Bicyclic compound, method for preparing same, and use thereof

Abstract

Provided are a bicyclic compound of formula I that achieves a degradative or inhibitory effect on NRF2 by means of activating KEAP1, an isotopically labeled form, an enantiomer, a diastereomer, an atropisomer, or a pharmaceutically acceptable salt thereof, a method for preparing the compound, and use thereof in treating cancers.

Description

A class of bicyclic compounds, their preparation methods and uses

[0001] This application claims priority to Chinese patent application 2024116112867, filed November 12, 2024; Chinese patent application 2024117905673, filed December 6, 2024; Chinese patent application 2025102334221, filed February 28, 2025; Chinese patent application 2025104782951, filed April 16, 2025; and Chinese patent application 2025116049586, filed November 4, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to an NRF2 degradation or inhibitor, its preparation method and application, and more particularly to a class of bicyclic compounds, their compositions and their use in the treatment and prevention of cancer. Background Technology

[0003] A growing body of research indicates that activation of NRF2 (Nuclear factor erythroid 2-related factor 2) and its associated signaling pathways can promote tumor progression and metastasis, and confer resistance to chemotherapy and radiotherapy to tumor cells (Satoh H et al. Cancer Res. 2013, 73(13):4158–4168; Singh A et al. PLoS Med. 2006, 3(10):e420). In tumor cells, mutations in the NRF2 encoding gene NFE2L2 and its regulatory genes KEAP1 and CUL3, as well as epigenetic silencing of KEAP1, CUL3, and RBX1, can lead to persistent activation of NRF2 and tumor development (Jaramillo MC et al. Genes Dev. 2013, 27(20):2179–2191). Approximately 12% of cancer patients in the TCGA (The Cancer Genome Atlas) database carry mutations in at least three of the following: KEAP1, CUL3, and NFE2L2. Among them, 10-30% of lung cancer patients carry KEAP1 or NFE2L2 mutations; the frequencies of KEAP1, CUL3 and NFE2L2 mutations in head and neck cancer patients are 4%, 2% and 6%, respectively (Cancer Genome Atlas Network. Nature 2015, 517(7536):576–582; Jin X et al. Oncogenesis 2024, 13(1):35); while in gallbladder cancer, liver cancer and gastric cancer, the mutation frequencies of KEAP1 are 31%, 8.9% and 11%, respectively; in addition, the frequencies of NFE2L2 mutations in esophageal cancer, skin cancer and laryngeal cancer are 11%, 6% and 13%, respectively (Sporn MB et al. Nature Rev. Cancer 2012, 12(8):564–571).

[0004] The level of NRF2 protein is mainly regulated by the KEAP1-CUL3 E3 ubiquitin ligase complex: Under non-stress conditions, the homodimer KEAP1 binds to NRF2 through the DLG and ETGE motifs of the Neh2 domain, and maintains NRF2 at a very low level through the KEAP1-CUL3 E3 ubiquitin ligase-proteasome degradation pathway; after sensing external stresses such as reactive oxygen species (ROS) and toxic compounds (usually electrophilic agents), the active cysteine ​​on KEAP1 is modified, thereby reducing the ubiquitination activity of the KEAP1-CUL3 complex, ultimately inhibiting the degradation of NRF2 and promoting the transcriptional expression of its downstream genes (Kobayashi A et al. Mol Cell Biol. 2004, 24(16):7130-7139). Studies have found that overexpression of KEAP1 in tumor cells can promote the degradation of NRF2 and enhance the sensitivity of tumor cells to chemotherapy and radiotherapy (Kanninen KM et al. Free Radic Biol Med. 2015, 88:350-361). Therefore, by targeting KEAP1 and activating the activity of the KEAP1-CUL3 E3 ubiquitin ligase complex, the degradation of NRF2 can be promoted, thereby inhibiting tumor development, metastasis, and drug resistance, thus meeting the urgent treatment needs of cancer patients. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, this invention provides a class of compounds, their preparation methods, and applications. The compounds of this invention exhibit good degradation or inhibition activity against NRF2.

[0006] This invention provides a compound of formula (I), its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof:

[0007] in,

[0008] p is 0, 1, 2 or 3;

[0009] n is 0, 1, 2, or 3;

[0010] m can be 0, 1, 2, or 3;

[0011] Z represents O, S(=O)2, and C(R). 1 )2 or NR 4 ;

[0012] R 4 For R 4a -C(=O)R 4a S(=O)R 4a or S(=O)2R 4a; Each R 4a It is independently a C1-C6 alkyl or a C3-C6 cycloalkyl;

[0013] Each R 1 Independently, it can be hydrogen, halogen, cyano, hydroxyl, oxo (=O), C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or -C(=O)NR. 1a R 1b ;

[0014] Or two adjacent R 1 Together with the carbon atoms between them, they form unsubstituted or substituted C3-C6 cycloalkyl groups; the group A substituents are selected from: C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, deuterium, halogen, hydroxyl and cyano;

[0015] Or two R atoms connected to the same carbon atom 1 Together with the carbon atom, they form an unsubstituted or substituted C3-C6 cycloalkyl group; the group A substituents are selected from: C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, deuterium, halogen, hydroxyl and cyano;

[0016] R 3 It is H, deuterium, C1-C6 alkyl, or deuterated C1-C6 alkyl;

[0017] R 2 for R 2a H, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, or halo-C1-C6 alkyl; R 2b and R 2c Each is independently either H or deuterium;

[0018] W is a naphthyl group that is unsubstituted or substituted with one or more group B substituents, a benzo5-6 heteroaryl group that is unsubstituted or substituted with one or more group B substituents, a 6-membered heteroaryl group that is unsubstituted or substituted with one or more group B substituents, or a benzo5-6 heterocyclic group that is unsubstituted or substituted with one or more group B substituents; the 5-6 heteroaryl group contains 1-3 heteroatoms selected from N, O, and S; the 6-membered heteroaryl group contains 1-2 N atoms;

[0019] Group B substituents are selected from: oxo group (=O), deuterium, halogen, hydroxyl group, carboxyl group, cyano group, NR. x R y -C(=O)NRx R y -NR x C(=O)R y -R 5 and -OR 6 ;R 5 and R 6 It can be independently an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-6 membered heterocyclic or an unsubstituted or substituted 5-6 membered heteroaryl.

[0020] R 5 and R 6 The substitution mentioned herein refers to substitution by one or more group C substituents; group C substituents are selected from: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR c1 R c2 -C(=O)NR c1 R c2 and -NR c1 C(=O)R c2 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group independently contain 1-3 heteroatoms selected from N, O and S;

[0021] R 1a R 1b R c1 R c2 R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S.

[0022] As a preferred technical solution, the compound of formula (I) has the following structure:

[0023] As a preferred technical solution, W is a benzo6-membered heteroaryl group that is unsubstituted or substituted by one or more group B substituents, or a 6-membered heteroaryl group that is unsubstituted or substituted by one or more group B substituents; the 6-membered heteroaryl group contains 1-3 heteroatoms selected from N.

[0024] Preferably, it is benzopyrazine group without substitution or substituted by one or more group B substituents, benzopyrimidin group without substitution or substituted by one or more group B substituents, benzotriazine group without substitution or substituted by one or more group B substituents, or pyridinylpyrazine group without substitution or substituted by one or more group B substituents.

[0025] As a preferred technical solution, the substituents in group B are selected from: D, F, Cl, Br, CN, -CH3, -CD3, -CF3, -CH2CH3, -CH2CF3, -OCH3, -OCH2CH3, -NH2, -NHCH3, -C(=O)NH2、

[0026] As a preferred technical solution,

[0027] p is 0, 1, 2 or 3;

[0028] n is 0, 1, 2, or 3;

[0029] m can be 0, 1, 2, or 3;

[0030] Z represents O, S(=O)2, and C(R). 1 )2 or NR 4 ;

[0031] R 4 For R 4a -C(=O)R 4a S(=O)R 4a or S(=O)2R 4a ;R 4a It is a C1-C6 alkyl or C3-C6 cycloalkyl;

[0032] Each R 1 Independently, it can be hydrogen, halogen, cyano, hydroxyl, oxo (=O), C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or -C(=O)NR. 1a R 1b ;

[0033] Or two adjacent R 1Together with the carbon atoms between them, they form unsubstituted or substituted C3-C6 cycloalkyl groups; the group A substituents are selected from: C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, deuterium, halogen, hydroxyl and cyano;

[0034] R 3 It is H, deuterium, C1-C6 alkyl, or deuterated C1-C6 alkyl;

[0035] R 2 for R 2a H, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl; R 2b and R 2c Each is independently either H or deuterium;

[0036] W represents a naphthyl group that is unsubstituted or substituted with one or more group B substituents, or a benzo6-membered heteroaryl group that is unsubstituted or substituted with one or more group B substituents. 1 6-membered heteroaryl groups that are unsubstituted or substituted by one or more group B substituents 2 And 6-membered heteroaryl 1 The 6-membered heteroaryl group 1 Contains 1-3 heteroatoms of N, O, and S; the 6-membered heteroaryl group 2 It contains 1-2 nitrogen atoms;

[0037] Group B substituents include: oxo (=O), deuterium, halogen, hydroxyl, carboxyl, cyano, and NR. x R y -C(=O)NR x R y -NR x C(=O)R y -R 5 -OR 6 ;R 5 and R 6 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 ynyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-6 membered heterocyclic group, or an unsubstituted or substituted 5-6 membered heteroaryl; R 5 and R 6The substitution mentioned herein refers to substitution by one or more group C substituents; group C substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR c1 R c2 -C(=O)NR c1 R c2 -NR c1 C(=O)R c2 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group contain 1-3 heteroatoms selected from N, O and S;

[0038] R 1a R 1b R c1 R c2 R x R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, or a C3-C6 cycloalkyl 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S.

[0039] As a preferred technical solution,

[0040] W is

[0041] in,

[0042] X 1 For N or CR 9a X 2 For N or CR 10a X 3 For N or CR 11a X 4 For N or CR 12a X 5 For N or CR 13a Preferably, X 1 X 2 X 3 X 4 and X 5 At least one of them is N;

[0043] Y 1 For N or CR 24 Y 2For N or CR 25 Y 3 For N or CR 26 And Y 1 Y 2 and Y 3 At least one of them is N;

[0044] R 7 R 8 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 9a R 10a R 11a R 12a and R 13a Each is independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y -R 5 or -OR 6 ;R 5 and R 6 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 ynyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-6 membered heterocyclic group, or an unsubstituted or substituted 5-6 membered heteroaryl; R 5 and R 6 The substitution mentioned herein refers to substitution by one or more group C substituents; group C substituents are selected from: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR c1 R c2 -C(=O)NR c1 R c2 and -NR c1 C(=O)R c2 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group independently contain 1-3 heteroatoms selected from N, O and S;

[0045] R c1 Rc2 R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S.

[0046] As a preferred technical solution,

[0047] W is

[0048] in,

[0049] R 7 R 8 R 20 R 21 R 22 R 23 R 25 R 26 R 9a R 10a R 11a R 12a and R 13a Each is independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y -R 5 -OR 6 ;R 5 and R 6 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 ynyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-6 membered heterocyclic group, or an unsubstituted or substituted 5-6 membered heteroaryl; R 5 and R 6 The substitution mentioned herein refers to substitution by one or more group C substituents; group C substituents are selected from: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NRc1 R c2 -C(=O)NR c1 R c2 and -NR c1 C(=O)R c2 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group contain 1-3 heteroatoms selected from N, O and S;

[0050] R c1 R c2 R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S;

[0051] Preferably,

[0052] R 7 R 8 R 20 R 21 R 22 R 23 R 25 R 26 R 9a R 10a R 11a R 12a and R 13a Each is independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y The 3-6 membered heterocyclic group includes C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, and unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogen, hydroxyl, amino, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, and halo-C1-C6 alkyl; the 3-6 membered heterocyclic group and the 5-6 membered heterocyclic group contain 1-3 heteroatoms selected from N, O, and S.

[0053] R x and R yEach of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S;

[0054] Preferably,

[0055] R 7 R 20 R 21 R 22 R 9a and R 10a Independently, it is hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or deuterated C1-C6 alkoxy;

[0056] R 8 R 23 R 25 R 26 R 11a R 12a and R 13a Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y The following are categorized as follows: C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, and unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogens, amino groups, and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S.

[0057] R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S;

[0058] Preferably,

[0059] R 7 R 20 R 21 R 22 R 9a R 10a It can be hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, or deuterated C1-C6 alkyl;

[0060] R 8 R 23 R 25 R 26 R 11a R 12a R 13a Independently, it can be hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, -CF3, -CH2CF3, -NH2, -NHCH3, -C(=O)NH2,

[0061] As a preferred technical solution,

[0062] W is

[0063] in,

[0064] R 7 R 10a and R 21 It can be hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy or deuterated C1-C6 alkoxy independently;

[0065] R 8 R 12a R 23 R 25 and R 26 Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R yC1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, 5-6-membered heteroaryl, unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogens, amino groups and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups independently contain 1-3 heteroatoms selected from N, O and S;

[0066] R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S;

[0067] Preferably,

[0068] R 7 R 10a and R 21 It can be independently a halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, or deuterated C1-C6 alkyl;

[0069] R 8 R 12a R 23 R 25 R 26 Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y The following are categorized as follows: C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, and unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from halogens, amino groups, and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S.

[0070] R x R yEach of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S;

[0071] Preferably,

[0072] R 7 R 10a and R 21 It can be chlorine, fluorine, bromine, deuterium, or -CD3 independently;

[0073] R 8 R 12a R 23 R 25 and R 26 The radicals are hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, -CF3, -CH2CF3, -NH2, -NHCH3, -C(=O)NH2,

[0074] As a preferred technical solution, the compound of formula (I) has the following structure:

[0075] The definitions of R1, R2, R3, W, and p are the same as those described above.

[0076] Preferably, p is 0 or 1; preferably, p is 0.

[0077] Preferably, R 2 for

[0078] Preferably, R 3 It is hydrogen.

[0079] As a preferred technical solution, the compound of formula (I) has the following structure,

[0080] The definition of W is the same as described above.

[0081] As a preferred technical solution, formula III is formula (R)-III or (S)-III:

[0082] As a preferred technical solution, the compound of formula (I) has the following structure,

[0083] The definition of W is the same as described above.

[0084] As a preferred technical solution, in any of the above general formulas IV to XIII, the C connected to W is either the C of the R configuration or the C of the S configuration.

[0085] As a preferred technical solution, the compound of formula (I) has the following structure:

[0086] in,

[0087] R 7 R 21 and R 9a Independently, it is hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or deuterated C1-C6 alkoxy;

[0088] R 8 R 12a R 23 R 25 R 26 Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, 5-6-membered heteroaryl, unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogens, amino groups and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups independently contain 1-3 heteroatoms selected from N, O and S;

[0089] R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S;

[0090] Preferably,

[0091] R 7 R21 and R 9a It can be independently a halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, or deuterated C1-C6 alkyl;

[0092] R 8 R 12a R 23 R 25 and R 26 Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, 5-6-membered heteroaryl, unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogens, amino groups and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups independently contain 1-3 heteroatoms selected from N, O and S;

[0093] R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S;

[0094] Preferably,

[0095] R 7 R 21 and R 9a Independently chlorine, fluorine, bromine, deuterium, -CD3;

[0096] R 8 R 12a R 23 R 25 and R 26 Independently, it can be hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, -CF3, -CH2CF3, -NH2, -NHCH3, -C(=O)NH2,

[0097] As a preferred technical solution, the compound of formula (I) has the following structure:

[0098] in,

[0099] R 7 R 9a R 10a and R 12a Independently, it is hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or deuterated C1-C6 alkoxy;

[0100] R 8 Independent for NR x R y 3-6 membered heterocyclic groups that are unsubstituted or substituted by one or more group C substituents; group C substituents include: halogens, amino groups, and C1-C6 alkyl groups; the 3-6 membered heterocyclic group contains 1-3 N heteroatoms;

[0101] R x R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl group, C1-C6 alkyl substituted with a C3-C6 cycloalkyl group, C3-C6 cycloalkyl group, or 4-6-membered heterocyclic group; the 5-membered heteroaryl group contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S;

[0102] Preferably,

[0103] R 7 R 9a R 10a and R 12a It can be hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, or deuterated C1-C6 alkyl independently;

[0104] R 8 Independent for NR x R y ;R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S;

[0105] Preferably,

[0106] R 7 It is a halogen;

[0107] R 9a R 10a and R 12a It can be hydrogen, deuterium, or halogen independently;

[0108] R 8 -NH2, -NHCH3,

[0109] Preferably,

[0110] R 7 It is chlorine;

[0111] R 9a R 10a and R 12a Independently hydrogen or deuterium;

[0112] R 8 -NH2, -NHCH3,

[0113] As a preferred technical solution, the compound of formula (I) has any of the following structures:

[0114] As a preferred technical solution, the compound of formula (I) has any of the following structures:

[0115] Enantiomer Under the following chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0116] Enantiomer In chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0117] Chiral separation conditions: Column: normal phase chiral column, stationary phase is spherical silica gel coated with amylose-tris(3,5-dimethylphenylcarbamate); mobile phase: mobile phase A is CO2, mobile phase B is an alcohol organic solvent.

[0118] Preferably, the chiral separation conditions are as follows: chromatographic column: ChiralPakAD-H; mobile phase: mobile phase A is CO2, mobile phase B is ethanol or 0.2% NH4OH isopropanol, and the volume ratio of mobile phase A to mobile phase B is (6-7):(4-3).

[0119] The temperature, flow rate, and pressure in the chiral separation conditions described are all conventional in the art.

[0120] As a preferred technical solution, the compound of formula (I) is any of the following specific compounds: or its racemic form;

[0121] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0122] Preferably, the enantiomers described above are compounds that elute at a retention time of 3.160 min or 3.600 min under the following chiral separation conditions 1;

[0123] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0124] Preferably, the enantiomers described above are compounds that elute at retention times of 2.333 min or 2.713 min under the following chiral separation conditions 2;

[0125] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0126] Preferably, the enantiomers described above are compounds that elute at retention times of 3.179 min or 3.918 min under the following chiral separation conditions 2;

[0127] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0128] Preferably, the enantiomers described above are compounds that elute at retention times of 3.055 min or 3.442 min under the following chiral separation conditions 2;

[0129] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0130] Preferably, the enantiomers described above are compounds that elute at retention times of 3.286 min or 2.906 min under the following chiral separation conditions 2;

[0131] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0132] Preferably, the enantiomers described above are compounds that elute at retention times of 2.785 min or 3.334 min under the following chiral separation conditions 2;

[0133] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0134] Preferably, the enantiomers described above are compounds that elute at retention times of 2.834 min or 3.332 min under the following chiral separation conditions 2;

[0135] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0136] Preferably, the enantiomers described above are compounds that elute at retention times of 2.686 min or 1.931 min under the following chiral separation conditions 1.

[0137] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0138] Preferably, the enantiomers described above are compounds that elute at retention times of 2.83 min and 3.58 min under the following chiral separation conditions 2;

[0139] Or, enantiomers Under the chiral separation conditions described above, the compound is either the first eluting compound, the second eluting compound, the third eluting compound, or the fourth eluting compound.

[0140] Preferably, the diastereomers mentioned above are compounds that elute at retention times of 3.34 min, 4.28 min, 4.82 min, or 6.11 min under chiral separation condition 3.

[0141] Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later;

[0142] Preferably, the enantiomers mentioned above are compounds that elute at retention times of 0.802 min or 1.34 min under chiral separation condition 2.

[0143] Chiral separation conditions 1: Column: ChiralPakAD-H; Mobile phase: Mobile phase A is CO2, mobile phase B is ethanol, mobile phase A: mobile phase B (volume ratio) = 60:40;

[0144] Chiral separation conditions 2: Column: ChiralPakAD-H; Mobile phase: Mobile phase A is CO2, mobile phase B is ethanol, mobile phase A: mobile phase B (volume ratio) = 70:30;

[0145] Chiral separation conditions 3: Column: ChiralPakAD-H; Mobile phase: Mobile phase A is CO2, mobile phase 0.2% NH4OH in isopropanol, mobile phase A:mobile phase B (volume ratio) = 40:60.

[0146] Those skilled in the art can obtain the aforementioned stereoisomers by selecting and adjusting the column chromatography conditions according to the above separation parameters. When using high-performance liquid chromatography (HPLC), the HPLC analysis conditions in the above detection parameters can be used, or other analytical conditions can be used, as long as the detection parameters of the obtained product are consistent with the above separation parameters. This invention also provides a method for preparing compounds of formula (I), their isotope labels, enantiomers, diastereomers, transisomers, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0147] (1) In the presence of a catalyst and / or a base, the compound shown in formula (I-1) is coupled with the compound shown in (I-1-A) to give the compound shown in formula (I-2).

[0148] (2) In the presence of acid, the compound shown in formula (I-2) undergoes a deprotection reaction to obtain the compound shown in formula (I-3);

[0149] (3) The compound shown in formula (I-3) is reduced in the presence of a reducing agent to obtain the compound shown in formula (I-4);

[0150] (4) In the presence of a base, the compound shown in formula (I-4) and the compound shown in formula (I-5) are reacted in a solvent to obtain the compound shown in formula (I').

[0151] Among them, Z and R 1 R 2 The definitions of X, W, m, n, and p are as described above; 10 It consists of boronic acid ester groups and phosphate ester groups, etc.; X 11 Halogen or trifluoromethanesulfonate group, borate group, borate group, zinc bromine group or tributyltin group, etc.

[0152] Preferably,

[0153] The catalyst mentioned in step (1) is a palladium catalyst, such as 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, etc.; the base can be an inorganic base (such as potassium carbonate, etc.) or an organic base (such as sodium tert-butoxide, etc.);

[0154] The acid mentioned in step (2) can be trifluoroacetic acid, etc.;

[0155] The reducing agent mentioned in step (3) is selected from sodium borate and sodium cyanoboroate, etc.;

[0156] In step (4), the base can be an inorganic base (such as sodium bicarbonate) or an organic base (such as N,N-diisopropylethylamine).

[0157] The present invention also provides a pharmaceutical composition comprising the compound shown in formula (I) above, its isotopic label, enantiomer, diastereomer, transisomer or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

[0158] In the composition described herein, the amount of the compound represented by formula (I), its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof may be an effective therapeutic amount.

[0159] The present invention also provides the use of the above-described compound of formula (I), its isotopic label, enantiomer, diastereomer, transisomer or pharmaceutically acceptable salt thereof in the preparation of NRF2 degradation or inhibitor drugs.

[0160] The drug is a drug used to treat and / or prevent diseases by activating KEAP1 to degrade or inhibit NRF2.

[0161] The present invention also provides the use of the above-described compound as shown in formula (I), its isotopic label, enantiomer, diastereomer, transisomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer.

[0162] Preferably, the cancer is esophageal cancer, head and neck cancer, or squamous cell carcinoma of the lung.

[0163] Preferably, the cancer is selected from cancers containing NRF2 / KEAP1 / CUL3 mutations and NRF2-dependent cancers, including but not limited to squamous cell carcinoma of the lung, adenocarcinoma of the lung, endometrial cancer, head and neck cancer, bladder cancer, cervical cancer, hepatobiliary cancer, and esophageal cancer.

