Quinazoline compound, and pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a quinazoline compound, and a pharmaceutical composition thereof and the use thereof. Provided in the present invention is a compound as represented by formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The compounds of the present invention have a good degradation effect on the KRAS protein with a G12D mutation, have a good inhibitory activity against the proliferation of tumor cells with a KRAS G12D mutation, and exhibit good pharmacokinetic properties.

Description

Quinazoline compounds, pharmaceutical compositions and applications thereof

[0001] This application claims the benefit of Chinese Patent Application No. 2024101776206, filed on February 8, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention relates to a quinazoline compound, a pharmaceutical composition and application thereof. Background Art

[0003] The KRAS gene is a frequently mutated proto-oncogene in human cancers. Approximately 25% of cancer patients harbor KRAS mutations, with KRAS G12D mutations accounting for a high proportion, particularly in pancreatic and colorectal cancers. Due to the small size of the KRAS protein, it is difficult to find binding sites for small molecule drugs. Its strong affinity for GTP makes it difficult for drugs to compete with it. Small molecules targeting the active site of mutant KRAS often also inhibit the activity of wild-type KRAS. Furthermore, the complexity of signaling pathways and the drug resistance of KRAS-mutant tumors contribute to the inefficiency of drug therapies targeting KRAS mutations. Proteolysis-targeting chimeras (PROTACs) can transiently form a ternary complex within the cell, tagging the target protein with ubiquitination, which is then recognized and degraded by the ubiquitin-proteasome system. After labeling, PROTACs can be reused within the cell to form new ternary complexes, inducing multiple rounds of degradation of the target protein. Complete protein removal also results in stronger drug efficacy. PROTAC-mediated KRAS G12D degradation is a feasible method to intervene in KRAS G12D mutations in cancer and inhibit tumor growth. Currently, there are no PROTAC drugs targeting KRAS G12D on the market. Summary of the Invention

[0004] The present invention aims to overcome the shortcomings of prior art KRAS inhibitors with G12D mutations, such as insufficient activity, by providing novel quinazoline compounds, pharmaceutical compositions thereof, and their uses. The compounds of the present invention exhibit excellent degradation of G12D-mutated KRAS proteins, exhibit good inhibitory activity against the proliferation of KRAS G12D-mutated tumor cells, and exhibit favorable pharmacokinetic properties.

[0005] The present invention provides a compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof;

[0006] in:

[0007] G is N or CRG , R G is H, halogen or cyano;

[0008] J is N or CR J , R J is H, halogen or cyano;

[0009] X is -O- or -NH-;

[0010] R 1 is C3-C7 cycloalkyl, 7-12 membered heterocycloalkyl, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl;

[0011] Each R 1-1 is a 4-12 membered heterocycloalkyl group or -S(O)2R 1-1-3 The heteroatom species in the 4-12 membered heterocycloalkyl group is S, the number of heteroatoms is 1 or 2, and the S atoms are independently replaced by one or more R 1-1-2 replace;

[0012] Each R 1-1-2 are independently oxo (=O) or =NR 1-1-1-3 ;

[0013] R 1-1-1-3 is hydrogen or C1-C6 alkyl;

[0014] R 1-1-3 is a C3-C7 cycloalkyl group or a C1-C6 alkyl group;

[0015] Each R 1-2 are independently deuterium, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, 4-12 membered heterocycloalkyl, 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, one or more R 1-2-3 Substituted 4-12 membered heterocycloalkyl, -S(O)2R 1-1-3 , -O-C3-C7 cycloalkyl, -C(O)NHR 1-2-4 or -NHC(O)R 1-2-4 ;

[0016] Each R 1-2-1 are independently halogen, hydroxy or C1-C6 alkoxy;

[0017] Each R 1-2-2 are independently deuterium, halogen or C3-C7 cycloalkyl;

[0018] Each R 1-2-3 independently halogen, C1-C6 alkyl, C1-C6 alkoxy, 1-2-3-1 Substituted C1-C6 alkyl or one or more R 1- 2-3-2 Substituted C1-C6 alkoxy;

[0019] Each R 1-2-3-1 are independently halogen;

[0020] Each R 1-2-3-2 are independently deuterium or halogen;

[0021] Each R 1-2-4 are independently C3-C7 cycloalkyl or C1-C6 alkyl;

[0022] Each R 1-3 are independently oxo, deuterium, C1-C6 alkyl or substituted by one or more R 1-3-1 Substituted C1-C6 alkyl;

[0023] Each R 1-3-1 are independently halogen;

[0024] E is absent, -O- or -NR e -;

[0025] R e is hydrogen or C1-C6 alkyl;

[0026] R 2 is a 4-12 membered heterocycloalkyl group or is replaced by one or more R 2-1 substituted 4-12 membered heterocycloalkyl;

[0027] Each R 2-1 are independently halogen, C1-C6 alkyl or substituted by one or more R 2-1-1 Substituted C1-C6 alkyl; each R 2-1-1 are independently halogen, hydroxy or alkoxy;

[0028] R 3 is halogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl or is replaced by one or more R 3-1 Substituted C1-C6 alkyl;

[0029] Each R 3-1 are independently halogen, hydroxy or C1-C6 alkoxy;

[0030] R 4 is hydrogen or halogen;

[0031] R 5is C1-C6 alkyl, C3-C7 cycloalkyl, or C1-C6 alkyl substituted by one or more deuteriums;

[0032] R 10 is methylene, monodeuteromethylene or dideuteromethylene;

[0033] Y is absent, -O-, -NH-, C1-C6 alkylene, C3-C7 cycloalkylene, 4-12 membered heterocycloalkylene or -OR Y-1 -;

[0034] R Y-1 is C1-C6 alkylene or 4-12 membered heterocycloalkylene;

[0035] Z is absent, a 5-10 membered heteroarylene group or -H 1 -H 2 -, and Y and Z do not exist at the same time; H 1 C3-C 12 Cycloalkylene, 4-12 membered heterocycloalkylene, one or more R h1 Substituted C3-C 12 Cycloalkylene or one or more R h2 Substituted 4-12 membered heterocycloalkylene; H 2 is C1-C6 alkylene, -O- or -NH-; H 1 Connect with Y, H 2 Connected to LL;

[0036] LL is the E3 ligase ligand;

[0037] Each "heterocycloalkyl" (excluding R 1-1 In the “4-12 membered heterocycloalkyl” and “heterocycloalkylene”, the heteroatom species are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2, 3, 4 or 5;

[0038] In each "heteroarylene group", the heteroatom species are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

[0039] In a certain embodiment, in the compound represented by Formula I, its stereoisomers or pharmaceutically acceptable salts thereof, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any embodiment of the present invention (this paragraph is hereinafter referred to as "in a certain embodiment").

[0040] In a certain embodiment, in the compound shown in Formula I, each R 1-1 Independently, it can also be R 1-1-4It is a C1-C6 alkyl group.

[0041] In a certain embodiment, in the compound shown in Formula I, each R 2-1 Independently, it can also be s is 0, 1, 2, or 3.

[0042] In one embodiment, the compound represented by formula I is not any of the following compounds (any of the compounds on pages 9-30 of patent application document WO2024199266A1):

[0043] In one embodiment, the compound represented by formula I is a compound represented by formula I':

[0044] Wherein, * indicates that the carbon atom has a chiral center and the stereoisomer form is an atropisomer.

[0045] In one embodiment, the compound represented by Formula I is a compound represented by Formula Ia or Ib:

[0046] In one embodiment, each halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0047] In one embodiment, each C1-C6 alkyl group may independently be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, an isobutyl group or a sec-butyl group, preferably a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0048] In a certain embodiment, each C3-C7 cycloalkyl group can independently be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0049] In a certain embodiment, each 4-12 membered heterocycloalkyl group can independently be a 4-6 membered monocyclic heterocycloalkyl group or a 7-12 membered polycyclic (eg, spirocyclic, fused or bridged) heterocycloalkyl group.

[0050] In a certain embodiment, each 7-12 membered heterocycloalkyl group can independently be a 7-12 membered polycyclic (eg, spirocyclic, fused or bridged) heterocycloalkyl group.

[0051] In one embodiment, the 4-6 membered monocyclic heterocycloalkyl group can be independently More preferred It can also be

[0052] In one embodiment, each of the 7-12 membered polycyclic heterocycloalkyl groups is independently Preferred Further optimization

[0053] In a certain embodiment, each C1-C6 alkoxy group can independently be a C1-C4 alkoxy group, and can also be a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group, isobutoxy group or sec-butoxy group, preferably a methoxy group, ethoxy group or isopropoxy group.

[0054] In one embodiment, each C1-C6 alkylene group can be independently a C1-C4 alkylene group, or a Preferred

[0055] In one embodiment, each C3-C7 cycloalkylene and C3-C 12 Cycloalkylene groups can independently be

[0056] In a certain embodiment, each 4-12 membered heterocycloalkylene group can independently be a 4-6 membered monocyclic heterocycloalkylene group or a 7-12 membered polycyclic (e.g., spirocyclic, fused or bridged) heterocycloalkylene group, and the 4-6 membered monocyclic heterocycloalkylene group is preferably a piperazinylene group, for example

[0057] In a certain embodiment, each 5-10 membered heteroaryl group can be independently a 5-8 membered monocyclic heteroaryl group or an 8-10 membered bicyclic (e.g., bicyclic) heteroaryl group, wherein the 5-8 membered monocyclic heteroaryl group is preferably a 5-6 membered monocyclic heteroaryl group, more preferably Further optimization

[0058] In a certain embodiment, each 5-10 membered heteroaryl group can be independently a 5-8 membered monocyclic heteroaryl group or an 8-10 membered bicyclic (eg, bicyclic) heteroaryl group, wherein the 5-8 membered monocyclic heteroaryl group is preferably a 5-6 membered monocyclic heteroaryl group, more preferably Further optimization

[0059] In one scheme, each C6-C 10 Aryl may be phenyl or naphthyl, preferably phenyl.

[0060] In one embodiment, X is -O-.

[0061] In one embodiment, G is N or CH; preferably N.

[0062] In one embodiment, J is N.

[0063] In one scenario, R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the 7-12 membered heterocycloalkyl and one or more R 1-3 The heteroatoms in the 7-12 membered heterocycloalkyl group of the substituted 7-12 membered heterocycloalkyl group are independently O and / or N, and the number of heteroatoms is independently 1 or 2; preferably, R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the heteroatom species in the 7-12 membered heterocycloalkyl is O, the number of heteroatoms is 1 or 2, and the one or more R 1-3 The type of heteroatom in the substituted 7-12-membered heterocycloalkyl group is N, and the number of heteroatoms is 1 or 2.

[0064] In one scheme, each R 1-1-2 are independently oxo or =NR 1-1-1-3 ; preferably oxo.

[0065] In one scenario, R 1-1-3 It is a C1-C6 alkyl group.

[0066] In one scheme, each R 1-2 are independently deuterium, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, 4-12 membered heterocycloalkyl, 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, -S(O)2R 1-1-3 , -O-C3-C7 cycloalkyl or -NHC(O)R 1- 2-4 The heteroatom species in the 4-12 membered heterocycloalkyl group is N and / or O, and the number of heteroatoms is 1 or 2; preferably halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, 4-12 membered heterocycloalkyl, one or more R 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, -S(O)2R1-1-3 or -NHC(O)R 1-2-4 The heteroatom species in the 4-12 membered heterocycloalkyl group is N and / or O, and the number of heteroatoms is 1 or 2; more preferably, hydroxyl, C1-C6 alkoxy, or one or more R 1-2-1 Substituted C1-C6 alkyl or -NHC(O)R 1-2-4 ; Further preferably hydroxyl, C1-C6 alkoxy or one or more R 1-2-1 Substituted C1-C6 alkyl.

[0067] In one scheme, each R 1-2-1 are independently halogen, hydroxy or C1-C6 alkoxy; preferably halogen or C1-C6 alkoxy; more preferably C1-C6 alkoxy.

[0068] In one scheme, each R 1-2-1 are independently hydroxy or C1-C6 alkoxy.

[0069] In one scheme, each R 1-2-2 is independently deuterium or a halogen.

[0070] In one scheme, each R 1-2-2 are independently halogen.

[0071] In one scenario, R 1-2-4 It is a C1-C6 alkyl group.

[0072] In one scheme, each R 1-3 are independently deuterated or replaced by one or more R 1-3-1 Substituted C1-C6 alkyl; preferably, each R 1-3 Independently by one or more R 1-3-1 Substituted C1-C6 alkyl.

[0073] In one scenario, R 1 is a 7-12 membered heterocycloalkyl group or is replaced by one or more R 1-3 a substituted 7-12 membered heterocycloalkyl group, wherein the 7-12 membered heterocycloalkyl group is a bridged ring;

[0074] Preferably, the compound represented by formula I is any one of the following compounds:

[0075] In one scenario, R 1 For one or more R 1-1 Substituted C1-C6 alkyl; each R 1-1 independently 4-12 membered heterocycloalkyl or -S(O)2R 1-1-3The heteroatom species in the 4-12 membered heterocycloalkyl group is S, the number of heteroatoms is 1 or 2, and the S atoms are independently replaced by one or more R 1-1-2 replace;

[0076] Preferably, the compound represented by formula I is any one of the following compounds:

[0077] In one scenario, R 1 For one or more R 1-1 Substituted C1-C6 alkyl; each R 1-1 for R 1-1-4 is a C1-C6 alkyl group;

[0078] Preferably, the compound shown in formula I is

[0079] In one scenario, R 1 For one or more R 1-2 Substituted C3-C7 cycloalkyl, each R 1-2 are independently deuterium, halogen, hydroxyl, cyano, C1-C6 alkane, 4-12 membered heterocycloalkyl, 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, one or more R 1-2-3 Substituted 4-12 membered heterocycloalkyl, -S(O)2R 1-1-3 , -O-C3-C7 cycloalkyl, -C(O)NHR 1-2-4 or -NHC(O)R 1-2-4 Preferably, each R 1- 2 are independently deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, 4-12 membered heterocycloalkyl, 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, -S(O)2R 1-1-3 、-C(O)NHR 1-2-4 or -NHC(O)R 1-2-4 More preferably, each R 1-2 are independently deuterium, hydroxyl, -NHC(O)R 1-2-4 or by one or more R 1-2-1 Substituted C1-C6 alkyl;

[0080] More preferably, the compound represented by formula I is any one of the following compounds:

[0081] In one scenario, R1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the 7-12 membered heterocycloalkyl and one or more R 1-3 The 7-12 membered heterocycloalkyl in the substituted 7-12 membered heterocycloalkyl is a bridged ring;

[0082] Each R 1-1 independently 4-12 membered heterocycloalkyl or -S(O)2R 1-1-3 The heteroatom species in the 4-12 membered heterocycloalkyl group is S, the number of heteroatoms is 1 or 2, and the S atoms are independently replaced by one or more R 1-1-2 replace;

[0083] Each R 1-2 are independently deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, 4-12 membered heterocycloalkyl, 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, one or more R 1-2-3 Substituted 4-12 membered heterocycloalkyl, -S(O)2R 1-1-3 , -O-C3-C7 cycloalkyl, -C(O)NHR 1-2-4 or -NHC(O)R 1-2-4 ; Each R 1-3 are independently oxo, deuterium, C1-C6 alkyl or substituted by one or more R 1-3-1 Substituted C1-C6 alkyl.

[0084] In one scenario, R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the 7-12 membered heterocycloalkyl and one or more R 1-3 The 7-12 membered heterocycloalkyl in the substituted 7-12 membered heterocycloalkyl is a bridged ring;

[0085] Each R 1-1 independently 4-12 membered heterocycloalkyl or -S(O)2R 1-1-3 The heteroatom species in the 4-12 membered heterocycloalkyl group is S, the number of heteroatoms is 1 or 2, and the S atoms are independently replaced by one or more R 1-1-2 replace;

[0086] Each R 1-2 are independently deuterium, hydroxyl, -NHC(O)R 1-2-4 or by one or more R 1-2-1 Substituted C1-C6 alkyl;

[0087] Each R 1-3 independently deuterium.

[0088] In one scenario, R 2 is a 4-12 membered heterocycloalkyl group or is replaced by one or more R 2-1 substituted 4-12 membered heterocycloalkyl, wherein the 4-12 membered heterocycloalkyl and one or more R 2-1 The heteroatom species in the 4-12-membered heterocycloalkyl group of the substituted 4-12-membered heterocycloalkyl group is N, and the number of heteroatoms is independently 1, 2 or 3; preferably, R 2 is a 4-6 membered monocyclic heterocycloalkyl, a 7-12 membered polycyclic heterocycloalkyl, or one or more R 2-1 substituted 4-6 membered monocyclic heterocycloalkyl or one or more R 2-1 substituted 7-12 membered polycyclic heterocycloalkyl, wherein the 4-6 membered monocyclic heterocycloalkyl, 7-12 membered polycyclic heterocycloalkyl, 2-1 The 4-6 membered monocyclic heterocycloalkyl in the substituted 4-6 membered monocyclic heterocycloalkyl and the substituted 4-6 membered monocyclic heterocycloalkyl 2-1 The heteroatom species in the 7-12-membered polycyclic heterocycloalkyl group in the substituted 7-12-membered polycyclic heterocycloalkyl group is N, and the number of heteroatoms is independently 1 or 2; more preferably, R 2 is a 5-6 membered monocyclic heterocycloalkyl, a 7-8 membered polycyclic heterocycloalkyl, or one or more R 2-1 substituted 5-6 membered monocyclic heterocycloalkyl or one or more R 2-1 substituted 7-8 membered polycyclic heterocycloalkyl, wherein the 5-6 membered monocyclic heterocycloalkyl, 7-8 membered polycyclic heterocycloalkyl, 2-1 The 5-6 membered monocyclic heterocycloalkyl in the substituted 5-6 membered monocyclic heterocycloalkyl and the substituted 5-6 membered monocyclic heterocycloalkyl 2-1 The heteroatom species in the 7-8 membered polycyclic heterocycloalkyl group in the substituted 7-8 membered polycyclic heterocycloalkyl group is N, and the number of heteroatoms is independently 1 or 2; preferably, R 2 It is a 5-6 membered monocyclic heterocycloalkyl group or a 7-8 membered polycyclic heterocycloalkyl group, wherein the heteroatom type in the 5-6 membered monocyclic heterocycloalkyl group and the 7-8 membered polycyclic heterocycloalkyl group is N, and the number of heteroatoms is independently 1 or 2.

[0089] In one scheme, each R 2-1 are independently C1-C6 alkyl.

[0090] In one embodiment, E is absent or -NR e -.

[0091] In one scenario, R e It is a C1-C6 alkyl group.

[0092] In one scenario, R 3 is halogen or C3-C7 cycloalkyl; preferably C3-C7 cycloalkyl.

[0093] In one scenario, R 4 It is a halogen.

[0094] In one scenario, R 5 It is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuterium groups; preferably a C1-C6 alkyl group.

[0095] In one scenario, R 10 is methylene or dideuterimethylene; preferably methylene.

[0096] In one scenario, Y is absent, OR Y-1 -; Preferably, Y is absent or -OR Y-1 - or Y is absent or More preferably, it is absent.

[0097] In one scenario, H 2 It is a C1-C6 alkylene group.

[0098] In one embodiment, Z is a 5-10 membered heteroarylene group or -H 1 -H 2 -, the heteroatom species in the 5-10 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2, 3 or 4; H 1 is a 4-12 membered heterocycloalkylene group or is replaced by one or more R h2 substituted 4-12 membered heterocycloalkylene, wherein the 4-12 membered heterocycloalkylene is replaced by one or more R h2 The heteroatom species of the 4-12-membered heterocycloalkylene in the substituted 4-12-membered heterocycloalkylene is N, and the number of heteroatoms is independently 1, 2 or 3; H 2 is C1-C6 alkylene; H 1 Connect with Y, H 2 is connected to LL; preferably, Z is a 5-10 membered heteroarylene group, the heteroatom species in the 5-10 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2, 3 or 4; more preferably, Z is a 5-6 membered heteroarylene group, the heteroatom species in the 5-6 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2, 3 or 4.

[0099] In one scenario, H 1 is a 4-12 membered heterocycloalkylene group or is replaced by one or more R h2 Substituted 4-12 membered heterocycloalkylene; said 4-12 membered heterocycloalkylene or one or more R h2 The heteroatom species in the 4-12-membered heterocycloalkylene in the substituted 4-12-membered heterocycloalkylene is N, and the number of heteroatoms is 1, 2 or 3; preferably, H 1 For one or more R h2 substituted 4-6 membered monocyclic heterocycloalkane; said one or more R h2 The type of heteroatom in the 4- to 6-membered monocyclic heterocycloalkane in the substituted 4- to 6-membered monocyclic heterocycloalkane is N, and the number of heteroatoms is 1, 2 or 3.

[0100] In one scenario, Y is Z is -H 1 -H 2 -, H 1 is a 4-12 membered heterocycloalkylene group or is replaced by one or more R h2 substituted 4-12 membered heterocycloalkylene, wherein the 4-12 membered heterocycloalkylene is replaced by one or more R h2 The heteroatom species of the 4-12-membered heterocycloalkylene in the substituted 4-12-membered heterocycloalkylene is N, and the number of heteroatoms is independently 1, 2 or 3; H 2 is C1-C6 alkylene; H 1 Connect with Y, H 2 Connects to LL.

[0101] In one embodiment, Y is absent, and Z is a 5-10 membered heteroarylene group, wherein the heteroatom species in the 5-10 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2, 3 or 4.

[0102] The LL is a ligand of the following ligases, VHL, CRBN, MDM2, cIAP, XIAP, E3A, APC, UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB 1. E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH8, Mind Bomb 1 / MIB1, Mind Bomb 2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3, more preferably VHL, CRBN, MDM2 or cIAP.

[0103] In one embodiment, LL is the following formula L-1, L-2, L-3, L-4 or L-5;

[0104] In formula L-1, A is -CH2- or -C(=O)-, R d is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0105] In formula L-2, each R 6a and R 6b are independently hydrogen or C1-C6 alkyl, or, R 6a and R6b Can form a C3-C7 cycloalkyl group together with the carbon atom to which it is attached;

[0106] R 7 is C1-C6 alkyl or is replaced by one or more R 7-1 Substituted C1-C6 alkyl;

[0107] Each R 7-1 are independently hydroxy or halogen;

[0108] Each R 8 are independently halogen or C1-C6 alkoxy;

[0109] m is 0, 1, 2, or 3;

[0110] R 9 is a 5-10 membered heteroaryl, C6-C 10 Aryl, one or more R 9-1 substituted 5-10 membered heteroaryl or one or more R 9-2 Substituted C6-C 10 Aryl, the 5-10 membered heteroaryl and one or more R 9-1 The heteroatom species in the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2, 3, 4 or 5;

[0111] Each R 9-1 and R 9-2 independently halogen, C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl;

[0112] Each R 9-1-1 are independently halogen or C3-C7 cycloalkyl;

[0113] In formula L-3, M is O or -NR M , R M is a C1-C6 alkyl group;

[0114] Preferably, LL is formula L-2 or L-3; more preferably, it is formula L-2.

[0115] In one embodiment, LL is the following formula L-2:

[0116] Each R 6a and R 6b are independently hydrogen, C1-C6 alkyl or hydroxy, or, R 6a and R 6b Can form a C3-C7 cycloalkyl group together with the carbon atom to which it is attached;

[0117] R 7 is C1-C6 alkyl or is replaced by one or more R 7-1 Substituted C1-C6 alkyl;

[0118] Each R 7-1 are independently hydroxy or halogen;

[0119] Each R 8 are independently halogen or C1-C6 alkoxy;

[0120] m is 0, 1, 2, or 3;

[0121] R 9 is a 5-10 membered heteroaryl, C6-C 10 Aryl, one or more R 9-1 substituted 5-10 membered heteroaryl or one or more R 9-2 Substituted C6-C 10 Aryl, the 5-10 membered heteroaryl and one or more R 9-1 The heteroatom species in the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2, 3, 4 or 5;

[0122] Each R 9-1 and R 9-2 independently halogen, C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl;

[0123] Each R 9-1-1 are independently halogen or C3-C7 cycloalkyl.

[0124] In one scheme, each R 6a and R 6b are independently hydrogen or C1-C6 alkyl.

[0125] In one scheme, each R 6a and R 6b are independently hydrogen, C1-C6 alkyl or hydroxy.

[0126] In one scenario, R 6a is hydrogen or hydroxyl, R 6b It is a C1-C6 alkyl group.

[0127] In one scenario, R 7 For one or more R 7-1 Substituted C1-C6 alkyl.

[0128] In one scheme, each R7-1 It is a hydroxyl group.

[0129] In one scenario, R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl or one or more R 9-2 Substituted phenyl, said phenyl being replaced by one or more R 9-1 The heteroatom species in the substituted 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3; preferably, one or more R 9-1 Substituted 5-6 membered heteroaryl, said substituted by one or more R 9-1 The heteroatom species in the substituted 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3.

[0130] In one scheme, each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl.

[0131] In one scheme, each R 9-1-1 are independently C3-C7 cycloalkyl.

[0132] In one scheme, each R 9-2 are independently halogen.

[0133] In one embodiment, M is -NR M .

[0134] In one scenario, R 1 is a 7-12 membered heterocycloalkyl group or is replaced by one or more R 1-2 a substituted C3-C7 cycloalkyl group, wherein the heteroatom type in the 7-12 membered heterocycloalkyl group is O and the number of heteroatoms is 1;

[0135] Each R 1-2 are independently hydroxy or C1-C6 alkoxy.

[0136] In one scenario, R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl or one or more R 1-2 a substituted C3-C7 cycloalkyl group, wherein the heteroatom type in the 7-12 membered heterocycloalkyl group is O and the number of heteroatoms is 1;

[0137] Each R 1-1 are independently -S(O)2R 1-1-3 ;

[0138] R 1-1-3 are independently C1-C6 alkyl;

[0139] Each R 1-2 is independently hydroxy or C1-C6 alkoxy or is replaced by one or more R 1-2-1 Substituted C1-C6 alkyl;

[0140] Each R 1-2-1 are independently C1-C6 alkoxy.

[0141] In one plan,

[0142] X is -O-; G is N or CH; J is N;

[0143] R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the 7-12 membered heterocycloalkyl and one or more R 1-3 The heteroatom species in the 7-12-membered heterocycloalkyl group in the substituted 7-12-membered heterocycloalkyl group are independently O and / or N, and the number of heteroatoms is independently 1 or 2;

[0144] Each R 1-1 is a 4-12 membered heterocycloalkyl group or -S(O)2R 1-1-3 The heteroatom species in the 4-12 membered heterocycloalkyl group is S, the number of heteroatoms is 1 or 2, and the S atom is replaced by one or more R 1-1-2 Replace, each R 1-1-2 are independently oxo (=O) or =NR 1-1-1-3 ;

[0145] R 1-1-3 is a C1-C6 alkyl group;

[0146] R 1-1-1-3 is hydrogen or C1-C6 alkyl;

[0147] Each R 1-2 are independently deuterium, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, 4-12 membered heterocycloalkyl, 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, -S(O)2R 1-1-3 , -O-C3-C7 cycloalkyl or -NHC(O)R 1-2-4 , the heteroatom species in the 4-12 membered heterocycloalkyl group is N and / or O, and the number of heteroatoms is 1 or 2;

[0148] Each R1-2-1 are independently halogen, hydroxy or C1-C6 alkoxy;

[0149] Each R 1-2-2 are independently deuterium, halogen or C3-C7 cycloalkyl;

[0150] R 1-2-4 is a C1-C6 alkyl group;

[0151] Each R 1-3 are independently deuterated or replaced by one or more R 1-3-1 Substituted C1-C6 alkyl;

[0152] Each R 1-3-1 are independently halogen;

[0153] E is absent, -O- or -NR e -;

[0154] R e is hydrogen or C1-C6 alkyl;

[0155] R 2 is a 4-12 membered heterocycloalkyl group or is replaced by one or more R 2-1 substituted 4-12 membered heterocycloalkyl, wherein the 4-12 membered heterocycloalkyl and one or more R 2-1 The heteroatom type in the 4-12-membered heterocycloalkyl group in the substituted 4-12-membered heterocycloalkyl group is N, and the number of heteroatoms is independently 1, 2 or 3;

[0156] Each R 2-1 are independently halogen or C1-C6 alkyl;

[0157] R 3 is halogen or C3-C7 cycloalkyl;

[0158] R 4 is a halogen;

[0159] R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums;

[0160] R 10 is methylene or dideuterated methylene;

[0161] Y does not exist, OR Y-1 -;

[0162] R Y-1 is a C1-C6 alkylene group;

[0163] Z is a 5-6 membered heteroarylene group or -H 1 -H 2-, the heteroatom species in the 5-6 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2, 3 or 4; H 1 C3-C 12 Cycloalkylene, 4-12 membered heterocycloalkylene, one or more R h1 Substituted C3-C 12 Cycloalkylene or one or more R h2 Substituted 4-12 membered heterocycloalkylene; H 2 is C1-C6 alkylene; H 1 Connect with Y, H 2 Connected to LL; the 4-12 membered heterocycloalkyl group and one or more R h2 The number of heteroatoms N in the substituted 4-12 membered heterocycloalkyl group is independently 1, 2 or 3;

[0164] LL is the following formula L-2 or L-3:

[0165] Each R 6a and R 6b are independently hydrogen or C1-C6 alkyl, or, R 6a and R 6b Can form a C3-C7 cycloalkyl group together with the carbon atom to which it is attached;

[0166] R 7 is C1-C6 alkyl or is replaced by one or more R 7-1 Substituted C1-C6 alkyl;

[0167] Each R 7-1 are independently hydroxyl groups;

[0168] m is 0;

[0169] R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl or one or more R 9-2 Substituted phenyl, said phenyl being replaced by one or more R 9-1 The heteroatom species in the 5-6-membered heteroaryl group in the substituted 5-6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3;

[0170] Each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl;

[0171] Each R 9-1-1 are independently halogen or C3-C7 cycloalkyl;

[0172] Each R9-2 are independently halogen;

[0173] M is -NR M , R M It is a C1-C6 alkyl group.

[0174] In one plan,

[0175] X is -O-; G is N; J is N;

[0176] R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the 7-12 membered heterocycloalkyl and one or more R 1-3 The heteroatom species in the 7-12-membered heterocycloalkyl group in the substituted 7-12-membered heterocycloalkyl group are independently O and / or N, and the number of heteroatoms is independently 1 or 2;

[0177] Each R 1-1 are independently 4-12 membered heterocycloalkyl or -S(O)2R 1-1-3 The heteroatom species in the 4-12 membered heterocycloalkyl group is S, the number of heteroatoms is 1 or 2, and the S atom is replaced by one or more R 1-1-2 Replace, each R 1-1-2 are independently oxo (=O) or =NH;

[0178] R 1-1-3 is a C1-C6 alkyl group;

[0179] Each R 1-2 are independently deuterium, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, 4-12 membered heterocycloalkyl, 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, -S(O)2R 1-1-3 or -NHC(O)R 1-2-4 , the heteroatom species in the 4-12 membered heterocycloalkyl group is N and / or O, and the number of heteroatoms is 1 or 2;

[0180] Each R 1-2-1 are independently deuterium, halogen or C1-C6 alkoxy;

[0181] Each R 1-2-2 are independently deuterium or halogen;

[0182] R 1-2-4 is a C1-C6 alkyl group;

[0183] Each R 1-3 Independently by one or more R 1-3-1 Substituted C1-C6 alkyl;

[0184] Each R 1-3-1 are independently halogen;

[0185] E is absent, -O- or -NR e -;

[0186] R e is hydrogen or C1-C6 alkyl;

[0187] R 2 is a 4-12 membered heterocycloalkyl group or is replaced by one or more R 2-1 substituted 4-12 membered heterocycloalkyl, wherein the 4-12 membered heterocycloalkyl and one or more R 2-1 The heteroatom type in the 4-12-membered heterocycloalkyl group in the substituted 4-12-membered heterocycloalkyl group is N, and the number of heteroatoms is independently 1, 2 or 3;

[0188] Each R 2-1 are independently C1-C6 alkyl;

[0189] R 3 is halogen or C3-C7 cycloalkyl;

[0190] R 4 is a halogen;

[0191] R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums;

[0192] R 10 is methylene or dideuterated methylene;

[0193] Y is absent;

[0194] Z is a 5-6 membered heteroarylene group, wherein the heteroatom species in the 5-6 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2, 3 or 4;

[0195] LL is the following formula L-2:

[0196] Each R 6a and R 6b are independently hydrogen or C1-C6 alkyl, or, R 6a and R 6b Can form a C3-C7 cycloalkyl group together with the carbon atom to which it is attached;

[0197] R 7is C1-C6 alkyl or is replaced by one or more R 7-1 Substituted C1-C6 alkyl;

[0198] Each R 7-1 are independently hydroxyl groups;

[0199] m is 0;

[0200] R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl or one or more R 9-2 Substituted phenyl, said phenyl being replaced by one or more R 9-1 The heteroatom species in the 5-6-membered heteroaryl group in the substituted 5-6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3;

[0201] Each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl;

[0202] Each R 9-1-1 are independently C3-C7 cycloalkyl;

[0203] Each R 9-2 are independently halogen.

[0204] In one plan,

[0205] X is -O-; G is N; J is N;

[0206] R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the 7-12 membered heterocycloalkyl and one or more R 1-3 The type of heteroatoms in the 7-12-membered heterocycloalkyl group in the substituted 7-12-membered heterocycloalkyl group is O, and the number of heteroatoms is 1 or 2;

[0207] Each R 1-1 are independently 4-6 membered monocyclic heterocycloalkyl or -S(O)2R 1-1-3 The heteroatom type in the 4-6 membered monocyclic heterocycloalkyl is S, and the number of heteroatoms is 1; the S atom is replaced by one or more R 1-1-2 Replace, each R 1-1-2 is oxo (=O);

[0208] R 1-1-3 is a C1-C6 alkyl group;

[0209] Each R 1-2 are independently deuterium, hydroxyl, C1-C6 alkoxy, one or more R 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy or -NHC(O)R 1-2-4 ;

[0210] Each R 1-2-1 are independently hydroxy or C1-C6 alkoxy;

[0211] Each R 1-2-2 independently for deuterium;

[0212] R 1-2-4 is a C1-C6 alkyl group;

[0213] Each R 1-3 independently for deuterium;

[0214] E is absent, -O- or -NR e -;

[0215] R e is hydrogen or C1-C6 alkyl;

[0216] R 2 is a 4-12 membered heterocycloalkyl group, wherein the heteroatom species in the 4-12 membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3;

[0217] R 3 is a C3-C7 cycloalkyl group;

[0218] R 4 is a halogen;

[0219] R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums;

[0220] R 10 is methylene or dideuterated methylene;

[0221] Y is absent;

[0222] Z is a 5-6 membered heteroarylene group, wherein the heteroatom species in the 5-6 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2, 3 or 4;

[0223] LL is the following formula L-2:

[0224] Each R 6a and R 6b are independently hydrogen or C1-C6 alkyl;

[0225] R 7 For one or more R 7-1 Substituted C1-C6 alkyl;

[0226] Each R 7-1 are independently hydroxyl groups;

[0227] m is 0;

[0228] R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl, said substituted by one or more R 9-1 The heteroatom species in the 5-6-membered heteroaryl group in the substituted 5-6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3;

[0229] Each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl;

[0230] Each R 9-1-1 are independently C3-C7 cycloalkyl.

[0231] In one plan,

[0232] X is -O-; G is N; J is N;

[0233] R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C3-C7 cycloalkyl, wherein the heteroatom species in the 7-12 membered heterocycloalkyl is O, and the number of heteroatoms is 1 or 2;

[0234] Each R 1-1 are independently 4-6 membered monocyclic heterocycloalkyl groups, wherein the heteroatom species in the 4-6 membered monocyclic heterocycloalkyl group is S and the number of heteroatoms is 1; the S atom is independently replaced by one or more R 1-1-2 replace;

[0235] Each R 1-1-2 are independently oxo;

[0236] Each R 1-2 are independently deuterium, hydroxyl, C1-C6 alkoxy, one or more R 1-2-1 Substituted C1-C6 alkyl or one or more R 1-2-2 Substituted C1-C6 alkoxy;

[0237] Each R 1-2-1 are independently hydroxy or C1-C6 alkoxy;

[0238] Each R 1-2-2 independently for deuterium;

[0239] E is absent, -O- or -NR e -;

[0240] R e is hydrogen or C1-C6 alkyl;

[0241] R 2 is a 4-12 membered heterocycloalkyl group, wherein the heteroatom species in the 4-12 membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3;

[0242] R 3 is a C3-C7 cycloalkyl group;

[0243] R 4 is a halogen;

[0244] R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums;

[0245] R 10 is methylene or dideuterated methylene;

[0246] Y is absent;

[0247] Z is a 5-6 membered heteroarylene group, wherein the heteroatom species in the 5-6 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2, 3 or 4;

[0248] LL is the following formula L-2:

[0249] Each R 6a and R 6b are independently hydrogen or C1-C6 alkyl;

[0250] R 7 For one or more R 7-1 Substituted C1-C6 alkyl;

[0251] Each R 7-1 are independently hydroxyl groups;

[0252] m is 0;

[0253] R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl, said substituted by one or more R 9-1 The heteroatom species in the 5-6-membered heteroaryl group in the substituted 5-6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3;

[0254] Each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl;

[0255] Each R 9-1-1 are independently C3-C7 cycloalkyl.

