SRPK inhibitor compound and use thereof

Abstract

The present invention relates to an SRPK inhibitor compound and the use thereof. The present invention further relates to the use of the SRPK inhibitor compound in the preparation of a drug for preventing and / or treating SRPK-related diseases.

Description

An SRPK inhibitor compound and its uses Technical Field

[0001] This invention relates to an SRPK inhibitor compound and its use, particularly its use in the preparation of medicaments for the prevention and / or treatment of SRPK-related diseases. Background Technology

[0002] Serine-arginine protein kinase 1 (SRPK1) is a serine / arginine-rich, specific protein kinase that specifically phosphorylates serine / arginine splicing molecules. Studies have shown that SRPK1 regulates many cellular biological activities through its interaction with serine-arginine proteins, including multiple steps of RNA maturation, chromatin reorganization, cell cycle progression, and immune responses. Abnormally elevated SRPK1 expression can be observed in most malignant tumors and is closely related to multiple prognostic factors (tumor grade, stage, subtype) and patient survival.

[0003] Studies have shown that SRPK1 participates in the splicing of angiogenesis-related genes such as VEGF and FGF-2 in various cancers and ophthalmic diseases, leading to the production of angiogenesis-promoting splice variants that enhance cell survival and invasion. SPHINX31 is a potent, selective inhibitor of serine / arginine-rich protein kinase 1 (SRPK1), which inhibits the phosphorylation of serine / arginine-rich splice factor 1 (SRSF1). SPHINX31 also reduces the levels of the pro-angiogenic gene VEGF-A. 165 Subtype a mRNA expression. SPHINX31 is currently in Phase II clinical trials in the United States, with the indication of neovascular ophthalmopathy. Its structure is shown below:

[0004] However, the number of drugs available for treating SRPK1-mediated diseases is far from meeting clinical needs. Therefore, it is necessary to develop new small molecule inhibitors of SRPK1 for the prevention or treatment of SRPK1-related diseases in order to continuously meet clinical needs. Summary of the Invention

[0005] In a first aspect, the present invention provides a compound having a structure as shown in Formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having a structure as shown in Formula (I).

[0006] Where Z is CR 1 Or N; R 1It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, or cycloalkyl;

[0007] X is CR 5 Or N;

[0008] A is a 5-6 membered heterocyclic ring;

[0009] B is a 5-6 member heterocyclic aromatic ring;

[0010] R 2 It can be H, deuterium, hydroxyl, halogen, amino, cyano, alkyl, alkoxy, or cycloalkyl;

[0011] R 3 For optional use by R 7 The substituted aryl, heteroaryl, heterocyclic or cycloalkyl groups;

[0012] R 5 It is an alkoxy group, a haloalkoxy group, a haloalkenoxy group, an alkylthio group, a haloalkoxy group, a haloalkenthio group, a Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached thereto, they form independently optional R 6 Substituted 5-6 membered carbon rings or 5-6 membered heterocycles;

[0013] R 6 It can be H, halogen, alkyl, alkenyl, or cycloalkyl;

[0014] R 4 For optional use by R 8 The substituted alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups;

[0015] R 7 and R 8 Each can be independently hydrogen, deuterium, cyano, hydroxyl, alkyl, alkoxy, alkylthio, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0016] In some embodiments, wherein the compound,

[0017] R 2 H, deuterium, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0018] R 3 For optional use by R 7 The C that was replaced 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8cycloalkyl;

[0019] R 4 For optional use by R 8 The C that was replaced 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl C 1-6 alkyl;

[0020] R 7 and R 8 Each is independently hydrogen, deuterium, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0021] In some embodiments, wherein the compound,

[0022] R 2 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, C 1-4 alkoxy or cyclopropyl;

[0023] R 3 For optional use by R 7 The substituted cyclopropane, cyclobutane, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, cyclohexane, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazine, cycloheptane, acrylonitrile, or oxoheptane;

[0024] R 4 For optional use by R 8 The C that was replaced 6-10 Aryl C 1-3 Alkyl or C 1-9 heteroaryl C 1-3 alkyl;

[0025] R 7 and R 8 Each is independently hydrogen, deuterium, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C3-6 Cycloalkyl.

[0026] In some embodiments, wherein the compound,

[0027] A is a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a tetrahydropyrrole ring, a tetrahydrothiophene ring, or a piperazine ring;

[0028] B can be a furan ring, imidazole ring, pyrrole ring, thiophene ring, indole ring, carbazole ring, thiazole ring, thiadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring.

[0029] In some embodiments, the compound has a structure as shown in Formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in Formula (II).

[0030] Among them, R 1 X is defined in equation (I).

[0031] In some embodiments, wherein the compound,

[0032] R 1 H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl or C 3-8 cycloalkyl;

[0033] X is CR 5 Or N;

[0034] R 5 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 2- 6-Halogenated thiols, Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached thereto, they form independently optional R 6 Substituted 5-6 membered carbon rings or 5-6 membered heterocycles;

[0035] R 6 H, halogen, C 1-6 Alkyl, C 2-6 alkenyl or C 3-8 Cycloalkyl.

[0036] In some other embodiments, wherein the compound,

[0037] R 1 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Heteroalkyl or cyclopropyl;

[0038] R 5 C substituted with fluorine 1-3 alkoxy, fluorine-substituted C 1-3 alkylthio, fluorine-substituted C 2-4 Alkenyloxy, fluorine-substituted C 2-4 Benzyl thioyl, Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached thereto, they form independently optional R 6 Substituted 5-6 membered carbon rings or 5-6 membered heterocycles;

[0039] R 6 H, F, Cl or C 1-3 alkyl.

[0040] In some embodiments, wherein R in the compound is... 5 For SF5, Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached to it, they form the following structure

[0041] In a second aspect, the present invention provides a compound having a structure as shown in formula (I'), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having a structure as shown in formula (I').

[0042] Among them, R 1a It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, or cycloalkyl;

[0043] Y is CR 5a Or N;

[0044] B' is a 5-6 member heterocyclic aromatic ring;

[0045] R 2a It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, alkoxy, or cycloalkyl;

[0046] R 3aTo be independently and arbitrarily R 7a The substituted cycloalkyl, aryl, heteroaryl, heterocyclic or cycloalkyl groups;

[0047] R 5a It is a haloalkyl, alkoxy, haloalkoxy, haloalkenoxy, alkylthio, haloalkylthio or Me2P(=O)-;

[0048] R 4a It is cyano, R 8a R 10a NC (=O), R 8a OC (=O), alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylheteroaryl, alkylheteroarylalkyl;

[0049] Q is a 7-8 fused heterocycle, 7-8 spirocyclic heterocycle, 7-8 bridged heterocycle, or -CH2-NH(CR) selected from deuterium, hydroxyl, halogen, amino, alkyl, aryl, heteroaryl, and cycloalkyl, optionally substituted by 1, 2, 3, or 4 alkyl groups. 6a R 9a ) n’ NH- or -CH2-NR 11a (CR 6a R 9a ) n’ CH2-;

[0050] n' is 1, 2 or 3;

[0051] R 6a R 7a R 8a R 9a R 10a and R 11a Each can be independently hydrogen, deuterium, cyano, hydroxyl, alkyl, alkoxy, alkylthio, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0052] Or R 6a R 7a Together with the carbon atom it is attached to, they form C=O or C=S.

[0053] In some embodiments, wherein R in the compound is... 2a H, deuterium, hydroxyl, halogen, cyano, amino, C 1- 6-alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0054] R 3a To be independently and arbitrarily R 7a The C that was replaced 3-8 cycloalkyl, C 6-10 Aryl, C1-9 heteroaryl, C 1-9 Heterocyclic group or C 3- 8-cycloalkyl;

[0055] R 5a C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio group or Me2P(=O)-;

[0056] R 7a It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0057] In some embodiments, wherein R in the compound is... 2a H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, C 1-4 alkoxy or cyclopropyl;

[0058] R 3a To be independently and arbitrarily R 7a The substituted cyclopropane, cyclobutane, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, cyclohexane, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazine, cycloheptane, acrylonitrile, or oxoheptane;

[0059] R 5a C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy group; preferably -CF3, -OMe or -OCF3;

[0060] R 7a It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl.

[0061] In some embodiments, B' in the compound is a furan ring, an imidazole ring, a pyrrole ring, a thiophene ring, an indole ring, a carbazole ring, a thiazole ring, a thiadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring.

[0062] In some embodiments, the compound has a structure as shown in formula (II'), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formula (II').

[0063] Q is independently and optionally composed of 1, 2, 3, or 4 elements selected from deuterium, hydroxyl, F, Cl, Br, amino, C. 1-6 Alkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl-substituted 7-8 fused heterocycles, 7-8 spiroheterocycles, 7-8 bridged heterocycles, or -NH(CR) 6a R 9a ) n’ NH- or -NR 11a (CR 6a R 9a ) n’ CH2-;

[0064] n' is 1, 2 or 3;

[0065] R 4a It is cyano, R 8a R 10a NC (=O), R 8a OC (=O), C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 6- 10 Aryl, C 1-9 heteroaryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl C 1-6 Alkyl, C 1-6 Alkyl C 1-9 heteroaryl, C 1-6 Alkyl C 1-9 heteroaryl C 1-6 alkyl;

[0066] R 6a R 7a R 8a R 9a R 10a and R 11a Each is independently hydrogen, deuterium, cyano, hydroxyl, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatics;

[0067] Or R 6a R 7a Together with the carbon atom it is attached to, they form C=O or C=S.

[0068] In some embodiments, wherein the compound,

[0069] Q is

[0070] In some embodiments, wherein R in the compound is... 4a It is cyano, H2NC(=O)-, R 8a OC (=O), C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Cyanoalkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-3 Alkyl, C 1-3 Alkyl C 1-9 heteroaryl, C 1-3 Alkyl C 1-9 heteroaryl C 1-3 Alkyl; preferably cyano, H2NC(=O)-, R 8a OC (=O)

[0071] R 8a It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Hydroxyalkyl or cyclopropyl.

[0072] Thirdly, the present invention provides a compound having the following structures, or its stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0073] Fourthly, the present invention provides a compound having the structure shown in formula (I”), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure shown in formula (I”).

[0074] Among them, R 1b It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, or cycloalkyl;

[0075] E is CR 5b Or N;

[0076] "B" is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring;

[0077] R 2b It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, alkoxy, or cycloalkyl;

[0078] R 3b To be independently and optionally controlled by 1, 2 or 3 R 7b The substituted aryl, heteroaryl, heterocyclic or cycloalkyl groups;

[0079] L is -C(=O)NR 6b -、-NR 6b C(=O)-、-NR 6b C(=O)NR 8b -、-NR 6b C(=O)NR 8b CR 9b R 10b -or-NR 6b S(=O)2-;

[0080] R 5b It can be hydrogen, halogen, hydroxyl, cyano, haloalkyl, alkoxy, haloalkoxy, haloalkenoxy, alkylthio, haloalkylthio, or Me2P(=O)-;

[0081] R 4b It is cyano, R 6b R 8b NC(=O)-、R 8b OC(=O)-, alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylheteroaryl or alkylheteroarylalkyl;

[0082] R 6b and R 8b Each can be independently hydrogen, deuterium, alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0083] R 7b Hydrogen, deuterium, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, Cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0084] R 9b and R 10bEach can be independently hydrogen, deuterium, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0085] In some embodiments, wherein R in the compound is... 1b H, deuterium, hydroxyl, halogen, cyano, amino, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl or C 3-8 cycloalkyl;

[0086] R 2b H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0087] R 5b It consists of hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio or Me2P(=O)-.

[0088] In some embodiments, wherein R in the compound is... 2b H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, C 1-4 alkoxy or cyclopropyl;

[0089] R 5b It consists of hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Haloalkylthio group; preferably -CF3, -OMe, -OCF3 or -SCF3.

[0090] In some embodiments, the compound has a structure as shown in formula (II”), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formula (II”).

[0091] Among them, B”, L, R 3b R 5b Same as the definition in formula (I”).

[0092] In some embodiments, in the compound, B” is a furan ring, an imidazole ring, a pyrrole ring, a thiophene ring, an indole ring, a carbazole ring, a thiazole ring, a thiadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring;

[0093] L is -C(=O)NR 6b -、-NR 6b C(=O)-、-NR 6b C(=O)NR 8b -、-NR 6b C(=O)NR 8b CR 9b R 10b -or-NR 6b S(=O)2-;

[0094] R 5b It consists of hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Haloalkylthio group; preferably -CF3, -OMe, -OCF3 or -SCF3;

[0095] R 6b and R 8b Each is independently hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6- 10 Aryl or C 1-9 Mixed aromatics;

[0096] R 9b and R 10b Each of these can be independently represented by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0097] In some embodiments, wherein R in the compound is... 3b To be independently and optionally controlled by 1, 2 or 3 R 7b The C that was replaced 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl;

[0098] R 7bIt can be hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0099] In some embodiments, wherein R in the compound is... 3b To be independently and optionally controlled by 1, 2 or 3 R 7b The substituted furanyl, pyrrolyl, thiophene, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, phenyl, pyridinyl, 2H-pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyclopropane, cyclobutane, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophene, cyclohexane, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, cycloheptane, acrylonitrile, oxeheptane, benzofuranyl, benzothiophene, indolyl, inazolyl, benzisoxazolyl, 3H-indolyl, 1H-indolyl, or benzoxazolyl;

[0100] R 7b For hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1- 3-hydroxyalkyl, Or C 3-6 Cycloalkyl.

[0101] Fifthly, the present invention also provides a pharmaceutical composition comprising the above-mentioned compound and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

[0102] In a sixth aspect, the present invention provides the use of the compounds or pharmaceutical compositions of the present invention in the preparation of medicaments for the prevention and / or treatment of diseases associated with or caused, mediated and / or proliferated by SRPK1 inhibitors.

[0103] In some implementations, the diseases mentioned are selected from: hyperproliferative disorders, cancer, metastases, tumors, angiogenesis disorders, tumor angiogenesis, benign hyperplasia, hemangioma, glioma, melanoma, Kaposi's sarcoma, prostate diseases related to angiogenesis or angiogenesis, inflammation, pancreatitis, retinopathy, retinopathy of prematurity, diabetic retinopathy, diabetes, pain, restenosis, psoriasis, eczema, scleroderma, and age-related macular degeneration.

[0104] In a seventh aspect, the present invention provides a method for preventing and / or treating diseases associated with or caused, mediated, and / or proliferated by SRPK1 inhibitors, comprising administering to a patient an effective amount of the compound or the pharmaceutical composition thereof.

[0105] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below. Detailed Implementation

[0106] Definitions and general terms

[0107] Unless otherwise stated, the terms used in the specification and claims of this invention have the following definitions.

[0108] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0109] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0110] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0111] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the periodic table (CAS edition) and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0112] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0113] The term "patient" as used in this invention refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0114] The term "subject" as used in this invention refers to a mammal or other animal. In some embodiments, "subject" refers to a mammal. In some embodiments, "subject" refers to a human (including adults and children).

[0115] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0116] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, and blocked isomers, etc. "Diastereomers" are stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC. The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols used to specify the plane-polarized light rotation caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

[0117] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.

[0118] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0119] 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.

[0120] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.

[0121] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound shown in this invention in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C14) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0122] Racemic mixtures of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating their diastereomeric salts. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0123] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0124] The salts mentioned in this invention are pharmaceutically acceptable salts, and the term "pharmaceutically acceptable salts" is well known in the field, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Pharmaceutically acceptable, non-limiting examples of salts include inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, metaphosphates, sulfates, sulfites, nitrates, and perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, and thiocarboxylates, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, bis(hydroxynaphthyl) salts, salicylates, galactobionates, gluconates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, hydroxyethylsulfonates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalic acid, or obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, undecanoate, valerate, etc. Furthermore, pharmaceutically acceptable salts also include those obtained by means of appropriate bases, such as alkali metals, alkaline earth metals, ammonium, and N+(C) salts. 1-4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1- 8. Sulfonates and aromatic sulfonates.

[0125] Medicinal salts can form with inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, theophylline salts, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, glucuronide, hippurate, hydroiodide / iodide, hydroxyethyl sulfonate, lactates, lacturonide, lauryl sulfate, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, pyrates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalactosates, propions, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0126] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

[0127] As used herein, the term "nitrogen oxide" refers to a compound containing several amine functional groups, which can oxidize one or more nitrogen atoms to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen atoms in nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), wherein the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane.

[0128] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0129] As used in this application, the term "metabolite" refers to the product obtained in vivo through the metabolism of a specific compound or its salt. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this application. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this application includes metabolites of compounds, including metabolites produced by sufficiently exposing the compound of this application to mammals for a period of time.

[0130] The term "protecting group" or "PG" refers to a substituent that, when reacting with other functional groups, is typically used to block or protect specific functionalities. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect its functionality; suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect its functionality. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphine)ethyl, nitroethyl, etc. For a general description of protecting groups, please refer to: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0131] "Pharmaceutical composition" means a salt of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug, mixed with other chemical components, such as physiologically / pharmaceutical acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0132] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0133] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0134] On the other hand, the compounds described in this invention include isotopically enriched compounds as defined in this invention, for example, compounds containing radioactive isotopes, such as... 3 H, 14 C and 18 Those compounds of F, or those containing non-radioactive isotopes, such as 2 H and 13 C. Compounds enriched by this type of isotope can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) which includes the determination of drug or substrate tissue distribution, may be used in the patient's radiotherapy. 18F-enriched compounds are particularly desirable for PET or SPECT studies. The isotope-enriched compounds can be prepared using conventional techniques familiar to those skilled in the art, or by replacing the previously used unlabeled reagent with a suitable isotope-labeled reagent, as described in the examples and preparation procedures of this invention.

[0135] In addition, heavier isotopes, especially deuterium (i.e., 2 Substitution with H or D can provide certain therapeutic advantages resulting from increased metabolic stability. For example, this may lead to an increased half-life in vivo, a reduced dose requirement, or an improved therapeutic index. It should be understood that deuterium in this invention is considered a substituent of the compound. The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotope enrichment factor. As used in this invention, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of the specified isotope and its native abundance. If the substituent of the compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) with respect to each designated deuterium atom. The pharmaceutically usable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D2O, acetone-d6, DMSO-d6.

[0136] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "optionally," whether or not it precedes the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula is substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents mentioned therein can be, but are not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)2-, hydroxy-substituted alkyl-S (=O), hydroxy-substituted alkyl-S (=O)2, carboxyalkoxy, etc.

[0137] As used in this invention, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Examples of alkyl groups include, but are not limited to, methyl (Me,-CH3), ethyl (Et,-CH2CH3), n-propyl (n-Pr,-CH2CH2CH3), isopropyl (i-Pr,-CH(CH3)2), n-butyl (n-Bu,-CH2CH2CH2CH3), isobutyl (i-Bu,-CH2CH(CH3)2), sec-butyl (s-Bu,-CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3) ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alkane" are used herein to refer to both straight-chain and branched saturated carbon chains. The term "alkane" is used herein to refer to a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight-chain or branched saturated hydrocarbon; examples of such groups include, but are not limited to, methylene, methine, methinepropyl, etc.

[0138] The term "alkoxy" as used in this invention refers to an alkyl group, as defined herein, that is attached to the main carbon chain by an oxygen atom. Examples of such alkyl groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. Furthermore, the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, etc.

[0139] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp2 double bond, wherein the alkenyl group may be independently and optionally substituted by one or more substituents described in this invention, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0140] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group with 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described in this invention, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), etc.

[0141] The term "cycloalkyl" or "carbocyclic" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring that does not contain heteroatoms, including monocyclic rings of 3-12 carbon atoms or bicyclic rings of 7-12 carbon atoms. Bicyclic carbocyclic rings with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic carbocyclic rings with 9 or 10 atoms can be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of cyclic aliphatic groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Furthermore, the "cyclic aliphatic group" or "carbocyclic", "carbocyclic group", and "cycloalkyl" may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0142] The terms “heterocyclic,” “heterocyclic group,” “heterocyclic alicyclic group,” or “heterocyclic” are used interchangeably herein to refer to monocyclic, bicyclic, or tricyclic systems in which one or more carbon atoms on the ring are independently and optionally substituted with heteroatoms, which have the meaning as described herein. The ring may be fully saturated or contain one or more unsaturations, but is by no means aromatic, and has only one connection point to another molecule. One or more hydrogen atoms on the ring are independently and optionally substituted with one or more substituents described herein. Some of these embodiments are that the "heterocycle", "heterocyclic group", "heterocyclic alicyclic group" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to obtain a group such as SO, SO2, PO, PO2, and when the ring is a three membered ring, there is only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to obtain a group such as SO, SO2, PO, PO2).

[0143] Heterocyclic groups can be carbonyl or heteroatomyl. "Heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolyl, oxazolyl, piperazine, homopiperazine, aziridine, oxacyclobutyl, thiohexacyclobutyl, piperidinyl, homopiperidinyl, glycidyl, aziridineheptyl, oxacycloheptyl, thiohexacycloheptyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxacyclobutyl... 2-diaza Base, sulfur nitrogen 1-pyrrololin-1-yl, 2-pyrrololin-3-pyrrololin-1-yl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)acetone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)acetone-4-yl, 5,6-dihydro-4 H-1,2,4-oxadiazine-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl) acetone-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazol[4,3-c]pyridin-5-yl, 3H-indolyl-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl, quinazinyl and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholino, and those in which two carbon atoms on the ring are replaced by oxygen atoms, such as pyrimidinide groups. Furthermore, the heterocyclic group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, oxo(=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0144] The term "aryl" or "aromatic ring" can be used alone or as a part of "aralkyl," "ararylalkoxy," or "aryloxyalkyl," referring to monocyclic, bicyclic, and tricyclic carbocyclic systems containing a total of 6-14 membered rings, wherein at least one ring system is aromatic, and each ring system contains 3-7 membered rings with only one attachment point connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," as aromatic rings can include phenyl, naphthyl, and anthracene. Furthermore, the aryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0145] The term "heteroaryl" or "heteroaromatic ring" refers to monocyclic, bicyclic, and tricyclic systems containing 5-14 membered rings, wherein at least one ring system is aromatic and contains one or more heteroatoms, wherein the heteroatoms have the meaning as described in this invention, wherein each ring system contains 3-7 membered rings and has only one attachment site connected to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "aromatic heterocyclic" or "heteroaromatic compound". Furthermore, the heteroaryl group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, etc.

[0146] Other embodiments include, but are not limited to, the following monocyclic compounds: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl) ), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes the following bis Cyclic, but not limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), benzo[d]thiazolyl-2-yl, imidazo[1,5-a]pyridin-6-yl.

[0147] The term “heteroatom” refers to one or more O, S, N, P, and Si atoms, including N, S, and P in any oxidation state; primary, secondary, tertiary amines, and quaternary ammonium salts; or in the form where the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrole), NH (e.g., NH in pyrroleyl), or NR (e.g., NR in N-substituted pyrroleyl).

[0148] The term "halogen" refers to F, Cl, Br, or I.

[0149] In this invention, "halogenated" means replacing the following group with a halogen, and the number of substitutions can be one or more.

[0150] In this invention, "hydroxyl-substituted" means that the group following it is replaced by a hydroxyl group, and the number of substitutions can be one or more.

[0151] When the term "substituted" is used between two groups in this invention, it is preceded by a substituent, such as "aryl-substituted alkyl" indicating that the alkyl group has an aryl substituent, and "alkoxycarbonyl-substituted alkyl" indicating that the alkyl group has an alkoxycarbonyl substituent.

[0152] When multiple groups of the present invention are used in combination, from left to right, they are in a substitution relationship, such as "arylalkyl", which means aryl-substituted alkyl, and "alkoxyalkyl", which means alkoxy-substituted alkyl.

[0153] The term "unsaturated" as used in this invention means that a structural portion contains one or more degrees of unsaturation.

[0154] Description of the compounds of the present invention

[0155] In a first aspect, the present invention provides a compound having a structure as shown in Formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having a structure as shown in Formula (I).

