SRPK inhibitor compound and use thereof

Abstract

The present invention relates to an SRPK inhibitor compound and a use thereof. The compound of the present invention has a structure as shown in formula (I), or is a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure as shown in formula (I). The present invention further relates to the use of the SRPK inhibitor compound in the preparation of a medicament 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] Among them, R 1It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, cycloalkyl, haloalkoxy, haloalkenoxy, alkylthio, haloalkylthio or Me2P(=O)-;

[0007] X is CR 5 ;

[0008] Y 1 and Y 2 Each independently for CR 6 Or N;

[0009] A is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring;

[0010] R 2 R 5 and R 6 Each of these can be independently H, deuterium, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclic, or cycloalkyl.

[0011] R 3 It is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocycle that is independently and optionally substituted with 1, 2, 3 or 4 deuterium, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, hydroxyalkyl or alkoxy groups;

[0012] R 4 It is cyano, alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, R 7 -Q-、 R 10 C(=O)-、R 10 C(=S)-、R 10 C(=O)-alkyl or R 11 S(=O)2-;

[0013] R 7 It is hydrogen, deuterium, cyano, hydroxyl, alkyl, aryl, heteroaryl, R 9 C(=O)-、R 15 C(=O)-alkyl, hydroxyalkyl, cyanoalkyl, R 20 R 21 N-;R 7 The aryl and heteroaryl groups described herein may optionally be replaced by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, or alkoxy groups;

[0014] Q represents O, S, NR 12 -CR 13 R 14 -、-(CR 13 R 14 ) m -、-(CR13 R 14 ) n -O-、-(CR 13 R 14 ) n -NH-, -S(=O)2- or -S(=O)(=NH)-;

[0015] R 12 It can be hydrogen, cyano, alkyl, haloalkyl, cycloalkyl, or alkyl-OC(=O)-;

[0016] L is -(CR) 16 R 17 ) t -、-O(CR 16 R 17 ) t -, -NH(CR) 16 R 17 ) t -、-C(=O)-、-C(=O)(CR 16 R 17 ) t -、-C(=O)O(CR 16 R 17 ) t -or-OC(=O)(CR) 16 R 17 ) t -;

[0017] t can be 0, 1, 2, or 3;

[0018] m and n are each independently 0, 1, 2 or 3;

[0019] R 8 R 9 R 10 R 11 and R 15 Each can be independently hydrogen, deuterium, amino, hydroxyl, alkyl, alkoxy, alkylamino, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0020] R 13 and R 14 Each can be independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic or alkyl-OC(=O)-;

[0021] or R 13 R 14 Together with the carbon atom attached to it, they form double bonds, cycloalkyl groups,

[0022] R 16 and R17 Each can be independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic.

[0023] R 20 and R 21 Each is independently hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 20 and R 21 The groups described herein are independently and optionally replaced by 1, 2, 3 or 4 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, ynyl or cycloalkyl.

[0024] In some embodiments, wherein R in the compound 1 H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio groups, Me2P(=O)-;

[0025] X is CR 5 ;

[0026] R 5 H, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl;

[0027] In some embodiments, wherein R in the compound 1 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, F-substituted C 1-4 Alkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, SF5 Or Me2P(=O)-;

[0028] X is CR 5 ;

[0029] R 5 It can be H, deuterium, hydroxyl, F, Cl, Br, hydroxyl, methyl, ethyl, isopropyl, methoxy, ethoxy, or cyclopropyl.

[0030] In some embodiments, wherein A in the compound is a 5-6 membered heteroaryl group; preferably, A is a furan ring, imidazole ring, pyrrole ring, thiophene ring, thiazole ring, thiadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring;

[0031] R 2 For H, deuterium, hydroxyl, F, Cl, Br, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl;

[0032] R 3 To be independently and optionally occupied by 1, 2, 3 or 4 deuterium, F, Cl, Br, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy-substituted 5-6 membered heteroaromatic rings or 5-6 membered heterocycles.

[0033] In some embodiments, the compound has a structure as shown in formulas (II), (III), (IV), and (V), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formulas (II), (III), (IV), and (V).

[0034] Among them, R 1 R 4 L, Y 2 Same as the definition in equation (I);

[0035] R 18 and R 19Each of the following groups is independently deuterium, F, Cl, Br, hydroxyl, cyano, amino, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 1-4 Alkyl group.

[0036] In some embodiments, wherein R in the compound 1 H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio groups, Me2P(=O)-;

[0037] R 4 It is cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 6-10 Aryl, C 1-9 heteroaryl, R 7 -Q-、 R 10 C(=O)-、R 10 C(=S)-、R 10 C(=O)-C 1-6 Alkyl or R 11 S(=O)2-;

[0038] m can be 0, 1, 2, or 3;

[0039] Y 2 For CR 6 Or N;

[0040] R 6 H, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl;

[0041] R 7 It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-6 Alkyl, C 6-10 Aryl, C 1-9 heteroaryl, R9 C(=O)-、R 15 C(=O)-alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, R 20 R 21 N-;R 7 The C mentioned in 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl groups are substituted;

[0042] Q is -(CR) 13 R 14 ) m -or-(CR) 13 R 14 ) n -O-、-CR 13 R 14 -、-(CR 13 R 14 ) n -NH- or -S(=O)2-;

[0043] m is 2 or 3;

[0044] n is 1, 2, or 3;

[0045] R 12 For hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl or C 1-6 Alkyl-OC(=O)-;

[0046] R 8 R 9 R 10 R 11 and R 15 Each can be independently composed of hydrogen, deuterium, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatics;

[0047] R 13 and R 14 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group or C 1-6 Alkyl OC (=O)-;

[0048] or R 13 R 14 Together with the carbon atom it is attached to, they form a double bond, C 3-8 cycloalkyl,

[0049] R 20 and R 21 Each independently is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl or C 1-9 Heterocyclic groups;

[0050] R 1 R 4 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 20 and R 21 The groups described herein are independently and optionally composed of 1, 2, 3, or 4 groups selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Substituents of cycloalkyl groups.

[0051] In some embodiments, wherein R in the compound 1 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, F-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, SF5, Me2P(=O)-; preferably, R 1 It can be H, deuterium, hydroxyl, F, Cl, Br, CF3, CHF2, OCF3, OCH3, or cyclopropyl.

[0052] In some embodiments, wherein Y in the compound 2 For CR 6 Or N;

[0053] R 6 H, deuterium, hydroxyl, F, Cl, Br, C 1-4 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl; preferably, R 6 It can be H, deuterium, hydroxyl, F, Cl, Br or methyl.

[0054] In some embodiments, L in the compound is -(CR 16 R 17 ) t -、-O(CR 16 R 17 ) t -, -NH(CR) 16 R 17 ) t -、-C(=O)-、-C(=O)(CR 16 R 17 ) t -、-C(=O)O(CR 16 R 17 ) t -or-OC(=O)(CR) 16 R 17 ) t -;

[0055] t can be 0, 1, 2, or 3;

[0056] R 16 and R 17 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl or C 1-9 Heterocyclic groups;

[0057] Preferably, R 16 and R 17 Each of the following is independently represented as hydrogen, deuterium, F, Cl, Br, hydroxyl, cyano, amino, C 1-4 Alkyl, F-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl, C 1-9 heteroaryl, C 3-6 cycloalkyl or C 1-9 Heterocyclic group.

[0058] In some embodiments, wherein R in the compound 4 It is cyano, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, C 1-9 heteroaryl, R 7 -Q-、 R 10 C(=O)-、R 10 C(=S)-、R 10 C(=O)-C 1-4 Alkyl or R 11 S(=O)2-;

[0059] Q is -(CR) 13 R 14 ) m -、-(CR 13 R 14 ) n -O-、-CR 13 R 14 -、-(CR 13 R 14 ) n -NH- or -S(=O)2-;

[0060] m is 2 or 3;

[0061] n is 1, 2, or 3;

[0062] R 7 It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-4 Alkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, R 20 R 21 N-, R 9 C(=O)-、R 15 C(=O)-C 1-6 Alkyl; R7 The C mentioned in 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 1-4 Alkyl groups are substituted;

[0063] R 12 For hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 cycloalkyl or C 1-4 Alkyl OC (=O)-;

[0064] R 8 R 9 R 10 R 11 and R 15 Each can be independently composed of hydrogen, deuterium, amino, hydroxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatics;

[0065] R 13 and R 14 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group or C 1-4 Alkyl OC (=O)-;

[0066] or R 13 R 14 Together with the carbon atom attached to it, it forms double bonds, cyclopropyl groups, cyclobutyl groups, etc.

[0067] R 20 and R 21 Each is independently hydrogen, deuterium, and C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0068] In some embodiments, wherein R in the compound 4 It is cyano, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, phenyl, C 1-9 heteroaryl, R 9 C(=O)-、R 10 C(=O)-C 1-4 Alkyl, R 11 S(=O)2-、

[0069] R 7 It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-4 Alkyl, C 1-9 heteroaryl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, R 20 R 21 N-, R 9 C(=O)-、R 15 C(=O)-C 1-4 Alkyl; R 7 The C mentioned in 1-9 The heteroaryl group is optionally surrounded by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 1-4 Alkyl groups are substituted;

[0070] R 12 It is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, or C 1-4 Alkyl OC (=O)-;

[0071] R 9 and R 15 Each can be independently classified as amino, hydroxyl, or C. 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 cycloalkyl;

[0072] R 10 For amino, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 cycloalkyl;

[0073] R 11 Amino or C 1-4 alkyl;

[0074] R 13 and R 14Each of the following C groups is independently substituted with hydrogen, deuterium, F, Cl, Br, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, or F. 1-4 Alkyl, C 1-4 Hydroxyalkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, C 1-9 Heterocyclic group or C 1-4 Alkyl OC (=O)-;

[0075] or R 13 R 14 Together with the carbon atom attached to it, it forms double bonds, cyclopropyl groups, cyclobutyl groups, etc.

[0076] R 20 and R 21 Each can be independently hydrogen, deuterium, methyl, ethyl, or C. 1-4 Halogenated alkyl groups.

[0077] In a second aspect, 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.

[0078] Thirdly, 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 by, mediated by, and / or proliferated by SRPK1 inhibitors.

[0079] 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.

[0080] Fourthly, 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.

[0081] 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

[0082] Definitions and general terms

[0083] Unless otherwise stated, the terms used in the specification and claims of this invention have the following definitions.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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).

[0091] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound of formula (I) or (II) 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 (C) 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.

[0098] 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).

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] "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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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).

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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).

[0124] The term "halogen" refers to F, Cl, Br, or I.

[0125] In this invention, "halogenated" means replacing the following group with a halogen, and the number of substitutions can be one or more.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] The term "unsaturated" as used in this invention means that a structural portion contains one or more degrees of unsaturation.

[0130] Description of the compounds of the present invention

[0131] 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).

[0132] Among them, R 1 It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, cycloalkyl, haloalkoxy, haloalkenoxy, alkylthio, haloalkylthio or Me2P(=O)-;

[0133] X is CR 5 ;

[0134] Y 1 and Y 2 Each independently for CR 6 Or N;

[0135] A is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring;

[0136] R 2 R 5 and R 6 Each of these can be independently H, deuterium, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclic, or cycloalkyl.

[0137] R 3 It is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocycle that is independently and optionally substituted with 1, 2, 3 or 4 deuterium, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, hydroxyalkyl or alkoxy groups;

[0138] R 4 It is cyano, alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, R 7 -Q-、 R 10 C(=O)-、R 10 C(=S)-、R 10 C(=O)-alkyl or R 11 S(=O)2-;

[0139] R7 It is hydrogen, deuterium, cyano, hydroxyl, alkyl, aryl, heteroaryl, R 9 C(=O)-、R 15 C(=O)-alkyl, hydroxyalkyl, cyanoalkyl, R 20 R 21 N-;R 7 The aryl and heteroaryl groups described herein may optionally be replaced by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, or alkoxy groups;

[0140] Q represents O, S, NR 12 -CR 13 R 14 -、-(CR 13 R 14 ) m -、-(CR 13 R 14 ) n -O-、-(CR 13 R 14 ) n -NH-, -S(=O)2- or -S(=O)(=NH)-;

[0141] R 12 It can be hydrogen, cyano, alkyl, haloalkyl, cycloalkyl, or alkylOC(=O)-;

[0142] L is -(CR) 16 R 17 ) t -、-O(CR 16 R 17 ) t -, -NH(CR) 16 R 17 ) t -、-C(=O)-、-C(=O)(CR 16 R 17 ) t -、-C(=O)O(CR 16 R 17 ) t -or-OC(=O)(CR) 16 R 17 ) t -;

[0143] t can be 0, 1, 2, or 3;

[0144] m and n are each independently 0, 1, 2 or 3;

[0145] R 8 R 9 R 10 R 11and R 15 Each can be independently hydrogen, deuterium, amino, hydroxyl, alkyl, alkoxy, alkylamino, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0146] R 13 and R 14 Each can be independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic or alkyl OC(=O)-;

[0147] or R 13 R 14 Together with the carbon atom attached to it, they form double bonds, cycloalkyl groups,

[0148] R 16 and R 17 Each can be independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic.

[0149] R 20 and R 21 Each is independently hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 20 and R 21 The groups described herein are independently and optionally replaced by 1, 2, 3 or 4 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, ynyl or cycloalkyl.

[0150] In some embodiments, wherein R in the compound 1 H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups, C1-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio groups, Me2P(=O)-;

[0151] X is CR 5 ;

[0152] R 5 H, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 Cycloalkyl.

[0153] In some embodiments, wherein R in the compound 1 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, F-substituted C 1-4 Alkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, SF5 Or Me2P(=O)-;

[0154] X is CR 5 ;

[0155] R 5 It can be H, deuterium, hydroxyl, F, Cl, Br, hydroxyl, methyl, ethyl, isopropyl, methoxy, ethoxy, or cyclopropyl.

[0156] In some embodiments, wherein A in the compound is a 5-6 membered heteroaryl group; preferably, A is a furan ring, imidazole ring, pyrrole ring, thiophene ring, thiazole ring, thiadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring;

[0157] R 2 For H, deuterium, hydroxyl, F, Cl, Br, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl;

[0158] R 3 To be independently and optionally occupied by 1, 2, 3 or 4 deuterium, F, Cl, Br, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4Alkoxy-substituted 5-6 membered heteroaromatic rings or 5-6 membered heterocycles.

[0159] In some embodiments, the compound has a structure as shown in formulas (II), (III), (IV), and (V), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formulas (II), (III), (IV), and (V).

[0160] Among them, R 1 R 4 L, Y 2 Same as the definition in equation (I);

[0161] R 18 and R 19 Each of the following groups is independently deuterium, F, Cl, Br, hydroxyl, cyano, amino, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 1-4 Alkyl group.

[0162] In some embodiments, wherein R in the compound 1 H, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio groups, Me2P(=O)-;

[0163] R 4 It is cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 6-10 Aryl, C 1-9 heteroaryl, R 7 -Q-、 R 10 C(=O)-、R 10 C(=S)-、R 10 C(=O)-C 1-6 Alkyl or R 11 S(=O)2-;

[0164] m can be 0, 1, 2, or 3;

[0165] Y2 For CR 6 Or N;

[0166] R 6 H, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl;

[0167] R 7 It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-6 Alkyl, C 6-10 Aryl, C 1-9 heteroaryl, R 9 C(=O)-、R 15 C(=O)-alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, R 20 R 21 N-;R 7 The C mentioned in 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl groups are substituted;

[0168] Q is -(CR) 13 R 14 ) m -、-(CR 13 R 14 ) n -O-、-CR 13 R 14 -、-(CR 13 R 14 ) n -NH- or -S(=O)2-;

[0169] m is 2 or 3;

[0170] n is 1, 2, or 3;

[0171] R 12 For hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl or C 1-6 Alkyl-OC(=O)-;

[0172] R 8 R 9 R 10 R 11 and R 15 Each can be independently composed of hydrogen, deuterium, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatics;

[0173] R 13 and R 14 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group or C 1-6 Alkyl OC (=O)-;

[0174] or R 13 R 14 Together with the carbon atom it is attached to, they form a double bond, C 3-8 cycloalkyl,

[0175] R 20 and R 21 Each independently is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl or C 1-9 Heterocyclic groups;

[0176] R 1 R 4 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 20 and R 21The groups described herein are independently and optionally composed of 1, 2, 3, or 4 groups selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Substituents of cycloalkyl groups.

[0177] In some embodiments, wherein R in the compound 1 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, F-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, SF5, Me2P(=O)-; preferably, R 1 It can be H, deuterium, hydroxyl, F, Cl, Br, CF3, CHF2, OCF3, OCH3, or cyclopropyl.

[0178] In some embodiments, wherein Y in the compound 2 For CR 6 Or N;

[0179] R 6 H, deuterium, hydroxyl, F, Cl, Br, C 1-4 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl; preferably, R 6 It can be H, deuterium, hydroxyl, F, Cl, Br or methyl.

[0180] In some embodiments, L in the compound is -(CR 16 R 17 ) t -、-O(CR 16 R 17 ) t -, -NH(CR) 16 R 17 ) t -、-C(=O)-、-C(=O)(CR 16 R 17 ) t -、-C(=O)O(CR 16 R 17 ) t -or-OC(=O)(CR) 16 R 17) t -;

[0181] t can be 0, 1, 2, or 3;

[0182] R 16 and R 17 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl or C 1-9 Heterocyclic groups;

[0183] Preferably, R 16 and R 17 Each of the following is independently represented as hydrogen, deuterium, F, Cl, Br, hydroxyl, cyano, amino, C 1-4 Alkyl, F-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl, C 1-9 heteroaryl, C 3-6 cycloalkyl or C 1-9 Heterocyclic group.

[0184] In some embodiments, wherein R in the compound 4 It is cyano, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, C 1-9 heteroaryl, R 7 -Q-、 R 10 C(=O)-、R 10 C(=S)-、R 10 C(=O)-C 1-4 Alkyl or R 11 S(=O)2-;

[0185] Q is -(CR) 13 R 14 ) m -、-(CR 13 R 14 ) n -O-、-CR 13 R 14 -、-(CR 13 R 14 ) n -NH- or -S(=O)2-;

[0186] m is 2 or 3;

[0187] n is 1, 2, or 3;

[0188] R 7 It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-4 Alkyl, C 6-10 Aryl, C 1-9 heteroaryl, R 9 C(=O)-、R 15 C(=O)-C 1-6 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, R 20 R 21 N-;R 7 The C mentioned in 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 1-4 Alkyl groups are substituted;

[0189] R 12 For hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 cycloalkyl or C 1-4 Alkyl-OC(=O)-;

[0190] R 8 R 9 R 10 R 11 and R 15 Each can be independently composed of hydrogen, deuterium, amino, hydroxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatics;

[0191] R 13 and R 14 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group or C 1-4 Alkyl OC (=O)-;

[0192] or R 13 R 14 Together with the carbon atom attached to it, it forms double bonds, cyclopropyl groups, cyclobutyl groups, etc.

[0193] R 20 and R 21 Each is independently hydrogen, deuterium, and C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0194] In some embodiments, wherein R in the compound 4 It is cyano, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, phenyl, C 1-9 heteroaryl, R 9 C(=O)-、R 10 C(=O)-C 1-4 Alkyl, R 11 S(=O)2-、

[0195] R 7 It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-4 Alkyl, C 1-9 heteroaryl, R 9 C(=O)-、R 15 C(=O)-C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, R 20 R 21 N-;R 7 The C mentioned in 1-9 The heteroaryl group is optionally surrounded by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 1-4 Alkyl groups are substituted;

[0196] R 12 It is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, or C 1-4 Alkyl OC (=O)-;

[0197] R 9 and R 15Each can be independently classified as amino, hydroxyl, or C. 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 cycloalkyl;

[0198] R 10 For amino, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 cycloalkyl;

[0199] R 11 Amino or C 1-4 alkyl;

[0200] R 13 and R 14 Each of the following C groups is independently substituted with hydrogen, deuterium, F, Cl, Br, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, or F. 1-4 Alkyl, C 1-4 Hydroxyalkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, C 1-9 Heterocyclic group or C 1-4 Alkyl OC (=O)-;

[0201] or R 13 R 14 Together with the carbon atom attached to it, it forms double bonds, cyclopropyl groups, cyclobutyl groups, etc.

[0202] R 20 and R 21 Each can be independently hydrogen, deuterium, methyl, ethyl, or C. 1-4 Halogenated alkyl groups.

[0203] In some embodiments, the compound has the following structure, or its stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs: stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0204] Compositions, formulations and administration of the compounds of the present invention

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] Uses of the compounds and compositions of the present invention

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] General Synthesis Process

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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).

[0221] Example

[0222] Example 1: N-(2-(4-(2-(1-methyl-1H-pyrazol-3-yl)propyl-2-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 1)

[0223] Step 1: Methyl 5-(3,6-dihydro-2H-pyran-4-yl)furan-2-carboxylate (1b)

[0224] In a 500 mL round-bottom flask, compound 1a (20.10 g, 100 mmol) was dissolved in 1,4-dioxane / water (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 (48.80 g, 150 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (3.00 mmol, 2.45 g). The reaction was carried out under nitrogen protection and at 95 °C for 8 h. After the reaction was complete, the solvent was removed under reduced pressure. 200 mL of 20% (ethyl acetate / petroleum ether) solution was added, and stirring continued for 1 h. The mixture was filtered through a silica gel-lined sintered funnel. The filter cake was washed with 20% (ethyl acetate / petroleum ether), and the filtrate was evaporated to dryness. The mixture was then stirred for another 1 h with 5% (ethyl acetate / petroleum ether), filtered, and the filter cake was dried to give compound 1b, a white solid (15.70 g, 75% yield). LCMS: 209.1 [M+H] + .

[0225] Step 2: Methyl 5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxylate (1c)

[0226] In a 250 mL round-bottom flask, compound 1b (18.00 g, 86.50 mmol) was dissolved in ethyl acetate (200 mL), 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 1c, a colorless oil (16.00 g, 89% yield). LCMS: 211.1 [M+H] + .

[0227] Step 3: tert-butyl-4-(2-nitro-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (1e)

[0228] In a 500 mL round-bottom flask, N-tert-butyloxycarbonylpiperazine (9.80 g, 52.61 mmol), compound 1d (10.00 g, 47.82 mmol), potassium carbonate (9.90 g, 71.73 mmol), and N,N-dimethylformamide (100 mL) were added sequentially. 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 (16.90 g, 94% yield). LCMS: 376.1 [M+H] + .

[0229] Step 4: 1-(2-nitro-4-(trifluoromethyl)phenyl)piperazine (1f)

[0230] In a 250 mL round-bottom flask, compound 1e (10.00 g, 26.67 mmol) was dissolved in 100 mL of dichloromethane. Dioxane hydrochloride (27 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 1f, a yellow solid (8.60 g, 85% yield), which could be used directly in the next step without purification. LCMS: 276.1 [M+H] + Step 5: (1-Methyl-1H-pyrazole-3-yl)(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl ketone (1g)

[0231] In a 250 mL round-bottom flask, compound 1f (5.00 g, 18.12 mmol), 1-methylpyrazol-3-carboxylic acid (2.75 g, 21.74 mmol), and N,N-diisopropylethylamine (9.35 g, 72.48 mmol) were dissolved in N,N-dimethylformamide (50 mL). 1-Butylphosphine anhydride (19.60 g, 27.18 mmol, 50% ethyl acetate solution) was added under ice bath conditions, and the reaction was 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 of compound as a yellow solid (6.26 g, yield: 90%). 1 H NMR (500MHz, DMSO-d6) δ9.42(s,2H),8.24(s,1H),7.94(d,1H),7.55(d,1H),3.39(s,4H),3.20(s,4H)ppm; LCMS:384.1[M+H] + .

[0232] Step 6: (4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)(1-methyl-1H-pyrazole-3-yl)methyl ketone (1h)

[0233] Under a hydrogen atmosphere, 1 g (6.26 g, 16.34 mmol) of the compound and 1.25 g (10%) of palladium on carbon were dissolved in 100 mL of ethanol in a 250 mL round-bottom flask, 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 evaporated to dryness under reduced pressure to give the compound 1 h as a white solid (5.10 g, yield: 88%), which could be used directly in the next step without further purification. LCMS: 354.1 [M+H] + .

[0234] Step 7: tert-butyl(2-(4-(1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)carbamate (1j)

[0235] In a 250 mL round-bottom flask, compound 1h (4.00 g, 11.33 mmol), di-tert-butyl dicarbonate (3.00 g, 13.60 mmol), triethylamine (1.72 g, 17.00 mmol), and dichloromethane (50 mL) were added sequentially, and the reaction was carried out at room temperature for 8 h. The reaction 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 column chromatography to give compound 1j as a white solid (5.10 g, 99%). LCMS: 454.2 [M+H] + .

[0236] Step 8: tert-butyl(2-(4-(2-(1-methyl-1H-pyrazol-3-yl)propyl-2-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)carbamate (1k)

[0237] Under nitrogen protection, in a 100 mL three-necked flask, compound 1j (1.20 g, 2.64 mmol) and tetraisopropyl titanate (7 mL, 7.39 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). The mixture was cooled to -30 °C in a dry ice bath, and methyl magnesium bromide (12 mL, 1 M) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 24 h. After the reaction was complete, saturated ammonium chloride was added in an ice bath to quench the reaction. The mixture was 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 1k as a white solid (255 mg, yield: 20%). 1 H NMR(400MHz, CDCl3)δ7.46(d,1H),7.31(d,1H),7.26(s,2H),6.47(d,1H),4.00(s,1H),3.96(s,3H), 3.73(d,2H),3.45(t,2H),3.16(d,2H),3.05(d,2H),1.92(s,6H),1.58(s,9H)ppm; LCMS:468.3[M+H] + .