[0256] In one plan,

[0257] X is -O-; G is N; J is N;

[0258] R 1 is a 7-12 membered heterocycloalkyl group or is replaced by one or more R 1-2 A substituted C3-C7 cycloalkyl group, wherein the heteroatom species in the 7-12 membered heterocycloalkyl group is O and the number of heteroatoms is 1;

[0259] Each R 1-2 are independently deuterium, hydroxyl, C1-C6 alkoxy, one or more R 1-2-1 Substituted C1-C6 alkyl or one or more R 1-2-2 Substituted C1-C6 alkoxy;

[0260] Each R 1-2-1 are independently hydroxy or C1-C6 alkoxy;

[0261] Each R 1-2-2 independently for deuterium;

[0262] E does not exist or -NR e -;

[0263] R e is a C1-C6 alkyl group;

[0264] R 2 is a 5-6 membered monocyclic heterocycloalkyl group or a 7-8 membered polycyclic heterocycloalkyl group, wherein the heteroatom species in the 5-6 membered monocyclic heterocycloalkyl group and the 7-8 membered polycyclic heterocycloalkyl group is N, and the number of heteroatoms is independently 1 or 2;

[0265] R 3 is a C3-C7 cycloalkyl group;

[0266] R 4 is a halogen;

[0267] R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums;

[0268] R 10 is methylene or dideuterated methylene;

[0269] Y is absent;

[0270] Z is a 5-6 membered heteroarylene group, wherein the heteroatom species in the 5-6 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2 or 3;

[0271] LL is the following formula L-2:

[0272] Each R 6a and R 6b are independently hydrogen or C1-C6 alkyl;

[0273] R 7 For one or more R 7-1 Substituted C1-C6 alkyl;

[0274] Each R 7-1 are independently hydroxyl groups;

[0275] m is 0;

[0276] R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl, said substituted by one or more R 9-1 The heteroatom species in the 5-6 membered heteroaryl group in the substituted 5-6 membered heteroaryl group is selected from N and / or S, and the number of heteroatoms is 1 or 2;

[0277] Each R 9-1 are independently C1-C6 alkyl.

[0278] In one plan,

[0279] X is -O-;

[0280] G is N;

[0281] J is N;

[0282] R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the 7-12 membered heterocycloalkyl and one or more R 1-3 The 7-12 membered heterocycloalkyl in the substituted 7-12 membered heterocycloalkyl is a bridged ring;

[0283] Each R 1-1 independently 4-12 membered heterocycloalkyl, -S(O)2R 1-1-3 or The heteroatom type in the 4-12 membered heterocycloalkyl is S, the number of heteroatoms is 1 or 2, and the S atom is independently replaced by one or more R 1-1-2 replace;

[0284] Each R 1-2 are independently deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, 4-12 membered heterocycloalkyl, 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, one or more R 1-2-3 Substituted 4-12 membered heterocycloalkyl, -S(O)2R 1-1-3 , -O-C3-C7 cycloalkyl, -C(O)NHR 1-2-4 or -NHC(O)R 1-2-4 ;

[0285] Each R 1-3 are independently oxo, deuterium, C1-C6 alkyl or substituted by one or more R 1-3-1 Substituted C1-C6 alkyl;

[0286] R 1-1-3 is a C1-C6 alkyl group;

[0287] R 1-1-4 is a C1-C6 alkyl group;

[0288] Each R 1-2-1 are independently halogen, hydroxy or C1-C6 alkoxy;

[0289] Each R 1-2-2 are independently deuterium or halogen;

[0290] Each R 1-2-3 are independently halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0291] R 1-2-4 are independently C1-C6 alkyl;

[0292] E does not exist or -NR e -;

[0293] R e is hydrogen or C1-C6 alkyl;

[0294] R 2 is a 5-6 membered monocyclic heterocycloalkyl, a 7-8 membered polycyclic heterocycloalkyl, or one or more R 2-1 substituted 5-6 membered monocyclic heterocycloalkyl or one or more R 2-1 substituted 7-8 membered polycyclic heterocycloalkyl, wherein the 5-6 membered monocyclic heterocycloalkyl, 7-8 membered polycyclic heterocycloalkyl,2-1 The 5-6 membered monocyclic heterocycloalkyl in the substituted 5-6 membered monocyclic heterocycloalkyl and the substituted 5-6 membered monocyclic heterocycloalkyl 2-1 The heteroatom type in the 7-8 membered polycyclic heterocycloalkyl group in the substituted 7-8 membered polycyclic heterocycloalkyl group is N, and the number of heteroatoms is independently 1 or 2;

[0295] Each R 2-1 are independently C1-C6 alkyl;

[0296] R 3 is a C3-C7 cycloalkyl group;

[0297] R 4 is a halogen;

[0298] R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums;

[0299] R 10 is methylene or dideuterated methylene;

[0300] The definitions of Y, Z, and LL are as described in Scheme 1 or Scheme 2:

[0301] Solution 1: Y is Z is -H 1 -H 2 -, H 1 is a 4-12 membered heterocycloalkylene group or is replaced by one or more R h2 substituted 4-12 membered heterocycloalkylene, wherein the 4-12 membered heterocycloalkylene is replaced by one or more R h2 The heteroatom species of the 4-12-membered heterocycloalkylene in the substituted 4-12-membered heterocycloalkylene is N, and the number of heteroatoms is independently 1, 2 or 3; H 2 is C1-C6 alkylene; H 1 Connect with Y, H 2 Connected to LL;

[0302] LL is

[0303] M is -NR M , R M is a C1-C6 alkyl group;

[0304] Scheme 2: Y is absent, Z is a 5-10 membered heteroarylene group, the heteroatom species in the 5-10 membered heteroarylene group is N and / or O, and the number of heteroatoms is 1, 2, 3 or 4;

[0305] LL is

[0306] Each R 6aand R 6b are independently hydrogen or C1-C6 alkyl, or, R 6a and R 6b Can form a C3-C7 cycloalkyl group together with the carbon atom to which it is attached;

[0307] R 7 is C1-C6 alkyl or is replaced by one or more R 7-1 Substituted C1-C6 alkyl;

[0308] Each R 7-1 are independently hydroxyl groups;

[0309] m is 0;

[0310] R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl or one or more R 9-2 Substituted phenyl, said phenyl being replaced by one or more R 9-1 The heteroatom species in the 5-6-membered heteroaryl group in the substituted 5-6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3;

[0311] Each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl;

[0312] Each R 9-1-1 are independently halogen or C3-C7 cycloalkyl;

[0313] Each R 9-2 are independently halogen.

[0314] In one plan,

[0315] X is -O-;

[0316] G is N;

[0317] J is N;

[0318] R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the 7-12 membered heterocycloalkyl and one or more R 1-3 The 7-12 membered heterocycloalkyl in the substituted 7-12 membered heterocycloalkyl is a bridged ring;

[0319] Each R 1-1independently 4-12 membered heterocycloalkyl or -S(O)2R 1-1-3 The heteroatom species in the 4-12 membered heterocycloalkyl group is S, the number of heteroatoms is 1 or 2, and the S atoms are independently replaced by one or more R 1-1-2 replace;

[0320] Each R 1-2 are independently deuterium, hydroxyl, -NHC(O)R 1-2-4 or by one or more R 1-2-1 Substituted C1-C6 alkyl;

[0321] Each R 1-3 independently for deuterium;

[0322] R 1-1-3 is a C1-C6 alkyl group;

[0323] Each R 1-2-1 are independently hydroxy or C1-C6 alkoxy;

[0324] Each R 1-1-2 are independently oxo or =NR 1-1-1-3 ;

[0325] R 1-1-1-3 is hydrogen or C1-C6 alkyl;

[0326] R 1-2-4 is a C1-C6 alkyl group;

[0327] E does not exist or -NR e -;

[0328] R e is hydrogen or C1-C6 alkyl;

[0329] R 2 is a 5-6 membered monocyclic heterocycloalkyl, a 7-8 membered polycyclic heterocycloalkyl, or one or more R 2-1 substituted 5-6 membered monocyclic heterocycloalkyl or one or more R 2-1 substituted 7-8 membered polycyclic heterocycloalkyl, wherein the 5-6 membered monocyclic heterocycloalkyl, 7-8 membered polycyclic heterocycloalkyl, 2-1 The 5-6 membered monocyclic heterocycloalkyl in the substituted 5-6 membered monocyclic heterocycloalkyl and the substituted 5-6 membered monocyclic heterocycloalkyl 2-1 The heteroatom type in the 7-8 membered polycyclic heterocycloalkyl group in the substituted 7-8 membered polycyclic heterocycloalkyl group is N, and the number of heteroatoms is independently 1 or 2;

[0330] Each R 2-1 are independently C1-C6 alkyl;

[0331] R 3is a C3-C7 cycloalkyl group;

[0332] R 4 is a halogen;

[0333] R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums;

[0334] R 10 is methylene or dideuterated methylene;

[0335] Y is absent, Z is a 5-10 membered heteroarylene group, the heteroatom species in the 5-10 membered heteroarylene group is selected from one or both of N and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0336] LL is

[0337] Each R 6a and R 6b are independently hydrogen or C1-C6 alkyl, or, R 6a and R 6b Can form a C3-C7 cycloalkyl group together with the carbon atom to which it is attached;

[0338] R 7 is C1-C6 alkyl or is replaced by one or more R 7-1 Substituted C1-C6 alkyl;

[0339] Each R 7-1 are independently hydroxyl groups;

[0340] m is 0;

[0341] R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl, said substituted by one or more R 9-1 The heteroatom species in the 5-6-membered heteroaryl group in the substituted 5-6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3;

[0342] Each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl;

[0343] Each R 9-1-1 are independently halogen or C3-C7 cycloalkyl.

[0344] In one plan,

[0345] X is -O-;

[0346] G is N;

[0347] J is N;

[0348] R 1 For one or more R 1-1 Substituted C1-C6 alkyl; each R 1-1 for R 1-1-4 is a C1-C6 alkyl group;

[0349] E does not exist or -NR e -;

[0350] R e is hydrogen or C1-C6 alkyl;

[0351] R 2 is a 5-6 membered monocyclic heterocycloalkyl, a 7-8 membered polycyclic heterocycloalkyl, or one or more R 2-1 substituted 5-6 membered monocyclic heterocycloalkyl or one or more R 2-1 substituted 7-8 membered polycyclic heterocycloalkyl, wherein the 5-6 membered monocyclic heterocycloalkyl, 7-8 membered polycyclic heterocycloalkyl, 2-1 The 5-6 membered monocyclic heterocycloalkyl in the substituted 5-6 membered monocyclic heterocycloalkyl and the substituted 5-6 membered monocyclic heterocycloalkyl 2-1 The heteroatom type in the 7-8 membered polycyclic heterocycloalkyl group in the substituted 7-8 membered polycyclic heterocycloalkyl group is N, and the number of heteroatoms is independently 1 or 2;

[0352] Each R 2-1 are independently C1-C6 alkyl;

[0353] R 3 is a C3-C7 cycloalkyl group;

[0354] R 4 is a halogen;

[0355] R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums;

[0356] R 10 is methylene or dideuterated methylene;

[0357] Y is absent, Z is a 5-10 membered heteroarylene group, the heteroatom species in the 5-10 membered heteroarylene group is selected from one or both of N and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0358] LL is

[0359] Each R 6a and R 6b are independently hydrogen or C1-C6 alkyl, or, R6a and R 6b Can form a C3-C7 cycloalkyl group together with the carbon atom to which it is attached;

[0360] R 7 is C1-C6 alkyl or is replaced by one or more R 7-1 Substituted C1-C6 alkyl;

[0361] Each R 7-1 are independently hydroxyl groups;

[0362] m is 0;

[0363] R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl, said substituted by one or more R 9-1 The heteroatom species in the 5-6-membered heteroaryl group in the substituted 5-6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3;

[0364] Each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl;

[0365] Each R 9-1-1 are independently halogen or C3-C7 cycloalkyl.

[0366] In one embodiment, the compound of formula I is a compound of formula I-1:

[0367] Among them, R 1 、R 2 、R 5 、R 10 , E, Y, Z and LL are defined as described in any embodiment of the present invention.

[0368] In one embodiment, the compound of formula I is a compound of formula I-1a or formula I-1b:

[0369] In one embodiment, the compound of formula I is a compound of formula I-2:

[0370] Among them, R 1 、R 2 、R 3 、R 5 、R 6a 、R 6b 、R 7 、R 9 、R 10, E and Z are defined as described in any embodiment of the present invention.

[0371] In one embodiment, the compound of formula I is a compound of formula I-2a or I-2b:

[0372] In one embodiment, the compound of formula I is a compound of formula I-3:

[0373] Among them, R 1 、R 2 、R 5 、R 7 、R 9 、R 10 , E and Z are defined as described in any embodiment of the present invention.

[0374] In one embodiment, the compound of formula I is a compound of formula I-3a or I-3b:

[0375] In one scenario, R 1 for For example

[0376] In one scenario, R 1 It can also be

[0377] In one scenario, -ER 2 for For example

[0378] In one scenario, R 3 is chloro or cyclopropyl.

[0379] In one scenario, R 4 For fluorine.

[0380] In one scenario, R 5 is methyl or trideuterated methyl, for example methyl.

[0381] In one scenario, Y is absent, For example Or does not exist, for example does not exist.

[0382] In one scheme, Z is For example

[0383] In one scenario, YZ is For example

[0384] In one scenario, R 6a is hydrogen, R 6b isopropyl, or R 6a and R 6b A cyclopropyl group is formed.

[0385] In one scenario, R 7 It is -CH3 or -CH2-OH.

[0386] In one scenario, R 9 for For example

[0387] In one scenario, R 10 is methylene or dideuterated methylene, for example methylene.

[0388] In one scenario, -H 1 -for Preferably, The "1" is connected to Y, and the "2" is connected to H 2 connection; better, for Best, for

[0389] In one scenario, -H 2 -for

[0390] In one embodiment, formula L-3 is For example

[0391] In one embodiment, formula L-2 is For example

[0392] In one embodiment, formula L-2 is

[0393] The present invention provides a quinazoline compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the quinazoline compound is any one of the following compounds:

[0394] in Expressed as

[0395] In a certain embodiment, the quinoline compound is any one of the following compounds:

[0396] In a certain embodiment, the quinoline compound is any one of the following compounds:

[0397] 1 H NMR (400 MHz, DMSO-d6) is shown below δ8.99(s,1H),8.65(s,1H),8.49(d,J=7.8Hz,1H),8.05(s,1H),7.67(d, J=7.9Hz,2H),7.55(s,1H),7.47–7.42(m,3H),7.40–7.35(m,2H),6.80–6 .76(m,2H),5.35–5.30(m,2H),5.21–5.15(m,3H),5.10–5.08(m,1H),4. 88–4.84(m,2H),4.83–4.81(m,1H),4.81–4.78(m,1H),4.48–4.43(m,2H) ,4.34–4.30(m,2H),3.89–3.84(m,3H),3.79–3.74(m,4H),3.09–3.05(m ,1H),3.02–2.99(m,1H),2.68–2.66(m,1H),2.46(s,3H),2.34–2.32(m,1 H),2.09–2.04(m,3H),2.00–1.96(m,3H),1.90–1.86(m,1H),1.76–1.69 (m,3H),1.25–1.22(m,2H),1.08(d,J=6.5Hz,3H),0.72(d,J=6.5Hz,3H);

[0398] 1H NMR (400 MHz, DMSO-d6) is shown below δ13.11(s,1H),8.99(s,1H),8.64(s,1H),8.48(d,J=7.9Hz,1H),7.63(d, J=8.0Hz,2H),7.48–7.42(m,5H),7.40–7.36(m,2H),6.76(d,J=8.1Hz,2H ),5.33(dd,J=10.8,5.1Hz,2H),5.17(d,J=3.9Hz,1H),5.10–5.08(m,1H) ,4.89–4.84(m,2H),4.77(d,J=11.4Hz,1H),4.47–4.42(m,3H),4.35–4.2 6(m,3H),3.87–3.84(m,1H),3.82–3.75(m,3H),3.72–3.66(m,2H),3.27– 3.26(m,2H),3.00(s,3H),2.46(s,3H),2.22–2.15(m,3H),2.12–2.04(m, 2H),1.98(d,J=2.5Hz,3H),1.94–1.91(m,1H),1.81–1.75(m,2H),1.37–1 .33(m,1H),1.11–1.05(m,4H),0.72(d,J=6.6Hz,3H),0.67–0.57(m,4H);

[0399] 1 H NMR (400 MHz, DMSO-d6) is shown below δ13.11(s,1H),8.98(s,1H),8.63(s,1H),8.48(d,J=8.0Hz,1H),7.64(d,J=7.9Hz,2H),7.49(s,1H),7.47–7.41(m,4H),7.41–7.35(m,3H),6.72(d,J=7.9Hz,2H),5.32(d,J=10.5Hz,2H),5.19–5.15(m,1H),5.07–4.95(m,3H),4.89–4.83(m,2H),4.76–4.71(m,1H),4.48–4.43(m,1H),4.34–4.30(m,1H),4.25–4.20(m,1H),3.77–3.71(m,4H),3.62–3.59(m,3H),3.20(s,3H),3.10–3.07(m,1H),3.00–2.97(m,1H),2.46(s,3H),2.13–2.04(m,3H),1.99(d,J=2.5Hz,6H),1.90–1.85(m,1H),1.83–1.78(m,1H),1.74–1.70(m,1H),1.56–1.45(m,3H),1.38–1.34(m,1H),1.07(d,J=6.6Hz,3H),0.72(d,J=6.5Hz,3H),0.67–0.59(m,3H),0.58–0.54(m,1H);

[0400] 1 1H NMR(400 MHz, DMSO-d6) is as follows δ13.11(s,1H),8.65(s,1H),8.61–8.54(m,1H),7.69–7.64(m,2H),7.50–7.44(m,3H),7.43–7.38(m,4H),6.79–6.74(m,2H),6.32(d,J=1.9Hz,1H),5.35–5.26(m,2H),5.22–5.15(m,2H),5.07–4.99(m,2H),4.90–4.84(m,1H),4.74–4.68(m,1H),4.49–4.44(m,1H),4.34–4.30(m,1H),4.26–4.21(m,1H),3.99(d,J=6.8Hz,2H),3.89–3.83(m,2H),3.82–3.77(m,2H),3.76–3.65(m,3H),2.12–2.04(m,3H),2.02–1.96(m,4H),1.92–1.85(m,2H),1.83–1.61(m,6H),1.39–1.32(m,2H),1.13–1.05(m,4H),0.72(d,J=6.6Hz,3H),0.66–0.50(m,5H),0.45–0.38(m,3H),0.20–0.15(m,3H); [

[0401] [ 1 [ 1H NMR(400 MHz, DMSO-d6) is as follows [ δ8.99(s,1H),8.65–8.64(m,1H),7.67–7.61(m,3H),7.49–7.42(m,4H),7.40–7.34(m,3H),6.77–6.72(m,2H),5.35–5.30(m,3H),5.05–5.02(m,2H),4.99–4.95(m,2H),4.87–4.82(m,3H),4.49–4.43(m,3H),4.34–4.26(m,4H),4.24–4.19(m,3H),4.05–4.01(m,2H),2.11–2.06(m,3H),2.01–1.97(m,3H),1.91–1.85(m,3H),1.81–1.75(m,3H),1.70–1.65(m,3H),1.54–1.47(m,5H),1.37–1.33(m,2H),1.10–1.05(m,3H),0.88–0.83(m,3H),0.72(d,J=6.5Hz,3H),0.63–0.58(m,3H); [

[0402] [ 1 [H NMR (400 MHz, DMSO-d6) is shown below δ8.99(s,1H),8.64(s,1H),7.67–7.62(m,3H),7.50–7.43(m,4H),7.40–7.34(m,3H),6.78–6.72(m,2H),5.37–5.30(m ,3H),5.05–4.97(m,3H),4.87–4.83(m,2H),4.77–4.69(m,2H),4.48–4.42(m,3H),4.34–4.30(m,2H),4.27–4.20(m,3H) ),4.06–4.00(m,2H),2.09–2.04(m,3H),2.01–1.96(m,4H),1.90–1.85(m,3H),1.81–1.75(m,3H),1.71–1.63(m,3H), 1.53–1.44(m,6H),1.39–1.33(m,2H),1.11–1.05(m,3H),0.88–0.83(m,3H),0.72(d,J=6.6Hz,3H),0.62–0.58(m,3H);

[0403] 1 H NMR (400 MHz, DMSO-d6) is shown below δ13.11(s,1H),8.99(s,1H),8.64(s,1H),8.47(d,J=7.8Hz,1H),7.72–7.68(m ,2H),7.50(s,1H),7.46–7.42(m,3H),7.40–7.35(m,3H),6.92(d,J=7.9Hz,2H) ,5.35–5.29(m,3H),5.16(d,J=3.9Hz,1H),5.05–5.03(m,1H),4.88–4.84(m,2 H),4.77–4.73(m,2H),4.65–4.60(m,1H),4.48–4.43(m,2H),4.34–4.30(m,2H) ,4.25–4.21(m,2H),3.92–3.86(m,2H),3.82–3.78(m,2H),3.76–3.72(m,2H), 3.66–3.58(m,4H),2.23–2.18(m,2H),2.11–2.07(m,2H),2.01(d,J=2.4Hz,3H) ,1.90–1.86(m,2H),1.81–1.70(m,6H),1.44–1.40(m,2H),1.37–1.32(m,3H),1 .10–1.05(m,4H),0.88–0.83(m,3H),0.72(d,J=6.5Hz,3H),0.66–0.58(m,3H);

[0404] 1 H NMR (400 MHz, DMSO-d6) is shown below δ13.14(s,1H),8.91(d,J=4.5Hz,1H),8.65(s,1H),8.65–8.55(m,1H),7.71– 7.62(m,2H),7.53–7.46(m,3H),7.45(s,1H),7.42–7.36(m,3H),6.81–6.72(m ,2H),5.37–5.25(m,2H),5.23–5.13(m,2H),5.09–4.98(m,2H),4.89–4.80(m, 1H),4.75–4.65(m,1H),4.51–4.43(m,1H),4.39–4.27(m,2H),4.27–4.20(m,1 H),3.96–3.81(m,3H),3.82–3.66(m,4H),3.66–3.52(m,4H),3.13–3.06(m,1H ),3.04–2.91(m,1H),2.16–2.04(m,4H),1.99(s,3H),1.91–1.87(m,1H),1.86 –1.78(m,1H),1.75–1.60(m,3H),1.37–1.32(m,1H),1.08(d,J=6.6Hz,3H),0. 97–0.89(m,4H),0.72(d,J=6.5Hz,3H),0.66–0.58(m,3H),0.57–0.49(m,1H);

[0405] 1 H NMR (400 MHz, DMSO-d6) is shown below δ10.02(s,1H),8.99(s,1H),8.95(s,1H),8.62(s,1H),8.48(d,J=7.9Hz,1H),7.94(dd,J=9.3,6.0Hz,1H),7.69–7.62(m,2H),7.47–7.41(m,2H),7.41–7.34(m,3H),7.34(d,J=2.5Hz,1H),7.10(d,J=2.5Hz,1H),7.00–6.93(m,2H),5.36–5.29(m,2H),5.26–5.18(m,2H),5.19–5.14(m,1H),5.14–5.07(m,2H),4.90–4.82(m,2H),4.53–4.41(m,3H),4.34–4.29(m,1H),4.29–4.22(m,2H),4.17–4.00(m,4H),3.90–3.85(m,1H),3.72–3.68(m,2H),3.66–3.59(m,3H),3.56–3.51(m,4H),3.10–3.04(m,2H),2.99(s,1H),2.46(s,3H),2.16–2.02(m,4H),2.00–1.95(m,2H),1.85–1.73(m,3H),1.70–1.64(m,3H),1.08(d,J=6.5Hz,3H),0.72(d,J=6.5Hz,3H);

[0406] 1 1H NMR(500MHz,MeOH-d4) is as follows δ8.88(s,1H),8.41(s,1H),7.55–7.51(m,2H),7.49–7.45(m,5H),7.39(s,1H),7.28(d,J=9.6Hz,1H),6.81(d,J=8.0Hz,2H),6.16(d,J=10.1Hz,1H),6.12(d,J=10.0Hz,2H),6.06(d,J=2.4Hz,1H),6.02(d,J=2.4Hz,1H),5.52(d,J=2.4Hz,1H),5.50(d,J=2.4Hz,1H),5.35(d,J=10.2Hz,1H),5.29–5.24(m,2H),5.07–5.04(m,1H),4.62–4.58(m,1H),4.51–4.45(m,3H),4.44–4.40(m,1H),4.29–4.27(m,1H),4.01(d,J=10.1Hz,1H),3.94(dd,J=11.2,4.1Hz,1H),3.89–3.84(m,3H),2.69–2.63(m,3H),2.48(s,3H),2.28–2.22(m,2H),2.08(d,J=2.4Hz,3H),2.04–2.01(m,1H),1.47–1.43(m,1H),1.16(d,J=6.6Hz,3H),0.91–0.88(m,1H),0.83(d,J=6.6Hz,3H),0.66–0.60(m,3H);

[0407] 1 1H NMR(500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.41(s,1H),7.53–7.49(m,3H),7.47–7.44(m,4H),7.43–7.40(m,1H),7.27(d,J=9.6Hz,1H),6.77(d,J=8.3Hz,2H),6.16(d,J=10.2Hz,1H),6.12(d,J=10.2Hz,2H),6.04(d,J=2.4Hz,2H),6.00(d,J=2.3Hz,1H),5.50(d,J=2.3Hz,1H),5.48(d,J=2.4Hz,1H),5.35(d,J=10.3Hz,):

[0408] 1 The 1H NMR (400 MHz, DMSO-d6) is as follows δ13.11(s,1H),8.99(s,1H),8.64(s,1H),8.48(d,J = 7.8Hz,1H),7.65(d,J = 7.8Hz,2H),7.50–7.47(m,1H),7.46–7.41(m,3H),7.40–7.36(m,2H),6.76(d,J = 8.0Hz,2H),5.35–5.28(m,2H),5.17(d,J = 3.8Hz,1H),5.08–5.03(m,2H),4.88–4.83(m,2H),4.73(d,J = 11.3Hz,1H),4.48–4.43(m,1H),4.34–4.30(m,1H),4.26–4.22(m,1H),3.80–3.73(m,4H),3.72–3.67(m,2H),3.65–3.57(m,4H),3.23(s,3H),3.13(d,J = 9.9Hz,2H),3.02(d,J = 9.7Hz,2H),2.46(s,3H),2.10–2.06(m,1H),1.99(d,J = 2.4Hz,3H),1.92–1.88(m,1H),1.81–1.75(m,5H),1.55–1.50(m,2H),1.39–1.32(m,2H),1.08(d,J = 6.5Hz,3H),0.72(d,J = 6.6Hz,3H),0.66–0.59(m,3H),0.58–0.53(m,1H);

[0409] 1 1H NMR (400 MHz, DMSO-d6) is as follows δ13.12(s,1H),8.65(s,1H),8.48(d,J=8.1Hz,1H),7.68(d,J=7.8Hz,2H),7.51–7.44(m,3H),7.42–7.38(m,4H),6.78(d,J=7.9Hz,2H),6.30(d,J=1.8Hz,1H),5.31(dd,J=21.1,10.7Hz,2H),5.21–5.14(m,2H),5.08–5.04(m,1H),4.91–4.84(m,2H),4.71(d,J=11.1Hz,1H),4.49–4.43(m,1H),4.35–4.30(m,1H),4.28–4.22(m,1H),4.13(d,J=7.2Hz,2H),3.91–3.74(m,6H),3.73–3.58(m,4H),3.11(d,J=9.8Hz,1H),3.01(d,J=9.9Hz,1H),2.71–2.63(m,2H),2.13–2.04(m,3H),2.03–1.95(m,4H),1.93–1.82(m,4H),1.80–1.60(m,8H),1.40–1.33(m,1H),1.08(d,J=6.6Hz,3H),0.72(d,J=6.5Hz,3H),0.67–0.59(m,3H),0.58–0.52(m,1H);

[0410] 1 1H NMR(400 MHz, CDCl3) is as follows δ8.60(s,1H),8.06–7.99(m,1H),7.81(s,1H),7.39–7.28(m,5H),7.08(d,J=9.4Hz,1H),7.02–6.97(m,2H),6.41(d,J=7.9Hz,2H),5. 32–5.17(m,4H),5.11–5.03(m,1H),4.90–4.71(m,3H),4.55–4.51(m,1H),4.32–4.25(m,2H),4.14–4.04(m,3H),3.98–3.88(m,3H),3. 82–3.73(m,2H),3.31(d,J=10.3Hz,1H),3.23–3.16(m,1H),2.63–2.56(m,1H),2.43(s,2H),2.34–2.16(m,5H),2.13–2.06(m,2H),2.0 3–1.98(m,3H),1.96–1.83(m,5H),1.38–1.30(m,2H),1.02(d,J=6.5Hz,2H),0.79–0.74(m,4H),0.55–0.50(m,1H),0.47–0.37(m,3H);

[0411] 1 H NMR (400 MHz, DMSO-d6) is shown below δ13.12(s,1H),8.99(s,1H),8.64(s,1H),8.49(d,J=7.8Hz,1H),7.68–7. 63(m,2H),7.49–7.47(m,1H),7.46–7.42(m,3H),7.40–7.37(m,2H),6.80( d,J=8.1Hz,2H),5.35–5.29(m,2H),5.19–5.15(m,1H),5.07–5.05(m,1H) ,4.90–4.83(m,2H),4.78–4.73(m,1H),4.48–4.43(m,1H),4.34–4.31(m,1 H),4.27–4.18(m,3H),3.81–3.67(m,5H),3.65–3.56(m,3H),3.20–3.08( m,4H),3.06–2.98(m,3H),2.46(s,3H),2.13–2.05(m,4H),1.99(d,J=2.5H z,3H),1.91–1.86(m,1H),1.80–1.70(m,4H),1.39–1.33(m,1H),1.08(d,J =6.7Hz,3H),0.72(d,J=6.5Hz,3H),0.67–0.60(m,3H),0.58–0.51(m,1H);

[0412] 1 H NMR (400 MHz, DMSO-d6) is shown below δ13.16(s,1H),8.66(s,1H),8.54(d,J=7.9Hz,1H),8.48–8.38(m,4H),7.68(d,J =8.1Hz,2H),7.50–7.48(m,1H),7.46–7.44(m,1H),7.41–7.39(m,3H),7.24–7.19 (m,2H),6.78(d,J=8.1Hz,2H),5.36–5.26(m,3H),5.23–5.15(m,2H),5.08–5.04( m,1H),4.89–4.86(m,1H),4.71(d,J=11.4Hz,1H),4.49–4.45(m,1H),4.35–4.31( m,1H),4.27–4.22(m,1H),3.90–3.83(m,3H),3.79–3.76(m,2H),3.73–3.68(m,2 H),3.65–3.61(m,2H),3.13–3.10(m,1H),3.03–2.99(m,1H),2.13–2.05(m,3H),2 .00(d,J=2.5Hz,3H),1.91–1.87(m,1H),1.83–1.71(m,3H),1.70–1.64(m,2H),1. 38–1.33(m,2H),1.08(d,J=6.5Hz,3H),0.72(d,J=6.5Hz,3H),0.68–0.60(m,4H);

[0413] 1 H NMR (400 MHz, MeOH-d4) is shown below δ8.88(s,1H),8.41(s,1H),7.57–7.50(m,3H),7.48–7.40(m,5H),7.27(d,J=9.7Hz,1H),6.82(d,J=8.0Hz,2H),5.35(d,J=10.2Hz,1 H),5.28–5.23(m,1H),5.21–5.19(m,1H),5.08–5.03(m,1H),4.63–4.56(m,2H),4.52–4.47(m,1H),4.33–4.28(m,1H),4.22(d,J=6.5 Hz,2H),3.95–3.88(m,3H),3.86–3.81(m,3H),3.33(s,3H),3.16–3.10(m,3H),2.67–2.62(m,1H),2.48(s,3H),2.27–2.20(m,1H),2 .13–2.06(m,6H),1.97–1.87(m,4H),1.86–1.77(m,1H),1.48–1.41(m,1H),1.21–1.10(m,7H),0.85–0.81(m,3H),0.69–0.59(m,4H);

[0414] 1 H NMR (400 MHz, MeOH-d4) is shown below δ 8.87 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 7.54–7.48 (m, 3H), 7.47–7.44 (m, 4H), 7.39 (s, 1H), 7.28 (d, J = 9.5 Hz, 1H), 6.76 (d, J = 8.1 Hz, 2H), 5.48–5.40 (m, 1H), 5.35 (d, J = 10.2 Hz, 1H), 5.27 (d, J = 11.2 Hz, 1H), 5.21 (s, 1H), 5.05 (t, J = 6.1 Hz, 1H), 4.82–4.77 (m, 2H), 4.63–4.56 (m, 3H), 4.49 (s, 1H), 4.34 (d, J = 9.8 Hz, 1H), 4.19–4.14 (m, 1H), 4.04–3.99 (m, 1H), 3.96–3.91 (m, 1H), 3.85 (d, J = 6.0 Hz, 2H), 3.44 (t, J = 7.1 Hz, 1H), 3.26–3.24 (m, 3H), 3.20–3.16 (m, 1H), 2.68–2.60 (m, 1H), 2.49–2.47 (m, 4H), 2.38–2.32 (m, 1H), 2.27–2.20 (m, 1H), 2.17–2.12 (m, 1H), 2.07 (d, J = 2.1 Hz, 3H), 2.05–2.00 (m, 2H), 1.94 (d, J = 10.8 Hz, 1H), 1.16 (d, J = 6.6 Hz, 3H), 0.91–0.88 (m, 1H), 0.83 (d, J = 6.6 Hz, 3H), 0.70–0.65 (m, 1H), 0.65–0.57 (m, 3H);

[0415] 1 1H NMR (500 MHz, DMSO-d6) is as follows δ13.13(s,1H),8.99(s,1H),8.65(s,1H),8.50(d,J=7.8Hz,1H),7.66(d,J=7.8Hz,2H),7.49(s,1H),7.46–7.43(m,3H),7.41–7.37(m,3H),6.81(d,J=7.9Hz,2H),5.35–5.28(m,2H),5.18(d,J=3.8Hz,1H),5.04(s,1H),4.90–4.82(m,2H),4.75(d,J=11.5Hz,1H),4.48–4.43(m,1H),4.34–4.29(m,1H),4.26–4.21(m,1H),4.18–4.12(m,1H),4.12–4.06(m,1H),3.80–3.68(m,4H),3.65–3.56(m,2H),3.09(d,J=9.8Hz,1H),2.99(d,J=9.7Hz,1H),2.46(s,3H),2.22–2.15(m,1H),2.11–2.05(m,1H),2.00(d,J=2.5Hz,3H),1.90–1.83(m,5H),1.82–1.75(m,2H),1.75–1.70(m,1H),1.37–1.32(m,1H),1.29–1.20(m,4H),1.11–1.03(m,5H),0.71(d,J=6.4Hz,3H),0.67–0.53(m,4H);

[0416] 1 1H NMR(500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.42(s,1H),7.57–7.53(m,2H),7.51–7.50(m,1H),7.47–7.42(m,5H),7.27(d,J=9.6Hz,1H),6.85(d,J=8.1Hz,2H),5.35(d,J=10.3Hz,1H),5.23(d,J=11.8Hz,1H),5.18–5.16(m,1H),5.07–5.03(m,2H),4.77(d,J=11.7Hz,1H),4.60–4.56(m,1H),4.51–4.47(m,1H),4.46–4.45(m,2H),4.34–4.27(m,3H),3.95–3.91(m,2H),3.90–3.81(m,4H),3.14–3.11(m,1H),2.66–2.61(m,1H),2.48(s,3H),2.25–2.20(m,1H),2.11–2.08(m,5H),2.04–1.96(m,4H),1.92–1.88(m,1H),1.62–1.50(m,5H),1.47–1.41(m,1H),1.16(d,J=6.6Hz,3H),0.83(d,J=6.5Hz,3H),0.70–0.64(m,1H),0.63–0.57(m,3H);