[0156] Where Z is CR 1 Or N; R 1 It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, or cycloalkyl;

[0157] X is CR 5 Or N;

[0158] A is a 5-6 membered heterocyclic ring;

[0159] B is a 5-6 member heterocyclic aromatic ring;

[0160] R 2 It can be H, deuterium, hydroxyl, halogen, amino, cyano, alkyl, alkoxy, or cycloalkyl;

[0161] R 3 For optional use by R 7 The substituted aryl, heteroaryl, heterocyclic or cycloalkyl groups;

[0162] R 5 It is an alkoxy group, a haloalkoxy group, a haloalkenoxy group, an alkylthio group, a haloalkoxy group, a haloalkenthio group, a Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached thereto, they form independently optional R 6 Substituted 5-6 membered carbon rings or 5-6 membered heterocycles;

[0163] R 6 It can be H, halogen, alkyl, alkenyl, or cycloalkyl;

[0164] R 4 For optional use by R 8 The substituted alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups;

[0165] R 7and R 8 Each can be independently hydrogen, deuterium, cyano, hydroxyl, alkyl, alkoxy, alkylthio, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0166] In some embodiments, wherein the compound,

[0167] R 2 H, deuterium, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0168] R 3 For optional use by R 7 The C that was replaced 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl;

[0169] R 4 For optional use by R 8 The C that was replaced 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl C 1-6 alkyl;

[0170] R 7 and R 8 Each is independently hydrogen, deuterium, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0171] In some embodiments, wherein the compound,

[0172] R 2 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, C 1-4 alkoxy or cyclopropyl;

[0173] R 3 For optional use by R 7The substituted cyclopropane, cyclobutane, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, cyclohexane, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazine, cycloheptane, acrylonitrile, or oxoheptane;

[0174] R 4 For optional use by R 8 The C that was replaced 6-10 Aryl C 1-3 Alkyl or C 1-9 heteroaryl C 1-3 alkyl;

[0175] R 7 and R 8 Each is independently hydrogen, deuterium, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl.

[0176] In some embodiments, wherein the compound,

[0177] A is a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a tetrahydropyrrole ring, a tetrahydrothiophene ring, or a piperazine ring;

[0178] B can be a furan ring, imidazole ring, pyrrole ring, thiophene ring, indole ring, carbazole ring, thiazole ring, thiadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring.

[0179] In some embodiments, the compound has a structure as shown in Formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in Formula (II).

[0180] Among them, R 1 X is defined in equation (I).

[0181] In some embodiments, wherein the compound,

[0182] R 1 H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl or C 3-8 cycloalkyl;

[0183] X is CR 5 Or N;

[0184] R5 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 2- 6-Halogenated thiols, Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached thereto, they form independently optional R 6 Substituted 5-6 membered carbon rings or 5-6 membered heterocycles;

[0185] R 6 H, halogen, C 1-6 Alkyl, C 2-6 alkenyl or C 3-8 Cycloalkyl.

[0186] In some other embodiments, wherein the compound,

[0187] R 1 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Heteroalkyl or cyclopropyl;

[0188] R 5 C substituted with fluorine 1-3 alkoxy, fluorine-substituted C 1-3 alkylthio, fluorine-substituted C 2-4 Alkenyloxy, fluorine-substituted C 2-4 Benzyl thioyl, Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached thereto, they form independently optional R 6 Substituted 5-6 membered carbon rings or 5-6 membered heterocycles;

[0189] R 6 H, F, Cl or C 1-3 alkyl.

[0190] In some embodiments, wherein R in the compound is... 5 For SF5, Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached to it, they form the following structure

[0191] In some embodiments, the compound has the following structures, or its stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0192] In a second aspect, the present invention provides a compound having a structure as shown in formula (I'), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having a structure as shown in formula (I').

[0193] Among them, R 1a It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, or cycloalkyl;

[0194] Y is CR 5a Or N;

[0195] B' is a 5-6 member heterocyclic aromatic ring;

[0196] R 2a It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, alkoxy, or cycloalkyl;

[0197] R 3a To be independently and arbitrarily R 7a The substituted cycloalkyl, aryl, heteroaryl, heterocyclic or cycloalkyl groups;

[0198] R 5a It is a haloalkyl, alkoxy, haloalkoxy, haloalkenoxy, alkylthio, haloalkylthio or Me2P(=O)-;

[0199] R 4a It is cyano, R 8a R 10a NC (=O), R 8a OC (=O), alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylheteroaryl, alkylheteroarylalkyl;

[0200] Q is a 7-8 fused heterocycle, 7-8 spirocyclic heterocycle, 7-8 bridged heterocycle, or -CH2-NH(CR) selected from deuterium, hydroxyl, halogen, amino, alkyl, aryl, heteroaryl, and cycloalkyl, optionally substituted by 1, 2, 3, or 4 alkyl groups. 6a R 9a ) n’ NH- or -CH2-NR 11a (CR 6a R 9a ) n’ CH2-;

[0201] n' is 1, 2 or 3;

[0202] R 6a R 7a R 8a R 9a R 10a and R 11a Each can be independently hydrogen, deuterium, cyano, hydroxyl, alkyl, alkoxy, alkylthio, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0203] Or R 6a R 7a Together with the carbon atom it is attached to, they form C=O or C=S.

[0204] In some embodiments, wherein R in the compound is... 2a H, deuterium, hydroxyl, halogen, cyano, amino, C 1- 6-alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0205] R 3a To be independently and arbitrarily R 7a The C that was replaced 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3- 8-cycloalkyl;

[0206] R 5a C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio group or Me2P(=O)-;

[0207] R 7a It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0208] In some embodiments, wherein R in the compound is... 2a H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, C 1-4alkoxy or cyclopropyl;

[0209] R 3a To be independently and arbitrarily R 7a The substituted cyclopropane, cyclobutane, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, cyclohexane, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazine, cycloheptane, acrylonitrile, or oxoheptane;

[0210] R 5a C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy group; preferably -CF3, -OMe or -OCF3;

[0211] R 7a It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl.

[0212] In some embodiments, B' in the compound is a furan ring, an imidazole ring, a pyrrole ring, a thiophene ring, an indole ring, a carbazole ring, a thiazole ring, a thiadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring.

[0213] In some embodiments, the compound has a structure as shown in formula (II'), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formula (II').

[0214] Q is independently and optionally composed of 1, 2, 3, or 4 elements selected from deuterium, hydroxyl, F, Cl, Br, amino, C. 1-6 Alkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl-substituted 7-8 fused heterocycles, 7-8 spiroheterocycles, 7-8 bridged heterocycles, or -NH(CR) 6a R 9a ) n’ NH- or -NR 11a (CR 6a R 9a ) n’ CH2-;

[0215] n' is 1, 2 or 3;

[0216] R 4a It is cyano, R 8a R10a NC (=O), R 8a OC (=O), C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 6- 10 Aryl, C 1-9 heteroaryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl C 1-6 Alkyl, C 1-6 Alkyl C 1-9 heteroaryl, C 1-6 Alkyl C 1-9 heteroaryl C 1-6 alkyl;

[0217] R 6a R 7a R 8a R 9a R 10a and R 11a Each is independently hydrogen, deuterium, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatics;

[0218] Or R 6a R 7a Together with the carbon atom it is attached to, they form C=O or C=S.

[0219] In some embodiments, wherein the compound,

[0220] Q is

[0221] In some embodiments, wherein R in the compound is... 4a It is cyano, H2NC(=O)-, R 8a OC (=O), C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Cyanoalkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-3 Alkyl, C 1-3 Alkyl C 1-9 heteroaryl, C 1-3 Alkyl C1-9 heteroaryl C 1-3 Alkyl; preferably cyano, H2NC(=O)-, R 8a OC (=O) R 8a It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Hydroxyalkyl or cyclopropyl.

[0222] Thirdly, the present invention provides a compound having the following structures, or its stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0223] Fourthly, the present invention provides a compound having the structure shown in formula (I”), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure shown in formula (I”).

[0224] Among them, R 1b It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, or cycloalkyl;

[0225] E is CR 5b Or N;

[0226] "B" is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring;

[0227] R 2b It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, alkoxy, or cycloalkyl;

[0228] R 3b To be independently and optionally controlled by 1, 2 or 3 R 7b The substituted aryl, heteroaryl, heterocyclic or cycloalkyl groups;

[0229] L is -C(=O)NR 6b -、-NR 6b C(=O)-、-NR 6b C(=O)NR 8b -、-NR 6b C(=O)NR 8b CR 9b R 10b -or-

[0230] NR 6b S(=O)2-;

[0231] R 5bIt can be hydrogen, halogen, hydroxyl, cyano, haloalkyl, alkoxy, haloalkoxy, haloalkenoxy, alkylthio, haloalkylthio, or Me2P(=O)-;

[0232] R 4b It is cyano, R 6b R 8b NC(=O)-、R 8b OC(=O)-, alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylheteroaryl or alkylheteroarylalkyl;

[0233] R 6b and R 8b Each can be independently hydrogen, deuterium, alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0234] R 7b Hydrogen, deuterium, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, Cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0235] R 9b and R 10b Each can be independently hydrogen, deuterium, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0236] In some embodiments, wherein R in the compound is... 1b H, deuterium, hydroxyl, halogen, cyano, amino, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl or C 3-8 cycloalkyl;

[0237] R 2b H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0238] R 5b It consists of hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio or Me2P(=O)-.

[0239] In some embodiments, wherein R in the compound is... 2bH, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, C 1-4 alkoxy or cyclopropyl;

[0240] R 5b It consists of hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Haloalkylthio group; preferably -CF3, -OMe, -OCF3 or -SCF3.

[0241] In some embodiments, the compound has a structure as shown in formula (II”), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formula (II”).

[0242] Among them, B”, L, R 3b R 5b Same as the definition in formula (I”).

[0243] In some embodiments, in the compound, B” is a furan ring, an imidazole ring, a pyrrole ring, a thiophene ring, an indole ring, a carbazole ring, a thiazole ring, a thiadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring;

[0244] L is -C(=O)NR 6b -、-NR 6b C(=O)-、-NR 6b C(=O)NR 8b -、-NR 6b C(=O)NR 8b CR 9b R 10b -or-

[0245] NR 6b S(=O)2-;

[0246] R 5b It consists of hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Haloalkylthio group; preferably -CF3, -OMe, -OCF3 or -SCF3;

[0247] R 6b and R 8b Each is independently hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6- 10 Aryl or C 1-9 Mixed aromatics;

[0248] R 9b and R 10b Each of these can be independently represented by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0249] In some embodiments, wherein R in the compound is... 3b To be independently and optionally controlled by 1, 2 or 3 R 7b The C that was replaced 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl;

[0250] R 7b It can be hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0251] In some embodiments, wherein R in the compound is... 3b To be independently and optionally controlled by 1, 2 or 3 R 7b The substituted furanyl, pyrrolyl, thiophene, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, phenyl, pyridinyl, 2H-pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyclopropane, cyclobutane, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophene, cyclohexane, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, cycloheptane, acrylonitrile, oxeheptane, benzofuranyl, benzothiophene, indolyl, inazolyl, benzisoxazolyl, 3H-indolyl, 1H-indolyl, or benzoxazolyl;

[0252] R 7b For hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-3 Alkyl, C1-3 Alkoxy, C 1-3 Alkylthio, C 1- 3-hydroxyalkyl, Or C 3-6 Cycloalkyl.

[0253] In some embodiments, the compound has one of the following structures, or is a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug.

[0254] Fifthly, the present invention also provides a pharmaceutical composition comprising the above-mentioned compound and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

[0255] In a sixth aspect, the present invention provides the use of the compounds or pharmaceutical compositions of the present invention in the preparation of medicaments for the prevention and / or treatment of diseases associated with or caused, mediated and / or proliferated by SRPK1 inhibitors.

[0256] In some implementations, the diseases mentioned are selected from: hyperproliferative disorders, cancer, metastases, tumors, angiogenesis disorders, tumor angiogenesis, benign hyperplasia, hemangioma, glioma, melanoma, Kaposi's sarcoma, prostate diseases related to angiogenesis or angiogenesis, inflammation, pancreatitis, retinopathy, retinopathy of prematurity, diabetic retinopathy, diabetes, pain, restenosis, psoriasis, eczema, scleroderma, and age-related macular degeneration.

[0257] In a seventh aspect, the present invention provides a method for preventing and / or treating diseases associated with or caused, mediated, and / or proliferated by SRPK1 inhibitors, comprising administering to a patient an effective amount of the compound or the pharmaceutical composition thereof.

[0258] Compositions, formulations and administration of the compounds of the present invention

[0259] The pharmaceutical composition comprises any of the compounds of the present invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

[0260] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0261] When applicable for treatment, a therapeutically effective amount of the compound of the present invention may be administered as an unprocessed chemical drug or as an active ingredient in a pharmaceutical composition. Therefore, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of the compound of the present invention and one or more pharmaceutically acceptable carriers, diluents, or excipients. The term "therapeuticly effective amount" as used herein refers to the total amount of each active component sufficient to demonstrate a meaningful patient benefit (e.g., reduction of viral load). When administered alone using a single active ingredient, the term refers only to that component. When used in combination, the term refers to the combined amount of active ingredients that, regardless of combination, sequential or simultaneous administration, produce a therapeutic effect. The carrier, diluent, or excipient must be acceptable in the sense of compatibility with other components of the formulation and harmlessness to the recipient. According to another aspect of the present invention, a method for preparing a pharmaceutical formulation is also provided, comprising mixing the compound of the present invention with one or more pharmaceutically acceptable carriers, diluents, or excipients. As used in this invention, the term "pharmaceutically acceptable" means that the compounds, raw materials, compositions, and / or dosage forms of this invention are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, within the limits of reasonable medical judgment.

[0262] It should be understood that, in addition to the ingredients specifically mentioned above, the formulation may also include other ingredients commonly used in the art in relation to the type of formulation, such as flavoring agents, for example, such formulations suitable for oral administration may include flavoring agents.

[0263] Uses of the compounds and compositions of the present invention

[0264] This invention provides the use of the compound or pharmaceutical composition described herein in the preparation of a medicament for the prevention and / or treatment of diseases associated with or caused by, mediated by, and / or proliferated by SRPK1 inhibitors.

[0265] The diseases described in this invention include, but are not limited to, one or more of the following: hyperproliferative disorders, cancer, metastatic tumors, tumors, angiogenesis disorders, tumor angiogenesis, benign hyperplasia, hemangioma, glioma, melanoma, Kaposi's sarcoma, prostate diseases related to angiogenesis or angiogenesis, inflammation, pancreatitis, retinopathy, retinopathy of prematurity, diabetic retinopathy, diabetes, pain, restenosis, psoriasis, eczema, scleroderma, and age-related macular degeneration.

[0266] The “effective amount” or “effective dose” of the compounds or pharmaceutically acceptable compositions of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the compounds and compositions thereof can be administered at any dosage and via any route of administration to effectively treat or reduce the severity of the disease. The precise amount required will vary depending on the patient’s condition, which may depend on race, age, the patient’s general condition, the severity of the infection, specific factors, the route of administration, etc. The compounds or compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed in the present invention.

[0267] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0268] General Synthesis Process

[0269] Generally, the compounds of the present invention can be prepared by the methods described herein. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0270] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0271] The examples described below, unless otherwise stated, all temperatures are in Celsius. Reagents were purchased from commodity suppliers such as Energie, Shaoyuan, Merrill, Bide, Aladdin, Icon, Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0272] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0273] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0274] The chromatographic column used is a silica gel column. Nuclear magnetic resonance spectroscopy uses CDCl3, d6-DMSO, CD3OD, or d6-acetone as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets are observed, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant is expressed in Hertz (Hz).

[0275] Example

[0276] Example 1: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((1,1,2,2-tetrafluoroethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 1)

[0277] Step 1: Methyl 5-(3,6-dihydro-2H-pyran-4-yl)furan-2-carboxylate (1b)

[0278] In a 500 mL round-bottom flask, compound 1a (20.10 g, 100 mmol) was dissolved in 1,4-dioxane / water (v / v = 5 / 1, 300 mL), followed by the addition of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (23.10 g, 110 mmol), cesium carbonate (48.81 g, 150 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (3.0 mmol, 2.45 g). The reaction was carried out at 95 °C for 8 h. Remove the solvent, add 20% ethyl acetate / petroleum ether and continue stirring for 1 hour. Filter using a silica gel-lined sintered funnel. Wash the filter cake with 20% ethyl acetate / petroleum ether, evaporate the solvent, add 5% ethyl acetate / petroleum ether and continue stirring for 1 hour. Filter again, and dry the filter cake to give a white solid compound 1b (15.70 g, 75% yield). LCMS: 209.1 [M+H] + .

[0279] Step 2: Methyl 5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxylate (1c)

[0280] In a 250 mL round-bottom flask, compound 1b (18.04 g, 86.5 mmol) was dissolved in ethyl acetate (200 mL), and Pd / C (900 mg, 5%) was added. The reaction was carried out at room temperature for 1.5 h under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth-lined funnel, the filter cake was washed with ethyl acetate, concentrated, and purified by silica gel column chromatography to give compound 1c, a colorless oil (16.00 g, 89% yield). LCMS: 211.1 [M+H] + .

[0281] Step 3: tert-butyl 4-(4-bromo-2-nitrophenyl)piperazine-1-carboxylic acid ester (1e)

[0282] In a 500 mL round-bottom flask, N-tert-butyloxycarbonylpiperazine (12.02 g, 63.44 mmol), compound 1d (10.00 g, 42.29 mmol), potassium carbonate (11.70 g, 84.58 mmol), and acetonitrile (100 mL) were added sequentially, and the mixture was heated to 90 °C and reacted for 4 h. After cooling to room temperature, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 1e as a yellow solid (9.52 g, 58% yield). LCMS: 386.1 [M+H] + .

[0283] Step 4: tert-butyl 4-(4-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-2-nitrophenyl)piperazine-1-carboxylate (1f)

[0284] Under nitrogen protection, in a 250 mL round-bottom flask, compound 1e (9.52 g, 24.66 mmol), 2-ethylhexyl 3-mercaptopropionate (8.10 g, 36.99 mmol), tris(dibenzylacetone)dipalladium (2.30 g, 2.47 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (2.90 g, 4.93 mmol), potassium carbonate (10.20 g, 73.98 mmol), and 1,4-dioxane (100 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 12 h. After cooling to room temperature, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 1f (12.00 g, yield: 93%), a yellow oily solid. LCMS: 524.3 [M+H] + .

[0285] Step 5: tert-butyl 4-(4-mercapto-2-nitrophenyl)piperazine-1-carboxylate (1g)

[0286] In a 250 mL round-bottom flask, compound 1f (12.00 g, 22.94 mmol) was dissolved in anhydrous tetrahydrofuran (120 mL). Sodium ethoxide (3.20 g, 45.89 mmol) was added under ice bath conditions, and the reaction was slowly allowed to return to room temperature for 2 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give 1 g (7.20 g, yield: 92%) of a yellow solid. LCMS: 340.1 [M+H] + .

[0287] Step 6: Tert-butyl 4-(4-((2-bromo-1,1,2,2-tetrafluoroethyl)thio)-2-nitrophenyl)piperazine-1-carboxylic acid ester (1h)

[0288] In a 250 mL round-bottom flask, 1 g (5.00 g, 14.75 mmol) of the compound was dissolved in 50 mL of anhydrous N,N-dimethylformamide. The mixture was cooled to -50 °C in a dry ice bath, and sodium hydroxide (885 mg, 22.13 mmol) was added. After reacting at this temperature for 30 min, 1,2-dibromotetrafluoroethane (4.60 g, 17.70 mmol) was slowly added dropwise, and the reaction was allowed to return to room temperature for 3 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give the compound 1 h as a yellow oily solid (6.60 g, yield: 87%). LCMS: 518.0 [M+H] + .

[0289] Step 7: Tert-butyl 4-(2-nitro-4-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperazine-1-carboxylate (1j)

[0290] In a 100 mL round-bottom flask, compound 1h (2.00 g, 3.86 mmol) and lithium chloride (491 mg, 11.58 mmol) were dissolved in N,N-dimethylformamide. Sodium borohydride (438 mg, 11.58 mmol) was slowly added with stirring, and the reaction was carried out at room temperature for 4 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 1j as a yellow solid (1.20 g, yield: 71%). LCMS: 440.1 [M+H] + .

[0291] Step 8: tert-butyl 4-(2-amino-4-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperazine-1-carboxylate (1k)

[0292] In a 100 mL round-bottom flask, compound 1j (1.10 g, 2.51 mmol), ammonium chloride (1.35 g, 25.10 mmol), and zinc powder (815 mg, 12.55 mmol) were dissolved in 20 mL of methanol and refluxed for 4 h. The mixture was filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 1k as a white solid (458 mg, yield: 47%). LCMS: 410.1 [M+H] + .

[0293] Step 9: Tert-butyl 4-(4-((1,1,2,2-tetrafluoroethyl)thio)-2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)phenyl)piperazine-1-carboxylate (1m)

[0294] In a 100 mL reaction tube, potassium tert-butoxide (165 mg, 1.47 mmol) was dissolved in tetrahydrofuran (10 mL). A mixed solution of compound 1k (200 mg, 0.49 mmol) and compound 1c (144 mg, 0.68 mmol) in tetrahydrofuran was added, and the reaction was carried out at room temperature for 4 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 1m as a white solid (206 mg, yield: 71%). LCMS: 588.2 [M+H] + Step 10: N-(2-(piperazin-1-yl)-5-((1,1,2,2-tetrafluoroethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (1n)

[0295] In a 250 mL round-bottom flask, compound 1m (206 mg, 0.35 mmol) was dissolved in 10 mL of dichloromethane. Dioxane hydrochloride (3 mL, 4 M) was added dropwise under ice bath conditions, and the mixture was slowly heated to room temperature for 4 h. The organic solvent was removed under reduced pressure to give compound 1n, a white solid (147 mg, yield: 86%), which could be used directly in the next step without purification. LCMS: 488.2 [M+H] + Step 11: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((1,1,2,2-tetrafluoroethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 1)

[0296] In a 100 mL round-bottom flask, compound 1n (147 mg, 0.30 mmol) and 3-aldehyde-1-methylpyrazole (67 mg, 0.60 mmol) were dissolved in methanol (5 mL) and reacted at room temperature for 2 h. Sodium cyanoborohydride (77 mg, 1.21 mmol) was added and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 1 (110 mg, yield: 57%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.42(s,1H),8.58(s,1H),8.15(s,1H),7.62(d,1H),7.40(s,2H),7.24(d,1H),6.47(d,1H),6.15(d,1H),3.99(d,2H) ,3.79(s,3H),3.53(t,2H),3.47(s,2H),3.09(t,1H),2.91(s,4H),2.64(s,3H),1.99(d,2H),1.78(m,2H),1.24(s,1H)ppm; LCMS: 582.2[M+H] + .

[0297] Example 2: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 2)

[0298] Step 1: tert-butyl 4-(2-amino-4-bromophenyl)piperazine-1-carboxylate (2a)

[0299] In a 250 mL round-bottom flask, compound 1e (8.60 g, 22.28 mmol), ammonium chloride (12.00 g, 222.80 mmol), and zinc powder (7.24 g, 111.40 mmol) were dissolved in 100 mL of methanol, and the mixture was refluxed for 8 h. After cooling to room temperature, the mixture was filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 2a as a white solid (3.30 g, yield: 26%). LCMS: 356.1 [M+H] + .

[0300] Step 2: tert-butyl 4-(4-bromo-2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)phenyl)piperazine-1-carboxylate (2b)

[0301] In a 125 mL reaction tube, potassium tert-butoxide (3.10 g, 27.63 mmol) was dissolved in tetrahydrofuran (30 mL), and a mixed solution of compound 2a (3.30 g, 9.20 mmol) and compound 1c (2.70 g, 12.89 mmol) in tetrahydrofuran was added. The reaction was carried out at room temperature for 4 h. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 2b as a white solid (3.30 g, yield: 65%). LCMS: 534.2 [M+H] + .

[0302] Step 3: tert-butyl 4-(4-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)phenyl)piperazine-1-carboxylate (2c)

[0303] Under nitrogen protection, in a 100 mL round-bottom flask, compound 2b (3.30 g, 6.18 mmol), 2-ethylhexyl 3-mercaptopropionate (1.95 g, 8.95 mmol), tris(dibenzylacetone)dipalladium (547 mg, 0.60 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (691 mg, 1.19 mmol), potassium carbonate (2.50 g, 17.91 mmol), and 1,4-dioxane (40 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 12 h. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 2c, a white oily solid (3.60 g, yield: 90%). LCMS: 672.4 [M+H] + .

