3.06 mmol) and mercaptoacetic acid (0.14 g, 1.52 mmol) were added to a sealed tube, and the mixture was reacted at 90 °C for 24 h, then cooled to room temperature, concentrated under reduced pressure, and the concentrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatograph; column: XBridge® Prep C18 (19 mm x 250 mm); mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile) and lyophilized to obtain compound 11 (8.4 mg).

[0557] LCMS m / z = 438.2 [M+1] +

[0558] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, 1H), 7.82 (s, 1H), 7.64 (s, 1H), 7.56 (m, 2H), 7.36 (m, 1H), 4.86 (s, 2H), 4.24 (s, 2H), 3.76 (s, 3H), 2.30 (s, 3H).

[0559] Example 12: Preparation of compound 12

[0560] Compound 12 (81.4 mg) was obtained according to the synthetic method of the fifth to ninth steps of Reference Example 2.

[0561] LCMS m / z = 364.1 [M+H] +

[0562] 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, 1H), 7.88 (s, 1H), 7.84 (d, 1H), 7.75 (d, 1H), 7.65 (m, 1H), 7.51 (s, 1H), 7.43 (m, 1H), 7.38 (m, 2H), 5.60 (t, 1H), 4.92 (d, 2H), 4.60 (s, 2H), 2.36 (s, 3H).

[0563] Example 13: Preparation of compound 13

[0564] Reference to the synthesis method of compound 1, the reaction solution of the second step was concentrated under reduced pressure, and further purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30mmx150mm); mobile phase composition: acetonitrile / water(containing 0.1% trifluoroacetic acid)) to obtain a preparation liquid, dichloromethane(50mL) and sodium bicarbonate solution(50mL) were added, extracted and separated, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 13(42mg).

[0565] LCMS m / z = 447.1 [M+H] +

[0566] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.77 (s, 1H), 7.73-7.66 (m, 1H), 7.64 (s, 1H), 7.60-7.52 (m, 2H), 7.40-7.29 (m, 2H), 4.23 (s, 2H), 4.19 (d, 2H), 3.65 (d, 2H), 2.36 (s, 3H).

[0567] Example 14: Preparation of compound 14

[0568] First step: preparation of compound 14A

[0569] Reference to the synthesis method of the first step of Example 1 to obtain the crude compound 14A(38mg).

[0570] LCMS m / z = 379.1 [M+H] +

[0571] Second step: preparation of compound 14

[0572] To a solution of compound 14A (38 mg), 1C (20 mg, 0.20 mmol), NaBH(OAc)3 (32 mg, 0.15 mmol), acetic acid (6.0 mg, 0.10 mmol) in dichloromethane (2.0 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and further purified by preparative HPLC (Instrument: Waters 2767 preparative liquid; Column: XBridge® Prep C18 (19 mm x 250 mm); Mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile) and lyophilized to give compound 14.

[0573] LCMS m / z = 462.2 [M+H] +

[0574] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 7.69 (m, 2H), 7.39 (s, 1H), 7.31 (m, 1H), 6.94 (s, 1H), 6.89 (m, 1H), 6.73 (m, 1H), 4.19 (d, 2H), 4.04 (s, 2H), 3.25 (m, 2H), 2.36 (s, 3H), 1.94-1.85 (m, 1H), 0.98-0.92 (m, 2H), 0.72-0.66 (m, 2H).

[0575] Example 15: Preparation of compound 15-1 and compound 15-2

[0576] First step: Preparation of 15B

[0577] To a solution of 2B (25.0 g, 78.3 mmol), 15A (24.1 g, 156.5 mmol) and anhydrous potassium carbonate (21.6 g, 156.3 mmol) in a mixture solvent of 1,4-dioxane (142 mL) and water (6 mL) was added 1,1’-bis(diphenylphosphino)ferrocene palladium(II) dichloride (5.73 g) after three times of N2 replacement, and heated to 100 °C overnight after three times of N2 replacement again. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added, extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: petroleum ether) to give 15B (12.0 g, yield 58%).

[0578] 1H NMR (400 MHz, DMSO-d6) δ 7.21 - 7.13 (m, 2H), 7.01 - 6.95 (m, 1H), 6.70 (dd, 1H), 5.84 (d, 1H), 5.30 (d, 1H), 4.69 (s, 2H), 0.89 (s, 9H), 0.07 (s, 6H).

[0579] Second Step: Preparation of 15D

[0580] 15B (12.0 g, 45 mmol) and 15C (32.1 g, 90.1 mmol, CAS#: 1449521-05-4) were added to a sealed tube, then 1,3,5-trimethylbenzene (33 mL) was added, and the reaction was carried out at 90 °C for 8 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: petroleum ether) to obtain 15D crude product, which was directly used in the next step.

[0581] 1 H NMR (400 MHz, DMSO-d6) δ 7.21 - 7.13 (m, 2H), 7.01 - 6.95 (m, 1H), 6.70 (dd, 1H), 5.84 (d, 1H), 5.30 (d, 1H), 4.69 (s, 2H), 0.89 (s, 9H), 0.07 (s, 6H).

[0582] The third to ninth steps were synthesized according to the synthesis method of the third to ninth steps of Example 2, and compound 15 (680 mg) was obtained by freeze-drying. The final product of compound 15 was separated by chiral preparation (instrument: CAS-05-Prep-SFC-E preparation chromatographic column: IG column; mobile phase composition: CO2 / methanol (0.1% NH3·H2O), and freeze-drying to obtain compound 15-1 (chiral column retention time: 2.686 min, 193 mg) and compound 15-2 (chiral column retention time: 2.882 min, 165 mg), which were obtained by measuring the chiral column retention time by an analytical instrument CAS-05-ANA-SFC-D (chiral chromatographic column: IG column; mobile phase composition: CO2 / methanol (0.05% DEA), flow rate: 3 mL / min; column temperature: 35 °C). One of compound 15-1 and compound 15-2 is compound 15-A, and the other is compound 15-B.

[0583] Compound 15: LCMS m / z = 417.1 [M+H] +

[0584] Compound 15-1: LCMS m / z = 417.2 [M+H] +

[0585] 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, 1H), 7.73 (m, 1H), 7.45 (m, 2H), 7.32 (m, 1H), 7.15 (s, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 5.63 (m, 1H), 4.91 (m, 2H), 4.10 (s, 2H), 3.32 (s, 3H), 3.10-2.93 (m, 1H), 2.36 (s, 3H), 2.08-1.92 (m, 2H).

[0586] Compound 15-2: LCMS m / z = 417.2 [M+H] +

[0587] Example 16: Preparation of compound 16

[0588] First step: Preparation of 16B

[0589] Take 16A (synthesis method for reference WO2024 / 146559) as raw material, and refer to the synthesis method of example 2 step 5 to obtain 16B (650 mg).

[0590] LCMS m / z = 264.0 [M+H] +

[0591] Second step: Preparation of 16C

[0592] Compound 16B (650 mg, 2.47 mmol) was added to 2J (15 mL) and ethanol (15 mL) and reacted at 90°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude compound 16C (750 mg) which was directly used in the next step.

[0593] LCMS m / z = 276.1 [M+H] +

[0594] Third step: Preparation of 16D

[0595] The crude compound 16C (750 mg) and 2L (509 mg, 2.99 mmol) were added to ethanol (10 mL), and then acetic acid (16 mg, 0.27 mmol) was added, and reacted at 80°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (V / V=0-5%) to obtain 16D (790 mg).

[0596] LCMS m / z = 428.2 [M+H] +

[0597] Fourth step: Preparation of 16E

[0598] Reference to the synthesis method of Example 2, step 8, to obtain 16E (750 mg).

[0599] LCMS m / z = 400.2 [M+H] +

[0600] Fifth step: preparation of compound 16

[0601] Reference to the synthesis method of Example 2, step 9, to obtain compound 16 (395 mg).

[0602] LCMS m / z = 399.2 [M+H] +

[0603] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, 1H), 7.72 (s, 1H), 7.53 (s, 1H), 7.51-7.43 (m, 2H), 7.41-7.30 (m, 3H), 5.62 (t, 1H), 4.90 (d, 2H), 4.16 (s, 2H), 3.00 (s, 2H), 2.63-2.53 (m, 2H), 2.35 (s, 3H).

[0604] Example 17: preparation of compound 17

[0605] First step: preparation of compound 17A

[0606] Compound 11D (4.6 g, 16.84 mmol) was added to acetonitrile (200 mL), potassium permanganate (25 g, 158.20 mmol) was added, and the reaction was carried out at 50°C overnight, cooled to room temperature, and filtered with diatomite. The filtrate was concentrated, saturated sodium thiosulfate solution (100 mL) was added, extracted with ethyl acetate (100 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 5)) to obtain 17A (2.38 g, yield 49%).

[0607] LCMS m / z = 288.0 [M+1] +

[0608] Second step: preparation of compound 17C

[0609] Into a three-necked flask was placed compound 17B (3.23 g, 8.7 mmol) and tetrahydrofuran (10 mL) at room temperature. The reaction mixture was cooled to 0 °C, and n-butyllithium in n-hexane (3.48 mL, 2.5 mmol / L) was added. The reaction mixture was stirred at 0 °C for 1 h, and then 17A (1 g, 3.48 mmol) was added. The reaction was continued at room temperature for 2 h. Saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 5)) gave 17C (0.18 g, yield 17%).

[0610] LCMS m / z = 300.0 [M+1] +

[0611] Step 3: Preparation of compound 17D

[0612] Compound 17C (200 mg, 0.67 mmol) was added to methanol (10 mL), and 10% Pd / C (100 mg) was added. The reaction was carried out at room temperature under a hydrogen atmosphere overnight. The mixture was filtered and concentrated to give crude compound 17D (200 mg), which was used directly in the next step.

[0613] LCMS m / z = 302.1 [M+1] +

[0614] Step 4: Preparation of compound 17E

[0615] The crude 17D (200 mg) obtained in the previous step was added to hydrazine hydrate (2J) (5 mL) and ethanol (5 mL), and the reaction was carried out at 90 °C overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude compound 17E (100 mg), which was used directly in the next step.

[0616] LCMS m / z = 314.2 [M+1] +

[0617] Step 5: Preparation of compound 17F

[0618] The crude 17E (100 mg) obtained in the previous step and 2L (60 mg, 0.35 mmol) were added to ethanol (10.0 mL), and then acetic acid (2 mg, 0.03 mmol) was added. The reaction was carried out at 80 °C overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude compound 17F (100 mg), which was used directly in the next step.

[0619] LCMS m / z = 466.2 [M+1] +

[0620] Step 6: Preparation of compound 17

[0621] To the crude 17F (100 mg) from previous step was added methanol (2 mL), THF (2 mL) and water (1 mL), lithium hydroxide monohydrate (44 mg, 1.05 mmol) was added, the reaction was stirred at room temperature for 3 hours, hydrogen chloride-1,4-dioxane solution (0.3 mL, 4 mol / L) was added, concentrated under reduced pressure, DMF (10 mL) was added, ammonium chloride (34 mg, 0.64 mmol), HATU (160 mg, 0.42 mmol) and diisopropylethylamine (136 mg, 1.05 mmol) were added, the reaction was stirred at room temperature overnight, concentrated under reduced pressure, and further purified by prep-HPLC (Instrument: waters 2767 prep liquid; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) and lyophilized to give compound 17 (10 mg).

[0622] LCMS m / z = 437.1 [M+H] +

[0623] 1 H NMR (400 MHz, MeOH-d4) δ 8.43 (d, 1H), 7.85 (s, 1H), 7.50 (s, 1H), 7.46-7.41 (m, 1H), 7.41-7.37 (m, 1H), 7.34-7.28 (m, 1H), 4.94 (s, 2H), 4.16 (t, 1H), 2.45 (s, 3H), 2.28-2.13 (m, 2H), 0.95 (t, 3H).

[0624] Example 18: Preparation of compound 18

[0625] First Step: Preparation of 18B

[0626] Reference to the second step of the synthesis method in Example Six, 18B (300 mg) was obtained.

[0627] LCMS m / z = 354.2 [M+1] +

[0628] Second Step: Preparation of compound 18

[0629] Compound 18 (20 mg, yield: 6%) was obtained after purification by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) and lyophilization.

[0630] LCMS m / z = 397.1 [M+H] +

[0631] 1 H NMR (400 MHz, MeOH-d4) δ 8.37 (d, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.38-7.29 (m, 2H), 7.22 (d, 1H), 4.19 (s, 2H), 3.95-3.84 (m, 4H), 2.21-2.06 (m, 2H).

[0632] Example 19: Preparation of compound 19

[0633] Compound 19 (5 mg) was obtained by taking 19A as the starting material and referring to the synthetic method of Example 8.

[0634] LCMS m / z = 462.0 [M+H] + .

[0635] 1 H NMR (400 MHz, MeOH-d4) δ 8.59 (d, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 7.52 (s, 1H), 7.46-7.43 (m, 1H), 7.42-7.33 (m, 2H), 7.27-7.21 (m, 1H), 7.03-6.95 (m, 1H), 4.80 (s, 2H), 4.29 (s, 2H).

[0636] Example 20: Preparation of compound 20

[0637] Compound 20 (90 mg) was obtained by taking 20A as the starting material and referring to the synthetic method of Example 8.

[0638] LCMS m / z = 462.1 [M+H] + .

[0639] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.09-7.90 (m, 1H), 7.85-7.33 (m, 7H), 7.18-6.98 (m, 2H), 4.75 (s, 2H), 4.27 (s, 2H).

[0640] Example 21: Preparation of compound 21

[0641] Compound 21 (70 mg) was obtained by referring to the synthetic method of Example 18, taking 6B as the starting material.

[0642] LCMS m / z = 381.1 [M+H] + .

[0643] 1 H NMR (400 MHz, MeOH-d4) δ 8.35 (d, 1H), 8.21 (s, 1H), 7.53-7.41 (m, 2H), 7.37-7.27 (m, 2H), 7.21-7.03 (m, 2H), 4.18 (s, 2H).

[0644] Example 22: Preparation of compound 22

[0645] First step: preparation of 22B

[0646] 22B (4.2 g) was obtained by referring to the synthetic method of Example 2, step 5.

[0647] LCMS m / z = 371.1 [M+H] +

[0648] Second step: preparation of 22C

[0649] 22B (3.2 g, 8.64 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added, and the reaction was carried out at room temperature for three hours. After being concentrated under reduced pressure, saturated sodium bicarbonate solution (30 mL) was added, dichloromethane (30 mL x 3) was extracted, anhydrous sodium sulfate was dried, filtered, and concentrated under reduced pressure to obtain compound 22C crude (2.3 g) for the next reaction.

[0650] LCMS m / z = 271.1 [M+1] +

[0651] Third step: preparation of compound 22E

[0652] The 22C crude product obtained in the previous step (2.3 g) was added to tetrahydrofuran (50 mL), triethylamine (4.37 g, 43.2 mmol) was added, stirred at room temperature for 10 min, 22D (1.49 g, 9.52 mol) was added, and the reaction was carried out at room temperature for 5 h. Water (50 mL) was added, and ethyl acetate (50 mL x 3) was extracted, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V=1 / 3)) to obtain 22E (1.9 g).

[0653] LCMS m / z = 391.0 [M+H] +

[0654] Fourth step: preparation of compound 22G

[0655] 22E (660 mg, 1.69 mmol), 22F (190 mg, 2.53 mmol), and diisopropyl ethylamine (655 mg, 5.07 mmol) were added to DMF (10 mL), and the reaction was carried out at 50°C for 3 h, concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V=2 / 3)) to obtain 22G (550 mg, yield 88%).

[0656] LCMS m / z = 372.1 [M+H] +

[0657] Fifth step: preparation of compound 22H

[0658] To a solution of 22G (560 mg, 1.51 mmol) in THF (10 mL) was added a solution of potassium tert-butoxide in tetrahydrofuran (3.8 mL, 1 mol / L) at 0°C, followed by p-toluenesulfonyl chloride (345 mg, 1.81 mmol); the mixture was stirred at 0°C for 40 min, and then the temperature was raised to room temperature, and the mixture was filtered with diatomite, washed with THF (10 ml), and the filtrate was concentrated, and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V=3 / 2)) to obtain 22H (164 mg, yield 31%).

[0659] LCMS m / z = 354.1 [M+H]+

[0660] Sixth step: preparation of compound 22

[0661] Compound 22 (40 mg, yield: 18%) was obtained after purification by preparative HPLC (Instrument: waters 2767 preparative liquid; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) and lyophilization. LCMS m / z = 397.1 [M+H] +

[0662] Chiral resolution:

[0663] The final product of compound 22 was subjected to chiral preparation (Instrument: CAS-05-Prep-SFC-A preparative column: AS column; mobile phase composition: CO2 / isopropanol (0.1% NH3-H2O)) and lyophilization to obtain compound 22-1 (chiral column retention time: 1.043 min, 104 mg) and compound 22-2 (chiral column retention time: 1.258 min, 104 mg), which were obtained by analytical instrument CAS-05-ANA-SFC-D (chiral column: AS column; mobile phase composition: CO2 / isopropanol (0.05% NH3); flow rate: 3 mL / min; column temperature: 35 °C). Among compound 22-1 and compound 22-2, one is compound 22-A and the other is compound 22-B.

[0664] Compound 22-1: LCMS m / z = 397.1 [M+H] +

[0665] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1H), 8.03 (s, 1H), 7.65-7.43 (m, 4H), 7.24 (s, 1H), 7.06 (dd, 1H), 4.37-4.26 (m, 1H), 4.13 (s, 2H), 4.07 (dd, 1H), 3.63 (dd, 1H), 1.31 (d, 3H).