[0417] 1 1H NMR(500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.42(s,1H),7.58–7.54(m,2H),7.52–7.51(m,1H),7.48–7.42(m,5 H),7.28(d,J=9.7Hz,1H),6.83(d,J=8.3Hz,2H),5.36(d,J=10.3Hz,1H),5.29–5.2 5(m,1H),5.21–5.19(m,1H),5.10–5.04(m,2H),4.82–4.79(m,1H),4.62–4.59(m, 1H),4.51–4.48(m,1H),4.35–4.28(m,2H),3.99–3.96(m,1H),3.96–3.92(m,1H),3 .90–3.83(m,4H),3.23–3.14(m,3H),2.66–2.61(m,2H),2.49(s,3H),2.26–2.19( m,3H),2.14–2.11(m,1H),2.09(d,J=2.4Hz,3H),2.06–2.00(m,3H),1.94–1.90(m, 1H),1.87–1.82(m,1H),1.48–1.41(m,3H),1.17(d,J=6.5Hz,3H),1.13–1.08(m,1H ),1.01–0.96(m,1H),0.83(d,J=6.7Hz,3H),0.70–0.65(m,1H),0.64–0.58(m,3H);

[0418] 1 H NMR (500 MHz, MeOH-d4) is shown below δ8.88(s,1H),8.42(s,1H),7.58–7.54(m,2H),7.52–7.51(m,1H),7.48–7.42(m,5 H),7.28(d,J=9.7Hz,1H),6.83(d,J=8.3Hz,2H),5.36(d,J=10.3Hz,1H),5.32–5. 28(m,1H),5.20–5.18(m,1H),5.10–5.04(m,2H),4.82–4.79(m,1H),4.62–4.58(m ,1H),4.51–4.48(m,1H),4.34–4.31(m,1H),3.98–3.92(m,2H),3.90–3.83(m,4H) ,3.27(s,3H),3.18–3.13(m,2H),2.68–2.62(m,2H),2.49(s,3H),2.25–2.17(m,3 H),2.14–2.11(m,1H),2.09(d,J=2.4Hz,3H),2.05–1.99(m,3H),1.94–1.90(m,1H ),1.87–1.82(m,1H),1.47–1.41(m,2H),1.17(d,J=6.7Hz,3H),1.12–1.08(m,1H) ,0.92–0.88(m,1H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.64–0.58(m,3H);

[0419] 1 H NMR (500 MHz, MeOH-d4) is shown below δ8.87(s,1H),8.41(s,1H),7.56–7.53(m,2H),7.51–7.49(m,1H),7.47–7.42 (m,5H),7.29–7.25(m,1H),6.83–6.80(m,2H),5.35(d,J=10.2Hz,1H),5.29–5 .25(m,1H),5.18–5.15(m,1H),5.07–5.00(m,2H),4.81–4.77(m,1H),4.62–4 .58(m,1H),4.51–4.47(m,1H),4.32–4.28(m,1H),3.95–3.88(m,3H),3.86–3. 81(m,3H),3.11(dd,J=10.3,2.0Hz,1H),2.66–2.59(m,1H),2.47(s,3H),2.2 4–2.17(m,3H),2.10–2.06(m,4H),2.04–1.98(m,1H),1.91–1.87(m,1H),1.76 –1.71(m,2H),1.52–1.36(m,5H),1.15(d,J=6.6Hz,3H),1.04–0.95(m,2H),0. 84(d,J=6.6Hz,3H),0.82–0.80(m,3H),0.68–0.63(m,1H),0.62–0.56(m,3H);

[0420] 1 H NMR (500 MHz, MeOH-d4) is shown below δ8.88(s,1H),8.40(s,1H),7.59–7.56(m,2H),7.55–7.50(m,2H),7.48–7. 42(m,4H),7.28(d,J=9.7Hz,1H),6.86(d,J=8.1Hz,3H),5.39–5.31(m,1H) ,5.21–5.16(m,2H),5.10–5.01(m,2H),4.63–4.57(m,1H),4.52–4.47(m,1 H),4.33–4.27(m,1H),3.97–3.88(m,3H),3.87–3.80(m,2H),3.14–3.09(m ,1H),2.68–2.58(m,1H),2.48(s,3H),2.39–2.30(m,2H),2.26–2.14(m,3H ),2.11–2.06(m,1H),2.04(d,J=2.4Hz,3H),2.03–1.96(m,3H),1.92–1.85 (m,1H),1.63–1.50(m,3H),1.48–1.42(m,2H),1.16(d,J=6.6Hz,3H),0.93 –0.87(m,2H),0.82(d,J=6.5Hz,3H),0.75–0.68(m,1H),0.66–0.56(m,3H);

[0421] 1 H NMR (500 MHz, DMSO-d6) is shown below δ13.23(s,1H),8.99(s,1H),8.68–8.63(m,2H),7.65(d,J=8.1Hz,2H),7.48–7.46(m,1H),7.45–7.41(m,4H),7.39–7.37(m,2H),6.76(d,J=8.1Hz,2H),5.34–5.31(m,1H),5.26(d,J=3.7Hz,1H),5.13–5.10(m,1H),5.08–5.04(m,2H),5.04–5.01(m,1H),4.93–4.89(m,1H),4.85–4.80(m,1H),4.46(t,J=7.9Hz,1H),4.33–4.29(m,1H),4.26–4.20(m,1H),3.83–3.78(m,1H),3.77–3.72(m,2H),3.70–3.65(m,1H),3.64–3.57(m,2H),3.34–3.31(m,4H),3.11–3.08(m,1H),3.04–3.01(m,1H),3.00–2.97(m,1H),2.46(s,4H),2.14–2.05(m,2H),1.98(d,J=2.1Hz,3H),1.91–1.86(m,3H),1.81–1.75(m,2H),1.74–1.71(m,2H),1.36–1.32(m,1H),1.07(d,J=6.5Hz,3H),0.71(d,J=6.6Hz,3H),0.66–0.57(m,3H),0.54–0.49(m,1H);

[0422] 1 1H NMR (500 MHz, DMSO-d6) is as follows δ13.24(s,1H),8.99(s,1H),8.66(d,J=7.5Hz,1H),8.64(s,1H),7.66(d,J=8.1Hz,2H),7.46(s,1H),7.44–7.41(m,4H),7.39–7.37(m,2H),5.31(d,J=10.2Hz,1H),5.26(d,J=3.8Hz,1H),5.17–5.13(m,1H),5.05–5.01(m,3H),4.97–4.92(m,1H),4.85–4.79(m,1H),4.46(t,J=8.0Hz,1H),4.32–4.29(m,1H),4.26–4.20(m,1H),3.82–3.78(m,1H),3.77–3.73(m,2H),3.68–3.64(m,1H),3.63–3.58(m,2H),3.35–3.33(m,4H),3.10–3.06(m,1H),3.00–2.96(m,1H),2.83–2.78(m,1H),2.46(s,4H),2.10–2.03(m,4H),1.97(d,J=2.3Hz,3H),1.89–1.86(m,1H),1.80–1.77(m,1H),1.74–1.71(m,1H),1.58–1.56(m,2H),1.36–1.32(m,1H),1.07(d,J=6.5Hz,3H),0.70(d,J=6.6Hz,3H),0.66–0.58(m,3H),0.53–0.49(m,1H);

[0423] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.42(s,1H),7.58–7.55(m,2H),7.54–7.53(m,1H),7.51–7.50(m,1H),7.47–7.43(m,4H),7.28(d,J=9.8Hz,1H),6.85–6.82(m,2H),5.35(d,J=10.3Hz,1H),5.23–5.21(m,1H),5.19–5.15(m,1H),5.07–5.04(m,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.33–4.25(m,3H),3.96–3.91(m,2H),3.90–3.82(m,4H),3.14–3.11(m,1H),2.67–2.59(m,1H),2.48(s,3H),2.27–2.18(m,2H),2.11–2.07(m,2H),2.03(d,J=2.6Hz,3H),1.96–1.90(m,3H),1.82–1.72(m,2H),1.62–1.57(m,1H),1.48–1.43(m,2H),1.42–1.36(m,3H),1.16(d,J=6.6Hz,3H),0.91–0.88(m,1H),0.83(d,J=6.7Hz,3H),0.72–0.68(m,1H),0.65–0.58(m,3H);

[0424] 1 1H NMR(500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.41(s,1H),7.56–7.50(m,3H),7.49–7.39(m,5H),7.30– 7.26(m,1H),6.79(d,J=7.8Hz,2H),5.36–5.33(m,1H),5.28–5.25(m,1H) ,5.22–5.14(m,3H),5.07–5.03(m,1H),4.62–4.57(m,2H),4.51–4.47(m ,1H),4.36–4.32(m,1H),4.23–4.18(m,1H),4.02–4.00(m,1H),3.93(dd, J=11.0,3.7Hz,1H),3.89–3.83(m,3H),3.20–3.15(m,1H),2.66–2.62(m ,1H),2.48(s,3H),2.26–2.17(m,5H),2.10–2.08(m,3H),2.05–2.00(m,2 H),1.96–1.92(m,1H),1.74–1.70(m,2H),1.63–1.56(m,3H),1.16(d,J= 6.5Hz,3H),0.92–0.88(m,2H),0.83(d,J=6.5Hz,3H),0.69–0.58(m,4H);

[0425] 1 H NMR (500 MHz, MeOH-d4) is shown below δ8.88(s,1H),8.41(s,1H),7.55–7.49(m,3H),7.48–7.39(m,5H),7.28(d,J=9.7Hz,1H),6.75(d,J=8.2Hz,2H),5.35(d,J=10.4Hz,1H),5.29–5.25(m,1H),5.20–5.18(m,1H),5.15–5.09(m,1H),5.07–5.03(m,1H),4.81–4.77(m,1H),4.61–4.57(m,1H),4.51–4.47(m,1H),4.34–4.31(m,1H),3.98–3.88(m,3H),3.87–3.83(m,3H),3.71–3.64(m,1H),3.17–3.13(m,1H),2.67–2.61(m,1H),2.48(s,3H),2.31–2.17(m,4H),2.14–2.06(m,4H),2.04–1.98(m,3H),1.94–1.90(m,1H),1.65–1.58(m,2H),1.48–1.39(m,3H),1.16(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.58(m,4H);

[0426] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ 8.89 (s, 1H), 8.43 (s, 1H), 7.55–7.50 (m, 3H), 7.48–7.44 (m, 4H), 7.43–7.41 (m, 1H), 7.29 (d, J = 9.6 Hz, 1H), 6.75 (d, J = 8.1 Hz, 2H), 5.36 (d, J = 10.3 Hz, 1H), 5.30–5.26 (m, 1H), 5.20–5.17 (m, 1H), 5.15–5.09 (m, 1H), 5.07–5.04 (m, 1H), 4.79 (d, J = 11.2 Hz, 1H), 4.62–4.57 (m, 1H), 4.51–4.48 (m, 1H), 4.34–4.30 (m, 1H), 3.96–3.89 (m, 3H), 3.89–3.82 (m, 3H), 3.57–3.50 (m, 2H), 3.44–-3.38 (m, 1H), 3.16–3.11 (m, 1H), 2.67–2.61 (m, 1H), 2.49 (s, 3H), 2.28–2.20 (m, 3H), 2.13–2.07 (m, 6H), 2.04–1.97 (m, १H), 1.94–1.89 (m, 1H), 1.66–1.58 (m, 2H), 1.49–1.35 (m, 4H), 1.20–1.13 (m, 6H), 0.83 (d, J = 6.6 Hz, 3H), 0.69–0.64 (m, 1H), 0.63–0.57 (m, 3H);

[0427] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.42(s,1H),7.55(d,J=8.3Hz,2H),7.51(s,1H),7.48–7.44(m,4H),7.43(s,1H),7.27(d,J=9.7Hz,1H),6.82(d,J=8.3Hz,2H),5.35(d,J=10.3Hz,1H),5.31–5.25(m,1H),5.21–5.16(m,1H),5.12–5.04(m,2H),4.81–4.77(m,1H),4.62–4.57(m,1H),4.53–4.47(m,1H),4.34–4.28(m,1H),3.96–3.91(m,2H),3.90–3.86(m,1H),3.86–3.79(m,3H),3.15–3.11(m,1H),2.68–2.60(m,1H),2.48(s,3H),2.27–2.20(m,1H),2.09(d,J=2.3Hz,3H),2.05–1.96(m,3H),1.90(d,J=10.2Hz,1H),1.80–1.69(m,2H),1.56–1.47(m,2H),1.47–1.41(m,1H),1.34–1.23(m,4H),1.16(d,J=6.6Hz,3H),0.98(s,3H),0.89(s,3H),0.82(d,J=6.6Hz,3H),0.69–0.64(m,1H),0.64–0.56(m,3H);

[0428] 1 1H NMR(500 MHz, DMSO-d6) is as follows δ13.11(s, 1H), 8.99(s, 1H), 8.64(s, 1H), 8.49(d, J = 7.9 Hz, 1H), 7.66(s, 1H), 7.64(s, 1H), 7.50–7.47(m, 1H), 7.47–7.41(m, 3H), 7.43–7.35(m, 3H), 6.75–6.70(m, 2H), 5.37–5.29(m, 3H), 5.16(d, J = 3.8 Hz, 1H), 5.06–5.02(m, 1H), 5.03–4.96(m, 1H), 4.89–4.81(m, 2H), 4.74(d, J = 11.3 Hz, 1H), 4.49–4.42(m, 1H), 4.34–4.30(m, 1H), 4.26–4.21(m, 1H), 3.79–3.74(m, 2H), 3.72–3.66(m, 1H), 3.65–3.56(m, 2H), 3.20(s, 3H), 3.10(d, J = 9.8 Hz, 1H), 2.99(d, J = 9.7 Hz, 1H), 2.46(s, 3H), 2.19–2.14(m, 1H), 2.12–2.05(m, 2H), 2.01–2.00(m, 1H), 1.99–1.99(m, 3H), 1.98–1.96(m, 1H), 1.91–1.86(m, 1H), 1.83–1.76(m, 1H), 1.75–1.70(m, 1H), 1.54–1.47(m, 2H), 1.39–1.33(m, 1H), 1.08(d, J = 6.6 Hz, 3H), 0.88–0.82(m, 1H), 0.72(d, J = 6.4 Hz, 3H), 0.68–0.59(m, 3H), 0.59–0.52(m, 1H);

[0429] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.43(s,1H),7.56–7.49(m,3H),7.48–7.44(m,4H),7.40(s,1H),7.27(d,J=9.6Hz,1H),6.79(d,J=7.9Hz,2H),5.36(d,J=10.3Hz,1H),5.25(d,J=11.5Hz,1H),5.20–5.18(m,1H),5.08–5.04(m,1H),4.78(d,J=11.5Hz,1H),4.63–4.57(m,1H),4.52–4.48(m,1H),4.34–4.30(m,1H),3.96–3.88(m,3H),3.87–3.79(m,3H),3.65–3.60(m,1H),3.30–3.28(m,1H),3.22(s,3H),3.16–3.11(m,1H),2.91–2.83(m,2H),2.68–2.61(m,1H),2.48(s,3H),2.27–2.18(m,1H),2.12–1.98(m,8H),1.93–1.88(m,1H),1.47–1.40(m,1H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.4Hz,3H),0.69–0.57(m,4H);

[0430] 1 1H NMR(500 MHz, MeOH-d4) is as follows δ8.89(s,1H),8.43(s,1H),7.57–7.50(m,3H),7.49–7.41(m,5H),7.28(d ,J=9.6Hz,1H),6.82–6.78(m,2H),5.39–5.28(m,3H),5.21–5.17(m,1H), 5.08–5.03(m,1H),4.81–4.77(m,1H),4.62–4.57(m,1H),4.52–4.47(m,1 H),4.34–4.30(m,1H),3.96–3.91(m,2H),3.90–3.79(m,4H),3.43–3.39(m ,2H),3.16–3.12(m,1H),2.68–2.60(m,1H),2.58–2.52(m,1H),2.49(s,3 H),2.38–2.32(m,4H),2.29–2.16(m,2H),2.13–2.07(m,4H),2.05–1.97(m ,2H),1.93–1.89(m,1H),1.46–1.41(m,1H),1.38–1.32(m,2H),1.17(d,J =6.7Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.64–0.57(m,3H);

[0431] 1 H NMR (500 MHz, MeOH-d4) is shown below δ8.89(s,1H),8.45(s,1H),7.61–7.56(m,2H),7.53–7.51(m,1H),7.49–7.44(m,4H),7.29(d,J=9.6Hz,1H),6.90–6.84(m,2H),5.35(d,J=10.3Hz,1H),5.23–5.18(m,2H),5.12–5.04(m,3H),4.74(d,J=11.3Hz,1H),4.61–4.57(m,1H),4.51–4.47(m,1H),4.35–4.31(m,1H),3.97–3.91(m,2H),3.90–3.82(m,4H),3.17–3.07(m,3H),2.87(s,3H),2.68–2.61(m,1H),2.48(s,3H),2.44–2.39(m,2H),2.28–2.20(m,3H),2.13–2.08(m,4H),2.05–1.98(m,1H),1.93–1.89(m,1H),1.67–1.58(m,4H),1.47–1.42(m,1H),1.16(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.71–0.65(m,1H),0.64–0.58(m,3H);

[0432] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.89(s,1H),8.46(s,1H),7.63–7.58(m,2H),7.51–7.43(m,5H),7.42(s,1H),7.29(d,J=9.6Hz,1H),6.96(d,J=8.0Hz,2H),5.37(d,J=10 .4Hz,1H),5.26–5.24(m,1H),5.22–5.19(m,2H),5.07–5.05(m,1H),4.63–4.58(m,4H),4.53–4.49(m,1H),4.43–4.39(m,1H),4.23–4.18( m,2H),4.15–4.10(m,1H),3.95–3.91(m,3H),3.87–3.84(m,2H),3.48–3.44(m,2H),3.20–3.16(m,3H),2.49(s,3H),2.26–2.21(m,3H),2. 13–2.09(m,4H),2.05–1.98(m,3H),1.85–1.79(m,2H),1.17(d,J=6.7Hz,3H),0.85(d,J=6.7Hz,3H),0.72–0.68(m,1H),0.65–0.61(m,3H);

[0433] 1 H NMR (500 MHz, MeOH-d4) is shown below δ 8.88 (s, 1H), 7.52–7.40 (m, 7H), 7.40–7.39 (m, 1H), 7.28–7.23 (m, 1H), 6.82–6.76 (m, 2H), 6.71 (s, 1H), 5.32–5.26 (m, 1H), 5.20–5.17 (m, 1H), 5.14–5.08 (m, 1H), 5.07–5.03 (m, 1H), 4.83–4.76 (m, 2H), 4.62–4.56 (m, 1H), 4.49–4.45 (m, 1H), 4.33–4.27 (m, 1H), 3.91–3.87 (m, 2H), 3.87–3.80 (m, 3H), 3.71–3.67 (m, 1H), 3.33 (s, 3H), 3.29–3.26 (m, 1H), 3.13–3.09 (m, 1H), 2.50–2.43 (m, 4H), 2.25–2.18 (m, 3H), 2.12–2.06 (m, 6H), 2.04–1.98 (m, 1H), 1.92–1.87 (m, 1H), 1.66–1.57 (m, 2H), 1.45–1.32 (m, 4H), 1.10 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.69–0.63 (m, 1H), 0.62–0.56 (m, 3H);

[0434] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.45–8.42(m,1H),7.56–7.52(m,2H),7.50–7.49(m,1H),7.47– 7.44(m,5H),7.29(dd,J=9.7,3.3Hz,1H),6.78(d,J=8.2Hz,2H),5.38–5.34(m, 1H),5.27–5.23(m,1H),5.16–5.11(m,1H),5.08–5.04(m,1H),5.02–4.97(m,2H ),4.85(dd,J=11.4,5.2Hz,1H),4.62–4.58(m,1H),4.51–4.48(m,1H),3.96–3. 88(m,2H),3.84(d,J=6.2Hz,2H),3.42–3.34(m,2H),3.32(s,6H),3.22–3.16(m ,1H),3.11–3.01(m,2H),2.67–2.60(m,1H),2.48(s,3H),2.26–2.17(m,4H),2. 12–2.02(m,7H),1.68–1.56(m,3H),1.48–1.43(m,1H),1.40–1.32(m,3H),1.16 (d,J=6.6Hz,3H),0.82(d,J=6.5Hz,3H),0.73–0.68(m,1H),0.67–0.58(m,3H);

[0435] 1 H NMR (500 MHz, MeOH-d4) is shown below δ 8.89 (s, 1H), 8.43 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.50–7.44 (m, 6H), 7.29 (d, J = 9.7 Hz, 1H), 6.78 (d, J = 8.0 Hz, 2H), 5.36 (d, J = 10.3 Hz, 1H), 5.26 (d, J = 11.5 Hz, 1H), 5.19–5.07 (m, 3H), 5.06 (t, J = 6.1 Hz, 1H), 4.86–4.83 (m, 1H), 4.60 (t, J = 8.3 Hz, 1H), 4.52–4.47 (m, 1H), 3.97–3.87 (m, 2H), 3.84 (d, J = 6.1 Hz, 2H), 3.55–3.50 (m, 1H), 3.45–3.41 (m, 1H), 3.33 (s, 3H), 3.07–3.01 (m, 1H), 2.69–2.61 (m, 1H), 2.48 (s, 3H), 2.33–2.27 (m, 1H), 2.27–2.17 (m, 4H), 2.16–2.08 (m, 3H), 2.08–2.05 (m, 3H), 2.04–1.99 (m, 1H), 1.87–1.80 (m, 1H), 1.72–1.56 (m, 3H), 1.48–1.44 (m, 1H), 1.43–1.37 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.0 Hz, 3H), 0.73–0.69 (m, 1H), 0.68–0.59 (m, 3H);

[0436] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.40(s,1H),7.52–7.49(m,3H),7.47–7.44(m,3H),7.40–7.36(m,2H),7.28–7.25(m,1H),6.73(d,J=8.0Hz,2H),5.37–5.3 2(m,2H),5.19–5.16(m,1H),5.07–5.03(m,1H),4.50–4.48(m,1H),4.33–4.30(m,1H),4.01–3.97(m,2H),3.93–3.88(m,4H),3.86–3.82( m,3H),3.39(s,3H),2.48(s,3H),2.26–2.20(m,2H),2.07(d,J=2.4Hz,3H),2.04–2.00(m,2H),1.91–1.88(m,1H),1.46–1.42(m,2H),1.1 6(d,J=6.6Hz,3H),1.12(d,J=6.6Hz,1H),1.09–1.07(m,2H),0.98–0.93(m,3H),0.85–0.80(m,3H),0.69–0.65(m,1H),0.63–0.59(m,3H);

[0437] 1 H NMR (500 MHz, MeOH-d4) is shown below δ 8.88 (s, 1H), 8.42 (s, 1H), 7.54–7.50 (m, 3H), 7.49–7.45 (m, 4H), 7.41 (s, 1H), 7.29 (d, J = 9.5 Hz, 1H), 6.77 (d, J = 8.1 Hz, 2H), 5.61–5.55 (m, 1H), 5.38–5.35 (m, 1H), 5.29–5.25 (m, 1H), 5.21 (s, 1H), 5.08–5.04 (m, 2H), 4.78 (d, J = 11.2 Hz, 1H), 4.70–4.64 (m, 1H), 4.60 (t, J = 8.4 Hz, 1H), 4.53–4.47 (m, 1H), 4.37–4.32 (m, 1H), 4.26–4.21 (m, 1H), 4.18–4.14 (m, 1H), 4.00–3.96 (m, 1H), 3.94–3.88 (m, 2H), 3.85 (d, J = 6.2 Hz, 2H), 3.19–3.16 (m, 1H), 2.82–2.75 (m, 1H), 2.68–2.62 (m, 1H), 2.49 (s, 3H), 2.45–2.40 (m, 1H), 2.22–2.17 (m, 1H), 2.15–2.11 (m, 1H), 2.09 (d, 3H), 2.05–2.02 (m, 1H), 1.95–1.91 (m, 1H), 1.89–1.82 (m, 1H), 1.65–1.58 (m, 1H), 1.48–1.43 (m, 1H), 1.17 (d, J = 6.6 Hz, 3H), 0.92–0.89 (m, 1H), 0.83 (d, J = 6.5 Hz, 3H), 0.70–0.66 (m, 1H), 0.65–0.60 (m, 3H);

[0438] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.89(s,1H),8.42(s,1H),7.54–7.49(m,3H),7.48–7.45(m,4H),7.40(s,1H),7.29(d,J=9.7Hz,1H),6.77(d,J=8.1Hz,2H),5.63–5.55(m,1H),5.39–5.35(m,1H),5.29–5.25(m,1H),5.21(s,1H),5.06(t,J=6.0Hz,1H),4.80(d,J=11.3Hz,1H),4.66(s,1H),4.60(t,J=8.3Hz,1H),4.50(s,1H),4.38–4.33(m,1H),4.27–4.22(m,1H),4.20–4.13(m,1H),4.02–3.97(m,1H),3.94–3.88(m,2H),3.86–3.83(m,2H),3.19–3.16(m,1H),2.81–2.73(m,1H),2.67–2.60(m,1H),2.49(s,3H),2.46–2.42(m,1H),2.26–2.20(m,1H),2.20–2.14(m,1H),2.09(d,J=2.0Hz,3H),2.05–2.02(m,1H),1.96–1.91(m,1H),1.90–1.85(m,1H),1.64–1.57(m,1H),1.49–1.43(m,1H),1.17(d,J=6.6Hz,3H),0.92–0.87(m,1H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.65–0.59(m,3H);

[0439] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.42(s,1H),7.54–7.50(m,3H),7.48–7.45(m,4H),7.40(s,1H),7.30–7.25(m,1H),6.79(dd,J=8.2,2.4Hz,2H),5.43–5.40(m,1H),5.36(d,J=10.3Hz,1H),5.28(d,J=11.6Hz,1H),5.21(s,1H),5.06(t,J=6.1Hz,1H),4.81(dd,J=11.5,2.3Hz,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.36–4.31(m,1H),3.99–3.96(m,1H),3.96–3.89(m,2H),3.88–3.82(m,4H),3.29–3.28(m,3H),3.17–3.13(m,1H),2.68–2.61(m,1H),2.50–2.47(m,3H),2.46–2.42(m,1H),2.26–2.21(m,1H),2.14–2.11(m,1H),2.10–2.08(m,3H),2.06–1.99(m,3H),1.95–1.80(m,5H),1.48–1.41(m,1H),1.17(d,J=6.6Hz,3H),0.82(d,J=5.2Hz,3H),0.69–0.65(m,1H),0.64–0.58(m,3H);

[0440] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.43(s,1H),7.55(d,J=8.0Hz,2H),7.53–7.51(m,1H),7.48–7.43(m,5H),7.28(d,J=8.2Hz,1H),6.80(d,J=8.1Hz,2H),5.37(d,J=10.3Hz,1H),5.27(d,J=11.4Hz,1H),5.18(s,1H),5.13–5.08(m,1H),5.07–5.04(m,1H),4.78(d,J=11.4Hz,1H),4.60(t,J=8.3Hz,1H),4.53–4.47(m,1H),4.31(d,J=8.8Hz,1H),3.96–3.88(m,3H),3.86–3.80(m,3H),3.73–3.66(m,1H),3.30–3.27(m,1H),3.12(d,J=9.8Hz,1H),2.67–2.60(m,1H),2.48(s,3H),2.32–2.22(m,3H),2.12–2.10(m,1H),2.10–2.07(m,3H),2.04–2.00(m,1H),2.00–1.95(m,2H),1.90(s,3H),1.66–1.58(m,2H),1.48–1.42(m,1H),1.41–1.26(m,3H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.65–0.58(m,3H);

[0441] 1 1H NMR(500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.01(s,1H),7.52–7.49(m,3H),7.46(s,4H),7.38–7.37( m,1H),7.27(d,J=9.8Hz,1H),6.76–6.73(m,2H),5.25(d,J=11.4Hz,1H), 5.20–5.16(m,2H),5.15–5.10(m,1H),5.06–5.02(m,1H),4.82–4.79(m, 1H),4.60–4.56(m,1H),4.49–4.46(m,1H),4.33–4.29(m,1H),3.95–3.90 (m,2H),3.85–3.82(m,3H),3.77–3.74(m,1H),3.33(s,3H),3.16–3.12( m,1H),2.92–2.87(m,1H),2.48(s,3H),2.25–2.16(m,4H),2.11–2.07(m, 5H),2.04–2.00(m,1H),1.93–1.89(m,1H),1.65–1.60(m,2H),1.44–1.36 (m,4H),1.13(d,J=6.7Hz,3H),0.82(d,J=6.6Hz,3H),0.66–0.58(m,5H);

[0442] 1 H NMR (500 MHz, MeOH-d4) is shown below δ8.88(s,1H),7.86(d,J=1.3Hz,1H),7.61(d,J=1.3Hz,1H),7.53–7.49(m, 2H),7.48–7.41(m,6H),7.30(d,J=9.7Hz,1H),6.71–6.68(m,2H),5.23–5.2 2(m,1H),5.19–5.12(m,2H),5.07–5.04(m,1H),4.83–4.80(m,2H),4.62–4 .58(m,2H),4.51–4.48(m,1H),4.39–4.34(m,1H),4.12–4.09(m,1H),3.91– 3.87(m,2H),3.86–3.78(m,3H),3.42–3.38(m,1H),3.33(s,3H),3.24–3.2 1(m,1H),2.48(s,3H),2.26–2.17(m,4H),2.14–2.07(m,3H),2.02(d,J=2.4 Hz,3H),1.98–1.94(m,1H),1.67–1.60(m,2H),1.48–1.37(m,4H),1.11(d, J=6.6Hz,3H),0.81(d,J=6.7Hz,3H),0.74–0.68(m,1H),0.66–0.58(m,3H);

[0443] 1 H NMR (500 MHz, MeOH-d4) is shown below δ8.88(s,1H),8.41(s,1H),7.55–7.50(m,3H),7.48–7.44(m,4H),7.42(s,1H),7.27(d,J=9.7Hz,1H),6.78(d,J=8.2Hz,2H),5.35(d,J=10.3Hz,1H),5.26(d,J=11.5Hz,1H),5.23–5.18(m,2H),5.06(t,J=6.1Hz,1H),4.79(d,J=11.4Hz,1H),4.62–4.58(m,1H),4.52–4.48(m,1H),4.35–4.29(m,1H),3.96–3.87(m,3H),3.86–3.84(m,2H),3.78–3.73(m,1H),3.30–3.28(m,2H),3.15–3.10(m,1H),2.68–2.61(m,1H),2.48(s,3H),2.27–2.20(m,1H),2.12–2.09(m,1H),2.09(d,J=2.2Hz,3H),2.08–2.06(m,1H),2.06–1.99(m,2H),1.92–1.88(m,1H),1.84–1.78(m,4H),1.75–1.67(m,2H),1.48–1.41(m,1H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.65–0.58(m,3H);

[0444] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.89(s,1H),8.41(s,1H),7.52–7.50(m,2H),7.50–7.44(m,5H),7.39(s,1H),7.28(d,J=9.6Hz,1H),6.74(d,J=8.2Hz,2H),5.50–5.44(m,1H),5.37–5.34(m,1H),5.28(d,J=11.3Hz,1H),5.20(s,1H),5.06(t,J=6.0Hz,1H),4.81–4.79(m,1H),4.63–4.61(m,1H),4.60–4.55(m,2H),4.51–4.48(m,1H),4.36–4.29(m,1H),3.97–3.91(m,2H),3.91–3.87(m,1H),3.87–3.83(m,2H),3.16–3.12(m,1H),2.67–2.61(m,1H),^{2.57–2.54(m,1H),2.49(s,3H),2.47–2.42(m,2H),2.27–2.21(m,1H),2.21–2.17(m,1H),2.13–2.09(m,1H),2.07(d,J=2.2Hz,3H),2.05–1.99(m,2H),1.94–1.89(m,1H),1.49–1.41(m,1H),1.17(d,J=6.6Hz,3H),0.84(d,J=6.6Hz,3H),0.71–0.57(m,4H);

[0445] 1 1H NMR(500MHz,MeOH-d4) is as follows Note: There seems to be a formatting issue in the original text where the line break within the chemical shift data might be incorrect. I've tried to keep the translation as close as possible while maintaining the integrity of the data. If this is a critical error in the source text, it might need to be corrected before translation for a more accurate result.δ8.89(s,1H),8.42(s,1H),7.53(s,1H),7.52–7.50(m,2H),7.48–7.47(m,3H),7. 46–7.45(m,1H),7.40(s,1H),7.27(d,J=9.5Hz,1H),6.78(d,J=8.1Hz,2H),5.36( d,J=10.3Hz,1H),5.28–5.25(m,1H),5.22–5.20(m,1H),5.06(t,J=6.1Hz,2H),4. 80–4.78(m,1H),4.63–4.57(m,3H),4.51–4.48(m,1H),4.35–4.31(m,1H),3.96–3 .92(m,3H),3.91–3.88(m,1H),3.86–3.84(m,2H),3.16–3.13(m,1H),2.94–2.89( m,2H),2.68–2.62(m,1H),2.49(s,3H),2.27–2.21(m,1H),2.15–2.10(m,3H),2.0 8(d,J=2.1Hz,3H),2.04–1.99(m,1H),1.91(d,J=9.1Hz,1H),1.47–1.42(m,1H),1 .17(d,J=6.5Hz,3H),0.84(d,J=6.6Hz,3H),0.69–0.65(m,1H),0.64–0.60(m,3H);

[0446] 1 H NMR (500 MHz, MeOH-d4) is shown below δ8.88(s,1H),8.41(s,1H),7.53–7.50(m,3H),7.47–7.44(m,4H),7.41–7.41(m,1H),7.28(d,J=9.6Hz,1H),6.75(d,J=8.4Hz,2H),5.56–5.50(m,1H),5.37–5.33(m,1H),5.29–5.25(m,1H),5.19–5.17(m,1H),5.07–5.04(m,1H),4.80(d,J=11.5Hz,1H),4.63–4.58(m,1H),4.51–4.44(m,3H),4.34–4.30(m,1H),3.97–3.89(m,3H),3.88–3.83(m,3H),3.17–3.13(m,1H),2.67–2.61(m,1H),2.48(s,3H),2.27–2.17(m,4H),2.11–2.07(m,3H),2.05–1.99(m,2H),1.94–1.87(m,3H),1.85–1.78(m,4H),1.47–1.42(m,1H),1.16(d,J=6.6Hz,3H),0.84–0.81(m,3H),0.69–0.64(m,1H),0.63–0.58(m,3H);

[0447] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.89(s,1H),8.46–8.41(m,1H),7.55(d,J=7.9Hz,2H),7.49–7.44(m,5H),7.36(s,1H),7.30–7.27(m,1H),6.79(d,J=7.8Hz,2H),5.38–5.32(m,2H),5.26(d,J=11.3Hz,1H),5.16–5.10(m,1H),5.05(t,J=6.1Hz,1H),4.83–4.79(m,1H),4.64(s,1H),4.61–4.57(m,1H),4.49(s,1H),3.96–3.87(m,2H),3.84(d,J=6.1Hz,2H),3.56(d,J=13.0Hz,1H),3.32(s,3H),3.29–3.25(m,2H),2.83(dd,J=12.4,6.0Hz,1H),2.80–2.75(m,1H),2.68–2.62(m,1H),2.48(s,3H),2.26–2.17(m,4H),2.12–2.08(m,2H),2.05(d,J=2.2Hz,3H),2.04–1.98(m,2H),1.67–1.57(m,3H),1.46–1.41(m,1H),1.17(d,J=6.6Hz,3H),0.90(t,J=6.9Hz,1H),0.83(d,J=6.6Hz,3H),0.72–0.66(m,1H),0.66–0.59(m,3H);

[0448] 1 1H NMR (500 MHz, Methanol-d4) is as follows δ8.88(s,1H),8.41(s,1H),7.53–7.49(m,3H),7.47–7.44(m,4H),7.42–7. 41(m,1H),7.27(d,J=9.5Hz,1H),6.77(d,J=8.1Hz,2H),5.81–5.57(m,1H) ,5.40–5.37(m,1H),5.37–5.33(m,1H),5.27–5.21(m,2H),5.08–5.04(m,1 H),4.79(d,J=11.2Hz,1H),4.62–4.58(m,1H),4.51–4.48(m,1H),4.33–4.2 9(m,1H),3.97–3.89(m,3H),3.88–3.82(m,3H),3.16–3.12(m,1H),2.67–2 .61(m,1H),2.48(s,3H),2.24–2.18(m,3H),2.11–2.07(m,4H),2.05–1.98 (m,2H),1.92–1.84(m,2H),1.75–1.64(m,6H),1.47–1.41(m,1H),1.16(d, J=6.5Hz, 3H), 0.83 (d, J=6.6Hz, 3H), 0.69–0.63 (m, 1H), 0.62–0.56 (m, 3H).