[0164] The present invention also provides a method for treating and / or preventing cancer, which involves administering to a patient a therapeutically effective amount of the above-described compound as shown in formula (I), its isotopic label, enantiomer, diastereomer, transisomer, or a pharmaceutically acceptable salt thereof.

[0165] This invention also provides a compound of formula A:

[0166] Among them, R0 It is an amino protecting group (e.g., -Boc or -C(=O)CF3); Indicates a single or double bond; W, Z, and R 1 The definitions are the same as those described above.

[0167] The present invention also provides any of the following compounds:

[0168] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0169] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0170] The "-" at the end of a group indicates that the group is attached to the rest of the molecule through that site. For example, CH3-C(=O)- refers to an acetyl group.

[0171] exist In the diagram, the wavy line indicates the connection point between the group and other parts of the molecule.

[0172] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0173] The term "oxo" refers to the =O group, where an oxygen atom replaces two hydrogen atoms on the same carbon atom; that is, a carbonyl group replaces a methylene group.

[0174] The term "alkyl" refers to a straight-chain or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6, C2-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0175] The term "alkoxy" refers to the group R. X -O-,R X The definition is the same as the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0176] The term "alkenyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bond. Alkenyl groups include, but are not limited to: vinyl groups, wait.

[0177] The term "alkynyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6) and possessing one or more (e.g., 1, 2, or 3) carbon-carbon triple bonds. Alkenyl groups include, but are not limited to: ethynyl, wait.

[0178] The term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-C6), which can be monocyclic, bridged, or spirocyclic. Cycloalkyl groups include, but are not limited to: wait.

[0179] The term "cycloalkenyl" refers to an alicyclic hydrocarbon group having one, two, or three double bonds and a specified number of carbon atoms (e.g., C3-C12, C3-C8, C3-C6). Cycloalkyl groups include, but are not limited to: wait.

[0180] The term "cycloalkoxy" refers to the group R Y -O-,R Y The definition is the same as the term "cycloalkyl". Cycloalkoxy groups include, but are not limited to, cyclopropoxy groups.

[0181] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 10 Aryl groups are cyclic, unsaturated monovalent hydrocarbon groups, which can be monocyclic or polycyclic (e.g., two or three). When polycyclic, the monocyclic rings share two atoms and one bond, and each ring is aromatic. Aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0182] In this invention, the term "heterocyclic group" refers to a non-aromatic cyclic group comprising at least one carbon atom and at least one (e.g., 1-3) cyclic heteroatoms selected from N, O, and S, wherein the sulfur atom may optionally be oxidized or amination. Examples of "heterocyclic groups" specifically include cycloalkyl groups in which one or more cyclic carbons are selected from -O-, -N=, -NR-, -S-, -S(=O)-, and -S(=O)2-, as defined in this invention. The group formed by partial substitution, wherein R is hydrogen, C is C 1-4 Alkyl, C 3-6Cycloalkyl or nitrogen-protected groups (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). "Heterocyclic groups" include monocyclic and fused rings, bridged rings, spirocyclic, and other bicyclic structures, and may be partially or completely saturated, such as 4-10 membered saturated or unsaturated heterocyclic groups, 4-6 membered saturated or unsaturated heterocyclic groups, 3-8 membered heterocyclic groups, 3-6 membered heterocyclic groups, etc.; such as tetrahydrofuranyl, pyrrolidinyl, oxetyl, oxetylhexyl, aziridine, ethylene oxide, aziridinyl, thioheterocyclic, 1,2-dithioheterocyclic, 1,3-dithioheterocyclic, azirheptanyl, oxetylheptanyl, etc. For example, the heterocyclic groups described in this invention may preferably be selected from the following groups:

[0183] In this invention, the term "heteroaryl" refers to a monocyclic, bicyclic, or fused polycyclic cyclic aromatic hydrocarbon group having a specified number of ring atoms (e.g., 5-10), which contains at least one (e.g., 1-3) cyclic heteroatoms independently selected from N, O, and S (e.g., N), with the remaining ring atoms being carbon atoms; such as imidazolyl, pyridinyl, pyrrololyl, thiazolyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophene, pyrimidinyl, 1,2,4-triazolyl, benzoxazolyl, imidazopyridyl, triazolylpyridinyl, benzofuranyl, pyrazolylpyrimidinyl, benzo-m-dioxacyclopentenyl, indolyl, quinolinyl, isoquinolinyl, etc.

[0184] The term “heteroary ring” satisfies at least one of the following conditions, and the rest are defined the same as the term “heteroaryl”: 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0185] The term "isotope-labeled compound" refers to an isotope-labeled compound in which one or more atoms, compared to a compound of formula (I), are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 32 P, 35 S, 18 F and 36Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, and their pharmaceutically acceptable salts. Certain isotopically labeled compounds of the present invention, such as those doped with radioactive isotopes (e.g., ... 3 H and 14 Compounds in (C) can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium, i.e., 2 Hydrogen (H or D) substitution can provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain circumstances. The compounds of the present invention may be specifically defined as being substituted with deuterium or tritium. Furthermore, the presence of hydrogen in the substituents without a separate mention of the terms deuterium or tritium does not exclude deuterium or tritium, but may also include deuterium or tritium.

[0186] The term "therapeutic effective dose" refers to the amount given to a patient that is sufficient to effectively treat the disease. Therapeutic effective doses will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0187] The term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0188] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0189] The term "prevention" refers to reducing the risk of developing a disease.

[0190] The term "patient" refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0191] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0192] The reagents and raw materials used in this invention are all commercially available.

[0193] The positive and progressive effects of this invention are that the compounds of this invention have better degradation or inhibition activity against NRF2. Attached Figure Description

[0194] Figure 1 shows the X-ray single-crystal diffraction pattern of compound Cpd-1;

[0195] Figure 2 shows the tumor growth curves of the control group and each experimental group in the pharmacodynamic evaluation experiment of the mouse KYSE-70 human esophageal cancer xenograft model.

[0196] Figure 3 shows the body weight change curves of mice in the control group and each experimental group in the pharmacodynamic evaluation experiment of the mouse KYSE-70 human esophageal cancer xenograft model.

[0197] Figure 4 shows the tumor growth curves of the control group and each experimental group in the pharmacodynamic evaluation experiment of the mouse HCC95 human lung cancer xenograft model.

[0198] This represents a tumor growth curve for "Vehicle Control, PO, QD x 35 days, n = 6".

[0199] The tumor growth curve represents "Nab-Paclitaxel, 7.5 mg / kg, IV, QW x 5 weeks, n = 6".

[0200] This represents the tumor growth curve for "Ref. 1, 5 mg / kg, PO, QD x 35 days, n = 6".

[0201] This represents a tumor growth curve for a treatment regimen of "Cpd-1, 5 mg / kg, PO, QD x 35 days, n = 6".

[0202] This represents a tumor growth curve for "Cpd-8, 5mg / kg, PO, QD x 35 days, n=6".

[0203] The tumor growth curve represents the treatment regimen of "Ref. 1, 5 mg / kg, PO, QD x 35 days + Nab-Paclitaxel, 7.5 mg / kg, IVQW x 5 weeks, n = 6".

[0204] The tumor growth curve represents the treatment regimen of "Cpd-1, 5mg / kg, PO, QD x 35 days + Nab-Paclitaxel, 7.5mg / kg, IV, QW x 5 weeks, n = 6".

[0205] The tumor growth curve represents “Cpd-8, 5mg / kg, PO, QD x 35 days + Nab-Paclitaxel, 7.5mg / kg, IV, QW x 5 weeks, n=6”.

[0206] Figure 5 shows the body weight changes of mice in the control group and each experimental group during the pharmacodynamic evaluation experiment of the mouse HCC95 human lung cancer xenograft model.

[0207] This represents the weight change curve for "Vehicle Control, PO, QD x 35 days, n = 6".

[0208] The weight change curve represents "Nab-Paclitaxel, 7.5mg / kg, IV, QW x 5 weeks, n=6".

[0209] This represents the weight change curve for "Ref. 1, 5 mg / kg, PO, QD x 35 days, n = 6".

[0210] This represents the weight change curve for "Cpd-1, 5mg / kg, PO, QD x 35 days, n=6".

[0211] This represents the weight change curve for "Cpd-8, 5mg / kg, PO, QD x 35 days, n=6".

[0212] This represents the weight change curve for "Ref. 1, 5mg / kg, PO, QD x 35 days + Nab-Paclitaxel, 7.5mg / kg, IVQW x 5 weeks, n=6".

[0213] This represents the weight change curve for the patient who underwent a treatment regimen of "Cpd-1, 5 mg / kg, PO, QD x 35 days + Nab-Paclitaxel, 7.5 mg / kg, IV, QW x 5 weeks, n = 6".

[0214] The weight change curve represents the following: “Cpd-8, 5mg / kg, PO, QD x 35 days + Nab-Paclitaxel, 7.5mg / kg, IV, QW x 5 weeks, n=6”. Detailed Implementation

[0215] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0216] In each embodiment, 1 H NMR was recorded using a BRUKER AVANCE NEO 400MHz JNM-ECZ400s NMR spectrometer, and chemical shifts are expressed as δ (ppm). Liquid chromatography-mass spectrometry (LC-MS) was recorded using a Shimadzu LC-20AD Agilent 1260 mass spectrometer. Preparative HPLC separation was performed using a WATERS2545 Shimadzu LP-20AP liquid chromatograph.

[0217] The following abbreviations may be used in the following experimental descriptions:

[0218] Boc2O: ditert-butyl dicarbonate; DMAP: 4-dimethylaminopyridine; THF: tetrahydrofuran; NaHMDS: sodium bis(trimethylsilyl)amino; Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene palladium chloride; DMF: N,N-dimethylformamide; DCM: dichloromethane; TFA: trifluoroacetic acid; Pd(PPh3)4: tetra(triphenylphosphine)palladium.

[0219] Single-crystal diffraction testing methods and conditions:

[0220] Testing instrument: D8 Venture; Instrument model: D8 Venture

[0221] Instrument parameters:

[0222] Structural analysis and refinement process:

[0223] After integrating and restoring the diffraction data using the SAINT program, the data were empirically absorbed and corrected using the SADABS program. The single crystal structure was analyzed using the SHELXT2014 direct method, and the structure was refined using the least squares method. The hydrogen atom refinement process was obtained by isotropic calculation. The hydrogen atoms on N and O were obtained by residual electron density, and the hydrogen atoms on CH were obtained by calculated hydrogen addition. The structure was then refined using a riding model.

[0224] Preparation of intermediate compound Int-1

[0225] Step 1: 3-O-morpholine-4-carboxylic acid tert-butyl ester

[0226] Morpholin-3-one (50 g, 495 mmol) was dissolved in acetonitrile (500 mL), and then 4-dimethylaminopyridine (6.04 g, 49.5 mmol), triethylamine (214 mL, 1.48 mol), and di-tert-butyl dicarbonate (125 mL, 544 mmol) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was quenched with water (1 L) and extracted with ethyl acetate (500 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–30%) to give tert-butyl 3-oxomorpholino-4-carboxylic acid (83 g, yield: 83.4%). LCMS calculated value (calc.for) C9H 16 NO4[M+H] + m / z = 202.1; Found value: 102.1 [M+H-C5H8O2] + .

[0227] Step 2: tert-butyl 5-((diphenoxyphospho)oxo)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester

[0228] 3-O-morpholine-4-carboxylic acid tert-butyl ester (83 g, 412 mmol) was dissolved in tetrahydrofuran (500 mL). Sodium di(trimethylsilyl)aminoacetic acid (247 mL, 2.0 mol / L, 494 mmol) was slowly added at -30 °C. The reaction mixture was stirred at -30 °C for 30 minutes. Then, diphenyl chlorophosphate (122 g, 454 mmol) was added to the reaction mixture, and the reaction was continued with stirring for 1 hour. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride solution (600 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–30%) to give tert-butyl 5-((diphenoxyphospho)oxo)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (113 g, yield: 63.2%). LCMS calculated value (calc.for) C 21 H 25 NO7P[M+H] + m / z = 434.1; Found value: 333.8 [M+H-C5H8O2] + .

[0229] Step 3: Tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester

[0230] 10 g (23.1 mmol) of tert-butyl 5-((diphenoxyphospho)oxo)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester was dissolved in dioxane (150 mL). Dipinacol boronic acid ester (7.03 g, 27.7 mmol), tetrakis(triphenylphosphine)palladium (2.67 g, 2.31 mmol), and potassium tert-pentanoate (4.85 g, 34.6 mmol) were added to the reaction solution. The mixture was purged with argon three times, heated to 100 °C, and stirred for 16 hours. After the reaction was complete, water (300 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–10%) to give tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (3.2 g, yield: 44.6%). LCMS calculated value (calc.for) C 15 H 27 BNO5[M+H] + m / z = 312.2; Found value: 256.1 [M+H-C4H8] + .1H NMR (400MHz, CDCl3) δ6.30 (s, 1H), 4.07 (t, J = 4.4Hz, 2H), 3.61 (t, J = 4.4Hz, 2H), 1.48 (s, 9H), 1.29 (s, 12H).

[0231] Preparation of intermediate compound Int-2

[0232] Step 1: (4-Bromo-2-chloro-6-nitrophenyl)glycine ethyl ester

[0233] Potassium carbonate (21.7 g, 157 mmol) was added to a solution of 5-bromo-1-chloro-2-fluoro-3-nitrobenzene (20.0 g, 78.6 mmol) and glycine ethyl ester (16.2 g, 157 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was then stirred at 80 °C for 3 hours. After the reaction was complete, the reaction solution was cooled, quenched with water (300 mL), and the aqueous phase was extracted twice with ethyl acetate (150 mL). The combined organic phases were washed successively with water (200 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–10%) to obtain (4-bromo-2-chloro-6-nitrophenyl)glycine ethyl ester (26.0 g, yield: 98.0%). 1H NMR (400MHz, CDCl3) δ8.09 (d, J = 2.4Hz, 1H), 7.65 (d, J = 2.4Hz, 1H), 7.24 (s, 1H), 4.22 (q, J = 7.2Hz, 2H), 4.16 (s, 2H), 1.27 (t, J = 7.2Hz, 3H).

[0234] Step 2: 7-Bromo-5-chloro-3,4-dihydroquinoxaline-2(1H)-one

[0235] Ethyl (4-bromo-2-chloro-6-nitrophenyl)glycine (25.0 g, 74.1 mmol) and ammonium chloride (19.8 g, 370 mmol) were added to ethanol (200 mL) and water (40 mL), followed by the addition of iron powder (20.7 g, 370 mmol). The reaction mixture was stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a Buchner funnel lined with diatomaceous earth. The filter cake was washed with ethyl acetate (3.0 L), and the filtrates were combined and concentrated to give 7-bromo-5-chloro-3,4-dihydroquinoxalin-2(1H)-one (15.0 g, yield: 77.5%). LCMS calculated value (calc. for): C8H7BrClN2O[M+H] + m / z = 260.9 / 262.9; Found value: 260.9 / 262.9.

[0236] Step 3: 7-Bromo-5-chloroquinoxaline-2(1H)-one

[0237] Manganese dioxide (4.99 g, 57.4 mmol) was added to a solution of 3.0 g (11.5 mmol) of 7-bromo-5-chloro-3,4-dihydroquinoxalin-2(1H)-one in 30 mL of dioxane. The reaction mixture was then stirred at 80 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered through a Buchner funnel lined with diatomaceous earth. The filter cake was washed with ethyl acetate (500 mL), and the filtrates were combined and concentrated to give 7-bromo-5-chloroquinoxalin-2(1H)-one (2.0 g, yield: 672%). LCMS calculated value (calc. for): C8H5BrClN2O[M+H + m / z = 258.9 / 260.9; Found value: 258.9 / 260.9.

[0238] Step 4: 7-Bromo-2,5-Dichloroquinoline

[0239] A solution of 7-bromo-5-chloroquinoxaline-2(1H)-one (2.5 g, 9.63 mmol) and N,N-diisopropylethylamine (2.49 g, 19.3 mmol) in acetonitrile (30 mL) was added, and phosphorus oxychloride (1.35 mL, 14.5 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to 20 °C, poured into 100 mL of water, and filtered. The solid collected by filtration was dried under reduced pressure to give 7-bromo-2,5-dichloroquinoxaline (2.0 g, yield: 74.7%). 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 8.33-8.36 (m, 2H).

[0240] Preparation of intermediate compound Int-3

[0241] Step 1: (4-Bromo-2-chloro-6-nitrophenyl)glycine ethyl ester

[0242] Potassium carbonate (21.7 g, 157 mmol) was added to a solution of 5-bromo-1-chloro-2-fluoro-3-nitrobenzene (20.0 g, 78.6 mmol) and glycine ethyl ester hydrochloride (16.5 g, 118 mmol) in acetonitrile (100 mL). The reaction mixture was stirred at 80 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (300 mL), and the aqueous phase was extracted twice with ethyl acetate (150 mL). The combined organic phases were washed successively with water (200 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–10%) to give (4-bromo-2-chloro-6-nitrophenyl)glycine ethyl ester (25.0 g, yield: 94%). LCMS calculated value (calc.for) C 10 H 11 BrClN2O4[M+H] + m / z = 337.0 / 339.0; Found value: 336.9 / 338.9.

[0243] Step 2: (2-chloro-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)glycine ethyl ester

[0244] Under a nitrogen atmosphere, ethyl (4-bromo-2-chloro-6-nitrophenyl)glycine (25 g, 74.1 mmol), pinacol diboronate (22.57 g, 88.9 mmol), and potassium acetate (21.8 g, 222 mmol) were dissolved in dioxane (250 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (2.71 g, 3.70 mmol) was added. The mixture was reacted at 90 °C for 2 hours. After the reaction was complete, water (300 mL) was added to quench the reaction, and the aqueous phase was extracted three times with ethyl acetate (300 mL). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl glycine (28 g, crude product, a mixture of boric acid and borate esters), which was used directly in the next step. LCMS calculated value (calc.for) C 16 H 23 BClN2O6[M+H] + m / z = 385.1; Found value: 385.1.

[0245] Step 3: tert-butyl 5-(3-chloro-4-((2-ethoxy-2-carbonylethyl)amino)-5-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester

[0246] Under a nitrogen atmosphere, ethyl glycine (28 g, 72.8 mmol), tert-butyl-5-((diphenoxyphospho)oxo)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (22.1 g, 51.0 mmol), and potassium phosphate (49.2 g, 146 mmol) were dissolved in dioxane (360 mL) and water (73 mL), followed by the addition of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (2.66 g, 3.64 mmol), and the reaction was carried out at 90 °C for 2 hours. After the reaction was completed, the mixture was quenched with water (300 mL) and extracted three times with dichloromethane (300 mL). The combined organic phases were washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0%–10%) to give tert-butyl 5-(3-chloro-4-((2-ethoxy-2-carbonylethyl)amino)-5-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (14 g, two-step yield: 42.8%). LCMS calculated value (calc.for) C 19 H 25 ClN3O7[M+H] +m / z = 442.1; Found value: 442.0.

[0247] Step 4: (2-chloro-4-(5,6-dihydro-2H-1,4-oxazin-3-yl)-6-nitrophenyl)glycine ethyl ester

[0248] Under a nitrogen atmosphere, tert-butyl 5-(3-chloro-4-((2-ethoxy-2-carbonylethyl)amino)-5-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (14 g, 31.7 mmol) was dissolved in dichloromethane (120 mL), cooled to 0 °C, and then trifluoroacetic acid (30 mL) was added. The mixture was then brought to room temperature and reacted for 2 hours at room temperature. The reaction solution was used directly in the next step. LCMS calculated value (calc.for) C 14 H 17 ClN3O5[M+H] + m / z = 342.1; Found value: 360.0 [M+H+18] + .

[0249] Step 5: (2-chloro-4-(morpholin-3-yl)-6-nitrophenyl)glycine ethyl ester

[0250] Cool the reaction solution from the previous step to 0°C, then add sodium cyanoborohydride (3.99 g, 63.3 mmol), and raise the temperature to room temperature. React at room temperature for 2 hours. Cool to 0°C, adjust the pH to 8 with 200 mL of saturated sodium bicarbonate solution, and use the reaction solution directly in the next step. LCMS calculated value (calc.for) C 14 H 19 ClN3O5[M+H] + m / z = 344.1; Found value: 344.1.

[0251] Step Six: Tert-Butyl 3-(3-chloro-4-((2-ethoxy-2-carbonylethyl)amino)-5-nitrophenyl)morpholine-4-carboxylic acid ester

[0252] Under a nitrogen atmosphere, the reaction solution from the previous step was cooled to 0°C, and then di-tert-butyl dicarbonate (5.70 g, 26.2 mmol) was added. The mixture was then brought to room temperature and reacted for 16 h at room temperature. The mixture was extracted three times with dichloromethane (100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0%–10%) to give tert-butyl-3-(3-chloro-4-((2-ethoxy-2-carbonylethyl)amino)-5-nitrophenyl)morpholine-4-carboxylic acid ester (7.7 g, three-step yield: 54.7%). LCMS calculated value (calc.for) C 19 H 27 ClN3O7[M+H] + m / z = 444.2; Found value: 444.1.

[0253] Step 7: tert-butyl 3-(8-chloro-3-carbonyl-1,2,3,4-tetrahydroquinoxalo-6-yl)morpholine-4-carboxylic acid ester

[0254] 7.7 g (17.3 mmol) of tert-butyl 3-(3-chloro-4-((2-ethoxy-2-carbonylethyl)amino)-5-nitrophenyl)morpholine-4-carboxylic acid ester and 4.63 g (86.7 mmol) of ammonium chloride were added to 80 mL of ethanol and 15 mL of water. Then, iron powder (4.85 g (86.7 mmol) was added to the reaction solution and the mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the solution was concentrated and then N,N-dimethylformamide (100 mL) was added. The mixture was stirred for 1 hour and filtered through a funnel lined with diatomaceous earth. The filter cake was washed with N,N-dimethylformamide (20 mL). The filtrates were combined and water (150 mL) was added. A solid precipitated out. The solid was filtered and the filter cake was collected. The cake was dried under vacuum to give tert-butyl 3-(8-chloro-3-carbonyl-1,2,3,4-tetrahydroquinoxaloline-6-yl)morpholine-4-carboxylic acid ester (5.2 g, yield: 83.9%). LCMS calculated value (calc.for) C 17 H 23 ClN3O4[M+H] + m / z = 368.1; Found value: 312.0 [M+H-C4H8] + .

[0255] Step 8: tert-butyl 3-(8-chloro-3-carbonyl-3,4-dihydroquinoxaloline-6-yl)morpholine-4-carboxylic acid ester

[0256] To a solution of tert-butyl 3-(8-chloro-3-carbonyl-1,2,3,4-tetrahydroquinoxaloline-6-yl)morpholine-4-carboxylic acid ester (5.2 g, 14.1 mmol) in dioxane (40 mL) and tetrahydrofuran (40 mL), manganese dioxide (6.15 g, 70.7 mmol) was added. The reaction mixture was stirred at 80 °C for 4 hours. After cooling to room temperature, the mixture was filtered through a funnel lined with diatomaceous earth, and the filtrates were combined and concentrated. After collecting the filter cake, N,N-dimethylformamide (50 mL) was added, and the mixture was stirred for 1 hour. The mixture was then filtered through a funnel lined with diatomaceous earth. The filter cake was washed with N,N-dimethylformamide (10 mL), and the filtrates were combined. Water (100 mL) was added, and a solid precipitated. The solid was filtered, and the filter cake was collected and dried under vacuum to obtain tert-butyl 3-(8-chloro-3-carbonyl-3,4-dihydroquinoxaloline-6-yl)morpholine-4-carboxylic acid ester (4.0 g, yield: 76.9%). LCMS calculated value (calc.for) C 17 H 21 ClN3O4[M+H] + m / z = 366.1; Found value: 366.1.

