Acrylamide compounds and medical use thereof

Abstract

The present invention relates to the technical field of medicine, and specifically relates to an XPO1 inhibitor, a preparation method therefor, and a pharmaceutical application thereof. Provided in the present invention are the XPO1 inhibitor of formula (IA) or (IB), and a composition and use thereof. The compound can be used for treating or preventing XPO1-mediated diseases or disorders and related diseases or disorders.

Description

Acrylamide compounds and their pharmaceutical uses Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a class of acrylamide compounds, including their stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. Furthermore, this invention also discloses a method for preparing such acrylamide compounds and their pharmaceutical uses, which can be used as XPO1 inhibitors to treat diseases related to abnormal XPO1 signaling pathways. Background Technology

[0002] Exportin 1 (XPO1), also known as chromosomal region maintenance protein 1 (CRM1), plays a crucial role in maintaining cellular homeostasis by regulating the export of a series of "cargo" (including proteins and RNA) from the nucleus to the cytoplasm.

[0003] XPO1-mediated nuclear export dysregulation is closely related to tumorigenesis, and XPO1 protein is mutated or overexpressed in almost all malignant tumors. Abnormal XPO1 mediates increased nuclear export of various tumor-related proteins or mRNAs, leading to incorrect cytoplasmic localization and consequently inactivation or erroneous activation of these proteins. XPO1 mutations or overexpression are highly associated with tumor progression, poor prognosis, and acquired drug resistance. Therefore, inhibiting XPO1 is a novel anti-tumor therapy with significant potential for application as monotherapy or in combination therapy for various malignant tumors, and it can overcome acquired resistance to existing standard therapies, demonstrating great promise in the field of cancer treatment.

[0004] The unique mechanism of action of XPO1 inhibitors offers new treatment options for cancer therapy and overcoming resistance to existing therapies. Currently, only one XPO1 inhibitor, Selinexor, developed by Karyopharm, has been approved for marketing. While Selinexor has made significant progress in clinical application, it has also shown significant toxic side effects, which are related to its high blood-brain barrier permeability.

[0005] Eltanexor (KPT-8602, also known as compound 124 disclosed in patent CN105339358A) is a second-generation XPO1 inhibitor developed by Karyopharm. Preclinical studies have shown that Eltanexor reduces blood-brain barrier permeability and improves tolerability. Toxicological studies in rats and monkeys have shown that Eltanexor reduces central nervous system-mediated side effects, but its pharmacokinetic properties and safety still need to be improved.

[0006] Shenzhen Jikang Pharmaceutical Technology Co., Ltd.'s SZJK-0421 (i.e., compound 1 disclosed in patent CN113045550A) has initiated Phase I clinical trials. However, the inventors have found through relevant biological evaluations that the compound has the following defects: insufficient activity in in vitro cell experiments; low exposure and low bioavailability in in vivo pharmacokinetic studies; and further pharmacodynamic experiments have confirmed that its therapeutic effect is unsatisfactory.

[0007] Therefore, there is an urgent need to develop second-generation XPO1 inhibitors with high activity, better pharmacokinetic properties, and fewer toxic side effects for the treatment of various tumors. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a novel acrylamide compound, the derivative of which can inhibit the activity of XPO1 (XPO16A and / or XPO16B) and has significant antitumor activity.

[0009] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0010] This invention provides an acrylamide compound, which is a compound, isomer, or pharmaceutically acceptable salt thereof having the following general structural formula (I):

[0011] in:

[0012] X 1 Selected from CR 2 Or N;

[0013] Y 1 Selected from CR 11 Or N;

[0014] R 1 R 2 R 3 R 4 R 5 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, -NR a R b C, substituted or unsubstituted 1- 6-alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 alkyl sulfone, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14aryl, substituted or substituted 5-14 heteroaryl groups, when R 1 R 2 R 3 R 4 R 5 The C mentioned in 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group;

[0015] Or, R 3 R 4 Together with the carbon atoms on their respective connected benzene rings, they form substituted or unsubstituted benzo[a] heterocycles;

[0016] Or, R 1 R 5 Together with the carbon atoms on their respective connected benzene rings, they form substituted or unsubstituted benzo[a] heterocycles;

[0017] Ring B 1 Selected from substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl, and cyclic B 1 Excluding piperazine ring and pyrrole ring, when ring B 1 The C mentioned in 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 When an aryl group has substituents, it can be substituted by at least one of the following groups: deuterium, halogen, cyano, amino, hydroxyl, amide, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic or C 6-14 Aryl;

[0018] Ring B 1 It is connected to a six-membered aromatic heterocycle by carbon-carbon bonds;

[0019] R 6 R 7 R 8 R9 R 10 R 11 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 alkyl sulfone, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 aryl, substituted or substituted 5-14 heteroaryl groups, when R 6 R 7 R 8 R 9 R 10 R 11 The C mentioned in 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 Alkyl sulfone group;

[0020] Or, R 7 R 8 Together with their respective connected nitrogen atoms, they form substituted or unsubstituted 3-10 heterocyclic groups;

[0021] R a R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 alkyl sulfone, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 aryl, substituted or substituted 5-14 heteroaryl groups, when R a R b The C mentioned in1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3- 8-cycloalkyl, 3-10 membered heterocyclic, C 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 Alkyl sulfone group;

[0022] The heterocyclic group or heteroaryl group contains at least one heteroatom, which is selected from N, O or S.

[0023] In some implementation schemes, X 1 Selected from CR 2 Or N; R 2 Selected from hydrogen, deuterium, halogen, or cyano;

[0024] Y 1 The definition is as described in general formula (I).

[0025] In some embodiments, the compound having the following general structural formula (I-1) or a pharmaceutically acceptable salt thereof is used:

[0026] in:

[0027] X 1 Selected from C or N;

[0028] Y 1 Selected from CR 11 Or N;

[0029] R 1 R 3 Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, when R 1 R 3 The C mentioned in 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 When cycloalkyl groups are present with substituents, they can be substituted by at least one of the following groups: deuterium or halogen;

[0030] Ring B 1 Selected from substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, and cyclic B 1Excluding piperazine ring and pyrrole ring, when ring B 1 The C mentioned in 3-8 When cycloalkyl or 3-10 membered heterocyclic groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, cyano, amino, hydroxyl, or C. 3-8 cycloalkyl;

[0031] Ring B 1 It is connected to a six-membered aromatic heterocycle by carbon-carbon bonds;

[0032] R 7 R 8 R 11 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, when R 7 R 8 R 11 The C mentioned in 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 When cycloalkyl or 3-10 membered heterocyclic groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, or cyano;

[0033] The heterocyclic group contains at least one heteroatom, which is selected from N, O or S.

[0034] In some implementation schemes, X 1 Selected from C or N;

[0035] Y 1 Selected from CR 11 Or N;

[0036] R 1 R 3 Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 3-8 cycloalkyl, when R 1 R 3 The C mentioned in 1-6 Alkyl, C 3-8 When cycloalkyl groups are present with substituents, they can be substituted by at least one of the following groups: deuterium or halogen;

[0037] Ring B 1 Selected from substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, and cyclic B 1 Excluding piperazine ring and pyrrole ring, when ring B 1The C mentioned in 3-8 When cycloalkyl or 3-10 membered heterocyclic groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, cyano, amino, or hydroxyl;

[0038] Ring B 1 It is connected to a six-membered aromatic heterocycle by carbon-carbon bonds;

[0039] R 7 R 8 R 11 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C. 1-6 Alkyl, when R 7 R 8 R 11 The C mentioned in 1-6 When an alkyl group has substituents, it can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, or cyano;

[0040] The heterocyclic group contains at least one heteroatom, which is selected from N, O or S.

[0041] In some embodiments, the compound having the following general structural formula (ii) or a pharmaceutically acceptable salt thereof is used:

[0042] in:

[0043] X 1 Selected from CR 2 Or N; R 2 Selected from hydrogen, deuterium, halogen, or cyano;

[0044] Ring B 1 Selected from substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl, and cyclic B 1 Excluding piperazine ring and pyrrole ring, when ring B 1 The C mentioned in 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 When an aryl group has substituents, it can be substituted by at least one of the following groups: deuterium, halogen, cyano, amino, hydroxyl, C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic or C 6- 14 Aryl;

[0045] Ring B 1 It is connected to a six-membered aromatic heterocycle by carbon-carbon bonds;

[0046] Y 1 R 1 R3 R a R b The definition is as described in general formula (I);

[0047] The heterocyclic group or heteroaryl group contains at least one heteroatom, which is selected from N, O or S.

[0048] In some embodiments, the compound having the following general structural formula (II-1) or a pharmaceutically acceptable salt thereof is used:

[0049] in:

[0050] X 1 Selected from C or N;

[0051] R 1 R 3 Each is independently selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 cycloalkyl, when R 1 R 3 The C mentioned in 1-6 Alkyl, C 3-8 When cycloalkyl groups are present with substituents, they can be substituted by at least one of the following groups: deuterium or halogen;

[0052] Ring B 1 Selected from substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, and cyclic B 1 Excluding piperazine ring and pyrrole ring, when ring B 1 The C mentioned in 3-8 When cycloalkyl or 3-10 membered heterocyclic groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, amino, or hydroxyl;

[0053] Ring B 1 It is connected to a six-membered aromatic heterocycle by carbon-carbon bonds;

[0054] The heterocyclic group contains at least one heteroatom, which is selected from N, O or S.

[0055] In some embodiments, the compound having the following general structural formula (iii) or a pharmaceutically acceptable salt thereof is used:

[0056] in:

[0057] Ring B 1 Selected from substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl, and cyclic B 1Excluding piperazine ring and pyrrole ring, when ring B 1 The C mentioned in 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 When an aryl group has substituents, it can be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic or C 6-14 Aryl;

[0058] Ring B 1 It is connected to a six-membered aromatic heterocycle by carbon-carbon bonds;

[0059] The heterocyclic group or heteroaryl group contains at least one heteroatom, which is selected from N, O or S.

[0060] An acrylamide compound, which is a compound, isomer or pharmaceutically acceptable salt thereof having the following general structural formula (iv):

[0061] R 1 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 alkyl sulfone, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 aryl, substituted or substituted 5-14 heteroaryl groups, when R 1 The C mentioned in 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C. 1- 6-alkyl, C 3-8 cycloalkyl or C 1-6 Alkyl sulfone group;

[0062] R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when R2 R 3 The C mentioned in 1-6 Alkyl, C 1-6 When an alkoxy group has a substituent, it can be substituted by at least one of the following groups: halogen;

[0063] Or, R 2 R 3 Together with the carbon atoms on their respective connected benzene rings, they form substituted or unsubstituted benzo[a] heterocycles;

[0064] Ring A 1 Selected from substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, when ring A 1 The C mentioned in 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, cyano, -SO2R. 4 -SO2NHR 5 C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 Alkyl sulfone group, wherein when C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine group, C 1-6 When the alkyl sulfone group has substituents, it can be substituted by at least one of the following groups: deuterium, halogen, amino, C. 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups;

[0065] R 4 R 5 Selected from substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, when R 4 R 5 The C mentioned in 3-8 When cycloalkyl or 3-10 membered heterocyclic groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen;

[0066] R 6 R 7 Each is independently selected from hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 3-8 cycloalkyl, when R 6 R7 The C mentioned in 1-6 Alkyl, C 3-8 When cycloalkyl groups are present with substituents, they can be substituted by at least one of the following groups: deuterium, halogen, cyano, or hydroxyl;

[0067] n is 0, 1, 2, or 3;

[0068] The heterocyclic group or heteroaryl group contains at least one heteroatom, which is selected from N, O or S.

[0069] In some embodiments, the compound, isomer, or pharmaceutically acceptable salt thereof has the following general structural formula (IV-1):

[0070] in:

[0071] R 1 Selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkylamine group, when R 1 The C mentioned in 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 When an alkylamine group has substituents, it can be replaced by at least one of the following groups: deuterium or halogen;

[0072] Ring A 1 Selected from substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, when ring A 1 The C mentioned in 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: halogen, cyano, -SO2R. 4 -SO2NHR 5 C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 Alkyl sulfone group, wherein when C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine group, C 1-6When the alkyl sulfone group has substituents, it can be substituted by at least one of the following groups: halogen, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups;

[0073] R 6 Selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 cycloalkyl, when R 6 The C mentioned in 1-6 Alkyl, C 3-8 When cycloalkyl groups are present with substituents, they can be substituted by at least one of the following groups: halogen, cyano, or hydroxyl;

[0074] n is 0, 1, 2, or 3;

[0075] R 2 R 3 R 4 R 5 The definition is as described in general formula (iv);

[0076] The heterocyclic group or heteroaryl group contains at least one heteroatom, which is selected from N, O or S.

[0077] In some embodiments, the compound having the following general structural formula (quad-2) or a pharmaceutically acceptable salt thereof is used:

[0078] in:

[0079] R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when R 2 R 3 The C mentioned in 1-6 Alkyl, C 1-6 When an alkoxy group has a substituent, it can be substituted by at least one of the following groups: halogen;

[0080] Ring A 1 Selected from substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, when ring A 1 The C mentioned in 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, cyano, -SO2R. 4 -SO2NHR 5 C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 Alkyl sulfone group, wherein when C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine group, C 1-6 When the alkyl sulfone group has substituents, it can be substituted by at least one of the following groups: halogen, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups;

[0081] R 1 R 6 The definition is as stated in general formula (IV-1); R 4 R 5 The definition is as described in general formula (iv);

[0082] The heterocyclic group or heteroaryl group contains at least one heteroatom, which is selected from N, O or S.

[0083] In some implementation schemes, R 2 R 3 Each is independently selected from: hydrogen, deuterium, halogen, substituted or unsubstituted C. 1-6 Alkyl, when R 2 R 3 The C mentioned in 1-6 When an alkyl group has substituents, it can be substituted by at least one of the following groups: halogens;

[0084] Ring A 1 Selected from substituted or unsubstituted 5-14 membered heteroaryl groups, when ring A 1 When the 5-14 membered heteroaryl group described herein has substituents, it can be substituted by at least one of the following groups: deuterium, halogen, cyano, -SO2R 4 -SO2NHR 5 C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 Alkyl sulfone group, wherein when C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine group, C 1-6 When the alkyl sulfone group has substituents, it can be substituted by at least one of the following groups: halogen, amino, C1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups;

[0085] R 4 R 5 The definition is as described in general formula (iv);

[0086] The heterocyclic group or heteroaryl group contains at least one heteroatom, which is selected from N, O or S.

[0087] In some embodiments, the compound having the following general structural formula (IV-3) or a pharmaceutically acceptable salt thereof is used:

[0088] in:

[0089] R 2 R 3 Each is independently selected from: hydrogen, deuterium, halogen, substituted or unsubstituted C. 1-6 Alkyl, when R 2 R 3 The C mentioned in 1-6 When an alkyl group has substituents, it can be substituted by at least one of the following groups: halogens;

[0090] Ring A 1 Selected from substituted or unsubstituted 5-14 membered heteroaryl groups, when ring A 1 When the 5-14 membered heteroaryl group described herein has substituents, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 alkylamine group, where when C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 When an alkylamine group has substituents, it can be substituted by at least one of the following groups: halogen, C 1-6 Alkyl or C 3-8 cycloalkyl;

[0091] The heterocyclic group or heteroaryl group contains at least one heteroatom, which is selected from N, O or S.

[0092] In some implementation schemes, R 2 R 3 Each is independently selected from: hydrogen, deuterium, halogen, substituted or unsubstituted C. 1-6 Alkyl, when R 2 R 3 The C mentioned in 1-6 When an alkyl group has substituents, it can be substituted by at least one of the following groups: halogens;

[0093] Ring A 1 Selected from substituted or unsubstituted 5-14 membered heteroaryl groups, when ring A 1 When the 5-14 membered heteroaryl group described herein has substituents, it may be substituted by at least one of the following groups: deuterium, halogen-substituted, or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 alkylamine group, where when C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 When an alkylamine group has substituents, it can be substituted by at least one of the following groups: halogen or C. 1-6 alkyl;

[0094] The heterocyclic group or heteroaryl group contains at least one heteroatom, which is selected from N, O or S.

[0095] This invention provides an acrylamide compound, which is a compound, isomer, or pharmaceutically acceptable salt thereof having the following general structural formula (W):

[0096] in:

[0097] X' is selected from CR2' or N;

[0098] Y' is selected from CR 11 'or N;

[0099] R1', R2', R3', R4', and R5' are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and -NR. a R b C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 alkyl sulfone, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted 5-14 heteroaryl groups, when C is specified in R1', R2', R3', R4', R5' 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group;

[0100] Alternatively, R3' and R4' together with the carbon atoms on their respective connected benzene rings form substituted or unsubstituted benzo[a] heterocycles;

[0101] Alternatively, R1' and R5' together with the carbon atoms on their respective connected benzene rings form substituted or unsubstituted benzo[a] heterocycles;

[0102] Ring B' is selected from substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl group, and ring B' does not include piperazine ring or pyrrole ring, when the C in ring B... 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 When an aryl group has substituents, it can be substituted by at least one of the following groups: deuterium, halogen, cyano, amino, hydroxyl, amide, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic or C 6-14 Aryl;

[0103] Ring B' is connected to a six-membered aromatic heterocycle by carbon-carbon bonds;

[0104] R6', R9', R 10 '、R 11 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 alkyl sulfone, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 aryl, substituted or substituted 5-14 heteroaryl groups, when R6', R9', R 10 '、R 11 The C mentioned in ' 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 Alkyl sulfone group;

[0105] R7' and R8' are each independently selected from hydrogen or -OCH3;

[0106] R a '、R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 alkyl sulfone, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 aryl, substituted or substituted 5-14 heteroaryl groups, when R a '、R b The C mentioned in ' 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3- 8-cycloalkyl, 3-10 membered heterocyclic, C 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 Alkyl sulfone group;

[0107] The aforementioned heterocyclic and heteroaryl groups contain at least one heteroatom, which is selected from N, O, or S.

[0108] In some implementations, in the aforementioned structural formula (W),

[0109] X' is selected from CR2' or N;

[0110] Y' is selected from CR 11 'or N;

[0111] R2' is selected from hydrogen, deuterium, halogen, or cyano;

[0112] R 11 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 alkyl sulfone, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 6-14 aryl, substituted or substituted 5-14 heteroaryl groups, when R 11 The C mentioned in ' 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 When aryl or 5-14 membered heteroaryl groups have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 Alkyl sulfone group;

[0113] The aforementioned heterocyclic and heteroaryl groups contain at least one heteroatom, which is selected from N, O, or S.

[0114] In some embodiments, the compound having the following general structural formula (W1) or a pharmaceutically acceptable salt thereof is used:

[0115] in:

[0116] X' is selected from CR2' or N; R2' is selected from hydrogen, deuterium, halogen or cyano;

[0117] The definitions of Y', R1', R3', and ring B' are as described in general formula (W).

[0118] In some embodiments, the compound having the following general structural formula (W1-1) or a pharmaceutically acceptable salt thereof is used:

[0119] Wherein: the definition of ring B' is as described in general formula (W).

[0120] In some embodiments, the compound having the following general structural formula (W1-2) or a pharmaceutically acceptable salt thereof is used:

[0121] Wherein: the definition of ring B' is as described in general formula (W).

[0122] In some embodiments, the compound having the following general structural formulas (W1-3) or a pharmaceutically acceptable salt thereof is used:

[0123] The ring B' is defined as described in general formula (W).

[0124] In some embodiments, the compound having the following general structural formulas (W1-4) or a pharmaceutically acceptable salt thereof is used:

[0125] Wherein: the definition of ring B' is as described in general formula (W).

[0126] In some embodiments, the compound having the following general structural formulas (W1-5) or a pharmaceutically acceptable salt thereof is used:

[0127] Where: R 11 Selected from hydrogen, deuterium, halogen, or cyano;

[0128] The ring B' is defined as described in general formula (W).

[0129] This invention provides an acrylamide compound, which is a compound having the following general structural formula (IA) or (IB), its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0130] in:

[0131] X is selected from CR2 or N;

[0132] Y is selected from CR 11 Or N;

[0133] R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and -NR. a R b C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 The aryl or 5-14 heteroaryl group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group;

[0134] R A Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl or 3-10 membered heterocyclic group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, cyano, amino, hydroxyl, amide, C 1-6 Alkyl, C 1-6 alkenyl, C 1- 6-alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic or C 6-14 Aryl, the R A Not selected from piperazine or tetrahydropyrrole;

[0135] R6, R7, R8, R9, R 10 R 11 R a R b R B1 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 The aryl or 5-14 heteroaryl group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 3-8cycloalkyl or C 1-6 Alkyl sulfone group;

[0136] R B2 R B3 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine or C 3-8 The cycloalkyl group may optionally be further substituted with one or more groups selected from the following: deuterium or halogen;

[0137] Ring A is selected from C 6-14 Aryl or 5-14 heteroaryl, wherein C 6-14 The aryl or 5-14 heteroaryl group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, -NR. i R j -SO2R c -SO2NR i R j C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine or C 1-6 Alkyl sulfone group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine or C 1-6 The alkyl sulfone group may optionally be further substituted by one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, -CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 alkylamine group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups;

[0138] R c R i R j Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl or 3-10-membered heterocyclic group may optionally be further substituted with one or more groups selected from the following: deuterium or halogen;

[0139] Or, R i R j The N atom attached thereto forms a 3-10 membered heterocyclic group, which may optionally be further substituted by one or more groups selected from deuterium or halogens;

[0140] R B4 R B5 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 The cycloalkyl group may optionally be further substituted by one or more groups selected from the following: deuterium, halogen, cyano or hydroxyl;

[0141] n is selected from 0, 1, 2 or 3.