[0449] 1 H NMR (500 MHz, MeOH-d4) is shown below δ 8.88 (s, 1H), 8.41 (s, 1H), 7.53–7.49 (m, 3H), 7.47–7.44 (m, 4H), 7.40–7.38 (m, 1H), 7.26 (d, J = 9.6 Hz, 1H), 6.77 (d, J = 8.2 Hz, 2H), 5.35 (d, J = 10.3 Hz, 1H), 5.28–5.24 (m, 1H), 5.21–5.17 (m, 2H), 5.07–5.04 (m, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.62–4.58 (m, 1H), 4.51–4.48 (m, 1H), 4.32–4.28 (m, 1H), 3.95–3.88 (m, 3H), 3.86–3.81 (m, 3H), 3.41 (d, J = 6.2 Hz, 2H), 3.32 (s, 3H), 3.13–3.10 (m, 1H), 2.65–2.57 (m, 3H), 2.48 (s, 3H), 2.26–2.19 (m, 2H), 2.10–2.06 (m, 4H), 2.04–1.93 (m, 4H), 1.91–1.87 (m, 1H), 1.46–1.41 (m, 1H), 1.16 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H), 0.68–0.63 (m, 1H), 0.62–0.57 (m, 3H);

[0450] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ 8.89 (s, 1H), 8.42 (s, 1H), 7.53–7.50 (m, 3H), 7.48–7.45 (m, 4H), 7.39 (s, 1H), 7.28 (d, J = 9.5 Hz, 1H), 6.76 (d, J = 8.2 Hz, 2H), 5.40–5.34 (m, 2H), 5.30–5.26 (m, 1H), 5.22–5.20 (m, 1H), 5.08–5.04 (m, 1H), 4.64–4.58 (m, 2H), 4.51–4.48 (m, 1H), 4.35–4.31 (m, 1H), 3.97–3.92 (m, 2H), 3.90–3.83 (m, 4H), 3.61 (d, J = 6.9 Hz, 2H), 3.17–3.14 (m, 1H), 2.67–2.62 (m, 1H), 2.53–2.46 (m, 5H), 2.39–2.34 (m, 4H), 2.26–2.21 (m, 1H), 2.14–2.10 (m, 1H), 2.08 (d, J = 2.4 Hz, 3H), 2.05–2.00 (m, 1H), 1.94–1.90 (m, 1H), 1.46–1.42 (m, 1H), 1.17 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H), 0.68–0.65 (m, 1H), 0.63–0.59 (m, 3H);

[0451] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.41(s,1H),7.53–7.49(m,3H),7.48–7.44(m,4H),7.38(s,1H),7.27(d,J=9.5Hz,1H),6.77(d,J=8.2Hz,2H),5.35(d,J=10.3Hz,1H),5.28–5.25(m,1H),5.23–5.19(m,2H),5.07–5.04(m,1H),4.82–4.78(m,1H),4.62–4.57(m,2H),4.51–4.48(m,1H),4.34–4.31(m,1H),3.98–3.89(m,3H),3.87–3.83(m,3H),3.56(d,J=6.0Hz,2H),3.18–3.14(m,1H),2.66–2.57(m,3H),2.48(s,3H),2.26–2.20(m,1H),2.16–2.10(m,2H),2.07(d,J=2.4Hz,3H),2.04–2.01(m,1H),1.99–1.90(m,3H),1.46–1.41(m,1H),1.16(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.68–0.64(m,1H),0.63–0.57(m,3H);

[0452] 1 The 1H NMR (500 MHz, MeOH-d4) is as follows δ8.89(s,1H),8.43(s,1H),7.58–7.54(m,2H),7.51(s,1H),7.49–7.42(m,5H), 7.28(d,J=9.7Hz,1H),6.85(d,J=8.3Hz,2H),5.38–5.34(m,1H),5.30–5.26(m,1 H),5.19–5.17(m,1H),5.07–5.02(m,2H),4.81–4.77(m,1H),4.62–4.57(m,1H) ,4.51–4.48(m,1H),4.34–4.30(m,1H),3.95–3.91(m,2H),3.90–3.87(m,1H),3. 86–3.82(m,2H),3.25(s,3H),3.15–3.11(m,2H),2.67–2.61(m,1H),2.49(s,3H ),2.27–2.21(m,3H),2.12–2.08(m,4H),2.04–1.98(m,2H),1.92–1.89(m,1H),1 .86–1.80(m,3H),1.62–1.55(m,2H),1.51–1.43(m,3H),1.17(d,J=6.6Hz,3H), 1.03–0.97(m,2H),0.83(d,J=6.7Hz,3H),0.70–0.66(m,1H),0.64–0.58(m,3H);

[0453] 1 H NMR (500 MHz, MeOH-d4) is shown below δ8.88(s,1H),8.42(s,1H),7.57–7.54(m,2H),7.50–7.48(m,1H),7.47–7.43(m,4H),7.40(s,1H),7.32–7.29(m,1H),6.83–6.79(m,2H),5.36(d,J=10.1Hz,1H),5.30–5.26(m,1H),5.18–5.12(m,1H),5.07–5.03(m,1H),4.74–4.69(m,1H),4.61–4.57(m,1H),4.51–4.48(m,1H),3.96–3.92(m,1H),3.90–3.87(m,1H),3.84(d,J=6.1Hz,2H),3.81–3.77(m,2H),3.46–3.41(m,1H),3.32(s,3H),3.07–3.04(m,1H),2.67–2.61(m,1H),2.48(s,3H),2.38–2.33(m,1H),2.25–2.17(m,5H),2.12–2.05(m,6H),2.04–1.98(m,2H),1.67–1.59(m,3H),1.49–1.45(m,1H),b1.43–1.37(m,5H),1.16(d,J=6.6Hz,3H),0.83(d,J=6.5Hz,3H),0.76–0.72(m,1H),0.67–0.60(m,3H);

[0454] 1 1H NMR(500 MHz, MeOH-d4) is as follows δ8.42(s,1H),7.55–7.48(m,6H),7.45–7.41(m,3H),7.28(d,J=9.8Hz,1H),6.79 (d,J=8.2Hz,2H),6.31(d,J=2.0Hz,1H),5.36(d,J=10.2Hz,1H),5.29–5.25(m,1H ),5.22–5.17(m,2H),5.09–5.06(m,1H),4.82–4.78(m,1H),4.62–4.58(m,1H),4 .51–4.48(m,1H),4.35–4.32(m,1H),4.19–4.14(m,2H),4.00–3.97(m,1H),3.96– 3.89(m,2H),3.88–3.84(m,3H),3.34(s,3H),3.18–3.15(m,1H),2.68–2.62(m,1 H),2.27–2.17(m,2H),2.15–2.11(m,1H),2.09(d,J=2.4Hz,3H),2.05–1.96(m,3H ),1.94–1.84(m,5H),1.69–1.63(m,2H),1.47–1.43(m,1H),1.37–1.33(m,4H),1. 17(d,J=6.7Hz,3H),0.83(d,J=6.7Hz,3H),0.69–0.65(m,1H),0.64–0.57(m,3H);

[0455] 1 H NMR (500 MHz, MeOH-d4) is shown below δ 8.44 (s, 1H), 7.55–7.48 (m, 6H), 7.45–7.39 (m, 3H), 7.28 (d, J = 9.8 Hz, 1H), 6.80 (d, J = 8.2 Hz, 2H), 6.31 (d, J = 1.9 Hz, 1H), 5.36 (d, J = 10.4 Hz, 1H), 5.25 (d, J = 11.5 Hz, 1H), 5.21–5.19 (m, 1H), 5.09–5.06 (m, 1H), 4.80–4.77 (m, 1H), 4.62–4.58 (m, 1H), 4.51–4.48 (m, 1H), 4.35–4.31 (m, 1H), 4.19–4.14 (m, 2H), 3.96–3.88 (m, 3H), 3.86–3.82 (m, 3H), 3.66–3.61 (m, 1H), 3.22 (s, 3H), 3.16–3.13 (m, 1H), 2.90–2.84 (m, 2H), 2.67–2.61 (m, 1H), 2.26–2.20 (m, 1H), 2.12–2.06 (m, 6H), 2.04–1.98 (m, 2H), 1.93–1.89 (m, 1H), 1.46–1.42 (m, 1H), 1.34 (t, J = 7.2 Hz, 4H), 1.17 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H), 0.69–0.65 (m, 1H), 0.63–0.58 (m, 3H);

[0456] 1 1H NMR (500 MHz, MeOH-d4) is as follows δ8.89(s,1H),8.42(s,1H),7.54–7.51(m,3H),7.47–7.45(m,4H),7.41–7.40(m,1H),7.28(d,J=9.6Hz,1H),6.81–6.78(m,2H),5.36(d,J=10.3Hz,1H),5.27–5.21(m,2H),5.07–5.04(m,1H),4.83–4.79(m,1H),4.64–4.53(m,4H),4.51–4.48(m,1H),4.35–4.31(m,1H),3.97–3.92(m,2H),3.91–3.83(m,4H),3.42–3.37(m,2H),3.17–3.13(m,1H),3.04(d,J=1.7Hz,3H),2.67–2.61(m,1H),2.49(s,3H),2.37–2.31(m,2H),2.26–2.21(m,1H),2.13–2.10(m,1H),2.08(d,J=2.4Hz,3H),2.04–2.00(m,1H),1.93–1.90(m,1H),1.47–1.43(m,1H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.64–0.59(m,3H);

[0457] 1 1H NMR(500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.41(s,1H),7.55–7.53(m,1H),7.53–7.51(m,1H),7.49–7.48(m,1H),7.47–7.47(m,3H),7.46–7.42(m,2H),7.28(d,J=9.6Hz,1H),6.76(d,J=7.4Hz,2H),5.37–5.33(m,2H),5.32–5.27(m,2H),5.15–5.11(m,1H),5.08–5.04(m,2H),4.78(dd,J=11.2,4.3Hz,1H),4.62(s,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.43–4.38(m,1H),4.29(d,J=2.9Hz,1H),4.09(s,1H),3.93–3.91(m,1H),3.90–3.86(m,1H),3.86–3.84(m,2H),3.84–3.80(m,1H),3.74–3.69(m,1H),3.68–3.63(m,1H),2.68–2.62(m,1H),2.49(s,3H),2.29–2.25(m,2H),2.24–2.19(m,2H),2.09(d,J=2.1Hz,{3H}),2.05–2.01(m,3H),1.67–1.60(m,2H),1.49–1.42(m,3H),1.47–1.43(m,2H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.60(m,4H);

[0458] 1 1H NMR(500 MHz, MeOH-d4) is as follows δ8.88(s,1H),8.42(s,1H),7.53(d,J=8.1Hz,2H),7.49–7.45(m,6H),7.28(d,J=9.6Hz,1H),6.76(d,J=8.2Hz,2H),5.35(d,J=10.3Hz,1H),5.31(d,J=10.9Hz,1H),5.26–5.22(m,1H),5.16–5.09(m,1H),5.06(t,J=6.1Hz,1H),4.79–4.75(m,1H),4.74–4.71(m,1H),4.62–4.57(m,1H),4.52–4.47(m,1H),4.37(d,J=9.3Hz,1H),3.98–3.86(m,3H),3.85(d,J=6.2Hz,2H),3.77–3.73(m,1H),3.73–3.72(m,1H),3.69–3.66(m,2H),3.63–3.59(m,1H),2.69–2.60(m,1H),2.51–2.46(m,3H),2.31–2.21(m,3H),2.20–2.17(m,1H),2.13–2.09(m,1H),2.08(d,J=2.2Hz,3H),2.08–1.97(m,4H),1.68–1.59(m,2H),1.50–1.41(m,3H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.58(m,4H);

[0459] 1 1H NMR(500 MHz, MeOH-d4) is as follows: δ8.88(s,1H),7.54–7.50(m,3H),7.48–7.44(m,5H),7.24(d,J=9.7Hz,1H),6.83(d,J=8.0Hz,2H),6.79(s,1H),5.35–5.32(m,1H),5.24 –5.19(m,2H),5.14–5.09(m,1H),5.07–5.03(m,1H),4.66–4.61(m,3H),4.38–4.34(m,2H),4.07(s,1H),3.92–3.86(m,2H),3.86–3.83( m,2H),3.39–3.36(m,1H),3.33(s,3H),3.23–3.19(m,1H),2.88–2.84(m,1H),2.48(s,3H),2.21–2.16(m,4H),2.05–2.02(m,5H),1.97– 1.94(m,1H),1.88–1.83(m,1H),1.65–1.57(m,4H),1.01(d,J=6.7Hz,3H),0.84(d,J=6.9Hz,3H),0.70–0.65(m,2H),0.63–0.58(m,3H);

[0460] 1 H NMR (500 MHz, MeOH-d4) is shown below: δ8.88(s,1H),8.41(s,1H),7.54–7.50(m,3H),7.48–7.44(m,4H),7.41(s,1H),7.27(d,J=9.7Hz,1H),6.78(d,J=8.2Hz,2H),5.35(d,J=10.3Hz,1H),5.26–5.23(m,1H),5.23–5.19(m,2H),5.07–5.04(m,1H),4.78(d,J=11.5Hz,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.47–4.42(m,1H),4.33–4.29(m,1H),3.95–3.91(m,2H),3.90–3.82(m,4H),3.16–3.12(m,1H),2.67–2.61(m,1H),2.48(s,3H),2.26–2.20(m,1H),2.11–2.00(m,10H),1.96–1.88(m,3H),1.84–1.77(m,2H),1.47–1.42(m,1H),1.16(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.69–0.64(m,1H),0.63–0.57(m,3H);

[0461] 1 1H NMR (500 MHz, MeOH-d4) is as follows: δ8.88(s,1H),8.42(s,1H),7.55–7.50(m,3H),7.48–7.44(m,4H),7.40–7.39( m,1H),7.27(d,J=9.6Hz,1H),6.80(d,J=8.4Hz,2H),5.35(d,J=10.2Hz,1H),5. 27–5.23(m,1H),5.20–5.18(m,1H),5.07–5.04(m,1H),4.94–4.92(m,1H),4.80 –4.77(m,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.33–4.30(m,1H),3.95–3 .91(m,2H),3.90–3.81(m,4H),3.72–3.68(m,1H),3.43–3.38(m,2H),3.29–3.2 8(m,1H),3.15–3.12(m,1H),2.89–2.82(m,2H),2.67–2.61(m,1H),2.48(s,3H) ,2.26–2.20(m,1H),2.12–2.06(m,6H),2.04–1.99(m,1H),1.92–1.89(m,1H),1 .47–1.40(m,1H),1.18–1.13(m,6H),0.83(d,J=6.7Hz,3H),0.68–0.57(m,4H);

[0462] Preferably, the quinazoline compound is any one of the following compounds:

[0463] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.22 min;

[0464] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.827 min;

[0465] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 9.327 min;

[0466] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 9.425 min;

[0467] The compound that elutes second under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes second is 8.595 min;

[0468] The compound that elutes third under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes third is 8.658 min;

[0469] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.636 min;

[0470] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 9.419 min;

[0471] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.541 min;

[0472] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.295 min;

[0473] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.682 min;

[0474] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.064 min;

[0475] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.069 min;

[0476] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 9.047 min;

[0477] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.409 min;

[0478] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.136 min;

[0479] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 5.439 min;

[0480] The compound that elutes first under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes first is 5.535 min;

[0481] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound eluting later is 5.617 min;

[0482] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 5.856 min;

[0483] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.172 min;

[0484] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.248 min;

[0485] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.598 min;

[0486] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 9.114 min;

[0487] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.531 min;

[0488] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.601 min;

[0489] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.828 min;

[0490] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 5.407 min;

[0491] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 6.882 min;

[0492] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.501 min;

[0493] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.48 min;

[0494] The compound that elutes first under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes first is 7.347 min;

[0495] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.683 min;

[0496] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.107 min;

[0497] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 8.365 min;

[0498] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.778 min;

[0499] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.946 min;

[0500] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.171 min;

[0501] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.099 min;

[0502] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.037 min;

[0503] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.530 min;

[0504] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 9.207 min;

[0505] The compound eluting later under liquid phase conditions is preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, and B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; and the analysis time is 13 min. Preferably, under the liquid phase conditions, the retention time of the compound eluting later is 7.872 min;

[0506] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 8.381 min.

[0507] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 7.719 min.

[0508] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 7.312 min.

[0509] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 7.239 min.

[0510] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 8.291 min.

[0511] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 5.034 min.

[0512] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 8.248 min.

[0513] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 7.943 min.

[0514] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 7.677 min.

[0515] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 6.798 min.

[0516] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 7.100 min.

[0517] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 7.827 min.

[0518] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 7.844 min.

[0519] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 8.927 min.

[0520] The compound that elutes later under liquid phase conditions, the liquid phase conditions are preferably: the stationary phase is C18, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the flow rate is 1 mL / min; preferably, the column model is Waters XBridge C18 5μm, 150x4.6mm, the mobile phase is a mixture of A and B, wherein A is a 0.1% (v / v) ammonia aqueous solution, B is a 0.1% (v / v) ammonia acetonitrile solution, and the volume percentage of B in the mobile phase is 20%-95%; the flow rate is 1 mL / min; the analysis time is 13 min; preferably, under the liquid phase conditions, the retention time of the compound that elutes later is 8.098 min.

[0521] The present invention also provides a pharmaceutical composition comprising (a therapeutically effective amount of) substance A and a pharmaceutically acceptable excipient, wherein the substance A is a compound as shown in Formula I according to any embodiment of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a quinoline compound as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0522] The present invention also provides the use of substance A or the aforementioned pharmaceutical composition in the preparation of a G12D mutant KRAS degrader. In such applications, the G12D KRAS degrader can be used in mammals in vivo or in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or being formulated into a kit according to conventional methods in the art to provide rapid testing for the inhibitory effect of the G12D mutant KRAS.

[0523] The present invention also provides a substance A for use as a drug, wherein the substance A is a compound as shown in Formula I according to any embodiment of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a quinoline compound as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; preferably, the drug can be used to treat and / or prevent tumors, preferably hematologic tumors and solid tumors.

[0524] The present invention also provides a substance A for treating and / or preventing tumors, wherein the substance A is a compound as shown in Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a quinoline compound as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any embodiment of the present invention; preferably, the tumor is a hematological tumor or a solid tumor.

[0525] The present invention also provides a substance A for treating and / or preventing a disease mediated by KRAS G12D, wherein the substance A is a compound as shown in Formula I according to any embodiment of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a quinoline compound as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; preferably, the disease is a tumor, preferably a hematological tumor or a solid tumor.

[0526] The present invention also provides a substance A used as a G12D mutant KRAS degrader, wherein the substance A is a compound as shown in Formula I according to any embodiment of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a quinoline compound as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0527] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing a disease mediated by KRAS G12D; the substance A is a compound as shown in Formula I according to any embodiment of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a quinoline compound as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; preferably, the substance A or the above-mentioned pharmaceutical composition is in a therapeutically effective amount, and / or the disease may be a tumor, preferably a hematological tumor or a solid tumor.

[0528] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing tumors; the substance A is a compound as shown in Formula I according to any embodiment of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof, or the quinoline compound as described above, its stereoisomers, or pharmaceutically acceptable salts thereof; preferably, the substance A or the above-mentioned pharmaceutical composition is in a therapeutically effective amount, and / or the tumor is preferably a hematological tumor or a solid tumor.

[0529] The present invention provides a method for treating and / or preventing a disease mediated by KRAS G12D, comprising administering a substance A or the aforementioned pharmaceutical composition to a patient; the substance A is a compound as shown in Formula I according to any embodiment of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a quinoline compound as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; preferably, the substance A or the aforementioned pharmaceutical composition is in a therapeutically effective amount, and / or the disease may be a tumor, preferably a hematological tumor or a solid tumor.

[0530] The present invention provides a method for treating and / or preventing tumors, comprising administering a substance A or the aforementioned pharmaceutical composition to a patient; the substance A is a compound as shown in Formula I according to any embodiment of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or the aforementioned quinoline compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; preferably, the substance A or the aforementioned pharmaceutical composition is in a therapeutically effective amount, and / or the tumor is preferably a hematological tumor or a solid tumor.

[0531] In the present invention, the tumor includes but is not limited to blood tumors and solid tumors. In certain embodiments, the blood tumor includes but is not limited to leukemia and lymphoma. Wherein, the leukemia includes but is not limited to acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL) and / or other leukemias, the lymphoma includes but is not limited to all subtypes of Hodgkin lymphoma or non-Hodgkin lymphoma, and the other blood tumors include but are not limited to multiple myeloma (MM). In certain embodiments, the solid tumor includes but is not limited to pancreatic cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, squamous cell lung carcinoma, cervical rhabdomyosarcoma, ovarian cancer, esophageal cancer, prostate cancer, breast cancer, bladder cancer, endometrial cancer, gastric cancer, melanoma, hepatocellular carcinoma, head and neck cancer, cholangiocarcinoma, malignant glioma, thyroid cancer, schwannoma, skin cancer, testicular cancer or soft tissue sarcoma, etc.

[0532] In addition to the foregoing, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the following meanings:

[0533] The term "pharmaceutically acceptable salt" refers to salts prepared from compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts, such as methanesulfonate salts, can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.

[0534] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0535] The term "alkyl" refers to a group having the specified number of carbon atoms (e.g., C 1-6 or C1-C6, C 1-3 or C1-C3), linear or branched, saturated monovalent hydrocarbon group. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0536] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, for example, C1-C6 alkylene.

[0537] The term "cycloalkyl" refers to a group having the specified number of ring carbon atoms (e.g., C 3-8 or C3-C8, C 6-8 or C6-C8), saturated monocyclic, spirocyclic, bridged, or paracyclic cyclic groups whose ring atoms consist solely of carbon atoms. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0538] The term "cycloalkylene" refers to a divalent cycloalkyl group, wherein cycloalkyl is as defined above, for example, C3-C7 cycloalkylene.

[0539] The term "heterocycloalkyl" refers to a saturated monocyclic, spirocyclic, bridged or paracyclic cyclic group having a specified number of ring atoms (e.g., 4-6, 4-12, 6-12 members), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified heteroatom species (1, 2 or 3 of N, O and S). When it is a polycyclic ring, each ring is saturated. Heterocycloalkyl can be connected to other fragments in the molecule through carbon atoms or heteroatoms on the ring. Heterocycloalkyl includes but is not limited to oxetane, azetidinyl, tetrahydropyrrolyl, piperazinyl, piperidinyl, morpholinyl, etc., for example

[0540] The term "heterocycloalkylene" refers to a divalent heterocycloalkyl group, wherein heterocycloalkyl is as defined above, for example, a 4- to 12-membered heterocycloalkylene group.

[0541] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-membered, 5-10-membered, 5-6-membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (e.g., one, two, or more of N, O, and S), which can be monocyclic or polycyclic (e.g., cyclic, spirocyclic, and bridged), and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, or 1,2,3,4-tetrahydroisoquinolinyl, for example

[0542] The term "heteroarylene" refers to a divalent heteroaryl group, wherein heteroaryl is as defined above, for example, a 5-membered heteroarylene group.

[0543] The term "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0544] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0545] When the linking groups listed in the present invention do not specify their connection direction, their connection direction is the same as the reading order from left to right, as shown below: The connecting group L1 is -CD-, in which case -CD- connects ring A and ring B in the same direction as the reading order from left to right to form Rather than constituting Specifically in the present invention, L is -N(H)C(O)-, which means that N is connected to ring B via a single bond, rather than C being connected to ring B.

[0546] As used herein, the compound shown in Formula I of the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains one chiral center, the compound comprises enantiomers. The present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compound shown in Formula I contains more than one chiral center, diastereomers may exist. The present invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography. The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers, etc. The compounds of the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomorphs, racemates, equal mixtures of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof. The atropisomers of the present invention are stereoisomers with axial or planar chirality based on restricted intramolecular rotation.

[0547] As mentioned above, the present invention provides compounds represented by the above-mentioned various structures, or their cis-trans isomers, meso-isomers, racemates, enantiomers, diastereomers, atropisomers, tautomers or mixtures thereof, wherein "their mixtures" include any mixtures of any of the aforementioned stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, atropisomers), tautomers and / or mixtures (meso-isomers, racemates), such as mixtures of cis-trans isomers, mixtures of enantiomers and diastereomers, mixtures of diastereomers, mixtures of atropisomers, or mixtures of cis-trans isomers and racemates, mixtures of enantiomers and diastereomer mixtures, mixtures of cis-trans isomers and tautomers, mixtures of atropisomers and diastereomer mixtures, etc.

[0548] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances, other than the active ingredient, contained in a pharmaceutical preparation. For more information, see Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0549] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0550] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0551] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0552] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0553] The reagents and raw materials used in the present invention are commercially available.

[0554] The positive progress of the present invention is that: the defects of insufficient inhibitory activity of G12D mutant KRAS are overcome. The present invention provides a quinazoline compound with novel structure, its stereoisomer or pharmaceutically acceptable salt. The compound of the present invention has a good degradation effect on G12D mutant KRAS protein, has good inhibitory activity on the proliferation of KRAS G12D mutant tumor cells, and shows good pharmacokinetic properties; it can be expected that the deuterated compound of the present application or its pharmaceutically acceptable salt will also have similar effects. DETAILED DESCRIPTION

[0555] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0556] Intermediate M1

[0557] At 0°C, SOCl2 (48.93 g, 411.3 mmol, 30 mL) was added to compound M1-1 (3 g, 22.7 mmol), and the temperature was raised to 80°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography [PE (petroleum ether)] to obtain a white solid M1 (3.3 g, yield 97%). 1 H NMR (400MHz, DMSO-d6) δ7.50-7.43 (m, 4H), 4.78 (s, 2H), 4.23 (s, 1H).

[0558] Intermediate M2

[0559] Compound M2-1 (10 g, 46 mmol) was dissolved in DMF (N,N-dimethylformamide, 20 mL), and DIPEA (N,N-diisopropylethylamine, 19 g, 147 mmol) and HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 21 g, 55 mmol) were added. The mixture was stirred at room temperature for 10 minutes, and a solution of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (8 g, 44 mmol) in DMF (20 mL) was added dropwise. The mixture was reacted at room temperature for 2 hours. 50 mL of water was added for dilution and the mixture was extracted with EA (ethyl acetate, 3×100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to obtain a yellow oil M2-2 (14 g, yield 92%). 1 H NMR (500MHz, CDCl3) δ5.33 (s, 1H), 4.70 (t, J = 8.5Hz, 1H), 4.54 (s, 1H), 4.15–4.08 (m, 2H), 3.74 (s, 3H), 3.70 (dd, J = 11.2, 3.4Hz, 1 H), 2.38 (dd, J=13.2, 8.1Hz, 1H), 2.05–1.98 (m, 2H), 1.43 (s, 9H), 1.30–1.23 (m, 1H), 1.02 (d, J=6.7Hz, 3H), 0.98 (d, J=6.7Hz, 3H).

[0560] To a solution of M2-2 (13 g, 37.8 mmol) in THF (tetrahydrofuran, 80 mL) was added dropwise a solution of LiOH (lithium hydroxide, 2.72 g, 113.2 mmol) in water (40 mL) at 0°C and allowed to react at room temperature for 2 hours. The solution was adjusted to pH 5 with 2M HCl (hydrochloric acid) and extracted with EA (3 × 100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford M2 (11 g, 88% yield) as a white solid. LCMS m / z = 331.2 [M+H] + .

[0561] Intermediates M3 and M4

[0562] To a solution of compound M3-1 (25 g, 115.7 mmol) in DCM (dichloromethane, 250 mL) was added Boc2O (di-tert-butyl dicarbonate, 75.75 g, 347.1 mmol) and TEA (triethylamine, 58.54 g, 578.5 mmol), and the mixture was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (PE / EA) to give M3-2 (39.1 g, 81% yield) as a white solid. LCMS m / z = 438.0 [M+Na] + .

[0563] Under a nitrogen atmosphere, compound M3-2 (15 g, 36 mmol), 4-methylthiazole (7.15 g, 72 mmol), KOAc (potassium acetate 7.07 g, 72 mmol), and Pd(AcO)2 (palladium acetate, 809 mg, 3.6 mmol) were dissolved in 150 mL of DMF and reacted at 90°C overnight. The mixture was returned to room temperature, diluted with 50 mL of water, and extracted with EA (ethyl acetate, 3 × 100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oil, M3-3 (7.8 g, 50% yield). LCMS m / z = 435.1 [M+H] + .

[0564] To a solution of M3-3 (7 g, 16.1 mmol) in DCM (30 mL) was added dropwise 30 mL of 4M HCl (1,4-dioxane) at 0°C. The mixture was allowed to react at room temperature for 2 hours. The mixture was filtered and dried under vacuum to afford a yellow solid M3-4 (4.3 g, 98% yield). LCMS m / z = 235.1 [M+H] + .

[0565] To a solution of M2 (7.60 g, 16.1 mmol) in DMF (30 mL) were added DIPEA (6.24 g, 48.3 mmol) and HATU (6.73 g, 17.7 mmol), stirred at room temperature for 15 minutes, and then slowly added dropwise to a solution of M3-4 (4.36 g, 16.1 mmol) and DIPEA (4.16 g, 32.2 mmol) in DMF (30 mL) at 0°C. The mixture was reacted at room temperature for half an hour. 100 mL of water was added for dilution, and the mixture was extracted with EA (3×150 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (DCM / MeOH) to give M3-5 (7.9 g, 90% yield) as a yellow solid. LCMS m / z=547.4 [M+H] + .

[0566] To a solution of M3-5 (7.9 g, 14.5 mmol) in DCM (30 mL) was added 15 mL of 4M HCl (1,4-dioxane) dropwise at 0°C and allowed to react at room temperature for 2 hours. The mixture was filtered and dried under vacuum to afford a yellow solid, M3-6 (6.4 g, 99% yield). LCMS m / z = 447.3 [M+H] + .

[0567] To a solution of M3-6 (1.6 g, 3.6 mmol) in MeOH (15 mL) were added 1H-imidazole-1-sulfonyl azide hydrochloride (751 mg, 3.6 mmol), copper sulfate pentahydrate (90 mg, 358.3 μmol), and K2CO3 (potassium carbonate, 990 mg, 7.2 mmol). The mixture was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by flash silica gel column chromatography (DCM / MeOH) to give M3 (1.1 g, 65% yield) as a light yellow solid. LCMS m / z = 473.3 [M+H] + .

[0568] To a solution of M3 (500 mg, 1.1 mmol) in THF (2 mL), t-BuOH (2 mL) and H2O (2 mL) were added M1 (319 mg, 2.1 mmol), copper sulfate (84 mg, 529 μmol) and sodium ascorbate (314 mg, 1.6 mmol) and reacted at 50°C for 3 hours. The mixture was returned to room temperature, extracted with EA (3×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (DCM / MeOH) to give M4 (450 mg, 68% yield) as a white solid. LCMS m / z=624.4 [M+H] + .

[0569] Intermediates M5 and M6

[0570] To a solution of M5-1 (20 g, 47.4 mmol) in DCM (100 mL) at 0°C was added DIPEA (31 g, 237 mmol). After stirring for 5 minutes, (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (10.3 g, 52.2 mmol) was added and the mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by flash silica gel column chromatography (PE / EA) to afford M5-2 (25.4 g, 92% yield) as a yellow solid. LCMS m / z = 584.8 [M+H] + .

[0571] To compound M5-2 (5 g, 8.6 mmol) and tetrahydropyran-4-ol (3.5 g, 34.3 mmol) in THF (20 mL) and DMF (20 mL) were added Cs2CO3 (11.2 g, 34.3 mmol) and DABCO (triethylenediamine, 481 mg, 4.28 mmol), and the mixture was allowed to react at room temperature overnight. 20 mL of water was added, and the mixture was extracted with EA (3×30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give M5-3 (5.55 g, 99% yield) as a yellow solid. LCMS m / z=649.1 [M+H] + .

[0572] To a solution of compound M5-3 (5.55 g, 8.5 mmol) and benzyl alcohol (1 g, 9.4 mmol) in THF (20 mL) was added t-BuOK (potassium tert-butoxide, 1.44 g, 12.8 mmol) at 0°C and allowed to react at room temperature for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give a yellow solid M5-4 (4.5 g, 71% yield). LCMS m / z = 739.2 [M+H] + .

[0573] Under a nitrogen atmosphere, M5-4 (4.5 g, 6.1 mmol), K3PO4 (potassium phosphate, 4.7 g, 22 mmol), cyclopropylboronic acid (1.05 g, 12.2 mmol), Pd(dppf)Cl2·DCM ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 500 mg, 710 μmol), ACN (acetonitrile, 16 mL), 1,4-dioxane (2 mL), and H2O (4 mL) were added to a microwave tube and reacted at 100°C for 5 hours. The mixture was returned to room temperature, diluted with 20 mL of water, extracted with EA (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give M5-5 (2.4 g, 60% yield) as a white solid. LCMS m / z = 653.2 [M+H] + .

[0574] Under nitrogen atmosphere, SPhos Pd G2 [chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-)palladium(II), 53 mg, 74 μmol] and K3PO4 (469 mg, 2.21 mmol), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (758 mg, 1.47 mmol), 1,4-dioxane (6 mL), and H2O (0.6 mL) were added to M5-5 (600 mg, 737 μmol) and reacted at 100 °C overnight. The mixture was returned to room temperature, diluted with 10 mL of water, extracted with EA (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give a yellow solid M5-6 (660 mg, yield 76%), LCMS m / z = 805.5 [M+H] + .

[0575] A solution of M5-6 (660 mg, 623 μmol) in MeOH (10 mL) was purged with nitrogen three times, and Pd / C (palladium on carbon, 10% purity, 663 mg, 623 μmol) was added. The atmosphere was purged with hydrogen three times and allowed to react at room temperature for 2 hours. The mixture was filtered through Celite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give M5 (500 mg, 97% yield) as a yellow solid. LCMS m / z = 715.4 [M+H] + .

[0576] To a solution of M5 (400 mg, 492 μmol) and M1 (82 mg, 542 μmol) in DMF (4 mL) was added Cs2CO3 (481 mg, 1.48 mmol) and the mixture was allowed to react at 60°C for 2 hours. The mixture was returned to room temperature, 20 mL of water was added, and the combined organic phases were washed with saturated brine and extracted with EA (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give M6 (350 mg, 53% yield) as a white solid. LCMS m / z = 829.4 [M+H] + .

[0577] Intermediate M7

[0578] To a solution of M7-1 (4.93 g, 21.3 mmol) in DMF (10 mL) were added HATU (9.7 g, 25.6 mmol, 2.2) and DIPEA (8.3 g, 64 mmol), stirred at room temperature for 15 minutes, and then slowly added dropwise to a solution of M3-4 (5 g, 21.3 mmol) and DIPEA (8.3 g, 64 mmol) in DMF (10 mL) at 0°C. The mixture was reacted at room temperature for half an hour. 20 mL of water was added, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (DCM / MeOH) to give M7-2 (6.3 g, 66% yield) as a yellow solid. LCMS m / z = 447.9 [M+H] + .

[0579] To a solution of M7-2 (5.7 g, 12.74 mmol) in DCM (50 mL) was added 15 mL of 4 M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 4 hours. The mixture was concentrated under reduced pressure and dried in vacuo to afford a yellow solid M7 (4.7 g, 88% yield). LCMS m / z = 444.0 [M+H] + .

[0580] Intermediate M8

[0581] Substituting 4-methylthiazole with 4-cyclopropylthiazole, the synthetic method of M4 was used to obtain M8: a white solid, LCMS m / z = 665.3 [M+H] + .

[0582] Intermediate M9

[0583] To a solution of compound M9-1 (5 g, 39.3 mmol) in 1,4-dioxane (50 mL) was added DIPEA (9.6 g, 78.6 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (16.8 g, 78.6 mmol) under a nitrogen atmosphere and reacted at 70°C for 2 hours. The mixture was returned to room temperature, diluted with 300 mL of water, extracted with ethyl acetate (3 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (DCM / MeOH) to give M9 (5.2 g, 69.3% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ6.01–5.63(m,1H),4.04–4.01(m,1H),3.23–3.15(m,2H),2 .72–2.63(m,2H),2.15–2.04(m,4H),1.90–1.88(m,2H),1.65(d,J=13.6Hz,2H).

[0584] Intermediate M10

[0585] Under nitrogen atmosphere, (Boc)2O (20.2 g, 92.6 mmol) and saturated aqueous NaHCO3 (sodium bicarbonate) solution (100 mL) were added to a solution of M10-1 (20 g, 92.6 mmol) in THF (200 mL). The mixture was reacted at room temperature for 2 hours. The mixture was extracted with EA (50 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give M10-2 (29 g, 99% yield) as a white solid. LCMS m / z = 259.9 [M+H] + .