[0238] Step 9: 2-(4-(2-(1-methyl-1H-pyrazol-3-yl)propyl-2-yl)piperazin-1-yl)-5-(trifluoromethyl)aniline (1m)

[0239] In a 50 mL round-bottom flask, compound 1k (255 mg, 0.55 mmol) was dissolved in 10 mL of dichloromethane. Dioxane hydrochloride (1 mL, 4 M) was added dropwise under ice bath conditions, and the mixture was slowly brought to room temperature for 4 h. After the reaction was complete, the organic solvent was removed under reduced pressure to give compound 1m, a white solid (148 mg, yield: 74%), which could be used directly in the next step without purification. 1H NMR(500MHz, CDCl3)δ7.44(d,1H),7.05(q,2H),6.96(s,1H),6.43(d,1H),3.94(s,3 H),3.73(d,3H),3.33–3.21(m,5H),3.01(t,2H),1.89(s,6H)ppm; LC-MS:368.2[M+H] + .

[0240] Step 10: N-(2-(4-(2-(1-methyl-1H-pyrazol-3-yl)propyl-2-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 1)

[0241] In a 50 mL round-bottom flask, compound 1m (0.12 g, 0.33 mmol) and compound 1c (0.10 g, 0.5 mmol) were dissolved in tetrahydrofuran (3 mL) and added dropwise to a tetrahydrofuran (2 mL) solution of potassium tert-butoxide (78 mg, 0.70 mmol). The reaction was allowed to proceed for 30 min. After the reaction was complete, 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 1 as a white solid (5 mg, yield 3%). 1 H NMR(500MHz, CDCl3)δ9.37(s,1H),8.84(s,1H),7.35(d,1H),7.32–7.25(m,2H),7.20(d,1H),6.28–6.21(m,2H),4.14–4.06(m,2H),3.90(s,3H) ,3.58(t,2H),3.06–2.98(m,1H),2.97–2.88(m,4H),2.84–2.65(m,4H), 2.08–1.98(m,2H),1.94–1.80(m,2H),1.48(s,6H)ppm; LCMS:546.2[M+H] + .

[0242] Example 2: (R)-N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 2-1) and (S)-N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 2-2)

[0243] Step 1: 1-(1-(1-methyl-1H-pyrazole-3-yl)ethyl)-4-(2-nitro-4-(trifluoromethyl)phenyl)piperazine (2a)

[0244] In a 100 mL round-bottom flask, compound 1f (2.20 g, 8.06 mmol), 1-(1-methylpyrazol-3-yl)acetone (1.00 g, 8.06 mmol), and methanol (20 mL) were added sequentially, and the mixture was reacted at room temperature for 1 h. After 1 h, sodium cyanoborohydride (1.52 g, 24.18 mmol) was added, and the mixture was reacted 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 2a as a yellow solid (185 mg, yield: 6%). LCMS: 384.2 [M+H] + .

[0245] Step 2: 2-(4-(1-(1-methyl-1H-pyrazole-3-yl)ethyl)piperazin-1-yl)-5-(trifluoromethyl)aniline (2b)

[0246] In a 100 mL round-bottom flask, compound 2a (185 mg, 0.48 mmol) and palladium on carbon (37 mg, 10% palladium on carbon) were dissolved in ethanol (5 mL). The mixture was purged three times with hydrogen and reacted overnight at 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 2b as a white solid (108 mg, yield: 58%). LCMS: 354.2 [M+H] + .

[0247] Step 3: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 2)

[0248] In a 100 mL round-bottom flask, compound 2b (108 mg, 0.31 mmol) and compound 1c (77 mg, 0.37 mmol) were dissolved in dichloromethane (5 mL). Trimethylaluminum (0.46 mL, 0.96 mmol, 2 M) was added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature for 12 h. The reaction 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 medium-pressure preparation to give compound 2 as a white solid (63 mg, yield: 38%). LCMS: 532.2 [M+H] + .

[0249] Step 4: (R)-N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 2-1) and (S)-N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 2-2) were separated by SFC to obtain compound 2-1 (20 mg, yield: 32%) and compound 2-2 (20 mg, yield: 32%).

[0250] Compound 2-1: 1 H NMR(500MHz,DMSO-d6)δ9.37(s,1H),8.58(s,1H),7.61(s,1H),7.46(s,2H),7.23(d,1H),6.46(d,1H),6.15(s,1H),3.97(d,2H),3.79(s,3H) ,3.63(s,1H),3.51(t,2H),3.06(t,1H),2.91(s,4H),2.71(s,2H),2.62(s,2H),1.97(d,2H),1.73(dd,2H),1.34(s,3H)ppm; LCMS:532.2[M+H] + .

[0251] Compound 2-2: 1 H NMR(500MHz,DMSO-d6)δ9.37(s,1H),8.59(s,1H),7.60(s,1H),7.46(s,2 H),7.23(d,1H),6.46(d,1H),6.14(s,1H),3.97(d,2H),3.79(s,3H),3.66 –3.59(m,1H),3.51(t,2H),3.06(t,1H),2.91(s,4H),2.70(s,2H),2.62( s,2H),1.97(d,2H),1.79–1.67(m,2H),1.33(d,3H)ppm; LCMS:532.2[M+H] + .

[0252] Example 3: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 3)

[0253] Step 1: 1-(1-Methyl-1H-pyrazole-3-yl)cyclopropane-1-ol (3b)

[0254] In a 1000 mL three-necked flask, compound 3a (15.00 g, 107.00 mmol) and tetraisopropyl titanate (107 mL, 139.10 mmol, 1.3 M) were dissolved in anhydrous tetrahydrofuran (150 mL). Ethyl magnesium bromide (300 mL, 1 M) was added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature for 24 h. The reaction was quenched by saturated ammonium chloride, 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 3b, a colorless oil (1.56 g, yield: 10%). 1 H NMR (400MHz, CDCl3) δ7.29(d,1H),6.07(d,1H),3.88(s,3H),1.23(q,2H),1.04(q,2H)ppm; LCMS:138.1[M+H] + .

[0255] Step 2: Cyclopropyl 1-(1-methyl-1H-pyrazole-3-yl)methanesulfonate (3c)

[0256] In a 100 mL round-bottom flask, compound 3b (1.56 g, 11.30 mmol) and triethylamine (2.30 g, 22.61 mmol) were dissolved in dichloromethane (20 mL). Methanesulfonic anhydride (2.40 g, 13.56 mmol) was added under ice bath conditions, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain compound 3c, which was used directly in the next step without purification. 1 H NMR (400MHz, CDCl3) δ7.35(d,1H),6.38(d,1H),3.91(s,3H),2.90(s,3H),1.68(t,2H),1.31(q,2H)ppm; LCMS:217.0[M+H] + .

[0257] Step 3: 1-(1-(1-methyl-1H-pyrazole-3-yl)cyclopropyl)-4-(2-nitro-4-(trifluoromethyl)phenyl)piperazine (3d)

[0258] In a 100 mL round-bottom flask, compound 3c (2.44 g, 11.30 mmol), compound 1f (3.74 g, 13.56 mmol), and potassium carbonate (3.12 g, 22.6 mmol) were dissolved in acetonitrile (30 mL), and the mixture was heated under reflux 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 3d as a yellow solid (1.20 g, yield: 26%). LCMS: 396.2 [M+H] + .

[0259] Step 4: 2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)aniline (3e)

[0260] In a 100 mL round-bottom flask, compound 3d (900 mg, 2.28 mmol), ammonium chloride (1.20 g, 22.78 mmol), and zinc powder (741 mg, 11.4 mmol) were dissolved in 20 mL of methanol and the mixture was refluxed for 6 h. After the reaction was complete, the mixture was filtered, evaporated to dryness under reduced pressure, and the residue was purified by column chromatography to give compound 3e as a white oily solid (498 mg, yield: 60%). LCMS: 366.2 [M+H] + .

[0261] Step 5: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 3)

[0262] In a 50 mL round-bottom flask, compound 3e (0.20 g, 0.55 mmol) and compound 1c (0.10 g, 0.75 mmol) were dissolved in tetrahydrofuran (3 mL) and added dropwise to a mixture of tetrahydrofuran (3 mL) and potassium tert-butoxide (123 mg, 1.10 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 3 as a white solid (50 mg, yield 17%). 1H NMR(500MHz, CDCl3)δ9.51(s,1H),8.85(s,1H),7.39–7.31(m,2H),7.30–7.25(m, 1H),7.21(d,1H),6.46(d,1H),6.25(d,1H),5.77(s,1H),5.33(s,1H),4.18–4.08( m,2H),3.92(s,3H),3.62(t,2H),3.49(s,2H),3.10–3.04(m,1H),3.03–2.94(m,4 H),2.93–2.60(m,4H),2.11–2.01(m,2H),1.99–1.85(m,2H)ppm; LCMS:544.2[M+H] + .

[0263] Example 4: N-(2-(4-(1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 4)

[0264] Step 1: 5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxylic acid (4a)

[0265] In a 250 mL round-bottom flask, compound 1c (5.00 g, 23.80 mmol) was dissolved in methanol / water (50 mL, 5:1), 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 4a, a white solid (3.90 g, 85% yield). LCMS: 195.1 [M⁻¹] - .

[0266] Step 2: (1-Methyl-1H-pyrazole-3-yl)(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl ketone (4b)

[0267] In a 100 mL round-bottom flask, compound 1f (0.93 g, 3.00 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of 1-methylpyrazol-3-carboxylic acid (0.50 g, 4.00 mmol), triethylamine (0.61 g, 6.00 mmol), and finally 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.77 g, 4.00 mmol). The reaction was carried out at room temperature for 2 h. The mixture was quenched with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain the crude product. The residue was purified by column chromatography to give compound 4b as a yellow solid (1.06 g, 92% yield). LCMS: 384.1 [M+H] + .

[0268] Step 2: (4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)(1-methyl-1H-pyrazole-3-yl)methyl ketone (4c)

[0269] In a 100 mL round-bottom flask, compound 4b (1.06 g, 2.77 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 4c as a white solid (0.98 g, 96% yield). LCMS: 354.2 [M+H] + .

[0270] Step 3: N-(2-(4-(1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 4)

[0271] In a 50 mL round-bottom flask, compound 4c (176 mg, 0.50 mmol) was dissolved in acetonitrile (5 mL), followed by compound 4a (0.12 g, 0.60 mmol), N-methylimidazole (0.12 g, 1.50 mmol), and then N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (0.28 g, 1.00 mmol). The reaction was carried out at room temperature for 24 h. The reaction was quenched with water, extracted with dichloromethane, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain the crude product. The residue was purified by column chromatography to give compound 4 as a white solid (173 mg, 65% yield). 1H NMR(500MHz, CDCl3)δ9.37(s,1H),8.85(s,1H),7.41(s,1H),7.37(d,1H),7.30–7.24(m,1H),7.22(d,1H),6.77(d,1H),6.26(d,1H),4.48 –4.21(m,2H),4.10–3.99(m,4H),3.96(s,3H),3.56(t,2H),3.11–2.94(m,5H),2.05–1.94(m,2H),1.91–1.78(m,2H)ppm; LCMS:532.2[M+H] + .

[0272] Example 5: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 5)

[0273] Step 1: 4-(3-cyanoxoxetane-3-yl)piperazine-1-carboxylic acid benzyl ester (5b)

[0274] In a 250 mL round-bottom flask, compound 5a (4.00 g, 55.50 mmol), trimethylcyanosilane (13.80 g, 139 mmol), and zinc iodide (532 mg, 1.67 mmol) were dissolved in methyl tert-butyl ether (100 mL), and the mixture was reacted overnight at room temperature. Benzyl-1-piperazine carboxylate (12.20 g, 55.50 mmol) was added, and the reaction was continued for 12 h. The mixture was filtered under reduced pressure, and the solid was purified by column chromatography to give compound 5b, a yellowish-brown oil (9.00 g, yield: 54%). 1 H NMR (400MHz, DMSO-d6) δ7.39(d,5H),5.12(s,2H),4.77(d,2H),4.62(d,2H),3.51(s,4H),2.35(t,4H)ppm; LCMS:302.1[M+H] + .

[0275] Step 2: 3-(piperazin-1-yl)oxetane-3-carboxynitrile (5c)

[0276] Under a hydrogen atmosphere, compound 5b (9.00 g, 29.90 mmol) and palladium on carbon (1.80 g, 10%) were dissolved in 100 mL of ethanol in a 250 mL round-bottom flask, 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 to obtain a colorless oily solid compound 5c (8.00 g), which was used directly in the next step without purification. LCMS: 168.1 [M+H] +Step 3: 3-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)oxetane-3-carboxylonitrile (5d)

[0277] In a 250 mL round-bottom flask, compound 5c (4.99 g, 29.90 mmol), compound 1d (7.50 g, 35.88 mmol), potassium carbonate (8.30 g, 59.80 mmol), and acetonitrile (50 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 5d as a yellow solid (3.28 g, yield 31%). 1 H NMR (400MHz, CDCl3) δ8.11(s,1H),7.74(d,1H),7.23(d,1H),4.88(d,2H),4.72(d,2H),3.33–3.20(m,4H),2.72–2.59(m,4H)ppm; LCMS:357.1[M+H] + .

[0278] Step 4: 3-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)oxetane-3-carboxylonitrile (5e)

[0279] Under a hydrogen atmosphere, compound 5d (100 mg, 0.28 mmol) and palladium on carbon (20 mg, 10%) were dissolved in 10 mL of ethanol in a 100 mL round-bottom flask, 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 to give compound 5e as a colorless oily solid (88 mg, yield: 96%), which was used directly in the next step without purification. LCMS: 327.1 [M+H] + .

[0280] Step 5: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 5)

[0281] In a 100 mL reaction tube, potassium tert-butoxide (91 mg, 0.81 mmol) was dissolved in tetrahydrofuran (10 mL), and a mixed solution of compound 5e (88 mg, 0.27 mmol) and compound 1c (80 mg, 0.38 mmol) in tetrahydrofuran was added. 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 preparative liquid chromatography to give compound 5 as a white solid (20 mg, yield: 14%). 1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.62(s,1H),7.52(s,2H),7.27(d,1H),6.52–6.42(m,1H),4.81(d,2H),4.67(d,2H),3.9 1(dd,2H),3.54–3.44(m,2H),3.10(s,1H),3.05(d,4H),2.65(s,4H),1.98–1.90(m,2H),1.67(dd,2H)ppm; LC-MS:505.2[M+H] + .

[0282] Example 6: N-(2-(4-(3-(1H-pyrazol-3-yl)oxecyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 6)

[0283] Step 1: 3-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)oxecyclobutane-3-carboxylic acid (6a)

[0284] In a 250 mL round-bottom flask, compound 5d (1.50 g, 4.21 mmol), barium hydroxide (14.50 g, 8.43 mmol), isopropanol (30 mL), and water (30 mL) were added sequentially, and the mixture was refluxed for 24 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, and the pH was adjusted to acidic with 3 M hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give crude compound 6a as a yellow solid (1.03 g, yield: 65%), which was used directly as a raw product in the next step. LCMS: 376.1 [M+H] + .

[0285] Step 2: N-methoxy-N-methyl-3-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)oxetane-3-carboxamide (6b)

[0286] In a 100 mL round-bottom flask, compound 6a (1.02 g, 2.72 mmol), methylmethoxyamine hydrochloride (398 mg, 4.08 mmol), N,N-diisopropylethylamine (351 mg, 2.72 mmol), and dichloromethane (20 mL) were added sequentially. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (782 mg, 4.08 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the mixture 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 column chromatography to give compound 6b as a pale yellow solid (900 mg, yield: 78%). 1 H NMR(400MHz,DMSO-d6)δ8.18(d,1H),7.88(dd,1H),7.49(d,1H),4.66(dd,4H), 3.73(d,3H),3.28–3.20(m,4H),3.16(s,3H),2.73(d,4H)ppm; LCMS:419.1[M+H] + .

[0287] Step 3: 3-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)-N-methoxy-N-methyloxetane-3-carboxamide (6c)

[0288] Under a hydrogen atmosphere, compound 6b (900 mg, 2.16 mmol) and palladium on carbon (180 mg, 10%) were dissolved in ethanol (20 mL) in a 100 mL round-bottom flask, 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 evaporated to dryness under reduced pressure to give compound 6c, a colorless oily solid (788 mg, yield: 93%), which was used directly in the next step without purification. LCMS: 389.2 [M+H] + .

[0289] Step 4: 1-(3-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)oxecyclobutane-3-yl)ethane-1-one (6d)

[0290] Under nitrogen protection, compound 6c (780 mg, 2.02 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) in a 100 mL three-necked flask. The mixture was cooled to 0 °C in an ice bath, and methyl magnesium bromide (1.7 mL, 3 M) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. The reaction was quenched with saturated ammonium chloride, 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 6d as a grayish-white solid (450 mg, yield 64%). LCMS: 344.2 [M+H] + .

[0291] Step 5: N-(2-(4-(3-acetyloxetane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (6e)

[0292] In a 100 mL reaction tube, potassium tert-butoxide (442 mg, 3.93 mmol) was dissolved in tetrahydrofuran (10 mL). A mixed tetrahydrofuran solution of compound 6d (450 mg, 1.31 mmol) and compound 1c (386 mg, 1.83 mmol) 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 6e as a white oily solid (307 mg, yield: 45%). LCMS: 522.2 [M+H] + .

[0293] Step 6: (E)-N-(2-(4-(3-(3-(dimethylamino)acryloyl)oxetane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (6f)

[0294] In a 100 mL round-bottom flask, compound 6e (300 mg, 0.58 mmol) was dissolved in 10 mL of N,N-dimethylformamide dimethyl acetal, and the mixture was heated to 100 °C and reacted for 18 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 medium-pressure preparation to give compound 6f as a grayish-white solid (270 mg, yield: 46%). LCMS: 577.3 [M+H] + .

[0295] Step 7: N-(2-(4-(3-(1H-pyrazol-3-yl)oxecyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 6)

[0296] In a 100 mL round-bottom flask, compound 6f (270 mg, 0.47 mmol), hydrazine hydrate (5 mL), and ethanol (10 mL) were added sequentially, and the mixture was heated to 90 °C and reacted for 4 h. After cooling to room temperature, the organic solvent was removed under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound 6, a white solid (100 mg, yield: 39%). 1H NMR(500MHz,DMSO-d6)δ12.81(s,1H),9.13(s,1H),8.45(s,1H),7.80(s,1H),7.47(q,2H),7.15(s,1H),6.43(s,1H),6.26(s,1H),4.78(s ,4H),3.88(d,2H),3.47(s,2H),2.97(s,4H),2.90(s,1H),2.54(s,2H),1.85(d,2H),1.67–1.59(m,2H),1.24(s,2H)ppm; LCMS:546.2[M+H] + .

[0297] Example 7: N-(2-(4-(3-(1-methyl-1H-pyrazol-3-yl)oxetane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 7-1), N-(2-(4-(3-(1-methyl-1H-pyrazol-5-yl)oxetane-3-yl)piperazin-1-yl) -5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 7-2) and N-methyl-N-(2-(4-(3-(1-methyl-1H-pyran-3-yl)oxetane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 7-3)

[0298] In a 100 mL round-bottom flask, compound 6 (45 mg, 0.08 mmol) and sodium hydroxide (10 mg, 0.24 mmol) were dissolved in acetonitrile (10 mL), and iodomethane (13 mg, 0.09 mmol) was added dropwise with stirring. The reaction was allowed to proceed overnight at 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 preparative liquid chromatography to give compound 7-1 (white solid, 6.7 mg, yield: 14%), compound 7-2 (white solid, 1.3 mg, yield: 3%), and compound 7-3 (white solid, 5.1 mg, yield: 11%).

[0299] Compound 7-1: 1¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.50 (d, 1H), 7.42 (d, 1H), 7.17 (d, 1H), 6.45 (d, 1H), 6.36 (s, 1H), 4.92 (s, 2H), 4.81 (d, 2H), 3.90 (s, 3H), 3.08 (s, 3H), 2.96 (dd, 1H), 2.85–2.67 (m, 2H), 2.04–1.99 (m, 1H), 1.88 (d, 1H), 1.70–1.62 (m, 1H), 1.47 (d, 1H), 1.28 (s, 1H), 1.25 (s, 6H) ppm; LCMS: 560.2 [M+H] + .

[0300] Compound 7-2: 1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.62 (s, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 7.26 (d, 1H), 6.48 (d, 1H), 6.39 (s, 1H), 5.08 (d, 2H), 4.83 (d, 2H), 3.96 (d, 2H), 3.75 (s, 3H), 3.49 (d, 2H), 2.99 (s, 2H), 2.81 (s, 2H), 2.05–1.99 (m, 1H), 1.93 (d, 1H), 1.72 (d, 1H), 1.47 (s, 1H), 1.25 (s, 6H) ppm; LCMS: 560.2 [M+H] + .

[0301] Compound 7-3: 1 ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (s, 1H), 7.63–7.52 (m, 2H), 7.24 (t, 1H), 6.41 (d, 1H), 6.31 (s, 1H), 6.10 (d, 1H), 4.95 (s, 2H), 4.82 (d, 2H), 3.96 (s, 3H), 3.73 (s, 2H), 3.70 (s, 2H), 3.30 (s, 1H), 3.27 (s, 1H), 3.24 (s, 3H), 3.08 (s, 1H), 2.96 (s, 1H), 2.60 (d, 1H), 1.41 (d, 1H), 1.25 (s, 6H), 1.17–1.11 (m, 1H) ppm; LCMS: 574.3 [M+H] + .

[0302] Example 8: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)propyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 8)

[0303] Step 1: 2-(4-(1-(1-methyl-1H-pyrazol-3-yl)propyl)piperazin-1-yl)-5-(trifluoromethyl)aniline (8a)

[0304] Under a hydrogen atmosphere, compound 3d (300 mg, 0.76 mmol) and palladium on carbon (60 mg, 10%) were dissolved in ethanol (15 mL) in a 100 mL round-bottom flask, and the mixture was heated to 60 °C and reacted for 12 h. After the reaction was completed, the mixture was filtered under reduced pressure, and the filtrate was rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give compound 8a as a white solid (225 mg, yield: 81%). LCMS: 368.2 [M+H] + Step 2: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)propyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 8)

[0305] In a 100 mL reaction tube, potassium tert-butoxide (206 mg, 1.84 mmol) was dissolved in tetrahydrofuran (10 mL), and a mixed solution of compound 8a (225 mg, 0.61 mmol) and compound 1c (181 mg, 0.85 mmol) in tetrahydrofuran 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 preparative high-performance liquid chromatography to give compound 8 as a white solid (130 mg, yield: 38%). 1 H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.63(s,1H),7.57(s,1H),7.50(s,2H),7.27(s,1H),6.47(d,1H),6.10(s,1H),3.94(d,2H),3.79(s ,3H),3.50–3.39(m,5H),3.12–3.03(m,2H),2.96(s,3H),2.72(d,3H),1.97(d,2H),1.80–1.68(m,2H),1.25(s,4H)ppm; LCMS:546.3[M+H] + .

[0306] Example 9: N-(2-(4-(3-(2H-tetrazol-5-yl)oxetane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 9)

[0307] Step 1: 1-(3-(2H-tetrazol-5-yl)oxecyclobutane-3-yl)-4-(2-nitro-4-(trifluoromethyl)phenyl)piperazine (9a)

[0308] In a 100 mL round-bottom flask, compound 5d (200 mg, 0.56 mmol), azidotrimethylsilane (97 mg, 0.84 mmol), and tetrabutylammonium fluoride (0.3 mL, 0.28 mmol, 1 M) were added sequentially, and the mixture was heated to 85 °C and reacted 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 9a as a yellow oily solid (177 mg, yield: 78%). LCMS: 400.1 [M+H] + .

[0309] Step 2: 2-(4-(3-(2H-tetrazol-5-yl)oxetane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)aniline (9b)

[0310] Under a hydrogen atmosphere, compound 9a (177 mg, 0.44 mmol) and palladium on carbon (36 mg, 10%) were dissolved in 10 mL of ethanol in a 100 mL round-bottom flask, 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 evaporated to dryness under reduced pressure to give compound 9b, a colorless oily solid (160 mg, yield: 97%), which was used directly in the next step without purification. LCMS: 370.2 [M+H] + .

[0311] Step 3: N-(2-(4-(3-(2H-tetrazol-5-yl)oxetane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 9)

[0312] In a 100 mL reaction tube, potassium tert-butoxide (164 mg, 1.34 mmol) was dissolved in tetrahydrofuran (10 mL), and a mixed solution of compound 9b (160 mg, 0.44 mmol) and compound 1c (132 mg, 0.62 mmol) in tetrahydrofuran was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, 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 9 as a white solid (48 mg, yield: 19%). 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.49(s,1H),7.54–7.44(m,2H),7.19(d,1H),6.44(d,1H),4.90(d,2H),4.86(d,2H),3.96– 3.86(m,2H),3.64(dd,2H),3.00(t,4H),2.96–2.87(m,1H),2.54(s,4H),1.85(d,2H),1.68–1.53(m,2H)ppm; LC-MS:548.2[M+H] + .

[0313] Example 10: N-(2-(4-(1-methyl-1H-pyrazole-3-thiocarbonyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 10)

[0314] Step 1: (4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)(1-methyl-1H-pyrazole-3-yl)meththione (10a)

[0315] In a 100 mL round-bottom flask, compound 4b (353 mg, 1.00 mmol) was dissolved in toluene (10 mL), and Lawson's reagent (282 mg, 0.70 mmol) was added. The reaction mixture was reacted at 120 °C for 2 h. The reaction solution was purified by direct column chromatography to give compound 10a as a yellow solid (221 mg, yield 61%). LCMS: 370.1 [M+H] + .

[0316] Step 2: N-(2-(4-(1-methyl-1H-pyrazole-3-thiocarbonyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 10)

[0317] In a 50 mL round-bottom flask, compound 10a (200 mg, 0.54 mmol) was dissolved in acetonitrile (5 mL), followed by compound 4a (0.12 g, 0.60 mmol), N-methylimidazole (0.12 g, 1.50 mmol), and then N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (0.28 g, 1.00 mmol). The reaction was carried out at room temperature for 24 h. After the reaction was complete, the mixture 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 10 as a white solid (200 mg, 68% yield). 1 H NMR(500MHz, CDCl3)δ9.29(s,1H),8.85(s,1H),7.39(d,1H),7.36(s,1H),7 .28(s,1H),7.23(d,1H),6.74(s,1H),6.26(d,1H),4.79–4.47(m,2H),4.30( s,2H),4.08(d,2H),3.93(s,3H),3.59(t,2H),3.19(s,2H),3.07(s,2H),3. 04–2.96(m,1H),2.04–1.96(m,2H),1.91–1.78(m,2H)ppm; LCMS:548.2[M+H] + .