[0142] In some implementation schemes, R B2 R B3 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1- 6-alkyl or C 1-6 The alkoxy group may optionally be further substituted with one or more groups selected from the following: halogens;

[0143] Ring A is selected from C 6-14 Aryl or 5-14 heteroaryl, wherein C 6-14 The aryl or 5-14 heteroaryl group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, cyano, -SO2R c -SO2NHR d C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine or C 1-6 Alkyl sulfone group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine or C 1-6 The alkyl sulfone group may optionally be further substituted by one or more groups selected from the following: deuterium, halogen, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups;

[0144] R c R jEach was independently selected from C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-10-membered heterocyclic group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen;

[0145] R B4 R B5 Each is independently selected from hydrogen and C. 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, cyano or hydroxyl.

[0146] In some embodiments, the compound having the following general structural formula (IIA) or (IIB), its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0147] in:

[0148] X is selected from CR2 or N, wherein R2 is selected from hydrogen, deuterium, halogen or cyano;

[0149] R B1 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkoxy or C 1-6 alkylamine group, the C 1-6 Alkyl, C 3- 8-cycloalkyl, C 1-6 Alkoxy or C 1-6 The alkylamine group may optionally be further substituted by one or more groups selected from the following: deuterium or halogen;

[0150] Y, R1, R3, R A R7, R8, R B2 R B3 Ring A, R B4 The definition is as stated in general formula (IA) or (IB).

[0151] In some embodiments, the compound is a compound having the following general structural formula (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIB-3), (IIIB-4) or (IIIB-5), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

[0152] Among them, X, Y6, and Y7 are each independently selected from CH or N;

[0153] Y is selected from CR 11 Or N, the R 11 Selected from hydrogen, deuterium, halogen, or cyano;

[0154] Z1 is selected from O or NR g The R g Selected from hydrogen, deuterium, and C 1-3 Alkyl or 3-6 membered heterocyclic groups;

[0155] R1, R3, R B1 R B2 R B3 Each is independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 alkylamine group, the C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 The alkylamine group may optionally be further substituted with one or more groups selected from hydrogen, deuterium or halogen;

[0156] R7, R B4 Each element is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy or C 3-5 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy or C 3- The 5-cycloalkyl group may optionally be further substituted with one or more groups selected from hydrogen, deuterium, halogen, hydroxyl or cyano;

[0157] Y1, Y2, Y3, Y4, and Y5 are each independently selected from CR. h Or N;

[0158] R h Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -NR i R j -SO2R c or -SO2NR i R j The C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups may optionally be further coupled with one or more R groups. e replace;

[0159] R e Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, -CONH2, C 1-3Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamine group;

[0160] R c Selected from hydrogen, deuterium, or C 3-6 cycloalkyl;

[0161] R i R j Each element is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0162] Or, R i R j The N atom attached thereto forms a 3-7 membered heterocyclic group, which may optionally be further substituted by one or more groups selected from hydrogen, deuterium or halogen;

[0163] p and q are each independently selected from 0, 1, 2 or 3.

[0164] In some embodiments, the compound, its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof are compounds having the following general structural formulas: (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVA-6), (IVB-1), (IVB-2), (IVB-3), (IVB-4), (IVB-5), (IVB-6), or (IVB-7).

[0165] Among them, X, Y, R g R1, R3, R B1 R B2 R B3 R7, R B4 Y4, R h R e The definitions of and p are as described in general formulas (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIB-3), (IIIB-4), or (IIIB-5).

[0166] In some embodiments, the compound having the following general structural formula (VA-1), (VA-2), (VA-3) or (VB-1), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof:

[0167] Among them, X, R1, R3, R B1 R B2 R B3 R7, Re p, R i R j The definition is as described in general formulas (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIB-3), (IIIB-4), or (IIIB-5).

[0168] In some implementations, R1, R3, R B1 R B2 R B3 Each element is independently selected from hydrogen, deuterium, halogen, cyclopropyl, and C. 1-3 Alkyl or C 1- 3-Halogenated alkyl groups.

[0169] In some implementations, R7, R B4 Each is independently selected from -H, -OCH3, In some implementations, the R e Selected from -H, -F, -OH, -NH2, -CN, -CH3, -OCH3, -NHCH3 or -CONH2.

[0170] In some implementations, the R h Selected from -H, -F, -CN, -CH3, -CF3,

[0171] The present invention also provides an acrylamide compound, comprising the following compounds, stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0172] In another aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound, stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof as described above, and at least one pharmaceutically acceptable carrier.

[0173] In another aspect, the present invention provides the use of the compounds, stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof as described above, and the use of the above pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of diseases related to XPO1.

[0174] The present invention also provides the compounds, stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof as described above, and the use of the above pharmaceutical compositions in the prevention or treatment of diseases related to XPO1.

[0175] The present invention provides a method for treating and / or preventing diseases, comprising administering to a therapeutically effective amount of the aforementioned compound, stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, and the aforementioned pharmaceutical composition.

[0176] In some implementations, the XPO1 is XPO16A and / or XPO16B.

[0177] In some implementations, the tumor is selected from hematologic malignancies or solid tumors.

[0178] In some implementations, the hematologic malignancy is selected from multiple myeloma, B-cell lymphoma, myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, histiocytic lymphoma, acute megakaryocytic leukemia, prolymphocytic leukemia, T-lymphoblastic leukemia, T-lymphoblastic lymphoma, etc.

[0179] In some implementations, the solid tumor is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, nasopharyngeal carcinoma, glioma, etc.

[0180] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears in this document, it is intended to refer to the corresponding product or its active ingredient.

[0181] The "compound" described in this invention includes, but is not limited to, the following forms of compounds: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0182] The "compound" described in this invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention can be isolated in optically active pure form or in racemic form. Optically active pure form can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0183] In this invention, "isomer" refers to stereoisomers or tautomers unless otherwise specified. Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include, but are not limited to, enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and transisomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example by chromatography and / or fractional crystallization. Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons.

[0184] In this invention, "isotope" refers to a compound of this invention, unless otherwise specified, existing in an isotopically traced or enriched form, containing one or more atoms whose atomic weight or mass number differs from the atomic weight or mass number of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Commonly used isotopes for isotopic labeling include hydrogen isotopes, including but not limited to... 2 H and 3 H; Carbon isotopes: including but not limited to 13 C and 14 C; Chlorine isotopes: including but not limited to 35 Cl and 37 Cl; Fluorine isotopes: including but not limited to 18 F; Iodine isotopes: including but not limited to 123 I and 125 I; Nitrogen isotopes: including but not limited to 13 N and 15 N; oxygen isotopes: including but not limited to 15 O、 17 O and 18 O; sulfur isotopes: including but not limited to 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues, especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0185] In this invention, "pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, which are compounds with specific substituents discovered in this invention, and are compatible with 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetate, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucohepose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthalene, hydroxyethanesulfonic acid, lactic acid, lactose, and dodecyl sulfonic acid. A base addition salt can be obtained by contacting a compound in its neutral form with a sufficient amount of base in a pure solution or a suitable inert solvent when it contains a relatively acidic functional group, such as maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, or organic amine salts. Examples include alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkyl sulfonates, aryl sulfonates, organic acid salts, and amino acid salts.

[0186] The terms used in this article have the following meanings:

[0187] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0188] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group composed of carbon and hydrogen atoms, such as C... 1-6 Alkyl groups, including but not limited to methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), and hexyl (n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, and 2,2-dimethylbutyl).

[0189] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, possessing at least one double bond. For example, "C..." 2-"6-Alkenyl" means that the group is alkenyl and the number of carbon atoms on the carbon chain is between 2 and 6 (i.e., 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, etc.

[0190] The term "cycloalkyl" refers to a monocyclic alkyl group composed of carbon and hydrogen atoms, such as C1. 3-8 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0191] The term "alkoxy" refers to a straight-chain or branched alkyl group linked by an oxygen atom, such as C... 1-6 Alkoxy groups, including but not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy, and neopentoxy), and hexoxy (n-hexoxy, 2-methylpentoxy, 3-methylpentoxy, 2,3-dimethylbutoxy, and 2,2-dimethylbutoxy).

[0192] The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group linked by a sulfone group, i.e., -SO2-alkyl, such as C 1-6 Alkyl sulfone groups, including but not limited to methyl sulfone, ethyl sulfone, propane sulfone (including n-propane sulfone and isopropane sulfone), butyl sulfone (including n-butyl sulfone, isobutyl sulfone, sec-butyl sulfone, and tert-butyl sulfone), pentyl sulfone (including n-pentyl sulfone, isopentyl sulfone, and neopentyl sulfone), and hexyl sulfone (n-hexyl sulfone, 2-methylpentyl sulfone, 3-methylpentyl sulfone, 2,3-dimethylbutyl sulfone, and 2,2-dimethylbutyl sulfone), etc.

[0193] The term "alkylamine" refers to an open-chain alkyl group containing a nitrogen atom, including monosubstituted and disubstituted alkylamine groups, such as C... 1-6 Alkylamine groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0194] The term "aryl" refers to a monocyclic or fused polycyclic group with 6-14 carbon atoms, possessing a fully conjugated π-electron system, including but not limited to phenyl, naphthyl, anthracene, etc., with phenyl being preferred.

[0195] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., spirocyclic, bridged, etc.) group containing 3-10 ring atoms, and having a non-aromatic structure. The polycyclic group may consist entirely of non-aromatic rings, or at least one ring may be aromatic while the rest are non-aromatic. The aforementioned 3-10 ring atoms contain one or more (e.g., 2, 3, 4, or more) heteroatoms, with the remainder being carbon atoms selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic group may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. Non-limiting examples of "heterocyclic group" include, but are not limited to, azirropropyl, oxadiropropyl, thioherropropyl, azirrobutyl, oxadirobutyl, thioherrobutyl, furanyl, piperidinyl, piperazinyl, morpholinyl, pyrroleyl, and thiomorpholinyl.

[0196] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic (e.g., fused ring) group containing 5-14 ring atoms, wherein the aforementioned 5-14 ring atoms contain one or more (e.g., 2, 3, 4 or more) heteroatoms, and the remainder are carbon atoms selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic group may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. The aforementioned "heteroaryl" preferably contains 5-14, 5-12, 5-10, or 5-8 ring atoms, more preferably 5-6 ring atoms. Non-limiting examples of "heteroaryl" include, but are not limited to, tetrahydrofuranyl, thiophenyl, oxazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, etc.

[0197] The term "pharmaceutical composition" as used in this invention refers to a formulation comprising one or more compounds of the invention or salts thereof, and a carrier commonly accepted in the art for delivering a bioactive compound to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate drug delivery to the organism.

[0198] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0199] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0200] The present invention also provides the administration routes of the above-mentioned pharmaceutical compositions, including but not limited to oral, rectal, transmucosal, enteric administration, or local transdermal, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0201] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0202] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0203] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0204] This invention, based on the target design of XPO1 inhibitors, has developed a series of novel acrylamide compounds. Related biological experiments have shown that these compounds significantly inhibit the proliferation of various tumor cell lines and exhibit excellent in vivo antitumor efficacy, superior to KPT-8602. Furthermore, the compounds possess good hepatic microsomal metabolic stability, improved pharmacokinetic properties, and low hERG toxicity. In addition, the compounds have lower blood-brain barrier permeability, which helps reduce potential side effects in the central nervous system. The synthetic route provided by this invention is novel, safe, environmentally friendly, and feasible for production. Detailed Implementation

[0205] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0206] Furthermore, all operations involving readily oxidizable or hydrolyzable raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification.

[0207] All reaction starting materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or prepared in-house. The preparation process of the starting materials and common intermediates that need to be prepared in-house is detailed below:

[0208] Explanation of abbreviations related to chemical reagents:

[0209] DMF: N,N-dimethylformamide; TLC: thin-layer chromatography; DABCO: triethylenediamine; DMSO: dimethyl sulfoxide; PdCl2(dppf): 1,1-bis(diphenylphosphine)ferrocene palladium dichloride; PdCl2(dppf)·DCM: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex; DCE: 1,2-dichloroethane; DAST: diethylaminosulfur trifluoride; LC-MS: liquid chromatography-mass spectrometry; SPhos Pd G3: (2-Dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-3-yl)palladium(II)methanesulfonic acid; DIPEA: N,N-diisopropylethylamine; HBTU: benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate; DMA: N,N-dimethylaniline; Pd(PPh3)4: tetratetraphenylphosphine palladium; NM P: N-methylpyrrolidone; TBAF: tetrabutylammonium fluoride; Pd2(dba)3: tris(dibenzylacetone)dipalladium; X-Phos: 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; TMSCl: trimethylchlorosilane; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT: 1-hydroxybenzotriazole; NaH: sodium hydride.

[0210] All reaction starting materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or prepared in-house. The preparation process of the common intermediate that needs to be prepared in-house is detailed below:

[0211] I. Preparation of common intermediate M1:

[0212] Step 1: Synthesis of compound M1-1

[0213] M1-0 (4.0 g, 16.7 mmol) was dissolved in DMF (20 mL). NaSH·xH2O (70%) (1.87 g, 33.5 mmol) was added in portions over an ice bath for 15 minutes. After the addition was complete, MgCl2·6H2O (3.73 g, 18.4 mmol) was added in portions. The mixture was stirred for 15 minutes and then allowed to react at room temperature for 2 hours. The reaction was monitored by TLC until complete. The reaction solution was poured into an ice-water mixture, and the pH was adjusted to 2-3 with 1 mol / L hydrochloric acid. The mixture was extracted with methyl tert-butyl ether, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was slurried with n-hexane, filtered, and the filter cake was dried to give compound M1-1 (3.89 g) as a yellow solid, with a yield of 85.5%.

[0214] MS m / z: 272.0 [MH] - .

[0215] Step 2: Synthesis of compound M1-2

[0216] M1-1 (2.0 g, 7.3 mmol) was dissolved in DMF (12 mL), and 80% hydrazine hydrate (0.92 g, 4.7 mmol) was added dropwise under ice bath conditions. The mixture was stirred for 20 minutes, and then formic acid (10 mL) was added dropwise. After the addition was complete, the reaction was heated to 95 °C and reacted for 4 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, poured into ice water, stirred, filtered, and the filter cake was dried. The mixture was then slurried with n-hexane, filtered, and the filter cake was dried to give compound M1-2 (1.67 g) as a pale yellow solid, with a yield of 81.5%.

[0217] MS m / z: 280.0 [MH] - .

[0218] Step 3: Synthesis of compound M1-3

[0219] M1-2 (0.9 g, 3.2 mmol) and DABCO (0.9 g, 8.0 mmol) were dissolved in DMF (15 mL). The mixture was stirred at room temperature for 30 minutes. Then, ethyl (Z)-3-iodoacrylate (0.81 g, 3.5 mmol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 17 h. The reaction was monitored by TLC until complete. The reaction solution was poured into an ice-water mixture, stirred, filtered, and the filter cake was dried to give compound M1-3 (0.9 g) as a white solid, with a yield of 74.4%.

[0220] MS m / z: 380.1 [M+H] + .

[0221] Step 4: Synthesis of M1-4

[0222] M1-3 (0.9 g, 2.4 mmol) was dissolved in dichloromethane (15 mL), and liquid bromine (0.76 g, 4.7 mmol) was slowly added dropwise under ice bath conditions. The reaction mixture was then stirred at room temperature for 4 h. The reaction was monitored by TLC until complete. The reaction mixture was quenched with saturated sodium bisulfite solution until colorless, diluted with water, extracted with dichloromethane, and the organic phases were combined and washed with water and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound M1-4 (1.26 g) as a grayish-white solid, with a yield of 98.5%.

[0223] Step 5: Synthesis of compound M1

[0224] M1-4 (1.26 g, 2.3 mmol) was dissolved in tetrahydrofuran (20 mL). After stirring in an ice bath for 10 minutes, triethylamine (0.48 g, 4.6 mmol) was added dropwise to the reaction mixture, and stirring was continued for another 30 minutes. The reaction mixture was then transferred to room temperature and stirred for another 12 hours. The reaction was monitored by TLC until complete. The mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined and washed with water and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography was used to separate compound M1 (0.67 g) as a pale yellow solid, with a yield of 62.5%.

[0225] MS m / z: 458.0 [M+H] + .

[0226] 1 H NMR (400MHz, Chloroform-d) δ8.75(s,1H),8.56(s,2H),7.93(s,1H),7.65(s,1H),4.38(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0227] II. Preparation of common intermediate M2

[0228] Step 1: Synthesis of compound M2-1

[0229] M2-0 (5.7 g, 38.5 mmol) and DABCO (8.6 g, 77.0 mmol) were dissolved in DMF (50 mL). The mixture was stirred at room temperature for 30 minutes. Then, ethyl (Z)-3-iodoacrylate (8.7 g, 38.5 mmol) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 1 h. The reaction was monitored by TLC until complete. The reaction solution was poured into an ice-water mixture, stirred, filtered, and the filter cake was dried to give compound M2-1 (5.5 g) as a white solid, with a yield of 58.5%.

[0230] MS m / z: 246.0 [M+H] + .

[0231] Step 2: Synthesis of compound M2-2

[0232] M2-1 (5.5 g, 22.4 mmol) was dissolved in dichloromethane (50 mL), and liquid bromine (7.15 g, 44.7 mmol) was slowly added dropwise under ice bath conditions. The reaction was then stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with saturated sodium bisulfite solution until colorless, diluted with water, extracted with dichloromethane, and the organic phases were combined and washed with water and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound M2-2 (8.6 g) as a yellow solid, with a yield of 94.8%.

[0233] Step 3: Synthesis of compound M2

[0234] M2-2 (8.6 g, 21.2 mmol) was dissolved in tetrahydrofuran (80 mL). After stirring in an ice bath for 10 minutes, triethylamine (4.3 g, 42.4 mmol) was added dropwise to the reaction solution, and stirring was continued for 30 minutes. The reaction was then moved to room temperature and stirred for 12 hours. The reaction was monitored by TLC until complete. An ice-water mixture was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with water and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound M2 (2.2 g) as a white solid, with a yield of 32.0%.

[0235] MS m / z: 323.9 [M+H] + .

[0236] 1 H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.83 (s, 1H), 4.31 (q, J = 7.1Hz, 2H), 1.30 (t, J = 7.1Hz, 3H).

[0237] III. Preparation of the common intermediate M3

[0238] Step 1: Synthesis of compound M3-1

[0239] M3-0 (1.0 g, 4.1 mmol), ethyl 2-chloroacetoacetate (1.0 g, 6.2 mmol), and potassium carbonate (1.1 g, 8.3 mmol) were dissolved in DMF (15 mL), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined and washed with water and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound M3-1 (1.0 g) as a colorless liquid, in a yield of 65.8%.

[0240] MS m / z: 366.9 [MH] - .

[0241] Step 2: Synthesis of compound M3-2

[0242] M3-1 (1.0 g, 2.7 mmol) was dissolved in 98% sulfuric acid (6 mL), and the reaction was heated to 40 °C and carried out overnight. The reaction was monitored by TLC until complete. The reaction solution was added dropwise to an ice-water mixture, stirred, filtered, and the filter cake was dried to give compound M3-2 (0.85 g) as a white solid, with a yield of 90.9%.

[0243] Step 3: Synthesis of compound M3-3

[0244] M3-2 (0.85 g, 2.5 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred in an ice bath for 10 minutes. A solution of lithium hydroxide (0.1 g, 4.2 mmol) in water (2 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure to remove the tetrahydrofuran. The pH of the residual solution was adjusted to 1-2 with 1 mol / L hydrochloric acid, resulting in the precipitation of a solid. The mixture was stirred for 30 minutes, filtered, and the filter cake was dried to obtain compound M3-3 (0.55 g) as a white solid, with a yield of 70.5%.

[0245] MS m / z: 320.9 [MH] - .

[0246] Step 4: Synthesis of compound M3-4

[0247] M3-3 (0.55 g, 1.7 mmol), silver carbonate (47 mg, 0.2 mmol), and acetic acid (5 mg, 0.1 mmol) were dissolved in DMSO (5 mL). Under nitrogen protection, the mixture was stirred at 120 °C for 12 h. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound M3-4 (0.35 g) as white crystals, with a yield of 74.5%.

[0248] 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 2.24 (d, J = 1.3Hz, 3H).

[0249] Step 5: Synthesis of compound M3

[0250] M3-4 (0.25 g, 0.9 mmol), pinacol diboronate (0.28 g, 1.1 mmol), potassium acetate (0.18 g, 1.8 mmol), and PdCl2 (dppf) (0.07 g, 0.09 mmol) were dissolved in 1,4-dioxane (6 mL) and reacted at 80 °C for 4 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth filter, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound M3 (0.3 g), which was used directly in the next reaction without purification.

[0251] IV. Preparation of the common intermediate M4

[0252] Step 1: Synthesis of compound M4-1

[0253] M3-3 (1.85 g, 5.74 mmol), a selective fluorinating agent (4.5 g, 12.6 mmol), and potassium fluoride (1.33 g, 23.0 mmol) were dissolved in a mixed solution of DCE (20 mL) and water (10 mL), and the mixture was heated to 70 °C and reacted overnight. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound M4-1 (0.6 g) as a pale yellow solid, in a yield of 35.3%.

[0254] 1H NMR (400MHz, DMSO-d6) δ8.21(s,1H),7.83(s,1H),2.22-2.02(m,3H).