[0586] Under nitrogen atmosphere, Pd(dppf)Cl2 (1,1-bis(diphenylphosphino)diphenylferric palladium chloride, 1.3 g, 1.6 mmol) was added to a solution of M10-2 (5 g, 15.870 mmol), pinacol diboron (6 g, 23.8 mmol), and KOAc (4.7 g, 47.6 mmol) in 1,4-dioxane (50 mL). The mixture was reacted at 110°C for 2 hours. The mixture was returned to room temperature, diluted with 1000 mL of water, extracted with EA (3 × 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to afford M10 (5.36 g, 93% yield) as a white solid. LCMS m / z = 364.3 [M+H] + .

[0587] Intermediate M11

[0588] Substituting 4-methylthiazole for 2,6-difluorophenylboronic acid, the synthetic method of M4 was used to obtain M11: a white solid, LCMS m / z = 654.3 [M+H] + .

[0589] Intermediate M12

[0590] Under nitrogen atmosphere, a solution of M12-1 (5 g, 43 mmol) and imidazole (4.4 g, 64.6 mmol) in DMF (50 mL) was cooled to 0°C, TBDPSCl (tert-butyldiphenylsilyl chloride) was added dropwise, and the temperature was raised to room temperature for 16 hours. The mixture was diluted with 50 mL of water and extracted with DCM (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / DCM) to give M12-2 (7.14 g, 49% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.62–7.56(m,4H),7.37–7.26(m,6H),3.66–3.53(m, 2H),1.86–1.67(m,4H),1.45–1.30(m,4H),1.19–1.04(m,2H),0.97(s,9H).

[0591] Under nitrogen atmosphere, a solution of M12-2 (2.4 g, 6.7 mmol) in DMF (25 mL) was cooled to 0°C, and NaH (sodium hydride, 60% purity, 2.2 g, 53.6 mmol) was added. The mixture was reacted at 0°C for half an hour, and iodoethane (2.2 g, 13.5 mmol) was added. The mixture was warmed to room temperature and reacted for 16 hours. The mixture was quenched with saturated ammonium chloride, extracted with EA (3 × 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / DCM) to give M12-3 (1.6 g, 64% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.67 (dd, J=7.8, 1.4Hz, 4H), 7.44–7.34 (m, 6H), 3.72–3.65 (m, 1H), 3.44 (q, J=7.0Hz, 2H), 3.29–3. 21(m,1H),1.96–1.88(m,2H),1.83–1.75(m,2H),1.44–1.35(m,2H),1.27–1.17(m,2H),1.22-1.10(m,3H),1.05(s,9H).

[0592] To a solution of M12-3 (1.6 g, 4.4 mmol) in THF (16 mL) was added 1 M TBAF (THF, 1.4 g, 5.3 mmol) at 0°C, and the temperature was raised to 50°C for 16 hours. The mixture was returned to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give M12 (480 mg, 75% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ3.72–3.61(m,1H),3.50(q,J=7.0Hz,2H),3.32–3.19(m, 1H), 2.08–1.91 (m, 4H), 1.59 (s, 1H), 1.37–1.27 (m, 4H), 1.19 (t, J = 7.0Hz, 3H).

[0593] Intermediate M13

[0594] M13 was obtained by replacing iodoethane with diisopropyl sulfate using the synthetic method of M12: 1 H NMR (400MHz, CDCl3) δ3.67–3.54(m,2H),3.31–3.19(m,1H),1.96–1.80(m,4H),1.44(s,1H),1.29–1.19(m,4H),1.07(d,J=6.1Hz,6H).

[0595] Intermediate M14

[0596] Under nitrogen atmosphere, sodium periodate (6.61 g, 30.9 mmol) was added to a solution of M14-1 (4.5 g, 28.1 mmol) in MeOH (200 mL) and the mixture was allowed to react at room temperature for 16 hours. The mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. 100 mL of saturated brine was added to the residue, and the mixture was extracted with EA (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give M14-2 (3.6 g, 73% yield) as a yellow solid. 1 H NMR (500MHz, CDCl3) δ3.72(s,3H),3.12–3.01(m,2H),2.83–2.72(m,1H),2.72–2.44(m,4H),2.12–1.90(m,2H).

[0597] To a solution of M14-2 (3.4 g, 19.3 mmol) in MeOH (50 mL) were added iodobenzene diacetate (24.86 g, 77.2 mmol) and ammonium carbamate (7.53 g, 96.5 mmol) and the mixture was allowed to react at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was washed with PE (2 × 50 mL). The filter cake was added with EA (100 mL) and stirred for 1 hour, filtered, and the filter cake was rinsed with EA (2 × 50 mL). The filtrate was concentrated under reduced pressure to obtain a yellow solid M14-3 (3.6 g, yield 97%). 1 HNMR(500MHz, CDCl3)δ3.73(s,3H),3.30–3.16(m,2H),3.16–3.01(m,2H),2.72–2.59(m,1H),2.46–2.31(m,4H).

[0598] To a solution of M14-3 (1.5 g, 7.5 mmol) in THF (30 mL) was added NaH (60% purity, 627 mg, 15.7 mmol) at 0°C, and the temperature was raised to room temperature for 2 hours. Boc2O (3.42 g, 15.7 mmol) was added and the reaction was continued at room temperature for 6 hours. The mixture was quenched with saturated ammonium chloride, extracted with EA (3 × 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (PE / EA) to give M14-4 (450 mg, 20% yield) as a yellow solid. 1 H NMR (500MHz, CDCl3) δ3.73–3.66(m,3H),3.66–3.58(m,1H),3.47–3.35(m,1H),3.25 –3.18(m,1H),3.15–2.82(m,1H),2.69–2.55(m,1H),2.45–2.23(m,4H),1.44(s,9H).

[0599] To a solution of M14-4 (450 mg, 1.54 mmol) in THF (15 mL) was added 4.6 mL of 1 M diisobutylaluminum hydride (THF) at 0°C and the mixture was allowed to react at room temperature for 3 hours. The mixture was quenched with saturated ammonium chloride, extracted with EA (3×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give M14 (230 mg, 57% yield) as a yellow solid. 1 H NMR(500MHz, CDCl3)δ3.89–3.79(m,1H),3.69–3.56(m,1H),3.54–3.46(m,2H),

[0600] 3.15–3.04(m,1H),3.02–2.89(m,1H),2.19–2.08(m,2H),1.92–1.61(m,4H),1.42(d,J=3.1Hz,9H).

[0601] Intermediate M15

[0602] M15-1 was synthesized with reference to WO2022029617 A1, a yellow oil, 1 H NMR (500MHz, CDCl3) δ7.82(d,J=8.3Hz,2H),7.48(d,J=8.2Hz,2H),6.60(s,1H),4.63(s,2H),3.76( s,3H),3.70(d,J=8.7Hz,1H),2.50–2.36(m,1H),1.04(d,J=6.7Hz,3H),0.95(d,J=6.7Hz,3H), LCMS m / z=308.1[M+H] + .

[0603] To a solution of M15-1 (0.2 g, 650 μmol) in THF (1 mL) was added a solution of LiOH (78 mg, 3.25 mmol) in water (1 mL) dropwise and allowed to react at room temperature for 0.5 h. The solution was adjusted to pH 5 with 1 M HCl (hydrochloric acid) and extracted with DCM (3 × 10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford M15-2 (0.19 g, 99% yield) as a white solid. LCMS m / z = 294.1 [M+H] + .

[0604] To a solution of M15-2 (0.19 g, 645 μmol) in DMF (1 mL) was added DIPEA (251 mg, 1.94 mmol) and HATU (271 mg, 712 μmol). The mixture was stirred at room temperature for 15 minutes, cooled to 0°C, and slowly added dropwise to a solution of M7 (225 mg, 585 μmol) in DMF (1 mL). The mixture was reacted at room temperature for 4 hours. 10 mL of water was added for dilution, and the mixture was extracted with EA (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (DCM / MeOH) to give M15 (0.14 g, 35% yield) as a yellow solid. LCMS m / z = 623.4 [M+H] + .

[0605] Intermediate M16

[0606] M16-1 was synthesized with reference to WO2022029617 A1 and WO2005105779 A1, a yellow oil. 1 HNMR(400MHz,MeOH-d4)δ8.08(s,1H),7.83(d,J=8.1Hz,2H),7.47(d,J=8.1Hz,2H),5.12(d,J=8.6Hz,1H), 4.65(s,2H),3.73(s,3H),2.81(dd,J=15.0,6.9Hz,1H),1.07(d,J=6.8Hz,3H),0.94(d,J=6.7Hz,3H), LCMS m / z=308.2[M+H] + .

[0607] To a solution of M16-1 (0.2 g, 650 μmol) in THF (1 mL) was added a solution of LiOH (78 mg, 3.25 mmol) in water (1 mL) dropwise and allowed to react at room temperature for 0.5 h. The system was adjusted to pH 5 with 1 M HCl (hydrochloric acid) and extracted with DCM (3 × 10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford M16-2 (0.19 g, 99% yield) as a white solid. LCMS m / z = 294.2 [M+H] + .

[0608] To a solution of M16-2 (0.19 g, 645 μmol) in DMF (1 mL) was added DIPEA (251 mg, 1.94 mmol) and HATU (271 mg, 712 μmol). The mixture was stirred at room temperature for 15 minutes, cooled to 0°C, and slowly added dropwise to a solution of M7 (237 mg, 616 μmol) in DMF (1 mL). The mixture was reacted at room temperature for 4 hours. 10 mL of water was added for dilution, and the mixture was extracted with EA (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH) to afford M16 (0.13 g, 30% yield) as a yellow solid. LCMS m / z = 623.3 [M+H] + .

[0609] Intermediate M17

[0610] M17-1 was synthesized with reference to WO2022029617 A1 and WO2001077100 A2, and the product was a yellow solid. 1HNMR(400MHz,MeOH-d4)δ8.08(s,1H),7.83(d,J=8.1Hz,2H),7.47(d,J=8.1Hz,2H),5.12(d,J=8.6Hz,1H), 4.65(s,2H),3.73(s,3H),2.81(dd,J=15.0,6.9Hz,1H),1.07(d,J=6.8Hz,3H),0.94(d,J=6.7Hz,3H), LCMS m / z=307.1[M+H]+.

[0611] To a solution of M17-1 (0.2 g, 652 μmol) in THF (1 mL) was added a solution of LiOH (78 mg, 3.25 mmol) in water (1 mL) dropwise and allowed to react at room temperature for 0.5 h. The system was adjusted to pH 5 with 1 M HCl (hydrochloric acid) and extracted with DCM (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford M17-2 (0.14 g, 73% yield) as a white solid. LCMS m / z = 293.2 [M+H] + .

[0612] To a solution of M17-2 (0.11 g, 376 μmol) in DMF (1 mL) was added DIPEA (146 mg, 1.13 mmol) and HATU (157 mg, 413 μmol). The mixture was stirred at room temperature for 15 minutes, cooled to 0°C, and slowly added dropwise to a solution of M7 (131 mg, 376 μmol) in DMF (1 mL). The mixture was reacted at room temperature for 1 hour. The mixture was diluted with 10 mL of water and extracted with EA (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH) to afford M17 (80 mg, 34% yield) as a yellow solid. LCMS m / z = 624.4 [M+H] + .

[0613] Intermediate M18

[0614] Trans-4-methoxycyclohexanol was used to replace tetrahydropyran-4-ol, and the synthesis method of intermediate M5 was used to obtain intermediate M18: brown solid, LCMS m / z = 743.5 [M+H] + .

[0615] Intermediate M19

[0616] To M5-2 (2.47 g, 4.23 mmol) and M19-1 (550 mg, 4.23 mmol) in THF (15 mL) and DMF (15 mL) were added Cs2CO3 (5.52 g, 16.93 mmol) and DABCO (237 mg, 2.12 mmol) and reacted at room temperature overnight. 20 mL of water was added, and the mixture was extracted with EA (3×30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give M19-2 (2.6 g, 91% yield) as a yellow solid. LCMS m / z=677.0 [M+H] + .

[0617] Under a nitrogen atmosphere, a solution of M19-2 (2.6 g, 3.84 mmol) in THF (50 mL) was cooled to 0°C and 11.5 mL of 1 M diisobutylaluminum hydride (THF) was added. The mixture was allowed to warm to room temperature and reacted for 3 hours. The mixture was quenched with 50 mL of saturated ammonium chloride, extracted with EA (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to afford M19 (2.2 g, 88% yield) as a yellow solid. LCMS m / z = 649.0 [M+H] + .

[0618] Intermediate M20

[0619] To a solution of M20-1 (1 g, 6.32 mmol) in THF (15 mL) were added 3,4-dihydro-2H-pyran (0.46 mL, 5.04 mmol, Amberlystreg15 ion exchange resin (100 mg, 0.72 mmol), and the mixture was reacted at room temperature overnight. 100 mL of water was added, and the mixture was extracted with DCM (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give a yellow oil M20-2 (1 g, yield 67%). 1 H NMR(400MHz,DMSO-d6)δ4.72–4.63(m,1H),3.80–3.74(m,1H),3.58(s,3H),3.53–3.45m,1H),3.44–3.40(m,1H),2.31–2.24 (m,1H),1.99–1.88(m,4H),1.76–1.67(m,1H),1.62–1.56(m,1H),1.50–1.39(m,5H),1.38–1.28(m,3H),1.23–1.11(m,1H).

[0620] Under nitrogen atmosphere, a solution of M20-2 (1 g, 4.13 mmol) in THF (5 mL) was cooled to 0°C, and a solution of lithium aluminum hydride (234 mg, 6.17 mmol) in THF (4 mL) was slowly added dropwise. The reaction was continued at 0°C for 3 hours. 0.4 mL of EA was slowly added dropwise while maintaining the temperature at 0°C, followed by 0.25 mL of water, 0.25 mL of 15% sodium hydroxide solution, and then 0.7 mL of water. The mixture was heated to room temperature and stirred for 1 hour. The mixture was filtered, the filter cake was washed with EA, the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a colorless oil M20-3 (967 mg, yield 99%). 1 H NMR(400MHz, DMSO-d6)δ4.70(d,J=4.2Hz,1H),4.37(t,J=5.4Hz,1H),3.80-3.75(m,1H),3.48-3.39(m,2H),3.19(t,J=5.8Hz,2H),2 .01–1.88(m,2H),1.80–1.65(m,3H),1.63–1.55(m,1H),1.51–1.36(m,4H),1.34–1.17(m,3H),1.10-1.03(m,1H),0.96–0.80(m,2H).

[0621] To a solution of M20-3 (967 mg, 4.5 mmol) in THF (10 mL), add NaH (60% purity, 0.235 g, 9.8 mmol), heat to 60 ° C, and react for one hour. Cool to room temperature, add iodomethane (1.28 g, 9.0 mmol), and react at room temperature overnight. Saturated ammonium chloride is slowly added to quench, and the mixture is extracted with methyl tert-butyl ether (3×50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oil M20-4 (1 g, yield 97%). 1 H NMR (400MHz, DMSO-d6) δ4.69-4.67(m,1H),3.79-3.74(m,1H),3.48–3.37(m,2H),3.20(s,3H),3.11(d,J=6.6Hz,2H),1.99–1. 87(m,2H),1.72-1.67(m,3H),1.62–1.54(m,1H),1.50–1.36(m,5H),1.29–1.18(m,1H),1.13–1.03(m,1H),1.00–0.85(m,2H).

[0622] To a solution of M20-4 (1 g, 4.38 mmol) in MeOH (10 mL) was added p-toluenesulfonic acid monohydrate (41.7 mg, 219 μmol) and the mixture was allowed to react at room temperature for 16 hours. Saturated sodium bicarbonate was added to a pH of 7-8, and the mixture was extracted with EA (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give M20 (299 mg, 47% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ4.46(d,J=4.4Hz,1H),3.31–3.25(m,1H),3.20(s,3H),3.10(d,J=6.4Hz,2 H),1.82–1.78(m,2H),1.72–1.60(m,2H),1.42–1.39(m,1H),1.14–1.04(m,2H),0.95–0.85(m,2H).

[0623] Intermediate M21

[0624] To a solution of M21-1 (7.8 g, 41.88 mmol) in MeOH (200 mL) was added acetaldehyde (1.42 g, 32.25 mmol), cooled to 0°C, added sodium cyanoborohydride (7.9 g, 125.63 mmol), and allowed to warm to room temperature overnight. Saturated sodium bicarbonate was added to quench the reaction, and the mixture was extracted with DCM (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase C18 column chromatography (0.1% ammonium bicarbonate / water / acetonitrile) and lyophilized to give a brown liquid M20 (916 mg, 10% yield). 1 H NMR (400MHz, DMSO-d6) δ3.39–3.24(m,4H),3.22–3.16(m,2H),2.97–2.93(m,1H),2.56–2. 52(m,1H),1.97–1.85(m,1H),1.68–1.58(m,1H),1.39(s,9H),1.00(t,J=7.2Hz,3H), LCMS m / z=215.2[M+H]+.

[0625] Intermediate M22

[0626] To a solution of M18 (400 mg, 538 μmol) and methyl 4-chloromethylbenzoate (149 mg, 808 μmol) in DMF (5 mL) was added Cs2CO3 (526 mg, 1.62 mmol) and allowed to react at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with EA (3 × 50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel flash column chromatography (PE / EA) afforded M22-1 (420 mg, 87% yield) as a yellow solid. LCMS m / z = 446.3 [M+2H] 2 + / 2.

[0627] To a solution of M22-1 (420 mg, 471 μmol) in THF (2 mL) and MeOH (2 mL) was added a solution of NaOH (94 mg, 2.36 mmol) in H2O (2 mL) and allowed to react at room temperature overnight. The system was adjusted to pH 5 with 2M HCl, extracted with EA (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford M22 (400 mg, 9% yield) as a yellow solid. LCMS m / z = 878.4 [M+2H] 2 + / 2.

[0628] Intermediate M23

[0629] To M5-2 (3 g, 5.14 mmol) and 3-methylthiopropanol (546 mg, 5.14 mmol) in THF (20 mL) and DMF (20 mL) were added Cs2CO3 (6.7 g, 20.56 mmol) and DABCO (288 mg, 2.57 mmol) and reacted at room temperature overnight. 20 mL of water was added and the mixture was extracted with EA (3×30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give M23-1 (3 g, 89% yield) as a yellow solid. LCMS m / z=652.9 [M+H] + .

[0630] To a solution of M23-1 (3 g, 4.59 mmol) in MeOH (50 mL) were added iodobenzene diacetate (3.7 g, 11.48 mmol) and ammonium carbamate (717 mg, 9.18 mmol), and the mixture was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE / EA) to give M23 (1.9 g, 60% yield) as a yellow solid. LCMS m / z = 683.9 [M+H] + .

[0631] Intermediate M24

[0632] To a solution of M24-1 (950 mg, 5.33 mmol) in DMF (10 mL) at 0°C, NaH (60% purity, 426 mg, 10.66 mmol) was added, the temperature was raised to 60°C, and the reaction was allowed to proceed for one hour. The mixture was cooled to room temperature, iodoethane (2.078 g, 10.66 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The mixture was quenched by slowly adding glacial saturated ammonium chloride, extracted with EA (3 × 50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give M24-2 (880 mg, 80% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.39–7.22(m,5H),4.35(s,2H),3.64–3.52(m,2H),3. 33–3.28(m,2H),2.58–2.54(m,2H),1.79–1.66(m,2H),1.08(t,J=7.0Hz,3H).

[0633] A solution of M24-2 (880 mg, 4.27 mmol) in MeOH (10 mL) was purged with nitrogen three times, and Pd / C (10% purity, 311 mg, 292 μmol) was added. The atmosphere was purged with hydrogen three times and the mixture was reacted at 50°C for 16 hours. The mixture was filtered through Celite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to obtain M24 (366 mg, 74% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ3.78–3.71(m,1H),3.44–3.31(m,1H),3.24–3.19(m,2H),2.61–2.49(m,2H),1.78–1.63(m,2H),1.02(t,J=7.0Hz,3H).

[0634] In the following examples, HPLC was a general method: Agilent 1200 HPLC, Waters XBridge C18 5 μm, 150 x 4.6 mm; the mobile phase was a mixture of A and B: mobile phase A: 0.1% NH3.H2O in H2O; mobile phase B: 0.1% NH3.H2O in ACN; analysis time: 16 min; from min 0 to min 13, the volume percentage of mobile phase B in the mobile phase was increased from 20% to 95%; from min 13 to min 16, the volume percentage of mobile phase B in the mobile phase was 95%; flow rate: 1.0 mL / min.

[0635] Example 1

[0636] To a solution of 1-1 (2 g, 6.1 mmol) in DCM (10 mL) was added DIPEA (3.9 g, 30.3 mmol). After stirring until completely dissolved, (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (1.26 g, 6.36 mmol) was added and the mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by flash silica gel column chromatography (PE / EA) to afford 1-2 (2.86 g, 96% yield) as a yellow solid. LCMS m / z = 493.1 [M+H] + .

[0637] To a THF (2 mL) and DMF (2 mL) solvent of 1-2 (1 g, 2 mmol) and tetrahydropyran-4-ol (208 mg, 2 mmol) were added DABCO (114 mg, 1 mmol) and Cs2CO3 (cesium carbonate, 2.65 g, 8.13 mmol), and the mixture was allowed to react at room temperature overnight. 20 mL of water was added for dilution, and the mixture was extracted with EA (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 1-3 as a yellow solid (850 mg, 75% yield). LCMS m / z = 559.1 [M+H] + .

[0638] To a solution of 1-3 (0.85 g, 1.5 mmol) and benzyl alcohol (247 mg, 2.3 mmol) in THF (10 mL) was added t-BuOK (342 mg, 3.1 mmol) at 0°C and allowed to react at room temperature for 1 hour. The mixture was filtered, the filter cake washed with DCM, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to afford 1-4 as a white solid (0.87 g, 88% yield). LCMS m / z = 647.3 [M+H] + .

[0639] Under nitrogen atmosphere, 1-4 (167 mg, 464 μmol), K3PO4 (197 mg, 929 μmol), SPhosPdG2 (22 mg, 31 μmol), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (167 mg, 464 μmol), 1,4-dioxane (2 mL), and H2O (0.2 mL) were added to a microwave tube and reacted at 100 °C overnight. The mixture was returned to room temperature, diluted with 5 mL of water, extracted with EA (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 1-5 as a white solid (0.2 g, yield 81%), LCMS m / z = 799.2 [M+H] + .

[0640] A solution of 1-5 (0.2 g, 250 μmol) in MeOH (2.5 mL) was purged with nitrogen three times, and Pd / C (10% purity, 266 mg, 250 μmol) was added. The atmosphere was purged with hydrogen three times and the mixture was allowed to react at room temperature for 5 hours. The mixture was filtered through Celite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 1-6 (0.15 g, 73% yield) as a yellow solid. LCMS m / z = 709.4 [M+H] + .

[0641] To a solution of 1-6 (0.15 g, 212 μmol) and M4 (145 mg, 233 μmol) in DMF (1 mL) was added cesium carbonate (207 mg, 635 μmol) and reacted at 60°C for 3 hours. The mixture was returned to room temperature, diluted with 5 mL of water, and extracted with EA (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (DCM / MeOH) to give 1-7 (65 mg, 24% yield) as an off-white solid. LCMS m / z = 648.5 [M+H] + .

[0642] To a solution of 1-7 (35 mg, 27 μmol) in DCM (1 mL) was added 0.5 mL of 4 M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 1 (6.1 mg, 20.32% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 8.65 (s, 1H), 8.49 (d, J = 7.8Hz, 1H), 8. 05(s,1H),7.67(d,J=7.9Hz,2H),7.55(s,1H),7.47–7.42(m,3H),7.40–7.3 5(m,2H),6.80–6.76(m,2H),5.35–5.30(m,2H),5.21–5.15(m,3H),5.10–5. 08(m,1H),4.88–4.84(m,2H),4.83–4.81(m,1H),4.81–4.78(m,1H),4.48–4. 43(m,2H),4.34–4.30(m,2H),3.89–3.84(m,3H),3.79–3.74(m,4H),3.09–3 .05(m,1H),3.02–2.99(m,1H),2.68–2.66(m,1H),2.46(s,3H),2.34–2.32(m ,1H),2.09–2.04(m,3H),2.00–1.96(m,3H),1.90–1.86(m,1H),1.76–1.69( m,3H),1.25–1.22(m,2H),1.08(d,J=6.5Hz,3H),0.72(d,J=6.5Hz,3H), LCMS m / z=556.9[M+2H] 2+ / 2.

[0643] Example 2

[0644] Compound 2-1 (174 mg, 863 μmol) was dissolved in DMF (1 mL), and DIPEA (335 mg, 2.59 mmol, 451 μL) and HATU (361 mg, 950 μmol) were added. The mixture was allowed to react at room temperature for 20 minutes, then cooled to 0°C. The mixture was then added dropwise to a solution of M7 (300 mg, 863 μmol) and DIPEA (223 mg, 1.73 mmol) in DMF (1 mL) and allowed to react at room temperature for half an hour. The mixture was diluted with 5 mL of water and extracted with EA (3×10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (DCM / MeOH) to afford 2-2 (340 mg, 80% yield) as a yellow solid. LCMS m / z=531.2 [M+H] + .

[0645] To a solution of 2-2 (340 mg, 641 μmol) in DCM (3 mL) was added 1.5 mL of 4M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure and dried in vacuo to afford a yellow solid 2-3 (290 mg, 97% yield). LCMS m / z = 431.3 [M+H] + .

[0646] To a solution of 2-3 (290 mg, 621 μmol) in MeOH (3 mL) were added 1H-imidazole-1-sulfonyl azide hydrochloride (146 mg, 697 μmol), copper sulfate pentahydrate (17 mg, 70 μmol), and K2CO3 (193 mg, 1.39 mmol), and the mixture was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (DCM / MeOH) to give 2-4 (70 mg, 20% yield) as a yellow solid. LCMS m / z = 457.3 [M+H] + .

[0647] To a solution of 2-4 (50 mg, 42 μmol) and M6 (21 mg, 42 μmol) in THF (0.2 mL), t-BuOH (0.2 mL), and H2O (0.2 mL) were added copper sulfate (4 mg, 21 μmol) and sodium ascorbate (13 mg, 63 μmol) and reacted at room temperature for 3 hours. 20 mL of water was added, the mixture was filtered, and the filter cake was purified by flash silica gel column chromatography (DCM / MeOH) to give 2-5 as a white solid (55 mg, 92% yield). LCMS m / z = 643.5 [M+H] + .

[0648] To a solution of 2-5 (55 mg, 39 μmol) in DCM (0.5 mL) was added 0.2 mL of 4M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 2 as a white solid (0.55 mg, 2.3% yield). LCMS m / z = 551.6 [M+2H] 2+ .

[0649] Example 3

[0650] To a solvent of M4-3 (1 g, 1.7 mmol) and 3-methylsulfonyl-1-propanol (237 mg, 1.71 mmol) in THF (3 mL) and DMF (3 mL) were added DABCO (96 mg, 857 μmol) and Cs2CO3 (2.2 g, 6.9 mmol) and allowed to react at room temperature overnight. 20 mL of water was added, and the mixture was extracted with EA (3×30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 3-1 as a yellow solid (1.1 g, 94% yield). LCMS m / z=687.1 [M+H] + .

[0651] To a solution of 3-1 (1.1 g, 1.6 mmol) and benzyl alcohol (260 mg, 2.4 mmol) in THF (10 mL) was added t-BuOK (360 mg, 3.2 mmol) at 0°C and stirred at room temperature for 1 hour. The mixture was filtered, the filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 3-2 as a yellow solid (1.03 g, yield 88%). LCMS m / z = 775.1 [M+H] + .

[0652] Under a nitrogen atmosphere, 3-2 (0.9 g, 1.16 mmol), K3PO4 (889 mg, 4.2 mmol), cyclopropylboronic acid (200 mg, 2.33 mmol), Pd(dppf)Cl2·DCM (95 mg, 116 μmol), ACN (8 mL), 1,4-dioxane (1 mL), and H2O (2 mL) were added to a microwave tube and reacted at 100°C for 5 hours. The mixture was returned to room temperature, diluted with 10 mL of water, extracted with EA (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 3-3 as a white solid (200 mg, 25% yield). LCMS m / z = 687.3 [M+H] + .

[0653] Under nitrogen atmosphere, SPhos Pd G2 (53 mg, 74 μmol) and K3PO4 (469 mg, 2.21 mmol), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (157 mg, 436 μmol), 1,4-dioxane (2 mL), and H2O (0.2 mL) were added to 3-3 in a microwave tube and reacted at 100 ° C overnight. The mixture was returned to room temperature, diluted with 5 mL of water, extracted with EA (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give a yellow solid 3-4 (180 mg, yield 74%), LCMS m / z = 841.4 [M+H] + .

[0654] A solution of 3-4 (0.18 g, 214 μmol) in MeOH (10 mL) was purged with nitrogen three times, and Pd / C (10% purity, 228 mg, 214 μmol) was added. The atmosphere was purged with hydrogen three times and the mixture was allowed to react at room temperature for 2 hours. The mixture was filtered through Celite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 3-5 (100 mg, 62% yield) as a yellow solid. LCMS m / z = 751.4 [M+H] + .

[0655] To a solution of 3-5 (0.1 g, 133 μmol) and M4 (100 mg, 159 μmol) in DMF (1 mL) was added Cs2CO3 (130 mg, 400 μmol) and the mixture was reacted at 60°C for 3 hours. The mixture was returned to room temperature, 5 mL of water was added, and the mixture was extracted with EA (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 3-6 as a white solid (55 mg, 81% yield). LCMS m / z = 669.5 [M+2H] 2+ / 2.

[0656] To a solution of 3-6 (55 mg, 41 μmol) in DCM (1 mL) was added 0.5 mL of 4M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 3 (6.2 mg, 13% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ13.11(s,1H),8.99(s,1H),8.64(s,1H),8.48(d,J= 7.9Hz,1H),7.63(d,J=8.0Hz,2H),7.48–7.42(m,5H),7.40–7.36(m,2H),6.7 6(d,J=8.1Hz,2H),5.33(dd,J=10.8,5.1Hz,2H),5.17(d,J=3.9Hz,1H),5.10 –5.08(m,1H),4.89–4.84(m,2H),4.77(d,J=11.4Hz,1H),4.47–4.42(m,3H), 4.35–4.26(m,3H),3.87–3.84(m,1H),3.82–3.75(m,3H),3.72–3.66(m,2H), 3.27–3.26(m,2H),3.00(s,3H),2.46(s,3H),2.22–2.15(m,3H),2.12–2.04( m,2H),1.98(d,J=2.5Hz,3H),1.94–1.91(m,1H),1.81–1.75(m,2H),1.37–1. 33(m,1H),1.11–1.05(m,4H),0.72(d,J=6.6Hz,3H),0.67–0.57(m,4H), LCMS m / z=577.6[M+2H] 2+ / 2.

[0657] Example 4

[0658] 3-Methylsulfonyl-1-propanol was replaced with trans-4-methoxycyclohexanol, and the synthesis method of Example 3 was used to obtain Example 4: 1H NMR (400MHz, DMSO-d6) δ13.11(s,1H),8.98(s,1H),8.63(s,1H),8.48(d,J=8.0Hz,1 H),7.64(d,J=7.9Hz,2H),7.49(s,1H),7.47–7.41(m,4H),7.41–7.35(m,3H),6.72( d,J=7.9Hz,2H),5.32(d,J=10.5Hz,2H),5.19–5.15(m,1H),5.07–4.95(m,3H),4.89 –4.83(m,2H),4.76–4.71(m,1H),4.48–4.43(m,1H),4.34–4.30(m,1H),4.25–4.20( m,1H),3.77–3.71(m,4H),3.62–3.59(m,3H),3.20(s,3H),3.10–3.07(m,1H),3.00– 2.97(m,1H),2.46(s,3H),2.13–2.04(m,3H),1.99(d,J=2.5Hz,6H),1.90–1.85(m,1 H),1.83–1.78(m,1H),1.74–1.70(m,1H),1.56–1.45(m,3H),1.38–1.34(m,1H),1.0 7(d,J=6.6Hz,3H),0.72(d,J=6.5Hz,3H),0.67–0.59(m,3H),0.58–0.54(m,1H), LCMS m / z=573.7[M+2H] 2+ / 2.

[0659] Example 5

[0660] At -78 ° C, n-BuLi (n-butyllithium, 2.5M n-hexane solution, 17.7 mL, 44.2 mmol) was added to a solution of 5-1 (4.5 g, 36.8 mmol) in THF (45 mL) and stirred for 1 hour. A solution of I2 (iodine, 11.2 g, 44.2 mmol) in THF (10 mL) was added and the temperature was raised to room temperature for 2 hours. The mixture was quenched with 800 mL of saturated ammonium chloride, extracted with EA (3×400 ml), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to obtain a yellow oil 5-2 (7 g, yield 76%). 1H NMR (400MHz, DMSO-d6) δ7.50(d,J=1.8Hz,1H),6.47(d,J=1.8Hz,1H),4.03(d,J=7.0Hz,2H),1.27–1.15(m,1H),0.53–0.46(m,2H),0.41–0.35(m,2H).

[0661] Under nitrogen atmosphere, M10 (3.3 g, 9 mmol), K2CO3 (2.49 g, 18 mmol) and Pd(dppf)Cl2 (0.49 g, 0.6 mmol) were added to a solution of 5-2 (1.5 g, 6.0 mmol) in 1,4-dioxane (15 mL) and H2O (5 mL), and the mixture was reacted at 100°C for 2 hours. The mixture was returned to room temperature, diluted with 300 mL of water, extracted with EA (3 × 200 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 5-3 as a yellow oil (2 g, yield 95%), LCMS m / z = 358.2 [M+H] + .

[0662] To a solution of 5-3 (2 g, 5.58 mmol) in DCM (10 mL) was added 5 mL of 4 M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure and dried in vacuo to afford a yellow solid 5-4 (1.6 g, 99% yield). LCMS m / z = 258.2 [M+H] + .

[0663] To a solution of M2 (2.25 g, 6.82 mmol) in DMF (10 mL) were added HATU (3.54 g, 9.3 mmol) and DIPEA (2.4 g, 18.6 mmol), stirred at room temperature for 15 minutes, and then slowly added dropwise to a solution of 5-4 (1.6 g, 6.2 mmol) and DIPEA (1.6 g, 12.4 mmol) in DMF (10 mL) at 0°C. The mixture was reacted at room temperature for half an hour. 50 mL of water was added, and the mixture was extracted with EA (100 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (DCM / MeOH) to give 5-5 (1.3 g, 33% yield) as a yellow solid. LCMS m / z = 570.5 [M+H] + .

[0664] To a solution of 5-5 (1 g, 0.88 mmol) in DCM (10 mL) was added 5 mL of 4 M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure and dried in vacuo to afford a yellow solid 5-6 (800 mg, 97% yield). LCMS m / z = 407.2 [M+H] + .

[0665] To a solution of 5-6 (0.5 g, 1.1 mmol) in MeOH (10 mL) were added 1H-imidazole-1-sulfonyl azide hydrochloride (446 mg, 2.2 mmol), copper sulfate pentahydrate (55 mg, 0.22 mmol), and K2CO3 (304 mg, 2.2 mol). The mixture was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (DCM / MeOH) to give 5-7 (480 mg, 88% yield) as a light yellow solid. LCMS m / z = 496.3 [M+H] + .

[0666] To a solution of 5-7 (380 mg, 0.77 mmol) in THF (4 mL), t-BuOH (4 mL) and H2O (4 mL) were added M1 (231 mg, 1.5 mmol), copper sulfate (144 mg, 0.58 mmol) and sodium ascorbate (38 mg, 0.19 mmol) and reacted at 50°C for 2 hours. The mixture was returned to room temperature, extracted with EA (3×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (DCM / MeOH) to give 5-8 as a white solid (330 mg, yield 66%), LCMS m / z=646.2 [M+H] + .

[0667] To a solution of M5 (60 mg, 84 μmol) and 5-8 (54 mg, 84 μmol) in DMF (1 mL) was added Cs2CO3 (81 mg, 252 μmol) and the mixture was allowed to react at 60°C for 3 hours. The mixture was returned to room temperature, 5 mL of water was added, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 5-9 (40 mg, 32% yield) as a white solid. LCMS m / z = 663.1 [M+2H] 2+ / 2.