[0666] Compound 22-2: LCMS m / z = 397.1 [M+H] +

[0667] Example 23: Preparation of compounds 23-1 and 23-2

[0668] First Step: Preparation of 23A

[0669] To 11D (1.0 g, 3.66 mmol) in THF (30 mL) was cooled to -78 °C, n-butyllithium (1.61 mL, 2.5 mol / L in n-hexane) was added, the reaction was carried out for 0.5 h, then iodomethane (0.57 g, 4.02 mmol) was added, slowly warmed to room temperature, and the reaction was continued for 1 h. Water (100 mL) was added to the reaction, extracted with ethyl acetate (100 mL), the organic phase was concentrated under reduced pressure and then purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 0-20%)) to obtain 23A (0.9 g, yield 86%).

[0670] LCMS m / z = 288.0 [M+H] +

[0671] The second to fifth steps were obtained by the synthetic method of the sixth to ninth steps of Example 2 to obtain compound 23 (300 mg). Compound 23 was purified by chiral preparation (instrument: SHIMADZU LC-20AP preparation column: Chiral IA column; mobile phase composition: n-hexane / isopropyl alcohol and acetonitrile (containing 0.1% isopropylamine)), and freeze-dried to obtain compound 23-1 (chiral column retention time: 2.442 min, 135 mg) and 23-2 (chiral column retention time: 2.954 min, 129 mg), which were obtained by measuring the chiral column retention time by the analytical instrument SHIMADZU LC-20AD (chiral analysis column: Chiral IA column mobile phase: n-hexane / isopropyl alcohol and acetonitrile (containing 0.1% isopropylamine); flow rate: 1 mL / min; column temperature: 35 °C). Among compound 23-1 and compound 23-2, one is compound 23-A and the other is compound 23-B.

[0672] Compound 23 LCMS m / z = 423.1 [M+H] +

[0673] Compound 23-1 LCMS m / z = 423.1 [M+H] +

[0674] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, 1H), 7.79 (s, 1H), 7.67-7.61 (m, 2H), 7.57-7.33 (m, 4H), 5.61 (t, 1H), 4.90 (d, 2H), 4.53 (q, 1H), 2.36 (s, 3H), 1.67 (d, 3H).

[0675] Compound 23-2 LCMS m / z = 423.1 [M+H] +

[0676] Example 24: Preparation of compound 24

[0677] First step: Preparation of 24C

[0678] To a solution of 24A (1.5 g, 8.37 mmol), 24B (1.47 g, 8.35 mmol) and anhydrous potassium carbonate (2.31 g, 16.7 mmol) in DMF (30 mL) was added 1,1’- bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.61 g) under nitrogen atmosphere. After three times nitrogen replacement, the reaction was stirred at 90 °C overnight. After the reaction was completed, it was cooled to room temperature, diluted with water (100 mL) and extracted with dichloromethane (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (V / V) = 5-10%) to give 24C (704 mg, yield 31%).

[0679] LCMS m / z = 275.0 [M+H] +

[0680] Second step: Preparation of 24E

[0681] To a solution of 24C (704 mg, 2.57 mmol) and NaH (0.12 g, 3.0 mmol, 60%) in THF (10 mL) was stirred at room temperature for 15 min, then 24D (0.55 g, 3.87 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, water (30 mL) was added and extracted with dichloromethane (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (V / V) = 5-10%) to give 24E (504 mg, yield 68%).

[0682] LCMS m / z = 289.1 [M+H] +

[0683] The third to sixth steps were performed according to the synthetic method of the sixth to ninth steps of Example 2 to give compound 24 (35.2 mg).

[0684] LCMS m / z = 424.2 [M+H] +

[0685] 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, 1H), 7.70-7.61 (m, 3H), 7.44 (m, 2H), 7.21 (m, 1H), 6.83 (m, 1H), 4.79 (s, 2H), 3.44 (s, 3H), 2.34 (s, 3H).

[0686] Example 25: Preparation of compound 25

[0687] Compound 25 (80 mg) was obtained by using 22E as starting material, following the synthetic method of Example 22, fourth to sixth steps.

[0688] LCMS m / z = 411.1 [M+H] + .

[0689] 1 H NMR (400 MHz, MeOH-d4) δ 8.26 (d, 1H), 8.13-8.07 (m, 1H), 7.42 (s, 1H), 7.34-7.26 (m, 2H), 7.02-6.98 (m, 1H), 4.13 (s, 2H), 3.83 (s, 2H), 1.63 (s, 6H).

[0690] Example 26: Preparation of compound 26

[0691] Compound 26 (56 mg) was obtained by using 22E as starting material, following the synthetic method of Example 22, fourth to sixth steps.

[0692] LCMS m / z = 397.1 [M+H] + .

[0693] Chiral resolution:

[0694] The final product of compound 26 was subjected to chiral preparation (instrument: CAS-05-Prep-SFC-G, preparative chiral column: WHELK column; mobile phase composition: CO2 / ethanol (0.1% NH3-H2O)), and was lyophilized to obtain compound 26-1 (chiral column retention time: 1.294 min, 55 mg) and compound 26-2 (chiral column retention time: 1.529 min, 58 mg), which were obtained by measuring the chiral column retention time by analytical instrument CAS-05-ANA-SFC-D (chiral column: WHELK column; mobile phase composition: CO2 / ethanol (0.05% NH3); flow rate: 3 mL / min; column temperature: 35 °C). One of compound 26-1 and compound 26-2 is compound 26-A, and the other is compound 26-B.

[0695] Compound 26-1: LCMS m / z = 397.1 [M+H] +

[0696] Compound 26-2: LCMS m / z = 397.1 [M+H] +

[0697] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, 1H), 7.94 (s, 1H), 7.60-7.41 (m, 4H), 7.27 (s, 1H), 7.08-7.03 (m, 1H), 4.76-4.62 (m, 1H), 4.13 (s, 2H), 3.97-3.84 (m, 1H), 3.49-3.40 (m, 1H), 1.30 (d, 3H).

[0698] Example 27: Preparation of compound 27

[0699] First step: Preparation of compound 27A

[0700] Compound 17A (1500 mg, 5.22 mmol) was added into dichloromethane (2.5 mL), diethylamine sulfide (12621 mg, 78.3 mmol) was added slowly under nitrogen atmosphere, and the reaction was carried out at room temperature overnight. Methanol (3 mL) was added, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-20%) to obtain 27A (400 mg, yield 25%).

[0701] LCMS m / z = 310.0 [M+1] +

[0702] Second step: Preparation of compound 27B

[0703] The synthesis method of reference example 2, step 6 was referred to, and 27B (432 mg) was obtained.

[0704] LCMS m / z = 322.1 [M+H] +

[0705] Third step: Preparation of compound 27C

[0706] The synthesis method of reference example 2, step 7 was referred to, and 27C (460 mg) was obtained.

[0707] LCMS m / z = 474.2 [M+H] +

[0708] Fourth step: Preparation of compound 27D

[0709] Reference to the synthesis method of Example 2, step 8, afforded 27D (320 mg).

[0710] LCMS m / z = 446.0 [M+H] +

[0711] Step 5: Preparation of compound 27

[0712] Reference to the synthesis method of Example 2, step 9, afforded compound 27 (135 mg).

[0713] LCMS m / z = 445.1 [M+H] +

[0714] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, 1H), 8.07-8.01 (m, 2H), 7.98-7.93 (m, 2H), 7.77-7.71 (m, 1H), 7.58-7.39 (m, 2H), 5.49 (t, 1H), 4.96 (d, 2H), 2.38 (s, 3H).

[0715] Example 28: Preparation of compound 28

[0716] Reference to the synthesis method of Example 18, starting from 6B, afforded compound 28 (55 mg).

[0717] LCMS m / z = 431.1 [M+H] +

[0718] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, 1H), 8.19-8.07 (m, 2H), 8.02-7.93 (m, 1H), 7.86 (s, 1H), 7.73-7.65 (m, 1H), 7.63 (s, 1H), 7.56 (d, 2H), 7.42 (d, 1H), 7.25-7.16 (m, 2H), 4.25 (s, 2H).

[0719] Example 29: Preparation of compound 29

[0720] Reference to the synthesis method of Example 18, starting from 6B, afforded compound 29 (113 mg).

[0721] LCMS m / z = 467.0 [M+H] +

[0722] 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, 1H), 8.16-8.04 (m, 2H), 8.04-7.98 (m, 1H), 7.95-7.90 (m, 1H), 7.89 (s, 1H), 7.61 (s, 1H), 7.58-7.51 (m, 2H), 7.41 (d, 1H), 4.23 (s, 2H).

[0723] Example 30: Preparation of compound 30

[0724] First step: Preparation of compound 30A

[0725] Compound 17A (1400 mg, 4.87 mmol) was added into tetrahydrofuran (20 mL), cooled to 0 °C, methyl magnesium bromide in tetrahydrofuran (4.87 mL, 3 M) was added slowly under nitrogen atmosphere, and the reaction was carried out at room temperature for 4 hours. Saturated ammonium chloride solution (5 mL) was added, extracted with ethyl acetate (10 mL x 3), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-35%) to obtain 30A (1.2 g, yield 81%).

[0726] LCMS m / z = 304.0 [M+1] +

[0727] Second step: Preparation of compound 30B

[0728] Compound 30A (1.2 g, 3.96 mmol) was added into dichloromethane (20 mL), cooled to 0 °C, diethylamine sulfide (1404 mg, 8.71 mmol) was added slowly under nitrogen atmosphere, and the reaction was carried out at room temperature for 4 hours. Methanol (1 mL) was added, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-25%) to obtain 30B (1.31 g) as a crude product.

[0729] LCMS m / z = 306.1 [M+1] +

[0730] Third step: Preparation of compound 30C

[0731] Reference to the synthesis method of Example 2, sixth step, to obtain 30C (1.41 g).

[0732] LCMS m / z = 318.1 [M+H] +

[0733] Third step: Preparation of compound 30D

[0734] Reference to the synthesis method of example 2, step 7, to obtain 30D (1.1 g).

[0735] LCMS m / z = 470.2 [M+H] +

[0736] Fourth step: Preparation of compound 30E

[0737] Reference to the synthesis method of example 2, step 8, to obtain 30E (890 mg).

[0738] LCMS m / z = 442.2 [M+H] +

[0739] Fifth step: Preparation of compound 30

[0740] Reference to the synthesis method of example 2, step 9, to obtain compound 30 (443 mg).

[0741] LCMS m / z = 441.1 [M+H] +

[0742] 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, 1H), 7.93-7.90 (m, 1H), 7.82-7.78 (m, 1H), 7.74-7.70 (m, 2H), 7.57-7.54 (m, 1H), 7.53-7.45 (m, 1H), 7.45-7.35 (m, 1H), 5.54 (t, 1H), 4.92 (d, 2H), 2.37 (s, 3H), 2.20 (d, 3H).

[0743] Example 31: Preparation of compound 31

[0744] First step: Preparation of 31B

[0745] Reference to the synthesis method of example 2, step 7, to obtain 30D (1.1 g).

[0746] LCMS m / z = 407.1 [M+H] +

[0747] Step 2: Preparation of compound 31

[0748] Compound 31B (300 mg, 0.74 mmol) and lithium hydroxide monohydrate (124 mg, 2.96 mmol) were added to a mixed solvent of THF (10 mL), MeOH (2 mL) and water (2 mL) and reacted at room temperature for 4 h. After the reaction was completed, the pH was adjusted to 2 with 2M HC1, and then the filter cake was collected by suction filtration and dried. The obtained solid, ammonium chloride (79 mg, 1.48 mmol), N,N-diisopropylethylamine (290 mg, 2.24 mmol) and HATU (370 mg, 0.97 mmol) were added to DMF (10 mL) and reacted at room temperature overnight. Concentration under reduced pressure, and the concentrate was purified by a thin layer chromatography preparation plate (methanol / dichloromethane = 1 / 20) to obtain compound 31 (7 mg, yield: 2%).

[0749] LCMS m / z = 392.1 [M+H] +

[0750] 1 H NMR (400 MHz, DMSO-d6) δ 8.81-8.74 (m, 1H), 8.54 (d, 1H), 8.47-8.42 (m, 1H), 8.14-8.08 (m, 1H), 7.76 (s, 1H), 7.67-7.62 (m, 2H), 7.59-7.52 (m, 2H), 7.51-7.48 (m, 1H), 6.64-6.58 (m, 1H), 4.22 (s, 2H).

[0751] Example 32: Preparation of compound 32

[0752] Compound 32 (80.3 mg) was obtained by the first to fourth steps according to the synthetic method of the sixth to ninth steps of Example 2, using compound 24C as a starting material.

[0753] LCMS m / z = 410.1 [M+H] +

[0754] 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.25 (d, 1H), 7.51-7.40 (m, 3H), 7.38 (m, 1H), 7.34 (s, 1H), 7.30 (m, 1H), 7.09 (m, 1H), 5.83 (t, 1H), 4.88 (d, 2H), 2.35 (s, 3H).

[0755] Example 33: Preparation of compound 33

[0756] Reference to the synthesis method of Example 1, the product was purified by preparative liquid phase (instrument: Waters 2767 preparative liquid phase; column: XBridge@Prep C18(19mmx250mm); mobile phase composition: water(5mmol / L NH4HCO3 in H2O) / acetonitrile) and lyophilized to give compound 33(11mg).

[0757] LCMS m / z = 436.2 [M+H] +

[0758] 1 H NMR (400MHz, DMSO-d6) δ 8.64 (s, 1H), 8.44 (d, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.61-7.51 (m, 2H), 7.45-7.33 (m, 1H), 7.20 (s, 1H), 4.22 (s, 2H), 4.05 (s, 2H), 2.50-2.4 (m, 2H), 2.36 (s, 3H), 0.95 (t, 3H).

[0759] Example 34: Preparation of compound 34

[0760] First step: preparation of compound 34A

[0761] 1A (200mg, 0.49mmol), diphenyl phosphazide (200mg, 0.73mmol), DBU (150mg, 0.99mmol) were added into THF (5mL), reaction at room temperature for 4h. Then triphenylphosphine (260mg, 0.99mmol) and water (1mL) were added, reaction at room temperature for another 2h. Diluted with water (10mL), extracted with dichloromethane (10mLx2), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane(V / V)=0-10%) to give 34A crude (0.25g).

[0762] LCMS m / z = 408.2 [M+H] +

[0763] The crude 34A was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30mmx150mm); mobile phase composition: acetonitrile / water(containing 0.1% trifluoroacetic acid)) and lyophilized to give the trifluoroacetate salt of 34A (82mg).

[0764] LCMS m / z = 408.1 [M+H] +

[0765] Step 2: Preparation of compound 34

[0766] The crude 34A (0.2 g), triethylamine (74 mg, 0.73 mmol) was added to super dry DCM (5 mL), the system was cooled to 0 °C, then acetic anhydride (55 mg, 0.54 mmol) was slowly added, and the reaction was carried out at 0 °C for 2 h. The reaction solution was concentrated under reduced pressure, the concentrate was purified by preparative liquid phase (instrument: Waters 2767 preparative liquid phase; column: XBridge® Prep C18 (19 mm x 250 mm); mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile), and then freeze-dried to obtain compound 34 (23 mg).

[0767] LCMS m / z = 450.2 [M+H] +

[0768] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.43-8.37 (m, 1H), 8.14-8.05 (m, 1H), 7.80 (s, 1H), 7.63 (s, 1H), 7.61-7.52 (m, 2H), 7.38 (s, 1H), 7.32 (d, 1H), 4.76 (d, 2H), 4.22 (s, 2H), 2.32 (s, 3H), 1.73 (s, 3H).

[0769] Example 35: Preparation of compound 35

[0770] The crude 34A (0.12 g), formic acid (18 mg, >88%), HATU (99 mg, 0.26 mmol), DIPEA (52 mg, 0.40 mmol) was added to DMF (3 mL), and the reaction was carried out at room temperature overnight. The reaction solution was purified by preparative liquid phase (instrument: Waters 2767 preparative liquid phase; column: XBridge® Prep C18 (19 mm x 250 mm); mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile), and then freeze-dried to obtain compound 35 (18 mg).

[0771] LCMS m / z = 436.2 [M+H] +

[0772] 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.40 (m, 2H), 8.30-8.20 (m, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.64 (s, 1H), 7.61-7.52 (m, 2H), 7.48-7.40 (m, 1H), 7.36-7.29 (m, 1H), 4.81 (t, 2H), 4.23 (s, 2H), 2.33 (s, 3H).

[0773] Example 36: Preparation of compound 36

[0774] First step: Preparation of compound 36B

[0775] To 11D (400 mg, 1.46 mmol), 36A (340 mg, 2.16 mmol), triethylamine (300 mg, 2.96 mmol) were added into DMF (10 mL) and reacted at 110 °C overnight. Cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (15 mL x 2), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-50%) to obtain 36B crude product (0.288 g).

[0776] LCMS m / z = 411.2 [M+H] +

[0777] Second to third steps were prepared according to the synthetic method of the eighth to ninth steps of Example 2 to obtain compound 36 (85 mg).