[0255] Step 2: Synthesis of compound M4

[0256] M4-1 (0.2 g, 0.68 mmol), pinacol diboronate (0.2 g, 0.81 mmol), potassium acetate (0.13 g, 1.35 mmol), and Pd(dppf)Cl2 (49 mg, 0.07 mmol) were dissolved in 1,4-dioxane (6 mL) and reacted at 85 °C for 3 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth filter, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound M4 (0.4 g), which was used directly in the next reaction without purification.

[0257] V. Preparation of common intermediate M5

[0258] Step 1: Synthesis of compound M5-1

[0259] In a sealed tube, M3-4 (3.0 g, 0.011 mol) and SeO2 (3.0 g, 0.027 mmol) were dissolved in 1,4-dioxane (30 mL), and the mixture was heated to 115 °C and reacted for 24 h. The reaction was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to give compound M5-1 (1.5 g) as a yellow solid, with a yield of 47.6%.

[0260] 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),9.21(s,1H),8.47(d,J=1.9Hz,1H),8.04(d,J=1.9Hz,1H).

[0261] Step 2: M5-2 Synthesis of Compound

[0262] M5-1 (0.3 g, 1.03 mmol) was dissolved in dichloromethane (3 mL), and DAST (0.33 g, 2.05 mmol) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred for 0.5 h and then allowed to react at room temperature for 4 h. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound M5-2 (0.15 g) as a pale yellow solid, with a yield of 46.5%.

[0263] 1 H NMR (400MHz, DMSO-d6) δ8.70(t,J=2.7Hz,1H),8.25(d,J=1.8Hz,1H),8.00(d,J=1.0Hz,1H),7.40(t,J=54.3Hz,1H).

[0264] Step 3: M5 synthesis of the compound

[0265] M5-2 (0.15 g, 0.48 mmol), pinacol diboronate (0.134 g, 0.53 mmol), potassium acetate (0.094 g, 0.96 mmol), and PdCl2 (dppf) (18 mg, 0.05 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted overnight at 80 °C under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth filter, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound M5 (0.3 g), which was used directly in the next reaction without purification.

[0266] Example 1: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclopropylpyrimidin-5-yl)acrylamide (A1)

[0267] Step 1: Synthesis of compound A1-1

[0268] Dissolve A1-0 (25 g, 0.21 mol) in ethanol (200 mL), add 140 mL (0.41 mol) of 20% sodium ethoxide in ethanol, stir at 50 °C for 30 minutes, add dropwise 10 mL of ethanol solution of bromic acid (48 g, 0.19 mol), stir at 50 °C for 60 minutes, add 140 mL (0.41 mol) of 20% sodium ethoxide in ethanol, and continue stirring for 30 minutes. Concentrate under reduced pressure to remove the solvent, adjust the pH to 1-2 with 1 mol / L hydrochloric acid solution, extract with dichloromethane, combine the organic phases and wash with saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound A1-1 (30 g), a yellow oily substance, which was used directly in the next reaction without purification.

[0269] MS m / z: 243.0 [M+H] + .

[0270] Step 2: Synthesis of compound A1-2

[0271] A1-1 (30 g, crude product) was dissolved in xylene (70 mL) and reacted at 140 °C for 5 h. The reaction was monitored by LC-MS until the starting material was completely reacted. The solvent was removed by concentration under reduced pressure, and the product was purified by column chromatography to give compound A1-2 (4.8 g) as a pale yellow solid. The two-step yield was 11.6%.

[0272] MS m / z: 199.0 [M+H] + .

[0273] Step 3: Synthesis of compound A1-3

[0274] A1-2 (0.5 g, 2.51 mmol), pinacol diboronate (0.83 g, 3.26 mmol), potassium acetate (0.5 g, 5.03 mmol), and SPhos Pd G3 (0.1 g, 0.13 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 80 °C for 6 h under nitrogen protection. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with ethyl acetate. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound A1-3, which was used directly in the next reaction without purification.

[0275] MS m / z: 246.9 [M+H] + .

[0276] Step 4: Synthesis of compound A1-4

[0277] M1 (0.4 g, 0.88 mmol), A1-3 (crude product from step 3), sodium acetate (0.14 g, 1.75 mmol), and PdCl2 (dppf) (64 mg, 0.09 mmol) were dissolved in a mixed solution of 1,4-dioxane (10 mL) and water (1 mL). The reaction was carried out at 85 °C for 2 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with ethyl acetate. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A1-4 (0.3 g) as a white solid. The two-step yield was 24%.

[0278] MS m / z: 498.2 [M+H] + .

[0279] Step 5: Synthesis of compound A1-5

[0280] A1-4 (0.3 g, 0.60 mmol) was dissolved in tetrahydrofuran (9 mL). After stirring in an ice bath for 10 minutes, a solution of lithium hydroxide (29 mg, 1.20 mmol) in water (3 mL) was added dropwise. The mixture was stirred for another 10 minutes, and then the reaction was carried out at 30 °C for 2 hours. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure, and the solution was diluted with water. The pH of the solution was adjusted to 1-2 with 1 mol / L hydrochloric acid. A solid precipitated out. The mixture was stirred for 30 minutes, filtered, and the filter cake was dried to give compound A1-5 (0.2 g) as a pale yellow solid, with a yield of 70.7%.

[0281] MS m / z: 470.2 [M+H] + .

[0282] Step 6: Synthesis of compound A1

[0283] A1-5 (0.2 g, 0.43 mmol) was dissolved in DMF (5 mL), and DIPEA (0.17 g, 1.28 mmol) and HBTU (0.32 g, 0.85 mmol) were added. After the addition was complete, the mixture was stirred at room temperature for 0.5 h. Then, ammonium chloride (0.2 g, 1.28 mmol) was added, and the reaction was allowed to proceed for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was poured into an ice-water mixture and stirred for 30 min. The mixture was then filtered, the filter cake was dried, and purified by column chromatography and preparative liquid chromatography to obtain the target compound A1 (30 mg) as a white solid, with a yield of 15%.

[0284] MS m / z: 469.1 [M+H] + .

[0285] 1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.52(s,2H),8.36(s,1H),8.23(s,1H),8.13 (s,2H),7.59(s,1H),7.37(s,1H),2.27(tt,J=7.8,5.0Hz,1H),1.11-1.03(m,4H).

[0286] Example 2: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclobutylpyrimidin-5-yl)acrylamide (A2)

[0287] Step 1: Synthesis of compound A2-1

[0288] 30 mL of methyl tert-butyl ether and 8.7 g (0.27 mol) of methanol were added to a reaction flask. Acetyl chloride solution (19.4 g, 0.25 mol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to react at room temperature for 1 h. Then, 5 mL of methyl tert-butyl ether solution containing 2.0 g (24.6 mmol) of A2-0 was slowly added, and the mixture was allowed to react overnight at room temperature. The solvent was removed by concentration under reduced pressure to obtain compound A2-1 (3.8 g), a white solid, which was used directly in the next reaction without purification.

[0289] Step 2: Synthesis of compound A2-2

[0290] A2-1 (3.8 g, 24.6 mmol) was dissolved in methanol (20 mL), and a methanol solution of 7 mol / L ammonia (7 mL) was added at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 h. The solvent was removed by concentration under reduced pressure to obtain compound A2-2 (2.2 g), a white solid, which was used directly in the next reaction without purification.

[0291] Step 3: Synthesis of compound A2-3

[0292] Dissolve A2-2 (2.2 g, 14.9 mmol) in ethanol (20 mL), add 10.2 mL of 20% sodium ethoxide in ethanol (30.0 mmol), stir at 50 °C for 30 minutes, then add dropwise 10 mL of ethanol solution of bromic acid (3.3 g, 12.8 mmol), stir at 50 °C for 60 minutes, add 10.2 mL of 20% sodium ethoxide in ethanol (30.0 mmol), and continue stirring for 30 minutes. Concentrate under reduced pressure to remove the solvent, adjust the pH to 1-2 with 1 mol / L hydrochloric acid, extract with dichloromethane, combine the organic phases and wash with saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give compound A2-3 (1.2 g), a yellow solid, which was used directly in the next reaction without purification.

[0293] MS m / z: 257.0 [M+H] + .

[0294] Step 4: Synthesis of compound A2-4

[0295] A2-3 (1.2 g, 4.69 mmol) was dissolved in xylene (20 mL) and reacted at 140 °C for 5 h. The reaction was monitored by LC-MS until complete. The solvent was removed by concentration under reduced pressure, and the product was purified by column chromatography to give compound A2-4 (0.4 g) as a yellow liquid. The four-step yield was 7.6%.

[0296] MS m / z: 212.9 [M+H] + .

[0297] Step 5: Synthesis of compound A2-5

[0298] A2-4 (0.4 g, 1.89 mmol), pinacol diboronate (0.53 g, 1.04 mmol), potassium acetate (0.37 g, 3.77 mmol), and PdCl2(dppf)·DCM (0.08 g, 0.10 mmol) were dissolved in 1,4-dioxane (8 mL) and reacted at 85 °C for 5 h under nitrogen protection. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound A2-5, which was used directly in the next reaction without purification.

[0299] Step 6: Synthesis of compound A2-6

[0300] M1 (0.6 g, 1.31 mmol), A2-5 (crude product from step 5), sodium acetate (0.22 g, 2.63 mmol), and PdCl2 (dppf)·DCM (54 mg, 0.07 mmol) were dissolved in a mixed solution of 1,4-dioxane (10 mL) and water (1 mL). The reaction was carried out at 85 °C for 3 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with ethyl acetate. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A2-6 (0.56 g) as a pale yellow solid. The two-step yield was 58.3%.

[0301] MS m / z: 512.1 [M+H] + .

[0302] Step 7: Synthesis of compound A2-7

[0303] A2-6 (0.56 g, 1.10 mmol) was dissolved in tetrahydrofuran (10 mL). A solution of lithium hydroxide (53 mg, 2.19 mmol) in water (2 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure. A suitable amount of water was added, and the pH of the solution was adjusted to 1-2 with 1 mol / L hydrochloric acid. A solid precipitated. The mixture was stirred for 30 minutes, filtered, and the filter cake was dried to obtain compound A2-7 (0.3 g), a pale yellow solid, with a yield of 56.6%.

[0304] MS m / z: 484.1 [M+H] + .

[0305] Step 8: Synthesis of compound A2

[0306] A2-7 (0.3 g, 0.62 mmol) was dissolved in DMF (6 mL), and DIPEA (0.24 g, 1.86 mmol) and HBTU (0.47 g, 1.24 mmol) were added. After the addition was complete, the mixture was stirred at room temperature for 1 h, and then ammonium chloride (0.29 g, 1.86 mmol) was added, and the reaction was allowed to proceed for another 1 h. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by thin-layer chromatography and preparative liquid chromatography to obtain the target compound A2 (90 mg) as a white solid, with a yield of 30%.

[0307] MS m / z: 483.1 [M+H] + .

[0308] 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.65(s,2H),8.38(s,1H),8.22(s,1H),8.12(s,2H),7.61(s,1H), 7.39(s,1H),3.80(p,J=8.6Hz,1H),2.47-2.29(m,4H),2.09(dq,J=10.8,8.8Hz,1H),1.95-1.83(m,1H).

[0309] Example 3: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(oxecyclobutan-3-yl)pyrimidin-5-yl)acrylamide (A3)

[0310] Step 1: Synthesis of compound A3-1

[0311] A3-0 (8.8 g, 30.88 mmol) and 3-iodoxetane (6.82 g, 37.05 mmol) were dissolved in DMA (100 mL). Nickel chloride dimethoxyethane (0.68 g, 3.09 mmol), 2-amidinylpyridine hydrochloride (0.49 g, 3.09 mmol), trifluoroacetic acid (0.35 g, 3.09 mmol), sodium iodide (2.32 g, 15.44 mmol), and zinc powder (4.04 g, 61.75 mmol) were added all at once. The mixture was reacted at 60 °C for 4 h under nitrogen protection. The reaction was monitored by TLC until it was complete. The reaction was cooled to room temperature, filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A3-1 (0.64 g) as a white solid with a yield of 9.7%.

[0312] MS m / z: 214.9 [M+H] + .

[0313] Step 2: Synthesis of compound A3-2

[0314] A3-1 (0.64 g, 3.0 mmol), pinacol diboronate (0.91 g, 3.59 mmol), potassium acetate (0.59 g, 5.99 mmol), and PdCl2(dppf)·DCM (0.13 g, 0.16 mmol) were dissolved in 1,4-dioxane (13 mL) and reacted at 85 °C for 4 h under nitrogen protection. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound A3-2, which was used directly in the next reaction without purification.

[0315] MS m / z: 262.9 [M+H] + .

[0316] Step 3: Synthesis of compound A3-3

[0317] M1 (0.65 g, 1.42 mmol), A3-2 (crude product from step 2), sodium acetate (0.23 g, 2.84 mmol), and PdCl2(dppf)·DCM (0.11 g, 0.13 mmol) were dissolved in a mixed solution of 1,4-dioxane (20 mL) and water (2 mL). The reaction was carried out at 85 °C for 3 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A3-3 (0.18 g), with a two-step yield of 11.8%.

[0318] MS m / z: 514.1 [M+H] + .

[0319] Step 4: Synthesis of compound A3-4

[0320] A3-3 (0.18 g, 0.35 mmol) was dissolved in tetrahydrofuran (5 mL). A solution of lithium hydroxide (17 mg, 0.7 mmol) in water (1 mL) was added dropwise to the reaction solution, and the reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure, and an appropriate amount of water was added. The pH of the solution was adjusted to 1-2 with 1 mol / L hydrochloric acid, and a solid precipitated. The mixture was stirred for 30 minutes, filtered, and the filter cake was dried to obtain compound A3-4 (0.13 g) as a pale yellow solid, with a yield of 76.5%.

[0321] MS m / z: 486.1 [M+H] + .

[0322] Step 5: Synthesis of compound A3

[0323] A3-4 (0.13 g, 0.27 mmol) was dissolved in DMF (4 mL), and DIPEA (0.11 g, 0.80 mmol) and HBTU (0.21 g, 0.54 mmol) were added. After the addition was complete, the mixture was stirred at room temperature for 0.5 h, and then ammonium chloride (0.12 g, 0.80 mmol) was added, and the reaction was allowed to proceed for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by thin-layer chromatography and preparative liquid chromatography to obtain the target compound A3 (33 mg) as a white solid, with a yield of 25.4%.

[0324] MS m / z: 485.1 [M+H] + .

[0325] 1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.75(s,2H),8.43(s,1H),8.23(s,1H),8.08 (s,2H),7.66(s,1H),7.37(s,1H),5.00-4.91(m,4H),4.53(tt,J=8.6,6.7Hz,1H).

[0326] Example 4: Synthesis of compound (E)-3-(3-(3-cyclopropyl-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclopropylpyrimidin-5-yl)acrylamide (A4)

[0327] Step 1: Synthesis of compound A4-1

[0328] A4-0 (2.0 g, 9.3 mmol), cyclopropylboronic acid (0.8 g, 9.3 mmol), palladium acetate (105 mg, 0.47 mmol), tricyclohexylphosphine (0.26 g, 0.93 mmol), and potassium phosphate (6.9 g, 32.55 mmol) were dissolved in a mixed solution of toluene (25 mL) and water (2.5 mL). The reaction was carried out at 100 °C for 3 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A4-1 (1.5 g) as a pale yellow oil, with a yield of 73.2%.

[0329] Step 2: Synthesis of compound A4-2

[0330] Pd2(dba)3 (0.29 g, 0.32 mmol) and tricyclohexylphosphine (0.21 g, 0.76 mmol) were dissolved in 1,4-dioxane (20 mL). Under nitrogen protection, the mixture was stirred at room temperature for 30 minutes. Then, A4-1 (1.4 g, 6.35 mmol), pinacol diborate (2.4 g, 9.53 mmol), and potassium acetate (1.24 g, 12.7 mmol) were added. The mixture was then reacted at 80 °C for 12 h under nitrogen protection. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, and the filter cake was washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound A4-2, which was used directly in step 3 without purification.

[0331] Step 3: Synthesis of compound A4-3

[0332] M2 (4.0 g, 12.31 mmol), A1-3 (6.06 g, crude), sodium acetate (2.03 g, 24.62 mmol), and PdCl2(dppf)·DCM (0.51 g, 0.62 mmol) were dissolved in a mixed solution of dioxane (40 mL) and water (4 mL). The reaction was carried out at 85 °C for 4 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A4-3 (1.5 g), with a yield of 33.5%.

[0333] MS m / z: 364.1 [M+H] + .

[0334] Step 4: Synthesis of compound A4-4

[0335] A4-3 (1.4 g, 3.84 mmol) was dissolved in tetrahydrofuran (20 mL). A solution of lithium hydroxide (185 mg, 7.69 mmol) in water (4 mL) was added dropwise to the reaction mixture, and the reaction was allowed to proceed at room temperature for 2.5 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure, and an appropriate amount of water was added. The pH of the solution was adjusted to 3 with 1 mol / L hydrochloric acid, resulting in the precipitation of a solid. The mixture was stirred for 30 minutes, filtered, and the filter cake was dried to obtain compound A4-4 (0.97 g) as a pale yellow solid, with a yield of 75.1%.

[0336] MS m / z: 336.1 [M+H] + .

[0337] Step 5: Synthesis of compound A4-5

[0338] A4-4 (0.97 g, 2.89 mmol) was dissolved in tetrahydrofuran (15 mL), and isobutyl chloroformate (0.79 g, 5.78 mmol) and N-methylmorpholine (0.58 g, 5.78 mmol) were added at 0 °C. The reaction was stirred at 0 °C for 1 h. Then, 10 mL of a 7 mol / L ammonia methanol solution was added to the reaction solution. After the addition was complete, the reaction was allowed to proceed in an ice bath for 1.5 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the residue was poured into an ice-water mixture and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A4-5 (0.56 g), with a yield of 57.9%.

[0339] MS m / z: 335.1 [M+H] + .

[0340] Step 6: Synthesis of compound A4

[0341] A4-5 (0.5 g, 1.49 mmol), A4-2 (crude product from step 2), potassium carbonate (618 mg, 4.47 mmol), and Pd(PPh3)4 (172 mg, 0.15 mmol) were dissolved in a mixed solution of 1,4-dioxane (15 mL) and water (1.5 mL). The reaction was carried out at 80 °C for 12 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography and preparative liquid chromatography to obtain the target compound A4 (183 mg) as a white solid, with a yield of 27.9%.

[0342] MS m / z: 441.1 [M+H] + .

[0343] 1 H NMR(600MHz,DMSO-d6)δ9.03(s,1H),8.50(s,2H),8.33(s,1H),7.66(s,1H),7.54(d,J=17.6Hz,3H),7.33(s,1H) ,2.29(ddd,J=10.2,7.9,4.9Hz,1H),2.09(td,J=8.4,4.3Hz,1H),1.13-1.02(m,6H),0.76(dt,J=6.5,3.3Hz,2H).

[0344] Example 5: Synthesis of compound (E)-3-(3-(2,6-bis(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclopropylpyrimidin-5-yl)acrylamide (A5)

[0345] Step 1: Synthesis of compound A5-1

[0346] Pinaryl diboronate (0.77 g, 3.02 mmol), methoxy(cyclooctadiene)iridium dimer (1.6 mg, 0.007 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (3 mg, 0.014 mmol) were added to cyclohexane (10 mL). Under nitrogen protection, the mixture was stirred for ten minutes. Then, A5-0 (0.5 g, 2.32 mmol) was added, and the mixture was reacted at 55 °C for 24 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature, quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound A5-1, which was used directly in the next reaction without purification.

[0347] Step 2: Synthesis of compound A5

[0348] A4-5 (150 mg, 0.44 mmol), A5-1 (0.6 g, crude), potassium carbonate (124 mg, 0.88 mmol), and Pd(PPh3)4 (101 mg, 0.08 mmol) were dissolved in a mixed solution of 1,4-dioxane (15 mL) and water (1.5 mL). The reaction was carried out at 85 °C for 4 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by thin-layer chromatography and preparative liquid chromatography to obtain the target compound A5 (75 mg) as a white solid, with a yield of 35.7%.

[0349] MS m / z: 470.1 [M+H] + .

[0350] 1 H NMR (600MHz, DMSO-d6) δ9.21(s,1H),8.53(s,2H),8.39(s,1H),8.12(s,2H),7.62(s,1H),7.40(s,1H),2.31-2.26(m,1H),1.12-1.04(m,4H).

[0351] Example 6: Synthesis of compound (E)-3-(3-(2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclopropenyrimidin-5-yl)acrylamide (A6)

[0352] Step 1: Synthesis of compound A6-1

[0353] A6-0 (1.8 g, 7.96 mmol), cyclopropylboronic acid (1.36 g, 15.92 mmol), potassium carbonate (3.3 g, 23.88 mmol), and PdCl2 (dppf) (0.33 g, 0.4 mmol) were dissolved in a mixed solution of 1,4-dioxane (40 mL) and water (4 mL). The reaction was carried out at 90 °C for 12 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A6-1 (0.5 g), with a yield of 33.5%.

[0354] Steps 2-3: Synthesis of compound A6

[0355] The synthesis of steps 2-3 in Example 6 was performed using the same method as steps 1-2 in Example 5, except that A5-0 in step 1 of Example 5 was replaced with A6-1. The target compound A6 (11 mg) was prepared as a white solid with a yield of 8.4%.

[0356] MS m / z: 442.1 [M+H] + .

[0357] 1 H NMR (600MHz, DMSO-d6) δ9.12(s,1H),8.51(s,2H),8.36(s,1H),7.75(d,J=1.3Hz,1H),7.58(s,1H),7.56( d,J=1.3Hz,1H),7.37(s,1H),2.32-2.26(m,2H),1.14-1.09(m,4H),1.08-1.05(m,2H),0.98-0.95(m,2H).

