Protein inhibitors or degrading agents, pharmaceutical compositions containing them, and pharmaceutical uses

Abstract

The present invention discloses a protein inhibitor or decomposer, a pharmaceutical composition containing the same, and a pharmaceutical use thereof. The present invention provides a compound represented by general formula (I) and a pharmaceutical composition containing the same. The present invention also discloses the application of the compound of the general formula as a protein inhibitor and / or a protein decomposer, and a pharmaceutical use thereof. [Formula 1] TIFF2024524162000621.tif8170

Description

[Technical Field]

[0001] This application claims priority over the following application: Chinese patent application 2021107162100, filed on June 25, 2021. Chinese patent application 2021109795818, filed on August 24, 2021. Chinese patent application 2022102345294, filed on March 10, 2022. Chinese patent application 2022105564005, filed on May 20, 2022.

[0002] The full text of the above-mentioned Chinese patent application is incorporated herein by reference.

[0003] Technical field The present invention belongs to the field of pharmaceutical technology and, in particular, relates to PROTAC molecules, pharmaceutical compositions, and pharmaceutical uses that target ALK, ROS1, EGFR protein, and their mutant proteins. [Background technology]

[0004] PROTACs (proteolysis targeting chimeras), or protein degradation-inducing chimeric molecules, are a newly emerging research area that has attracted considerable attention in recent years. PROTAC molecules are generally divided into three parts: one end is a small molecule fragment (war head) that binds to a specific target protein, the other end is an E3 ligase ligand with ubiquitination function, and the other end is a linker that connects the two. PROTAC molecules can selectively degrade target proteins by utilizing the cellular protein ubiquitination degradation pathway. Specifically, since both ends of a PROTAC molecule are ligand fragments for the target protein and E3 ligase, respectively, the PROTAC molecule can simultaneously bind to the target protein and E3 ligase, promoting the ubiquitination of the target protein, which is then recognized and degraded by the proteasome.

[0005] Lung cancer is a serious disease that threatens human health, and it is the leading cause of death among all malignancies. Among patients with non-small cell lung cancer, cases with activating mutations in EGFR (Epidermal Growth Factor Receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1 receptor tyrosine kinase) account for approximately 30%, 8%, and 2%, respectively.

[0006] International patents such as WO2020249048, WO2019113071, WO2019042444, WO2017204445, WO2020069106, and WO2019114770 each design a PROTAC molecule that targets the ALK protein.

[0007] Further development has significant research and potential practical value in order to develop more effective and / or selective PROTAC molecules for combating drug resistance to existing EGFR inhibitors, ALK inhibitors, and ROS1 inhibitors. [Overview of the project]

[0008] The present invention aims to develop novel compounds that inhibit and induce EGFR degradation.

[0009] The present invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. [ka] Among them, PIN is a ligand that binds to EGFR, [ka] It is expressed as, " [Chemical formula] " is the binding point between the PIN and the Linker, Ring Cy1 is a C 32 , 00 , 00 , 00 , 12 , 31 , 12 , 00 , 00 , 32 , 31 , 31 , 12 , 12 , 32 aryl group or a 5- to 14-member heteroaryl group, and q4 is 0, 1, 2, 3, or 4, R cy is -O-R cy2 , -S-R cy2 , -NR 00 -R cy2 and -(CR 10 R 11 ) m3 -R cy2 selected from, R cy2 is hydrogen, deuterium, cyano group, carboxy group, nitro group, halogen, C 1-10 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​, -S(O)OR 12 S(O)2OR 12 -OC(O)R 12 -OS(O)R 12 -OS(O)2R 12 -OC(O)OR 12 -OS(O)OR 12 -OS(O)2OR 12 ,-P(O)R 31 R 32 , C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Selected from an aryl group or a 5- to 14-membered heteroaryl group, the above C 1-10 Alkyl, halo C 1-10 Alkyl alkyl groups, hydroxy C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl groups and 5- to 14-membered heteroaryl groups are optionally R 21 Substituted with 0, 1, 2, 3, or 4 substituents selected from, R 10 , R 11 , R 12 , R 31 , R 32 These are, independently, hydrogen, deuterium, hydroxyl group, cyano group, carboxyl group, nitro group, halogen, acetyl group, and -C(O)NR. a R b , NR a R b , -C(O)R 13 ,-S(O)R 13 SO2R 13 -C(O)NR a R b -S(O)NR a R b -SO2NR a R b , C 1-10 Alkyl, halo C 1-10 Alkyl alkyl groups, hydroxy C 1-10 Alkyl alkyl group, C1-10 An alkoxy group, C 1-10 An alkylthio group, C 2-10 An alkenyl group, C 2-10 An alkynyl group, C 3-8 A cycloalkyl group, a 3- to 8-membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5- to 14-membered heteroaryl group, or, R 10 , R 11 Together with the C atom to which it is attached, forms a C 3-8 Cycloalkyl group or a 3- to 8-membered heterocyclyl group, and the above C 1-10 Alkyl group, halo C 1-10 Alkyl group, hydroxy C 1-10 Alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl group, 3- to 8-membered heterocyclyl group, C 6-10 Aryl group and 5- to 14-membered heteroaryl group, and the above C 3-8 The cycloalkyl group or 3- to 8-membered heterocyclyl group is optionally substituted with 1, 2, 3 or 4 substituents selected from R 21 , m3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, V1 is N or CR1, V2 is N or CR2, V3 is N or CR3, V4 is N or CR4, R1, R2, R3, R4 are each independently -X 2 -(CR 18 2) q1 -X 3 -(CR 14 2) q2 -R 15 Selected from, X 2 , X 3 Are each independently a bond, O, S, NR 00 , -C(O)-, -S(O)-, SO2, -C(O)NR 00 -, -S(O)NR 00 -, -SO2NR 00 -, -NR 00 C(O)-, -NR00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 SO2NR 00 -, -NR 00 C(O)O-, -OC(O)O-, -C(O)O-, -OC(O)-, -SO2-O-, -OSO2-, -OSO2O-, C 2-10 Alkenylene group, C 2-10 Alkynylene group, -(CR 16 R 17 ) q3 -, C 3-8 Cycloalkylene group, 3-membered to 8-membered heterocyclene group, C 6-10 Selected from an arylene group or a 5-membered to 14-membered heteroarylene group, the above C 2-10 Alkenylene group, C 2-10 Alkynylene group, C 3-8 Cycloalkylene group, 3-membered to 8-membered heterocyclene group, C 6-10 Arylene groups and 5-membered to 14-membered heteroarylene groups are optionally R 21 Substituted with one, two, three, or four substituents selected from: R 14 , R 15 , R 16 , R 17 , R 18 These are, independently, hydrogen, deuterium, hydroxyl group, cyano group, carboxyl group, nitro group, halogen, and NR. a R b -C(O)NR a R b acetyl group, C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Selected from an aryl group or a 5- to 14-membered heteroaryl group, the above C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group or the 5-membered to 14-membered heteroaryl group can be optionally selected as R 21 Substituted with one, two, three, or four substituents selected from: Alternatively, V3 and V4, together with substituents attached thereto, form a 5- to 6-membered heteroaryl group or benzene, or V2 and V3, together with substituents attached thereto, form a 5- to 6-membered heteroaryl group or benzene, and the above 5- to 6-membered heteroaryl group or benzene is optionally R 21 Substituted with one, two, three, or four substituents selected from: K1 is N or CR k1 K2 is N or CR k2 K4 is N or CR k4 And, R k1 , R k2 , R k4 These are, independently, hydrogen, deuterium, hydroxyl group, cyano group, acetyl group, and -C(O)NR. a R b , halogen, C 1-10 Alkyl alkyl group, C 1-5 Alkilen OC 1-5 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, NR a R b , C 3-8 Cycloalkyl groups, C 3-8 Heterocyclyl group, -OC 3-8 Cycloalkyl group, -O-3-membered to 8-membered heterocyclyl group, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, R k3 It is not hydrogen, and R k3 This is represented as -X1-Rx, X1 is O, S, NR 00, -C(O)-, -S(O)-, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)O-, -C(O)O-, -OC(O)-, -CH=CH-, -C≡C-, -(CR x1 R x2 ) x -, C 3-8 Cycloalkylene group, 3-membered to 8-membered heterocyclene group, C 6-10 Selected from arylene groups and 5-membered to 14-membered heteroarylene groups, Rx is -(CR x3 R x4 ) x2 -R xn It is expressed as, R x1 , R x2 , R x3 , R x4 , R xn These are, independently, hydrogen, deuterium, cyano group, hydroxyl group, acetyl group, halogen, nitro group, aldehyde group, carboxyl group, amino group, and C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, or R x1 , R x2 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycline group. x and x2 are independently 0, 1, 2, 3, 4, or 5, and x and x2 cannot be 0 at the same time. Alternatively, R J3 , R k3 They connect to form chemical bonds, L5 and L6 are independently coupled, O, S, NR 00 , C(O)NR 00 , NR 00 C(O), C 1-10 Alkylene group, Halo C 1-10 Alkylene group, C 1-10 Alkylene oxy group, C 2-10 Alkenylene group or C 2-10 Selected from alkynylene groups, where L5 is NH, at least one Rcy is -S(O)R 12 SO2R 12 -C(O)NR 31 R 32 -S(O)NR 31 R 32 -SO2NR 31 R 32 , -NR 00 C(O)R 12 , -NR 00 S(O)R 12 , -NR 00 SO2R 12 , -NR 00 C(O)NR 31 R 32 , -NR 00 S(O)NR 31 R 32 , -NR 00 SO2NR 31 R 32 and -P(O)R 31 R 32 Selected from, Ring A is a bonded, saturated or unsaturated monocyclic alkylene group, monocyclic heterocyclylene group, polycyclic alkylene group, or polycyclic heterocyclylene group, or if ring A is present and substituted, then R k3 C is formed along with the substituents of ring A and the ring atoms linked to them. 5-7 Forming a cycloalkyl group or a 6- to 8-membered heterocyclyl group, R is a chemical bond, a saturated or unsaturated monocyclic alkylene group, a monocyclic heterocyclylene group, a polycyclic alkylene group, or a polycyclic heterocyclylene group. Linker does not exist, or Linker is C 1-20It is represented as an alkylene chain, and any one or more methylene groups are optionally one or more R L It may be replaced with R L They are homologous or different, and R L is bond, O, S, NR 00 , -C(O)-, SO, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)-, -C(O)O-, -OC(O)O-, -CR 00 =CR 00 -, -C≡C-, -(CH2) r -, C 3-8 Cycloalkylene group, 3-membered to 8-membered heterocyclene group, C 6-10 Selected from arylene groups and 5- to 14-membered heteroarylene groups, and any one of the methylene groups is either one or two R L’ It may be replaced with R L’ They are homologous or different, and are hydrogen, deuterium, halogen, amino group, nitro group, cyano group, acetyl group, C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, Halo C 1-10 Alkyl alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It is an aryl group or a 5- to 14-membered heteroaryl group, or two R groups. L’ It surrounds the C atom with the linked C atom. 3-8 It forms a cycloalkyl group or a 3- to 8-membered heterocyclyl group, and r is 1, 2, 3, 4, or 5. E is [ka] It is expressed as, G1 is N or CR G1 G2 is N or CR G2 G3 is N or CR G3 G4 is N or CR G4 And, R G1 , R G2 , R G3 , R G4 One of them is linked to W, and the others are independently hydrogen, deuterium, hydroxyl group, cyano group, acetyl group, amide group, halogen, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, NR a R b , C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, Since ring D does not exist, L7 is linked to a C or N atom on the aromatic ring where G1 is located, or ring D is a substituted or unsubstituted C atom. 6-10 An aryl group or a substituted or unsubstituted 5- to 14-membered heteroaryl group, where substitution means C 6-10 An aryl group or a 5- to 14-membered heteroaryl group can optionally contain hydrogen, deuterium, halogen, or carbon within the permissible range of each valency. 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, Halo C 1-10 Alkyl, halo C 1-10 Alkoxy group, C 2-10 Alkenyl group, C 2-10 This means that the group is substituted with one, two, or three substituents selected from alkynyl, cyano, nitro, amide, amino, and acetyl groups. Alternatively, ring D is [ka] And, G5, G6, and G7 are O, S, N, or C atoms, and optionally one or two R atoms. G Replaced with R G Hydrogen, deuterium, hydroxyl group, amino group, cyano group, acetyl group, carboxyl group, nitro group, halogen, C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It is an aryl group or a 5- to 14-membered heteroaryl group, or two R groups. G Together with the linked C atom, it forms a C=O, 3- to 8-membered cycloalkyl group, or 3- to 8-membered heterocycline group. Z3 and Z4 are independently O, S, and NR, respectively. 00 Selected from, the Z5 is CR 00 Or it is N, or there is no ring where Z5 is located. L7 is a chemical bond, O, S, NR 00 , C(O)NR 00 , NR 00 C(O), C 1-5 Alkylene group, Halo C 1-5 Alkylene group, C 1-5 Alkylene oxy group, C 2-6 Alkenylene group or C 2-6 It is an alkynylene group, W is a chemical bond, O, S, NR 00 , -C(O)-, -S(O)-, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)O-, -C(O)O-, -OC(O)-, -CR 00 =CR 00 -, -C≡C-, -(CR 23 R 24 ) r2 -, C 3-8 Cycloalkylene group, 3-membered to 8-membered heterocyclene group, C 6-10 It is an arylene group or a 5-membered to 14-membered heteroarylene group. R a , R b , R 00 , R 01 , R 02 , R 03 , R04 , R 23 , R 24 , R 13 , R 21 These are, independently, hydrogen, deuterium, cyano group, hydroxyl group, carboxyl group, nitro group, halogen, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl groups, hydroxy C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, NR c R d , C(O)NR c R d , C(O)R d -SO2NR c R d , C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5-membered to 14-membered heteroaryl group, -OC 3-8 Cycloalkyl groups, -O-3- to 8-membered heterocyclyl groups, -OC 1-10 Alkylene-C 3-8 Cycloalkyl groups, -OC 1-10 Alkylene-3 to 8-membered heterocyclyl group, -C 1-10 Alkilen-NR c R d , -C 1-10 Alkylene C(O)NR c R d , -C 1-10 Alkylene C(O)R d , -C 1-10 Alkilen C 3-8 Cycloalkyl groups, -C 1-10 Alkylene group, 3-membered to 8-membered heterocyclyl group, -C 1-10 Alkilen C 6-10 Aryl group and -C 1-10 Selected from alkylene groups and 5- to 14-membered heteroaryl groups, Alternatively, R 01 , R 02 or R 03 , R 04 or R 23 , R 24It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycline group, or R a , R b It surrounds the linked N atom to form a 3- to 8-membered heterocycline group. r2 is 0, 1, 2, 3 or 4, R c , R d These are hydrogen, deuterium, and C, respectively, independently. 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, Halo C 1-5 It is an alkyl group, or R c , R d It surrounds the linked N atom to form a 3- to 8-membered heterocycline group. C above 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl groups or 5- to 14-membered heteroaryl groups, saturated or unsaturated monocycles, monocyclic heterocycles, polycyclic and polycyclic heterocycles are either unsubstituted or, within the permissible range of valence, independently contain hydrogen, deuterium, cyano groups, hydroxyl groups, carboxyl groups, nitro groups, halogens, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl groups, hydroxy C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, NR e R f , C(O)NR e R f , C(O)R g -SO2NR e R f , C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5-membered to 14-membered heteroaryl group, -OC 3-8Cycloalkyl groups, -O-3- to 8-membered heterocyclyl groups, -OC 1-10 Alkylene-C 3-8 Cycloalkyl groups, -OC 1-10 Alkylene-3 to 8-membered heterocyclyl group, -C 1-10 Alkilen-NR e R f , -C 1-10 Alkylene C(O)NR e R f , -C 1-10 Alkylene C(O)R g , -C 1-10 Alkilen C 3-8 Cycloalkyl groups, -C 1-10 Alkylene group, 3-membered to 8-membered heterocyclyl group, -C 1-10 Alkilen C 6-10 Aryl group and -C 1-10 Substituted with 1, 2, 3, 4 or more groups from the B2 group selected from 5-membered to 14-membered heteroaryl alkylene groups, of which R e , R f , R g These are hydrogen, deuterium, and C, respectively, independently. 1-5 Alkyl alkyl group, C 1-5 Alkoxy group or halo C 1-5 It is an alkyl group.

[0010] The present invention further provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. [ka] E is a compound that can bind to ubiquitin ligase, The Linker is a coupling part, and the Linker is covalently coupled to at least one PIN and at least one E. Eventually, PIN is, [ka] It is expressed as, Q is C(Rq1 )3, C(O)R q1 , S(O)R q1 SO2R q1 P(O)R q1 R q2 or NR q1 R q2 And R q1 , R q2 These are, independently, hydrogen, amino group, and -C. 1-5 Alkilen R qn ,-HaroC 1-5 Alkilen R qn , -C 1-5 Alkylene Oxy R qn , -C 3-8 Cycloalkylene R qn , -3-member to 8-member heterocycloalkylene R qn , -C(O)R qn ,-S(O)R qn SO2R qn -C(O)NR 00 R qn , -NR 00 C(O)R qn and -SO2NR 00 R qn Selected from, R qn is hydrogen, C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, NR a R b , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, J1 is N or CR J1 J2 is N or CR J2 J3 is N or CR J3 J4 is N or CR J4 And, V1 is N or CR1, V2 is N or CR2, V3 is N or CR3, V4 is N or CR4. R1, R2, R3, R4, R J1, R J2 , R J3 , R J4 These are, independently, hydrogen, hydroxyl group, cyano group, acetyl group, carboxyl group, nitro group, halogen, amino group, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, NR a R b , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, Alternatively, R3 and R4, together with the atoms they are linked to, form substituted or unsubstituted 5- to 6-membered heteroaryl groups or benzene rings. Alternatively, R J2 , R J3 These, together with the atoms linked to them, form substituted or unsubstituted 5- to 6-membered heteroaryl groups or benzene, or R J3 , R J4 These, together with the atoms linked to them, form substituted or unsubstituted 5- to 6-membered heteroaryl groups or benzene rings, where substitution means that the 5- to 6-membered heteroaryl group or benzene ring can optionally be hydrogen, halogen, amino group, cyano group, acetyl group, or C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, Halo C 1-3 Alkyl alkyl group, C 3-8 This means that it is substituted with one, two, three, or four substituents selected from cycloalkyl groups and 3- to 8-membered heterocycloalkyl groups. K1 is N or CR k1 K2 is N or CR k2 K4 is N or CR k4 And, R k1 , R k2 , R k4 These are homologous or different, and each is independently a hydrogen, hydroxyl group, cyano group, acetyl group, and -C(O)NR a R b , halogen, C1-10 Alkyl alkyl group, C 1-5 Alkilen OC 1-5 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, NR a R b , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, -OC 3-8 Cycloalkyl groups, -O-3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, R k3 It is not hydrogen, and R k3 This is represented as -X1-Rx, X1 is O, S, NR 00 , -C(O)-, -S(O)-, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)O-, -C(O)O-, -OC(O)-, -CH=CH-, -C≡C-, -(CR x1 R x2 ) x -, C 3-8 Cycloalkylene group, 3-membered to 8-membered heterocycloalkylene group, C 6-10 Selected from arylene groups and 5-membered to 14-membered heteroarylene groups, R x is, -(CR x3 R x4 ) x2 -R xn Alternatively, it is represented as deuterium, R x1 , R x2 , R x3 , R x4 , R xnThese are, independently, hydrogen, cyano group, hydroxyl group, acetyl group, halogen, nitro group, aldehyde group, carboxyl group, amino group, and C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, or R x1 , R x2 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycloalkyl group. x and x2 are independently 0, 1, 2, 3, 4, or 5, and x and x2 cannot be 0 at the same time. Alternatively, R J3 , R k3 They connect to form chemical bonds, L5 and L6 are independently O, S, and NR, respectively. 00 , C(O)NR 00 , NR 00 C(O), C 1-10 Alkylene group, Halo C 1-10 Alkylene group, C 1-10 Alkylene oxy group, C 2-10 Alkenylene group and C 2-10 Selected from the alkynylene group, Ring A is a saturated or unsaturated monocyclic alkylene group, a monocyclic heterocyclylene group, a polycyclic alkylene group, or a polycyclic heterocyclylene group. Ring B is a saturated or unsaturated monocyclic alkylene group, a monocyclic heterocyclylene group, a polycyclic alkylene group, or a polycyclic heterocyclylene group. R is a chemical bond, a saturated or unsaturated monocyclic alkylene group, a monocyclic heterocyclylene group, a polycyclic alkylene group, a polycyclic heterocyclylene group, a 7- to 11-membered monospiroheterocyclylene group substituted with 1, 2, or 3 R0s, a 3- to 8-membered monocyclic heterocyclylene group, and an 8- to 10-membered bicyclic heteroarylene group, where R0 is hydrogen, deuterium, halogen, =O, or C. 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-8 The heteroatoms are selected from cycloalkyl groups and 3- to 8-membered heterocyclyl groups, or the same C atom, together with two R0 atoms linked to it, forms a 3- to 6-membered cycloalkyl group, the heteroatoms of the monospiroheterocyclylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the bicyclic heteroarylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the monocyclic heterocyclylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the 3- to 8-membered heterocyclyl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3 Linker does not exist, or Linker is C 1-20 It is represented as an alkylene chain, and any one or more methylene groups are optionally one or more R L It may be replaced with R L They are homologous or different, and R L O, S, NR 00 , -C(O)-, SO, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)-, -C(O)O-, -OC(O)O-, -CR 00 =CR00 -, -C≡C-, -(CH2) r -, C 3-8 Cycloalkylene group or 3- to 8-membered heterocyclene group, C 6-10 Selected from arylene groups and 5- to 14-membered heteroarylene groups, and any one of the methylene groups is either one or two R L’ It may be replaced with R L’ They are homologous or different, and are hydrogen, halogen, amino group, nitro group, cyano group, acetyl group, C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, Halo C 1-10 Alkyl alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 An aryl group or a 5- to 14-membered heteroaryl group, or two R groups L’ It surrounds the C atom with the linked C atom. 3-8 It forms a cycloalkyl group or a 3- to 8-membered heterocyclyl group, and r is 1, 2, 3, 4, or 5. E is [ka] It is expressed as, G1 is N or CR G1 G2 is N or CR G2 G3 is N or CR G3 G4 is N or CR G4 And, R G1 , R G2 , R G3 , R G4 One of them is linked to W, and the others are independently hydrogen, hydroxyl group, cyano group, acetyl group, amide group, halogen, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, NR a R b , C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, Since ring D does not exist, L7 is linked to a C or N atom on the aromatic ring where G1 is located, or ring D is a substituted or unsubstituted C atom. 6-10 An aryl group or a substituted or unsubstituted 5- to 14-membered heteroaryl group, where substitution means C 6-10 An aryl group or a 5- to 14-membered heteroaryl group can optionally contain hydrogen, halogen, or carbon within the permissible range of each valency. 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, Halo C 1-10 Alkyl, halo C 1-10 Alkoxy group, C 2-10 Alkenyl group, C 2-10 This means that the group is substituted with one, two, or three substituents selected from alkynyl, cyano, nitro, amide, amino, and acetyl groups. Alternatively, ring D is [ka] And, G5, G6, and G7 are O, S, N, or C atoms, and optionally one or two R atoms. G Replaced with R G Hydrogen, hydroxyl group, amino group, cyano group, acetyl group, carboxyl group, nitro group, halogen, C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 An aryl group or a 5- to 14-membered heteroaryl group, or two R groups G Together with the linked C atom, it forms a C=O, 3- to 8-membered cycloalkyl group, or 3- to 8-membered heterocycline group. Z3 and Z4 are independently O, S, or NR. 00 Selected from, the Z5 is CR 00 Or it is N, or there is no ring where Z5 is located. L7 is a chemical bond, O, S, NR 00 , C(O)NR00 , NR 00 C(O), C 1-5 Alkylene group, Halo C 1-5 Alkylene group, C 1-5 Alkylene oxy group, C 2-6 Alkenylene group or C 2-6 It is an alkynylene group, W is a chemical bond, O, S, NR 00 , -C(O)-, -S(O)-, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)O-, -C(O)O-, -OC(O)-, -CR 00 =CR 00 -, -C≡C-, -(CR 23 R 24 ) r2 -, C 3-8 Cycloalkylene group, 3-membered to 8-membered heterocyclene group, C 6-10 It is an arylene group or a 5-membered to 14-membered heteroarylene group. R a , R b , R 00 , R 01 , R 02 , R 03 , R 04 , R 23 , R 24 These are, independently, hydrogen, cyano group, acetyl group, hydroxyl group, carboxyl group, nitro group, halogen, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, NR c R d , C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, Alternatively, R 01 , R 02 or R 03 , R04 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, or R 23 , R 24 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycline group, or R a , R b It surrounds the linked N atom to form a 3- to 8-membered heterocycline group. r2 is 0, 1, 2, 3 or 4, R c , R d These are hydrogen and C, respectively, independently. 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, Halo C 1-5 It is an alkyl group, or R c , R d It surrounds the linked N atom to form a 3- to 8-membered heterocycline group. C above 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl groups or 5- to 14-membered heteroaryl groups, saturated or unsaturated monocycles, monocyclic heterocycles, polycyclic and polycyclic heterocycles are either unsubstituted or independently substituted with hydrogen, =O, cyano groups, acetyl groups, hydroxyl groups, carboxyl groups, nitro groups, halogens, and C, respectively, within the permissible range of valence. 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-5 Alkylthio group, NR e R f , 3- to 8-membered cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Substituted with 1, 2, 3, 4 or more groups of group B2 selected from aryl groups or 5-membered to 14-membered heteroaryl groups, of which R e , R fThese are hydrogen and C, respectively, independently. 1-5 Alkyl alkyl group, C 1-5 Alkoxy groups and halo C 1-5 It is an alkyl group, however, If PIN is formula (Ia) and Q is an S(O)2-isopropyl group, then R k3 , R k4 None of them are methyl groups, PIN is equation (Ib), ring B is [ka] If Q is P(O)(CH3)2, J1, J2, J3, J4, V3, K1 are CH, and V1, V2 are N, then R4 is not bromine, or R k3 , R k4 None of them are methyl groups, PIN is formula (Ic), AR is [ka] In this case, the Linker is a full carbon chain system, W does not contain heteroatoms, and the Linker is not a methylene group, ethylene group, or propylene group.

[0011] In one embodiment, the present invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. [ka] Eventually, the PIN will [ka] It is expressed as, E is [ka] It is expressed as, Q is C(R q1 )3, C(O)R q1 , S(O)Rq1 SO2R q1 P(O)R q1 R q2 or NR q1 R q2 And R q1 , R q2 These are, independently, hydrogen, amino group, and -C. 1-5 Alkilen R qn ,-HaroC 1-5 Alkilen R qn , -C 1-5 Alkylene Oxy R qn , -C 3-8 Cycloalkylene R qn , -3-member to 8-member heterocycloalkylene R qn , -C(O)R qn ,-S(O)R qn SO2R qn -C(O)NR 00 R qn , -NR 00 C(O)R qn and -SO2NR 00 R qn Selected from, R qn is hydrogen, C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, NR a R b , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups or 5- to 14-membered heteroaryl groups, J1 is N or CR J1 J2 is N or CR J2 J3 is N or CR J3 J4 is N or CR J4 And, V1 is N or CR1, V2 is N or CR2, V3 is N or CR3, V4 is N or CR4. R1, R2, R3, R4, R J1 , R J2 , R J3 , RJ4 These are, independently, hydrogen, hydroxyl group, cyano group, acetyl group, carboxyl group, nitro group, halogen, amino group, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, NR a R b , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, Alternatively, R3 and R4, together with the atoms they are linked to, form substituted or unsubstituted 5- to 6-membered heteroaryl groups or benzene rings. Alternatively, R J2 , R J3 These, together with the atoms linked to them, form substituted or unsubstituted 5- to 6-membered heteroaryl groups or benzene, or R J3 , R J4 These, together with the atoms linked to them, form substituted or unsubstituted 5- to 6-membered heteroaryl groups or benzene rings. Substitution refers to the selective replacement of a 5- to 6-membered heteroaryl group or benzene with hydrogen, halogen, amino group, cyano group, acetyl group, or C. 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, Halo C 1-3 Alkyl alkyl group, C 3-8 This means that it is substituted with one, two, three, or four substituents selected from cycloalkyl groups or 3- to 8-membered heterocycloalkyl groups. K1 is N or CR k1 K2 is N or CR k2 K4 is N or CR k4 And, R k1 , R k2 , R k4 These are homologous or different, and each is independently a hydrogen, hydroxyl group, cyano group, acetyl group, amino group, halogen, and C 1-10 Alkyl alkyl group, C 1-5 Alkilen OC 1-5Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, NR a R b , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, -OC 3-8 Cycloalkyl groups, -O-3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, R k3 This is represented as -X1-Rx, X1 is O, S, NR 00 , -C(O)-, -S(O)-, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)O-, -C(O)O-, -OC(O)-, -CH=CH-, -C≡C-, -(CR x1 R x2 ) x -, C 3-8 Cycloalkylene group, 3-membered to 8-membered heterocycloalkylene group, C 6-10 Selected from arylene groups and 5-membered to 14-membered heteroarylene groups, Rx is -(CR x3 R x4 ) x2 -R xn It is expressed as, R x1 , R x2 , R x3 , R x4 , R xn These are, independently, hydrogen, cyano group, hydroxyl group, acetyl group, halogen, nitro group, aldehyde group, carboxyl group, amino group, and C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, C2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, or R x1 , R x2 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycloalkyl group. x and x2 are independently 0, 1, 2, 3, 4, or 5, and x and x2 cannot be 0 at the same time. Alternatively, R J3 , R k3 They connect to form chemical bonds, Ring A is a saturated or unsaturated monocyclic alkylene group, a monocyclic heterocyclylene group, a polycyclic alkylene group, or a polycyclic heterocyclylene group. Ring B is a saturated or unsaturated monocyclic alkylene group, a monocyclic heterocyclylene group, a polycyclic alkylene group, or a polycyclic heterocyclylene group. R is a chemical bond, a saturated or unsaturated monocyclic alkylene group, a monocyclic heterocyclylene group, a polycyclic alkylene group, or a polycyclic heterocyclylene group. Linker [ka] It is expressed as, L1, L2, L3, and L4 are each independently set to -R L1 -(CR 21 R 22 ) n3 -R L2 -(CR 31 R 32 ) n2 - is expressed as R L1 , R L2 These are, independently, chemical bonds: O, S, NR 00 , -C(O)-, SO, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)-, -C(O)O-, -OC(O)O-, -CH=CH-, -C≡C-, -(CR 41 R 42 ) r -, -(CR 41 R 42 ) r -O-, -O-(CR 41 R 42 ) r -, C 3-8 a cycloalkylene group or a 3- to 8-membered heterocycloalkylene group, C 6-10 an arylene group or a 5- to 14-membered heteroarylene group, and n2, n3, and r are each independently 0, 1, 2, 3, or 4, R 21 , R 22 , R 31 , R 32 , R 41 , R 42 are each independently hydrogen, a cyano group, an acetyl group, a hydroxy group, a halogen, C 1-10 an alkyl group, a haloC 1-10 an alkyl group, C 1-10 an alkoxy group, C 1-10 an alkylthio group, NR a R b , C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, C 6-10 an aryl group, and a 5- to 14-membered heteroaryl group, or R 21 , R 22 together with the C atoms to which they are attached form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, L5 and L6 are each independently O, S, NR 00 , C(O)NR 00 , NR 00 C(O), C 1-10 an alkylene group, a haloC 1-10 an alkylene group, C 1-10 an alkyleneoxy group, C 2-10 an alkenylene group, and C 2-10 an alkynylene group, W is a chemical bond, O, S, NR 00 , -C(O)-, -S(O)-, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)O-, -C(O)O-, -OC(O)-, -CH=CH-, -C≡C-, -(CR 23 R 24 ) r2 -, C 3-8 cycloalkylene group, 3- to 8-membered heterocycloalkylene group, C 6-10 arylene group or 5- to 14-membered heteroarylene group, and R 23 , R 24 are each independently hydrogen, cyano group, acetyl group, hydroxy group, halogen, C 1-10 alkyl group, haloC 1-10 alkyl group, C 1-10 alkoxy group, C 1-10 alkylthio group, NR a R b , C 3-8 cycloalkyl group, 3- to 8-membered heterocycloalkylene group, C 6-10 aryl group and 5- to 14-membered heteroarylene group, or R 23 , R 24 together with the connecting C atoms enclose to form a 3- to 8-membered cycloalkyl group or 3- to 8-membered heterocycloalkyl group, r2 is 0, 1, 2, 3 or 4, and Z1 is CH or N, Z2 is CR z1 R​​​​​​​​​​​​​​​​​​a R b , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, or R z1 , R z2 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycloalkyl group. G1 is N or CR G1 G2 is N or CR G2 G3 is N or CR G3 G4 is N or CR G4 And, R G1 , R G2 , R G3 , R G4 One of them is linked to W, and the others are independently hydrogen, hydroxyl group, cyano group, acetyl group, halogen, amino group, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, NR a R b , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, R 00 , R a , R b These are, independently, hydrogen, cyano group, acetyl group, hydroxyl group, carboxyl group, nitro group, halogen, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, NR c R d , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 It is an aryl group or a 5-membered to 14-membered heteroaryl group, or R a , R b It surrounds the N atom it links to to form a 3- to 8-membered heterocycloalkyl group, R c and R d are each independently hydrogen, C 1-5 alkyl group, C 1-5 alkoxy group or halo C 1-5 alkyl group, or R c and R d together with the connecting N atom form a 3- to 8-membered heterocycloalkyl group, wherein the above C 1-10 alkyl group, halo C 1-10 alkyl group, C 1-10 alkoxy group, C 1-10 alkylthio group, C 1-5 alkyl group, halo C 1-5 alkyl group, C 1-5 alkoxy group, C 3-8 cycloalkyl group, 3- to 8-membered heterocycloalkyl group, C 6-10 aryl group or 5- to 14-membered heteroaryl group, saturated or unsaturated monocyclic, monocyclic heterocyclic, polycyclic and polycyclic heterocyclic rings are unsubstituted or, within the valence allowable range, each independently hydrogen, cyano group, acetyl group, hydroxy group, carboxy group, nitro group, halogen, C 1-5 alkyl group, C 1-5 alkoxy group, C 1-5 alkylthio group, NR e R f and 1, 2, 3, 4 or more groups of group B2 selected from 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocycloalkyl group, C 6-10 aryl group or 5- to 14-membered heteroaryl group, wherein R e and R f are each independently hydrogen, C 1-5 alkyl group, C 1-5 alkoxy group and halo C 1-5 alkyl group, provided that when PIN is of formula (Ia) and Q is S(O)2-isopropyl group, R k3 and R k4 are not both methyl groups, when PIN is of formula (Ib) and ring B is pyrazine, R k3 and R k4None of them are methyl groups, PIN is formula (Ic), AR is [ka] In this case, the Linker is a full carbon chain system, W does not contain heteroatoms, and the Linker is not a methylene group, ethylene group, or propylene group.

[0012] R k1 , R k2 These are, independently, hydrogen, F, Cl, Br, I, amino group, hydroxyl group, cyano group, acetyl group, and C. 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-3 Alkilen OC 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl groups or C 3-6 It is a heterocycloalkyl group, preferably R k2 is hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, or -O-oxetanyl group, preferably R k2 , R k4 These are, independently, hydrogen, deuterium, halogen, cyano group, amide group, and C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-3 Alkilen OC 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl groups or C 3-6 Selected from heterocycloalkyl groups, the above C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-3 Alkilen OC 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl groups or C 3-6 Heterocycloalkyl groups can optionally contain deuterium, a hydroxyl group, a cyano group, and C 1-5 Alkyl, halo C 1-5Alkyl alkyl group or C 1-5 It is substituted with 0, 1, 2, 3 or more substituents selected from alkoxy groups, preferably R K4 is hydrogen, deuterium, amide group, cyano group or C 1-5 Selected from alkyl groups, preferably methyl, ethyl, propyl, isopropyl, and halo C 1-5 Alkyl and C 1-5 It is an alkoxy group.

[0013] In some examples, the pharmaceutically acceptable salt may be a hydrochloride salt, a formate salt, or a trifluoroacetate salt.