[0257] Step 9: tert-butyl-3-(3,8-dichloroquinoxalo-6-yl)morpholine-4-carboxylic acid ester

[0258] 0.8 g (2.18 mmol) of tert-butyl 3-(8-chloro-3-carbonyl-3,4-dihydroquinoxalin-6-yl)morpholine-4-carboxylic acid ester and N,N-diisopropylethylamine (1.41 g, 10.9 mmol) were dissolved in acetonitrile (10 mL), and then phosphorus oxychloride (1.67 g, 10.9 mmol) was added. The mixture was stirred at 80 °C for 4 hours. After cooling to room temperature, the residue was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0%–20%) to tert-butyl 3-(3,8-dichloroquinoxalin-6-yl)morpholine-4-carboxylic acid ester (0.3 g, yield: 47.7%). LCMS calculated value (calc.for) C 17 H 20 Cl2N3O3[M+H] + m / z = 384.1; Found value: 384.0 1 H NMR(400MHz, DMSO-d6)δ9.10(s,1H),8.06(d,J=1.7Hz,1H),7.90(s,1H),5.22(s,1H),4.42(d,J=12.4 Hz,1H),3.91-3.80(m,2H),3.76(d,J=12.0Hz,1H),3.57-3.49(m,1H),3.16-3.06(m,1H),1.41(s,9H).

[0259] Preparation of intermediate compound Int-4

[0260] Step 1: (2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine ethyl ester

[0261] At 0 °C, trifluoroacetic anhydride (13.6 mL, 97.6 mmol) was added dropwise to a solution of (2-chloro-4-(morpholin-3-yl)-6-nitrophenyl)glycine ethyl ester (30.5 g, 88.7 mmol) and triethylamine (25.7 mL, 177 mmol) in dichloromethane (300 mL). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was poured into water (500 mL) and extracted with dichloromethane (200 mL x 2). The combined organic layers were washed with water (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine ethyl ester (46.6 g, crude product). LCMS calculated value (calc.for) C 16 H 18 ClF3N3O6[M+H] + m / z = 440.1; Found value: 440.0.

[0262] Step 2: 5-Chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one

[0263] At room temperature, iron powder (13.0 g, 232 mmol), ammonium chloride (12.4 g, 232 mmol), and water (50 mL) were added to an ethanol (200 mL) solution of (2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine ethyl ester (46.6 g, crude) in ethanol (200 mL). The reaction solution was stirred at 80 °C for 2 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with ethyl acetate (400 mL), filtered through diatomaceous earth, and washed with ethyl acetate (300 mL). The resulting organic phase was washed with water (300 mL x 2), dried, and concentrated to give 5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one (41.0 g, crude). LCMS calculated value (calc.for) C 14 H 14 ClF3N3O3[M+H] + m / z = 364.1; Found value: 363.9.

[0264] Step 3: 5-Chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-2(1H)-one

[0265] At room temperature, activated manganese dioxide (33.5 g, 385 mmol) was added to a 1,4-dioxane (300 mL) solution of 5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one (41.0 g, crude) in 1,4-dioxane. The reaction solution was stirred at 80 °C for 2 hours. After the reaction was complete, the solution was cooled to room temperature and diluted with ethyl acetate (300 mL). The reaction solution was filtered through diatomaceous earth, and the resulting organic phase was dried and concentrated to give 5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-2(1H)-one (40.8 g, crude). LCMS calculated value (calc.for) C 14 H 12 ClF3N3O3[M+H] + m / z = 362.0; Found value: 361.9.

[0266] Step 4: 1-(3-(3,8-dichloroquinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one

[0267] At room temperature, phosphorus oxychloride (21.5 mL, 231 mmol), N,N-diisopropylethylamine (26.7 mL, 153 mmol), and N,N-dimethylformamide (3.0 mL) were added to a solution of 40.8 g crude 5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxaline-2(1H)-one in acetonitrile (300 mL). The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction mixture was quenched in a saturated aqueous solution of sodium bicarbonate (300 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with water (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0%–30%) to give 1-(3-(3,8-dichloroquinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (17.5 g, total yield of four steps: 49.0%). LCMS calculated value (calc.for) C 14 H 11 Cl2F3N3O2[M+H] + m / z = 380.0; Found value: 379.9. 1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.09-8.03(m,1H),8.01-7.97(m,1H),5.73-5.64(m,1H),4.62 (d,J=12.7Hz,1H),4.04-3.94(m,2H),3.78(d,J=14.0Hz,1H),3.71-3.65(m,1H),3.56-3.43(m,1H).

[0268] Example 1: Preparation of compounds Cpd-1 and Cpd-1A

[0269] Step 1: 7-Bromo-5-chloro-N-methylquinoxaloline-2-amine

[0270] At room temperature, an aqueous solution of methylamine (2.5 mL, 30% aqueous solution) was added to a solution of 7-bromo-2,5-dichloroquinoxaline (1.1 g, 3.96 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted twice with ethyl acetate (30 mL). The resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 7-bromo-5-chloro-N-methylquinoxaline-2-amine (1.01 g, yield: 93.6%). LCMS calculated value (calc. for) C9H8BrClN3[M+H + m / z = 271.9 / 273.9; Found value: 271.9 / 273.9.

[0271] Step 2: tert-butyl 5-(8-chloro-3-(methylamino)quinoxaloline-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester

[0272] At room temperature, tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (2.51 g, 8.07 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (295 mg, 0.4 mmol), potassium carbonate (1.67 g, 12.1 mmol), and water (0.25 mL) were added to a 1,4-dioxane (10 mL) solution of 7-bromo-5-chloro-N-methylquinoxaline-2-amine (1.1 g, 4.04 mmol). The reaction mixture was stirred at 100 °C under an argon atmosphere for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30%) to give tert-butyl 5-(8-chloro-3-(methylamino)quinoxaloline-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (710 mg, yield: 46.7%). LCMS calculated values ​​(calc.for) C 18 H 22 ClN4O3[M+H] + m / z = 377.1; Found value: 377.0.

[0273] Step 3: 5-Chloro-N-methyl-7-(morpholin-3-yl)quinoxaline-2-amine

[0274] At room temperature, trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl 5-(8-chloro-3-(methylamino)quinoxaloline-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (710 mg, 1.88 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was concentrated under vacuum at 30 °C. The residue was diluted with methanol (10 mL). Sodium borohydride (356 mg, 9.42 mmol) was added to the reaction mixture at room temperature. The mixture was stirred at room temperature for 10 minutes. After the reaction was complete, the mixture was quenched in a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted twice with dichloromethane (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-8%) to give 5-chloro-N-methyl-7-(morpholin-3-yl)quinoxalin-2-amine (130 mg, yield: 24.8%). LCMS calculated value (calc.for) C 13 H 16 ClN4O[M+H] + m / z = 279.1; Found value: 279.1.

[0275] Step 4: 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0276] At room temperature, saturated sodium bicarbonate aqueous solution (2.5 mL) was added to a tetrahydrofuran (10 mL) solution of 5-chloro-N-methyl-7-(morpholin-3-yl)quinoxaline-2-amine (130 mg, 0.47 mmol). Acryloyl chloride (42.2 mg, 0.47 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was quenched in water (50 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by high-performance liquid chromatography (HPLC): (column: SHIMADZU Prep C18, 10μm, 20*250mm; mobile phase: A (0.1% FA in H2O), B (ACN)); to obtain 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one (30 mg, yield: 19.3%). LCMS calculated value (calc.for) C 16 H 18 ClN4O2[M+H] + m / z = 333.1; Found value: 333.2.

[0277] Step 5: (R)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0278] 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one (30 mg, 0.09 mmol) was prepared chirally (Column: ChiralPak AD-H 250*30mm ID, 5 μm; Mobile phase A: supercritical CO2, Mobile phase B: EtOH; A:B = 70:30 at 50 mL / min; Column Temp: 38℃; Nozzle Pressure: 100 Bar; Wavelength: 220 nm) to (R)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one (8.4 mg, yield: 28.2%, retention time: 2.798 min). LCMS calculated values ​​(calc. for) C 16 H 18 ClN4O2[M+H] + m / z = 333.1; Found value: 333.2.1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.02-7.77(m,1H),7.62-7.17(m,2H),7.00-6.75 (m,1H),6.40-6.10(m,1H),5.90-5.71(m,1H),5.72-5.25(m,1H),4.50(d,J=12.3Hz,1 H), 4.36–3.74 (m, 3H), 3.59–3.43 (m, 1H), 3.32–3.10 (m, 1H), 2.92 (d, J = 4.8 Hz, 3H). (S)-1-(3-(8-chloro-3-(methylamino)quinoxalo-6-yl)morpholino)prop-2-en-1-one (11.9 mg, yield: 39.7%, retention time: 3.351 min). LCMS calculated value (calc. for) C 16 H 18 ClN4O2[M+H] + m / z = 333.1; Found value: 333.2. 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.97-7.78(m,1H),7.58-7.24(m,2H),6.97-6.74(m,1H),6.32-6.17(m,1H),5.78(d,J=10.4Hz, 1H),5.72-5.27(m,1H),4.50(d,J=12.3Hz,1H),4.39-3.72(m,3H),3.52(t,J=11.5Hz,1H),3.30-3.11(m,1H),2.91(d,J=4.7Hz,3H).

[0279] At room temperature, compound Cpd-1 (30 mg, 0.03 mmol) was placed in a 1.5 mL liquid chromatography vial, dissolved in 0.5 mL acetonitrile and 0.5 mL water, and then allowed to stand at room temperature for 4 days to precipitate crystals. In X-ray single-crystal diffraction, the Flack constant of compound Cpd-1 was 0.028 (15), and C7 was the R configuration. The X-ray single-crystal diffraction pattern is shown in Figure 1.

[0280] Example 2 Preparation of compounds Cpd-2 and Cpd-2A

[0281] Note: "or 1" in the structural formulas Cpd-2 and Cpd-2A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0282] Step 1: 7-Bromo-5-chloroquinoxaline-2-amine

[0283] A solution of 7-bromo-5-chloroquinoxaline-2(1H)-one (2.5 g, 9.63 mmol) and N,N-diisopropylethylamine (2.49 g, 19.3 mmol) dissolved in acetonitrile (30 mL) was added, and phosphorus oxychloride (1.35 mL, 14.5 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to 20 °C, poured into 100 mL of water, and filtered. The solid collected by filtration was dried under reduced pressure to give 7-bromo-2,5-dichloroquinoxaline (2.0 g, crude product). 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 8.33-8.36 (m, 2H).

[0284] 7-Bromo-2,5-dichloroquinoxaline (2.0 g, crude product) was added to dioxane (30 mL) and concentrated ammonia (10 mL, 30% aqueous solution), and heated at 120 °C for 3 hours in a sealed tube. The reaction solution was cooled to 20 °C, concentrated under reduced pressure, and the residue was poured into 100 mL of water. The mixture was filtered, and the solid was collected and dried under reduced pressure to give 7-bromo-5-chloroquinoxaline-2-amine (1.8 g, two-step yield: 74.7%). LCMS calculated value (calc. for): C8H6BrClN3[M+H + m / z = 257.9 / 259.9; Found value: 257.6 / 260.0

[0285] Step 2: 5-(3-amino-8-chloroquinoxalin-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester

[0286] 7-Bromo-5-chloroquinoxalin-2-amine (1.0 g, 3.87 mmol), potassium carbonate (1.6 g, 11.6 mmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester (2.4 g, 7.74 mmol) were dissolved in a solution of dioxane (10 mL). 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (280 mg, 0.39 mmol) and water (2.0 mL) were added. The reaction mixture was stirred at 100 °C under an argon atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure after cooling, and the residual oil was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30%) to give 5-(3-amino-8-chloroquinoxalin-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester (0.5 g, yield: 35.6%). LCMS calculated value (calc.for) C 17 H 20 ClN4O3[M+H]+ m / z = 363.1; Found value: 363.1

[0287] Step 3: 5-Chloro-7-(5,6-dihydro-2H-1,4-oxazin-3-yl)quinoxaloline-2-amine

[0288] 100 mg (0.27 mmol) of 5-(3-amino-8-chloroquinoxalin-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester was dissolved in 3.0 mL of dichloromethane, and 3.0 mL of trifluoroacetic acid was added. The reaction mixture was stirred at 20 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to give 400 mg (crude product) of 5-chloro-7-(5,6-dihydro-2H-1,4-oxazine-3-yl)quinoxalin-2-amine. LCMS calculated value (calc.for) C 12 H 12 ClN4O[M+H] + m / z = 263.1; Found value: 263.1

[0289] Step 4: 5-Chloro-7-(morpholin-3-yl)quinoxaline-2-amine

[0290] 5-Chloro-7-(5,6-dihydro-2H-1,4-oxazin-3-yl)quinoxaloline-2-amine (300 mg, 1.14 mmol) was dissolved in methanol (8.0 mL), and sodium borohydride (216 mg, 5.71 mmol) was added. The reaction mixture was stirred at 20 °C for 2 hours. After quenching with saturated sodium bicarbonate solution (10 mL), the aqueous phase was extracted twice with dichloromethane (10 mL). The combined organic phases were washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. Purification by silica gel column chromatography (dichloromethane:methanol = 0-20%) yielded 5-chloro-7-(morpholin-3-yl)quinoxaloline-2-amine (70.2 mg, yield: 23.2%). LCMS calculated value (calc.for) C 12 H 14 ClN4O[M+H] + m / z = 265.1; Found value: 265.1

[0291] Step 5: (R)-1-(3-(3-amino-8-chloroquinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(3-amino-8-chloroquinoxalin-6-yl)morpholino)prop-2-en-1-one

[0292] 5-Chloro-7-(morpholin-3-yl)quinoxaline-2-amine (70.0 mg, 0.26 mmol) was dissolved in a solution of tetrahydrofuran (5.0 mL), and saturated sodium bicarbonate aqueous solution (2.0 mL) and acryloyl chloride (24.0 mg, 0.26 mmol) were added. The reaction solution was stirred at 20 °C for 0.3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 0-10%) and SFC chromatography (column: ChiralPakAD-H 250*30mm ID, 5μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 60:40 at 50mL / min; column temperature: 38℃; pressure (nozzle pressure): 100Bar; wavelength: 220nm) to obtain (R)-1-(3-(3-amino-8-chloroquinoxolin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(3-amino-8-chloroquinoxolin-6-yl)morpholino)prop-2-en-1-one).

[0293] Cpd-2: 9.8 mg, yield: 11.2%, retention time: 3.160 min. LCMS calculated value (calc.for) C 15 H 16 ClN4O2[M+H] + m / z = 319.1; Found value: 319.3 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.44(d,J=1.9Hz,1H),7.36(s,1H),7.21(s,2H),6.99-6.79(m,1H),6.24(dd,J=16.6 ,2.3Hz,1H),5.77(d,J=10.5Hz,1H),5.60-5.30(m,1H),4.48(d,J=12.3Hz,1H),4.25-3.75(m,4H),3.52(t,J=11.6Hz,1H).

[0294] Cpd-2A: 11.0 mg, yield: 12.4%, retention time: 3.600 min. LCMS calculated value (calc.for) C 15 H 16 ClN4O2[M+H] + m / z = 319.1; Found value: 319.3 1H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.44(d,J=1.9Hz,1H),7.36(s,1H),7.21(s,2H),6.99-6.79(m,1H),6.24(dd,J=16.6 ,2.3Hz,1H),5.77(d,J=10.5Hz,1H),5.60-5.30(m,1H),4.48(d,J=12.3Hz,1H),4.25-3.75(m,4H),3.52(t,J=11.6Hz,1H).

[0295] Example 3 Preparation of compounds Cpd-3 and Cpd-3A

[0296] (R)-1-(3-(8-chloro-3-(isopropylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(isopropylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0297] Note: "or 1" in the structural formulas Cpd-3 and Cpd-3A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0298] Using the same synthetic route as compounds Cpd-1 and Cpd-1A, the starting material in step one was replaced with 2-isopropylamine instead of the original aqueous methylamine solution. The final products were prepared chirally (chromatographic column: ChiralPakAD-H 250*30mm ID, 5μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 70:30 at 50mL / min; column temperature: 38℃; pressure (nozzle pressure): 100Bar; wavelength: 220nm.), yielding (R)-1-(3-(8-chloro-3-(isopropylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(isopropylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one).

[0299] Cpd-3: Retention time: 2.333 min. LCMS calculated value (calc.for) C 18 H 22 ClN4O2[M+H] + m / z = 361.1; Found value: 361.2. 1H NMR (400MHz, DMSO-d6) δ8.30(s,1H),7.78(d,J=7.5Hz,1H),7.55-7.22(m,2H),6.99-6.78(m,1H),6.25(dd,J=16.6,2.3Hz,1H),5.78(d,J =10.4Hz,1H),5.70-5.16(m,1H),4.49(d,J=12.4Hz,1H),4.35-3.70(m,4H),3.59-3.47(m,1H),3.28-2.87(m,1H),1.22(d,J=6.4Hz,6H).

[0300] Cpd-3A: Retention time: 2.713 min. LCMS calculated value (calc.for) C 18 H 22 ClN4O2[M+H] + m / z = 361.1; Found value: 361.2. 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),7.78(d,J=7.4Hz,1H),7.56-7.18(m,2H),6.98-6.76(m,1H),6.25(dd,J=16.6,2.3Hz,1H),5.78(d,J =10.3Hz,1H),5.71-5.15(m,1H),4.49(d,J=12.3Hz,1H),4.39-3.68(m,4H),3.60-3.45(m,1H),3.26-2.82(m,1H),1.22(d,J=6.5Hz,6H).

[0301] Example 4 Preparation of compounds Cpd-4 and Cpd-4A

[0302] (R)-1-(3-(8-chloro-3-(cyclopropylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(cyclopropylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0303] Note: "or 1" in the structural formulas Cpd-4 and Cpd-4A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0304] The same synthetic route was used as for compounds Cpd-1 and Cpd-1A, with the starting material in step one replaced by cyclopropaneamine instead of the original aqueous methylamine solution. The final products were prepared chirally (chromatographic column: ChiralPak AD-H 250*30mm ID, 5μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 70:30 at 50mL / min; column temperature: 38℃; pressure (nozzle pressure): 100Bar; wavelength: 220nm), yielding (R)-1-(3-(8-chloro-3-(cyclopropylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(cyclopropylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one).

[0305] Cpd-4: Retention time: 3.179 min. LCMS calculated value (calc.for) C 18 H 20 ClN4O2[M+H] + m / z = 359.1; Found value: 359.2. 1 H NMR (400MHz, DMSO-d6) δ8.32 (s, 1H), 8.06 (d, J = 3.7Hz, 1H), 7.55-7.30 (m, 2H), 6.89 ( dd,J=16.6,10.5Hz,1H),6.26(dd,J=16.6,2.4Hz,1H),5.78(d,J=10.2Hz,1H),5.60- 5.30(m,1H),4.51(d,J=12.3Hz,1H),4.10-3.70(m,3H),3.61-3.47(m,1H),3.20-2.9 0(m,1H),2.86(tq,J=7.2,3.8Hz,1H),0.80(td,J=6.9,4.7Hz,2H),0.59-0.45(m,2H).

[0306] Cpd-4A: Retention time: 3.918 min. LCMS calculated value (calc.for) C 18 H 20 ClN4O2[M+H] + m / z = 359.1; Found value: 359.2. 1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.06(s,1H),7.55-7.25(m,2H),6.97- 6.78(m,1H),6.25(d,J=18.9Hz,1H),5.78(d,J=9.0Hz,1H),5.70-5.25(m,1 H),4.51(d,J=12.5Hz,1H),4.15-3.70(m,3H),3.59-3.47(m,1H),3.20-2.9 0(m,1H),2.86(dq,J=7.1,3.6Hz,1H),0.88-0.69(m,2H),0.58-0.46(m,2H).

[0307] Example 5 Preparation of compounds Cpd-5 and Cpd-5A

[0308] (R)-1-(3-(8-chloro-3-((cyclopropylmethyl)amino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-((cyclopropylmethyl)amino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0309] Note: "or 1" in the structural formulas Cpd-5 and Cpd-5A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0310] The same synthetic route was used as for compounds Cpd-1 and Cpd-1A, except that the starting material in step one was replaced with cyclopropylmethylamine instead of the original aqueous methylamine solution. The final products were prepared chirally (chromatographic column: ChiralPak AD-H 250*30mm ID, 5μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 70:30 at 50mL / min; column temperature: 38℃; pressure (nozzle pressure): 100Bar; wavelength: 220nm), yielding (R)-1-(3-(8-chloro-3-((cyclopropylmethyl)amino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-((cyclopropylmethyl)amino)quinoxalin-6-yl)morpholino)prop-2-en-1-one).

[0311] Cpd-5: Retention time: 3.055 min. LCMS calculated value (calc.for) C 19 H 22 ClN4O2[M+H] + m / z = 373.1; Found value: 373.2.1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.00(s,1H),7.45-7.20(m,2H),6.86(t,J=14 .6Hz,1H),6.25(dd,J=16.6,2.4Hz,1H),5.77(d,J=10.4Hz,1H),5.75-5.25(m,1H), 4.49(d,J=12.3Hz,1H),4.05-3.60(m,3H),3.57-3.46(m,1H),3.26(dd,J=6.9,5.3H z,2H),3.20-2.75(m,1H),1.20-1.05(m,1H),0.61-0.43(m,2H),0.34-0.20(m,2H).

[0312] Cpd-5A: Retention time: 3.442 min. LCMS calculated value (calc.for) C 19 H 22 ClN4O2[M+H] + m / z = 373.1; Found value: 373.2. 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.00(s,1H),7.55-7.25(m,2H),6.88(t,J=1 3.8Hz,1H),6.25(dd,J=16.6,2.4Hz,1H),5.85-5.75(m,1H),5.75-5.25(m,1H),4. 49(d,J=12.3Hz,1H),4.25-3.70(m,3H),3.60-3.46(m,1H),3.26(dd,J=6.9,5.3Hz ,2H),3.20-2.75(m,1H),1.20-1.05(m,1H),0.56-0.44(m,2H),0.35-0.22(m,2H).

[0313] Example 6 Preparation of compounds Cpd-6 and Cpd-6A

[0314] Note: "or 1" in the structural formulas Cpd-6 and Cpd-6A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0315] Step 1: 4-Bromo-6-chloro-3-fluoro-2-nitroaniline

[0316] At room temperature, N-chlorosuccinimide (15.0 g, 112 mmol) was added to a solution of 4-bromo-3-fluoro-2-nitroaniline (22.0 g, 93.6 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–15%) to give 4-bromo-6-chloro-3-fluoro-2-nitroaniline (25.0 g, yield: 99.1%). LCMS calculated value (calc. for): C6H4BrClFN2O2[M+H] + m / z = 268.9 / 270.9; Found value: 269.1 / 271.1.