[0668] To a solution of 5-9 (40 mg, 30 μmol) in DCM (1 mL) was added 1 mL of 4M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 5 (2.2 mg, 6% yield) as a white solid.1 H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.65(s,1H),8.61–8.54(m,1H),7.69 –7.64(m,2H),7.50–7.44(m,3H),7.43–7.38(m,4H),6.79–6.74(m,2H),6.3 2(d,J=1.9Hz,1H),5.35–5.26(m,2H),5.22–5.15(m,2H),5.07–4.99(m,2H) ,4.90–4.84(m,1H),4.74–4.68(m,1H),4.49–4.44(m,1H),4.34–4.30(m,1H ),4.26–4.21(m,1H),3.99(d,J=6.8Hz,2H),3.89–3.83(m,2H),3.82–3.77( m,2H),3.76–3.65(m,3H),2.12–2.04(m,3H),2.02–1.96(m,4H),1.92–1.85 (m,2H),1.83–1.61(m,6H),1.39–1.32(m,2H),1.13–1.05(m,4H),0.72(d,J =6.6Hz,3H),0.66–0.50(m,5H),0.45–0.38(m,3H),0.20–0.15(m,3H), LCMS m / z=571.1[M+2H] 2+ / 2.

[0669] Examples 6 and 7

[0670] 3-Methylsulfonyl-1-propanol was replaced with 6-oxaspiro[4.5]decan-9-ol, and the synthesis method of Example 3 was used to obtain Example 6 or 7: Compound 6, a white solid, 1H NMR(400MHz, DMSO-d6)δ8.99(s,1H),8.65–8.64(m,1H),7.67–7.61(m,3H),7.49–7.42(m,4H),7.40–7.34(m,3H),6.77–6.72( m,2H),5.35–5.30(m,3H),5.05–5.02(m,2H),4.99–4.95(m,2H),4.87–4.82(m,3H),4.49–4.43(m,3H),4.34–4.26(m,4H),4.24 –4.19(m,3H),4.05–4.01(m,2H),2.11–2.06(m,3H),2.01–1.97(m,3H),1.91–1.85(m,3H),1.81–1.75(m,3H),1.70–1.65(m,3 LCMS m / z=1171.6[M+H] + ; Compound 7, white solid, 1 H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.64(s,1H),7.67–7.62(m,3H),7.50–7.43(m,4H),7.40–7.34(m,3H),6.78–6.72(m,2H ),5.37–5.30(m,3H),5.05–4.97(m,3H),4.87–4.83(m,2H),4.77–4.69(m,2H),4.48–4.42(m,3H),4.34–4.30(m,2H),4.27–4 .20(m,3H),4.06–4.00(m,2H),2.09–2.04(m,3H),2.01–1.96(m,4H),1.90–1.85(m,3H),1.81–1.75(m,3H),1.71–1.63(m,3H LCMS m / z=586.6[M+2H] 2+ / 2.

[0671] Example 8

[0672] The 3-methylsulfonyl-1-propanol was replaced with trans-1-hydroxy-4-(morpholin-4-yl)-cyclohexane, and the synthesis method of Example 3 was used to obtain Example 8: a white solid. 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),8.99(s,1H),8.64(s,1H),8.47(d,J=7.8Hz ,1H),7.72–7.68(m,2H),7.50(s,1H),7.46–7.42(m,3H),7.40–7.35(m,3H),6.92( d,J=7.9Hz,2H),5.35–5.29(m,3H),5.16(d,J=3.9Hz,1H),5.05–5.03(m,1H),4.8 8–4.84(m,2H),4.77–4.73(m,2H),4.65–4.60(m,1H),4.48–4.43(m,2H),4.34–4.3 0(m,2H),4.25–4.21(m,2H),3.92–3.86(m,2H),3.82–3.78(m,2H),3.76–3.72(m, 2H),3.66–3.58(m,4H),2.23–2.18(m,2H),2.11–2.07(m,2H),2.01(d,J=2.4Hz,3H ),1.90–1.86(m,2H),1.81–1.70(m,6H),1.44–1.40(m,2H),1.37–1.32(m,3H),1. 10–1.05(m,4H),0.88–0.83(m,3H),0.72(d,J=6.5Hz,3H),0.66–0.58(m,3H), LCMS m / z=601.1[M+2H] 2+ / 2.

[0673] Example 9

[0674] M4 was replaced by M8, and the synthesis method of Example 3 was used to obtain Example 9: a white solid, 1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.91(d,J=4.5Hz,1H),8.65(s,1H),8.65– 8.55(m,1H),7.71–7.62(m,2H),7.53–7.46(m,3H),7.45(s,1H),7.42–7.36(m,3H ),6.81–6.72(m,2H),5.37–5.25(m,2H),5.23–5.13(m,2H),5.09–4.98(m,2H),4. 89–4.80(m,1H),4.75–4.65(m,1H),4.51–4.43(m,1H),4.39–4.27(m,2H),4.27–4 .20(m,1H),3.96–3.81(m,3H),3.82–3.66(m,4H),3.66–3.52(m,4H),3.13–3.06 (m,1H),3.04–2.91(m,1H),2.16–2.04(m,4H),1.99(s,3H),1.91–1.87(m,1H),1. 86–1.78(m,1H),1.75–1.60(m,3H),1.37–1.32(m,1H),1.08(d,J=6.6Hz,3H),0.9 7–0.89(m,4H),0.72(d,J=6.5Hz,3H),0.66–0.58(m,3H),0.57–0.49(m,1H), LCMS m / z=572.7[M+2H] 2+ / 2.

[0675] Example 10

[0676] 5-1 was replaced with 1-cyclobutylpyrazole, and the synthesis method of Example 5 was used to obtain Example 10: a white solid. 1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.99(s,1H),8.95(s,1H),8.62(s,1H),8.48( d,J=7.9Hz,1H),7.94(dd,J=9.3,6.0Hz,1H),7.69–7.62(m,2H),7.47–7.41(m,2H), 7.41–7.34(m,3H),7.34(d,J=2.5Hz,1H),7.10(d,J=2.5Hz,1H),7.00–6.93(m,2H), 5.36–5.29(m,2H),5.26–5.18(m,2H),5.19–5.14(m,1H),5.14–5.07(m,2H),4.90–4. 82(m,2H),4.53–4.41(m,3H),4.34–4.29(m,1H),4.29–4.22(m,2H),4.17–4.00(m,4 H),3.90–3.85(m,1H),3.72–3.68(m,2H),3.66–3.59(m,3H),3.56–3.51(m,4H),3.1 0–3.04(m,2H),2.99(s,1H),2.46(s,3H),2.16–2.02(m,4H),2.00–1.95(m,2H),1.8 5–1.73(m,3H),1.70–1.64(m,3H),1.08(d,J=6.5Hz,3H),0.72(d,J=6.5Hz,3H), LCMS m / z=571.1[M+2H] 2+ / 2.

[0677] Example 11

[0678] 3-Methylsulfonyl-1-propanol was replaced with (3,3-difluorocyclobutyl)methanol, and the synthesis method of Example 3 was used to obtain Example 11: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.55–7.51(m,2H),7.49–7.45(m,5H) ,7.39(s,1H),7.28(d,J=9.6Hz,1H),6.81(d,J=8.0Hz,2H),6.16(d,J=10.1Hz,1H),6.1 2(d,J=10.0Hz,2H),6.06(d,J=2.4Hz,1H),6.02(d,J=2.4Hz,1H),5.52(d,J=2.4Hz,1H) ,5.50(d,J=2.4Hz,1H),5.35(d,J=10.2Hz,1H),5.29–5.24(m,2H),5.07–5.04(m,1H),4 .62–4.58(m,1H),4.51–4.45(m,3H),4.44–4.40(m,1H),4.29–4.27(m,1H),4.01(d,J=1 0.1Hz,1H),3.94(dd,J=11.2,4.1Hz,1H),3.89–3.84(m,3H),2.69–2.63(m,3H),2.48(s ,3H),2.28–2.22(m,2H),2.08(d,J=2.4Hz,3H),2.04–2.01(m,1H),1.47–1.43(m,1H),1 .16(d,J=6.6Hz,3H),0.91–0.88(m,1H),0.83(d,J=6.6Hz,3H),0.66–0.60(m,3H), LCMS m / z=569.5[M+2H] 2+ / 2.

[0679] Example 12

[0680] 3-Methylsulfonyl-1-propanol was replaced with M9, and the synthesis method of Example 3 was used to obtain Example 12: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.53–7.49(m,3H),7.47–7.44(m,4H),7.43 –7.40(m,1H),7.27(d,J=9.6Hz,1H),6.77(d,J=8.3Hz,2H),6.16(d,J=10.2Hz,1H),6.12(d,J= 10.2Hz,2H),6.04(d,J=2.4Hz,2H),6.00(d,J=2.3Hz,1H),5.50(d,J=2.3Hz,1H),5.48(d,J=2. 4Hz,1H),5.35(d,J=10.3Hz,1H),5.31–5.28(m,1H),5.26–5.20(m,2H),5.07–5.04(m,1H),4.7 7(d,J=11.3Hz,1H),4.63–4.58(m,1H),4.52–4.48(m,1H),4.34–4.29(m,1H),3.97–3.92(m,2H ),3.89–3.83(m,4H),3.17–3.14(m,1H),2.80–2.72(m,2H),2.48(s,3H),2.29(d,J=7.7Hz,2H) ,2.23–2.18(m,2H),2.08(d,J=2.5Hz,3H),2.04–1.98(m,4H),1.93–1.89(m,1H),1.46–1.41(m ,1H),1.16(d,J=6.4Hz,3H),0.92–0.88(m,1H),0.83(d,J=6.6Hz,3H),0.63–0.58(m,3H), LCMS m / z=569.5[M+2H] 2+ / 2.

[0681] Example 13

[0682] 3-Methylsulfonyl-1-propanol was replaced with cis-4-methoxycyclohexanol, and the synthesis method of Example 3 was used to obtain Example 13: a white solid. 1H NMR (400MHz, DMSO-d6) δ13.11(s,1H),8.99(s,1H),8.64(s,1H),8.48(d,J=7.8Hz,1H ),7.65(d,J=7.8Hz,2H),7.50–7.47(m,1H),7.46–7.41(m,3H),7.40–7.36(m,2H),6.7 6(d,J=8.0Hz,2H),5.35–5.28(m,2H),5.17(d,J=3.8Hz,1H),5.08–5.03(m,2H),4.88– 4.83(m,2H),4.73(d,J=11.3Hz,1H),4.48–4.43(m,1H),4.34–4.30(m,1H),4.26–4.22 (m,1H),3.80–3.73(m,4H),3.72–3.67(m,2H),3.65–3.57(m,4H),3.23(s,3H),3.13(d ,J=9.9Hz,2H),3.02(d,J=9.7Hz,2H),2.46(s,3H),2.10–2.06(m,1H),1.99(d,J=2.4H z,3H),1.92–1.88(m,1H),1.81–1.75(m,5H),1.55–1.50(m,2H),1.39–1.32(m,2H),1. 08(d,J=6.5Hz,3H),0.72(d,J=6.6Hz,3H),0.66–0.59(m,3H),0.58–0.53(m,1H), LCMS m / z=573.5[M+2H] 2+ / 2.

[0683] Example 14

[0684] 5-1 was replaced with 1-(cyclobutylmethyl)-1H-pyrazole, and the synthesis method of Example 5 was used to obtain Example 14: a white solid. 1H NMR (400MHz, DMSO-d6) δ13.12(s,1H),8.65(s,1H),8.48(d,J=8.1Hz,1H),7.68(d, J=7.8Hz,2H),7.51–7.44(m,3H),7.42–7.38(m,4H),6.78(d,J=7.9Hz,2H),6.30(d ,J=1.8Hz,1H),5.31(dd,J=21.1,10.7Hz,2H),5.21–5.14(m,2H),5.08–5.04(m,1H ),4.91–4.84(m,2H),4.71(d,J=11.1Hz,1H),4.49–4.43(m,1H),4.35–4.30(m,1H) ,4.28–4.22(m,1H),4.13(d,J=7.2Hz,2H),3.91–3.74(m,6H),3.73–3.58(m,4H),3 .11(d,J=9.8Hz,1H),3.01(d,J=9.9Hz,1H),2.71–2.63(m,2H),2.13–2.04(m,3H), 2.03–1.95(m,4H),1.93–1.82(m,4H),1.80–1.60(m,8H),1.40–1.33(m,1H),1.08( d,J=6.6Hz,3H),0.72(d,J=6.5Hz,3H),0.67–0.59(m,3H),0.58–0.52(m,1H), LCMS m / z=578.2[M+2H] 2+ / 2.

[0685] Example 17

[0686] The synthetic method of Example 3 was used to obtain Example 17: a white solid, by replacing 3-methylsulfonyl-1-propanol with endo-8-oxabicyclo[3.2.1]octan-3-ol. 1H NMR (400MHz, CDCl3) δ8.60(s,1H),8.06–7.99(m,1H),7.81(s,1H),7.39–7.28(m,5H),7.08(d,J=9.4Hz,1H),7.02–6.97(m,2H),6.41(d,J=7 .9Hz,2H),5.32–5.17(m,4H),5.11–5.03(m,1H),4.90–4.71(m,3H),4 .55–4.51(m,1H),4.32–4.25(m,2H),4.14–4.04(m,3H),3.98–3.88(m, 3H),3.82–3.73(m,2H),3.31(d,J=10.3Hz,1H),3.23–3.16(m,1H),2. 63–2.56(m,1H),2.43(s,2H),2.34–2.16(m,5H),2.13–2.06(m,2H),2. 03–1.98(m,3H),1.96–1.83(m,5H),1.38–1.30(m,2H),1.02(d,J=6.5Hz,2H),0.79–0.74(m,4H),0.55–0.50(m,1H),0.47–0.37(m,3H), LCMS m / z=572.6[M+2H] 2+ / 2.

[0687] Example 19

[0688] 3-Methylsulfonyl-1-propanol was replaced with (1,1-dioxotetrahydrothiopyran-4-yl)methanol, and the synthesis method of Example 3 was used to obtain Example 19: a white solid. 1H NMR (400MHz, DMSO-d6) δ13.12(s,1H),8.99(s,1H),8.64(s,1H),8.49(d,J=7 .8Hz,1H),7.68–7.63(m,2H),7.49–7.47(m,1H),7.46–7.42(m,3H),7.40–7.3 7(m,2H),6.80(d,J=8.1Hz,2H),5.35–5.29(m,2H),5.19–5.15(m,1H),5.07– 5.05(m,1H),4.90–4.83(m,2H),4.78–4.73(m,1H),4.48–4.43(m,1H),4.34–4 .31(m,1H),4.27–4.18(m,3H),3.81–3.67(m,5H),3.65–3.56(m,3H),3.20–3 .08(m,4H),3.06–2.98(m,3H),2.46(s,3H),2.13–2.05(m,4H),1.99(d,J=2.5 Hz,3H),1.91–1.86(m,1H),1.80–1.70(m,4H),1.39–1.33(m,1H),1.08(d,J= 6.7Hz,3H),0.72(d,J=6.5Hz,3H),0.67–0.60(m,3H),0.58–0.51(m,1H), LCMS m / z=590.5[M+2H] 2+ / 2.

[0689] Example 20

[0690] 3-Methylsulfonyl-1-propanol was replaced by tetrahydropyran-4-ol, M4 was replaced by M11, and the synthesis method of Example 3 was used to obtain Example 20: a white solid. 1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),8.66(s,1H),8.54(d,J=7.9Hz,1H),8.48–8.3 8(m,4H),7.68(d,J=8.1Hz,2H),7.50–7.48(m,1H),7.46–7.44(m,1H),7.41–7.39(m, 3H),7.24–7.19(m,2H),6.78(d,J=8.1Hz,2H),5.36–5.26(m,3H),5.23–5.15(m,2H) ,5.08–5.04(m,1H),4.89–4.86(m,1H),4.71(d,J=11.4Hz,1H),4.49–4.45(m,1H),4. 35–4.31(m,1H),4.27–4.22(m,1H),3.90–3.83(m,3H),3.79–3.76(m,2H),3.73–3.6 8(m,2H),3.65–3.61(m,2H),3.13–3.10(m,1H),3.03–2.99(m,1H),2.13–2.05(m,3H) ,2.00(d,J=2.5Hz,3H),1.91–1.87(m,1H),1.83–1.71(m,3H),1.70–1.64(m,2H),1.3 8–1.33(m,2H),1.08(d,J=6.5Hz,3H),0.72(d,J=6.5Hz,3H),0.68–0.60(m,4H), LCMS m / z=567.2[M+2H] 2+ / 2.

[0691] Example 21

[0692] 3-Methylsulfonyl-1-propanol was replaced with (trans-4-methoxycyclohexyl)methanol, and the synthesis method of Example 3 was used to obtain Example 21: a white solid. 1H NMR(400MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.57–7.50(m,3H),7.48–7.40(m,5H),7.27(d,J=9.7Hz,1H),6.82(d,J=8.0Hz,2H),5.35 (d,J=10.2Hz,1H),5.28–5.23(m,1H),5.21–5.19(m,1H),5.08–5.03(m,1H),4.63–4.56(m,2H),4.52–4.47(m,1H),4.33–4.28(m,1H),4.22 (d,J=6.5Hz,2H),3.95–3.88(m,3H),3.86–3.81(m,3H),3.33(s,3H),3.16–3.10(m,3H),2.67–2.62(m,1H),2.48(s,3H),2.27–2.20(m,1H) ,2.13–2.06(m,6H),1.97–1.87(m,4H),1.86–1.77(m,1H),1.48–1.41(m,1H),1.21–1.10(m,7H),0.85–0.81(m,3H),0.69–0.59(m,4H), LCMS m / z=580.6[M+2H] 2+ / 2.

[0693] Example 22

[0694] 3-Methylsulfonyl-1-propanol was replaced with trans-3-methoxycyclobutanol, and the synthesis method of Example 3 was used to obtain Example 22: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.87(s,1H),8.54(s,1H),8.40(s,1H),7.54–7.48(m,3H),7.47–7.44 (m,4H),7.39(s,1H),7.28(d,J=9.5Hz,1H),6.76(d,J=8.1Hz,2H),5.48–5.40(m,1H),5.35(d ,J=10.2Hz,1H),5.27(d,J=11.2Hz,1H),5.21(s,1H),5.05(t,J=6.1Hz,1H),4.82–4.77(m,2H ),4.63–4.56(m,3H),4.49(s,1H),4.34(d,J=9.8Hz,1H),4.19–4.14(m,1H),4.04–3.99(m,1H ),3.96–3.91(m,1H),3.85(d,J=6.0Hz,2H),3.44(t,J=7.1Hz,1H),3.26–3.24(m,3H),3.20–3 .16(m,1H),2.68–2.60(m,1H),2.49–2.47(m,4H),2.38–2.32(m,1H),2.27–2.20(m,1H),2.17 –2.12(m,1H),2.07(d,J=2.1Hz,3H),2.05–2.00(m,2H),1.94(d,J=10.8Hz,1H),1.16(d,J=6. 6Hz,3H),0.91–0.88(m,1H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.65–0.57(m,3H), LCMS m / z=559.9[M+2H] 2+ / 2.

[0695] Example 23

[0696] 3-Methylsulfonyl-1-propanol was replaced with trans-(4-(trifluoromethyl)cyclohexyl)methanol, and the synthesis method of Example 3 was used to obtain Example 23: a white solid. 1H NMR(500MHz,DMSO-d6)δ13.13(s,1H),8.99(s,1H),8.65(s,1H),8.50(d,J=7.8Hz,1H) ,7.66(d,J=7.8Hz,2H),7.49(s,1H),7.46–7.43(m,3H),7.41–7.37(m,3H),6.81(d,J=7 .9Hz,2H),5.35–5.28(m,2H),5.18(d,J=3.8Hz,1H),5.04(s,1H),4.90–4.82(m,2H),4. 75(d,J=11.5Hz,1H),4.48–4.43(m,1H),4.34–4.29(m,1H),4.26–4.21(m,1H),4.18–4. 12(m,1H),4.12–4.06(m,1H),3.80–3.68(m,4H),3.65–3.56(m,2H),3.09(d,J=9.8Hz,1 H),2.99(d,J=9.7Hz,1H),2.46(s,3H),2.22–2.15(m,1H),2.11–2.05(m,1H),2.00(d,J =2.5Hz,3H),1.90–1.83(m,5H),1.82–1.75(m,2H),1.75–1.70(m,1H),1.37–1.32(m,1H) ),1.29–1.20(m,4H),1.11–1.03(m,5H),0.71(d,J=6.4Hz,3H),0.67–0.53(m,4H), LCMS m / z=599.4[M+2H] 2+ / 2.

[0697] Example 24

[0698] 3-Methylsulfonyl-1-propanol was replaced with 2-oxaspiro[3.5]nonan-7-ol, and the synthesis method of Example 3 was used to obtain Example 24: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.42(s,1H),7.57–7.53(m,2H),7.51–7.5 0(m,1H),7.47–7.42(m,5H),7.27(d,J=9.6Hz,1H),6.85(d,J=8.1Hz,2H),5.35 (d,J=10.3Hz,1H),5.23(d,J=11.8Hz,1H),5.18–5.16(m,1H),5.07–5.03(m,2H ),4.77(d,J=11.7Hz,1H),4.60–4.56(m,1H),4.51–4.47(m,1H),4.46–4.45(m, 2H),4.34–4.27(m,3H),3.95–3.91(m,2H),3.90–3.81(m,4H),3.14–3.11(m,1H ),2.66–2.61(m,1H),2.48(s,3H),2.25–2.20(m,1H),2.11–2.08(m,5H),2.04– 1.96(m,4H),1.92–1.88(m,1H),1.62–1.50(m,5H),1.47–1.41(m,1H),1.16(d, J=6.6Hz,3H),0.83(d,J=6.5Hz,3H),0.70–0.64(m,1H),0.63–0.57(m,3H), LCMS m / z=579.4[M+2H] 2+ / 2.

[0699] Examples 26 and 27

[0700] 3-Methylsulfonyl-1-propanol was replaced with cis-3-methoxycyclohexanol, and the synthesis method of Example 3 was used to obtain Examples 26 and 27: Example 26, a white solid, 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.42(s,1H),7.58–7.54(m,2H),7.52–7.51(m,1 H),7.48–7.42(m,5H),7.28(d,J=9.7Hz,1H),6.83(d,J=8.3Hz,2H),5.36(d,J=10.3Hz ,1H),5.29–5.25(m,1H),5.21–5.19(m,1H),5.10–5.04(m,2H),4.82–4.79(m,1H),4. 62–4.59(m,1H),4.51–4.48(m,1H),4.35–4.28(m,2H),3.99–3.96(m,1H),3.96–3.92( m,1H),3.90–3.83(m,4H),3.23–3.14(m,3H),2.66–2.61(m,2H),2.49(s,3H),2.26–2 .19(m,3H),2.14–2.11(m,1H),2.09(d,J=2.4Hz,3H),2.06–2.00(m,3H),1.94–1.90(m ,1H),1.87–1.82(m,1H),1.48–1.41(m,3H),1.17(d,J=6.5Hz,3H),1.13–1.08(m,1H) ,1.01–0.96(m,1H),0.83(d,J=6.7Hz,3H),0.70–0.65(m,1H),0.64–0.58(m,3H), LCMS m / z=573.4[M+2H] 2+ / 2; Example 27, white solid, 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.42(s,1H),7.58–7.54(m,2H),7.52–7.51(m, 1H),7.48–7.42(m,5H),7.28(d,J=9.7Hz,1H),6.83(d,J=8.3Hz,2H),5.36(d,J=10.3 Hz,1H),5.32–5.28(m,1H),5.20–5.18(m,1H),5.10–5.04(m,2H),4.82–4.79(m,1H), 4.62–4.58(m,1H),4.51–4.48(m,1H),4.34–4.31(m,1H),3.98–3.92(m,2H),3.90–3. 83(m,4H),3.27(s,3H),3.18–3.13(m,2H),2.68–2.62(m,2H),2.49(s,3H),2.25–2.1 7(m,3H),2.14–2.11(m,1H),2.09(d,J=2.4Hz,3H),2.05–1.99(m,3H),1.94–1.90(m, 1H),1.87–1.82(m,1H),1.47–1.41(m,2H),1.17(d,J=6.7Hz,3H),1.12–1.08(m,1H), 0.92–0.88(m,1H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.64–0.58(m,3H), LCMS m / z=573.4[M+2H] 2+ / 2.

[0701] Example 28

[0702] 3-Methylsulfonyl-1-propanol was replaced with trans-4-methylcyclohexanol, and the synthesis method of Example 3 was used to obtain Example 28: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.87(s,1H),8.41(s,1H),7.56–7.53(m,2H),7.51–7.49 (m,1H),7.47–7.42(m,5H),7.29–7.25(m,1H),6.83–6.80(m,2H),5.35(d,J=10.2 Hz,1H),5.29–5.25(m,1H),5.18–5.15(m,1H),5.07–5.00(m,2H),4.81–4.77(m, 1H),4.62–4.58(m,1H),4.51–4.47(m,1H),4.32–4.28(m,1H),3.95–3.88(m,3H), 3.86–3.81(m,3H),3.11(dd,J=10.3,2.0Hz,1H),2.66–2.59(m,1H),2.47(s,3H) ,2.24–2.17(m,3H),2.10–2.06(m,4H),2.04–1.98(m,1H),1.91–1.87(m,1H),1.7 6–1.71(m,2H),1.52–1.36(m,5H),1.15(d,J=6.6Hz,3H),1.04–0.95(m,2H),0.8 4(d,J=6.6Hz,3H),0.82–0.80(m,3H),0.68–0.63(m,1H),0.62–0.56(m,3H), LCMS m / z=565.3[M+2H] 2+ / 2.

[0703] Example 29

[0704] (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane was replaced with (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester, and 3-methylsulfonyl-1-propanol was replaced with trans-4-(trifluoromethyl)cyclohexanol. The synthetic method of Example 3 was used to obtain Example 29: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.40(s,1H),7.59–7.56(m,2H),7.55–7. 50(m,2H),7.48–7.42(m,4H),7.28(d,J=9.7Hz,1H),6.86(d,J=8.1Hz,3H),5. 39–5.31(m,1H),5.21–5.16(m,2H),5.10–5.01(m,2H),4.63–4.57(m,1H),4.5 2–4.47(m,1H),4.33–4.27(m,1H),3.97–3.88(m,3H),3.87–3.80(m,2H),3.14 –3.09(m,1H),2.68–2.58(m,1H),2.48(s,3H),2.39–2.30(m,2H),2.26–2.14( m,3H),2.11–2.06(m,1H),2.04(d,J=2.4Hz,3H),2.03–1.96(m,3H),1.92–1.8 5(m,1H),1.63–1.50(m,3H),1.48–1.42(m,2H),1.16(d,J=6.6Hz,3H),0.93–0 .87(m,2H),0.82(d,J=6.5Hz,3H),0.75–0.68(m,1H),0.66–0.56(m,3H), LCMS m / z=592.5[M+2H] 2+ / 2.

[0705] Examples 30 and 31

[0706] (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane was replaced with (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester, and 3-methylsulfonyl-1-propanol was replaced with 4-hydroxycyclohexanecarbonitrile. The synthetic method of Example 3 was used to obtain Examples 30 and 31: Example 30, a white solid, 1H NMR(500MHz,DMSO-d6)δ13.23(s,1H),8.99(s,1H),8.68–8.63(m,2H),7.65(d,J=8.1Hz,2H) ,7.48–7.46(m,1H),7.45–7.41(m,4H),7.39–7.37(m,2H),6.76(d,J=8.1Hz,2H),5.34–5.31( m,1H),5.26(d,J=3.7Hz,1H),5.13–5.10(m,1H),5.08–5.04(m,2H),5.04–5.01(m,1H),4.93– 4.89(m,1H),4.85–4.80(m,1H),4.46(t,J=7.9Hz,1H),4.33–4.29(m,1H),4.26–4.20(m,1H), 3.83–3.78(m,1H),3.77–3.72(m,2H),3.70–3.65(m,1H),3.64–3.57(m,2H),3.34–3.31(m,4H ),3.11–3.08(m,1H),3.04–3.01(m,1H),3.00–2.97(m,1H),2.46(s,4H),2.14–2.05(m,2H),1 .98(d,J=2.1Hz,3H),1.91–1.86(m,3H),1.81–1.75(m,2H),1.74–1.71(m,2H),1.36–1.32(m, 1H),1.07(d,J=6.5Hz,3H),0.71(d,J=6.6Hz,3H),0.66–0.57(m,3H),0.54–0.49(m,1H), LCMS m / z=571.5[M+2H] 2+ ; Example 31, white solid, 1H NMR(500MHz,DMSO-d6)δ13.24(s,1H),8.99(s,1H),8.66(d,J=7.5Hz,1H),8.64(s,1H),7.66 (d,J=8.1Hz,2H),7.46(s,1H),7.44–7.41(m,4H),7.39–7.37(m,2H),5.31(d,J=10.2Hz,1H) ,5.26(d,J=3.8Hz,1H),5.17–5.13(m,1H),5.05–5.01(m,3H),4.97–4.92(m,1H),4.85–4.79 (m,1H),4.46(t,J=8.0Hz,1H),4.32–4.29(m,1H),4.26–4.20(m,1H),3.82–3.78(m,1H),3.7 7–3.73(m,2H),3.68–3.64(m,1H),3.63–3.58(m,2H),3.35–3.33(m,4H),3.10–3.06(m,1H), 3.00–2.96(m,1H),2.83–2.78(m,1H),2.46(s,4H),2.10–2.03(m,4H),1.97(d,J=2.3Hz,3H) ,1.89–1.86(m,1H),1.80–1.77(m,1H),1.74–1.71(m,1H),1.58–1.56(m,2H),1.36–1.32(m, 1H),1.07(d,J=6.5Hz,3H),0.70(d,J=6.6Hz,3H),0.66–0.58(m,3H),0.53–0.49(m,1H), LCMS m / z=571.5[M+2H] 2+ .

[0707] Example 32

[0708] (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane was replaced with (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester, and 3-methylsulfonyl-1-propanol was replaced with (4,4-difluorocyclohexyl)methanol. The synthetic method of Example 3 was used to obtain Example 32: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.42(s,1H),7.58–7.55(m,2H),7.54–7.53(m ,1H),7.51–7.50(m,1H),7.47–7.43(m,4H),7.28(d,J=9.8Hz,1H),6.85–6.82(m,2 H),5.35(d,J=10.3Hz,1H),5.23–5.21(m,1H),5.19–5.15(m,1H),5.07–5.04(m,1H ),4.62–4.57(m,1H),4.51–4.48(m,1H),4.33–4.25(m,3H),3.96–3.91(m,2H),3.9 0–3.82(m,4H),3.14–3.11(m,1H),2.67–2.59(m,1H),2.48(s,3H),2.27–2.18(m,2 H),2.11–2.07(m,2H),2.03(d,J=2.6Hz,3H),1.96–1.90(m,3H),1.82–1.72(m,2H) ,1.62–1.57(m,1H),1.48–1.43(m,2H),1.42–1.36(m,3H),1.16(d,J=6.6Hz,3H),0 .91–0.88(m,1H),0.83(d,J=6.7Hz,3H),0.72–0.68(m,1H),0.65–0.58(m,3H), LCMS m / z=583.5[M+2H] 2+ / 2.

[0709] Example 33

[0710] 3-Methylsulfonyl-1-propanol was replaced with M12-1, and the synthesis method of Example 3 was used to obtain Example 33: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.56–7.50(m,3H),7.49– 7.39(m,5H),7.30–7.26(m,1H),6.79(d,J=7.8Hz,2H),5.36–5.33(m,1H),5 .28–5.25(m,1H),5.22–5.14(m,3H),5.07–5.03(m,1H),4.62–4.57(m,2H), 4.51–4.47(m,1H),4.36–4.32(m,1H),4.23–4.18(m,1H),4.02–4.00(m,1H), 3.93(dd,J=11.0,3.7Hz,1H),3.89–3.83(m,3H),3.20–3.15(m,1H),2.66–2 .62(m,1H),2.48(s,3H),2.26–2.17(m,5H),2.10–2.08(m,3H),2.05–2.00(m ,2H),1.96–1.92(m,1H),1.74–1.70(m,2H),1.63–1.56(m,3H),1.16(d,J=6 .5Hz,3H),0.92–0.88(m,2H),0.83(d,J=6.5Hz,3H),0.69–0.58(m,4H), LCMS m / z = 566.3 [M + 2H] 2+ / 2.

[0711] Example 34

[0712] 3-Methylsulfonyl-1-propanol was replaced with trans-4-(difluoromethoxy)cyclohexanol, and the synthesis method of Example 3 was used to obtain Example 34: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.55–7.49(m,3H),7.48– 7.39(m,5H),7.28(d,J=9.7Hz,1H),6.75(d,J=8.2Hz,2H),5.35(d,J=10.4H z,1H),5.29–5.25(m,1H),5.20–5.18(m,1H),5.15–5.09(m,1H),5.07–5.03 (m,1H),4.81–4.77(m,1H),4.61–4.57(m,1H),4.51–4.47(m,1H),4.34–4.3 1(m,1H),3.98–3.88(m,3H),3.87–3.83(m,3H),3.71–3.64(m,1H),3.17–3. 13(m,1H),2.67–2.61(m,1H),2.48(s,3H),2.31–2.17(m,4H),2.14–2.06(m ,4H),2.04–1.98(m,3H),1.94–1.90(m,1H),1.65–1.58(m,2H),1.48–1.39( m,3H),1.16(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.58(m,4H), LCMS m / z=591.4[M+2H] 2+ / 2.

[0713] Example 35

[0714] 3-Methylsulfonyl-1-propanol was replaced with M12, and the synthesis method of Example 3 was used to obtain Example 35: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.43(s,1H),7.55–7.50(m,3H),7.48–7.44(m ,4H),7.43–7.41(m,1H),7.29(d,J=9.6Hz,1H),6.75(d,J=8.1Hz,2H),5.36(d,J=1 0.3Hz,1H),5.30–5.26(m,1H),5.20–5.17(m,1H),5.15–5.09(m,1H),5.07–5.04(m ,1H),4.79(d,J=11.2Hz,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.34–4.30(m,1 H),3.96–3.89(m,3H),3.89–3.82(m,3H),3.57–3.50(m,2H),3.44–3.38(m,1H),3. 16–3.11(m,1H),2.67–2.61(m,1H),2.49(s,3H),2.28–2.20(m,3H),2.13–2.07(m, 6H),2.04–1.97(m,1H),1.94–1.89(m,1H),1.66–1.58(m,2H),1.49–1.35(m,4H),1 .20–1.13(m,6H),0.83(d,J=6.6Hz,3H),0.69–0.64(m,1H),0.63–0.57(m,3H), LCMS m / z=580.3[M+2H] 2+ / 2.

[0715] Example 36

[0716] Substituting 3-methylsulfonyl-1-propanol with M13, the synthetic method of Example 3 was used to obtain Example 36: a white solid, LCMS m / z=587.3 [M+2H] 2+ / 2.

[0717] Example 37

[0718] 3-Methylsulfonyl-1-propanol was replaced with 4,4-dimethylcyclohexan-1-ol, and the synthesis method of Example 3 was used to obtain Example 37: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.42(s,1H),7.55(d,J=8.3Hz,2H),7.51(s,1H),7 .48–7.44(m,4H),7.43(s,1H),7.27(d,J=9.7Hz,1H),6.82(d,J=8.3Hz,2H),5.35(d,J=1 0.3Hz,1H),5.31–5.25(m,1H),5.21–5.16(m,1H),5.12–5.04(m,2H),4.81–4.77(m,1H), 4.62–4.57(m,1H),4.53–4.47(m,1H),4.34–4.28(m,1H),3.96–3.91(m,2H),3.90–3.86( m,1H),3.86–3.79(m,3H),3.15–3.11(m,1H),2.68–2.60(m,1H),2.48(s,3H),2.27–2.20 (m,1H),2.09(d,J=2.3Hz,3H),2.05–1.96(m,3H),1.90(d,J=10.2Hz,1H),1.80–1.69(m, 2H),1.56–1.47(m,2H),1.47–1.41(m,1H),1.34–1.23(m,4H),1.16(d,J=6.6Hz,3H),0.9 8(s,3H),0.89(s,3H),0.82(d,J=6.6Hz,3H),0.69–0.64(m,1H),0.64–0.56(m,3H), LCMS m / z=572.4[M+2H] 2+ / 2.