[0014] In some examples, R k1 , R k2 These are, independently, hydrogen, F, Cl, Br, I, amino group, hydroxyl group, cyano group, acetyl group, and C. 1-5 Alkyl, halo C 1-5 Alkyl, -CONH2, C 1-5 Alkoxy group, C 1-3 Alkilen OC 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl groups or C 3-6 It is a heterocycloalkyl group, preferably R k2 is hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, or -O-oxetanyl group, preferably R k2 , R k4 These are, independently, hydrogen, deuterium, halogen, cyano group, amide group, and C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-3 Alkilen OC 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl groups and C 3-6 Selected from heterocycloalkyl groups, the above C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-3 Alkilen OC1-3 Alkyl alkyl group, C 3-6 Cycloalkyl groups or C 3-6 Heterocycloalkyl groups can optionally contain deuterium, halogen, hydroxyl group, cyano group, or C 1-5 Alkyl, halo C 1-5 Alkyl and C 1-5 It is substituted with 0, 1, 2, 3 or more substituents selected from alkoxy groups, preferably R K4 These are hydrogen, deuterium, amide group, cyano group and C 1-5 Selected from alkyl groups, preferably methyl, ethyl, propyl, isopropyl, and halo C 1-5 Alkyl alkyl group, C 1-5 It is an alkoxy group.

[0015] In some examples, R k2 These are hydrogen, cyano group, F, Cl, Br, I, C 1-5 Alkyl, -CONH2, Halo C 1-5 Alkyl alkyl group or C 1-5 It is an alkoxy group, C 1-5 Alkyl alkyl group or C 1-5 The alkoxy group can optionally consist of deuterium, halogen, hydroxyl group, cyano group, or C. 1-5 Alkyl, halo C 1-5 Alkyl and C 1-5 It is substituted with 1, 2, 3, 4 or more groups from the B2 group selected from alkoxy groups.

[0016] In some examples, R k2 These are hydrogen, F, Cl, Br, I, and C. 1-5 Alkyl, -CONH2, Halo C 1-5 Alkoxy group or C 1-5 It is an alkoxy group. In some examples, R k4 is hydrogen, F, Cl, Br, I, cyano group, acetyl group or C 1-5 It is an alkoxy group, preferably hydrogen or C 1-5 It is an alkoxy group.

[0017] In some examples, R k2 It is -CONH2.

[0018] In some embodiments, X1 is O, S, NR 00 , -C(O)-, -S(O)-, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)O-, -CH=CH-, -C≡C-, C 1-5 Alkylene group, C 3-6 Selected from cycloalkylene groups, 3- to 6-membered heterocycloalkylene groups, phenylene, 5- to 6-membered heteroarylene groups, and 8- to 10-membered bicyclic heteroarylene groups, R 00 is hydrogen or C 1-3 Selected from alkyl groups (preferably a methyl group, an ethyl group, or a propyl group, and preferably a hydrogen or methyl group).

[0019] In some embodiments, X1 is -(CR x1 R x2 ) x -and, R x1 , R x2 These are hydrogen and C, respectively, independently. 1-5 Alkyl alkyl group (preferably C 1-3 Alkyl group, more preferably methyl group, ethyl group, propyl group or isopropyl group) and C 1-5 Selected from alkoxy groups, Alternatively, R x1 , R x2 It surrounds C together with the connecting C 3-6 A cycloalkyl group (preferably a cyclopropanyl group or a cyclobutanyl group) or a 3- to 6-membered heterocycloalkyl group (preferably an oxetanyl group) is formed. x is 0, 1, 2, 3, or 4.

[0020] Preferably, the hydrogen atoms in the compound described in the general formula (I) above are optionally substituted with deuterium.

[0021] In some examples, Rx is hydrogen, cyano group, hydroxyl group, acetyl group, halogen, amino group, C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-6 These are cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, benzene, 5- to 6-membered heteroaryl groups, or 8- to 10-membered bicyclic heteroaryl groups.

[0022] In some examples, R k3 F, Cl, Br, I, hydroxyl group, cyano group, aldehyde group, nitro group, carboxyl group, acetyl group, SOC 1-5 Alkyl alkyl, SO2C 1-5 Alkyl alkyl group, C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-5 Alkilen OC 1-5 Alkyl alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, -OC 3-6 Selected from cycloalkyl groups and -O-3- to 6-membered heterocycloalkyl groups, Preferably, R k3 These are a hydroxyl group, a cyano group, an aldehyde group, a nitro group, a carboxyl group, an acetyl group, a -CO amino group, or a -SO2 methyl group. Preferably, R k3 These are F, Cl, Br, I, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2.

[0023] Preferably, R k3C 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-5 Alkilen OC 1-5 Alkyl alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, -OC 3-6 The above C is a cycloalkyl group or a -O-3- to 6-membered heterocycloalkyl group. 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-5 Alkylene group, C 1-5 Alkyl alkyl group, C 3-6 Cycloalkyl groups and 3- to 6-membered heterocycloalkyl groups can optionally contain deuterium, halogens, hydroxyl groups, cyano groups, and C. 1-3 Alkyl, halo C 1-3 Alkyl and C 1-3 Substituting with 0, 1, 2, 3, 4, or 5 substituents selected from alkoxy groups, preferably C 1-6 Alkyl alkyl groups, more C 1-3 It is an alkyl group, preferably a methyl group, more preferably an ethyl group, more preferably a propyl group, more preferably a cyclopropyl group, more preferably an isopropyl group, more preferably a C 3-6 A cycloalkyl group, more preferably a halogen, preferably a trifluoromethyl group, more preferably an ethyl group substituted with 1, 2, 3, 4 or 5 deuterium atoms, preferably a cyano group, preferably C 1-6 Alkoxy group, more preferably halo C 1-6 Alkyl alkyl groups, more C 1-3 Alkilen OC 1-3 Alkyl alkyl groups, more preferably halogens, C 1-3 Alkyl and Halo C 1-3 It is a five-membered heterocyclyl group substituted with one or two substituents selected from alkyl groups.

[0024] In some examples, R k3 This is represented as -X1-Rx, X1 is C 3-8Cycloalkylene group, 3-membered to 8-membered heterocycloalkylene group, C 6-10 Selected from an arylene group or a 5-membered to 14-membered heteroarylene group, Rx is -(CR x3 R x4 ) x2 -R xn It is expressed as, R x3 , R x4 , R xn These are, independently, hydrogen, cyano group, hydroxyl group, acetyl group, halogen, nitro group, aldehyde group, carboxyl group, amino group, and C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-5 Alkylthio group, C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 Selected from aryl groups and 5- to 14-membered heteroaryl groups, or R x1 , R x2 The x2 atoms surround the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, and x2 is 0, 1, 2, 3, or 4.

[0025] In some examples, X1 is a 5- to 6-membered heteroarylene group or an 8- to 10-membered bicyclic heteroarylene group. Rx is H, F, Cl, Br, I, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2.

[0026] In some examples, R k3 teeth, [ka] Selected from, preferably R k3teeth, [ka] Selected from, R a , R b These are H, F, Cl, Br, I, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2.

[0027] Preferably, R k3 R b A 5-membered or 6-membered heterocyclyl group substituted with 0, 1, or 2 substituents selected from R b is hydrogen, deuterium, halogen, cyano group, C 1-5 Alkyl, halo C 1-5 Alkyl and C 1-5 Selected from alkoxy groups.

[0028] Preferably, R k3 teeth, [ka] , halogen, cyano group, acetyl group, C 1-5 Alkyl alkyl group, C 1-5 Alkilen OC 1-5 Alkyl and C 3-6 Selected from cycloalkyl groups, the above C 1-5 Alkyl groups can optionally include deuterium, halogen, hydroxyl group, cyano group, and C. 1-3 Alkyl, halo C 1-3 Alkyl and C 1-3 Substituted with 0, 1, 2, 3, 4, or 5 substituents selected from the alkoxy group, R a , R bThese are H, F, Cl, Br, I, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2.

[0029] Preferably, R k3 teeth, [ka] F, Cl, Br, I, cyano group, acetyl group, ethyl group, C 1-5 Alkilen OC 1-5 Alkyl and C 3-6 Selected from cycloalkyl groups, the above C 1-5 Alkyl groups can optionally consist of deuterium, hydroxyl, cyano, and C. 1-3 Alkyl and C 1-3 Substituted with 0, 1, 2, 3, 4, or 5 substituents selected from the alkoxy group, R a is H, methyl group, ethyl group, propyl group or isopropyl group, and R b These are H, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2.

[0030] Preferably, R k3 teeth, [ka] F, Cl, Br, I, cyano group, acetyl group, ethyl group, C 1-5 Alkilen OC 1-5 Alkyl and C 3-6Selected from cycloalkyl groups, the above C 1-5 Alkyl groups can optionally consist of deuterium, hydroxyl, cyano, and C. 1-3 Alkyl and C 1-3 Substituted with 0, 1, 2, or 3 substituents selected from alkoxy groups, R a is H, methyl group, ethyl group, propyl group or isopropyl group, and R b This is H, a methyl group, an ethyl group, a propyl group, or an isopropyl group.

[0031] In some examples, R k1 , R k4 It is hydrogen. In some examples, R4 is a hydroxyl group, cyano group, acetyl group, carboxyl group, nitro group, halogen, amino group, C 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, NR a R b , C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The above C is an aryl group or a 5- to 14-membered heteroaryl group. 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group or 5- to 14-membered heteroaryl group can be optionally 0, 1, 2, or 3 R 41 Replaced by, Preferably, R4 is a halogen, C(O)NR a R b , C 3-8The C is a cycloalkyl group, a 3- to 8-membered heterocyclyl group, a phenyl group, a 5- or 6-membered heteroaryl group, a 7- to 11-membered spirocyclyl group, or an 8- to 12-membered spiroheterocyclyl group. 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, phenyl groups, 5- or 6-membered heteroaryl groups, 7- to 11-membered spirocyclyl groups, or 8- to 12-membered spiroheterocyclyl groups may be optionally present in 0, 1, 2, or 3 R groups. 41 Replaced by, Preferably, R4 is fluorine, chlorine, bromine, amino group, amide group, acetyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, cyclopentyl group, trifluoromethyl group and C 1-5 Selected from alkyl groups, preferably R4 is hydrogen, -OC 0-5 Alkylene-C 3-8 Cycloalkyl groups, -OC 0-5 The alkylene is a 3- to 8-membered heterocyclyl group, preferably R4 has 0, 1, or 2 R 41 A phenyl group or a 5-membered or 6-membered heteroaryl group substituted with, Preferably, R4 has 0, 1 or 2 R 41 Selected from the furyl group, thienyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, phenyl group, pyridyl group, pyrimidinyl group, cyclopentyl group, tetrahydrofuryl group, tetrahydrothiophenyl group, tetrahydropyrrolyl group, cyclohexyl group, oxanyl group, piperidinyl group, piperazinyl group and morpholinyl group, R 41 is hydrogen, deuterium, halogen, C 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, OC 3-8 Selected from cycloalkyl groups and -O-3- to 8-membered heterocyclyl groups (R 41Preferably, the group is hydrogen, deuterium, hydroxyl group, methyl group, ethyl group, propyl group, isopropyl group, trifluoromethyl group, trifluoroethyl group, methoxy group, ethoxy group, propoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, cyclopentyl group, or azacyclopentyl group. [ka] ).

[0032] In some examples, R4 is hydrogen, a hydroxyl group, a cyano group, or C(O)NR a R b , halogen, 0, 1 or 2 R 41 C replaced by 1-10 Alkyl group or 0, 1, or 2 R 41 A 5- to 6-membered heteroaryl group substituted with a 5- to 6-membered heteroaryl group, wherein the heteroatoms of the 5- to 6-membered heteroaryl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. Alternatively, R3 and R4 may have 0, 1, or 2 R atoms linked to them. 41 A 5- to 6-membered heteroaryl group or benzene is formed by substitution with , and the heteroatoms of the above 5- to 6-membered heteroaryl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. R a , R b These are, independently, hydrogen, cyano group, acetyl group, hydroxyl group, carboxyl group, nitro group, halogen, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, NR c R d , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 It is an aryl group or a 5-membered to 14-membered heteroaryl group, or R a , R bThe group surrounds the N atom it links to to form a 3- to 8-membered heterocycloalkyl group, and the heteroatoms of the 5- to 14-membered heteroaryl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. The heteroatoms of the 3- to 8-membered heterocycloalkyl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. R 41 is hydrogen, deuterium, halogen, C 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, OC 3-8 R4 is selected from cycloalkyl groups and -O-3- to 8-membered heterocyclyl groups, and the heteroatoms of the above 3- to 8-membered heterocycloalkyl groups are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. In some examples, R4 is hydrogen, a hydroxyl group, a cyano group, or C(O)NR a R b , halogen, 0, 1 or 2 R 41 C replaced by 1-10 Alkyl group or 0, 1, or 2 R 41 A 5- to 6-membered heteroaryl group substituted with, wherein the heteroatoms of the above 5- to 6-membered heteroaryl group are nitrogen and / or oxygen, and the number of heteroatoms is 1, 2, or 3. Alternatively, R3 and R4 may have 0, 1, or 2 R atoms linked to them. 41 A 5- to 6-membered heteroaryl group or benzene is formed by substitution with , the heteroatoms of the 5- to 6-membered heteroaryl group are nitrogen and / or oxygen, and the number of heteroatoms is 1, 2 or 3. R a , R b Each is independently of hydrogen or C 1-5 It is an alkyl group, R 41 is hydrogen, deuterium, halogen, C 1-5 Alkyl, halo C1-5 Alkyl and C 1-5 Selected from alkoxy groups.

[0033] In some examples, R4 is hydrogen, a halogen, or a 5- to 6-membered heteroaryl group, where the heteroatom of the 5- to 6-membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2, or 3. Alternatively, R3 and R4, together with the atoms linked to them, form a 5- to 6-membered heteroaryl group or benzene, and the heteroatom of the above 5- to 6-membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2, or 3. R a , R b Each is independently of hydrogen or C 1-10 It is an alkyl group.

[0034] In some examples, ring A is a 3- to 8-membered monocyclic heterocyclylene group, a 7- to 16-membered spirocyclic heterocyclylene group, a 7- to 14-membered fused-cyclic heterocyclylene group, a 7- to 10-membered bridged heterocyclylene group, a phenylene group, a 5- or 6-membered monocyclic heteroarylene group, or an 8- to 10-membered bicyclic heteroarylene group. Preferably, ring A is a 5- to 7-membered monocyclic heterocyclylene group, and preferably, ring A is a 7- to 11-membered monospiroheterocyclylene group. Preferably, R is a 7- to 11-membered monospiroheterocyclylene group or an 8- to 10-membered bicyclic heteroarylene group substituted with 0, 1, 2, or 3 R0 atoms, and R0 is hydrogen, deuterium, halogen, =O, or C. 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 3-8 Selected from cycloalkyl groups or 3- to 8-membered heterocyclyl groups, or the same C atom, together with two R0s linked to it, forms a 3- to 6-membered cycloalkyl group or heterocyclyl group.

[0035] In some examples, ring A is a 3- to 8-membered monocyclic heterocyclylene or a 7- to 16-membered spirocyclic heterocyclylene, the heteroatoms of the monocyclic heterocyclylene are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is one, two, or three; the heteroatoms of the spirocyclic heterocyclylene are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is one, two, or three.

[0036] In some examples, ring A is a 3- to 6-membered monocyclic heterocyclylene or a 7- to 11-membered spirocyclic heterocyclylene, the heteroatoms of the monocyclic heterocyclylene are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3, and the heteroatoms of the spirocyclic heterocyclylene are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3.

[0037] In some examples, ring A is a 3- to 8-membered monocyclic heterocyclene or a 7- to 11-membered spirocyclic heterocyclene, wherein the heteroatom of the monocyclic heterocyclene is N and there are 1 or 2 heteroatoms, and the heteroatom of the spirocyclic heterocyclene is N and there are 1 or 2 heteroatoms.

[0038] In some examples, R is a chemical bond, a 7- to 11-membered monospiroheterocyclylene group substituted with 0, 1, 2, or 3 R0s, a 3- to 8-membered monocyclic heterocyclylene group, and an 8- to 10-membered bicyclic heteroarylene group, where R0 is hydrogen, deuterium, halogen, =O, or C. 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-8The groups are selected from cycloalkyl groups and 3- to 8-membered heterocyclyl groups, or the same C atom forms a 3- to 6-membered cycloalkyl group together with two R0 atoms linked to it, the heteroatoms of the monospiroheterocyclylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is one, two, or three, the heteroatoms of the bicyclic heteroarylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is one, two, or three, the heteroatoms of the monocyclic heterocyclylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is one, two, or three, and the heteroatoms of the 3- to 8-membered heterocyclyl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is one, two, or three.

[0039] In some examples, R is a chemical bond, a 7- to 11-membered monospiroheterocyclylene group substituted with 0, 1, 2, or 3 R0s, a 3- to 8-membered monocyclic heterocyclylene group, and an 8- to 10-membered bicyclic heteroarylene group, where R0 is hydrogen, =O, and C 1-6 Selected from alkyl groups, or the same C atom together with two R0s linked to it to form a 3- to 6-membered cycloalkyl group, the heteroatoms of the bicyclic heteroarylene group are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the spirocyclic heterocyclylene group are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the monocyclic heterocyclylene group are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3.

[0040] In some examples, R is a chemical bond, a 7- to 11-membered monospiroheterocyclylene group substituted with 0, 1, 2, or 3 R0s, a 5- or 6-membered monocyclic heterocyclylene group, and an 8- to 10-membered bicyclic heteroarylene group, where R0 is hydrogen, =O, and C 1-6Selected from alkyl groups, or the same C atom together with two R0s linked to it to form a 3- to 6-membered cycloalkyl group, wherein the type of heteroatom of the monospiroheterocyclylene group is N and the number of heteroatoms is 1 or 2, the type of heteroatom of the bicyclic heteroarylene group is N and the number of heteroatoms is 1 or 2, and the type of heteroatom of the 6-membered monocyclic heterocyclylene group is N and the number of heteroatoms is 1 or 2.

[0041] In one embodiment, the present invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. [ka] Eventually, the PIN will [ka] It is expressed as, R is a chemical bond, a 7- to 11-membered monospiroheterocyclylene group substituted with 0, 1, 2, or 3 R0 atoms, a 3- to 8-membered monocyclic heterocyclylene group, or an 8- to 10-membered bicyclic heteroarylene group, where R0 is hydrogen, deuterium, halogen, =O, or C. 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-8The heteroatoms are selected from cycloalkyl groups and 3- to 8-membered heterocyclyl groups, or the same C atom, together with two R0 atoms linked to it, forms a 3- to 6-membered cycloalkyl group, the heteroatoms of the monospiroheterocyclylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the bicyclic heteroarylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the monocyclic heterocyclylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the 3- to 8-membered heterocyclyl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3 Q, V1, V2, V3, V4, J1, J2, J3, J4, K1, K2, K4, R k3 L5, L6, ring A, ring E, and Linker are defined in any one of the above terms.

[0042] In one embodiment, the present invention provides compounds of general formula (I) or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. [ka] Eventually, the PIN will [ka] It is expressed as, R k3 teeth, [ka] , halogen, cyano group, acetyl group, C 1-5 Alkyl alkyl group, C 1-5 Alkilen OC 1-5 Alkyl alkyl group or C 3-6 Selected from cycloalkyl groups, the above C 1-5Alkyl groups can optionally include deuterium, halogen, hydroxyl group, cyano group, and C. 1-3 Alkyl, halo C 1-3 Alkyl and C 1-3 Substituted with 0, 1, 2, 3, 4, or 5 substituents selected from the alkoxy group, R a , R b These are H, F, Cl, Br, I, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2. Q, V1, V2, V3, V4, J1, J2, J3, J4, K1, K2, K4, R, L5, L6, ring A, ring E, and Linker are defined in any one of the above terms.

[0043] In one embodiment, the present invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. [ka] Eventually, the PIN will [ka] It is expressed as, Q, V1, V2, V3, V4, J1, J2, J3, J4, K1, K2, K4, R, L5, L6, ring A, ring E, and Linker are defined in any one of the above terms.

[0044] In some embodiments, ring A is [ka] It is expressed as, Of these, Y1 and Y2 are independently CH or N, Y3 and Y4 are independently CH or N, t1, t2, t3, and t4 are independently 0, 1, 2, or 3, t5 and t6 are independently 0, 1, 2, or 3, t1 and t3 are never 0 at the same time, and t2 and t4 are never 0 at the same time.

[0045] In some embodiments, ring A is [ka] They are selected from among them.

[0046] In some examples, R is a chemical bond, or R is a 3- to 8-membered monocyclic heterocyclylene group, a 7- to 16-membered spirocyclic heterocyclylene group, a 7- to 10-membered bicyclic solid heterocyclylene group, a 7- to 10-membered bridged heterocyclylene group, a 5- or 6-membered heteroarylene group, or an 8- to 10-membered bicyclic heteroarylene group. Preferably, R is a chemical bond, preferably R is a 5- to 7-membered monocyclic heterocyclylene group, and preferably R is a 7- to 11-membered monospiroheterocyclylene group or an 8- to 10-membered bicyclic heteroarylene group.

[0047] In some embodiments, R is [ka] It is expressed as, Ring C1 is a 5- to 6-membered heteroaryl group or benzene, and ring C2 is a 5- to 6-membered saturated or unsaturated monoring or a 5- to 6-membered saturated or unsaturated monoheteroring, and the 5- to 6-membered heteroaryl group, benzene, 5- to 6-membered saturated or unsaturated monoring or 5- to 6-membered saturated or unsaturated monoheteroring can each be optionally composed of hydrogen, D, halogen, amino group, hydroxyl group, cyano group, acetyl group, C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 3-8It is substituted with 0, 1, 2, 3 or more substituents selected from cycloalkyl groups, 5- to 7-membered heterocycloalkyl groups, 6- to 10-membered aryl groups, and 5- to 14-membered heteroaryl groups, preferably the ring C2 is a 5- to 7-membered azaheterocyclic ring. Y5 and Y6 are independently CH or N, Y7 and Y8 are independently CH or N, s1, s2, s3, and s4 are independently 0, 1, 2, or 3, s5 and s6 are independently 0, 1, 2, or 3, s1 and s3 are never 0 at the same time, and s2 and s4 are never 0 at the same time.

[0048] In some examples, ring C1 is selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, benzene, pyridine, pyrimidine, pyrazine, or pyridazine, and ring C2 is selected from cyclopentane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, cyclohexane, oxocyclohexane, piperidine, piperazine, morpholine, benzene, pyridine, pyrimidine, pyrazine, and pyridazine.

[0049] In some embodiments, R is [ka] That is the case.

[0050] In some embodiments, R is [ka] Selected from, Preferably, R is [ka] Selected from among, [ka] It connects to the Linker, and the other end connects to ring A, or, [ka] One end is connected to ring A, and the other end is connected to the Linker.

[0051] In some embodiments, L1, L2, L3, and L4 are each independently -R L1 -(CH2) n5 -R L2 -(CH2) n6 - Selected from, R L1 , R L2 These are O, S, and NR, respectively, independently. 00 -C(O)-, -C(O)NR 00 -, -NR 00 C(O)-, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)NR 00 -, -NR 00 C(O)O-, -OC(O)-, -C(O)O-, -OC(O)O- and (CH2) r4 And n5, n6, and r4 are each independently 0, 1, 2, 3, or 4. R 00 is C 1-3 It is an alkyl group (preferably a methyl group). Alternatively, R 00 It is hydrogen.

[0052] Preferably, R L1 , R L2 Each is independently bonded, consisting of a 5-membered or 6-membered heteroarylene group, a phenylene group, and C 3-8 Cycloalkylene group, C 3-8 Heterocyclylene group, CH2, CH2CH2, OCH2CH2, CH2CH2O, CH2CH2CH2, vinylidene group, ethynylene group, [ka] Selected from among, of which the above 5-membered or 6-membered heteroarylene group, phenylene group, C 3-8Cycloalkylene group, C 3-8 The heterocyclylene group or any methylene group may be optionally a hydroxyl group, cyano group, halogen, or C group within the acceptable range of each valency. 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-5 Alkylthio group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, NR a R b acetyl group, -C(O)NR a R b , C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It is substituted with 0, 1, 2, or 3 substituents selected from aryl groups and 5- to 14-membered heteroaryl groups.

[0053] In some embodiments, L1 is (CR 21 R 22 ) n3 And R 21 , R 22 Each of these is independently a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, a methoxy group, an ethoxy group, or a propoxy group, and n3 is 0, 1, 2, or 3. Preferably, L1 is (CR 21 R 22 ) n3 And R 21 , R 22 The carbon atoms are surrounded by the linked carbon atoms to form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or an oxetanyl group, and n3 is 1 or 2, more preferably -C(CH3)2-, and even more preferably [ka] And, Preferably, L1 is O, S, NR 00 , C(O), C(O)NR 00 , NR 00 C(O), -C(O)O-, -OC(O)-, SO, SO2, SO2NR00 or NR 00 SO2, R 00 L1 is hydrogen or a methyl group, preferably L1 is -CH=CH- or -C≡C-, preferably L1 is CH2, CH2CH2 or CH2CH2CH2 (preferably CH2, more preferably CH2CH2, even more preferably CH2CH2CH2), preferably L1 is O, preferably L1 is NH or N(CH3), preferably C(O), more preferably CH2CH2O, even more preferably a chemical bond. In some embodiments, L1 is C 3-6 The group is a cycloalkylene group, a 4- to 7-membered heterocyclylene group, a phenylene group, or a 5- or 6-membered heteroarylene group (preferably a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, an azocyclopentylene group, a cyclohexylene group, a piperidinylene group, a piperadinylene group, or a 1,4-phenylene group, more preferably a 1,3-cyclobutylene group, and even more preferably a 1,4-piperidinylene group or a 1,4-piperazinylene group).

[0054] In some embodiments, L2 is (CR 21 R 22 ) n3 And R 21 , R 22 Each of these is independently a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, a methoxy group, an ethoxy group, or a propoxy group, and n3 is 0, 1, 2, or 3. Preferably, L2 is (CR 21 R 22 ) n3 And R 21 , R 22 The carbon atoms are surrounded by the linked carbon atoms to form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or an oxetanyl group, and n3 is 1 or 2, more preferably -C(CH3)2-, and even more preferably [ka] And, Preferably, L2 is O, S, NR00 , C(O), C(O)NR 00 , NR 00 C(O), -C(O)O-, -OC(O)-, SO, SO2, SO2NR 00 or NR 00 SO2, R 00 L2 is hydrogen or a methyl group, preferably L2 is -CH=CH- or -C≡C-, preferably L2 is CH2, CH2CH2 or CH2CH2CH2 (preferably CH2, more preferably CH2CH2, even more preferably CH2CH2CH2), preferably L2 is O, preferably L2 is NH or N(CH3), preferably C(O), more preferably CH2CH2O, preferably L2 is a chemical bond. Preferably, L2 is C 3-6 The group is a cycloalkylene group, a 4- to 7-membered heterocyclylene group, a phenylene group, or a 5- or 6-membered heteroarylene group, preferably a 1,3-cyclobutylene group, and preferably a 1,4-piperidineylene group or a 1,4-piperazinylene group.

[0055] In some embodiments, L3 is (CR 21 R 22 ) n3 And R 21 , R 22 Each of these is independently a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, a methoxy group, an ethoxy group, or a propoxy group, and n3 is 0, 1, 2, or 3. Preferably, L3 is (CR 21 R 22 ) n3 And R 21 , R 22 The carbon atoms are surrounded by the linked carbon atoms to form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or an oxetanyl group, and n3 is 1 or 2, more preferably -C(CH3)2-, and even more preferably [ka] And, Preferably, L3 is O, S, NR 00, C(O), C(O)NR 00 , NR 00 C(O), -C(O)O-, -OC(O)-, SO, SO2, SO2NR 00 or NR 00 SO2, R 00 is hydrogen or C 1-3 It is an alkyl group (preferably a methyl group, an ethyl group, or a propyl group), preferably L3 is -CH=CH- or -C≡C-, preferably L3 is CH2, CH2CH2, or CH2CH2CH2 (preferably CH2, more preferably CH2CH2, even more preferably CH2CH2CH2), preferably L3 is O, preferably L3 is NH or N(CH3), preferably C(O), more preferably CH2CH2O, preferably L3 is a chemical bond. Preferably, L3 is C 3-6 The group is a cycloalkylene group, a 4- to 7-membered heterocyclylene group, a phenylene group, or a 5- or 6-membered heteroarylene group, more preferably a 1,3-cyclobutylene group, and more preferably a 1,4-piperidinylene group or a 1,4-piperazinylene group.

[0056] In some embodiments, L4 is (CR 21 R 22 ) n3 And R 21 , R 22 Each of these is independently a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, a methoxy group, an ethoxy group, or a propoxy group, and n3 is 0, 1, 2, or 3. Preferably, L4 is (CR 21 R 22 ) n3 And R 21 , R 22 The carbon atoms are surrounded by the linked carbon atoms to form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or an oxetanyl group, and n3 is 1 or 2, more preferably -C(CH3)2-, and even more preferably [ka] And, Preferably, L4 is O, S, NR 00 , C(O), C(O)NR 00 , NR 00 C(O), -C(O)O-, -OC(O)-, SO, SO2, SO2NR 00 or NR 00 SO2, R 00 L4 is H or a methyl group, preferably L4 is -CH=CH- or -C≡C-, preferably L4 is CH2, CH2CH2 or CH2CH2CH2 (preferably CH2, more preferably CH2CH2, even more preferably CH2CH2CH2), preferably L4 is O, preferably L4 is NH or N(CH3), preferably C(O), more preferably CH2CH2O, preferably L4 is a chemical bond.

[0057] In some embodiments, L4 is C 3-6 The group is a cycloalkylene group, a 4- to 7-membered heterocyclylene group, a phenylene group, or a 5- or 6-membered heteroarylene group (preferably a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, an azocyclopentylene group, a cyclohexylene group, a piperidinylene group, a piperadinylene group, or a 1,4-phenylene group, more preferably a 1,3-cyclobutylene group, and even more preferably a 1,4-piperidinylene group or a 1,4-piperazinylene group).

[0058] In some embodiments, the linker [ka] It is expressed as, R L1 , R L3 These are O, S, CO, SO, SO2, and N(R) respectively, independently. 00 ) or (CR 21 R 22 ) r And R 21 , R 22 is hydrogen, acetyl group, halogen, amino group, C 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 2-10Alkenyl group, C 2-10 Alkynyl group, C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 It is an aryl group or a 5-membered to 14-membered heteroaryl group, or R 21 , R 22 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycloalkyl group. R L2 They are homologous or different, and R L2 O, S, CO, N(R) 00 ), C(O)O, OC(O), C(O)NH, NHC(O) or NHC(O)NH, phenylene group, alkylylene group, cyclopropylene group, 1,4-piperazinylene group or triazolylene group, R 00 is hydrogen or C 1-10 It is an alkyl group, n2 and n4 are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, respectively. r, n0, and n3 are 0, 1, 2, 3, or 4.

[0059] In some embodiments, the linker [ka] It is expressed as, R L1 , R L3 These are O, CO, and N(R) independently of each other. 00 ) or (CR 21 R 22 ) r And R 21 , R 22 is hydrogen, acetyl group, C 1-5 Alkyl alkyl group, C 6-10 Aryl group or halo C 1-5 It is an alkyl group, or R 21 , R 22 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group, R L2 They are homologous or different, and R L2 O, CO, N(R) 00), alkynylene group ( [ka] ) or a cyclopropylene group, R 00 is hydrogen or C 1-5 It is an alkyl group, n2 and n4 are independently 0, 1, 2, or 3. r, n0, and n3 are 0, 1, 2, 3, or 4.

[0060] Linker [ka] It is expressed as, L1, L2, L3, and L4 are each independently set to -R L1 -(CR 21 R 22 ) n3 -R L2 -(CR 31 R 32 ) n2 - is expressed as R L1 , R L2 These are, independently, chemical bonds, O, NR 00 , -C(O)-, -CH=CH-, -C≡C-, -(CR 41 R 42 ) r - or C 3-8 It is a cycloalkylene group, n2, n3, and r are each independently 0, 1, 2, 3, or 4. R 41 and R 42 These are, independently, hydrogen, acetyl group, halogen, and C. 1-5 Alkyl, halo C 1-5 Alkyl alkyl group or C 6-10 Selected from aryl groups, or R 21 , R 22 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group.

[0061] In some embodiments, the linker [ka] It is expressed as, R L1 , R L3 These are O and N(R) respectively, independently. 00 ) or (CR 21 R 22 ) r And R 21 , R 22 is hydrogen or C 1-5 It is an alkyl group, or R 21 , R 22 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group, R L2 They are homologous or different, and R L2 O, CO, N(R) 00 ), alkynylene group ( [ka] ), alkenylene group ( [ka] ) or cyclopropylene group ( [ka] ) and R 00 is hydrogen or C 1-5 It is an alkyl group, n2 and n4 are independently 0, 1, 2, or 3. r, n0, and n3 are 0, 1, 2, 3, or 4.

[0062] Linker [ka] It is expressed as, L1, L2, L3, and L4 are each independently set to -R L1 -(CR 21 R 22 ) n3 -R L2 -(CR 31 R 32 ) n2- is expressed as R L1 These are, independently, chemical bonds, O, NR 00 -C(O)-, -(CR 41 R 42 ) r - or C 3-8 It is a cycloalkylene group, R L2 These are, independently, chemical bonds, O, NR 00 , -C(O)-, -CH=CH-, -C≡C-, C 3-8 It is a cycloalkylene group, n2, n3, and r are each independently 0, 1, 2, 3, or 4. R 41 and R 42 These are, independently, hydrogen or C 1-5 Selected from alkyl groups, or R 21 , R 22 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group.

[0063] In some embodiments, the linker is [ka] It is expressed as follows.

[0064] In some examples, R L1 These are chemical bonds, O, S, CO, SO, SO2, NH, N(CH3), CONH, NHCO, methylene group, [ka] or vinylidene group, R L2 These are chemical bonds, O, S, CO, SO, SO2, NH, N(CH3), CONH, NHCO, methylene group, [ka] , a 1,4-phenylene group or a 1,4-piperazinerene group, R L3 These are chemical bonds, O, S, CO, SO, SO2, NH, N(CH3), CONH, NHCO, methylene group, [ka] Alternatively, it is a vinylidene group.

[0065] In some examples, W is a chemical bond, O, S, NR 00 , -C(O)-, -S(O)-, SO2, -C(O)NR 00 -, -NR 00 C(O)-, -NR 00 C(O)NR 00 -, -SO2NR 00 -, -NR 00 SO2-, -NR 00 C(O)O-, -C(O)O-, -OC(O)-, -OC(O)O-, -CH=CH-, -C≡C-, -(CR 43 R 44 ) n8 -, C 3-6 A cycloalkylene group, a 3- to 6-membered heterocycloalkylene group, a phenylene group, a 5- to 6-membered heteroarylene group, or an 8- to 10-membered arylene group or heteroarylene group, R 00 , R 43 , R 44 Each of these is independently a hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, isopropoxy group, cyclopentyl group, or cyclohexyl group, or R 43 , R 44 The carbon atoms surround the linked carbon atoms to form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or an oxetanyl group, and n8 is 0, 1, 2, or 3. Preferably, W is a 1,2-phenylene group, a 1,3-phenylene group, a 1,4-phenylene group, a piperazinylene group, or a pyridylene group; preferably, W is CH2, O, S, -N(methyl)-, -CH=CH-, or C≡C; preferably, W is CH2; preferably, W is O or S; preferably, W is -CH=CH- or C≡C; preferably, C≡C.

[0066] In some examples, ring B is selected from a 3- to 8-membered saturated or unsaturated cycloalkyl group, a 3- to 8-membered saturated or unsaturated heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 14-membered heteroaryl group, preferably ring B is a 5- to 7-membered saturated monoheterocyclyl group, benzene, or a 5- to 6-membered heteroaryl group, preferably ring B is benzene or a 5- to 6-membered heteroaryl group, preferably ring B is a 5- to 7-membered saturated monoheterocyclyl group, preferably ring B is cyclopentane, tetrahydropyrrole, or 1,3-dioxo The compounds are lan, oxocyclopentane, 1,4-dioxane, furan, thiophene, thiazole, isothiazole, oxazole, isoxazole, pyrrole, imidazole, pyrazole, piperidine, piperazine, benzene, pyridine, pyridazine, or pyrimidine, preferably ring B is 1,3-dioxolane, oxocyclopentane, 1,4-dioxane, imidazole, benzene, or pyrimidine, preferably ring B is a 5- to 6-membered heteroaryl group, preferably ring B is 1,4-dioxane or 1,3-dioxolane.

[0067] In some embodiments, ring B is [ka] Selected from, " [ka]

[0068] " represents the joining site, Rc consists of hydrogen, F, Cl, Br, I, hydroxyl group, cyano group, aldehyde group, nitro group, carboxyl group, acetyl group, and SOC. 1-5 Alkyl alkyl, SO2C 1-5 Alkyl alkyl group, C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 1-5 Alkyl OC 1-5 Alkyl alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, -OC3-6 It is a cycloalkyl group or an O-3- to 6-membered heterocycloalkyl group. r3 is 0, 1, 2, or 3.