[0318] Example 11: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide

[0319] Step 1: tert-butyl 4-(2-amino-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (11a)

[0320] At room temperature, compound 1e (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. 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 11a, a colorless oil (9.10 g, 98% yield). LCMS: 346.2 [M+H] + .

[0321] Step 2: 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (11b)

[0322] At room temperature, potassium tert-butoxide (4.87 g, 43.43 mmol) and tetrahydrofuran (60 mL) were added to a 250 mL round-bottom flask. Compound 11a (5.00 g, 14.47 mmol) and compound 1c (4.57 g, 21.72 mmol) were dissolved in tetrahydrofuran (60 mL) and added to the above system. The reaction was carried out at 25 °C for 12 h. The mixture was extracted with water and ethyl acetate, and the organic phases were combined. The solutions were washed first with saturated sodium carbonate, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 11b, a white solid (8.70 g). LCMS: 524.2 [M+H] + .

[0323] Step 3: N-(2-(piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (11c)

[0324] At room temperature, compound 11b (8.70 g, 16.62 mmol), 1,4-dioxane (30 mL), and dioxane hydrochloride solution (30 mL) were added to a 250 mL round-bottom flask. The reaction was carried out at 25 °C for 12 h. The organic solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound 11c as a white solid (3.90 g, 63% yield in two steps). LCMS: 424.1 [M+H] + .

[0325] Step 4: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 11)

[0326] Compound 11c (100 mg, 0.24 mmol), bromoacetonitrile (31 mg, 0.26 mmol), and potassium carbonate (98 mg, 0.71 mmol) were added sequentially to anhydrous N,N-dimethylformamide (3 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 (70 mg, yield: 63%). 1H NMR(400MHz, CDCl3)δ9.22(s,1H),8.87(s,1H),7.42–7.35(m,1H),7.28–7.22(m,2H),6.28–6.23(m,1H),4.12–4.01(m,2H),3.69(s,2H) ,3.67–3.59(m,2H),3.21–3.11(m,1H),3.11–3.01(m,4H),2.95–2.81(m,4H),2.08–1.96(m,2H),1.90–1.75(m,2H)ppm; LCMS: 463.2[M+H] + .

[0327] Example 12: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 12)

[0328] Step 1: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 12)

[0329] At room temperature, compound 11 (150 mg, 0.33 mmol), ethanol (2 mL), water (2 mL), hydrogen peroxide (74 mg, 0.65 mmol, 30%), sodium hydroxide (26 mg, 0.65 mmol), and dimethyl sulfoxide (51 mg, 0.65 mmol) were added to a 25 mL round-bottom flask. The reaction was carried out 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 preparative high-performance liquid chromatography to give compound 12 as a white solid (21 mg, 13% yield). 1 H NMR(500MHz,DMSO-d6)δ9.46(s,1H),8.69–8.56(m,1H),7.52–7.43(m,2H),7 .32–7.22(m,2H),7.20–7.15(s,1H),6.49–6.42(m,1H),4.01–3.89(m,2H),3 .55–3.46(m,2H),3.32–3.29(m,2H),3.12–3.03(m,1H),2.98–2.96(m,4H),2 .79–2.62(m,4H),1.99–1.91(m,2H),1.80–1.67(m,2H)ppm; LCMS: 481.2[M+H] + .

[0330] Example 13: (R)-N-(2-(4-(cyano(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 13-1) and (S)-N-(2-(4-(cyano(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 13-2)

[0331] Step 1: N-(2-(4-(cyano(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 13)

[0332] 3-Aldehyde-1-methylpyrazole (180 mg, 1.64 mmol), zinc iodide (209 mg, 0.65 mmol), and trimethylcyanosilane (195 mg, 1.96 mmol) were added to a tetrahydrofuran (10 mL) solution. The mixture was stirred for 5 min at 25 °C under nitrogen protection. Then, a solution of compound 11c (623 mg, 1.47 mmol) and triethylamine (165 mg, 1.64 mmol) in anhydrous methanol (10 mL) was added. The mixture was stirred for 8 h at 60 °C 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 13 (500 mg, yield: 56%). LCMS: 543.2 [M+H] + .

[0333] Step 2: (R)-N-(2-(4-(cyano(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 13-1) and (S)-N-(2-(4-(cyano(1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 13-2) were separated by SFC to obtain compound 13-1 (150 mg) and compound 13-2 (120 mg).

[0334] Compound 13-1 1H NMR(400MHz, CDCl3)δ9.24(s,1H),8.85(d,1H),7.40(d,1H),7.37–7.34(m,1H),7.27–7.22(m,2H),6.40(d,1H),6.24(d,1H),5.00(s,1H),4.09 –4.02(m,2H),3.95(s,3H),3.74–3.65(m,2H),3.27–3.18(m,1H),3.14– 2.69(m,8H),2.09–2.01(m,2H),1.87–1.74(m,2H)ppm; LCMS: 543.2[M+H] + .

[0335] Compound 13-2 1 H NMR(400MHz, CDCl3)δ9.25(s,1H),8.87(s,1H),7.42(d,1H),7.40–7.34(m,1H),7.28–7.22(m,2H),6.41(d,1H),6.25(d,1H),5.02(s,1H),4.13 –4.02(m,2H),3.97(s,3H),3.77–3.65(m,2H),3.29–3.18(m,1H),3.17– 2.73(m,8H),2.12–2.01(m,2H),1.91–1.77(m,2H)ppm; LCMS: 543.2[M+H] + .

[0336] Example 14: N-(2-(4-(1-cyanocyclobutyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 14)

[0337] Step 1: N-(2-(4-(1-cyanocyclobutyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 14)

[0338] Cyclobutanone (20 mg, 0.28 mmol), zinc iodide (30 mg, 0.09 mmol), and trimethylcyanosilane (33 mg, 0.33 mmol) were added to a tetrahydrofuran (2 mL) solution. After stirring for 5 min at 25 °C under nitrogen protection, an anhydrous methanol (2 mL) solution of compound 11c (100 mg, 0.24 mmol) and triethylamine (36 mg, 0.35 mmol) was added. The mixture was stirred for 8 h at 60 °C under nitrogen protection. 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 14 (50 mg, yield: 41%). 1 H NMR(400MHz, CDCl3)δ9.21(s,1H),8.86(s,1H),7.40–7.35(m,1H),7.28–7 .22(m,2H),6.26–6.22(m,1H),4.08–3.99(m,2H),3.70–3.62(m,2H),3.23– 3.13(m,1H),3.08–2.99(m,4H),2.85–2.55(m,4H),2.52–2.43(m,2H),2.3 6–2.15(m,3H), 2.06–1.93(m,3H),1.83–1.72(m,2H)ppm; LCMS: 503.2[M+H] + .

[0339] Example 15: tert-butyl-3-cyano-3-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)azacyclobutane-1-carboxylate (Compound 15)

[0340] Step 1: tert-butyl-3-cyano-3-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)azacyclobutane-1-carboxylate (15b)

[0341] In a 100 mL round-bottom flask, compound 15a (931 mg, 5.43 mmol), trimethylcyanosilane (809 mg, 8.15 mmol), zinc iodide (463 mg, 1.45 mmol), and tetrahydrofuran (10 mL) were added sequentially. After reacting overnight at room temperature, compound 1f (1.00 g, 3.62 mmol), triethylamine (549 mg, 5.43 mmol), and methanol (10 mL) were added, and the mixture was heated to 60 °C and reacted for 12 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 15b as a yellow oily solid (582 mg, yield: 34%). LCMS: 456.2 [M+H] + .

[0342] Step 2: tert-butyl 3-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)-3-cyanoazacyclobutane-1-carboxylic acid ester (15c)

[0343] Under a hydrogen atmosphere, compound 15b (474 ​​mg, 1.04 mmol) and palladium on carbon (95 mg, 10%) were dissolved in 10 mL of ethanol in a 100 mL round-bottom flask, and the mixture was heated to 60 °C and reacted for 12 h. After the reaction was completed, the mixture was filtered under reduced pressure, the filtrate was removed under reduced pressure, and the residue was purified by column chromatography to give compound 15c as a colorless oily solid (260 mg, yield: 58%). LCMS: 426.2 [M+H] + .

[0344] Step 3: Tert-butyl-3-cyano-3-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)azacyclobutane-1-carboxylate (Compound 15)

[0345] In a 100 mL round-bottom flask, compound 15c (260 mg, 0.61 mmol), compound 4a (169 mg, 0.85 mmol), and N-methylimidazole (101 mg, 1.22 mmol) were dissolved in acetonitrile. N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (258 mg, 0.91 mmol) was added with stirring, and the mixture was reacted overnight at room temperature. 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 15 as a white solid (210 mg, yield: 56%). 1H NMR(500MHz,DMSO-d6)δ9.29(s,1H),8.59(s,1H),7.52–7.43(m,2H),7.26(d,1H),6.48–6.42(m,1H),4.16(s,2H),4.02(d,2H),3.93–3.86 (m,2H),3.51–3.44(m,2H),3.02(s,4H),2.75–2.60(m,3H),1.93(d,2H),1.70–1.61(m,2H),1.41(s,9H),1.24(s,2H)ppm; LCMS:604.3[M+H] + .

[0346] Example 16: N-(2-(4-(3-cyanozazetane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 16)

[0347] In a 100 mL round-bottom flask, compound 15 (160 mg, 0.27 mmol) was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (3 mL) was added under ice bath conditions, and the mixture was slowly heated to room temperature for 4 h. After the reaction was complete, the mixture was quenched with water, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative liquid chromatography to give compound 16 as a white solid (120 mg, yield: 90%). 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.62(s,1H),7.50(s,2H),7.27(d,1H),6.47(d,1H),3.91(d,2H),3.67(d,2H),3.61(d,2H) ,3.50(t,3H),3.16–3.06(m,1H),3.02(s,4H),2.61(s,3H),1.95(d,2H),1.74–1.60(m,2H),1.25(s,1H)ppm; LC-MS: 504.2[M+H] + .

[0348] Example 17: N-(2-(4-(3-cyano-1-methylazacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 17)

[0349] In a 100 mL round-bottom flask, compound 16 (50 mg, 0.10 mmol), paraformaldehyde (15 mg, 0.50 mmol), and methanol (10 mL) were added sequentially, and the mixture was reacted at room temperature for 1 h. After 1 h, sodium cyanoborohydride (63 mg, 0.10 mmol) was added, and the mixture was reacted 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 then subjected to medium pressure to prepare compound 17, a white solid (21 mg, yield: 42%). 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.62(s,1H),7.50(s,2H),7.27(d,1H),6.47(d,1H),3.91(d,2H),3.69(d,2H),3.50(t,2H),3. 13(d,1H),3.06(d,2H),3.01(s,4H),2.61(s,3H),2.31(s,3H),1.94(d,2H),1.74–1.58(m,2H),1.25(s,1H)ppm; LC-MS: 518.2[M+H] + .

[0350] Example 18: N-(2-(4-(cyanomethyl)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 18)

[0351] Step 1: 2-(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-4-yl)acetonitrile (18b)

[0352] At room temperature, compound 1d (1.00 g, 4.78 mmol), N,N-dimethylformamide (8 mL), potassium carbonate (1.98 g, 14.35 mmol), and compound 18a (0.85 g, 5.26 mmol) were added to a 50 mL round-bottom flask. The mixture was stirred at 25 °C for 8 h. After the reaction was complete, water was added to the reaction solution, and a solid precipitated. The solid was filtered, the filter cake was washed with water, and the solid was collected and dried under reduced pressure to give compound 18b, a yellow solid (1.20 g, 80% yield). LCMS: 314.1 [M+H] + .

[0353] Step 2: 2-(1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-4-yl)acetonitrile (18c)

[0354] Compound 18b (300 mg, 0.96 mmol), ethanol (8 mL), and palladium on carbon (100 mg) were added to a 50 mL round-bottom flask at room temperature. 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 18c, a colorless oil (270 mg, 99% yield). LCMS: 284.1 [M+H] + Step 3: N-(2-(4-(cyanomethyl)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 18)

[0355] At room temperature, potassium tert-butoxide (214 mg, 1.91 mmol) and tetrahydrofuran (4 mL) were added to a 50 mL round-bottom flask. Compound 18c (180 mg, 0.64 mmol) and compound 1c (200 mg, 0.95 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 give compound 18 as a white solid (137 mg, yield 46%). 1 H NMR(500MHz,DMSO-d6)δ9.32(s,1H),8.68–8.57(m,1H),7.49–7.41(m,2H),7.27–7.20(m,1H),6.49–6.41(m,1H),3.97–3.88(m,2H),3.52–3.43 (m,2H),3.13–3.05(m,3H),2.82–2.73(m,2H),2.63–2.58(m,2H),1.96– 1.83(m,5H),1.77–1.65(m,2H),1.60–1.50(m,2H)ppm; LCMS: 462.1[M+H] + .

[0356] Example 19: Methyl 2-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetate (Compound 19)

[0357] Step 1: Methyl 2-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetate (Compound 19)

[0358] Compound 11c (50 mg, 0.12 mmol), methyl bromoacetate (22 mg, 0.14 mmol), and potassium carbonate (49 mg, 0.35 mmol) were added sequentially to anhydrous 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 19 (25 mg, yield: 42%). 1 H NMR(400MHz, CDCl3)δ9.42(s,1H),8.86(s,1H),7.36(d,1H),7.28(s,1H),7.21(d,1H),6.24(d,1H),4.16–4.07(m,2H),3.78(s,3H) ,3.66–3.55(m,2H),3.38(s,2H),3.13–3.00(m,5H),2.98–2.78(m,4H),2.09–2.00(m,2H),1.96–1.85(m,2H)ppm; LCMS: 496.2[M+H] + .

[0359] Example 20: 2-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetic acid (compound 20)

[0360] Step 1: 2-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetic acid (compound 20)

[0361] Compound 19 (100 mg, 0.20 mmol) and lithium hydroxide monohydrate (13 mg, 0.30 mmol) were added sequentially to methanol (4 mL) and water (2 mL), and stirred at 25 °C for 8 h. After the reaction was completed, the pH was adjusted to 7, and the reaction solution was directly purified by preparative liquid chromatography to obtain compound 20 (60 mg, yield: 62%). 1H NMR(400MHz, CDCl3)δ9.40(s,1H),8.95(s,1H),7.39(d,1H),7.33(d,1H),7.24(d,1H),6.29(d,1H),4.35–4.25(m,2H),4.1 0(brs,1H),3.72–3.58(m,2H),3.51(s,2H),3.15–2.98(m,9H),2.16–1.99(m,2H),1.96–1.85(m,2H)ppm; LCMS: 482.2[M+H] + .

[0362] Example 21: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 21)

[0363] Step 1: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 21)

[0364] Compound 11c (60 mg, 0.14 mmol), bromoethanol (22 mg, 0.17 mmol), and potassium carbonate (59 mg, 0.43 mmol) were added sequentially to anhydrous 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 21 (10 mg, yield: 15%). 1 H NMR (400MHz, CDCl3) δ9.45(s,1H),8.87(s,1H),7.37(d,1H),7.29(d,1H),7.21(d,1H),6.25(d,1H),4.15–4.07(m,2H),3.77–3. 70(m,2H),3.61–3.52(m,2H),3.07–2.98(m,5H),2.96–2.74(m,4H),2.73–2.65(m,2H),2.05–1.89(m,4H)ppm; LCMS: 468.2[M+H] + .

[0365] Example 22: N-(2-(4-(methylsulfonyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 22)

[0366] Step 1: N-(2-(4-(methylsulfonyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 22)

[0367] At room temperature, compound 11c (150 mg, 0.35 mmol), dichloromethane (8 mL), and triethylamine (108 mg, 1.06 mmol) were added to a 50 mL round-bottom flask, and the mixture was stirred at 0 °C for 2 min. Methanesulfonic anhydride (74 mg, 0.43 mmol) was then added, and the reaction was continued at 0 °C for 15 min. Water and dichloromethane were added for extraction and separation. 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 preparative high-performance liquid chromatography to give compound 22 as a white solid (108 mg, 60% yield). 1 H NMR(500MHz, CDCl3)δ9.25(s,1H),8.93–8.83(m,1H),7.39–7.35(m,1H),7.29–7.26(m,1H),7.22–7.19(m,1H),6.33–6.20(m,1H),4.10–3.9 8(m,2H),3.62–3.41(m,6H),3.11–3.04(m,4H),3.03–2.95(m,1H),2.92(s,3H),1.98–1.91(m,2H),1.91–1.81(m,2H)ppm; LCMS: 502.2[M+H] + .

[0368] Example 23: N-(2-(4-(1-carbamoylcyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 23)

[0369] Step 1: 1-(4-benzylpiperazin-1-yl)cyclopropane-1-carboxylonitrile (23b)

[0370] In a 250 mL round-bottom flask, compound 23a (7.00 g, 2.61 mmol), 1-amino-1-cyclopropyl cyanurate hydrochloride (1.03 g, 0.87 mmol), and ethanol (80 mL) were added sequentially. N,N-diisopropylethylamine (40 mL) was then added with stirring, and the mixture was refluxed for 18 h. After the reaction was complete, the mixture was cooled to room temperature, and the organic solvent was removed under reduced pressure. The residue was dissolved in 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 23b as a colorless oily solid (1.10 g, yield: 54%).1 H NMR(500MHz,DMSO-d6)δ7.60(dd,2H),7.50–7.43(m,3H),4.31(d,2H),3.32(d,2H),3.02(d,2H ),2.97–2.89(m,2H),2.86(t,2H),1.30–1.26(m,2H),1.10–1.05(m,2H)ppm; LCMS: 242.2[M+H] + .

[0371] Step 2: 1-(piperazin-1-yl)cyclopropane-1-carboxynitrile (23c)

[0372] In a 100 mL round-bottom flask, compound 23b (1.10 g, 4.56 mmol), potassium carbonate (1.90 g, 13.69 mmol), and 1-chloroethyl chloroformate (978 mg, 6.84 mmol) were dissolved in acetone (15 mL) and reacted overnight at room temperature. The filtrate was collected, and the organic solvent was removed under reduced pressure. The residue was dissolved in methanol (15 mL), and the mixture was refluxed for 1 h. The organic solvent was removed under reduced pressure to give compound 23c, a pale yellow oily solid (688 mg, yield: 100%), which could be used directly in the next step without purification. LCMS: 152.1 [M+H] + .

[0373] Step 3: 1-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxylonitrile (23d)

[0374] In a 100 mL round-bottom flask, compound 1d (954 mg, 4.56 mmol), compound 23c (688 mg, 4.56 mmol), potassium carbonate (1.26 g, 9.12 mmol), and acetonitrile (20 mL) were added sequentially. The mixture was heated to 60 °C and reacted for 4 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 23d as a yellow solid (882 mg, 57% yield). LCMS: 341.1 [M+H] + Step 4: 1-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxamide (23e)

[0375] In a 100 mL round-bottom flask, compound 23d (200 mg, 0.59 mmol), potassium carbonate (82 mg, 0.59 mmol), hydrogen peroxide (34 mg, 1.76 mmol, 30% aqueous solution), and dimethyl sulfoxide (10 mL) were added sequentially. The mixture was heated to 60 °C and reacted for 4 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 23e as a yellow oily solid (134 mg, yield: 64%). LCMS: 359.1 [M+H] + .

[0376] Step 5: 1-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxamide (23f)

[0377] In a 100 mL round-bottom flask, compound 23e (130 mg, 0.36 mmol), ammonium chloride (196 mg, 3.63 mmol), and zinc powder (118 mg, 1.82 mmol) were dissolved in 10 mL of methanol, and the mixture was refluxed for 6 h. The mixture was filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 23f as a white oily solid (107 mg, yield: 90%). LCMS: 329.2 [M+H] + .

[0378] Step 6: N-(2-(4-(1-carbamoylcyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 23)

[0379] In a 100 mL round-bottom flask, compound 23f (107 mg, 0.33 mmol), compound 4a (90 mg, 0.46 mmol), and N-methylimidazole (54 mg, 0.65 mmol) were dissolved in acetonitrile. N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (138 mg, 0.49 mmol) was added with stirring, 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 23 as a white solid (60 mg, yield: 36%). 1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.66(s,1H),7.50(d,2H),7.27(d,1H),6.47(d,1H),3.97(d,2H),3.54(s,2H),3.13(d ,1H),3.05(s,5H),2.90(s,4H),2.00–1.90(m,2H),1.78–1.63(m,2H),1.25(s,1H),1.18–1.06(m,4H)ppm; LCMS: 507.2[M+H] + .

[0380] Example 24: N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 24)

[0381] Step 1: 1-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxynitrile (24a)

[0382] In a 100 mL round-bottom flask, compound 23d (66 mg, 0.19 mmol), ammonium chloride (105 mg, 1.9 mmol), and zinc powder (63 mg, 0.97 mmol) were dissolved in 10 mL of methanol, and the mixture was refluxed for 6 h. The mixture was filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 24a as a white oily solid (58 mg, yield: 97%). LCMS: 311.1 [M+H] + .

[0383] Step 2: N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 24)

[0384] In a 100 mL round-bottom flask, compound 24a (58 mg, 0.19 mmol), compound 4a (51 mg, 0.26 mmol), and N-methylimidazole (31 mg, 0.37 mmol) were dissolved in acetonitrile. N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (79 mg, 0.28 mmol) was added with stirring, and the reaction was carried out overnight at room temperature. 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 preparative high-performance liquid chromatography to give compound 24 as a white solid (42 mg, yield: 46%). 1H NMR(500MHz,DMSO-d6)δ9.47(s,1H),8.62(s,1H),7.49(s,1H),7.47(s,1H),7.25 (d,1H),6.47(d,1H),5.92(d,1H),5.33(t,1H),3.97(d,1H),3.49(dd,1H),3.25–3 .20(m,1H),3.12–3.04(m,1H),2.96(t,2H),2.67(s,2H),2.03–1.97(m,1H),1.94 (d,1H),1.77(d,1H),1.46(d,1H),1.30(s,1H),1.24(s,6H)ppm; LCMS: 489.2[M+H] + .

[0385] Example 25: N-(2-(4-(1-cyano-3-hydroxycyclobutyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 25)

[0386] Step 1: N-(2-(4-(1-cyano-3-hydroxycyclobutyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 25)

[0387] In a 100 mL round-bottom flask, trimethylcyanosilane (198 mg, 2.00 mmol), cyclobutyl 3-oxoacetate (128 mg, 1.00 mmol), and zinc iodide (127 mg, 0.40 mmol) were sequentially added to tetrahydrofuran (5 mL), and the reaction was carried out at room temperature for 12 h. Then, compound 11c (212 mg, 0.50 mmol) and triethylamine (202 mg, 2.00 mmol) were dissolved in methanol (3 mL) and added to the above reaction solution, and the reaction was continued at 60 °C for 6 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 25 as a white solid (165 mg, yield 64%). 1H NMR(500MHz, CDCl3)δ9.20(s,1H),8.86(d,1H),7.37(d,1H),7.27–7.20(m,2H) ,6.24(d,1H),4.26–4.19(m,1H),4.09–3.99(m,2H),3.67–3.58(m,2H),3.21–3. 09(m,1H),3.09–2.99(m,5H),2.98–2.95(m,1H),2.95–2.89(m,2H),2.86–2.72( m,2H),2.28(s,3H),2.06–1.95(m,2H),1.85–1.73(m,2H)ppm; LCMS:519.2[M+H] + .

[0388] Example 26: N-(2-(4-((1r,3r)-1,3-dicyanocyclobutyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 26-1) and N-(2-(4-((1s,3s)-1,3-dicyanocyclobutyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 26-2)

[0389] Step 1: N-(2-(4-(1,3-dicyanocyclobutyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 26)

[0390] In a 100 mL round-bottom flask, trimethylcyanosilane (198 mg, 2.00 mmol), 3-oxocyclobutyronitrile (95 mg, 1.00 mmol), and zinc iodide (127 mg, 0.40 mmol) were sequentially added to tetrahydrofuran (5 mL), and the reaction was carried out at room temperature for 12 h. Then, compound 11c (212 mg, 0.50 mmol) and triethylamine (202 mg, 2.00 mmol) were dissolved in methanol (3 mL) and added to the above reaction solution, and the reaction was continued at 60 °C for 6 h. The reaction was quenched with aqueous 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 a white solid compound 26 (100 mg, yield 38%). LCMS: 528.2 [M+H] + .

[0391] Step 2: N-(2-(4-((1r,3r)-1,3-dicyanocyclobutyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 26-1) and N-(2-(4-((1s,3s)-1,3-dicyanocyclobutyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 26-2)

[0392] Compound 26-1 (19 mg, 7% yield) and compound 26-2 (32 mg, 12% yield) were obtained by chiral resolution.

[0393] Compound 26-1: 1 H NMR(500MHz, CDCl3)δ9.15(s,1H),8.86(d,1H),7.38(d,1H),7.26(d,1H) ,7.24(d,1H),6.24(d,1H),4.07–3.98(m,2H),3.65–3.57(m,2H),3.38–3. 29(m,1H),3.19–3.10(m,1H),3.09–2.98(m,4H),2.94–2.85(m,2H),2.85 –2.55(m,6H),2.04–1.94(m,2H),1.84–1.72(m,2H)ppm; LCMS:528.2[M+H] + .

[0394] Compound 26-2: 1 H NMR(500MHz, CDCl3)δ9.15(s,1H),8.87(d,1H),7.41–7.35(m,1H),7.30–7.2 6(m,1H),7.24(d,1H),6.24(d,1H),4.08–3.98(m,2H),3.65–3.55(m,2H),3. 38–3.26(m,1H),3.18–3.09(m,1H),3.09–2.99(m,4H),2.98–2.91(m,2H),2. 83–2.42(m,6H),2.05–1.94(m,2H),1.85–1.73(m,2H)ppm; LCMS:528.2[M+H] + .