[0304] Step 4: tert-butyl 4-(4-mercapto-2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)phenyl)piperazine-1-carboxylate (2d)

[0305] In a 100 mL round-bottom flask, compound 2c (3.60 g, 5.37 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL). Sodium ethoxide (730 mg, 10.73 mmol) was added under ice bath conditions, and the reaction was slowly allowed to return to room temperature for 2 h. The mixture was then quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 2d as a white solid (610 mg, yield: 23%). LCMS: 488.2 [M+H] + .

[0306] Step 5: tert-butyl 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-((trifluoromethyl)thio)phenyl)piperazine-1-carboxylate (2e)

[0307] In a 100 mL round-bottom flask, compound 2d (100 mg, 0.21 mmol), triethylamine (63 mg, 0.16 mmol), (2,2'-dipyridine)trifluoromethyl thiocopper (179 mg, 0.41 mmol), and N,N-dimethylformamide (5 mL) were added sequentially. The reaction was carried out under nitrogen protection at 40 °C for 6 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 2e as a white solid (66 mg, yield: 57%). LCMS: 556.2 [M+H] + .

[0308] Step 6: N-(2-(piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (2f)

[0309] In a 50 mL round-bottom flask, compound 2e (66 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL). Dioxane hydrochloride (1 mL, 4 M) was added dropwise under ice bath conditions, and the mixture was slowly heated to room temperature for 4 h. The organic solvent was removed under reduced pressure to give compound 2f, a white solid, which could be used directly in the next step without purification. LCMS: 456.1 [M+H] + .

[0310] Step 7: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 2)

[0311] In a 50 mL round-bottom flask, compound 2f (54 mg, 0.12 mmol) and 3-formaldehyde-1-methylpyrazole (27 mg, 0.24 mmol) were dissolved in methanol (5 mL) and reacted at room temperature for 2 h. Sodium cyanoborohydride (30 mg, 0.48 mmol) was added, and the reaction was continued at room temperature for 12 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 2 as a white solid (38 mg, yield: 58%). 1 H NMR(500MHz,DMSO-d6)δ9.40(s,1H),8.61(s,1H),7.62(s,1H),7.43(dd,2H),7.24(s,1H),6.46(s,1H),6.17(s,1H),3.99(d,2H) ,3.80(s,3H),3.52(t,4H),3.09(t,1H),2.93(s,4H),2.67(s,3H),1.99(d,2H),1.77(dd,2H),1.24(s,1H)ppm; LCMS:550.2[M+H] + .

[0312] Example 3: N-(5-(difluoromethoxy)-2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 3)

[0313] Step 1: 5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxylic acid (3a)

[0314] In a 250 mL round-bottom flask, compound 1c (5.00 g, 23.8 mmol) was dissolved in methanol / water (50 mL), and lithium hydroxide (1.12 g, 47.60 mmol) was added. The reaction was carried out at room temperature for 4 h. Methanol was removed by rotary evaporation, and the mixture was acidified with 2 M hydrochloric acid, precipitating a white solid. The solid was filtered, the filter cake was washed with water, and dried to give compound 3a, a white solid (3.90 g, 85% yield). LCMS: 195.1 [MH] ― .

[0315] Step 2: 4-(4-methoxy-2-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (3c)

[0316] At room temperature, compound 3b (5.00 g, 29.22 mmol), N,N-dimethylformamide (60 mL), potassium carbonate (12.11 g, 87.65 mmol), and N-tert-butyloxycarbonyl-piperazine (5.44 g, 29.22 mmol) were added to a 250 mL round-bottom flask. The reaction was carried out at 100 °C for 8 h. The mixture was extracted with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 3c as a yellow solid (8.80 g, 89% yield). LCMS: 338.0 [M+H] + .

[0317] Step 3: 3-Nitro-4-(piperazin-1-yl)phenol (3d)

[0318] In a 100 mL three-necked flask, compound 3c (930 mg, 2.76 mmol) was added to dichloromethane (20 mL), and boron tribromide (6 mL, 12.13 mmol) was slowly added dropwise. The reaction mixture was reacted at 25 °C for 12 h. The reaction solution was then slowly added to methanol and water, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 3d, a yellow oil (530 mg, yield 86%). LCMS: 224.0 [M+H] + .

[0319] Step 4: 4-(4-((1-methyl-1H-pyrazole-3-yl)methyl)piperazin-1-yl)-3-nitrophenol (3e)

[0320] In a 250 mL round-bottom flask, compound 3d (3.00 g, 13.44 mmol), 1,2-dichloroethane (120 mL), 3-formaldehyde-1-methylpyrazole (2.22 g, 20.16 mmol), and sodium triacetoxyborohydride (8.50 g, 40.32 mmol) were added. The mixture was reacted under nitrogen protection at 25 °C for 2 h. The mixture was extracted with water and dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3e, a yellow oil (2.65 g, 62% yield). LCMS: 318.1 [M+H] + .

[0321] Step 5: 3-Amino-4-(4-(1-methyl-1H-pyrazole-3-yl)methyl)piperazin-1-yl)phenol (3f)

[0322] In a 50 mL round-bottom flask, compound 3e (130 mg, 0.41 mmol), ethanol (5 mL), and palladium on carbon (100 mg, 10%) were added. The mixture was purged three times with hydrogen gas and reacted at 25 °C for 4 h under hydrogen balloon conditions. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 3f, a colorless oil (100 mg, 85% yield). LCMS: 288.0 [M+H] + .

[0323] Step 6: 5-((tert-butyldimethylsilyl)oxy)-2-(4-((1-methyl-1H-pyrazole-3-yl)methyl)piperazin-1-yl)aniline (3g)

[0324] In a 50 mL round-bottom flask, compound 3f (100 mg, 0.35 mmol), dichloromethane (6 mL), imidazole (213 mg, 3.13 mmol), and tert-butyldimethylchlorosilane (189 mg, 1.25 mmol) were added. The mixture was reacted under nitrogen protection at 25 °C for 8 h. The mixture was extracted with water and dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography to give 3 g of compound as a white solid (120 mg, 86% yield). LCMS: 402.2 [M+H] + .

[0325] Step 7: N-(5-((tert-butyldimethylsilyl)oxy)-2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (3h)

[0326] In a 25 mL round-bottom flask, 3 g (110 mg, 0.27 mmol) of compound 3a, 6 mL of acetonitrile, 54 mg (0.27 mmol) of compound 3a, 45 mg (0.55 mmol) of N-methylimidazole, and 154 mg (0.55 mmol) of N,N,N',N'-tetramethylchloromethanemidane hexafluorophosphate were added. The mixture was reacted under nitrogen protection at 25 °C for 8 h. The mixture was extracted with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography to give compound 3a as a white solid (130 mg, 82% yield). LCMS: 580.2 [M+H] + Step 8: N-(5-hydroxy-2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (3j)

[0327] In a 25 mL round-bottom flask, compound 3h (130 mg, 0.22 mmol), tetrahydrofuran (4 mL), and tetrabutylammonium fluoride solution (2 mL) were added, and the reaction was carried out at 25 °C for 2 h. The mixture was extracted with water and ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 3j (100 mg, yield 96%). LCMS: 466.0 [M+H] + .

[0328] Step 9: N-(5-(difluoromethoxy)-2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 3)

[0329] In a 25 mL round-bottom flask, compound 3j (130 mg, 0.28 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of potassium hydroxide solution (0.8 mL, 25%) and compound 3k (158 mg, 0.70 mmol). The reaction was carried out at 60 °C for 4 h. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain compound 3 as a white solid (62 mg, 43% yield). 1 H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.21–8.16(m,1H),7.63–7.59(m,1H),7.41–7.35(m, 1H),7.23–7.15(m,2H),6.94–6.87(m,1H),6.48–6.44(m,1H),6.17–6.13(m,1H),4.01–3. 96(m,2H),3.79(s,3H),3.56–3.51(m,2H),3.47–3.45(m,2H),3.16–3.00(m,1H),2.89–2. 79(m,6H),2.66–2.59(m,2H),2.01–1.97(m,2H),1.86–1.72(m,2H)ppm; LCMS: 516.1[M+H] + .

[0330] Example 4: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 4)

[0331] Step 1: 4-(4-((tert-Butoxycarbonyl)oxy)-2-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (4a)

[0332] Compound 3d (4.40 g, 19.71 mmol), dichloromethane (80 mL), triethylamine (9.97 g, 98.55 mmol), and di-tert-butyl dicarbonate (4.30 g, 19.71 mmol) were added to a 250 mL round-bottom flask at room temperature and reacted at 25 °C for 4 h. The mixture was extracted with water and dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 4a (8.00 g), which was used directly in the next step. LCMS: 424.1 [M+H] + .

[0333] Step 2: 4-(4-hydroxy-2-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (4b)

[0334] Compound 4a (7.00 g, 16.53 mmol), ethanol (30 mL), water (30 mL), and sodium hydroxide (2.64 g, 66.12 mmol) were added to a 250 mL round-bottom flask at room temperature and reacted at 25 °C for 2 h. The organic phase was removed by concentration under reduced pressure. The pH of the reaction solution was adjusted to 6 by adding 2 M hydrochloric acid, and the mixture was extracted with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 4b, a pale yellow gel (2.71 g, 48% yield in two steps). LCMS: 324.1 [M+H] + .

[0335] Step 3: 4-(4-(bromodifluoromethoxy)-2-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (4c)

[0336] At room temperature, compound 4b (2.00 g, 6.18 mmol) and N,N-dimethylformamide (20 mL) were added to a 25 mL sealed tube. Sodium hydroxide (0.49 g, 12.37 mmol) was added under ice bath conditions, and the reaction was carried out at 0 °C for 30 min. Dibromodifluoromethane (5.19 g, 24.74 mmol) was then added, and the reaction was carried out at 0 °C for 12 h. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 4c as a yellow solid (1.20 g, 43% yield). LCMS: 452.1 [M+H] + .

[0337] Step 4: 1-(2-nitro-4-(trifluoromethoxy)phenyl)piperazine (4d)

[0338] Compound 4c (1.20 g, 2.65 mmol), 1,2-dichloroethane (40 mL), and silver tetrafluoroborate (2.58 g, 13.2 mmol) were added to a 100 mL round-bottom flask at room temperature. The reaction was carried out at 50 °C for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 4d as a pale yellow solid (560 mg, yield 72%). LCMS: 292.1 [M+H] + .

[0339] Step 5: 1-((1-methyl-1H-pyrazol-3-yl)methyl)-4-(2-nitro-4-(trifluoromethoxy)phenyl)piperazine (4e)

[0340] At room temperature, compound 4d (280 mg, 0.96 mmol), 1,2-dichloroethane (15 mL), 3-aldehyde-1-methylpyrazole (159 mg, 144 mmol), and sodium triacetoxyborohydride (608 mg, 2.88 mmol) were added to a 50 mL round-bottom flask. The mixture was reacted at 25 °C for 2 h under nitrogen protection. The mixture was extracted with water and dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 4e, a pale yellow oil (325 mg, 87% yield). LCMS: 386.1 [M+H] + .

[0341] Step 6: 2-(4-((1-methyl-1H-pyrazole-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)aniline (4f)

[0342] At room temperature, compound 4e (240 mg, 0.62 mmol), ethanol (8 mL), and palladium on carbon (100 mg) were added to a 50 mL round-bottom flask. The mixture was purged three times with hydrogen gas and reacted at 55 °C for 3 h under hydrogen balloon conditions. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 4f, a colorless oil (220 mg, 99% yield). LCMS: 356.1 [M+H] + Step 7: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 4)

[0343] At room temperature, potassium tert-butoxide (104 mg, 0.93 mmol) and tetrahydrofuran (4 mL) were added to a 50 mL round-bottom flask. Compound 4f (110 mg, 0.31 mmol) and compound 1c (98 mg, 0.47 mmol) were dissolved in tetrahydrofuran (4 mL) and added to the above system. The reaction was carried out at 25 °C for 3 h. Water and ethyl acetate were added for extraction and separation. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound 4, a white solid (17 mg, yield 10%). 1 H NMR(500MHz, CDCl3)δ9.58(s,1H),8.52–8.41(m,1H),7.32–7.29(m,1H),7 .20–7.14(m,2H),6.96–6.86(m,1H),6.27–6.16(m,2H),4.16–4.08(m,2H), 3.88(s,3H),3.65–3.55(m,4H),3.07–2.99(m,1H),2.98–2.89(m,4H),2.8 8–2.12(m,4H),2.08–2.00(m,2H),1.96–1.85(m,2H)ppm; LCMS: 534.2[M+H] + .

[0344] Example 5: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 5)

[0345] Step 1: N-(5-(2-bromo-1,1,2,2-tetrafluoroethoxy)-2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (5a)

[0346] At room temperature, compound 3j (300 mg, 0.64 mmol) and N,N-dimethylformamide (6 mL) were added to a 25 mL sealed tube. Sodium hydroxide (52 mg, 1.29 mmol) was added under ice bath conditions, and the reaction was carried out at 0 °C for 30 min. Then, 1,2-dibromotetrafluoroethane (837 mg, 3.22 mmol) was added, and the reaction was carried out at 0 °C for 12 h. The reaction was quenched with methanol, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 5a as a white solid (280 mg, 67% yield). LCMS: 643.9 [M+H] + .

[0347] Step 2: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 5)

[0348] Compound 5a (150 mg, 0.23 mmol), dimethyl sulfoxide (3 mL), and cesium fluoride (106 mg, 0.70 mmol) were added to a 25 mL round-bottom flask at room temperature, and the reaction was carried out at 120 °C for 3 h. The reaction solution was filtered through a membrane filter, and the residue was purified by preparative liquid chromatography to give compound 5 as a white solid (32 mg, yield 24%). 1 H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.31–8.25(m,1H),7.64–7.58(m,1H),7.44–7.37(m, 1H),7.25–7.18(m,1H),7.03–6.63(m,2H),6.49–6.43(m,1H),6.18–6.12(m,1H),4.02–3. 95(m,2H),3.78(s,3H),3.56–3.45(m,4H),3.33–3.28(m,2H),3.14–3.04(m,1H),2.89–2. 83(m,4H),2.67–2.59(m,2H),2.03–1.95(m,2H),1.85–1.71(m,2H)ppm; LCMS: 566.2[M+H] + .

[0349] Example 6: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((1,2,2-trifluorovinyl)oxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 6)

[0350] Step 1: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((1,2,2-trifluorovinyl)oxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 6)

[0351] At room temperature, compound 5a (130 mg, 0.20 mmol) and tetrahydrofuran (3 mL) were added to a 25 mL three-necked flask. Ethyl magnesium bromide (0.3 mL, 2 mol / L) was added under ice bath conditions, and the reaction was carried out at 25 °C for 8 h. The reaction was quenched with methanol, filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to give compound 6 as a white solid (15 mg, yield 13%).1 H NMR(500MHz, CDCl3)δ9.67(s,1H),8.44–8.33(m,1H),7.33–7.29(m,1H),7 .20–7.14(m,2H),6.82–6.77(m,1H),6.24–6.20(m,2H),4.16–4.08(m,2H), 3.88(s,3H),3.65–3.55(m,4H),3.07–2.99(m,1H),2.98–2.89(m,4H),2.8 8–2.15(m,4H),2.09–2.01(m,2H),1.97–1.85(m,2H)ppm; LCMS: 546.2[M+H] + .

[0352] Example 7: N-(2,2-difluoro-6-(4-(((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzo[d][1,3]dioxopentane-5-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 7)

[0353] Step 1: N,N-Dibenzyl-6-bromo-2,2-difluorobenzo[d][1,3]dioxolane-5-amine (7b)

[0354] In a 100 mL round-bottom flask, compound 7a (3.00 g, 11.90 mmol) was dissolved in N,N-dimethylformamide. Sodium hydrogen hydride (1.90 g, 47.60 mmol) was added under ice bath conditions. After 30 min, benzyl chloride (3.40 g, 26.19 mmol) was added, and the reaction was carried out at room temperature for 8 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 7b as a colorless oily solid (1.80 g, yield: 35%). 1 H NMR (400MHz, CDCl3) δ7.34(q,9H),7.28(d,2H),6.76(s,1H),4.14(s,4H)ppm; LCMS:432.0[M+H] + .

[0355] Step 2: Tert-butyl 4-(6-(dibenzylamino)-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)piperazine-1-carboxylate (7c)

[0356] Under nitrogen protection, in a 100 mL round-bottom flask, compound 7b (1.80 g, 4.19 mmol), N-tert-butyloxycarbonylpiperazine (1.17 g, 6.28 mmol), tris(dibenzylacetone)dipalladium (384 mg, 0.42 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (485 mg, 0.838 mmol), cesium carbonate (4.10 g, 12.57 mmol), and 1,4-dioxane (20 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 12 h. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 7c, a white oily solid (180 mg, yield: 8%). LCMS: 538.2 [M+H] + .

[0357] Step 3: Tert-butyl 4-(6-amino-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)piperazine-1-carboxylate (7d)

[0358] In a 100 mL round-bottom flask, compound 7c (180 mg, 0.34 mmol) and palladium on carbon (36 mg, 10%) were dissolved in 10 mL of ethanol, and the mixture was heated to 60 °C and reacted for 12 h. After the reaction was complete, the mixture was filtered under reduced pressure, and the filtrate was removed under reduced pressure. Column chromatography was used to purify compound 7d as a white solid (40 mg, yield: 33%). LCMS: 358.2 [M+H] + .

[0359] Step 4: tert-butyl 4-(2,2-difluoro-6-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide)benzo[d][1,3]dioxolane-5-yl)piperazine-1-carboxylate (7e)

[0360] In a 100 mL round-bottom flask, compound 7d (40 mg, 0.11 mmol) and compound 1c (33 mg, 0.16 mmol) were dissolved in dichloromethane (5 mL). Trimethylaluminum (0.17 mL, 2 M) was added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. The solution was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative chromatography under medium pressure to give compound 7e as a white solid (48 mg, yield: 80%). LCMS: 536.2 [M+H] + .

[0361] Step 5: N-(2,2-difluoro-6-(piperazin-1-yl)benzo[d][1,3]dioxolane-5-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (7f)

[0362] In a 50 mL round-bottom flask, compound 7e (48 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL). Dioxane hydrochloride (1 mL, 4 M) was added dropwise under ice bath conditions, and the mixture was slowly heated to room temperature for 4 h. The organic solvent was removed under reduced pressure to give compound 7f, a white solid, which could be used directly in the next step without purification. LCMS: 436.2 [M+H] + .

[0363] Step 6: N-(2,2-difluoro-6-(4-(((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzo[d][1,3]dioxopentane-5-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 7)

[0364] In a 50 mL round-bottom flask, compound 7f (39 mg, 0.09 mmol) and 3-aldehyde-1-methylpyrazole (20 mg, 0.18 mmol) were dissolved in methanol (5 mL) and reacted at room temperature for 2 h. After 2 h, sodium cyanoborohydride (23 mg, 0.36 mmol) was added and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 7 as a white solid (7 mg, yield: 15%). 1 H NMR(500MHz,DMSO-d6)δ9.69(s,1H),8.30(s,1H),7.60(d,2H),7.22(d,1H),6.46(d,1H),6.15(s,1H),4.00(d,2H),3.79(s, 3H),3.53(t,2H),3.47(s,2H),3.09(t,1H),2.85(s,4H),2.64(s,4H),2.00(d,2H),1.86–1.71(m,2H)ppm; LCMS:530.2[M+H] + .

[0365] Example 8: N-(6-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzo[1,3]dioxolane-5-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 8)

[0366] Step 1: tert-butyl 4-(6-nitrobenzo[1,3]dioxolane-5-yl)piperazine-1-carboxylate (8b)

[0367] Compound 8a (500 mg, 2.03 mmol), N-tert-butyloxycarbonyl-piperazine (757 mg, 4.07 mmol), and potassium carbonate (843 mg, 6.10 mmol) were sequentially added to anhydrous N,N-dimethylformamide (10 mL). The mixture was stirred at 100 °C for 8 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 8b (500 mg, yield: 70%). LCMS: 352.2 [M+H] + .

[0368] Step 2: tert-butyl-4-(6-aminobenzo[1,3]dioxolane-5-yl)piperazine-1-carboxylate (8c)

[0369] Compound 8b (100 mg, 0.29 mmol) and palladium on carbon (20 mg, 10%) were dissolved in ethanol (2 mL), purged three times with hydrogen, and stirred at 55 °C for 8 h. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to give compound 8c (80 mg, yield: 87%). LCMS: 322.2 [M+H] + .

[0370] Step 3: Tert-butyl 4-(6-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)benzo[1,3]dioxo-5-yl)piperazine-1-carboxylate (8d)

[0371] Compound 3a (74 mg, 0.37 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (140 mg, 0.50 mmol), and 1-methylimidazole (82 mg, 1.00 mmol) were sequentially added to acetonitrile (6 mL). After the addition was complete, the mixture was stirred at 25 °C for 10 min. Then, compound 8c (80 mg, 0.25 mmol) was added, and the mixture was stirred at 25 °C under nitrogen protection for 8 h. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography to obtain compound 8d (50 mg, yield: 40%). LCMS: 500.5 [M+H] + .

[0372] Step 4: N-(6-(piperazin-1-yl)benzo[1,3]dioxolane-5-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (8e)

[0373] Compound 8d (40 mg, 0.08 mmol) was added to hydrochloric acid / 1,4-dioxane (2 mL, 4 M), and stirred at 25 °C for 8 h. After the reaction was complete, the solution was directly evaporated under reduced pressure to obtain the crude compound 8e (40 mg). LCMS: 400.2 [M+H] + Step 5: N-(6-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzo[1,3]dioxolane-5-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 8)

[0374] Compound 8e (40 mg, 0.10 mmol), 3-aldehyde-1-methylpyrazole (17 mg, 0.15 mmol), and sodium cyanoborohydride (19 mg, 0.30 mmol) were added sequentially to a solution of anhydrous dichloromethane (1 mL). After the addition was complete, the mixture was stirred at 25 °C for 8 h under nitrogen protection. After the reaction was completed, methanol was added to quench the reaction. Then, compound 8 (40 mg, yield: 78%) was obtained by preparative liquid chromatography. 1 H NMR(500MHz, CDCl3)δ9.63(s,1H),8.16(s,1H),7.32(d,1H),7.14(d,1H),6. 80(s,1H),6.23(d,1H),6.21(d,1H),5.95(s,2H),4.18–4.10(m,2H),3.90(s, 3H),3.66–3.61(m,2H),3.59(s,2H),3.09–3.00(m,1H),2.97–2.85(m,4H),2 .85–2.37(m,4H),2.10–2.03(m,2H),1.98–1.86(m,2H)ppm; LCMS: 494.2[M+H] + .

[0375] Example 9: N-(4-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 9)

[0376] Step 1: tert-butyl-4-(3-nitropyridin-4-yl)piperazine-1-carboxylate (9b)

[0377] Compound 9a (500 mg, 3.15 mmol), N-tert-butyloxycarbonyl-piperazine (587 mg, 3.15 mmol), and potassium carbonate (1.31 g, 9.46 mmol) were sequentially added to anhydrous N,N-dimethylformamide (10 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 9b (900 mg, yield: 93%). LCMS: 309.2 [M+H] + .

[0378] Step 2: tert-butyl-4-(3-aminopyridin-4-yl)piperazine-1-carboxylate (9c)

[0379] Compound 9b (300 mg, 0.97 mmol) and palladium on carbon (100 mg, 10%) were dissolved in ethanol (10 mL), purged three times with hydrogen, and stirred at 55 °C for 8 h. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to give compound 9c (250 mg, yield: 92%). LCMS: 279.2 [M+H] + .