[0069] In some examples, both V1 and V2 are N, V3 is CR3, V4 is CR4, R3 is hydrogen, R4 is hydrogen, halogen, amino group, cyano group, acetyl group, C 1-3 Alkyl alkyl group, C 1-3 Alkoxy group or halo C 1-3 It is an alkyl group (preferably fluorine or chlorine), Preferably, both V1 and V2 are N, V3 is CR3, and V4 is CR4, and R3 and R4, together with the atoms linked to them, form substituted or unsubstituted 5- to 6-membered heteroaryl groups, where substitution means the 5- to 6-membered heteroaryl group can optionally be hydrogen, halogen, amino group, cyano group, acetyl group, or C 1-3 Alkyl alkyl group, C 1-3 Alkoxy group or halo C 1-3 This means that it is substituted with one, two, or three substituents selected from alkyl groups. Preferably, R3 and R4, together with the atoms linked to them, form 1H-pyrrole, 1H-pyrazole, or 1H-imidazole.

[0070] In some examples, L5 and L6 are independently chemically bonded, NH, CONH, NHCO, and C. 1-3 Alkylene group (preferably a methylene group or ethylene group), C 2-6 Alkenylene group or C 2-6 Selected from alkynylene groups.

[0071] In some embodiments, E further [ka] It is expressed as, Z2, G1, G2, G3, G4, and W are defined as described above.

[0072] In some examples, G1 is N and G2 is CR. G2 G3 is CRG3 G4 is CR G4 Preferably, G1 is CR G1 G2 is N, G3 is CR G3 G4 is CR G4 Preferably, G1 is CR G1 G2 is CR G2 G3 is N, G4 is CR G4 Preferably, G1 is CR G1 G2 is CR G2 G3 is CR G3 G4 is N, preferably G1 is N, G2 is N, and G3 is CR G3 G4 is CR G4 Preferably, G1 is N and G2 is CR. G2 G3 is N, G4 is CR G4 Preferably, G1 is N and G2 is CR. G2 G3 is CR G3 G4 is N, and preferably G1 is CR G1 G2 is N, G3 is N, G4 is CR G4 Preferably, G1 is CR G1 G2 is N, G3 is CR G3 G4 is N, and preferably G1 is CR G1 G2 is CR G2 G3 is N, G4 is N, preferably G1 is N, G2 is N, G3 is N, G4 is CR G4 Preferably, G1 is N, G2 is N, and G3 is CR. G3 G4 is N, preferably G1 is N and G2 is CR. G2 G3 is N, G4 is N, and preferably G1 is CR G1 G2 is N, G3 is N, G4 is N, and preferably G1 is CR G1 G2 is CR G2 G3 is CR G3 G4 is CR G4 And R G1 , R G2 , R G3 , R G4 This is defined as described above.

[0073] In some examples, R G1 , R G2, R G3 , R G4 One of them is linked to W, and the others are each independently selected from hydrogen, hydroxyl group, cyano group, acetyl group, fluorine, chlorine, bromine, amino group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2, preferably R G1 , R G2 , R G3 , R G4 These are, independently, hydrogen, halogen (preferably F), and C. 1-3 Alkyl or halo C 1-3 It is an alkyl group.

[0074] In some embodiments, Z1 is N and Z2 is CH2 or C(O).

[0075] In some embodiments, E further [ka] [ka] Selected from, Of these, Z1, Z2, G1, G2, G3, G4, and w are as described in any one of the above items.

[0076] Preferably, R G1 , R G2 , R G3 , R G4 R0 is independently hydrogen, deuterium, cyano group, halogen (preferably F), and C 1-3 Alkyl or halo C 1-3 It is an alkyl group (preferably a methyl group or a trifluoromethyl group).

[0077] In some embodiments, J1 is N and J2 is CR. J2 J3 is CR J3 J4 is CRJ4 Preferably, J1 is CR J1 J2 is N, J3 is CR J3 J4 is CR J4 Preferably, J1 is CR J1 J2 is CR J2 J3 is N, J4 is CR J4 Preferably, J1 is CR J1 J2 is CR J2 J3 is CR J3 J4 is N, preferably J1 is N, J2 is N, and J3 is CR J3 J4 is CR J4 Preferably, J1 is N and J2 is CR. J2 J3 is N, J4 is CR J4 Preferably, J1 is N and J2 is CR. J2 J3 is CR J3 J4 is N, preferably J1 is CR J1 J2 is N, J3 is N, J4 is CR J4 Preferably, J1 is CR J1 J2 is N, J3 is CR J3 J4 is N, preferably J1 is CR J1 J2 is CR J2 J3 is N, J4 is N, and R J1 , R J2 , R J3 , R J4 This is as described in one of the above items.

[0078] R0 is hydrogen, halogen (preferably F), C 1-3 Alkyl or halo C 1-3 Selected from alkyl groups, preferably F, a methyl group, a trifluoromethyl group, a cyano group, or a difluoromethyl group. In some examples, R J1 , R J2 , R J3 , R J4Each is independently selected from H, F, Cl, Br, I, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2. Preferably, R J3 , R J4 Each of them is hydrogen, and R J1 , R J2 Each is independently selected from F, Cl, Br, I, methyl group, ethyl group, propyl group, cyclopropyl group, substituted or unsubstituted benzene or 5- to 6-membered heteroaryl group, where substitution means that the benzene or 5- to 6-membered heteroaryl group is optionally replaced by hydrogen, halogen, amino group, cyano group, acetyl group, or C 1-3 Alkyl alkyl group, C 1-3 Alkoxy group or halo C 1-3 This means that it is substituted with one, two, or three substituents selected from alkyl groups. Preferably, R J1 , R J3 , R J4 Each of them is hydrogen, and R J2 These are hydrogen, F, Cl, Br and C 1-5 Selected from alkyl groups, Preferably, R J3 , R J4 Each of them is hydrogen, and R J1 , R J2 These are, independently, hydrogen, F, Cl, Br, and C. 1-5 Selected from alkyl groups.

[0079] Preferably, R J1 , R J3 , R J4 Each of them is hydrogen, and R J2 The group is selected from H, F, Cl, Br, methyl group, ethyl group, 3- to 8-membered cycloalkyl group, benzene, and 5- to 6-membered heteroaryl group, preferably R J1 , R J2 , RJ3 , R J4 Each of these is hydrogen, preferably R J1 , R J3 , R J4 Each of them is hydrogen, and R J2 This is a methyl group, an ethyl group, a cyclopropyl group, a benzene ring, or 1-methyl-1H-pyrazole-4-yl, 1-methyl-1H-imidazole-4-yl, 1-ethyl-1H-pyrazole-4-yl, 1-ethyl-1H-imidazole-4-yl, 1-isopropyl-1H-pyrazole-4-yl, or 1-isopropyl-1H-imidazole-4-yl.

[0080] In some examples, R J1 , R J2 , R J4 Each of them is hydrogen, and R J3 is R k3 It connects to form a chemical bond, which is a single, double, or triple bond (preferably forming a CC single bond).

[0081] In some embodiments, Q is C(R q1 )3, C(O)R q1 , S(O)R q1 SO2R q1 P(O)R q1 R q2 or NR q1 R q2 And R q1 , R q2 Each is independently selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an amino group, an acetyl group, a methanesulfonyl group, an amide group, and an aminoacyl group. Preferably, R q1 , R q2 Each of them is independently C 1-6 Alkyl alkyl group or C 1-6 It is an alkoxy group.

[0082] In some embodiments, Q is P(O)R q1 R q2 And R q1 , R q2 Each of them is independently C 1-6Alkyl alkyl group or C 1-6 It is an alkoxy group.

[0083] In some embodiments, J1 is N or CH.

[0084] In some embodiments, J2 is N or CH.

[0085] In some examples, J3 is N or CH.

[0086] In some embodiments, J4 is N or CH.

[0087] In some embodiments, V1 is N or CH.

[0088] In some examples, V2 is N or CH.

[0089] In some examples, V3 is N or CR3, R3 is hydrogen, or R3 and R4 are 0, 1 or 2 R atoms together with the atoms linked to them. 41 A 5- to 6-membered heteroaryl group or benzene is formed by substitution with , and the heteroatom of the above 5- to 6-membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2, or 3.

[0090] In some examples, K1 is N or CH.

[0091] In some examples, K2 is N or CR k2 That is the case.

[0092] In some examples, L5 is NH.

[0093] In some examples, L6 is NH.

[0094] In some examples, [ka] teeth [ka] That is the case.

[0095] In some embodiments, W is O or -C≡C-.

[0096] In some embodiments, Q is P(O)R q1 R q2 And R q1 , R q2 Each of them is independently C 1-6 Alkyl alkyl group or C 1-6 It is an alkoxy group, J1 is N or CH. J2 is N or CH, J3 is N or CH. J4 is N or CH. V1 is N or CH. V2 is N or CH. V3 is N or CR 3 R3 is hydrogen, V4 is N or CR4, and R4 is hydrogen, hydroxyl group, cyano group, or C(O)NR a R b , halogen, 0, 1 or 2 R 41 C replaced by 1-10 Alkyl alkyl group or 0, 1, or 2 R 41 A 5- to 6-membered heteroaryl group substituted with a 5- to 6-membered heteroaryl group, wherein the heteroatoms of the 5- to 6-membered heteroaryl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. Alternatively, R3 and R4 may have 0, 1, or 2 R atoms linked to them. 41 A 5- to 6-membered heteroaryl group or benzene is formed by substitution with , and the heteroatoms of the above 5- to 6-membered heteroaryl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. R a , R bThese are, independently, hydrogen, cyano group, acetyl group, hydroxyl group, carboxyl group, nitro group, halogen, and C. 1-10 Alkyl, halo C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 1-10 Alkylthio group, NR c R d , C 3-8 Cycloalkyl groups, 3-membered to 8-membered heterocycloalkyl groups, C 6-10 It is an aryl group or a 5-membered to 14-membered heteroaryl group, or R a , R b The group surrounds the N atom it links to to form a 3- to 8-membered heterocycloalkyl group, and the heteroatoms of the 5- to 14-membered heteroaryl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. The heteroatoms of the 3- to 8-membered heterocycloalkyl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. R 41 is hydrogen, deuterium, halogen, C 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, OC 3-8 A cycloalkyl group or an O-3- to 8-membered heterocyclyl group is selected, and the heteroatoms of the above 3- to 8-membered heterocycloalkyl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. K2 is N or CR k2 And R k2 These are hydrogen, F, Cl, Br, I, amino group, hydroxyl group, cyano group, acetyl group, C 1-5 Alkyl, halo C 1-5 Alkyl, -CONH2, C 1-5 Alkoxy group, C 1-3 Alkilen OC 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl groups or C 3-6It is a heterocycloalkyl group, optionally containing deuterium, halogen, hydroxyl group, cyano group, and C 1-5 Alkyl, halo C 1-5 Alkyl and C 1-5 It is substituted with 0, 1, 2, 3 or more substituents selected from alkoxy groups, preferably R K4 These are hydrogen, deuterium, amide group, cyano group and C 1-5 Selected from alkyl groups, R k3 teeth, [ka] , halogen, cyano group, acetyl group, C 1-5 Alkyl alkyl group, C 1-5 Alkilen OC 1-5 Alkyl alkyl group or C 3-6 Selected from cycloalkyl groups, the above C 1-5 Alkyl groups can optionally include deuterium, halogen, hydroxyl group, cyano group, and C. 1-3 Alkyl, halo C 1-3 Alkyl and C 1-3 Substituted with 0, 1, 2, 3, 4, or 5 substituents selected from the alkoxy group, R a , R b These are H, F, Cl, Br, I, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2. K4 is N or CR k4 And R k4 These are hydrogen, F, Cl, Br, I, amino group, hydroxyl group, cyano group, acetyl group, C 1-5 Alkyl, halo C 1-5 Alkyl, -CONH2, C 1-5 Alkoxy group, C 1-3 Alkilen OC 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl groups or C3-6 It is a heterocycloalkyl group, optionally containing deuterium, halogen, hydroxyl group, cyano group, and C 1-5 Alkyl, halo C 1-5 Alkyl and C 1-5 Substituted with 1, 2, 3, 4 or more groups of group B2 selected from alkoxy groups, L5 is NH, L6 is NH, Ring A is a 3- to 8-membered monocyclic heterocyclylene or a 7- to 16-membered spirocyclic heterocyclylene, where the heteroatoms of the monocyclic heterocyclylene are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3; where the heteroatoms of the spirocyclic heterocyclylene are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. R is a chemical bond, a 7- to 11-membered monospiroheterocyclylene group substituted with 0, 1, 2, or 3 R0 atoms, a 3- to 8-membered monocyclic heterocyclylene group, or an 8- to 10-membered bicyclic heteroarylene group, where R0 is hydrogen, deuterium, halogen, =O, or C. 1-5 Alkyl, halo C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, C 3-8 The heteroatoms are selected from cycloalkyl groups and 3- to 8-membered heterocyclyl groups, or the same C atom, together with two R0 atoms linked to it, forms a 3- to 6-membered cycloalkyl group, the heteroatoms of the monospiroheterocyclylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the bicyclic heteroarylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the monocyclic heterocyclylene group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the 3- to 8-membered heterocyclyl group are one or more selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3 The grounder [ka] It is expressed as, R L1 , R L3 These are O, CO, and N(R) independently of each other. 00 ) or (CR 21 R 22 ) r And R 21 , R 22 is hydrogen, acetyl group, C 1-5 Alkyl alkyl group, C 6-10 Aryl group or halo C 1-5 It is an alkyl group, or R 21、 R 22 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group, R L2 They are homologous or different, and R L2 O, CO, N(R) 00 ), alkynylene group ( [ka] ) or a cyclopropylene group, R 00 is hydrogen or C 1-5 It is an alkyl group, n2 and n4 are independently 0, 1, 2, or 3. r, n0, and n3 are 0, 1, 2, 3, or 4.

[0097] In some embodiments, Q is P(O)R q1 R q2 And R q1 , R q2 Each of them is independently C 1-5 Alkyl alkyl group or C 1-5 It is an alkoxy group, J1 is N or CH. J2 is N or CH, J3 is N or CH. J4 is N or CH. V1 is N or CH. V2 is N or CH. V3 is N or CR 3And R3 is hydrogen, V4 is N or CR4, and R4 is hydrogen, hydroxyl group, cyano group, or C(O)NR a R b , halogen, 0, 1 or 2 R 41 C replaced by 1-10 Alkyl alkyl group or 0, 1, or 2 R 41 A 5- to 6-membered heteroaryl group substituted with, wherein the heteroatoms of the above 5- to 6-membered heteroaryl group are nitrogen and / or oxygen, and the number of heteroatoms is 1, 2, or 3. Alternatively, R3 and R4 may have 0, 1, or 2 R atoms linked to them. 41 A 5- to 6-membered heteroaryl group or benzene is formed by substitution with , the heteroatoms of the 5- to 6-membered heteroaryl group are nitrogen and / or oxygen, and the number of heteroatoms is 1, 2 or 3. R a , R b Each is independently of hydrogen or C 1-5 It is an alkyl group, R 41 is hydrogen, deuterium, halogen, C 1-5 Alkyl, halo C 1-5 Alkyl alkyl group or C 1-5 Selected from alkoxy groups, K1 is N or CH. K2 is N or CR k2 And R k2 These are hydrogen, cyano group, F, Cl, Br, I, C 1-5 Alkyl, -CONH2, Halo C 1-5 Alkyl alkyl group or C 1-5 It is an alkoxy group, C 1-5 Alkyl and C 1-5 The alkoxy group can optionally consist of deuterium, halogen, hydroxyl group, cyano group, or C. 1-5 Alkyl, halo C 1-5 Alkyl and C 1-5 Substituted with 1, 2, 3, 4 or more groups of group B2 selected from alkoxy groups, R k3 teeth, [ka] F, Cl, Br, I, cyano group, acetyl group, ethyl group, C 1-5 Alkilen OC 1-5 Alkyl alkyl group or C 3-6 Selected from cycloalkyl groups, the above C 1-5 Alkyl groups can optionally consist of deuterium, hydroxyl, cyano, and C. 1-3 Alkyl and C 1-3 Substituted with 0, 1, 2, 3, 4, or 5 substituents selected from the alkoxy group, R a is H, methyl group, ethyl group, propyl group or isopropyl group, and R b These are H, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, oxetanyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2. K4 is N or CR k4 And R k4 is hydrogen, F, Cl, Br, I, cyano group, acetyl group or C 1-5 The group is an alkoxy group, preferably hydrogen, F, Cl, Br, I, or C. 1-5 It is an alkoxy group, L5 is NH, L6 is NH, Ring A is a 3- to 6-membered monocyclic heterocyclylene or a 7- to 11-membered spirocyclic heterocyclylene, where the heteroatoms of the monocyclic heterocyclylene are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3; where the heteroatoms of the spirocyclic heterocyclylene are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3. R is a chemical bond, a 7- to 11-membered monospiroheterocyclylene group substituted with 0, 1, 2, or 3 R0 atoms, a 3- to 8-membered monocyclic heterocyclylene group, or an 8- to 10-membered bicyclic heteroarylene group, where R0 atoms are hydrogen, =O, and C. 1-5Selected from alkyl groups, or the same C atom together with two R0 atoms linked to it to form a 3- to 6-membered cycloalkyl group, the heteroatoms of the bicyclic heteroarylene group are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the spirocyclic heterocyclylene group are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3, the heteroatoms of the monocyclic heterocyclylene group are nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3. Linker [ka] It is expressed as, R L1 , R L3 These are O and N(R) respectively, independently. 00 ) or (CR 21 R 22 ) r And R 21 , R 22 is hydrogen or C 1-5 It is an alkyl group, or R 21 , R 22 It surrounds the linked C atom to form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycloalkyl group. R L2 They are homologous or different, and R L2 O, CO, N(R) 00 ), an alkynylene group, an alkenylene group, or a cyclopropylene group, R 00 is hydrogen or C 1-5 It is an alkyl group, n2 and n4 are independently 0, 1, 2, or 3. r, n0, and n3 are 0, 1, 2, 3, or 4.

[0098] In some embodiments, Q is P(O)R q1 R q2 And R q1 , R q2 Each of them is independently C 1-5 Alkyl alkyl group or C 1-5 It is an alkoxy group, J1 is N or CH. J2 is N or CH, J3 is N or CH. J4 is N or CH. V1 is N or CH. V2 is N or CH. V3 is N or CR 3 And R3 is hydrogen, V4 is N or CR4, R4 is hydrogen, halogen, or a 5- to 6-membered heteroaryl group, the heteroatom of the 5- to 6-membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2, or 3. Alternatively, R3 and R4, together with the atoms linked to them, form a 5- to 6-membered heteroaryl group or benzene, and the heteroatom of the above 5- to 6-membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2, or 3. R a , R b Each is independently of hydrogen or C 1-10 It is an alkyl group, K1 is N or CH. K2 is N or CR k2 And R k2 These are hydrogen, F, Cl, Br, I, and C. 1-5 Alkyl, halo C 1-5 Alkoxy group or C 1-5 It is an alkoxy group, R k3 teeth, [ka] F, Cl, Br, I, cyano group, acetyl group, ethyl group, C 1-5 Alkilen OC 1-5 Alkyl alkyl group or C 3-6 Selected from cycloalkyl groups, the above C 1-5 Alkyl groups can optionally consist of deuterium, hydroxyl, cyano, and C. 1-3 Alkyl alkyl group or C 1-3 Substituted with 0, 1, 2, or 3 substituents selected from alkoxy groups, R a is H, methyl group, ethyl group, propyl group or isopropyl group, and Rb is H, methyl group, ethyl group, propyl group or isopropyl group, K4 is N or CR k4 And R k4 is hydrogen or C 1-5 It is an alkoxy group, L5 is NH, L6 is NH, Ring A is a 3- to 8-membered monocyclic heterocyclylene or a 7- to 11-membered spirocyclic heterocyclylene, wherein the heteroatom of the monocyclic heterocyclylene is N and the number of heteroatoms is 1 or 2, and the heteroatom of the spirocyclic heterocyclylene is N and the number of heteroatoms is 1 or 2. R is a chemical bond, a 7- to 11-membered monospiroheterocyclylene group substituted with 0, 1, 2, or 3 R0 atoms, a 6-membered monocyclic heterocyclylene group, or an 8- to 10-membered bicyclic heteroarylene group, where R0 is hydrogen, =O, and C. 1-5 Selected from alkyl groups, or the same C atom together with two R0s linked to it to form a 3- to 6-membered cycloalkyl group, wherein the type of heteroatom of the monospiroheterocyclylene group is N and the number of heteroatoms is 1 or 2, the type of heteroatom of the bicyclic heteroarylene group is N and the number of heteroatoms is 1 or 2, and the type of heteroatom of the 6-membered monocyclic heterocyclylene group is N and the number of heteroatoms is 1 or 2.

[0099] In some embodiments, the PIN is further, [ka] It is expressed as, V1, V2, V3, V4, J1, J2, J3, J4, R k2 , R k3 R3, R4, ring A, and R are defined in any one of the above terms, Alternatively, R3 and R4, together with the atoms linked to them, form 1H-pyrrole. Of these, "---" is either a single link or absent, and r5 is 0, 1, 2, 3, 4, or 5. U, T, and M are each independently C, N, O, or S, and within the permissible range of valence, U, T, and M are each independently one or two R 0 Replaced with R 0 These are hydrogen, hydroxyl group, halogen, cyano group, acetyl group, C 1-5 Alkyl alkyl group (preferably C 1-3 (Alkyl alkyl group), C 1-5 Alkoxy group (preferably C) 1-3 Alkoxy group), Halo C 1-5 Alkyl alkyl group (preferably halo C) 1-3 (Alkyl alkyl group), C 3-6 Selected from cycloalkyl groups or 3- to 6-membered heterocycloalkyl groups, m2 is 0, 1, or 2, preferably R 0 This is hydrogen or a halogen (preferably fluorine or chlorine).

[0100] In some embodiments, further, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is expressed as, R J1 , R J2 V1, V2, V3, V4, R k2 , R k3 Y1, Y2, t1, t2, t3, t4, L1, L2, L3, L4, W, G1, G2, G3, G4, Z1, Z2, R0 are as defined above, and preferably, the hydrogen atoms of the compound represented by formula (I) may be optionally substituted with 1, 2, 3, 4, 5 or more deuterium atoms. In some examples, the compound represented by formula (I), or its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants, and mixtures thereof are further represented by formula (III-1-1) or (III-1-2), [ka] R4 is a halogen (preferably chlorine or bromine), R k2 is hydrogen, C 1-5 It is an alkoxy group (preferably C 1-3 (alkoxy group, more preferably methoxy group), R k3 These are halogens, acetyl groups, cyano groups, and C 1-5 Alkyl alkyl group, C 3-6 Cycloalkyl groups, Halo C 1-5 Alkyl alkyl group or C 1-5 It is an alkoxy group, L1 is a chemical bond, CH2, CH2CH2, CH2CH2CH2, CO, NH, CONH, NHCO, -N(methyl)-, O, C(O)O, OC(O), or (CR 21 R 22 )n3, R 21 , R 22 These are, independently, a hydrogen or a methyl group, or R 21 , R 22 It surrounds the C atom with the linked C atom. 3-6It forms a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, and n3 is 0, 1, 2, or 3. L2 is a chemical bond, CH2, CH2CH2, CH2CH2CH2, CO, NH, CONH, NHCO, O, C(O)O, OC(O), or (CR 21 R 22 )n3, R 21 , R 22 These are, independently, a hydrogen or a methyl group, or R 21 , R 22 It surrounds the C atom with the linked C atom. 3-6 It forms a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, and n3 is 0, 1, 2, or 3. L3 is a chemical bond, CH2, CH2CH2, CH2CH2CH2, CO, NH, CONH, NHCO, O, C(O)O, OC(O), or (CR 21 R 22 )n3, R 21 , R 22 These are, independently, a hydrogen or a methyl group, or R 21 , R 22 It surrounds the C atom with the linked C atom. 3-6 It forms a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, and n3 is 0, 1, 2, or 3. L4 is a chemical bond, CH2, CH2CH2, CH2CH2CH2, CO, NH, CONH, NHCO, O, C(O)O, OC(O), or (CR 21 R 22 )n3, R 21 , R 22 These are, independently, a hydrogen or a methyl group, or R 21 , R 22 It surrounds the C atom with the linked C atom. 3-6 It forms a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, where n3 is 0, 1, 2, or 3, Z1 is CH or N, Z2 is CH2 or C(O), and W is CH2, O, S, an alkenylene group, or C≡C. R0 can be H, D, halogen, hydroxyl group, cyano group, or C 1-3 Alkyl alkyl group or C 1-3 It is an alkoxy group.

[0101] Furthermore, in the above formula (III-1-1) or (III-1-2), R4 is chlorine or bromine (preferably chlorine), and R k2 R is a hydrogen or methoxy group, k3 This is selected from fluorine, chlorine, bromine, acetyl group, methyl group, ethyl group, isopropyl group, propyl group, cyclopropyl group, -O-oxetanyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F and -CHFCHF2. L1, L2, L3, and L4 are each independently a chemical bond, CH2, and CH2CH2 (preferably L1, L2, L3, and L4 are each independently CH2, more preferably L1 and L2 are a chemical bond or CH2, and L3 and L4 are CH2), Z1 is CH or N, Z2 is CH2 or C(O), W is CH2, O, S, or C≡C (preferably CH2 or C≡C, more preferably C≡C), R0 is H, D, fluorine, chlorine, bromine, hydroxyl group, cyano group, methyl group, ethyl group, propyl group, or isopropyl group, R0 is preferably hydrogen, preferably F, and more preferably C 1-3 Alkyl or halo C 1-3 An alkyl group, more preferably a trifluoromethyl group.

[0102] In some examples, the compound represented by formula (I), or its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants, and mixtures thereof, are further represented by formula (III-2-1) or formula (III-2-5), [ka] Q is P(O)(C 1-3 Alkyl)2 or N(C) 1-3 It is an alkyl)methanesulfonyl group, Y1 is CH or N, Y2 is CH or N, and t1, t2, t3, and t4 are each independently 1 or 2. Ring A is a 5- to 7-membered heterocyclylene group or a 3- to 8-membered cycloalkylene group, and R0 is hydrogen, deuterium, cyano group, F, C 1-6 Alkyl and C 1-6 Selected from alkoxy groups, R J1 , R J2 , R k2 , R k3 R4, L1, L2, L3, L4, W, G1, G2, G3, G4, Z1, Z2 are defined in any one of the above terms.

[0103] In some examples, the compound represented by formula (I), or its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants, and mixtures thereof are further represented as (III-2-2) or (III-2-3), [ka] R4 is chlorine or bromine. Y1 is N, Y2 is CH, and t1, t2, t3, and t4 are each independently 1 or 2. R k2 These are hydrogen, a methoxy group, an ethoxy group, or an O-oxetanyl group. R k3 This is selected from fluorine, chlorine, bromine, cyano group, acetyl group, methyl group, ethyl group, isopropyl group, propyl group, cyclopropyl group, -O-oxetanyl group, trifluoromethyl group, -CH2CH2F, -CHFCH3, -CH2CHF2, -CF2CH3, -CHFCH2F, -CH2CF3, -CF2CH2F, or -CHFCHF2. L1, L2, L3, and L4 are each independently chemically bonded, CH2, and CH2CH2 (preferably L1, L2, L3, and L4 are each independently CH2, more preferably L1 and L2 are chemically bonded or CH2, L3, and L4 are CH2, and more preferably L1, L2, L3, and L4 are each independently chemically bonded). W is CH2, O, or S (preferably O), Z1 is CH or N, Z2 is CH2 or C(O), R0 is selected from hydrogen, fluorine, chlorine, or a methyl group.

[0104] In some examples, the compound represented by formula (I), or its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants, and mixtures thereof, are further represented by formula (Ib-1) or (Ib-2), [ka] U, T, M, V1, V2, V3, V4, R k2 , R k3 A, R, L1, L2, L3, L4, W, Z1, Z2, R0, and m2 are defined in any one of the above terms.

[0105] In some examples, the compound represented by formula (I), or its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants, and mixtures thereof, are further represented by formula (IV) or (IV-1), [ka] R4, R k2 , R k3 A, R, Linker, W, Z1, Z2, and R0 are defined in any one of the above terms.

[0106] In some examples, the compound represented by formula (I), or its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants, and mixtures thereof, are further represented by formula (VIII), [ka] V1, V2, V3, V4, R k2 , R k3 A, R, W, Z1, and Z2 are defined in any one of the above terms.

[0107] In some embodiments, T is O, S, or C, preferably T is O or N. In some embodiments, M is O, S, or C, preferably M is O or N. In some embodiments, U is C or N.

[0108] In some embodiments, m2 is 0 or 1, R 0 These are hydrogen, fluorine, chlorine, bromine, iodine, cyano group, acetyl group, and C 1-5 Alkyl alkyl group, C 1-5 Alkoxy group, Halo C 1-5 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups or 3- to 6-membered heterocycloalkyl groups, preferably R 0 is selected from fluorine, chlorine, and bromine, preferably R 0 The group is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, or an ethoxy group.

[0109] In some examples, the compound represented by formula (V), or its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystalline polymorphs, prodrugs or isotopic variants, and mixtures thereof are further represented as (V-1) or (V-2), [ka] V1 and V2 are both N, V3 is CR3, V4 is CR4, R3 is hydrogen, R4 is chlorine or bromine, R k2 is hydrogen, C 1-3 Alkyl, halo C 1-3 Alkyl alkyl group or C 1-3 Alkoxy group (preferably a methoxy group), C 3-6 It is a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, R k3 This includes acetyl groups, cyano groups, fluorine, chlorine, bromine, methyl groups, ethyl groups, propyl groups, isopropyl groups, cyclopropyl groups, O-oxetanyl groups, or halo C 1-3It is an alkyl group, where L1, L2, L3, and L4 are each independently chemically bonded, CH2, or CH2CH2, W is CH2, O, S, or C≡C, Z1 is CH, Z2 is CO, or CH2, and R0 is H, D, fluorine, chlorine, bromine, or C 1-3 Alkyl alkyl group or C 1-3 It is an alkoxy group, U, T, M, and m2 are defined in any one of the above terms.

[0110] In some embodiments, E is further represented as (II-i-1), [ka] L7 is a chemical bond or NH, and Z5 is N or CH. R 05 These are hydrogen, halogen, cyano group, acetyl group, amide group, C 1-3 Alkyl alkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkyl or halo C 1-3 It is an alkoxy group, Ring D is absent, L7 is linked to a benzene ring, or ring D is selected from benzene, pyridine, pyrimidine, pyrazine, pyridazine, cyclohexane, oxocyclohexane, cyclopentane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole and triazole, and ring D contains hydrogen and C within an acceptable range of valence. 1-3 Alkyl alkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkyl, halo C 1-3 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 It is substituted with one, two, or three substituents selected from heterocycloalkyl groups and halogens, where W is as defined in any one of the above examples.

[0111] In some embodiments, E is [ka] Selected from, R 05 is hydrogen, fluorine, cyano group, acetyl group, amide group, fluoromethyl group, difluoromethyl group, or trifluoromethyl group, preferably R 05 is hydrogen, deuterium, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, cyano group, or halo C 1-6 It is an alkyl group, R 00 These are hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a cyclopropyl group. W is CH2, O, S, NH, -N(methyl)-, or -C≡C.

[0112] In some examples, L5 is a bond or NH, and ring Cy1 is a phenyl group. [ka] Selected from, Rcy is hydrogen, deuterium, halogen, C 1-6 Alkyl, halo C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, hydroxy C 1-6 Selected from alkoxy groups, cyano groups, amino groups, -P(O)(CH3)2, -N(CH3)S(O)2CH3, or -S(O)2(CH)(CH3)2.

[0113] In some examples, the above compounds are selected from Table 1, and the pharmaceutically acceptable salts of the compounds shown in Formula I above are selected from the hydrochloride or formate salts of the compounds in Table 1.

[0114] [Table 1-1] [Table 1-2] [Table 1-3] Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35

[0115] Another aspect of the present invention provides compounds represented by (1c-1), (1e-1), (1c-1-1), (1e-1-1), (1c-1-2), or (1e-1-2), [ka] In formula (1c-1), if R is a bond, NH is the NH in ring A; if R is not a bond, NH is the NH in ring R. Sub is selected from OH, SH, C(O)OH, S(O)OH, S(O)2OH, NH or a leaving group, and the leaving group is selected from fluorine, chlorine, bromine, iodine, boric acid, borate ester, -OMs or -OTF, and the variables in the formula are as defined in any one of the above. Preferably, ring A is selected from a 5- to 7-membered azaheteroring or a 7- to 16-membered azaspiroring, and R is selected from a 5- to 7-membered azaheteroring or a 7- to 16-membered azaspiroring. Preferably, Sub is selected from OH, SH, C(O)OH, S(O)OH, S(O)2OH, or NH, and Sub is selected from bromine, iodine, boric acid, boric acid ester, -OMs, or -OTF.

[0116] In another embodiment, the present invention further provides a method for producing compounds of general formula (X-1) or (X-2), [ka] This includes producing a compound of general formula (X-1) or (X-2) by reacting a compound of general formula (1c-1) or (1c-2) with a compound of general formula (1d-1).

[0117] Specifically, the manufacturing method involves a nucleophilic substitution reaction between the -NH of formula (1c-1) or (1c-2) and the leaving group of formula (1d-1) to obtain a compound of formula (X-1) or formula (X-2), where LG is the leaving group, and R J1 , R J2 Q, R4, R k2 , R k3Rings A, R, Linker, W, G1, G2, G3, G4, Z1, and Z2 are as defined in any one of the above terms. The -NH in formula (1c-1) or (1c-2) may be an NH on ring R, or an NH linked to R. In some embodiments, when R is a bond, the leaving group reacts with the NH on ring A.

[0118] The leaving group is preferably a halogen (chlorine, bromine, or iodine), -OMs (methanesulfonic acid ester), -OTf (trifluoromethanesulfonic acid ester), or -OTs (p-toluenesulfonic acid ester). The nucleophilic substitution reaction is preferably carried out in a polar solvent and an alkaline system. Specifically, the polar solvent is preferably one or more selected from the group consisting of DMF, DMSO, NMP, acetonitrile, THF, or toluene, and the alkaline system is preferably triethylamine, DIEA, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, cesium fluoride, etc. In some embodiments, an alkali metal catalyst may be added, such as NaI, KI, or CuI.

[0119] In another embodiment, the present invention further provides another method for producing compounds of general formula (X-1) or (X-2), [ka] This includes producing a compound of general formula (X-1) or (X-2) by reacting general formula (1e-1) or (1e-2) with general formula (1f).

[0120] Specifically, the manufacturing method involves a reductive amination reaction between the -C=O of formula (1e-1) or formula (1e-2) and the NH of R in formula (1f) to obtain a compound of formula (X-1) or formula (X-2), with rings B, Q, R4, R k2 , R k3 The rings A, R, Linker, W, G1, G2, G3, G4, Z1, and Z2 are defined in any one of the above terms.

[0121] Preferably, the reducing agent is sodium borohydride cyanohydride or NaBH(OAc)3, and the reaction is preferably carried out in a solvent, the solvent of which can be selected from 1,2-dichloroethane, dichloromethane, or DMF.

[0122] In another embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and optionally pharmaceutically acceptable excipients.

[0123] In another embodiment, the present invention provides a pharmaceutical composition comprising, in addition to the compound of the present invention and a pharmaceutically acceptable excipient, other therapeutic agents.

[0124] In another embodiment, the present invention provides an application of the above compound or pharmaceutical composition in the production of a protein inhibitor or degradation agent, wherein the protein in the protein inhibitor or degradation agent is at least one selected from the group consisting of EGFR, ROS1, or ALK.

[0125] In another embodiment, the present invention provides a reagent kit comprising the compound of the present invention, other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0126] In another embodiment, the present invention provides applications of the compounds in the manufacture of drugs for treating and / or preventing cancer.

[0127] In another embodiment, the present invention provides a method for treating and / or preventing cancer in a subject, comprising administering a compound or composition of the present invention to the subject.

[0128] In another embodiment, the present invention provides compounds or compositions of the present invention for treating and / or preventing cancer.

[0129] In specific embodiments, the cancers are selected from lung cancer, lymphoma, inflammatory myofibroblastoma, colorectal cancer, glioma, glioblastoma, ovarian cancer, bone marrow cancer, transplant-related cancer, neutropenia, leukemia, Wagner-Amberlicht syndrome, bronchial cancer, prostate cancer, breast cancer, thyroid cancer, pancreatic cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, colorectal adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer, sarcoma, tumors resistant to targeted drugs, or tumors or diseases dependent on ALK, ROS1, EGFR or any of its mutant proteins.