[0395] Example 27: 1-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxylic acid (Compound 27)

[0396] Step 1: 2-Chloro-N-(2-Chloroethyl)-N-(4-Methoxybenzyl)ethyl-1-amine (27b)

[0397] In a 250 mL round-bottom flask, compound 27a (8.00 g, 44.82 mmol), triethylamine (9.10 g, 89.64 mmol), and dichloromethane (100 mL) were added sequentially, followed by 4-methoxybenzyl chloride (8.40 g, 3.78 mmol). The reaction was allowed to proceed overnight at room temperature. The mixture 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 column chromatography to give compound 27b as a colorless oily solid (4.00 g, yield: 23%). LCMS: 262.1 [M+H] + Step 2: Ethyl 1-(4-(4-methoxybenzyl)piperazin-1-yl)cyclopropane-1-carboxylate (27c)

[0398] In a 250 mL round-bottom flask, compound 27b (4.00 g, 15.33 mmol), ethyl 1-aminocyclopropane-1-carboxylate hydrochloride (1.69 g, 10.22 mmol), and ethanol (40 mL) were added sequentially. N,N-diisopropylethylamine (20 mL) was added with stirring, and the mixture was refluxed for 18 h. After the reaction was complete, the mixture was cooled to room temperature, and the organic solvent was removed under reduced pressure. The residue was dissolved in 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 27c as a colorless oily solid (1.50 g, yield: 31%). LCMS: 319.2 [M+H] + .

[0399] Step 3: Ethyl 1-(piperazin-1-yl)cyclopropane-1-carboxylate (27d)

[0400] Under a hydrogen atmosphere, compound 27c (1.20 g, 3.77 mmol) and palladium on carbon (240 mg, 10%) were dissolved in 10 mL of ethanol in a 100 mL round-bottom flask, 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 evaporated to dryness under reduced pressure to give compound 27d, a colorless oily solid (746 mg), which was used directly in the next step without purification. LCMS: 199.1 [M+H] + Step 4: Ethyl 1-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxylate (27e)

[0401] In a 100 mL round-bottom flask, compound 1d (843 mg, 4.52 mmol), compound 27d (746 mg, 3.77 mmol), potassium carbonate (1.04 g, 7.54 mmol), and acetonitrile (20 mL) were added sequentially. The mixture was heated to 60 °C and reacted for 4 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 27e as a yellow solid (1.45 g, 99% yield). LCMS: 388.1 [M+H] + Step 5: 1-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxylic acid (27f)

[0402] In a 100 mL round-bottom flask, compound 27e (140 mg, 0.36 mmol), sodium hydroxide (116 mg, 2.89 mmol), water (5 mL), and methanol (5 mL) were added sequentially, and the mixture was refluxed for 6 h. After cooling to room temperature, the pH was adjusted to acidic with hydrochloric acid solution, and the mixture was 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 27f as a yellow oily solid (115 mg, yield: 88%). LCMS: 360.1 [M+H] + .

[0403] Step 6: 1-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxylic acid (27g)

[0404] Under a hydrogen atmosphere, compound 27f (115 mg, 0.32 mmol) and palladium on carbon (23 mg, 10%) were dissolved in 10 mL of ethanol in a 100 mL round-bottom flask, 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 evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 27 g as a colorless oily solid (100 mg, yield: 95%). LCMS: 330.1 [M+H] + .

[0405] Step 7: 1-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxylic acid (Compound 27)

[0406] In a 100 mL round-bottom flask, compound 27 g (100 mg, 0.30 mmol), compound 4a (90 mg, 0.45 mmol), and N-methylimidazole (45 mg, 0.45 mmol) were dissolved in acetonitrile. N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (126 mg, 0.45 mmol) was added with stirring, 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 27 as a white solid (7 mg, yield: 4%). 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.66(s,1H),7.45(q,2H),7.27(d,1H),6.46(d,1H),3.92(d,2H),3.55(t, 2H),3.31-3.07(m,6H),2.85(s,3H),1.99(d,2H),1.66(d,2H),1.23(s,2H),0.93(s,2H)ppm; LCMS:508.2[M+H] + .

[0407] Example 28: Ethyl 1-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxylate (Compound 28)

[0408] Step 1: 1-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxylic acid ethyl ester (28a)

[0409] Under a hydrogen atmosphere, compound 27e (120 mg, 0.31 mmol) and palladium on carbon (24 mg, 10%) were dissolved in 10 mL of ethanol in a 100 mL round-bottom flask, 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 to obtain compound 28a, a colorless oily solid (101 mg), which was used directly in the next step without purification. LCMS: 358.2 [M+H] + Step 2: 1-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)cyclopropane-1-carboxylic acid ethyl ester (compound 28)

[0410] In a 100 mL reaction tube, potassium tert-butoxide (95 mg, 0.84 mmol) was dissolved in tetrahydrofuran (10 mL), and a mixed solution of compound 28a (100 mg, 0.28 mmol) and compound 1c (83 mg, 0.39 mmol) in tetrahydrofuran was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, 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 liquid chromatography to give compound 28 as a white solid (6 mg, yield: 4%). 1 H NMR(500MHz,DMSO-d6)δ9.35(s,1H),8.62(s,1H),7.45(dd,2H),7.26(d, 1H),6.46(d,1H),4.12–4.05(m,2H),3.95(d,2H),3.50(t,2H),3.15(d,3H ),2.83(s,3H),2.01(s,1H),2.00(s,1H),1.74–1.59(m,2H),1.24(s,4H), 1.20–1.13(m,3H),0.99(d,2H),0.89–0.84(m,1H)ppm; LC-MS: 536.2[M+H] + .

[0411] Example 29: N-(2-(4-cyanopiperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 29)

[0412] Step 1: N-(2-(4-cyanopiperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 29)

[0413] At room temperature, compound 11c (100 mg, 0.24 mmol), N,N-dimethylformamide (6 mL), potassium carbonate (98 mg, 0.71 mmol), and bromonitrile (33 mg, 0.31 mmol) were added to a 25 mL round-bottom flask. The reaction was carried out at 25 °C for 3 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 give compound 29 as a white solid (76 mg, 72% yield). 1H NMR(500MHz,DMSO-d6)δ8.58(s,1H),7.74–7.63(m,1H),6.68–6.61(m,2H),6.45–6.41(m,1H),5.66–5.55(m,1H),3.15–3.04 (m,2H),2.67–2.57(m,6H),2.27–2.19(m,1H),2.18–2.13(m,4H),1.13–1.06(m,2H),0.93–0.78(m,2H)ppm; LCMS: 449.2[M+H] + .

[0414] Example 30: N-(2-(4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 30)

[0415] Step 1: N-(2-(4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 30)

[0416] At room temperature, in a 50 mL round-bottom flask, compound 11c (120 mg, 0.28 mmol), 1,4-dioxane (15 mL), sodium tert-butoxide (82 mg, 0.85 mmol), 3-bromo-1-methylpyrazole (91 mg, 0.57 mmol), 2-bicyclohexylphosphine-2”,6”-diisopropoxybiphenyl (27 mg, 0.06 mmol), and tris(dibenzylacetone)dipalladium (26 mg, 0.03 mmol) were added. The reaction was carried out 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 preparative high-performance liquid chromatography to give compound 30 as a white solid (31 mg, 21% yield). 1H NMR(500MHz,DMSO-d6)δ9.61(s,1H),8.64–8.56(m,1H),7.53–7.46(m,3H), 7.25–7.22(m,1H),6.44–6.39(m,1H),5.77–5.73(m,1H),3.73–3.69(m,2H) ,3.68(s,3H),3.32–3.28(m,4H),3.22–3.14(m,2H),3.07–3.00(m,4H),2.9 6–2.87(m,1H),1.89–1.82(m,2H),1.63–1.53(m,2H)ppm; LCMS: 504.5[M+H] + .

[0417] Example 31: 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-carboxamide (Compound 31)

[0418] Step 1: 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-carboxamide (Compound 31)

[0419] At room temperature, compound 11c (100 mg, 0.24 mmol) and dichloromethane (6 mL) were added to a 50 mL round-bottom flask. N,N-diisopropylethylamine (92 mg, 0.71 mmol) and triphosgene (23 mg, 0.08 mmol) were added sequentially at 0 °C, and the reaction was carried out at 25 °C for 8 h. Ammonia water (6 mL) was then added, and the reaction was carried out at 25 °C for 3 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 give compound 31 as a white solid (19 mg, 17% yield). 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.55(s,1H),7.55–7.41(m,2H),7.32–7.21(m,1H),6.49–6.39(m,1H),6.13(s,2H),3.95–3 .84(m,2H),3.52–3.41(m,6H),3.09–2.99(m,1H),2.94–2.78(m,4H),1.97–1.86(m,2H),1.74–1.61(m,2H)ppm; LCMS: 467.5[M+H] + .

[0420] Example 32: Methyl 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (Compound 32)

[0421] Step 1: Methyl 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (Compound 32)

[0422] At room temperature, compound 11c (100 mg, 0.24 mmol), N,N-dimethylformamide (3 mL), N,N'-carbonyldiimidazole (57 mg, 0.36 mmol), and methanol (3 mL) were added to a 50 mL round-bottom flask, and the reaction was carried out at 25 °C for 12 h. N,N-diisopropylethylamine (92 mg, 0.71 mmol) was then added, and the reaction was continued at 80 °C for another 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, and the organic solvent was removed under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 32 as a white solid (43 mg, 37% yield). 1 H NMR(500MHz,DMSO-d6)δ9.49(s,1H),8.61–8.51(m,1H),7.50–7.44(m,2H),7.28–7.24(m,1H),6.46–6.43(m,1H),3.93–3.85(m,2H),3.64(s, 3H),3.62–3.56(m,4H),3.47–3.39(m,2H),3.09–3.01(m,1H),2.95–2.87(m,4H),1.93–1.86(m,2H),1.74–1.62(m,2H)ppm; LCMS: 482.3[M+H] + Example 33: N-(2-(4-(3-cyanothioheterobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 33)

[0423] Step 1: N-(2-(4-(3-cyanothioheptan-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 33)

[0424] In a 100 mL round-bottom flask, thiocyclobutanone (174 mg, 1.77 mmol), trimethylcyanosilane (264 mg, 2.66 mmol), and zinc iodide (151 mg, 0.47 mmol) were dissolved in tetrahydrofuran (10 mL), and the mixture was reacted at room temperature for 6 h. A methanol (5 mL) solution of triethylamine (179 mg, 1.77 mmol) and compound 11c (500 mg, 1.18 mmol) was added, and the mixture was reacted at 60 °C 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 obtain compound 33 as a white solid (432 mg, yield: 70%). 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.62(s,1H),7.50(s,2H),7.27(d,1H),6.47(d,1H),3.92(d,2H),3.61(d,2H), 3.50(t,2H),3.33(d,2H),3.11(s,1H),3.01(s,4H),2.59(s,4H),1.95(d,2H),1.67(dd,2H)ppm; LC-MS: 521.2[M+H] + .

[0425] Example 34: N-(2-(4-(3-cyano-1-imino-1-oxo-1λ) 6 -Thiocyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 34)

[0426] Step 1: N-(2-(4-(3-cyano-1-imino-1-oxo-1λ) 6 -Thiocyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 34)

[0427] In a 100 mL round-bottom flask, compound 33 (200 mg, 0.38 mmol) and ammonium carbamate (120 mg, 1.54 mmol) were dissolved in methanol (10 mL), and the mixture was stirred and reacted at room temperature for 12 h at room temperature. After the reaction was complete, the mixture was quenched with sodium sulfite solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative liquid chromatography to give compound 34 as a white solid (19 mg, yield: 9%). 1H NMR(400MHz, DMSO-d6)δ9.02(d,1H),8.03(d,1H),7.56(d,1H),7.13(d,1H),6.41(d,1H),4.45(dd,2H),4.07(t,2H),3.93(d,2H),3.51–3. 40(m,3H),3.36(dd,2H),3.20(t,2H),3.10–2.96(m,2H),2.90(d,2H),2.01(d,2H),1.73–1.60(m,2H),1.25(s,2H)ppm; LC-MS: 552.2[M+H] + .

[0428] Example 35: N-(2-(4-(3-oxocyclobut-1-en-1-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 35)

[0429] Step 1: N-(2-(4-(3-oxocyclobut-1-en-1-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 35)

[0430] In a 100 mL round-bottom flask, trimethylcyanosilane (297 mg, 3.00 mmol), 3,3-difluorocyclobutane-1-one (200 mg, 2.00 mmol), and zinc iodide (127 mg, 0.40 mmol) were sequentially added to tetrahydrofuran (10 mL), and the reaction was carried out at room temperature for 12 h. Then, compound 11c (212 mg, 0.5 mmol) and triethylamine (202 mg, 2.00 mmol) were dissolved in methanol (3 mL) and added to the above reaction solution, and the reaction was continued at 60 °C for 6 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 35 as a white solid (140 mg, yield 57%). 1 H NMR(500MHz, CDCl3)δ9.25(s,1H),8.84(s,1H),7.39(d,1H),7.32–7.26(m,1H),7.22(d,1H),6.27(d,1H),4.77(s,1H),4.09–4.02(m,2H),3.72 –3.60(m,4H),3.59–3.50(m,2H),3.21(s,2H),3.14–3.06(m,4H),3.04– 2.94(m,1H),2.02–1.93(m,2H),1.92–1.82(m,2H)ppm; LCMS:490.2[M+H]+ .

[0431] Example 36: N-(2-(4-(1,3-dicyanoazonobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 36)

[0432] Step 1: N-(2-(4-(1,3-dicyanoazonobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 36)

[0433] In a 100 mL round-bottom flask, compound 16 (50 mg, 0.10 mmol), potassium carbonate (28 mg, 0.20 mmol), and cyanogen bromide (13 mg, 0.20 mmol) were dissolved in acetonitrile (10 mL) and reacted at room temperature for 4 h. The reaction 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 liquid chromatography to give compound 36 as a white solid (20 mg, yield: 38%). 1 H NMR(500MHz,DMSO-d6)δ9.29(s,1H),8.59(s,1H),7.50(s,2H),7.26(d,1H),6.46(d,1H),4.55(d,2H),4.38(d,2H),3.89(d d,2H),3.47(dd,2H),3.13–2.97(m,5H),2.64(s,3H),1.92(dd,2H),1.72–1.60(m,2H),1.24(s,1H)ppm; LC-MS: 529.2[M+H] + .

[0434] Example 37: N-(2-(4-(3-cyano-1,1-dioxothionecyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 37)

[0435] Step 1: N-(2-(4-(3-cyano-1,1-dioxothionecyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 37)

[0436] In a 100 mL round-bottom flask, compound 33 (100 mg, 0.19 mmol) was dissolved in 10 mL of dichloromethane. Under ice bath conditions, m-chloroperoxybenzoic acid (100 mg, 0.58 mmol) was added, and the reaction was carried out at room temperature for 1 h. After the reaction was complete, the mixture was quenched with sodium sulfite solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 37 as a white solid (12 mg, yield: 11%). 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.04(d,1H),7.56(d,1H),7.14(d,1H),6.41(d,1H),4.45(d,2H),4.08(t,2H),3.93(d,2H),3.70( d,2H),3.45(t,2H),3.36(d,2H),3.19(t,2H),3.03(s,1H),3.00(s,1H),2.90(d,2H),2.00(d,2H),1.69(t,2H)ppm; LC-MS: 553.2[M+H] + .

[0437] Example 38: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 38)

[0438] Step 1: 2-(4-(2-nitro-4-(trifluoromethoxy)phenyl)piperazin-1-yl)acetonitrile (38b)

[0439] Compound 38a (190 mg, 0.65 mmol), N,N-dimethylformamide (6 mL), potassium carbonate (270 mg, 1.96 mmol), and bromoacetonitrile (118 mg, 0.98 mmol) were added to a 25 mL round-bottom flask at room temperature. The reaction was carried out 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, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 38b as a pale yellow solid (140 mg, 65% yield). LCMS: 331.1 [M+H] + .

[0440] Step 2: 2-(4-(2-amino-4-(trifluoromethoxy)phenyl)piperazin-1-yl)acetonitrile (38c)

[0441] At room temperature, compound 38b (130 mg, 0.39 mmol), tetrahydrofuran (2 mL), methanol (1 mL), water (1 mL), iron powder (66 mg, 1.18 mmol), and ammonium chloride (63 mg, 1.18 mmol) were added to a 25 mL round-bottom flask. The mixture was reacted at 60 °C for 12 h under nitrogen protection. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 38c as a white solid (65 mg, 55% yield). LCMS: 300.9 [M+H] + .

[0442] Step 3: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 38)

[0443] At room temperature, potassium tert-butoxide (93 mg, 0.83 mmol) and tetrahydrofuran (3 mL) were added to a 25 mL round-bottom flask. Compound 38c (50 mg, 0.17 mmol) and compound 1c (105 mg, 0.50 mmol) were dissolved in tetrahydrofuran (3 mL) and added to the above system. The reaction was carried out at 25 °C for 5 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 give compound 38 as a white solid (12 mg, yield 15%). 1 H NMR(500MHz,DMSO-d6)δ9.41(s,1H),8.38–8.28(m,1H),7.47–7.42(m,1H),7.29–7.19(m,1H),7.15–7.06(m,1H),6.51–6.41(m,1H),3.95–3.83 (m,4H),3.55–3.44(m,2H),3.16–3.06(m,1H),3.97–2.88(m,4H),2.81– 2.65(m,4H),1.98–1.89(m,2H),1.74–1.61(m,2H)ppm; LCMS: 479.2[M+H] + .

[0444] Example 39: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (Compound 39)

[0445] Step 1: (2,6-Diaminopyridin-4-yl)boronic acid (compound 39b)

[0446] At room temperature, compound 39a (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(diphenylphosphine)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 39b as a blue-green solid (0.60 g, 73% yield). LCMS: 154.1 [M+H] + .

[0447] Step 2: 2-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetonitrile (39c)

[0448] Compound 1f (3.90 g, 14.17 mmol) was reacted with N,N-dimethylformamide (30 mL), potassium carbonate (5.87 g, 42.51 mmol), and bromoacetonitrile (2.21 g, 18.42 mmol) in a 100 mL round-bottom flask at room temperature for 12 h at 25 °C. 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 concentrated under reduced pressure to give crude compound 39c, a yellow oil (4.30 g). LCMS: 315.2 [M+H] + .

[0449] Step 3: 2-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetonitrile (39d)

[0450] Compound 39c (4.30 g, 13.68 mmol), ethanol (60 mL), and palladium on carbon (800 mg, 10%) were added to a 250 mL round-bottom flask at room temperature. The mixture was purged three times with hydrogen gas, and the reaction was carried out at 55 °C for 12 h under hydrogen balloon conditions. The reaction solution was filtered through diatomaceous earth, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 39d as a colorless oil (1.90 g, 50% yield). LCMS: 285.2 [M+H] + .

[0451] Step 4: 5-Bromo-N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (39e)

[0452] At room temperature, potassium tert-butoxide (119 mg, 1.06 mmol) and tetrahydrofuran (5 mL) were added to a 50 mL round-bottom flask. Compound 39d (100 mg, 0.35 mmol) and methyl 5-bromofuran-2-carboxylate (109 mg, 0.53 mmol) were dissolved in tetrahydrofuran (5 mL) and added to the above system. The reaction was carried out at 25 °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, and the organic solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography to give compound 39e as a pale yellow solid (170 mg). LCMS: 457.3 [M+H] + .

[0453] Step 5: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (Compound 39)

[0454] At room temperature, in a 50 mL round-bottom flask, compound 39e (170 mg, 1.06 mmol), 1,4-dioxane (20 mL), water (2 mL), compound 39b (86 mg, 0.56 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (28 mg, 0.04 mmol), and potassium carbonate (103 mg, 0.75 mmol) were added, and the mixture was reacted at 100 °C for 3 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 give compound 39 as a white solid (15 mg, 9% yield in two steps). 1 H NMR(500MHz,DMSO-d6)δ9.48(s,1H),8.34–8.31(m,1H),7.54–7.29(m,1H),7.45–7.40(m,2H),7.04–7.00(m, 1H),6.07(s,2H),5.72–5.53(m,4H),3.73(s,2H),3.03–2.97(m,4H),2.77–2.69(m,4H)ppm; LCMS: 486.3[M+H] + .

[0455] Example 40: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 40)

[0456] Step 1: Methyl 5-(1H-pyrazol-4-yl)furan-2-carboxylate (40b)

[0457] At room temperature, compound 40a (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 40b as a pale yellow solid (610 mg, 65% yield). LCMS: 193.1 [M+H] + .

[0458] Step 2: Methyl 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)furan-2-carboxylate (40c)

[0459] At room temperature, compound 40b (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 40c as a pale yellow solid (230 mg, 80% yield). LCMS: 277.2 [M+H] + .

[0460] Step 3: 2-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetonitrile (40d)

[0461] Compound 1f (3.90 g, 14.17 mmol) was reacted with N,N-dimethylformamide (30 mL), potassium carbonate (5.87 g, 42.51 mmol), and bromoacetonitrile (2.21 g, 18.42 mmol) in a 100 mL round-bottom flask at room temperature for 12 h at 25 °C. 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 concentrated under reduced pressure to give crude compound 40d, a yellow oil (4.30 g). LCMS: 315.2 [M+H] + .

[0462] Step 4: 2-(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetonitrile (40e)

[0463] Compound 40d (4.30 g, 13.68 mmol), ethanol (60 mL), and palladium on carbon (800 mg, 10%) were added to a 250 mL round-bottom flask at room temperature. The mixture was purged three times with hydrogen gas, and the reaction was carried out at 55 °C for 12 h under hydrogen balloon conditions. The reaction solution was filtered through diatomaceous earth, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 40e as a colorless oil (1.90 g, 50% yield). LCMS: 285.2 [M+H] + .

[0464] Step 5: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide (40f)

[0465] At room temperature, potassium tert-butoxide (166 mg, 1.48 mmol) and tetrahydrofuran (4 mL) were added to a 50 mL round-bottom flask. Compound 40e (140 mg, 0.49 mmol) and compound 40c (204 mg, 0.74 mmol) were dissolved in tetrahydrofuran (4 mL) and added to the above system. The reaction was carried out at 25 °C for 3 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 thin-layer chromatography to give compound 40f as a white solid (170 mg, 65% yield). LCMS: 529.3 [M+H] + .

[0466] Step 6: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 40)

[0467] At room temperature, compound 40f (100 mg, 0.19 mmol) and 1,4-dioxane (3 mL), along with 3 mL of dioxane hydrochloride solution, were added to a 50 mL round-bottom flask, and 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 preparative liquid chromatography to give compound 40 as a white solid (38 mg, 45% yield). 1 H NMR(500MHz,DMSO-d6)δ13.17(s,1H),9.35(s,1H),8.53–8.47(m,1H),8.25(s,1H),7.97(s,1H),7.51–7.44(m,2H ),7.40–7.36(m,1H),6.84–6.79(m,1H),3.81(s,2H),3.02–2.97(m,4H),2.79–2.72(m,4H)ppm; LCMS: 445.1[M+H]+ .

[0468] Example 41: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (Compound 41)

[0469] Step 1: Methyl 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridinecarboxylate (41b)

[0470] At room temperature, compound 41a (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 a gray solid compound 41b (1.52 g, 76% yield). LCMS: 288.2 [M+H] + .

[0471] Step 2: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridinecarboxamide (41c)

[0472] At room temperature, potassium tert-butoxide (119 mg, 1.06 mmol) and tetrahydrofuran (4 mL) were added to a 50 mL round-bottom flask. Compound 40e (100 mg, 0.35 mmol) and compound 41b (152 mg, 0.53 mmol) were dissolved in tetrahydrofuran (4 mL) and added to the above system. The reaction was carried out at 25 °C for 3 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 thin-layer chromatography to give a white solid compound 41c (100 mg, yield 52%). LCMS: 540.3 [M+H] + .

[0473] Step 3: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (compound 41)

[0474] At room temperature, compound 41c (100 mg, 0.19 mmol), 1,4-dioxane (5 mL), and dioxane hydrochloride solution (5 mL) were added to a 50 mL round-bottom flask, and the reaction was carried out at 25 °C for 3 h. The organic solvent was removed from the reaction solution under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain a white solid compound 41 (35 mg, yield 41%). 1 H NMR(500MHz,DMSO-d6)δ13.29(s,1H),11.24(s,1H),9.10–9.03(m,1H),8.75(s,1H),8.41–8.27(m,2H),8.18–8.1 3(m,1H),8.06(s,1H),7.49–7.45(m,2H),3.92(s,2H),3.02–2.99(m,4H),2.88–2.85(m,4H)ppm; LCMS: 456.3[M+H] + .

[0475] Example 42: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (Compound 42)

[0476] Step 1: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (Compound 42)

[0477] At room temperature, compound 39 (100 mg, 0.21 mmol), ethanol (2 mL), water (2 mL), sodium hydroxide (17 mg, 0.42 mmol), hydrogen peroxide (14 mg, 0.42 mmol, 30%), and dimethyl sulfoxide (33 mg, 0.42 mmol) were added to a 50 mL round-bottom flask, and the mixture was reacted at 40 °C for 4 h. The reaction solution was directly purified by preparative high-performance liquid chromatography to obtain compound 42, a white solid (38 mg, yield 36%). 1H NMR(500MHz,DMSO-d6)δ9.43(s,1H),8.54–8.47(m,1H),7.54–7.49(m,1H),7.46–7.43(m,1H),7.42–7.39(m,1H),7.26–7.22(m,1H),7.18 –7.14(m,1H),7.04–7.00(m,1H),6.07(s,2H),5.59(s,4H),3.01–2.97(m,4H),2.96–2.94(m,2H),2.76–2.69(m,4H)ppm; LCMS: 504.3[M+H] + .