[0719] Example 39

[0720] 3-Methylsulfonyl-1-propanol was replaced with 3-oxabicyclo[3.1.0]hexane-6-ylethanol, and the synthesis method of Example 3 was used to obtain Example 39: a white solid. 1H NMR(500MHz,DMSO-d6)δ13.11(s,1H),8.99(s,1H),8.64(s,1H),8.49(d,J=7.9Hz,1H),7.66(s,1H) ,7.64(s,1H),7.50–7.47(m,1H),7.47–7.41(m,3H),7.43–7.35(m,3H),6.75–6.70(m,2H),5.37–5.2 9(m,3H),5.16(d,J=3.8Hz,1H),5.06–5.02(m,1H),5.03–4.96(m,1H),4.89–4.81(m,2H),4.74(d,J =11.3Hz,1H),4.49–4.42(m,1H),4.34–4.30(m,1H),4.26–4.21(m,1H),3.79–3.74(m,2H),3.72–3.6 6(m,1H),3.65–3.56(m,2H),3.20(s,3H),3.10(d,J=9.8Hz,1H),2.99(d,J=9.7Hz,1H),2.46(s,3H) ,2.19–2.14(m,1H),2.12–2.05(m,2H),2.01–2.00(m,1H),1.99–1.99(m,3H),1.98–1.96(m,1H),1.9 1–1.86(m,1H),1.83–1.76(m,1H),1.75–1.70(m,1H),1.54–1.47(m,2H),1.39–1.33(m,1H),1.08(d ,J=6.6Hz,3H),0.88–0.82(m,1H),0.72(d,J=6.4Hz,3H),0.68–0.59(m,3H),0.59–0.52(m,1H), LCMS m / z=565.3[M+2H] 2+ / 2.

[0721] Example 40

[0722] 3-Methylsulfonyl-1-propanol was replaced with cis-3-methoxycyclobutanol, and the synthesis method of Example 3 was used to obtain Example 40: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.43(s,1H),7.56–7.49(m,3H),7.48–7 .44(m,4H),7.40(s,1H),7.27(d,J=9.6Hz,1H),6.79(d,J=7.9Hz,2H),5.36(d ,J=10.3Hz,1H),5.25(d,J=11.5Hz,1H),5.20–5.18(m,1H),5.08–5.04(m,1H) ,4.78(d,J=11.5Hz,1H),4.63–4.57(m,1H),4.52–4.48(m,1H),4.34–4.30(m, 1H),3.96–3.88(m,3H),3.87–3.79(m,3H),3.65–3.60(m,1H),3.30–3.28(m,1 H),3.22(s,3H),3.16–3.11(m,1H),2.91–2.83(m,2H),2.68–2.61(m,1H),2.4 8(s,3H),2.27–2.18(m,1H),2.12–1.98(m,8H),1.93–1.88(m,1H),1.47–1.40 (m,1H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.4Hz,3H),0.69–0.57(m,4H), LCMS m / z=559.3[M+2H] 2+ / 2.

[0723] Example 41

[0724] 3-Methylsulfonyl-1-propanol was replaced with trans-3-(methoxymethyl)cyclobutanol, and the synthesis method of Example 3 was used to obtain Example 41: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.43(s,1H),7.57–7.50(m,3H),7.49–7 .41(m,5H),7.28(d,J=9.6Hz,1H),6.82–6.78(m,2H),5.39–5.28(m,3H),5.2 1–5.17(m,1H),5.08–5.03(m,1H),4.81–4.77(m,1H),4.62–4.57(m,1H),4.5 2–4.47(m,1H),4.34–4.30(m,1H),3.96–3.91(m,2H),3.90–3.79(m,4H),3.43 –3.39(m,2H),3.16–3.12(m,1H),2.68–2.60(m,1H),2.58–2.52(m,1H),2.49 (s,3H),2.38–2.32(m,4H),2.29–2.16(m,2H),2.13–2.07(m,4H),2.05–1.97 (m,2H),1.93–1.89(m,1H),1.46–1.41(m,1H),1.38–1.32(m,2H),1.17(d,J= 6.7Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.64–0.57(m,3H), LCMS m / z=566.6[M+2H] 2+ / 2.

[0725] Example 42

[0726] 3-Methylsulfonyl-1-propanol was replaced with trans-4-(methylsulfonyl)cyclohexanol, and the synthesis method of Example 3 was used to obtain Example 42: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.45(s,1H),7.61–7.56(m,2H),7.53–7 .51(m,1H),7.49–7.44(m,4H),7.29(d,J=9.6Hz,1H),6.90–6.84(m,2H),5.35 (d,J=10.3Hz,1H),5.23–5.18(m,2H),5.12–5.04(m,3H),4.74(d,J=11.3Hz, 1H),4.61–4.57(m,1H),4.51–4.47(m,1H),4.35–4.31(m,1H),3.97–3.91(m,2 H),3.90–3.82(m,4H),3.17–3.07(m,3H),2.87(s,3H),2.68–2.61(m,1H),2. 48(s,3H),2.44–2.39(m,2H),2.28–2.20(m,3H),2.13–2.08(m,4H),2.05–1.9 8(m,1H),1.93–1.89(m,1H),1.67–1.58(m,4H),1.47–1.42(m,1H),1.16(d,J= 6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.71–0.65(m,1H),0.64–0.58(m,3H), LCMS m / z=597.3[M+2H] 2+ / 2.

[0727] Example 43

[0728] 3-Methylsulfonyl-1-propanol was replaced with M14, and the synthesis method of Example 3 was used to obtain Example 43: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.46(s,1H),7.63–7.58(m,2H),7.51–7.43(m,5H),7.42(s,1H),7.29(d,J=9.6Hz,1H),6.96(d,J=8.0Hz,2H ),5.37(d,J=10.4Hz,1H),5.26–5.24(m,1H),5.22–5.19(m,2H),5.07–5 .05(m,1H),4.63–4.58(m,4H),4.53–4.49(m,1H),4.43–4.39(m,1H),4.2 3–4.18(m,2H),4.15–4.10(m,1H),3.95–3.91(m,3H),3.87–3.84(m,2H) ,3.48–3.44(m,2H),3.20–3.16(m,3H),2.49(s,3H),2.26–2.21(m,3H),2 .13–2.09(m,4H),2.05–1.98(m,3H),1.85–1.79(m,2H),1.17(d,J=6.7H z,3H),0.85(d,J=6.7Hz,3H),0.72–0.68(m,1H),0.65–0.61(m,3H), LCMS m / z=589.8[M+2H] 2+ / 2.

[0729] Example 48

[0730] 3-Methylsulfonyl-1-propanol was replaced by trans-4-methoxycyclohexanol, M4 was replaced by M15, and the synthesis method of Example 3 was used to obtain Example 48: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),7.52–7.40(m,7H),7.40–7.39(m,1H), 7.28–7.23(m,1H),6.82–6.76(m,2H),6.71(s,1H),5.32–5.26(m,1H),5.20– 5.17(m,1H),5.14–5.08(m,1H),5.07–5.03(m,1H),4.83–4.76(m,2H),4.62– 4.56(m,1H),4.49–4.45(m,1H),4.33–4.27(m,1H),3.91–3.87(m,2H),3.87– 3.80(m,3H),3.71–3.67(m,1H),3.33(s,3H),3.29–3.26(m,1H),3.13–3.09( m,1H),2.50–2.43(m,4H),2.25–2.18(m,3H),2.12–2.06(m,6H),2.04–1.98( m,1H),1.92–1.87(m,1H),1.66–1.57(m,2H),1.45–1.32(m,4H),1.10(d,J=6 .4Hz,3H),0.92(d,J=6.8Hz,3H),0.69–0.63(m,1H),0.62–0.56(m,3H), LCMS m / z=573.4[M+2H] 2+ / 2.

[0731] Example 49

[0732] (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane was replaced with (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester, and 3-methylsulfonyl-1-propanol was replaced with trans-4-methoxycyclohexanol. The synthetic method of Example 3 was used to obtain Example 49: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.45–8.42(m,1H),7.56–7.52(m,2H),7.50– 7.49(m,1H),7.47–7.44(m,5H),7.29(dd,J=9.7,3.3Hz,1H),6.78(d,J=8.2Hz,2H) ,5.38–5.34(m,1H),5.27–5.23(m,1H),5.16–5.11(m,1H),5.08–5.04(m,1H),5.02 –4.97(m,2H),4.85(dd,J=11.4,5.2Hz,1H),4.62–4.58(m,1H),4.51–4.48(m,1H), 3.96–3.88(m,2H),3.84(d,J=6.2Hz,2H),3.42–3.34(m,2H),3.32(s,6H),3.22–3 .16(m,1H),3.11–3.01(m,2H),2.67–2.60(m,1H),2.48(s,3H),2.26–2.17(m,4H), 2.12–2.02(m,7H),1.68–1.56(m,3H),1.48–1.43(m,1H),1.40–1.32(m,3H),1.16( d,J=6.6Hz,3H),0.82(d,J=6.5Hz,3H),0.73–0.68(m,1H),0.67–0.58(m,3H), LCMS m / z=574.3[M+2H] 2+ / 2.

[0733] Example 51

[0734] (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane was replaced with (2R,4S)-2-methyl-4-(methylamino)tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester, and 3-methylsulfonyl-1-propanol was replaced with trans-4-methoxycyclohexanol. The synthesis method of Example 3 was used to obtain Example 51: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.43(s,1H),7.54(d,J=8.0Hz,2H),7.50–7.44(m,6 H),7.29(d,J=9.7Hz,1H),6.78(d,J=8.0Hz,2H),5.36(d,J=10.3Hz,1H),5.26(d,J=11.5H z,1H),5.19–5.07(m,3H),5.06(t,J=6.1Hz,1H),4.86–4.83(m,1H),4.60(t,J=8.3Hz,1H) ,4.52–4.47(m,1H),3.97–3.87(m,2H),3.84(d,J=6.1Hz,2H),3.55–3.50(m,1H),3.45–3. 41(m,1H),3.33(s,3H),3.07–3.01(m,1H),2.69–2.61(m,1H),2.48(s,3H),2.33–2.27(m, 1H),2.27–2.17(m,4H),2.16–2.08(m,3H),2.08–2.05(m,3H),2.04–1.99(m,1H),1.87–1. 80(m,1H),1.72–1.56(m,3H),1.48–1.44(m,1H),1.43–1.37(m,2H),1.28(d,J=6.4Hz,3H) ,1.17(d,J=6.6Hz,3H),0.82(d,J=6.0Hz,3H),0.73–0.69(m,1H),0.68–0.59(m,3H), LCMS m / z=581.3[M+2H] 2+ / 2.

[0735] Example 52

[0736] 3-Methylsulfonyl-1-propanol was replaced with 1-(methoxymethyl)cyclopropane-1-ol, and the synthesis method of Example 3 was used to obtain Example 5: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.40(s,1H),7.52–7.49(m,3H),7.47–7.44(m,3H),7.40–7.36(m,2H),7.28–7.25(m,1H),6.73(d,J=8.0Hz ,2H),5.37–5.32(m,2H),5.19–5.16(m,1H),5.07–5.03(m,1H),4.50–4. 48(m,1H),4.33–4.30(m,1H),4.01–3.97(m,2H),3.93–3.88(m,4H),3.8 6–3.82(m,3H),3.39(s,3H),2.48(s,3H),2.26–2.20(m,2H),2.07(d,J= 2.4Hz,3H),2.04–2.00(m,2H),1.91–1.88(m,1H),1.46–1.42(m,2H),1. 16(d,J=6.6Hz,3H),1.12(d,J=6.6Hz,1H),1.09–1.07(m,2H),0.98–0.9 3(m,3H),0.85–0.80(m,3H),0.69–0.65(m,1H),0.63–0.59(m,3H), LCMS m / z=559.4[M+2H] 2+ / 2.

[0737] Examples 53 and 54

[0738] 3-Methylsulfonyl-1-propanol was replaced with 6-oxabicyclo[3.1.0]hexane-3-ol, and the synthesis method of Example 3 was used to obtain Examples 53 and 54: Examples 53, 53, white solids, 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.42(s,1H),7.54–7.50(m,3H),7.49–7.45(m,4H),7.41(s,1 H),7.29(d,J=9.5Hz,1H),6.77(d,J=8.1Hz,2H),5.61–5.55(m,1H),5.38–5.35(m,1H),5.29–5.25 (m,1H),5.21(s,1H),5.08–5.04(m,2H),4.78(d,J=11.2Hz,1H),4.70–4.64(m,1H),4.60(t,J=8.4 Hz,1H),4.53–4.47(m,1H),4.37–4.32(m,1H),4.26–4.21(m,1H),4.18–4.14(m,1H),4.00–3.96(m ,1H),3.94–3.88(m,2H),3.85(d,J=6.2Hz,2H),3.19–3.16(m,1H),2.82–2.75(m,1H),2.68–2.62( m,1H),2.49(s,3H),2.45–2.40(m,1H),2.22–2.17(m,1H),2.15–2.11(m,1H),2.09(d,3H),2.05–2 .02(m,1H),1.95–1.91(m,1H),1.89–1.82(m,1H),1.65–1.58(m,1H),1.48–1.43(m,1H),1.17(d,J =6.6Hz,3H),0.92–0.89(m,1H),0.83(d,J=6.5Hz,3H),0.70–0.66(m,1H),0.65–0.60(m,3H), LCMS m / z=576.3[M+2H] 2+ / 2; Example 54, white solid, 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.42(s,1H),7.54–7.49(m,3H),7.48–7.45(m,4H),7.40(s, 1H),7.29(d,J=9.7Hz,1H),6.77(d,J=8.1Hz,2H),5.63–5.55(m,1H),5.39–5.35(m,1H),5.29–5.2 5(m,1H),5.21(s,1H),5.06(t,J=6.0Hz,1H),4.80(d,J=11.3Hz,1H),4.66(s,1H),4.60(t,J=8.3H z,1H),4.50(s,1H),4.38–4.33(m,1H),4.27–4.22(m,1H),4.20–4.13(m,1H),4.02–3.97(m,1H),3 .94–3.88(m,2H),3.86–3.83(m,2H),3.19–3.16(m,1H),2.81–2.73(m,1H),2.67–2.60(m,1H),2. 49(s,3H),2.46–2.42(m,1H),2.26–2.20(m,1H),2.20–2.14(m,1H),2.09(d,J=2.0Hz,3H),2.05–2 .02(m,1H),1.96–1.91(m,1H),1.90–1.85(m,1H),1.64–1.57(m,1H),1.49–1.43(m,1H),1.17(d,J =6.6Hz,3H),0.92–0.87(m,1H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.65–0.59(m,3H), LCMS m / z=576.4[M+2H] 2+ / 2.

[0739] Example 55

[0740] 3-Methylsulfonyl-1-propanol was replaced with cis-3-methoxycyclopentan-1-ol, and the synthesis method of Example 3 was used to obtain Example 55: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.42(s,1H),7.54–7.50(m,3H),7.48–7.45(m,4H ),7.40(s,1H),7.30–7.25(m,1H),6.79(dd,J=8.2,2.4Hz,2H),5.43–5.40(m,1H),5.36 (d,J=10.3Hz,1H),5.28(d,J=11.6Hz,1H),5.21(s,1H),5.06(t,J=6.1Hz,1H),4.81(dd ,J=11.5,2.3Hz,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.36–4.31(m,1H),3.99–3. 96(m,1H),3.96–3.89(m,2H),3.88–3.82(m,4H),3.29–3.28(m,3H),3.17–3.13(m,1H) ,2.68–2.61(m,1H),2.50–2.47(m,3H),2.46–2.42(m,1H),2.26–2.21(m,1H),2.14–2.1 1(m,1H),2.10–2.08(m,3H),2.06–1.99(m,3H),1.95–1.80(m,5H),1.48–1.41(m,1H),1 .17(d,J=6.6Hz,3H),0.82(d,J=5.2Hz,3H),0.69–0.65(m,1H),0.64–0.58(m,3H), LCMS m / z=566.3[M+2H] 2+ / 2.

[0741] Example 56

[0742] 3-Methylsulfonyl-1-propanol was replaced with trans-4-acetylaminocyclohexanol, and the synthesis method of Example 3 was used to obtain Example 56: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.43(s,1H),7.55(d,J=8.0Hz,2H),7.53–7.51(m,1H) ,7.48–7.43(m,5H),7.28(d,J=8.2Hz,1H),6.80(d,J=8.1Hz,2H),5.37(d,J=10.3Hz,1H),5 .27(d,J=11.4Hz,1H),5.18(s,1H),5.13–5.08(m,1H),5.07–5.04(m,1H),4.78(d,J=11.4H z,1H),4.60(t,J=8.3Hz,1H),4.53–4.47(m,1H),4.31(d,J=8.8Hz,1H),3.96–3.88(m,3H),3 .86–3.80(m,3H),3.73–3.66(m,1H),3.30–3.27(m,1H),3.12(d,J=9.8Hz,1H),2.67–2.60( m,1H),2.48(s,3H),2.32–2.22(m,3H),2.12–2.10(m,1H),2.10–2.07(m,3H),2.04–2.00(m, 1H),2.00–1.95(m,2H),1.90(s,3H),1.66–1.58(m,2H),1.48–1.42(m,1H),1.41–1.26(m,3 H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.65–0.58(m,3H), LCMS m / z=586.8[M+2H] 2+ / 2.

[0743] Example 57

[0744] 3-Methylsulfonyl-1-propanol was replaced by trans-4-methoxycyclohexanol, M4 was replaced by M16, and the synthesis method of Example 3 was used to obtain Example 57: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.01(s,1H),7.52–7.49(m,3H),7.46( s,4H),7.38–7.37(m,1H),7.27(d,J=9.8Hz,1H),6.76–6.73(m,2H),5.25(d, J=11.4Hz,1H),5.20–5.16(m,2H),5.15–5.10(m,1H),5.06–5.02(m,1H),4. 82–4.79(m,1H),4.60–4.56(m,1H),4.49–4.46(m,1H),4.33–4.29(m,1H),3. 95–3.90(m,2H),3.85–3.82(m,3H),3.77–3.74(m,1H),3.33(s,3H),3.16–3 .12(m,1H),2.92–2.87(m,1H),2.48(s,3H),2.25–2.16(m,4H),2.11–2.07(m ,5H),2.04–2.00(m,1H),1.93–1.89(m,1H),1.65–1.60(m,2H),1.44–1.36( m,4H),1.13(d,J=6.7Hz,3H),0.82(d,J=6.6Hz,3H),0.66–0.58(m,5H), LCMS m / z=573.5[M+2H] 2+ / 2.

[0745] Example 58

[0746] 3-Methylsulfonyl-1-propanol was replaced by trans-4-methoxycyclohexanol, M4 was replaced by M17, and the synthesis method of Example 3 was used to obtain Example 58: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),7.86(d,J=1.3Hz,1H),7.61(d,J=1.3Hz, 1H),7.53–7.49(m,2H),7.48–7.41(m,6H),7.30(d,J=9.7Hz,1H),6.71–6.68( m,2H),5.23–5.22(m,1H),5.19–5.12(m,2H),5.07–5.04(m,1H),4.83–4.80(m ,2H),4.62–4.58(m,2H),4.51–4.48(m,1H),4.39–4.34(m,1H),4.12–4.09(m,1 H),3.91–3.87(m,2H),3.86–3.78(m,3H),3.42–3.38(m,1H),3.33(s,3H),3.2 4–3.21(m,1H),2.48(s,3H),2.26–2.17(m,4H),2.14–2.07(m,3H),2.02(d,J=2 .4Hz,3H),1.98–1.94(m,1H),1.67–1.60(m,2H),1.48–1.37(m,4H),1.11(d,J =6.6Hz,3H),0.81(d,J=6.7Hz,3H),0.74–0.68(m,1H),0.66–0.58(m,3H), LCMS m / z=573.0[M+2H] 2+ / 2.

[0747] Example 59

[0748] Reference WO2022029617 A1, CN112552248 A synthesized 59-1, yellow oil, 1 HNMR(400MHz,MeOH-d4)δ8.64(s,1H),8.02(d,J=8.4Hz,2H),7.49(d,J=8.3Hz,2H),5.00(d,J=8.4Hz ,1H),4.67(s,2H),3.78(s,3H),2.73–2.59(m,1H),1.06(d,J=6.7Hz,3H),0.94(d,J=6.7Hz,3H), LCMS m / z=308.2[M+2H] 2+ / 2. Under nitrogen atmosphere, Cs2CO3 (197 mg, 606 μmol) was added to a solution of M18 (150 mg, 202 μmol) and 59-1 (75 mg, 242 μmol) in DMF (2 mL), and the mixture was reacted at 60°C for 1 hour. The mixture was returned to room temperature, diluted with 5 mL of water, and extracted with EA (3×10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (DCM / MeOH) to give 59-2 (180 mg, 88% yield) as a white oil. LCMS m / z=508.0 [M+2H] 2+ / 2.

[0749] A solution of 59-2 (150 mg, 202 μmol) in THF (1 mL) and MeOH (1 mL) was added dropwise to a solution of LiOH (20 mg, 838 μmol) in H2O (1 mL) and allowed to react at room temperature for 3 hours. The solution was adjusted to pH 5 with 2M HCl (hydrochloric acid) and extracted with EA (3 × 10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 59-3 as a white solid (170 mg, 96% yield). LCMS m / z = 501.0 [M+2H] 2+ / 2.

[0750] To a solution of 59-3 (179 mg, 170 μmol) in DMF (2 mL) was added DIPEA (66 mg, 510 μmol) and HATU (71 mg, 187 μmol). The mixture was stirred at room temperature for 15 minutes, cooled to 0°C, and slowly added dropwise to a solution of M7 (59 mg, 170 μmol) in DMF (1 mL). The mixture was reacted at room temperature for 4 hours. 10 mL of water was added for dilution, and the mixture was extracted with EA (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH) to afford 59-4 (30 mg, 13% yield) as a yellow solid. LCMS m / z = 665.6 [M+H] + .

[0751] To a solution of 59-4 (10 g, 7.5 μmol) in DCM (1 mL) was added 0.2 mL of 4 M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 59 as a white solid (1 mg, 12% yield). LCMS m / z = 573.3 [M+2H] 2+ / 2.

[0752] Example 60

[0753] 3-Methylsulfonyl-1-propanol was replaced with cis-1,4-cyclohexanediol, and the synthesis method of Example 3 was used to obtain Example 60: a white solid. 1 H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.55–7.50(m,3H),7.48–7.44(m,4H), 7.42(s,1H),7.27(d,J=9.7Hz,1H),6.78(d,J=8.2Hz,2H),5.35(d,J=10.3Hz,1H),5.26( d,J=11.5Hz,1H),5.23–5.18(m,2H),5.06(t,J=6.1Hz,1H),4.79(d,J=11.4Hz,1H),4.62 –4.58(m,1H),4.52–4.48(m,1H),4.35–4.29(m,1H),3.96–3.87(m,3H),3.86–3.84(m,2H) ,3.78–3.73(m,1H),3.30–3.28(m,2H),3.15–3.10(m,1H),2.68–2.61(m,1H),2.48(s,3H ),2.27–2.20(m,1H),2.12–2.09(m,1H),2.09(d,J=2.2Hz,3H),2.08–2.06(m,1H),2.06– 1.99(m,2H),1.92–1.88(m,1H),1.84–1.78(m,4H),1.75–1.67(m,2H),1.48–1.41(m,1H) ,1.17(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.65–0.58(m,3H), LCMS m / z=566.3[M+2H] 2+ / 2.

[0754] Example 61

[0755] 3-Methylsulfonyl-1-propanol was replaced with trans-3-((tert-butyldimethylsilyl)oxy)cyclobutanol, and the synthesis method of Example 3 was used to obtain Example 61: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.41(s,1H),7.52–7.50(m,2H),7.50–7.44(m,5H ),7.39(s,1H),7.28(d,J=9.6Hz,1H),6.74(d,J=8.2Hz,2H),5.50–5.44(m,1H),5.37–5 .34(m,1H),5.28(d,J=11.3Hz,1H),5.20(s,1H),5.06(t,J=6.0Hz,1H),4.81–4.79(m, 1H),4.63–4.61(m,1H),4.60–4.55(m,2H),4.51–4.48(m,1H),4.36–4.29(m,1H),3.97– 3.91(m,2H),3.91–3.87(m,1H),3.87–3.83(m,2H),3.16–3.12(m,1H),2.67–2.61(m,1 H),2.57–2.54(m,1H),2.49(s,3H),2.47–2.42(m,2H),2.27–2.21(m,1H),2.21–2.17(m ,1H),2.13–2.09(m,1H),2.07(d,J=2.2Hz,3H),2.05–1.99(m,2H),1.94–1.89(m,1H),1 .49–1.41(m,1H),1.17(d,J=6.6Hz,3H),0.84(d,J=6.6Hz,3H),0.71–0.57(m,4H), LCMS m / z=552.3[M+2H] 2+ / 2.

[0756] Example 62

[0757] 3-Methylsulfonyl-1-propanol was replaced with cis-3-((tert-butyldimethylsilyl)oxy)cyclobutanol, and the synthesis method of Example 3 was used to obtain Example 62: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.42(s,1H),7.53(s,1H),7.52–7.50(m,2H),7. 48–7.47(m,3H),7.46–7.45(m,1H),7.40(s,1H),7.27(d,J=9.5Hz,1H),6.78(d,J=8. 1Hz,2H),5.36(d,J=10.3Hz,1H),5.28–5.25(m,1H),5.22–5.20(m,1H),5.06(t,J=6. 1Hz,2H),4.80–4.78(m,1H),4.63–4.57(m,3H),4.51–4.48(m,1H),4.35–4.31(m,1H) ,3.96–3.92(m,3H),3.91–3.88(m,1H),3.86–3.84(m,2H),3.16–3.13(m,1H),2.94–2 .89(m,2H),2.68–2.62(m,1H),2.49(s,3H),2.27–2.21(m,1H),2.15–2.10(m,3H),2. 08(d,J=2.1Hz,3H),2.04–1.99(m,1H),1.91(d,J=9.1Hz,1H),1.47–1.42(m,1H),1.1 7(d,J=6.5Hz,3H),0.84(d,J=6.6Hz,3H),0.69–0.65(m,1H),0.64–0.60(m,3H), LCMS m / z=552.3[M+2H] 2+ / 2.

[0758] Example 65

[0759] 3-Methylsulfonyl-1-propanol was replaced with exo-8-oxabicyclo[3.2.1]octan-3-ol and the synthesis method of Example 3 was used to obtain Example 65: a white solid. 1HNMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.53–7.50(m,3H),7.47– 7.44(m,4H),7.41–7.41(m,1H),7.28(d,J=9.6Hz,1H),6.75(d,J=8.4Hz,2H), 5.56–5.50(m,1H),5.37–5.33(m,1H),5.29–5.25(m,1H),5.19–5.17(m,1H),5 .07–5.04(m,1H),4.80(d,J=11.5Hz,1H),4.63–4.58(m,1H),4.51–4.44(m,3H ),4.34–4.30(m,1H),3.97–3.89(m,3H),3.88–3.83(m,3H),3.17–3.13(m,1H) ,2.67–2.61(m,1H),2.48(s,3H),2.27–2.17(m,4H),2.11–2.07(m,3H),2.05– 1.99(m,2H),1.94–1.87(m,3H),1.85–1.78(m,4H),1.47–1.42(m,1H),1.16(d ,J=6.6Hz,3H),0.84–0.81(m,3H),0.69–0.64(m,1H),0.63–0.58(m,3H), LCMS m / z=572.5[M+2H] 2+ / 2.

[0760] Example 74

[0761] The synthetic method of Example 3 was used to obtain Example 74: a white solid, LCMS m / z = 587.3 [M+2H], by replacing (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane with 1,7-diazaspiro[4.4]nonane-7-carboxylic acid, 1,1-dimethylethyl ester, and replacing 3-methylsulfonyl-1-propanol with trans-4-methoxycyclohexanol. 2+ / 2.

[0762] Example 76

[0763] (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane was replaced with 3,6-diazabicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester, and 3-methylsulfonyl-1-propanol was replaced with trans-4-methoxycyclohexanol. The synthesis method of Example 3 was used to obtain Example 76: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.46–8.41(m,1H),7.55(d,J=7.9Hz,2H),7.49–7.4 4(m,5H),7.36(s,1H),7.30–7.27(m,1H),6.79(d,J=7.8Hz,2H),5.38–5.32(m,2H),5.26 (d,J=11.3Hz,1H),5.16–5.10(m,1H),5.05(t,J=6.1Hz,1H),4.83–4.79(m,1H),4.64(s, 1H),4.61–4.57(m,1H),4.49(s,1H),3.96–3.87(m,2H),3.84(d,J=6.1Hz,2H),3.56(d,J= 13.0Hz,1H),3.32(s,3H),3.29–3.25(m,2H),2.83(dd,J=12.4,6.0Hz,1H),2.80–2.75(m ,1H),2.68–2.62(m,1H),2.48(s,3H),2.26–2.17(m,4H),2.12–2.08(m,2H),2.05(d,J=2. 2Hz,3H),2.04–1.98(m,2H),1.67–1.57(m,3H),1.46–1.41(m,1H),1.17(d,J=6.6Hz,3H) ,0.90(t,J=6.9Hz,1H),0.83(d,J=6.6Hz,3H),0.72–0.66(m,1H),0.66–0.59(m,3H), LCMS m / z=573.4[M+2H] 2+ / 2.

[0764] Example 78

[0765] 3-Methylsulfonyl-1-propanol was replaced with cis-4-(difluoromethyl)cyclohexanol, and the synthesis method of Example 3 was used to obtain Example 78: a white solid. 1H NMR(500MHz,Methanol-d4)δ8.88(s,1H),8.41(s,1H),7.53–7.49(m,3H),7.4 7–7.44(m,4H),7.42–7.41(m,1H),7.27(d,J=9.5Hz,1H),6.77(d,J=8.1Hz,2H) ,5.81–5.57(m,1H),5.40–5.37(m,1H),5.37–5.33(m,1H),5.27–5.21(m,2H), 5.08–5.04(m,1H),4.79(d,J=11.2Hz,1H),4.62–4.58(m,1H),4.51–4.48(m,1H ),4.33–4.29(m,1H),3.97–3.89(m,3H),3.88–3.82(m,3H),3.16–3.12(m,1H) ,2.67–2.61(m,1H),2.48(s,3H),2.24–2.18(m,3H),2.11–2.07(m,4H),2.05–1 .98(m,2H),1.92–1.84(m,2H),1.75–1.64(m,6H),1.47–1.41(m,1H),1.16(d,J =6.5Hz,3H),0.83(d,J=6.6Hz,3H),0.69–0.63(m,1H),0.62–0.56(m,3H), LCMS m / z=583.5[M+2H] 2+ / 2.

[0766] Example 79

[0767] 3-Methylsulfonyl-1-propanol was replaced with cis-3-(methoxymethyl)cyclobutanol, and the synthesis method of Example 3 was used to obtain Example 79: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.53–7.49(m,3H),7.47–7. 44(m,4H),7.40–7.38(m,1H),7.26(d,J=9.6Hz,1H),6.77(d,J=8.2Hz,2H),5. 35(d,J=10.3Hz,1H),5.28–5.24(m,1H),5.21–5.17(m,2H),5.07–5.04(m,1H) ,4.79(d,J=11.4Hz,1H),4.62–4.58(m,1H),4.51–4.48(m,1H),4.32–4.28(m,1 H),3.95–3.88(m,3H),3.86–3.81(m,3H),3.41(d,J=6.2Hz,2H),3.32(s,3H), 3.13–3.10(m,1H),2.65–2.57(m,3H),2.48(s,3H),2.26–2.19(m,2H),2.10–2. 06(m,4H),2.04–1.93(m,4H),1.91–1.87(m,1H),1.46–1.41(m,1H),1.16(d,J =6.6Hz,3H),0.83(d,J=6.7Hz,3H),0.68–0.63(m,1H),0.62–0.57(m,3H), LCMS m / z=566.5[M+2H] 2+ / 2.

[0768] Example 80

[0769] M5-3 was replaced by M19, and the synthesis method of Example 3 was used to obtain Example 80: a white solid, 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.42(s,1H),7.53–7.50(m,3H),7.48–7. 45(m,4H),7.39(s,1H),7.28(d,J=9.5Hz,1H),6.76(d,J=8.2Hz,2H),5.40–5. 34(m,2H),5.30–5.26(m,1H),5.22–5.20(m,1H),5.08–5.04(m,1H),4.64–4.5 8(m,2H),4.51–4.48(m,1H),4.35–4.31(m,1H),3.97–3.92(m,2H),3.90–3.83( m,4H),3.61(d,J=6.9Hz,2H),3.17–3.14(m,1H),2.67–2.62(m,1H),2.53–2.4 6(m,5H),2.39–2.34(m,4H),2.26–2.21(m,1H),2.14–2.10(m,1H),2.08(d,J=2 .4Hz,3H),2.05–2.00(m,1H),1.94–1.90(m,1H),1.46–1.42(m,1H),1.17(d,J =6.5Hz,3H),0.84(d,J=6.7Hz,3H),0.68–0.65(m,1H),0.63–0.59(m,3H), LCMS m / z=559.5[M+2H] 2+ / 2.

[0770] Example 81

[0771] M18-1 was replaced with cis-3-hydroxycyclobutylcarboxylic acid methyl ester, and the synthesis method of Example 80 was used to obtain Example 81: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.53–7.49(m,3H),7.48–7. 44(m,4H),7.38(s,1H),7.27(d,J=9.5Hz,1H),6.77(d,J=8.2Hz,2H),5.35(d, J=10.3Hz,1H),5.28–5.25(m,1H),5.23–5.19(m,2H),5.07–5.04(m,1H),4.82 –4.78(m,1H),4.62–4.57(m,2H),4.51–4.48(m,1H),4.34–4.31(m,1H),3.98–3 .89(m,3H),3.87–3.83(m,3H),3.56(d,J=6.0Hz,2H),3.18–3.14(m,1H),2.66 –2.57(m,3H),2.48(s,3H),2.26–2.20(m,1H),2.16–2.10(m,2H),2.07(d,J=2 .4Hz,3H),2.04–2.01(m,1H),1.99–1.90(m,3H),1.46–1.41(m,1H),1.16(d,J =6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.68–0.64(m,1H),0.63–0.57(m,3H), LCMS m / z=559.5[M+2H] 2+ / 2.

[0772] Example 82

[0773] 3-Methylsulfonyl-1-propanol was replaced with M20, and the synthesis method of Example 3 was used to obtain Example 82: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.43(s,1H),7.58–7.54(m,2H),7.51(s,1H), 7.49–7.42(m,5H),7.28(d,J=9.7Hz,1H),6.85(d,J=8.3Hz,2H),5.38–5.34(m,1H) ,5.30–5.26(m,1H),5.19–5.17(m,1H),5.07–5.02(m,2H),4.81–4.77(m,1H),4.62 –4.57(m,1H),4.51–4.48(m,1H),4.34–4.30(m,1H),3.95–3.91(m,2H),3.90–3.87( m,1H),3.86–3.82(m,2H),3.25(s,3H),3.15–3.11(m,2H),2.67–2.61(m,1H),2.49 (s,3H),2.27–2.21(m,3H),2.12–2.08(m,4H),2.04–1.98(m,2H),1.92–1.89(m,1H) ,1.86–1.80(m,3H),1.62–1.55(m,2H),1.51–1.43(m,3H),1.17(d,J=6.6Hz,3H),1 .03–0.97(m,2H),0.83(d,J=6.7Hz,3H),0.70–0.66(m,1H),0.64–0.58(m,3H), LCMS m / z=580.6[M+2H] 2+ / 2.

[0774] Example 91

[0775] (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane was replaced by M21, and 3-methylsulfonyl-1-propanol was replaced by trans-4-methoxycyclohexanol. The synthesis method of Example 3 was used to obtain Example 91: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.42(s,1H),7.57–7.54(m,2H),7.50–7.48(m,1 H),7.47–7.43(m,4H),7.40(s,1H),7.32–7.29(m,1H),6.83–6.79(m,2H),5.36(d,J=1 0.1Hz,1H),5.30–5.26(m,1H),5.18–5.12(m,1H),5.07–5.03(m,1H),4.74–4.69(m,1 H),4.61–4.57(m,1H),4.51–4.48(m,1H),3.96–3.92(m,1H),3.90–3.87(m,1H),3.84( d,J=6.1Hz,2H),3.81–3.77(m,2H),3.46–3.41(m,1H),3.32(s,3H),3.07–3.04(m,1H) ),2.67–2.61(m,1H),2.48(s,3H),2.38–2.33(m,1H),2.25–2.17(m,5H),2.12–2.05(m ,6H),2.04–1.98(m,2H),1.67–1.59(m,3H),1.49–1.45(m,1H),1.43–1.37(m,5H),1. 16(d,J=6.6Hz,3H),0.83(d,J=6.5Hz,3H),0.76–0.72(m,1H),0.67–0.60(m,3H), LCMS m / z=581.3[M+2H] 2+ / 2.