[0130] In another specific embodiment, the above cancers include small cell lung cancer, non-small cell lung cancer, diffuse large B-cell lymphoma, non-Hodgkin lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, CD20-positive lymphoma, primary lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin lymphoma, refractory B-cell non-Hodgkin lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), previously treated myelodysplastic syndrome, and phenotypes. The selection includes cellular myeloma, smoldering myeloma, smoldering multiple myeloma, myelofibrosis, acute myeloid leukemia (AML), leukemia-associated anemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, Wagner-Amberlicht syndrome, bronchial cancer, prostate cancer, triple-negative breast cancer, incidental breast cancer, Cowden disease patients, thyroid cancer, pancreatic cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, gastric cancer, gastrointestinal stromal tumors, esophageal cancer, colorectal adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer, rhabdomyosarcoma, various adipose-derived tumors, Ewing sarcoma / anaplastic neuroectodermatoma (Ewing / PNETs), leiomyosarcoma, and tumors resistant to EGFR, ROS1, or ALK-targeted drugs.

[0131] In another specific embodiment, the cancers include anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-positive non-small cell lung cancer, EGFR mutation-positive non-small cell lung cancer, lung adenocarcinoma, lung cancer resistant to EGFR, ROS1, or ALK-targeted drugs, lymphoma resistant to ALK-targeted drugs, or lung cancer, lymphoma, inflammatory myofibroblastoma, and colon cancer that depend on ALK, ROS1, EGFR, or any of their mutant proteins. The diagnosis is selected from tumors, cancers, or diseases such as rectal cancer, glioma, astrocytoma, ovarian cancer, leukemia, breast cancer, thyroid cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, esophageal squamous cell carcinoma, renal cell carcinoma, bronchial cancer, prostate cancer, breast cancer, thyroid cancer, pancreatic cancer, stomach cancer, gastrointestinal stromal tumor, esophageal cancer, colorectal adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer, or sarcoma.

[0132] Other objects and advantages of the present invention will be apparent to those skilled in the art from the specific embodiments, examples, and claims described below.

[0133] In another embodiment, the present invention further provides compounds which are any one of the compounds in Table 2 or a salt thereof.

[0134] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0135] definition chemistry definition The following provides a more detailed explanation of the definitions of specific functional groups and chemical terms.

[0136] chemistry definition The following provides a more detailed explanation of the definitions of specific functional groups and chemical terms.

[0137] When a range of values ​​is listed, it means that each value and a subrange within that range are included. For example, "C 1-5 "Alkyl" refers to C1, C2, C3, C4, C5, C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-5 , C 2-4 , C 2-3 , C 3-5 , C 3-4 and C 4-5 Contains alkyl groups.

[0138] "Alkyl group" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, C 1-10 The alkyl group is an alkyl group containing 1 to 10 carbon atoms, preferably C 1-8 Alkyl alkyl groups, more C 1-5 Alkyl alkyl groups, more preferably C 1-3 It is an alkyl group. 1-10Non-limiting examples of alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl Xyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, This includes 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.

[0139] The "alkylene group" represents a divalent group obtained by removing other hydrogen atoms from the above-mentioned "alkyl group," and may be substituted or unsubstituted. Preferably C 1-10 Alkylene group, more preferably C 1-5 Alkylene group, more preferably C 1-3 These are alkylene groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene groups.

[0140] "C 2-10An "alkenyl group" refers to a linear or branched hydrocarbon group having 2 to 10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-6 An alkenyl group is preferred, and in some embodiments, C 2-4 An alkenyl group is preferred. 2-10 Examples of alkenyl groups include ethenyl group (C2), 1-propenyl group (C3), 2-propenyl group (C3), 1-butenyl group (C4), 2-butenyl group (C4), butadienyl group (C4), pentenyl group (C5), bendienyl group (C5), hexenyl group (C6), heptenyl group (C7), octenyl group (C8), etc. 2-10 The term “alkenyl group” further includes heteroalkenyl groups in which one or more (e.g., one, two, three, or four) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, e.g., one to five substituents, one to three substituents, or one substituent.

[0141] "C 2-10 An "alkynyl group" refers to a linear or branched hydrocarbon group having 2 to 10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, C 2-6 An alkynyl group is preferred, and in some embodiments, C 2-4 Alkynyl group is preferred. 2-10 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), heptynyl (C7), and octinyl (C8). 2-10 The term “alkynyl group” further includes heteroalkynyl groups in which one or more (e.g., one, two, three, or four) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted with one or more substituents, e.g., one to five substituents, one to three substituents, or one substituent.

[0142] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0143] Therefore, "HaruC 1-5 "Alkyl group" refers to the above "C" which is substituted with one or more halogen groups. 1-5 This refers to an alkyl group. In some embodiments, halo C 1-4 Alkyl alkyl groups are particularly preferred, and halo C 1-2 Alkyl groups are even more preferred. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, and 2,2,2-trifluoro-1,1-dimethylethyl groups. Haloalkyl groups may be substituted with any available bond sites, for example, one to five substituents, one to three substituents, or one substituent.

[0144] "C 3-8 A "cycloalkyl group" refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms and 0 heteroatoms. In some embodiments, C 3-6 Cycloalkyl groups and C 3-5Cycloalkyl groups are particularly preferred. A cycloalkyl group further comprises a ring system in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bond site is located on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptadienyl (C7), cycloheptadienyl (C7), and cycloheptatrielinyl (C7). The cycloalkyl group may be optionally substituted with one or more substituents, for example, one to five substituents, one to three substituents, or one substituent.

[0145] "3- to 8-membered heterocycloalkyl group" refers to a 3- to 8-membered non-aromatic ring system having a ring carbon atom and 1 to 5 cycloheteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and the heteroatoms are preferably independently nitrogen and / or oxygen, for example nitrogen, and the number of heteroatoms is preferably 1 or 2. In a heterocyclyl group containing one or more nitrogen atoms, the bond site may be carbon or nitrogen atom, as long as the valence is acceptable. Preferably, it is a 3- to 7-membered heterocyclyl group, preferably a 3- to 6-membered heterocyclyl group, preferably a 4- to 8-membered heterocyclyl group, and more preferably a 5- to 6-membered heterocyclyl group, which is a 5- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 cycloheteroatoms. Exemplary 3- to 8-membered heterocycloalkyl groups include, but are not limited to, azacyclopropanyl, oxocyclopropanyl, thiorenyl-azacyclobutanyl, oxetanyl, thiocyclobutanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxocyclopentane, oxasulfuranyl, disulfuranyl, oxazolidine-2-one, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridyl, thianyl, piperazinyl, morpholinyl, dithioheterocyclohexyl, and dioxanyl groups.

[0146] As used herein, "cycloalkyl" and "cycloalkyl ring" are interchangeable.

[0147] "C 6-10An "aryl group" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic configuration) having 6 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl group," e.g., phenyl group). In some embodiments, the aryl group has 10 ring carbon atoms ("C6 aryl group"). 10 An aryl group (e.g., naphthyl groups such as 1-naphthyl and 2-naphthyl groups). The aryl group further comprises a ring system in which the aryl ring is fused with one or more cycloalkyl or heterocyclyl groups, and the bond site is located on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0148] A "5-membered to 14-membered heteroaryl group" refers to a 5-membered to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1 to 4 cycloheteroatoms (for example, having 6, 10, or 14 π electrons shared in a cyclic configuration), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur, and in a 5-membered to 14-membered heteroaryl group, the heteroatoms are preferably independently nitrogen and / or oxygen, for example nitrogen, and the number of heteroatoms is preferably 1, 2, or 3. In a heteroaryl group containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, as long as the valence is acceptable. A heteroaryl bicyclic system may contain one or more heteroatoms in one or two rings. A heteroaryl group further includes a ring system in which the heteroaryl ring is fused with one or more cycloalkyl or heterocyclyl groups, and the bond site is located on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. Preferably, it is a 5- to 10-membered heteroaryl group, and more preferably a 5- to 6-membered heteroaryl group. Exemplary 5- to 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), thiadiazolyl, tetrazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, tetradinyl, azacycloheptatrienyl, oxacycloheptatrienyl, and thiocycloheptatrienyl groups. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzoisofuryl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indenadinyl, and prinyl groups.Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthilidinyl, pteridinyl, quinolinyl, isoquinolinyl, synnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl groups. The heteroaryl group may be optionally substituted with one or more substituents, for example, one to five substituents, one to three substituents, or one substituent.

[0149] "C 6-10 The "arylene group" and the "5-membered to 14-membered heteroarylene group" are, respectively, the same as the "C" mentioned above. 6-10 This represents a divalent group obtained by removing other hydrogen atoms from an "aryl group" and a "5- to 14-membered heteroaryl group," and may be substituted or unsubstituted. Preferably, C 6-10 These are arylene groups and 5- to 10-membered heteroarylene groups. Typical C 6-10The arylene group includes 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 1,7-naphthylene, 1,8-naphthylene, 2,3-naphthylene, 2,5-naphthylene, 2,6-naphthylene, and 2,7-naphthylene. Typical 5- to 10-membered heteroarylenes include 1,2-pyrrolylene group, 1,3-pyrrolylene group, 2,3-pyrrolylene group, 2,4-pyrrolylene group, 2,5-pyrrolylene group, 3,4-pyrrolylene group, 2,3-furanylene group, 2,4-furanylene group, 2,5-furanylene group, 3,4-furanylene group, 2,3-thienylene group, 2,4-thienylene group, 2,5-thienylene group, 3,4-thienylene group, 1,2-imidazoylene group, 1,4-imidazoylene group, and 1,5-imidazoylene group. , 2,4-imidazoylene group, 2,5-imidazoylene group, 4,5-imidazoylene group, 1,3-pyrazoylene group, 1,4-pyrazoylene group, 1,5-pyrazoylene group, 3,4-pyrazoylene group, 3,5-pyrazoylene group, 4,5-pyrazoylene group, 2,4-oxazolylene group, 2,5-oxazolylene group, 4,5-oxazolylene group, 3,4-isoxazolylene group, 3,5-isoxazolylene group, 4,5-isoxazolylene group, 2,4-thiazoylene group, 2,5- Thiazolylene group, 4,5-thiazoylene group, 3,4-isothiazoylene group, 3,5-isothiazoylene group, 4,5-isothiazoylene group, 1,4-triazolylene group, 1,5-triazolylene group, 4,5-triazolylene group, 1,2,4-oxadiazole-3,5-ylidene, 1,2,3-oxadiazole-4,5-ylidene, 1,2,4-thiadiazole-3,5-ylidene, 1,2,3-thiadiazole-4,5-ylidene, 2,3-pyridylene group, 2,4-pyridylene Dilene group, 2,5-pyridylene group, 2,6-pyridylene group, 3,4-pyridylene group, 3,5-pyridylene group, 3,4-pyridadinylene group, 3,5-pyridadinylene group, 3,6-pyridadinylene group, 4,5-pyridadinylene group, 2,4-pyrimidinylene group, 2,5-pyrimidinylene group, 4,5-pyrimidinylene group, 4,6-pyrimidinylene group, 2,3-pyridinylene group, 2,5-pyridinylene group, 2,6-pyridinylene group, 1,2,3-triazinyl-4,5-ylidene, 1,This includes 2,3-triazinyl-4,6-ylidene, 1,2,4-triazinyl-3,5-ylidene, 1,2,4-triazinyl-3,6-ylidene, 1,2,5-triazinyl-3,4-ylidene, 1,2,5-triazinyl-3,6-ylidene, 1,2,5-triazinyl-4,6-ylidene, 1,3,5-triazinyl-2,4-ylidene, 1,2,3,4-tetradinyl-5,6-ylidene, 1,2,3,5-tetradinyl-4,6-ylidene, 1,2,4,6-tetradinyl-3,5-ylidene, etc.

[0150] The terms "heteroaryl ring" and "heteroaryl group" are interchangeable and refer to monocyclic or fused polycyclic groups (i.e., rings sharing adjacent carbon atoms or heteroatom pairs) having 1 to 4 heteroatoms and 5 to 14 ring atoms, preferably 5 to 10 ring atoms, more preferably 5, 6, 8, 9, or 10 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen, where the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom may be optionally quaternarily ammoniumlated. In the "heteroaryl ring" and "heteroaryl group," the heteroatoms are preferably nitrogen and / or oxygen independently, for example, nitrogen, and the number of heteroatoms is preferably 1, 2, or 3. The heteroaryl group has 6, 10, or 14 π electrons shared in the ring system. At least one ring in the ring system is aromatic. In the present invention, C 5-14 Heteroaryl groups include 5-membered or 6-membered monocyclic heteroaryl groups, 8- to 10-membered bicyclic heteroaryl groups, 11- to 14-membered tricyclic heteroaryl groups, heteroaryl groups formed by the condensation of a 5-membered or 6-membered monocyclic heteroaryl ring with a 5- to 6-membered saturated or unsaturated monoheterocyclic ring, heteroaryl groups formed by the condensation of a 5-membered or 6-membered monocyclic heteroaryl ring with a 5- to 6-membered saturated or unsaturated monocyclic ring, and heteroaryl groups formed by the condensation of a benzene ring with a 5- to 6-membered saturated or unsaturated monoheterocyclic ring.

[0151] A "5-membered to 6-membered heteroaryl group" refers to a monocyclic heteroaryl ring containing 5 to 6 ring atoms, and includes, but is not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, or pyrazine. In a 5-membered to 6-membered heteroaryl group, the heteroatoms are preferably nitrogen and / or oxygen independently, for example, nitrogen, and the number of heteroatoms is preferably 1, 2, or 3.

[0152] "8- to 10-membered bicyclic heteroaryl groups" refers to 9- or 10-membered bicyclic heteroaryl groups formed by the condensation of a benzene ring with a 5- or 6-membered monocyclic heteroaryl group, and 8- to 10-membered bicyclic heteroaryl groups formed by the condensation of a 5- or 6-membered monocyclic heteroaryl group with a 5- or 6-membered monocyclic heteroaryl group. Of these, the 5- or 6-membered monocyclic heteroaryl groups are selected from thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, or pyrazine. In an 8- to 10-membered bicyclic heteroaryl group, the heteroatoms are preferably nitrogen and / or oxygen independently, for example, nitrogen, and the number of heteroatoms is preferably one, two, or three.

[0153] As used herein, “saturated or unsaturated monocyclic” and “saturated or unsaturated monocycloalkyl” are interchangeable and refer to a saturated or unsaturated all-carbon monocyclic system, where “unsaturated” refers to a ring portion containing at least one double or triple bond. Preferably 3- to 6 members, more preferably 4- to 6 members, and even more preferably 5- to 6 members.

[0154] "Saturated or unsaturated monoheterocycles," "saturated or unsaturated monocyclic heterocycles," and "monocyclic heterocyclyl groups" are interchangeable, and in saturated or unsaturated monocycles, one, two, or three ring carbon atoms are nitrogen, oxygen, or S(O). t It is substituted with heteroatoms selected from (where t is an integer between 0 and 2), but does not contain the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms are carbon. Preferably it is 3- to 6-membered, more preferably 4- to 6-membered, and even more preferably 5- to 6-membered. In "saturated or unsaturated monoheterocycles," "saturated or unsaturated monocyclic heterocycles," and "monocyclic heterocyclyl groups," the heteroatoms are preferably nitrogen and / or oxygen independently, for example, nitrogen, and the number of heteroatoms is preferably 1, 2, or 3.

[0155] A "3- to 8-membered monocyclic heterocycline group" refers to a monoheterocyclic group containing 3 to 8 ring atoms, where the heteroatoms are nitrogen, oxygen, sulfur, etc., and are preferably 5- to 7-membered monocyclic heterocycles, including (but not limited to) oxocyclopentane, azacyclopentane, thiocyclopentane, 1,3-dioxopentane, piperidine, piperazine, morpholine, etc. In a "3- to 8-membered monocyclic heterocycline group," the heteroatoms are preferably nitrogen and / or oxygen independently, for example, nitrogen, and the number of heteroatoms is preferably 1, 2, or 3.

[0156] The terms "polycyclic" and "polycycloalkyl group" are interchangeable and refer to saturated or unsaturated bicyclic, tricyclic, and more than one-carbon cyclic hydrocarbon systems. Of these, bicyclic systems include a spiro ring and a fused ring, and tricyclic systems include a bridging ring. Preferably, the fused ring and spiro ring are used.

[0157] "Polycyclic heterocyclic" and "polycycloheteroalkyl group" are interchangeable, and one, two, three, or four ring carbon atoms in a saturated or unsaturated polycyclic group are nitrogen, oxygen, or S(O). t It is substituted with a heteroatom selected from (where t is an integer between 0 and 2), but does not contain the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms are carbon. Preferably it is a spiroheterocycle (also called a spiroheterocyclyl group) or a bicyclic condensed heterocyclyl group, more preferably a 7- to 16-membered spirocycloheterocyclyl group or a 7- to 10-membered bicyclic condensed heterocyclyl group. The terms "5-membered or 6-membered monocyclic heteroaryl ring" and "5-membered or 6-membered monocyclic heteroaryl group" are interchangeable and both refer to monoheteroaryl rings containing 5 or 6 ring atoms, including (but not limited to) thiophene rings, N-alkylpyrrole rings, furan rings, thiazole rings, imidazole rings, oxazole rings, pyrrole rings, pyrazole rings, triazole rings, 1,2,3-triazole rings, 1,2,4-triazole rings, 1,2,5-triazole rings, 1,3,4-triazole rings, tetrazole rings, isoxazole rings, oxadiazole rings, 1,2,3-oxadiazole rings, 1,2,4-oxadiazole rings, 1,2,5-oxadiazole rings, 1,3,4-oxadiazole rings, thiadiazole rings, pyridine rings, pyridazine rings, pyrimidine rings, and pyrazine rings. In "polycyclic heterocycles" and "polycycloheteroalkyl groups," the heteroatoms are preferably nitrogen and / or oxygen independently, for example, nitrogen, and the number of heteroatoms is preferably one, two, or three.

[0158] The terms "8- to 10-membered bicyclic heteroaryl ring" and "8- to 10-membered bicyclic heteroaryl group" are interchangeable and both refer to bisheteroaryl rings containing 8 to 10 ring atoms, such as benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthiridine, 1,7-naphthiridine, 1,6-naphthiridine, and 1,5-naphthiridine (but not limited to these). In the "8- to 10-membered bicyclic heteroaryl ring" and the "8- to 10-membered bicyclic heteroaryl group," the heteroatoms are preferably nitrogen and / or oxygen independently, for example, nitrogen, and the number of heteroatoms is preferably one, two, or three.

[0159] The term "spirocycloalkyl group" refers to a polycyclic group with 5 to 20 members, in which monocyclic rings share one carbon atom (referred to as a spiro atom), and may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, they have 6 to 14 members, more preferably 7 to 14 members. Spirocycloalkyl groups are classified into monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups depending on the number of spiro atoms shared between the rings, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferably, they are 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0160] A "condensed cycloalkyl group" refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares one adjacent pair of carbon atoms with the other rings in the system. One or more of these rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, they have 6 to 14 members, more preferably 7 to 14 members. Depending on the number of constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl groups, with bicyclic being preferred. Non-limiting examples of condensed cycloalkyl groups include: [ka] Includes.

[0161] A "crosslinked cycloalkyl group" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 14 members, and most preferably 7 to 9 members. Depending on the number of rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic crosslinked cycloalkyl groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups are: [ka] Includes.

[0162] A "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group with 5 to 20 members, in which monocyclic rings share one atom (called a spiro atom), and one or more of these ring atoms are nitrogen, oxygen, or S(O). g The heteroatom is selected from (where g is an integer from 0 to 2), and the remaining ring atom is carbon. It may contain one or more double bonds, but there are no rings having a fully conjugated π-electron system. In the "spiroheterocyclyl group," the heteroatom is preferably nitrogen and / or oxygen independently, for example, nitrogen, and the number of heteroatoms is preferably one, two, or three.

[0163] Spiroheterocyclyl groups are classified into monospiroheterocyclyl groups, bisspiroheterocyclyl groups, or polyspiroheterocyclyl groups depending on the number of spiro atoms shared between the rings, with monospiroheterocyclyl groups and bisspiroheterocyclyl groups being preferred. More preferably, they are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, or 6-membered / 6-membered monospiroheterocyclyl groups or bisspiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0164] The term "condensed heterocyclyl group" refers to a polycyclic heterocyclyl group with 5 to 20 members, in which each ring in the system shares one pair of adjacent atoms with the other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, and one or more of the ring atoms are nitrogen, oxygen, or S(O). g The heteroatom is selected from (where g is an integer from 0 to 2), and the remaining ring atom is carbon. Preferably, it is a 7- to 14-membered condensed heterocyclyl group, and more preferably a 7- to 10-membered group (for example, 7-membered, 8-membered, or 9-membered). Depending on the number of rings that make up the group, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclyl groups, preferably bicyclic or tricyclic, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic condensed heterocyclyl group. In the "condensed heterocyclyl group," the heteroatoms are preferably nitrogen and / or oxygen independently, for example nitrogen, and the number of heteroatoms is preferably 1, 2, or 3.

[0165] Unless otherwise defined, the “substituents selected independently from…” as described in this invention means that when one or more hydrogens in the group are substituted by substituents, the types of substituents may be homologous or different, and the selected substituents are each of independent types. What needs to be explained in this specification is “C 3-8Subunits such as "cycloalkylene group", "3- to 8-membered heterocycloalkylene group", "monocyclic alkylene group", "monocyclic heterocyclylene group", "polycyclic alkylene group", "polycyclic heterocyclylene group", "5- to 6-membered heteroarylene group", "8- to 10-membered bicyclic heteroarylene group", and "monospiroheterocyclylene group" are the same as the above "C 3-8 This represents a divalent group from which other hydrogen atoms have been removed, such as a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a monocyclic alkyl group, a monocyclic heterocyclyl group, a polycyclic alkyl group, a polycyclic heterocyclyl group, a 5- to 6-membered heteroaryl group, an 8- to 10-membered bicyclic heteroaryl group, or a monospiroheterocyclyl group, and may be substituted or unsubstituted.

[0166] "Oxetanyl group": [ka] "Acetyl group": [ka] , methanesulfonyl group: [ka]

[0167] "Amino group": -NH2,

[0168] "Cyano group": [ka]

[0169] Alkyl groups, alkylene groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkylene groups, heterocycloalkyl groups, heterocycloalkylene groups, aryl groups, arylene groups, heteroaryl groups, and heteroarylene groups as defined herein are optionally substituted groups.

[0170] Exemplary substituents on carbon atoms include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR cc )2, -CO2R aa -OC(=O)R aa , -OCO2R aa -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa -C(=NR bb )OR aa -OC(=NR bb )R aa -OC(=NR bb )OR aa -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa -S(=O)R aa -OS(=O)R aa , -Si(R aa)3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa , -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), including, but not limited to, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, of which each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may independently have 0, 1, 2, 3, 4 or 5 R dd Substituted with the base, Alternatively, two geminal hydrogen atoms on a carbon atom are =O, =S, =NN(R) bb )2, =NNR bb C(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bbS(=O)2R aa ,=NR bb OR = NOR cc It is replaced by the following basis: R aa Each of them is independently selected from alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, or two R aa The groups bond to form a heterocyclyl group or a heteroaryl ring, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently have 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base, R bb Each of these is independently hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, selected from alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, or two R bbThe groups bond to form a heterocyclyl group or a heteroaryl ring, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently have 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base, R cc Each of them is independently selected from hydrogen, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, or two R cc The groups bond to form a heterocyclyl group or a heteroaryl ring, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently have 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base, R dd Each of these is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee , -OCO2R ee -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee -OC(=NR ff )R ee -OC(=NR ff )ORee -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2. Selected from alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, of which each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be independently present in 0, 1, 2, 3, 4, or 5 R groups. gg Substituted by the base, or two geminal R dd The substituents may bond to form =O or =S. R ee Each of these is independently selected from alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclyl groups, and heteroaryl groups. Exemplary substituents on a nitrogen atom include hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa-C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, including but not limited to alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, or two R groups linked to a nitrogen atom cc The groups bond to form a heterocyclyl group or a heteroaryl ring, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently have 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the group and R aa , R bb , R cc and R dd The above is true.

[0171] Other definitions As used herein, the term “treatment” refers to the progression of a disorder or condition to which the term applies, or to the reversal, reduction, or inhibition of one or more symptoms of such disorder or condition. As used herein, the noun “treatment” refers to the act of the verb treatment as defined above.

[0172] As used herein, the term “pharmaceutically acceptable salt” refers to carboxylate salts and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the bounds of reliable medical judgment, without causing inappropriate toxicity, irritation, allergies, etc., in proportion to a reasonable benefit / risk ratio, and include (where possible) amphoteric forms of the compounds of the present invention, and are effective for their intended use.

[0173] The salt may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, etc., produced from inorganic acids. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, acetate, oxalate, palmitate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, methanesulfonate, etc. They may also be produced from organic acids, including acetate, propionate, octanoate, isobutyrate, oxalate, etc. The salt may further include cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0174] The “subjects” of administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young people, middle-aged or elderly)) and / or non-human animals, such as primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats and / or dogs. In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are interchangeable herein.

[0175] In this specification, the terms "disease," "disorder," and "medical condition" are interchangeable.

[0176] Unless otherwise stated, the term “treatment” as used herein includes an effect that reduces the severity of a disease, disorder, or condition, or that delays or mitigates the progression of a disease, disorder, or condition, occurring while the subject has a particular disease, disorder, or condition ("therapeutic treatment"), and further includes an effect that occurred before the subject had a particular disease, disorder, or condition ("preventive treatment").

[0177] Generally, the “effective amount” of a compound refers to an amount sufficient to induce a target biological response. As those skilled in the art will understand, the effective amount of the compound of the present invention may vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health condition, and symptoms of the subject. The effective amount includes the therapeutic effective amount and the prophylactic effective amount.

[0178] The present invention also includes isotope-labeled compounds (isotope variants) equivalent to those described in formula (I), but in which one or more atoms are substituted by atoms having atomic masses or mass numbers different from those of the ordinary atomic masses or mass numbers in nature. Examples of isotopes that can be introduced into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 and F 36 Contains Cl. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs, and pharmaceutically acceptable salts of the above compounds or prodrugs are all within the scope of the present invention. Radioactive isotopes (e.g., 3 H and 14 The compounds of the present invention, which are specific isotope-labeled, such as those incorporating C), are applicable to drug and / or substrate tissue distribution measurements. Tritium, i.e. 3 H and carbon-14, that is 1413C isotopes are particularly preferred because they are easy to produce and detect. Furthermore, heavier isotopes, such as deuterium, i.e. 2 Substitution with H may be preferable in some cases because higher metabolic stability can provide therapeutic benefits, such as an extended in vivo half-life or a reduction in the required dose. The isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting the non-isotopically labeled reagent with a readily available isotopely labeled reagent when carrying out the processes disclosed in the following flowchart and / or examples and production examples.

[0179] A positive and progressive effect of the present invention is that the compounds of the present invention have good inhibitory activity against the GFR mutant BaF3 cell proliferation activity test. The compounds of the present invention have good selectivity for the GFR mutant BaF3 cell proliferation activity test. [Modes for carrying out the invention]

[0180] Production of intermediates Intermediate 3a [ka]

[0181] Step 1: Compounds 1-ethyl-2-fluoro-4-methoxy-5-nitrobenzene (2 g, 10 mmol) and tert-butyl 4-(piperidine-4-yl)piperazine-1-carboxylate (4 g, 15 mmol) were added to a reaction flask, followed by the addition of DMF (100 mL) and K2CO3 (4.1 g, 30 mmol). The mixture was stirred at 110°C for 24 hours. After concentrating the reaction mixture, water was added, and the mixture was extracted with dichloromethane. The mixture was washed with water, and the organic phase was concentrated and purified by normal-phase column chromatography (dichloromethane:methanol = 10:1) to obtain compound 3a-1. MS m / z (ESI): 449.5. [M+H] + .

[0182] Step 2: Compound 3a-1 (2.3 g, 5.13 mmol) was added to the reaction flask, followed by MeOH:EA=1:1 (150 mL), and then Pd / C (1.14 g, 1.07 mmol) was added in sequence. After the addition was complete, the mixture was stirred at room temperature under an H2 atmosphere for 2 hours. The mixture was filtered and concentrated to obtain compound 3a. MS m / z (ESI): 419.9 [M+H] + .

[0183] Intermediate 7a [ka]

[0184] Step 1: Compound 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene (0.5 g, 2.43 mmol) and compound tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (680 mg, 2.68 mmol) were dissolved in DMF (10 mL). K2CO3 (672 mg, 4.86 mmol) was added while stirring, and the reaction was then stirred at 60°C for 2 hours until the reaction was complete, and the mixture was cooled to room temperature. The reaction system was poured into ice water to precipitate the solid, filtered, and dried under vacuum to obtain compound 7a-1, which was then used directly in the next reaction. MS m / z (ESI): 440.4 [M+H] + .

[0185] Step 2: Compound 7a-1 (1 g, 2.27 mmol) was added to a mixed solution of ethanol (30 mL) and water (10 mL). Then, iron powder (762 mg, 13.64 mmol) and ammonium chloride (1.22 g, 22.73 mmol) were added. The reaction was carried out at 90°C for 2 hours with stirring under nitrogen gas protection. After the reaction was complete, the reaction solution was cooled to 25°C, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the ethanol. The aqueous phase was then extracted with EA, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 7a, which was then used directly in the next reaction. MS m / z (ESI): 411.2 [M+H]+.

[0186] Intermediate 8a [ka]

[0187] Step 1: 2-Chloro-1-fluoro-4-nitrobenzene (0.76 g, 4.33 mmol) was added to a solution of acetonitrile (10 mL), then 7-azaspiro[3.5]nonyl-2-ylcarbamate (1.04 g, 4.34 mmol) and N,N-diisopropylethylamine (1.4 g, 10.82 mmol, 1.89 mL) were added, and the mixture was reacted at 85°C for 5 hours with stirring under nitrogen gas protection. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to remove acetonitrile, diluted with water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 8a-1, which was then used directly in the next reaction. MS m / z (ESI): 396.0 [M+H] +

[0188] Step 2: Compound 8a-1 (1.6 g, 4.04 mmol, 1 eq) was added to a tetrahydrofuran (16 mL) solution, cooled to 0°C, and sodium hydride (0.64 g, 16.16 mmol, 60% purity) was added to the reaction mixture. The reaction was then carried out for 1 hour at 0°C to 25°C with stirring under nitrogen gas protection. Iodomethane (40.42 mmol, 2.51 mL) was added, and the reaction was carried out for another 1 hour with stirring. After the reaction was complete, saturated ammonium chloride aqueous solution was added, followed by extraction with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 8a-2, a yellow solid. MS m / z (ESI): 410.2 [M+H]+.

[0189] Step 3: Compound 8a-2 (900 mg, 2.2 mmol) was added to a mixed solution of ethanol (18 mL) and water (18 mL). Then, iron powder (306.54 mg, 5.49 mmol) and ammonium chloride (234.89 mg, 4.39 mmol) were added. The mixture was reacted at 80°C for 1 hour with stirring under nitrogen gas protection. After the reaction was complete, the temperature was lowered to 25°C, filtered through diatomaceous earth, the filter cake was washed twice with ethanol, the filtrate was collected, concentrated under reduced pressure to remove ethanol, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 8a. This compound was used directly in the next reaction. MS m / z (ESI): 380.2 [M+H] + .

[0190] Intermediate 46a [ka]

[0191] Step 1: Following Step 1 of intermediate 8a, compound 46a-1 was prepared. MS m / z (ESI): 503.2 [M+H] + .

[0192] Step 2: Compound 46a-2 was prepared by referring to intermediate 5d. MS m / z(ESI): 451.3[M+H] + .

[0193] Step 3: Compound 46a-2 (500 mg, 1.11 mmol) was added to the reaction flask, followed by the addition of MeOH:THF = 1:1 (20 mL), and then Rh(PPh3)Cl (0.1 g, 0.11 mmol) in sequence. After the addition was complete, the mixture was stirred at room temperature under an H2 atmosphere for 2 hours. The mixture was filtered and concentrated to obtain compound 46a-3 (brown solid, 400 mg). MS m / z (ESI): 453.3 [M + H] + .

[0194] Step 4: Compound 46a was prepared by referring to Step 2 of intermediate 7a. MS m / z(ESI): 423.2[M+H] + .

[0195] Intermediate 98a [ka]

[0196] Step 1: Compound 39a-1 (1 g, 4.6 mmol) was dissolved in HOAc (6 mL), and concentrated HNO3 (1.4 g, 5.0 mmol) was gradually added in an ice bath. After the addition was complete, the mixture was stirred at 0°C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was poured into ice water to precipitate the solid, and filtered to obtain 98a-1 (yellow solid, 800 mg). MS m / z (ESI): 262.0 [M+H] + .

[0197] Step 2: Compound 98a-2 was prepared by referring to intermediate 5d. MS m / z(ESI): 365.2[M+H] + .

[0198] Step 3: Compound 98a was prepared by referring to Step 2 of intermediate 3a. MS m / z(ESI): 337.4[M+H] + .

[0199] Intermediate 165a [ka]

[0200] Step 1: Compound 165c (170 mg, 0.23 mmol), pyrazole (31 mg, 0.46 mmol), CuI (19 mg, 0.1 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (14 mg, 0.1 mmol), Cs2CO3 (223 mg, 0.69 mmol), and DMF (6 mL) were added to a reaction flask. The mixture was bubbled with a nitrogen balloon for 1 minute, and the reaction was carried out at 150°C under microwave conditions for 1 hour. After the reaction was complete, the mixture was filtered, concentrated, and then obtained by normal-phase column chromatography (MeOH / DCM = 0-5%) to obtain compound 165a-1. MS m / z (ESI): 730.8.[M+H] + .

[0201] Step 2: Compound 165a-1 (60 mg, 0.08 mmol) and DCM (4 mL) were added to the reaction flask, then TFA (2 mL) was added, and the mixture was stirred at 20°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated, diluted with DCM, washed with saturated sodium bicarbonate until the pH was 7-8, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 165a. MS m / z (ESI): 630.6 [M+H] + .

[0202] Intermediate 166a [ka]

[0203] Step 1: Compounds 165c (200 mg, 0.27 mmol), 166a.1 (139 mg, 0.41 mmol), catalyst Pd(PPh3)4 (22.3 mg, 0.02 mmol), and 1,4-dioxane (6 mL) were added to a microwave tube. The mixture was bubbling with a nitrogen balloon for 1 minute, and the reaction was carried out at 150°C under microwave conditions for 1 hour. After the reaction was complete, saturated KF solution was added, the mixture was stirred at room temperature for 0.5 hours, liquid-liquid was separated, and the mixture was extracted by DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 166a-1 (yellow oil, 120 mg) was obtained by normal-phase column chromatography (MeOH / DCM = 0-5%). MS m / z (ESI): 731.7. [M+H] + .

[0204] Step 2: Refer to Step 2 of intermediate 3b to prepare compound 166a. MS m / z(ESI): 631.5[M+H] + .

[0205] Intermediate 176a [ka]

[0206] Step 1: Compound 165c (200 mg, 0.27 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (112 mg, 0.54 mmol), catalyst Pd(PPh3)4 (16 mg, 0.014 mmol), K2CO3 (112 mg, 0.81 mmol), and 1,4-dioxane / H2O (v / v=6 / 1, 7 mL) were added to a microwave tube. After addition was complete, the mixture was bubbling with a nitrogen balloon for 1 minute, and the reaction was carried out at 130°C under microwave for 1 hour. After the reaction was complete, water was added and the mixture was separated, extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and then compound 176a-1 was obtained by normal-phase column chromatography (DCM / MeOH=0~5%). MS m / z (ESI): 744.8 [M+H] + .

[0207] Step 2: Compound 176a-1 (50 mg, 0.067 mmol) and solvent DCM (4 mL) were added to the reaction flask, then TFA (2 mL) was added, and the mixture was stirred at 20°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated, diluted with DCM, washed with saturated sodium bicarbonate until the pH was 7-8, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 176a. MS m / z (ESI): 644.5 [M+H] + .

[0208] Intermediate 177a [ka]

[0209] Step 1: Compound 132c-3 (200 mg, 0.28 mmol), hydrazine hydrate (33 mg, 0.56 mmol), and DCM (6 mL) were added to a three-necked flask. Under N2 protection, CDI (48.6 mg, 0.3 mmol) was added in an ice bath, and the mixture was reacted at 20°C for 1 hour. After the reaction was complete, water was added, and the mixture was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 177a-1 (yellow solid, 120 mg) was obtained by normal-phase column chromatography (DCM / MeOH = 0-5%). MS m / z (ESI): 722.5 [M+H] + .

[0210] Step 2: Compound 177a-1 (70 mg, 0.09 mmol), triethyl orthoacetate (73 mg, 0.45 mmol), and solvent NMP (3 mL) were added to a reaction flask and stirred at 150°C for 1 hour under an air atmosphere. After the reaction was complete, the mixture was concentrated and then obtained compound 177a-2 (yellow oil, 60 mg) by normal-phase column chromatography (DCM / MeOH = 0-5%). MS m / z (ESI): 746.7.[M+H] + 。

[0211] Step 3: Refer to Step 2 for intermediate 3b to prepare compound 177a. MS m / z(ESI): 646.5.[M+H] + .