[0478] Example 43: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 43)

[0479] Step 1: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide (43a)

[0480] At room temperature, compound 40f (170 mg, 0.32 mmol), ethanol (3 mL), water (3 mL), sodium hydroxide (65 mg, 1.61 mmol), dimethyl sulfoxide (51 mg, 0.65 mmol), and hydrogen peroxide (22 mg, 0.65 mmol) were added to a 50 mL round-bottom flask, and the mixture was reacted at 25 °C for 5 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 concentrated under reduced pressure to give a pale yellow oily crude product 43a (200 mg), which was used directly in the next step. LCMS: 547.3 [M+H] + .

[0481] Step 2: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 43)

[0482] Compound 43a (200 mg, 0.37 mmol), 1,4-dioxane (5 mL), and dioxane hydrochloride solution (5 mL, 4 M) were added to a 50 mL round-bottom flask at room temperature, and the reaction was carried out at 25 °C for 3 h. The organic solvent was removed from the reaction solution under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain a white solid compound 43 (58 mg, two-step yield 39%). 1H NMR(500MHz,DMSO-d6)δ13.33(s,1H),9.48(s,1H),8.64–8.54(m,1H),8.28(s,1H),8.00(s,1H),7.51–7.44(m,2H), 7.38–7.34(m,1H),7.28–7.16(m,2H),6.83–6.79(m,1H),3.01–2.95(m,6H),2.80–2.67(m,4H)ppm; LCMS: 463.3[M+H] + .

[0483] Example 44: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (Compound 44)

[0484] Step 1: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridinecarboxamide (44a)

[0485] At room temperature, compound 41c (200 mg, 0.37 mmol), ethanol (4 mL), water (4 mL), sodium hydroxide (30 mg, 0.74 mmol), dimethyl sulfoxide (60 mg, 0.74 mmol), and hydrogen peroxide (26 mg, 0.74 mmol, 30%) were added to a 50 mL round-bottom flask, and the mixture was reacted at 25 °C for 3 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 give a pale yellow oily crude product 44a (310 mg), which was used directly in the next step. LCMS: 558.3 ​​[M+H] + .

[0486] Step 2: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (compound 44)

[0487] Compound 44a (200 mg, 0.36 mmol), 1,4-dioxane (5 mL), and dioxane hydrochloride solution (5 mL) were added to a 50 mL round-bottom flask at room temperature, and the reaction was carried out at 25 °C for 3 h. The organic solvent was removed from the reaction solution under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain a white solid compound 44 (44 mg, two-step yield 38%). 1H NMR(500MHz,DMSO-d6)δ10.89(s,1H),9.08–9.03(m,1H),8.84–8.79(m,1H),8.37(s,2H),8.32–8.28(m,1H),8.17–8.13(m ,1H),7.50–7.41(m,2H),7.30–7.20(m,2H),3.08–3.04(m,2H),3.03–2.97(m,4H),2.85–2.73(m,4H)ppm; LCMS: 474.1[M+H] + .

[0488] Example 45: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 45)

[0489] Step 1: tert-butyl 4-(2-(5-bromofuran-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid ester (45a)

[0490] 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 11a (2.00 g, 5.80 mmol) and compound 40a (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 45a (2.90 g, yield: 96%) as a white oily solid. LC-MS: 518.1 [M+H] + .

[0491] Step 2: 5-Bromo-N-(2-(piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (45b)

[0492] In a 100 mL round-bottom flask, compound 45a (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 45b (2.21 g, yield: 96%), which could be used directly in the next step without purification. LCMS: 418.0 [M+H] + Step 3: 5-Bromo-N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (45c)

[0493] In a 100 mL round-bottom flask, compound 45b (148 mg, 0.69 mmol), compound 3c (283 mg, 0.69 mmol), and potassium carbonate (190 mg, 1.37 mmol) were dissolved in acetonitrile (10 mL), and the mixture was heated under reflux for 8 h. The mixture was filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 45c (110 mg, yield: 30%) as a pale yellow solid. LCMS: 538.1 [M+H] + .

[0494] Step 4: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 45)

[0495] Under nitrogen protection, compound 45c (110 mg, 0.21 mmol), compound 39b (73 mg, 0.31 mmol), potassium carbonate (58 mg, 0.42 mmol), 1,1'-bis(diphenylphosphine)ferrocene]palladium dioxide (16 mg, 0.02 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 then subjected to medium pressure to prepare a pale yellow solid compound 45 (66 mg, yield: 57%). 1 H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.26(s,1H),7.76(s,1H),7.62(d,2H),7.59(s,1H),7.43(d,2H),7.39(d,2H),6.65(s,1H),6.36 (s,2H),6.02(s,1H),4.24(s,2H),3.85(s,3H),3.47(s,4H),3.20(s,2H),2.69(s,1H),2.35(s,1H),1.25(s,2H)ppm; LCMS: 567.2[M+H] + .

[0496] Example 46: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 46)

[0497] Step 1: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 46)

[0498] Under nitrogen protection, compound 45c (100 mg, 0.19 mmol), N-tert-butoxycarbonyl-pyrazole-4-boronic acid (60 mg, 0.28 mmol), potassium carbonate (52 mg, 0.38 mmol), 1,1'-bis(diphenylphosphine)ferrocene]palladium dioxide (14 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 preparative liquid chromatography to obtain a pale yellow solid compound 46 (44 mg, yield: 45%). 1 H NMR(400MHz,DMSO-d6)δ9.50(s,1H),8.55(s,1H),8.27(s,1H),7.97(s,1H),7.69(d,1H),7.49(dd,2H),7.40(d,1H),6.84 (d,1H),6.50(d,1H),5.73(d,1H),5.24(s,2H),4.87(s,1H),3.85(s,3H),3.07(s,4H),2.95(d,4H)ppm; LCMS: 526.2[M+H] + .

[0499] Example 47: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)pyridinecarboxamide (Compound 47)

[0500] Step 1: 5-Bromo-N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)pyridinecarboxamide (47a)

[0501] In a 50 mL round-bottom flask, compound 3e (0.30 g, 0.82 mmol) and potassium tert-butoxide (185 mg, 1.65 mmol) were dissolved in tetrahydrofuran (10 mL). A solution of methyl 5-bromopyridine-2-carboxylate (231 mg, 1.10 mmol) in tetrahydrofuran (3 mL) was added dropwise, and the reaction was allowed to proceed for 30 min. The reaction was quenched with saturated ammonium chloride solution, 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 a white solid, compound 47a (236 mg, yield 52%). LCMS: 549.1 [M+H] + .

[0502] Step 2: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)pyridinecarboxamide (compound 47)

[0503] Under nitrogen protection, compound 47a (140 mg, 0.26 mmol), N-tert-butoxycarbonyl-pyrazole-4-boronic acid (81 mg, 0.38 mmol), potassium carbonate (71 mg, 0.51 mmol), 1,1'-bis(diphenylphosphine)ferrocene]palladium dioxide (19 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 passed through a medium-pressure solution to obtain compound 47a (71 mg, yield: 52%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ10.84(d,1H),9.13–8.91(m,1H),8.79(s,1H),8.48 (s,1H),8.41–8.29(m,1H),8.19(d,1H),8.14(s,1H),7.72(dd,1H),7.59–7. 45(m,1H),6.63(dd,1H),6.13(s,1H),5.77(s,2H),5.71(d,1H),5.23(s,1H ),4.62(d,1H),3.85(s,3H),3.27(s,6H),3.20(s,2H)ppm; LCMS: 537.2[M+H] + .

[0504] Example 48: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 48)

[0505] Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine (48a)

[0506] At room temperature, compound 1f (3.00 g, 10.90 mmol), N,N-dimethylformamide (30 mL), potassium carbonate (4.52 g, 32.70 mmol), and 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.28 g, 10.90 mmol) were added to a 100 mL round-bottom flask. The reaction was carried out at 80 °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, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 48a as a yellow oily liquid (3.80 g, yield: 86%). LCMS: 404.1 [M+H] + .

[0507] Step 2: 2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)-5-(trifluoromethyl)aniline (48b)

[0508] Compound 48a (1.50 g, 3.72 mmol), ethanol (20 mL), and palladium on carbon (300 mg, 10%) were added to a 100 mL round-bottom flask at room temperature. The mixture was purged three times with hydrogen and reacted at 55 °C for 8 h. The reaction solution was filtered and evaporated to dryness under reduced pressure to give a colorless oily compound 48b (1.30 g, 93% yield). LCMS: 374.2 [M+H] + .

[0509] Step 3: 5-Bromo-N-(2-(4-(((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (48c)

[0510] At room temperature, potassium tert-butoxide (451 mg, 4.02 mmol) and tetrahydrofuran (10 mL) were added to a 100 mL round-bottom flask. 48b (500 mg, 1.34 mmol) and methyl 5-bromofuran-2-carboxylate (412 mg, 2.01 mmol) were dissolved in tetrahydrofuran (10 mL) and added to the above system. The reaction was carried out at 25 °C for 3 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 a white solid compound 48c (550 mg, 75% yield). LCMS: 546.2 [M+H] + .

[0511] Step 4: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (48d)

[0512] At room temperature, in a 50 mL round-bottom flask, compound 48c (250 mg, 0.46 mmol) and 1,4-dioxane (20 mL), water (2 mL), compound 39b (105 mg, 0.69 mmol), potassium carbonate (127 mg, 0.92 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (34 mg, 0.05 mmol) were added. The mixture was reacted at 100 °C for 3 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 thin-layer chromatography to give a colorless oily compound 48d (250 mg, 95% yield). LCMS: 575.4 [M+H] + .

[0513] Step 5: 5-(2,6-diaminopyridin-4-yl)-N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 48)

[0514] Compound 48d (250 mg, 0.43 mmol), 1,4-dioxane (10 mL), and dioxane hydrochloride solution (10 mL) were added to a 50 mL round-bottom flask at room temperature, and the reaction was carried out at 25 °C for 3 h. The organic solvent was removed from the reaction solution under reduced pressure, and the residue was purified by preparative liquid chromatography to give compound 48 (98 mg, yield 45%). 1 H NMR(500MHz,DMSO-d6)δ9.45(s,1H),8.52–8.47(m,1H),7.53–7.43(m,2H),7.43–7.40(m,1H),7.05–6.99(m,1H),6.07(s,2H),5 .57(s,4H),4.47–4.39(m,1H),3.55–3.46(m,2H),2.98–2.89(m,4H),2.76–2.59(m,4H),2.48–2.43(m,2H)ppm; LCMS: 491.2[M+H] + .

[0515] Example 49: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 49)

[0516] Step 1: 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-N-(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (49a)

[0517] At room temperature, potassium tert-butoxide (181 mg, 1.61 mmol) and tetrahydrofuran (8 mL) were added to a 100 mL round-bottom flask. Compound 48b (200 mg, 0.54 mmol) and compound 40c (222 mg, 0.80 mmol) were dissolved in tetrahydrofuran (8 mL) and added to the above system. The reaction was carried out at 25 °C for 3 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 thin-layer chromatography to give a colorless oily compound 49a (90 mg, yield 27%). LCMS: 618.3 [M+H] + .

[0518] Step 7: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 49)

[0519] Compound 49a (90 mg, 0.15 mmol), 1,4-dioxane (10 mL), and dioxane hydrochloride solution (10 mL) were added to a 50 mL round-bottom flask at room temperature, and the reaction was carried out at 25 °C for 3 h. The organic solvent was removed from the reaction solution under reduced pressure, and the residue was purified by preparative liquid chromatography to give a white solid compound 49 (30 mg, 45% yield). 1 H NMR(400MHz, DMSO-d6)δ9.87(s,1H),9.37(s,1H),8.52–8.38(m,1H),8.16(s,2H),7.57–7.51(m,1H),7.48–7.44(m,1H),7.43–7.41(m, 1H),6.82–6.77(m,1H),5.44(s,1H),3.78–3.75(m,2H),3.71–3.59(m,4H),3.28–3.25(m,4H),3.22–3.17(m,2H)ppm; LCMS: 450.3[M+H] + .

[0520] Example 50: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (Compound 50)

[0521] Step 1: 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-N-(2-(4-(2-((tetrahydro-2,H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)pyridinecarboxamide (50a)

[0522] At room temperature, potassium tert-butoxide (181 mg, 1.61 mmol) and tetrahydrofuran (8 mL) were added to a 100 mL round-bottom flask. Compound 48b (200 mg, 0.54 mmol) and compound 41b (231 mg, 0.80 mmol) were dissolved in tetrahydrofuran (8 mL) and added to the above system. The reaction was carried out at 25 °C for 3 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 a white solid crude compound 50a (300 mg, yield 89%), which was used directly in the next step. LCMS: 629.4 [M+H] + .

[0523] Step 2: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (Compound 50)

[0524] Compound 50a (300 mg, 0.48 mmol), 1,4-dioxane (10 mL), and dioxane hydrochloride solution (10 mL) were added to a 100 mL round-bottom flask at room temperature, and the reaction was carried out at 25 °C for 3 h. The organic solvent was removed from the reaction solution under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain a white solid compound 50 (115 mg, yield 52%). 1 H NMR(400MHz,DMSO-d6)δ13.25(s,1H),10.86(s,1H),9.08–8.99(m,1H),8.84–8.79(m,1H),8.54(s,1H),8.33–8.27(m,1H),8.23–8.13(m,2 H),7.50–7.41(m,2H),4.51–4.43(m,1H),3.63–3.53(m,2H),2.97–2.93(m,4H),2.79–2.69(m,4H),2.59–2.55(m,2H)ppm; LCMS: 461.1[M+H] + Example 51: N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (Compound 51)

[0525] Step 1: 5-Bromo-N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)pyridinecarboxamide (51a)

[0526] In a 100 mL reaction tube, potassium tert-butoxide (109 mg, 0.97 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran mixture of methyl 5-bromopyridine-2-carboxylate (105 mg, 0.48 mmol) and compound 24a (100 mg, 0.32 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, 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 medium-pressure preparation to give compound 51a (103 mg, yield: 64%) as a colorless oily solid. LC-MS: 494.1 [M+H] + .

[0527] Step 2: N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (compound 51)

[0528] Under nitrogen protection, compound 51a (103 mg, 0.21 mmol), 1-tert-butyloxycarbonyl-pyrazole-4-boronic acid pinacol ester (92 mg, 0.31 mmol), potassium carbonate (58 mg, 0.42 mmol), 1,1'-bis(diphenylphosphine)ferrocene]palladium dioxide (16 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 preparative liquid chromatography to obtain a white solid compound 51 (49 mg, yield: 48%). 1 H NMR(400MHz,DMSO-d6)δ13.29(s,1H),11.33(s,1H),9.09(d,1H),8.75(s,1H),8.33(dd,2H),8.18(d ,1H),8.04(s,1H),7.52–7.41(m,2H),3.00(d,8H),1.35(q,2H),1.14(dd,2H)ppm; LCMS: 482.2[M+H] + .

[0529] Example 52: N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 52)

[0530] Step 1: 5-Bromo-N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (52a)

[0531] In a 100 mL reaction tube, potassium tert-butoxide (229 mg, 2.03 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran mixture of methyl 5-bromo-2-carboxylate (209 mg, 1.02 mmol) and compound 24a (210 mg, 0.68 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, 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 medium-pressure preparation to give compound 52a (234 mg, yield: 72%) as a colorless oily solid. LCMS: 483.1 [M+H] + .

[0532] Step 2: N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)furan-2-carboxamide (Compound 52)

[0533] Under nitrogen protection, compound 52a (110 mg, 0.23 mmol), 1-tert-butyloxycarbonyl-pyrazole-4-boronic acid pinacol ester (101 mg, 0.34 mmol), potassium carbonate (63 mg, 0.46 mmol), 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (17 mg, 0.023 mmol), and 1,4-dioxane / water (10 mL / 2 mL) mixed solvent 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 subjected to preparative-grade liquid chromatography to give compound 52a (71 mg, yield: 66%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.50(d,1H),8.13(s,2H),7.52–7.48(dd,1H),7.43(d,1H),7. 41(d,1H),6.84(d,1H),2.99(s,4H),2.90(d,4H),1.29(dd,2H),1.12(dd,2H)ppm; LCMS: 471.2[M+H] + .

[0534] Example 53: N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (Compound 53)

[0535] Step 1: N-(2-(4-(1-cyanocyclopropyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (Compound 53)

[0536] Under nitrogen protection, compound 52a (100 mg, 0.21 mmol), compound 39b (74 mg, 0.31 mmol), potassium carbonate (63 mg, 0.41 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dioxide (16 mg, 0.02 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 preparative liquid chromatography to obtain compound 53, a white solid (60 mg, yield: 57%). 1 H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.22(s,1H),7.51(dd,2H),7.37(d,1H),7.04(d,1H),6.09 (s,2H),5.60(s,4H),3.00(s,4H),2.87(d,4H),1.26(d,2H),1.10(dd,2H)ppm; LCMS: 512.2[M+H] + .

[0537] Example 54: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (Compound 54)

[0538] Step 1: 5-Bromo-N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (54a)

[0539] In a 100 mL round-bottom flask, compound 5e (400 mg, 1.23 mmol) and methyl 5-bromofuran-2-carboxylate (374 mg, 1.84 mmol) were dissolved in tetrahydrofuran (10 mL), and the solution was 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 a yellow solid compound 54a (520 mg, 85% yield). LCMS: 499.2 [M+H] +.

[0540] Step 2: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (compound 54)

[0541] In a 100 mL round-bottom flask, compound 54a (0.15 g, 0.30 mmol), compound 39b (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 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. The residue was purified by C18 column chromatography to give compound 54 (85 mg, 54% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.29(s,1H),7.63–7.50(m,2H),7.46(d,1H),7.41–7.21(m,5H) ,6.27(s,2H),4.76(d,2H),4.64(d,2H),3.15–3.00(m,4H),2.69–2.56(m,4H)ppm; LCMS:528.2[M+H] + .

[0542] Example 55: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 55)

[0543] In a 100 mL round-bottom flask, compound 54a (0.15 g, 0.30 mmol), (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boric acid (127 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 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 C18 column chromatography to give compound 55 (75 mg, 48% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),9.36(s,1H),8.48(s,1H),8.23(s,1H),7.92(s,1H),7.62–7.44(m,2H),7 .39(d,1H),6.82(d,1H),4.80(d,2H),4.66(d,2H),3.17–2.99(m,4H),2.75–2.57(m,4H)ppm; LCMS:487.2[M+H] + .

[0544] Example 56: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (Compound 56)

[0545] Step 1: 5-Bromo-N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)pyridinecarboxamide (56a)

[0546] In a 100 mL round-bottom flask, compound 5e (200 mg, 0.62 mmol) and methyl 5-bromopyridinecarboxylate (215 mg, 1.00 mmol) were dissolved in tetrahydrofuran (10 mL) and added dropwise to a mixture of tetrahydrofuran (5 mL) and potassium tert-butoxide (212 mg, 2.00 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 56a (200 mg, 63% yield) as a yellow solid. LCMS: 510.1 [M+H] + .

[0547] Step 2: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazole-4-yl)pyridinecarboxamide (compound 56)

[0548] In a 100 mL round-bottom flask, compound 56a (0.20 g, 0.39 mmol), N-tert-butoxycarbonyl-pyrazole-4-boronic acid (141 mg, 0.60 mmol), and potassium carbonate (110 mg, 0.80 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 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 crude product was purified by C18 column chromatography to give compound 56a (70 mg, 36% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),11.28(s,1H),9.03(s,1H),8.73(s,1H),8.40–8.25(m,2H),8.17(d,1H ),8.01(s,1H),7.56–7.44(m,2H),4.86(d,2H),4.70(d,2H),3.08(d,4H),2.73(d,4H)ppm; LCMS:498.2[M+H] + .

[0549] Example 57: N-(2-(4-(3-cyano-1-methylazacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 57)

[0550] Step 1: 3-(4-(2-(5-bromofuran-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)-3-cyanoazacyclobutane-1-carboxylic acid tert-butyl ester (57a)

[0551] In a 100 mL round-bottom flask, trimethylcyanosilane (297 mg, 3.00 mmol), tert-butyl 3-oxazacyclobutane-1-carboxylate (342 mg, 2.00 mmol), and zinc iodide (127 mg, 0.40 mmol) were sequentially added to tetrahydrofuran (10 mL), and the reaction was carried out at room temperature for 12 h. Then, compound 45b (417 mg, 1.00 mmol) and triethylamine (202 mg, 2.00 mmol) dissolved in methanol (3 mL) were added to the above reaction solution, and the reaction was continued at 60 °C for 6 h. The reaction was quenched with aqueous 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 57a (420 mg, 70% yield) as a yellow solid. LCMS: 598.2 [M+H] + .

[0552] Step 2: 5-Bromo-N-(2-(4-(3-cyanozynebutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (57b)

[0553] In a 100 mL round-bottom flask, compound 57a (420 mg, 0.70 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of 1,4-dioxane hydrochloride solution (4 M) was added. The reaction was carried out at room temperature for 2 h. After the reaction was complete, the solution was directly concentrated to give a yellow solid compound 57b (375 mg). LCMS: 498.2 [M+H] + .

[0554] Step 3: 5-Bromo-N-(2-(4-(3-cyano-1-methylazacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (57c)

[0555] In a 100 mL round-bottom flask, compound 57b (375 mg, 0.70 mmol) was dissolved in methanol (10 mL), and a formaldehyde methanol solution (2 mL, 30%) was added. Sodium triacetoxyborohydride (636 mg, 3.00 mmol) was then added, and the reaction was carried out at room temperature for 2 h. The reaction was quenched with aqueous 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 a yellow solid compound 57c (300 mg, 84% yield). LCMS: 512.1 [M+H] + .

[0556] Step 4: N-(2-(4-(3-cyano-1-methylazacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 57)

[0557] In a 100 mL round-bottom flask, compound 57c (0.15 g, 0.30 mmol), N-tert-butoxycarbonyl-pyrazole-4-boronic acid (141 mg, 0.60 mmol), and potassium carbonate (110 mg, 0.80 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 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. The residue was purified by C18 column chromatography to give a light red solid compound 57 (72 mg, yield 48%). 1 H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.39(s,1H),8.12(s,2H),7.59–7.50(m,1H),7.46(d,1H),7.41(d,1H),6.81(d ,1H),4.72–4.44(m,2H),4.39–4.20(m,2H),3.17–3.00(m,4H),2.95(s,3H),2.87–2.61(m,4H)ppm; LCMS:500.2[M+H] + .

[0558] Example 58: N-(2-((1-(1-methyl-1H-pyrazol-3-yl)piperidin-4-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 58)

[0559] Step 1: 4-(2-amino-4-(trifluoromethyl)benzyl)piperidine-1-carboxylic acid tert-butyl ester (58b)

[0560] At room temperature, compound 58a (200 mg, 0.62 mmol), 1,4-dioxane (8 mL), water (1 mL), 2-bromo-5-(trifluoromethyl)aniline (163 mg, 0.68 mmol), potassium carbonate (257 mg, 1.86 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (45 mg, 0.06 mmol) were added to a 50 mL round-bottom flask. The reaction was carried out under nitrogen protection and at 90 °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, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography to give compound 58b (160 mg, 72% yield) as a white solid. LCMS: 357.1 [M+H] + .

[0561] Step 2: 4-(2-amino-4-(trifluoromethyl)benzyl)piperidine-1-carboxylic acid tert-butyl ester (58c)

[0562] Compound 58b (160 mg, 0.45 mmol), ethanol (10 mL), and palladium on carbon (100 mg, 10%) were added to a 50 mL round-bottom flask at room temperature. The mixture was purged three times with hydrogen and reacted at 55 °C for 3 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a colorless oily compound 58c (180 mg). LCMS: 359.2 [M+H] + .

[0563] Step 3: 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperidine-1-carboxylic acid tert-butyl ester (58d)

[0564] At room temperature, potassium tert-butoxide (169 mg, 1.51 mmol) and tetrahydrofuran (4 mL) were added to a 50 mL round-bottom flask. Compound 58c (180 mg, 0.50 mmol) and compound 1c (158 mg, 0.75 mmol) were dissolved in tetrahydrofuran (4 mL) and added to the above reaction mixture. The reaction was carried out at 25 °C for 3 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 thin-layer chromatography to give a white solid compound 58d (190 mg, 78% yield in two steps). LCMS: 537.1 [M+H] + .

[0565] Step 4: N-(2-(piperidin-4-ylmethyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (58e)

[0566] Compound 58d (190 mg, 0.35 mmol), 1,4-dioxane (5 mL), and dioxane hydrochloride solution (5 mL, 4 M) were added to a 50 mL round-bottom flask at room temperature. The reaction was carried out at 25 °C for 3 h. The mixture was concentrated under reduced pressure to give the residue as a white solid, compound 58e (150 mg, 97% yield). LCMS: 437.2 [M+H] + .

[0567] Step 5: N-(2-((1-(1-methyl-1H-pyrazol-3-yl)piperidin-4-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 58)

[0568] At room temperature, in a 50 mL round-bottom flask, compound 58e (120 mg, 0.28 mmol), 1,4-dioxane (15 mL), 3-bromo-1-methyl-pyrazole (89 mg, 0.55 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (26 mg, 0.06 mmol), sodium tert-butoxide (79 mg, 0.83 mmol), and tris(dibenzylacetone)dipalladium (25 mg, 0.03 mmol) were added. Under nitrogen protection, the reaction was carried out 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, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give a white solid compound 58 (23 mg, 16% yield). 1 H NMR(500MHz,DMSO-d6)δ9.77(s,1H),7.81–7.77(m,1H),7.57–7.47(m,2H),7.38–7.33(m,1H), 7.27–7.21(m,1H),6.41–6.35(m,1H),5.61–5.55(m,1H),3.94–3.85(m,2H),3.60(s,3H),3.56 –3.49(m,2H),3.47–3.39(m,2H),3.04–2.94(m,1H),2.71–2.65(m,2H),2.45–2.37(m,2H),1.9 5–1.86(m,2H),1.72–1.61(m,3H),1.55–1.47(m,2H),1.29–1.15(m,2H)ppm; LCMS: 517.2[M+H] + .