[0778] LCMS m / z = 382.1 [M+H] +

[0779] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (d, 1H), 7.54 (s, 1H), 7.52-7.47 (m, 2H), 7.35-7.26 (m, 1H), 6.86-6.78 (m, 2H), 6.51-6.46 (m, 1H), 4.37-4.28 (m, 1H), 4.27-4.17 (m, 1H), 3.95 (s, 2H), 2.87-2.66 (m, 2H), 2.34-2.23 (m, 1H), 1.92-1.83 (m, 1H), 1.74-1.51 (m, 2H), 1.49-1.30 (m, 1H).

[0780] Example 37: Preparation of compound 37

[0781] Step 1: Preparation of compound 37B

[0782] 37A (2.0 g, 11.35 mmol), 11D (3.10 g, 11.35 mmol) and anhydrous potassium carbonate (7.84 g, 56.73 mmol) were added to DMSO (20 mL) and reacted at 110 °C overnight. After the reaction was completed, it was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 30%-50%) to give 37B (1.5 g, yield 31%).

[0783] LCMS m / z = 430.1 [M+H] +

[0784] The second step to the third step were synthesized according to the method of Example 2, eighth step to the ninth step, to give compound 37 (86 mg).

[0785] LCMS m / z = 415.1 [M+H] +

[0786] 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.53 (m, 2H), 8.41 (s, 1H), 8.10 (m, 1H), 8.05 (m, 1H), 7.93 (m, 1H), 7.66 (s, 1H), 7.61 (m, 1H), 7.56 (m, 1H), 7.41 (m, 1H), 7.28 (m, 1H), 4.32 (s, 2H).

[0787] Example 38: Preparation of compound 38

[0788] Step 1: Preparation of compound 38B

[0789] 22E (970 mg, 2.49 mmol), 38A (500 mg, 3.02 mmol) and sodium bicarbonate (1.05 g, 12.5 mmol) were added to DMF (15 mL) and reacted at 50 °C overnight. The solid was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 2 / 3)) to give 38B (660 mg, yield: 62%).

[0790] LCMS m / z = 426.1 [M+H] +

[0791] Step 2: Preparation of compound 38C

[0792] To a solution of 38B (650 mg, 1.53 mmol) in THF (20 mL) was added potassium tert-butoxide in tetrahydrofuran (3.8 mL, 1 mol / L) at 0 °C, then p-toluenesulfonyl chloride (350 mg, 1.84 mmol) was added; the mixture was stirred at 0 °C for 40 min, then was allowed to warm to room temperature overnight. The reaction was filtered with celite, rinsed with THF (20 mL), and the filtrate was concentrated. The crude 38C (300 mg) was purified by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (V / V = 3 / 2)) to give 38C (300 mg).

[0793] LCMS m / z = 408.1 [M+H] +

[0794] Third step: Preparation of compound 38

[0795] The crude 38C (300 mg) was added to dichloromethane (15 mL), and 6E (524 mg, 3.7 mmol) was added at -78 °C. The mixture was slowly warmed to room temperature and reacted overnight. The reaction was concentrated under reduced pressure, and hydrochloric acid solution (2 M, 15 mL) was added to the concentrate. The mixture was reacted at 100 °C for 30 min. After cooling to room temperature, the reaction was concentrated, purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge®Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile / water containing 0.1% trifluoroacetic acid), and lyophilized to give compound 38 (15 mg).

[0796] LCMS m / z = 451.1 [M+H] +

[0797] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, 1H), 7.98 (s, 1H), 7.63-7.38 (m, 5H), 7.16-7.09 (m, 1H), 5.25-5.15 (m, 1H), 4.36-4.22 (m, 1H), 4.22-4.03 (m, 3H).

[0798] Example 39: Preparation of compound 39

[0799] First step: Preparation of 39B

[0800] To a solution of 22C (500 mg, 1.85 mmol), 39A (486 mg, 2.77 mmol), DIPEA (598 mg, 4.63 mmol) in DMF (10 mL) was added HATU (844 mg, 2.22 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1)) to give 39B (635 mg, yield: 80%).

[0801] LCMS m / z = 428.2 [M+H] +

[0802] Second Step: Preparation of 39D

[0803] To a solution of 39B (500 mg, 1.17 mmol) was added hydrogen chloride-1,4-dioxane solution (10 mL, 4 mol / L) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. To the concentrate was added DCM (15 mL) and triethylamine (592 mg, 5.85 mmol) and the reaction mixture was cooled to 0°C. 39C (139 mg, 0.47 mmol) was slowly added and the reaction mixture was stirred at the same temperature for 5 h. To the reaction mixture was added water (50 mL) and the mixture was extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (mobile phase: dichloromethane / methanol (V / V = 20 / 1)) to give 39D (265 mg, yield: 64%).

[0804] LCMS m / z = 354.1 [M+1] +

[0805] Third Step: Preparation of Compound 39

[0806] To a solution of 39D (250 mg, 0.71 mmol) in dichloromethane (20 mL) was added 6E (502 mg, 3.55 mmol) at -78°C. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. To the concentrate was added hydrochloric acid solution (2 M, 5 mL) and the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)) and lyophilized to give Compound 39 (36 mg, yield: 13%).

[0807] LCMS m / z = 397.1 [M+H] +

[0808] 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, 1H), 7.66-7.45 (m, 5H), 7.38-7.21 (m, 2H), 4.37 (s, 2H), 4.22 (s, 2H).

[0809] Example 40: Preparation of compound 40

[0810] First Step: Preparation of 40B

[0811] Reference to the synthetic method of example 2, step 5, 40B (1.5 g) was obtained.

[0812] LCMS m / z = 290.1 [M+H] +

[0813] Second Step: Preparation of 40D

[0814] 40B (400 mg, 1.38 mmol), 40C (330 mg, 2.10 mmol), sodium carbonate (440 mg, 4.15 mmol), Pd2(dba)3(130 mg) and Xantphos (160 mg, 0.28 mmol) were added into 1,4-dioxane (8 mL) and reacted at 100 °C for 2 h under nitrogen atmosphere. The reaction was cooled to room temperature and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-50%) to obtain 40D (252 mg, yield 44%).

[0815] LCMS m / z = 411.2 [M+H] +

[0816] Third Step: Preparation of compound 40

[0817] Reference to the synthetic method of example 17, step 6, the reaction was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (19 mm x 250 mm); mobile phase composition: acetonitrile / water (containing 5 mmol ammonium bicarbonate)) and lyophilized to obtain compound 40 (27 mg)

[0818] LCMS m / z = 382.2 [M+H] +

[0819] 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, 1H), 8.16 (s, 1H), 7.65-7.37 (m, 4H), 7.19 (s, 1H), 7.13-7.01 (m, 1H), 4.14 (s, 2H), 4.08-3.96 (m, 1H), 3.95-3.86 (m, 1H), 3.56 (t, 1H), 2.31-2.14 (m, 2H).

[0820] Example 41: Preparation of compound 41

[0821] First step: Preparation of compound 41B

[0822] 41A (2.0 g, 12.34 mmol), NBS (2.86 g, 16.07 mmol) and azobisisobutyronitrile (0.12 g, 0.73 mmol) were added to 1,2-dichloroethane (10 mL) and reacted at 85 °C overnight. After the reaction was completed, it was cooled to room temperature, concentrated, and the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-5%) to obtain 41B crude (1.2 g).

[0823] 1 H NMR (400 MHz, CDCl3) δ 7.28 (s, 2H), 4.32 (s, 2H).

[0824] Second step: Preparation of compound 41D

[0825] 41B crude (1.2 g), 41C (1.24 g, 5.96 mmol) and anhydrous potassium carbonate (2.06 g, 14.9 mmol) were added to a mixed solvent of 1,4-dioxane (20 mL) and water (0.8 mL), and after replacing N2 three times, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.18 g) was added. After replacing N2 three times again, it was heated to 90 °C and reacted overnight. After the reaction was completed, it was cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 5%-10%) to obtain 41D (0.84 g).

[0826] LCMS m / z = 324.0 [M+H] +

[0827] Third step: Preparation of compound 41E

[0828] To a mixture of 2C (177 mg, 2.06 mmol), 41D (0.80 g, 2.47 mmol) and anhydrous cesium carbonate (1.48 g, 4.54 mmol) in a mixture solvent of 1,4-dioxane (20 mL) and water (4 mL), 1,1’-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.15 g) was added after three times of N2 replacement. After three times of N2 replacement again, the reaction was heated to 90 °C overnight. After the reaction was completed, the reaction was cooled to room temperature, water (50 mL) was added, and the reaction was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 5%-10%) to obtain 41E (495 mg, yield 73%).

[0829] LCMS m / z = 330.1 [M+1] +

[0830] Fourth step: preparation of compound 41F

[0831] Compound 41E (395 mg, 1.20 mmol) was added to hydrazine hydrate 2J (3.86 mL) and ethanol (4.0 mL), and the reaction was heated to 100 °C overnight. After the reaction was completed, the reaction was cooled to room temperature, and the reaction was concentrated under reduced pressure to obtain crude compound 41F (462 mg).

[0832] LCMS m / z = 326.2 [M+1] +

[0833] Fifth to seventh steps were obtained by the synthetic method of the seventh to ninth steps of Example 2 to obtain compound 41 (6.5 mg).

[0834] LCMS m / z = 449.2 [M+H] +

[0835] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.54 (m, 4H), 7.36 (s, 1H), 7.30 (s, 1H), 4.91 (s, 2H), 4.15 (s, 2H), 2.33 (s, 3H), 2.12 (m, 1H), 0.98 (m, 4H).

[0836] Example 42: Preparation of compound 42

[0837] First step: preparation of compound 42B

[0838] Compound 42B (8.36 g, 43.30 mmol), imidazole (4.42 g, 64.92 mmol) and 42C (8.48 g, 56.26 mmol) were added to dichloromethane (200 mL) at 0 °C, and the mixture was stirred at room temperature for 4 h. Water (100 mL) was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether (V / V) = 0-5%) to give 42D (12.87 g, yield: 97%).

[0839] Second Step: Preparation of compound 42D

[0840] Compound 42B (8.36 g, 43.30 mmol), imidazole (4.42 g, 64.92 mmol) and 42C (8.48 g, 56.26 mmol) were added to dichloromethane (200 mL) at 0 °C, and the mixture was stirred at room temperature for 4 h. Water (100 mL) was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether (V / V) = 0-5%) to give 42D (12.87 g, yield: 97%).

[0841] Third Step: Preparation of compound 42E

[0842] Compound 42D (12.87 g, 41.88 mmol), 5D (11.07 g, 83.76 mmol), cesium carbonate (27.29 g, 83.76 mmol), cuprous iodide (0.80 g, 4.20 mmol) and trans-4-hydroxy-L-proline (CAS#: 51-35-4) (1.10 g, 8.39 mmol) were added to dimethyl sulfoxide (200 mL), and the mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether (V / V) = 0-20%) to give compound 42E (5.05 g, yield: 34%).

[0843] LCMS m / z = 303.1 [M-55] +

[0844] Fourth Step: Preparation of compound 42F

[0845] To a solution of 42E (5.05 g, 14.08 mmol), tetrabutylammonium fluoride in tetrahydrofuran (1 M, 18.3 mL) in tetrahydrofuran (150 mL) was added and stirred at room temperature for 1 h. Concentrated under reduced pressure, the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 0-25%) to give the crude compound 42F (4.5 g).

[0846] LCMS m / z = 189.1 [M-55] +

[0847] Fifth Step: Preparation of compound 42G

[0848] To a solution of 42F (2.71 g), triphenylphosphine (8.73 g, 33.28 mmol) and carbon tetrabromide (11.03 g, 33.26 mmol) in dichloromethane (150 mL) was added and stirred at room temperature for 1 h. Concentrated under reduced pressure, the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 0-10%) to give compound 42G (303 mg).

[0849] LCMS m / z = 251.0 [M-55] +

[0850] Sixth Step: Preparation of compound 42H

[0851] Following the procedure of Reference Example 41, second step, 42H (151 mg) was obtained.

[0852] LCMS m / z = 335.1 [M-55] +

[0853] Seventh Step: Preparation of compound 42I

[0854] Following the procedure of Reference Example 5, third step, the crude 42I (149 mg) was obtained.

[0855] LCMS m / z = 443.2 [M+H] +

[0856] Eighth Step: Preparation of compound 42J

[0857] Following the procedure of Reference Example 2, eighth step, the crude 42J (155 mg) was obtained.

[0858] LCMS m / z = 415.0 [M+H] +

[0859] Ninth Step: Preparation of compound 42

[0860] Following the procedure of Reference Example 2, ninth step, compound 42 (11 mg) was obtained.

[0861] LCMS m / z = 414.1 [M+H] +

[0862] 1 H NMR (400 MHz, DMSO-d6) δ 7.54-7.45 (m, 3H), 7.40-7.31 (m, 2H), 7.24-7.22 (m, 1H), 7.21 (s, 1H), 5.76 (t, 1H), 4.59 (d, 2H), 4.07 (s, 2H), 2.31 (s, 3H).

[0863] Example 43: Preparation of compound 43

[0864] First step: Preparation of compound 43B

[0865] Reference to the synthesis method of example 22 fourth step, 43B (760 mg) was obtained.

[0866] LCMS m / z = 426.1 [M+H] +

[0867] Second step: Preparation of compound 43D

[0868] To the solution of 43B (660 mg, 1.55 mmol) in THF (30 mL) was added potassium tert-butoxide in tetrahydrofuran (3.88 mL, 1 mol / L) at 0 °C, then 43C (355 mg, 1.86 mmol) was added; the mixture was stirred at 0 °C for 40 min, then was raised to room temperature and reacted overnight, the reaction liquid was suction filtered with diatomite, THF (20 mL) was used to rinse, the filtrate was concentrated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1)) to obtain 43D (776 mg, yield: 86%).

[0869] LCMS m / z = 580.2 [M+H] +

[0870] Third step: Preparation of compound 43E

[0871] Compound 43D (555 mg, 0.96 mmol), sodium hydride (77 mg, 1.93 mmol, purity 60%) were added to DMF (10 mL), and reacted at 30 °C overnight, then saturated ammonium chloride solution (20 mL) was added, extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 3 / 2)) to obtain the crude product of 43E (180 mg).

[0872] Step 4: Preparation of compound 43

[0873] Reference to the synthesis method of Example 38, Step 3, compound 43 (28 mg) was obtained.

[0874] LCMS m / z = 451.1 [M+H] +

[0875] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (d, 1H), 7.91 (s, 1H), 7.61-7.32 (m, 5H), 7.17-7.13 (m, 1H), 5.83-5.69 (m, 1H), 4.17 (s, 2H), 4.14-4.05 (m, 1H), 3.91-3.85 (m, 1H).

[0876] Example 44: Preparation of compound 44

[0877] Step 1: Preparation of compound 44A

[0878] Compound 17A (1.25 g, 4.35 mmol) was added to methanol (30 mL), sodium borohydride (0.49 g, 12.95 mmol) was added, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the residue was concentrated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 1 / 5) to obtain 44A (800 mg, yield: 64%).

[0879] LCMS m / z = 290.1 [M+1] +

[0880] Step 2: Preparation of compound 44B

[0881] Compound 44A (800 mg, 2.77 mmol) was added to dichloromethane (50 mL), and diethylamine trifluoride (4.46 g, 27.7 mmol) was slowly added at 0°C. The reaction was carried out at room temperature for 1 h. Saturated sodium bicarbonate solution (30 mL) was added, dichloromethane (20 mL x 3) was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 1 / 5) to obtain 44B (795 mg, yield: 99%).

[0882] LCMS m / z = 292.0 [M+1] +

[0883] Reference to the synthesis method of Example 2, Step 6 to Step 9, compound 44 (220 mg) was obtained.

[0884] LCMS m / z = 427.1 [M+1] +

[0885] Chiral resolution:

[0886] Compound 44 was prepared by chiral preparation (Instrument: CAS-05-Prep-SFC-F Preparative column: AD column; mobile phase composition: CO2 / methanol (0.1% NH3H2O)), and lyophilized to obtain compound 44-1 (chiral column retention time: 1.080 min, 81 mg) and compound 44-2 (chiral column retention time: 1.270 min, 83 mg), which were obtained from analytical instrument CAS-05-ANA-SFC-D (chiral column: AD column; mobile phase composition: CO2 / methanol (0.05% MNH3); flow rate: 3 mL / min; column temperature: 35 °C). One of compound 44-1 and compound 44-2 is compound 44-A, and the other is compound 44-B.

[0887] Compound 44-1: LCMS m / z = 427.0 [M+H] +

[0888] Compound 44-2: LCMS m / z = 427.0 [M+H] +

[0889] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, 1H), 7.94 (s, 1H), 7.82-7.73 (m, 3H), 7.60-7.29 (m, 3H), 7.03 (d, 1H), 5.53 (t, 1H), 4.94 (d, 2H), 2.37 (s, 3H).

[0890] Example 45: Preparation of compound 45

[0891] First step: preparation of compound 45B

[0892] Compound 45A (synthesized according to the patent US2011 / 53974) (1 g, 4.58 mmol) and compound 45B (1.28 g, 6.87 mmol) were added to toluene (30 mL) and reacted at 70 °C overnight, concentrated, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 20 / 1) to obtain 45C (1.4 g, yield 79%).

[0893] LCMS m / z = 387.1 [M+1] +

[0894] Step 2: Preparation of compound 45D

[0895] Compound 45C (800 mg, 2.07 mmol), compound 2H (583 mg, 4.14 mmol) and potassium carbonate (858 mg, 6.21 mmol) were added into 1,4-dioxane (30 mL) and reacted at 110 °C overnight, cooled to room temperature, concentrated, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 1 / 5) to give 45D (113 mg, yield: 18%).