[0212] Intermediate 193a [ka]

[0213] Step 1: Compounds 165c (550 mg, 0.74 mmol), 193a.1 (431 mg, 1.11 mmol), catalyst Pd(PPh3)4 (45 mg, 0.04 mmol), and DMF (8 mL) were added to a microwave tube. The mixture was bubbling with a nitrogen balloon for 1 minute, and the reaction was carried out at 150°C under microwave for 1 hour. After the reaction was complete, saturated KF solution was added, the mixture was stirred at room temperature for 0.5 hours, liquid-liquid separated, extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. K2CO3 and methanol were added, the mixture was stirred at room temperature for 0.5 hours, filtered, and concentrated again. Compound 193a-1 (yellow solid, 230 mg) was obtained by normal-phase column chromatography (DCM / MeOH = 0-5%). MS m / z (ESI): 688.5.[M+H] + .

[0214] Step 2: Compound 193a-1 (150 mg, 0.22 mmol), TMSN3 (34 mg, 0.264 mmol), CuSO4 (3 mg, 0.02 mmol), sodium ascorbate (4 mg, 0.02 mmol), and solvents DMF, water, and t-BuOH (3 mL, v / v / v=1 / 1 / 1) were added to the reaction flask. The mixture was then stirred at 20°C for 2 hours under an air atmosphere. After the reaction was complete, the mixture was filtered, DCM and water were added, and the mixture was separated. Extraction was performed with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Compound 193a-2 (yellow solid, 130 mg) was obtained by normal-phase column chromatography (MeOH / DCM=0~5%). MS m / z(ESI): 817.8.[M+H] + .

[0215] Step 3: Compound 193a-2 (130 mg, 0.16 mmol), solvent THF (2 mL), and one drop of water were added to the reaction flask. A 1.0 M TBAF (1 mL, 1 mmol) solution in THF was added dropwise over an ice bath, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction was complete, DCM and H2O were added, the mixture was separated, extracted with DCM, dried, and concentrated. Compound 193a-3 (yellow oil, 80 mg) was obtained by normal-phase column chromatography (DCM / MeOH = 0-5%). MS m / z (ESI): 746.1 [M + H] + 。

[0216] Step 4: Refer to Step 2 of 165a to prepare compound 193a. MS m / z(ESI): 645.9.[M+H] + .

[0217] Intermediate 210a [ka]

[0218] Step 1: Compound 165c (400 mg, 0.54 mmol), trimethyl((tributylstannyl)ethynyl)silane (313 mg, 0.81 mmol), catalyst Pd(PPh3)4, and DMF (8 mL) were added to a 20 mL microwave tube. After addition, the mixture was bubbling with a nitrogen balloon for 1 minute, and the reaction was carried out at 150°C under microwave for 1 hour. After the reaction was complete, saturated KF solution was added, the mixture was stirred at room temperature for 0.5 hours, liquid-liquid was separated, extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and then compound 210a-1 (yellow solid, 250 mg) was obtained by normal-phase column chromatography (DCM / MeOH = 0-5%). MS m / z (ESI): 761.2. [M+H] + .

[0219] Step 2: Compound 210a-1 (190 mg, 0.25 mmol), PMBN3 (49 mg, 0.3 mmol), and toluene were added to the reaction flask. The mixture was then stirred at 130°C for 16 hours under an air atmosphere. After the reaction was complete, the mixture was concentrated and then analyzed by normal-phase column chromatography (MeOH / DCM = 0-5%) to obtain compound 210a-2 (yellow solid, 200 mg). MS m / z (ESI): 923.4. [M+H] + .

[0220] Step 3: Add compound 210a-2 (200 mg, 0.22 mmol) and solvent DCM to the reaction flask, add TFA dropwise in an ice bath, stir at 65°C for 2 hours, and after the reaction is complete, concentrate, dilute with DCM, wash with saturated sodium bicarbonate until pH = 7-8, extract with DCM, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and then purify and separate by prep-HPLC to obtain 210a-3 (pale yellow solid, 90 mg, hydrochloride). MS m / z (ESI): 704.1.[M+H] + .

[0221] Step 4: Compound 210a-3 (80 mg, 0.11 mmol), K2CO3 (45.5 mg, 0.33 mmol), and solvent MeOH were added to the reaction flask. The mixture was then stirred at 65°C for 2 hours under an air atmosphere. After the reaction was complete, the mixture was filtered and concentrated. Compound 210a was obtained by normal-phase column chromatography (DCM / MeOH = 0-20%). MS m / z (ESI): 631.8. [M+H] + .

[0222] Preparation of the intermediate represented by general formula (a) [ka]

[0223] Referring to the method shown in any one of Examples 3a to 46a, an intermediate compound of general formula (a) was prepared using appropriate substituted nitrobenzenes and amines as raw materials, as shown in Table 3 below.

[0224] [Table 3]

[0225] Intermediate 1b [ka]

[0226] Step 1: Compound 1 (5.0 g, 15.5 mmol), buto-3-in-1-ol (3.25 g, 46.5 mmol), Pd(PPh3)2Cl2 (0.22 g, 0.31 mmol), and cuprous iodide (0.12 g, 0.62 mmol) were added to a reaction flask, followed by the addition of anhydrous DMF (60 mL) and triethylamine (10 mL). The mixture was gradually heated to 90°C under a nitrogen atmosphere and stirred for 16 hours. After complete reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure until dry. Ethyl acetate and petroleum ether were then added to form a slurry, which was filtered by suction. The filtrate cake was dissolved in a mixed solution of dichloromethane and methanol, and the crude product was separated by normal-phase column purification to obtain Compound 1b-1 (pale yellow solid, 6.0 g). MS m / z (ESI): 313.2 [M+H] + .

[0227] Step 2: Compound 1b-1 (5.7 g, 18.2 mmol), triethylamine (9.2 g, 91 mmol), and anhydrous dichloromethane (1600 mL) were added together to the reaction flask, and then methylsulfonyl chloride (6.0 g, 54.6 mmol) was gradually added dropwise in an ice bath. After the addition was complete, the mixture was stirred in an ice bath for 1 hour. After complete reaction, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was slurryed with petroleum ether:ethyl acetate and filtered to obtain target compound 1b (pale yellow solid, 4.5 g), which was used directly in the next reaction. MS m / z (ESI): 391.2 [M+H] + .

[0228] Intermediate 3b [ka]

[0229] Step 1: At 25°C, compound 3-(4-hydroxy-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate tert-butyl (350 mg, 971.25 μmol) was added to a solution of 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate tert-butyl (248.01 mg, 971.25 μmol) in THF (10 mL). Then, under nitrogen gas conditions, azodicarbonamide (83.62 mg, 485.62 μmol) and tributylphosphine (98.25 mg, 485.62 μmol, 119.82 μL) were gradually added, and the reaction was carried out at room temperature with stirring for 8 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain compound 3b-1. MS m / z (ESI): 398.2 [M + H - 200] + .

[0230] Step 2: Under conditions of 25°C, trifluoroacetic acid (2.70 mmol, 0.2 mL) was added to a 1 mL solution of compound 3b-1 (100 mg, 167.31 μmol) in dichloromethane, and the mixture was reacted for 1 hour with stirring. The reaction mixture was concentrated under reduced pressure to obtain compound 3b. The crude product was used directly in the next reaction. MS m / z (ESI): 398.2 [M + H] + .

[0231] Intermediate 4b [ka]

[0232] Step 1: Compound 3d (500 mg, 1.47 mmol) and compound pent-4-in-1-ol (247 mg, 2.93 mmol) were dissolved in DMF (6 mL). Et3N (1.06 mL, 7.33 mmol), CuI (56 mg, 0.29 mmol), and Pd(PPh3)2Cl2 (103 mg, 0.15 mmol) were added while stirring. The reaction was carried out at 100°C for 16 hours with stirring under nitrogen gas protection until complete. The reaction solution was poured into ice water, the aqueous phase was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, the filtration cake was dissolved, and the title compound 4b-1 (white solid, 400 mg) was obtained by column chromatography (methanol / dichloromethane: 5%~10%). MS m / z (ESI): 345.3 [M+H] + .

[0233] Step 2: Compound 4b-1 (200 mg, 0.58 mmol) was dissolved in EtOH / EA / MeOH (1:1:0.5, 25 mL). Wet Pd / C (40 mg) was added while stirring under nitrogen gas protection. The reaction was terminated by stirring at 60°C for 16 hours under hydrogen gas protection. The reaction system was filtered, and the filtrate was concentrated to obtain compound 4b-2 (white solid, 202 mg), which was used directly in the next reaction. MS m / z (ESI): 349.3 [M+H] + .

[0234] Step 3: Compound 4b-2 (200 mg, 0.574 mmol) was dissolved in a solution of DCM (10 mL) and THF (20 mL). Et3N (0.5 mL, 3.44 mmol) and MsCl (197 mg, 0.14 mL, 1.72 mmol) were added while stirring, and the mixture was reacted at room temperature for 2 hours with stirring. After the reaction was complete, the reaction mixture was diluted with water and quenched, then extracted with DCM, the organic layers were combined, the organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting solid was slurryed with PE:EA = 10:1 (20 mL), filtered, and the filtered cake was dried under vacuum to obtain compound 4b. MS m / z (ESI): 427.2 [M + H] + .

[0235] Intermediate 5b [ka]

[0236] Compound 5b was obtained by referring to the method for intermediate 4b. MS m / z(ESI): 427.5[M+H] + .

[0237] Intermediate 27b [ka]

[0238] Compound 27b was prepared referring to Example 21c. MS m / z(ESI): 540.3[M+H] + .

[0239] Intermediate 43b [ka]

[0240] Compound 43b was prepared by referring to the method for producing intermediate 21c. MS M / Z(ESI): 616.1, 618.1[M+H] + .

[0241] Intermediate 44b [ka]

[0242] Compound 44b was prepared by referring to step 4 of intermediate 21c. MS m / z(ESI): 542.2[M+H] + .

[0243] Intermediate 51b [ka]

[0244] Step 1: To a solution of 5-nitro-1H-indazole (3 g, 18.39 mmol) in anhydrous tetrahydrofuran (30 mL), tetrabutylammonium bisulfate (100 mg, 294.52 μmol) and sodium hydride (1.84 g, 45.97 mmol, 60% purity) were added. The mixture was then stirred at 25°C for 1 hour, after which benzenesulfonyl chloride (3.57 g, 20.23 mmol, 2.59 mL) was added, and the reaction was carried out at 25°C with stirring for 11 hours. After the reaction was complete, the reaction was quenched with aqueous ammonium chloride at 0°C, the reaction mixture was extracted with water and ethyl acetate and separated into layers, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 51b-1 (brown solid, 3 g). MS m / z (ESI): 304.0 [M+H] + .

[0245] Step 2: Refer to Step 3 of 45c to obtain compound 51b-2. MS m / z(ESI): 273.8[M+H] + .

[0246] Step 3: NIS (1.98 g, 8.78 mmol) was added to a solution of 51b-2 (2 g, 7.32 mmol) in acetonitrile (8 mL), and the reaction was carried out at 25°C for 1 hour with stirring. After the reaction was complete, the reaction mixture was filtered directly and concentrated under reduced pressure to obtain compound 51b-3. MS m / z (ESI): 399.8 [M+H] + .

[0247] Steps 4-5: Refer to steps 1-2 of 12c to obtain compound 51b-5. MS m / z(ESI): 495.8[M+H] + .

[0248] Steps 6-7: Refer to steps 3-4 of 21c to prepare compound 51b-7. MS m / z(ESI): 708.1[M+H] + .

[0249] Step 8: To a mixture of 5 mL of anhydrous tetrahydrofuran (560 mg, 225.94 μmol) of 51b-7 and water (1 mL), sodium hydroxide (18.07 mg, 451.87 μmol) was added, and the mixture was stirred at 80°C for 5 hours. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to obtain the crude product. Compound 51b was obtained by normal-phase purification of the crude product. MS m / z (ESI): 568.2 [M + H] + .

[0250] Intermediate 52b [ka]

[0251] Step 1: 103c-1 (6.39 g, 17.12 mmol) and CuCN (7.67 g, 85.61 mmol, 18.70 mL) were added to DMF (50 mL) and reacted in an autoclave at 140°C with stirring for 72 hours. After the reaction was complete, the reaction mixture was diluted with water, further extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated, separated and purified by column chromatography (PE / EA = 5 / 1 to 2 / 1) to obtain compound 52b-1 (yellow solid, 2.80 g). MS m / z (ESI): 320.1 [M+H] + .

[0252] Step 2: Refer to Step 3 of 45c to obtain compound 52b-2. MS m / z(ESI): 290.2[M+H] + .

[0253] Step 3: Compounds 52b-2 and 52b-2 were added to a solution of tetrahydrofuran (25 mL), then sodium tert-butoxide (1.46 g, 15.21 mmol) and tBuXPhosPdG3 (604.02 mg, 760.38 μmol) were added, and the mixture was reacted at 65°C for 12 hours with stirring. After the reaction was complete, the reaction mixture was diluted with water, then extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was separated and purified by silica gel column (PE / EA = 100 / 1 to 25 / 1) to obtain compound 52b-3. MS m / z (ESI): 569.2 [M + H] + .

[0254] Step 4: Refer to Step 4 of intermediate 21c to prepare compound 52b. MS m / z(ESI): 525.0[M+H] + .

[0255] Intermediate 54b [ka]

[0256] Step 1: 2,2,6,6-tetramethylpiperidine (1.7 g, 12 mmol) and anhydrous THF (50 mL) were added together to a 250 mL three-necked flask. The reaction system was then cooled to -45°C under nitrogen gas protection, and n-butyllithium (4.8 mL, 12 mmol, 2.5 M) was gradually added dropwise. After the addition was complete, the mixture was maintained at -45°C and stirred for 1 hour. Next, a solution of 3-bromo-4-fluorobenzoic acid (2.2 g, 10 mmol) in THF (10 mL) was gradually added dropwise. After the addition was complete, the mixture was stirred at the same temperature for 5 hours. Finally, CH3I (0.79 mL, 12 mmol) was gradually added dropwise, and the reaction was gradually raised to room temperature and allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was quenched at 0°C by dilution with 3N HCl, then extracted with EA, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-10%) to obtain compound 54d-1. MS m / z(ESI): 233.1[M+H] + 。

[0257] Step 2: Compound 54d-1 (1500 mg, 6.44 mmol) was dissolved in a single-necked flask containing 20 mL of anhydrous MeOH. SOCl2 (920 mg, 1.29 mmol) was then gradually added dropwise in an ice bath. After the addition was complete, the temperature was gradually increased until reflux was achieved, and the mixture was stirred for 2 hours. The reaction was completed, and the mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (EA / PE = 0-5%) to obtain compound 54d-2. MS m / z (ESI): 247.1 [M+H] + 。

[0258] Steps 3-4: Refer to steps 2-3 for intermediate 3d to prepare compound 54d. MS m / z(ESI): 341.2[M+H] + 。

[0259] Steps 5-6: Refer to steps 1-2 of intermediate 1b to prepare compound 54b. MS m / z(ESI): 409.1[M+H] + .

[0260] Intermediate 56b [ka]

[0261] Referencing steps 3 and 4 of intermediate 21c, compound 56b was obtained. MS M / Z(ESI): 630.2, 632.2[M+H] +

[0262] Intermediate 61b [ka]

[0263] Step 1: 52b-3 (900 mg, 1.58 mmol) was added to a mixed solution of dimethyl sulfoxide (3 mL), ethanol (6 mL), and water (0.6 mL). At 0°C, aqueous sodium hydroxide solution (2 M, 3.95 mL) and hydrogen peroxide (31.63 mmol, 3.04 mL, 30% purity) were added, and the mixture was reacted at 25°C for 72 hours with stirring. After the reaction was complete, the reaction mixture was quenched with sodium thiosulfate, further extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 61b-1. MS m / z (ESI): 587.1 [M + H] +

[0264] Step 2: Refer to Step 4 of intermediate 21c to prepare compound 61b. MS m / z(ESI): 543.1[M+H] + .

[0265] Intermediate 65b [ka]

[0266] Step 1: Compound 6-bromo-1H-indazole-3-amine (1.0 g, 4.74 mmol) was dissolved in DMF and cooled to 0°C. Then NaH (284 mg, 7.1 mmol) was added and the reaction was carried out at 0°C for 20 minutes. Iodomethane (1007 mg, 7.1 mmol) was then added, and the reaction system was carried out at 25°C for 16 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was washed with saline solution, dried and concentrated over anhydrous sodium sulfate, and purified by column chromatography (MeOH / DCM ~10%) to obtain compound 65b-1. MS m / z (ESI): 226.1 [M + H] +

[0267] Step 2: Compound 65b-1 (575 mg, 1.47 mmol) was dissolved in acetic acid (5 mL) and water (5 mL), acrylic acid (212 mg, 2.94 mmol) was added, and the mixture was heated to 105°C and reacted for 4 hours. Then, saturated sodium bicarbonate aqueous solution was added to adjust the pH to 5, and the mixture was extracted by DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography (MeOH / DCM ~10%) to obtain 65b-2. MS m / z (ESI): 299.1 [M + H] +

[0268] Step 3: Compound 65b-2 (290 mg, 0.97 mmol) was dissolved in acetic acid (5 mL), urea (30.5 mg, 1.95 mmol) was added, and the mixture was heated to 120°C and reacted for 4 hours. Then concentrated hydrochloric acid was added, and the mixture was heated and refluxed for 30 minutes. The solvent was dried by rotation, and saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7. The mixture was extracted by DCM, and the organic phase was dried over anhydrous sodium sulfate to concentrate it. The mixture was purified by column chromatography (MeOH / DCM ~10%) to obtain compound 65b-3. MS m / z (ESI): 323.1 [M + H] +

[0269] Steps 4-6: Refer to steps 1-3 of intermediate 4b to prepare compound 65b. MS m / z(ESI): 409.2[M+H] + .

[0270] Intermediate 73b [ka]

[0271] Compound 73b was prepared by referring to Step 1 of Example 3d for Step 1 and Step 2 of Example 1b for Step 2. MS m / z(ESI): 405.1[M+H] + .

[0272] Intermediate 77b [ka]

[0273] Step 1: Refer to Step 1 of intermediate 8a to prepare compound 77b-1. MS m / z(ESI): 377.1.[M+H] +

[0274] Step 2: Compound 77b-2 was prepared by referring to the preparation of intermediate 5d. MS m / z(ESI): 325.1.[M+H] +

[0275] Step 3: Refer to Step 3 of intermediate 46a to prepare compound 77b-3. MS m / z(ESI): 327.1.[M+H] +

[0276] Step 4: Refer to Step 2 of intermediate 7a to prepare compound 77b-4. MS m / z(ESI): 297.1.[M+H] +

[0277] Steps 5-6: Refer to steps 3-4 of intermediate 21c to prepare compound 77b. MS m / z(ESI): 532.2[M+H] +

[0278] Intermediate 79b [ka]

[0279] Step 1: Ammonium chloride (1.22 g, 22.73 mmol), diisopropylethylamine (2.94 g, 22.73 mmol, 3.96 mL), and HATU (4.32 g, 11.36 mmol) were added to a solution of 79d (2 g, 7.58 mmol) in DMF (20 mL), and the mixture was reacted at 25°C for 4 hours with stirring. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain the title compound 79b-1 (yellow solid, 1.80 g). MS m / z (ESI): 263.1 [M+H] +

[0280] Step 2: Triethylamine (9.12 mmol, 1.27 mL) was added to a solution of 79b-1 (1.6 g, 6.08 mmol) in anhydrous tetrahydrofuran (50 mL) at 0°C. Then, anhydrous trifluoroacetic acid (9.12 mmol, 1.27 mL) was gradually added, and the reaction was carried out at 25°C with stirring for 2 hours. After the reaction was complete, the reaction mixture was extracted with water and ethyl acetate to separate the layers, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 79b-2 (yellow solid, 1.5 g, crude product). MS m / z (ESI): 245.1 [M+H] +

[0281] Step 3: To a solution of 79b-2 (800 mg, 3.27 mmol) in isopropanol (10 mL), diisopropylethylamine (422.01 mg, 3.27 mmol, 568.75 μL) and 1,4-dioxa-8-azaspiro[4.5]decane (467.53 mg, 3.27 mmol, 417.43 μL) were added, and the mixture was reacted at 100°C for 1 hour with stirring. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the title compound 79b-3 (yellow solid, 1.00 g, crude product). MS m / z (ESI): 367.9 [M+H] +

[0282] Step 4: Refer to intermediate 5d and prepare compound 79b-4. MS m / z(ESI): 316.1[M+H] +

[0283] Step 5: Refer to Step 4 of intermediate 94c to prepare compound 79b-5. MS m / z(ESI): 288.1[M+H] +

[0284] Step 6: 2,5-Dichloro-N-(2-dimethylphosphorophenyl)pyrimidine-4-amine (242.02 mg, 765.60 μmol), 79b-5 (220 mg, 765.60 μmol), tris(dibenzylideneacetone)dipalladium (70.11 mg, 76.56 μmol), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (44.3 mg, 76.56 μmol), and cesium carbonate (498.89 mg, 1.53 mmol) were added to a solution of 1,4-dioxane (2 mL), and the mixture was reacted under a nitrogen atmosphere at 100°C with stirring for 8 hours. After the reaction was complete, the mixture was extracted with water and ethyl acetate, separated into layers, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 79b-6. MS m / z (ESI): 567.2 [M+H] +

[0285] Step 7: Refer to Step 4 of intermediate 21c to prepare compound 79b. MS m / z(ESI): 523.1[M+H] + .

[0286] Intermediate 80b [ka]

[0287] Step 1: Compound piperazine-1-carboxylate tert-butyl (1 g, 5.37 mmol) and compound 4-bromobuto-1-yin (785 mg, 5.91 mmol) were dissolved in CH3CN (20 mL), and then K2CO3 (1.11 g, 8.05 mmol) was added. The reaction system was stirred at 60°C for 8 hours until the reaction was complete. The reaction system was concentrated, EA and H2O were added to the residue, the aqueous phase was further extracted with EA, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (EA / PE: ~20%) to obtain the colorless oily compound 80b-1 (colorless oily liquid, 950 mg).

[0288] Step 2: Compound 80b-2 was prepared by referring to Step 1 of intermediate 1b. MS m / z(ESI): 481.5[M+H] +

[0289] Step 3: Compound 80b was prepared by referring to Step 2 of intermediate 3b. MS m / z(ESI): 381.5[M+H] + .

[0290] Intermediate 93b [ka]

[0291] Step 1: Add NBS (5.29 g, 29.74 mmol) to a solution of 2-methoxy-4-nitroaniline (5 g, 29.74 mmol) in dichloromethane (50 mL) at 0°C, and then react at 25°C with stirring for 4 hours. After the reaction was complete, the reaction was concentrated under reduced pressure, and then purified by normal-phase separation (PE / EA = 1:0 to 5:1) to obtain the title compound 93b-1 (yellow solid, 3 g). 1 HNMR(400MHz,DMSO-d6)δ=7.97(d,J=2.1Hz,1H),8.20-7.88(m,1H),7.58(d,J=2.0Hz,1H),6.41(brs,2H),4.18-3.70(m,3H).MS m / z(ESI):247.1[M+H] + .

[0292] Step 2: At 0°C, 93b-1 (2g, 8.10 mmol) and sodium nitrite (1.40g, 20.24 mmol) were dissolved in hydrochloric acid (40 mL). Cuprous chloride (1.60g, 16.19 mmol, 387.18 μL) was then added, and the temperature was raised to 25°C. The reaction was carried out for 5 hours with stirring under nitrogen gas protection. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and purified by normal-phase separation (PE / EA = 1:0~10:1) to obtain the title compound 93b-2 (white solid, 2g). MS m / z (ESI): 266.1 [M+H] + .

[0293] Step 3: Add 20 mL of dimethyl sulfoxide (2.15 g, 15.01 mmol) of 93b-2 (2 g, 7.51 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (2.15 g, 15.01 mmol) to N,N-diisopropylethylamine (2.91 g, 22.52 mmol), and then react at 80°C for 1 hour with stirring. After the reaction was complete, the reaction mixture was diluted with water, extracted with EA, and purified by normal-phase separation (PE / EA = 1:0 to 5:1) to obtain the title compound 93b-3 (yellow solid, 2.3 g). MS m / z (ESI): 373.1 [M + H] + .

[0294] Step 4: Compound 93b-4 was prepared by referring to intermediate 5d. MS m / z(ESI): 321.1[M+H] + .

[0295] Step 5: Refer to Step 2 of intermediate 3a to prepare compound 93b-5. MS m / z(ESI): 293.1[M+H] + .

[0296] Steps 6-7: Refer to steps 3-4 of 21c to prepare compound 93b. MS m / z(ESI): 528.4[M+H] +

[0297] Intermediate 97b [ka]

[0298] Compound 97b was prepared by referring to step 2 of intermediate 1b. MS m / z(ESI): 405.2[M+H] + .

[0299] Intermediate 106b [ka]

[0300] Step 1: Compound 106b-1 was prepared referring to the synthesis of Example C-1. MS m / z (ESI): 318.1 [M+H] + .

[0301] Step 2: Compound 106b was prepared by referring to Step 2 of intermediate 1b. MS m / z(ESI): 396.8[M+H] +

[0302] Intermediate 109b [ka]

[0303] Step 1: Compound 109b-1 was prepared by referring to Step 1 of intermediate 114d. MS m / z(ESI): 331.2[M+H] + .

[0304] Step 2: Refer to Step 2 of intermediate 3a to prepare compound 109b-2. MS m / z(ESI): 333.1[M+H] + .

[0305] Step 3: Compound 109b was prepared by referring to Step 2 of intermediate 1b. MS m / z(ESI): 411.2[M+H] + .

[0306] Intermediate 111b: [ka]

[0307] Step 1: Compound 9-oxo-3-azaspiro[5.5]undecane-3-formate tert-butyl (3000 mg, 11.22 mmol) and anhydrous THF (30 mL) were added together to a three-necked reaction flask. Under a nitrogen atmosphere, NaBH4 (849 mg, 22.44 mmol) was added in several portions in an ice bath. After the addition was complete, the mixture was heated to room temperature and stirred overnight. After the reaction was complete, anhydrous Na2SO4 was added to the reaction mixture, followed by the gradual addition of water to quench the reaction. The mixture was filtered by suction, washed with DCM, and the filtrate was concentrated to obtain crude product 111a-1 (pale yellow oily substance, 3000 mg). The crude product was used directly in the next reaction.

[0308] Step 2: Compound 111a-2 was prepared by referring to Step 1 of intermediate 110d.

[0309] Step 3: Refer to Step 2 of intermediate 3b to prepare compound 111a-3.

[0310] Step 4: Compound 111a-4 was prepared by referring to Step 1 of intermediate 3a. MS m / z(ESI): 499.6[M+H] +

[0311] Step 5: Compound 111a-5 was prepared following the procedure for intermediate 5d. MS m / z(ESI): 447.8[M+H] +

[0312] Step 6: Compound 111a was prepared by referring to Step 2 of intermediate 3a. MS m / z(ESI): 419.7[M+H] +

[0313] Step 7: Compound 111b-1 was prepared by referring to Step 1 of intermediate 4c. MS m / z(ESI): 699.0[M+H] +

[0314] Step 8: Compound 111b-2 was prepared by referring to Step 2 of intermediate 110d. MS m / z(ESI): 656.2[M+H] +

[0315] Step 9: Refer to Step 2 of Intermediate 1b to prepare Compound 111b. MS m / z(ESI): 734.3[M+H] +

[0316] Intermediate 145b [ka]

[0317] Compound 145b was prepared following the method for intermediate 65b. MS m / z(ESI): 391.2[M+H] + .

[0318] Intermediate 155b [ka]

[0319] Compound 155b was prepared following the method for intermediate 4b. MS m / z(ESI): 409.2[M+H] + .

[0320] Intermediate 159b [ka]

[0321] Step 1: 3-(benzyloxy)cyclobutan-1-one (4.73 g, 26.84 mmol) and tert-butylpiperazine-1-carboxylate (5 g, 26.84 mmol) were dissolved in MeOH (150 mL) solution, AcOH (8.06 g, 134.21 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Next, NaBH3CN (5.06 g, 80.53 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. After the reaction was complete, saturated NaHCO3 solution was added to quench the mixture, then water and DCM were added for extraction and layering. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain compound 159b-1 (colorless oily substance, 6.5 g).1 HNMR(500MHz,CDCl3)δ7.38-7.30(m,5H),4.42(s,2H),3.83-3.73(m,1H),3.47-3.37(m,4H),2.44-2 .40(m,2H),2.33-2.22(m,5H),2.18-2.14(m,1H),1.90-1.82(m,2H),1.72(brs,1H),1.45(s,9H).MS m / z(ESI):257.2[M+H] + .

[0322] Step 2: Compound 159b-1 (6.5 g, 18.76 mmol) was dissolved in methanol solution (80 mL). Catalytic amounts of acetic acid (0.5 mL), Pd / C (2 g), and Pd(OH)2 / C (1 g) were added under nitrogen gas protection. The mixture was then purged with hydrogen gas and reacted at 45°C for 48 hours with stirring under hydrogen balloon protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and then purified by column chromatography (MeOH / DCM: 3%~10%) to obtain compound 159b-2 (colorless oil, 3 g). MS m / z (ESI): 409.2 [M+H] + .

[0323] Step 3: Compound 159b-2 (95 mg, 0.36 mmol) and Compound 3 (80 mg, 0.3 mmol) were dissolved in THF (10 mL), and PPh3 (242 mg, 0.9 mmol) and DIAD (187 mg, 0.9 mmol) were added. The mixture was reacted for 16 hours at room temperature with stirring under nitrogen gas protection. After the reaction was complete, the reaction mixture was extracted with water and EA, the organic phase was dried and concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-TLC (DCM:MeOH = 15:1) to obtain Compound 159b-3 (pale yellow solid, 75 mg). MS m / z (ESI): 499.2 [M + H] + .

[0324] Step 4: Refer to Step 2 of intermediate 3b to prepare compound 159b. MS m / z(ESI): 399.2[M+H] + .

[0325] Intermediate 163b [ka]

[0326] Step 1: Add 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300 mg, 1.16 mmol) to the reaction flask, add NMP (3 mL), then add DIEA (0.5 mL) and 1,2-dibromoethane (1007 mg, 5.8 mmol), raise the temperature to 80°C and stir for 16 hours. Add water to the reaction mixture, extract with DCM, dry over anhydrous sodium sulfate and concentrate, concentrate the reaction mixture and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 163b-1 (white solid, 200 mg). MS m / z (ESI): 366.2, 368.2 [M+H] + .

[0327] Step 2: Compound 163b-1 (100 mg, 0.27 mmol) was dissolved in acetonitrile (5 mL) and water (0.1 mL). A 37% aqueous formaldehyde solution (0.5 mL, 6.1 mmol) was added, and the mixture was stirred at 20°C for 2 hours. Then NaCNBH3 (80 mg, 1.4 mmol) was added, and the mixture was stirred at 20°C for 16 hours. After the reaction was complete, water was added to quench the mixture, and it was extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated. The reaction mixture was concentrated and then purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 163b (white solid, 45 mg). MS m / z (ESI): 382.0 [M+H] + .

[0328] Example 207b [ka]

[0329] Step 1: Compound 4c (400 mg, 0.67 mmol) was dissolved in DMF (8 mL), followed by the addition of methyl 2-bromo-2-methylpropionate (145 mg, 0.80 mmol) and K2CO3 (185 mg, 1.34 mmol), respectively. After the addition was complete, the temperature was raised to 80°C and the mixture was stirred for 16 hours. After the completion of the reaction was detected by LC-MS, the reaction solution was filtered by suction, and the filtrate was rotated dry under reduced pressure. The crude product was separated by normal-phase column chromatography (MeOH / DCM = 0-5%) to obtain crude product compound 207b-1 (pale yellow solid, 300 mg, yield 63%). MS m / z (ESI): 697.3 [M+H] + .

[0330] Step 2: Referring to the synthesis method of Step 2 of Example 110d, title compound 207b-2 (pale yellow oily substance, 130 mg, yield 45%) was prepared. The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 669.3 [M+H] + .

[0331] Step 3: Referring to the synthesis method of Step 2 of Example 1b, title compound 207b (130 mg, 90% yield) was prepared. MS m / z (ESI): 747.3 [M+H] + .

[0332] Intermediate 209b [ka]

[0333] Step 1: Compound 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1000 mg, 3.80 mmol), pinacol diboronate (1100 mg, 4.10 mmol), and anhydrous acetonitrile (20 mL) were added together to a single-necked flask. While stirring, tert-butyl nitrite (600 mg, 5.70 mmol) was gradually added, and after the addition was complete, the mixture was stirred at room temperature for 5 hours. After complete reaction, the reaction mixture was evaporated directly under reduced pressure and homogeneously mixed with silica gel. The crude product was separated by normal-phase column chromatography to obtain compound 209b-1 (pale yellow solid, 700 mg). MS m / z (ESI): 371.2 [M+H] + .

[0334] Step 2: Compound 209b-1 (500 mg, 1.40 mmol), tetrahydrofuran (8 mL), and water (2 mL) were added to a single-necked flask, and sodium periodate (870 mg, 4.20 mmol) was gradually added while stirring well. After the addition was complete, the mixture was stirred at room temperature for 2 hours, then a 1 N dilute HCl (2 mL) solution was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was evaporated under reduced pressure, then dichloromethane and water were added, the mixture was stirred at room temperature for 1 hour, filtered by suction, washed with water, and freeze-dried to obtain compound 209b (pale yellow solid, 320 mg). 1 HNMR (500MHz, DMSO-d 6) δ10.97(s,1H),8.33(s,2H),8.03(d,J=7.3Hz,1H),7.76(d,J=7.3Hz,1H),7.50(t,J=7.4Hz,1H),5.13(dd,J=13.3,5.1Hz,1H) ,4.54(d,J=18.1Hz,1H),4.45(d,J=18.1Hz,1H),2.94-2.86(m,1H),2.62-2.56(m,1H),2.45-2.37(m,1H),2.04-1.98(m,1H). MS m / z(ESI):289.5[M+H] +

[0335] Intermediate 223b [ka]

[0336] Steps 1 and 2: Refer to steps 2 and 3 of intermediate 3d to prepare compound 223b-2. MS m / z (ESI): 290.2 [M+H] + .

[0337] Step 3: Refer to Step 2 of intermediate 3a to prepare compound 223b-3. MS m / z(ESI): 260.2[M+H] + .

[0338] Steps 4 and 5: Compound 223b was prepared by referring to steps 1 and 2 of intermediate 163b. MS m / z(ESI): 382.2[M+H] + .

[0339] Preparation of the compound represented by general formula (a-2) [ka]

[0340] Using a suitable lenalidomide derivative as a raw material, an intermediate compound of general formula (a-2) was prepared by referring to one of the methods in Examples 1b, 3b, 4b, 5b to 223b, as shown in Table 4 below. [Table 4]

[0341] Intermediate 1c [ka]

[0342] Step 1: Compound 13a (300 mg, 0.80 mmol) was added to the reaction flask, followed by the addition of Compound 2 (252 mg, 0.80 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), Xant-phos (48 mg, 0.08 mmol), anhydrous Cs2CO3 (781 mg, 2.40 mmol), and anhydrous DMF (8 mL), respectively. After the addition was complete, the reaction system was purged three times with argon gas, and then the temperature was raised to 105°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was filtered and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) and rotated-dried to obtain Compound 1c-1. MS m / z (ESI): 655.3 [M+H] + .

[0343] Step 2: Compound 1c-1 (350 mg, 0.53 mmol) was added to a single-necked flask, followed by the addition of anhydrous dichloromethane (15 mL) and TFA (3 mL), respectively. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After complete reaction, the solvent was removed from the reaction mixture under reduced pressure, the crude product was dissolved in dichloromethane and methanol, and then saturated NaHCO3 solution was gradually added to the system to adjust the pH to approximately 8-9. Subsequently, the mixture was extracted with dichloromethane:methanol (10:1), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound 1c. MSm / z: 555.7 [M+H] + .

[0344] intermediate 3c [ka]

[0345] Compound 3c (brown solid) was prepared by referring to intermediate 21c. MS m / z(ESI): 500.3[M+H]+

[0346] Intermediate 4c [ka]

[0347] Step 1: Compound 3a (500 mg, 1.2 mmol), Compound 2 (628.5 mg, 1.5 mmol), and p-toluenesulfonic acid monohydrate (412 mg, 2.4 mmol) were added to a reaction flask, followed by the addition of i-PrOH (50 mL), and the mixture was stirred at 80°C for 16 hours. After concentrating the reaction mixture, a 5% NaOH solution was added, and the mixture was extracted with dichloromethane. The mixture was concentrated and purified by normal-phase column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 4c-1 (white solid, 500 mg). MS m / z (ESI): 698.6.[M+H] + .