[0569] Example 59: N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 59)

[0570] Step 1: tert-butyl 4-(2-amino-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (59c)

[0571] Compound 59a (1.00 g, 4.17 mmol), compound 59b (1.28 g, 4.17 mmol), cesium carbonate (4.07 g, 12.50 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (200 mg, 0.42 mmol), and palladium acetate (90 mg, 0.42 mmol) were sequentially added to a mixed solution of 1,4-dioxane (20 mL) and water (4 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 obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 59c (1.20 g, yield: 80%). LCMS: 360.2 [M+H] + .

[0572] Step 2: tert-butyl 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (59d)

[0573] A tetrahydrofuran (10 mL) solution of compound 59c (680 mg, 1.89 mmol) and compound 1c (796 mg, 3.78 mmol) was added to a tetrahydrofuran (10 mL) solution of potassium tert-butoxide (637 mg, 5.68 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. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give compound 59d (800 mg, yield: 79%). LCMS: 538.2 [M+H] + .

[0574] Step 3: N-(2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (59e)

[0575] Compound 59d (700 mg, 1.30 mmol) was added to hydrochloric acid / 1,4-dioxane (15 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 59e (550 mg). LCMS: 438.2 [M+H] + .

[0576] Step 4: N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (compound 59)

[0577] Compound 59e (150 mg, 0.34 mmol), 3-bromo-1-methylpyrazole (61 mg, 0.38 mmol), sodium tert-butoxide (99 mg, 1.03 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (32 mg, 0.07 mmol), and tris(dibenzylacetone)palladium (32 mg, 0.03 mmol) were added sequentially to anhydrous 1,4-dioxane (5 mL) solution. The mixture was stirred at 100 °C for 8 h under nitrogen protection. After the reaction was completed, 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 preparative liquid chromatography to obtain compound 59 (80 mg, yield: 45%). 1 H NMR(500MHz, CDCl3)δ11.20(s,1H),8.71(s,1H),7.34–7.26(m,2H),7.22–7.17(m,2H),6.19(s,1H),5.65(s,1H),3.96–3.89(m,2H),3.78 (s,3H),3.75(s,2H),3.40–3.27(m,6H),2.97–2.87(m,1H),2.75–2.61(m,4H),1.93–1.85(m,2H),1.78–1.66(m,2H)ppm; LCMS: 518.2[M+H] + .

[0578] Example 60: N-(2-((4-cyanopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 60)

[0579] Step 1: N-(2-((4-cyanopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 60)

[0580] Compound 59e (200 mg, 0.46 mmol), cyanogen bromide (73 mg, 0.69 mmol), and triethylamine (139 mg, 1.37 mmol) were added sequentially to anhydrous tetrahydrofuran (5 mL) solution. The mixture was stirred at 100 °C for 8 h under nitrogen protection. After the reaction was completed, methanol was added to quench the reaction. Compound 60 (30 mg, yield: 14%) was obtained by separation and purification by preparative liquid chromatography. 1 H NMR(500MHz, CDCl3)δ10.50(s,1H),8.74(s,1H),7.39–7.16(m,3H),6.27(s,1H),4.17–4.04(m,2H),3.76(s,2H),3.62–3.50 (m,2H),3.43–3.31(m,4H),2.99–2.88(m,1H),2.74–2.57(m,4H),2.03–1.91(m,2H),1.90–1.75(m,2H)ppm; LCMS: 463.2[M+H] + .

[0581] Example 61: 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxamide (Compound 61)

[0582] Step 1: 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxamide (Compound 61)

[0583] Compound 59e (100 mg, 0.23 mmol), 1,1'-carbonyldiimidazole (41 mg, 0.25 mmol), and triethylamine (46 mg, 0.46 mmol) were added sequentially to anhydrous tetrahydrofuran (2 mL) solution. The mixture was stirred at 25 °C for 8 h under nitrogen protection. Then, a methanol solution of ammonia (2 mL, 1 M) was added. The mixture was then sealed in a pressure-resistant bottle and stirred at 25 °C for 8 h. After the reaction was completed, compound 61 (20 mg, yield: 22%) was obtained by preparative liquid chromatography. 1H NMR(500MHz, CDCl3)δ10.81(s,1H),8.74(s,1H),7.33(d,1H),7.27(d,1H),7.21(d,1H),6.25(d,1H),4.59(s,2H),4.11–4.03(m,2H ),3.74(s,2H),3.60–3.48(m,6H),3.01–2.91(m,1H),2.63–2.48(m,4H),1.97–1.89(m,2H),1.89–1.78(m,2H)ppm; LCMS: 481.2[M+H] + .

[0584] Example 62: Methyl 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylic acid ester (Compound 62)

[0585] Step 1: Methyl 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylic acid ester (Compound 62)

[0586] Compound 59e (100 mg, 0.23 mmol), 1,1'-carbonyldiimidazole (41 mg, 0.25 mmol), and triethylamine (46 mg, 0.46 mmol) were added sequentially to anhydrous tetrahydrofuran (2 mL) solution. The mixture was stirred at 25 °C for 8 h under nitrogen protection. Then, methanol (3 mL) was added, and the mixture was stirred at 25 °C for 8 h under nitrogen protection. After the reaction was complete, compound 62 (20 mg, yield: 22%) was obtained by preparative liquid chromatography. 1 H NMR(500MHz, CDCl3)δ10.91(s,1H),8.75(s,1H),7.32(d,1H),7.26(d,1H),7.20(d,1H),6.23(d,1H),4.10–4.02(m,2H),3.75(s,3H),3.72(s ,2H),3.68–3.56(m,4H),3.56–3.47(m,2H),2.97–2.88(m,1H),2.62–2 .40(m,4H),1.98–1.89(m,2H),1.86–1.75(m,2H)ppm; LCMS: 496.2[M+H] + .

[0587] Example 63: N-(2-(4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-carbonyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 63)

[0588] Step 1: 2-Amino-4-(trifluoromethyl)benzoic acid (63b)

[0589] Compound 63a (3.00 g, 13.69 mmol) and lithium hydroxide monohydrate (1.72 g, 41.67 mmol) were added to a mixed solution of methanol (25 mL) and water (5 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, methanol was removed by rotary evaporation under reduced pressure. The pH was adjusted to 7 with dilute hydrochloric acid, and the mixture was filtered. The filter cake was evaporated under reduced pressure to give compound 63b (2.60 g, yield: 93%). LCMS: 206.1 [M+H] + .

[0590] Step 2: tert-butyl-4-(2-amino-4-(trifluoromethyl)benzoyl)piperazine-1-carboxylate (63c)

[0591] Compound 63b (1.00 g, 4.88 mmol), N-tert-butyloxycarbonyl-piperazine (0.91 g, 4.88 mmol), diisopropylethylamine (1.89 g, 14.63 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.78 g, 7.31 mmol) were sequentially added to anhydrous N,N-dimethylformamide (10 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 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 63c (1.50 g, yield: 83%). LCMS: 374.2 [M+H] + .

[0592] Step 3: Tert-butyl 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzoyl)piperazine-1-carboxylate (63d)

[0593] A tetrahydrofuran (8 mL) solution of compound 63c (800 mg, 2.14 mmol) and compound 1c (676 mg, 3.21 mmol) was added to a tetrahydrofuran (8 mL) solution of potassium tert-butoxide (721 mg, 6.43 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 63d (1.10 g, yield: 93%). LCMS: 552.2 [M+H] + .

[0594] Step 4: N-(2-(piperazin-1-carbonyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (63e)

[0595] Compound 63d (1.00 g, 1.81 mmol) and zinc bromide (2.04 g, 9.07 mmol) were added to anhydrous dichloromethane (5 mL). The mixture was stirred at 25 °C for 8 h. After the reaction was complete, the reaction was quenched with saturated sodium carbonate aqueous solution. 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 63e (600 mg, yield: 73%). LCMS: 452.2 [M+H] + .

[0596] Step 5: N-(2-(4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-carbonyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 63)

[0597] Compound 63e (100 mg, 0.22 mmol), 3-bromo-1-methylpyrazole (39 mg, 0.24 mmol), sodium tert-butoxide (64 mg, 0.67 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (21 mg, 0.04 mmol), and tris(dibenzylideneacetone)palladium (21 mg, 0.02 mmol) were sequentially added to anhydrous 1,4-dioxane (5 mL) solution. The mixture was stirred at 100 °C for 8 h under nitrogen protection. After the reaction was completed, 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 preparative liquid chromatography to obtain compound 63 (50 mg, yield: 42%). 1H NMR(500MHz, CDCl3)δ9.81(s,1H),8.82(s,1H),7.45–7.37(m,2H),7.22–7 .15(m,2H),6.20(d,1H),5.65(d,1H),4.10–4.03(m,2H),4.02–3.84(m,2H) ,3.76(s,3H),3.70–3.59(m,2H),3.59–3.50(m,2H),3.41–3.08(m,4H),3.0 4–2.95(m,1H),2.05–1.96(m,2H),1.88–1.76(m,2H)ppm; LCMS: 532.2[M+H] + .

[0598] Example 64: N-(2-(4-cyanopiperazine-1-carbonyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 64)

[0599] Step 1: N-(2-(4-cyanopiperazine-1-carbonyl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 64)

[0600] Compound 63e (100 mg, 0.22 mmol), cyanogen bromide (39 mg, 0.24 mmol), and triethylamine (21 mg, 0.02 mmol) were added sequentially to anhydrous tetrahydrofuran (5 mL) solution. 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 64 (20 mg, yield: 95%). 1 H NMR(500MHz, CDCl3)δ9.65(s,1H),8.57(s,1H),7.42(d,1H),7.35(d,1H),7.19(d,1H),6.22(d,1H),4.11–4.05(m,2H),4.02–3. 61(m,4H),3.60–3.52(m,2H),3.44–3.23(m,4H),3.04–2.95(m,1H),2.04–1.95(m,2H),1.90–1.78(m,2H)ppm; LCMS: 477.2[M+H] + .

[0601] Example 65: N-(2-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 65)

[0602] Step 1: N-(2-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 65)

[0603] Compound 11c (100 mg, 0.24 mmol), 2-(2-bromoethoxy)ethanol (60 mg, 0.35 mmol), and potassium carbonate (98 mg, 0.71 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 65 (40 mg, yield: 33%). 1 H NMR(500MHz, CDCl3)δ9.44(s,1H),8.85(s,1H),7.37(d,1H),7.35(d,1H),7.20(d,1H),6.25(d,1H),4.11–4.06(m,2H) ,3.77–3.71(m,4H),3.68–3.64(m,2H),3.60–3.52(m,2H),3.09–2.60(m,11H),2.02–1.87(m,4H)ppm; LCMS: 512.2[M+H] + .

[0604] Example 66: N-(2-(4-(1,3-dihydroxypropane-2-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 66)

[0605] Step 1: N-(2-(4-(1,3-dihydroxypropane-2-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 66)

[0606] Compound 11c (100 mg, 0.24 mmol) and 1,3-dihydroxyacetone (21 mg, 0.24 mmol) were added to methanol (5 mL) and stirred at 25 °C for 30 min. Then sodium cyanoborohydride (22 mg, 0.35 mmol) was added and stirred at 25 °C for 8 h. After the reaction was completed, the reaction solution was directly separated and purified by preparative liquid chromatography to obtain compound 66 (30 mg, yield: 25%). 1 H NMR(500MHz, CDCl3)δ9.39(s,1H),8.95(s,1H),7.38(d,1H),7.31(d,1H),7.23(d,1H),6.27(d,1H),4.19–4.10(m,2H),3.72– 3.63(m,4H),3.62–3.54(m,2H),3.34(s,2H),3.18–2.87(m,10H),2.14–2.01(m,2H),1.93–1.84(m,2H)ppm; LCMS: 498.2[M+H] + .

[0607] Example 67: N-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 67)

[0608] Step 1: N-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 67)

[0609] Compound 11c (100 mg, 0.24 mmol), N,N-dimethylaminobromoethane hydrobromide (66 mg, 0.28 mmol), and potassium carbonate (163 mg, 1.18 mmol) were added to N,N-dimethylformamide (3 mL). The mixture was stirred at 80 °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 67 (10 mg, yield: 9%). 1H NMR(500MHz, CDCl3)δ9.46(s,1H),8.85(s,1H),7.36(d,1H),7.28(d,1H),7.20(d,1H),6.25(d,1H),4.15–4.04(m,2H),3.62–3.51(m, 2H),3.07–2.96(m,5H),2.95–2.61(m,4H),2.63–2.46(m,4H),2.33(s,6H),2.07–1.99(m,2H),1.98–1.88(m,2H)ppm; LCMS: 495.2[M+H] + .

[0610] Example 68: N-(2-(4-(2-aminoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 68)

[0611] Step 1: tert-butyl(2-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)carbamate (68a)

[0612] Compound 11c (100 mg, 0.24 mmol), tert-butyl (2-bromoethyl) carbamate (58 mg, 0.26 mmol), and potassium carbonate (98 mg, 0.71 mmol) were sequentially added to N,N-dimethylformamide (3 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 preparative high-performance liquid chromatography (HPLC) to obtain compound 68a (30 mg, yield: 25%). LCMS: 567.2 [M+H] + .

[0613] Step 2: N-(2-(4-(2-aminoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 68)

[0614] Compound 68a (60 mg, 0.11 mmol) was added to hydrochloric acid / 1,4-dioxane (1 mL, 4 mol / L) and stirred at 25 °C for 8 h. After the reaction was completed, the hydrochloride salt of compound 68 was directly evaporated under reduced pressure to obtain 30 mg, yield: 56%. 1H NMR (500MHz, CDCl3) δ11.70(s,1H),9.34(s,1H),8.50(s,1H),8.41(s,2H),7.53(d,1H),7.45(d,1H),7.35(d,1H),6.45(d,1H),4.0 1–3.90(m,2H),3.87–3.46(m,6H),3.32–3.16(m,8H),3.15–3.04(m,1H),2.00–1.88(m,2H),1.79–1.62(m,2H)ppm; LCMS: 467.2[M+H] + .

[0615] Example 69: N-(2-(4-(2-(methylamino)-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 69)

[0616] Step 1: N-(2-(4-(2-(methylamino)-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 69)

[0617] Compound 11c (100 mg, 0.24 mmol), 2-bromo-N-methylacetamide (43 mg, 0.28 mmol), and potassium carbonate (98 mg, 0.71 mmol) were added to N,N-dimethylformamide (3 mL). The mixture was stirred at 80 °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 69 (60 mg, yield: 51%). 1 H NMR (500MHz, CDCl3) δ9.37(s,1H),8.85(s,1H),7.37(d,1H),7.28(d,1H),7.20(d,1H),7.13(s,1H),6.25(d,1H),4.17–4. 05(m,2H),3.64–3.53(m,2H),3.16(s,2H),3.09–2.98(m,5H),2.94–2.71(m,7H),2.05–1.83(m,4H)ppm; LCMS: 495.2[M+H] + .

[0618] Example 70: N-(2-(4-(2-(dimethylamino)-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 70)

[0619] Step 1: N-(2-(4-(2-(dimethylamino)-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 70)

[0620] Compound 11c (100 mg, 0.24 mmol), 2-bromo-N,N-dimethylacetamide (47 mg, 0.28 mmol), and potassium carbonate (98 mg, 0.71 mmol) were added to N,N-dimethylformamide (3 mL). The mixture was stirred at 80 °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 70 (60 mg, yield: 50%). 1 H NMR(500MHz, CDCl3)δ9.43(s,1H),8.85(s,1H),7.36(d,1H),7.28(d,1H),7.19(d,1H),6.24(d,1H),4.15–4.06(m,2H),3.63–3. 53(m,2H),3.34(s,2H),3.12(s,3H),3.09–3.00(m,5H),2.99(s,3H),2.95–2.68(m,4H),2.08–1.83(m,4H)ppm; LCMS: 509.2[M+H] + .

[0621] Example 71: Methyl 4-(2-(5-(1H-pyrazol-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 71)

[0622] Step 1: Methyl 5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)furan-2-carboxylate (71a)

[0623] Compound 40b (600 mg, 3.12 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL round-bottom flask at room temperature. Sodium hydroxide (187 mg, 4.68 mmol, 60% purity) was added under ice-water bath conditions. The reaction was carried out at 0 °C for 30 min, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (1041 mg, 6.24 mmol). The reaction was carried out at 25 °C for 3 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 71a (710 mg, yield: 70%). LCMS: 323.1 [M+H] + .

[0624] Step 2: 5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)furan-2-carboxylic acid (71b)

[0625] Compound 71a (710 mg, 2.20 mmol), methanol (5 mL), water (5 mL), and lithium hydroxide monohydrate (277 mg, 6.60 mmol) were added to a 50 mL round-bottom flask at room temperature. The reaction was carried out at 25 °C for 3 h. The pH of the reaction solution was adjusted to 4 by adding 2 M hydrochloric acid, and a solid precipitated. The solid was filtered, the filter cake was collected, and the residual solvent was removed under reduced pressure to obtain compound 71b (550 mg, yield: 80%). LCMS: 309.1 [M+H] + .

[0626] Step 3: tert-butyl 4-(4-(trifluoromethyl)-2-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)furan-2-carboxamido)benzyl)piperazine-1-carboxylate (71c)

[0627] At room temperature, compound 71b (500 mg, 1.61 mmol), acetonitrile (20 mL), compound 59c (580 mg, 1.61 mmol), N-methylimidazole (397 mg, 4.83 mmol), and N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (1358 mg, 4.83 mmol) were added to a 100 mL round-bottom flask. The reaction was carried out at 25 °C for 8 h. After the reaction was complete, 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, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 71c (210 mg, 20% yield). LCMS: 650.3 [M+H] + .

[0628] Step 5: N-(2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (71d)

[0629] Compound 71c (190 mg, 0.29 mmol), 1,4-dioxane (5 mL), and hydrochloric acid / 1,4-dioxane solution (3 mL, 4 M) were added to a 50 mL round-bottom flask at room temperature, and the mixture was reacted at 25 °C for 12 h. After the reaction was complete, the organic solvent was removed under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain crude compound 71d (180 mg). LCMS: 420.1 [M+H] + .

[0630] Step 6: Methyl 4-(2-(5-(1H-pyrazol-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 71)

[0631] At room temperature, compound 71d (180 mg, 0.43 mmol), N,N-dimethylformamide (6 mL), N,N-diisopropylethylamine (277 mg, 2.15 mmol), and N,N'-carbonyldiimidazole (104 mg, 0.64 mmol) were added sequentially to a 50 mL round-bottom flask, and the mixture was stirred at 25 °C for 5 minutes. Methanol (6 mL) was added, and the mixture was reacted at 80 °C for 12 h under nitrogen protection. 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 71 (41 mg, 18% yield). 1 H NMR(500MHz,DMSO-d6)δ13.26(s,1H),11.15(s,1H),8.66–8.60(m,1H),8.21(s,1H),7.90(s,1H),7.55–7.49(m,1H),7.48–7.43(m ,1H),7.33–7.30(m,1H),6.80–6.76(m,1H),3.84(s,2H),3.57(s,3H),3.31–3.25(m,4H),2.47–2.39(m,4H)ppm; LCMS: 478.2[M+H] + .

[0632] Example 72: N-(2-((4-cyanopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 72)

[0633] Step 1: N-(2-((4-cyanopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 72)

[0634] Compound 71d (100 mg, 0.24 mmol), bromocyanide (38 mg, 0.36 mmol), and triethylamine (72 mg, 0.72 mmol) were added sequentially to tetrahydrofuran (5 mL), and stirred at 25 °C for 8 h. After the reaction was completed, methanol was added to quench the reaction, and compound 72 (10 mg, yield: 9%) was obtained by preparative liquid chromatography. 1 H NMR(500MHz, CDCl3)δ10.83(s,1H),8.74(s,1H),7.88(s,2H),7.36–7.31(m,2H),7.28(d, 1H),6.58(d,1H),3.78(s,2H),3.27–3.18(m,4H),2.67–2.54(m,4H)ppm; LCMS: 445.1[M+H] + .

[0635] Example 73: 5-(2,6-diaminopyridin-4-yl)-N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 73)

[0636] Step 1: tert-butyl 4-(1-methyl-1H-pyrazole-3-yl)piperazine-1-carboxylate (73a)

[0637] In a 100 mL round-bottom flask, N-tert-butoxycarbonyl-piperazine (3.72 g, 20.0 mmol), 3-bromo-1-methyl-1H-pyrazole (2.3 g, 15.0 mmol), potassium tert-butoxide (2.5 g, 22.5 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (700 mg, 1.5 mmol), and tris(dibenzylacetone)dipalladium (656 mg, 0.62 mmol) were successively dissolved in N,N-dimethylformamide (50 mL), and the reaction was carried out at 90 °C for 8 h. 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 73a (2.7 g, yield 68%), LCMS: 267.2 [M+H]. + Step 2: 1-(1-Methyl-1H-pyrazole-3-yl)piperazine (73b)

[0638] In a 50 mL round-bottom flask, compound 73a (2.7 g, 10.2 mmol) was dissolved in 100 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. After removing the organic solvent under reduced pressure, dichloromethane and a saturated sodium bicarbonate solution were added. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give crude compound 73b (1.20 g). LCMS: 167.1 [M+H] + .

[0639] Step 3: 1-(1-Methyl-1H-pyrazole-3-yl)-4-(2-nitro-4-(trifluoromethyl)benzyl)piperazine (73c)

[0640] In a 100 mL round-bottom flask, compound 73b (0.5 g, 3.0 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of 1-(bromomethyl)-2-nitro-4-(trifluoromethyl)benzene (1.0 g, 3.5 mmol) and cesium carbonate (1.9 g, 6.0 mmol). The reaction was carried out at room temperature for 6 h. The mixture was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was evaporated to dryness under reduced pressure. The crude product was purified by column chromatography to give compound 73c (0.8 g, 72% yield). LCMS: 370.2 [M+H] + .

[0641] Step 4: 2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (73d)

[0642] In a 100 mL round-bottom flask, compound 73c (0.8 g, 2.2 mmol) was dissolved in 20 mL of ethanol, and 10% palladium on carbon (80 mg) was added. The reaction was carried out at 60 °C for 8 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 73d (0.65 g). LCMS: 340.2 [M+H] + .

[0643] Step 5: 5-Bromo-N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (73e)

[0644] In a 100 mL round-bottom flask, compound 73d (170 mg, 0.5 mmol) and methyl 5-bromofuran-2-carboxylate (203 mg, 1.0 mmol) were dissolved in THF (10 mL), and then added dropwise to a mixture of tetrahydrofuran (10 mL) and potassium tert-butoxide (259 mg, 1.5 mmol). The reaction was allowed to proceed for 30 min. The reaction was quenched with saturated ammonium chloride solution, 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 column chromatography to give compound 73e (200 mg, 78% yield). LCMS: 512.1 [M+H] + .

[0645] Step 6: 5-(2,6-diaminopyridin-4-yl)-N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 73)

[0646] In a 100 mL round-bottom flask, compound 73e (153 mg, 0.3 mmol), compound 39b (181 mg, 0.6 mmol), and potassium carbonate (83 mg, 0.6 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL). Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (24.6 mg, 0.03 mmol) was added, and the mixture was reacted at 100 °C for 6 h under a nitrogen atmosphere. The mixture was diluted with water, 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 preparative liquid chromatography to obtain compound 73 (90 mg, yield 56%). 1 H NMR(500MHz,DMSO-d6)δ11.33(s,1H),8.69(s,1H),7.56(d,1H),7.47(d,1H),7.38(d,1H),7.32(d,1H),7.00(d,1H ),6.02(s,2H),5.57(s,4H),5.55(d,1H),3.87(s,2H),3.61(s,3H),3.06(s,4H),2.57(s,4H)ppm; LCMS:541.2[M+H] + .

[0647] Example 74: N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 74)

[0648] Step 1: N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 74)

[0649] In a 100 mL round-bottom flask, compound 73e (153 mg, 0.3 mmol), (1-(tert-butyloxycarbonyl)-1H-pyrazol-4-yl)boric acid (127 mg, 0.6 mmol), and potassium carbonate (83 mg, 0.6 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (24.6 mg, 0.03 mmol). The reaction was carried out under nitrogen atmosphere and at 100 °C for 8 h. The mixture was diluted with water, 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 preparative liquid chromatography to obtain compound 74 (100 mg, 67% yield). 1 H NMR(500MHz,DMSO-d6)δ13.22(s,1H),11.30(s,1H),8.70(s,1H),8.20(s,1H),7.90(s,1H),7.54(d,1H),7.45(d,1H),7.38(s ,1H),7.30(s,1H),6.77(s,1H),5.51(s,1H),3.87(s,2H),3.61(s,3H),3.01(s,4H),2.61–2.53(m,4H)ppm; LCMS:500.2[M+H] + .

[0650] Example 75: N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)pyridinecarboxamide (Compound 75)

[0651] Step 1: 5-Bromo-N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)pyridinecarboxamide (75a)

[0652] In a 100 mL round-bottom flask, compound 73d (170 mg, 0.5 mmol) and methyl 5-bromopyridinecarboxylate (216 mg, 1.0 mmol) were dissolved in tetrahydrofuran (10 mL), and then added dropwise to a mixture of tetrahydrofuran (10 mL) and potassium tert-butoxide (259 mg, 1.5 mmol). The reaction was allowed to proceed for 30 min. The reaction was quenched with saturated ammonium chloride solution, 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 column chromatography to obtain compound 75a (180 mg, 70% yield). LCMS: 523.1 [M+H] + .

[0653] Step 2: N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(1H-pyrazol-4-yl)pyridinecarboxamide (Compound 75)

[0654] In a 100 mL round-bottom flask, compound 75a (157 mg, 0.3 mmol), (1-(tert-butyloxycarbonyl)-1H-pyrazol-4-yl)boric acid (127 mg, 0.6 mmol), and potassium carbonate (83 mg, 0.6 mmol) were dissolved in 1,4-dioxane / water (10:1, 10 mL), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (24.6 mg, 0.03 mmol). The reaction was carried out under nitrogen atmosphere and at 100 °C for 6 h. The mixture was diluted with water, 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 preparative liquid chromatography to obtain compound 75 (85 mg, yield 56%). 1 H NMR(500MHz,DMSO-d6)δ12.50(s,1H),10.81(s,1H),9.78(s,1H),9.15–8.65(m,1H),8.47–8.20(m,3H),8.15(d,1H),8.09–7.68 (m,1H),7.55(s,1H),7.45(s,1H),5.72(d,1H),3.79(s,2H),3.64(s,3H),3.26(s,4H),2.78–2.55(m,4H)ppm; LCMS:511.2[M+H] + .