[0896] LCMS m / z = 300.1 [M+1] +

[0897] The third to sixth steps were synthesized by the method of the fourth to seventh steps of Example 3 to give compound 45 (45 mg).

[0898] LCMS m / z = 435.1 [M+1] +

[0899] 1 H NMR (400 MHz, DMSO-d6) d 8.47 (d, 1H), 7.70 (s, 1H), 7.59-7.31 (m, 3H), 7.26 (d, 1H), 7.15 (d, 1H), 4.93 (s, 2H), 4.65 (t, 1H), 3.29-3.14 (m, 1H), 3.13-2.96 (m, 1H), 2.78-2.59 (m, 1H), 2.35 (s, 3H), 2.26-2.10 (m, 1H).

[0900] Example 46: Preparation of compound 46

[0901] Step 1: Preparation of compound 46C

[0902] 46A (4.01 g, 27.06 mmol) (synthetic method reference: Arzneimittelforschung 2012; 62: 537-544; DOI: 10.1055 / s-0032-1323760) and 46B (7.56 g, 40.59 mmol) were added into methanol (100 mL) and reacted at 70 °C overnight. Cooled to room temperature, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0-10%) to give compound 46C (4.1 g, yield: 48%).

[0903] LCMS m / z = 317.1 [M+H] +

[0904] Step 2: Preparation of compound 46D

[0905] 46C (4.1 g, 12.96 mmol), 41C (5.39 g, 25.92 mmol), potassium carbonate (5.37 g, 38.85 mmol) were added into toluene (100 mL) and reacted at 110 °C overnight under nitrogen atmosphere. Cooled to room temperature, concentrated under reduced pressure, added water (50 mL) into the concentrate, extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated the organic phase under reduced pressure, the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0-10%) to obtain compound 46D (2.57 g, yield: 67%).

[0906] LCMS m / z = 297.1 [M+H] +

[0907] Step 3: Preparation of compound 46E

[0908] Nitrous tetrafluoroboric acid (CAS#: 14635-75-7) (1.12 g, 9.59 mmol) was added into dichloromethane (108 mL) under nitrogen atmosphere, cooled to 0 °C, added 46D (1.89 g, 6.38 mmol) into the reaction solution, reacted at room temperature overnight. Added water (100 mL), separated the organic phase, extracted the aqueous phase with dichloromethane (50 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-10%) to obtain 46E (517 mg, yield: 27%).

[0909] LCMS m / z = 300.1 [M+H] +

[0910] Step 4: Preparation of compound 46F

[0911] Refer to the synthesis method of Step 2 in Reference Example 16 to obtain 46F (650 mg).

[0912] LCMS m / z = 312.1 [M+H] +

[0913] Step 5: Preparation of compound 46G

[0914] Refer to the synthesis method of Step 7 in Reference Example 2 to obtain 46G (550 mg).

[0915] LCMS m / z = 464.2 [M+H] +

[0916] Step 6: Preparation of compound 46H

[0917] Reference to the synthesis method of Example 2, step 8, gave compound 46H (390 mg).

[0918] LCMS m / z = 436.1 [M+H] +

[0919] Step 7: Preparation of compound 46

[0920] Reference to the synthesis method of Example 2, step 9, gave compound 46 (81 mg).

[0921] LCMS m / z = 435.2 [M+H] +

[0922] Chiral resolution:

[0923] Compound 46 was resolved by chiral preparation (Instrument: CAS-05-Prep-SFC-F Prep column: IC column; mobile phase composition: CO2 / isopropanol and acetonitrile (0.1% NH3·H2O); flow rate: 140 mL / min; column temperature: room temperature), and lyophilized to give compound 46-1 (chiral column retention time: 1.093 min, 26 mg) and compound 46-2 (chiral column retention time: 1.298 min, 34 mg). The chiral column retention times were measured by analytical instrument CAS-05-ANA-SFC-C (analytical column: IC column; mobile phase composition: CO2 / isopropanol and acetonitrile (0.05% NH3); flow rate: 3 mL / min; column temperature: 35 °C). Of compound 46-1 and compound 46-2, one is compound 46-A and the other is compound 46-B.

[0924] Compound 46-1: LCMS m / z = 435.2 [M+H] +

[0925] 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.63-7.58 (m, 1H), 7.57 (s, 1H), 7.51-7.42 (m, 2H), 7.41-7.31 (m, 1H), 7.28 (s, 1H), 5.65 (s, 1H), 4.94-4.82 (m, 2H), 4.73-4.65 (m, 1H), 3.22-3.13 (m, 1H), 3.07-2.97 (m, 1H), 2.72-2.60 (m, 1H), 2.30 (s, 3H), 2.26-2.14 (m, 1H).

[0926] Compound 46-2: LCMS m / z = 435.1 [M+H]+

[0927] Example 47: Preparation of compound 47

[0928] First Step: Preparation of compound 47B

[0929] Under nitrogen atmosphere, 5B (5 g, 19.45 mmol), 47A (5.93 g, 23.35 mmol), tetrakis triphenylphosphine palladium (1.12 g, 0.97 mmol) and potassium carbonate (8.06 g, 58.32 mmol) were added into 1,4-dioxane (100 mL) and reacted at 100 °C overnight. Cooled to room temperature, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-10%) to obtain 47B (4.36 g, yield: 74%).

[0930] Second Step: Preparation of compound 47D

[0931] Under nitrogen atmosphere, 47B (3.30 g, 10.85 mmol), 47C (2.1 g, 10.86 mmol), DPPF palladium dichloride (CAS#: 72287-26-4) (0.79 g, 1.08 mmol) and potassium carbonate (4.50 g, 32.56 mmol) were added into 1,4-dioxane (20 mL) and water (5 mL) and reacted at 90 °C for 4 h. Cooled to room temperature, added water (20 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, the residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-20%) to obtain compound 47D (950 mg, yield: 30%).

[0932] LCMS m / z = 291.0 [M+H] +

[0933] Third Step: Preparation of compound 47E

[0934] Reference to the synthesis method of Example 6, second step, obtained 47E (690 mg).

[0935] LCMS m / z = 341.1 [M+H] +

[0936] Fourth Step: Preparation of compound 47

[0937] Reference to the synthesis method of Example 6, third step, obtained compound 47.

[0938] LCMS m / z = 384.1 [M+H] +

[0939] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (d, 1H), 8.29-8.25 (m, 1H), 7.61 (s, 1H), 7.59-7.53 (m, 2H), 7.50-7.29 (m, 2H), 4.19 (s, 2H), 4.12-4.03 (m, 2H), 3.88-3.76 (m, 2H).

[0940] Example 48: Preparation of compound 48

[0941] First Step: Preparation of compound 48B

[0942] Reference Example 22, fourth step of synthesis method was followed to obtain 48B (1.105 g).

[0943] LCMS m / z = 398.2 [M+H] +

[0944] Second Step: Preparation of compound 48C

[0945] Reference Example 43, second step of synthesis method was followed to obtain 48C (160 mg).

[0946] LCMS m / z = 380.1 [M+H] +

[0947] Third Step: Preparation of compound 48

[0948] Reference Example 6, third step of synthesis method was followed to obtain compound 48 (31 mg).

[0949] LCMS m / z = 423.2 [M+H] +

[0950] Chiral resolution:

[0951] Compound 48 was prepared by chiral preparation (Instrument: CAS-05-Prep-SFC-E prep column: Whelk column; mobile phase composition: CO2 / ethanol (0.1% NH3H2O); flow rate: 120 mL / min; column temperature: room temperature), and lyophilized to give compound 48-1 (chiral column retention time: 1.340 min, 23 mg) and compound 48-2 (chiral column retention time: 1.519 min, 26 mg), which were obtained from analytical instrument CAS-05-ANA-SFC-D (analytical column: Whelk column; mobile phase composition: CO2 / ethanol (0.05% MNH3); flow rate: 3 mL / min; column temperature: 35 °C). One of compound 48-1 and compound 48-2 is compound 48-A, and the other is compound 48-B.

[0952] Compound 48-1: LCMS m / z = 423.1 [M+H] +

[0953] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1H), 8.03 (s, 1H), 7.63-7.45 (m, 4H), 7.24 (s, 1H), 7.06 (dd, 1H), 4.14 (s, 2H), 4.04-3.94 (m, 2H), 3.78-3.69 (m, 1H), 1.22-1.10 (m, 1H), 0.63-0.44 (m, 2H), 0.44-0.34 (m, 1H), 0.28-0.19 (m, 1H).

[0954] Compound 48-2: LCMS m / z = 423.1 [M+H] +

[0955] Example 49: Preparation of compound 49

[0956] First step: preparation of compound 49B

[0957] Compound 41D (2 g, 6.17 mmol), 49A (3.71 g, 61.7 mmol) were added to a flask containing ethanol (10 mL), and reacted at 90 °C overnight, concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 1 / 1)) to give 49B (1.91 g, yield: 89%).

[0958] LCMS m / z = 347.8 [M+H] +

[0959] Second step: preparation of compound 49C

[0960] To a solution of 39C (0.65 g, 2.19 mmol) in THF (50 mL) was cooled to 0 °C, a solution of 49B (1.91 g, 5.49 mmol) and triethylamine (1.11 g, 10.97 mmol) in THF (50 mL) was added dropwise slowly, and the mixture was stirred at 0 °C for 20 min. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1)) to give 49C (1.65 g, yield: 80%).

[0961] LCMS m / z = 374.1 [M+H] +

[0962] Step 3: Preparation of compound 49E

[0963] 49C (300 mg, 0.80 mmol), 49D (110 mg, 0.88 mmol), potassium carbonate (442 mg, 3.2 mmol), and tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmol) were added to dry 1,4-dioxane (10 mL) under nitrogen, and the mixture was stirred at 110 °C overnight. The mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1)) to give 49E (206 mg, yield: 73%).

[0964] LCMS m / z = 354.1 [M+H] +

[0965] Step 4: Preparation of compound 49

[0966] Compound 49 (120 mg) was obtained according to the synthetic method of Reference Example 38, Step 3.

[0967] LCMS m / z = 397.1 [M+H] +

[0968] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.60-7.41 (m, 4H), 7.24 (s, 1H), 6.92 (s, 1H), 4.08 (s, 2H), 4.00-3.90 (m, 2H), 3.80-3.70 (m, 2H), 2.38 (s, 3H).

[0969] Example 50: Preparation of compound 50

[0970] Step 1: Preparation of compound 50A

[0971] To a solution of 49C (350 mg, 0.94 mmol), 15A (217 mg, 1.41 mmol), potassium carbonate (390 mg, 2.82 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (38 mg, 0.05 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 80 °C for 3 h, cooled to room temperature, filtered by celite, concentrated under reduced pressure, purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1)) to give 50A (320 mg) as a crude product.

[0972] LCMS m / z = 366.1 [M+H] +

[0973] Second step: preparation of compound 50B

[0974] To a solution of compound 50A (320 mg) and 10% palladium carbon (150 mg) in tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at room temperature overnight, the atmosphere of the reaction system was replaced with hydrogen by hydrogen balloon, filtered by celite, the filtrate was concentrated under reduced pressure, the concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 1 / 1) to give 50B (170 mg) as a crude product.

[0975] LCMS m / z = 368.2 [M+H] +

[0976] Third step: preparation of compound 50

[0977] Compound 50 (55 mg) was obtained according to the synthetic method of the third step in Reference Example 38.

[0978] LCMS m / z = 411.2 [M+H] +

[0979] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.59-7.41 (m, 4H), 7.24 (s, 1H), 6.94 (s, 1H), 4.09 (s, 2H), 4.01-3.90 (m, 2H), 3.80-3.68 (m, 2H), 2.66 (q, 2H), 1.20 (t, 3H).

[0980] Example 51: preparation of compound 51

[0981] Compound 51 (120 mg) was obtained according to the synthetic method of Reference Example 50, taking 49C as the starting material.

[0982] LCMS m / z = 425.2 [M+H] +

[0983] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.58 - 7.41 (m, 4H), 7.24 (s, 1H), 6.96 (s, 1H), 4.10 (s, 2H), 4.02 - 3.92 (m, 2H), 3.83 - 3.71 (m, 2H), 2.98 - 2.85 (m, 1H), 1.20 (d, 6H).

[0984] Example 52: Preparation of compound 52

[0985] First Step: Preparation of compound 52B

[0986] Reference Example 22, fourth step of the synthesis procedure was followed to obtain 52B (1.92 g).

[0987] LCMS m / z = 388.0 [M+H] +

[0988] Second Step: Preparation of compound 52C

[0989] Reference Example 43, second step of the synthesis procedure was followed to obtain 52C (320 mg).

[0990] LCMS m / z = 370.1 [M+H] +

[0991] Third Step: Preparation of compound 52D

[0992] Reference Example 30, second step of the synthesis procedure was followed to obtain 52D (81 mg).

[0993] LCMS m / z = 372.2 [M+H] +

[0994] Fourth Step: Preparation of compound 52

[0995] Reference Example 38, third step of the synthesis procedure was followed to obtain compound 52 (12 mg).

[0996] LCMS m / z = 415.2 [M+H] +

[0997] 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, 1H), 8.03 (s, 1H), 7.64-7.57 (m, 1H), 7.57-7.52 (m, 2H), 7.51-7.46 (m, 1H), 7.45-7.35 (m, 1H), 7.09-7.04 (m, 1H), 4.82-4.43 (m, 3H), 4.14 (s, 2H), 4.13-4.07 (m, 1H), 4.01-3.93 (m, 1H).

[0998] Example 53: Preparation of compound 53

[0999] First Step: Preparation of 53B

[1000] Reference to the synthesis method of example 22 fourth step, 53B (540 mg) was obtained.

[1001] LCMS m / z = 386.1 [M+H] +

[1002] Second Step: Preparation of 53C

[1003] To the solution of 53B (600 mg, 1.56 mmol) in THF (10 mL) was added potassium tert-butoxide in tetrahydrofuran (3.9 mL, 1 mol / L) at 0 °C, then p-toluenesulfonyl chloride (357 mg, 1.87 mmol) was added; the mixture was stirred at 0 °C for 40 min, then was raised to room temperature overnight, saturated ammonium chloride (10 mL) and water (10 mL) were added, extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, the concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-50%) to give 53C (100 mg, yield 17%).

[1004] LCMS m / z = 368.2 [M+H] +

[1005] Third Step: Preparation of compound 53

[1006] Compound 53 (28 mg, yield 25%) was obtained after purification by prep-LC (Instrument: Waters 2767 Prep-LC; Column: XBridge® Prep C18 (19 mm x 250 mm); Mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile) and lyophilization.

[1007] LCMS m / z = 411.2 [M+H] +

[1008] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, 1H), 8.04 (s, 1H), 7.64-7.43 (m, 4H), 7.26 (s, 1H), 7.11-7.03 (m, 1H), 4.26-4.18 (m, 1H), 4.14 (s, 2H), 4.09-3.98 (m, 1H), 3.81-3.68 (m, 1H), 1.88-1.72 (m, 1H), 1.70-1.57 (m, 1H), 0.83 (t, 3H).

[1009] Example 54: Preparation of compound 54

[1010] Compound 54 (29 mg) was obtained by taking 22E as the starting material and following the synthetic method of Example 53.

[1011] LCMS m / z = 411.1 [M+H] +

[1012] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, 1H), 8.04 (s, 1H), 7.66-7.44 (m, 4H), 7.30-7.22 (m, 1H), 7.10-7.00 (m, 1H), 4.27-4.20 (m, 1H), 4.14 (s, 2H), 4.09-3.99 (m, 1H), 3.82-3.71 (m, 1H), 1.90-1.73 (m, 1H), 1.72-1.56 (m, 1H), 0.83 (t, 3H).

[1013] Example 55: Preparation of compound 55

[1014] Step 1: Preparation of compound 55B

[1015] Compound 55A (2 g, 12.59 mmol), 55B (3.24 g, 12.61 mmol), potassium carbonate (3.48 g, 25.18 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.51 g, 0.62 mmol) were added into a three-necked flask, protected by nitrogen, 1,4-dioxane (30 mL) and water (5 mL) were added, and the mixture was reacted at 90 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 5) to obtain the crude product 55B (0.47 g).

[1016] LCMS m / z = 292.0 [M+1] +

[1017] Step 2: Preparation of compound 55D

[1018] The crude product 55B (470 mg), 55C (420 mg, 2.41 mmol) and diisopropylethylamine (420 mg, 3.25 mmol) were added into a microwave reactor, and the mixture was reacted at 150 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1) to obtain 55D (80 mg).

[1019] LCMS m / z = 446.2 [M+1] +

[1020] Step 3: Preparation of compound 55E

[1021] The 55D (80 mg, 0.18 mmol) was added into a 1,4-dioxane solution of hydrogen chloride (10 mL, 4 mol / L), and the mixture was reacted at room temperature for three hours. After the reaction was completed, the mixture was concentrated under reduced pressure, triethylamine (91 mg, 0.90 mmol) and THF (5 ml) were added, and the mixture was slowly added into a THF (5 mL) solution of 39C (21 mg, 0.07 mmol) at 0 °C. The mixture was reacted at 0 °C for 1 h, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 55E (64 mg) which was directly used in the next step.

[1022] LCMS m / z = 372.1 [M+H] +

[1023] Step 4: Preparation of compound 55

[1024] The crude 55E (64 mg) was added to dichloromethane (5 mL), 6E (120 mg, 0.85 mmol) was added at -78 °C, slowly warmed to room temperature and reacted overnight. Concentrated under reduced pressure, hydrochloric acid solution (2 M, 5 mL) was added to the concentrate, reacted at 100 °C for 30 minutes. Cooled to room temperature, concentrated the reaction solution, purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: SUNFIRE® Prep C18 (19 mm x 250 mm); mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile) and lyophilized to obtain compound 55 (18 mg).