[0317] Step 2: tert-butyl (4-bromo-6-chloro-3-fluoro-2-nitrophenyl) (tert-butoxycarbonyl) carbamate

[0318] At room temperature, 4-dimethylaminopyridine (0.91 g, 7.42 mmol) and di-tert-butyl dicarbonate (17.9 mL, 77.9 mmol) were added to a tetrahydrofuran (100 mL) solution of 4-bromo-6-chloro-3-fluoro-2-nitrophenyl (10.0 g, 37.1 mmol) and stirred at room temperature for 1 hour. After the reaction was complete, water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)(tert-butoxycarbonyl)carbamate (16.0 g, yield: 91.8%). LCMS calculated value (calc.for) C 16 H 20 BrClFN2O6[M+H] + m / z = 469.0 / 471.0; Found value: 469.1 / 471.1.

[0319] Step 3: (4-Bromo-6-chloro-3-fluoro-2-nitrophenyl) tert-butyl carbamate

[0320] At room temperature, trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)(tert-butoxycarbonyl)carbamate (7.5 g, 16.0 mmol) in dichloromethane (75 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give tert-butyl(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)carbamate (5.5 g, yield: 93.2%). LCMS calculated value (calc.for) C 11 H 10 BrClFN2O4[MH] - m / z = 367.0 / 369.0; Found value: 366.8 / 368.8.

[0321] Step 4: N-(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)-N-(tert-butoxycarbonyl)glycine ethyl ester

[0322] At room temperature, cesium carbonate (9.70 g, 29.8 mmol) and ethyl 2-bromoacetate (2.98 g, 17.9 mmol) were added to a solution of tert-butyl 4-bromo-6-chloro-3-fluoro-2-nitrophenyl)carbamate (5.50 g, 14.9 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–20%) to give N-(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)-N-(tert-butoxycarbonyl)glycine ethyl ester (5.8 g, yield: 85.5%). LCMS calculated value (calc.for) C 11 H 10 BrClFN2O6[M+H-C4H8] + m / z = 399.0 / 401.0; Found value: 398.7 / 400.7.

[0323] Step 5: (4-Bromo-6-chloro-3-fluoro-2-nitrophenyl)glycine ethyl ester

[0324] N-(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)-N-(tert-butoxycarbonyl)glycine ethyl ester (5.8 g, 12.7 mmol) was dissolved in 4 M dioxane hydrochloride (30 mL), and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the pH was adjusted to 5 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–20%) to give (4-bromo-6-chloro-3-fluoro-2-nitrophenyl)glycine ethyl ester (4.2 g, yield: 92.8%). LCMS calculated value (calc.for) C 10 H 10 BrClFN2O4[M+H] + m / z = 354.9 / 356.9; Found value: 354.8 / 356.8.

[0325] Step Six: (6-Chloro-3-fluoro-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)glycine ethyl ester

[0326] At room temperature, pinacol borate (3.9 g, 15.4 mmol), potassium acetate (2.90 g, 29.5 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.86 g, 1.18 mmol) were added to a solution of (4-bromo-6-chloro-2-nitro-2-nitrophenyl)glycine ethyl ester (4.2 g, 11.8 mmol) in dioxane (40 mL). The reaction solution was heated to 95 °C and stirred under an argon atmosphere for 2 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give (6-chloro-3-fluoro-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)glycine ethyl ester (4.7 g, yield: 99.0%). LCMS calculated value (calc.for) C 16 H 20 BClFN2O6[M+H] + m / z = 403.1; Found value: 402.9.

[0327] Step 7: tert-butyl 5-(5-chloro-4-((2-ethoxy-2-carbonylethyl)amino)-2-fluoro-3-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester

[0328] At room temperature, 4.7 g (11.7 mmol) of ethyl glycine in dioxane (40 mL) and water (5 mL) were mixed with tert-butyl 3-diphenoxyphosphoryloxy-5,6-dihydro-1,4-oxazine-4-carboxylic acid (6.58 g (15.2 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.85 g (1.17 mmol), and potassium phosphate (7.43 g (35.0 mmol)). The reaction mixture was heated to 95 °C and stirred for 3 hours under an argon atmosphere. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–30%) to give tert-butyl 5-(5-chloro-4-((2-ethoxy-2-carbonylethyl)amino)-2-fluoro-3-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (1.0 g, yield: 21.3%). LCMS calculated value (calc.for) C 15 H 16 ClFN3O7[M+H-C4H8] + m / z = 404.1; Found value: 403.9.

[0329] Step 8: (6-chloro-3-fluoro-4-(morpholin-3-yl)-2-nitrophenyl)glycine ethyl ester

[0330] At room temperature, trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 5-(5-chloro-4-((2-ethoxy-2-carbonylethyl)amino)-2-fluoro-3-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (1.0 g, 2.47 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium cyanoborohydride (0.21 g, 3.34 mmol) was added to the reaction mixture, and the reaction mixture was stirred for another 0.5 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give ethyl (6-chloro-3-fluoro-4-(morpholin-3-yl)-2-nitrophenyl)glycine (0.58 g, yield: 64.9%). LCMS calculated value (calc.for) C 14 H 18 ClFN3O5[M+H] + m / z = 362.1; Found value: 361.9.

[0331] Step Nine: (6-chloro-3-fluoro-2-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine ethyl ester

[0332] At room temperature, triethylamine (0.7 mL, 4.81 mmol) and trifluoroacetic anhydride (0.33 mL, 2.40 mmol) were added to a solution of (6-chloro-3-fluoro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine ethyl ester (0.58 g, 1.60 mmol) in dichloromethane (5.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the residue was concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–10%) to give (6-chloro-3-fluoro-2-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine ethyl ester (0.70 g, yield: 95.4%). LCMS calculated value (calc.for) C 16 H 17 ClF4N3O6[M+H] + m / z = 458.1; Found value: 457.8.

[0333] Step 10: 5-Chloro-8-fluoro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one

[0334] At room temperature, reduced iron powder (0.43 g, 7.65 mmol) and ammonium chloride (0.41 g, 7.65 mol) were added to a mixed solution of ethyl glycine (0.70 g, 1.53 mmol) in ethanol (6 mL) and water (1 mL). The reaction solution was heated to 80 °C and stirred for 1 hour. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate (20 mL x 2), the combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 5-chloro-8-fluoro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one (0.55 g, yield: 94.2%). LCMS calculated value (calc.for) C 14 H 13 ClF4N3O3[M+H] + m / z = 382.1; Found value: 381.9.

[0335] Step 11: 1-(3-(8-chloro-5-fluoro-3-hydroxyquinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one

[0336] At room temperature, manganese dioxide (0.63 g, 7.2 mmol) was added to an 8 mL solution of 5-chloro-8-fluoro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one (0.55 g, 1.44 mmol) in dioxane. The reaction mixture was heated to 100 °C and stirred for 1 hour. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (20 mL x 2), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 1-(3-(8-chloro-5-fluoro-3-hydroxyquinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (0.5 g, yield: 91.4%). LCMS calculated value (calc.for) C 14 H 11 ClF4N3O3[M+H] + m / z = 380.0; Found value: 379.9.

[0337] Step 12: 1-(3-(3,8-dichloro-5-fluoroquinoxalo-6-yl)morpholino)-2,2,2-trifluoroethane-1-one

[0338] At room temperature, phosphorus oxychloride (0.37 mL, 3.95 mmol) and N,N-dimethylformamide (0.1 mL, 1.32 mol) were added to an acetonitrile (8 mL) solution of 1-(3-(8-chloro-5-fluoro-3-hydroxyquinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (0.5 g, 1.32 mmol). The reaction solution was heated to 80 °C and stirred for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–15%) to give 1-(3-(3,8-dichloro-5-fluoroquinoxalo-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (0.5 g, yield: 95.4%). LCMS calculated value (calc.for) C 14 H 10 Cl2F4N3O2[M+H] + m / z = 398.0; Found value: 397.9.

[0339] Step Thirteen: 1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one

[0340] At room temperature, an aqueous solution of methylamine (0.43 g, 33%, 4.52 mmol) was added to an 8 mL solution of 1-(3-(3,8-dichloro-5-fluoroquinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (0.45 g, 1.13 mmol). The reaction mixture was heated to 100 °C and stirred for 1 hour. After the reaction was completed, the solution was concentrated under vacuum to obtain 1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (0.4 g, yield: 90.1%). LCMS calculated value (calc.for) C 15 H 14 ClF4N4O2[M+H] + m / z = 393.1; Found value: 392.9.

[0341] Step Fourteen: 5-Chloro-8-fluoro-N-methyl-7-(morpholin-3-yl)quinoxaline-2-amine

[0342] Potassium carbonate (0.56 g, 4.07 mmol) was added to a methanol (5 mL) solution of 1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (0.4 g, 1.02 mmol) at room temperature. The reaction solution was heated to 60 °C and stirred for 1 hour. The reaction solution was concentrated under vacuum to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0%–5%) to give 5-chloro-8-fluoro-N-methyl-7-(morpholin-3-yl)quinoxalin-2-amine (0.2 g, yield: 66.2%). LCMS calculated value (calc.for) C 13 H 15 ClFN4O[M+H] + m / z = 297.1; Found value: 296.9.

[0343] Step 15: 1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0344] At room temperature, a solution of 5-chloro-8-fluoro-N-methyl-7-(morpholin-3-yl)quinoxalin-2-amine (200 mg, 0.67 mmol) in tetrahydrofuran (4.0 mL) was reacted with sodium bicarbonate aqueous solution (0.67 mL, 2.0 mol / L, 1.35 mmol) and acryloyl chloride (61.0 mg, 0.67 mol). The reaction mixture was stirred at room temperature for half an hour. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: SHIMADZU Prep C18, 10 μm, 20*250 mm; mobile phase: A (0.1% FA in H2O) B (ACN)) to give 1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one (120 mg, yield: 50.8%). LCMS calculated value (calc.for) C 16 H 17 ClFN4O2[M+H] + m / z = 351.1; Found value: 351.1

[0345] Step Sixteen: (R)-1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0346] 1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one (120 mg, 0.34 mmol) was purified by SFC (column: ChiralPakAD-H 250*30 mm ID, 5 μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 70:30 at 50 mL / min; column temperature: 38 ℃; nozzle pressure: 100 Bar; wavelength: 220 nm) to obtain (R)-1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-5-fluoro-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one.

[0347] Cpd-6: 59.0 mg, yield: 49.2%, retention time: 3.286 min. LCMS calculated value (calc.for) C 16 H 17 ClFN4O2[M+H]+ m / z = 351.1; Found value: 351.1. 1 HNMR (400MHz, DMSO-d6) δ8.40(s,1H),8.12(d,J=5.0Hz,1H),7.50(d,J=6.3Hz,1H),6.88(dd,J=16.6,10.4Hz,1H),6.19(dd,J=16.6,2.4Hz,1H),5.8 7-5.58(m,2H),4.29(d,J=12.2Hz,1H),4.19-3.93(m,2H),3.87(dd,J=12. 3,3.9Hz,1H),3.61-3.51(m,1H),3.32-3.13(m,1H),2.93(d,J=4.7Hz,3H).

[0348] Cpd-6A: 60.0 mg, yield: 50.0%, retention time: 2.906 min. LCMS calculated value (calc.for) C 16 H 17 ClFN4O2[M+H] + m / z = 351.1; Found value: 351.1. 1 HNMR (400MHz, DMSO-d6) δ8.40(s,1H),8.12(d,J=5.0Hz,1H),7.50(d,J=6.3Hz,1H),6.88(dd,J=16.6,10.4Hz,1H),6.19(dd,J=16.6,2.4Hz,1H),5.8 7-5.58(m,2H),4.29(d,J=12.2Hz,1H),4.19-3.93(m,2H),3.87(dd,J=12. 3,3.9Hz,1H),3.61-3.51(m,1H),3.32-3.13(m,1H),2.93(d,J=4.7Hz,3H).

[0349] Example 7 Preparation of compounds Cpd-7 and Cpd-7A

[0350] Note: "or 1" in the structural formulas Cpd-7 and Cpd-7A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0351] Step 1: 1,4-Dibromo-3,5,6-d3-2-nitrobenzene

[0352] 1,4-Dibromo-2,3,5,6-tetradeuterium benzene (31.0 g, 129 mmol) was dissolved in a mixed solution of dichloromethane (100 mL) and concentrated sulfuric acid (60 mL). Then, a mixed solution of fuming nitric acid (12.7 g, 90%, 181 mmol) and concentrated sulfuric acid (30 mL) was added dropwise in small batches of about 5 mL every 5 minutes. After the addition was complete, stirring was continued for 30 minutes. After the reaction was complete, the reaction solution was poured into ice water (500 mL) and extracted with dichloromethane (200 mL x 2). The combined organic phases were washed with water (200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1,4-dibromo-3,5,6-d3-2-nitrobenzene (33.0 g, crude product yield: 90.0%).

[0353] Step 2: (4-Bromo-2-nitrophenyl-3,5,6-d3) tert-butyl carbamate

[0354] At room temperature, tert-butyl carbamate (7.43 g, 63.4 mmol), chloro[(4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene)-2-(2-aminobiphenyl)]palladium(II) (2.35 g, 2.64 mmol), and cesium carbonate (43.0 g, 132 mmol) were added to a solution of 1,4-dibromo-3,5,6-d3-2-nitrobenzene (15.0 g, 52.8 mmol) in 1,4-dioxane (150 mL). The reaction mixture was heated to 100 °C and stirred for 1 hour under an argon atmosphere. After the reaction was complete, the residue was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–10%) to give (4-bromo-2-nitrophenyl-3,5,6-d3)carbamate (10.7 g, yield: 63.3%). LCMS calculated value (calc.for): C6H3BrD3N2O2[M+H-C5H8O2] + m / z = 220.0 / 222.0; Found value: 219.9 / 222.1.

[0355] Step 3: 4-Bromo-2-nitro-3,5,6-d3-aniline

[0356] At room temperature, tert-butyl (4-bromo-2-nitrophenyl-3,5,6-d3)carbamate (10.7 g, 33.4 mmol) was dissolved in trifluoroacetic acid (30 mL) and stirred for 1 hour. After the reaction was complete, the reaction solution was quenched in a saturated aqueous solution of sodium bicarbonate (300 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-bromo-2-nitro-3,5,6-d3-aniline (7.2 g, crude yield: 97.9%). LCMS calculated value (calc. for) C6H3BrD3N2O2[M+H + m / z = 220.0 / 222.0; Found value: 219.8 / 221.8.

[0357] Step 4: 4-Bromo-2-chloro-6-nitro-3,5-d2-aniline

[0358] At room temperature, chlorosuccinimide (4.81 g, 36.0 mmol) was added to a solution of 4-bromo-2-nitro-3,5,6-d3-aniline (7.2 g, 32.7 mmol) in N,N-dimethylmethylamine (70 mL), and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched in water (300 mL) and extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-bromo-2-chloro-6-nitro-3,5-d2-aniline (8.11 g, crude yield: 97.8%).

[0359] Step 5: tert-butyl(4-bromo-2-chloro-6-nitrophenyl-3,5-d2)(tert-butoxycarbonyl)carbamate

[0360] At room temperature, 4-dimethylaminopyridine (0.78 g, 6.4 mmol) and di-tert-butyl dicarbonate (15.5 mL, 67.2 mmol) were added to a tetrahydrofuran (80 mL) solution of 4-bromo-2-chloro-6-nitro-3,5-d2-aniline (8.11 g, 32.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the residue was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–10%) to give tert-butyl(4-bromo-2-chloro-6-nitrophenyl-3,5-d2)(tert-butoxycarbonyl)carbamate (10.6 g, yield: 73.0%). LCMS calculated value (calc.for) C 16 H 18 BrClD2N2O6Na[M+Na] +m / z = 475.0 / 477.0; Found value: 474.7 / 476.7.

[0361] Step 6: tert-butyl (4-bromo-2-chloro-6-nitrophenyl-3,5-d2) carbamate

[0362] At room temperature, trifluoroacetic acid (3.0 mL) was added to a solution of tert-butyl(4-bromo-2-chloro-6-nitrophenyl-3,5-d2)(tert-butoxycarbonyl)carbamate (10.6 g, 23.4 mmol) in dichloromethane (90 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched in a saturated sodium bicarbonate aqueous solution (200 mL) and extracted with dichloromethane (200 mL x 2). The organic phases were combined and concentrated to give tert-butyl(4-bromo-2-chloro-6-nitrophenyl-3,5-d2)carbamate (8.11 g, crude yield: 98.2%). LCMS calculated value (calc. for): C6H3D2BrClN2O2[M+H-C5H8O2 + m / z = 253.0 / 255.0; Found value: 252.7 / 254.7.

[0363] Step 7: N-(4-bromo-2-chloro-6-nitrophenyl-3,5-d2)-N-(tert-butoxycarbonyl)glycine ethyl ester

[0364] At room temperature, cesium carbonate (11.2 g, 34.4 mmol) and ethyl 2-bromoacetate (3.83 g, 22.9 mmol) were added to a solution of tert-butyl(4-bromo-2-chloro-6-nitrophenyl-3,5-d2)carbamate (8.11 g, 22.9 mmol) in N,N-dimethylmethylamine (80 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched in water (300 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–10%) to give N-(4-bromo-2-chloro-6-nitrophenyl-3,5-d2)-N-(tert-butoxycarbonyl)glycine ethyl ester (9.88 g, yield: 98.0%). LCMS calculated value (calc.for) C 15 H 16 BrClD2N2O6Na[M+Na] + m / z = 461.0 / 463.0; Found value: 460.7 / 462.7.

[0365] Step 8: tert-butyl 5-(4-((tert-butoxycarbonyl)(2-ethoxy-2-carbonylethyl)amino)-3-chloro-5-nitrophenyl-2,6-d2)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester

[0366] At room temperature, pinacol borate (2.77 g, 10.9 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.33 g, 0.45 mmol), and potassium acetate (2.23 g, 22.7 mmol) were added to a solution of N-(4-bromo-2-chloro-6-nitrophenyl-3,5-d2)-N-(tert-butoxycarbonyl)glycine ethyl ester (4.0 g, 9.1 mmol) in 1,4-dioxane (80 mL). The reaction mixture was heated to 90 °C and stirred for 1 hour under an argon atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature. Then, 3-diphenoxyphosphono-5,6-dihydro-1,4-oxazine-4-carboxylic acid tert-butyl ester (4.73 g, 10.9 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.33 g, 0.45 mmol), potassium phosphate (4.83 g, 22.7 mmol), and water (20 mL) were added. The reaction solution was stirred at 90 °C under an argon atmosphere for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–10%) to give tert-butyl 5-(4-((tert-butoxycarbonyl)(2-ethoxy-2-carbonylethyl)amino)-3-chloro-5-nitrophenyl-2,6-d2)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (3.16 g, yield: 63.9%). LCMS calculated value (calc.for) C 24 H 30 D2ClN3O9Na[M+Na] + m / z = 566.2; Found value: 566.1.

[0367] Step Nine: (2-chloro-4-(morpholin-3-yl)-6-nitrophenyl-3,5-d2)glycine ethyl ester

[0368] At room temperature, trifluoroacetic acid (20 mL) was added to a solution of tert-butyl 5-(4-((tert-butoxycarbonyl)(2-ethoxy-2-carbonylethyl)amino)-3-chloro-5-nitrophenyl-2,6-d2)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (3.16 g, 5.81 mmol) in dichloromethane (20 mL). After stirring the reaction mixture at room temperature for 30 minutes, sodium cyanoborohydride (0.36 g, 5.81 mmol) was added in portions, and stirring continued for another 30 minutes at room temperature. Once the reaction was complete, the mixture was quenched in a saturated sodium bicarbonate solution (300 mL) and extracted with dichloromethane (200 mL x 2). The organic phases were combined and concentrated to give ethyl (2-chloro-4-(morpholin-3-yl)-6-nitrophenyl-3,5-d2)glycine (2.0 g, crude product yield: 99.6%). LCMS calculated value (calc.for) C 14 H 17 D2ClN3O5[M+H] + m / z = 346.1; Found value: 345.9.

[0369] Step 10: (2-chloro-6-nitro-4-4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-phenyl-3,5-d2)glycine ethyl ester

[0370] At 0 °C, trifluoroacetic anhydride (0.8 mL, 5.78 mmol) was added dropwise to a solution of (2-chloro-4-(morpholin-3-yl)-6-nitrophenyl-3,5-d2)glycine ethyl ester (2.0 g, 5.78 mmol) and N,N-diisopropylethylamine (1.5 g, 11.6 mmol) in dichloromethane (20 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched in a saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (50 mL x 2). The organic phases were combined and concentrated to give (2-chloro-6-nitro-4-4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-phenyl-3,5-d2)glycine ethyl ester (2.1 g, crude yield: 82.2%). LCMS calculated value (calc.for) C 16 H 16 D2ClF3N3O6[M+H] + m / z = 442.1; Found value: 441.9.

[0371] Step 11: 5-Chloro-6,8-d2-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one

[0372] At room temperature, reduced iron powder (0.8 g, 14.3 mmol), ammonium chloride (0.76 g, 14.3 mmol), and water (5.0 mL) were added to a solution of ethyl glycine (2.1 g, 4.75 mmol) in ethanol (20 mL). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was washed with water (50 mL). The organic phase was concentrated to give 5-chloro-6,8-d2-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one (1.2 g, crude yield: 69.0%). LCMS calculated C 14 H 12 D2ClF3N3O3[M+H] + m / z = 366.1; Found value: 365.9.

[0373] Step 12: 1-(3-(8-chloro-3-hydroxyquinoxalo-6-yl-5,7-d2)morpholino)-2,2,2-trifluoroethane-1-one

[0374] At room temperature, activated manganese dioxide (1.43 g, 16.4 mmol) was added to a 1,4-dioxane (15 mL) solution of 5-chloro-6,8-d2-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one (1.2 g, 3.28 mmol). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (50 mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 1-(3-(8-chloro-3-hydroxyquinoxalin-6-yl-5,7-d2)morpholino)-2,2,2-trifluoroethane-1-one (1.0 g, crude yield: 83.8%). LCMS calculated value (calc.for) C 14 H 10 D2ClF3N3O3[M+H] + m / z = 364.1; Found value: 363.8.

[0375] Step Thirteen: 1-(3-(3,8-dichloroquinoxalin-6-yl-5,7-d2)morpholino)-2,2,2-trifluoroethane-1-one

[0376] At room temperature, phosphorus oxychloride (0.77 mL, 8.25 mmol) was added to a solution of 1-(3-(8-chloro-3-hydroxyquinoxalin-6-yl-5,7-d2)morpholino)-2,2,2-trifluoroethane-1-one (1.0 g, 2.75 mmol) and N,N-dimethylmethylamine (0.64 mL, 8.25 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-(3-(3,8-dichloroquinoxalin-6-yl-5,7-d2)morpholino)-2,2,2-trifluoroethane-1-one (0.8 g, crude yield: 76.1%). LCMS calculated value (calc.for) C 14 H9D2Cl2F3N3O2[M+H] + m / z = 382.0; Found value: 381.8.