[0380] Step 3: Tert-butyl 4-(3-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (9d)

[0381] A tetrahydrofuran (3 mL) solution of compound 9c (250 mg, 0.90 mmol) and compound 1c (283 mg, 1.35 mmol) was added to a tetrahydrofuran (3 mL) solution of potassium tert-butoxide (303 mg, 2.69 mmol). The mixture was stirred at 25 °C under nitrogen protection for 8 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give compound 9d (300 mg, yield: 73%). LCMS: 457.2 [M+H] + .

[0382] Step 4: N-(4-(piperazin-1-yl)pyridin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (9e)

[0383] Compound 9d (100 mg, 0.22 mmol) was added to hydrochloric acid / 1,4-dioxane (4 mL, 4 M), and stirred at 25 °C for 8 h. After the reaction was complete, the solution was directly evaporated under reduced pressure to obtain crude compound 9e (80 mg). LCMS: 357.2 [M+H] +Step 5: N-(4-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 9)

[0384] Compound 9e (80 mg, 0.22 mmol), 3-aldehyde-1-methylpyrazole (37 mg, 0.34 mmol), and sodium cyanoborohydride (42 mg, 0.67 mmol) were added sequentially to a solution of anhydrous dichloromethane (5 mL). After the addition was complete, the mixture was stirred at 25 °C for 8 h under nitrogen protection. After the reaction was completed, methanol was added to quench the reaction. Then, compound 9 (40 mg, yield: 37%) was obtained by preparative liquid chromatography. 1 H NMR(500MHz, CDCl3)δ9.58(s,1H),8.72(s,1H),8.32(d,1H),7.33(d,1H),7.20(d,1H),7.02(d,1H),6.24–6.23(m,2H),4.15–4.07(m,2H),3. 89(s,3H),3.63(s,2H),3.62–3.58(m,2H),3.11–2.99(m,5H),2.87–2.66(m,4H),2.07–1.99(m,2H),1.95–1.84(m,2H)ppm; LCMS: 451.2[M+H] + .

[0385] Example 10: N-(5-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 10)

[0386] Step 1: (2-((2-bromo-4-fluoro-5-nitrophenoxy)methoxy)ethyl)trimethylsilyl(10b)

[0387] Compound 10a (500 mg, 2.12 mmol) and sodium hydroxide (127 mg, 3.18 mmol, 60% purity) were added sequentially to anhydrous N,N-dimethylformamide (5 mL) at 0 °C. The mixture was stirred for 30 min under nitrogen protection at 0 °C. Then, 2-(trimethylsilyl)ethoxymethyl chloride (389 mg, 2.33 mmol) was added, and the mixture was stirred for 8 h under nitrogen protection at 25 °C. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude compound 10b (800 mg). LCMS: 365.1 [M+H] + .

[0388] Step 2: tert-butyl 4-(5-bromo-2-nitro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)piperazine-1-carboxylic acid ester (10c)

[0389] Compound 10b (700 mg, 1.91 mmol), N-tert-butyloxycarbonylpiperazine (392 mg, 2.10 mmol), and potassium carbonate (792 mg, 5.73 mmol) were sequentially added to anhydrous N,N-dimethylformamide (5 mL). The mixture was stirred at 80 °C for 8 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 10c (1.00 g, yield: 98%). LCMS: 532.1 [M+H] + .

[0390] Step 3: Tert-butyl 4-(2-nitro-4-((2-(trimethylsilyl)ethoxy)methoxy)-5-((trimethylsilyl)ethynyl)phenyl)piperazine-1-carboxylic acid ester (10d)

[0391] Compound 10c (750 mg, 1.41 mmol), trimethylsilylacetylene (692 mg, 7.04 mmol), tetra(triphenylphosphine)palladium (163 mg, 0.14 mmol), cuprous iodide (54 mg, 0.28 mmol), and triethylamine (2 mL) were sequentially added to anhydrous tetrahydrofuran (6 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 10d (700 mg, yield: 90%). LCMS: 550.2 [M+H] + .

[0392] Step 4: tert-butyl-4-(6-nitrobenzofuran-5-yl)piperazine-1-carboxylate (10e)

[0393] Compound 10d (500 mg, 0.91 mmol) was added to a tetrabutylammonium fluoride solution in tetrahydrofuran (10 mL, 1 mol / L), and stirred at 25 °C for 36 h. After the reaction was complete, water was added to quench the reaction, followed by extraction with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 10e (100 mg, yield: 32%). LCMS: 348.1 [M+H] + .

[0394] Step 5: tert-butyl-4-(6-aminobenzofuran-5-yl)piperazine-1-carboxylate (10f)

[0395] Compound 10e (60 mg, 0.17 mmol), iron powder (48 mg, 0.86 mmol), and ammonium chloride (92 mg, 1.73 mmol) were sequentially added to a mixed solution of ethanol (2 mL) and water (1 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, ethyl acetate and water were added, and the mixture was filtered. The aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude compound 10f (60 mg). LCMS: 318.1 [M+H] + .

[0396] Step 6: Tert-butyl 4-(6-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)benzofuran-5-yl)piperazine-1-carboxylate (10g)

[0397] Compound 10f (60 mg, 0.19 mmol), compound 3a (45 mg, 0.23 mmol), N-methylimidazole (62 mg, 0.76 mmol), and N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (106 mg, 0.38 mmol) were sequentially added to acetonitrile (5 mL). The mixture was stirred at 25 °C for 8 h under nitrogen protection. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 10 g (30 mg, yield: 32%). LCMS: 496.2 [M+H] + .

[0398] Step 7: N-(5-(piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (10h)

[0399] 10 g (20 mg, 0.04 mmol) of the compound was added to a hydrochloric acid / 1,4-dioxane solution (2 mL, 4 mol / L), and stirred at 25 °C for 8 h. After the reaction was complete, the solution was evaporated under reduced pressure to obtain 10 h of crude compound (20 mg). LCMS: 396.1 [M+H] + .

[0400] Step 8: N-(5-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 10)

[0401] Compound 10 (20 mg, 0.05 mmol), 3-formaldehyde-1-methylpyrazole (8 mg, 0.08 mmol), and sodium borohydride (10 mg, 0.15 mmol) were added sequentially to methanol (2 mL), and stirred at 25 °C for 8 h. After the reaction was completed, the trifluoroacetate of compound 10 (10 mg, yield: 39%) was obtained by preparative liquid chromatography. 1 H NMR(500MHz,DMSO-d6)δ10.33(s,1H),9.51(s,1H),8.53(s,1H),7.99(d,1 H),7.84(s,1H),7.62(s,1H),7.27(d,1H),6.95(d,1H),6.48(d,1H),6.45( s,1H),4.38(s,2H),4.03–3.95(m,2H),3.90(s,3H),3.71–3.48(m,4H),3.2 6–2.99(m,7H),2.03–1.91(m,2H),1.84–1.69(m,2H)ppm; LCMS: 490.2[M+H] + Example 11: N-(5-(4-(cyanomethyl)piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 11)

[0402] Step 1: N-(5-(4-(cyanomethyl)piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 11)

[0403] Compound 10h (65 mg, 0.16 mmol), bromoacetonitrile (22 mg, 0.18 mmol), and potassium carbonate (68 mg, 0.49 mmol) were added sequentially to N,N-dimethylformamide (2 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain compound 11 (50 mg, yield: 69%). 1H NMR(500MHz, CDCl3)δ9.63(s,1H),8.80(s,1H),7.62(d,1H),7.44(s,1H),7.22(d,1H),6.72(d,1H),6.23(d,1H),4.08–4.01(m,2H),3.69(s, 2H),3.68–3.59(m,2H),3.23–3.14(m,1H),3.10–3.01(m,4H),2.95–2.78(m,4H),2.06–1.98(m,2H),1.88–1.77(m,2H)ppm; LCMS: 435.2[M+H] + .

[0404] Example 12: N-(5-(4-(2-hydroxyethyl)piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 12)

[0405] Step 1: N-(5-(4-(2-hydroxyethyl)piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 12)

[0406] Compound 10h (65 mg, 0.16 mmol), 2-bromoethanol (31 mg, 0.18 mmol), and potassium carbonate (68 mg, 0.49 mmol) were added sequentially to N,N-dimethylformamide (2 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain compound 12 (40 mg, yield: 55%). 1 HNMR(500MHz, CDCl3)δ9.86(s,1H),8.80(s,1H),7.62(d,1H),7.46(s,1H),7.20(d,1H),6.73(d,1H),6.24(d,1H),4 .15–4.07(m,2H),3.79–3.72(s,2H),3.61–3.52(m,2H),3.16–2.54(m,11H),2.07–1.90(m,4H)ppm; LCMS: 440.2[M+H] + .

[0407] Example 13: N-(3-chloro-5-(4-(cyanomethyl)piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 13)

[0408] Step 1: N-(3-chloro-5-(4-(cyanomethyl)piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 13)

[0409] Compound 11 (10 mg, 0.02 mmol) and N-bromosuccinimide (4 mg, 0.03 mmol) were added to N,N-dimethylformamide (1 mL) and stirred at 25 °C for 8 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain compound 13 (5 mg, yield: 46%). 1 H NMR(500MHz, CDCl3)δ9.58(s,1H),8.74(s,1H),7.32(s,1H),7.22(d,1H),6.52(s,1H),6.24(d,1H),4.08–4.01(m,2H),3.68(s,2H),3 .67–3.60(m,2H),3.22–3.13(m,1H),3.07–2.99(m,4H),2.93–2.76(m,4H),2.05–1.98(m,2H),1.88–1.77(m,2H)ppm; LCMS: 469.1[M+H] + .

[0410] Example 14: N-[5-(dimethylphosphono)-2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 14)

[0411] Step 1: (3-Amino-4-bromophenyl)dimethylphosphine oxide (14b)

[0412] Compound 14a (9.87 g, 33.13 mmol) and dimethylphosphine oxide (2.56 g, 32.80 mmol) were sequentially added to 1,4-dioxane (250 mL), followed by triethylamine (3.82 g, 37.72 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.90 g, 3.28 mmol), and tris(dibenzylacetone)dipalladium (1.50 g, 1.64 mmol). The mixture was stirred at 90 °C for 4 h under nitrogen protection. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 14b (6.71 g). LCMS: 248.0 [M+H] + .

[0413] Step 2: (3-(dibenzylamino)-4-bromophenyl)dimethylphosphine oxide (14c)

[0414] Compound 14b (5.61 g, 22.62 mmol) was added to N,N-dimethylformamide (40 mL). Sodium hydride (2.71 g, 67.85 mmol) was added at 0 °C, followed immediately by benzyl chloride (8.59 g, 67.85 mmol). The mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction was quenched in a saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 14c (8.55 g, yield: 88%). LCMS: 428.1 [M+H] + .

[0415] Step 3: 1-tert-Butoxycarbonyl-4-[2-(dibenzylamino)-4-(dimethylphosphono)phenyl]piperazine (14d)

[0416] Compound 14c (3.00 g, 7.00 mmol), N-tert-butoxycarbonyl-piperazine (1.96 g, 10.51 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.44 g, 0.70 mmol), cesium carbonate (6.85 g, 21.01 mmol), and palladium acetate (0.03 g, 0.14 mmol) were sequentially added to 1,4-dioxane (60 mL). The mixture was stirred at 100 °C for 72 h under nitrogen protection. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 14d (2.65 g). LCMS: 534.3 [M+H] + .

[0417] Step 4: [3-(dibenzylamino)-4-(piperazin-1-yl)phenyl]dimethylphosphine oxide (14e)

[0418] Compound 14d (2.65 g, 4.97 mmol) was added to ethyl acetate (3 mL), followed by the addition of hydrochloric acid / methanol (20 mL, 4 mol / L) at 0 °C. The mixture was stirred at 25 °C for 2 h, and then evaporated to dryness under reduced pressure to obtain the hydrochloride salt of compound 14e (2.30 g). LCMS: 434.2 [M+H] + .

[0419] Step 5: [3-(dibenzylamino)-4-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)phenyl]dimethylphosphine oxide (14f)

[0420] The hydrochloride salt of compound 14e (2.30 g, 4.89 mmol) and potassium carbonate (1.84 g, 13.35 mmol) were added to N,N-dimethylformamide (10 mL), followed by 3-(chloromethyl)-1-methyl-1H-pyrazole (0.58 g, 4.45 mmol). The mixture was stirred at 25 °C for 12 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 14f (1.75 g, yield: 75%). LCMS: 528.3 [M+H] + .

[0421] Step 6: [3-amino-4-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)phenyl]dimethylphosphine oxide (14g)

[0422] Compound 14f (1.75 g, 3.32 mmol) was added to ethanol, followed by palladium on carbon (0.98 g, 9.21 mmol) and palladium hydroxide (0.40 g, 0.57 mmol). The mixture was stirred for 3 days under a hydrogen atmosphere at 60 °C. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filter cake was washed with ethanol, and the filtrate was evaporated to dryness under reduced pressure to give compound 14f (500 mg, yield: 43%). LCMS: 348.2 [M+H] + .

[0423] Step 7: N-[5-(dimethylphosphono)-2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 14)

[0424] Potassium tert-butoxide (404 mg, 3.60 mmol) was added to tetrahydrofuran (5 mL), followed by a tetrahydrofuran solution containing compound 14 g (500 mg, 1.44 mmol) and compound 1c (454 mg, 2.16 mmol). The mixture was stirred at 25 °C for 1 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. Compound 14 (12 mg, yield: 2%) was purified by preparative liquid chromatography. 1 H NMR(500MHz,DMSO-d6)δ9.45(s,1H),8.63(s,1H),7.60(s,1H),7.50–7.44(m,1H),7.42– 7.37(m,1H),7.21–7.19(m,1H),6.44(d,1H),6.14(d,1H),4.01–3.94(m,2H),3.78(s,3H ),3.55–3.48(m,2H),3.47–3.44(m,2H),3.11–3.04(m,1H),2.92–2.86(m,4H),2.78–2.5 2(m,4H),2.01–1.93(m,2H),1.81–1.70(m,2H),1.66–1.60(m,6H)ppm; LCMS: 526.3[M+H] + .

[0425] Example 15: N-[2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 15)

[0426] Step 1: N-[3-(pentafluorine-λ) 6 [-thioalkyl)phenyl]-1,1-diphenylmethylene (15b)

[0427] Compound 15a (4.46 g, 15.76 mmol), sodium methoxide (1.19 g, 22.06 mmol), benzophenone imine (3.43 g, 18.91 mmol), tris(dibenzylacetone)dipalladium (0.72 g, 0.79 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.47 g, 2.36 mmol) were sequentially added to toluene (40 mL). The mixture was stirred at 80 °C for 5 h under nitrogen protection. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give compound 15b (5.81 g, yield: 96%). LCMS: 384.1 [M+H] + .

[0428] Step 2: 3-(pentafluoro-λ) 6 -Thioalkyl)aniline (15c)

[0429] Compound 15b (5.81 g, 15.15 mmol) was added to ethyl acetate (200 mL), and a hydrochloric acid / ethyl acetate solution (40 mL, 4 mol / L) was added at 0 °C. The mixture was stirred at 25 °C for 12 h. After the reaction was complete, the pH was adjusted to 8 with saturated sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 15c (2.92 g, yield: 88%). LCMS: 220.0 [M+H] + .

[0430] Step 3: 2-Bromo-5-(pentafluoro-λ) 6 -Thio)aniline (15d)

[0431] Compound 15c (2.82 g, 12.89 mmol) was added to 1,4-dioxane (25 mL), and N-bromosuccinimide (2.29 g, 12.89 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 30 min. After the reaction was complete, the mixture was quenched in water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 15d (2.91 g, yield: 76%). LCMS: 297.9 [M+H] + .

[0432] Step 4: 2-Bromo-5-(pentafluoro-λ) 6 (-Thioalkyl)-N,N-Dibenzylaniline (15e)

[0433] Compound 15d (2.91 g, 9.75 mmol) was added to N,N-dimethylformamide (40 mL). Sodium hydride (1.17 g, 29.24 mmol) was added at 0 °C, followed immediately by benzyl chloride (3.70 g, 29.24 mmol). The mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction was quenched in a saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 15e (3.98 g, yield: 85%). LCMS: 478.0 [M+H] + .

[0434] Step 4: 1-tert-Butoxycarbonyl-4-[2-(dibenzylamino)-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]piperazine(15f)

[0435] Compound 15e (2.11 g, 4.41 mmol), N-tert-butoxycarbonyl-piperazine (1.23 g, 6.62 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.55 g, 0.88 mmol), cesium carbonate (4.31 g, 13.23 mmol), and palladium acetate (0.10 g, 0.44 mmol) were sequentially added to 1,4-dioxane (50 mL). The mixture was stirred at 100 °C for 8 h under nitrogen protection. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give compound 15f (1.41 g, yield: 52%). LCMS: 584.2 [M+H] + .

[0436] Step 5: N,N-Dibenzyl-2-(piperazin-1-yl)-5-(pentafluoro-λ) 6 -Thioalkyl)aniline (15g)

[0437] Compound 15f (1.41 g, 2.42 mmol) was added to ethyl acetate, followed by the addition of hydrochloric acid / methanol (15 mL, 4 mol / L) at 0 °C. The mixture was stirred at 25 °C for 2 h, and then evaporated under reduced pressure to obtain 1.30 g of the hydrochloride salt of compound 15 g. LCMS: 484.2 [M+H] + .

[0438] Step 6: N,N-Dibenzyl-2-[4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl]-5-(pentafluoro-λ) 6 -Thioalkyl)aniline (15h)

[0439] 15 g of the compound's hydrochloride (1.30 g, 2.50 mmol) and potassium carbonate (1.04 g, 7.50 mmol) were added to N,N-dimethylformamide (10 mL), followed by 3-(chloromethyl)-1-methyl-1H-pyrazole (0.33 g, 2.50 mmol). The mixture was stirred at 25 °C for 3 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 15h (1.29 g, yield: 90%). LCMS: 578.2 [M+H] + .

[0440] Step 7: 2-[4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl]-5-(pentafluoro-λ) 6 -Thioalkyl)aniline (15j)

[0441] Compound 15h (1.29 g, 2.24 mmol) was added to ethanol (200 mL), followed by palladium on carbon (1.91 g, 17.93 mmol) and palladium hydroxide (2.20 g, 15.69 mmol). The mixture was stirred at 60 °C under hydrogen atmosphere for 6 days. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filter cake was washed with ethanol, and the filtrate was evaporated to dryness under reduced pressure to give compound 15j (236 mg, yield: 26%). LCMS: 398.1 [M+H] + .

[0442] Step 8: N-(5-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzofuran-6-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 15)

[0443] Potassium tert-butoxide (166 mg, 1.48 mmol) was added to tetrahydrofuran (5 mL), followed by a tetrahydrofuran solution (5 mL) containing compound 15j (236 mg, 0.59 mmol) and compound 1c (212 mg, 1.01 mmol). The mixture was stirred at 25 °C for 3.5 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. Compound 15 (40 mg, yield: 12%) was purified by preparative liquid chromatography. 1H NMR(500MHz,DMSO-d6)δ9.40(s,1H),8.84–8.74(m,1H),7.66–7.58(m,2H),7.48 –7.40(m,1H),7.28–7.21(m,1H),6.47–6.43(m,1H),6.16–6.12(m,1H),4.01–3. 93(m,2H),3.78(s,3H),3.55–3.44(m,4H),3.13–3.03(m,1H),2.95–2.88(m,4H) ,2.76–2.52(m,4H),2.01–1.94(m,2H),1.81–1.70(m,2H)ppm; LCMS: 576.2[M+H] + .

[0444] Example 16: N-(2-(6-((1-methyl-1H-pyrazol-3-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 16)

[0445] Step 1: tert-butyl 6-(2-nitro-4-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (16g)

[0446] Compound 16d (1.00 g, 5.04 mmol), compound 16f (1.05 g, 5.04 mmol), and potassium carbonate (1.74 g, 12.60 mmol) were sequentially added to anhydrous N,N-dimethylformamide (20 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, water was added to quench the reaction. The mixture was filtered, and the filter cake was evaporated under reduced pressure to give compound 16 g (1.70 g, yield: 87%). LCMS: 388.2 [M+H] + .

[0447] Step 2: tert-butyl-6-(2-amino-4-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (16h)

[0448] 16 g (1.50 g, 3.87 mmol) of compound and 120 mg (10%) of palladium on carbon were dissolved in methanol (15 mL), purged three times with hydrogen, and stirred at 25 °C for 8 h. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to give compound 16h (1.35 g, yield: 98%). LCMS: 358.2 [M+H] + .

[0449] Step 3: tert-butyl 6-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (16j)

[0450] A tetrahydrofuran (3 mL) solution of compound 16h (300 mg, 0.84 mmol) and compound 1c (265 mg, 1.26 mmol) was added to a tetrahydrofuran (3 mL) solution of potassium tert-butoxide (283 mg, 2.52 mmol). The mixture was stirred at 25 °C under nitrogen protection for 1 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give compound 16j (400 mg, yield: 89%). LCMS: 536.2 [M+H] + .

[0451] Step 4: N-(2-(2,6-diazaspiro[3.3]heptane-2-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (16k)

[0452] Compound 16j (400 mg, 0.75 mmol) and zinc bromide (1.68 g, 7.47 mmol) were added to anhydrous dichloromethane (5 mL), and stirred at 25 °C for 8 h. After the reaction was complete, dichloromethane and water were added, and the mixture was filtered. The filtrate was separated, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography to obtain compound 16k (40 mg, yield: 12%). LCMS: 436.2 [M+H] + .

[0453] Step 5: N-(2-(6-((1-methyl-1H-pyrazol-3-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 16)

[0454] Compound 16k (40 mg, 0.09 mmol), 3-aldehyde-1-methylpyrazole (20 mg, 0.18 mmol), and acetic acid (1 mg, 0.01 mmol) were added sequentially to a methanol (2 mL) solution. After the addition was complete, the mixture was stirred at 25 °C for 1 h under nitrogen protection. Then, sodium cyanoborohydride (29 mg, 0.46 mmol) was added, and the mixture was stirred at 25 °C for 8 h under nitrogen protection. After the reaction was complete, compound 16 (20 mg, yield: 41%) was obtained by preparative liquid chromatography. 1H NMR(500MHz, CDCl3)δ8.06(s,1H),7.77(s,1H),7.36(d,1H),7.30(d,1H),7.20(d,1H),6.68(d,1H),6.25(d,1H),6.15(d,1H),4.13–4.02(m, 6H),3.89(s,3H),3.61(s,2H),3.60–3.51(m,2H),3.45(s,4H),3.08–2 .96(m,1H),2.07–1.97(m,2H),1.94–1.81(m,2H)ppm; LCMS: 530.2[M+H] + .

[0455] Example 17: N-(2-((1R,5S)-3-((1-methyl-1H-pyrazol-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 17)

[0456] Step 1: tert-butyl(1R,5S)-8-(2-nitro-4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid ester (17b)

[0457] Compound 16d (1.00 g, 4.71 mmol), compound 17a (0.98 g, 4.71 mmol), and potassium carbonate (1.63 g, 11.78 mmol) were sequentially added to anhydrous N,N-dimethylformamide (10 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, water was added to quench the reaction, and ethyl acetate was extracted. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give crude compound 17b (1.80 g, yield: 95%). LCMS: 402.2 [M+H] + .

[0458] Step 2: (1R,5S)-8-(2-nitro-4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane (17c)

[0459] Compound 17b (1.89 g, 4.71 mmol) was dissolved in 1,4-dioxane hydrochloride (10 mL, 4 M) and dichloromethane (10 mL). The mixture was stirred at 25 °C for 1 h. After the reaction was complete, the solution was directly evaporated to dryness to give compound 17c (1.59 g). LCMS: 302.1 [M+H] + .

[0460] Step 3: (1R,5S)-3-((1-methyl-1H-pyrazol-3-yl)methyl)-8-(2-nitro-4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane (17d)

[0461] Compound 17c (1.59 g, 4.71 mmol) and 3-aldehyde-1-methylpyrazole (0.62 g, 5.65 mmol) were added sequentially to a methanol (20 mL) solution. After the addition was complete, the mixture was stirred at 25 °C for 1 h under nitrogen protection. Then, sodium cyanoborohydride (0.89 g, 14.12 mmol) was added, and the mixture was stirred at 25 °C for 8 h under nitrogen protection. After the reaction was complete, the mixture was directly mixed with silica gel and purified by column chromatography to obtain compound 17d (1.50 g, yield: 81%). LCMS: 396.2 [M+H] + .