[0358] Example 7: Synthesis of compound (E)-2-(2-cyclopropylpyrimidin-5-yl)-3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide (A7)

[0359] Step 1: Synthesis of compound A7-1

[0360] A7-0 (100 mg, 0.39 mmol), pinacol diborate (198 mg, 0.78 mmol), potassium acetate (77 mg, 0.78 mmol), and PdCl2 (dppf) (29 mg, 0.04 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 85 °C for 2 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound A7-1, which was used directly in the next reaction without purification.

[0361] Step 2: Synthesis of compound A7

[0362] The synthesis of step 2 in Example 7 was performed using the same method as step 6 in Example 4, except that A4-2 in step 6 of Example 4 was replaced with A7-1. The rest of the method was the same, and the target compound A7 (9 mg) was prepared as a white solid with a yield of 10.7%.

[0363] MS m / z: 431.0 [M+H] + .

[0364] 1 H NMR(600MHz,DMSO-d6)δ9.05(s,1H),8.50(s,2H),8.33(s,1H),7.54(s,1H),7.46(s,1H),7.44-7.41(m,1H),7. 33(s,1H),7.32(t,J=2.0Hz,1H),3.87(s,3H),2.25(tt,J=8.0,4.8Hz,1H),1.07(dtd,J=10.0,8.0,5.2Hz,4H).

[0365] Example 8: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-hydroxycyclopropyl)pyrimidin-5-yl)acrylamide (A20)

[0366] Step 1: Synthesis of compound A20-1

[0367] A20-0 (9.6 g, 52.2 mmol) was dissolved in 100 mL of diethyl ether. Under nitrogen protection, a solution of magnesium methyl bromide in diethyl ether (15.8 mL, 3.0 M) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred for 30 minutes and then allowed to react at room temperature for 3 h. The reaction mixture was quenched in a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A20-1 (6.2 g) as a yellow solid, with a yield of 59.4%.

[0368] MS m / z: 200.8 [M+H] + .

[0369] Step 2: Synthesis of compound A20-2

[0370] A20-1 (6.0 g, 30.0 mmol) and triethylamine (6.1 g, 60.0 mmol) were dissolved in dichloromethane (120 mL). Tert-butyldimethylsilyltrifluoromethanesulfonate (15.8 g, 59.8 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was allowed to react at room temperature for 16 h. The reaction solution was extracted with water. The organic phase was washed successively with 5% citric acid aqueous solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A20-2 (6.0 g) as a yellow oil, with a yield of 63.7%.

[0371] MS m / z: 315.0 [M+H] + .

[0372] Step 3: Synthesis of compound A20-3

[0373] A hexane solution of diethylzinc (18.0 mL, 1.0 M) was added to dichloromethane (35 mL). Under nitrogen protection, chloroiodomethane (6.47 g, 36.7 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was stirred for 30 minutes. Then, a dichloromethane solution of A20-2 (1.8 g, 5.73 mmol) was slowly added dropwise at 0 °C, and the reaction was carried out at 0 °C for 3 h. The reaction solution was quenched in saturated ammonium chloride solution, filtered, and the filtrate was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A20-3 (0.45 g) as a yellow liquid, with a yield of 23.9%.

[0374] MS m / z: 329.0 [M+H] + .

[0375] Step 4: Synthesis of compound A20-4

[0376] A20-3 (0.33 g, 1.0 mmol), pinacol diboronate (0.31 g, 1.2 mmol), potassium acetate (0.2 g, 2.0 mmol), and PdCl2(dppf)·DCM (42 mg, 0.05 mmol) were dissolved in 1,4-dioxane (6 mL) and reacted at 80 °C for 3 h under nitrogen protection. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound A20-4, which was used directly in the next reaction without purification.

[0377] Step 5: Synthesis of compound A20-5

[0378] M1 (0.5 g, 1.09 mmol), A20-4 (crude product from step 4), sodium acetate (0.18 g, 2.19 mmol), and PdCl2 (dppf)·DCM (45 mg, 0.05 mmol) were dissolved in a mixed solution of dioxane (10 mL) and water (1 mL). The reaction was carried out at 85 °C for 3 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A20-5 (0.1 g), with a two-step yield of 15.9%.

[0379] Step 6: Synthesis of compound A20-6

[0380] A20-5 (0.1 g, 0.16 mmol) was dissolved in tetrahydrofuran (2 mL). A solution of lithium hydroxide (8 mg, 0.32 mmol) in water (0.3 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure. A suitable amount of water was added, and the pH of the solution was adjusted to 1-2 with 1 mol / L hydrochloric acid. The solution was extracted with dichloromethane, and the organic phases were combined and washed with saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound A20-6 (90 mg) as a yellowish-brown oil, with a yield of 94.0%.

[0381] MS m / z: 600.1 [M+H] + .

[0382] Step 7: Synthesis of compound A20-7

[0383] A20-6 (75 mg, 0.13 mmol) was dissolved in tetrahydrofuran (3 mL). After stirring in an ice bath for 10 minutes, isobutyl chloroformate (25 mg, 0.18 mmol) and N-methylmorpholine (25 mg, 0.25 mmol) were added to the reaction solution, and the reaction was continued to be stirred in an ice bath for 1 hour. Then, 1 mL of a 7 mol / L ammonia methanol solution was added to the reaction solution. After the addition was complete, the reaction was carried out in an ice bath for 30 minutes. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the residue was poured into an ice-water mixture and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound A20-7 (80 mg) as a brown oily substance with a yield of 88.8%.

[0384] MS m / z: 599.2 [M+H] + .

[0385] Step 8: Synthesis of compound A20

[0386] A20-7 (80 mg, 0.54 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of TBAF (4 mL, 1.0 M) was added at 0 °C. After the addition was complete, the reaction was carried out at 0 °C for 2 h. The reaction was monitored by TLC until complete. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by thin-layer chromatography and preparative liquid chromatography to obtain the target compound A20 (17 mg) as a white solid, with a yield of 26.3%.

[0387] MS m / z: 485.2 [M+H] + .

[0388] 1 H NMR(600MHz,DMSO-d6)δ9.12(s,1H),8.62(s,2H),8.37(s,1H),8.23(s,1H),8.15(s,2H ),7.59(s,1H),7.44(s,1H),5.91(s,1H),1.35(q,J=4.1Hz,2H),1.20(q,J=4.1Hz,2H).

[0389] Example 9: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-cyanocyclopropyl)pyrimidin-5-yl)acrylamide (A23)

[0390] Step 1: Synthesis of compound A23-1

[0391] NaH (8.5 g, 212.5 mmol) was dissolved in tetrahydrofuran (50 mL). A23-0 (16.44 g, 85.0 mmol) was added under ice bath conditions, and stirring continued for 1 h under ice bath conditions. Tert-butyl cyanoacetate (10 g, 70.84 mmol) was added to the reaction mixture, and the reaction was brought to room temperature and allowed to proceed overnight at room temperature. The reaction was monitored by TLC until complete. Water was added to quench the reaction mixture, resulting in the precipitation of a large amount of solid. The solid was filtered to obtain compound A23-1 (6.8 g), a yellow solid, with a yield of 44.0%.

[0392] MS m / z: 299.1 [M+H] + .

[0393] Step 2: Synthesis of compound A23-2

[0394] A23-1 (6.3 g, 21.14 mmol) was dissolved in dichloromethane (50 mL). Trifluoroacetic acid (20 mL) was added dropwise to the reaction solution under ice bath conditions. The reaction was brought to room temperature and allowed to proceed for 2 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, the residue was diluted with water, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A23-2 (2.4 g) as a yellow solid, with a yield of 57.3%.

[0395] MS m / z: 198.1 [M+H] + .

[0396] Step 3: Synthesis of compound A23-3

[0397] A23-2 (2.4 g, 12.11 mmol) and 1,2-dibromoethane (9.09 g, 48.43 mmol) were dissolved in toluene (40 mL), and TEBAC (276 mg, 1.21 mmol) and sodium hydroxide (3.86 g, 96.7 mmol) were added. The reaction was carried out at room temperature for 48 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A23-3 (1.24 g) as a pale yellow solid, with a yield of 45.6%.

[0398] MS m / z: 225.1 [M+H] + .

[0399] Step 4: Synthesis of compound A23-4

[0400] A23-3 (1.2 g, 5.4 mmol), pinacol diborate (2.73 g, 10.74 mmol), Pd2(dba)3 (164 mg, 0.179 mmol), X-Phos (171 mg, 0.359 mmol), and potassium acetate (1.05 g, 10.74 mmol) were dissolved in 1,4-dioxane (30 mL) and reacted at 80 °C for 2 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound A23-4, which was used directly in the next reaction without purification.

[0401] Steps 5-7: Synthesis of compound A23

[0402] The synthesis of steps 5 to 7 in Example 9 was performed using the same method as steps 4 to 6 in Example 1, except that A23-4 was used instead of A1-3 in step 4 of Example 1. The target compound A23 (73 mg) was prepared as a yellow solid with a yield of 55.1%.

[0403] MS m / z: 494.1 [M+H] + .

[0404] 1 H NMR(600MHz,DMSO-d6)δ9.17(s,1H),8.68(s,2H),8.44(s,1H),8.23(s,1H),8.0 7(s,2H),7.62(s,1H),7.30(s,1H),1.94(q,J=4.2Hz,2H),1.78(q,J=4.2Hz,2H).

[0405] Example 10: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(6-cyclopropyl-5-fluoropyridin-3-yl)acrylamide (A25)

[0406] Step 1: Synthesis of compound A25-1

[0407] A25-0 (1.0 g, 3.92 mmol), cyclopropylboronic acid (0.5 g, 5.88 mmol), potassium phosphate (2.5 g, 11.76 mmol), and tetrakis(triphenylphosphine)palladium (0.45 g, 0.4 mmol) were dissolved in a mixture of toluene (20 mL) and water (2 mL). The reaction was carried out at 110 °C for 12 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A25-1 (0.65 g), with a two-step yield of 76.7%.

[0408] MS m / z: 216.1 [M+H] + .

[0409] Step 2: Synthesis of compound A25-2

[0410] A25-1 (0.6 g, 2.78 mmol), pinacol diboronate (0.78 g, 3.06 mmol), PdCl2 (dppf) (0.12 g, 0.28 mmol), and potassium acetate (0.82 g, 8.34 mmol) were dissolved in toluene (10 mL) and reacted at 100 °C for 4 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth filter, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound A25-2, which was used directly in the next reaction without purification.

[0411] Step 3: Synthesis of compound A25-3

[0412] M1 (0.62 g, 1.35 mmol), A25-2 (the crude product from the previous step), potassium acetate (0.26 g, 2.7 mmol), and PdCl2 (dppf)·DCM (0.11 g, 0.14 mmol) were dissolved in a mixed solution of dioxane (12 mL) and water (1.2 mL). The reaction was carried out at 80 °C for 2 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A25-3 (0.59 g) as a yellow solid, with a yield of 84.8%.

[0413] MS m / z: 515.1 [M+H] + .

[0414] The synthesis of steps 4-5 in Example 10 was carried out by referring to the synthesis method of steps 4-5 in Example 4, except that A25-3 was used instead of A4-3 in step 4 of Example 4. The rest of the method was the same, and the target compound A25 (17 mg) was prepared as a white solid with a yield of 3.3%.

[0415] MS m / z: 486.1 [M+H] + .

[0416] 1 H NMR(600MHz,DMSO-d6)δ9.06(s,1H),8.31(s,1H),8.21(s,1H),8.12(s,3H),7.59(dd,J =10.7,1.8Hz,1H),7.56(s,1H),7.19(s,1H),2.36(t,J=6.6Hz,1H),1.08-1.00(m,4H).

[0417] Example 11: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(5-cyano-6-cyclopropylpyridin-3-yl)acrylamide (A27)

[0418] The synthesis of steps 1-2 in Example 11 was performed according to the synthesis method of steps 2-3 in Example 10, except that A27-0 was used instead of A25-1 in step 2 of Example 10, and the rest of the methods were the same; the synthesis of step 3 in Example 11 was performed according to the synthesis method of step 1 in Example 10, except that A27-2 was used instead of A25-0 in step 1 of Example 10, and the rest of the methods were the same; the synthesis of steps 4-5 in Example 11 was performed according to the synthesis method of steps 4-5 in Example 4, except that A27-3 was used instead of A4-3 in step 4 of Example 4, and the rest of the methods were the same. The target compound A27 (59 mg) was prepared as a white solid with a yield of 33.1%.

[0419] MS m / z: 493.1 [M+H] + .

[0420] 1H NMR (600MHz, DMSO-d6) δ9.13(s,1H),8.53(d,J=2.2Hz,1H),8.38(s,1H),8.23(s,1H),8.19(d,J=2.2Hz,1H),8.07(d,J= 1.7Hz,2H),7.60(s,1H),7.22(s,1H),2.48(dd,J=8.1,4.6Hz,1H),1.24-1.17(m,2H),1.12(dq,J=6.8,4.0,3.5Hz,2H).

[0421] Example 12: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(3,3-difluorocyclobutyl)pyrimidin-5-yl)acrylamide (A31)

[0422] Step 1: Synthesis of compound A31-1

[0423] A31-0 (3.0 g, 31.55 mmol) was dissolved in dichloromethane (50 mL), and a solution of diethylaminosulfur trifluoride (10.2 g, 63.09 mmol) was slowly added dropwise under an ice bath. The reaction was carried out at room temperature for 12 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction solution was poured into a saturated sodium bicarbonate solution in portions under an ice bath and stirred for 1 h. The mixture was extracted with dichloromethane, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound A31-1 (3.3 g) as a brown solid, with a yield of 89.4%.

[0424] Step 2: Synthesis of compound A31-2

[0425] Under nitrogen protection and at 0°C, acetyl chloride (18.8 g, 239.11 mmol) was slowly added dropwise to a mixed solution of methyl tert-butyl ether (30 mL) and methanol (8.4 g, 263.03 mmol). After the addition was complete, the reaction was carried out at 0°C for 1 h. Then, a solution of A31-1 (2.8 g, 23.91 mmol) in methyl tert-butyl ether (5 mL) was slowly added, and the reaction was carried out at 0°C for 5 h. The reaction solution was concentrated under reduced pressure to obtain compound A31-2 (3.8 g), a yellow solid, which was used directly in the next reaction without purification.

[0426] Step 3: Synthesis of compound A31-3

[0427] A31-2 (3.8 g, the crude product from the previous step) was dissolved in methanol (40 mL), and a methanol solution of 7 mol / L ammonia (8.8 mL) was added at 0 °C. After the addition was complete, the reaction was allowed to proceed at 0 °C for 3.5 h. The reaction solution was concentrated under reduced pressure and slurried with petroleum ether to obtain compound A31-3 (3.4 g), a yellow solid, which was used directly in the next step of the reaction without purification.

[0428] Step 4: Synthesis of compound A31-4

[0429] Dissolve 3.4 g of A31-3 (the crude product from the previous step) in ethanol (40 mL), add 13.7 mL of 20% sodium ethoxide in ethanol (50.70 mmol), stir at 50 °C for 5 minutes, add dropwise 10 mL of ethanol solution of bromic acid (4.6 g, 22.81 mmol), stir at 50 °C for 1 hour, add 13.7 mL of 20% sodium ethoxide in ethanol (50.70 mmol), and continue stirring for 30 minutes. Concentrate the reaction solution under reduced pressure, adjust the pH to 2-3 with 1 mol / L hydrochloric acid, extract with dichloromethane, combine the organic phases and wash with saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound A31-4 (2.6 g), a brown solid, which was used directly in the next reaction without purification.

[0430] Step 5: Synthesis of compound A31-5

[0431] A31-4 (2.5 g, crude product from the previous step) was dissolved in xylene (30 mL) and reacted at 140 °C for 5 h. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain compound A31-5 (0.69 g), a yellow liquid, with a yield of 32.5%.

[0432] MS m / z: 248.9 [M+H] + .

[0433] Step 6: Synthesis of compound A31

[0434] The synthesis of step 6 in Example 12 was performed according to the synthesis method of step 4 in Example 9, except that A23-3 in step 4 of Example 9 was replaced by A31-5, and the rest of the method was the same. The synthesis of steps 7-9 in Example 12 was performed according to the synthesis method of steps 3-5 in Example 4, except that A1-3 and M2 in step 3 of Example 4 were replaced by A31-6 and M1, respectively, and the rest of the method was the same. The target compound A31 (63 mg) was prepared as a white solid with a yield of 7.9%.

[0435] MS m / z: 519.1 [M+H] + .

[0436] 1H NMR(600MHz,DMSO-d6)δ9.15(s,1H),8.72(s,2H),8.41(s,1H),8.22(s,1H),8.10(d,J =1.8Hz,2H),7.63(s,1H),7.35(s,1H),3.65(qd,J=8.5,3.4Hz,1H),3.09-2.94(m,4H).

[0437] Example 13: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)acrylamide (A32)

[0438] Step 1: Synthesis of compound A32-1

[0439] A3-0 (1.0 g, 3.51 mmol) was dissolved in anhydrous toluene (20 mL). Under nitrogen protection, a solution of n-butyllithium in n-hexane (1.5 mL, 2.5 M) was added dropwise at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 1 h. Cyclobutanone (0.27 g, 3.86 mmol) was added, and the mixture was stirred for 30 min. The mixture was then allowed to react at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A32-1 (0.33 g) as a yellow solid, with a yield of 41.3%.

[0440] MS m / z: 228.9 [M+H] + .

[0441] Step 2: Synthesis of compound A32-2

[0442] A32-1 (1.0 g, 4.39 mmol) and imidazole (0.6 g, 8.77 mmol) were dissolved in dichloromethane (20 mL). TMSCl (0.96 g, 8.77 mmol) was added at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until complete. The mixture was extracted with an appropriate amount of water. The organic phase was washed successively with 5% citric acid aqueous solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A32-2 (0.33 g) as a colorless liquid, with a yield of 76.0%.

[0443] Steps 3-6: Synthesis of compound A32

[0444] The synthesis of steps 3 to 6 in Example 13 was performed using the same method as steps 5 to 8 in Example 2, except that A2-4 in step 5 of Example 2 was replaced with A32-2. The target compound A32 (120 mg) was obtained as a white solid with a yield of 44.4%.

[0445] MS m / z: 499.1 [M+H] + .

[0446] 1 H NMR(600MHz,DMSO-d6)δ9.15(s,1H),8.76(s,2H),8.40(s,1H),8.22(s,1H),8.15(s,2H),7.65(s,1H),7.46(s,1H),5.51(s, 1H), 2.64 (ddd, J=12.4, 9.1, 4.9Hz, 2H), 2.32 (tdd, J=9.8, 7.9, 2.5Hz, 2H), 1.96-1.88 (m, 1H), 1.85 (dt, J=10.7, 8.5Hz, 1H).

[0447] Example 14: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(tetrahydrofuran-3-yl)pyrimidin-5-yl)acrylamide (A33)

[0448] The synthesis of step 1 in Example 14 was performed according to the synthesis method of step 1 in Example 3, except that 3-iodotetrahydrofuran was used instead of 3-iodooxetane in step 1 of Example 3, and the rest of the method was the same. The synthesis of steps 2-5 in Example 14 was performed according to the synthesis method of steps 4-7 in Example 9, except that A33-1 was used instead of A23-3 in step 4 of Example 9, and the rest of the method was the same. The target compound A33 (107 mg) was prepared as a white solid with a yield of 41.2%.

[0449] MS m / z: 499.1 [M+H] + .

[0450] 1 H NMR(600MHz,DMSO-d6)δ9.15(s,1H),8.67(s,2H),8.39(s,1H),8.23(s,1H),8.12(d,J=1.8Hz,2H),7.62 (s,1H),7.39(s,1H),4.16(t,J=8.1Hz,1H),3.94-3.84(m,3H),3.73(p,J=7.8Hz,1H),2.35-2.30(m,2H).

[0451] Example 15: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-yl)acrylamide (A34)

[0452] The synthesis of step 1 in Example 15 was performed according to the synthesis method of step 1 in Example 3, except that 3-iodooxetane in step 1 of Example 3 was replaced with 4-iodotetrahydro-2H-pyran, and the rest of the method was the same; the synthesis of steps 2-5 in Example 15 was performed according to the synthesis method of steps 4-7 in Example 9, except that A23-3 in step 4 of Example 9 was replaced with A34-1, and the rest of the method was the same. The target compound A34 (107 mg) was prepared as a white solid with a yield of 41.2%.

[0453] MS m / z: 513.1 [M+H] + .

[0454] 1 H NMR(600MHz,DMSO-d6)δ9.13(s,1H),8.67(s,2H),8.38(s,1H),8.22(s,1H),8.12(d,J=1.8Hz,2H),7.60(s,1H ),7.42(s,1H),4.01-3.95(m,2H),3.53-3.47(m,2H),3.15-3.07(m,1H),1.97-1.90(m,2H),1.90-1.82(m,2H).

[0455] Example 16: Synthesis of compound (E)-2-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide (A35)

[0456] Step 1: Synthesis of compound A35-1

[0457] Cyclobutanone (1.0 g, 14.3 mmol) and tert-butylsulfinamide (1.9 g, 15.7 mmol) were dissolved in tetrahydrofuran (20 mL), and tetraethyl propylene titanate (8.12 g, 28.6 mmol) was added. The mixture was reacted overnight at 60 °C. The reaction solution was concentrated under reduced pressure, and saturated sodium carbonate aqueous solution and ethyl acetate were added. The mixture was stirred for 10 minutes, filtered through a diatomaceous earth sieve, and the filter cake was washed with ethyl acetate. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A35-1 (1.4 g) as a yellow oil, with a yield of 56.7%.