[0776] Example 105

[0777] Under nitrogen atmosphere, triethylsilane (653 mg, 5.62 mmol), TEA (853 mg, 8.43 mmol), and Pd(dppf)Cl2 (229 mg, 281 μmol) were added to a solution of 105-1 (950 mg, 2.81 mmol) in DMF (10 mL). The mixture was reacted at 110°C overnight. The mixture was returned to room temperature and filtered. The filtrate was purified by reverse phase C18 chromatography (0.1% formic acid / water / acetonitrile) and lyophilized to give 105-2 (435 mg, 51% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.95(s,1H),7.76–7.63(m,2H),7.41–7.32(m,1H),5.48(d d,J=12.8,5.4Hz,1H),3.42(s,3H),2.97–2.84(m,1H),2.78–2.62(m,2H),2.13–2.01(m,1H), LCMS m / z=288.1[M+H] + .

[0778] To a solution of 105-2 (100 mg, 348 μmol) and (S)-1-N-Boc-2-methylpiperazine (105 mg, 522 μmol) in THF (2 mL) were added KOAc (205 mg, 2.1 mmol) and sodium triacetoxyborohydride (111 mg, 522 μmol). The mixture was allowed to react at room temperature for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (DCM / MeOH) to afford 105-3 (120 mg, 73% yield) as a white solid. LCMS m / z = 472.3 [M+H] + .

[0779] To a solution of 105-3 (100 mg, 212 μmol) in DCM (1 mL) was added 1 mL of 4M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 3 hours. Lyophilization afforded a yellow solid 105-4 (50 mg, 63% yield), LCMS m / z = 372.2 [M+H] + .

[0780] To a solution of M22 (30 mg, 34 μmol) and 105-4 (13 mg, 34 μmol) in DMF (1 mL) were added HATU (14 mg, 37 μmol) and DAPEA (13 mg, 103 μmol) and allowed to react at room temperature for 1 hour. Water was added to precipitate a solid, which was then lyophilized and filtered to afford 105-5 (15 mg, 35% yield) as a colorless oil. LCMS m / z = 616.1 [M+2H] 2+ / 2.

[0781] To a solution of 105-5 (15 mg, 12 μmol) in DCM (1 mL) was added 1 mL of 4 M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 105 as a white solid (1 mg, 7% yield). LCMS m / z = 1047.4 [M+H] + .

[0782] Example 127

[0783] The synthesis method of Example 5 was used to obtain Example 127: a white solid, by replacing 5-1 with 1-ethylpyrazole and tetrahydropyran-4-ol with cis-4-methoxycyclohexanol. 1 H NMR(500MHz,MeOH-d4)δ8.42(s,1H),7.55–7.48(m,6H),7.45–7.41(m,3H),7.28(d, J=9.8Hz,1H),6.79(d,J=8.2Hz,2H),6.31(d,J=2.0Hz,1H),5.36(d,J=10.2Hz,1H),5 .29–5.25(m,1H),5.22–5.17(m,2H),5.09–5.06(m,1H),4.82–4.78(m,1H),4.62–4. 58(m,1H),4.51–4.48(m,1H),4.35–4.32(m,1H),4.19–4.14(m,2H),4.00–3.97(m,1H ),3.96–3.89(m,2H),3.88–3.84(m,3H),3.34(s,3H),3.18–3.15(m,1H),2.68–2.62 (m,1H),2.27–2.17(m,2H),2.15–2.11(m,1H),2.09(d,J=2.4Hz,3H),2.05–1.96(m,3 H),1.94–1.84(m,5H),1.69–1.63(m,2H),1.47–1.43(m,1H),1.37–1.33(m,4H),1.1 7(d,J=6.7Hz,3H),0.83(d,J=6.7Hz,3H),0.69–0.65(m,1H),0.64–0.57(m,3H), LCMS m / z=572.1[M+2H] 2+ / 2.

[0784] Example 128

[0785] 5-1 was replaced by 1-ethylpyrazole, and tetrahydropyran-4-ol was replaced by cis-3-methoxycyclobutanol. The synthesis method of Example 5 was used to obtain Example 128: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.44(s,1H),7.55–7.48(m,6H),7.45–7.39(m,3H),7.28(d ,J=9.8Hz,1H),6.80(d,J=8.2Hz,2H),6.31(d,J=1.9Hz,1H),5.36(d,J=10.4Hz,1H ),5.25(d,J=11.5Hz,1H),5.21–5.19(m,1H),5.09–5.06(m,1H),4.80–4.77(m,1H) ,4.62–4.58(m,1H),4.51–4.48(m,1H),4.35–4.31(m,1H),4.19–4.14(m,2H),3.96 –3.88(m,3H),3.86–3.82(m,3H),3.66–3.61(m,1H),3.22(s,3H),3.16–3.13(m,1H ),2.90–2.84(m,2H),2.67–2.61(m,1H),2.26–2.20(m,1H),2.12–2.06(m,6H),2.0 4–1.98(m,2H),1.93–1.89(m,1H),1.46–1.42(m,1H),1.34(t,J=7.2Hz,4H),1.17( d,J=6.7Hz,3H),0.83(d,J=6.7Hz,3H),0.69–0.65(m,1H),0.63–0.58(m,3H), LCMS m / z=558.1[M+2H] 2+ / 2.

[0786] Example 129

[0787] M5-3 was replaced by M23, and the synthesis method of Example 3 was used to obtain Example 129: a white solid, 1H NMR(500MHz,MeOH-d4)δ8.89(s,1H),8.42(s,1H),7.54–7.51(m,3H),7.47–7.45 (m,4H),7.41–7.40(m,1H),7.28(d,J=9.6Hz,1H),6.81–6.78(m,2H),5.36(d,J=1 0.3Hz,1H),5.27–5.21(m,2H),5.07–5.04(m,1H),4.83–4.79(m,1H),4.64–4.53 (m,4H),4.51–4.48(m,1H),4.35–4.31(m,1H),3.97–3.92(m,2H),3.91–3.83(m,4 H),3.42–3.37(m,2H),3.17–3.13(m,1H),3.04(d,J=1.7Hz,3H),2.67–2.61(m,1 H),2.49(s,3H),2.37–2.31(m,2H),2.26–2.21(m,1H),2.13–2.10(m,1H),2.08(d ,J=2.4Hz,3H),2.04–2.00(m,1H),1.93–1.90(m,1H),1.47–1.43(m,1H),1.17(d ,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.65(m,1H),0.64–0.59(m,3H), LCMS m / z=577.0[M+2H] 2+ / 2.

[0788] Example 130

[0789] To a solution of 33 (50 mg, 44.2 μmol) and glycolic acid (4 mg, 53 μmol) in DMF (1 mL) at 0°C were added HATU (20 mg, 53 μmol) and DIPEA (29 mg, 221 μmol), and the mixture was allowed to warm to room temperature for 4 hours. 5 mL of water was added, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 130 (3.1 mg, 6% yield) as a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.55–7.53(m,1H),7.53–7.51(m,1H),7.49– 7.48(m,1H),7.47–7.47(m,3H),7.46–7.42(m,2H),7.28(d,J=9.6Hz,1H),6.76(d,J=7.4Hz,2H ),5.37–5.33(m,2H),5.32–5.27(m,2H),5.15–5.11(m,1H),5.08–5.04(m,2H),4.78(dd,J=11. 2,4.3Hz,1H),4.62(s,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.43–4.38(m,1H),4.29(d,J= 2.9Hz,1H),4.09(s,1H),3.93–3.91(m,1H),3.90–3.86(m,1H),3.86–3.84(m,2H),3.84–3.80( m,1H),3.74–3.69(m,1H),3.68–3.63(m,1H),2.68–2.62(m,1H),2.49(s,3H),2.29–2.25(m,2H ),2.24–2.19(m,2H),2.09(d,J=2.1Hz,3H),2.05–2.01(m,3H),1.67–1.60(m,2H),1.49–1.42( LCMS m / z=595.3[M+2H] 2+ / 2.

[0790] Example 131

[0791] To a solution of 33 (60 mg, 53 μmol) and dimethyl dicarbonate (7 mg, 53 μmol) in MeOH (1 mL) was added DIPEA (7 mg, 53 μmol) and allowed to react at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to afford 130 (3.1 mg, 6% yield) as a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.42(s,1H),7.53(d,J=8.1Hz,2H),7.49–7.45(m,6 H),7.28(d,J=9.6Hz,1H),6.76(d,J=8.2Hz,2H),5.35(d,J=10.3Hz,1H),5.31(d,J=10.9 Hz,1H),5.26–5.22(m,1H),5.16–5.09(m,1H),5.06(t,J=6.1Hz,1H),4.79–4.75(m,1H), 4.74–4.71(m,1H),4.62–4.57(m,1H),4.52–4.47(m,1H),4.37(d,J=9.3Hz,1H),3.98–3. 86(m,3H),3.85(d,J=6.2Hz,2H),3.77–3.73(m,1H),3.73–3.72(m,1H),3.69–3.66(m,2H ),3.63–3.59(m,1H),2.69–2.60(m,1H),2.51–2.46(m,3H),2.31–2.21(m,3H),2.20–2.1 7(m,1H),2.13–2.09(m,1H),2.08(d,J=2.2Hz,3H),2.08–1.97(m,4H),1.68–1.59(m,2H) ,1.50–1.41(m,3H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.70–0.58(m,4H), LCMS m / z=595.3[M+2H] 2+ / 2.

[0792] Example 132

[0793] Under nitrogen atmosphere, Cs2CO3 (197 mg, 606 μmol) was added to a solution of M18 (150 mg, 202 μmol) and M15-1 (75 mg, 242 μmol) in DMF (2 mL) and reacted at 60°C for 1 hour. The mixture was returned to room temperature, diluted with 5 mL of water, and extracted with EA (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (DCM / MeOH) to afford 132-1 (200 mg, 96% yield) as a white oil. LCMS m / z = 1030.8 [M+H] + .

[0794] A solution of 132-1 (0.2 g, 197 μmol) in THF (1 mL) and MeOH (1 mL) was added dropwise to a solution of LiOH (24 mg, 986 μmol) in H2O (1 mL) and allowed to react at room temperature for 3 hours. The solution was adjusted to pH 5 with 1 M HCl (hydrochloric acid) and extracted with EA (3 × 10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 132-2 as a white solid (125 mg, 62% yield). LCMS m / z = 516.7 [M+2H] 2+ / 2.

[0795] To a solution of 132-2 (0.17 g, 170 μmol) in DMF (2 mL) was added DIPEA (66 mg, 510 μmol) and HATU (71 mg, 187 μmol). The mixture was stirred at room temperature for 15 minutes, cooled to 0°C, and slowly added dropwise to a solution of M7 (59 mg, 170 μmol) in DMF (1 mL). The mixture was reacted at room temperature for 4 hours. 10 mL of water was added for dilution, and the mixture was extracted with EA (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH) to afford 132-3 (30 mg, 13% yield) as a yellow solid. LCMS m / z = 673.7 [M+H] + .

[0796] To a solution of 132-3 (50 mg, 37 μmol) in DCM (1 mL) was added 0.2 mL of 4 M HCl (1,4-dioxane) at 0°C and allowed to react at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 132 as a white solid (6 mg, 14% yield). 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),7.54–7.50(m,3H),7.48–7.44(m,5H),7.24(d,J=9.7Hz,1H),6.83(d,J=8.0Hz,2H),6.79(s,1H),5.35–5 .32(m,1H),5.24–5.19(m,2H),5.14–5.09(m,1H),5.07–5.03(m,1H),4 .66–4.61(m,3H),4.38–4.34(m,2H),4.07(s,1H),3.92–3.86(m,2H),3. 86–3.83(m,2H),3.39–3.36(m,1H),3.33(s,3H),3.23–3.19(m,1H),2. 88–2.84(m,1H),2.48(s,3H),2.21–2.16(m,4H),2.05–2.02(m,5H),1.9 7–1.94(m,1H),1.88–1.83(m,1H),1.65–1.57(m,4H),1.01(d,J=6.7Hz,3H),0.84(d,J=6.9Hz,3H),0.70–0.65(m,2H),0.63–0.58(m,3H), LCMS m / z=581.6[M+2H] 2+ / 2.

[0797] Example 133

[0798] 3-Methylsulfonyl-1-propanol was replaced with cis-4-trifluoromethoxycyclohexanol, and the synthesis method of Example 3 was used to obtain Example 133: a white solid. 1H NMR(500MHz,MeOH-d4)δ8.88(s,1H),8.41(s,1H),7.54–7.50(m,3H),7.48– 7.44(m,4H),7.41(s,1H),7.27(d,J=9.7Hz,1H),6.78(d,J=8.2Hz,2H),5.3 5(d,J=10.3Hz,1H),5.26–5.23(m,1H),5.23–5.19(m,2H),5.07–5.04(m,1H ),4.78(d,J=11.5Hz,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.47–4.42 (m,1H),4.33–4.29(m,1H),3.95–3.91(m,2H),3.90–3.82(m,4H),3.16–3.1 2(m,1H),2.67–2.61(m,1H),2.48(s,3H),2.26–2.20(m,1H),2.11–2.00(m, 10H),1.96–1.88(m,3H),1.84–1.77(m,2H),1.47–1.42(m,1H),1.16(d,J=6 .6Hz,3H),0.83(d,J=6.6Hz,3H),0.69–0.64(m,1H),0.63–0.57(m,3H), LCMS m / z = 600.5 [M + 2H] 2+ / 2.

[0799] Example 134

[0800] 3-Methylsulfonyl-1-propanol was replaced with M24, and the synthesis method of Example 3 was used to obtain Example 134: a white solid. 1H NMR(500MHz,MeOH-d4))δ8.88(s,1H),8.42(s,1H),7.55–7.50(m,3H),7.48–7.44 (m,4H),7.40–7.39(m,1H),7.27(d,J=9.6Hz,1H),6.80(d,J=8.4Hz,2H),5.35(d,J =10.2Hz,1H),5.27–5.23(m,1H),5.20–5.18(m,1H),5.07–5.04(m,1H),4.94–4.92 (m,1H),4.80–4.77(m,1H),4.62–4.57(m,1H),4.51–4.48(m,1H),4.33–4.30(m,1H ),3.95–3.91(m,2H),3.90–3.81(m,4H),3.72–3.68(m,1H),3.43–3.38(m,2H),3.2 9–3.28(m,1H),3.15–3.12(m,1H),2.89–2.82(m,2H),2.67–2.61(m,1H),2.48(s,3 H),2.26–2.20(m,1H),2.12–2.06(m,6H),2.04–1.99(m,1H),1.92–1.89(m,1H),1. 47–1.40(m,1H),1.18–1.13(m,6H),0.83(d,J=6.7Hz,3H),0.68–0.57(m,4H), LCMS m / z=566.5[M+2H] 2+ / 2.

[0801] Effect Experiment Example

[0802] Experimental Example 1

[0803] The cell proliferation inhibitory activity of the compounds of the present invention was evaluated by three-dimensional culture.

[0804] Cell lines and culture methods

[0805] Experimental reagents and consumables

[0806] Experimental methods:

[0807] 1. AsPC-1 cells were cultured in RPMI1640 + 10% FBS + 1% P / S in a 37°C CO2 incubator. 2000 cells were plated per well of a 96-well low-adhesion flat-bottom cell culture plate in the logarithmic growth phase and cultured overnight.

[0808] 2. The next day, add compound dilutions. Perform a 3-fold concentration gradient with duplicates. DMSO serves as a control. The final DMSO concentration in the cell culture medium is 0.1%.

[0809] 3. The compound was incubated with AsPC-1 cells in a carbon dioxide incubator at 37°C for 6 days before use. Reagent testing.

[0810] The cell proliferation inhibition rate (Inhibition Rate) data were processed using the following formula: Inhibition Rate (Inh%) = 100-(RLUDrug-RLUMin) / (RLUMax-RLUMin)*100%. The inhibition rates corresponding to different concentrations of the compound were calculated in Excel, and then the inhibition rate curve was plotted using GraphPad Prism software and related parameters were calculated, including the maximum and minimum inhibition rates of the cells, IC 50 The results are shown in Table 1.

[0811] Table 1

[0812] The experimental results show that the compound of the present invention has good AsPC-1 cell proliferation inhibitory activity.

[0813] Experimental Example 2

[0814] KRAS G12D protein degradation experiment in cells by the compounds of the present invention (Western Blot).

[0815] Cell lines and culture methods

[0816] Experimental reagents and consumables

[0817] Experimental methods:

[0818] 1. AsPC-1 cells were cultured in RPMI1640 + 10% FBS + 1% P / S in a 37°C CO2 incubator. Cells in the logarithmic growth phase were resuspended in growth medium and diluted to the target density, and seeded into 6-well plates.

[0819] 2. Dilute the compound with DMSO. According to the test requirements, dilute the compound 3-fold. Pipette the compound into a 6-well plate seeded with cells, and then add DMSO control. After mixing, incubate the 6-well plate in a 37°C, 5% CO2 incubator for 16 hours.

[0820] 3. After 16 hours, equilibrate the 6-well plate to room temperature and collect the cells into a 1.5 mL centrifuge tube.

[0821] 4. Lyse the cell pellet using RIPA lysis buffer. Add protease inhibitors to the lysis buffer. After lysis, use the BCA protein concentration assay kit to determine the protein concentration of each sample and quantify it uniformly. Add 5X protein loading buffer, boil at 95°C for 10 minutes, cool on ice, and store the sample at -80°C or use it immediately for Western blotting analysis.

[0822] 5. Load the obtained protein sample into the wells of 10% SDS gel, keeping the same loading volume in each well. After loading, turn on the power supply for electrophoresis.

[0823] 6. Transfer the proteins on the SDS gel to the PVDF membrane.

[0824] 7. After transfer, the PVDF membrane was blocked and washed, and then incubated with the primary antibody at 4°C overnight, diluted 1:1000. The next day, the membrane was washed three times with TBST and incubated with the HRP secondary antibody (HRP-anti-Rabbit IgG, CST, 7074S), diluted 1:3000. After washing, the membrane was exposed to a chemiluminescence imager and the image was saved.

[0825] 8. Use Image J2X software to analyze the grayscale values ​​of the KRAS-G12D and Vinculin bands in the Western Blot results. The grayscale value results are displayed in two ways:

[0826] Bar graph: The horizontal axis is the compound concentration, and the vertical axis value is calculated using the following formula:

[0827] pN / N (% control) = gray value compound / gray value DMSO*100%;

[0828] Curve graph: The horizontal axis is the concentration of the compound, and the vertical axis value is calculated using the following formula:

[0829] Degradation (% control) = [1 - gray value compound / gray value DMSO] * 100%.

[0830] The results are shown in Table 2.

[0831] Table 2

[0832] The experimental results show that the compound of the present invention has a good degradation effect on KRAS G12D protein in cells.

[0833] Experimental Example 3

[0834] KRAS G12D protein degradation experiment in cells by the compounds of the present invention (HiBiT).

[0835] Cell lines and culture methods

[0836] Method for constructing HiBiT cell line

[0837] Experimental reagents and consumables

[0838] Experimental methods:

[0839] 1. AsPC-1HiBiT-KRAS G12D were cultured in RPMI1640 + 10% FBS + 1% Antibiotic-antimycotic in a 37°C, 5% CO2 incubator. Cells in the logarithmic growth phase were resuspended in growth medium and diluted to the target density for plating, with 10,000 cells per well. The cells were cultured overnight in a 37°C, 5% CO2, and 100% relative humidity incubator.

[0840] 2. The next day, add the compound of the invention in dilution. Perform a 3-fold concentration gradient dilution of the compound of the invention in duplicate, with DMSO as a control. The final DMSO concentration in the cell culture medium is 0.25%. Return the 96-well cell plate to the incubator and incubate for 24 hours.

[0841] 3. After 24 hours, use Promega Detection was performed using the HiBiT Lytic Detection System kit, and the cell status was observed under a microscope before plate reading.

[0842] 4. Calculate the target protein degradation rate (DR) of the test compound using the following formula: DR (%) = (1 – (RLU compound – RLU blank control) / (RLU vehicle control – RLU blank control)) * 100%. Calculate the target protein degradation rate at different concentrations of the compound in Excel, then use GraphPad Prism software to plot the inhibition curve and calculate relevant parameters, including minimum degradation rate, maximum degradation rate, and DC. 50 , the results are shown in Table 3.

[0843] Table 3

[0844] The experimental results show that the compound of the present invention has a good degradation effect on KRAS G12D protein in cells.

[0845] Experimental Example 4

[0846] Pharmacokinetic experiments of the compounds of the present invention

[0847] By experimental method:

[0848] The test substance was administered as a solution to ICR mice (Zhejiang Weitong Lihua, 6-8 weeks old, weighing 20-30g). Animals were not fasting prior to administration and had free access to water. For the intravenous administration group, the dose was 2 mg / kg. Blood was collected (approximately 0.030 mL) at the following time points after administration: 0.033, 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours. Heparin sodium was pre-added to the blood collection tube as an anticoagulant. Blood samples were centrifuged at 6800g for 6 minutes, and plasma was collected and stored at -80°C.

[0849] Sample preparation for LC-MS / MS analysis: Protein precipitation was performed on 10 μL plasma sample with 200 μL methanol containing internal standard (wherein the volume ratio of plasma sample to methanol was 1:20). The mixture was vortexed for 1 minute and then centrifuged at 14,000 rpm for 7 minutes. The supernatant was transferred to a 96-well plate. The supernatant was subjected to LC-MS / MS analysis. ICR mouse blank matrix was used for detection. Mass spectrometry analysis was performed using an Applied Biosystems Sciex TQ6500+ (triple quadrupole) instrument and an ESI ion source.

[0850] LC-MS / MS analysis method:

[0851] Mobile phase A: 0.1% formic acid in water;

[0852] Mobile phase B: 0.1% formic acid in acetonitrile;

[0853] Flow rate: 0.60 mL / min;

[0854] Column temperature: 40℃.

[0855] Gradient elution program: .

[0856] The conditions for the pharmacokinetic experiments of the compounds of the present invention are shown in Table 4.

[0857] Table 4

[0858] The pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0. The main pharmacokinetic parameters are shown in Table 5 below.

[0859] Table 5

[0860] Among them, the structure of compound X is

[0861] The experimental results show that the compound of the present invention has a good exposure amount in the pharmacokinetic test in mice and has a low clearance rate in the body, showing good pharmacokinetic properties.

Claims

1. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; in: G is N or CR G , R G is H, halogen or cyano; J is N or CR J , R J is H, halogen or cyano; X is -O- or -NH-; R 1 is C3-C7 cycloalkyl, 7-12 membered heterocycloalkyl, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl; Each R 1-1 is a 4-12 membered heterocycloalkyl group, -S(O)2R 1-1-3 or The heteroatom type in the 4-12 membered heterocycloalkyl is S, the number of heteroatoms is 1 or 2, and the S atom is independently replaced by one or more R 1-1-2 replace; Each R 1-1-2 are independently oxo (=O) or =NR 1-1-1-3 ; R 1-1-1-3 is hydrogen or C1-C6 alkyl; R 1-1-3 is a C3-C7 cycloalkyl group or a C1-C6 alkyl group; R 1-1-4 is a C1-C6 alkyl group; Each R 1-2 are independently deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, 4-12 membered heterocycloalkyl, 1-2-1 Substituted C1-C6 alkyl, one or more R 1-2-2 Substituted C1-C6 alkoxy, one or more R 1-2-3 Substituted 4-12 membered heterocycloalkyl, -S(O)2R 1-1-3 , -O-C3-C7 cycloalkyl, -C(O)NHR 1-2-4 or -NHC(O)R 1-2-4 ; Each R 1-2-1 are independently halogen, hydroxy or C1-C6 alkoxy; Each R 1-2-2 are independently deuterium, halogen or C3-C7 cycloalkyl; Each R 1-2-3 independently halogen, C1-C6 alkyl, C1-C6 alkoxy, 1-2-3-1 Substituted C1-C6 alkyl or one or more R 1- 2-3-2 Substituted C1-C6 alkoxy; Each R 1-2-3-1 are independently halogen; Each R 1-2-3-2 are independently deuterium or halogen; Each R 1-2-4 are independently C3-C7 cycloalkyl or C1-C6 alkyl; Each R 1-3 are independently oxo, deuterium, C1-C6 alkyl or substituted by one or more R 1-3-1 Substituted C1-C6 alkyl; Each R 1-3-1 are independently halogen; E is absent, -O- or -NR e -; R e is hydrogen or C1-C6 alkyl; R 2 is a 4-12 membered heterocycloalkyl group or is replaced by one or more R 2-1 substituted 4-12 membered heterocycloalkyl; Each R 2-1 are independently halogen, C1-C6 alkyl, or by one or more R 2-1-1 Substituted C1-C6 alkyl; each R 2-1-1 are independently halogen, hydroxy or alkoxy; s is 0, 1, 2, or 3; R 3 is halogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl or is replaced by one or more R 3-1 Substituted C1-C6 alkyl; Each R 3-1 are independently halogen, hydroxy or C1-C6 alkoxy; R 4 is hydrogen or halogen; R 5 is C1-C6 alkyl, C3-C7 cycloalkyl, or C1-C6 alkyl substituted by one or more deuteriums; R 10 is methylene, monodeuteromethylene or dideuteromethylene; Y is absent, -O-, -NH-, C1-C6 alkylene, C3-C7 cycloalkylene, 4-12 membered heterocycloalkylene or -OR Y-1 -; R Y-1 is C1-C6 alkylene or 4-12 membered heterocycloalkylene; Z is absent, a 5-10 membered heteroarylene group or -H 1 -H 2 -, and Y and Z do not exist at the same time; H 1 C3-C 12 Cycloalkylene, 4-12 membered heterocycloalkylene, one or more R h1 Substituted C3-C 12 Cycloalkylene or one or more R h2 Substituted 4-12 membered heterocycloalkylene; H 2 is C1-C6 alkylene, -O- or -NH-; H 1 Connect with Y, H 2 Connected to LL; LL is the E3 ligase ligand; In each "heterocycloalkyl" and "heterocycloalkylene", the heteroatom species are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; In each "heteroarylene group", the heteroatom species are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

2. The compound of formula I according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: Each R 1-1 is a 4-12 membered heterocycloalkyl group or -S(O)2R 1-1-3 The heteroatom species in the 4-12 membered heterocycloalkyl group is S, the number of heteroatoms is 1 or 2, and the S atoms are independently replaced by one or more R 1-1-2 replace; Each R 2-1 are independently halogen, C1-C6 alkyl or substituted by one or more R 2-1-1 Substituted C1-C6 alkyl.

3. The compound of formula I according to claim 1 or 2, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: The compound shown in formula I satisfies one or more of the following conditions: (1) Each halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine; (2) Each C1-C6 alkyl group is independently a C1-C4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, preferably methyl, ethyl, propyl or isopropyl; (3) each C3-C7 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (4) each 4-12 membered heterocycloalkyl group is independently a 4-6 membered monocyclic heterocycloalkyl group or a 7-12 membered polycyclic (e.g., spirocyclic, fused or bridged) heterocycloalkyl group; (5) each 7-12 membered heterocycloalkyl group is independently a 7-12 membered polycyclic (e.g., spirocyclic, fused or bridged) heterocycloalkyl group; (6) Each C1-C6 alkoxy group is independently a C1-C4 alkoxy group, which may be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a tert-butoxy group, an isobutoxy group or a sec-butoxy group, preferably a methoxy group, an ethoxy group or an isopropoxy group; (7) Each C1-C6 alkylene group is independently a C1-C4 alkylene group, which may be Preferred (8) Each C3-C7 cycloalkylene and C3-C 12 The cycloalkylene groups are independently (9) Each 4-12 membered heterocycloalkylene group is independently a 4-6 membered monocyclic heterocycloalkylene group or a 7-12 membered polycyclic (e.g., spirocyclic, fused or bridged) heterocycloalkylene group, and the 4-6 membered monocyclic heterocycloalkylene group is preferably a piperazinylene group, for example (10) Each 5-10 membered heteroarylene group is independently a 5-8 membered monocyclic heteroarylene group or an 8-10 membered bicyclic (e.g., bicyclic) heteroarylene group, wherein the 5-8 membered monocyclic heteroarylene group is preferably a 5-6 membered monocyclic heteroarylene group, more preferably Further optimization (11) Each 5-10 membered heteroaryl group is independently a 5-8 membered monocyclic heteroaryl group or an 8-10 membered bicyclic (e.g., fused) heteroaryl group, wherein the 5-8 membered monocyclic heteroaryl group is preferably a 5-6 membered monocyclic heteroaryl group, and more preferably Further optimization (12) Each C6-C 10 Aryl is phenyl or naphthyl, preferably phenyl; Preferably, the compound as shown in Formula I satisfies one or more of the following conditions: (1) The 4-6 membered monocyclic heterocycloalkyl groups are independently More preferred It can also be (2) Each of the 7-12 membered polycyclic heterocycloalkyl groups is independently Preferred Further optimization 4. The compound of formula I according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: The compound shown in Formula I is the following Scheme 1 or Scheme 2: Option 1: X is -O-; G is N; J is N; R 1 is a 7-12 membered heterocycloalkyl group, 1-1 Substituted C1-C6 alkyl, one or more R 1-2 Substituted C3-C7 cycloalkyl or one or more R 1-3 substituted 7-12 membered heterocycloalkyl, wherein the 7-12 membered heterocycloalkyl and one or more R 1-3 The 7-12 membered heterocycloalkyl in the substituted 7-12 membered heterocycloalkyl is a bridged ring; Each R 1-1 independently 4-12 membered heterocycloalkyl or -S(O)2R 1-1-3 The heteroatom species in the 4-12 membered heterocycloalkyl group is S, the number of heteroatoms is 1 or 2, and the S atoms are independently replaced by one or more R 1-1-2 replace; Each R 1-2 are independently deuterium, hydroxyl, -NHC(O)R 1-2-4 or by one or more R 1-2-1 Substituted C1-C6 alkyl; Each R 1-3 independently for deuterium; R 1-1-3 is a C1-C6 alkyl group; Each R 1-2-1 are independently hydroxy or C1-C6 alkoxy; Each R 1-1-2 are independently oxo or =NR 1-1-1-3 ; R 1-1-1-3 is hydrogen or C1-C6 alkyl; R 1-2-4 is a C1-C6 alkyl group; E does not exist or -NR e -; R e is hydrogen or C1-C6 alkyl; R 2 is a 5-6 membered monocyclic heterocycloalkyl, a 7-8 membered polycyclic heterocycloalkyl, or one or more R 2-1 substituted 5-6 membered monocyclic heterocycloalkyl or one or more R 2-1 substituted 7-8 membered polycyclic heterocycloalkyl, wherein the 5-6 membered monocyclic heterocycloalkyl, 7-8 membered polycyclic heterocycloalkyl, 2-1 The 5-6 membered monocyclic heterocycloalkyl in the substituted 5-6 membered monocyclic heterocycloalkyl and the substituted 5-6 membered monocyclic heterocycloalkyl 2-1 The heteroatom type in the 7-8 membered polycyclic heterocycloalkyl group in the substituted 7-8 membered polycyclic heterocycloalkyl group is N, and the number of heteroatoms is independently 1 or 2; Each R 2-1 are independently C1-C6 alkyl; R 3 is a C3-C7 cycloalkyl group; R 4 is a halogen; R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums; R 10 is methylene or dideuterated methylene; Y is absent, Z is a 5-10 membered heteroarylene group, the heteroatom species in the 5-10 membered heteroarylene group is selected from one or both of N and O, and the number of heteroatoms is 1, 2, 3 or 4; LL is Each R 6a and R 6b are independently hydrogen or C1-C6 alkyl, or, R 6a and R 6b Can form a C3-C7 cycloalkyl group together with the carbon atom to which it is attached; R 7 is C1-C6 alkyl or is replaced by one or more R 7-1 Substituted C1-C6 alkyl; Each R 7-1 are independently hydroxyl groups; m is 0; R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl, said substituted by one or more R 9-1 The heteroatom species in the 5-6-membered heteroaryl group of the substituted 5-6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3; Each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl; Each R 9-1-1 are independently halogen or C3-C7 cycloalkyl; Option 2: X is -O-; G is N; J is N; R 1 For one or more R 1-1 Substituted C1-C6 alkyl; each R 1-1 for R 1-1-4 is a C1-C6 alkyl group; E does not exist or -NR e -; R e is hydrogen or C1-C6 alkyl; R 2 is a 5-6 membered monocyclic heterocycloalkyl, a 7-8 membered polycyclic heterocycloalkyl, or one or more R 2-1 substituted 5-6 membered monocyclic heterocycloalkyl or one or more R 2-1 substituted 7-8 membered polycyclic heterocycloalkyl, wherein the 5-6 membered monocyclic heterocycloalkyl, 7-8 membered polycyclic heterocycloalkyl, 2-1 The 5-6 membered monocyclic heterocycloalkyl in the substituted 5-6 membered monocyclic heterocycloalkyl and the substituted 5-6 membered monocyclic heterocycloalkyl 2-1 The heteroatom type in the 7-8 membered polycyclic heterocycloalkyl group in the substituted 7-8 membered polycyclic heterocycloalkyl group is N, and the number of heteroatoms is independently 1 or 2; Each R 2-1 are independently C1-C6 alkyl; R 3 is a C3-C7 cycloalkyl group; R 4 is a halogen; R 5 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more deuteriums; R 10 is methylene or dideuterated methylene; Y is absent, Z is a 5-10 membered heteroarylene group, the heteroatom species in the 5-10 membered heteroarylene group is selected from one or both of N and O, and the number of heteroatoms is 1, 2, 3 or 4; LL is Each R 6a and R 6b are independently hydrogen or C1-C6 alkyl, or, R 6a and R 6b Can form a C3-C7 cycloalkyl group together with the carbon atom to which it is attached; R 7 is C1-C6 alkyl or is replaced by one or more R 7-1 Substituted C1-C6 alkyl; Each R 7-1 are independently hydroxyl groups; m is 0; R 9 For one or more R 9-1 substituted 5-6 membered heteroaryl, said substituted by one or more R 9-1 The heteroatom species in the 5-6-membered heteroaryl group of the substituted 5-6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2 or 3; Each R 9-1 are independently C1-C6 alkyl, C3-C7 cycloalkyl or substituted by one or more R 9-1-1 Substituted C1-C6 alkyl; Each R 9-1-1 are independently halogen or C3-C7 cycloalkyl.

5. The compound of formula I according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: The compound shown in Formula I is a compound shown in Formula I', Formula I-1, Formula I-2 or Formula I-3: * indicates that the carbon atom has a chiral center and the stereoisomer is an atropisomer; R 1 、R 2 、R 3 、R 4 、R 5 、R 6a 、R 6b 、R 7 、R 9 、R 10 , E, Y, Z and LL are as defined in any one of claims 1-4; Preferably, the compound represented by Formula I is a compound represented by Formula Ia, Ib, I-1a, I-1b, I-2a, I-2b, I-3a or I-3b:

6. The compound of formula I according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: The compound shown in formula I satisfies one or more of the following conditions: (1)R 1 for For example (2)-ER 2 for For example (3)R 3 is chloro or cyclopropyl; (4)R 4 For fluorine; (5)R 5 is methyl or trideuterated methyl, for example methyl; (6) Y does not exist, For example or does not exist; or for another example does not exist; (7) Z is For example (8)R 6a is hydrogen, R 6b isopropyl, or R 6a and R 6b Formation of cyclopropyl group; (9)R 7 is -CH3 or -CH2-OH; (10)R 9 for For example (11)R 10 is methylene or dideuterated methylene, such as methylene; (12)-H 1 -for Preferably, The "1" is connected to Y, and the "2" is connected to H 2 connection; better, for Best, for (13)-H 2 -for Preferably, the compound as shown in Formula I satisfies one or more of the following conditions: (1)Y-Z is For example (2) Formula L-3 is For example (3) Formula L-2 is 7. A quinazoline compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the quinazoline compound is any one of the following compounds: in Expressed as 8. A pharmaceutical composition comprising substance A and a pharmaceutically acceptable excipient, wherein substance A is a compound of formula I according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a quinoline compound according to claim 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. Use of a substance A or the pharmaceutical composition according to claim 8 in preparing a G12D mutant KRAS degrader, wherein the substance A is a compound of Formula I according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a quinoline compound according to claim 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. Use of a substance A or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing tumors; the substance A is a compound of formula I according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a quinoline compound according to claim 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; the tumor is preferably a hematological tumor or a solid tumor; the hematological tumor may be leukemia, lymphoma, or multiple myeloma; the solid tumor may be pancreatic cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, squamous cell carcinoma of the lung, cervical rhabdomyosarcoma, ovarian cancer, esophageal cancer, prostate cancer, breast cancer, bladder cancer, endometrial cancer, gastric cancer, melanoma, hepatoma, head and neck cancer, cholangiocarcinoma, malignant glioma, thyroid cancer, schwannoma, skin cancer, testicular cancer, or soft tissue sarcoma; The leukemia may be acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, chronic myeloid leukemia or acute monocytic leukemia, and the lymphoma may be Hodgkin's lymphoma or non-Hodgkin's lymphoma.

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