[0462] Step 4: 2-((1R,5S)-3-((1-methyl-1H-pyrazol-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(trifluoromethyl)aniline (17e)

[0463] Compound 17d (400 mg, 1.01 mmol) and palladium on carbon (300 mg, 10%) were dissolved in ethanol (5 mL), purged three times with hydrogen, and stirred at 55 °C for 8 h. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to give crude compound 17e (369 mg). LCMS: 366.2 [M+H] + .

[0464] Step 5: N-(2-((1R,5S)-3-((1-methyl-1H-pyrazol-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 17)

[0465] A tetrahydrofuran (3 mL) solution of compound 17e (369 mg, 1.01 mmol) and compound 1c (318 mg, 1.52 mmol) was added to a tetrahydrofuran (3 mL) solution of potassium tert-butoxide (453 mg, 4.04 mmol). The mixture was stirred at 25 °C under nitrogen protection for 1 h. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain compound 17 (150 mg, yield: 27%). 1H NMR(500MHz, CDCl3)δ9.03(s,1H),8.79(s,1H),7.32(s,1H),7.27(d,1H),7.21(d,1H),7.03(d,1H),6.26–6.20(m,2H),4.14–4.06(m,2H),3.88 (s,3H),3.72–3.55(m,6H),3.12–3.03(m,1H),2.94–2.86(m,2H),2.69– 2.60(m,2H),2.11–2.00(m,4H),1.99–1.82(m,4H)ppm; LCMS: 544.2[M+H] + .

[0466] Example 18: N-(2-((1R,5S)-8-((1-methyl-1H-pyrazol-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 18)

[0467] Step 1: tert-butyl(1R,5S)-3-(2-nitro-4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (18b)

[0468] Compound 16d (1.00 g, 4.71 mmol), compound 18a (0.98 g, 4.71 mmol), and potassium carbonate (1.63 g, 11.78 mmol) were sequentially added to anhydrous N,N-dimethylformamide (5 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, water was added to quench the reaction, and ethyl acetate was extracted. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 18b (1.40 g, yield: 74%). LCMS: 402.2 [M+H] + .

[0469] Step 2: (1R,5S)-3-(2-nitro-4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane(18c)

[0470] Compound 18b (400 mg, 1.00 mmol) was dissolved in 1,4-dioxane hydrochloride (15 mL, 4 M), and stirred at 25 °C for 8 h. After the reaction was complete, the solution was directly evaporated to dryness to give compound 18c (336 mg). LCMS: 302.1 [M+H] + .

[0471] Step 3: (1R,5S)-8-((1-methyl-1H-pyrazol-3-yl)methyl)-3-(2-nitro-4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane (18d)

[0472] Compound 18c (336 mg, 1.00 mmol) and 3-aldehyde-1-methylpyrazole (132 mg, 1.19 mmol) were added sequentially to a methanol (5 mL) solution. After the addition was complete, the mixture was stirred at 25 °C for 30 min under nitrogen protection. Then, sodium cyanoborohydride (186 mg, 3.00 mmol) was added, and the mixture was stirred at 25 °C for 8 h under nitrogen protection. After the reaction was complete, compound 18d (220 mg, yield: 56%) was obtained by thin-layer chromatography (LCMS: 396.2 [M+H)). + .

[0473] Step 4: 2-((1R,5S)-8-((1-methyl-1H-pyrazol-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(trifluoromethyl)aniline (18e)

[0474] Compound 18d (200 mg, 0.51 mmol) and palladium on carbon (40 mg, 10%) were dissolved in ethanol (5 mL), purged three times with hydrogen, and stirred at 25 °C for 8 h. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to give crude compound 18e (200 mg). LCMS: 366.2 [M+H] + .

[0475] Step 5: N-(2-((1R,5S)-8-((1-methyl-1H-pyrazol-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 18)

[0476] Compound 18e (100 mg, 0.27 mmol) was added to anhydrous dichloromethane (5 mL) solution, and trimethylaluminum (0.5 mL, 2 M) was added at 0 °C. The mixture was stirred for 1 h at 0 °C under nitrogen protection. Then, compound 1c (86 mg, 0.41 mmol) was added, and the mixture was stirred for 2 h at 25 °C under nitrogen protection. After the reaction was completed, methanol and water were added to quench the reaction. The mixture was filtered, and the filtrate was directly purified by preparative liquid chromatography to obtain compound 18 (30 mg, yield: 20%). 1H NMR(500MHz, CDCl3)δ9.49(s,1H),8.59(s,1H),7.60(s,1H),7.55(d,1H),7.45(d, 1H),7.26(d,1H),6.46(d,1H),6.23(s,1H),3.99–3.91(m,2H),3.78(s,3H),3.53–3 .44(m,4H),3.31–3.24(m,2H),3.06–2.98(m,1H),2.99–2.91(m,2H),2.78–2.71(m, 2H), 2.16–2.04(m,4H), 1.98–1.89(m,2H), 1.77–1.65(m,2H)ppm; LCMS: 544.2[M+H] + .

[0477] Example 19: N-(2-(5-((1-methyl-1H-pyrazol-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 19)

[0478] Step 1: 5-(2-nitro-4-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester (19b)

[0479] In a 100 mL round-bottom flask, compound 16d (0.63 g, 3.00 mmol) and compound 19a (0.85 g, 4.00 mmol) were dissolved in acetonitrile (10 mL), followed by potassium carbonate (0.90 g, 5.00 mmol). The reaction was carried out at 80 °C for 2 h. The mixture was filtered through a diatomaceous earth-lined sintered funnel, the filter cake was washed with dichloromethane, the solvent was evaporated, and 200 mL of 10% ethyl acetate / petroleum ether was added. The mixture was stirred for another 2 h, filtered, and dried to give compound 19b as a yellow solid (1.03 g, 85% yield). LCMS: 402.2 [M+H] + .

[0480] Step 2: 2-(2-nitro-4-(trifluoromethyl)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride (19c)

[0481] In a 100 mL round-bottom flask, compound 19b (1.00 g, 2.50 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of 3 mL of 1,4-dioxane hydrochloride solution (4 M). The mixture was then reacted at room temperature for 4 h. The solvent was directly evaporated to give compound 19c, a yellow solid (0.85 g, 99% yield). LCMS: 302.1 [M+H] +.

[0482] Step 3: 2-((1-methyl-1H-pyrazol-3-yl)methyl)-5-(2-nitro-4-(trifluoromethyl)phenyl)octahydropyrrolo[3,4-c]pyrrole (19d)

[0483] In a 100 mL round-bottom flask, compound 19c (0.85 g, 2.50 mmol) was dissolved in 10 mL of methanol. 3-Formaldehyde-1-methylpyrazole (0.5 g, 5.0 mmol) was added, followed by the addition of sodium cyanoborohydride (0.62 g, 10 mmol) in portions. The reaction was carried out at room temperature for 6 h. The mixture was quenched with water, concentrated, and extracted with ethyl acetate. The concentrated organic phase was collected to obtain the crude product. The residue was purified by column chromatography to give compound 19d as a yellow solid (0.79 g, 80% yield). LCMS: 396.2 [M+H] + .

[0484] Step 4: 2-(5-((1-methyl-1H-pyrazol-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-5-(trifluoromethyl)aniline (19e)

[0485] In a 100 mL round-bottom flask, compound 19d (0.79 g, 2.0 mmol) was dissolved in 10 mL of ethanol, and 10% Pd / C was added. The reaction was carried out at 60 °C for 8 h under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth-lined sintered funnel, the filter cake was washed with ethanol, and the solution was concentrated to give compound 19e as a white solid (0.70 g, 96% yield). LCMS: 366.2 [M+H] + .

[0486] Step 5: N-(2-(5-((1-methyl-1H-pyrazol-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 19)

[0487] In a 50 mL round-bottom flask, compound 19e (0.18 g, 0.50 mmol) and compound 1c (0.16 g, 0.75 mmol) were dissolved in tetrahydrofuran (5 mL) and added dropwise to a mixture of tetrahydrofuran (2 mL) and potassium tert-butoxide (0.17 g, 1.50 mmol). The reaction was allowed to proceed for 30 min. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The residue was purified by column chromatography to give compound 19 as a white solid (0.20 g, 36% yield). 1H NMR(500MHz, CDCl3)δ8.83(s,1H),8.70(s,1H),7.37–7.29(m,2H),7.26–7.18(m,2H) ,6.23(d,1H),6.20(s,1H),4.09–4.00(m,2H),3.88(s,3H),3.70(s,2H),3.57–3.48( m,2H),3.26–3.15(m,2H),3.09–3.01(m,1H),3.01–2.96(m,2H),2.95–2.88(m,2H),2 .87–2.79(m,2H),2.57(d,2H),2.00(d,2H),1.91–1.77(m,2H)ppm; LCMS:544.2[M+H] + .

[0488] Example 20: N-(2-(((2-cyanoethyl)amino)methyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 20)

[0489] Step 1: 5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxylic acid (20a)

[0490] In a 250 mL round-bottom flask, compound 1c (5.00 g, 23.8 mmol) was dissolved in methanol / water (50 mL), and lithium hydroxide (1.12 g, 47.60 mmol) was added. The reaction was carried out at room temperature for 4 h. Methanol was removed by rotary evaporation, and the mixture was acidified with 2 M hydrochloric acid, precipitating a white solid. The solid was filtered, the filter cake was washed with water, and dried to give compound 20a (3.90 g, 85% yield). LCMS: 195.1 [MH] - .

[0491] Step 2: 3-((2-nitro-4-(trifluoromethyl)benzyl)amino)propionitrile (20c)

[0492] Compound 20b (500 mg, 2.26 mmol), triethylamine (686 mg, 6.78 mmol), and methanesulfonic anhydride (473 mg, 2.71 mmol) were sequentially added to 10 mL of anhydrous dichloromethane at 0 °C. The mixture was stirred at 0 °C for 1 h under nitrogen protection. Then, 3-aminopropionitrile (238 mg, 3.39 mmol) was added, and the mixture was stirred at 25 °C for 8 h under nitrogen protection. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 20c (300 mg, yield: 49%). LCMS: 274.0 [M+H]+ .

[0493] Step 3: Tert-butyl (2-cyanoethyl)(2-nitro-4-(trifluoromethyl)benzyl)carbamate (20d)

[0494] Compound 20c (300 mg, 1.10 mmol), di-tert-butyl dicarbonate (252 mg, 1.15 mmol), and triethylamine (333 mg, 3.29 mmol) were sequentially added to dichloromethane (10 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 20d (400 mg, yield: 98%). LCMS: 374.1 [M+H] + .

[0495] Step 4: tert-butyl(2-amino-4-(trifluoromethyl)benzyl)(2-cyanoethyl)carbamate (20e)

[0496] Compound 20d (250 mg, 0.67 mmol), ammonium chloride (358 mg, 6.70 mmol), and iron powder (189 mg, 3.35 mmol) were sequentially added to a mixed solution of ethanol (5 mL) and water (1 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, the mixture was filtered directly, and the filtrate was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 20e (200 mg, yield: 87%). LCMS: 344.1 [M+H] + .

[0497] Step 5: tert-butyl(2-cyanoethyl)(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)carbamate (20f)

[0498] Compound 20e (150 mg, 0.44 mmol), compound 20a (129 mg, 0.66 mmol), N-methylimidazole (143 mg, 1.75 mmol), and N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (245 mg, 0.87 mmol) were sequentially added to acetonitrile (5 mL). The mixture was stirred at 25 °C for 8 h under nitrogen protection. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 20f (180 mg, yield: 79%). LCMS: 522.2 [M+H] + .

[0499] Step 6: N-(2-(((2-cyanoethyl)amino)methyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 20)

[0500] Compound 20f (140 mg, 0.27 mmol) was added to a mixed solution of trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and stirred at 25 °C for 8 h. After the reaction was completed, sodium carbonate aqueous solution was added to quench the reaction, followed by extraction with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain compound 20 (20 mg, yield: 18%). 1 H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.72(s,1H),7.35–7.29(m,2H),7.19(d,1H),6.23(d,1H),4.13–4.03(m,4H), 3.62–3.51(m,2H),3.06–2.93(m,3H),2.64–2.56(m,2H),2.10–1.91(m,3H),1.90–1.77(m,2H)ppm; LCMS: 422.1[M+H] + .

[0501] Example 21: N-(2-(((2-cyanoethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 21-1) and N-(2-(((2-cyanoethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-N-methyl-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 21-2)

[0502] Compound 20 (6 mg, 0.01 mmol), iodomethane (4 mg, 0.03 mmol), and potassium carbonate (8 mg, 0.06 mmol) were sequentially added to anhydrous N,N-dimethylformamide (2 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, methanol was added to quench the reaction. Compound 21-1 (0.7 mg, yield: 11%) was obtained by preparative liquid chromatography. 1 HNMR(500MHz,DMSO-d6)δ10.97(s,1H),8.73(s,1H),7.36–7.30(m,2H),7.17(d,1H),6.20(d,1H),4.11–4.05(m,4H),3.61– 3.52(m,2H),3.07–2.92(m,3H),2.61–2.52(m,2H),2.45(m,3H),2.11–1.90(m,2H),1.89–1.76(m,2H)ppm; LCMS: 436.1[M+H] + ) and compound 21-2 (0.9 mg, yield: 14%) 1 H NMR(500MHz,DMSO-d6)δ8.70(s,1H),7.37–7.30(m,2H),7.20(d,1H),6.24(d,1H),4.12–4.07(m,4H),3.59–3.51(m,2H),3 .08–2.93(m,3H),2.78(m,3H),2.60–2.51(m,2H),2.44(m,3H),2.09–1.89(m,2H),1.88–1.75(m,2H)ppm; LCMS: 450.1[M+H] + ).

[0503] Example 22: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxopiperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 22)

[0504] Step 1: tert-butyl 4-((1-methyl-1H-pyrazole-3-yl)methyl)-3-oxopiperazine-1-carboxylic acid ester (22c)

[0505] In a 250 mL round-bottom flask, compound 22a (1.38 g, 10.66 mmol), compound 22b (6.40 g, 31.99 mmol), sodium tert-butoxide (1.54 g, 15.99 mmol), potassium iodide (1.77 g, 10.66 mmol), and acetonitrile (60 mL) were added sequentially, and the mixture was refluxed for 2 h. After cooling to room temperature, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 22c (1.90 g, yield: 60%). LCMS: 295.2 [M+H] + .

[0506] Step 2: 1-((1-methyl-1H-pyrazole-3-yl)methyl)piperazin-2-one (22d)

[0507] In a 50 mL round-bottom flask, compound 22c (1.90 g, 6.46 mmol) was dissolved in 20 mL of dichloromethane. Hydrochloric acid / 1,4-dioxane solution (10 mL, 4 M) was added dropwise under ice bath conditions, and the mixture was slowly heated to room temperature for 4 h. After the reaction was complete, the organic solvent was removed under reduced pressure to give the crude compound 22d. LCMS: 195.2 [M+H] + .

[0508] Step 3: 1-((1-methyl-1H-pyrazol-3-yl)methyl)-4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-2-one (22e)

[0509] In a 100 mL round-bottom flask, compound 22d (1.90 g, 9.79 mmol), potassium carbonate (4.05 g, 29.38 mmol), 2-nitro-4-trifluoromethylfluorobenzene (2.05 g, 9.79 mmol), and acetonitrile (30 mL) were added sequentially, and the mixture was heated to 60 °C and reacted for 2 h. After cooling to room temperature, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 22e (1.45 g, yield: 38%). LC-MS: 384.1 [M+H] + Step 4: 4-(2-amino-4-(trifluoromethyl)phenyl)-1-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-2-one (22f)

[0510] In a 100 mL round-bottom flask, compound 22e (1.45 g, 3.78 mmol), palladium on carbon (290 mg, 10%), and ethanol (20 mL) were added sequentially. The mixture was heated to 60 °C for 2 h under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the organic solvent was removed from the filtrate under reduced pressure to give compound 22f (1.20 g, yield: 90%). LCMS: 354.1 [M+H] + .

[0511] Step 5: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxopiperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 22)

[0512] In a 100 mL round-bottom flask, compound 22f (100 mg, 0.28 mmol), compound 20a (84 mg, 0.42 mmol), and N-methylimidazole (46 mg, 0.56 mmol) were dissolved in acetonitrile. N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (1188 mg, 0.42 mmol) was added with stirring, and the mixture was reacted at room temperature for 12 h. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain compound 22 (15 mg, yield: 11%). 1 H NMR(500MHz, CDCl3)δ9.12(s,1H),8.84(s,1H),7.39–7.32(m,2H),7.24–7.15(m,2H),6.27(d,1H),6.24(d,1H),4.69(s,2H),4.15–4.02(m,2H) ,3.90(s,3H),3.76(s,2H),3.62–3.49(m,4H),3.27–3.18(m,2H),3.04– 2.95(m,1H),2.01–1.90(m,2H),1.90–1.77(m,2H)ppm; LCMS: 532.2[M+H] + .

[0513] Example 23: (N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-sulfonamide (Compound 23)

[0514] Step 1: 4-(2-nitro-4-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (23b)

[0515] In a 500 mL round-bottom flask, compound 16d (20.90 g, 100 mmol) was dissolved in acetonitrile (300 mL), followed by the addition of piperazine-1-carboxylic acid tert-butyl ester (19.50 g, 105 mmol), and then potassium carbonate (20.70 g, 150 mmol). The reaction was carried out at 80 °C for 2 h. The mixture was filtered through a diatomaceous earth-lined sintered funnel, the filter cake was washed with dichloromethane, the solvent was evaporated, and then 200 mL of 10% ethyl acetate / petroleum ether was added. The mixture was stirred for another 2 h, filtered, and dried to give compound 23b as a yellow solid (32.00 g, 85% yield). LCMS: 376.1 [M+H] + .

[0516] Step 2: 1-(2-nitro-4-(trifluoromethyl)phenyl)piperazine hydrochloride (23c)

[0517] In a 500 mL round-bottom flask, compound 23b (10.00 g, 26.67 mmol) was dissolved in 150 mL of dichloromethane, and 20 mL of 1,4-dioxane hydrochloric acid solution (4 M) was added. The mixture was then reacted at room temperature for 4 h. The solvent was directly evaporated to give compound 23c, a yellow solid (8.40 g, 99% yield). LCMS: 276.1 [M+H] + .

[0518] Step 3: 1-((1-methyl-1H-pyrazole-3-yl)methyl)-4-(2-nitro-4-(trifluoromethyl)phenyl)piperazine (23d)

[0519] In a 250 mL round-bottom flask, compound 23c (8.40 g, 26.67 mmol) was dissolved in methanol (150 mL), followed by the addition of 3-aldehyde-1-methylpyrazole (4.40 g, 40.00 mmol), and then sodium cyanoborohydride (5.04 g, 80.00 mmol) in portions. The reaction was carried out at room temperature for 6 h. The mixture was quenched with water, concentrated, extracted with ethyl acetate, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give a yellow solid compound 23d (8.30 g, 85% yield). LCMS: 370.1 [M+H] + .

[0520] Step 4: 2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)aniline (23e)

[0521] In a 250 mL round-bottom flask, compound 23d (5.00 g, 13.55 mmol) was dissolved in 50 mL of ethanol, and 10% palladium on carbon was added. The reaction was carried out at 60 °C for 8 h under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth-lined sintered funnel, the filter cake was washed with ethanol, and the solution was concentrated to give compound 23e as a white solid (4.10 g, 89% yield). LCMS: 340.2 [M+H] + .

[0522] Step 5: Methyl 5-(3,6-dihydro-2H-pyran-4-yl)furan-2-carboxylate (23g)

[0523] In a 500 mL round-bottom flask, compound 23f (20.10 g, 100 mmol) was dissolved in 1,4-dioxane / water (v / v = 5 / 1, 300 mL), followed by the addition of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (23.10 g, 110.00 mmol), cesium carbonate (48.80 g, 150.00 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (3.00 mmol, 2.45 g). The reaction was carried out at 95 °C for 8 h. Remove the solvent, add 200 mL of 20% (ethyl acetate / petroleum ether) and continue stirring for 1 h. Filter using a silica gel-lined sintered funnel. Wash the filter cake with 20% (ethyl acetate / petroleum ether), evaporate the solvent, and then add 5% (ethyl acetate / petroleum ether) and continue stirring for 1 h. Filter and dry to give 23 g of the compound as a white solid (15.70 g, yield 75%). LCMS: 209.1 [M+H] + .

[0524] Step 6: Methyl 5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxylate (23h)

[0525] In a 250 mL round-bottom flask, 23 g (18 g, 86.5 mmol) of the compound was dissolved in 200 mL of ethyl acetate, and palladium on carbon (900 mg, 5%) was added. The reaction was carried out at room temperature for 1.5 h under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth-lined funnel, the filter cake was washed with ethyl acetate, concentrated, and purified by silica gel column chromatography to give compound 23h as a colorless oil (16.00 g, 89% yield). LCMS: 211.1 [M+H] + .

[0526] Step 7: 5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxylic acid (23j)

[0527] In a 250 mL round-bottom flask, compound 23j (5.00 g, 23.80 mmol) was dissolved in methanol / water (50 mL), and lithium hydroxide (1.12 g, 47.60 mmol) was added. The reaction was carried out at room temperature for 4 h. The mixture was acidified with 2 M hydrochloric acid to remove methanol, resulting in the precipitation of a white solid. The solid was filtered, washed with water, and dried to give compound 23j as a white solid (3.90 g, 85% yield). LCMS: 195.1 [M+H] + .

[0528] Step 8: 4-(5-bromofuran-2-yl)tetrahydro-2H-pyran (23k)

[0529] In a 100 mL round-bottom flask, compound 23j (0.80 g, 4.1 mmol) was dissolved in 20 mL of dichloromethane. Triethylamine (0.61 g, 6.00 mmol) and tribromopyridine (1.57 g, 4.90 mmol) were added sequentially under ice bath conditions, and the reaction was carried out at room temperature for 4 h. The reaction was quenched with saturated ammonium chloride, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 23k as a white solid (720 mg, 75% yield). LCMS: 231.1 [M+H] + .

[0530] Step 9: Sodium 5-(tetrahydro-2H-pyran-4-yl)furan-2-sulfinate (23m)

[0531] In a 100 mL round-bottom flask, compound 23k (0.71 g, 3.10 mmol) was dissolved in tetrahydrofuran (20 mL). Butyllithium (1.5 mL, 3.60 mmol) was added at -78 °C, and the reaction was allowed to proceed for 1 h. Then, 1,4-diazabicyclo[2.2.2]octane-1,4-dizonium-1,4-disulfinic acid (0.48 g, 2.00 mmol) was added, and the reaction was allowed to proceed slowly to room temperature for 4 h. After quenching with saturated sodium carbonate, the solution was diluted with water, concentrated, and purified by a C18 reverse-phase column to give compound 23m as a white solid (521 mg, 71% yield). LCMS: 239.1 [M+H] + .

[0532] Step 10: (N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-sulfonamide (Compound 23)

[0533] In a 100 mL round-bottom flask, compound 23m (180 mg, 0.75 mmol) and compound 23e (185 mg, 0.50 mmol) were dissolved in dimethyl sulfoxide (5 mL). Sodium bisulfite (208 mg, 2.0 mmol) and stannous chloride dihydrate (192 mg, 0.75 mmol) were added sequentially. The mixture was reacted at 60 °C for 4 h and then cooled to room temperature. After quenching with water, the mixture was extracted with ethyl acetate, concentrated, and purified by C18 reversed-phase column chromatography to give compound 23 as a white solid (100 mg, 36% yield). 1 H NMR(500MHz, CDCl3)δ8.00(s,1H),7.83(s,1H),7.36–7.30(m,2H),7.23(d,1H),7.08(d,1H),6.22(s,1H),6.10(d,1H),3.97(d,2 H),3.92(s,3H),3.67(s,2H),3.46(t,2H),2.91–2.80(m,5H),2.71(s,4H),1.83(d,2H),1.76–1.61(m,2H)ppm; LCMS:554.2[M+H] + .