[0377] Step Fourteen: 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-5,7-d2)morpholino)-2,2,2-trifluoroethane-1-one

[0378] At room temperature, methylamine (1.0 mL, 33% aqueous solution) was added to a solution of 1-(3-(3,8-dichloroquinoxalin-6-yl-5,7-d2)morpholino)-2,2,2-trifluoroethane-1-one (800 mg, 2.09 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was completed, the solution was concentrated under vacuum to give 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-5,7-d2)morpholino)-2,2,2-trifluoroethane-1-one (710 mg, crude product yield: 90.0%). LCMS calculated value (calc.for) C 15 H 13 D2ClF3N4O2[M+H] + m / z = 377.1; Found value: 376.9.

[0379] Step 15: 5-Chloro-N-methyl-7-(morpholin-3-yl)quinoxaline-6,8-d2-2-amine

[0380] Potassium carbonate (781 mg, 5.65 mmol) was added to a methanol (10 mL) solution of 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-5,7-d2)morpholino)-2,2,2-trifluoroethane-1-one (710 mg, 1.88 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. After the reaction was complete, the residue was concentrated. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0%–50%) to give 5-chloro-N-methyl-7-(morpholin-3-yl)quinoxalin-6,8-d2-2-amine (260 mg, yield: 49.1%). LCMS calculated value (calc.for) C 13 H 14 D2ClN4O[M+H] + m / z = 281.1; Found value: 280.9.

[0381] Step Sixteen: 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-5,7-d2)morpholino)prop-2-en-1-one

[0382] At room temperature, a saturated sodium bicarbonate aqueous solution (1.0 mL) was added to a tetrahydrofuran (4.0 mL) solution of 5-chloro-N-methyl-7-(morpholin-3-yl)quinoxaline-6,8-d2-2-amine (150 mg, 0.53 mmol). Acryloyl chloride (48.4 mg, 0.53 mol) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for 10 minutes. After the reaction was complete, the mixture was extracted with dichloromethane (30 mL). The resulting organic phase was concentrated under vacuum, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: SHIMADZU Prep C18, 10 μm 20*250 mm; mobile phase: A (0.1% FA in H2O); B (ACN)) to give 1-(3-(8-chloro-3-(methylamino)quinoxaloline-6-yl-5,7-d2)morpholino)prop-2-en-1-one (60 mg, yield: 33.5%). LCMS calculated value (calc. for) C 16 H 16 D2ClN4O2[M+H] + m / z = 335.1; Found value: 335.1.

[0383] Step 17: (R)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-5,7-d2)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-5,7-d2)morpholino)prop-2-en-1-one

[0384] (R)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-5,7-d2)morpholino)prop-2-en-1-one (60.0 mg, 0.18 mmol) was purified by SFC (column: ChiralPakAD-H 250*30mm ID, 5 μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 70:30 at 50 mL / min; column temperature: 38℃; nozzle pressure: 100 Bar; wavelength: 220 nm) to obtain (R)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-5,7-d2)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-5,7-d2)morpholino)prop-2-en-1-one.

[0385] Cpd-7: 25.0 mg, yield: 41.7%, retention time: 2.785 min. LCMS calculated value (calc.for) C 16 H 16 D2ClN4O2[M+H] + m / z = 335.1; Found value: 335.1. 1 HNMR(400MHz,DMSO-d6)δ8.33(s,1H),7.96-7.79(m,1H),7.00-6.80(m,1H),6.25(dd,J=16.6,2.4Hz,1H),5.86-5.73(m,1H) ,5.71-5.21(m,1H),4.50(d,J=12.3Hz,1H),4.41-3.74(m,3H),3.59-3.47(m,1H),3.27-2.97(m,1H),2.92(d,J=4.7Hz,3H).

[0386] Cpd-7A: 25.0 mg, yield: 41.7%, retention time: 3.334 min. LCMS calculated value (calc.for) C 16 H 16 D2ClN4O2[M+H] + m / z = 335.1; Found value: 335.1. 1HNMR (400MHz, DMSO-d6) δ8.33(s,1H),7.87(d,J=5.5Hz,1H),6.88(t,J=13.6Hz,1H),6.25(dd,J=16.6,2.4Hz,1H),5.78(d,J=10.4 Hz,1H),5.71-5.20(m,1H),4.50(d,J=12.3Hz,1H),4.38-3.77(m,3H),3.56-3.49(m,1H),3.27-3.00(m,1H),2.92(d,J=4.7Hz,3H).

[0387] Example 8 Preparation of compounds Cpd-8 and Cpd-8A

[0388] Note: "or 1" in the structural formulas Cpd-8 and Cpd-8A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0389] Step 1: 6,8-Dichloropyrido[2,3-b]pyrazin-3-ol

[0390] At room temperature, a methanol (50 mL) solution of 4,6-dichloropyridin-2,3-diamine (5.0 g, 28.1 mmol) was mixed with an aqueous solution of glyoxylic acid (20.8 g, 281 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (500 mL) was added to the reaction mixture, and the mixture was stirred and filtered. The filter cake was concentrated under vacuum to obtain 6,8-dichloropyrido[2,3-b]pyrazin-3-ol (6.8 g, crude product). LCMS calculated value (calc. for): C7H4Cl2N3O[M+H) + m / z = 216.0; Found value: 215.9.

[0391] Step 2: 3,6,8-Trichloropyrido[2,3-b]pyrazine

[0392] At room temperature, phosphorus oxychloride (9.27 mL, 99.4 mmol) and N,N-dimethylformamide (7.69 mL, 99.4 mmol) were added to a solution of 6,8-dichloropyrido[2,3-b]pyrazin-3-ol (7.16 g, 33.1 mmol) in acetonitrile (70 mL). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was poured into water (300 mL), extracted with dichloromethane (100 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to give 3,6,8-trichloropyrido[2,3-b]pyrazine (5.5 g, yield: 70.8%). LCMS calculated value (calc. for) C7H3Cl3N3[M+H + m / z = 233.9; Found value: 234.0.

[0393] Step 3: 6,8-Dichloro-N-(4-methoxybenzyl)-N-methylpyrido[2,3-b]pyrazin-3-amine

[0394] At room temperature, 1-(4-methoxyphenyl)-N-methylmethylamine (5.2 g, 34.1 mmol) was added to a solution of 3,6,8-trichloropyridino[2,3-b]pyrazine (4.0 g, 17.1 mmol) in 1,4-dioxane (40 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30%) to give 6,8-dichloro-N-(4-methoxybenzyl)-N-methylpyridino[2,3-b]pyrazine-3-amine (4.3 g, yield: 72.2%). LCMS calculated value (calc.for) C 16 H 15 Cl2N4O[M+H] + m / z = 349.1; Found value: 349.0.

[0395] Step 4: tert-butyl 5-(8-chloro-3-((4-methoxybenzyl)(methyl)amino)pyrido[2,3-b]pyrazin-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester

[0396] At room temperature, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester (4.2 g, 13.5 mmol), bis(triphenylphosphine)palladium(II) chloride (432 mg, 0.62 mmol), potassium phosphate (6.5 g, 30.8 mmol), and water (12.5 mL) were added to a solution of 6,8-dichloro-N-(4-methoxybenzyl)-N-methylpyrido[2,3-b]pyrazine-3-amine (4.3 g, 12.3 mmol) in 1,4-dioxane (60 mL). The reaction mixture was stirred at 90 °C under an argon atmosphere for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-40%) to give tert-butyl 5-(8-chloro-3-((4-methoxybenzyl)(methyl)amino)pyrido[2,3-b]pyrazin-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (3.26 g, yield: 53.2%). LCMS calculated value (calc.for) C 25 H 29 ClN5O4[M+H] + m / z = 498.2; Found value: 498.2.

[0397] Step 5: 8-Chloro-N-(4-methoxybenzyl)-N-methyl-6-(morpholin-3-yl)-1,2-dihydropyrido[2,3-b]pyrazin-3-amine

[0398] At room temperature, trifluoroacetic acid (5.0 mL) was added to a solution of tert-butyl 5-(8-chloro-3-((4-methoxybenzyl)(methyl)amino)pyrido[2,3-b]pyrazin-6-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid ester (3.26 g, 6.55 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 16 hours. Sodium cyanoborohydride (823 mg, 13.1 mmol) was then added in portions to the reaction mixture. After the reaction was complete, the mixture was quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10%) to give 8-chloro-N-(4-methoxybenzyl)-N-methyl-6-(morpholin-3-yl)-1,2-dihydropyrido[2,3-b]pyrazin-3-amine (115 mg, yield: 43.7%). LCMS calculated value (calc.for) C 20 H 25 ClN5O2[M+H] +m / z = 402.2; Found value: 402.1.

[0399] Step Six: 8-Chloro-N-(4-methoxybenzyl)-N-methyl-6-(morpholin-3-yl)pyrido[2,3-b]pyrazin-3-amine

[0400] At room temperature, activated manganese dioxide (519 mg, 5.97 mmol) was added to a solution of 8-chloro-N-(4-methoxybenzyl)-N-methyl-6-(morpholin-3-yl)-1,2-dihydropyrido[2,3-b]pyrazin-3-amine (800 mg, 1.99 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered and washed with ethyl acetate. The resulting organic phases were combined and concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10%) to give 8-chloro-N-(4-methoxybenzyl)-N-methyl-6-(morpholin-3-yl)pyrido[2,3-b]pyrazin-3-amine (670 mg, yield: 84.2%). LCMS calculated value (calc.for) C 20 H 23 ClN5O2[M+H] + m / z = 400.2; Found value: 400.4.

[0401] Step 7: 8-Chloro-N-methyl-6-(morpholin-3-yl)pyrido[2,3-b]pyrazin-3-amine

[0402] At room temperature, trifluoromethanesulfonic acid (754 mg, 5.03 mmol) was added to a solution of 8-chloro-N-(4-methoxybenzyl)-N-methyl-6-(morpholin-3-yl)pyrido[2,3-b]pyrazin-3-amine (670 mg, 1.68 mmol) in trifluoroacetic acid (5.0 mL). The reaction mixture was stirred at 70 °C for 1 hour. After the reaction was complete, the reaction was quenched with water (30 mL) and extracted with dichloromethane (30 mL). The aqueous phase was adjusted to pH > 7 with saturated sodium bicarbonate solution and extracted with a dichloromethane solution containing 10% methanol (50 mL x 2). The resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10%) to give 8-chloro-N-methyl-6-(morpholin-3-yl)pyrido[2,3-b]pyrazin-3-amine (148 mg, yield: 31.6%). LCMS calculated value (calc.for) C 12 H 15 ClN5O[M+H] + m / z = 280.1; Found value: 280.0.

[0403] Step 8: 1-(3-(8-chloro-3-(methylamino)pyrido[2,3-b]pyrazin-6-yl)morpholino)prop-2-en-1-one

[0404] At room temperature, acryloyl chloride (47.9 mg, 0.53 mol) was added dropwise to a solution of 8-chloro-N-methyl-6-(morpholin-3-yl)pyridino[2,3-b]pyrazin-3-amine (148 mg, 0.53 mmol) and sodium bicarbonate (133 mg, 1.59 mmol) in water (1.0 mL) and tetrahydrofuran (4.0 mL). The reaction mixture was stirred at room temperature for 10 minutes. After the reaction was complete, the reaction mixture was extracted with dichloromethane (30 mL), and the resulting organic phase was concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10%) to give 1-(3-(8-chloro-3-(methylamino)pyridino[2,3-b]pyrazin-6-yl)morpholino)prop-2-en-1-one (61 mg, yield: 34.5%). LCMS calculated value (calc.for) C 15 H 17 ClN5O2[M+H] + m / z = 334.1; Found value: 333.8.

[0405] Step Nine: (R)-1-(3-(8-chloro-3-(methylamino)pyrido[2,3-b]pyrazin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(methylamino)pyrido[2,3-b]pyrazin-6-yl)morpholino)prop-2-en-1-one

[0406] 1-(3-(8-chloro-3-(methylamino)pyridino[2,3-b]pyrazin-6-yl)morpholino)prop-2-en-1-one (61.0 mg, 0.18 mmol) was chromatographically analyzed by SFC (column: ChiralPakAD-H 250*30 mm ID, 5 μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 70:30 at 50 mL / min; column temperature (Temp): 38℃; pressure (Nozzle) Pressure: 100 Bar; Wavelength: 220 nm) Purification yielded (R)-1-(3-(8-chloro-3-(methylamino)pyrido[2,3-b]pyrazin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(methylamino)pyrido[2,3-b]pyrazin-6-yl)morpholino)prop-2-en-1-one.

[0407] Cpd-8: 21.0 mg, yield: 34.4%, retention time: 2.834 min. LCMS calculated value (calc.for) C 15 H 17 ClN5O2[M+H] + m / z = 334.1; Found value: 334.0. 1 HNMR(400MHz,DMSO-d6)δ8.38(s,1H),8.26(s,1H),7.38(s,1H),7.05-6.63(m,1H),6.29-6.13(m,1H),5.87-5.6 2(m,1H),5.55-5.37(m,1H),4.66(d,J=11.9Hz,1H),4.29-3.81(m,3H),3.63-3.46(m,2H),2.96(d,J=4.7Hz,3H).

[0408] Cpd-8A: 22.0 mg, yield: 36.1%, retention time: 3.332 min. LCMS calculated value (calc.for) C 15 H 17 ClN5O2[M+H] + m / z = 334.1; Found value: 334.0. 1 HNMR(400MHz,DMSO-d6)δ8.38(s,1H),8.26(s,1H),7.37(s,1H),7.06-6.65(m,1H),6.32-6.14(m,1H),5.91-5.6 2(m,1H),5.55-5.37(m,1H),4.66(d,J=11.9Hz,1H),4.34-3.73(m,3H),3.71-3.42(m,2H),2.96(d,J=4.8Hz,3H).

[0409] Example 9: Preparation of compound Cpd-9

[0410] The same synthetic route as compound Cpd-1 was used, except that the starting material in step one was replaced by aqueous dimethylamine solution instead of aqueous methylamine solution. The final product was prepared by high performance liquid chromatography (column: SHIMADZU Prep C18, 10μm 20*250mm, mobile phase: A (0.1% FA in H2O), B (ACN)).

[0411] 1-(3-(8-chloro-3-(dimethylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0412] LCMS calculated value (calc.for) of 1-(3-(8-chloro-3-(dimethylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one 17 H 20 ClN4O2[M+H] + m / z = 347.1; Found value: 347.2. 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),7.45(d,J=1.8Hz,2H),6.88(t,J=13.5Hz,1H),6.25(dd,J=16.6,2.3Hz,1H),5.78(d,J=10.4Hz,1H), 5.53(d,J=76.8Hz,1H),4.51(d,J=12.4Hz,1H),4.24(s,1H),3.85(dd,J=29.3,11.6Hz,2H),3.59-3.47(m,1H),3.24(s,6H),2.99(s,1H).

[0413] Example 10 Preparation of compounds Cpd-10 and Cpd-10A

[0414] Note: "or 1" in the structural formulas Cpd-10 and Cpd-10A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0415] Step 1: (3R)-1-(5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-2-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0416] At room temperature, (R)-pyrrolidine-3-ylcarbamate tert-butyl ester (162 mg, 0.87 mmol) and N,N-diisopropylethylamine (224 mg, 1.74 mmol) were added to 1,4-dioxane (5.0 mL) of 1-(3-(3,8-dichloroquinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (220 mg, 0.58 mmol). The reaction mixture was heated to 100 °C and stirred for 4 hours. After the reaction was completed, the mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–80%) to give (3R)-1-(5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholino-3-yl)quinoxalin-2-yl)pyrrolidine-3-yl)carbamate tert-butyl ester (250 mg, yield: 81.5%). LCMS calculated value (calc.for) C 23 H 28ClF3N5O4[M+H] + m / z = 530.2; Found value: 530.3.

[0417] Step 2: ((3R)-1-(5-chloro-7-(morpholin-3-yl)quinoxalin-2-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0418] At room temperature, potassium carbonate (196 mg, 1.42 mmol) was added to a solution of (3R)-1-(5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-2-yl)pyrrolidine-3-yl)carbamate (250 mg, 0.47 mmol) in methanol (5.0 mL). The reaction mixture was heated to 60 °C and stirred for 2 hours. After the reaction was completed, the mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0%–5%) to obtain ((3R)-1-(5-chloro-7-(morpholin-3-yl)quinoxalin-2-yl)pyrrolidine-3-yl)carbamate (150 mg, yield: 73.3%). LCMS calc. for C 21 H 29 ClN5O3[M+H] + m / z = 434.2; Found value: 434.1.

[0419] Step 3: ((3R)-1-(7-(4-acryloylmorpholin-3-yl)-5-chloroquinoxalin-2-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0420] At room temperature, sodium bicarbonate aqueous solution (0.35 mL, 2.0 mol / L, 0.70 mmol) and acryloyl chloride (31.3 mg, 0.35 mmol) were added to a tetrahydrofuran (4.0 mL) solution of ((3R)-1-(5-chloro-7-(morpholin-3-yl)quinoxalin-2-yl)pyrrolidine-3-yl)carbamate (150 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–50%) to give ((3R)-1-(7-(4-acryloylmorpholin-3-yl)-5-chloroquinoxalin-2-yl)pyrrolidine-3-yl)tert-butyl carbamate (130 mg, yield: 77.1%). LCMS calculated value (calc.for) C 24 H 31 ClN5O4[M+H] +m / z = 488.2; Found value: 488.1.

[0421] Step 4: 1-(3-(3-((R)-3-aminopyrrolidone-1-yl)-8-chloroquinoxalin-6-yl)morpholino)prop-2-en-1-one

[0422] At room temperature, trifluoroacetic acid (2.0 mL) was added to a solution of ((3R)-1-(7-(4-acrylomorpholin-3-yl)-5-chloroquinoxalin-2-yl)pyrrolidine-3-yl)carbamate tert-butyl ester (130 mg, 0.27 mmol) in dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the residue was concentrated. The residue was purified by high-performance liquid chromatography (HPLC) (column: Durashell C18, 10 μm 21.2*250 mm; mobile phase: A (10 mM NH4HCO3 aqueous solution), B (ACN)) to give 1-(3-(3-((R)-3-aminopyrrolidine-1-yl)-8-chloroquinoxalin-6-yl)morpholino)prop-2-en-1-one (53.0 mg, yield: 51.3%). LCMS calculated value (calc.for) C 19 H 23 ClN5O2[M+H] + m / z = 388.2; Found value: 388.1.

[0423] Step 5: 1-((R)-3-(3-((R)-3-aminopyrrolidone-1-yl)-8-chloroquinoxalin-6-yl)morpholino)prop-2-en-1-one and 1-((S)-3-(3-((R)-3-aminopyrrolidone-1-yl)-8-chloroquinoxalin-6-yl)morpholino)prop-2-en-1-one

[0424] 1-(3-(3-((R)-3-aminopyrrolidone-1-yl)-8-chloroquinoxalin-6-yl)morpholino)prop-2-en-1-one (53 mg, 0.14 mmol) was analyzed by SFC (column: ChiralPakAD-H 250*30 mm ID, 5 μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 60:40, flow rate 50 mL / min; column temperature (Temp): 38 ℃; pressure (Nozzle) Pressure: 100 Bar; Wavelength: 220 nm) Purification yielded 1-((R)-3-(3-((R)-3-aminopyrrolidone-1-yl)-8-chloroquinoxalin-6-yl)morpholino)prop-2-en-1-one and 1-((S)-3-(3-((R)-3-aminopyrrolidone-1-yl)-8-chloroquinoxalin-6-yl)morpholino)prop-2-en-1-one.

[0425] Cpd-10: 1.2 mg, yield: 2.3%, retention time: 2.686 min. LCMS calculated value (calc.for) C 19 H 23 ClN5O2[M+H] + m / z = 388.2; Found value: 388.2. 1 HNMR (400MHz, DMSO-d6) δ8.52(s,1H),7.43(s,2H),6.87(d,J=15.5Hz,1H),6.25(dd,J=16.6,2.4Hz,1H),5.78(d ,J=10.3Hz,1H),5.59(s,1H),4.51(d,J=12.4Hz,1H),4.35-4.07(m,1H),3.92-3.48(m,10H),1.99-1.73(m,2H).

[0426] Cpd-10A: 1.7 mg, yield: 3.2%, retention time: 1.931 min. LCMS calculated value (calc.for) C 19 H 23 ClN5O2[M+H] + m / z = 388.2; Found value: 388.2. 1 HNMR (400MHz, DMSO-d6) δ8.52(d,J=1.6Hz,1H),7.52-7.37(m,2H),6.87(d,J=15.7Hz,1H),6.25(dd,J=16.6,2.4Hz,1H) ,5.78(d,J=10.4Hz,1H),5.58(s,1H),4.51(d,J=12.3Hz,1H),4.32-4.07(m,1H),3.96-3.46(m,10H),1.99-1.73(m,2H).

[0427] Example 11 Preparation of compounds Cpd-11 and Cpd-11A

[0428] Note: The "or 1" in the structural formulas Cpd-11 and Cpd-11A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0429] Step 1: 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one

[0430] At room temperature, an aqueous solution of methylamine (0.43 g, 33%, 4.52 mmol) was added to an 8 mL solution of 1-(3-(3,8-dichloroquinoxolin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (0.45 g, 1.13 mmol). The reaction mixture was heated to 100 °C and stirred for 1 hour. After the reaction was completed, the solution was concentrated under vacuum to obtain 1-(3-(8-chloro-3-(methylamino)quinoxolin-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (0.4 g, yield: 90.1%). LCMS calculated value (calc.for) C 15 H 15 ClF3N4O2[M+H] + m / z = 375.1; Found value: 374.9.

[0431] Step 2: (2-(methylamino)-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-5-yl)boronic acid

[0432] At room temperature, to a solution of 1-(3-(8-chloro-3-(methylamino)quinoxalo-6-yl)morpholino)-2,2,2-trifluoroethane-1-one (200 mg, 0.53 mmol) in 1,4-dioxane (4.0 mL), bis(pinarate)diboron (271 mg, 1.07 mmol), tris(dibenzylacetone)dipalladium(0) (48.9 mg, 0.05 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (50.8 mg, 0.11 mmol), and potassium acetate (157 mg, 1.60 mmol) were added. The reaction solution was purged with argon three times, and the reaction was heated to 110 °C for 1 hour using a microwave reactor. After the reaction was completed, the residue was concentrated. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0%–10%) to give (2-(methylamino)-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-5-yl)boronic acid (200 mg, yield: 97.6%). LCMS calculated value (calc.for) C 15 H 17 BF3N4O4[M+H] + m / z = 385.1; Found value: 385.0.

[0433] Step 3: 2,2,2-trifluoro-1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)ethane-1-one

[0434] At room temperature, a mixture of 1,4-dioxane (3.0 mL) and water (0.5 mL) containing (150 mg, 0.39 mmol) of 2-(methylamino)-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-5-yl)boric acid (35.2 mg, 0.04 mmol) and potassium phosphate (249 mg, 1.17 mmol) was added. The reaction mixture was purged with argon three times and heated to 50 °C for 4 hours. After the reaction was complete, the residue was concentrated. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0%–5%) to give 2,2,2-trifluoro-1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)ethane-1-one (110 mg, yield: 78.8%). LCMS calculated value (calc.for) C 16 H 15 D3F3N4O2[M+H] + m / z = 358.2; Found value: 358.1.