[0458] Step 2: Synthesis of compound A35-2

[0459] A3-0 (3 g, 10.5 mmol) was dissolved in anhydrous toluene (30 mL). Under nitrogen protection, a solution of n-butyllithium in n-hexane (4.6 mL, 2.5 M) was added dropwise at -78 °C. After the addition was complete, the mixture was stirred for 1 h. Then, A35-1 (2.0 g, 11.6 mmol) was added, and the mixture was stirred for 30 min. The mixture was then allowed to react at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A35-2 (0.7 g) as a yellow solid, with a yield of 20.1%.

[0460] MS m / z: 331.9 [M+H] + .

[0461] Steps 3-6: Synthesis of compound A35-6

[0462] The synthesis of steps 3-6 in Example 16 is the same as that of steps 4-7 in Example 9, except that A35-2 is used instead of A23-3 in step 4 of Example 9, and PdCl2(dppf)·DCM is used instead of PdCl2(dppf) in step 5 of Example 9. The rest of the methods are the same.

[0463] Step 7: Synthesis of compound A35

[0464] A35-6 (0.22 g, 0.37 mmol) was dissolved in 1,4-dioxane (5 mL), and 4 mol / L dioxane hydrochloride solution (1.5 mL) was added. The reaction was carried out at room temperature for 1 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, diluted with an appropriate amount of water, and the pH was adjusted to 8 with saturated sodium carbonate solution. A solid precipitated out. The solid was filtered, dried, and purified by preparative liquid chromatography to obtain the target compound A35 (78 mg) as a white solid, which is a trifluoroacetate, with a yield of 35.0%.

[0465] MS m / z: 498.1 [M+H] + .

[0466] 1H NMR (600MHz, DMSO-d6) δ9.14(s,1H),8.91(s,2H),8.79(s,3H),8.43(s,1H),8.25(s,1H),8.19(s,2H),7.63(d,J=45.1Hz, 2H), 2.75(ddd,J=12.6,9.2,5.9Hz,2H), 2.54(dtd,J=12.5,9.1,8.1,4.7Hz,2H), 2.22(dtdd,J=18.5,9.2,6.8,4.0Hz,2H).

[0467] Example 17: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(3-fluorooxocyclobutane-3-yl)pyrimidin-5-yl)acrylamide (A37)

[0468] Step 1: Synthesis of compound A37-1

[0469] A3-0 (5.0 g, 17.55 mmol) was dissolved in anhydrous toluene (20 mL). Under nitrogen protection, a solution of n-butyllithium in n-hexane (10 mL, 2.5 M) was added dropwise at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 1 h. Then, a solution of cyclobutanone (1.52 g, 21.09 mmol) in toluene (20 mL) was added dropwise. After the addition was complete, the mixture was stirred for 30 min, and then the mixture was allowed to react at room temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A37-1 (1.18 g) as a yellow solid, with a yield of 25.7%.

[0470] Step 2: Synthesis of compound A37-2

[0471] Diethylaminosulfur trifluoride (1.25 g, 7.75 mmol) was dissolved in dichloromethane (10 mL). A solution of A37-1 (1.15 g, 4.98 mmol) in dichloromethane (10 mL) was slowly added dropwise under an ice bath. The reaction was carried out at room temperature for 2.5 h under nitrogen protection. The reaction mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A37-2 (533 mg) as a yellow solid, with a yield of 40.4%.

[0472] Steps 3-5: Synthesis of compound A37

[0473] The synthesis of steps 3-5 in Example 17 was performed according to the synthesis method of steps 4-6 in Example 9, except that A23-3 in step 4 of Example 9 was replaced by A37-2, and the rest of the methods were the same. The synthesis of step 6 in Example 15 was performed according to the synthesis method of step 5 in Example 4, except that A4-4 in step 5 of Example 4 was replaced by A37-5, and the rest of the methods were the same. The target compound A37 (111 mg) was prepared as a white solid with a yield of 44.61%.

[0474] MS m / z: 503.1 [M+H] + .

[0475] 1 H NMR(600MHz,DMSO-d6)δ9.18(s,1H),8.88(s,2H),8.47(s,1H),8.21(s,1H),8.07(s,2H),7.6 8(s,1H),7.35(s,1H),5.14(ddd,J=22.8,8.4,1.2Hz,2H),5.01(ddd,J=21.6,8.4,1.2Hz,2H).

[0476] Example 18: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(3-hydroxyoxetane-3-yl)pyrimidin-5-yl)acrylamide (A38)

[0477] The synthesis of step 1 in Example 18 was performed using the same method as step 2 in Example 13, except that A37-1 was used instead of A32-1 in step 2 of Example 13. The synthesis of steps 2 to 5 in Example 18 was performed using the same method as steps 5 to 8 in Example 2, except that A38-1 was used instead of A2-4 in step 5 of Example 2. The target compound A38 (20 mg) was prepared as a white solid with a yield of 18.4%.

[0478] MS m / z: 501.1 [M+H] + .

[0479] 1 H NMR(600MHz,DMSO-d6)δ9.14(s,1H),8.82(s,2H),8.43(s,1H),8.22(s,1H),8.12(d,J=1.8H z,2H),7.65(s,1H),7.42(s,1H),6.24(s,1H),5.02(d,J=6.2Hz,2H),4.74(d,J=6.2Hz,2H).

[0480] Example 19: Synthesis of compound (E)-3-(3-(2,6-bis(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclobutylpyrimidin-5-yl)acrylamide (A39)

[0481] The synthesis of steps 1 to 4 in Example 16 was performed by referring to the synthesis method of steps 3 to 6 in Example 4, except that A2-5 replaced A1-3 in step 3 of Example 4, and A5-1 replaced A4-2 in step 6 of Example 4. The rest of the method was the same, and the target compound A39 (12 mg) was prepared as a white solid with a yield of 21.6%.

[0482] MS m / z: 484.2 [M+H] + .

[0483] 1 H NMR(600MHz,DMSO-d6)δ9.21(s,1H),8.66(s,2H),8.40(s,1H),8.12(s,2H),7.64(s,1H),7.42(s,1H),3.81(p,J =8.6Hz,1H),2.43(dq,J=12.0,9.4Hz,2H),2.35(qd,J=8.6,4.5Hz,2H),2.08(q,J=9.4Hz,1H),1.96-1.86(m,1H).

[0484] Example 20: Synthesis of compound (E)-2-(2-cyclobutylpyrimidin-5-yl)-3-(3-(2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylamide (A40)

[0485] The synthesis of Example 20 was carried out by referring to the synthesis method of step 6 of Example 4, except that A39-3 replaced A4-5 in step 6 of Example 4, and A6-2 replaced A4-2 in step 6 of Example 4. The rest of the method was the same, and the target compound A40 (23 mg) was prepared as a white solid with a yield of 29.4%.

[0486] MS m / z: 456.2 [M+H] + .

[0487] 1H NMR(600MHz,DMSO-d6)δ9.13(s,1H),8.64(s,2H),8.38(s,1H),7.78(s,1H),7.6 1(s,1H),7.52(s,1H),7.39(s,1H),3.82(p,J=8.6Hz,1H),2.43(qd,J=9.1,2.6H z,2H),2.35(qt,J=8.9,3.0Hz,2H),2.26(tt,J=8.3,4.7Hz,1H),2.13-2.03(m,1 H),1.94-1.85(m,1H),1.08(dq,J=6.6,3.8Hz,2H),0.95(dq,J=6.9,3.9Hz,2H).

[0488] Example 21: Synthesis of compound (E)-3-(3-(2,6-bis(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)-2-(2-(oxecyclobutan-3-yl)pyrimidin-5-yl)acrylamide (A41)

[0489] In Example 21, steps 1 to 4 were synthesized using the same method as steps 3 to 6 of Example 4, except that A1-3 in step 3 of Example 4 was replaced by A3-2, and A4-2 in step 6 of Example 4 was replaced by A5-1. The rest of the method was the same, and the target compound A41 (11 mg) was prepared as a white solid with a yield of 17.0%.

[0490] MS m / z: 486.1 [M+H] + .

[0491] 1 H NMR(600MHz,DMSO-d6)δ9.23(s,1H),8.75(s,2H),8.44(s,1H),8.09(s,2H),7.68(s,1H),7.40(s, 1H), 4.98 (dd, J=8.6, 5.6Hz, 2H), 4.92 (dd, J=6.8, 5.6Hz, 2H), 4.54 (ddd, J=15.4, 8.5, 6.8Hz, 1H).

[0492] Example 22: Synthesis of compound (E)-3-(3-(2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)-2-(2-(oxecyclobutane-3-yl)pyrimidin-5-yl)acrylamide (A42)

[0493] The synthesis of Example 22 was carried out by referring to the synthesis method of step 6 of Example 4, except that A41-3 was used to replace A4-5 in step 6 of Example 4, and A6-2 was used to replace A4-2 in step 6 of Example 4. The rest of the method was the same, and the target compound A42 (23 mg) was prepared as a white solid with a yield of 29.4%.

[0494] MS m / z: 458.2 [M+H] + .

[0495] 1 H NMR (600MHz, DMSO-d6) δ9.14(s,1H),8.73(s,2H),8.41(s,1H),7.74(d,J=1.3Hz,1H),7.65(s,1H),7.50(d,J=1.3Hz,1H),7.37(s,1H),4.98(dd ,J=8.6,5.6Hz,2H),4.93(dd,J=6.8,5.6Hz,2H),4.56(tt,J=8.6,6.7Hz ,1H),2.26(tt,J=8.1,4.7Hz,1H),1.11-1.05(m,2H),0.98-0.90(m,2H).

[0496] Example 23: Synthesis of compound (E)-3-(3-(2,6-bis(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)acrylamide (A43)

[0497] The synthesis of steps 1 to 4 in Example 23 was carried out by referring to the synthesis method of steps 3 to 6 in Example 4, except that A1-3 in step 3 of Example 4 was replaced by A32-3, and A4-2 in step 6 of Example 4 was replaced by A5-1. The rest of the method was the same, and the target compound A43 (4 mg) was prepared as a white solid with a yield of 2.3%.

[0498] MS m / z: 500.1 [M+H] + .

[0499] 1 H NMR(600MHz,DMSO-d6)δ9.22(s,1H),8.76(s,2H),8.42(s,1H),8.15(s,2H),7.66(s,1H),7.49( s,1H),5.50(s,1H),2.67-2.61(m,2H),2.36-2.29(m,2H),1.97-1.89(m,1H),1.87-1.79(m,1H).

[0500] Example 24: Synthesis of compound (E)-3-(3-(2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)acrylamide (A44)

[0501] The synthesis of Example 24 was carried out by referring to the synthesis method of step 6 of Example 4, except that A43-3 was used to replace A4-5 in step 6 of Example 4, and A6-2 was used to replace A4-2 in step 6 of Example 4. The rest of the method was the same, and the target compound A44 (4 mg) was prepared as a white solid with a yield of 2.6%.

[0502] MS m / z: 472.1 [M+H] + .

[0503] 1 H NMR(600MHz,DMSO-d6)δ9.13(s,1H),8.74(s,2H),8.40(s,1H),7.71(s,1H),7.62(d,J=9.7Hz,2H),7.45(s,1H),5.57 (s,1H),2.66(s,2H),2.32(d,J=9.8Hz,2H),2.27(s,1H),1.93-1.80(m,2H),1.08-1.03(m,2H),0.95(d,J=4.5Hz,2H).

[0504] Example 25: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-fluorocyclobutyl)pyrimidin-5-yl)acrylamide (A45)

[0505] The synthesis of step 1 in Example 25 was performed according to the synthesis method of step 2 in Example 17, except that A32-1 was used instead of A37-1 in step 2 of Example 17, and the rest of the methods were the same; the synthesis of steps 2-4 was performed according to the synthesis method of steps 4-6 in Example 9, except that A45-1 was used instead of A23-3 in step 4 of Example 9, and the rest of the methods were the same; the synthesis of step 5 in Example 15 was performed according to the synthesis method of step 5 in Example 4, except that A45-4 was used instead of A4-4 in step 5 of Example 4, and the rest of the methods were the same. The target compound A45 (67 mg) was prepared as a white solid with a yield of 18.9%.

[0506] MS m / z: 501.1 [M+H] + .

[0507] 1H NMR(600MHz,DMSO-d6)δ9.14(s,1H),8.61(s,2H),8.38(s,1H),8.21(s,1H),8.11(s,2H),7.58(s ,1H),7.39(s,1H),4.95(s,1H),4.87(s,1H),1.42(dt,J=6.6,3.6Hz,2H),1.25(q,J=3.6Hz,2H).

[0508] Example 26: Synthesis of compound (E)-2-(2-cyclopropylpyrimidin-5-yl)-3-(3-(3,5-dicyclopropylphenyl)-1H-1,2,4-triazol-1-yl)acrylamide (A46)

[0509] The synthesis of Example 26 was carried out by referring to the synthesis method of step 6 of Example 4, except that A46-0 was used instead of A4-2 in step 6 of Example 4. The rest of the method was the same, and the target compound A46 (32 mg) was prepared as a white solid with a yield of 32.3%.

[0510] MS m / z: 413.2 [M+H] + .

[0511] 1 H NMR (600MHz, DMSO-d6) δ8.94(s,1H),8.49(s,2H),8.30(s,1H),7.51(s,1H),7.30(s,1H),7.10(d,J=1.7Hz,2H),6.87(t,J=1.7Hz,1H),2 .30(td,J=7.5,3.9Hz,1H),1.88(tt,J=8.4,4.9Hz,2H),1.09(t,J=6.0Hz,4H),0.96(dt,J=8.4,3.3Hz,4H),0.64(dt,J=6.3,4.4Hz,4H).

[0512] Example 27: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclopropylpyrimidin-5-yl)-N-(3-hydroxycyclobutyl)acrylamide (A49)

[0513] The synthesis of Example 27 was carried out by referring to the synthesis method of step 6 of Example 1, except that 3-aminocyclobutanol was used to replace ammonium chloride in step 6 of Example 1. The rest of the method was the same, and the target compound A49 (37 mg) was prepared as a white solid with a yield of 31.8%.

[0514] MS m / z: 539.1 [M+H] + .

[0515] 1 H NMR (600MHz, DMSO-d6) δ9.12(s,1H),8.49(s,2H),8.29(s,1H),8.22(s,1H),8.12(s,2H),8.06(d,J=7.2Hz,1H),5.07(d,J=5.4Hz,1H),3.9 0-3.78(m,2H),2.47(dd,J=6.6,3.0Hz,1H),2.28(td,J=7.8,3.6Hz,1H),2.25-2.07(m,1H),1.86(qd,J=8.4,3.0Hz,2H),1.12-1.05(m,4H).

[0516] Example 28: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclopropylpyrimidin-5-yl)-N-(2,2,2-trifluoroethyl)acrylamide (A51)

[0517] The synthesis of Example 28 was carried out by referring to the synthesis method of step 6 of Example 1, except that trifluoroethylamine hydrochloride was used instead of ammonium chloride in step 6 of Example 1. The rest of the method was the same, and the target compound A51 (7 mg) was prepared as a white solid with a yield of 1.9%.

[0518] MS m / z: 551.1 [M+H] + .

[0519] 1 H NMR(600MHz,DMSO-d6)δ9.19(s,1H),8.53(s,1H),8.48(s,1H),8.43(d,J=4.5Hz,2H ),8.23(s,1H),8.13(s,2H),3.98(t,J=8.5Hz,2H),2.29(s,1H),1.13-1.05(m,4H).

[0520] Example 29: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(cyanomethyl)-2-(2-cyclopropylpyrimidin-5-yl)acrylamide (A52)

[0521] The synthesis of Example 29 was carried out by referring to the synthesis method of step 6 of Example 1, except that aminoacetonitrile was used to replace ammonium chloride in step 6 of Example 1. The rest of the method was the same, and the target compound A52 (73 mg) was prepared as a white solid with a yield of 41.7%.

[0522] MS m / z: 508.1 [M+H] + .

[0523] 1 H NMR(600MHz,DMSO-d6)δ9.20(s,1H),8.56(s,2H),8.48(s,1H),8.37(s,1H),8.22 (s,1H),8.11(s,2H),4.19(s,2H),2.30(tt,J=8.4,4.8Hz,1H),1.14-1.04(m,4H).

[0524] Example 30: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclopropylpyrimidin-5-yl)-N-methoxyacrylamide (A53)

[0525] The synthesis of Example 30 was carried out by referring to the synthesis method of step 6 of Example 1, except that methoxyamine hydrochloride was used instead of ammonium chloride in step 6 of Example 1. The rest of the method was the same, and the target compound A53 (21 mg) was prepared as a white solid with a yield of 19.8%.

[0526] MS m / z: 499.1 [M+H] + .

[0527] 1H NMR(600MHz,DMSO-d6)δ11.25(s,1H),9.16(s,1H),8.53(s,2H),8.34(s,1H),8.23(s,1H),8.12(s,2H), 3.65(s,3H),2.28(tt,J=8.0,4.7Hz,1H),1.09(dq,J=5.9,3.5,2.7Hz,2H),1.06(dt,J=5.1,2.9Hz,2H).

[0528] Example 31: Synthesis of compound (E)-3-(3-(2,6-bis(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclopropylpyrimidin-5-yl)-N-methoxyacrylamide (A54)

[0529] Step 1: Synthesis of compound A54-1

[0530] A4-4 (50 mg, 0.1 mmol) was added to dichloroethane (2 mL). EDCI (114 mg, 0.4 mmol) and HOBT (110 mg, 0.55 mmol) were added at 0 °C, and the mixture was stirred for 30 minutes. DIPEA (211 mg, 1.1 mmol) and methoxyamine hydrochloride (50 mg, 0.4 mmol) were added at room temperature, and the reaction was allowed to proceed for 3 hours. The reaction was monitored by TLC until complete. The reaction mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A54-1 (30 mg), with a yield of 55.2%.

[0531] MS m / z: 365.1 [M+H] + .

[0532] Step 2: Synthesis of compound A54

[0533] The synthesis of step 2 in Example 31 was carried out by referring to the synthesis method of step 6 in Example 4, except that A4-5 in step 6 of Example 4 was replaced by A54-1, and A4-2 in step 6 of Example 4 was replaced by A5-1. The rest of the method was the same, and the target compound A54 (2 mg) was prepared as a white solid with a yield of 5.4%.

[0534] MS m / z: 500.1 [M+H] + .

[0535] 1 H NMR(600MHz,DMSO-d6)δ11.25(s,1H),9.22(s,1H),8.53(s,2H),8.35(s,1H ),8.12(s,2H),3.65(s,3H),2.28(tt,J=8.3,4.7Hz,1H),1.13-1.03(m,4H).

[0536] Example 32: Synthesis of compound (E)-2-(2-cyclopropylpyrimidin-5-yl)-3-(3-(3,5-dichlorophenyl)-1H-1,2,4-triazol-1-yl)acrylamide (A55)

[0537] The synthesis of Example 32 was performed using the same method as in step 6 of Example 4, except that pinacol ester of 3,5-dichlorophenylboronic acid was used instead of A4-2 in step 6 of Example 4. The rest of the method was the same, and the target compound A55 (16 mg) was prepared as a white solid with a yield of 13.4%.

[0538] MS m / z: 401.1 [M+H] + .

[0539] 1 H NMR(600MHz,DMSO-d6)δ9.05(s,1H),8.50(s,2H),8.33(s,1H),7.71(t,J=2.0Hz,1H), 7.56(s,1H),7.53(d,J=2.0Hz,2H),7.34(s,1H),2.33-2.28(m,1H),1.13-1.09(m,4H).

[0540] Example 33: Synthesis of compound (E)-2-(2-cyclopropylpyrimidin-5-yl)-3-(3-(2,6-dicyclopropylpyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylamide (A56)

[0541] The synthesis of Example 33 was performed using the same method as in step 6 of Example 4, except that A4-2 in step 6 of Example 4 was replaced with A56-0. The target compound A56 (13 mg) was obtained as a white solid with a yield of 13.9%.

[0542] MS m / z: 414.2 [M+H] + .

[0543] 1 H NMR(600MHz,DMSO-d6)δ9.02(s,1H),8.49(s,2H),8.33(s,1H),7.55(s,1H),7.34(s,1H),7.14(s,2H),2.31(tt,J=8.4,4.8Hz ,1H),2.01(tt,J=8.4,4.8Hz,2H),1.09(qd,J=8.4,4.8Hz,4H),0.92(dq,J=6.6,3.6Hz,4H),0.85(dq,J=7.2,4.2,3.6Hz,4H).

[0544] Example 34: Synthesis of compound (E)-1-(5-(3-amino-1-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-3-oxopropyl-1-en-2-yl)pyrimidin-2-yl)cyclopropane-1-carboxamide (A58)

[0545] First, a Parkins catalyst was prepared. Tetra(triphenylphosphine)platinum (0.2 g, 0.16 mmol) and dimethylphosphine oxide (64 mg, 0.8 mmol) were dissolved in toluene (5 mL). The reaction was carried out at room temperature for 2 h under nitrogen protection, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in a mixed solution of ethanol (12 mL) and water (3 mL), and A23 (200 mg, 0.51 mmol) was added. The reaction was carried out overnight at 80 °C under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with methanol and dichloromethane, filtered, and the filter cake was dispersed with methanol and water and then lyophilized to obtain the target compound A58 (55 mg) as a white solid with a yield of 26.5%.

[0546] MS m / z: 512.1 [M+H] + .