[1025] LCMS m / z = 415.2 [M+H] +

[1026] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.06 (d, 1H), 7.63-7.40 (m, 4H), 7.25 (s, 1H), 4.38-4.27 (m, 1H), 4.21 (s, 2H), 4.11-4.01 (m, 1H), 3.64-3.55 (m, 1H), 1.31 (d, 3H).

[1027] Example 56: Preparation of compound 56

[1028] Step 1: Preparation of compound 56A

[1029] Reference to the synthesis method of Example 55 second step, 56A (1.05 g) was obtained.

[1030] LCMS m / z = 446.2 [M+H] +

[1031] Step 2: Preparation of compound 56B

[1032] Compound 56A (1.05 g, 2.36 mmol) was added to hydrogen chloride-1,4-dioxane (20 mL, 4 mol / L) and reacted at room temperature for 3 h, concentrated, added triethylamine (1.19 g, 11.76 mmol) and THF (10 mL), and the mixture was slowly added to a THF (10 mL) solution of 39C (280 mg, 0.94 mmol) at 0 °C. The mixture was continuously reacted at 0 °C for 1 h, added saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL x 3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1) gave compound 56B (448 mg, yield: 51%).

[1033] LCMS m / z = 372.1 [M+H] +

[1034] Step 3: Preparation of compound 56

[1035] Reference to the synthesis method of the third step of Example 38, compound 56 (325 mg) was obtained.

[1036] LCMS m / z = 415.1 [M+H] +

[1037] Chiral resolution:

[1038] Compound 56 was prepared by chiral preparation (instrument: CAS-05-Prep-SFC-E; preparation chromatographic column: IG column; mobile phase composition: CO2 / ethanol (0.1% NH3·H2O)), and freeze-dried to obtain compound 56-1 (chiral column retention time: 1.041 min, 111 mg) and compound 56-2 (chiral column retention time: 1.417 min, 118 mg). The chiral column retention time was measured by analytical instrument CAS-05-ANA-SFC-D (chiral chromatographic column: IG column; mobile phase composition: CO2 / ethanol (0.05% NH3); flow rate: 3 mL / min; column temperature: 35 °C). One of compound 56-1 and compound 56-2 is compound 56-A, and the other is compound 56-B.

[1039] Compound 56-1: LCMS m / z = 415.1 [M+H] +

[1040] Compound 56-2: LCMS m / z = 415.1 [M+H] +

[1041] 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.24 (s, 1H), 7.81-7.61 (m, 3H), 7.56 (s, 1H), 7.28 (s, 1H), 7.23-7.16 (m, 1H), 6.94 (d, 1H), 4.41-4.27 (m, 1H), 4.14-4.04 (m, 1H), 3.71-3.60 (m, 1H), 1.32 (d, 3H).

[1042] Example 57: Preparation of compound 57

[1043] Compound 57 (53 mg) was obtained by using 22E as starting material, according to the synthetic method of Example 53.

[1044] LCMS m / z = 411.2 [M+H] +

[1045] Chiral resolution:

[1046] Compound 57 was chiral prepared (Instrument: CAS-05-Prep-SFC-F Prep column: AS column; mobile phase composition: CO2 / isopropanol (0.1% NH3-H2O); flow rate: 120 mL / min; column temperature: room temperature), and lyophilized to give compound 57-1 (chiral column retention time: 0.779 min, 8.7 mg) and compound 57-2 (chiral column retention time: 0.912 min, 12.3 mg). The chiral column retention times were measured by analytical instrument CAS-05-ANA-SFC-D (analytical column: AS column; mobile phase composition: CO2 / isopropanol (0.05% NH3); flow rate: 3 mL / min; column temperature: 35 °C). One of compound 57-1 and compound 57-2 is compound 57-A, and the other is compound 57-B.

[1047] Compound 57-1: LCMS m / z = 411.2 [M+H] +

[1048] Compound 57-2: LCMS m / z = 411.1 [M+H] +

[1049] 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, 1H), 8.04 (s, 1H), 7.62-7.40 (m, 4H), 7.29 (s, 1H), 7.09-6.99 (m, 1H), 4.36-4.25 (m, 1H), 4.13 (s, 2H), 3.99-3.84 (m, 1H), 1.39-1.18 (m, 6H).

[1050] Example 58: Preparation of compound 58

[1051] First Step: Preparation of 58B

[1052] Into an oven-dried Schlenk tube, 6B (1.30 g, 3.89 mmol), 58A (1.0 g, 4.67 mmol), cesium carbonate (6.33 g, 19.43 mmol), palladium acetate (44 mg, 0.20 mmol) and 1,1'-binaphthalene-2,2'-diphenylphosphine (145 mg, 0.23 mmol) were added into dry toluene (20 mL) and stirred at 95 °C for 5 h under nitrogen atmosphere. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether (V / V) = 0-50%) to give 58B (1.3 g, yield 71%).

[1053] LCMS m / z = 468.3 [M+H] +

[1054] Second Step: Preparation of 58D

[1055] Into an oven-dried Schlenk tube, 58B (660 mg, 1.41 mmol) was added into dichloromethane (8 mL) and trifluoroacetic acid (8 mL) and stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure. The residue was added into saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was added into 58C (250 mg, 1.54 mmol) and dichloromethane (10 mL) and stirred at room temperature overnight. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether (V / V) = 0-50%) to give 58D (260 mg, yield 47%).

[1056] LCMS m / z = 394.1 [M+H] +

[1057] Third Step: Preparation of compound 58

[1058] Compound 58 (94 mg) was obtained according to the synthetic method of Reference Example 53, third step.

[1059] LCMS m / z = 437.2 [M+H] +

[1060] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, 1H), 7.62-7.49 (m, 3H), 7.47-7.36 (m, 2H), 7.28-7.19 (m, 1H), 7.17-7.09 (m, 1H), 4.14 (s, 2H), 3.74-3.63 (m, 1H), 3.54-3.40 (m, 1H), 2.84-2.72 (m, 1H), 2.57-2.52 (m, 1H), 1.89-1.69 (m, 2H), 1.60-1.40 (m, 3H), 1.37-1.20 (m, 1H).

[1061] Example 59: Preparation of compound 59

[1062] Compound 59 (145 mg) was obtained by referring to the synthetic method of Example 58, using 6B as the starting material.

[1063] LCMS m / z = 437.1 [M+H] +

[1064] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, 1H), 7.58 (s, 1H), 7.56-7.49 (m, 2H), 7.46 (s, 1H), 7.43-7.37 (m, 1H), 7.29-7.17 (m, 1H), 7.16-7.09 (m, 1H), 4.14 (s, 2H), 3.75-3.64 (m, 1H), 3.54-3.42 (m, 1H), 2.86-2.71 (m, 1H), 2.63-2.52 (m, 1H), 1.85-1.69 (m, 2H), 1.48 (m, 3H), 1.29 (m, 1H).

[1065] Example 60: Preparation of compound 60

[1066] First Step: Preparation of 60B

[1067] 6D (624 mg, 1.84 mmol) and 60A (560 mg, 1.38 mmol) were added to toluene (20 mL) and reacted at 100 °C overnight. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 25-50%) to obtain 60B (374 mg).

[1068] LCMS m / z = 356.1 [M+H] +

[1069] Second Step: Preparation of compound 60

[1070] 60B (168 mg, 0.47 mmol), 60C (88 mg, 0.56 mmol) and N,N-diisopropylethylamine (120 mg, 0.93 mmol) were added into dichloromethane (10 mL) and reacted at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 25-50%)) to obtain 60D (191 mg, yield 85%).

[1071] LCMS m / z = 476.2 [M+H] +

[1072] Second Step: Preparation of compound 60

[1073] 60D (191 mg, 0.40 mmol), 20 (43 mg, 0.80 mmol) and triethylamine (240 mg, 2.37 mmol) were added into DMF (2.5 mL) and reacted at room temperature for 24 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and further purified by preparative HPLC (instrument: Waters preparative liquid phase; column: XBridge (19 mm x 250 mm); mobile phase composition: acetonitrile / water (containing 5 mmol / L ammonium bicarbonate)) and freeze-dried to obtain compound 60 (4.12 mg, yield 3%).

[1074] LCMS m / z = 399.0 [M+H] +

[1075] 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.40 (d, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.60-7.49 (m, 3H), 7.25 (dd, 1H), 4.18 (s, 2H), 4.17-4.10 (m, 2H), 4.07-4.00 (m, 2H).

[1076] Example 61: Preparation of compound 61

[1077] Compound 61 (210 mg) was obtained according to the synthetic method of Reference Example 23.

[1078] LCMS m / z = 441.1 [M+H] +

[1079] Chiral resolution:

[1080] Compound 61 was prepared by chiral preparation (Instrument: CAS-05-Prep-SFC-C Preparative column: AD column; Mobile phase composition: C02 / ethanol (0.1% NH3H20); Flow rate: 70 mL / min; Column temperature: room temperature) and lyophilized to obtain Compound 61-1 (chiral column retention time: 0.925 min, 82 mg) and Compound 61-2 (chiral column retention time: 1.007 min, 72 mg). The chiral column retention times were measured by analytical instrument CAS-05-ANA-SFC-D (analytical column: AD column; Mobile phase composition: C02 / ethanol (0.05% NH3); Flow rate: 3 mL / min; Column temperature: 35 °C). Of Compound 61-1 and Compound 61-2, one is Compound 61-A and the other is Compound 61-B.

[1081] Compound 61-1: LCMS m / z = 441.1 [M+H] +

[1082] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, 1H), 7.86 (d, 1H), 7.61-7.55 (m, 3H), 7.54-7.32 (m, 2H), 5.50 (t, 1H), 4.93-4.83 (m, 2H), 4.74-4.65 (m, 1H), 2.37 (s, 3H), 1.69 (d, 3H).

[1083] Compound 61-2: LCMS m / z = 441.1 [M+H] +

[1084] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, 1H), 7.86 (d, 1H), 7.61-7.55 (m, 3H), 7.54-7.32 (m, 2H), 5.50 (t, 1H), 4.93-4.83 (m, 2H), 4.74-4.65 (m, 1H), 2.37 (s, 3H), 1.69 (d, 3H).

[1085] Example 62: Preparation of Compound 62

[1086] First Step: Preparation of Compound 62A

[1087] To a solution of 46D (2 g, 6.75 mmol) in tetrahydrofuran (30 mL) was added diisopropylethylamine (1.74 g, 13.5 mmol) and 22D (1.16 g, 7.41 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. Purification on silica gel column (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 2)) gave 62A (1.7 g, yield: 60%).

[1088] LCMS m / z = 417.1 [M+H] +

[1089] Second Step: Preparation of compound 62C

[1090] To a solution of 62A (1.7 g, 4.08 mmol), 62B (541 mg, 7.20 mmol) and diisopropylethylamine (1.58 g, 12.22 mmol) in DMF (20 mL) was stirred at 50 °C overnight. The mixture was concentrated under reduced pressure. Purification on silica gel column (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1)) gave 62C (1.45 g, yield 89%).

[1091] LCMS m / z = 398.2 [M+H] +

[1092] Third Step: Preparation of compound 62D

[1093] To a solution of 62C (1.7 g, 4.28 mmol) in THF (100 mL) was added potassium tert-butoxide (10.27 mL, 1 mol / L in THF) at 0 °C, followed by p-toluenesulfonyl chloride (0.98 g, 5.14 mmol). The mixture was stirred at 0 °C for 40 min, then was allowed to warm to room temperature overnight. The mixture was filtered through celite, and the filter cake was washed with THF (50 mL). The filtrate was concentrated under reduced pressure. Purification on silica gel column (mobile phase: ethyl acetate / petroleum ether (V / V = 3 / 2)) gave 62D (0.75 g, yield: 46%).

[1094] LCMS m / z = 380.1 [M+H]+

[1095] Fourth Step: Preparation of compound 62

[1096] Compound 62 (325 mg) was obtained according to the synthetic method of Reference Example 38, third step.

[1097] LCMS m / z = 423.2 [M+H] +

[1098] Chiral resolution:

[1099] Compound 62 was prepared by chiral preparation (Instrument: SFC Prep 150AP; Preparative chromatography column: Chiralpak® IC (19 mm x 250 mm); Mobile phase composition: C02 / isopropanol (0.05% NH3-H20)), concentrated under reduced pressure and lyophilized to obtain Compound 62-1 (Chiral column retention time: 14.3 min, 135 mg) and Compound 62-2 (Chiral column retention time: 15.6 min, 129 mg). Of Compound 62-1 and Compound 62-2, one is Compound 62-A and the other is Compound 62-B.

[1100] Compound 62-1: LCMS m / z = 423.2 [M+H] +

[1101] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.67 (s, 1H), 7.63 - 7.32 (m, 4H), 7.15 (s, 1H), 4.60 (t, 1H), 4.34 - 4.22 (m, 1H), 4.15 - 3.97 (m, 1H), 3.71 - 3.56 (m, 1H), 3.18 - 3.00 (m, 1H), 3.00 - 2.83 (m, 1H), 2.68 - 2.56 (m, 1H), 2.17 - 2.03 (m, 1H), 1.30 (d, 3H).

[1102] Compound 62-2: LCMS m / z = 423.2 [M+H] +

[1103] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.65 (s, 1H), 7.63 - 7.32 (m, 4H), 7.16 (s, 1H), 4.60 (t, 1H), 4.34 - 4.22 (m, 1H), 4.14 - 4.03 (m, 1H), 3.64 - 3.55 (m, 1H), 3.18 - 3.00 (m, 1H), 3.00 - 2.83 (m, 1H), 2.68 - 2.56 (m, 1H), 2.17 - 2.03 (m, 1H), 1.30 (d, 3H).

[1104] Example 63: Preparation of Compound 63

[1105] First Step: Preparation of Compound 63B

[1106] Compound 63A (500 mg, 2.85 mmol), 5B (733 mg, 2.85 mmol), sodium carbonate (600 mg, 5.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (120 mg, 0.15 mmol) were added into a three-necked flask, protected by nitrogen, added ethylene glycol dimethyl ether (7.5 mL) and water (5 mL), reacted at 100 ℃ for 3 h. After the reaction was completed, it was cooled to room temperature, filtered with diatomite, added water (10 mL), extracted with ethyl acetate (15 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 5) to obtain 63B (700 mg, yield: 80%).

[1107] LCMS m / z = 308.0 [M+1] +

[1108] Second step: preparation of compound 63C

[1109] The second step of the synthesis method in Reference Example 55 was referred to to obtain 63C (300 mg).

[1110] LCMS m / z = 462.2 [M+H] +

[1111] Third step: preparation of compound 63D

[1112] The second step of the synthesis method in Reference Example 56 was referred to to obtain 63D (126 mg).

[1113] LCMS m / z = 388.1 [M+H] +

[1114] Fourth step: preparation of compound 63

[1115] The third step of the synthesis method in Reference Example 38 was referred to to obtain compound 63 (48 mg).

[1116] LCMS m / z = 431.1 [M+H] +

[1117] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.07 (s, 1H), 7.65-7.20 (m, 5H), 4.39-4.28 (m, 1H), 4.26 (s, 2H), 4.12-4.02 (m, 1H), 3.65-3.56 (m, 1H), 1.32 (d, 3H).

[1118] Example 64: Preparation of compound 64

[1119] First Step: Preparation of compound 64A

[1120] Following the synthetic procedure of Reference Example 55, Step 2, 64A (0.65 g) was obtained.

[1121] LCMS m / z = 428.1 [M+H] +

[1122] Second Step: Preparation of compound 64B

[1123] Following the synthetic procedure of Reference Example 56, Step 2, 64B (213 mg) was obtained.

[1124] LCMS m / z = 354.1 [M+H] +

[1125] Third Step: Preparation of compound 64

[1126] 64B (100 mg, 0.28 mmol) was added to 64C (5 mL) and reacted at 110 °C overnight, concentrated under reduced pressure, purified by preparative HPLC (Instrument: waters 2767 preparative liquid; column: SUNFIRE® Prep C18 (19 mm x 250 mm); mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile) and lyophilized to give compound 64 (35 mg, yield: 32%).

[1127] LCMS m / z = 396.2 [M+H] +

[1128] 1 H NMR (400 MHz, DMSO-d6) d 8.29 (d, 1H), 8.10 (d, 1H), 7.61 - 7.40 (m, 3H), 7.08 (d, 1H), 4.44 - 4.30 (m, 1H), 4.14 (s, 2H), 4.05 (dd, 1H), 3.65 (dd, 1H), 2.41 (s, 3H), 1.28 (d, 3H).

[1129] Example 65: Preparation of compound 65

[1130] First Step: Preparation of 65B

[1131] Compound 65B (310 mg, yield: 20%) was obtained by column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0-5%) from the resulting solid.

[1132] LCMS m / z = 368.1 [M+H] +

[1133] Second Step: Preparation of compound 65

[1134] Reference to the synthesis method of example 6, third step, compound 65 (151 mg) was obtained.

[1135] LCMS m / z = 411.1 [M+H] +

[1136] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1H), 8.08 (s, 1H), 7.62-7.44 (m, 4H), 7.34-7.17 (m, 1H), 7.13-7.07 (m, 1H), 4.44-4.36 (m, 1H), 4.35-4.26 (m, 1H), 4.11-4.01 (m, 1H), 3.68-3.58 (m, 1H), 1.61 (d, 3H), 1.35-1.27 (m, 3H).