[0435] Step 4: N-methyl-5-(methyl-d3)-7-(morpholin-3-yl)quinoxaline-2-amine

[0436] At room temperature, potassium carbonate (128 mg, 0.92 mmol) was added to a methanol (4.0 mL) solution of 2,2,2-trifluoro-1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)ethyl-1-one (110 mg, 0.31 mmol), and the reaction solution was heated to 60 °C and stirred for 2 hours. The reaction solution was concentrated under vacuum to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0%–10%) to give N-methyl-5-(methyl-d3)-7-(morpholino-3-yl)quinoxalin-2-amine (70.0 mg, yield: 87.0%). LCMS calculated value (calc.for) C 14 H 16 D3N4O[M+H] + m / z = 262.2; Found value: 262.1.

[0437] Step 5: 1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0438] At room temperature, sodium bicarbonate aqueous solution (0.27 mL, 2.0 mol / L, 0.54 mmol) and acryloyl chloride (24.3 mg, 0.27 mol) were added to a tetrahydrofuran (3.0 mL) solution of N-methyl-5-(methyl-d3)-7-(morpholin-3-yl)quinoxaline-2-amine (70.0 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by high-performance liquid chromatography (HPLC) (column: SHIMADZU Prep C18, 10 μm 20*250 mm; mobile phase: A (0.1% FA aqueous solution), B (ACN)) to give 1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one (19.0 mg, yield: 22.5%). LCMS calculated value (calc.for) C 17 H 18 D3N4O2[M+H] + m / z = 316.2; Found value: 316.3.

[0439] Step Six: (R)-1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one

[0440] 1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one (19.0 mg, 0.06 mmol) was purified by SFC (column: ChiralPakAD-H 250*30mm ID, 5 μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 70:30, flow rate 50 mL / min; column temperature: 38℃; nozzle pressure: 100 Bar, wavelength: 220 nm) to obtain (R)-1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one and (S)-1-(3-(8-(methyl-d3)-3-(methylamino)quinoxalin-6-yl)morpholino)prop-2-en-1-one.

[0441] Cpd-11: 6.8 mg, yield: 35.8%, retention time: 2.83 min. LCMS calculated value (calc.for) C 17 H18 D3N4O2[M+H] + m / z = 316.2; Found value: 316.3. 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.56 (d, J = 5.1Hz, 1H), 7.32 (s, 1H), 7. 15(d,J=2.1Hz,1H),6.86(s,1H),6.24(dd,J=16.6,2.4Hz,1H),5.76(d,J=1 0.3Hz,1H),5.48(d,J=98.7Hz,1H),4.49(d,J=12.2Hz,1H),4.32-3.74(m,3 H),3.51(td,J=11.7,2.9Hz,1H),3.29-2.96(m,1H),2.89(d,J=4.8Hz,3H).

[0442] Cpd-11A: 6.9 mg, yield: 36.3%, retention time: 3.58 min. LCMS calculated value (calc.for) C 17 H 18 D3N4O2[M+H] + m / z = 316.2; Found value: 316.3. 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.56 (d, J = 5.6Hz, 1H), 7.33 (s, 1H), 7. 15(d,J=2.1Hz,1H),6.86(s,1H),6.24(dd,J=16.6,2.4Hz,1H),5.76(d,J=1 0.3Hz,1H),5.47(d,J=97.5Hz,1H),4.49(d,J=12.2Hz,1H),4.34-3.74(m,3 H),3.51(td,J=11.7,2.9Hz,1H),3.30-2.97(m,1H),2.89(d,J=4.7Hz,3H).

[0443] Example 12 Preparation of compounds Cpd-12, Cpd-12A, Cpd-12B and Cpd-12C

[0444] Note: "or 1" and "or 2" in the structural formulas Cpd-12, Cpd-12A, Cpd-12B and Cpd-12C indicate that the compound has a single stereoconfiguration, but its configuration is uncertain. That is, the site of the compound may be a single R configuration or a single S configuration.

[0445] Step 1: 5-Chloro-N-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoxalin-2-amine

[0446] Under a nitrogen atmosphere, pinacol diboronic acid ester (4.01 g, 15.8 mmol), potassium acetate (2.07 g, 21.1 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (770 mg, 1.05 mmol) were added to a solution of 7-bromo-5-chloro-N-methylquinoxaline-2-amine (2.87 g, 10.5 mmol) in dioxane (30 mL), and the mixture was reacted at 80 °C for 3 hours. After the reaction was complete, the mixture was quenched with water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20%–50%) to give 5-chloro-N-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoxalin-2-amine (2.1 g, yield: 62%). LCMS calculated value (calc.for) C 15 H 20 BClN3O2[M+H] + m / z = 320.1; Found value: 319.9.

[0447] Step 2: cis-2-chloro-N-(-2-hydroxycyclobutyl)acetamide

[0448] At 0 °C, a solution of ethyl chloroacetate (1.51 g, 13.4 mmol) in dichloromethane (7 mL) was slowly added dropwise to a solution of cis-2-aminocyclobut-1-ol hydrochloride (1.50 g, 12.1 mmol) in water (7 mL). The mixture was stirred for 1 hour. Then, a 1 M sodium hydroxide aqueous solution (27 mL, 27 mmol) was slowly added dropwise to the mixture at 0 °C. The mixture was brought to room temperature and stirred for 5 hours. After the reaction was complete, the solution was diluted with water (80 mL), extracted with dichloromethane (50 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain cis-2-chloro-N-(-2-hydroxycyclobutyl)acetamide (1 g, yield: 35.6%), which was used directly in the next reaction. LCMS calculated value (calc.for) C6H 11 ClNO2[M+H] + m / z = 164.0; Found value: 164.2.

[0449] Step 3: cis-2-oxa-5-azabicyclo[4.2.0]octane-4-one

[0450] At room temperature, potassium tert-butoxide (1.37 g, 12.2 mmol) was added in portions to a solution of cis-2-chloro-N-(-2-hydroxycyclobutyl)acetamide (1.0 g, 6.11 mmol) in isopropanol (10 mL), and the mixture was stirred for 2 hours. After the reaction was complete, the solution was diluted with water (80 mL), extracted with a 10 / 1 mixture of dichloromethane and isopropanol (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain cis-2-oxa-5-azabicyclo[4.2.0]octane-4-one (1 g, crude), which was used directly in the next reaction. LCMS calculated value (calc. for) C12H19N2O4[2M+H + m / z = 255.1; Found value: 255.2.

[0451] Step 4: cis-4-oxo-2-oxa-5-azabicyclo[4.2.0]octane-5-carboxylic acid tert-butyl ester

[0452] At room temperature, triethylamine (2.34 g, 23.6 mmol), 4-dimethylaminopyridine (192 mg, 1.57 mmol), and di-tert-butyl dicarbonate (2.57 g, 11.8 mmol) were added to a tetrahydrofuran (10 mL) solution of cis-2-oxa-5-azabicyclo[4.2.0]octane-4-one (1.0 g, 7.87 mmol). The reaction was stirred for 1 hour. The mixture was diluted with water (80 mL), extracted with dichloromethane (50 mL x 3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10%–40%) to give cis-4-oxo-2-oxa-5-azabicyclo[4.2.0]octane-5-carboxylic acid tert-butyl ester (0.8 g, two-step yield: 57.4%). LCMS calculated value (calc.for) C 22 H 34 N₂O₈Na[2M+Na] + m / z = 477.1; Found value: 477.2.

[0453] Step 5: cis-4-((diphenoxyphosphoryl)oxy)-2-oxa-5-azabicyclo[4.2.0]oct-3-ene-5-carboxylic acid tert-butyl ester

[0454] Cis-4-oxo-2-oxa-5-azabicyclo[4.2.0]octane-5-carboxylic acid tert-butyl ester (655 mg, 2.86 mmol) was dissolved in tetrahydrofuran (5 mL). The reaction system was cooled to -30 °C, and under a nitrogen atmosphere, bis(trimethylsilylaminolithium) (3.7 mL, 3.73 mmol, 1 M) was slowly added dropwise to the reaction solution. The mixture was stirred at -30 °C for 1 hour. Then, diphenyl chlorophosphate (1.0 g, 3.73 mmol) was slowly added dropwise to the reaction solution. The reaction system was then warmed to room temperature and stirred for another 3 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (80 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10%–40%) to obtain cis-4-((diphenoxyphosphoryl)oxy)-2-oxa-5-azabicyclo[4.2.0]oct-3-ene-5-carboxylic acid tert-butyl ester (610 mg, yield: 46.1%). LCMS calculated value (calc.for) C 46 H 52 N2O 14 P2Na[2M+Na] + m / z = 941.3; Found value: 941.2.

[0455] Step 6: cis-4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]oct-3-ene-5-carboxylic acid tert-butyl ester

[0456] Under a nitrogen atmosphere, a mixed solution of cis-4-((diphenoxyphosphoryl)oxy)-2-oxa-5-azabicyclo[4.2.0]oct-3-en-5-carboxylic acid tert-butyl ester (610 mg, 1.32 mmol) in dioxane / water (5 mL / 0.5 mL) was added, along with 5-chloro-N-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoxalin-2-amine (508 mg, 1.59 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (97 mg, 0.13 mmol), and anhydrous potassium phosphate (562 mg, 2.65 mmol). The mixture was stirred at 90 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (80 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10%–40%) to give cis-4-(8-chloro-3-(methylamino)quinoxaloline-6-yl)-2-oxa-5-azabicyclo[4.2.0]oct-3-ene-5-carboxylic acid tert-butyl ester (220 mg, yield: 41.2%). LCMS calculated value (calc.for) C 20 H 24 ClN4O3[M+H] + m / z = 403.2; Found value: 403.2.

[0457] Step 7: cis-7-2-oxa-5-azabicyclo[4.2.0]oct-4-en-4-yl)-5-chloro-N-methylquinoxaloline-2-amine

[0458] At room temperature, trifluoroacetic acid (1.5 mL) was added to a solution of cis-4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]oct-3-en-5-carboxylic acid tert-butyl ester (220 mg, 0.54 mmol) in dichloromethane (3 mL), and the mixture was stirred for 0.5 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain cis-7-2-oxa-5-azabicyclo[4.2.0]oct-4-en-4-yl)-5-chloro-N-methylquinoxalin-2-amine (150 mg, crude product), which was directly used in the next step of the reaction. LCMS calculated value (calc.for) C 15 H 16 ClN4O[M+H] + m / z = 303.1; Found value: 303.2.

[0459] Step 8: cis-7-2-oxa-5-azabicyclo[4.2.0]octane-4-yl)-5-chloro-N-methylquinoxalin-2-amine

[0460] Sodium borohydride (37 mg, 0.99 mmol) was added to a methanol (2 mL) solution of cis-7-2-oxa-5-azabicyclo[4.2.0]octane-4-en-4-yl)-5-chloro-N-methylquinoxalin-2-amine (150 mg, 0.49 mmol) at 0 °C. The mixture was then heated to room temperature and stirred for 0.5 hours. After the reaction was complete, saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give cis-7-2-oxa-5-azabicyclo[4.2.0]octane-4-yl)-5-chloro-N-methylquinoxalin-2-amine (90 mg, two-step yield: 54.2%). LCMS calculated value (calc.for) C 15 H 18 ClN4O[M+H] + m / z = 305.1; Found value: 305.1.

[0461] Step Nine: 1-((1R,4R,6S)4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]octan-5-yl)prop-2-en-1-one; 1-((1R,4S,6S)4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]octan-5-yl)prop-2-en-1 - Ketone; 1-((1S,4R,6R)4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]octan-5-yl)prop-2-en-1-one & 1-((1S,4S,6R)4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]octan-5-yl)prop-2-en-1-one

[0462] Acrylyl chloride (11 mg, 0.12 mmol) was added to a mixture of cis-7-2-oxa-5-azabicyclo[4.2.0]octane-4-yl)-5-chloro-N-methylquinoxalin-2-amine (90 mg, 0.12 mmol) in tetrahydrofuran / saturated sodium bicarbonate (2 mL / 2 mL), and the mixture was stirred for 0.5 hours. After the reaction was complete, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini-C18 150 x 21.2 mm, 5 μm, mobile phase: ACN-H2O (0.1% FA), gradient: 28-30) and SFC (column: Chiralpak-AD-H, mobile phase: CO2:IPA (0.2% FA)). After resolution of NH4OH (40:60), we obtain 1-((1R,4S,6S)4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]octan-5-yl)prop-2-en-1-one, 1-((1S,4R,6R)4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]octan-5-yl)prop-2-en-1-one. -2-en-1-one, 1-((1S,4S,6R)4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]octan-5-yl)prop-2-en-1-one, 1-((1R,4R,6S)4-(8-chloro-3-(methylamino)quinoxalin-6-yl)-2-oxa-5-azabicyclo[4.2.0]octan-5-yl)prop-2-en-1-one.

[0463] Cpd-12: 0.42 mg, retention time: 3.34 min. LCMS calculated value (calc.for) C 18 H 20 ClN4O2[M+H] + m / z = 359.1; Found value: 359.1. 1H NMR (400MHz, MeOD) δ8.23 (s, 1H), 7.69 (s, 1H), 7.56 (s, 1H), 6.78 (dd, J = 16. 9,10.6Hz,1H),6.31(d,J=16.6Hz,1H),5.85(d,J=10.5Hz,1H),5.41-5.36(m ,1H),5.36-5.32(m,1H),4.62-4.60(m,1H),4.47-4.28(m,1H),3.90-3.84(m ,1H),3.02(s,3H),2.52-2.45(m,1H),2.21-2.17(m,1H),2.07-2.00(m,2H).

[0464] Cpd-12A and Cpd-12B: 1.72 mg, retention times: 4.28 min and 4.82 min, respectively. LCMS calculated values ​​(calc.for) C 18 H 20 ClN4O2[M+H] + m / z = 359.1; Found value: 359.1. 1 H NMR (400MHz, MeOD) δ8.32-8.12(m,1H),7.37-7.34(m,2H),6.80-6.53(m,1H),6.37-6.14(m,1H),5.95-5.44(m,2H),5.42-5.20(m,1H),4.75-4. 60(m,1H),4.56-4.36(m,1H),3.92-3.72(m,1H),3.22-2.83(m,3H),2.5 8-2.43(m,1H),2.43-2.26(m,1H),2.26-2.15(m,1H),2.15-1.93(m,1H).

[0465] Cpd-12C: 1.50 mg, retention time: 6.11 min. LCMS calculated value (calc.for) C 18 H 20 ClN4O2[M+H] + m / z = 359.1; Found value: 359.1. 1H NMR(400MHz,MeOD)δ8.21(s,1H),7.54-7.30(m,2H),6.69-6.50(m,1H),6.28-6.15(m,1H),5.85-5.50(m,2H),5.27(d,J=17.9Hz,1 H),4.73-4.62(m,1H),4.54-4.37(m,1H),3.91-3.75(m,1H),3.01(s,3H),2.58-2.44(m,1H),2.43-2.27(m,1H),2.27-2.03(m,2H).

[0466] Example 13 Preparation of compounds Cpd-13 and Cpd-13A

[0467] Note: "or 1" in the structural formulas Cpd-13 and Cpd-13A indicates that the compound has a single stereoconfiguration, but its configuration is uncertain, meaning that the compound may have a single R configuration or a single S configuration.

[0468] Step 1: 2-(3-chloro-4-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclohexane

[0469] At room temperature, diphenylphosphoxyferrocene (0.22 g, 0.39 mmol), palladium acetate (0.09 g, 0.39 mmol), diphenoxylate (12.0 g, 47.2 mmol), potassium carbonate (10.9 g, 78.6 mmol), and 2-ethylhexyl acrylate (0.57 g, 3.93 mmol) were added to a dioxane (100 mL) solution of 5-bromo-1-chloro-2-fluoro-3-nitrobenzene (10.0 g, 39.3 mmol) in dioxane (100 mL). The reaction solution was purged with argon three times and heated to 75 °C with stirring for 2.5 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 2%) to obtain 2-(3-chloro-4-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboropentane (11.8 g, yield: 99.6%).

[0470] Step 2: 5-(3-chloro-4-fluoro-5-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester

[0471] At room temperature, 5-((diphenoxyphospho)oxo)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester (14.4 g, 33.2 mmol), tetraphenylphosphine palladium (0.77 g, 0.66 mmol), sodium carbonate (7.03 g, 66.3 mmol), and sodium formate (1.13 g, 16.6 mmol) were added to a mixed solution of 2-(3-chloro-4-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclohexane (10.0 g, 33.2 mmol) and water (80 mL). The reaction solution was purged with argon three times and heated to 80 °C with stirring for 2 hours. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–4%) to give 5-(3-chloro-4-fluoro-5-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester (8.54 g, yield: 71.8%). LCMS calculated value (calc.for) C 15 H 17 ClFN2O5[M+H] + m / z = 359.1; Found value: 359.1.

[0472] Step 3: 5-(4-amino-3-chloro-5-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester

[0473] At room temperature, 30% ammonia (4.88 g, 41.8 mmol) was added to a solution of 5-(3-chloro-4-fluoro-5-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester (5.0 g, 13.9 mmol) in dioxane (50 mL). The reaction solution was heated to 100 °C and stirred for 2 hours. After the reaction was completed, the solution was concentrated to give 5-(4-amino-3-chloro-5-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester (4.9 g, yield: 98.8%). LCMS calculated value (calc.for) C 11 H 11 ClN3O5[M-C4H8+H] + m / z = 300.1; Found value: 300.1.

[0474] Step 4: 2-Chloro-4-(morpholin-3-yl)-6-nitroaniline

[0475] At room temperature, trifluoroacetic acid (15 mL) was added to a solution of 4.90 g (13.8 mmol) of tert-butyl 5-(4-amino-3-chloro-5-nitrophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester (15 mL) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium cyanoborohydride (1.3 g, 20.7 mmol) was added to the reaction mixture, and the mixture was stirred for another 0.5 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give 2-chloro-4-(morpholin-3-yl)-6-nitroaniline (3.5 g, yield: 98.6%). LCMS calculated value (calc.for) C 10 H 13 ClN3O3[M+H] + m / z = 258.1; Found value: 258.2.

[0476] Step 5: 1-(3-(4-amino-3-chloro-5-nitrophenyl)morpholino)-2,2,2-trifluoroethane-1-one

[0477] Triethylamine (5.89 mL, 40.8 mmol) and trifluoroacetic anhydride (2.83 mL, 20.4 mmol) were added to a solution of 2-chloro-4-(morpholin-3-yl)-6-nitroaniline (3.5 g, 13.6 mmol) in dichloromethane (35 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the residue was concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–30%) to give 1-(3-(4-amino-3-chloro-5-nitrophenyl)morpholino)-2,2,2-trifluoroethane-1-one (3.3 g, yield: 68.7%).

[0478] Step 6: (tert-Butoxycarbonyl)(2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)tert-butyl carbamate

[0479] At room temperature, 4-dimethylaminopyridine (0.57 g, 4.67 mmol) and di-tert-butyl dicarbonate (4.72 mL, 20.5 mmol) were added to a tetrahydrofuran (30 mL) solution of 1-(3-(4-amino-3-chloro-5-nitrophenyl)morpholino)-2,2,2-trifluoroethane-1-one (3.3 g, 9.33 mmol), and the mixture was stirred for 1 hour. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give (tert-butyloxycarbonyl)(2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholino-3-yl)phenyl)carbamate (5.0 g, yield: 96.8%). LCMS calculated value (calc.for) C 18 H 20 ClF3N3O8[M-C4H8+H] + m / z = 498.1; Found value: 498.2.

[0480] Step 7: (2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)tert-butyl carbamate

[0481] At room temperature, trifluoroacetic acid (2.5 mL) was added to a solution of (tert-butyloxycarbonyl)(2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)carbamate (5.0 g, 9.03 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)carbamate (4.0 g, yield: 97.7%). LCMS calculated value (calc.for) C 17 H 18 ClF3N3O6[MH] - m / z = 452.1; Found value: 452.3.

[0482] Step 8: N-(tert-butoxycarbonyl)-N-(2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine methyl ester-d2

[0483] At room temperature, cesium carbonate (5.74 g, 17.6 mmol) and methyl 2-bromo-2,2-dideuterated acetate (1.37 g, 8.81 mmol) were added to a solution of tert-butyl (2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)carbamate (4.0 g, 8.81 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred at room temperature for 0.5 h. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–30%) to N-(tert-butoxycarbonyl)-N-(2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine methyl ester-d2 (4.0 g, yield: 86.0%). LCMS calculated value (calc.for) C 16 H 14 ClD2F3N3O8[M-C4H8+H] + m / z = 472.1; Found value: 472.2.

[0484] Step Nine: (2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine methyl ester-2,2-d2

[0485] At room temperature, trifluoroacetic acid (1.0 mL) was added to a solution of N-(tert-butoxycarbonyl)-N-(2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine methyl ester-d2 (1.0 g, 1.89 mmol) in dichloromethane (4.0 mL). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to 5 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–30%) to (2-chloro-6-nitro-4-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)phenyl)glycine methyl ester-2,2-d2 (0.80 g, yield: 98.7%). LCMS calc.forC 15 H 14 ClD2F3N3O6[M+H] + m / z = 428.1; Found value: 428.2.

[0486] Step 10: 5-Chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one-3,3-d2

[0487] At room temperature, iron powder (0.52 g, 9.35 mmol) and ammonium chloride (0.50 g, 9.35 mmol) were added to a mixture of ethanol (8.0 mL) and water (2.0 mL) containing methyl glycine ester-2,2-d2 (0.8 g, 1.87 mmol). The reaction mixture was heated to 80 °C and stirred for 1 hour. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL x 2). The combined organic phases were dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one-3,3-d2 (0.60 g, yield: 87.7%). LCMS calc.forC 14 H 12 ClD2F3N3O3[M+H] + m / z = 366.1; Found value: 366.2.

[0488] Step 11: 5-Chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-2(1H)-one-3-d

[0489] At room temperature, manganese dioxide (0.71 g, 8.20 mmol) was added to a solution of 5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one-3,3-d2 (0.60 g, 1.64 mmol) in dioxane (5.0 mL). The reaction mixture was heated to 90 °C and stirred for 1 hour. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (10 mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-2(1H)-one-3-d (0.4 g, yield: 67.2%). LCMS calculated value (calc.for) C 14 H 11 ClDF3N3O3[M+H] + m / z = 363.1; Found value: 363.2.

[0490] Step 12: 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)-2,2,2-trifluoroethane-1-one

[0491] At room temperature, methylamine hydrochloride (0.07 g, 1.10 mmol), N,N-diisopropylethylamine (0.21 g, 1.65 mmol), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (0.34 g, 0.66 mmol) were added to a solution of 5-chloro-7-(4-(2,2,2-trifluoroacetyl)morpholin-3-yl)quinoxalin-2(1H)-one-3-d (0.20 g, 0.55 mmol) in N,N-dimethylformamide (3.0 mL). The reaction mixture was heated to 50 °C and stirred for 1 hour. After the reaction was complete, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%–60%) to 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)-2,2,2-trifluoroethane-1-one (0.18 g, yield: 86.9%). LCMS calculated value (calc.for) C 15 H 14 ClDF3N4O2[M+H] + m / z = 376.1; Found value: 376.2.