[0534] Example 24: 1-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-3-(pyridin-4-ylmethyl)urea (Compound 24)

[0535] In a 100 mL round-bottom flask, compound 23e (150 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL), and 1,1'-carbonyldiimidazole (143 mg, 0.88 mmol) was added. The reaction was carried out at room temperature for 24 h. Then, pyridin-4-ylmethylamine (143 mg, 1.32 mmol) was added, and the reaction was continued at room temperature for 2 h. The mixture was quenched with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by C18 reversed-phase column chromatography to give compound 24 as a white solid (50 mg, 24% yield). 1 H NMR(500MHz, CDCl3)δ8.57(d,2H),8.52(s,1H),7.72(s,1H),7.34(s,1H),7.31(d,2H),7.25(d,1H),7.20(d,1H),6.30–6. 21(m,2H),5.32(s,1H),4.54(d,2H),3.89(s,3H),3.53(s,2H),2.93–2.82(m,4H),2.61–2.43(m,3H)ppm; LCMS:474.2[M+H] + .

[0536] Example 25: 1-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-3-(pyridin-4-yl)urea (Compound 25)

[0537] In a 100 mL round-bottom flask, compound 23e (150 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL), and 1,1'-carbonyldiimidazole (143 mg, 0.88 mmol) was added. The reaction was carried out at room temperature for 24 h. Then, 4-aminopyridine (124 mg, 1.32 mmol) was added, and the reaction was continued at room temperature for 2 h. The mixture was quenched with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by C18 reversed-phase column chromatography to give compound 25 as a white solid (15 mg, 7% yield). 1 H NMR(400MHz, CDCl3)δ8.74(s,1H),8.53(s,1H),8.50(d,2H),8.06(s,1H),7.53(d,2H),7.36(d,1H),7.34–7.30(m,1 H),7.24(d,1H),6.25(d,1H),3.92(s,3H),3.59(s,2H),2.97–2.89(m,4H),2.64–2.53(m,4H)ppm; LCMS:460.2[M+H] + .

[0538] Example 26: 1-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-3-((tetrahydro-2H-pyran-4-yl)methyl ester)urea (compound 26)

[0539] In a 100 mL round-bottom flask, compound 23e (150 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL), and 1,1'-carbonyldiimidazole (143 mg, 0.88 mmol) was added. The reaction was carried out at room temperature for 24 h. Then (tetrahydro-2H-pyran-4-yl)methylamine (152 mg, 1.32 mmol) was added, and the reaction was continued at room temperature for 2 h. The mixture was quenched with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by C18 reversed-phase column chromatography to give compound 26 as a white solid (60 mg, 28% yield). 1H NMR(500MHz, CDCl3)δ8.43(s,1H),7.49(s,1H),7.34(s,1H),7.24(d,1H), 7.19(d,1H),6.24(s,1H),4.93(s,1H),4.05–3.97(m,2H),3.91(s,3H),3. 64(s,2H),3.41(t,2H),3.20(t,2H),2.94(s,4H),2.80–2.59(m,2H),1.92 –1.79(m,1H),1.75–1.69(m,4H),1.42–1.31(m,2H)ppm; LCMS:481.2[M+H] + Example 27: 1-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)urea (compound 27)

[0540] In a 100 mL round-bottom flask, compound 23e (150 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL), and 1,1'-carbonyldiimidazole (143 mg, 0.88 mmol) was added. The reaction was carried out at room temperature for 24 h. Then, tetrahydro-2H-pyran-4-amine (133 mg, 1.32 mmol) was added, and the reaction was continued at room temperature for 2 h. The mixture was quenched with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by C18 reversed-phase column chromatography to give compound 27 as a white solid (20 mg, 10% yield). 1 H NMR(500MHz, CDCl3)δ8.44(s,1H),7.46(s,1H),7.35(s,1H),7.25(d,1H),7.20(d,1H),6.25(s,1H),4.68(d,1H),4.05–3.97(m,2H),3.95 –3.85(m,4H),3.67(s,2H),3.51(t,2H),2.98–2.89(m,4H),2.80–2.57(m,4H),2.05–1.96(m,2H),1.60–1.48(m,2H)ppm; LCMS:467.2[M+H] + .

[0541] Example 28: 8-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-yl)-5-(trifluoromethyl)quinazoline (Compound 28)

[0542] Step 1: 2-Chloro-8-methoxyquinazoline (28b)

[0543] In a 250 mL round-bottom flask, compound 28a (5.0 g, 21.80 mmol), palladium / carbon (200 mg, 10%), and sodium bicarbonate (5.00 g) were sequentially added to 70 mL of methanol. The reaction was carried out at room temperature for 4 h under a hydrogen atmosphere. The reaction was quenched with aqueous solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 28b as a white solid (3.60 g, 85% yield). LCMS: 195.1 [M+H] + .

[0544] Step 2: 5-Bromo-2-chloro-8-methoxyquinazoline (28c)

[0545] In a 250 mL round-bottom flask, compound 28b (3.60 g, 18.50 mmol) and N-bromosuccinimide (6.59 g, 37.00 mmol) were sequentially added to acetonitrile (70 mL), and the reaction was carried out at room temperature for 4 h. The reaction was quenched with aqueous solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 28c as a yellow solid (2.50 g, yield 54%). LCMS: 273.1 [M+H] + .

[0546] Step 3: 2-Chloro-8-methoxy-5-(trifluoromethyl)quinazoline (28d)

[0547] In a 250 mL round-bottom flask, compound 28c (2.50 g, 9.20 mmol), cuprous iodide (2.70 g, 14.30 mmol), and methyl fluorosulfonyl difluoroacetate (3.60 g, 19.00 mmol) were sequentially added to 70 mL of N,N-dimethylformamide and reacted at 90 °C for 24 h. The reaction was quenched with aqueous solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 28d as a yellow solid (1.30 g, yield 54%). LCMS: 263.1 [M+H] + .

[0548] Step 4: 8-Methoxy-2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-yl)-5-(trifluoromethyl)quinazoline (28e)

[0549] In a 100 mL round-bottom flask, compound 28d (1.30 g, 4.96 mmol), compound 23k (1.37 g, 5.93 mmol), ethylene glycol dimethyl ether nickel bromide (105 mg, 0.34 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (92 mg, 0.34 mmol), and zinc powder (640 mg, 10 mmol) were sequentially added to N,N-dimethylformamide (20 mL), and the reaction was carried out at 60 °C for 4 h. The reaction was quenched with aqueous solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 28e as a yellow solid (400 mg, yield 32%). LCMS: 379.1 [M+H] + .

[0550] Step 5: 2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-yl)-5-(trifluoromethyl)quinazoline-8-ol (28f)

[0551] In a 250 mL round-bottom flask, compound 28e (380 mg, 1.00 mmol) and boron tribromide (0.50 g, 2.00 mmol) were added sequentially to 10 mL of dichloromethane and reacted at -20 °C for 8 h. The reaction was quenched with sodium bicarbonate aqueous solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 28f as a yellow solid (0.30 g, 82% yield). LCMS: 365.1 [M+H] + .

[0552] Step 6: 2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-yl)-5-(trifluoromethyl)quinazoline-8-trifluoromethanesulfonate (28g)

[0553] In a 250 mL round-bottom flask, compound 28f (300 mg, 0.82 mmol), pyridine (240 mg, 3.00 mmol), and trifluoromethanesulfonic anhydride (0.46 g, 16.40 mmol) were sequentially added to 10 mL of dichloromethane and reacted at 0 °C for 8 h. The reaction was quenched with sodium bicarbonate aqueous solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 28g as a yellow solid (150 mg, yield 37%). LCMS: 497.1 [M+H] + .

[0554] Step 7: 8-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-yl)-5-(trifluoromethyl)quinazoline (compound 28)

[0555] In a 250 mL round-bottom flask, 28 g (150 mg, 0.30 mmol) of compound was dissolved in 1,4-dioxane (10 mL), followed by the addition of 1-((1-methyl-1H-pyrazol-3-yl)methyl)piperazine (181 mg, 1.00 mmol), cesium carbonate (195 mg, 0.60 mmol), and finally tris(dibenzylacetone)palladium (28 mg, 0.03 mmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (37 mg, 0.06 mmol). The reaction was carried out at 100 °C for 12 h. The reaction was quenched with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 28 as a white solid (30 mg, 19% yield). 1 H NMR(500MHz, CDCl3)δ9.65(s,1H),7.75(d,1H),7.36(d,2H),7.15(d,1H),6.38–6.30(m,1H),6.28(d,1H),4.11(d,2H),3.93(s,3H),3 .88–3.78(m,2H),3.78–3.64(m,4H),3.64–3.54(m,2H),3.14–2.86(m,5H),2.13–2.04(m,2H),1.94–1.83(m,2H)ppm; LCMS:527.2[M+H] + .

[0556] Example 29: 2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-N-(5-(tetrahydro-2H-pyran-4-yl)furan-2-yl)-5-(trifluoromethyl)benzamide (Compound 29)

[0557] Step 1: tert-butyl 4-(2-(methoxycarbonyl)-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (29b)

[0558] In a 250 mL round-bottom flask, compound 29a (4.00 g, 14.20 mmol) was dissolved in 1,4-dioxane (100 mL), followed by piperazine-1-carboxylic acid tert-butyl ester (5.30 g, 28.40 mmol), cesium carbonate (13.80 g, 42.60 mmol), and finally tris(dibenzylacetone)palladium (1.30 g, 1.40 mmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.76 g, 2.82 mmol). The reaction was carried out at 100 °C for 12 h. The reaction was quenched with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 29b as a yellow solid (1.81 g, 33% yield). LCMS: 389.2 [M+H] + .

[0559] Step 2: Methyl 2-(piperazin-1-yl)-5-(trifluoromethyl)benzoate hydrochloride (29c)

[0560] In a 100 mL round-bottom flask, compound 29b (1.8 g, 4.64 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of 1,4-dioxane hydrochloride solution (5 mL, 4 M), and the reaction was allowed to proceed at room temperature for 4 h. The solvent was directly evaporated to give compound 29c, a yellow solid (1.50 g, 99% yield). LCMS: 289.1 [M+H] + .

[0561] Step 3: Methyl 2-(4-((1-methyl-1H-pyrazole-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)benzoate (29d)

[0562] In a 100 mL round-bottom flask, compound 29c (1.50 g, 4.60 mmol) was dissolved in 20 mL of methanol, followed by the addition of 0.97 g, 8.80 mmol of 3-aldehyde-1-methylpyrazole, and then sodium cyanoborohydride (0.88 g, 14.00 mmol). The reaction was carried out at room temperature for 6 h. The mixture was quenched with water, extracted with ethyl acetate, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 29d as a yellow solid (1.41 g, 80% yield). LCMS: 382.2 [M+H] + .

[0563] Step 4: 2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)benzoic acid (29e)

[0564] In a 100 mL round-bottom flask, compound 29d (1.4 g, 3.67 mmol) was dissolved in methanol / water (5:1, 20 mL), and lithium hydroxide (264 mg, 11.00 mmol) was added. The reaction was carried out at room temperature for 6 h. The mixture was acidified with hydrochloric acid (2 M), extracted with ethyl acetate, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 29e as a white solid (1.10 g, 81% yield). LCMS: 369.2 [M+H] + .

[0565] Step 5: 2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)benzamide (29f)

[0566] In a 100 mL round-bottom flask, compound 29e (0.74 g, 2.00 mmol) was dissolved in N,N-dimethylformamide (10 mL). Under ice bath conditions, N,N-diisopropylethylamine (260 mg, 2.00 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (988 mg, 2.60 mmol) were added, and the reaction was continued under ice bath conditions for 5 min. Then, 4 mL of ammonia in methanol was added, and the reaction was continued for another 5 min. The mixture was quenched with water, extracted with ethyl acetate, and the concentrated organic phase was collected to obtain the crude product. Column chromatography was used to purify compound 29f as a white solid (0.50 g, 68% yield). LCMS: 368.2 [M+H] + .

[0567] Step 6: 2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-N-(5-(tetrahydro-2H-pyran-4-yl)furan-2-yl)-5-(trifluoromethyl)benzamide (compound 29)

[0568] In a 100 mL round-bottom flask, compound 29f (0.20 g, 0.54 mmol), compound 23k (230 mg, 1.00 mmol), and potassium carbonate (298 mg, 2.16 mmol) were dissolved in 1,4-dioxane (10 mL). Cuprous iodide (103 mg, 0.54 mmol) and N,N'-dimethylethylenediamine (48 mg, 0.54 mmol) were added under a nitrogen atmosphere, and the reaction was carried out at 100 °C for 1 h. The mixture was filtered through a silica gel short column after adding ethyl acetate (30 mL), and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 29 as a white solid (50 mg, yield 18%). 1 H NMR (400MHz, CDCl3) δ12.83(s,1H),8.58(s,1H),7.79–7.68(m,1H),7.43( d,1H),7.35(d,1H),6.43(d,1H),6.24(d,1H),6.08(d,1H),4.14–4.02(m, 2H),3.92(s,3H),3.65(s,2H),3.63–3.53(m,2H),3.22–3.11(m,4H),3.05 –2.56(m,5H),2.05–1.94(m,2H),1.91–1.77(m,2H)ppm; LCMS:518.2[M+H] + .

[0569] Example 30: 5-(2,6-dichloropyridin-4-yl)-N-(2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 30)

[0570] Step 1: 5-Bromo-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (30a)

[0571] In a 10 mL round-bottom flask, compound 23e (1.02 g, 3.00 mmol) and methyl 5-bromofuran-2-carboxylate (0.81 g, 4.50 mmol) were dissolved in tetrahydrofuran (10 mL) and then added dropwise to a tetrahydrofuran (10 mL) solution of potassium tert-butoxide (0.67 g, 6.00 mmol). The reaction was allowed to proceed for 30 min. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 30a as a white solid (1.10 g, 72% yield). LCMS: 512.1 [M+H] + Step 2: 5-(2,6-dichloropyridin-4-yl)-N-(2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 30)

[0572] In a 100 mL round-bottom flask, compound 30a (0.20 g, 0.40 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (273 mg, 1.00 mmol), and potassium carbonate (138 mg, 1.00 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (8 mg, 0.01 mmol) was added under a nitrogen atmosphere, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Column chromatography was used to purify compound 30 as a white solid (60 mg, yield 26%). 1 H NMR(500MHz,DMSO-d6)δ9.79(s,1H),8.39(s,1H),8.13(s,2H),7.75(d,1H),7.56(d,1H),7.54(d,1H),7.50(d,1H ),7.45(d,1H),6.09(d,1H),3.75(s,3H),3.48(s,2H),3.03–2.89(m,4H),2.73–2.55(m,4H)ppm; LCMS:579.2[M+H] + .

[0573] Example 31: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 31)

[0574] Step 1: (2,6-Diaminopyridin-4-yl)boronic acid (compound 31b)

[0575] At room temperature, compound 31a (1.00 g, 5.32 mmol), 1,4-dioxane (30 mL), pinacol diborate (5.40 g, 21.27 mmol), potassium acetate (2.09 g, 21.27 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.39 g, 0.53 mmol) were added to a 100 mL round-bottom flask. The mixture was reacted at 100 °C for 4 h under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol, the filtrate was collected, and the organic solvent was removed under reduced pressure. The residue was purified by preparative liquid chromatography to give compound 31b (0.60 g, 73% yield). LCMS: 154.1 [M+H] + .

[0576] Step 2: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 31)

[0577] In a 100 mL round-bottom flask, compound 30a (0.20 g, 0.40 mmol), compound 31b (235 mg, 1.00 mmol), and potassium carbonate (138 mg, 1.00 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (8 mg, 0.01 mmol) was added under a nitrogen atmosphere, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Column chromatography was used to purify compound 31, a white solid (110 mg, 51% yield). 1 H NMR(500MHz,DMSO-d6)δ9.45(s,1H),8.52(s,1H),7.58(s,1H),7.50(d,1H),7.45(d,1H),7.42(d,1H),7.04(d,1H),6 .20–6.03(m,3H),5.64(s,4H),3.77(s,3H),3.44(s,2H),3.02–2.85(m,4H),2.76–2.56(m,4H)ppm; LCMS:541.2[M+H]+ .

[0578] Example 32: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 32)

[0579] In a 100 mL round-bottom flask, compound 30a (0.20 g, 0.40 mmol), (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boric acid (212 mg, 1.00 mmol), and potassium carbonate (138 mg, 1.00 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (8 mg, 0.01 mmol) was added under argon atmosphere, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Column chromatography was used to purify compound 32 as a white solid (85 mg, 43% yield). 1 H NMR(400MHz, CDCl3)δ9.52(s,1H),8.93(s,1H),8.08(s,2H),7.40–7.35(m,2H),7.34(d,1H),7.31–7.27(m ,2H),6.59(d,1H),6.35(s,1H),3.93(s,3H),3.70(s,2H),3.07(s,4H),2.85(s,4H)ppm; LCMS:500.2[M+H] + .

[0580] Example 33: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)pyridinecarboxamide (Compound 33)

[0581] Step 1: Methyl 5-(1-(tert-Butoxycarbonyl)-1H-pyrazole-4-yl)pyridinecarboxylate (33b)

[0582] In a 100 mL round-bottom flask, compound 33a (1.05 g, 5.00 mmol), (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boric acid (1.59 g, 7.50 mmol), and potassium carbonate (408 mg, 6.00 mmol) were dissolved in 1,4-dioxane / water (10:1, 20 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (8 mg, 0.50 mmol) was added under argon atmosphere, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The residue was purified by column chromatography to give 33b as a white solid (770 mg, yield 51%). LCMS: 304.2 [M+H] + .

[0583] Step 2: N-(2-(4-((1-methyl-1H-pyrazole-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (compound 33)

[0584] In a 50 mL round-bottom flask, compound 23e (678 mg, 2.00 mmol) and compound 33b (591 mg, 1.95 mmol) were dissolved in tetrahydrofuran (10 mL) and added dropwise to a mixture of tetrahydrofuran (10 mL) and potassium tert-butoxide (448 mg, 4.00 mmol). The reaction was allowed to proceed for 30 min. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 33 as a white solid (50 mg, 5% yield). 1 H NMR (400MHz, CDCl3) δ11.05(s,1H),8.96(s,1H),8.86(s,1H),8.33(d,1H),8.08(s,2H),8.06–7.97(m,1H),7.43–7.34(m,2H),7.33 –7.21(m,1H),6.31(d,1H),3.92(s,3H),3.82–3.77(m,1H),3.75(s,2H),3.13–3.00(m,4H),2.98–2.72(m,4H)ppm; LCMS:511.2[M+H] + .

[0585] Example 34: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)pyridinecarboxamide (Compound 34)

[0586] Step 1: Methyl 5-(3,6-dihydro-2H-pyran-4-yl)pyridinecarboxylate (34a)

[0587] In a 100 mL round-bottom flask, compound 33a (500 mg, 2.30 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (840 mg, 4.00 mmol), and potassium carbonate (476 mg, 3.45 mmol) were dissolved in 1,4-dioxane / water (10:1, 20 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (188 mg, 0.23 mmol) was added under a nitrogen atmosphere, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Column chromatography purification yielded compound 34a as a white solid (450 mg, 89% yield). LCMS: 220.1 [M+H] + .

[0588] Step 2: Methyl 5-(tetrahydro-2H-pyran-4-yl)pyridinecarboxylate (34b)

[0589] In a 100 mL round-bottom flask, compound 34a (450 mg, 2.05 mmol) was dissolved in methanol / ethyl acetate (1:1, 20 mL), and palladium on carbon (225 mg, 10%) was added. The reaction was carried out at room temperature for 24 h under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth-lined funnel, the filter cake was washed with ethyl acetate, and the solution was concentrated to give compound 34b, a colorless oil (450 mg, 99% yield). LCMS: 222.1 [M+H] + .

[0590] Step 3: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)pyridinecarboxamide (compound 34)

[0591] In a 50 mL round-bottom flask, compound 23e (100 mg, 0.29 mmol) and compound 34b (105 mg, 0.50 mmol) were dissolved in THF (3 mL) and added dropwise to a mixture of tetrahydrofuran (3 mL) and potassium tert-butoxide (67 mg, 0.60 mmol). The reaction was allowed to proceed for 30 min. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 34 as a white solid (40 mg, yield 26%). 1H NMR(500MHz, CDCl3)δ11.05(s,1H),8.93(s,1H),8.56(d,1H),8.27(d,1H) ,7.84–7.68(m,1H),7.37(d,2H),7.25(d,1H),6.29(d,1H),4.23–4.11(m, 2H),3.92(s,3H),3.72(s,2H),3.66–3.56(m,2H),3.10–3.01(m,4H),3.00 –2.92(m,1H),2.92–2.64(m,4H),1.98–1.82(m,4H)ppm; LCMS:529.2[M+H] + .

[0592] Example 35: 5-(3,5-diaminophenyl)-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 35)

[0593] In a 100 mL round-bottom flask, compound 30a (0.1 g, 0.20 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl-1,3-diamine (117 mg, 0.50 mmol), and potassium carbonate (70 mg, 0.50 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (8 mg, 0.01 mmol) was added under a nitrogen atmosphere, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Column chromatography purification yielded compound 35, a pale yellow solid (25 mg, yield 23%). 1 H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.50(s,1H),8.26(s,1H),7.73(s,1H),7.51(d,2H),7.47–7.42(m,2H),7.42–7.38(m,1H),6.90–6 .82(m,1H),6.52–6.37(m,3H),6.31–6.22(m,1H),6.10–5.97(m,1H),4.33(s,3H),3.91–3.84(m,6H),3.24(s,4H)ppm; LCMS:540.2[M+H] + .

[0594] Example 36: 5-(4-amino-1H-indol-6-yl)-N-(2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 36)

[0595] In a 100 mL round-bottom flask, compound 30a (0.10 g, 0.20 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-indole-4-amine (130 mg, 0.50 mmol), and potassium carbonate (70 mg, 0.50 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (8 mg, 0.01 mmol) was added under a nitrogen atmosphere, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Column chromatography was used to purify compound 36, a pale yellow solid (25 mg, yield 21%). 1 H NMR (400MHz, CDCl3) δ11.53(s,1H),9.49(s,1H),9.06(s,1H),7.61(s,1H),7.46(s,1H),7.44–7.35(m,2H),7.35–7.22(m,3H),6.84–6. 71(m,2H),6.54(s,1H),6.52–6.34(m,1H),4.31–4.03(m,1H),3.98(s,3H),3.92–3.66(m,2H),3.33–2.65(m,8H)ppm; LCMS:564.2[M+H] + .

[0596] Example 37: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide (Compound 37)

[0597] Step 1: tert-butyl 4-(2-amino-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (37a)

[0598] Compound 23b (10.00 g, 26.64 mmol), ethanol (60 mL), and palladium on carbon (1.00 g, 10%) were added to a 250 mL round-bottom flask at room temperature. The mixture was purged three times with hydrogen gas, and reacted at 55 °C for 2 h under hydrogen balloon conditions. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 37a, a colorless oil (9.10 g, 98% yield). LCMS: 346.2 [M+H]+ .

[0599] Step 2: tert-butyl 4-(2-(5-bromofuran-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (37b)

[0600] In a 100 mL reaction tube, potassium tert-butoxide (1.95 g, 17.40 mmol) was dissolved in tetrahydrofuran (20 mL), and a mixed solution of compound 37a (2.00 g, 5.80 mmol) and methyl 5-bromo-furan-2-carboxylate (1.65 g, 8.12 mmol) in tetrahydrofuran (20 mL) was added. The reaction was carried out at room temperature for 4 h. The mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 37b (2.90 g, yield: 96%) as a white oily solid. LCMS: 518.1 [M+H] + .

[0601] Step 3: 5-Bromo-N-(2-(piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (37c)

[0602] In a 100 mL round-bottom flask, compound 37b (2.90 g, 5.60 mmol) was dissolved in dichloromethane (30 mL). Dioxane hydrochloride (10 mL, 4 M) was added dropwise under ice bath conditions, and the mixture was slowly heated to room temperature for 4 h. The organic solvent was removed under reduced pressure to give a white oily solid, compound 37c (2.21 g, yield: 96%). LCMS: 418.0 [M+H] + .