[0348] Step 2: Compound 4c-1 (1.4 g, 20 mmol) was added to the reaction flask, followed by DCM (30 mL), and then TFA (6 mL) was added in sequence. After the addition was complete, the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated, saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The mixture was then concentrated to obtain compound 4c (white solid, 1 g). MS m / z (ESI): 598.7 [M+H] + .

[0349] Intermediate 7c [ka]

[0350] Compound 1d (200 mg, 0.55 mmol) and compound 5a (344 mg, 0.83 mmol) were added to a single-necked reaction flask, followed by the addition of TsOHH2O (477 mg, 2.77 mmol) and n-BuOH (10 mL). The flask was purged three times with argon gas, and then the temperature was raised to 140°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by column chromatography and rotated-dried to obtain compound 7c (pale yellow solid, 0.2 g). MS(ESI) m / z: 628.3 [M+H] +

[0351] Intermediate 9c [ka]

[0352] Compound 9c (brown solid, 140 mg) was prepared following the method for intermediate 4c. MS m / z (ESI): 568.7 [M+H] + .

[0353] Intermediate 10c [ka]

[0354] Compound 10c was prepared by referring to the method for intermediate 4c. MS m / z(ESI): 605.4[M+H] + .

[0355] Intermediate 11c [ka]

[0356] Compound 11c was prepared by referring to the method for intermediate 4c. MS m / z(ESI): 590.4[M+H] + .

[0357] Intermediate 12c [ka]

[0358] Step 1: To a solution of 1-iodonaphthalene-2-amine (10 g, 37.16 mmol) in 1,4-dioxane (100 mL), dimethylphosphorus oxide (2.90 g, 37.16 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (4.30 g, 7.43 mmol), palladium acetate (835.00 mg, 3.72 mmol), and potassium phosphate (15.80 g, 74.43 mmol) were added, and the mixture was reacted at 100°C for 10 hours with stirring. After the reaction was complete, the reaction mixture was extracted with water (80 mL) and dichloromethane to separate the layers. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 12c-1 (brown solid, 5.6 g). MS m / z (ESI): 220.3 [M+H] +

[0359] Step 2: To a solution of compound 12c-1 (3 g, 13.68 mmol) in n-butanol (30 mL), 5-bromo-2,4-dichloropyrimidine (5.02 g, 22.03 mmol, 2.82 mL) and N,N-diisopropylethylamine (3.54 g, 27.39 mmol, 4.77 mL) were added, and the mixture was reacted at 120°C for 8 hours with stirring. After the reaction was complete, the reaction mixture was filtered and washed with ethanol to obtain the title compound 12c-2 (white solid, 3.27 g). MS m / z (ESI): 409.9 [M+H] + .

[0360] Step 3: To a solution of compound 12c-2 (500 mg, 1.22 mmol) and compound 11a in isopropanol (5 mL), p-toluenesulfonic acid monohydrate (231.61 mg, 1.22 mmol) was added, and the mixture was reacted under a nitrogen atmosphere at 100°C for 6 hours with stirring. After the reaction was complete, the reaction mixture was adjusted to a pH of 9 with sodium bicarbonate solution, then extracted with water and dichloromethane to separate the layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 12c. MS m / z (ESI): 663.3 [M+H] + .

[0361] Intermediate 13c [ka]

[0362] Compound 13c was prepared by referring to intermediate 4c. MS m / z(ESI): 610.2[M+H] + .

[0363] Intermediate 14c [ka]

[0364] Compound 14c was prepared by referring to intermediate 4c. MS m / z(ESI): 559.1[M+H] + .

[0365] Intermediate 15c [ka]

[0366] Compound 15c was prepared by referring to intermediate 4c. MS m / z(ESI): 584.1[M+H] + .

[0367] Intermediate 17c [ka]

[0368] Compound 17c was prepared by referring to the method for intermediate 4c. MS m / z(ESI): 574.3[M+H] + .

[0369] Intermediate 18c [ka]

[0370] Compound 18c was prepared by referring to the method for intermediate 4c. MS m / z(ESI): 559.6[M+H]+ .

[0371] Intermediate 21c [ka]

[0372] Step 1: 1-Ethyl-2-fluoro-4-methoxy-5-nitrobenzene (1 g, 5.02 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (1.44 g, 10.04 mmol, 1.28 mL) were added to a solution of DMSO (10 mL), then Cs2CO3 (4.91 g, 15.06 mmol) was added, and the reaction was carried out at 110°C with stirring for 12 hours. After the reaction was complete, the reaction mixture was diluted with water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 25:1~1:1) to obtain compound 21c-1 (yellow oily, 1.34 g). MS m / z (ESI): 323.2 [M+H] +

[0373] Step 2: Compound 21c-1 (1.2 g, 3.72 mmol) was added to a solution of ethanol (30 mL), then wet Pd / C (200 mg, 10% purity) was added, and the reaction was carried out at 40°C under a hydrogen atmosphere with stirring for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to obtain compound 21c-2 (1.02 g, crude product). This was used directly in the next reaction. MS m / z (ESI): 293.2 [M+H] +

[0374] Step 3: Compound 21c-2 (300 mg, 1.03 mmol) and Compound 2 (324.37 mg, 1.03 mmol) were added to a solution of ethylene glycol (10 mL), then p-toluenesulfonic acid monohydrate (292.77 mg, 1.54 mmol) was added, and the mixture was reacted at 90°C with stirring for 12 hours. After the reaction was complete, the reaction mixture was neutralized with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified using a silica gel plate (dichloromethane:methanol = 15:1) to obtain compound 21c-3 (black solid, 100 mg). This was used directly in the next reaction. MS m / z (ESI): 572.3 [M + H] +

[0375] Step 4: Compound 21c-3 (90 mg, 157.33 μmol) was added to a mixed solution of water (4.5 mL) and acetic acid (4.5 mL) and reacted at 90°C with stirring for 2 hours. After the reaction was complete, the reaction mixture was neutralized with saturated sodium bicarbonate aqueous solution, extracted with DCM, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 21c. This compound was used directly in the next reaction. MS m / z (ESI): 528.3 [M+H] +

[0376] Intermediate 22c [ka]

[0377] Compound 22c was prepared by referring to steps 3 and 4 of intermediate 21c. MS m / z(ESI): 630.2[M+H] + .

[0378] Intermediate 23c [ka]

[0379] Compound 23c was prepared by referring to the method for intermediate 4c. MS m / z(ESI): 570.3[M+H] + .

[0380] Intermediate 28c [ka]

[0381] Compound 28c was prepared by referring to intermediate 4c. LCMS: m / z (ESI): 685.0, 687.0 [M+H] +

[0382] Intermediate 34c [ka]

[0383] Step 1: 2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.9 g, 19.70 mmol) was dissolved in dichloromethane (150 mL), to which DIEA, (Boc)2O (5.59 g, 25.61 mmol) was added. The reaction was then carried out at 25°C for 2 hours with stirring. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (100 mL), washed twice with hydrochloric acid, and then washed again with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 34c-1. MS m / z (ESI): 192.0 [M-55] +

[0384] Step 2: At 25°C, silver trifluoroacetate and elemental iodine (4.69 g, 18.48 mmol) were added to a solution of 34c-1 (4.57 g, 18.48 mmol) in dichloromethane (50 mL). The reaction was carried out at 25°C with stirring for 16 hours until complete. The reaction mixture was concentrated to obtain the crude product, compound 34c-2 (brown oily, 0.7 g). MS m / z (ESI): 318.0 [M-55] + .

[0385] Step 3: To a mixed solution of dimethyl sulfoxide (15 mL) of 34c-2 (1.75 g, 4.69 mmol) and water (7.5 mL), cuprous oxide (67.09 mg, 468.88 μmol), N,N-dimethylethanolamine (1.25 g, 14.07 mmol), and potassium hydroxide (789.27 mg, 14.07 mmol) were added, and the mixture was reacted at 100°C for 12 hours with stirring. After the reaction was complete, the reaction mixture was extracted with water and EA and separated into layers. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column (PE:EA = 100:1 to 10:1) to obtain the title compound 34c-3. MS m / z (ESI): 208.1 [M-55] +

[0386] Steps 4-7: Compound 34c was prepared by referring to steps 2-5 of intermediate 120c. MS m / z(ESI): 406.3[M+H] +

[0387] Intermediate 36c [ka]

[0388] Compound 36c was prepared by referring to step 2 of intermediate 4c. MS m / z(ESI): 394.1[M+H] +

[0389] Intermediate 42c [ka]

[0390] Step 1: Compound 42c-1 was prepared by referring to the synthesis method for intermediate 1d. MS m / z (ESI): 347.3 [M+H] + .

[0391] Steps 2-3: Compound 42c was prepared by referring to steps 1-2 of intermediate 4c. MS m / z (ESI): 629.9 [M+H] + .

[0392] Intermediate 45c [ka]

[0393] Step 1: Potassium tert-butoxide (1.99 g, 17.76 mmol) was added to a solution of methyltriphenylphosphonium bromide (6.35 g, 17.76 mmol) in anhydrous tetrahydrofuran (60 mL) at -20°C. The temperature was then raised to 0°C and the mixture was stirred for 0.5 hours. After stirring, a solution of 45d (3 g, 11.84 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise under a nitrogen atmosphere, and the reaction mixture was allowed to react at 25°C for 3 hours with stirring. After the reaction was complete, the mixture was quenched with an aqueous solution of ammonium chloride, the reaction mixture was extracted with water and ethyl acetate and separated into layers, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain compound 45c-1 (white oily, 2.38 g).

[0394] Step 2: 45c-1 (1.1g, 4.38 mmol), Compound 1 (1.56g, 4.81 mmol), potassium chloride (326.25mg, 4.38 mmol), tetrabutylammonium acetate (2.64g, 8.75 mmol, 2.67mL), palladium acetate (392.99mg, 1.75 mmol), and potassium carbonate (1.21g, 8.75 mmol) were added to a solution in DMF (10mL) and reacted at 100°C with stirring under an N2 atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered directly and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (formic acid-based) to obtain 45c-2 (yellow solid, 1g). MS m / z (ESI): 494.2 [M+H] + .

[0395] Step 3: Add 100 mg of wet palladium-carbon to a solution of 45c-2 (100 mg, 202.60 μmol) in anhydrous tetrahydrofuran (2 mL), and then react under a hydrogen atmosphere at 25°C for 1 hour with stirring. After the reaction was complete, the solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain compound 45c-2 (white solid, 92 mg). MS m / z (ESI): 396.1 [M + H - 100] + .

[0396] Step 4: Refer to Step 2 of 3b to obtain 45c (grayish-white solid, 73 mg). MS m / z (ESI): 396.1 [M+H] + .

[0397] Intermediate 46c [ka]

[0398] Compound 46c was prepared by referring to the method for intermediate 4c. MS m / z(ESI): 602.3[M+H] + .

[0399] Intermediate 49c [ka]

[0400] Step 1: Dissolve compound 49c-1 (790 mg, 3.3 mmol) in DMF (8 mL), add potassium carbonate (1.15 g, mmol) and iodoethane (1.3 g, 8.37 mmol), stir at 80°C for 16 hours after addition, add water to quench, filter the precipitated solid by suction, and dry to obtain compound 49c-1 (pale yellow solid, 610 mg). MS m / z (ESI): 266.4 [M + H] + .

[0401] Step 2: Compound 49c-2 was prepared by referring to Step 1 of intermediate 8a. MS m / z(ESI): 515.5[M+H] + .

[0402] Step 3: Compound 49c-3 was prepared by referring to the preparation of intermediate 5d. MS m / z(ESI): 461.9[M+H] + .

[0403] Step 4: Refer to Step 2 of intermediate 3a to prepare compound 49c-4. MS m / z(ESI): 433.2[M+H] + .

[0404] Steps 5-6: Refer to steps 1-2 of intermediate 1c to prepare compound 49c. MS m / z(ESI): 612.2[M+H] + .

[0405] Intermediate 55c [ka]

[0406] Step 1: Refer to intermediate 5d and separate compound 55c-1. MS m / z (ESI): 212.2 [M+H] + .

[0407] Step 2: Compound 55c-2 was prepared by referring to Step 1 of intermediate 21c. MS m / z(ESI): 335.5[M+H] + .

[0408] Step 3: Compound 55c-3 was prepared by referring to Step 2 of intermediate 3a. MS m / z(ESI): 307.2[M+H] + .

[0409] Steps 4-5: Refer to steps 3-4 of intermediate 21c to prepare compound 55c. MS m / z(ESI): 542.7[M+H] + .

[0410] Intermediate 57c [ka]

[0411] Step 1: To a solution of compound 1-aminocyclopropane-1-ethyl formate (71.36 g, 265.67 mmol) in ethanol (100 mL), diisopropylethylamine (343.36 g, 2.66 mol), N-benzyl-2-chloro-N-(2-chloroethyl)ethyl-1-amine hydrochloride (44 g, 265.67 mmol), and sodium iodide (79.65 g, 531.34 mmol) were added, and the mixture was reacted at 78°C for 10 hours with stirring. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (PE:EA = 100:1~5:1) to obtain 57c-1 (brown oily, 49 g). MS m / z (ESI): 289.0 [M+H] +

[0412] Step 2: To a methanol (800 mL) solution of 57c-1 (49 g, 169.91 mmol), palladium carbon (10 g, 169.91 mmol, 10% purity) and (Boc)2O (41.17 g, 188.64 mmol) were added, and the reaction was carried out for 10 hours at 25°C under a hydrogen atmosphere with stirring. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. This was then purified by silica gel column chromatography (PE:EA = 100:1~20:1) to obtain 57c-2 (brown oily, 34 g, crude product). MS m / z (ESI): 299.2 [M+H] +

[0413] Step 3: A tetrahydrofuran solution (30 mL) of 57c-2 (30 g, 100.54 mmol) was cooled to -78°C and maintained at this temperature. Lithium aluminum hydride (11.45 g, 301.63 mmol) was gradually added in several portions, and the reaction was carried out at 0°C with stirring for 2 hours. The reaction was then quenched with sodium sulfate decahydrate, and the reaction solution was filtered and concentrated to obtain the title compound 57c-3 (white solid, 20.0 g). MS m / z (ESI): 257.2 [M+H] +

[0414] Step 4: Dimethyl sulfoxide (2.00 g, 25.60 mmol) was dissolved in dichloromethane (15 mL), oxalyl chloride (1.49 g, 11.70 mmol) was added, and the mixture was reacted at -78 °C for 20 min with stirring. Next, 57c-3 (0.5 g, 1.95 mmol) was dissolved in dichloromethane (3 mL), and the mixture was stirred at -78 °C for 1 hour. Then triethylamine (1.18 g, 11.70 mmol) was added and the mixture was stirred for 10 min. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, then diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 57c-4 (colorless oily, 0.5 g, crude product).

[0415] Step 5: At 0°C, potassium tert-butoxide (6.62 g, 120.4 mmol) was added to a solution of (methoxymethyl)triphenylphosphonium chloride (13.48 g, 39.32 mmol) in tetrahydrofuran (80 mL), and the mixture was stirred for 0.5 hours. Then 57c-4 (5.00 g, 19.66 mmol) was added, and the mixture was reacted under a nitrogen atmosphere at 25°C with stirring for 16 hours. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure, then further diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product. This was purified by silica gel column (PE / EA = 100 / 1 to 5 / 1) to obtain compound 57c-5 (brown oily, 0.8 g).

[0416] Step 6: Add dilute hydrochloric acid solution (0.1 M, 28.33 mL) to a solution of 57c-5 (0.4 g, 1.42 mmol) in acetone (4 mL) and stir at 25°C for 16 hours. After the reaction was complete, the mixture was directly concentrated under reduced pressure to obtain 0.4 g of crude product. The crude product was dissolved in methanol (5 mL), then potassium carbonate (412.03 mg, 2.98 mmol) was added, the mixture was cooled to 0°C, then (1-diazo-2-oxopropyl)phosphonate dimethyl ester (572.71 mg, 2.98 mmol) was added, and the reaction was allowed to continue for another 16 hours at room temperature. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure, diluted with ethyl acetate, washed three times with water, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product. The compound was purified by silica gel column chromatography (PE / EA = 100 / 1 to 20 / 1) to obtain compound 57c-6 (colorless oily, 0.2 g, crude product).

[0417] Step 7: Compound 57c was prepared by referring to Step 1 of intermediate 4b. MS m / z(ESI): 407.2[M+H] + .

[0418] intermediate 60c [ka]

[0419] Compound 60c was prepared by referring to step 1 of intermediate 4c. MS m / z(ESI): 583.2[M+H] + .

[0420] Intermediate 62c [ka]

[0421] Steps 1-2 followed the steps for intermediate 8a, and steps 3-4 followed the steps for intermediate 4c to prepare compound 62c. MS m / z(ESI): 595.2[M+H] + .

[0422] Intermediate 63c [ka]

[0423] Step 1: Under nitrogen gas protection at 0°C, 2,3-dimethyl-6-nitroaniline (5 g, 30.09 mmol), methanesulfonic acid (5.78 g, 60.18 mmol, 4.28 mL), tert-butyl nitrite (7.76 g, 75.22 mmol, 8.95 mL), and tetrabutylammonium iodide (16.67 g, 45.13 mmol) were added to acetonitrile (50 mL). The mixture was heated to 25°C and reacted for 4 hours with stirring. After the reaction, the reaction mixture was concentrated under reduced pressure and purified by normal-phase separation (PE / EA = 1 / 0 to 5 / 1) to obtain compound 63c-1 (brown solid, 2 g). MS m / z (ESI): 278.2 [M + H] + .

[0424] Step 2: Refer to Step 2 of 7a to prepare compound 63c-2. MS m / z(ESI): 248.2[M+H] + .

[0425] Step 3: Refer to Step 1 of 12c and obtain 63c-3. MS m / z(ESI): 198.2[M+H] + .

[0426] Step 4: 63c-3 (1 g, 5.07 mmol), 2,4,5-trichloropyrimidine (930.07 mg, 5.07 mmol), and N,N-diisopropylethylamine (1.97 g, 15.21 mmol, 2.65 mL) were dissolved in tetrahydrofuran (10 mL) and reacted at 65°C with stirring for 8 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by reverse-phase separation (formic acid system) to obtain the title compound 63c-4 (pale yellow solid, 300 mg). MS m / z (ESI): 344.1 [M+H] + .

[0427] Step 5: Refer to Step 3 of 52b and obtain 63c-5. MS m / z(ESI): 726.2[M+H] + .

[0428] Step 6: Refer to Step 2 of 3b and obtain 63c. MS m / z(ESI): 626.1[M+H] + .

[0429] Intermediate 68c [ka]

[0430] Compound 68c was prepared following the method for intermediate 165a. MS m / z(ESI): 644.3[M+H] + .

[0431] Intermediate 69c [ka]

[0432] Step 1: Compound 69c-1 was prepared by referring to Step 3 of intermediate 1d. MS m / z(ESI): 615.2[M+H] + .

[0433] Step 2: Following the procedure for intermediate 5d, compound 69c-2 was obtained. MS m / z(ESI): 618.2[M+H] + .

[0434] Step 3: Refer to Step 4 of intermediate 21c to prepare compound 69c. MS m / z(ESI): 574.2[M+H] + .

[0435] Intermediate 71c [ka]

[0436] Steps 1-2: Refer to steps 1-2 for intermediate 3a to obtain compound 71c-2. MS m / z(ESI): 392.0[M+H] + .

[0437] Steps 3-4: Refer to steps 1-2 of intermediate 4c to obtain compound 71c. MS m / z(ESI): 571.2[M+H] + .

[0438] Intermediate 75c [ka]

[0439] Referencing steps 2-5 of intermediate 120c, 75c was obtained. MS m / z(ESI): 392.2[M+H] + .

[0440] Intermediate 76c [ka]

[0441] Step 1: To a solution of 76d (2.5 g, 8.01 mmol) in 1,4-dioxane (50 mL), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (585.92 mg, 800.76 μmol), potassium acetate (1.57 g, 16.02 mmol), and bis(pinacolate)diborone (3.05 g, 12.01 mmol) were added, and the mixture was reacted at 100°C for 5 hours with stirring. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to obtain compound 76c-1 (yellow solid, 5.00 g, crude product). MS m / z (ESI): 304.0 [M-55] + .

[0442] Step 2: Hydrogen peroxide (15.78 g, 139.17 mmol) was added to a solution of 76c-1 (2.5 g, 6.96 mmol) in dichloromethane (50 mL) at 25°C, followed by the addition of an aqueous solution of sodium hydroxide (2.78 g, 69.59 mmol) (50 mL). The reaction was carried out at 25°C for 15 hours with stirring. After the reaction was complete, the reaction solution was diluted with water, quenched with saturated sodium thiosulfate, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 100 / 1 to 10 / 1) to obtain the title compound 76c-2 (yellow solid, 0.7 g). MS m / z (ESI): 194.1 [M-55] +

[0443] Steps 3-6: Refer to steps 2-5 of 120c to obtain compound 76c. MS m / z(ESI): 392.3[M+H] +

[0444] Intermediate 78c [ka]

[0445] Step 1: 57c-3 (0.4g, 1.56 mmol), 3-(4-hydroxy-1-oxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate tert-butyl (562.32 mg, 1.56 mmol), azodicarbonamide (806.05 mg, 4.68 mmol), and tributylphosphine (947.10 mg, 4.68 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted for 2 hours with stirring at 25°C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, separated and purified by high-performance liquid chromatography (hydrochloric acid system), and lyophilized to obtain 78c-1 (colorless liquid, 400 mg). MS m / z (ESI): 599.2 [M+H] +

[0446] Step 2: Refer to Step 2 of 3b and obtain 78c. MS m / z(ESI): 399.1[M+H] + .

[0447] intermediate 80c [ka]

[0448] Referring to steps 3-4 of intermediate 21c, a yellowish-brown solid compound 80c was prepared. MS m / z(ESI): 531.7[M+H] + .

[0449] Intermediate 84c [ka]

[0450] Step 1: At 0°C, potassium carbonate (434.74 mg, 3.15 mmol) was added to a methanol (5 mL) solution of 57c-4 (0.4 g, 1.57 mmol), and then (1-diazo-2-oxopropyl)phosphonate dimethyl ester (604.30 mg, 3.15 mmol) was added. The reaction was carried out under a nitrogen atmosphere at 25°C for 16 hours with stirring. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure, diluted with EA, washed with water, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, which was purified by silica gel column (PE / EA = 100 / 1 to 20 / 1) to obtain the title compound 84c-1 (brown oily, 0.3 g).

[0451] Step 2: Refer to Step 1 of 4b and obtain 84c-2. MS m / z(ESI): 493.2[M+H] +

[0452] Step 3: Refer to Step 2 of 3b and obtain 84c. MS m / z(ESI): 393.2[M+H] + .

[0453] Intermediate 86c [ka]

[0454] Step 1: At room temperature, compound 81d (50 mg, 110 μmol) and 4-oxopiperidine-1-carboxylate tert-butyl (44 mg, 220 μmol) were dissolved in DCM (5 mL). HOAc (13 mg, 220 μmol) was added, followed by TEA (44 mg, 440 μmol), and the mixture was adjusted to a weakly basic state. The mixture was then stirred and allowed to react for 1 hour. Sodium triacetoxyborohydride (93 mg, 440 μmol) was added, and the mixture was stirred and allowed to react for 12 hours. After complete reaction, DCM and H2O were added to the reaction mixture. The mixture was extracted with DCM, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column (DCM / MeOH = 100 / 1 to 20 / 1) to obtain compound 86c-1. MS m / z (ESI): 641.1 [M+H]+ .

[0455] Step 2: Compound 86c-1 (50 mg, 0.08 mmol) and solvent DCM (4 mL) were added to a 25 mL reaction flask, then TFA (2 mL) was added, and the mixture was stirred at 20°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated, diluted with DCM, washed with saturated sodium bicarbonate until the pH was 7-8, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 86c. MS m / z (ESI): 541.1 [M+H] + .

[0456] Intermediate 89c [ka]

[0457] Step 1: (4-hydroxyphenyl)carbamate tert-butyl (1000 mg, 4.78 mmol), 1,4-dibromobutane (2064 mg, 9.56 mmol), K2CO3 (1321 mg, 9.56 mmol), and anhydrous CH3CN (30 mL) were added to a single-necked flask and heated to 90°C under nitrogen gas protection, reacting with stirring for 16 hours. After complete reaction, water was added to quench the mixture, extracted with EA, combined the organic phases, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was obtained by normal-phase column chromatography (EA / PE = 0-20%) to obtain compound 89c-1 (pale yellow solid, 1300 mg). MS m / z (ESI): 344.1 [M+H] + .

[0458] Step 2: Compound 89c-1 (50 mg, 0.15 mmol), compound 15c (85 mg, 0.15 mmol), K2CO3 (41 mg, 0.30 mmol), NaI (22 mg, 0.15 mmol), and anhydrous DMF (3 mL) were added together to a reaction flask, then heated to 60°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was dried under reduced pressure, and the crude product was subsequently separated by normal-phase column chromatography (MeOH / DCM = 0-5%) to obtain intermediate product 89c-2 (pale yellow solid, 45 mg). MS m / z (ESI): 846.1.[M+H] + .

[0459] Step 3: Refer to Step 2 for intermediate 3b to prepare the crude product, compound 89c. MS m / z(ESI): 746.2[M+H] +

[0460] Intermediate 91c [ka]

[0461] Step 1: Dissolve compound 2-fluoro-4-methoxybenzaldehyde (1 g, 6.5 mmol) in concentrated sulfuric acid (5 mL), cool to 0°C, add concentrated nitric acid (441 mg, 7 mmol) dropwise, stir at 20°C for 2 hours after addition is complete, pour into ice water to precipitate a large amount of solid, filter by suction, and dry to obtain compound 91c-1 (pale yellow solid, 600 mg). MS m / z (ESI): 200.1 [M+H] + .

[0462] Step 2: Dissolve compound 91c-1 (300 mg, 1.5 mmol) in DMF (10 mL), then sequentially add compound a1 (300 mg, 2 mmol) and potassium carbonate (414 mg, 3 mmol). After the addition is complete, stir at 85°C for 16 hours. After the reaction is complete, add water to quench, filter the precipitated solid by suction, and dry to obtain compound 91c-2 (pale yellow solid, 320 mg). MS m / z (ESI): 323.2 [M+H] + .

[0463] Step 3: Compound 91c-2 (320 mg, 0.98 mmol) was dissolved in MeOH (10 mL), cooled to 0°C, sodium borohydride (137.8 mg, 4.9 mmol) was added, and after the addition was complete, the temperature was raised to room temperature and stirred for 3 hours. After the reaction was complete, water was added to quench, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 91c-3 (yellow oily substance, 265 mg). MS m / z (ESI): 325.1 [M+H] + .

[0464] Step 4: Compound 91c-3 (265 mg, 0.82 mmol) and imidazole (111 mg, 1.63 mmol) were dissolved in DCM (5 mL), cooled to 0°C, and TBS-Cl (244.5 mg, 1.63 mmol) was added. After the addition was complete, the temperature was raised to room temperature and stirred for 3 hours. After the reaction was complete, water was added to quench the mixture, and it was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The mixture was purified by normal-phase column chromatography (dichloromethane:methanol = 10:1) to obtain compound 91c-4 (yellow oily substance, 330 mg). MS m / z (ESI): 439.4 [M+H] + .

[0465] Step 5: Refer to Step 2 of intermediate 3a to prepare compound 91c-5. MS m / z(ESI): 409.1[M+H] + .

[0466] Step 6: Refer to Step 1 of intermediate 1c to prepare compound 91c-6. MS m / z(ESI): 688.3[M+H] + .

[0467] Step 7: Dissolve compound 91c-6 (100 mg, 0.15 mmol) in THF (2 mL), add 6N HCl (0.25 mL, 1.5 mmol), raise the temperature to 70°C, and react with stirring for 3 hours. Cool to room temperature, adjust the pH to 7 by adding saturated sodium carbonate aqueous solution, extract with dichloromethane, wash the organic layer with saturated brine, and dry over anhydrous sodium sulfate. Filter and rotary dry, and the crude product was purified by normal-phase column chromatography (dichloromethane:methanol = 10:1) to obtain compound 91c (yellow oily substance). MS m / z (ESI): 530.3 [M+H] + .

[0468] Intermediate 94c [ka]

[0469] Step 1: At 0°C, 2-amino-3-bromo-5-nitrobenzonitrile (10 g, 41.32 mmol) and sodium nitrite (7.13 g, 103.29 mmol) were added to hydrochloric acid (100 mL), the mixture was purged with nitrogen gas three times, and after 1 hour, cuprous chloride (6.14 g, 61.98 mmol) was added. The mixture was reacted at 0-25°C with stirring for 11 hours. After the reaction was complete, the reaction mixture was diluted with water, further extracted with ethyl acetate, the organic layers were combined, the organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 94c-1 (yellow solid, 10.0 g).

[0470] Step 2: Compound 94c-2 was prepared by referring to Step 1 of intermediate 21c. MS m / z(ESI): 368.1[M+H] + .

[0471] Step 3: Compound 94c-3 was prepared by referring to intermediate 5d. MS m / z(ESI): 316.0[M+H] +

[0472] Step 4: 94c-3 (600 mg, 1.90 mmol) was added to tetrahydrofuran (6 mL), then wet palladium-carbon (300 mg, 10% purity) was added, and the reaction was carried out at 25°C for 0.5 hours with stirring under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated to obtain the title compound 94c-4 (yellow solid, 300 mg). This was used directly in the next reaction. MS m / z (ESI): 288.0 [M+H] +

[0473] Steps 5-6: Compound 94c was prepared by referring to steps 3-4 of intermediate 21c. MS m / z (ESI): 523.0 [M+H] +

[0474] Intermediate 98c [ka]

[0475] Steps 1 and 3 referred to intermediate 4c, and step 2 referred to the method of Example E67 to prepare compound 98c. MS m / z(ESI): 599.9[M+H] + .

[0476] Intermediate 99c [ka]

[0477] Step 1: Compound 2,6-dibromo-3-methoxy-5-nitropyridine (50 mg, 0.155 mmol) was dissolved in MeOH (6 mL), and concentrated NaOMe (50 mg, 0.155 mmol) was gradually added in an ice bath. After the addition was complete, the mixture was stirred at 0°C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated, quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then compound 90c-1 (yellow solid, 60 mg) was obtained by normal-phase column chromatography (PE / Â=0~20%). MS m / z(ESI):263.2.[M+H] + .

[0478] Step 2: Compound 99c-2 was prepared by referring to Step 1 of intermediate 7a. MS m / z(ESI): 452.1[M+H] +

[0479] Step 3: Compound 99c-3 was prepared by referring to Step 2 of intermediate 3a. MS m / z(ESI): 422.2[M+H] +

[0480] Steps 4-5: Compound 99c was prepared by referring to steps 1-2 of intermediate 4c. MS m / z (ESI): 601.9 [M+H] +

[0481] Intermediate 103c [ka]

[0482] Step 1: Potassium carbonate (3.32 g, 24.00 mmol, 2 eq) and 1,4-dioxa-8-azaspiro[4.5]decane (1.89 g, 13.20 mmol, 1.69 mL) were added to a solution of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (3 g, 12.00 mmol) in DMF (20 mL), and the mixture was then reacted at 60°C for 1 hour with stirring. After the reaction was complete, the reaction mixture was added to 300 mL of ice water at 0°C to precipitate the solid, which was then filtered and dried to obtain compound 103c-1 (yellow solid, 4.00 g, crude product). MS m / z (ESI): 372.8 [M+H] +

[0483] Step 2: 103c-1 (6.39 g, 17.12 mmol) and cuprous cyanide (7.67 g, 85.61 mmol, 18.70 mL) were added to DMF (50 mL) and reacted in an autoclave at 140°C with stirring for 72 hours. After the reaction was complete, the reaction mixture was diluted with water, further extracted with ethyl acetate, and the organic layers were combined. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (PE:EA = 5:1~2:1) to obtain the title compound 103c-2 (yellow solid, 2.80 g). MS m / z (ESI): 320.1 [M+H] +

[0484] Step 3: Compound 103c-3 was prepared by referring to Step 2 of intermediate 3a. MS m / z(ESI): 290.1[M+H] +

[0485] Steps 4-5: Refer to steps 3-4 of intermediate 21c to prepare compound 103c-5. MS m / z(ESI): 525.1[M+H] +

[0486] Step 6: Compound 103c-6 was prepared by referring to control compound C-6. MS m / z (ESI): 695.3 [M+H] +

[0487] Step 7: Compound 103c was prepared by referring to Step 2 of intermediate 3b. MS m / z(ESI): 595.3[M+H]

[0488] Intermediate 105c [ka]

[0489] Step 1 followed the procedure for intermediate 1d, and steps 2-3 followed the procedure for intermediate 4c to prepare compound 105c. MS m / z(ESI): 650.3[M+H] + .

[0490] Intermediate 108c [ka]

[0491] Compound 108c was prepared following the method for intermediate 86c. MS m / z(ESI): 626.4[M+H] + .

[0492] Intermediate 115c [ka]

[0493] Step 1: Compound 2,6-dibromo-3-nitropyridine (3000 mg, 10.64 mmol) and anhydrous MeOH (30 mL) were added together to a three-necked reaction flask. Under a nitrogen atmosphere, NaH (468 mg, 11.70 mmol, 60% wt) was added in several portions in an ice bath. After the addition was complete, the mixture was stirred in an ice bath for 0.5 hours. Subsequently, CH3ONa (575 mg, 10.64 mmol) was added in several portions, and the mixture was stirred in an ice bath for 3 hours. After the reaction was complete, saturated NH4Cl was added to the reaction mixture to quench it, followed by extraction with EA. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous Na2SO4, and rotated-dried under reduced pressure. The crude product was separated by normal-phase column chromatography (EA / PE = 0-15%) to obtain product 115c-1 (pale yellow solid, 2200 mg). MS m / z (ESI): 233.1 [M+H] +

[0494] Step 2: Compound 115c-1 (2200 mg, 9.44 mmol) and anhydrous TFA (20 mL) were added together to a single-necked flask, followed by the addition of dibromohydantoin (3240 mg, 11.33 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. After complete reaction, the reaction solvent was removed under reduced pressure, the crude product was slurryed with PE / EA (50:1), filtered by suction, washed with PE, and the filter cake was rotated dry under reduced pressure to obtain the crude product, compound 115c-2 (pale yellow solid, 2100 mg), which was used directly in the next reaction. MS m / z (ESI): 311.1 [M+H]+ .

[0495] Step 3: Refer to Step 1 of intermediate 21c to prepare the crude product, compound 115c-3. MS m / z(ESI): 374.3[M+H] +

[0496] Step 4: Refer to intermediate 5d and prepare the crude product, compound 115c-4. MS m / z(ESI): 322.5.[M+H] +

[0497] Step 5: Refer to Step 2 of intermediate 3a to prepare the crude product, compound 115c-5. MS m / z(ESI): 294.5.[M+H] +

[0498] Step 6: Refer to Step 1 of intermediate 1c to prepare compound 115c-6. MS m / z(ESI): 573.8[M+H] +

[0499] Step 7: Refer to Step 4 of intermediate 21c to prepare compound 115c-7. MS m / z(ESI): 529.8[M+H] +

[0500] Step 8: Refer to Example E67 to obtain product 115c-8. MS m / z (ESI): 700.0 [M+H] +

[0501] Step 9: Refer to Step 2 of intermediate 3b to prepare the crude product, compound 115c. MS m / z(ESI): 599.8[M+H] +

[0502] Intermediate 116c [ka]

[0503] Step 1: Compound 116c-1 was prepared by referring to the method of Step 1 for intermediate 3a. MS m / z(ESI): 444.1[M+H] + .

[0504] Step 2: Compound 116c-2 was prepared following the method for intermediate 5d. MS m / z(ESI): 392.1[M+H] + .

[0505] Step 3: Compound 116c-3 was prepared by referring to the method of Step 2 for intermediate 3a. MS m / z(ESI): 364.3[M+H] + .

[0506] Steps 4-5: Compound 116c was prepared by referring to the method of Steps 1-2 for intermediate 1c. MS m / z(ESI): 543.7.[M+H] + .

[0507] Intermediate 118c [ka]

[0508] Step 1: Compound 21c (1 g, 1.89 mmol) and tert-butyl (2-aminoethyl)carbamate (607 mg, 3.79 mmol) were dissolved in DCE (5 mL). Acetic acid (3.79 mL, 1 min DCM) and TEA (1.1 mL, 7.58 mmol) were added, and the reaction was carried out at 25°C for 2 hours with stirring. Sodium borohydride acetate (1.61 g, 7.58 mmol) was then added, and the reaction was carried out at 25°C for 16 hours with stirring. Saturated NaHCO3 was added, and the mixture was extracted by DCM and dried to concentrate. Compound 118c-1 (white solid, 1.2 g) was obtained by column chromatography (MeOH / DCM = ~10%). MS m / z (ESI): 673.4 [M + H] + .