[0492] Step Thirteen: 5-Chloro-N-methyl-7-(morpholin-3-yl)quinoxaline-3-d-2-amine

[0493] Potassium carbonate (0.13 g, 0.96 mmol) was added to a methanol (3.0 mL) solution of 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)-2,2,2-trifluoroethane-1-one (0.18 g, 0.48 mmol) at room temperature. The reaction solution was heated to 60 °C and stirred for 1 hour. The reaction solution was concentrated under vacuum to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0%–5%) to give 5-chloro-N-methyl-7-(morpholin-3-yl)quinoxalin-3-d-2-amine (0.12 g, yield: 89.6%). LCMS calculated value (calc.for) C 13 H 15 ClDN4O[M+H] + m / z = 280.1; Found value: 280.2

[0494] Step Fourteen: 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)prop-2-en-1-one

[0495] At room temperature, sodium bicarbonate (108 mg, 1.29 mmol) and acryloyl chloride (38.8 mg, 0.43 mmol) were added to a mixture of tetrahydrofuran (4.0 mL) and water (1.0 mL) containing 5-chloro-N-methyl-7-(morpholin-3-yl)quinoxaline-3-d-2-amine (120 mg, 0.43 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Durashell C18(L), 10 μm, 21.2*250 mm; mobile phase: A (0.1% FA aqueous solution) B (ACN)) to give 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)prop-2-en-1-one (65.0 mg, yield: 45.4%). LCMS calculated value (calc.for) C 16 H 17 ClDN4O2[M+H] + m / z = 334.1; Found value: 334.3.

[0496] Step 15: (R)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)prop-2-en-1-one

[0497] 1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)prop-2-en-1-one (65.0 mg, 0.19 mmol) was purified by SFC (column: Daicel ChiralPak AD-H 250*30mm ID, 5 μm; mobile phase A: supercritical CO2, mobile phase B: EtOH; A:B = 70:30, flow rate 50 mL / min, column temperature: 38℃, nozzle pressure: 100 Bar) to obtain (R)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)prop-2-en-1-one and (S)-1-(3-(8-chloro-3-(methylamino)quinoxalin-6-yl-2-d)morpholino)prop-2-en-1-one.

[0498] Cpd-13: 27.0 mg, yield: 41.6%, retention time: 0.802 min. LCMS calculated value (calc.for) C 16 H 17ClDN4O2[M+H] + m / z = 334.1; Found value: 334.2. 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=5.5Hz,1H),7.56-7.27(m,2H),6.88(t,J=13.7Hz,1H),6.25(dd,J=16.6,2.4Hz,1H),5.78(d,J=10.4Hz ,1H),5.51(d,J=84.2Hz,1H),4.50(d,J=12.3Hz,1H),4.33-3.76(m,3H),3.52(t,J=11.6Hz,1H),3.30-3.08(m,1H),2.92(d,J=4.8Hz,3H).

[0499] Cpd-13A: 22.0 mg, yield: 33.9%, retention time: 1.34 min. LCMS calculated value (calc.for) C 16 H 17 ClDN4O2[M+H] + m / z = 334.1; Found value: 334.2. 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=4.9Hz,1H),7.61-7.28(m,2H),7.01-6.80(m,1H),6.25(dd,J=16.6,2.4Hz,1H),5.78(d,J=10.4Hz,1 H),5.51(d,J=80.4Hz,1H),4.50(d,J=12.3Hz,1H),4.35-3.75(m,3H),3.52(t,J=11.7Hz,1H),3.30-3.06(m,1H),2.91(d,J=4.8Hz,3H).

[0500] Biological experiment:

[0501] I. NRF2 transcriptional activity inhibition assay

[0502] NRF2 initiates the transcription of various downstream genes by binding to the promoter's antioxidant response element (ARE). The ARE luciferase reporter gene assay uses the luminescence signal of luciferase as a detection indicator to detect the effect of compounds on NRF2 transcriptional activity.

[0503] Cell line construction and maintenance: KYSE-70 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd., and were confirmed to be correct through short tandem repeat (STR) identification. After packaging the virus with the ARE-luciferase plasmid, KYSE-70 cells were infected according to standard viral infection procedures, followed by antibiotic selection to obtain stable ARE-luciferase transgenic cells. Stable transgenic cells were cultured in RPMI-1640 (Gibco, C11875500BT) medium supplemented with 10% fetal bovine serum (Gibco, 10099141C), 1% penicillin-streptomycin (Gibco, 15140-122), and 1.5 μg / mL puromycin (Beyotime, ST551).

[0504] Compound Assay: 30,000 ARE-luciferase KYSE-70 stable cell lines were seeded in 96-well flat-bottomed plates (corning, 3610) containing 100 μL of medium per well and cultured overnight to restore cell state. Compounds were added in an incremental concentration gradient: DMSO treatment served as a positive control (reading set at 100% activity); 0.3 μM Actinomycin D treatment served as a negative control (reading set at 0% activity). After 18 hours of treatment, the plates were equilibrated to room temperature for 30 minutes, and the luciferase luminescence signal was measured on a Spark (Tecan) microplate reader by adding ONE-Glo Luciferase substrate reagent (Promega, E6120). The calculation formula was used.

[0505] The relative activities of each group are expressed as percentage changes relative to the positive control group, fitted to a four-parameter nonlinear curve using the GraphPad Prism 10 program. Imax is calculated as 100-Bottom and used to evaluate compound activity.

[0506] Table 1: Inhibitory effect of compounds on NRF2 transcriptional activity in KYSE-70 cells

[0507] Ref.1 is Selected from WO2024073587A1.

[0508] *+ refers to IC 50 >1000nM, ++ indicates 100nM <IC 50 ≤1000nM, +++ indicates 10nM <IC 50 ≤100nM, ++++ refers to 3nM <IC 50 ≤10nM, +++++ refers to IC 50 ≤3nM.

[0509] *A refers to I max ≤50%, B refers to 50%. max ≤80%, C refers to 80%. max ≤90%, D refers to I max >90%.

[0510] Evaluation of drug interactions related to metabolic enzymes.

[0511] II. KEAP1 and CUL3 Interaction Experiment

[0512] This experiment used time-resolved resonance energy transfer fluorescence (HTRF) as the detection method to test the effect of compounds on the protein-protein interaction between KEAP1 and CUL3. Recombinant GST-labeled KEAP1 protein used in the HTRF experiment was expressed in insect SF9 cells and purified to 90% purity using a Glutathione Sepharose column. His and Avi-labeled CUL3 / RBX2 used in the HTRF experiment were expressed in insect SF9 cells and purified to 90% purity using a Ni-NTA column, followed by in vitro biotinylation with BirA enzyme.

[0513] The binding of recombinant GST-labeled KEAP1 protein and biotin-labeled CUL3 / RBX2 was measured using fluorescence resonance energy transfer (FRET). Specifically, the binding between KEAP1 and CUL3 / RBX2 was measured by detecting the fluorescence of the interaction between Tb-conjugated streptavidin (Revity, 610SATLB) and GST-bound XL665 antibody (Revity, 61GSTXLB). Compounds were prepared as 10 mM stock solutions and serially diluted 10 times at a 1:3 ratio in DMSO. 100 nL of the stock solution was transferred row-by-row to a 384 assay plate using an Echo, with 1% DMSO and two replicates per column. 2.5 μL of KEAP1 solution was added to the assay plate and incubated at room temperature for 30 min. 2.5 μL of biotin-CUL / RBX2 solution was added to the assay plate, followed by 5 μL of assay solution (GST-XL665 antibody and streptavidin-Tb) to each well of the assay plate. The assay plate was incubated at room temperature for 1 hour. Fluorescence was read on BMG (BMG LRBTECH) at 665 nm and 620 nm. The ratio of each well (ratio_665nm / 620nm - ratio_background), the percentage change in activation rate relative to DMSO treatment, was calculated and fitted to a four-parameter nonlinear curve using GraphPad Prism 10.

[0514] Table 2: Results of KEPA1 and CUL3 interaction experiments​​

[0515] *+ refers to IC 50 >1000nM, ++ indicates 100nM <IC 50 ≤1000nM, +++ indicates IC 50 ≤100nM.

[0516] III. NRF2 Degradation Experiment

[0517] This experiment used time-resolved fluorescence resonance energy transfer fluorescence as a detection method to test the effect of compounds on the degradation of NRF2 protein.

[0518] Cell line culture and maintenance: KYSE-70 and HCC95 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd., and were confirmed by short tandem repeat (STR) identification. KYSE-70 and HCC95 cells were cultured in RPMI-1640 (Gibco, C11875500BT) medium supplemented with 10% fetal bovine serum (Gibco, 10099141C) and 1% penicillin-streptomycin (Gibco, 15140-122). Cell lines were cultured according to the standard instructions of the American Center for Type Culture Collection.

[0519] Compound Assay: 75,000 KYSE-70 cells or 90,000 HCC95 cells were seeded in 96-well flat-bottomed plates (corning, 3610) containing 100 μL of culture medium per well and incubated overnight to recover. Compounds were added in an incremental concentration gradient, with DMSO treatment as a positive control, and incubated for 6 hours. During this time, the assay kit (HTRF Human TOTAL NRF2 DETECTION KITS, Revvity, 64NRF2TPEG) was removed, and the necessary reagents were equilibrated to room temperature. Cell lysis buffer and HTRF assay working solution were prepared according to the kit instructions. After compound treatment, the culture medium was aspirated from the plates, and 50 μL of cell lysis buffer was added to each well. The plates were incubated with shaking at room temperature for 60 minutes. 16 μL of cell lysis product was aspirated from each well and transferred to a new 384-well white assay plate (ProxiPlate 384-shallow well Plus, white, Revvity, 6008280). Then, 4 μL of HTRF detection working solution was added to each well of a 384-well white detection plate. After a brief centrifugation (1000 rpm, 30 s), the plates were sealed and incubated overnight at room temperature in the dark. HTRF signals were detected using a Spark microplate reader (Tecan): the excitation wavelength was set to 320 nm (Bandwidth 25 nm); two emission signals were detected at wavelengths of 620 nm (Bandwidth 10 nm, Lagtime 100 μs) and 665 nm (Bandwidth 8 nm, Lagtime 100 μs). The HTRF detection value was expressed as the ratio of the emission signal values ​​at the two wavelengths (Em665 / Em620 Ratio). The DMSO treatment group was set to 100% activity; the Lysis buffer treatment served as a negative control, with a reading set to 0% activity. After subtracting the negative control signal, the percentage degradation rate of NRF2 protein levels by each compound concentration was calculated based on the changes in each sample group relative to the positive control group. Using GraphPad Prism 10 software, the compound concentration log value and its response value (percentage inhibition rate) were fitted to a four-parameter logistic nonlinear curve.

[0520] Table 3: Results of NRF2-HTRF assays in KYSE-70 and HCC95 cells

[0521] *+ refers to DC 50 >1000nM, ++ indicates 100nM <DC 50 ≤1000nM, +++ indicates 10nM <DC 50 ≤100nM, ++++ refers to DC50 ≤10nM.

[0522] IV. Cell proliferation experiment under 3D culture conditions

[0523] 3D cell culture has many advantages over traditional 2D culture. It can better simulate the tumor microenvironment with hypoxia and nutrient gradients and the heterogeneity of tumors in vivo, and has a higher correlation with drug sensitivity and in vivo experiments.

[0524] In this experiment, the antiproliferative effects of the compounds on the human esophageal cancer cell line KYSE-70 and the human lung cancer cell line HCC95 were evaluated under 3D culture conditions using the ATP quantification method. The activity showed a good correlation with the number of viable cells. KYSE-70 and HCC95 cells were cultured in RPMI-1640 (Gibco, C11875500BT) medium supplemented with 10% fetal bovine serum (Gibco, 10099141C) and 1% penicillin-streptomycin (Gibco, 15140-122). Cell lines were cultured according to the standard instructions of the American Center for Type Culture Collection. Cell lines were identified by short tandem repeat profiles.

[0525] In proliferation assays, 400 KYSE-70 cells or 500 HCC95 cells were seeded overnight in 96-well clear, round-bottom, colorless, ultra-low adsorption treatment plates (Corning, 7007) containing 90 μL of medium per well to restore cell status. Compound diluted in 10 μL of medium was added in an incremental concentration gradient, with DMSO treatment serving as a positive control. On day 5 of compound treatment, 50 μL of medium was added to each well. On day 10 of compound treatment, the plates were equilibrated to room temperature for 30 minutes, and the number of viable cells was measured by adding 3D CellTiter-Glo reagent (Promega, G9683). Chemiluminescence readings were measured on a Spark (Tecan). Relative viability for each group was expressed as a percentage change relative to the positive control group and then fitted to a four-parameter nonlinear curve using the GraphPad Prism 10 program.

[0526] Table 4: Results of 3D CTG assay in KYSE-70 and HCC95 cells

[0527] *+ refers to IC 50 >1000nM, ++ indicates 100nM <IC 50 ≤1000nM, +++ indicates 10nM <IC 50 ≤100nM, ++++ refers to IC 50 ≤10nM.

[0528] V. Evaluation of in vitro metabolic stability: Study on the metabolic stability of liver microsomes

[0529] 1. Experimental objective: To evaluate the metabolic stability of the test compound in human / monkey / dog / rat / mouse liver microsomes.

[0530] 2. Experimental reagents and materials:

[0531] Reagents:

[0532] Material:

[0533] 3. Experimental methods:

[0534] 1) Buffer A: 1.0 L of 0.1 M potassium dihydrogen phosphate buffer (containing 1.0 mM EDTA dipotassium salt);

[0535] Buffer B: 1.0 L of 0.1 M dipotassium hydrogen phosphate buffer (containing 1.0 mM dipotassium EDTA);

[0536] Buffer C: Add buffer A to 700 mL of buffer B and adjust the pH to 7.4.

[0537] 2) Preparation of solutions for the reference compound (ketoselin) and the test compound:

[0538] 500 μM solution: Add 10 μL of 10 mM stock solution to 190 μL of ACN;

[0539] 1.5 μM Dosage Solution (dissolved in liver microsome solution (final concentration 0.75 mg / mL)): Add 1.5 μL of 500 μM solution and 18.75 μL of 20 mg / mL liver microsomes to 479.75 μL of buffer C (operate on ice), and gently vortex to mix.

[0540] 3) Dissolve NADPH in buffer C to prepare NADPH stock solution (6mM).

[0541] 4) Add 30 μL of 1.5 μM drug solution (containing 0.75 mg / mL liver microsomes) to the wells of a 96-well plate set at different time points (0 min, 5 min, 15 min, 30 min, 45 min) (operate on ice).

[0542] 5) Preparation of 0-minute sample: First, add 135 μL of ACN (including internal standard) to the 0-minute well, and then add 15 μL of 6 mM NADPH solution.

[0543] 6) Preheat the 96-well plate containing 1.5 μM drug solution and NADPH solution at 37°C for 5 minutes.

[0544] 7) Add 15 μL of preheated 6 mM NADPH solution to the wells set at 5 minutes, 15 minutes, 30 minutes and 45 minutes, start the reaction and start timing.

[0545] 8) When the timer displays 5 minutes, 15 minutes, 30 minutes and 45 minutes, add 135 μL of ACN (including internal standard) to terminate the reaction.

[0546] 9) After quenching, the 96-well plate was shaken for 10 minutes (600 rpm / min) on a shaker (IKA, MTS2 / 4), and then the sample was centrifuged for 15 minutes at 5594×g on a centrifuge (Thermo Multifuge×3R).

[0547] 10) Take 30 μL of supernatant from each well and transfer it to a 96-well sample plate containing 150 μL of purified water. Vortex and analyze by LC / MS / MS. 4. Data Processing Methods:

[0548] The slope (ke) was determined by plotting the natural logarithm of the percentage of the remaining compound against time, and T was calculated using the first-order kinetic formula. 1 / 2 and intrinsic clearance rate (CL) int ):

[0549] The remaining percentage of the compound is calculated as follows:

[0550] Intrinsic clearance rate CL int (μL / min / mg protein)=0.693*1000 / T 1 / 2 Protein concentration (0.5 mg protein / mL)

[0551] Table 5: Metabolic stability of compounds in liver microsomes of humans, monkeys, dogs, rats, and mice

[0552] The data above show that the compounds of the present invention have high metabolic stability in liver microsomes of humans, monkeys, dogs, rats, and mice, and are significantly better than the reference compounds.

[0553] VI. Pharmacokinetic Studies in Mice

[0554] 1. Experimental objective: To test the pharmacokinetics of the compound in CD-1 mice.

[0555] 2. Experimental instruments and materials:

[0556] Animal: Male CD-1 mouse

[0557] instrument:

[0558] Solvent:

[0559] Intravenous injection: PEG400 / Solutol HS15 / pH 7.0 PBS buffer = 10 / 10 / 80% aqueous solution; Oral gavage: PEG400 / Solutol HS15 / pH 7.0 PBS buffer = 10 / 10 / 80% aqueous solution.

[0560] 3. Experimental methods:

[0561] Six male mice were used. They were fasted the evening before administration but allowed free access to water. During the experiment, the mice had free access to food and water. The drugs were administered intravenously or orally. Animal condition was observed and any abnormal behavior was recorded after administration. Blood samples were collected from the orbital sinus at 0.0833, 0.25, 1, 2, 4, 8, and 24 hours after intravenous injection; and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after gavage. 20 μL of plasma was collected, and 250 μL of acetonitrile (containing dexamethasone as an internal standard) was added to precipitate proteins. The mixture was centrifuged at 4000 rpm for 20 minutes at 4°C. 180 μL of the supernatant was mixed with 180 μL of an aqueous solution containing 0.1% formic acid in a 96-well plate. 10 μL of the final sample was then used for LC-MS / MS analysis.

[0562] 4. Data processing methods and results:

[0563] A standard curve was established using the internal standard method, with the theoretical standard curve concentration plotted on the x-axis and the peak area ratio (peak area of ​​the tested compound / peak area of ​​the internal standard) plotted on the y-axis. A linear regression method (weighted factor 1 / X²) was used, and R0 was calculated. 2 >0.9900. Calculations for unknown samples were performed using a standard curve. Pharmacokinetic parameters were calculated using a non-compartmental analysis model in WinNonlin 8.2 software and presented in the report. Parameters include Clint, C... max And AUC, etc.

[0564] Table 6: Pharmacokinetic parameters of the compounds in CD-1 mice

[0565] The data above show that the compounds of the present invention have a lower clearance rate and a higher oral exposure in mice compared with the reference compounds.

[0566] VII. Pharmacokinetic Studies in Rats

[0567] 1. Experimental objective: To test the pharmacokinetics of the compound in SD rats.

[0568] 2. Experimental instruments and materials:

[0569] Animal: Male SD rat

[0570] instrument:

[0571] Reagents:

[0572] Solvent:

[0573] Oral gavage: DMSO / Solutol HS15 / pH7.0 PBS buffer (0.01M) = 5 / 10 / 85% aqueous solution.

[0574] 3. Experimental methods:

[0575] Three male rats were used. They were fasted the evening before administration but had free access to water. During the experiment, the rats had free access to food and water. After oral administration of the drug, the animals' condition was observed and any abnormal behaviors were recorded. Blood samples were collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after gavage. 50 μL of plasma was collected, and 500 μL of acetonitrile (containing dexamethasone as an internal standard) was added to precipitate proteins. The mixture was centrifuged at 4000 rpm for 20 minutes at 4°C. 300 μL of the supernatant was mixed with 300 μL of Watson's aqueous solution in a 96-well plate, and 5 μL of the sample was used for LC-MS / MS analysis.

[0576] 4. Data processing methods and results:

[0577] A standard curve was established using the internal standard method, with the theoretical standard curve concentration plotted on the x-axis and the peak area ratio (peak area of ​​the tested compound / peak area of ​​the internal standard) plotted on the y-axis. A linear regression method (weighted factor 1 / X²) was used, and R0 was calculated. 2 >0.9900. Calculations for unknown samples were performed using a standard curve. Pharmacokinetic parameters were calculated using a non-compartmental analysis model in WinNonlin 8.2 software and presented in the report. Parameters include C... max And AUC, etc.

[0578] Table 7: Pharmacokinetic parameters of the compounds in SD rats

[0579] The data above show that the compounds in the embodiments of the present invention have higher oral exposure levels in rats compared with the reference compounds.

[0580] VIII. In vivo efficacy experiment of KYSE-70 human esophageal cancer xenograft mouse model

[0581] 1. Experimental objective: To test the in vivo pharmacodynamic activity of the compound in a female BALB / c Nude mouse model with subcutaneous xenograft of KYSE-70 human esophageal cancer cells.

[0582] 2. Experimental materials:

[0583] Animals: 5-6 week old female BALB / c Nude mice;

[0584] Solvent information:

[0585] Solvent: 5% DMSO+10% Solutol HS15+85% pH 9.0Tris buffer (0.05M)

[0586] Main reagent and consumable information:

[0587] Main instrument information:

[0588] 3. Experimental Design:

[0589] Cell culture: KYSE70 cells were cultured in medium containing RPMI-1640 + 10% FBS + 1% P / S; the cells were cultured in an incubator at 37°C and 5% carbon dioxide.

[0590] Tumor modeling and grouping: KYSE70 cells were digested and collected, counted, and resuspended in a mixture of equal proportions of culture medium and Matrigel (Corning Biocoat 356234) to achieve a cell concentration of 2 × 10⁻⁶ cells / year. 7 / mL. Take a volume of 100μL (using 2×10⁻⁶) 6 Cells (per mouse) were transplanted subcutaneously into the right anterior shoulder and back of mice. Following inoculation, tumor growth was monitored until the average tumor volume reached 138.42 ± 2.05 mm. 3 The patients were randomly assigned to groups. The day the medication was started was designated Day 0.

[0591] 4. Experimental Design:

[0592] The grouping and administration information for this pharmacodynamic experiment are shown in Table 8. Mice in group G1 were administered the solvent control (5% DMSO + 10% Solutol HS15 + 85% pH 9.0 Tris buffer (0.05M)) orally once daily. Mice in groups G2 and G3 were administered Ref. 1 orally once daily at doses of 5 mg / kg and 25 mg / kg, respectively. Mice in groups G4 and G5 were administered Cpd-1 orally once daily at doses of 5 mg / kg and 25 mg / kg, respectively. The administration was carried out for a total of 49 days.

[0593] Table 8: In vivo pharmacodynamic design of KYSE-70 xenograft mouse model

[0594] 5. Experimental observation and result judgment:

[0595] Experimental observation: After cell inoculation, the mice's condition, mobility, food intake, and water consumption were closely monitored daily. Any deaths, abnormal behavior, or disease symptoms were immediately reported and recorded to determine appropriate intervention. After grouping the mice, their body weight was measured twice weekly. Tumor volume was measured twice weekly using calipers. The formula for calculating tumor volume was TV = 0.5 × length × width × width.

[0596] Data processing: Tumor volume inhibition rate (TGI) (%): The formula for calculating TGI (%) is as follows: TGI (%) = [1 – (mean tumor volume at the end of treatment – ​​mean tumor volume at the beginning of treatment) / (mean tumor volume at the end of treatment in the solvent control group – mean tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0597] Statistical analysis: Tumor volume and animal body weight are expressed as Mean ± SEM (mean standard error). Tumor volumes were statistically compared between different groups. All statistical analyses were performed in GraphPad Prism 9.0. t-tests were used to analyze significant differences in tumor volume between different groups, with the Vehicle group as a control. p ≥ 0.05 was considered no significant difference, p < 0.05 was considered significant, and p < 0.001 was considered highly significant.