[0547] 1 H NMR(600MHz,DMSO-d6)δ9.16(s,1H),8.94(s,1H),8.69(s,2H),8.44(s,1H),8.22(s,1H),8.1 0(s,2H),7.65(s,1H),7.47(s,1H),7.29(s,1H),1.64(d,J=4.4Hz,2H),1.53(q,J=3.0Hz,2H).

[0548] Example 35: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-methoxycyclobutyl)pyrimidin-5-yl)acrylamide (A59)

[0549] Step 1: Synthesis of compound A59-1

[0550] Under ice bath conditions, NaH (0.34 g, 8.78 mmol) was added to a 15 mL solution of A32-1 (1.0 g, 4.39 mmol) in DMF. After stirring for 30 minutes, iodomethane (0.94 g, 6.22 mmol) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. The reaction was quenched dropwise with methanol and water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A59-1 (0.8 g) as a colorless liquid, with a yield of 75.5%.

[0551] MS m / z: 242.9 [M+H] + .

[0552] Steps 2-5: Synthesis of compound A59

[0553] The synthesis of step 2 in Example 35 was performed according to the synthesis method of step 4 in Example 9, except that A59-1 was used instead of A23-3 in step 4 of Example 9, and the rest of the method was the same. The synthesis of steps 3-5 in Example 35 was performed according to the synthesis method of steps 3-5 in Example 4, except that A59-2 was used instead of A1-3 in step 3 of Example 4, and M1 was used instead of M2 in step 3 of Example 4, and the rest of the method was the same. The target compound A59 (45 mg) was prepared as a white solid with a yield of 45.0%.

[0554] MS m / z: 513.1 [M+H] + .

[0555] 1 H NMR(600MHz,DMSO-d6)δ9.15(s,1H),8.78(s,2H),8.40(s,1H),8.22(s,1H),8.16(s,2H),7.65(s,1H),7.47(s,1H),3.01 (s,3H),2.62(td,J=8.9,4.5Hz,2H),2.31(dt,J=12.3,9.3Hz,2H),1.89(tq,J=10.0,5.3,4.8Hz,1H),1.74-1.63(m,1H).

[0556] Example 36: Synthesis of compound (E)-2-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide (A60)

[0557] Step 1: Synthesis of compound A60-1

[0558] Under ice bath conditions, NaH (0.14 g, 3.32 mmol) was added to a tetrahydrofuran (30 mL) solution of A35-2 (0.73 g, 2.21 mmol). After stirring for 30 minutes, iodomethane (0.47 g, 3.32 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. Under ice bath conditions, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A60-1 (0.6 g) as a yellow solid, with a yield of 78.9%.

[0559] MS m / z: 346.05 [M+H] + .

[0560] Steps 2-6: Synthesis of compound A60

[0561] The synthesis of step 2 in Example 36 was performed according to the synthesis method of step 4 in Example 9, except that A23-3 in step 4 of Example 9 was replaced by A60-1, and the rest of the methods were the same; the synthesis of steps 3-5 in Example 36 was performed according to the synthesis method of steps 6-8 in Example 2, except that A2-5 in step 6 of Example 24 was replaced by A60-2, and the rest of the methods were the same; the synthesis of step 6 in Example 36 was performed according to the synthesis method of step 7 in Example 16, except that A35-6 in step 6 of Example 16 was replaced by A60-5, and the rest of the methods were the same. Compound A60 (36 mg) was prepared as a white solid, which is a formate salt, with a yield of 31.0%.

[0562] MS m / z: 512.4 [M+H] + .

[0563] 1 H NMR (600MHz, DMSO-d6) δ9.16(s,1H),8.79(s,2H),8.41(s,1H),8.23(s,1H),8.17(d,J=1.8Hz,2H),7.57(d,J=119.2Hz,2H ),3.78(s,2H),2.58-2.52(m,2H),2.27(ddd,J=11.9,9.3,6.3Hz,2H),2.13(s,3H),2.07-2.01(m,1H),1.92-1.86(m,1H).

[0564] Example 37: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-methylpiperidin-4-yl)pyrimidin-5-yl)acrylamide (A62)

[0565] Steps 1-3: Synthesis of compound A62-3

[0566] The synthesis of steps 1-3 in Example 37 is the same as that in Example 3, except that N-Boc-4-iodopiperidine is used instead of 3-iodooxyhexacyclobutane in step 1 of Example 3.

[0567] Step 4: Synthesis of compound A62-4

[0568] A62-3 (0.27 g, 1.1 mmol) was dissolved in 1,4-dioxane (4 mL). 4 mol / L dioxane hydrochloride solution (3 mL) was added to the reaction solution at 0 °C, and the reaction was allowed to proceed for 2 h at room temperature. The reaction was monitored by TLC until complete. The reaction solution was then concentrated under reduced pressure to obtain crude compound A3-2, which was used directly in the next reaction without purification.

[0569] LCMS:m / z 541.1[M+H] + .

[0570] Step 5: Synthesis of compound A62-5

[0571] A62-4 (0.23 g, 1.1 mmol) was dissolved in dichloroethane (5 mL). Formaldehyde aqueous solution (64 mg, 5.5 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Then, sodium triacetylborohydride (182 mg, 2.2 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and methanol, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound A62-5 (0.19 g), with a yield of 80.5%.

[0572] MS m / z: 555.1 [M+H] + .

[0573] Steps 6-7: Synthesis of compound A62

[0574] The synthesis of steps 6-7 in Example 37 was carried out by referring to the synthesis method of steps 4-5 in Example 3, except that A3-3 in step 4 of Example 3 was replaced by A62-5. The rest of the method was the same, and compound A62 (12 mg) was prepared as a white solid, which is a formate salt, with a yield of 9.0%.

[0575] MS m / z: 526.1 [M+H] + .

[0576] 1 H NMR (600MHz, DMSO-d6) δ9.13(s,1H),8.66(s,2H),8.38(s,1H),8.23(s,1H),8.17(s,1H),8.12(s,2H),7.61(s,1H),7.42(s,1H),3.03(d,J= 11.3Hz,2H),2.87(ddt,J=11.8,8.0,3.8Hz,1H),2.35(s,3H),2.27(d,J=12.3Hz,2H),2.01(d,J=13.1Hz,2H),1.91(qd,J=12.6,3.7Hz,2H).

[0577] Example 38: Synthesis of compound (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-(oxecyclobutan-3-yl)piperidin-4-yl)pyrimidin-5-yl)acrylamide (A63)

[0578] The synthesis of step 1 in Example 38 was performed according to the synthesis method of step 5 in Example 37, except that 3-oxacyclobutanone was used instead of formaldehyde in step 5 of Example 37, and the rest of the method was the same; the synthesis of steps 2-3 in Example 38 was performed according to the synthesis method of steps 4-5 in Example 3, except that A63-1 was used instead of A3-3 in step 4 of Example 3, and the rest of the method was the same, and compound A63 (7 mg) was prepared as a white solid with a yield of 10.7%.

[0579] MS m / z: 568.2 [M+H] + .

[0580] 1 H NMR(600MHz,DMSO-d6)δ9.13(s,1H),8.65(s,2H),8.37(s,1H),8.23(s,1H),8.12(s,2H),7.61(s,1H),7.43(s,1H),4.51( dt,J=58.1,6.4Hz,4H),3.48-3.42(m,1H),2.83(t,J=11.8Hz,3H),1.99(d,J=12.4Hz,2H),1.89(dt,J=37.5,12.1Hz,4H).

[0581] Example 39: Synthesis of compound (E)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide (B1)

[0582] Step 1: Synthesis of compound B1-1

[0583] M2 (2.1 g, 6.5 mmol), pinacol ester of pyrimidine-5-borate (2.0 g, 9.8 mmol), potassium acetate (1.27 g, 13.0 mmol), and PdCl2 (dppf) (0.47 g, 0.7 mmol) were dissolved in a mixed solution of 1,4-dioxane (20 mL) and water (2 mL). The reaction was carried out at 85 °C for 4.5 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound B1-1 (0.67 g) as a yellow solid, with a yield of 30.4%.

[0584] MS m / z: 324.0 [M+H] + .

[0585] Step 2: Synthesis of compound B1-2

[0586] B1-1 (0.67 g, 2.1 mmol) was dissolved in tetrahydrofuran (10 mL). After stirring in an ice bath for 10 minutes, a solution of lithium hydroxide (0.1 g, 4.2 mmol) in water (2 mL) was added dropwise, and stirring was continued in an ice bath for 1 hour. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure. The pH of the solution was adjusted to 1-2 with 1 mol / L hydrochloric acid, and a solid precipitated. The mixture was stirred for 30 minutes, filtered, and the filter cake was dried to give compound B1-2 (0.42 g) as a pale yellow solid, with a yield of 68.9%.

[0587] MS m / z: 296.9 [M+H] + .

[0588] Step 3: Synthesis of compound B1-3

[0589] B1-2 (0.42 g, 1.4 mmol) was dissolved in tetrahydrofuran (8 mL). After stirring in an ice bath for 10 minutes, isobutyl chloroformate (0.29 g, 2.1 mmol) and N-methylmorpholine (0.29 mg, 2.8 mmol) were added to the reaction solution, and the reaction was continued to be stirred in an ice bath for 1 hour. Then, 5 mL of 7 mol / L ammonia in methanol solution was added to the reaction solution. After the addition was complete, the reaction was carried out in an ice bath for 30 minutes. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the residue was poured into an ice-water mixture and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound B1-3 (0.3 g) as a yellow solid, with a yield of 71.4%.

[0590] MS m / z: 295.0 [M+H] + .

[0591] Step 4: Synthesis of compound B1

[0592] B1-3 (140 mg, 0.47 mmol), M3 (231 mg, 0.71 mmol), potassium carbonate (130 mg, 0.95 mmol), and Pd(PPh3)4 (55 mg, 0.05 mmol) were dissolved in a mixed solution of 1,4-dioxane (4 mL) and water (0.4 mL). The reaction was carried out overnight at 90 °C under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth filter, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography and preparative liquid chromatography to obtain the target compound B1 (42 mg) as a white solid, with a yield of 21.5%.

[0593] MS m / z: 415.1 [M+H] + .

[0594] 1 H NMR(400MHz,DMSO-d6)δ9.25(s,1H),9.07(s,1H),8.74(s,2H),8.42(s,1H),8 .14(s,1H),8.05(s,1H),7.71(s,1H),7.62(s,1H),7.38(s,1H),2.28(s,3H).

[0595] Example 40: Synthesis of compound (E)-2-(5-fluoropyridin-3-yl)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B2)

[0596] The synthesis of Example 40 was performed using the same method as in Example 39, except that 5-fluoropyridine-3-borate pinacol ester was used instead of pyrimidine-5-borate pinacol ester in step 1 of Example 39. The remaining steps were the same as in Example 39. The target compound B2 (28 mg) was prepared as a white solid with a yield of 16.9%.

[0597] MS m / z: 432.1 [M+H] + .

[0598] 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.64(d,J=2.8Hz,1H),8.36(s,1H),8.33(t,J=1.8Hz,1H),8.16(s,1H),8.05 (d,J=1.5Hz,1H),7.77(ddd,J=9.7,2.8,1.6Hz,1H),7.73(s,1H),7.60(s,1H),7.21(s,1H),2.28(d,J=1.4Hz,3H).

[0599] Example 41: Synthesis of compound (E)-2-(3-fluoropyridin-4-yl)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B3)

[0600] Step 1: Synthesis of compound B3-1

[0601] M2 (2.2 g, 6.8 mmol), 3-fluoropyridine-4-borate pinacol ester (2.0 g, 8.9 mmol), sodium acetate (1.12 g, 13.6 mmol), and PdCl2 (dppf) (0.3 g, 0.4 mmol) were dissolved in a mixed solution of 1,4-dioxane (30 mL) and water (3 mL). The reaction was carried out at 85 °C for 6 h under nitrogen protection. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, and the filter cake was washed with ethyl acetate. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography and preparative liquid chromatography to give compound B3-1 (0.1 g) as a white solid, with a yield of 4.3%.

[0602] MS m / z: 340.9 [M+H] + .

[0603] Step 2: Synthesis of compound B3-2

[0604] B3-1 (0.1 g, 0.29 mmol) was dissolved in tetrahydrofuran (3 mL). After stirring in an ice bath for 10 minutes, a solution of lithium hydroxide (14 mg, 0.59 mmol) in water (0.5 mL) was added dropwise, and stirring was continued in an ice bath for 1 hour. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure. The pH of the solution was adjusted to 1-2 with 1 mol / L hydrochloric acid, and a solid precipitated. The mixture was stirred for 30 minutes, filtered, and the filter cake was dried to give compound B3-2 (60 mg) as a pale yellow solid, with a yield of 65.2%.

[0605] MS m / z: 312.9 [M+H] + .

[0606] Step 3: Synthesis of compound B3-3

[0607] B3-2 (60 mg, 0.19 mmol) was dissolved in tetrahydrofuran (3 mL). After stirring in an ice bath for 10 minutes, isobutyl chloroformate (40 mg, 0.29 mmol) and N-methylmorpholine (39 mg, 0.38 mmol) were added to the reaction solution. The reaction was continued to be stirred in an ice bath for 1 hour. Then, 2 mL of 7 mol / L ammonia in methanol solution was added to the reaction solution. After the addition was complete, the reaction was carried out in an ice bath for 30 minutes. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the residue was poured into an ice-water mixture and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound B3-3 (40 mg) as a white solid, with a yield of 66.7%.

[0608] MS m / z: 311.9 [M+H]+ .

[0609] Step 4: Synthesis of compound B3

[0610] B3-3 (40 mg, 0.13 mmol), M3 (63 mg, 0.19 mmol), potassium carbonate (36 mg, 0.26 mmol), and Pd(PPh3)4 (15 mg, 0.02 mmol) were dissolved in a mixed solution of 1,4-dioxane (2 mL) and water (0.2 mL). The reaction was carried out at 85 °C for 1 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin-layer chromatography and preparative liquid chromatography to obtain the target compound B3 (18 mg) as a white solid, with a yield of 29.1%.

[0611] MS m / z: 432.1 [M+H] + .

[0612] 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),8.66(s,1H),8.52(d,J=4.8Hz,1H),8.42(s,1H),8.05(dd,J=4.9, 1.5Hz,2H),7.72(s,1H),7.59(s,1H),7.42(dd,J=6.3,4.8Hz,1H),7.33(s,1H),2.27(d,J=1.4Hz,3H).

[0613] Example 42: Synthesis of compound (E)-2-(2-fluoropyridin-4-yl)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B4)

[0614] The synthesis of Example 42 was performed using the same method as in Example 41, except that 2-fluoropyridine-4-borate pinacol ester was used instead of 3-fluoropyridine-4-borate pinacol ester in step 1 of Example 41. The remaining steps were the same as in Example 41. The target compound B4 (17 mg) was prepared as a white solid with a yield of 20.7%.

[0615] MS m / z: 432.1 [M+H] + .

[0616] 1H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.31(t,J=2.6Hz,2H),8.11(s,1H),8.05(d,J=1.5Hz,1H),7.76(s, 1H),7.61(s,1H),7.27(dt,J=5.2,1.7Hz,1H),7.20(d,J=1.7Hz,1H),7.14(s,1H),2.27(d,J=1.4Hz,3H).

[0617] Example 43: Synthesis of compound (E)-2-(5-cyanopyridin-3-yl)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B5)

[0618] The synthesis of Example 43 was performed using the same method as in Example 39, except that 3-cyanopyridine-5-borate pinacol ester was used instead of pyrimidine-5-borate pinacol ester in step 1 of Example 39. The remaining steps were the same as in Example 39. The target compound B5 (34 mg) was prepared as a white solid with a yield of 10.3%.

[0619] MS m / z: 439.0 [M+H] + .

[0620] 1 H NMR (400MHz, DMSO-d6) δ9.11(d,J=2.0Hz,1H),9.07(s,1H),8.76(d,J=2.0Hz,1H),8.41(s,1H),8. 38(t,J=2.0Hz,1H),8.11(s,1H),8.05(s,1H),7.68(s,1H),7.63(s,1H),7.24(s,1H),2.29(s,3H).

[0621] Example 44: Synthesis of compound (E)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(6-methylpyridin-3-yl)acrylamide (B6)

[0622] Step 1: Synthesis of compound B6-1

[0623] M2 (1 g, 3.08 mmol), pinacol ester of 2-methylpyridine-5-borate (877 mg, 4.0 mmol), PdCl2 (dppf) (225 mg, 0.31 mmol), and potassium acetate (605 mg, 6.16 mmol) were dissolved in a mixed solution of 1,4-dioxane (10 mL) and water (1 mL). The reaction was carried out at 85 °C for 4 h under nitrogen protection. The reaction was monitored by LC-MS until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with dichloromethane. The reaction solution was diluted with water and extracted with dichloromethane. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound B6-1 (380 mg) as a yellow oil, with a yield of 34.89%.

[0624] MS m / z: 337.0 [M+H] + .

[0625] Step 2: Synthesis of compound B6-2

[0626] Under ice bath conditions, B6-1 (370 mg, 1.10 mmol) and lithium hydroxide (66 mg, 2.76 mmol) were dissolved in a mixture of tetrahydrofuran (5 mL) and water (1 mL), and the mixture was stirred for 1 h under ice bath conditions. The reaction was monitored by LC-MS until complete. The solvent was removed by concentration under reduced pressure, and the solution was diluted with an appropriate amount of water. The pH of the solution was adjusted to 2-3 with 1 mol / L hydrochloric acid, and the mixture was concentrated under reduced pressure to obtain crude compound B6-2 (339 mg), which was used directly in the next reaction without purification.

[0627] MS m / z: 309.0 [M+H] + .

[0628] Step 3: Synthesis of compound B6-3

[0629] B6-2 (310 mg, 1.0 mmol), DIPEA (646 mg, 5.0 mmol), and HBTU (758 mg, 2.0 mmol) were dissolved in DMF (10 mL) and reacted at room temperature for 30 min. Ammonium chloride (160 mg, 3.0 mmol) was added to the reaction solution, and the reaction was continued at room temperature for 1 h. The reaction was monitored by LC-MS until complete. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin-layer chromatography to give compound B6-3 (58 mg) as a yellow-green oil, with a yield of 18.8%.

[0630] MS m / z: 308.0 [M+H] + .

[0631] Step 4: Synthesis of compound B6

[0632] B6-3 (48 mg, 0.16 mmol), M3 (76 mg, 0.23 mmol), Pd(PPh3)4 (18 mg, 0.016 mmol), and potassium carbonate (43 mg, 0.31 mmol) were dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (0.3 mL). The reaction was carried out at 90 °C for 1 h under nitrogen protection. The reaction was monitored by LC-MS until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by thin-layer chromatography and preparative liquid chromatography to obtain the target compound B6 (7 mg) as a white solid with a yield of 10.5%.

[0633] MS m / z: 428.1 [M+H] + .

[0634] 1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.32(s,1H),8.28(s,2H),8.04(s,1H),7.78(s, 1H),7.63-7.50(m,2H),7.35(d,J=8.0Hz,1H),7.14(s,1H),2.56(s,3H),2.28(s,3H).

[0635] Example 45: Synthesis of compound (E)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(quinoline-3-yl)acrylamide (B7) formate

[0636] The synthesis of Example 45 was performed using the same method as in Example 44, except that quinoline-3-borate pinacol ester was used instead of 2-methylpyridine-5-borate pinacol ester in step 1 of Example 44. The remaining steps were the same as in Example 44. The target compound B7 (30 mg) was prepared as a white solid, which was a formate salt, with a yield of 18.6%.

[0637] MS m / z: 464.1 [M+H] + .

[0638] 1H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.76(d,J=4.0Hz,1H),8.40(s,1H),8.30(d,J=4.0Hz,1H),8.17(s,1H),8.10(d,J=8.0H z,1H),8.02(d,J=8.0Hz,1H),7.96(s,1H),7.86(s,1H),7.82(t,J=8.0Hz,1H),7.67-7.56(m,3H),7.27(s,1H),2.06(s,3H).

[0639] Example 46: Synthesis of compound (E)-2-(2-((2,2-difluoroethyl)amino)pyrimidin-5-yl)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B8)

[0640] Step 1: Synthesis of compound B8-1

[0641] B8-0 (2 g, 8.32 mmol), difluoroethylamine hydrochloride (1.47 g, 12.51 mmol), and DIPEA (4.30 g, 33.27 mmol) were dissolved in NMP (20 mL). Under nitrogen protection, the mixture was heated to 130 °C and reacted for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound B8-1 (2.27 g) as a pale yellow solid, with a yield of 94.46%.

[0642] MS m / z: 285.8 [M+H] + .

[0643] Steps 2-5: Synthesis of compound B8

[0644] The synthesis of steps 2 to 5 in Example 46 was carried out by referring to the synthesis method of steps 1 to 4 in Example 44, except that B8-1 was used to replace 2-methylpyridine-5-borate pinacol ester in step 1 of Example 44. The rest of the method was the same, and the target compound B8 (25 mg) was prepared as a white solid with a yield of 15.8%.

[0645] MS m / z: 494.1 [M+H] + .

[0646] 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.25(s,1H),8.21(d,J=7.2Hz,3H),8.04(d,J=1.6Hz,1H),7.94(s,1H),7.73(t,J=6.4 Hz,1H),7.50(s,1H),7.36(s,1H),6.10(tt,J=56.4,4.4Hz,1H),3.74(tdd,J=15.2,6.4,4.4Hz,2H),2.27(d,J=1.2Hz,3H).