[0655] Example 76: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 76)

[0656] Step 1: tert-butyl 4-(4-bromo-2-nitrophenyl)piperazine-1-carboxylic acid ester (76a)

[0657] In a 500 mL round-bottom flask, N-tert-butoxycarbonylpiperazine (12.02 g, 63.44 mmol), compound 4-bromo-1-chloro-2-nitrobenzene (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 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 76a (9.52 g, 58% yield). LCMS: 386.1 [M+H] + .

[0658] Step 2: tert-butyl 4-(2-amino-4-bromophenyl)piperazine-1-carboxylic acid ester (76b)

[0659] In a 250 mL round-bottom flask, compound 76a (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 76b (3.30 g, yield: 26%). LCMS: 356.1 [M+H] + .

[0660] Step 3: tert-butyl 4-(4-bromo-2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)phenyl)piperazine-1-carboxylate (76c)

[0661] 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 76b (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 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 76c (3.30 g, yield: 65%). LCMS: 534.2 [M+H] + .

[0662] Step 4: 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 (76d)

[0663] Under nitrogen protection, in a 100 mL round-bottom flask, compound 76c (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 76d (3.60 g, yield: 90%). LCMS: 672.4 [M+H] + .

[0664] Step 5: tert-butyl 4-(4-mercapto-2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)phenyl)piperazine-1-carboxylate (76e)

[0665] In a 100 mL round-bottom flask, compound 76d (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 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 76e (610 mg, yield: 23%). LCMS: 488.2 [M+H] + .

[0666] Step 6: tert-butyl 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-((trifluoromethyl)thio)phenyl)piperazine-1-carboxylate (76f)

[0667] In a 100 mL round-bottom flask, compound 76e (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 76f (66 mg, yield: 57%). LCMS: 556.2 [M+H] +Step 7: N-(2-(piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (76g)

[0668] In a 50 mL round-bottom flask, compound 76f (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 obtain 76 g (70 mg) of crude compound, which could be used directly in the next step without purification. LCMS: 456.1 [M+H] + .

[0669] Step 8: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 76)

[0670] In a 100 mL round-bottom flask, trimethylcyanosilane (297 mg, 3 mmol), 3-oxetane (216 mg, 3.0 mmol), and zinc iodide (127 mg, 0.4 mmol) were sequentially added to tetrahydrofuran (10 mL), and the reaction was carried out at room temperature for 12 h. Then, compound 76 g (227.5 mg, 0.5 mmol) and triethylamine (202 mg, 2.0 mmol) were dissolved in methanol (3.0 mL) and added to the above reaction solution, and the reaction was continued at 60 °C for 6 h. The reaction was quenched with water, 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 high-performance liquid chromatography to obtain compound 76 (95 mg, yield 35%). 1 H NMR (500MHz, CDCl3) δ9.10(s,1H),8.86(s,1H),7.42(d,1H),7.26–7.19(m,2H),6.24(d,1H),4.86(d,2H),4.74(d,2H),4. 04(d,2H),3.62(t,2H),3.20–2.98(m,5H),2.81–2.52(m,4H),2.10–1.91(m,2H),1.88–1.69(m,2H)ppm; LCMS:537.2[M+H] + .

[0671] Example 77: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 77)

[0672] Step 1: N-(2-(4-(cyanomethyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 77)

[0673] In a 100 mL round-bottom flask, compound 76 g (300 mg, 0.66 mmol), cesium carbonate (434 mg, 1.32 mmol), and bromoacetonitrile (120 mg, 1.0 mmol) were sequentially added to N,N-dimethylformamide (5 mL), and the reaction was carried out at room temperature for 12 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 high-performance liquid chromatography to obtain compound 77 (281 mg, yield 85%). 1 H NMR(500MHz, CDCl3)δ9.16(s,1H),8.86(s,1H),7.44–7.34(m,1H),7.26–7.1 7(m,2H),6.28–6.22(m,1H),4.12–3.97(m,2H),3.83–3.71(m,1H),3.67(s,2 H),3.67–3.60(m,2H),3.21–3.11(m,1H),3.10–3.02(m,3H),2.99(s,1H),2. 93–2.79(m,3H),2.07–1.94(m,2H),1.90–1.75(m,2H)ppm; LCMS:495.2[M+H] + .

[0674] Example 78: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 78)

[0675] Step 1: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 78)

[0676] In a 100 mL round-bottom flask, compound 76 g (300 mg, 0.66 mmol), cesium carbonate (434 mg, 1.32 mmol), and bromoethanol (125 mg, 1.0 mmol) were sequentially added to N,N-dimethylformamide (5 mL), and the reaction was carried out at room temperature for 12 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 high-performance liquid chromatography to obtain compound 78 (281 mg, yield 85%). 1H NMR(500MHz, CDCl3)δ9.37(s,1H),8.87(d,1H),7.43–7.35(m,1H),7.26–7.16(m,2H),6.25(d,1H),4.15–4.02(m,2H),3.79–3. 67(m,2H),3.62–3.49(m,2H),3.09–2.93(m,5H),2.93–2.72(m,4H),2.73–2.64(m,2H),2.05–1.87(m,4H)ppm; LCMS:500.2[M+H] + .

[0677] Example 79: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 79)

[0678] Step 1: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 79)

[0679] In a 100 mL round-bottom flask, compound 77 (100 mg, 0.2 mmol), cesium carbonate (54 mg, 0.4 mmol), and 30% hydrogen peroxide (680 mg, 6.0 mmol) were sequentially added to dimethyl sulfoxide (5 mL), and the reaction was carried out at room temperature for 1 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 high-performance liquid chromatography to obtain compound 79 (70 mg, yield 69%). 1 H NMR(500MHz, CDCl3)δ9.32(s,1H),8.86(d,1H),7.43–7.35(m,1H),7.25–7.16(m,2H),7.00(s,1H),6.25(d,1H),5.79(s,1H),4. 16–4.05(m,2H),3.63–3.51(m,2H),3.15(s,2H),3.08–2.96(m,5H),2.97–2.66(m,4H),2.04–1.85(m,4H)ppm; LCMS:513.2[M+H] + .

[0680] Example 80: N-(2-(4-(3-cyano-1-methylazacyclobutane-3-yl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 80)

[0681] Step 1: tert-butyl-3-cyano-3-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-((trifluoromethyl)thio)phenyl)piperazin-1-yl)azacyclobutane-1-carboxylate (80a)

[0682] In a 100 mL round-bottom flask, trimethylcyanosilane (148 mg, 1.5 mmol), tert-butyl 3-oxazacyclobutane-1-carboxylate (256 mg, 1.5 mmol), and zinc iodide (127 mg, 0.4 mmol) were sequentially added to tetrahydrofuran (10 mL), and the reaction was carried out at room temperature for 12 h. Then, 76 g (227.5 mg, 0.5 mmol) of the compound and triethylamine (202 mg, 2.0 mmol) were dissolved in methanol (5 mL) and added to the above reaction solution, and the reaction was continued at 60 °C for 6 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 80a (200 mg, yield 64%). LCMS: 636.2 [M+H] + .

[0683] Step 2: N-(2-(4-(3-cyanozynebutane-3-yl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (80b)

[0684] In a 50 mL round-bottom flask, compound 80a (200 mg, 0.31 mmol) was dissolved in 10 mL of dichloromethane. Hydrochloric acid / 1,4-dioxane solution (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 80b (170 mg). LCMS: 536.2 [M+H] + .

[0685] Step 3: N-(2-(4-(3-cyano-1-methylazacyclobutane-3-yl)piperazin-1-yl)-5-((trifluoromethyl)thio)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 80)

[0686] In a 100 mL round-bottom flask, compound 80b (0.17 g, 0.32 mmol) was dissolved in methanol (10 mL), followed by the addition of a formaldehyde methanol solution (0.5 mL), and then sodium cyanoborohydride (0.12 g, 2.0 mmol) was added in portions. The reaction was carried out at room temperature for 1 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 high-performance liquid chromatography to obtain compound 80 (115 mg, yield 68%).1 H NMR(500MHz,DMSO-d6)δ9.21(s,1H),8.60(d,1H),7.50–7.45(m,1H),7.42(d,1H),7.25(d,1H),6.45(d,1H),3.95–3.84(m,2H),3.70(d,2H),3 .54–3.42(m,2H),3.16–3.03(m,3H),2.99(s,4H),2.67–2.54(m,4H),2 .31(s,3H),1.98–1.87(m,2H),1.71–1.59(m,2H)ppm; LCMS:550.2[M+H] + .

[0687] Example 81: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 81)

[0688] Step 1: tert-butyl 4-(2-nitro-4-(trifluoromethoxy)phenyl)piperazine-1-carboxylate (81a)

[0689] At room temperature, 1-chloro-2-nitro-4-(trifluoromethoxy)benzene (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, and the reaction was carried out 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 81a (16.5 g, 67% yield). LCMS: 392.2 [M+H] + .

[0690] Step 2: tert-butyl 4-(2-amino-4-(trifluoromethoxy)phenyl)piperazine-1-carboxylate (81b)

[0691] Compound 81a (500 mg, 1.27 mmol), ethanol (20 mL), and palladium on carbon (200 mg, 10%) were added to a 100 mL round-bottom flask at room temperature. 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 81b (450 mg, yield, 97%). LCMS: 362.3 [M+H] +Step 3: Tert-butyl 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethoxy)phenyl)piperazine-1-carboxylate (81c)

[0692] At room temperature, potassium tert-butoxide (419 mg, 3.74 mmol) and tetrahydrofuran (10 mL) were added to a 100 mL round-bottom flask. Compound 81b (450 mg, 1.25 mmol) and compound 1c (393 mg, 1.87 mmol) were dissolved in tetrahydrofuran (10 mL) and added to the above system. The reaction was carried out at 25 °C for 12 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 81c (180 mg, yield 27%). LCMS: 540.3 [M+H] + .

[0693] Step 4: N-(2-(piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (81d)

[0694] At room temperature, compound 81c (180 mg, 0.33 mmol), 1,4-dioxane (6 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 to give compound 81d (120 mg, 81% yield). LCMS: 440.2 [M+H] + .

[0695] Step 5: N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 81)

[0696] Compound 81d (120 mg, 0.27 mmol), N,N-dimethylformamide (8 mL), bromoethanol (38 mg, 0.30 mmol), and potassium carbonate (113 mg, 0.82 mmol) were added to a 50 mL round-bottom flask at room temperature, and the mixture was reacted at 50 °C for 8 h. Water and ethyl acetate were added, the mixture was extracted and separated, 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 81 (57 mg, yield 43%). 1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.37–8.27(m,1H),7.48–7.38(m,1H),7.26–7.19 (m,1H),7.14–7.05(m,1H),6.48–6.42(m,1H),4.50–4.42(m,1H),3.98–3.91(m,2H),3 .58–3.52(m,2H),3.50–3.43(m,2H),3.11–3.01(m,1H),2.89–2.86(m,4H),2.76–2.57 (m,4H),2.48–2.44(m,2H),2.00–1.93(m,2H),1.81–1.69(m,2H)ppm; LCMS: 484.3[M+H] + .

[0697] Example 82: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 82)

[0698] Step 1: N-(2-(4-(3-cyanoxacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 82)

[0699] In a 100 mL round-bottom flask, trimethylcyanosilane (200 mg, 2 mmol), oxetane-3-one (144 mg, 2.0 mmol), and zinc iodide (127 mg, 0.4 mmol) were sequentially added to tetrahydrofuran (10 mL), and the reaction was carried out at room temperature for 12 h. Then, compound 81d (220 mg, 0.5 mmol) and triethylamine (202 mg, 2.0 mmol) were dissolved in methanol (5 mL) and added to the above reaction solution, and the reaction was continued at 60 °C for 6 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 high performance liquid chromatography to obtain compound 82 (55 mg, yield 21%). 1H NMR(500MHz, CDCl3)δ9.31(s,1H),8.52(d,1H),7.25–7.18(m,2H),7.02–6.91(m,1H),6.24(d,1H),4.87(d,2H),4.73(t,2H),4.10–3.96( m,2H),3.70–3.53(m,2H),3.20–3.10(m,1H),3.09–2.99(m,4H),2.68(s,4H),2.06–1.93(m,2H),1.86–1.72(m,2H)ppm; LCMS:521.2[M+H] + .

[0700] Example 83: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 83)

[0701] Step 1: N-(2-(4-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 83)

[0702] In a 100 mL round-bottom flask, compound 3c (216 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), and compound 81d (220 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted at 80 °C for 6 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 high-performance liquid chromatography to obtain compound 83 (30 mg, yield 11%). 1 H NMR(500MHz, CDCl3)δ9.55(s,1H),8.50(d,1H),7.40(d,1H),7.25–7.14(m,2H) ,6.98–6.88(m,1H),6.82(d,1H),6.28–6.19(m,1H),4.14–4.04(m,2H),4.00(s, 3H),3.63–3.50(m,2H),3.34–3.21(m,2H),3.09–3.00(m,1H),3.00–2.89(m,6H) ,2.89–2.52(m,4H),2.09–1.97(m,2H),1.96–1.85(m,2H)ppm; LCMS:560.2[M+H] + .

[0703] Example 84: N-(2-(4-(3-cyano-1-methylazacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 84)

[0704] Step 1: tert-butyl-3-cyano-3-(4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethoxy)phenyl)piperazin-1-yl)azacyclobutane-1-carboxylate (84a)

[0705] In a 100 mL round-bottom flask, trimethylcyanosilane (148 mg, 1.5 mmol), tert-butyl 3-oxazacyclobutane-1-carboxylate (256 mg, 1.5 mmol), and zinc iodide (127 mg, 0.4 mmol) were sequentially added to tetrahydrofuran (10 mL), and the reaction was carried out at room temperature for 12 h. Then, compound 81d (220 mg, 0.5 mmol) and triethylamine (202 mg, 2.0 mmol) were dissolved in methanol (5 mL) and added to the above reaction solution, and the reaction was continued at 60 °C for 6 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 84a (200 mg, yield 65%). LCMS: 620.2 [M+H] + .

[0706] Step 2: N-(2-(4-(3-cyanozazetane-3-yl)piperazin-1-yl)-5-((trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (84b)

[0707] In a 50 mL round-bottom flask, compound 84a (200 mg, 0.31 mmol) was dissolved in 10 mL of dichloromethane. Hydrochloric acid / 1,4-dioxane solution (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 84b (200 mg). LCMS: 520.2 [M+H] + .

[0708] Step 3: N-(2-(4-(3-cyano-1-methylazacyclobutane-3-yl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 84)

[0709] In a 100 mL round-bottom flask, compound 84b (0.17 g, 0.32 mmol) was dissolved in methanol (10 mL), followed by the addition of a formaldehyde methanol solution (0.5 mL), and then sodium cyanoborohydride (0.12 g, 2.0 mmol) was added in portions. The reaction was carried out at room temperature for 1 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 high-performance liquid chromatography to obtain compound 84 (105 mg, yield 62%). 1 H NMR(500MHz,DMSO-d6)δ9.34(s,1H),8.33(s,1H),7.45(t,1H),7.26(d,1H ),7.16–7.08(m,1H),6.45(t,1H),3.97–3.84(m,2H),3.75–3.62(m,2H),3 .56–3.43(m,2H),3.18–3.01(m,3H),3.01–2.90(m,4H),2.66–2.56(m,4H) ,2.33(s,3H),2.00–1.88(m,2H),1.73–1.59(m,2H)ppm; LCMS:534.2[M+H] + .

[0710] Example 85: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 85)

[0711] Step 1: N-(2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 85)

[0712] At room temperature, compound 38 (190 mg, 0.39 mmol), ethanol (3 mL), water (3 mL), dimethyl sulfoxide (62 mg, 0.79 mmol), sodium hydroxide (32 mg, 0.79 mmol), and hydrogen peroxide (27 mg, 0.79 mmol, 30%) were added to a 50 mL round-bottom flask, and the mixture was reacted at 25 °C for 3 h. The mixture was then 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 the crude product. The crude product was purified by high-performance liquid chromatography to obtain compound 85 (48 mg, yield 24%). 1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.39–8.29(m,1H),7.39–7.47(m,1H), 7.27–7.22(m,2H),7.21–7.10(m,2H),6.51–6.44(m,1H),4.00–3.94(m,2H) ,3.55–3.47(m,2H),3.14–3.03(m,1H),2.97(s,2H),2.95–2.91(m,4H),2.7 8–2.65(m,4H),2.00–1.92(m,2H),1.82–1.69(m,2H)ppm; LCMS: 497.2[M+H] + .

[0713] Example 86: Methyl 4-(2-(5-(1H-pyrazol-4-yl)pyridinecarboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 86)

[0714] Step 1: Methyl 5-(1H-pyrazole-4-yl)pyridinecarboxylate (86a)

[0715] Compound 41b (2.20 g, 7.66 mmol), 1,4-dioxane (20 mL), and hydrochloric acid / 1,4-dioxane solution (5 mL) were added to a 100 mL round-bottom flask at room temperature. The reaction was carried out at 25 °C for 8 h. The organic solvent was removed under reduced pressure to give compound 86a (1.80 g). LCMS: 204.1 [M+H] + .

[0716] Step 2: Methyl 5-(1-(4-methoxybenzyl)-1H-pyrazole-4-yl)pyridinecarboxylate (86b)

[0717] Compound 86a (1.8 g, 8.86 mmol), acetonitrile (30 mL), potassium carbonate (3.67 g, 26.57 mmol), and 4-methoxybenzyl chloride (2.08 g, 13.29 mmol) were added to a 100 mL round-bottom flask at room temperature. The reaction was carried out at 60 °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 86b (1.37 g, 55%). LCMS: 324.1 [M+H] + Step 3: 5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridinecarboxylic acid (86c)

[0718] At room temperature, compound 86b (1.37 g, 4.23 mmol), methanol (10 mL), water (10 mL), and lithium hydroxide monohydrate (0.53 g, 12.66 mmol) were added to a 100 mL round-bottom flask. The reaction was carried out at 25 °C for 3 h. The pH of the reaction solution was adjusted to 4 by adding 2 M hydrochloric acid, and a solid precipitated. The solid was filtered, the filter cake was collected, and the residual solvent was removed under reduced pressure to obtain compound 86c (1.10 g, 83% yield). LCMS: 310.1 [M+H] + .

[0719] Step 4: Tert-butyl 4-(2-(5-(1-(4-methoxybenzyl)-1H-pyrazole-4-yl)pyridinecarboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (86d)

[0720] At room temperature, in a 100 mL round-bottom flask, compound 86c (1.10 g, 3.56 mmol), acetonitrile (50 mL), compound 59c (1.28 g, 3.56 mmol), N-methylimidazole (0.88 g, 10.68 mmol), and N,N,N',N'-tetramethylchloromethanemidane hexafluorophosphate (3.00 g, 10.68 mmol) were added sequentially, and the reaction was carried out 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 86d (750 mg, 32% yield). LCMS: 651.2 [M+H] + .

[0721] Step 5: 5-(1-(4-methoxybenzyl)-1H-pyrazole-4-yl)-N-(2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)pyridinecarboxamide (86e)

[0722] Compound 86d (750 mg, 1.15 mmol), 1,4-dioxane (10 mL), and a hydrochloric acid / 1,4-dioxane solution (5 mL) 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 86e (750 mg). LCMS: 551.2 [M+H] + .

[0723] Step 6: 4-(2-(5-(1-(4-methoxybenzyl)-1H-pyrazole-4-yl)pyridinecarboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (86f)

[0724] At room temperature, in a 100 mL round-bottom flask, compound 86e (280 mg, 0.51 mmol), N,N-dimethylformamide (6 mL), N,N-diisopropylethylamine (329 mg, 2.55 mmol), and N,N'-carbonyldiimidazole (124 mg, 0.76 mmol) were added, and the mixture was stirred at 25 °C for 5 minutes. Methanol (6 mL) was added, and the reaction was carried out under nitrogen protection at 100 °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, and the organic solvent was removed under reduced pressure to give compound 86f (210 mg, 67% yield). LCMS: 609.1 [M+H] + .

[0725] Step 7: Methyl 4-(2-(5-(1H-pyrazol-4-yl)pyridinecarboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 86)

[0726] Compound 86f (60 mg, 0.10 mmol) and trifluoroacetic acid (5 mL) were added to a 50 mL round-bottom flask at room temperature and reacted at 90 °C for 2 h. The solvent was removed under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain compound 86 (23 mg, yield 48%). 1 H NMR(500MHz,DMSO-d6)δ13.24(s,1H),12.35(s,1H),9.01–8.93(m,1H),8.80–8.75(m,1H),8.54(s,1H),8.32–8.26(m,1H),8.23–8.1 3(m,2H),7.55–7.49(m,1H),7.48–7.42(m,1H),3.77(s,2H),3.62(s,3H),3.59–3.50(m,4H),2.49–2.38(m,4H)ppm; LCMS: 489.1[M+H] + .

[0727] Example 87: N-(2-((4-cyanopiperazin-1-yl)methyl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 87)

[0728] Step 1: 4-(2-nitro-4-(trifluoromethoxy)benzyl)piperazine-1-carboxylic acid tert-butyl ester (87a)

[0729] At room temperature, in a 100 mL round-bottom flask, 1-bromo-2-nitro-4-(trifluoromethoxy)benzene (2.00 g, 6.99 mmol), 1,4-dioxane (30 mL), water (6 mL), potassium (4-tert-butyloxycarbonylpiperazin-1-yl)methyltrifluoroborate (2.14 g, 6.99 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.33 g, 0.70 mmol), palladium acetate (0.16 g, 0.70 mmol), and cesium carbonate (6.84 g, 20.98 mmol) were added. The mixture was reacted under nitrogen protection at 100 °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, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 87a (920 mg, 32% yield). LCMS: 406.3 [M+H] + Step 2: 4-(2-amino-4-(trifluoromethoxy)benzyl)piperazine-1-carboxylic acid tert-butyl ester (87b)

[0730] Compound 87a (920 mg, 2.27 mmol), ethanol (20 mL), and palladium on carbon (300 mg, 10%) were added to a 100 mL round-bottom flask at room temperature. The mixture was purged three times with a hydrogen balloon, and the reaction was carried out under a hydrogen atmosphere at 55 °C for 8 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethanol, the organic phase was collected, and the organic solvent was removed under reduced pressure to give compound 87b (820 mg, yield, 96%). LCMS: 376.2 [M+H] + .

[0731] Step 3: 4-(2-(5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamido)-4-(trifluoromethoxy)benzyl)piperazine-1-carboxylic acid tert-butyl ester (87c)

[0732] At room temperature, in a 100 mL round-bottom flask, compound 87b (820 mg, 2.18 mmol), acetonitrile (20 mL), compound 4a (642 mg, 3.27 mmol), N-methylimidazole (358 mg, 4.36 mmol), and N,N,N',N'-tetramethylchloromethanemidane hexafluorophosphate (1.22 g, 4.36 mmol) were added sequentially. The reaction was carried out at 25 °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, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 87c (350 mg, 28% yield). LCMS: 554.2 [M+H] + .

[0733] Step 4: N-(2-(piperazin-1-ylmethyl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (87d)

[0734] At room temperature, compound 87c (350 mg, 0.63 mmol), 1,4-dioxane (5 mL), and hydrochloric acid / 1,4-dioxane solution (5 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 to give crude compound 87d (300 mg). LCMS: 454.2 [M+H] + .

[0735] Step 5: N-(2-((4-cyanopiperazin-1-yl)methyl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 87)

[0736] At room temperature, compound 87d (120 mg, 0.26 mmol), N,N-dimethylformamide (5 mL), potassium carbonate (109 mg, 0.78 mmol), and bromonitrile (42 mg, 0.40 mmol) were added to a 50 mL round-bottom flask. The reaction was carried out at 25 °C for 3 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 87 (73 mg, 57% yield). 1 H NMR(500MHz,DMSO-d6)δ10.85(s,1H),8.26–8.18(m,1H),7.43–7.36(m,1H) ,7.23–7.18(m,1H),7.12–7.05(m,1H),6.49–6.43(m,1H),3.98–3.89(m,2H ),3.76(s,2H),3.52–3.43(m,2H),3.33–3.20(m,4H),3.05–2.96(m,1H),2. 55–2.51(m,4H),1.94–1.85(m,2H),1.72–1.60(m,2H)ppm; LCMS: 479.2[M+H] + .

[0737] Example 88: N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 88)

[0738] Step 1: N-(2-((4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethoxy)phenyl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 88)

[0739] At room temperature, in a 50 mL round-bottom flask, compound 87d (180 mg, 0.40 mmol), 1,4-dioxane (15 mL), 3-bromo-1-methylpyrazole (128 mg, 0.80 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (37 mg, 0.08 mmol), sodium tert-butoxide (115 mg, 1.20 mmol), and tris(dibenzylacetone)dipalladium (36 mg, 0.04 mmol) were added sequentially. The reaction was carried out under nitrogen atmosphere and at 100 °C for 8 h. After extraction with water and ethyl acetate, 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 88 (43 mg, 20% yield). 1 H NMR(500MHz,DMSO-d6)δ11.42(s,1H),8.29–8.21(m,1H),7.47–7.43(m,1H),7.4 2–7.37(m,1H),7.21–7.17(m,1H),7.09–7.04(m,1H),6.44–6.38(m,1H),5.65–5 .71(m,1H),3.82–3.73(m,4H),3.65(s,3H),3.25–3.11(m,6H),2.92–2.82(m,1H ),2.65–2.52(m,4H),1.85–1.72(m,2H),1.63–1.49(m,2H)ppm; LCMS: 534.2[M+H] + .