[0598] 6. Experimental Results:

[0599] Figure 2 shows the tumor growth curves of the control group and each experimental group in the pharmacodynamic evaluation experiment of the KYSE-70 mouse human esophageal cancer xenograft model, and Figure 3 shows the changes in relative body weight of the mice. Table 9 shows the average tumor volume, tumor volume inhibition rate (TGI%), and comparison results of each group at the end of the experiment.

[0600] At the experimental endpoint (day 49 after grouping), the mean tumor volume of mice in the solvent control group (G1) was 828.5 ± 25.9 mm. 3 The mean tumor volume in mice treated with 5 mg / kg Ref.1 (G2) was 539.0 ± 21.4 mm. 3 (TGI 42.0%, p < 0.001), the mean tumor volume in mice in the 25 mg / kg Ref.1 treatment group (G3) was 96.2 ± 6.5 mm. 3 (TGI 106.1%, p < 0.001), the mean tumor volume in the 5 mg / kg Cpd-1 treatment group (G4) was 423.8 ± 8.4 mm. 3(TGI 58.7%, p < 0.001), the mean tumor volume in the 25 mg / kg Cpd-1 treatment group (G5) mice was 69.1 ± 5.3 mm. 3 (TGI: 110.1%, p < 0.001). These results indicate that both Cpd-1 and Ref.1 exhibited dose-dependent tumor-suppressive activity in KYSE-70 xenograft mice, with Cpd-1 showing better activity than Ref.1 at the same test dose. The mice in all groups were in good condition with relatively stable body weight, and the test substances Cpd-1 and Ref.1 had no effect on mouse body weight.

[0601] Table 9: In vivo efficacy results of KYSE-70 xenograft mouse model

[0602] IX. In vivo efficacy experiment of HCC95 human lung cancer xenograft mouse model

[0603] 1. Experimental objective: To test the in vivo pharmacodynamic activity of the compound in a female NPG mouse model of subcutaneous xenograft of HCC95 human lung cancer cells.

[0604] 2. Experimental materials:

[0605] Animals: 6-8 week old female NPG mice;

[0606] Solvent information:

[0607] Vehicle: 5% DMSO / 10% Solutol HS15 / 85% PBS buffer (pH 7.0)

[0608] Main reagent and consumable information:

[0609] Main instrument information:

[0610] 3. Experimental Design:

[0611] Cell culture: HCC95 cells were cultured in RPMI 1640 medium with 10% fetal bovine serum at 37°C in a 5% CO2 incubator.

[0612] Tumor modeling and grouping: HCC95 cells were digested and collected, counted, and resuspended in a mixture of equal proportions of culture medium and Matrigel (YEASEN 40183ES10). 200 μL of the mixture (5 × 10⁻⁶ cells / mL) was taken. 6 Cells (per mouse) were transplanted subcutaneously into the right anterior shoulder and back of mice. Following inoculation, tumor growth was monitored until the average tumor volume reached approximately 143 mm². 3Students were randomly assigned to groups. The day on which medication began was designated Day 0.

[0613] 4. Experimental Design:

[0614] The grouping and administration information for this pharmacodynamic experiment are shown in Table 10. Mice in group G1 were administered the solvent control solution (5% DMSO / 10% Solutol HS15 / 85% PBS buffer, pH 15) orally once daily. 7.0)) Mice in group G2 were administered Nab-paclitaxel intravenously once a week at a dose of 7.5 mg / kg; mice in group G3 were administered Ref.1 orally once a day at a dose of 5 mg / kg; mice in group G4 were administered Cpd-1 orally once a day at a dose of 5 mg / kg; mice in group G5 were administered Cpd-8 orally once a day at a dose of 5 mg / kg; mice in group G6 were administered Ref.1 orally once a day at a dose of 5 mg / kg and Nab-paclitaxel intravenously once a week at a dose of 7.5 mg / kg; mice in group G7 were administered Cpd-1 orally once a day at a dose of 5 mg / kg and Nab-paclitaxel intravenously once a week at a dose of 7.5 mg / kg; mice in group G8 were administered Cpd-8 orally once a day at a dose of 5 mg / kg and Nab-paclitaxel intravenously once a week, for a total of 35 days.

[0615] Table 10: In vivo pharmacodynamic design of HCC95 xenograft mouse model

[0616] Experimental observation: After cell inoculation, the mice's condition, mobility, food intake, and water consumption were closely monitored daily. Any deaths, abnormal behavior, or disease symptoms were immediately reported and recorded to determine appropriate intervention. After grouping the mice, their weight was measured three times per week. Tumor volume was measured three times per week using calipers. The formula for calculating tumor volume was TV = 0.5 × length × width × width.

[0617] Data processing: Tumor volume inhibition rate (TGI) (%): The formula for calculating TGI (%) is as follows: TGI (%) = [1 – (mean tumor volume at the end of treatment – ​​mean tumor volume at the beginning of treatment) / (mean tumor volume at the end of treatment in the solvent control group – mean tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0618] Statistical analysis: Tumor volume and animal body weight are expressed as Mean ± SEM (mean standard error). Tumor volumes were statistically compared between different groups. All statistical analyses were performed in GraphPad Prism 10.0. ANOVA was used to analyze significant differences in tumor volume between different groups, with the Vehicle group as a control. p ≥ 0.05 was considered no significant difference, p < 0.05 was considered significant, and p < 0.001 was considered highly significant.

[0619] 6. Experimental Results:

[0620] Figure 4 shows the tumor growth curves of the control group and each experimental group in the pharmacodynamic evaluation experiment of the mouse HCC95 human lung cancer xenograft model, and Figure 5 shows the changes in relative body weight of the mice. Table 11 shows the mean tumor volume, tumor volume inhibition rate (TGI) (%), and comparison results of each group at the end of the experiment.

[0621] At the experimental endpoint (day 35 after grouping), the mean tumor volume of mice in the solvent control group (G1) was 545±67 mm. 3 The mean tumor volume in mice treated with 7.5 mg / kg Nab-paclitaxel (G2 group) was 211 ± 48 mm. 3 (TGI 83.1%, p < 0.0001), the mean tumor volume in mice in the 5 mg / kg Ref.1 treatment group (G3) was 134 ± 24 mm. 3 (TGI was 102.4%, p < 0.0001), the mean tumor volume in mice in the 5 mg / kg Cpd-1 treatment group (G4) was 109 ± 24 mm. 3 (TGI was 108.5%, p < 0.0001), the mean tumor volume in mice in the 5 mg / kg Cpd-8 treatment group (G5) was 116 ± 13 mm. 3 (TGI 106.9%, p < 0.0001), the mean tumor volume in mice in the 5 mg / kg Ref. 1 + 7.5 mg / kg Nab-paclitaxel treatment group (G6) was 36 ± 3 mm. 3 (TGI 126.7%, p < 0.0001), the mean tumor volume in mice in the 5 mg / kg Cpd-1 + 7.5 mg / kg Nab-paclitaxel treatment group (G7) was 40 ± 2 mm. 3 (TGI 125.7%, p < 0.0001), the mean tumor volume in mice treated with 5 mg / kg Cpd-8 and 7.5 mg / kg Nab-paclitaxel (G8 group) was 31 ± 7 mm. 3(TGI: 128.0%, p < 0.0001). These results indicate that Cpd-1, Cpd-8, and Ref.1 all exhibited significant tumor-suppressive activity in HCC95 xenograft mice, with Cpd-1 and Cpd-8 showing superior activity compared to Ref.1 at the same test dose. The combined administration of Cpd-1, Cpd-8, and Ref.1 with Nab-paclitaxel also demonstrated a significant synergistic effect in HCC95 xenograft mice. The mice in all groups were in good condition with relatively stable body weight, and the test substances Cpd-1, Cpd-8, and Ref.1 had no effect on mouse body weight.

[0622] Table 11: In vivo efficacy results of HCC95 xenograft mouse model

Claims

A compound of formula (I), its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof: in, p is 0, 1, 2 or 3; n is 0, 1, 2, or 3; m can be 0, 1, 2, or 3; Z is O, S(=O)2, C(R 1 )2 or NR 4 ; R 4 For R 4a -C(=O)R 4a S(=O)R 4a or S(=O)2R 4a ; Each R 4a It is independently a C1-C6 alkyl or a C3-C6 cycloalkyl; Each R 1 Independently, it can be hydrogen, halogen, cyano, hydroxyl, oxo (=O), C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or -C(=O)NR. 1a R 1b ; Or two adjacent R 1 Together with the carbon atoms between them, they form unsubstituted or substituted C3-C6 cycloalkyl groups; the group A substituents are selected from: C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, deuterium, halogen, hydroxyl and cyano; Or two R atoms connected to the same carbon atom 1 Together with the carbon atom, they form an unsubstituted or substituted C3-C6 cycloalkyl group; the group A substituents are selected from: C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, deuterium, halogen, hydroxyl and cyano; R 3 It is H, deuterium, C1-C6 alkyl, or deuterated C1-C6 alkyl; R 2 for R 2a H, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, or halo-C1-C6 alkyl; R 2b and R 2c Each is independently either H or deuterium; W is a naphthyl group that is unsubstituted or substituted with one or more group B substituents, a benzo5-6 heteroaryl group that is unsubstituted or substituted with one or more group B substituents, a 6-membered heteroaryl group that is unsubstituted or substituted with one or more group B substituents, or a benzo5-6 heterocyclic group that is unsubstituted or substituted with one or more group B substituents; the 5-6 heteroaryl group contains 1-3 heteroatoms selected from N, O, and S; the 6-membered heteroaryl group contains 1-2 N atoms; Group B substituents are selected from: oxo group (=O), deuterium, halogen, hydroxyl group, carboxyl group, cyano group, NR. x R y -C(=O)NR x R y -NR x C(=O)R y -R 5 and -OR 6 ;R 5 and R 6 It can be independently an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-6 membered heterocyclic or an unsubstituted or substituted 5-6 membered heteroaryl. R 5 and R 6 The substitution mentioned herein refers to substitution by one or more group C substituents; group C substituents are selected from: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR c1 R c2 -C(=O)NR c1 R c2 and -NR c1 C(=O)R c2 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group independently contain 1-3 heteroatoms selected from N, O and S; R 1a R 1b R c1 R c2 R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S. The compound of formula (I) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, It meets one or more of the following conditions: (1) The compound of formula (I) has the following structure: (2) W is a benzo6-membered heteroaryl group that is unsubstituted or substituted by one or more group B substituents, or a 6-membered heteroaryl group that is unsubstituted or substituted by one or more group B substituents; the 6-membered heteroaryl group contains 1-3 heteroatoms selected from N; Preferably, it is benzopyrazine group without substitution or substituted by one or more group B substituents, benzopyrimidin group without substitution or substituted by one or more group B substituents, benzotriazine group without substitution or substituted by one or more group B substituents, or pyridinyl benzopyrazine group without substitution or substituted by one or more group B substituents. And, (3) The substituents in group B are selected from: D, F, Cl, Br, CN, -CH3, -CD3, -CF3, -CH2CH3, -CH2CF3, -OCH3, -OCH2CH3, -NH2, -NHCH3, -C(=O)NH2、 The compound of formula (I) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, p is 0, 1, 2 or 3; n is 0, 1, 2, or 3; m can be 0, 1, 2, or 3; Z represents O, S(=O)2, and C(R). 1 )2 or NR 4 ; R 4 For R 4a -C(=O)R 4a S(=O)R 4a or S(=O)2R 4a ;R 4a It is a C1-C6 alkyl or C3-C6 cycloalkyl; Each R 1 Independently, it can be hydrogen, halogen, cyano, hydroxyl, oxo, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or -C(=O)NR. 1a R 1b ; Or two adjacent R 1 Together with the carbon atoms between them, they form unsubstituted or substituted C3-C6 cycloalkyl groups; the group A substituents are selected from: C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, deuterium, halogen, hydroxyl and cyano; R 3 It is H, deuterium, C1-C6 alkyl, or deuterated C1-C6 alkyl; R 2 for R 2a H, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl; R 2b and R 2c Each is independently either H or deuterium; W represents a naphthyl group that is unsubstituted or substituted with one or more group B substituents, or a benzo6-membered heteroaryl group that is unsubstituted or substituted with one or more group B substituents. 1 6-membered heteroaryl groups that are unsubstituted or substituted by one or more group B substituents 2 And 6-membered heteroaryl 1 The 6-membered heteroaryl group 1 Contains 1-3 heteroatoms of N, O, and S; the 6-membered heteroaryl group 2 It contains 1-2 nitrogen atoms; Group B substituents include: oxo (=O), deuterium, halogen, hydroxyl, carboxyl, cyano, and NR. x R y -C(=O)NR x R y -NR x C(=O)R y -R 5 -OR 6 ;R 5 and R 6 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 ynyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-6 membered heterocyclic group, or an unsubstituted or substituted 5-6 membered heteroaryl; R 5 and R 6 The substitution mentioned herein refers to substitution by one or more group C substituents; group C substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR c1 R c2 -C(=O)NR c1 R c2 -NR c1 C(=O)R c2 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group contain 1-3 heteroatoms selected from N, O and S; R 1a R 1b R c1 R c2 R x R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, or a C3-C6 cycloalkyl 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S. The compound of formula (I) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, W is in, X 1 For N or CR 9a X 2 For N or CR 10a X 3 For N or CR 11a X 4 For N or CR 12a X 5 For N or CR 13a ; Y 1 For N or CR 24 Y 2 For N or CR 25 Y 3 For N or CR 26 And Y 1 Y 2 and Y 3 At least one of them is N; R 7 R 8 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 9a R 10a R 11a R 12a and R 13a Each is independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y -R 5 or -OR 6 ;R 5 and R 6 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 ynyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-6 membered heterocyclic group, or an unsubstituted or substituted 5-6 membered heteroaryl; R 5 and R 6 The substitution mentioned herein refers to substitution by one or more group C substituents; group C substituents are selected from: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR c1 R c2 -C(=O)NR c1 R c2 and -NR c1 C(=O)R c2 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group independently contain 1-3 heteroatoms selected from N, O and S; R c1 R c2 R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S. The compound of formula (I) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, W selected in, R 7 R 8 R 20 R 21 R 22 R 23 R 25 R 26 R 9a R 10a R 11a R 12a and R 13a Each is independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y -R 5 -OR 6 ;R 5 and R 6 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 ynyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-6 membered heterocyclic group, or an unsubstituted or substituted 5-6 membered heteroaryl; R 5 and R 6 The substitution mentioned herein refers to substitution by one or more group C substituents; group C substituents are selected from: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR c1 R c2 -C(=O)NR c1 R c2 and -NR c1 C(=O)R c2 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group contain 1-3 heteroatoms selected from N, O and S; R c1 R c2 R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S; Preferably, R 7 R 8 R 20 R 21 R 22 R 23 R 25 R 26 R 9a R 10a R 11a R 12a and R 13a Each is independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y The 3-6 membered heterocyclic group includes C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, and unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogen, hydroxyl, amino, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, and halo-C1-C6 alkyl; the 3-6 membered heterocyclic group and the 5-6 membered heterocyclic group contain 1-3 heteroatoms selected from N, O, and S. R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S; Preferably, R 7 R 20 R 21 R 22 R 9a and R 10a Independently, it is hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or deuterated C1-C6 alkoxy; R 8 R 23 R 25 R 26 R 11a R 12a and R 13a Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y The following are categorized as follows: C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, and unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogens, amino groups, and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S. R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S; Preferably, R 7 R 20 R 21 R 22 R 9a R 10a It can be hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, or deuterated C1-C6 alkyl; R 8 R 23 R 25 R 26 R 11a R 12a R 13a Independently, it can be hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, -CF3, -CH2CF3, -NH2, -NHCH3, -C(=O)NH2, The compound of formula (I) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, W selected in, R 7 R 10a and R 21 It can be hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy or deuterated C1-C6 alkoxy independently; R 8 R 12a R 23 R 25 and R 26 Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, 5-6-membered heteroaryl, unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogens, amino groups and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups independently contain 1-3 heteroatoms selected from N, O and S; R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S; Preferably, R 7 R 10a and R 21 It can be independently a halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, or deuterated C1-C6 alkyl; R 8 R 12a R 23 R 25 R 26 Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y The following are categorized as follows: C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, and unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from halogens, amino groups, and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S. R x R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S; Preferably, R 7 R 10a and R 21 It can be chlorine, fluorine, bromine, deuterium, or -CD3 independently; R 8 R 12a R 23 R 25 and R 26 The radicals are hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, -CF3, -CH2CF3, -NH2, -NHCH3, -C(=O)NH2, The compound of formula (I) as claimed in any one of claims 1-6, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, Compound (I) has the following structure: Among them, R 1 R 2 R 3 The definitions of W and p are the same as those in any of the corresponding claims 1-6. The compound of formula (I) as claimed in any one of claims 1-6, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, Compounds of formula (I) have any of the following structures: The definition of W is the same as that described in the corresponding claims; Preferably, in any of the general formulas III to XIII above, the C connected to W is either the C of the R configuration or the C of the S configuration. The compound of formula (I) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, Compounds of formula (I) have any of the following structures: in, R 7 R 21 and R 9a Independently, it is hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or deuterated C1-C6 alkoxy; R 8 R 12a R 23 R 25 R 26 Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, 5-6-membered heteroaryl, unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogens, amino groups and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups independently contain 1-3 heteroatoms selected from N, O and S; R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S; Preferably, R 7 R 21 and R 9a It can be independently a halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, or deuterated C1-C6 alkyl; R 8 R 12a R 23 R 25 and R 26 Independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, NR x R y -C(=O)NR x R y -NR x C(=O)R y C1-C6 alkyl, halo-C1-C6 alkyl, amino-substituted C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, unsubstituted or substituted with one or more C-group substituents, 5-6-membered heteroaryl, unsubstituted or substituted with one or more C-group substituents; the C-group substituents are selected from: halogens, amino groups and C1-C6 alkyl groups; the 3-6-membered heterocyclic groups and 5-6-membered heteroaryl groups independently contain 1-3 heteroatoms selected from N, O and S; R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S; Preferably, R 7 R 21 and R 9a Independently chlorine, fluorine, bromine, deuterium, -CD3; R 8 R 12a R 23 R 25 and R 26 Independently, it can be hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, -CF3, -CH2CF3, -NH2, -NHCH3, -C(=O)NH2, The compound of formula (I) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, Compound (I) has the following structure: in, R 7 R 9a R 10a and R 12a Independently, it is hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or deuterated C1-C6 alkoxy; R 8 Independent for NR x R y 3-6 membered heterocyclic groups that are unsubstituted or substituted by one or more group C substituents; group C substituents include: halogens, amino groups, and C1-C6 alkyl groups; the 3-6 membered heterocyclic group contains 1-3 N heteroatoms; R x R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl group, C1-C6 alkyl substituted with a C3-C6 cycloalkyl group, C3-C6 cycloalkyl group, or 4-6-membered heterocyclic group; the 5-membered heteroaryl group contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S; Preferably, R 7 R 9a R 10a and R 12a It can be hydrogen, halogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, or deuterated C1-C6 alkyl independently; R 8 Independent for NR x R y ;R x and R y Each of the following is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkyl substituted with a 5-membered heteroaryl, C1-C6 alkyl substituted with a C3-C6 cycloalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic group; the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the 4-6-membered heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, and S; Preferably, R 7 It is a halogen; R 9a R 10a and R 12a It can be hydrogen, deuterium, or halogen independently; R 8 -NH2, -NHCH3, Preferably, R 7 It is chlorine; R 9a R 10a and R 12a Independently hydrogen or deuterium; R 8 -NH2, -NHCH3, The compound of formula (I) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, Compounds of formula (I) have any of the following structures: Or, enantiomers Under the following chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Or, enantiomers In chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Chiral separation conditions: Column: normal phase chiral column, stationary phase is spherical silica gel coated with amylose-tris(3,5-dimethylphenylcarbamate); mobile phase: mobile phase A is CO2, mobile phase B is an alcohol organic solvent; Preferably, the chiral separation conditions are as follows: chromatographic column: ChiralPakAD-H; mobile phase: mobile phase A is CO2, mobile phase B is ethanol or 0.2% NH4OH isopropanol, and the volume ratio of mobile phase A to mobile phase B is (6-7):(4-3). The compound of formula (I) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is characterized in that, Compounds of formula (I) are selected from the following structures: or its racemic form; Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers described above are compounds that elute at a retention time of 3.160 min or 3.600 min under the following chiral separation conditions 1; Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers described above are compounds that elute at retention times of 2.333 min or 2.713 min under the following chiral separation conditions 2; Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers described above are compounds that elute at retention times of 3.179 min or 3.918 min under the following chiral separation conditions 2; Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers described above are compounds that elute at retention times of 3.055 min or 3.442 min under the following chiral separation conditions 2; Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers described above are compounds that elute at retention times of 3.286 min or 2.906 min under the following chiral separation conditions 2; Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers described above are compounds that elute at retention times of 2.785 min or 3.334 min under the following chiral separation conditions 2; Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers described above are compounds that elute at retention times of 2.834 min or 3.332 min under the following chiral separation conditions 2; Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers described above are compounds that elute at retention times of 2.686 min or 1.931 min under the following chiral separation conditions 1. Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers described above are compounds that elute at retention times of 2.83 min and 3.58 min under the following chiral separation conditions 2; Or, enantiomers Under the chiral separation conditions described above, the compound is either the first eluting compound, the second eluting compound, the third eluting compound, or the fourth eluting compound. Preferably, the diastereomers mentioned above are compounds that elute at retention times of 3.34 min, 4.28 min, 4.82 min, or 6.11 min under chiral separation condition 3. Or, enantiomers In the above chiral separation conditions, it is either the compound that elutes first or the compound that elutes later; Preferably, the enantiomers mentioned above are compounds that elute at retention times of 0.802 min or 1.34 min under chiral separation condition 2. Chiral separation conditions 1: Column: ChiralPakAD-H; Mobile phase: Mobile phase A is CO2, mobile phase B is ethanol, mobile phase A: mobile phase B (volume ratio) = 60:40; Chiral separation conditions 2: Column: ChiralPakAD-H; Mobile phase: Mobile phase A is CO2, mobile phase B is ethanol, mobile phase A: mobile phase B (volume ratio) = 70:30; Chiral separation conditions 3: Column: ChiralPakAD-H; Mobile phase: Mobile phase A is CO2, mobile phase 0.2% NH4OH isopropanol, mobile phase A:mobile phase B (volume ratio) = 40:

60. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-12, an isotopic label thereof, an enantiomer, a diastereomer, a transisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients. The use of a compound of formula (I) as described in any one of claims 1-12, its isotopic label, enantiomer, diastereomer, transisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 13 in the preparation of an NRF2 degrader or a drug, wherein the drug is a drug that inhibits NRF2, or a drug for treating and / or preventing cancer. Preferably, the cancer is selected from cancers containing NRF2 / KEAP1 / CUL3 mutations or NRF2-dependent cancers; Preferably, the cancers include squamous cell carcinoma of the lung, adenocarcinoma of the lung, endometrial cancer, head and neck cancer, bladder cancer, cervical cancer, hepatobiliary cancer, and esophageal cancer. A compound of formula A: in, R 0 It is an amino protecting group; Indicates a single or double bond; W, Z, and R 1 The definitions are the same as those described above; Preferably, the compound is any one of the following compounds:

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