[1137] Example 66: Preparation of compound 66

[1138] Reference to the synthesis method of example 65, compound 66C (252 mg) was obtained.

[1139] Chiral resolution:

[1140] Compound 66C was prepared by first chiral preparation (Instrument: CAS-05-Prep-SFC-G Prep column: WHELK column; mobile phase composition: CO2 / isopropanol (0.1% NH3-H2O); flow rate: 130 mL / min; column temperature: room temperature) and lyophilized to obtain compound 65 (chiral column retention time: 1.545 min, 88 mg). Compound 66 was prepared by second chiral preparation (Instrument: CAS-05-Prep-SFC-G Prep column: AS column; mobile phase composition: CO2 / isopropanol (0.1% NH3-H2O); flow rate: 130 mL / min; column temperature: room temperature) and lyophilized to obtain compound 66 (chiral column retention time: 1.349 min, 90 mg). The chiral column retention time was measured by analytical instrument CAS-05-ANA-SFC-D (analytical column: WHELK column; mobile phase composition: CO2 / isopropanol (0.05% M NH3); flow rate: 3 mL / min; column temperature: 35 °C).

[1141] Compound 66: LCMS m / z = 411.1 [M+H] +

[1142] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1H), 8.08 (s, 1H), 7.62-7.47 (m, 4H), 7.31-7.19 (m, 1H), 7.12-7.07 (m, 1H), 4.45-4.36 (m, 1H), 4.36-4.26 (m, 1H), 4.11-4.00 (m, 1H), 3.66-3.58 (m, 1H), 1.61 (d, 3H), 1.34-1.28 (m, 3H).

[1143] Example 67: Preparation of compounds 67-1 and 67-2

[1144] First Step: Preparation of 67A

[1145] Compound 63B (1.8 g, 5.85 mmol) was added to THF (10 mL), cooled to -78 °C, and lithium bis(trimethylsilyl)amide (5.85 mL, 1.0 mol / L n-hexane solution) was added. The reaction was continued for 0.5 h, then iodomethane (1.25 g, 8.81 mmol) was added, and the reaction was slowly warmed to room temperature and continued for 1 h. Water (100 mL) was added to the reaction, and ethyl acetate (100 mL) was used to extract the organic phase. The organic phase was concentrated under reduced pressure and then purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 0-20%)) to obtain 67A (1.7 g, yield 90%).

[1146] LCMS m / z = 322.0 [M+H] +

[1147] The second step to the fifth step was obtained by reference to the synthetic method of the sixth step to the ninth step of example 2 to get compound 67 (660 mg).

[1148] Chiral resolution:

[1149] Compound 67 was prepared by chiral (Instrument: SFC Prep 150AP preparative chromatographic column: Chiralpak IC (19mm x 250mm); mobile phase composition: CO2 / isopropanol (0.05% NH3·H2O)), and freeze-dried to obtain compound 67-1 (chiral column retention time: 12.6mim, 330 mg) and 67-2 (chiral column retention time: 16.1mim, 305 mg), one of which is compound 67-A and the other is compound 67-B.

[1150] Compound 67-1 LCMS m / z = 457.1 [M+H] +

[1151] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.87 (s, 1H), 7.62-7.36 (m, 5H), 5.48 (t, 1H), 4.98-4.87 (m, 2H), 4.77-4.67 (m, 1H), 2.37 (s, 3H), 1.68 (d, 3H).

[1152] Compound 67-2 LCMS m / z = 457.1 [M+H] +

[1153] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.87 (s, 1H), 7.62-7.36 (m, 5H), 5.48 (t, 1H), 4.98-4.87 (m, 2H), 4.77-4.67 (m, 1H), 2.37 (s, 3H), 1.68 (d, 3H).

[1154] Example 68: Preparation of compound 68

[1155] The first step to the third step was obtained by reference to the synthetic method of the first step to the third step of example 67 to get 68C (0.81 g).

[1156] LCMS m / z = 486.1 [M+H] +

[1157] Fourth Step: Preparation of 68D

[1158] Reference the synthesis method of first step of example 50 to obtain 68D (0.75 g).

[1159] LCMS m / z = 478.2 [M+H] +

[1160] Fifth Step: Preparation of 68E

[1161] Compound 68D (0.75 g, 1.57 mmol) and 10% palladium carbon (0.75 g) were added to ethyl acetate (10 mL), the atmosphere of the reaction system was replaced with hydrogen by hydrogen balloon, and the reaction was carried out at room temperature for 1 hour. Silica gel was suction filtered, and the filtrate was concentrated under reduced pressure to obtain crude 68E (0.74 g).

[1162] LCMS m / z = 480.3 [M+H] +

[1163] Sixth to Seventh Step: Reference the synthesis method of eighth to ninth step of example 2 to obtain compound 68 (172 mg).

[1164] LCMS m / z = 451.1 [M+H] +

[1165] 1 H NMR (400 MHz, DMSO-d6) δ 7.66-7.60 (m, 2H), 7.59 (s, 1H), 7.55-7.35 (m, 3H), 7.34 (s, 1H), 5.63 (t, 1H), 4.91 (d, 2H), 4.53-4.44 (m, 1H), 2.83-2.72 (m, 2H), 2.35 (s, 3H), 1.66 (d, 3H), 1.24 (t, 3H).

[1166] Example 69: Preparation of compound 69

[1167] First Step: Preparation of compound 69B

[1168] Compound 69A (1 g, 4.44 mmol), 5B (1.71 g, 6.65 mmol), potassium carbonate (1.84 g, 13.31 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (162 mg) were added into a three-neck flask, protected by nitrogen, 1,4-dioxane (15 mL) and water (3 mL) were added, and the mixture was reacted at 90 °C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 0-30%)) to give 69B (460 mg, yield: 29%).

[1169] LCMS m / z = 358.0 [M+H] +

[1170] Second step: preparation of compound 69D

[1171] 69B (960 mg, 2.68 mmol), 69C (700 mg, 4.02 mmol), triethylamine (1.36 g, 13.44 mmol) were added into a microwave tube, and the mixture was reacted at 130 °C for 1 h. After the mixture was cooled to room temperature, the reaction solution was rotary evaporated under reduced pressure, and the crude product was separated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 0-50%)) to give 69D (800 mg, yield: 60%).

[1172] LCMS m / z = 496.2 [M+H] +

[1173] Third step to fourth step: compound 69 (100 mg) was obtained by the synthesis method of reference example 58, second step to third step.

[1174] LCMS m / z = 465.0 [M+H] +

[1175] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.08 (s, 1H), 7.66-7.56 (m, 1H), 7.54-7.23 (m, 4H), 4.39-4.28 (m, 3H), 4.15-4.04 (m, 1H), 3.71-3.61 (m, 1H), 1.32 (d, 3H).

[1176] Example 70: preparation of compound 70

[1177] First step: preparation of 70B

[1178] Compound 70B (2.07 g), 55C (1.01 g, 5.80 mmol) and triethylamine (2.93 g, 29.0 mmol) were added into a microwave reactor and reacted at 150 °C for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1) to obtain crude 70C (1.05 g).

[1179] LCMS m / z = 358.0 [M+H] +

[1180] Second step: Preparation of 70C

[1181] Compound 70B (2.07 g), 55C (1.01 g, 5.80 mmol) and triethylamine (2.93 g, 29.0 mmol) were added into a microwave reactor and reacted at 150 °C for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1) to obtain crude 70C (1.05 g).

[1182] LCMS m / z = 496.1 [M+1] +

[1183] Third step: Preparation of 70E

[1184] Compound 70C (1.05 g, 2.12 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (10 mL, 4 mol / L) and reacted at room temperature for three hours. After being concentrated under reduced pressure, 950 mg of the crude product and 70D (0.43 g, 2.65 mmol) were added to dichloromethane (20 mL) and reacted at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-50%) to obtain crude 70E (620 mg).

[1185] LCMS m / z = 422.1 [M+1] +

[1186] Fourth step: Preparation of compound 70

[1187] Compound 70 (327.8 mg) was obtained by adding 70E crude (620 mg) into dichloromethane (30 mL), adding 6E (1.04 g, 7.35 mmol) at -78 °C, slowly warming to room temperature and reacting overnight. Concentration under reduced pressure, adding hydrochloric acid solution (2 M, 10 mL) to the concentrate, reacting at room temperature for 30 minutes, concentrating the reaction solution, purifying with preparative HPLC (instrument: waters 2767 preparative liquid; column: SUNFIRE® Prep C18 (19 mm x 250 mm); mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile) and lyophilizing to obtain compound 70 (327.8 mg).

[1188] LCMS m / z = 465.1 [M+H] +

[1189] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.61 (s, 2H), 7.59-7.48 (m, 3H), 7.32 (s, 1H), 4.38-4.29 (m, 1H), 4.26 (s, 2H), 4.08 (m, 1H), 3.60 (m, 1H), 1.33 (d, 3H).

[1190] Example 71: Preparation of compound 71

[1191] First step: Preparation of 71B

[1192] Compound 11D (1.08 g, 3.95 mmol), 71A (0.95 g, 4.74 mmol) and triethylamine (2.00 g, 19.76 mmol) were added into a microwave reactor, reacted at 150 °C for 3 h, after the reaction was completed, cooled to room temperature, and the reaction solution was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1) to obtain crude 71B (402 mg).

[1193] LCMS m / z = 454.2 [M+H] +

[1194] Second step: Preparation of compound 71C

[1195] Reference to the second step of the synthesis method in Example 56, 71C (0.17 g) was obtained.

[1196] LCMS m / z = 380.2 [M+H] +

[1197] Third step: Preparation of compound 71

[1198] Reference Example 70, fourth step. Compound 71 (41 mg, yield: 21%) was obtained.

[1199] LCMS m / z = 423.1 [M+H] +

[1200] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, 1H), 8.03-7.99 (m, 1H), 7.61 (s, 1H), 7.57-7.45 (m, 3H), 7.25 (s, 1H), 7.05 (dd, 1H), 4.87 (ddd, 1H), 4.55-4.47 (m, 1H), 4.13 (s, 2H), 1.94-1.83 (m, 3H), 1.79-1.69 (m, 1H), 1.60-1.39 (m, 2H).

[1201] Example 72: Preparation of compound 72

[1202] Step 1: Preparation of compound 72

[1203] Acetic anhydride (5 mL) was added to formic acid (8 mL), reacted at 60 °C for 1 h, 64B (200 mg, 0.57 mmol) was added to the reaction solution, and the temperature was raised to 110 °C for overnight reaction. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and compound 72 (6 mg, yield: 3%) was obtained after purification by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile / water containing 0.1% trifluoroacetic acid) and lyophilization.

[1204] LCMS m / z = 382.1 [M+H] +

[1205] 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.30 (d, 1H), 8.07 (s, 1H), 7.61-7.46 (m, 3H), 7.16-7.09 (m, 1H), 4.38-4.25 (m, 1H), 4.22-4.12 (m, 3H), 3.72-3.64 (m, 1H), 1.35 (d, 3H).

[1206] Example 73: Preparation of compound 73

[1207] Step 1: Preparation of compound 73B

[1208] Reference to the synthesis method of Example 55, first step, to obtain 73B (5.69 g).

[1209] LCMS m / z = 308.0 [M+H] +

[1210] Second step: Preparation of compound 73C

[1211] Compound 73B (500 mg, 1.63 mmol), 55C (284 mg, 1.63 mmol) and triethylamine (824 mg, 8.14 mmol) were added to a microwave reactor and reacted at 120 °C for 1 h. After the reaction was completed, it was cooled to room temperature and separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1) to obtain 73C (475 mg, yield: 63%).

[1212] LCMS m / z = 462.2 [M+H] +

[1213] Third step: Preparation of compound 73D

[1214] Reference to the synthesis method of Example 56, second step, to obtain 73D (279 mg).

[1215] LCMS m / z = 388.1 [M+H] +

[1216] Reference to the synthesis method of Example 50, first to third steps, to obtain compound 73 (46 mg).

[1217] LCMS m / z = 425.1 [M+H] +

[1218] 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.64-7.38 (m, 4H), 7.21 (s, 1H), 6.94 (s, 1H), 4.38-4.23 (m, 1H), 4.17-4.01 (m, 3H), 3.68-3.59 (m, 1H), 2.66 (q, 2H), 1.31 (d, 3H), 1.20 (t, 3H).

[1219] Example 74: Preparation of compound 74

[1220] Reference to the synthesis method of compound 67 to obtain compound 74 (206 mg).

[1221] LCMS m / z = 491.1 [M+H] +

[1222] 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.97 (s, 1H), 7.77-7.70 (m, 2H), 7.60-7.39 (m, 3H), 5.33 (t, 1H), 4.98 (d, 2H), 4.71-4.62 (m, 1H), 2.37 (s, 3H), 1.72 (d, 3H).

[1223] Example 75: Preparation of compound 75

[1224] Compound 6 (0.20 g, 0.52 mmol) and 60A (0.32 g, 0.79 mmol) were added to toluene (20 mL) and reacted at 100 °C overnight. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: SUNFIRE® Prep C18 (19 mm x 250 mm); mobile phase composition: water (5 mmol / L NH4HCO3 in H2O) / acetonitrile), and lyophilized to give compound 75 (97 mg, yield: 47%).

[1225] LCMS m / z = 399.0 [M+H] +

[1226] 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.23 (s, 1H), 8.31 (d, 1H), 8.01 (s, 1H), 7.54 (m, 2H), 7.48 (m, 1H), 7.09 (m, 1H), 4.14 (s, 2H), 4.09 (m, 2H), 3.95 (m, 2H).

[1227] Example 76: Preparation of compound 76

[1228] First step: Preparation of compound 76B

[1229] Compound 44B (2400 mg, 8.24 mmol), 76A (1650 mg, 8.24 mmol) and triethylamine (10.02 g, 99.02 mmol) were added to a microwave reactor and reacted at 120 °C for 4 h. After the reaction was completed, it was cooled to room temperature and the reaction solution was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V = 1 / 1) to give 76B (550 mg, yield: 14%).

[1230] LCMS m / z = 472.2 [M+H]+

[1231] Second Step: Preparation of compound 76C

[1232] Following the synthetic procedure of Reference Example 70, third step, compound 76C (370 mg) was obtained.

[1233] LCMS m / z = 398.1 [M+H] +

[1234] Third Step: Preparation of compound 76

[1235] Following the synthetic procedure of Reference Example 18, second step, compound 76 (160 mg) was obtained.

[1236] LCMS m / z = 441.2 [M+H] +

[1237] Chiral resolution:

[1238] Compound 76 was subjected to a first chiral preparation (Instrument: CAS-05-Prep-SFC-F Preparative column: WHELK column; Mobile Phase Composition: C02 / isopropanol (0.1% NH3H20); Flow Rate: 140 mL / min; Column Temperature: room temperature) and lyophilized to give a mixture of Compound 76-1, Compound 76-2 and a mixture of Compound 76-3, Compound 76-4. The mixture of Compound 76-1, Compound 76-2 was subjected to a second chiral preparation (Instrument: CAS-05-Prep-SFC-F Preparative column: AD column; Mobile Phase Composition: C02 / methanol (0.1% NH3H20); Flow Rate: 130 mL / min; Column Temperature: room temperature) and lyophilized to give Compound 76-1 (Chiral Column Ret Time: 2.531 min, 34.7 mg) and Compound 76-2 (Chiral Column Ret Time: 2.640 min, 32.9 mg), as determined by analytical instrument CAS-05-ANA-SFC-C (Analytical column: IG column; Mobile Phase Composition: C02 / isopropanol (0.05% DEA); Flow Rate: 3 mL / min; Column Temperature: 35 °C). The mixture of Compound 76-3, Compound 76-4 was subjected to a third chiral preparation (Instrument: CAS-05-Prep-SFC-E Preparative column: OJ column; Mobile Phase Composition: C02 / methanol (0.1% NH3H20); Flow Rate: 70 mL / min; Column Temperature: room temperature) and lyophilized to give Compound 76-3 (Chiral Column Ret Time: 2.743 min, 38.9 mg) and Compound 76-4 (Chiral Column Ret Time: 2.940 min, 43 mg), as determined by analytical instrument CAS-05-ANA-SFC-C (Analytical column: IG column; Mobile Phase Composition: C02 / isopropanol (0.05% DEA); Flow Rate: 3 mL / min; Column Temperature: 35 °C). Of Compound 76-1, Compound 76-2, Compound 76-3 and Compound 76-4, one is Compound 76-A, one of the remaining three is Compound 76-B, one of the remaining two is Compound 76-C and the last remaining one is Compound 76-D

[1239] Compound 76-1 LCMS m / z = 441.1 [M+H] +

[1240] 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.23 (s, 1H), 7.79-7.74 (m, 1H), 7.70 (s, 1H), 7.68-7.61 (m, 1H), 7.56 (s, 1H), 7.26 (s, 1H), 7.19 (d, 1H), 6.94 (d, 1H), 4.07-3.93 (m, 2H), 3.77-3.72 (m, 1H), 1.22-1.14 (m, 1H), 0.63-0.55 (m, 1H), 0.54-0.45 (m, 1H), 0.45-0.34 (m, 1H), 0.32-0.19 (m, 1H).