[0647] Example 47: Synthesis of compound (E)-2-(2-((2,2-difluoropropyl)amino)pyrimidin-5-yl)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B9)

[0648] The synthesis of step 1 in Example 47 was performed according to the synthesis method of step 1 in Example 46, except that 2,2-difluoropropylamine hydrochloride was used instead of difluoroethylamine hydrochloride in step 1 of Example 46; the synthesis of steps 2 to 5 was performed according to the synthesis method of steps 1 to 4 in Example 41, except that B9-1 was used instead of 3-fluoropyridine-4-borate pinacol ester in step 1 of Example 41, and the rest of the methods were the same. The target compound B9 (21 mg) was prepared as a white solid with a yield of 17.9%.

[0649] MS m / z: 508.1 [M+H] + .

[0650] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.27(s,1H),8.21(s,2H),8.20(s,1H),8.05(s,1H),7.96(s,1H),7.74(t,J= 6.6Hz,1H),7.51(s,1H),7.39(s,1H),3.84(td,J=13.6,6.6Hz,2H),2.28(d,J=1.4Hz,3H),1.61(t,J=19.0Hz,3H).

[0651] Example 48: Synthesis of compound (E)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(((2,2,2-trifluoroethyl)amino)pyrimidin-5-yl)acrylamide (B10)

[0652] The synthesis of step 1 in Example 48 was performed according to the synthesis method of step 1 in Example 46, except that trifluoroethylamine hydrochloride was used instead of difluoroethylamine hydrochloride in step 1 of Example 46; the synthesis of steps 2 to 5 was performed according to the synthesis method of steps 1 to 4 in Example 41, except that B10-1 was used instead of 3-fluoropyridine-4-borate pinacol ester in step 1 of Example 41, and the rest of the methods were the same, and the target compound B10 (64 mg) was prepared as a white solid with a yield of 49.2%.

[0653] MS m / z: 512.1 [M+H] + .

[0654] 1 H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H), 8.26 (s, 3H), 8.22 (s, 1H), 8.04 (d, J = 1.5Hz, 1H), 7.97 (t ,J=6.7Hz,1H),7.94(s,1H),7.45(d,J=43.4Hz,2H),4.24-4.14(m,2H),2.28(d,J=1.4Hz,3H).

[0655] Example 49: Synthesis of compound (E)-2-(2-methyl-2H-pyrazolo[4,3-b]pyridin-6-yl)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B11)

[0656] Step 1: Synthesis of compound B11-1

[0657] Dissolve B11-0 (9.85 g, 52.7 mmol) and potassium acetate (6.2 g, 63.2 mmol) in chloroform (200 mL). Add acetic anhydride (16.1 g, 0.16 mol) dropwise. After the addition is complete, heat to 60 °C and react for 30 minutes. Add isoamyl nitrite (11.1 g, 94.8 mmol) dropwise and react at 60 °C for 24 h. Monitor the reaction by TLC until complete. Cool the reaction solution to room temperature, dilute with water, extract with dichloromethane, combine the organic phases, wash with saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give crude compound B11-1 (8.7 g), yield 69.0%.

[0658] MS m / z: 240.0 [M+H] + .

[0659] Step 2: Synthesis of compound B11-2

[0660] B11-1 (8.7 g, 52.7 mmol) was dissolved in a mixed solution of methanol (50 mL) and 10 mol / L hydrochloric acid (40 mL) at room temperature, and the reaction was heated to 60 °C for 1 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the pH was adjusted to neutral with 2 mol / L sodium hydroxide aqueous solution. The solution was extracted with dichloromethane, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound B11-2 (6.2 g), with a yield of 86.4%.

[0661] MS m / z: 197.9 [M+H] + .

[0662] Step 3: Synthesis of compound B11-3

[0663] B11-2 (4.0 g, 20.3 mmol) and cesium carbonate (13.2 g, 40.6 mmol) were dissolved in DMF (80 mL), and iodomethane (3.46 g, 24.45 mmol) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. The reaction was monitored by TLC until complete. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound B11-3 (0.8 g) as a yellow solid, with a yield of 18.7%.

[0664] MS m / z: 212.0 [M+H] + .

[0665] 1 H NMR (400MHz, Chloroform-d) δ8.56 (d, J = 2.0Hz, 1H), 8.22-8.15 (m, 2H), 4.25 (s, 3H).

[0666] Step 4: Synthesis of compound B11-4

[0667] B11-3 (0.8 g, 3.79 mmol), pinacol diboronate (1.2 g, 4.55 mmol), potassium acetate (0.74 g, 7.58 mmol), and PdCl2 (dppf)·DCM (0.14 g, 0.17 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted overnight at 85 °C under nitrogen protection. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, and the filter cake was washed with ethyl acetate. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1.5 g of crude product, which was used directly in the next reaction without purification.

[0668] Steps 5-8: Synthesis of compound B11

[0669] The synthesis of steps 5 to 8 in Example 49 was performed using the same method as in Example 41, except that B11-4 was used to replace 3-fluoropyridine-4-borate pinacol ester in step 1 of Example 41. The rest of the method was the same, and the target compound B11 (14 mg) was prepared as a white solid with a yield of 13.1%.

[0670] MS m / z: 468.2 [M+H] + .

[0671] 1 H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.71(s,1H),8.35(s,1H),8.32(d,J=1.9Hz,1H),8.01(d,J=1.5Hz,1H),7.9 8(d,J=1.6Hz,1H),7.97-7.94(m,1H),7.61(s,1H),7.57(s,1H),7.22(s,1H),4.25(s,3H),2.17(d,J=1.4Hz,3H).

[0672] Example 50: Synthesis of compound (E)-3-(3-(3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)acrylamide (B12)

[0673] The synthesis of step 1 in Example 50 was performed according to the synthesis method of step 4 in Example 49, except that B12-0 was used instead of B11-3; the synthesis of steps 2 to 5 was performed according to the synthesis method of steps 1 to 4 in Example 39, except that B12-1 was used instead of pinacol pyrimidine-5-borate in step 1 of Example 4, and the rest of the methods were the same. The target compound B12 (8 mg) was prepared as a white solid with a yield of 4.0%.

[0674] MS m / z: 468.2 [M+H] + .

[0675] 1 H NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.99(d,J=2.0Hz,1H),8.45(s,1H),8.33(d,J=2.0Hz,1H),8.0 0(d,J=14.0Hz,2H),7.71(s,1H),7.59(s,1H),7.46(s,1H),6.57(s,1H),2.45(s,3H),2.18(s,3H).

[0676] Example 51: Synthesis of compound (E)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide (B13)

[0677] The synthesis of Example 51 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M3 was replaced by the common intermediate M4. The rest of the method was the same, and the target compound B13 (18 mg) was prepared as a white solid with a yield of 8.3%.

[0678] MS m / z: 433.1 [M+H] + .

[0679] 1 H NMR(400MHz,DMSO-d6)δ9.24(s,1H),9.08(s,1H),8.74(s,2H),8.41(s,1H) ,8.08(s,1H),7.66(s,1H),7.62(s,1H),7.38(s,1H),2.17(d,J=1.7Hz,3H).

[0680] Example 52: Synthesis of compound (E)-3-(3-(3-(difluoromethyl)-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide (B14)

[0681] The synthesis of Example 52 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M3 was replaced by the common intermediate M5. The rest of the method was the same, and the target compound B14 (33 mg) was prepared as a white solid with a yield of 25.6%.

[0682] MS m / z: 451.1 [M+H] + .

[0683] 1 H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 9.10 (s, 1H), 8.73 (s, 2H), 8.69 (t, J = 2.7Hz, 1H), 8 .42(s,1H),8.25(s,1H),7.83(s,1H),7.62(s,1H),7.44(t,J=52.0Hz,1H),7.38(s,1H).

[0684] Example 53: Synthesis of compound (E)-2-(5-cyanopyridin-3-yl)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B15)

[0685] The synthesis of Example 53 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M4 was used to replace the common intermediate M3, and B5-3 was used to replace B1-3. The rest of the method was the same, and the target compound B15 (9 mg) was prepared as a white solid with a yield of 15.7%.

[0686] MS m / z: 457.1 [M+H] + .

[0687] 1 H NMR(400MHz,DMSO-d6)δ9.10(d,J=2.0Hz,1H),9.08(s,1H),8.75(d,J=2.0Hz,1H),8.41(s,1H) ,8.37(t,J=2.0Hz,1H),8.06(d,J=1.6Hz,1H),7.63(s,2H),7.24(s,1H),2.18(d,J=1.6Hz,3H).

[0688] Example 54: Synthesis of compound (E)-2-(2-((2,2-difluoroethyl)amino)pyrimidin-5-yl)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B16)

[0689] The synthesis of Example 54 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M3 was replaced by the common intermediate M4 and B1-3 was replaced by B8-4. The rest of the method was the same, and the target compound B16 (64 mg) was prepared as a white solid with a yield of 39.0%.

[0690] MS m / z: 512.2 [M+H] + .

[0691] 1 H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.21(d,J=8.0Hz,4H),7.90(s,1H),7.75(t,J=8.0Hz,1H),7 .52(s,1H),7.37(s,1H),6.10(tt,J=56.0,4.0Hz,1H),3.74(tt,J=15.2,5.2Hz,2H),2.17(s,3H).

[0692] Example 55: Synthesis of compound (E)-2-(2-((2,2-difluoropropyl)amino)pyrimidin-5-yl)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B17)

[0693] The synthesis of Example 55 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M3 was replaced by the common intermediate M4 and B1-3 was replaced by B9-4. The rest of the method was the same, and the target compound B17 (32 mg) was prepared as a white solid with a yield of 29.5%.

[0694] MS m / z: 526.2 [M+H] + .

[0695] 1 H NMR (400MHz, DMSO-d6) δ9.00(s,1H),8.21(d,J=2.0Hz,3H),8.20(s,1H),7.91(dd,J=1.6,0.8Hz,1H),7.76(t,J=6 .6Hz,1H),7.53(s,1H),7.40(s,1H),3.84(td,J=13.6,6.5Hz,2H),2.18(d,J=1.7Hz,3H),1.61(t,J=19.0Hz,3H).

[0696] Example 56: Synthesis of compound (E)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyrimidin-5-yl)acrylamide (B18)

[0697] The synthesis of Example 56 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M3 was replaced by the common intermediate M4 and B10-4 was replaced by B1-3. The rest of the method was the same, and the target compound B18 (70 mg) was prepared as a white solid with a yield of 47.3%.

[0698] MS m / z: 530.1 [M+H] + .

[0699] 1H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.25(s,2H),8.22(s,1H),8.20(d,J=1.6Hz,1H),7.99(t,J=6. 7Hz,1H),7.89(d,J=1.5Hz,1H),7.53(s,1H),7.40(s,1H),4.24-4.13(m,2H),2.17(d,J=1.7Hz,3H).

[0700] Example 57: Synthesis of compound (E)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(quinolin-3-yl)acrylamide (B19)

[0701] The synthesis of Example 57 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M4 was replaced with the common intermediate M3, and B7-3 was replaced with B1-3. The rest of the method was the same, and the target compound B19 (40 mg) was prepared as a white solid with a yield of 28.6%.

[0702] MS m / z: 482.0 [M+H] + .

[0703] 1 H NMR(400MHz, DMSO-d6)δ8.96(s,1H),8.69(d,J=2.2Hz,1H),8.33(s,1H),8.23(d,J=2.2Hz,1H),8.07-8.01(m,1H),7.95 (dd,J=8.2,1.4Hz,1H),7.80-7.71(m,2H),7.61-7.51(m,2H),7.47(d,J=1.6Hz,1H),7.21(s,1H),1.90(d,J=1.7Hz,3H).

[0704] Example 58: Synthesis of compound (E)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(2-methyl-2H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide (B20)

[0705] The synthesis of Example 58 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M4 was used instead of the common intermediate M3, and B11-7 was used instead of B1-3. The rest of the method was the same, and the target compound B20 (18 mg) was prepared as a white solid with a yield of 16.2%.

[0706] MS m / z: 486.1 [M+H] + .

[0707] 1 H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.71(s,1H),8.34(s,1H),8.32(d,J=2.0Hz,1H),8.0 1-7.89(m,2H),7.58(s,1H),7.55(s,1H),7.22(s,1H),4.25(s,3H),2.07(d,J=1.6Hz,3H).

[0708] Example 59: Synthesis of compound (E)-2-(2-cyclopropylpyrimidin-5-yl)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B21)

[0709] The synthesis of Example 59 was performed using the same method as in Example 41, except that A1-3 was used to replace 3-fluoropyridine-4-borate pinacol ester in step 1 of Example 41, and common intermediate M4 was used to replace common intermediate M3 in step 4 of Example 41. The rest of the method was the same, and the target compound B21 (40 mg) was obtained as a white solid with a yield of 14.2%.

[0710] MS m / z: 473.1 [M+H] + .

[0711] 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),8.53(s,2H),8.35(s,1H),8.13(d,J=1.6Hz,1H),7.75(s,1H),7.5 7(s,1H),7.35(s,1H),2.29(d,J=5.0Hz,1H),2.18(d,J=1.6Hz,3H),1.08(ddd,J=7.3,5.1,2.0Hz,4H).

[0712] Example 60: Synthesis of compound (E)-2-(2-(cyclopropyl(methyl)amino)pyrimidin-5-yl)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B22)

[0713] Step 1 of Example 60 is the same as step 1 of Example 46, except that N-methylcyclopropylamine hydrochloride is used instead of difluoroethylamine hydrochloride; Steps 2 to 5 are the same as the synthesis method of Example 41, except that B22-1 is used instead of 3-fluoropyridine-4-borate pinacol ester in step 1 of Example 41, and common intermediate M4 is used instead of common intermediate M3 in step 4 of Example 41. The rest of the methods are the same, and the target compound B22 (24 mg) is prepared as a white solid with a yield of 17.4%.

[0714] MS m / z: 502.1 [M+H] + .

[0715] 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.24(d,J=18.5Hz,4H),7.82(s,1H),7.42(d,J=71.2Hz,2H),3.15(s ,3H),2.82(tt,J=7.1,3.8Hz,1H),2.16(d,J=1.7Hz,3H),0.84(td,J=7.1,5.0Hz,2H),0.67-0.61(m,2H).

[0716] Example 61: Synthesis of compound (E)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(2-(oxecyclobutan-3-yl)pyrimidin-5-yl)acrylamide (B23)

[0717] The synthesis of Example 61 was performed using the same method as in Example 41, except that A3-2 was used to replace 3-fluoropyridine-4-borate pinacol ester in step 1 of Example 41, and common intermediate M4 was used to replace common intermediate M3 in step 4 of Example 41. The rest of the method was the same, and the target compound B23 (20 mg) was prepared as a white solid with a yield of 14.4%.

[0718] MS m / z: 489.1 [M+H] + .

[0719] 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.75(s,2H),8.41(s,1H),8.15(s,1H),7.67(s,1H),7.6 3(s,1H),7.35(s,1H),5.02-4.91(m,4H),4.56(tt,J=8.6,6.8Hz,1H),2.15(d,J=1.6Hz,3H).

[0720] Example 62: Synthesis of compound (E)-3-(3-(3-(difluoromethyl)-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(quinoline-3-yl)acrylamide (B24)

[0721] The synthesis of Example 62 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M5 was replaced with the common intermediate M3, and B7-3 was replaced with B1-3. The rest of the method was the same, and the target compound B24 (24 mg) was prepared as a white solid with a yield of 16.5%.

[0722] MS m / z: 500.1 [M+H] + .

[0723] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.72(d,J=2.2Hz,1H),8.60(t,J=2.7Hz,1H),8.35(s,1H),8.25(d,J=2.2Hz,1H),8.21( s,1H),8.04(d,J=8.4Hz,1H),7.97(d,J=8.1Hz,1H),7.78(ddd,J=8.5,6.8,1.4Hz,1H),7.63-7.50(m,3H),7.43-7.14(m,2H).

[0724] Example 63: Synthesis of compound (E)-2-(2-((2,2-difluoroethyl)amino)pyrimidin-5-yl)-3-(3-(3-(difluoromethyl)-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B25)

[0725] The synthesis of Example 63 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M5 was used instead of the common intermediate M3, and B8-4 was used instead of B1-3. The rest of the method was the same, and the target compound B25 (54 mg) was prepared as a white solid with a yield of 33.6%.

[0726] MS m / z: 530.0 [M+H] + .

[0727] 1H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H), 8.70 (t, J = 2.4Hz, 1H), 8.45 (s, 1H), 8.22 (s, 2H), 8.20 (s, 1H), 8. 02(s,1H),7.71(t,J=6.0Hz,1H),7.60-7.29(m,3H),6.09(tt,J=56.8,4.0Hz,1H),3.81-3.66(m,2H).

[0728] Example 64: Synthesis of compound (E)-2-(2-cyclopropylpyrimidin-5-yl)-3-(3-(3-(difluoromethyl)-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B26)

[0729] The synthesis of Example 64 was carried out by referring to the synthesis method of step 4 of Example 39, except that the common intermediate M5 was replaced by the common intermediate M3, and B21-3 was replaced by B1-3. The rest of the method was the same, and the target compound B26 (11 mg) was prepared as a white solid with a yield of 7.5%.

[0730] MS m / z: 491.1 [M+H] + .

[0731] 1 H NMR(400MHz, DMSO-d6)δ9.08(s,1H),8.70(t,J=2.7Hz,1H),8.53(s,2H),8.40(d,J=1.6Hz,1H),8.34(s,1H), 7.85(s,1H),7.57(s,1H),7.46-7.29(m,2H),2.28(ddd,J=7.8,4.5,2.4Hz,1H),1.08(dd,J=7.1,5.0Hz,4H).

[0732] Example 65: Synthesis of compound (E)-3-(3-(3-(difluoromethyl)-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(2-(oxecyclobutane-3-yl)pyrimidin-5-yl)acrylamide (B29)

[0733] The synthesis of Example 65 was carried out by referring to the synthesis method of step 4 of Example 39, except that B1-3 and M3 in step 4 of Example 39 were replaced by A41-3 and M5 respectively. The rest of the method was the same, and compound B29 (8 mg) was prepared as a white solid with a yield of 6.4%.

[0734] MS m / z: 507.1 [M+H]+ .

[0735] 1 H NMR (600MHz, DMSO-d6) δ9.10 (s, 1H), 8.74 (s, 2H), 8.70-8.68 (m, 1H), 8.40 (s, 1H), 8.30 (d, J = 1.6Hz, 1H), 7.85 (s, 1H), 7.61 ( s,1H),7.53-7.32(t,1H),7.34(s,1H),4.98(dd,J=8.6,5.6Hz,2H),4.93(dd,J=6.8,5.6Hz,2H),4.55(tt,J=8.6,6.8Hz,1H).

[0736] Example 66: Synthesis of compound (E)-2-(2-cyclobutylpyrimidin-5-yl)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B39)

[0737] The synthesis of Example 66 was performed by referring to the synthesis method of step 4 of Example 39, except that A39-3 and M4 were used to replace B1-3 and M3 in step 4 of Example 39, respectively. The rest of the method was the same, and compound B39 (17 mg) was prepared as a white solid with a yield of 30.3%.

[0738] MS m / z: 487.2 [M+H] + .

[0739] 1 H NMR(600MHz,DMSO-d6)δ9.06(s,1H),8.65(s,2H),8.36(s,1H),8.17(s,1H ),7.71(s,1H),7.61-7.49(m,1H),7.36(s,1H),3.82(p,J=8.6Hz,1H),2.44 (pd,J=9.2,2.5Hz,2H),2.35(dtd,J=14.5,8.8,7.6,4.4Hz,2H),2.16(d,J= 1.5Hz, 3H), 2.08 (dt, J=18.8, 9.2Hz, 1H), 1.90 (tq, J=9.8, 6.2, 4.7Hz, 1H).

[0740] Example 67: Synthesis of compound (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B42)

[0741] The synthesis of steps 1-4 in Example 67 was performed using the same method as steps 1-4 in Example 44, except that B42-0 and sodium acetate were used to replace 2-methylpyridine-5-borate pinacol ester and potassium acetate in step 1 of Example 44, respectively, and M4 was used to replace M3 in step 4 of Example 44. The rest of the method was the same, and the target compound B42 (68 mg) was prepared as a white solid with a yield of 18.3%.

[0742] MS m / z: 535.0 [M+H] + .

[0743] 1 H NMR(600MHz,DMSO-d6)δ8.75(s,1H),8.18(s,1H),8.05(d,J=1.6Hz,1H),7.96-7.92(m,2H),7.89-7.86(m,1H),7.59(s,1H),7.5 7-7.53(m,2H),7.30(s,1H),2.83(tt,J=8.0,4.8Hz,1H),2.15(d,J=1.6Hz,3H),1.16(tt,J=5.2,2.8Hz,2H),1.10-1.01(m,2H).

[0744] Example 68: Synthesis of compound (E)-2-(4-(N-cyclopropylaminosulfonyl)phenyl)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B43)

[0745] The synthesis of steps 1-4 in Example 68 was carried out by referring to the synthesis method of steps 1-4 in Example 44, except that B43-0 was used to replace 2-methylpyridine-5-borate pinacol ester in step 1 of Example 44, and M4 was used to replace M3 in step 4 of Example 44. The rest of the method was the same, and the target compound B43 (14 mg) was prepared as a white solid with a yield of 6.6%.

[0746] MS m / z: 550.1 [M+H] + .

[0747] 1H NMR (600MHz, DMSO-d6) δ8.63 (s, 1H), 8.16 (s, 1H), 8.08 (d, J = 1.6Hz, 1H), 7.96-7.92 (m, 2H), 7.87-7.83 (m, 2H), 7. 60(s,1H),7.53-7.49(m,2H),7.23(s,1H),2.16(d,J=1.6Hz,3H),2.13(dq,J=6.4,1.6Hz,1H),0.47-0.38(m,4H).