[0509] Step 2: Compound 118c-1 (1.3g, 1.93 mmol) was dissolved in DCM (50 mL), then Et3N (0.84 mL, 5.8 mmol) and chloroacetyl chloride (262 mg, 2.32 mmol) were added, and the mixture was reacted at room temperature with stirring for 16 hours. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM, the organic phase was washed with brine, dried, filtered and concentrated to obtain the crude product, which was dissolved in DMF (20 mL), and NaH (387 mg, 9.67 mmol) was added in several batches at room temperature, and the mixture was reacted at room temperature with stirring for 16 hours. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM, washed with brine, dried, filtered and concentrated to obtain the crude product, which was purified by column chromatography (MeOH / DCM = ~8%) to obtain compound 118c-2 (white solid, 0.65 g). MS m / z(ESI):713.3.

[0510] Step 3: Compound 118c was prepared by referring to Step 2 of intermediate 3b. MS m / z(ESI): 613.2[M+H] + .

[0511] Intermediate 120c [ka]

[0512] Step 1: To a mixed solution of tert-butyl 5-bromoisoindole-2-carboxylate (2.5 g, 8.43 mmol) in 1,4-dioxane (50 mL) and water (20 mL), methanesulfonic acid (2-tert-butylphosphin-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.52 g, 0.65 mmol) and potassium hydroxide (0.92 g, 16.42 mmol) were added, and the mixture was reacted at 80°C for 18 hours with stirring. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate. The mixture was then concentrated under reduced pressure to obtain compound 120c-1 (yellow solid, 1.6 g, crude product). MS m / z (ESI): 180.0 [M-55]+

[0513] Step 2: Potassium carbonate (822.38 mg, 5.95 mmol) and 2-bromo-6-fluorobenzaldehyde (603.99 mg, 2.98 mmol) were added to a solution of 120c-1 (0.7 g, 2.98 mmol) in DMF (4 mL), and the mixture was reacted at 60°C for 2 hours with stirring. After the reaction was complete, the reaction mixture was extracted with water and ethyl acetate to separate the layers, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 120c-2 (brown oily substance, 0.9 g, crude product). MS m / z (ESI): 362.3 [M-55] +

[0514] Step 3: Triethylamine (302.40 mg, 2.99 mmol) was added to a methanol solution (5 mL) of 120c-2 (0.5 g, 1.20 mmol), and the reaction was carried out at 25°C for 0.5 hours with stirring. Next, acetic acid (100.49 mg, 1.67 mmol) and 3-aminopiperidine-2,6-dione (196.75 mg, 1.20 mmol) were added, and the mixture was stirred at 25°C for 2 hours. Sodium cyanoborohydride (225.35 mg, 3.59 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and then separated and purified using a silica gel plate (dichloromethane:methanol = 10:1) to obtain the title compound 120c-3 (colorless oily, 0.6 g, crude product). This was used directly in the next step. MS m / z (ESI): 530.3 [M+H] +

[0515] Step 4: 120c-3 (0.5 g, 942.67 μmol) and 1,3-bis(dicyclohexylphosphino)propanebis(tetrafluoroborate) (57.72 mg, 94.27 μmol) were dissolved in DMF (20 mL). Palladium acetate (21.16 mg, 94.27 μmol) and potassium carbonate (195.43 mg, 1.41 mmol) were added, and the mixture was reacted under a carbon monoxide atmosphere at 80°C with stirring for 24 hours. After the reaction was complete, the reaction mixture was extracted with water and ethyl acetate, the organic phase was dried, and concentrated under reduced pressure to obtain the title compound 120c-4 (green solid, 600 mg, crude product). This was used directly in the next step. MS m / z (ESI): 378.1 [M+H-100] +

[0516] Step 5: A solution of 120c-4 (290.83 mg, 609.06 μmol) in ethyl acetate hydrochloride (4 M, 10 mL) was reacted at 25°C for 2 hours with stirring. After the reaction was complete, the reaction solution was concentrated directly to obtain the title compound 120c (green solid, 200 mg, HCl salt). MS m / z (ESI): 378.3 [M + H] +

[0517] Intermediate 121c [ka]

[0518] Step 1: Under a nitrogen atmosphere, ethyl 3-hydroxypropionate (90.78 mg, 768.51 μmol) was added to a solution of compound 3 (100 mg, 384.25 μmol), azodicarbonamide (198.49 mg, 1.15 mmol), and tributylphosphine (233.22 mg, 1.15 mmol, 284.42 μL) in tetrahydrofuran (3 mL), and the mixture was reacted at 25 °C for 10 hours with stirring. After the reaction was complete, the reaction mixture was directly transferred and concentrated under reduced pressure to obtain the crude product. The crude product was purified and separated by thin-layer chromatography to obtain compound 121c-1 (white solid, 46 mg). MS m / z (ESI): 361.2 [M+H] +

[0519] Step 2: To a solution of 121c-1 (40 mg, 111.00 μmol) in water (0.1 mL), a 4 M dioxane solution of hydrogen chloride (2 mL) was added, and the reaction was carried out at 80°C for 8 hours with stirring. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to obtain compound 121c (white solid, 24 mg). MS m / z (ESI): 333.1 [M + H] +

[0520] Intermediate 124c [ka]

[0521] Step 1 referred to Step 1 of intermediate 114d, Step 2 referred to intermediate 1d, and Steps 3-4 referred to intermediate 4c to prepare compound 124c. MS m / z(ESI): 616.2[M+H] + .

[0522] Intermediate 125c [ka]

[0523] Step 1: Compound 125c-1 was prepared referring to Example C-6. MS m / z(ESI): 601.1[M+H] +

[0524] Step 2: Compound 125c-1 (100 mg, 0.19 mmol) was dissolved in methanol (4 mL), 4 M HCl / 1,4-dioxane (0.5 mL, 2 mmol) was added, and the mixture was heated under reflux for 4 hours. After that, saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7, and the mixture was extracted by DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography (MeOH / DCM ~10%) to obtain 125c (white solid, 60 mg). MS m / z (ESI): 614.1 [M + H] +

[0525] Intermediate 127c [ka]

[0526] Compound 127c was prepared by referring to step 2 of intermediate 3b. MS m / z(ESI): 600.2[M+H] + .

[0527] Intermediate 129c [ka]

[0528] Step 1 was followed by E67, and Step 2 by following Step 2 of intermediate 15c to prepare compound 129c. MS m / z(ESI): 626.9[M+H] + .

[0529] Intermediate 131c [ka]

[0530] Step 1: Compound 131c-1 was prepared by referring to Step 1 of intermediate 7a. MS m / z(ESI): 459.1[M+H] +

[0531] Step 2: 131c-1 (2.0 g, 4.35 mmol) was added to a mixed solution of methanol (6 mL) and 1,4-dioxane (30 mL). Then sodium methoxide (2.35 g, 43.54 mmol) and cuprous iodide (829.19 mg, 4.35 mmol) were added, and the reaction was carried out at 100°C for 2 hours with stirring under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was diluted with water, then extracted with dichloromethane, and the organic layers were combined. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (PE / EA = 10:1 to 1:1) to obtain the title compound 131c-2. MS m / z (ESI): 451.1 [M + H] +

[0532] Step 3: Compound 131c-3 was prepared by referring to Step 2 of intermediate 3a. MS m / z(ESI): 421.1[M+H] +

[0533] Step 4: Compound 131c-4 was prepared by referring to Step 1 of intermediate 4c. MS m / z(ESI): 700.3[M+H] +

[0534] Step 5: Compound 131c was prepared by referring to Step 2 of intermediate 3b. MS m / z(ESI): 600.3[M+H] +

[0535] Intermediate 132c [ka]

[0536] Step 1: Compound 132c-1 was prepared by referring to intermediate 1d. MS m / z (ESI): 340.1 [M+H] +

[0537] Step 2: Compound 132c-2 was prepared by referring to Step 1 of intermediate 4c. MS m / z(ESI): 722.4[M+H] +

[0538] Step 3: To a mixed solution of 132c-2 (1.5 g, 2.08 mmol) in tetrahydrofuran (15 mL), methanol (15 mL), and water (1.5 mL), lithium hydroxide monohydrate (348.78 mg, 8.31 mmol) was added, and the reaction was carried out under a nitrogen atmosphere at 25°C with stirring for 16 hours. After the reaction was complete, the solution was concentrated to remove the solvent, and the residue was adjusted to pH = 3-5 with 1 M hydrochloric acid aqueous solution. Further extraction with dichloromethane was performed to separate the layers, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 132c-3 (dark brown solid, 1.0 g). MS m / z (ESI): 708.3 [M + H] +

[0539] Step 4: To a solution of 132c-3 (200 mg, 282.57 μmol) in DMF (5 mL), HATU (128.93 mg, 339.08 μmol), DIEA (109.56 mg, 847.70 μmol), and ammonium chloride (109.56 mg, 847.70 μmol) were added in sequence. The reaction was then carried out under a nitrogen atmosphere at 25°C with stirring for 3 hours. After the reaction was complete, the reaction mixture was filtered to obtain the crude product. The crude product was purified by reverse-phase separation (hydrochloric acid system) to obtain the title compound 132c-4 (yellow solid, 100 mg). MS m / z (ESI): 707.4 [M + H] +

[0540] Step 5: Compound 132c was prepared by referring to Step 2 of intermediate 3b. MS m / z(ESI): 607.4[M+H] +

[0541] Intermediate 133c [ka]

[0542] Step 1: Compound 132c-3 (150 mg, 0.22 mmol) and DMF (2 mL) were added together to a single-necked flask. Then HATU (120.87 mg, 0.32 mmol) and DIPEA (164.34 mg, 1.27 mmol) were added, and finally methylamine hydrochloride (42.93 mg, 0.64 mmol) was added. The reaction was carried out at 25°C for 12 hours with stirring. After the reaction was complete, the reaction mixture was diluted with water and further extracted with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified using a silica gel plate (dichloromethane:methanol = 10:1) to obtain the title compound 133c-1 (123 mg, crude product). MS m / z (ESI): 721.4 [M + H] +

[0543] Step 2: Compound 133c was prepared by referring to Step 2 of intermediate 1c. MS m / z(ESI): 621.4[M+H] +

[0544] Intermediate 134c [ka]

[0545] Compound 134c was prepared by referring to intermediate 133c. MS m / z(ESI): 635.4[M+H] +

[0546] Intermediate 135c [ka]

[0547] Compound 135c was prepared following the method for intermediate 133c. MS m / z(ESI): 649.4[M+H] +

[0548] Intermediate 136c [ka]

[0549] Compound 28c was prepared by referring to intermediate 4c. LCMS: m / z(ESI): 598.3[M+H] +

[0550] Intermediate 137c [ka]

[0551] Compound 137c was prepared following the method for intermediate 86c. MS m / z(ESI): 610.9[M+H] + .

[0552] Intermediate 140c [ka]

[0553] Referencing steps 5 and 6 of intermediate 154c, title compound 140c was prepared. MS m / z(ESI): 587.2[M+H] + .

[0554] Intermediate 141c [ka]

[0555] Compound 141c was prepared by referring to steps 5-6 of intermediate 154c. MS m / z(ESI): 603.3[M+H]

[0556] Intermediate 142c [ka]

[0557] Step 1: Compound 142c-1 was prepared by referring to Step 5 of intermediate 154c. MS m / z(ESI): 861.3[M+H] +

[0558] Step 2: Compound 142c-1 (650 mg, 0.75 mmol) and anhydrous THF (10 mL) were added to a three-necked flask, and methylmagnesium bromide (1 M, 8 mL) was gradually added dropwise in an ice bath under a nitrogen atmosphere. After the addition was complete, the reaction mixture was allowed to react at 0°C for 0.5 hours with stirring, then the temperature was raised to room temperature and stirred for 6 hours. After the reaction was complete, water was added to the reaction mixture to quench it, and it was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotated-dried. The crude product was separated by chromatography to obtain compound 142c-2 (pale yellow solid, 630 mg). MS m / z (ESI): 861.7 [M + H] +

[0559] Step 3: Refer to Step 6 of intermediate 154c to prepare compound 142c. MS m / z (ESI): 653.6 [M + Na] +

[0560] Intermediate 144c [ka]

[0561] Compound 144c was prepared following the method for intermediate 86c. MS m / z(ESI): 624.8[M+H] + .

[0562] Intermediate 146c [ka]

[0563] Step 1 followed Step 1 of intermediate 3a, Step 2 followed Step 5d, Step 3 followed Step 2 of 3a, and Steps 4-5 followed Steps 1-2 of 1c to prepare compound 146c. MS m / z(ESI): 650.3[M+H] + .

[0564] Intermediate 147c [ka]

[0565] Compound 147c was prepared following the method for intermediate 176a. MS m / z(ESI): 644.7[M+H] + .

[0566] Intermediate 148c [ka]

[0567] Step 1 referred to Step 1 of intermediate 133c, and Step 2 referred to Step 2 of intermediate 1c to prepare compound 148c. MS m / z(ESI): 661.6[M+H] + .

[0568] Intermediate 149c [ka]

[0569] Step 1: Compound 132c-3 (200 mg, 0.28 mmol) was dissolved in THF (50 mL), then CDI (115 mg, 0.71 mmol) was added, and the mixture was reacted at room temperature with stirring for 16 hours. Then (Z)-N'-hydroxyacetimide (52 mg, 0.71 mmol) was added, and the mixture was reacted at room temperature with stirring for 16 hours. After the reaction was complete, EA was added to dilute the mixture, ice water was injected, and the mixture was extracted with EA. The organic phase was washed with saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, compound 149c-1 (white solid, 250 mg, crude product). MS m / z (ESI): 763.4 [M + H] + .

[0570] Step 2: Compound 149c-1 (215 mg, 0.28 mmol) was dissolved in DMSO (50 mL), then KOH (47 mg, 0.84 mmol) was added, and the mixture was reacted at room temperature with stirring for 16 hours. After the reaction was complete, the reaction mixture was directly concentrated and purified by column chromatography (80 g, MeOH / DCM = ~8%) to obtain the title compound 149c-2 (white solid, 170 mg). MS m / z (ESI): 746.4 [M + H] + .

[0571] Step 3: Compound 149c was prepared by referring to Step 2 of intermediate 3b. MS m / z(ESI): 646.5[M+H] + .

[0572] Intermediate 151c [ka]

[0573] Step 1: Compound 4-bromo-5-fluoro-2-nitrophenol (0.5 g, 2.12 mmol) was dissolved in anhydrous DMF (10 mL). Then sodium difluorochloroacetate (1.13 g, 7.42 mmol) and potassium carbonate (351.38 mg, 2.54 mmol) were added, respectively. After the addition was complete, the reaction mixture was stirred at 90°C for 16 hours. After complete reaction, water was added to the reaction mixture to quench it, and it was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotated-dried. The crude product was separated by chromatography to obtain compound 151a-1 (yellow oily substance, 510 mg). MS m / z (ESI): 386.2 [M+H] + .

[0574] Step 2: Following the procedure described in Step 1 for intermediate 3a, compound 151a-2 (yellow solid, 1.84 g) was prepared. MS m / z (ESI): 535.3 [M+H] + .

[0575] Step 3: Compound 151a-3 (yellow oily substance, 1.2 g) was prepared following the procedure for intermediate 5d. MS m / z (ESI): 483.4 [M+H] + .

[0576] Step 4: Following the procedure described in Step 2 for intermediate 3a, compound 151a (red oily substance, 950 mg) was prepared. MS m / z (ESI): 455.3 [M+H]

[0577] Step 5: Compound 151a (500 mg, 1.10 mmol), Compound 2 (500 mg, 1.58 mmol), sodium tert-butoxide (250 mg, 2.60 mmol), and anhydrous THF (10 mL) were dissolved in a single-necked flask. The flask was purged three times with nitrogen gas, and then t-BuXphos (100 mg, 0.24 mmol) and t-BuXphosG3 (90 mg, 0.11 mmol) were added, respectively. After the addition was complete, the reaction mixture was stirred with nitrogen gas and at 65°C for 18 hours. After complete reaction, the reaction mixture was diluted with EA, then filtered, and the filtrate was rotated dry. The crude product was separated by chromatography column (EA / PE: 0-100%) to obtain Compound 151c-1 (pale red solid, 100 mg). MS m / z (ESI): 734.3 [M+H] + .

[0578] Step 6: Refer to Step 2 of intermediate 3b to prepare the crude product, compound 151c. MS m / z(ESI): 634.6[M+H] + .

[0579] Intermediate 152c [ka]

[0580] Step 1: Compound 1-bromo-2-fluoro-4-trifluoromethoxybenzene (2.5 g, 9.65 mmol) was dissolved in acetonitrile (37.5 mL), and then nitronium tetrafluoroborate (1.13 g, 7.42 mmol) was added at 0°C. The reaction mixture was allowed to react for 4 hours with stirring at 25°C. After diluting the reaction mixture with water, ethyl acetate was added and extracted three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotated-dried. The crude product was separated by chromatography column (0-2% ethyl acetate / petroleum ether) to obtain compound 152c-1 (yellow oily liquid, 1.5 g). MS m / z (ESI): 303.9 [M+H] +

[0581] Step 2: Compound 152c-2 was prepared by referring to Step 1 of intermediate 3a. MS m / z(ESI): 553.2[M+H] +

[0582] Step 3: Compound 152c-3 was prepared by referring to the preparation of intermediate 5d. MS m / z(ESI): 501.4[M+H] +

[0583] Step 4: Refer to Step 2 of intermediate 3a to prepare compound 152c-4. MS m / z(ESI): 473.3[M+H] +

[0584] Step 5: Refer to Step 5 of intermediate 151c to prepare compound 152c-5. MS m / z(ESI): 753.2[M+H] +

[0585] Step 6: Refer to Step 2 of intermediate 3b to prepare compound 152c. MS m / z(ESI): 652.3[M+H]

[0586] Intermediate 153c [ka]

[0587] Steps 1 and 3 refer to steps 1 and 2 of intermediate 3a, step 2 refers to intermediate 5d, and steps 4 and 5 refer to steps 5 and 6 of intermediate 154c to prepare compound 153c. MS m / z(ESI): 601.3[M+H] + .

[0588] Intermediate 154c [ka]

[0589] Step 1: At 20°C, 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (6.8g, 23.78mmol) was added to a solution of 4-fluoro-1-nitro-2-trifluoromethylbenzene (5.97g, 28.54mmol) in concentrated sulfuric acid (30mL). The reaction mixture was stirred at 20°C for 6 hours. The reaction mixture was poured into ice water, extracted with EA, washed the organic phase with saturated brine, dried, rotated-dried, and concentrated to obtain compound 154c-1 (pale yellow oily, 6.55g, crude product). MS m / z (ESI): 288.3 [M+H] + .

[0590] Step 2: Compound 154c-2 was prepared by referring to Step 1 of intermediate 3a. MS m / z(ESI): 537.3[M+H] + .

[0591] Step 3: Compound 154c-3 was prepared following the procedure for intermediate 5d. MS m / z(ESI): 485.5[M+H] + .

[0592] Step 4: Refer to Step 2 of intermediate 3a to prepare compound 154c-4. MS m / z(ESI): 457.3[M+H] + .

[0593] Step 5: Compound 154c-4 (1 g, 2.19 mmol), compound 142d (1.14 g, 2.52 mmol), and potassium phosphate (1.86 g, 8.76 mmol) were added to a mixture of t-BuXphos (400 mg, 941.97 μmol) and t-BuXphosPdG3 (350 mg, 440.60 μmol) in dioxane (12 mL) and DMF (3 mL). The reaction mixture was stirred with nitrogen gas and at 95°C for 16 hours. After the reaction was complete, water (100 mL) was added to the reaction mixture, extracted with EA, and the combined organic phase was washed with saturated ammonium chloride and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by chromatography to obtain compound 154c-5 (yellow solid, 510 mg). MS m / z (ESI): 871.4 [M+H] + .

[0594] Step 6: A solution of compound 154c-5 (510 mg, 351.30 μmol) and trifluoroacetic acid (2.90 g, 25.44 mmol) in dichloromethane (5 mL) was stirred at 20°C for 3 hours. The reaction mixture was concentrated. The crude product was dissolved in dichloromethane (3 mL), and ethylenediamine (72.49 mmol, 4.85 mL) was added. The reaction mixture was stirred at 20°C for 16 hours. The reaction was completely allowed to proceed. The reaction mixture was concentrated, dissolved in DCM, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 154c (pale yellow solid, 118 mg, crude product). MS m / z (ESI): 641.4[M+H]+.

[0595] Intermediate 156c [ka]

[0596] Step 1: Compound N-Boc piperazine (1 g, 5.37 mmol) was dissolved in THF (10 mL), TEA (5 mL) and CuCl (60 mg, 0.6 mmol) were added, and then 3-chloro-3-methyl-1-butyne (551 mg, 5.40 mmol) was added under nitrogen gas protection, and the mixture was stirred at room temperature for 30 min. After quenching with water, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA = 1:1) to obtain compound 156c-1 (white solid, 400 mg, crude product).

[0597] Step 2: Compound 156c-2 was prepared by referring to Step 1 of intermediate 1b. MS m / z(ESI): 495.3[M+H] +

[0598] Step 3: Compound 156c was prepared by referring to Step 2 of intermediate 3b. MS m / z(ESI): 395.3[M+H] + .

[0599] Intermediate 158c: [ka]

[0600] Compound 158c was prepared following the method for intermediate 176a. MS m / z(ESI): 643.4.[M+H] +

[0601] Intermediate 161c [ka]

[0602] Step 1: 4,6-Dichloropyrazolo[3,4-d]pyrimidine (2.9 g, 15.34 mmol) and (2-aminophenyl)dimethylphosphine oxide (1.30 g, 7.67 mmol) were added to tert-amyl alcohol (180 mL), followed by the addition of DIEA (9.92 g, 76.72 mmol, 13.36 mL). The reaction was carried out at 100°C with stirring for 12 hours. After the reaction was complete, the reaction mixture was diluted with water, further extracted with dichloromethane / methanol, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to reverse-phase preparative fractionation (hydrochloric acid system) to obtain compound 161c-1 (pale yellow solid, 525 mg). MS m / z (ESI): 322.0 [M+H] +

[0603] Step 2: Compound 3a (2.19 g, 3.82 mmol) and compound 161c-1 (1.23 g, 3.82 mmol) were added to ethylene glycol (80 mL), then TsOH.H2O (581.69 mg, 3.06 mmol) was added, and the reaction was carried out at 80°C with stirring for 12 hours. After the reaction was complete, the reaction mixture was adjusted to pH = 7-8 with saturated sodium bicarbonate aqueous solution, further extracted with dichloromethane / methanol, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to reverse-phase preparative fractionation (hydrochloric acid system) to obtain compound 161c-2 (brown solid, 1.04 g). MS m / z (ESI): 704.4 [M+H] +

[0604] Step 3: Compound 161c was prepared by referring to Step 2 of intermediate 3b. MS m / z(ESI): 604.4[M+H] +

[0605] Intermediate 162c [ka]

[0606] Step 1: Compound 162c-1 was prepared by referring to the method of Step 1 for intermediate 3a. MS m / z(ESI): 459.2[M+H] + .

[0607] Step 2: Compound 162c-1 (2.0 g, 4.35 mmol) was added to a mixed solution of methanol (6 mL) and 1,4-dioxane (30 mL). Then sodium methoxide (2.35 g, 43.54 mmol) and cuprous iodide (829.19 mg, 4.35 mmol) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere with stirring for 2 hours. After the reaction was complete, the reaction mixture was diluted with water, then extracted with dichloromethane, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain the title compound 162c-2 (yellow solid, 220 mg). MS m / z (ESI): 455.2 [M+H] + .

[0608] Step 3: Compound 162c-3 was prepared following the procedure for intermediate 5d. MS m / z(ESI): 447.2[M+H] +

[0609] Step 4: Compound 162c-4 was prepared by referring to the method of Step 2 for intermediate 3a. MS m / z(ESI): 419.3[M+H] + .

[0610] Steps 5-6: Compound 162c was prepared following the method for intermediate 4c. MS m / z(ESI): 598.4[M+H] + .

[0611] Intermediate 165c [ka]

[0612] Compound 165c was prepared following the method for intermediate 1d. MS m / z(ESI): 742.3, 744.3[M+H] + .

[0613] Intermediate 167c: [ka]

[0614] Compound 167c was prepared following the method for intermediate 176a. MS m / z(ESI): 630.5[M+H] +

[0615] Intermediate 170c [ka]

[0616] Compound 170c was prepared following the method for intermediate 165a. MS m / z(ESI): 630.5[M+H] + .

[0617] Intermediate 171c [ka]

[0618] Compound 171c was prepared following the method for intermediate 165a. MS m / z(ESI): 631.5[M+H] + .

[0619] Intermediate 173c [ka]

[0620] Compound 173c was prepared by referring to the method for intermediate 1c. MS m / z(ESI):394.1[M+H] + .

[0621] Intermediate 174c [ka]

[0622] Compound 174c was prepared following the method for intermediate 165a. MS m / z(ESI): 630.6[M+H] + .

[0623] Intermediate 175c [ka]

[0624] Compound 175c was prepared following the method for intermediate 165a. MS m / z(ESI): 644.6[M+H] + .

[0625] Intermediate 179c [ka]

[0626] Step 1: Compound 146c-1 (3.8g, 7.61 mmol), Compound 146c.1 (1.78g, 9.13 mmol), potassium fluoride (1M, 30.44 mL), and Pd(dppf)Cl2.CH2Cl2 (621.39 mg, 0.76 mmol) were added to dimethyl sulfoxide (150 mL), and the mixture was reacted at 100°C for 10 hours with stirring under nitrogen gas protection. After the reaction was complete, the reaction mixture was diluted with water, further extracted with ethyl acetate, washed with water, combined with the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then analyzed by column chromatography to obtain Compound 179c-1 (dark brown solid, 1.7 g). MS m / z (ESI): 488.2 [M+H] +

[0627] Step 2: 179c-1 (1.7g, 3.49 mmol) and potassium fluoride (1M, 10.46 mL) were added to a solution of methanol (25 mL) and reacted at 90°C for 10 hours with stirring under nitrogen gas protection. After the reaction was complete, the mixture was concentrated to remove methanol, the aqueous phase was further extracted with dichloromethane / methanol, the organic phase was washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 179c-2 (dark brown solid, 1.3 g). MS m / z (ESI): 460.2 [M+H] +

[0628] Step 3: Refer to Step 2 of intermediate 7a to prepare compound 179c-3 (dark brown solid, 363 mg). MS m / z (ESI): 430.2 [M+H] +

[0629] Step 4: Compound 179c-3 (360 mg, 0.84 mmol) and Compound 2 (264.94 mg, 0.84 mmol) were added to a solution of tetrahydrofuran (15 mL), then sodium tert-butoxide (161.08 mg, 1.68 mmol) and tBuXPhosPdG3 (66.57 mg, 83.81 μmol) were added, and the mixture was reacted at 65°C for 12 hours with stirring under nitrogen gas protection. After the reaction was complete, the mixture was filtered, the filter cake was washed with dichloromethane / methanol, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel plate to obtain Compound 179c-4 (dark brown solid, 360 mg, crude product). MS m / z (ESI): 709.4 [M+H] +

[0630] Step 5: Refer to Step 2 of intermediate 1c to prepare compound 179c. MS m / z(ESI): 609.1[M+H] + .

[0631] Intermediate 185c [ka]

[0632] Step 1: At -20°C, 2-fluoro-4-methoxyacetophenone (5 g, 29.73 mmol) was added to sulfuric acid (31.28 g, 318.93 mmol, 17 mL), and then nitric acid (3.75 g, 59.47 mmol, 2.68 mL) was gradually added dropwise. The reaction was then carried out at -20°C for 30 minutes with stirring. The reaction mixture was added to ice water, stirred for 30 minutes, and then filtered. The filter cake was washed with water until it became a pale yellow solid, dried, and compound 185c-1 (pale yellow solid, 6 g) was obtained. MS m / z (ESI): 214.1 [M+H] + .

[0633] Step 2: Compound 185c-2 was prepared by referring to Step 1 of intermediate 8a. MS m / z(ESI): 433.3[M+H] + .

[0634] Step 3: Compound 185c-2 (300 mg, 693.55 μmol), Compound 2 (250 mg, 790.83 μmol), and sodium tert-butoxide (150 mg, 1.56 mmol) were dissolved in tetrahydrofuran (8 mL), and t-BuXphos (65 mg, 153.07 μmol) and t-BuXphosPdG3 (70 mg, 88.12 μmol) were added. The reaction mixture was stirred with nitrogen gas and at 65°C for 18 hours. After diluting the reaction mixture with EA, it was filtered through diatomaceous earth and rotated dry. The crude product was separated by chromatography to obtain 185c-3 (yellow oily, 200 mg). MS m / z (ESI): 712.5 [M+H] +

[0635] Step 4: Compound 185c was prepared by referring to Step 2 of intermediate 3b. MS m / z(ESI): 612.4[M+H] + .

[0636] Intermediate 190c [ka]

[0637] Compound 190c was prepared following the method for intermediate 176a. MS m / z(ESI): 630.3[M+H] + .

[0638] Intermediate 192c [ka]

[0639] Compound 192c was prepared following the method for intermediate 176a. MS m / z(ESI): 644.3[M+H] + .

[0640] Intermediate 196c [ka]

[0641] Compound 196c was prepared following the method for intermediate 120c. MS m / z(ESI): 378.0[M+H] + .

[0642] Intermediate 198c [ka]

[0643] Step 1 referred to Step 1 of intermediate 166a, and Step 2 referred to Step 2 of intermediate 3b to prepare compound 198c. MS m / z(ESI): 648.0[M+H] + .

[0644] Intermediate 201c [ka]

[0645] Step 1: Compound 201c-1 was prepared by referring to Step 1 of intermediate 4c. MS m / z (ESI): 728.2 [M+H] + .

[0646] Steps 2-3: Compound 201c was prepared following the method for intermediate 176a. MS m / z (ESI): 630.2 [M+H] + .

[0647] Intermediate 212c [ka]

[0648] Step 1: A solution of compound 158c (0.7 g, 923.75 μmol) and potassium carbonate (1.66 g, 12.01 mmol) in acetonitrile (10 mL) was stirred at 20°C for 1 hour. Next, methyl 2-bromo-2-methylpropionate (1 g, 5.52 mmol) was added. The reaction mixture was stirred at 80°C for 15 hours. The reaction mixture was concentrated under reduced pressure. The crude product was separated by chromatography to obtain compound 212c-1 (brown solid, 440 mg). MS m / z (ESI): 744.6 [M+H] +

[0649] Step 2: LAH (90 mg, 2.37 mmol) was added to a solution of compound 212c-1 (440 mg, 591.50 μmol) in THF (10 mL). The reaction mixture was stirred at 20°C for 30 min. Water, 10% sodium hydroxide solution, and water were added to the reaction mixture, and the mixture was concentrated under reduced pressure. The crude product was obtained by column chromatography to obtain compound 212c (white solid, 170 mg). MS m / z (ESI): 716.6 [M+H] +

[0650] Intermediate 213c [ka]

[0651] Steps 1-2: Compound 213c-2 was prepared following the method for intermediate 3a. MS m / z(ESI): 419.5[M+H] + .

[0652] Step 3: Compound 213c-3 was prepared following the method for intermediate 165c. MS m / z(ESI): 742.2[M+H] + .

[0653] Steps 4 and 5: Compound 213c-5 was prepared following the method for intermediate 176a. MS m / z(ESI): 644.2[M+H] + .

[0654] Steps 6 and 7: Compound 213c was prepared by referring to the method for intermediate 212c. MS m / z (ESI): 716.6 [M+H] +

[0655] Intermediate 214c [ka]

[0656] Compound 214c was prepared following the method for intermediate 165a. MS m / z(ESI): 644.6[M+H] + .

[0657] Intermediate 215c [ka]

[0658] Compound 215c was prepared following the method for intermediate 176a. MS m / z(ESI): 658.4[M+H] + .

[0659] Intermediate 216c [ka]

[0660] Step 4 referred to intermediate 5d, and steps 1, 2, 3, and 5 referred to the method for intermediate 124c to prepare compound 216c. MS m / z(ESI): 588.3[M+H] + .

[0661] Intermediate 218c [ka]

[0662] Compound 218c was prepared following the method for intermediate 219c. MS m / z(ESI): 645.4[M+H] + .

[0663] Intermediate 219c [ka]

[0664] Step 1: Compound 165c (850 mg, 1.14 mmol), 4-methyltriazole (300 mg, 3.61 mmol), cuprous iodide (68.00 mg, 357.05 μmol), L-proline (42.50 mg, 369.15 μmol), and cesium carbonate (1.87 g, 5.74 mmol) were reacted in DMSO (5 mL) at 140 °C under microwave for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotated-dried. The crude product was separated by chromatography column, and compound 219c-1 was obtained by prep-HPLC (FA). MS m / z (ESI): 745.5 [M+H] +

[0665] Step 2: Compound 219c-1 (20 mg, 26.85 μmol) was dissolved in DCM (2 mL), and then TFA (1 mL) was added. The reaction was carried out for 1 hour with stirring at 20°C. The reaction mixture was rotated dry to obtain compound 219c. MS m / z (ESI): 645.5 [M + H] +

[0666] Intermediate 220c [ka]

[0667] Compound 220c was prepared by referring to the synthesis method of intermediate 219c. MS m / z(ESI):631.3[M+H] +

[0668] Intermediate 221c [ka]

[0669] Step 1: Compound 146c-1 (1 g, 2.00 mmol), ethynyltrimethylsilane (1.97 g, 20.02 mmol), cuprous iodide (50 mg, 262.54 μmol), Pd(PPh3)2Cl2 (210 mg, 299.19 μmol), and TEA (1.22 g, 12.01 mmol) were reacted in 10 mL of DMF under nitrogen gas protection at 85°C for 16 hours. The reaction mixture was diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotated-dried. The crude product was separated by chromatography to obtain compound 221c-1. MS m / z (ESI): 517.4 [M+H] +

[0670] Step 2: A methanol (20 mL) solution of compound 221c-1 (1.82 g, 3.52 mmol) and potassium carbonate (1 g, 7.24 mmol) was stirred at 20°C for 2 hours. The reaction mixture was concentrated. The crude product was separated by chromatography to obtain compound 221c-2. MS m / z (ESI): 445.4 [M+H] +

[0671] Step 3: Deuterium hydroxide (95.61 mmol, 2 mL) was added to a solution of compound 221c-2 (850 mg, 1.91 mmol) and potassium carbonate (550 mg, 3.98 mmol) in acetonitrile (8 mL). The reaction mixture was allowed to react at 20°C for 48 hours. The reaction mixture was diluted with EA, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 221c-3. MS m / z (ESI): 446.4 [M+H] +

[0672] Step 4: Compound 221c-3 (750 mg, 1.68 mmol) was dissolved in deuterated methanol (100 mL) and EA (50 mL), and after purging three times with nitrogen gas, palladium carbon (200 mg, 10% purity) was added. The reaction was carried out under a deuterium atmosphere at 20°C with stirring for 24 hours. The reaction mixture was filtered through diatomaceous earth and then rotated dry. The crude product was separated by chromatography to obtain compound 221c-4. MS m / z (ESI): 424.4 [M+H] +

[0673] Step 5: Refer to Step 3 of intermediate 185c to obtain compound 221c-5. MS m / z(ESI): 703.2[M+H] +

[0674] Step 6: Following the procedure for intermediate 219c in Step 2, compound 221c was obtained. MS m / z(ESI): 603.2[M+H] +

[0675] Intermediate 225c [ka]

[0676] Step 1 referred to Step 1 of intermediate 176a, and Step 2 referred to Step 6 of 154c to prepare compound 225c. MS m / z(ESI): 644.2[M+H] + .

[0677] Intermediate 1d [ka]

[0678] (2-aminophenyl)dimethylphosphine oxide (1.480 g, 8.8 mmol) and 5-bromo-2,4-dichloropyrimidine (1 g, 4.4 mmol) were added to the reaction flask, followed by DIEA (2.88 g, 22 mmol) and n-BuOH (10 mL). The reaction mixture was stirred at 140 °C under an argon atmosphere for 16 hours. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 20:1). It was then rotated to obtain compound 1d (pale yellow solid, 1.1 g). MS m / z (ESI): 362.1 [M + H] + .