[1241] Compound 76-2 LCMS m / z = 441.2 [M+H] +

[1242] Compound 76-3 LCMS m / z = 441.1 [M+H] +

[1243] Compound 76-4 LCMS m / z = 441.1 [M+H] +

[1244] Biological Test Example One:

[1245] GPR52 agonistic activity test

[1246] CHO cells overexpressing human GPR52 were cultured in F12 medium (containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B) at 37℃ with 5% CO2. 1×Stimulation Buffer was prepared according to the instruction of LANCE Ultra cAMP kit (PerkinElmer, Cat# TRF0264). The 1000× working solution of the test substance was prepared with DMSO, and then 10 nL / well was transferred into a 384-well plate (Greiner, Cat# 784075). The CHO cells overexpressing human GPR52 were treated with trypsin, and after centrifugation at 1000 rpm for 5 minutes, the cell precipitate was resuspended in 1×Stimulation Buffer, and after counting, 10 μL / well was added to a 384-well plate (Greiner, Cat# 784075). After centrifugation at 1000 rpm for 1 minute at room temperature, incubation was performed at 37℃ for 30 minutes. Eu-cAMP was diluted to 4× working concentration with Detection buffer, and 5 μL was added to the corresponding experimental wells. ULight-anti-cAMP was diluted to 4× working concentration with Detection buffer, and 5 μL was added to the corresponding experimental wells, and after centrifugation at 1000 rpm for 1 minute, incubation was performed at room temperature for 1 hour in the dark. After the completion of incubation, the fluorescence intensity of each well was detected by using an EnVision® FSX microplate reader (BMG) at an excitation wavelength of 330 nm and reading values at 665 nm and 620 nm. The signal ratio Ratio (Signal 665 / Signal 620*10 ) was calculated, and the Graphpad Prism software was used to fit the EC 4 values. 50

[1247] Table 1 EC 50 data of GPR52 agonism

[1248] Note: In Table 1, A < 20 nM, 20 nM ≤ B < 50 nM, 50 nM ≤ C < 0.5 μM, 0.5 μM ≤ D

[1249] Conclusion: The compound of the present application, for example, the compound of the example, has strong GPR52 agonism, for example, the EC 50 of compound 46 for GPR52 agonism is 1.45 nM.

[1250] Test Example 2: Mouse pharmacokinetic test

[1251] Test animals: male C57BL / 6J mice, 25-30 g. Purchased from Beijing Huafukang Biosciences Co., Ltd.

[1252] ​Test Design: On the day of the experiment, mice were randomized by body weight. Fasted for 14-18h with free access to water 1 day before dosing, and fed 4h after dosing.

[1253] Table 2 Dosing Information

[1254] Intravenous and Intragastric Administration Vehicle: 10% DMA + 10% Solutol + 80% Saline

[1255] (DMA: N,N-dimethylacetamide; Solutol: Polyethylene glycol-15-hydroxystearate; Saline: Normal saline)

[1256] Blood samples (0.06 mL) were collected from the orbital sinus under isoflurane anesthesia before and after dosing, and placed in EDTA K2 tubes. The tubes were centrifuged at 5000 rpm for 10 min at 4°C. The plasma was collected and the time points were 5, 15, 30 min, 1, 2, 4, 7, and 24 h. At 15 min, 2 h, and 24 h, 3 mice were sacrificed and brain and cerebrospinal fluid samples were collected. All samples were stored at -80°C before analysis. The samples were analyzed quantitatively by LC-MS / MS.

[1257] To calculate the brain-to-plasma unbound fraction ratio (K p,uu ), the rapid equilibrium dialysis method (RED) was used to determine the binding of the test substance in mouse plasma and brain homogenate, respectively. The test substance stock solution was prepared with DMSO, and the working solution was diluted with 50% methanol. The test substance was prepared into 1 ug / mL plasma samples and brain homogenate samples with blank mouse plasma and brain homogenate, respectively, and placed in the equilibrium dialysis device. The dialysis was performed with phosphate buffer solution (PBS) at 37°C for 6 hours. After incubation, the contents of each plasma / brain homogenate and buffer compartment were removed and mixed with an equal volume of blank control buffer or plasma / brain homogenate to maintain matrix similarity. After protein precipitation, the supernatant was centrifuged and analyzed by LC-MS / MS. The concentration of the test substance in the sample was semi-quantified using the ratio of the peak area of the test substance to the peak area of the internal standard (Area Ratio). The brain-to-plasma unbound fraction ratio (K p,uu ) was calculated by the following formula.

[1258] (1) Plasma protein unbound fraction (%Unbound ,Plasma ) = Buffer side concentration / Plasma side concentration * 100%

[1259] (2) Brain homogenate unbound fraction (%Unbound ,Brain ) = Buffer side concentration / Brain homogenate side concentration * 100%

[1260] (3) Unbound brain-to-plasma ratio (K p,uu ) = (%Unbound,Brain AUC brain Unbound ,Plasma AUC plasma )

[1261] Table 3-1 Pharmacokinetic parameters of test compounds in mice

[1262] Table 3-2 Pharmacokinetic parameters of test compounds in mice

[1263] Conclusion: The compounds of the present application, such as the example compounds, have good brain penetration ability, and specifically, compound 6 has a higher brain concentration in mice and can more effectively cross the blood-brain barrier of mice than the control compound 1.

[1264] The structure of the control compound 1 is as follows, and its synthesis is referred to the patent WO2021181122.

[1265] Test Example 3: Rat pharmacokinetic test

[1266] Test animals: male SD rats, 180-220 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[1267] Test design: On the test day, the rats were randomly divided according to body weight. Fasting without water for 14-18 h before administration, and feeding 4 h after administration.

[1268] Table 4 Dosing information

[1269] Intravenous and gavage administration vehicle: 10% DMA + 10% Solutol + 80% Saline

[1270] (DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline)

[1271] 0.15 mL of blood was taken from the orbit under isoflurane anesthesia before and after administration, and was placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm at 4°C for 10 min, and the plasma was collected. The blood sampling time points were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. At 15 min, 2 h, and 24 h, 3 rats were dissected and brain and cerebrospinal fluid samples were collected. Before analysis, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[1272] To calculate the brain-plasma ratio of unbound drugs (K p,uuThe binding rate of the test substance in rat plasma and brain homogenate was determined by using rapid equilibrium dialysis (RED), respectively. The test substance stock solution was prepared with DMSO, and the working solution was diluted with 50% methanol. The test substance was prepared into 1 ug / mL plasma sample and brain homogenate sample with blank rat plasma and brain homogenate, respectively, and placed in the equilibrium dialysis device. The phosphate buffer solution (PBS) was dialyzed at 37°C for 6 hours. After incubation, the contents of each plasma / brain homogenate and buffer compartment were taken out and mixed with an equal volume of blank control buffer or plasma / brain homogenate to maintain matrix similarity. After protein precipitation treatment, the supernatant was obtained by centrifugation and analyzed by LC-MS / MS. The concentration of the test substance in the sample was semi-quantified using the ratio of the peak area of the test substance to the peak area of the internal standard (Area Ratio). The unbound brain plasma ratio (K p,uu ) was calculated by the following formula.

[1273] (1) The plasma protein unbound fraction (%Unbound ,Plasma ) = buffer side concentration / plasma side concentration * 100%

[1274] (2) The brain homogenate unbound fraction (%Unbound ,Brain ) = buffer side concentration / brain homogenate side concentration * 100%

[1275] (3) The unbound brain plasma ratio (K p,uu ) = (%Unbound ,Brain *AUC brain ) / (%Unbound ,Plasma *AUC plasma )

[1276] Table 5 Pharmacokinetic parameters of test compounds in rats

[1277] Conclusion: The compounds of the present application, such as the example compounds, have good brain penetration ability. For example, compound 18 has higher brain concentration and CSF (cerebrospinal fluid) concentration in rats than the control compound 1, and can more effectively cross the blood-brain barrier of rats.

[1278] Test Example 4: Beagle pharmacokinetic test

[1279] Test animals: male beagles, 8-11 kg, purchased from Beijing Mass Biotechnology Co., Ltd.

[1280] Test design: On the test day, the beagles were randomly divided according to body weight. Fasting but not water restriction for 14-18 hours before administration, and feeding 4 hours after administration.

[1281] Table 6 Dosing information

[1282] Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline

[1283] Gavage administration solvent: 5% DMA + 5% Solutol + 90% Saline

[1284] (DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline)

[1285] Before and after administration, 1 mL of blood was taken through the jugular vein or the limb vein, placed in an EDTA K2 centrifuge tube, centrifuged at 5000 rpm at 4°C for 10 min, and the plasma was collected. The blood sampling time points were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[1286] Conclusion: The compound of the present application, for example, the compound of the examples, has good dog pharmacokinetic performance.

[1287] Test Example 5: Monkey pharmacokinetic test

[1288] Test animals: male cynomolgus monkeys, about 3-5 kg. Purchased from Hainan Xinzhenying Biological Technology Co., Ltd.

[1289] Test method: On the test day, the cynomolgus monkeys were randomly divided into groups according to body weight. Fasting without water for 14-18 h before administration, and feeding 4 h after administration.

[1290] Table 7 Administration information

[1291] Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline

[1292] Gavage administration solvent: 5% DMA + 5% Solutol + 90% Saline

[1293] Before and after administration, 1 mL of blood was taken through the jugular vein or the limb vein, placed in an EDTA K2 centrifuge tube, centrifuged at 5000 rpm at 4°C for 10 min, and the plasma was collected. The blood sampling time points were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[1294] Conclusion: The compound of the present application, for example, the compound of the examples, has good oral absorption in monkeys.

[1295] Test Example 6: hERG Potassium Channel Effect Test

[1296] Experimental Platform: Electrophysiological Manual Patch Clamp System

[1297] Cell Line: Chinese Hamster Ovary (CHO) cell line stably expressing hERG potassium channel

[1298] Experimental Method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel were used to record hERG potassium channel current at room temperature using whole-cell patch clamp technique. Glass microelectrode was drawn from glass electrode embryo (BF150-86-10, Sutter) by a puller, and the tip resistance after perfusing the electrode internal solution was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to be connected to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by computer through pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV, and the step voltage to induce hERG potassium current (I hERG ) was given from -80 mV to a 2s depolarization voltage to +20 mV, and then repolarized to -50 mV, and then returned to -80 mV after 1s. This voltage stimulation was given every 10s, and after the hERG potassium current was determined to be stable (at least 1 minute), the drug administration process was started. Each test concentration of the compound was given for at least 1 minute, and at least 2 cells were tested for each concentration (n≥2).

[1299] Data Processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5 and Excel software. The inhibition degree of different compound concentrations on hERG potassium current (peak value of hERG tail current induced at -50 mV) was calculated using the following formula: Inhibition% = [1-(I / Io)]x100%

[1300] where Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current after and before drug administration, respectively.

[1301] Compound IC 50 The IC was calculated by fitting the following equation using GraphPad Prism 5 software: Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[1302] where X is the Log value of the test concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[1303] Conclusion: The compounds of the present application, e.g. the example compounds, have weak hERG inhibition.

[1304] Test Example 7: SLC transporter inhibition

[1305] The objective of this study is to evaluate the inhibitory effect of the test substance on the activities of transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1 and MATE2-K.

[1306] The HEK293-OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1 and MATE2-K cells are incubated with and without the test substance (0-30 μM) for the corresponding time, and then the samples are collected. The content of the substrate in the samples is detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The transport activities of the transporters with and without the test substance are calculated to obtain the percentage of the transport activities of the transporter cells under the action of the test substance at different dosing concentrations (% VC (Vehicle Control, solvent control), the percentage of the transport activities of the transporters with and without the test substance), and the half-inhibitory concentration (IC 50 ) is calculated therefrom.

[1307] Conclusion: The compounds of the present application, e.g. the example compounds, have weak SLC transporter inhibition.

[1308] Test Example 8: CYP450 enzyme inhibition test

[1309] The objective of this study is to evaluate the influence of the test substance on the activities of five isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) by using an in vitro test system. The specific probe substrates of the CYP450 isozymes are incubated with human liver microsomes and different concentrations of the test substance, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) is added to start the reaction. After the reaction is completed, the samples are treated and the specific substrate metabolites are quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) to determine the changes in CYP enzyme activity, and the IC 50 values are calculated to evaluate the inhibitory potential of the test substance on each CYP enzyme subtype.

[1310] Conclusion: The compounds of the present application, e.g. the example compounds, have weak CYP inhibition.