[0603] Step 4: 5-Bromo-N-(2-(4-(((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (37d)

[0604] In a 50 mL round-bottom flask, compound 37c (1.00 g, 2.40 mmol) and 3-aldehyde-1-methylpyrazole (528 mg, 4.80 mmol) were dissolved in methanol (10 mL). The mixture was reacted at room temperature for 2 h, followed by the addition of sodium cyanoborohydride (756 mg, 12.00 mmol) and the reaction was continued at room temperature for 12 h. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 37d as a white solid (610 mg, yield: 50%). LCMS: 512.1 [M+H] + .

[0605] Step 5: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide (Compound 37)

[0606] Under nitrogen protection, compound 37d (123 mg, 0.24 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoborane-2-yl)-1-methylpyrazole (76 mg, 0.36 mmol), potassium carbonate (67 mg, 0.48 mmol), 1,1'-bis(diphenylphosphine)ferrocene]palladium dioxide (18 mg, 0.02 mmol), and a 1,4-dioxane / water mixture (10 mL / 2 mL) were added sequentially to a 100 mL three-necked flask. The mixture was heated to 100 °C and reacted for 6 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 37, a white solid (47 mg, yield: 38%). 1 H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.35(s,1H),8.21(s,1H),7.89(s,1H),7.72(s,1H),7.47(d,1H),7.35(s,2H) ,6.73(s,1H),6.32(s,1H),4.30(s,2H),3.87(s,3H),3.78(s,3H),3.67(s,4H),3.27(s,4H)ppm; LCMS:514.2[M+H] + .

[0607] Example 38: 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-(4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)pyridineamide (Compound 38)

[0608] Step 1: Methyl 5-(1-methyl-1H-pyrazole-4-yl)pyridinecarboxylate (38c)

[0609] Under nitrogen protection, in a 100 mL three-necked flask, compounds 38a (1.00 g, 4.63 mmol), 38b (1.45 g, 6.94 mmol), potassium carbonate (1.28 g, 9.26 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dioxide (339 mg, 0.46 mmol), and a 1,4-dioxane / water mixture (20 mL / 4 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 6 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 38c, a white solid (0.80 g, yield: 80%). LCMS: 218.1 [M+H] + .

[0610] Step 2: 5-(1-methyl-1H-pyrazole-4-yl)pyridinecarboxylic acid (38d)

[0611] In a 100 mL round-bottom flask, compound 38c (800 mg, 3.68 mmol), lithium hydroxide (170 mg, 7.37 mmol), and a tetrahydrofuran / water mixture (10 mL / 1 mL) were added sequentially, and the mixture was reacted at room temperature for 6 h. After the reaction was complete, 2 M hydrochloric acid was added to adjust the pH to acidic, and the mixture was filtered. The filter cake was evaporated to dryness under reduced pressure to give compound 38d as a white solid (718 mg, yield: 96%). LCMS: 204.1 [M+H] + .

[0612] Step 3: tert-butyl 4-(2-(5-(1-methyl-1H-pyrazole-4-yl)pyridinamido)-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (38e)

[0613] In a 100 mL round-bottom flask, compound 38d (500 mg, 2.46 mmol), compound 37a (773 mg, 2.24 mmol), and N-methylimidazole (340 mg, 3.36 mmol) were dissolved in acetonitrile. N,N,N',N'-tetramethylchloromethanemidane hexafluorophosphate (965 mg, 3.36 mmol) was added with stirring, and the reaction was carried out at room temperature for 12 h. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative chromatography under medium pressure to give 38e as a white solid (100 mg, yield: 8%). LCMS: 531.2 [M+H] + .

[0614] Step 4: 5-(1-Methyl-1H-pyrazole-4-yl)-N-(2-(piperazin-1-yl)-5-(trifluoromethyl)phenyl)pyridineamide (38f)

[0615] In a 50 mL round-bottom flask, compound 38e (100 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL). Dioxane hydrochloride (1 mL, 4 M) was added dropwise under ice bath conditions, and the mixture was slowly heated to room temperature for 4 h. The organic solvent was removed under reduced pressure to give compound 38f, a white solid, which could be used directly in the next step without purification. LCMS: 431.2 [M+H] + .

[0616] Step 5: 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-(4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)pyridineamide (compound 38)

[0617] In a 50 mL round-bottom flask, compound 38f (81 mg, 0.19 mmol) and 3-aldehyde 1-methylpyrazole (42 mg, 0.38 mmol) were dissolved in methanol (5 mL). After reacting at room temperature for 2 h, sodium cyanoborohydride (36 mg, 0.57 mmol) was added, and the reaction was continued at room temperature for 12 h. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 38 as a white solid (40 mg, yield: 40%). 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.04(s,1H),8.78(s,1H),8.44(s,1H),8.29(d,1H),8.18(d,1H),8.13(s,1H),7. 87(s,1H),7.50(dd,2H),6.59(s,1H),3.96(s,3H),3.89(s,3H),3.48(s,6H),3.30–3.20(m,4H)ppm; LC-MS: 525.2[M+H] + .

[0618] Example 39: 5-(2-aminopyridin-4-yl)-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 39)

[0619] Step 1: 5-(2-aminopyridin-4-yl)-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 39)

[0620] Under nitrogen protection, in a 100 mL three-necked flask, compound 30a (105 mg, 0.20 mmol), pinacol 2-aminopyridine-4-borate (68 mg, 0.30 mmol), potassium carbonate (57 mg, 0.41 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (15 mg, 0.02 mmol), and a mixed solvent of 1,4-dioxane / water (10 mL / 2 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 6 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 39 as a white solid (90 mg, yield: 83%). 1 H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.23(s,2H),8.12(d,1H),7.81(s,1H),7.69(s,1H),7.61(d, 1H),7.49–7.33(m,2H),6.41(s,1H),4.37(s,2H),3.86(s,3H),3.56(s,6H),3.39–3.16(m,4H)ppm.

[0621] Example 40: 5-(2-hydroxypyridin-4-yl)-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 40)

[0622] Step 1: 5-(2-hydroxypyridin-4-yl)-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 40)

[0623] Under nitrogen protection, compound 30a (145 mg, 0.28 mmol), pinacol 2-hydroxypyridine-4-borate (94 mg, 0.43 mmol), potassium carbonate (79 mg, 0.57 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (21 mg, 0.03 mmol), and a mixed solvent of 1,4-dioxane / water (10 mL / 2 mL) were added sequentially to a 100 mL three-necked flask. The mixture was heated to 100 °C and reacted for 6 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 40 as a white solid (110 mg, yield: 73%). 1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.43(s,1H),7.80(s,1H),7.58(t,2H),7.47(d,3H),7. 02(s,1H),6.73(d,1H),6.41(s,1H),4.47(s,1H),3.88(s,3H),3.68(s,6H),3.22(d,4H)ppm. LCMS:527.2[M+H] + .

[0624] Example 41: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)furan-2-carboxamide (Compound 41)

[0625] Step 1: 4-(4-bromo-2-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (41b)

[0626] Compound 41a (23 g, 100 mmol), N-tert-butyloxycarbonylpiperazine (20 g, 210 mmol), and potassium carbonate (27.6 g, 200 mmol) were sequentially added to anhydrous N,N-dimethylformamide (300 mL). The mixture was stirred at 80 °C for 8 h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 41b (31 g, yield: 81%). LCMS: 386.1 [M+H] + .

[0627] Step 2: 4-(4-((3-(2-ethylhexyl)oxy)-3-oxopropyl)thio)-2-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (41c)

[0628] In a 250 mL round-bottom flask, compound 41b (1.16 g, 3.0 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of 2-ethylhexyl 3-mercaptopropionate (981 mg, 4.5 mmol), potassium carbonate (828 mg, 6.0 mmol), and finally tris(dibenzylacetone)dipalladium (27.5 mg, 0.3 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (347 mg, 0.6 mmol). The reaction was carried out at 100 °C for 8 h. The reaction was quenched with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The residue was purified by column chromatography to give compound 41c (1.4 g, 92% yield). LCMS: 524.2 [M+H] + .

[0629] Step 3: 4-(2-amino-4-((3-(2-ethylhexyl)oxy)-3-oxopropyl)thio)phenyl)piperazine-1-carboxylic acid tert-butyl ester (41d)

[0630] Compound 41c (1.4 g, 2.68 mmol) and 10% palladium on carbon (140 mg) were added sequentially to ethanol (15 mL). The mixture was stirred at 60 °C for 8 h. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain crude compound 41d (1.35 g). LCMS: 494.2 [M+H] + .

[0631] Step 4: 4-(2-amino-4-mercaptophenyl)piperazine-1-carboxylic acid tert-butyl ester (41e)

[0632] Compound 41d (17 g, 34.48 mmol) and potassium tert-butoxide (5.8 g, 51.72 mmol) were added sequentially to tetrahydrofuran (200 mL). The mixture was stirred at 25 °C for 1 h. After the reaction was complete, saturated ammonium chloride was added to quench the reaction. The mixture was extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The residue was purified by column chromatography to give compound 41e (7.1 g, 44% yield). LCMS: 310.2 [M+H] + .

[0633] Step 5: 4-(2-amino-4-((trifluoromethyl)thio)phenyl)piperazine-1-carboxylic acid tert-butyl ester (41f)

[0634] Compound 41e (6.7 g, 21.68 mmol), triethylamine (6.5 g, 65 mmol), and 5-(trifluoromethyl)-5H-dithionthanthracene-5-onium trifluoromethanesulfonate (14 g, 32.5 mmol) were sequentially added to N,N-dimethylformamide (100 mL). The mixture was stirred at 40 °C for 2 h. After the reaction was complete, water was added to quench the reaction mixture. The mixture was extracted with ethyl acetate, and the concentrated organic phase was collected to obtain the crude product. The residue was purified by column chromatography to give compound 41f (3.8 g, 47% yield). LCMS: 378.2 [M+H] + .

[0635] Step 6: 4-(2-(5-bromofuran-2-carboxamido)-4-((trifluoromethyl)thio)phenyl)piperazine-1-carboxylic acid tert-butyl ester (41g)

[0636] In a 100 mL round-bottom flask, compound 41f (377 mg, 1.0 mmol) and methyl 5-bromofuran-2-carboxylate (374 mg, 1.84 mmol) were dissolved in THF (10 mL), and then added dropwise to a mixture of tetrahydrofuran (5 mL) and potassium tert-butoxide (346 mg, 3.1 mmol). The reaction was allowed to proceed for 30 min. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The residue was purified by column chromatography to give compound 41 g (480 mg, yield 87%). LCMS: 550.1 [M+H] + Step 7: 5-Bromo-N-(2-(piperazin-1-yl)-5-(trifluoromethyl)thio)phenyl)furan-2-carboxamide (41h)

[0637] In a 50 mL round-bottom flask, 41 g (480 mg, 0.87 mmol) of compound was dissolved in 10 mL of dichloromethane. Dioxane hydrochloride (1 mL, 4 mol / L) was added dropwise under ice bath conditions, and the mixture was slowly heated to room temperature for 4 h. The organic solvent was removed under reduced pressure to give crude compound 41 h (390 mg). LCMS: 450.2 [M+H] + .

[0638] Step 8: 5-Bromo-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)furan-2-carboxamide (41j)

[0639] In a 100 mL round-bottom flask, compound 41h (390 mg, 0.87 mmol) was dissolved in 10 mL of methanol. 1-Methyl-1H-pyrazole-3-carboxaldehyde (220 mg, 2.0 mmol) was added, followed by the addition of sodium cyanoborohydride (280 mg, 4.51 mmol) in portions. The reaction was carried out at room temperature for 6 h. The mixture was quenched with water, concentrated, extracted with ethyl acetate, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 41j (440 mg, 94% yield). LCMS: 544.1 [M+H] + .

[0640] Step 9: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)furan-2-carboxamide (Compound 41)

[0641] In a 100 mL round-bottom flask, compound 41j (163 mg, 0.30 mmol), compound 31b (141 mg, 0.60 mmol), and potassium carbonate (83 mg, 0.60 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (25 mg, 0.03 mmol) was added under a nitrogen atmosphere, and the reaction was carried out at 100 °C for 6 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by high-performance liquid chromatography to obtain compound 41 (110 mg, yield 64%). 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.25(d,1H),7.80(d,1H),7.61–7.41(m,6H),7.41–7.31(m, 2H),6.42(s,2H),6.39(d,1H),4.35(s,2H),3.87(s,3H),3.47–3.02(m,8H)ppm; LCMS:573.1[M+H] + .

[0642] Example 42: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 42)

[0643] In a 100 mL round-bottom flask, compound 41j (163 mg, 0.3 mmol), (1-(tert-butyloxycarbonyl)-1H-pyrazol-4-yl)boric acid (124 mg, 0.6 mmol), and potassium carbonate (83 mg, 0.6 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (24.6 mg, 0.03 mmol) was added under nitrogen atmosphere, and the reaction was carried out at 100 °C for 6 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by high-performance liquid chromatography to obtain compound 42 (95 mg, 60% yield). 1 H NMR(500MHz,DMSO-d6)δ10.38(s,1H),9.34(s,1H),8.40(d,1H),8.18(s,2H),7.79(d,1H),7.56–7.47(m,1H),7.40 (d,1H),7.37(d,1H),6.81(d,1H),6.35(d,1H),4.36(s,2H),3.86(s,3H),3.61–3.28(m,8H)ppm; LCMS:532.2[M+H]+ .

[0644] Example 43: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(1H-pyrazol-4-yl)pyridinecarboxamide (Compound 43)

[0645] Step 1: 4-(2-(5-bromopyridinecarboxamido)-4-((trifluoromethyl)thio)phenyl)piperazine-1-carboxylic acid tert-butyl ester (43a)

[0646] In a 100 mL round-bottom flask, compound 41f (377 mg, 1.0 mmol) and methyl 5-bromopyridinecarboxylate (324 mg, 1.5 mmol) were dissolved in tetrahydrofuran (10 mL), and then added dropwise to a mixture of tetrahydrofuran (20 mL) and potassium tert-butoxide (346 mg, 3.1 mmol). The reaction was allowed to proceed for 30 min. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 43a (460 mg, 82% yield). LCMS: 561.1 [M+H] + Step 2: 5-Bromo-N-(2-(piperazin-1-yl)-5-(trifluoromethyl)thio)phenyl)pyridinecarboxamide (43b)

[0647] In a 50 mL round-bottom flask, compound 43a (0.46 g, 0.82 mmol) was dissolved in 10 mL of dichloromethane. Hydrochloric acid / 1,4-dioxane (1 mL, 4 mol / L) was added dropwise under ice bath conditions, and the mixture was slowly heated to room temperature for 4 h. The organic solvent was removed under reduced pressure to give crude compound 43b (0.39 g). LCMS: 461.2 [M+H] + .

[0648] Step 3: 5-Bromo-N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)pyridinecarboxamide (43c)

[0649] In a 100 mL round-bottom flask, compound 43b (0.39 g, 0.82 mmol) was dissolved in methanol (10 mL), followed by the addition of 1-methyl-1H-pyrazole-3-carboxaldehyde (0.22 g, 2.0 mmol), and then sodium cyanoborohydride (0.28 g, 4.5 mmol) in portions. The reaction was carried out at room temperature for 6 h. The mixture was quenched with water, concentrated, extracted with ethyl acetate, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 43c (0.4 g, 88% yield). LCMS: 555.1 [M+H] + .

[0650] Step 4: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(1H-pyrazol-4-yl)pyridinecarboxamide (compound 43)

[0651] In a 100 mL round-bottom flask, compound 43c (111 mg, 0.2 mmol), (1-(tert-butyloxycarbonyl)-1H-pyrazol-4-yl)boric acid (141 mg, 0.6 mmol), and potassium carbonate (83 mg, 0.6 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (24.6 mg, 0.03 mmol) was added under a nitrogen atmosphere, and the reaction was carried out at 100 °C for 6 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by high-performance liquid chromatography to obtain compound 43 (20 mg, yield 19%). 1 H NMR(500MHz,DMSO-d6)δ13.27(s,1H),10.81(s,1H),9.01(d,1H),8.81(d,1H),8.55(s,1H),8.34–8.27(m,1H),8.21(s,1H),8.17(d,1H), 7.63(d,1H),7.48–7.42(m,1H),7.39(d,1H),6.20(d,1H),3.80(s,3H),3.59(s,2H),2.92(d,4H),2.81–2.58(m,4H)ppm; LCMS: 543.2[M+H] + .

[0652] Example 44: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(1H-pyrazol-4-yl)pyridinecarboxamide (Compound 44)

[0653] Step 1: Methyl 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridinecarboxylate (44a)

[0654] At room temperature, compound 33a (1.50 g, 6.94 mmol), 1,4-dioxane (30 mL), water (3 mL), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (2.90 g, 10.42 mmol), potassium carbonate (1.92 g, 13.89 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.51 g, 0.69 mmol) were added to a 100 mL round-bottom flask. The reaction was carried out under nitrogen protection at 100 °C for 5 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol, the filtrate was collected, the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound 44a (1.52 g, 76% yield). LCMS: 288.2 [M+H] + .

[0655] Step 2: tert-butyl-4-(2-nitro-4-(trifluoromethoxy)phenyl)piperazine-1-carboxylate (44c)

[0656] Compound 44b (15.00 g, 62.09 mmol), N,N-dimethylformamide (120 mL), potassium carbonate (25.75 g, 186.29 mmol), and N-tert-butyloxycarbonyl-piperazine (12.72 g, 68.31 mmol) were added to a 500 mL round-bottom flask at room temperature and reacted at 80 °C for 8 h. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 44c (16.5 g, 67% yield). LCMS: 392.2 [M+H] + .

[0657] Step 3: 1-(2-nitro-4-(trifluoromethoxy)phenyl)piperazine (44d)

[0658] Compound 44c (3.00 g, 7.67 mmol), 1,4-dioxane (10 mL), and hydrochloric acid / 1,4-dioxane solution (10 mL, 4 mol / L) were added to a 100 mL round-bottom flask at room temperature. The reaction was carried out at 25 °C for 3 h. The organic solvent was removed under reduced pressure to give crude compound 44d (2.80 g). LCMS: 292.2 [M+H] + .

[0659] Step 4: 1-((1-methyl-1H-pyrazol-3-yl)methyl)-4-(2-nitro-4-(trifluoromethoxy)phenyl)piperazine (44e)

[0660] At room temperature, compound 44d (300 mg, 1.03 mmol), 1,2-dichloroethane (20 mL), 1-methyl-1H-pyrazole-3-carboxaldehyde (170 mg, 1.55 mmol), and sodium borohydride acetate (652 mg, 3.09 mmol) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted under nitrogen protection at 25 °C for 8 h. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 44e (330 mg, yield, 83%). LCMS: 386.3 [M+H] + .

[0661] Step 5: 2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)aniline (44f)

[0662] Compound 44e (330 mg, 0.86 mmol), ethanol (10 mL), and palladium on carbon (150 mg, 10%) were added to a 50 mL round-bottom flask at room temperature. The mixture was purged three times with hydrogen and reacted under hydrogen balloon conditions at 55 °C for 3 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 44f (280 mg, yield, 92%). LCMS: 356.3 [M+H] + Step 6: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridinecarboxamide (44g)

[0663] At room temperature, in a 50 mL round-bottom flask, compound 44f (280 mg, 0.79 mmol), acetonitrile (10 mL), compound 44a (323 mg, 1.18 mmol), N-methylimidazole (129 mg, 1.57 mmol), and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (442 mg, 1.57 mmol) were added sequentially. The reaction was carried out under nitrogen protection at 25 °C for 8 h. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain crude compound 44 g (600 mg). LCMS: 611.2 [M+H] + .

[0664] Step 7: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(1H-pyrazol-4-yl)pyridinecarboxamide (compound 44)

[0665] At room temperature, compound 44 g (600 mg, 0.54 mmol), 1,4-dioxane (10 mL), and hydrochloric acid / 1,4-dioxane solution (10 mL, 4 mol / L) were added to a 50 mL round-bottom flask, and the mixture was reacted at 25 °C for 3 h. The organic solvent was removed under reduced pressure, and the residue was purified by high performance liquid chromatography to give compound 44 (22 mg, two-step yield 6%). 1 H NMR(400MHz,DMSO-d6)δ13.28(s,1H),10.99(s,1H),9.06–8.98(m,1H),8.56(s ,1H),8.50–8.47(m,1H),8.34–8.28(m,1H),8.22(s,1H),8.19–8.14(m,1H),7.6 7–7.60(m,1H),7.44–7.36(m,1H),7.17–7.05(m,1H),6.25–6.17(m,1H),3.81( s,3H),3.59(s,2H),2.93–2.88(m,4H),2.77–2.63(m,4H)ppm; LCMS: 527.1[M+H] + .

[0666] Example 45: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 45)

[0667] Step 1: Methyl 5-(1H-pyrazol-4-yl)furan-2-carboxylate (45b)

[0668] At room temperature, compound 45a (1.00 g, 4.88 mmol), 1,4-dioxane (30 mL), water (3 mL), (1-(tert-butyloxycarbonyl)-1H-pyrazol-4-yl)boric acid (1.24 g, 5.85 mmol), potassium carbonate (0.81 g, 5.85 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.36 g, 0.49 mmol) were added to a 100 mL round-bottom flask. The mixture was reacted at 90 °C for 4 h under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol, the filtrate was collected, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 45b as a pale yellow solid (610 mg, 65% yield). LCMS: 193.1 [M+H] + .

[0669] Step 2: Methyl 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)furan-2-carboxylate (45c)

[0670] At room temperature, compound 45b (200 mg, 1.04 mmol), dichloromethane (6 mL), 3,4-dihydro-2H-pyran (132 mg, 1.56 mmol), and p-toluenesulfonic acid (18 mg, 0.11 mmol) were added to a 50 mL round-bottom flask, and the mixture was reacted at 25 °C for 3 h. Water and dichloromethane were added for extraction and separation. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography to give compound 45c (230 mg, 80% yield). LCMS: 277.2 [M+H] + .

[0671] Step 3: 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)furan-2-carboxylic acid (45d)

[0672] Compound 45c (400 mg, 1.45 mmol), methanol (10 mL), water (10 mL), and lithium hydroxide (303 mg, 7.24 mmol) were added to a 100 mL round-bottom flask at room temperature and reacted at 25 °C for 5 h. The pH of the reaction mixture was adjusted to 5 with 2 M hydrochloric acid. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give compound 45d (300 mg, 79% yield). LCMS: 263.2 [M+H] + .

[0673] Step 4: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide (45e)

[0674] At room temperature, in a 100 mL round-bottom flask, compound 45d (300 mg, 1.14 mmol), acetonitrile (20 mL), compound 44f (270 mg, 0.76 mmol), N-methylimidazole (124 mg, 1.52 mmol), and N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (142 mg, 1.52 mmol) were added. The reaction was carried out under nitrogen protection at 25 °C for 8 h. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 45e (130 mg, yield, 28%). LCMS: 600.3 [M+H] + .

[0675] Step 5: N-(2-(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 45)

[0676] At room temperature, compound 45e (130 mg, 0.22 mmol), 1,4-dioxane (5 mL), and hydrochloric acid / 1,4-dioxane solution (3 mL, 4 mol / L) were added to a 50 mL round-bottom flask. The reaction was carried out at 25 °C for 3 h. The organic solvent was removed under reduced pressure, and the residue was purified by high-performance liquid chromatography to give compound 45 (66 mg, yield 59%). 1 H NMR(500MHz,DMSO-d6)δ13.38(s,1H),9.60(s,1H),8.36–8.25(m,2H),8.04(s,1H),7.61–7.55(m,1H),7.47–7.41(m,1H),7.38–7.33(m,1H),7 .13–7.07(m,1H),6.86–6.81(m,1H),6.16–6.10(m,1H),3.77(s,3H),3 .50(s,2H),2.85–2.93(m,4H),2.78–2.55(m,4H)ppm; LCMS: 516.2[M+H] + .