[0748] Example 69: Synthesis of compound (E)-3-(3-(2-fluoro-3-methyl-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)acrylamide (B72)

[0749] The synthesis of Example 69 was carried out by referring to the synthesis method of step 4 of Example 39, except that A43-3 and M4 were used to replace B1-3 and M3 in step 4 of Example 39, respectively. The rest of the method was the same, and compound B72 (5 mg) was prepared as a white solid, which is a formate, with a yield of 5.6%.

[0750] MS m / z: 503.1 [M+H] + .

[0751] 1 H NMR(600MHz,DMSO-d6)δ9.07(s,1H),8.75(s,2H),8.51(s,1H),8.38(s,1H),8.09(s,1H),7.83(s,1H),7.60(s,1H), 7.43(s,1H),5.54(s,1H),2.68-2.63(m,2H),2.37-2.28(m,2H),2.15(s,3H),1.94-1.88(m,1H),1.87-1.81(m,1H).

[0752] Example 70: Synthesis of compound (E)-3-(3-(3-(difluoromethyl)-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)-2-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)acrylamide (B73)

[0753] The synthesis of Example 70 was carried out by referring to the synthesis method of step 4 of Example 39, except that B1-3 and M3 in step 4 of Example 39 were replaced by A43-3 and M5 respectively, and the rest of the method was the same, to prepare compound B73 (7 mg), which was a white solid with a yield of 7.0%.

[0754] MS m / z: 521.1 [M+H] + .

[0755] 1 H NMR (600MHz, DMSO-d6) δ9.07(s,1H),8.76(s,2H),8.69(t,J=2.6Hz,1H),8.40(s,1H),8.38(s,1H),7.87(s,1H),7.60(s ,1H),7.44(d,J=12.1Hz,2H),5.49(s,1H),2.69-2.62(m,2H),2.35-2.30(m,2H),1.95-1.88(m,1H),1.89-1.82(m,1H).

[0756] Example 71: Synthesis of compound (E)-2-(2-cyclobutylpyrimidin-5-yl)-3-(3-(3-(difluoromethyl)-7-(trifluoromethyl)benzofuran-5-yl)-1H-1,2,4-triazol-1-yl)acrylamide (B76)

[0757] The synthesis of Example 71 was performed by referring to the synthesis method of step 4 of Example 39, except that B1-3 and M3 in step 4 of Example 39 were replaced by A39-3 and M5 respectively, and the rest of the method was the same. Compound B76 (19 mg) was prepared as a white solid with a yield of 41.8%.

[0758] MS m / z: 505.2 [M+H] + .

[0759] 1 H NMR(600MHz,DMSO-d6)δ9.08(s,1H),8.69(d,J=2.6Hz,1H),8.65(s,2H),8.38(s,1H),8.36(s,1H),7.84(s,1H),7.58(s,1H),7.43(t,1H),7 .38(s,1H),3.82(p,J=8.7Hz,1H),2.43(qd,J=9.2,2.6Hz,2H),2.34(dtd,J=11.9,8.6,2.9Hz,2H),2.07(h,J=9.3Hz,1H),1.94-1.86(m,1H).

[0760] Example 72: Synthesis of (E)-3-(3-(2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclopropenyrimidin-5-yl)-N-methoxyacrylamide (C3)

[0761] Step 1: Synthesis of compound C3-1

[0762] C3-0 (1.8 g, 7.96 mmol), cyclopropylboronic acid (1.36 g, 15.92 mmol), potassium carbonate (3.3 g, 23.88 mmol), and PdCl2 (dppf) (0.33 g, 0.4 mmol) were dissolved in a mixed solution of 1,4-dioxane (40 mL) and water (4 mL). The reaction was carried out at 90 °C for 12 h under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give compound C3-1 (0.5 g), with a yield of 33.5%.

[0763] Steps 2-5: Synthesis of compound C3

[0764] The synthesis of step 2 in Example 72 was performed according to the synthesis method of step 1 in Example 2, except that C2-0 in step 1 of Example 2 was replaced by C3-1, and the rest of the method was the same. The synthesis of step 3 in Example 72 was performed according to the synthesis method of step 5 in Example 2, except that C2-4 in step 5 of Example 2 was replaced by C2-2, and C2-1 in step 5 of Example 2 was replaced by C3-2, and the rest of the method was the same. The synthesis of steps 4-5 in Example 72 was performed according to the synthesis method of steps 3-4 in Example 2, except that C2-2 in step 3 of Example 2 was replaced by C3-3, and the rest of the method was the same. The target compound C3 (247 mg) was prepared as a white solid with a yield of 18.5%.

[0765] MS m / z: 472.1 [M+H] + .

[0766] 1 H NMR (600MHz, DMSO-d6) δ11.21(s,1H),9.16(s,1H),8.53(s,2H),8.36(s,1H),7.74(s,1H),7.53(d,J=1.3Hz,1H), 3.65(s,3H),2.32-2.26(m,2H),1.10(dq,J=7.1,3.7Hz,4H),1.07(dq,J=7.1,4.4,3.7Hz,2H),0.98-0.94(m,2H).

[0767] Example 73: Synthesis of (E)-2-(2-cyclopropylpyrimidin-5-yl)-3-(3-(2,6-dicyclopropylpyridin-4-yl)-1H-1,2,4-triazol-1-yl)-N-methoxyacrylamide (C4)

[0768] The synthesis of Example 4 was carried out by referring to the synthesis method of step 5 of Example 2, except that C2-1 in step 5 of Example 2 was replaced by C4-0. The rest of the method was the same, and the target compound C4 (145 mg) was prepared as a white solid with a yield of 22.6%.

[0769] MS m / z: 444.2 [M+H] + .

[0770] 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),9.06(s,1H),8.50(s,2H),8.31(s,1H),7.13(s,2H),3.64(s,3H),2.32(dq,J=8.0,4. 9,4.2Hz,1H),2.01(tt,J=8.3,4.7Hz,2H),1.13-1.07(m,4H),0.92(dt,J=8.0,3.2Hz,4H),0.85(dq,J=6.9,4.1,3.6Hz,4H).

[0771] Example 74: Synthesis of (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(2-cyclobutylpyrimidin-5-yl)-N-methoxyacrylamide (C5)

[0772] The synthesis of Example 5 was carried out by referring to the synthesis method of Steps 2-4 of Example 2, except that C1-3 in Step 2 of Example 2 was replaced by C5-0, and M2 in Step 2 of Example 2 was replaced by M1. The rest of the method was the same, and the target compound C5 (276 mg) was prepared as a white solid with a yield of 14.5%.

[0773] MS m / z: 513.1 [M+H] + .

[0774] 1H NMR (600MHz, DMSO-d6) δ11.23(s,1H),9.18(s,1H),8.67(s,2H),8.37(s,1H),8.23(s,1H),8.11(d,J=1.7Hz,2H),3. 84-3.78(m,1H),3.66(s,3H),2.47-2.40(m,2H),2.35(qt,J=8.7,2.4Hz,2H),2.11-2.05(m,1H),1.95-1.86(m,1H).

[0775] Example 75: Tumor cell proliferation inhibition activity (IC50) 50 )test

[0776] 1. Assay of MDA-MB-231 cell proliferation inhibition activity

[0777] MDA-MB-231 cells in good growth condition were collected into centrifuge tubes, and the cell density was adjusted to 8000 cells / well. The cells were then seeded into 96-well plates (95 μL / well) and cultured at 37°C in a 5% CO2 incubator for 24 h. Positive control drug and test compound were added separately, with a final concentration of 10000 nM - 0.61 nM. Three replicates were set up. After culturing for 72 hours, the culture medium was discarded, and the cells were fixed and stained according to the instructions of the SRB cell proliferation and cytotoxicity assay kit (manufacturer: Shanghai Beibo Biotechnology Co., Ltd.). The absorbance was measured at 515 nm using a microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 .

[0778] 2. Assay for the inhibitory activity of 22RV1 cell proliferation

[0779] 22RV1 cells in good growth condition were collected into centrifuge tubes, and the cell density was adjusted to 15,000 cells / well. The cells were then seeded into 96-well plates (90 μL / well) and cultured at 37°C in a 5% CO2 incubator for 24 h. Positive control drug and test compound were added separately, with a final concentration of 10,000 nM–4.57 nM. Three replicates were set up. After culturing for 72 hours, the culture medium was discarded, and the cells were fixed and stained according to the SRB cell proliferation and cytotoxicity assay kit (manufacturer: Shanghai Beibo Biotechnology Co., Ltd.). The absorbance was measured at 515 nm using a microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 .

[0780] 3. Assay of MM.1S cell proliferation inhibition activity

[0781] MM.1S cells in good growth condition were collected into centrifuge tubes, and the cell density was adjusted to 4000 cells / well. The cells were then seeded into 96-well white plates (95 μL / well) and cultured at 37°C in a 5% CO2 incubator for 24 h. Positive control drug and test compound were added to each well, with a final concentration of 10000 nM - 0.61 nM. Three replicates were set up. After culturing for 72 hours, 50 μL of CellTiter-Glo working solution (manufacturer: Nanjing Novizan Biotechnology Co., Ltd.) was added to each well. The plates were wrapped in aluminum foil to protect them from light, and shaken on a shaker for 2 minutes. The plates were then incubated at room temperature for 10 minutes to stabilize the luminescence signal. The luminescence signal was measured using a microplate reader, and four parameters were analyzed. A dose-response curve was fitted, and the IC50 was calculated. 50 .

[0782] 4. Assay for HCT116 cell proliferation inhibition activity

[0783] HCT116 cells in good growth condition were collected into centrifuge tubes, and the cell density was adjusted to 3000 / well. The cells were then seeded into 96-well plates (90 μL / well) and cultured at 37°C in a 5% CO2 incubator for 24 h. Positive control drug and test compound were added separately, with a final concentration of 10000 nM - 0.61 nM. Three replicates were set up. After culturing for 72 hours, the culture medium was discarded, and the cells were fixed and stained according to the SRB cell proliferation and cytotoxicity assay kit instructions (manufacturer: Shanghai Beibo Biotechnology Co., Ltd.). The absorbance was measured at 515 nm using a microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 .

[0784] The compounds in the examples exhibited inhibitory activity (IC50) against the proliferation of various tumor cells. 50 The test results are shown in Table 1.

[0785] Table 1. Inhibitory activity (IC50) of compounds against tumor cell proliferation 50 (nM) [Note]: 1nM < "+++" ≤ 30nM; 30nM < "++" ≤ 100nM; 100nM < "+"; "NT": Not measured.

[0786] As shown in Table 1, the compounds of the present invention exhibit good inhibitory activity against tumor cells, and the inhibitory effects of some compounds are significantly better than those of the control compounds KPT-8602 and SZJK-0421.

[0787] Example 73: In vivo drug metabolism kinetics test

[0788] This experiment aimed to investigate the plasma pharmacokinetics of a compound in male CD-1 mice after single intravenous and gavage administration. CD-1 mice (SPF grade, male, fasted) were used as experimental animals. The pharmacokinetic characteristics of the compound after intravenous and oral administration were tested using a standard protocol. In this experiment, the candidate compound was administered via gavage with 1% HPMC and via intravenous injection with 5% DMSO + 5% Kolliphor EL + 90% physiological saline. Mice were administered the compound via single gavage and single intravenous injection. The gavage dose was 10 MPa, and the intravenous injection dose was 1 MPa. Whole blood samples were collected within 24 hours and centrifuged at 2000 g / min for 10 min at 4°C. The supernatant was separated to obtain plasma samples, and one-tenth of the volume of internal standard solution was added, followed by the addition of methanol to precipitate proteins. The supernatant was then centrifuged at 17000 g / min for 10 min at 4°C, and the plasma concentration was quantitatively analyzed by LC-MS / MS. Using blood drug concentration data at different time points, Phoenix WinNonlin 8.4 was used to calculate pharmacokinetic parameters, providing T0... 1 / 2 T max C max AUC last Parameters such as Cl and Fabs.

[0789] The in vivo pharmacokinetic results of the compounds in the examples are shown in Table 2.

[0790] Table 2. Results of drug metabolism kinetics tests in mice

[0791] As shown in Table 2, the compounds of this invention exhibit excellent pharmacokinetic and mechanical properties, which are superior to those of the control compounds KPT-8602 and SZJK-0421.

[0792] Example 74: Evaluation of the brain penetration properties of the compound

[0793] This experiment aimed to investigate the concentrations and B / Pratio of the test compound in the brain and plasma of male CD1 mice at specific time points after oral administration. Animals were randomly divided into three groups of three males each. The compound was formulated into a specified preparation (5 mpk), which could be a clear or homogeneous suspension in 5% DMSO + 5% Koilliphor EL + 90% physiological saline. Whole blood samples were collected from the eyes at 30 minutes, 1 hour, and 2 hours after administration, and brain samples were also collected simultaneously. The whole blood samples were added to centrifuge tubes containing anticoagulant and centrifuged over 1 hour (centrifugation conditions: 2000 g / min, 10 min, 4 °C). The supernatant plasma was collected and stored at -20 °C until LC-MS / MS analysis. Approximately 300 mg of brain tissue was collected and homogenized in a 1:4 ratio (1 g: 4 mL) with 50% methanol aqueous solution. The homogenate was centrifuged (centrifugation conditions: 2000 g / min, 5 min, 4 °C), and the supernatant was transferred to another centrifuge tube and stored at -20 °C until LC-MS / MS analysis. AUC data were calculated using WinNonlin, and the AUC ratio (B / P ratio) of brain and plasma samples was calculated using Microsoft Excel.

[0794] The brain penetration evaluation results of the compounds in the examples are shown in Table 3.

[0795] Table 3. Evaluation results of the brain penetration properties of the compounds

[0796] As shown in Table 3, the compounds of the present invention have lower blood-brain barrier permeability, which is superior to the control compounds KPT-8602 and SZJK-0421.

Claims

1. An acrylamide compound, which is a compound having the following general structural formula (IA) or (IB), a stereoisomer, a tautomer, a deuterated form, or a pharmaceutically acceptable salt thereof: in: X is selected from CR2 or N; Y is selected from CR 11 or N; R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and -NR. a R b C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 The aryl or 5-14 heteroaryl group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group; R A Selected from C 1-6 Alkyl, C 3-8 cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl or 3-10 membered heterocyclic group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, cyano, amino, hydroxyl, amide, C 1-6 Alkyl, C 1-6 alkenyl, C 1- 6-alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic or C 6-14 Aryl, the R A Not selected from piperazine or tetrahydropyrrole; R6, R7, R8, R9, R 10 R 11 R a R b R B1 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl sulfone group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 The aryl or 5-14 heteroaryl group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 Alkyl sulfone group; R B2 , R B3 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-8 cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-8 cycloalkyl can be optionally further substituted by one or more radicals selected from deuterium or halogen; Ring A is selected from C 6-14 Aryl or 5-14 heteroaryl, wherein C 6-14 The aryl or 5-14 heteroaryl group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, -NR. i R j -SO2R c -SO2NR i R j C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine or C 1-6 Alkyl sulfone group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine or C 1-6 The alkyl sulfone group may optionally be further substituted by one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, -CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 alkylamine group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups; R c , R i , R j are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, or 3-10 membered heterocyclyl, said C 1-6 alkyl, C 3-8 cycloalkyl, or 3-10 membered heterocyclyl can be optionally further substituted with one or more groups selected from deuterium or halogen; or R i , R j and the N atom to which they are attached together form a 3-10 membered heterocyclyl group, which can be optionally further substituted by one or more groups selected from deuterium or halogen; R B4 , R B5 each independently is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy or C 3-8 cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy or C 3-8 cycloalkyl can be optionally further substituted by one or more groups selected from deuterium, halogen, cyano or hydroxy; n is selected from 0, 1, 2 or 3.

2. The acrylamide compound according to claim 1, wherein R B2 , R B3 each independently is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, which C 1-6 alkyl or C 1-6 alkoxy can be optionally further substituted by one or more groups selected from halogen; Ring A is selected from C 6-14 Aryl or 5-14 heteroaryl, wherein C 6-14 The aryl or 5-14 heteroaryl group may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, cyano, -SO2R c -SO2NHR j C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine or C 1-6 Alkyl sulfone group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-6 alkylamine or C 1-6 The alkyl sulfone group may optionally be further substituted by one or more groups selected from the following: deuterium, halogen, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups; R c , R j are each independently selected from C 3-8 cycloalkyl or 3-10 membered heterocyclyl, said C 3-8 cycloalkyl or 3-10 membered heterocyclyl can be optionally further substituted with one or more groups selected from deuterium or halogen; R B4 , R B5 each independently is selected from hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl can be optionally further substituted by one or more radicals selected from deuterium, halogen, cyano or hydroxy.

3. The acrylamide compound according to claim 1 or 2, wherein Compounds having the following structural general formula (IIA) or (IIB), stereoisomers, tautomers, deuterated forms, or pharmaceutically acceptable salts thereof: in: X is selected from CR2 or N, wherein R2 is selected from hydrogen, deuterium, halogen or cyano; R B1 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkoxy or C 1-6 alkylamine group, the C 1-6 Alkyl, C 3- 8-cycloalkyl, C 1-6 Alkoxy or C 1-6 The alkylamine group may optionally be further substituted by one or more groups selected from the following: deuterium or halogen; Y, R1, R3, R A , R7, R8, R B2 , R B3 , ring A, R B4 are as defined in claim 1 or 2.

4. The acrylamide compound according to any one of claims 1 to 3, wherein Compounds of the following structural formula (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIB-3), (IIIB-4), or (IIIB-5), stereoisomers, tautomers, deuterated forms, or pharmaceutically acceptable salts thereof: Among them, X, Y6, and Y7 are each independently selected from CH or N; Y is selected from CR 11 or N, said R 11 is selected from hydrogen, deuterium, halogen or cyano; Z1is selected from O or NR g , said R g is selected from hydrogen, deuterium, C 1-3 alkyl or 3-6 membered heterocyclyl; R1, R3, R B1 R B2 R B3 Each is independently selected from hydrogen, deuterium, halogen, cyano, cyclopropyl, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 alkylamine group, the C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 The alkylamine group may optionally be further substituted with one or more groups selected from hydrogen, deuterium or halogen; R7, R B4 Each element is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy or C 3-5 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy or C 3- The 5-cycloalkyl group may optionally be further substituted with one or more groups selected from hydrogen, deuterium, halogen, hydroxyl or cyano; Y1, Y2, Y3, Y4, Y5are each independently selected from CR h or N; R h Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -NR i R j -SO2R c or -SO2NR i R j The C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups may optionally be further coupled with one or more R groups. e replace; R e each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, -CONH2, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino; R c selected from hydrogen, deuterium or C 3-6 cycloalkyl; R i , R j are each independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl; or R i , R j and the N atom to which they are attached together form a 3-7 membered heterocyclyl group, which can be optionally further substituted by one or more groups selected from hydrogen, deuterium or halogen; p and q are each independently selected from 0, 1, 2 or 3.

5. The acrylamide compound according to any one of claims 1 to 4, wherein Compounds of the following structural formulae (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVA-6), (IVB-1), (IVB-2), (IVB-3), (IVB-4), (IVB-5), (IVB-6), or (IVB-7), stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: wherein X, Y, R g , R1, R3, R B1 , R B2 , R B3 , R7, R B4 , Y4, R h , R e , p are as defined in claim 4.

6. The acrylamide compound according to any one of claims 1 to 5, wherein Compounds of the following structural formula (VA-1), (VA-2), (VA-3) or (VB-1), stereoisomers, tautomers, deuterated forms, or pharmaceutically acceptable salts thereof: wherein the definitions of X, R1, R3, R B1 , R B2 , R B3 , R7, R e , p, R i , R j are as described in claim 4.

7. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein, R1, R3, R B1 , R B2 , R B3 are each independently selected from hydrogen, deuterium, halogen, cyclopropyl, C 1-3 alkyl or C 1-3 haloalkyl.

8. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein, The R7, R B4 Each is independently selected from -H, -OCH3, 9. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein, said R e is selected from -H, -F, -OH, -NH2, -CN, -CH3, -OCH3, -NHCH3, or -CONH2.

10. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein, said R h selected from -H, -F, -CN, -CH3, -CF3, 11. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-10, wherein, selected from the following compounds:

12. A pharmaceutical composition comprising, as an active ingredient, a compound, stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof as any one of claims 1-11, and at least one pharmaceutically acceptable carrier.

13. The use of any compound, stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition of claim 12 in the preparation of a medicament for treating XPO1-mediated diseases or conditions and related diseases or conditions.

14. The use of any compound, stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition of claim 12, for the treatment of diseases or conditions mediated by XPO1 and related diseases or conditions.

15. A method of treating and / or preventing a disease, comprising administering to a subject a therapeutically effective amount of any one of claims 1-11, or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12.

16. Use according to claim 13 or 14 or method according to claim 15, characterized in that, The disease in question is a tumor.

17. Use according to claim 16, characterized in that, The tumor is selected from hematologic malignancies or solid tumors.

18. The use according to claim 17, characterized in that, The hematologic malignancies mentioned are selected from multiple myeloma, B-cell lymphoma, myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, histiocytic lymphoma, acute megakaryocytic leukemia, prolymphocytic leukemia, T-lymphoblastic leukemia, and T-lymphoblastic lymphoma, etc.

19. The use according to claim 17, characterized in that, The solid tumors are selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, nasopharyngeal carcinoma, glioma, etc.

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