[0679] intermediate 2d [ka]

[0680] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (1 g, 4.00 mmol), cyclopropylboronic acid (343.56 mg, 4.00 mmol), Pd(dppf)Cl2 (585.31 mg, 799.93 μmol), and cesium carbonate (3.91 g, 12.00 mmol) were added to a mixture of ethylene glycol dimethyl ether (2 mL) and water (0.5 mL), and the mixture was reacted under a nitrogen atmosphere at 90°C with stirring for 12 hours. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 2d (white solid, 0.5 g). MS m / z (ESI): 212.2 [M+H] +

[0681] intermediate 3d [ka]

[0682] Step 1: Compound 4-bromo-5-fluoro-2-methylbenzoic acid (3 g, 12.87 mmol) was dissolved in DMF (50 mL). While stirring, NaHCO3 (3.24 g, 38.62 mmol) and MeI (1.2 mL, 19.31 mmol) were added, and the reaction was carried out at room temperature for 3 hours with stirring until the reaction was complete. The mixture was then cooled to room temperature. The reaction system was poured into ice water, and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 3d-1 (colorless oil, 3 g) was obtained by column chromatography (EA / PE = 0-5%). MS m / z (ESI): 247.1 [M + H] + .

[0683] Step 2: At 25°C, compound 3d-1 (2.7g, 10.93 mmol) was added to a solution of DCE (30 mL), and while stirring, NBS (2.14g, 12.02 mmol) and AIBN (180 mg, 1.1 mmol) were added. The reaction was carried out at 85°C for 16 hours with stirring. After the reaction was complete, the reaction mixture was diluted with water, then extracted with dichloromethane, and the organic layers were combined. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (PE:EA = 20:1~10:1) to obtain compound 3d-2 (pale yellow oily substance, 2 g). MS m / z (ESI): 324.8 [M+H] + .

[0684] Step 3: Compound 3d-2 (2 g, 6.14 mmol) was added to DMF (25 mL) solution, then 3-aminopiperidine-2,6-dione (1.51 g, 9.2 mmol, hydrochloride) and N,N-diisopropylethylamine (5.66 mL, 30.68 mol) were added, and the mixture was reacted at 85°C for 16 hours with stirring. After the reaction was complete, the reaction solution was poured into ice water to precipitate the solid, filtered, the filtered cake was slurryed with MTBE, and the filtered cake was dried under vacuum to obtain compound 3d (gray solid, 1.6 g). MS m / z (ESI): 341.2 [M+H] + .

[0685] intermediate 4d [ka]

[0686] Step 1: Dissolve 2,2,6,6-tetramethylpiperidine (8.05 g, 9.61 mL, 57 mmol) in THF (150 mL), stir, and add n-butyllithium (21.87 mL, 54.7 mmol, 2.5 M) under nitrogen gas protection at 0°C. Allow the reaction to proceed for 1 hour with stirring at 0°C. Next, lower the temperature of the reaction system to -45°C, and at this temperature, add 4-bromo-3-fluorobenzoic acid (4.99 g, 22.8 mmol) and dissolve it in THF (15 mL). After the addition is complete, continue stirring at this temperature for 5 hours, and gradually add DMF (2.65 mL, 34.2 mmol) dropwise to the reaction system. Next, gradually raise the temperature of the reaction to room temperature and allow it to proceed overnight at room temperature. After the reaction was complete, the mixture was quenched at 0°C by dilution with 3N HCl, then extracted with EA, combined with the organic layers, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 50%~100%) to obtain compound 4d-1 (white solid, 3.6 g). MS m / z (ESI): 247.1 [M+H] + .

[0687] Step 2 followed the instructions in Step 3 for intermediate 3d to prepare compound 4d. MS m / z(ESI): 341.2[M+H] + .

[0688] Intermediate 5d [ka]

[0689] Compound 2-bromo-1-fluoro-4-nitrobenzene (1.5 g, 6.8 mmol) and compound (3-(4-(tert-butoxycarbonyl)piperazine-1-yl)phenyl)boronic acid (1.4 mg, 17.6 mmol) were added to a reaction flask. Dioxane (30 mL), water (10 mL), potassium carbonate (2.8 g, 20.4 mmol), and Pd(dppf)Cl2 (250 mg, 0.34 mmol) were added in sequence. After the addition was complete, the mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. After the reaction was complete, water was added to quench the mixture, and the organic phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Compound 5d (pale yellow solid, 900 mg) was obtained by column chromatography (PE / EA = 0-10%). MS m / z (ESI): 168.1 [M + H] + .

[0690] Intermediate 6d [ka]

[0691] Step 1: Compound 6d-1 was prepared by referring to Step 1 of intermediate 1c. MS m / z (ESI): 582.4 [M+H] + .

[0692] Step 2: Refer to Step 2 of intermediate 3b to prepare compound 6d-2. MS m / z(ESI): 482.4[M+H] + .

[0693] Step 3: Compound 6d-2 (200 mg, 0.415 mmol) and compound 1b (178 mg, 0.456 mmol) were dissolved in CH3CN / CHCl3 (1:1, 20 mL). K2CO3 (172 mg, 1.25 mmol) was added while stirring. The mixture was stirred at 65°C for 48 hours under nitrogen gas protection until the reaction was complete. H2O was added to the reaction system, extracted by DCM, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was first purified by normal-phase column chromatography, and then compound 6d (white solid, 75 mg, hydrochloride) was obtained by prep-HPLC. MS m / z (ESI): 776.6 [M+H] + .

[0694] Intermediate 22d [ka]

[0695] Step 1: N-bromosuccinimide (52.62 g, 295.62 mmol) was added to a solution of 2-methoxy-5-nitrophenol (50 g, 295.62 mmol) in dichloromethane (300 mL), and the reaction was carried out at 25°C for 2 hours with stirring. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (formic acid system), lyophilized, and obtained the title compound 22d-1 (yellow solid, 20 g). MS m / z (ESI): 248.3 [M+H] +

[0696] Step 2: Add boron tribromide (80.64 mmol, 7.77 mL) to a solution of 22d-1 (10 g, 40.32 mmol) in dichloromethane (100 mL) at -75°C. The mixture was reacted at -75°C for 2 hours with stirring, then the temperature was raised to 25°C and the reaction was continued for 4 hours with stirring. After the reaction was complete, methanol was added at 0°C to quench the reaction mixture, and the mixture was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 22d-2 (yellow solid, 9 g). MS m / z (ESI): 234.3 [M+H] +

[0697] Step 3: Potassium carbonate (12.40 g, 89.74 mmol) and 1,2-dibromoethane (16.86 g, 89.74 mmol, 6.77 mL) were added to a solution of 22d-2 (7 g, 29.91 mmol) in DMF (40 mL), and the mixture was reacted at 90°C for 4 hours with stirring. After the reaction was complete, the reaction mixture was extracted with water and ethyl acetate to separate the layers, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 10:1~5:1) to obtain compound 22d-3 (yellow solid, 3.8 g). MS m / z (ESI): 257.3 [M+H] +

[0698] Step 4: Refer to Step 2 of intermediate 7a to prepare compound 22d-4. MS m / z(ESI): 230.4[M+H] +

[0699] Step 5: 22d-4 (500 mg, 2.17 mmol), dimethylphosphorus oxide (169.63 mg, 2.17 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (251.51 mg, 434.67 μmol), palladium acetate (48.79 mg, 217.34 μmol), and potassium phosphate (922.66 mg, 4.35 mmol) were added to a 5 mL solution of DMF, and the mixture was reacted under a nitrogen atmosphere at 145°C with microwave stirring for 8 hours. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (formic acid-based) to obtain compound 22d-5 (grayish-white solid, 140 mg). MS m / z (ESI): 228.3 [M + H] +

[0700] Step 6 followed the intermediate 1d to obtain compound 22d. MS m / z(ESI): 418.4[M+H] +

[0701] intermediate 35d [ka]

[0702] Step 1: Compound 35d-1 was prepared following the method for control compound C-1. MS m / z (ESI): 501.8 [M+H] +

[0703] Step 2: Refer to Step 2 of intermediate 3b to prepare compound 35d. MS m / z(ESI): 401.6[M+H] +

[0704] Intermediate 48d [ka]

[0705] Compound 4 (200 mg, 0.77 mmol) and compound 1,4-dibromobutane (830 mg, 3.84 mmol) were dissolved in DMF (10 mL). K2CO3 (106.2 mg, 0.77 mmol) was added while stirring. The mixture was stirred at 70°C for 48 hours under nitrogen gas protection until the reaction was complete. H2O was added to the reaction system, extr...

Claims

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof, 【Chemistry 1】 Eventually, PIN is, 【Chemistry 2】 It is expressed as, Q is P(O)R ｑ１ R ｑ２ And R ｑ１ , R ｑ２ Each of them is independently, C １－５ It is an alkyl group, J １ is CR Ｊ１ and J ２ is CR Ｊ２ and J ３ is CR Ｊ３ and J ４ is CR Ｊ４ and R Ｊ１ , R Ｊ２ , R Ｊ３ , R Ｊ４ These are, independently, hydrogen, hydroxyl group, halogen, amino group, and C. １－５ Alkyl and halo C １－５ Selected from alkyl groups, L ５、 L ６ Each of these is independently NR ００ Selected from, V １ is N, V ２ is N, V ３ CR ３ V ４ CR ４ And, R ３ It is hydrogen, R ４ is a hydroxyl group, C(O)NR ａ R ｂ , halogen, or 0, 1 or 2 R ４１ A 5- to 6-membered heteroaryl group substituted with, where the heteroatoms of the 5- to 6-membered heteroaryl group are selected from one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, R ａ , R ｂ These are, independently, hydrogen and C. １－５ Alkyl or halo C １－５ It is an alkyl group, or R ａ , R ｂ These, together with the N atoms linked to them, form a 3- to 8-membered heterocycloalkyl group, and the heteroatoms of the 3- to 8-membered heterocycloalkyl group are selected from one or more of nitrogen, oxygen, and sulfur, and the number of such heteroatoms is one, two, or three. Or, R ３ , R ４ These include zero, one, or two R atoms linked to them. ４１ A 5- to 6-membered heteroaryl group or benzene is formed by substitution with , the heteroatom of the 5- to 6-membered heteroaryl group is nitrogen, and the number of such heteroatoms is one, two, or three. R ４１ is hydrogen, deuterium, halogen, C １－６ Alkyl, Halo C １－６ alkyl group, C １－６ Alkoxy groups and C １－６ Selected from alkylthio groups, Ring B is, 【Transformation 3】 And, 【Chemistry 4】 " represents the joining site, Rc consists of hydrogen, F, Cl, Br, I, a hydroxyl group, and C. １－５ Alkyl or halo C １－５ It is an alkyl group, and r3 is 0, 1, 2, or 3. K １ CR ｋ１ And R ｋ１ is hydrogen, halogen, C １－５ Alkyl and halo C １－５ Selected from alkyl groups, K ２ CR ｋ２ And K ４ CR ｋ４ And, R ｋ２ , R ｋ４ These are, independently, hydrogen, deuterium, halogen, cyano group, acylamino group, and C. １－５ Alkyl, Halo C １－５ alkyl group, C １－５ Alkoxy group, C １－３ Alkilen OC １－３ Selected from alkyl groups, of which C １－５ Alkyl alkyl group, the halo C １－５ alkyl group, the C １－５ Alkoxy group, the C １－３ Alkilen OC １－３ The alkyl group is optionally substituted with zero, one, two, three or more substituents selected from deuterium, hydroxyl groups, and cyano groups. R ｋ３ teeth, 【Transformation 5】 Halogen, cyano group, acetyl group, C １－５ alkyl group, C １－５ alkylene OC １－５ alkyl group and C ３－６ cycloalkyl group, and among them, the C １－５ alkyl group is optionally substituted with 0, 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, hydroxy group and cyano group, and in R ｋ３ Ra and Rb are hydrogen, methyl group, ethyl group, propyl group, isopropyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH ２ CH ２ F, -CHFCH ３ -, -CH ２ CHF ２ -, -CF ２ CH ３ -, -CHFCH ２ F, -CH ２ CF ３ -, -CF ２ CH ２ F or -CHFCHF ２ and Or, R ｋ３ C １－５ Selected from alkoxy groups and -CO-amino groups, Ring A is a 3- to 8-membered monocyclic heterocyclylene group or a 7- to 11-membered spiroheterocyclylene group, wherein the heteroatom of the monocyclic heterocyclylene group is N, and the number of such heteroatoms is 1 or 2, and the heteroatom of the spiroheterocyclylene group is N, and the number of such heteroatoms is 1 or 2. R is a chemical bond, or R is a 3- to 8-member monocyclic heterocyclylene group, a 7- to 16-member spiroheterocyclylene group, a 7- to 10-member bridged heterocyclylene group or an 8- to 10-member bicyclic heteroarylene group, the heteroatoms of the spiroheterocyclylene group are selected from one or more of nitrogen, oxygen and sulfur, the number of the heteroatoms is 1, 2 or 3, the heteroatoms of the bicyclic heteroarylene group are selected from one or more of nitrogen, oxygen and sulfur, the number of the heteroatoms is 1, 2 or 3, the heteroatoms of the monocyclic heterocyclylene group are selected from one or more of nitrogen, oxygen and sulfur, the number of the heteroatoms is 1, 2 or 3, the bridged heterocyclylene group contains 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or S, does not contain a cyclic moiety of -O-O-, -O-S- or -S-S-, and the 3- to 8-member monocyclic heterocyclylene group, the 7- to 16-member spiroheterocyclylene group, the 7- to 10-member bridged heterocyclylene group, or the 8- to 10-member bicyclic heteroarylene group is unsubstituted or independently substituted with 1, 2, 3, 4 or more groups selected from the following group B2 within the allowable range of valence, group B2 is hydrogen, =O, hydroxy group, halogen, C １－５ alkyl group, C １－５ alkoxy group, C １－５ alkylthio group and NR ｅ R ｆ selected from, among which, R ｅ , R ｆ are each independently hydrogen, C １－５ alkyl group or halo C １－５ alkyl group, Linker is 【Transformation 6】 It is expressed as, L １ (CR ２１ R ２２ ) ｎ３ And among them, R ２１ , R ２２ These are, independently, hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, or propoxy group. ｎ３ is 0, 1, 2, or 3, Or, L １ (CR ２１ R ２２ ) ｎ３ And among them, R ２１ , R ２２ Together with the carbon atoms linked to them, they form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or an oxetanyl group. ｎ３ is 0, 1, 2, or 3, Or, L １ is a chemical bond, C ３－６ Cycloalkylene group, O, S, NR ００ , C(O), C(O)NR ００ , NR ００ C(O), -C(O)O-, -OC(O)-, SO, SO ２ SO ２ NR ００ Or NR ００ SO ２ And R ００ is a hydrogen or methyl group, L ２ (CR ２１ R ２２ ) ｎ３ And among them, R ２１ , R ２２ These are, independently, hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, or propoxy group. ｎ３ is 0, 1, 2, or 3, L ３ is a chemical bond, O, S or NR ００ And, L ４ (CR ２１ R ２２ ) ｎ３ And among them, R ２１ , R ２２ These are, independently, hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, or propoxy group. ｎ３ is 0, 1, 2, or 3, E is, 【Transformation 7】 It is expressed as, W represents a chemical bond, O, S, NR ００ , -CH=CH- or -C≡C-, Z １ N is Z ２ CH ２ or C(O), G １ is N or CR Ｇ１ G ２ is N or CR Ｇ２ G ３ is N or CR Ｇ３ G ４ is N or CR Ｇ４ And, R Ｇ１ , R Ｇ２ , R Ｇ３ and R Ｇ４ One of them is linked to W, and the others are independently linked to hydrogen, a hydroxyl group, a halogen, an amino group, and C. １－５ Alkyl and halo C １－５ Selected from alkyl groups, One or more hydrogen atoms in the compound of formula (I) may be substituted with deuterium. Compounds represented by general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates or hydrates thereof, or mixtures thereof (provided that the compound of formula (1) is 【Transformation 8】 (Except in the case of...)

2. PIN is, 【Chemistry 9】 It is expressed as, Among them, Q is P(O)R ｑ１ R ｑ２ And R ｑ１ , R ｑ２ It is a methyl group, J １ CR Ｊ１ And J ２ CR Ｊ２ And J ３ CR Ｊ３ And J ４ CR Ｊ４ And, R Ｊ１ , R Ｊ２ , R Ｊ３ , R Ｊ４ Each of these is independently selected from H, F, Cl, Br, I, methyl group, ethyl group, propyl group and isopropyl group, L ５ NH is, L ６ NH is, V １ is N, V ２ is N, V ３ CR ３ V ４ CR ４ And, R ３ It is hydrogen, R ４ C(O)NR ａ R ｂ , halogen, or 0, 1 or 2 R ４１ A 5- to 6-membered heteroaryl group substituted with, where the heteroatoms of the 5- to 6-membered heteroaryl group are selected from one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3, R ａ , R ｂ Each is independently hydrogen or C １－５ It is an alkyl group, or R ａ , R ｂ These, together with the N atoms linked to them, form a 3- to 8-membered heterocycloalkyl group, and the heteroatoms of the 3- to 8-membered heterocycloalkyl group are selected from one or more of nitrogen, oxygen, and sulfur, and the number of such heteroatoms is one, two, or three. Or, R ３ , R ４ These atoms, together with the atoms linked to them, form a 5- to 6-membered heteroaryl group, and the heteroatoms of this 5- to 6-membered heteroaryl group are nitrogen atoms, with one, two, or three heteroatoms. R ４１ These are hydrogen, deuterium, and C １－６ Selected from alkyl groups, K １ CH is, K ２ CR ｋ２ And K ４ CR ｋ４ And, R ｋ２ , R ｋ４ These are, independently, hydrogen, deuterium, halogen, cyano group, acylamino group, and C. １－５ Alkyl, halo C １－５ Alkyl and C １－５ Selected from alkoxy groups, of which C １－５ Alkyl alkyl group, the halo C １－５ alkyl group, the C １－５ The alkoxy group is optionally substituted with zero, one, two, three or more substituents selected from deuterium and hydroxyl groups. R ｋ３ teeth, 【Chemistry 10】 Halogen, cyano group, acetyl group, C １－５ Alkyl alkyl group, C １－５ Alkilen OC １－５ Alkyl and C ３－６ Selected from cycloalkyl groups, of which C １－５ The alkyl group is optionally substituted with 0, 1, 2, 3, 4, or 5 substituents selected from deuterium, halogen, hydroxyl group, and cyano group, R ｋ３ In R ａ , R ｂ These are hydrogen, a methyl group, an ethyl group, a propyl group, or an isopropyl group. Ring A is, 【Chemistry 11】 It is expressed as, Eventually, Y １ , Y ２ Each is independently CH or N, and Y ３ , Y ４ Each of them is independently CH or N, t1, t2, t3, t4 are independently 1 or 2, and t5, t6 are independently 0, 1, or 2. R is a chemical bond, or R is 【Chemistry 12】 And, Ring C1 is a 5- to 6-membered heteroaryl group or benzene, and ring C2 is a 5- to 7-membered azacyclo group, of which the 5- to 6-membered heteroaryl group, the benzene, and the 5- to 7-membered azacyclo group contain hydrogen, D, halogen, amino group, hydroxyl group, and C １－５ Alkyl and C １－５ It is optionally substituted with zero, one, two, three or more substituents selected from alkoxy groups. Y ５ , Y ６ Each is independently CH or N, and Y ７ , Y ８ Each of the members is independently CH or N, s1, s2, s3, and s4 are independently 1 or 2, s5 and s6 are independently 0, 1, or 2, the heteroatom of the 5- to 6-membered heteroaryl group is nitrogen, and the number of such heteroatoms is 1, 2, or 3. Linker is 【Chemistry 13】 It is expressed as, Eventually, L １ (CR ２１ R ２２ ) ｎ３ And R ２１ , R ２２ These are, independently, hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, or propoxy group. ｎ３ is 0, 1, 2, or 3, Or, L １ (CR ２１ R ２２ ) ｎ３ And R ２１ , R ２２ These, together with the carbon atoms linked to them, form a cyclopropyl group. ｎ３ is 1, Or, L １ is a chemical bond, C ３－６ Cycloalkylene group, O, S, NR ００ , C(O), C(O)NR ００ , NR ００ C(O), -C(O)O-, -OC(O)-, SO, SO ２ SO ２ NR ００ Or NR ００ SO ２ And R ００ is a hydrogen or methyl group, L ２ (CR ２１ R ２２ ) ｎ３ And R ２１ , R ２２ These are, independently, hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, or propoxy group. ｎ３ is 0, 1, 2, or 3, L ３ is a chemical bond, O, S or NR ００ And, L ４ (CR ２１ R ２２ ) ｎ３ And R ２１ , R ２２ These are, independently, hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, or propoxy group. ｎ３ is 0, 1, 2, or 3, E is 【Chemistry 14】 It is expressed as, W represents a chemical bond, O, S, NR ００ , -CH=CH- or -C≡C-, Z １ is N, Z ２ CH ２ or C(O), G １ is N or CR Ｇ１ G ２ is N or CR Ｇ２ G ３ is N or CR Ｇ３ G ４ is N or CR Ｇ４ And, R Ｇ１ , R Ｇ２ , R Ｇ３ and R Ｇ４ One of them is connected to W, and R Ｇ１ , R Ｇ２ , R Ｇ３ and R Ｇ４ The others selected from among them were, independently, hydrogen, halogen, and C. １－３ Alkyl or halo C １－３ Selected from alkyl groups, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

3. R ｋ２ These are hydrogen, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, or isopropoxy group. And / or, R ｋ４ is hydrogen, deuterium, acylamino group, cyano group or C １－５ Selected from alkyl groups, And / or, R ｋ３ F, Cl, Br, I, cyano group, acetyl group, -CO amino group, C １－５ Alkyl alkyl group, C １－５ Alkoxy group, C １－５ Alkilen OC １－５ Alkyl and C ３－６ Selected from cycloalkyl groups, And / or, R ４ This is 0, 1, or 2 R ４１ Selected from the furyl group, thienyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, pyridyl group and pyrimidinyl group substituted with R ４１ These are hydrogen, deuterium, methyl group, ethyl group, propyl group, isopropyl group, trifluoromethyl group, trifluoroethyl group, methoxy group, ethoxy group, or propoxy group. Furthermore / or, ring A is a 5- to 7-membered monocyclic heterocyclylene group, or ring A is a 7- to 11-membered monospiroheterocyclylene group. Furthermore / or, the pharmaceutically acceptable salt is a hydrochloride salt, a formate salt, or a trifluoroacetate salt. A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

4. R ｋ４ These are methyl group, ethyl group, propyl group, isopropyl group, halo C １－５ Alkyl and C １－５ Selected from alkoxy groups, And / or, R ｋ３ F, Cl, Br, I, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, -CH ２ CH ２ F, CHFCH ３ ien-CH ２ CHF ２ , -CF ２ CH ３ yan-CHFCH ２ F, -CH ２ CF ３ , -CF ２ CH ２ F or -CHFCHF ２ That is, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

5. R ｋ３ teeth, 【Chemistry 15】 Selected from, R ａ , R ｂ is either H or a methyl group. A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

6. Ring A is, 【Chemistry 16】 It is expressed as, Eventually, Y １ , Y ２ Each is independently CH or N, and Y ３ , Y ４ Each of them is independently CH or N, t1, t2, t3, t4 are independently 1 or 2, and t5, t6 are independently 1 or 2. A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

7. Ring A is, 【Chemistry 17】 Selected from, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

8. R is a chemical bond, Alternatively, R is a 5- to 7-membered monocyclic heterocyclylene group. Alternatively, R may be 0, 1, 2, or 3 R's. ０ A 7- to 11-membered monospiroheterocyclylene group or an 8- to 10-membered bicyclic heteroarylene group substituted with R ０ Hydrogen, halogen, =O, C １－５ Alkyl alkyl group or C １－５ Selected from alkoxy groups, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

9. R is, [Chemistry 18] It is expressed as, Ring C1 is a 5- to 6-membered heteroaryl group or benzene, and ring C2 is a 5- to 6-membered azacyclo group, of which the 5- to 6-membered heteroaryl group, the benzene, and the 5- to 6-membered azacyclo group can each be optionally composed of hydrogen, D, halogen, amino group, hydroxyl group, or C １－５ Alkyl and C １－５ Substituted with zero, one, two, three or more substituents selected from alkoxy groups, Y ５ , Y ６ Each is independently CH or N, and Y ７ , Y ８ Each of them is independently CH or N, s1, s2, s3, s4 are independently 1 or 2, and s5, s6 are independently 0, 1, or 2. A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

10. Ring C1 is selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, benzene, pyridine, pyrimidine, pyrazine, and pyridazine, and ring C2 is selected from tetrahydropyrrole, piperidine, and piperazine. A compound represented by general formula (I) as described in claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

11. R is, 【Chemistry 19】 Selected from among, 【Chemistry 20】 It is connected to Linker, and the other end is connected to ring A, or, 【Chemistry 21】 It is connected to ring A, and the other end is connected to Linker. A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

12. L １ CH ２ ,CH ２ CH ２ or CH ２ CH ２ CH ２ And, Furthermore / or, W is O, S, -CH=CH- or C≡C, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

13. Ring B is, 【Chemistry 22】 Selected from, 「 【Chemistry 23】 " represents the joining site, r3 is 0, and / or, V １ , V ２ Both are N, V ３ CR ３ V ４ CR ４ And among them, R ３ is hydrogen and R ４ is fluorine or chlorine, or R ３ , R ４ These, together with the atoms linked to them, form 1H-pyrrole, 1H-pyrazole, or 1H-imidazole. and / or, L ５ , L ６ NH is, And / or E is, 【Chemistry 24】 Selected from, R Ｇ１ , R Ｇ２ , R Ｇ３ , R Ｇ４ One of them is linked to W, and the others are independently hydrogen, hydroxyl group, fluorine, chlorine, bromine, amino group, methyl group, ethyl group, propyl group, isopropyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, and -CH ２ CH ２ F, CHFCH ３ ien-CH ２ CHF ２ , -CF ２ CH ３ yan-CHFCH ２ F, -CH ２ CF ３ , -CF ２ CH ２ F and -CHFCHF ２ Selected from, R ０ These are hydrogen, deuterium, halogen, and C, respectively, independently. １－３ Alkyl or halo C １－３ It is an alkyl group. A compound represented by general formula (I) as described in claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

14. R Ｇ１ , R Ｇ２ , R Ｇ３ , R Ｇ４ These are, independently, hydrogen, halogen, and C. １－３ Alkyl or halo C １－３ It is an alkyl group. A compound represented by general formula (I) as described in claim 13, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

15. R Ｇ１ , R Ｇ２ , R Ｇ３ , R Ｇ４ , R ０ These are, independently, a halogen, F, a methyl group, or a trifluoromethyl group. A compound represented by general formula (I) as described in claim 13, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

16. R Ｊ１ , R Ｊ２ , R Ｊ３ , R Ｊ４ These are, independently, H, F, Cl, Br, I, methyl group, ethyl group, propyl group, isopropyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, and -CH ２ CH ２ F, CHFCH ３ ien-CH ２ CHF ２ , -CF ２ CH ３ yan-CHFCH ２ F, -CH ２ CF ３ , -CF ２ CH ２ F and -CHFCHF ２ Selected from, Furthermore / or, Q is P(O)R ｑ１ R ｑ２ And among them, R ｑ１ , R ｑ２ Each of these is independently selected from a methyl group, an ethyl group, a propyl group, and an isopropyl group. A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

17. PIN is, 【Chemistry 25】 It is expressed as V １ , V ２ , V ３ , V ４ J １ J ２ J ３ J ４ , R ｋ２ , R ｋ３ , R ３ , R ４ Rings A and R are as defined in claim 1, Or, R ３ , R ４ These, together with the atoms linked to them, form 1H-pyrrole. A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

18. The compound represented by general formula (I) is one of the following compounds: 【Chemistry 26】 A compound represented by general formula (I) as described in claim 13, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

19. The compound represented by general formula (I) is one of the following compounds: 【Chemistry 27】 A compound represented by general formula (I) as described in claim 13, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

20. The compound represented by general formula (I) is the compound represented by formula (III-1-1) or (III-1-2), 【Chemistry 28】 R ４ is a halogen, R ｋ２ is hydrogen or C １－５ It is an alkoxy group, R ｋ３ These are halogens, acetyl groups, cyano groups, and C １－５ Alkyl alkyl group, C ３－６ Cycloalkyl groups or C １－５ It is an alkoxy group, L １ is a chemical bond, CH ２ ,CH ２ CH ２ ,CH ２ CH ２ CH ２ CO, NH, CONH, NHCO, -N(methyl)-, O, C(O)O, OC(O) or (CR ２１ R ２２ ) ｎ３ And among them, R ２１ , R ２２ These are, independently, hydrogen or a methyl group, or R ２１ , R ２２ Together with the C atoms linked to them, they form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or an oxetanyl group. ｎ３ is 0, 1, 2, or 3, L ２ (CR ２１ R ２２ ) ｎ３ And among them, R ２１ , R ２２ These are, independently, hydrogen or methyl group, ｎ３ is 0, 1, 2, or 3, L ３ is a chemical bond or O, L ４ (CR ２１ R ２２ ) ｎ３ And among them, R ２１ , R ２２ These are, independently, hydrogen or methyl group, ｎ３ is 0, 1, 2, or 3, Z １ is CH or N, Z ２ CH ２ or C(O), W is O, S, an alkenylene group, or C≡C. R ０ H, D, halogen, hydroxyl group, C １－３ Alkyl alkyl group or C １－３ It is an alkoxy group, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

21. R ４ is chlorine or bromine, R ｋ２ is a hydrogen or methoxy group, A compound represented by general formula (I) as described in claim 20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

22. R ４ is chlorine or bromine, R ｋ２ R is a hydrogen or methoxy group, ｋ３ Fluorine, chlorine, bromine, acetyl group, methyl group, ethyl group, isopropyl group, propyl group, trifluoromethyl group, -CH ２ CH ２ F, CHFCH ３ ien-CH ２ CHF ２ , -CF ２ CH ３ yan-CHFCH ２ F, -CH ２ CF ３ , -CF ２ CH ２ F and -CHFCHF ２ Selected from, L １ , L ２ , L ４ Each of these is a chemical bond, CH ２ or CH ２ CH ２ And, L ３ It is a chemical bond, Z １ is CH or N, Z ２ CH ２ Or C(O), W is O, S or C≡C, R ０ is H, D, fluorine, chlorine, bromine, hydroxyl group, methyl group, ethyl group, propyl group, or isopropyl group. A compound represented by general formula (I) as described in claim 20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

23. R ４ That is chlorine, And / or, W is C≡C, and / or, R ０ Hydrogen, F, C １－３ Alkyl or halo C １－３ It is an alkyl group. A compound represented by general formula (I) as described in claim 22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

24. The compound represented by general formula (I) is the compound represented by formula (III-2-1) or (III-2-5), 【Chemistry 29】 Among them, Q is P(O)(C １－３ Alkyl) ２ And, Y １ is CH or N, Y ２ is CH or N, and t1, t2, t3, and t4 are each independently 1 or 2, and R Ｊ１ , R Ｊ２ , R ３ , R ４ , R ｋ２ , R ｋ３ , L １ , L ２ , L ３ , L ４ , W, G １ G ２ G ３ G ４ Z １ and Z １ The following is described in claim 1, and ring A is a 3-membered to 8-membered cycloalkylene group, R ０ is hydrogen, F, C １－５ Alkyl alkyl group or C １－５ Selected from alkoxy groups, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

25. The compound represented by general formula (I) is the compound represented by (III-2-2) or (III-2-3), 【Transformation 30】 Eventually, R ４ is chlorine or bromine, Y １ is N, Y ２ is CH, and t1, t2, t3, and t4 are each independently 1 or 2, R ｋ２ R is hydrogen, a methoxy group, or an ethoxy group. ｋ３ Fluorine, chlorine, bromine, cyano group, acetyl group, methyl group, ethyl group, isopropyl group, propyl group, trifluoromethyl group, -CH ２ CH ２ F, CHFCH ３ ien-CH ２ CHF ２ , -CF ２ CH ３ yan-CHFCH ２ F, -CH ２ CF ３ , -CF ２ CH ２ F or -CHFCHF ２ Selected from, L １ , L ２ , L ４ Each of these is a chemical bond, CH ２ or CH ２ CH ２ And L ３ It is a chemical bond, W is either O or S, Z １ is CH or N, Z ２ CH ２ or C(O), R ０ It is selected from hydrogen, fluorine, chlorine and methyl groups. A compound represented by general formula (I) as described in claim 24, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

26. W is O, and / or, L １ , L ２ , L ３ , L ４ These are each an independent chemical bond. A compound represented by general formula (I) as described in claim 25, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

27. The aforementioned compound is one of the following compounds: 【Chemistry 31-1】 【Chemistry 31-2】 【Chemistry 31-3】 【Chemistry 31-4】 【Chemistry 31-5】 【Chemistry 31-6】 【Chemistry 31-7】 【Chemistry 31-8】 【Chemistry 31-9】 【Chemistry 31-10】 【Chemistry 31-11】 【Chemistry 31-12】 【Chemistry 31-13】 【Chemistry 31-14】 【Chemistry 31-15】 【Chemistry 31-16】 【Chemistry 31-17】 【Chemistry 31-18】 【Chemistry 31-19】 【Chemistry 31-20】 【Chemistry 31-21】 【Chemistry 31-22】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

28. R ｋ３ teeth, 【Chemistry 32】 F, Cl, Br, I, cyano group, acetyl group, ethyl group, C １－５ Alkilen OC １－５ Alkyl and C ３－６ Selected from cycloalkyl groups, the ethyl group is optionally substituted with 0, 1, 2, or 3 substituents selected from deuterium, hydroxyl groups, and cyano groups, R ａ is H, methyl group, ethyl group, propyl group or isopropyl group, and R ｂ is H, methyl group, ethyl group, propyl group or isopropyl group, Furthermore, Linker is 【Transformation 33】 It is expressed as, And / or, R Ｊ１ , R Ｊ３ , R Ｊ４ Each of them is hydrogen, And / or, R Ｊ２ These are hydrogen, F, Cl, Br, and C １－５ Selected from alkyl groups, Furthermore / or, W is O or -C≡C- A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

29. R １３ , R １４ It is hydrogen, And / or, R １１ , R １２ These are, independently, hydrogen, F, Cl, Br, and C. １－５ Selected from alkyl groups, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

30. A pharmaceutical composition comprising a compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof, and a pharmaceutically acceptable excipient.

31. The pharmaceutical composition according to claim 30, further comprising other therapeutic agents.

32. A pharmaceutical composition comprising a compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof, for inhibiting or degrading a protein, A pharmaceutical composition wherein the protein is at least one selected from the group consisting of EGFR, ROS1, or ALK.

33. A pharmaceutical composition for treating and / or preventing cancer, comprising a compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof.

34. The aforementioned cancers are selected from lung cancer, lymphoma, inflammatory myofibroblastoma, colorectal cancer, glioma, astrocytoma, ovarian cancer, bone marrow cancer, transplant-related cancer, neutropenia, leukemia, bronchial cancer, prostate cancer, breast cancer, thyroid cancer, pancreatic cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, colorectal adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer, sarcoma, tumors resistant to targeted drugs, or tumors or diseases dependent on ALK, ROS1, EGFR, or any of their mutant proteins, or The aforementioned cancers include small cell lung cancer, non-small cell lung cancer, diffuse large B-cell lymphoma, non-Hodgkin lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, CD20-positive lymphoma, primary lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin lymphoma, refractory B-cell non-Hodgkin lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin lymphoma, multiple myeloma, myelodysplastic syndrome, and previously treated Selected from myelodysplastic syndrome, plasmacytosis, smoldering myeloma, smoldering multiple myeloma, myelofibrosis, acute myeloid leukemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, bronchial cancer, prostate cancer, triple-negative breast cancer, incidental breast cancer, thyroid cancer, pancreatic cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, colorectal adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer, rhabdomyosarcoma, various adipose-derived tumors, Ewing's sarcoma / anaplastic neuroectodermatoma, leiomyosarcoma, EGFR, ROS1 or ALK-targeted tumors, or The aforementioned cancers include non-small cell lung cancer positive for anaplastic lymphoma kinase mutations, ROS1-positive non-small cell lung cancer, EGFR-mutated non-small cell lung cancer, lung adenocarcinoma, lung cancer resistant to EGFR, ROS1, or ALK-targeted drugs, lymphoma resistant to ALK-targeted drugs, or lung cancer, lymphoma, inflammatory myofibroblastoma, colorectal cancer, glioma, and astrocytosis cancer that depend on ALK, ROS1, EGFR, or any of their mutant proteins. A tumor, cancer, or disease selected from among glioblastoma, ovarian cancer, leukemia, breast cancer, thyroid cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, esophageal squamous cell carcinoma, renal cell carcinoma, bronchial cancer, prostate cancer, breast cancer, thyroid cancer, pancreatic cancer, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, colorectal adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer, or sarcoma, etc. The pharmaceutical composition according to claim 33.

35. A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate or hydrate thereof, or a mixture thereof, The compound represented by the above general formula (I) is one of the following compounds: 【Chemistry 36-1】 【Chemistry 36-2】

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