[0677] Example 46: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)furan-2-carboxamide (Compound 46)

[0678] Step 1: 5-Bromofuran-2-carboxylic acid (46a)

[0679] Compound 45a (1.00 g, 4.88 mmol), methanol (10 mL), water (10 mL), and lithium hydroxide (1.02 g, 24.39 mmol) were added to a 100 mL round-bottom flask at room temperature and reacted at 25 °C for 5 h. The pH of the reaction mixture was adjusted to 5 with 2 M hydrochloric acid. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give compound 46a (920 mg, 98% yield). LCMS: 190.9 [M+H] + .

[0680] Step 2: 5-Bromo-N-(2-(4-(((1-methyl-1H-pyrazole-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)furan-2-carboxamide (46b)

[0681] At room temperature, in a 100 mL round-bottom flask, compound 44f (370 mg, 1.04 mmol), acetonitrile (20 mL), compound 46a (298 mg, 1.56 mmol), N-methylimidazole (171 mg, 2.08 mmol), and N,N,N',N'-tetramethylchloromethanemidane hexafluorophosphate (584 mg, 2.08 mmol) were added sequentially. The reaction was carried out under nitrogen protection at 25 °C for 8 h. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 46b (340 mg, yield, 61%). LCMS: 528.2 [M+H] + Step 3: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)furan-2-carboxamide (Compound 46)

[0682] At room temperature, compound 46b (170 mg, 0.32 mmol), 1,4-dioxane (20 mL), water (4 mL), (2,6-diaminopyridin-4-yl)boric acid (74 mg, 0.48 mmol), potassium carbonate (89 mg, 0.64 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (24 mg, 0.03 mmol) were added to a 50 mL round-bottom flask. The mixture was reacted under nitrogen protection at 100 °C for 8 h. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by high-performance liquid chromatography to give compound 46 (126 mg, 70% yield). 1 H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.13–8.04(m,1H),7.85–7.78(m,1H),7.61–7.55(m,1H),7.46–7.34(m,6 H),7.28–7.19(m,1H),6.41–6.39(m,1H),6.36(s,2H),3.88(s,3H),3.58–3.52(m,10H)ppm; LCMS: 557.3[M+H] + .

[0683] Example 47: 5-{4-[amino(aza-methylene)methyl]phenyl}-N-(2-{4-[(1-methylpyrazol-3-yl)methyl]piperazin-1-yl}-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 47)

[0684] Step 1: {[(6E)-6-(4-bromophenyl)-2,2-dimethyl-4-oxoylide-5-aza-3-oxahexane-6-ylide]amino}methane-2-methylpropyl-2-yl ester (47b)

[0685] In a 100 mL round-bottom flask, compound 47a (792 mg, 4.0 mmol), 4-dimethylaminopyridine (49 mg, 0.4 mmol), and di-tert-butyl dicarbonate (3.5 g, 16 mmol) were sequentially added to 50 mL of dichloromethane and reacted at room temperature for 12 h. The reaction was quenched with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Compound 47b (1.4 g, 86% yield) was then purified directly by preparative high-performance liquid chromatography (HPLC). LCMS: 399.1 [M+H] + .

[0686] Step 2: {[(6E)-2,2-dimethyl-4-oxylidene-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl]-5-aza-3-oxahexyl-6-yl]amino}methane-2-methylpropyl-2-yl ester (47c)

[0687] In a 100 mL round-bottom flask, compound 47b (1.4 g, 3.5 mmol), pinacol diborate (1.1 g, 4.3 mmol), and potassium acetate (1.4 g, 14 mmol) were dissolved in 1,4-dioxane (25 mL). Under a nitrogen atmosphere, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (29 mg, 0.04 mmol) was added, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The residue was purified by column chromatography to give compound 47c (1.4 g, 90% yield). LCMS: 447.2 [M+H] + .

[0688] Step 3: {[(5E)-2,2-dimethyl-6-[4-(5-{[(2-{4-[(1-methylpyrazol-3-yl)methyl]piperazin-1-yl}-5-(trifluoromethyl)phenyl)amino]carbonyl}furan-2-yl)phenyl]-4-oxoylide-5-aza-3-oxahex-5-en-6-yl]amino}methane-2-methylpropyl-2-yl ester (47d)

[0689] In a 100 mL round-bottom flask, compound 47c (223 mg, 0.5 mmol), compound 37d (255 mg, 0.5 mmol), and potassium carbonate (136 mg, 1.0 mmol) were dissolved in 1,4-dioxane / water (10:1, 20 mL). Under a nitrogen atmosphere, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (29 mg, 0.04 mmol) was added, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. The crude product was purified by column chromatography to give compound 47d (250 mg, 67% yield). LCMS: 752.2 [M+H] + .

[0690] Step 4: 5-{4-[amino(aza-methylene)methyl]phenyl}-N-(2-{4-[(1-methylpyrazol-3-yl)methyl]piperazin-1-yl}-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 47)

[0691] In a 100 mL round-bottom flask, compound 47d (250 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.0 mL) was added. The reaction was carried out at room temperature for 4 h. The solvent was removed directly, and after the reaction was completed, the trifluoroacetate of compound 47 (135 mg, yield: 54%) was obtained by preparative liquid chromatography. 1 H NMR(500MHz,DMSO-d6)δ10.52(s,1H),9.75(s,1H),9.52–9.27(m,4H),8.28(s,1H),8.18(d,2H),8.01(d,2H),7.77(s,1H),7.62–7. 53(m,2H),7.51(d,1H),7.44(d,1H),6.36(s,1H),4.31(s,2H),3.84(s,3H),3.56–3.37(m,4H),3.25(s,4H)ppm; LCMS: 552.2[M+H]+.

[0692] Example 48: 5-(4-aminophenyl)-N-(2-{4-[(1-methylpyrazol-3-yl)methyl]piperazin-1-yl}-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 48)

[0693] Step 1: 5-(4-aminophenyl)-N-(2-{4-[(1-methylpyrazol-3-yl)methyl]piperazin-1-yl}-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 48)

[0694] In a 100 mL round-bottom flask, 4-aminophenylboronic acid (121 mg, 0.7 mmol), compound 37d (255 mg, 0.5 mmol), and potassium carbonate (136 mg, 1.0 mmol) were dissolved in 1,4-dioxane / water (10:1, 20 mL). Under a nitrogen atmosphere, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (29 mg, 0.04 mmol) was added, and the reaction was carried out at 100 °C for 8 h. The mixture was diluted with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Compound 48 (160 mg, 50% yield) was purified by preparative high-performance liquid chromatography. 1 H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.46(s,1H),7.82(d,1H),7.65(d,2H),7.55(d,1H),7.46(d,1H),7.42(d,1H),6.90(d,1H ),6.75(d,2H),6.39(d,1H),4.37(s,2H),4.06(s,2H),3.90(s,3H),3.70–3.48(m,2H),3.47–3.03(m,6H)ppm; LCMS:525.2[M+H] + Example 49: 5-(4-{[amino(aza-dimethyl)methyl]amino}phenyl)-N-(2-{4-[(1-methylpyrazol-3-yl)methyl]piperazin-1-yl}-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 49)

[0695] Step 1: 5-(4-{[amino(aza-indyl)methyl]amino}phenyl)-N-(2-{4-[(1-methylpyrazol-3-yl)methyl]piperazin-1-yl}-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 49)

[0696] In a 100 mL round-bottom flask, compound 48 (200 mg, 0.38 mmol), aminocyanide (80 mg, 1.91 mmol), and concentrated nitric acid (1.0 mmol) were dissolved in ethanol / water (1:1, 5 mL), and the mixture was reacted at 100 °C for 8 h. After dilution with water, the reaction solution was directly purified by preparative liquid chromatography to obtain nitrate of compound 49 (123 mg, yield 57%). 1H NMR(400MHz,DMSO-d6)δ10.57–10.07(m,1H),9.63(s,1H),8.38(s,1H),8.01(d,2H),7.90–7.68(m,5H),7.57(d,1H),7 .51(d,1H),7.49–7.37(m,3H),7.28(d,1H),6.39(d,1H),4.36(s,2H),3.86(s,3H),3.42(d,8H)ppm; LCMS:567.2[M+H] + .

[0697] Bioactivity test

[0698] Test Example 1: Determination of the inhibitory effect of the compound on SRPK1 kinase activity

[0699] The inhibitory effect of candidate compounds on SRPK1 kinase activity was evaluated using an in vitro kinase activity assay system (SRPK1 Kinase Enzyme System, Promega, catalog number VA7560). The specific methods are as follows:

[0700] 1. Experimental materials:

[0701] SRPK1 Kinase Enzyme System (Promega, VA7560); Reaction buffer; DTT (100 μM); ATP (30 μM); Substrate (0.2 mg / mL); ADP-Glo TM Reagents and Kinase Detection Reagent (Promega); Echo 655 liquid dispensing system (LABCYTE); 384-well white plates (PerkinElmer, catalog number 6007290); PHERAstar FSX multi-plate reader (BMG Labtech); GraphPad Prism 8.0 data analysis software.

[0702] 2. Experimental steps:

[0703] (1) The candidate compounds were prepared into 10 mM stock solutions with DMSO and then serially diluted 3 times to obtain 10 concentrations: 100 μM, 33.3 μM, 11.1 μM, 3.70 μM, 1.23 μM, 0.41 μM, 0.137 μM, 0.0457 μM, 0.0152 μM, and 0.005 μM.

[0704] (2) Use an Echo 655 dispensing system to transfer compounds of various concentrations to 384-well plates, 0.1 μL per well.

[0705] (3) Prepare 2×Kinase solution (containing 1×Reaction buffer, 0.3nM SRPK1 protein, 100μM DTT) and 2×ATP / Substrate solution (containing 1×Reaction buffer, 0.2mg / mL Substrate, 30μM ATP).

[0706] (4) Add 5 μL of 2×Kinase solution to each well in sequence, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 10 min.

[0707] (5) Add 5 μL of 2×ATP / Substrate solution to each well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 60 min.

[0708] (6) After the reaction was completed, add 5 μL of ADP-Glo ​​reagent to each well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 40 min; then add 10 μL of Kinase Detection Reagent, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 30 min.

[0709] 3. Detection and Analysis:

[0710] Chemiluminescence signals were detected using a BMG PHERAstar FSX microplate reader. Blank and control wells were included in the experiment. The inhibition rate (%) of the compounds against SRPK1 kinase activity was calculated based on the luminescence signals at each concentration. A nonlinear regression model was performed using GraphPad Prism 8.0, and the half-maximal inhibitory concentration (IC50) of the compounds was calculated using a four-parameter model. 50 The results are shown in Table 1.

[0711] Table 1

[0712] Test Example 2: Determination of the inhibitory effect of the compound on HUVEC cell tube formation in vitro

[0713] The inhibitory effect of the compound on angiogenesis was detected using an in vitro tube formation assay in HUVEC cells. The specific method is as follows:

[0714] 1. Experimental materials:

[0715] HUVEC cells (ATCC); ECGM medium (PromoCell, containing 5% fetal bovine serum (FBS) and 1% endothelial cell growth supplement ECGS); Matrigel (ThermoFisher, catalog number A1413202); 96-well cell culture plates (Corning, catalog number 3969); trypsin digestion solution; candidate compounds (DMSO stock solution); optical microscope and imaging system; image analysis software ImageJ.

[0716] 2. Experimental steps:

[0717] (1) Before the experiment, the Matrigel was melted at 4°C. After taking it out, 75 μL was added to each well and spread evenly on the bottom of the 96-well plate. It was then incubated at 37°C for 1 h to allow it to gel.

[0718] (2) HUVEC cells were routinely cultured in ECGM complete medium and placed in a 37°C, 5% CO2 incubator. When the cell confluence reached about 80%, the cells were harvested for experiments.

[0719] (3) The cells were seeded in 6-well plates, and the test compound was added to a final concentration of 2 μM. The cells were incubated overnight at 37°C and 5% CO2. An equal volume of DMSO was added to the blank control group.

[0720] (4) The next day, cells were digested with trypsin, collected, and resuspended in low-serum medium containing 2% FBS and 1% ECGS. Cells were counted and the concentration was adjusted to 2 × 10⁻⁶ cells / year. 5 cells / mL.

[0721] (5) Add 75 μL of cell suspension (containing the test compound or DMSO control) to each well, and finally seed 1.5 × 10⁶ cells per well. 4 Cells. Incubate the culture plate at 37°C in a 5% CO2 incubator for 6 hours.

[0722] 3. Detection and Analysis:

[0723] After incubation, each well was imaged using an inverted microscope at 100× field of view. The images were then quantitatively analyzed using ImageJ software to determine the number of nodes, meshes, and total length of each group. Based on the analyzed data, the inhibitory effect of each compound was scored (1-5 points, with 5 being the best) to evaluate its inhibitory effect on HUVEC tube formation. The results of the measurements and data analysis concluded that the compounds of this invention significantly inhibit HUVEC tube formation.

[0724] It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from its essential characteristics. Therefore, the embodiments are intended to be illustrative and non-limiting in all respects, and reference should be made to the appended claims rather than to the foregoing embodiments; thus, all variations within the meaning and scope of the equivalents of the appended claims are included herein.

Claims

1. A compound having a structure as shown in Formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having a structure as shown in Formula (I), in, Z is CR 1 Or N; R 1 It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, or cycloalkyl; X is CR 5 Or N; A is a 5-6 membered heterocyclic ring; B is a 5-6 member heterocyclic aromatic ring; R 2 It can be H, deuterium, hydroxyl, halogen, amino, cyano, alkyl, alkoxy, or cycloalkyl; R 3 For optional use by R 7 The substituted aryl, heteroaryl, heterocyclic or cycloalkyl groups; R 5 It is an alkoxy group, a haloalkoxy group, a haloalkenoxy group, an alkylthio group, a haloalkoxy group, a haloalkenthio group, a Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached thereto, they form independently optional R 6 Substituted 5-6 membered carbon rings or 5-6 membered heterocycles; R 6 It can be H, halogen, alkyl, alkenyl, or cycloalkyl; R 4 For optional use by R 8 The substituted alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups; R 7 and R 8 Each can be independently hydrogen, deuterium, cyano, hydroxyl, alkyl, alkoxy, alkylthio, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

2. The compound according to claim 1, wherein, R 2 H, deuterium, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; R 3 For optional use by R 7 The C that was replaced 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl; R 4 For optional use by R 8 The C that was replaced 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl C 1-6 alkyl; R 7 and R 8 Each is independently hydrogen, deuterium, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

3. The compound according to claim 1 or 2, wherein, R 2 For H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, C 1-4 alkoxy or cyclopropyl; R 3 For optional use by R 7 The substituted cyclopropane, cyclobutane, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, cyclohexane, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazine, cycloheptane, acrylonitrile, or oxoheptane; R 4 For optional use by R 8 The C that was replaced 6-10 Aryl C 1-3 Alkyl or C 1-9 heteroaryl C 1-3 alkyl; R 7 and R 8 Each is independently hydrogen, deuterium, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl.

4. The compound according to claim 1, wherein, A is a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a tetrahydropyrrole ring, a tetrahydrothiophene ring, or a piperazine ring; B can be a furan ring, imidazole ring, pyrrole ring, thiophene ring, indole ring, carbazole ring, thiazole ring, thiadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring.

5. The compound according to any one of claims 1-4, wherein, The compound has a structure as shown in formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formula (II). Among them, R 1 X is defined in equation (I).

6. The compound according to claim 1 or 5, wherein, R 1 H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl or C 3-8 cycloalkyl; X is CR 5 Or N; R 5 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 2- 6-Halogenated thiols, Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached thereto, they form independently optional R 6 Substituted 5-6 membered carbon rings or 5-6 membered heterocycles; R 6 H, halogen, C 1-6 Alkyl, C 2-6 alkenyl or C 3-8 Cycloalkyl.

7. The compound according to claim 6, wherein, R 1 For H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Heteroalkyl or cyclopropyl; R 5 C substituted with fluorine 1-3 alkoxy, fluorine-substituted C 1-3 alkylthio, fluorine-substituted C 2-4 Alkenyloxy, fluorine-substituted C 2-4 Benzyl thioyl, Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached thereto, they form independently optional R 6 Substituted 5-6 membered carbon rings or 5-6 membered heterocycles; R 6 H, F, Cl or C 1-3 alkyl.

8. The compound according to claim 7, wherein, R 5 For SF5, Me2P(=O)-; or R 1 and R 5 Together with the carbon atom attached to it, they form the following structure 9. The compound according to any one of claims 1-8, wherein, The compound has the following structures, or its stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

10. A compound having a structure as shown in formula (I'), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having a structure as shown in formula (I'). in, R 1a It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, or cycloalkyl; Y is CR 5a Or N; B' is a 5-6 member heterocyclic aromatic ring; R 2a It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, alkoxy, or cycloalkyl; R 3a To be independently and arbitrarily R 7a The substituted cycloalkyl, aryl, heteroaryl, heterocyclic or cycloalkyl groups; R 5a It is a haloalkyl, alkoxy, haloalkoxy, haloalkenoxy, alkylthio, haloalkylthio, or Me2P(=O)-; R 4a It is cyano, R 8a R 10a NC (=O), R 8a OC (=O), alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylheteroaryl, alkylheteroarylalkyl; Q is a 7-8 fused heterocycle, 7-8 spirocyclic heterocycle, 7-8 bridged heterocycle, or -CH2-NH(CR) selected from deuterium, hydroxyl, halogen, amino, alkyl, aryl, heteroaryl, and cycloalkyl, optionally substituted by 1, 2, 3, or 4 alkyl groups. 6a R 9a ) n’ NH- or -CH2-NR 11a (CR 6a R 9a ) n’ CH2-; n' is 1, 2 or 3; R 6a R 7a R 8a R 9a R 10a and R 11a Each can be independently hydrogen, deuterium, cyano, hydroxyl, alkyl, alkoxy, alkylthio, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl. Or R 6a R 7a Together with the carbon atom it is attached to, they form C=O or C=S.

11. The compound according to claim 10, wherein, R 2a H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; R 3a To be independently and arbitrarily R 7a The C that was replaced 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3- 8-cycloalkyl; R 5a C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio group or Me2P(=O)-; R 7a It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

12. The compound according to claim 10 or 11, wherein, R 2a For H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, C 1-4 alkoxy or cyclopropyl; R 3a To be independently and arbitrarily R 7a The substituted cyclopropane, cyclobutane, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, cyclohexane, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazine, cycloheptane, acrylonitrile, or oxoheptane; R 5a C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy group; preferably -CF3, -OMe or -OCF3; R 7a It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl.

13. The compound according to claim 10, wherein, B' can be a furan ring, imidazole ring, pyrrole ring, thiophene ring, indole ring, carbazole ring, thiazole ring, thiadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring.

14. The compound according to any one of claims 10-13, wherein, The compound has a structure as shown in formula (II'), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formula (II'). Q is independently and optionally composed of 1, 2, 3, or 4 elements selected from deuterium, hydroxyl, F, Cl, Br, amino, C. 1-6 Alkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl-substituted 7-8 fused heterocycles, 7-8 spiroheterocycles, 7-8 bridged heterocycles, -CH2-NH(CR) 6a R 9a ) n’ NH- or -CH2-NR 11a (CR 6a R 9a ) n’ CH2-; n' is 1, 2 or 3; R 4a It is cyano, R 8a R 10a NC (=O), R 8a OC (=O), C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 6- 10 Aryl, C 1-9 heteroaryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl C 1-6 Alkyl, C 1-6 Alkyl C 1-9 heteroaryl, C 1-6 Alkyl C 1-9 heteroaryl C 1-6 alkyl; R 6a R 7a R 8a R 9a R 10a and R 11a Each is independently hydrogen, deuterium, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatics; Or R 6a R 7a Together with the carbon atom it is attached to, they form C=O or C=S.

15. The compound according to claim 10 or 14, wherein, Q is 16. The compound according to claim 10 or 14, wherein, R 4a It is cyano, H2NC(=O)-, R 8a OC (=O), C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Cyanoalkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-3 Alkyl, C 1-3 Alkyl C 1-9 heteroaryl, C 1-3 Alkyl C 1-9 heteroaryl C 1-3 Alkyl; preferably cyano, H2NC(=O)-, R 8a OC (=O) R 8a It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Hydroxyalkyl or cyclopropyl.

17. A compound, wherein, The compound has one of the following structures, or is a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug.

18. A compound having a structure as shown in formula (I”), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having a structure as shown in formula (I”). in, R 1b It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, or cycloalkyl; E is CR 5b Or N; "B" is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; R 2b It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, alkoxy, or cycloalkyl; R 3b To be independently and optionally controlled by 1, 2 or 3 R 7b The substituted aryl, heteroaryl, heterocyclic or cycloalkyl groups; L is -C(=O)NR 6b -, -NR 6b C(=O)-, -NR 6b C(=O)NR 8b -, -NR 6b C(=O)NR 8b CR 9b R 10b - or -NR 6b S(=O)2-; R 5b It can be hydrogen, halogen, hydroxyl, cyano, haloalkyl, alkoxy, haloalkoxy, haloalkenoxy, alkylthio, haloalkylthio, or Me2P(=O)-; R 4b It is cyano, R 6b R 8b NC(=O)-、R 8b OC(=O)-, alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylheteroaryl or alkylheteroarylalkyl; R 6b and R 8b Each can be independently hydrogen, deuterium, alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 7b Hydrogen, deuterium, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, Cycloalkyl, heterocyclic, aryl, or heteroaryl; R 9b and R 10b Each can be independently hydrogen, deuterium, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

19. The compound according to claim 18, wherein, R 1b H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl or C 3-8 cycloalkyl; R 2b H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; R 5b It consists of hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio or Me2P(=O)-.

20. The compound according to claim 18 or 19, wherein, R 2b For H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, C 1-4 alkoxy or cyclopropyl; R 5b It consists of hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Haloalkylthio group; preferably -CF3, -OMe, -OCF3 or -SCF3.

21. The compound according to any one of claims 18-20, wherein, The compound has a structure as shown in formula (II”), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formula (II”). Among them, B”, L, R 3b R 5b Same as the definition in formula (I”).

22. The compound according to claim 18 or 21, wherein, B” can be a furan ring, imidazole ring, pyrrole ring, thiophene ring, indole ring, carbazole ring, thiazole ring, thiadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring; L is -C(=O)NR 6b -, -NR 6b C(=O)-, -NR 6b C(=O)NR 8b -, -NR 6b C(=O)NR 8b CR 9b R 10b - or -NR 6b S(=O)2-; R 5b It consists of hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Haloalkylthio group; preferably -CF3, -OMe, -OCF3 or -SCF3; R 6b and R 8b Each is independently hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6- 10 Aryl or C 1-9 Mixed aromatics; R 9b and R 10b Each of these can be independently represented by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

23. The compound according to claim 18 or 22, wherein, R 3b To be independently and optionally controlled by 1, 2 or 3 R 7b The C that was replaced 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3- 8-cycloalkyl; R 7b It can be hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

24. The compound according to claim 18 or 23, wherein, R 3b To be independently and optionally controlled by 1, 2 or 3 R 7b The substituted furanyl, pyrrolyl, thiophene, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, phenyl, pyridinyl, 2H-pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyclopropane, cyclobutane, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophene, cyclohexane, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, cycloheptane, acrylonitrile, oxeheptane, benzofuranyl, benzothiophene, indolyl, inazolyl, benzisoxazolyl, 3H-indolyl, 1H-indolyl, or benzoxazolyl; R 7b For hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1- 3-hydroxyalkyl, Or C 3-6 Cycloalkyl.

25. The compound according to any one of claims 18-24, wherein, The compound has the following structures, or its stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

26. A pharmaceutical composition comprising the compound of any one of claims 1-25, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

27. Use of the compound of any one of claims 1-25 or the pharmaceutical composition of claim 26 in the preparation of a medicament for the prevention and / or treatment of diseases associated with or caused, mediated and / or proliferated by SRPK1 inhibitors.

28. The use according to claim 27, wherein the disease is selected from: hyperproliferative disorders, cancer, metastatic tumors, tumors, angiogenesis disorders, tumor angiogenesis, benign hyperplasia, hemangioma, glioma, melanoma, Kaposi's sarcoma, prostate diseases related to angiogenesis or angiogenesis, inflammation, pancreatitis, retinopathy, retinopathy of prematurity, diabetic retinopathy, diabetes, pain, restenosis, psoriasis, eczema, scleroderma, and age-related macular degeneration.

Images