Claims

A compound or stereoisomer, pharmaceutically acceptable salt thereof, wherein, said compound is selected from the group consisting of compounds of general formula (I), Ring A is selected from Ring A1 or Ring A2; Ring A1is selected from Ring A2is selected from -8 to 10 membered heteroaryl-R a4 , -5 membered heteroaryl-R a4 , said 5 membered heteroaryl is attached to ring B through a carbon atom, said heteroaryl is optionally substituted with 1 to 4 R A ; Alternatively, when ring A2is selected from R A may form a C 3-8 carbocyclic or 5- to 8-membered heterocyclic ring, which is optionally substituted by 1 to 5 R k substituents; W is selected from -C 1-3 alkylene-, -NH-C 1-2 alkylene-, -C 1-2 alkylene-NH-, -C 1-2 alkylene-NH-C 1-2 alkylene-, -CH=N-, -N=CH-, said alkylene being optionally substituted with 1 to 5 R k substituents; a is selected from 0, 1, 2, 3, or 4; R a1 selected from -C(=O)NR aa1 R aa2 , -C(=O)R aa1 , -C(=S)NR aa1 R aa2 ; X is selected from CR x ; Y is selected from N or CR y ; or X is selected from N and Y is selected from N; Z is selected from CR z ; R x selected from C 1-6 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl, or heterocycloalkyl optionally substituted with 1 to 5 R k substituents; R y H, halogen, CN, C 1-6 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, which alkyl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 5 R k substituents; R z selected from -C 1-2 alkylene-C 3-7 ycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -NHC 2-6 alkenyl, -NHC 2-6 alkynyl, -C 1-2 alkylene-NH2, -C 1-2 alkylene-NH-C 1-6 alkyl, -C 1-2 alkylene-NH-C(O)R aa1 , -C 1-2 alkylene-N(C 1-6 alkyl)2, -C 1-2 alkylene-NH-C 3-7 ycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C=NR aa1 , said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl groups being optionally substituted with 1 to 5 R k groups; R AA selected from -C 1-2 alkylene-C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, said alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 5 R k substituents; R a3 selected from -S(=O)2NR aa1 R aa2 , -S(=O)(=N)NR aa1 R aa2 , -NR aa1 S(=O)2R aa2 , -NR aa1 C(=O)R aa2 , -S(=O)2R aa2 , -C(=O)NH-C(=NR aa3 )NR aa1 R aa2 , -C(=NR aa3 )NR aa1 R aa2 , -NR aa1 C(=O)NR aa1 R aa2 , -C(=S)NR aa1 R aa2 , -C(=O)NR aa1 -C 1-4 alkylene-C 3-7 cycloalkyl, -C(=O)NR aa1 -C 1-4 alkylene-4- to 7-membered heterocycloalkyl, -C(=O)NR aa1 -C 1-4 alkylene-O-C 3-7 cycloalkyl, -C(=O)NR aa1 -C 1-4 alkylene-O-4- to 7-membered heterocycloalkyl, said alkylene, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 3 R k substituted; R a4 selected from -C(=O)NR aa1 R aa2 or R a3 ; R aa1 , R aa2 each independently is selected from H, C 1-6 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, carbocyclic, cycloalkyl or heterocycloalkyl optionally substituted with 1 to 5 R k substituents; R aa3 H, CN, OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, which alkyl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 5 R k substituents; R A each independently selected from H, deuterium, halogen, CN, -C(=O)OH, NH2, -NHC(=O)R, 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-7 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl optionally substituted with 1 to 5 R k substituents; Ring B is selected from Ring B1 or Ring B2; Ring B1 is selected from one end is connected to Ring A and the other end is connected to L; T is selected from N or CR t ; R t each independently selected from H, deuterium, halogen, OH, CN, or C 1-6 alkyl, said alkyl being optionally substituted with 1 to 6 F; Ring B2is selected from 5-membered heteroaryl, *one end is connected to ring A, the other end is connected to L, said ring B2is optionally substituted with 1 to 3 R b2 substituted; R t1 with R t2 directly connected form C 3-8 carbocycle or 5- to 8-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 5 R k substituents; R t3 with R L1 directly to form C 3-8 carbocycle or 5- to 8-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 5 R k substituents; R t4 with R x directly to form C 5-10 carbocycle or 5- to 10-membered heterocycle, which is optionally substituted with 1 to 5 R k substituents; R t5 with R L1 directly to form C 3-8 carbocycle or 5- to 8-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 5 R k substituents; R b1 selected from C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-OH, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, which alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups are optionally substituted by 1 to 5 R k substituents; R b2 each independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted by 1 to 5 R k substituents; L is selected from L1 or L2; L1 is selected from -CH2-, -CH(D)-, -CD2-; L2is selected from -0-, -NH-, -S-, -NR L1 -CHR L1 - or -C(R L1 )2-; R L1 each independently is selected from the group consisting of CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted with 1 to 5 R k substituents; As an option, two R L1 Together with the atoms connected to form C 3-8 Carbon rings or 5- to 8-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 5 R... k replace; Ring C is selected from Ring C1 or Ring C2; Ring C1 is selected from V is selected from N or CR v ; Ring C2 is selected from 5-membered heteroaryl, 8- to 10-membered fused heteroaryl, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, C 5-10 bridged cycloalkyl, - phenyl-R c1 , - 6-membered heteroaryl-R c1 , said ring C2is optionally substituted with 1 to 4 R c2 substituted; R v1 with R L1 directly to form C 3-8 carbocycle or 5- to 8-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 5 R k substituents; R v each independently selected from H, deuterium, halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, said alkyl being optionally substituted with 1 to 6 F; R c1 -SF5, -CF(CF3)2, -C(=0)NHC 1-6 alkyl, -NHC(=0)C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, 3- to 7-membered heterocycle, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycle being optionally substituted by 1 to 5 R k substituents; R c2 each independently is selected from the group consisting of deuterium, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted with 1 to 5 R k substituents; R k Each element is independently selected from deuterium, =O, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and -NHC. 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally selected from 1 to 4 deuterium, halogens, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; with the proviso that when Ring A is selected from Ring A1, one of the following conditions is met: 1) Ring B is selected from Ring B2; 2) L is selected from L2; 3) Ring C is selected from Ring C2. The compound according to claim 1 or a stereoisomer, a pharmaceutically acceptable salt thereof, wherein, The compounds of general formula (I) are selected from compounds of general formula (la), (lb), (lc), (Id), (lb-1), (lb-2), (lb-3), (Ih), (Ii), (Ij) or (Ik), Ring E is selected from C 4-8 carbocyclic or 5- to 8-membered heterocyclic ring, said carbocyclic or heterocyclic ring being optionally substituted with 1 to 4 R k substituents; Ring EE is selected from a 5 to 8 membered heterocyclic ring, which is optionally substituted with 1 to 4 R k substituted; Y is selected from N; Ring B1 is selected from one end is connected to Ring A and the other end is connected to L; Ring C1 is selected from R x selected from C 1-4 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl, or heterocycloalkyl optionally substituted with 1 to 4 R k substituents; R z selected from -C 1-2 alkylene-C 3-6 ycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 1-4 haloalkyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -NHC 2-4 alkenyl, -NHC 2-4 alkynyl, -C 1-2 alkylene-NH2, -C 1-2 alkylene-NH-C 1-4 alkyl, -C 1-2 alkylene-NH-C(O)R aa1 , -C 1-2 alkylene-N(C 1-4 alkyl)2, -C 1-2 alkylene-NH-C 3-6 ycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C=NR aa1 , said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl groups being optionally substituted by 1 to 4 R k groups; R AA selected from -C 1-2 alkylene-C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, said alkylene, alkenyl, alkynyl, cycloalkyl being optionally substituted with 1 to 5 R k groups; R a3 selected from -S(=O)2NR aa1 R aa2 , -S(=O)(=N)NR aa1 R aa2 , -NR aa1 S(=O)2R aa2 , -NR aa1 C(=O)R aa2 , -S(=O)2R aa2 , -C(=O)NH-C(=NR aa3 )NR aa1 R aa2 , -C(=NR aa3 )NR aa1 R aa2 , -NR aa1 C(=O)NR aa1 R aa2 , -C(=S)NR aa1 R aa2 , -C(=O)NR aa1 -C 1-2 alkylene-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-C 3-6 cycloalkyl, -C(=O)NR aa1 -C 1-2 alkylene-O-4- to 7-membered heterocycloalkyl, said alkylene, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 3 R k substituents; R a4 selected from -C(=O)NR aa1 R aa2 or R a3 ; R aa1 , R aa2 are each independently selected from the group consisting of H, C 1-4 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, alkylene, cycloalkyl or heterocycloalkyl being optionally substituted with 1 to 4 R k ; R aa3 H, CN, OH, C 1-4 alkyl, -O-C 1-4 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, which alkyl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k substituents; R A each independently selected from H, deuterium, halogen, CN, -C(=O)OH, NH2, -NHC(=O)R, 1-4 alkyl, -N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, C 3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl optionally substituted with 1 to 4 R k substituents; R t each independently selected from H, deuterium, halogen, OH, CN, or C 1-4 alkyl, said alkyl being optionally substituted with 1 to 6 F; R b1 selected from C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-OH, -C 1-2 alkylene-OC 1-4 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, which alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups are optionally substituted by 1 to 4 R k substituents; R b2 each independently selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-OC 1-4 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted by 1 to 4 R k substituents; R L1 each independently selected from the group consisting of CN, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-OC 1-6 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, which alkyl, alkylene, alkenyl, alkynyl, cycloalkyl are optionally substituted with 1 to 4 R k substituents; R v each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, -OC 1-4 alkyl, said alkyl being optionally substituted with 1 to 6 F; R c1 -SF5, -CF(CF3)2, -C(=0)NHC 1-4 alkyl, -NHC(=0)C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, 3- to 7-membered heterocycle, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycle being optionally substituted by 1 to 4 R k substituents; R c2 each independently is selected from the group consisting of deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-OC 1-4 alkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl groups being optionally substituted with 1 to 4 R k substituents; R k Each element is independently selected from deuterium, =O, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally selected from 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; n is selected from 0, 1, 2, 3, or 4. The compound according to claim 2, or a stereoisomer, a pharmaceutically acceptable salt thereof, wherein, Ring A2is selected from - benzofuranyl-R a4 - pyridopyrrolyl-R a4 - pyrimidopyrrolyl-R a4 - thienyl-R a4 - furanyl-R a4 , said pyridopyrrolyl, pyrimidopyrrolyl, thienyl, furanyl groups being optionally substituted by 1 to 4 R A groups; Alternatively, when ring A2is selected from When, the R on two adjacent C atoms A It can form C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; R x selected from C 1-4 alkyl, -C 1-2 alkylene-O-C 1-4 alkyl, said alkylene, alkyl being optionally substituted with 1 to 4 R k substituents; R z selected from -C 1-2 alkylene-C 3-6 ycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 1-4 haloalkyl, -N(C 1-4 alkyl)2, -NHC 1-4 alkyl, -C 1-2 alkylene-NH2, -C 1-2 alkylene-NH-C 1-4 alkyl, -C 1-2 alkylene-NH-C(O)R aa1 , -C 1-2 alkylene-N(C 1-4 alkyl)2, -C 1-2 alkylene-NH-C 3-6 ycloalkyl, C 2-4 lenyl, C 2-4 ynyl, -C=NR aa1 , said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl groups being optionally substituted by 1 to 4 R k groups; R a3 selected from -S(=0)2NR aa1 R aa2 , -NR aa1 S(=O)2R aa2 -NR aa1 C(=O)R aa2 -S(=O)2R aa2 -C(=NR) aa3 )NR aa1 R aa2 -NR aa1 C(=O)NR aa1 R aa2 -C(=S)NR aa1 R aa2 -C(=O)NR aa1 -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C(=O)NR aa1 -C 1-2 Alkylene - 4 to 7-membered heterocyclic alkyl, -C(=O)NR aa1 -C 1-2 Alkylene-OC 3-6 Cycloalkyl, -C(=O)NR aa1 -C 1-2 Alkylene-O-4 to 7-membered heterocyclic alkyl groups, the alkylene, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 2 R k substituted; R aa1 , R aa2 each independently is selected from H, C 1-4 alkyl, C 1-2 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl groups being optionally substituted with 1 to 4 R k groups; R A Each is independently selected from H, deuterium, halogen, CN, -C(=O)OH, NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -OC 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, wherein the alkyl group is optionally surrounded by 1 to 4 R... k replace; Ring B2 is selected from thienyl, thiazolyl, imidazolyl, pyrazolyl, *one end is connected to ring A, the other end is connected to L, said ring B2is optionally substituted with 1 to 3 R b2 substituted; R t1 with R t2 directly connected form C 4-6 carbocycle or 5- to 6-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituents; R t3 with R L1 directly to form C 4-6 carbocycle or 5- to 6-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituents; R t4 with R x directly to form C 5-8 carbocycle or 5- to 8-membered heterocycle, which is optionally substituted with 1 to 4 R k substituents; R t5 with R L1 directly connected form C 4-6 carbocycle or 5- to 6-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituents; R b1 selected from C 2-4 alkenyl, C 2-4 alkynyl, OC 1-4 alkyl, -C 1-2 alkylene-CN, -C 1-2 alkylene-OH, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl being optionally substituted by 1 to 4 R k substituents; R b2 each independently selected from C 1-4 alkyl, -C 1-2 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkylene, alkyl, cycloalkyl being optionally substituted with 1 to 4 R k substituents; L1 is selected from -CH2-; L2is selected from -0-, -NH-, -S-, -NR L1 -CHR L1 - or -C(R L1 )2-; R L1 each independently selected from the group consisting of CN, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, cycloalkyl being optionally substituted with 1 to 4 R k substituents; As an option, two R L1 Together with the atoms connected to form C 3-8 Carbon rings or 5- to 8-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace; Ring C1 is selected from Ring C2 is selected from thienyl, furanyl, thiazolyl, 8- to 10-membered annulated heteroaryl, benzo 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, C 5-8 bridged cycloalkyl, - phenyl-R c1 , - 6-membered heteroaryl-R c1 , said ring C2is optionally substituted with 1 to 4 R c2 substituted; R v1 with R L1 directly to form C 3-8 carbocycle or 5- to 8-membered heterocycle, which carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituents; R v each independently selected from H, halogen, C 1-4 alkyl, -OC 1-4 alkyl, said alkyl being optionally substituted with 1 to 6 F; R c1 -SF5, -CF(CF3)2, -C(=0)NHC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycle, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle being optionally substituted by 1 to 4 R k substituents; R c2 each independently is selected from the group consisting of halogen, CN, C 1-4 alkyl, -C 1-2 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkylene, alkyl, cycloalkyl being optionally substituted with 1 to 4 R k substituents; R k each independently selected from the group consisting of deuterium, =0, F, CI, Br, I, CN, OH, -C(=0)OH, -C(=0)NH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, tert-butyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -0-cyclopropyl, -0-oxetanyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which methyl, ethyl, propyl, isopropyl, tert-butyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy. The compound according to claim 3, or a stereoisomer, a pharmaceutically acceptable salt thereof, wherein, Ring A2is selected from The optionally substituted by 1 to 4 R A substituents; Alternatively, when ring A2is selected from When, the R on two adjacent C atoms A It can form C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; R x selected from methyl, ethyl, propyl, isopropyl, methoxymethyl, said methylene, methyl, ethyl, propyl, isopropyl, methoxymethyl being optionally substituted with 1 to 4 R k substituents; R z selected from -CH2F, -CHF2, -CF3, said R z optionally substituted by 1 to 4 R k substituents; R a3 selected from -S(=0)2NH2, The optionally substituted with 1 to 2 R k substituents; R aa1 , R aa2 each independently is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl optionally substituted with 1 to 4 R k ; R aa3 selected from H, CN, OH, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, said methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, azetanyl being optionally substituted with 1 to 4 R k substituents; R A each independently is selected from F, CI, Br, I, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl optionally substituted with 1 to 4 R k substituents; R AA selected from The optionally substituted by 1 to 4 R k substituents; Ring B1 is selected from one end is connected to Ring A and the other end is connected to L; Ring B2 is selected from *one end is connected to ring A, the other end is connected to L, said ring B2is optionally substituted with 1 to 3 R b2 substituted; R t1 with R t2 directly to form C 4-6 carbocycle, which is optionally substituted with 1 to 4 R k substituents; R t3 with R L1 directly to form C 4-6 carbocycle, which is optionally substituted with 1 to 4 R k substituents; R t4 with R x directly connected form a 5- to 8-membered heterocycle, which is optionally substituted with 1 to 4 R k R t5 with R L1 directly connected form a C 4-6 carbocycle, which is optionally substituted with 1 to 4 R k ; R b1 selected from methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -Ocyclopropyl, -Ocyclobutyl, -Ocyclopentyl, -Ocyclohexyl, said methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with 1 to 4 R k substituents; R b2 each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl, isopropyl optionally substituted with 1 to 4 R k substituents; L1 is selected from -CH2-; L2is selected from -O-, -NH-, -S-, -NR L1 -CHR L1 - or -C(R L1 )2-; R L1 each independently selected from the group consisting of CN, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl being optionally substituted with 1 to 4 R k substituents; R2and R3are taken together with the atom to which they are attached to form a 3- to 8-membered heterocyclyl, the 3- to 8-membered heterocyclyl being optionally substituted with 1 to 4 R L1 R2and R3are taken together with the atom to which they are attached to form a 3- to 8-membered heterocyclyl, the 3- to 8-membered heterocyclyl being optionally substituted with 1 to 4 R k substituents; Ring C1 is selected from Ring C1 is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, which are optionally substituted with 1 to 4 F; Ring C2 is selected from - phenyl-R c1 , said ring C2 is optionally substituted with 1 to 4 R c2 groups; R c1 -SF5, -CF(CF3)2, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, azetidinyl, azetidinyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, said R c1 optionally substituted with 1 to 4 R k substituents; R c2 each independently is selected from the group consisting of F, Cl, Br, I, CN, methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl, isopropyl being optionally substituted with 1 to 4 R k substituents; R k each independently selected from deuterium, =0, F, CI, Br, I, CN, OH, -C(=0)OH, -C(=0)NH2, -CH2OH, methyl, ethyl, propyl, / -propyl, / -butyl, CD3, OCD3, CH2F, CHF2, CF3, vinyl, ethynyl, methoxy, ethoxy, methylthio, -0-cyclopropyl, -0-oxetanyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The compound according to claim 4, or a stereoisomer, a pharmaceutically acceptable salt thereof, wherein, Ring A2is selected from The optionally substituted by 1 to 4 R A substituents; Alternatively, when ring A2is selected from When, the R on two adjacent C atoms A It can form C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 6-membered heteroaryl, wherein the cycloalkyl, heterocycloalkylphenyl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; W is selected from -CH2-CH2-, -C(O)NH-CH2-, -N=CH-, -CH2-, said W being optionally substituted with 1 to 4 R k substituents; selected from the group consisting of Ring E is optionally substituted with 1 to 4 R k substituted, one end attached to Ring A and the other end attached to L; selected from the group consisting of Ring E is optionally substituted with 1 to 4 R k substituted, one end attached to Ring A and the other end attached to Ring C; selected from the group consisting of Ring E is optionally substituted with 1 to 4 R k substituted, one end attached to Ring A and the other end attached to Ring C; selected from the group consisting of Ring E is optionally substituted with 1 to 4 R k substituted, the * end is attached to Ring B; selected from the group consisting of selected from the group consisting of selected from the group consisting of m is selected from 0, 1, 2, 3, or 4; R a1 selected from -C(=O)NH2, -C(=O)CH3, -C(=O)H, -C(=S)NH2; R x selected from R z selected from R AA selected from R a3 selected from -S(=O)2NH2; R a4 selected from -C(=O)NH2; R A each independently is selected from F, CI, Br, I, CN, methyl, ethyl, -CH2F, -CHF2, -CF3, methoxy, cyclopropyl, Ring B2 is selected from one end is connected to Ring A and the other end is connected to L; L2is selected from -0-, -NH-, -S-, Ring C1 is selected from Ring C2 is selected from The compound according to claim 2 or a stereoisomer, a pharmaceutically acceptable salt thereof, wherein, The compounds of general formula (I) are selected from the group of compounds shown in (Ih-3), X is selected from CR x ; R x selected from Y is selected from N; R A Each is independently selected from H, deuterium, halogen, CN, -C(=O)OH, NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -OC 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, wherein the alkyl group is optionally surrounded by 1 to 4 R... k replace; R is preferably selected from the group consisting of F, CI, Br, I, CN, methyl, ethyl, -CH2F, -CHF2, -CF3, methoxy, cyclopropyl, A each independently selected from the group consisting of F, CI, Br, I, CN, methyl, ethyl, -CH2F, -CHF2, -CF3, methoxy, cyclopropyl, R L1’ selected from R L1 ; R L1 each independently selected from the group consisting of CN, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, said alkyl, cycloalkyl being optionally substituted with 1 to 4 R k substituents; Preferably, R L1 Each is independently selected from CN, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. k replace; T' is selected from N, CH, CR t ; V' is selected from N, CH, CR v ; T is selected from N or CR t ; R t each independently selected from H, deuterium, halogen, OH, CN, or C 1-4 alkyl, said alkyl being optionally substituted with 1 to 6 F; R is preferably selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl, said methyl, ethyl, propyl optionally substituted with 1 to 6 F; t each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl, said methyl, ethyl, propyl optionally substituted with 1 to 6 F; V is selected from N or CR v ; R v each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, -OC 1-4 alkyl, said alkyl being optionally substituted with 1 to 6 F; Preferably, R v each independently is selected from the group consisting of H, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, said methyl, ethyl, propyl optionally substituted with 1 to 6 F. The compound according to claim 1 or a stereoisomer, a pharmaceutically acceptable salt thereof, wherein, The compound is selected from one of the structures shown in Table E. A pharmaceutical composition comprising a compound according to any one of claims 1-7, or a stereoisomer, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, preferably the pharmaceutical composition comprises 1-1500 mg of a compound according to any one of claims 1-7, or a stereoisomer, a pharmaceutically acceptable salt thereof. Use of a compound according to any one of claims 1-7, or a stereoisomer, a pharmaceutically acceptable salt thereof, or a composition according to claim 8, for the manufacture of a medicament for the treatment of a psychiatric disorder. A method for treating or ameliorating a disease in a mammal, wherein, The method comprises administering to a subject a therapeutically effective amount of a compound according to any one of claims 1-7, or a stereoisomer, a pharmaceutically acceptable salt thereof, preferably 1-1500 mg, for the treatment of a disease, preferably a psychiatric disorder.

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