[0740] Example 89: Methyl 4-(2-(5-(2,6-diaminopyridin-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 89)

[0741] Step 1: 5-Bromofuran-2-carboxylic acid (89b)

[0742] Compound 89a (3000 mg, 14.63 mmol) and lithium hydroxide monohydrate (1840 mg, 43.89 mmol) were added sequentially to methanol (10 mL) and water (10 mL). The mixture was stirred at 25 °C for 3 h. After the reaction was complete, methanol was removed by concentration under reduced pressure. The pH of the reaction mixture was adjusted to 5 by adding 2 M hydrochloric acid, 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 compound 89b (2400 mg, yield: 85%). LCMS: 190.9 [M+H] + .

[0743] Step 2: 4-(2-(5-bromofuran-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylic acid tert-butyl ester (89c)

[0744] Compound 89b (1500 mg, 7.85 mmol), compound 59c (2820 mg, 7.85 mmol), N,N-diisopropylethylamine (5080 mg, 39.25 mmol), and 1-butylphosphine anhydride (16980 mg, 23.55 mmol, 50% purity) were sequentially added to N,N-dimethylformamide (30 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 89c (3520 mg, yield: 84%). LCMS: 532.1 [M+H] + .

[0745] Step 3: 5-Bromo-N-(2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (89d)

[0746] Compound 89c (1500 mg, 2.82 mmol) was added to a hydrochloric acid / 1,4-dioxane solution (10 mL, 4 mol / L), and stirred at 25 °C for 3 h. After the reaction was complete, the solution was evaporated under reduced pressure to obtain crude compound 89d (1100 mg). LCMS: 432.1 [M+H] + Step 4: Methyl 4-(2-(5-bromofuran-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (89e)

[0747] Compound 89d (300 mg, 0.69 mmol), N,N'-carbonyldiimidazole (169 mg, 1.04 mmol), and N,N-diisopropylethylamine (449 mg, 3.45 mmol) were sequentially added to N,N-dimethylformamide (6 mL). The mixture was stirred at 25 °C for 2 h, followed by the addition of methanol (6 mL). Under nitrogen protection, the mixture was stirred at 80 °C for another 12 h. The reaction was quenched with water, 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 89e (210 mg, yield: 61%). LCMS: 490.1 [M+H] + Step 5: Methyl 4-(2-(5-(2,6-diaminopyridin-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 89)

[0748] Compound 89e (190 mg, 0.39 mmol), (2,6-diaminopyridin-4-yl)boronic acid (89 mg, 0.58 mmol), [1,1”-bis(diphenylphosphino)ferrocene]palladium dichloride (29 mg, 0.04 mmol), and potassium carbonate (107 mg, 0.78 mmol) were added to 1,4-dioxane (10 mL) and water (0.5 mL). The mixture was stirred at 100 °C for 2 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the mother liquor was collected, and water and ethyl acetate were added for extraction. 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 high performance liquid chromatography to obtain compound 89 (12 mg, yield: 6%). 1 H NMR(500MHz,DMSO-d6)δ11.23(s,1H),8.74–8.57(m,1H),7.56–7.45(m,2H),7.36–7.31(m,1H),7.03–6.97(m,1H) ,6.02(s,2H),5.60(s,4H),3.84(s,2H),3.56(s,3H),3.33–3.30(m,4H),2.48–2.40(m,4H)ppm; LCMS: 519.2[M+H] + Example 90: N-(2-((4-cyanopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (compound 90-1) and 4-(2-(5-(2,6-diaminopyridin-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazin-1-carboxamide (compound 90-2)

[0749] Step 1: 5-Bromo-N-(2-((4-cyanopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (90a)

[0750] Compound 89d (400 mg, 0.92 mmol), cyanogen bromide (147 mg, 1.39 mmol), and potassium carbonate (383 mg, 2.77 mmol) were sequentially added to N,N-dimethylformamide (6 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 give compound 90a (370 mg, yield: 87%). LCMS: 457.1 [M+H] + .

[0751] Step 2: N-(2-((4-cyanopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (compound 90-1) and 4-(2-(5-(2,6-diaminopyridin-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazin-1-carboxamide (compound 90-2)

[0752] Compound 90a (170 mg, 0.37 mmol), (2,6-diaminopyridin-4-yl)boronic acid (85 mg, 0.56 mmol), [1,1”-bis(diphenylphosphine)ferrocene]palladium dichloride (27 mg, 0.04 mmol), and potassium carbonate (103 mg, 0.74 mmol) were added sequentially to 1,4-dioxane (10 mL) and water (2 mL). The mixture was stirred at 100 °C for 5 h under nitrogen protection. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the mother liquor was collected. The mother liquor was extracted with water and 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 high-performance liquid chromatography to obtain compounds 90-1 and 90-2 (31 mg, yield: 16%). Compound 90-1: 1 H NMR(500MHz,DMSO-d6)δ10.87(s,1H),8.63–8.56(m,1H),7.59–7.54(m,1H),7.51–7.46(m,1H),7.36–7.33(m,1H),7 .02–6.98(m,1H),6.01(s,2H),5.61(s,4H),3.85(s,2H),3.19–3.14(m,4H),2.57–2.52(m,4H)ppm; LCMS: 486.2[M+H] + Compound 90-2:1 H NMR(500MHz,DMSO-d6)δ11.31(s,1H),8.68–8.60(m,1H),7.57–7.51(m,1H),7.50–7.44(m,1H),7.35–7.30(m,1H),7.04–6. 99(m,1H),6.03(s,2H),5.95(s,2H),5.57(s,4H),3.83(s,2H),3.28–3.22(m,4H),2.43–2.38(m,4H)ppm; LCMS: 504.2[M+H] + .

[0753] Example 91: 4-(2-(5-(1H-pyrazol-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxamide (Compound 91)

[0754] Step 1: Methyl 5-(1-(4-methoxybenzyl)-1H-pyrazole-4-yl)furan-2-carboxylate (91a)

[0755] Compound 40b (3800 mg, 19.77 mmol), 4-methoxybenzyl chloride (4650 mg, 29.66 mmol), and potassium carbonate (8200 mg, 59.32 mmol) were sequentially added to acetonitrile (150 mL). The mixture was stirred at 60 °C for 8 h under nitrogen protection. 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 the crude product. The crude product was purified by silica gel column chromatography to obtain compound 91a (3200 mg, yield: 51%). LCMS: 313.1 [M+H] + .

[0756] Step 2: 5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)furan-2-carboxylic acid (91b)

[0757] Compound 91a (3200 mg, 10.24 mmol) and lithium hydroxide monohydrate (1290 mg, 30.72 mmol) were added sequentially to methanol (15 mL) and water (15 mL). The mixture was stirred at 25 °C for 3 h. After the reaction was complete, methanol was removed by concentration under reduced pressure. The pH of the reaction solution was adjusted to 5 by adding 2 M hydrochloric acid, and a solid precipitated. The solid was filtered, and the filter cake was collected to give compound 91b (2680 mg, yield: 87%). LCMS: 299.1 [M+H] + .

[0758] Step 3: 4-(2-(5-(1-(4-methoxybenzyl)-1H-pyrazole-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylic acid tert-butyl ester (91c)

[0759] Compound 91b (2160 mg, 7.23 mmol), compound 59c (2600 mg, 7.23 mmol), N-methylimidazole (1780 mg, 21.69 mmol), and N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (6090 mg, 21.69 mmol) were sequentially added to acetonitrile (80 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 91c (1200 mg, yield: 26%). LCMS: 640.3 [M+H] + .

[0760] Step 4: 5-(1-(4-methoxybenzyl)-1H-pyrazole-4-yl)-N-(2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)furan-2-carboxamide (91d)

[0761] Compound 91c (1200 mg, 1.87 mmol) was added to a hydrochloric acid / 1,4-dioxane solution (10 mL, 4 mol / L), and stirred at 25 °C for 3 h. After the reaction was complete, the solution was evaporated under reduced pressure to obtain crude compound 91d (1100 mg). LCMS: 540.2 [M+H] + .

[0762] Step 5: 4-(2-(5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxamide (91e)

[0763] Compound 91d (600 mg, 1.11 mmol), N,N'-carbonyldiimidazole (270 mg, 13.67 mmol), and N,N-diisopropylethylamine (719 mg, 5.56 mmol) were sequentially added to dichloromethane (8 mL), and the mixture was stirred at 25 °C for 2 h. Then, ammonia / methanol solution (8 mL, 7 mol / L) was added, and the mixture was stirred at 25 °C for another 12 h. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 91e (150 mg, yield: 23%). LCMS: 583.2 [M+H] +Step 6: 4-(2-(5-(1H-pyrazol-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxamide (Compound 91)

[0764] Compound 91e (150 mg, 0.25 mmol) was added to trifluoroacetic acid (10 mL) and stirred at 90 °C for 2 h. After the reaction was completed, the crude product was obtained by vacuum evaporation. The crude product was purified by high performance liquid chromatography to obtain compound 91 (36 mg, yield: 30%). 1 H NMR(500MHz,DMSO-d6)δ13.26(s,1H),11.21(s,1H),8.71–8.56(m,1H),8.21(s,1H),7.91(s,1H),7.57–7.49(m,1H),7.47–7.43(m ,1H),7.33–7.30(m,1H),6.77–6.81(m,1H),5.94(s,2H),3.48(s,2H),3.27–3.16(m,4H),2.44–2.36(m,4H)ppm; LCMS: 463.2[M+H] + Example 92: 4-(2-(5-(1H-pyrazol-4-yl)pyridinecarboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxamide (Compound 92)

[0765] Step 1: 4-(2-(5-(1-(4-methoxybenzyl)-1H-pyrazole-4-yl)pyridinecarboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxamide (92a)

[0766] Compound 86e (360 mg, 0.65 mmol), N,N'-carbonyldiimidazole (159 mg, 0.98 mmol), and N,N-diisopropylethylamine (422 mg, 3.25 mmol) were sequentially added to dichloromethane (6 mL), and the mixture was stirred at 25 °C for 2 h. Then, ammonia / methanol solution (6 mL, 7 mol / L) was added, and the mixture was stirred at 25 °C for another 12 h. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 92a (190 mg, yield: 48%). LCMS: 594.2 [M+H] + Step 2: 4-(2-(5-(1H-pyrazol-4-yl)pyridinecarboxamido)-4-(trifluoromethyl)benzyl)piperazine-1-carboxamide (Compound 92)

[0767] Compound 92a (170 mg, 0.28 mmol) was added to trifluoroacetic acid (10 mL) and stirred at 90 °C for 2 h. After the reaction was completed, the crude product was dried under reduced pressure. The crude product was purified by high performance chromatography to obtain compound 92 (27 mg, yield: 20%). 1 H NMR(500MHz,DMSO-d6)δ13.25(s,1H),12.41(s,1H),9.02–8.85(m,1H),8.83–8.72(m,1H),8.52(s,1H),8.34–8.25(m,1H),8.22–8.1 3(m,2H),7.56–7.50(m,1H),7.48–7.41(m,1H),6.00(s,2H),3.79(s,2H),3.53–3.42(m,4H),2.48–2.42(m,4H)ppm; LCMS: 474.2[M+H] + .

[0768] Example 93: 2-(4-(2-(5-(2,6-diaminopyridin-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetic acid (compound 93)

[0769] Step 1: 2-(4-(2-(5-(2,6-diaminopyridin-4-yl)furan-2-carboxamido)-4-(trifluoromethyl)phenyl)piperazin-1-yl)acetic acid (compound 93)

[0770] Compound 39 (120 mg, 0.25 mmol), dimethyl sulfoxide (39 mg, 0.50 mmol), hydrogen peroxide (56 mg, 0.50 mmol), and sodium hydroxide (2 mg, 0.50 mmol) were added to ethanol (3 mL) and water (3 mL). The mixture was stirred at 40 °C for 12 h under nitrogen protection. 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 93 (8 mg, yield: 6%). 1 H NMR(500MHz,DMSO-d6)δ9.21(s,1H),8.73–8.60(m,1H),7.52–7.43(m,2H),7.42–7.39(m,1H),7.06 –6.95(m,1H),6.11(s,2H),5.96(s,4H),3.00–2.94(m,4H),2.93–2.87(m,6H)ppm; LCMS: 505.2[M+H] + .

[0771] Example 94: 3-{4-[2-({[5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-2-furanyl]carbonyl}amino)-4-(trifluoromethyl)phenyl]piperazin-1-yl}propionamide (Compound 94)

[0772] Step 1: 3-{4-[2-({[5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-2-furanyl]carbonyl}amino)-4-(trifluoromethyl)phenyl]piperazin-1-yl}propionamide (Compound 94)

[0773] In a 100 mL round-bottom flask, compound 11c (423 mg, 1.0 mmol), cesium carbonate (650 mg, 2.0 mmol), and 3-bromopropionamide (225 mg, 1.5 mmol) were sequentially added to N,N-dimethylformamide (5 mL), and the reaction was carried out at room temperature for 12 h. The reaction was quenched with aqueous solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Compound 94 (300 mg, yield 61%) was obtained by direct separation and purification by preparative high-performance liquid chromatography. 1 H NMR(500MHz,DMSO-d6)δ9.33(s,1H),8.51(s,1H),7.58(s,1H),7.52(d,1H),7.47(d,1H),7.32(d,1H),7.16(s,1H),6.46(d,1H),3.99–3 .89(m,2H),3.77–3.53(m,2H),3.53–3.44(m,2H),3.30(d,4H),3.26–3.02(m,5H),2.62(s,2H),2.00–1.89(m,2H),1.78–1.63(m,2H)ppm. LCMS:495.2[M+H] + .

[0774] Example 95: N-{2-[4-(2-cyanoethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 95)

[0775] Step 1: N-{2-[4-(2-cyanoethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 95)

[0776] In a 100 mL round-bottom flask, compound 94 (200 mg, 0.41 mmol) and Burgess reagent (145 mg, 0.61 mmol) were added sequentially to dichloromethane (10 mL), and the reaction was carried out at room temperature for 2 h. The reaction was quenched with aqueous solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Compound 95 (135 mg, yield 69%) was obtained by direct separation and purification by preparative liquid chromatography. 1 H NMR(500MHz,DMSO-d6)δ9.36(s,1H),8.53(s,1H),7.54–7.44(m,2H),7.28(d,1H),6.44(d,1H),4.01–3.90(m,2H),3.91–3.54 (m,6H),3.54–3.41(m,2H),3.21–3.12(m,4H),3.13–3.04(m,1H),3.05–2.96(m,2H),1.99–1.85(m,2H),1.79–1.64(m,2H)ppm. LCMS:477.2[M+H] + .

[0777] Example 96: N-{2-[4-(3-hydroxypropyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 96)

[0778] Step 1: N-{2-[4-(3-hydroxypropyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 96)

[0779] In a 100 mL round-bottom flask, compound 11c (423 mg, 1.0 mmol), cesium carbonate (650 mg, 2.0 mmol), and 3-bromopropanol (209 mg, 1.5 mmol) were sequentially added to N,N-dimethylformamide (5 mL), and the reaction was carried out at room temperature for 12 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 then directly purified by preparative liquid chromatography to obtain compound 96 (350 mg, yield 73%). 1H NMR(500MHz,DMSO-d6)δ9.97(s,1H),9.34(s,1H),8.50(s,1H),7.57–7.50(m,1H),7.47(d,1H),7.32(d,1H),6.46(d,1H),3.98–3.86(m,2H ),3.79–3.65(m,2H),3.60–3.50(m,4H),3.38–3.29(m,2H),3.28–3.18(m,4H),3.18–3.02(m,3H),1.98–1.79(m,4H),1.78–1.63(m,2H)ppm. LCMS:482.2[M+H] + .

[0780] Example 97: 2-{4-[2-({[5-(pyridin-4-yl)furan-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]piperazin-1-yl}acetamide (Compound 97)

[0781] Step 1: 2-[4-(2-{[(5-bromofuran-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl)piperazin-1-yl]acetamide (compound 97a)

[0782] Compound 39e (400 mg, 0.88 mmol), hydrogen peroxide (300 mg, 2.63 mmol), and potassium carbonate (240 mg, 1.75 mmol) were sequentially added to dimethyl sulfoxide (5 mL). The mixture was stirred at 25 °C for 16 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, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 97a (300 mg, 72% yield). Second step: 2-{4-[2-({[5-(pyridin-4-yl)furan-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]piperazin-1-yl}acetamide (compound 97)

[0783] In a 100 mL round-bottom flask, pyridine 4-borate (123 mg, 1.0 mmol), compound 97a (237 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 97 (190 mg, 80% yield) was purified by preparative high-performance liquid chromatography. 1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.82(d,2H),8.37(s,1H),8.07–7.94(m,3H),7.77(s,1 H),7.68–7.53(m,3H),7.46(d,1H),4.02(s,2H),3.91(s,4H),3.51(s,2H),3.34(s,2H)ppm. LCMS:474.2[M+H] + .

[0784] Example 98: 3-{4-[2-({[5-(2,6-diaminopyridin-4-yl)furan-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]piperazin-1-yl}propionamide (Compound 98)

[0785] Step 1: 3-[4-(2-{[(5-bromofuran-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl)piperazin-1-yl]propionamide (compound 98a)

[0786] In a 100 mL round-bottom flask, compound 45b (417 mg, 1.0 mmol), cesium carbonate (650 mg, 2.0 mmol), and 3-bromopropionamide (225 mg, 1.5 mmol) were sequentially added to N,N-dimethylformamide (10 mL), and the reaction was carried out at room temperature for 12 h. The reaction was quenched with aqueous solution, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Compound 98a (420 mg, 86% yield) was then purified directly by preparative high-performance liquid chromatography (HPLC). LCMS: 489.1 [M+H] + .

[0787] Step 2: 3-{4-[2-({[5-(2,6-diaminopyridin-4-yl)furan-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]piperazin-1-yl}propionamide (Compound 98)

[0788] In a 100 mL round-bottom flask, compound 98a (195 mg, 0.4 mmol), compound 39b (141 mg, 0.60 mmol), and potassium carbonate (109 mg, 0.8 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 residue was purified by preparative high-performance liquid chromatography to obtain compound 98 (150 mg, yield 51%). 1H NMR(500MHz,DMSO-d6)δ9.93(s,1H),9.67(s,1H),8.28(d,1H),7.62(d,2H),7.60–7.53(m,1H),7.44(d,1H),7.41 –7.37(m,2H),7.36–7.29(m,2H),7.15(s,1H),6.35(s,2H),3.47(s,2H),3.38–3.01(m,8H),2.68–2.55(m,2H)ppm. LCMS:518.2[M+H] + .

[0789] Example 99: N-{2-[4-(2-cyanoethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (Compound 99)

[0790] Step 1: 5-Bromo-N-{2-[4-(2-cyanoethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}furan-2-carboxamide (Compound 99a)

[0791] In a 100 mL round-bottom flask, compound 98a (220 mg, 0.45 mmol) and Burgess reagent (161 mg, 0.68 mmol) were sequentially added to 10 mL of dichloromethane and reacted at room temperature for 2 h. The reaction was quenched with water, extracted with dichloromethane, and the concentrated organic phase was collected to obtain the crude product. Compound 99a (180 mg, 85% yield) was then purified directly by preparative high-performance liquid chromatography (HPLC). LCMS: 471.1 [M+H] + .

[0792] Step 2: N-{2-[4-(2-cyanoethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}-5-(2,6-diaminopyridin-4-yl)furan-2-carboxamide (Compound 99)

[0793] In a 100 mL round-bottom flask, compound 99a (180 mg, 0.38 mmol), compound 39b (141 mg, 0.60 mmol), and potassium carbonate (109 mg, 0.8 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 preparative high-performance liquid chromatography to obtain compound 99 (100 mg, yield 52%). 1H NMR (500MHz, DMSO-d6) δ12.68(s,1H),9.63(s,1H),8.28(s,1H),7.61–7.52(m,2H),7.48–7. 38(m,4H),7.36(d,1H),6.34(s,2H),3.66–3.51(m,2H),3.26–3.00(m,8H),2.94(s,2H)ppm. LCMS:500.2[M+H] + .

[0794] Example 100: 5-(1H-pyrazol-4-yl)-N-{2-[4-(2-cyanoethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}furan-2-carboxamide (Compound 100)

[0795] Step 1: 5-(1H-pyrazol-4-yl)-N-{2-[4-(2-cyanoethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}furan-2-carboxamide (Compound 100)

[0796] In a 100 mL round-bottom flask, compound 99a (235 mg, 0.5 mmol), N-tert-butoxycarbonyl-pyrazole-4-boronic acid (212 mg, 1.0 mmol), and potassium carbonate (136 mg, 1.0 mmol) were dissolved in 1,4-dioxane / water (10:1, 20 mL)....

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, R 1 It can be H, deuterium, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl, alkoxy, heteroalkyl, cycloalkyl, haloalkoxy, haloalkenoxy, alkylthio, haloalkylthio or Me2P(=O)-; X is CR 5 ; Y 1 and Y 2 Each independently for CR 6 Or N; A is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring; R 2 R 5 and R 6 Each of these can be independently H, deuterium, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclic, or cycloalkyl. R 3 It is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocycle that is independently and optionally substituted with 1, 2, 3 or 4 deuterium, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, hydroxyalkyl or alkoxy groups; R 4 It is cyano, alkyl, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, R 7 -Q-、 R 10 C(=O)-、R 10 C(=S)-、R 10 C(=O)-alkyl or R 11 S(=O)2-; R 7 It is hydrogen, deuterium, cyano, hydroxyl, alkyl, aryl, heteroaryl, R 9 C(=O)-、R 15 C(=O)-alkyl, hydroxyalkyl, cyanoalkyl, R 20 R 21 N-;R 7 The aryl and heteroaryl groups described herein may optionally be replaced by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, or alkoxy groups; Q is O, S, NR 12 , -CR 13 R 14 -, -(CR 13 R 14 ) m -, -(CR 13 R 14 ) n -O-, -(CR 13 R 14 ) n -NH-, -S(=O)2- or -S(=O)(=NH)-; R 12 It can be hydrogen, cyano, alkyl, haloalkyl, cycloalkyl, or alkyl-OC(=O)-; L is -(CR 16 R 17 ) t -, -O(CR 16 R 17 ) t -, -NH(CR 16 R 17 ) t -, -C(=O)-, -C(=O)(CR 16 R 17 ) t -, -C(=O)O(CR 16 R 17 ) t - or -OC(=O)(CR 16 R 17 ) t -; t can be 0, 1, 2, or 3; m and n are each independently 0, 1, 2 or 3; R 8 R 9 R 10 R 11 and R 15 Each can be independently hydrogen, deuterium, amino, hydroxyl, alkyl, alkoxy, alkylamino, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 13 and R 14 Each can be independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic or alkyl-OC(=O)-; Or R 13 R 14 Together with the carbon atom attached to it, they form double bonds, cycloalkyl groups, R 16 and R 17 Each can be independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic. R 20 and R 21 Each can be independently hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic. R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 20 and R 21 The groups described herein are independently and optionally replaced by 1, 2, 3 or 4 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, ynyl or cycloalkyl.

2. The compound according to claim 1, 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, C 3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio groups, Me2P(=O)-; X is CR 5 ; R 5 H, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 Cycloalkyl.

3. The compound according to claim 1 or 2, wherein, R 1 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, F-substituted C 1-4 Alkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, SF5 Or Me2P(=O)-; X is CR 5 ; R 5 It can be H, deuterium, hydroxyl, F, Cl, Br, hydroxyl, methyl, ethyl, isopropyl, methoxy, ethoxy, or cyclopropyl.

4. The compound according to claim 1, wherein, A is a 5-6 membered heteroaryl group; preferably, A is a furan ring, imidazole ring, pyrrole ring, thiophene ring, thiazole ring, thiadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring; R 2 For H, deuterium, hydroxyl, F, Cl, Br, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl; R 3 To be independently and optionally occupied by 1, 2, 3 or 4 deuterium, F, Cl, Br, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy-substituted 5-6 membered heteroaromatic rings or 5-6 membered heterocycles.

5. The compound according to any one of claims 1-4, wherein, The compound has a structure as shown in formulas (II), (III), (IV), and (V), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with a structure as shown in formulas (II), (III), (IV), and (V). Among them, R 1 R 4 L, Y 2 Same as the definition in equation (I); R 18 and R 19 Each of the following groups is independently deuterium, F, Cl, Br, hydroxyl, cyano, amino, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 1-4 Alkyl group.

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, C 3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkenyloxy group, C 1-6 Alkylthio, C 1-6 Haloalkylthio groups, Me2P(=O)-; R 4 It is cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 6-10 Aryl, C 1-9 heteroaryl, R 7 -Q-、 R 10 C(=O)-、R 10 C(=S)-、R 10 C(=O)-C 1-6 Alkyl or R 11 S(=O)2-; m can be 0, 1, 2, or 3; Y 2 For CR 6 Or N; R 6 H, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl; R 7 It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-6 Alkyl, C 6-10 Aryl, C 1-9 heteroaryl, R 9 C(=O)-、R 15 C(=O)-alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, R 20 R 21 N-;R 7 The C mentioned in 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl groups are substituted; Q is -CR 13 R 14 -, -S(=O)₂-, -(CR 13 R 14 ) m -, -(CR 13 R 14 ) n -NH- or -(CR 13 R 14 ) n -O-; m is 2 or 3; n is 1, 2, or 3; R 12 For hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl or C 1-6 Alkyl OC (=O)-; R 8 R 9 R 10 R 11 and R 15 Each can be independently composed of hydrogen, deuterium, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatics; R 13 and R 14 Each is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group or C 1-6 Alkyl-OC(=O)-; Or R 13 R 14 Together with the carbon atom it is attached to, they form a double bond, C 3-8 cycloalkyl, R 20 and R 21 Each independently is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl or C 1-9 Heterocyclic groups; R 1 R 4 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 20 and R 21 The groups described herein are independently and optionally composed of 1, 2, 3, or 4 groups selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Substituents of cycloalkyl groups.

7. The compound according to claim 6, wherein, R 1 H, deuterium, hydroxyl, F, Cl, Br, cyano, amino, C 1-4 Alkyl, F-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-8 cycloalkyl, SF5, Me2P(=O)-; preferably, R 1 The following are the possible values: H, deuterium, hydroxyl, F, Cl, Br, CF3, CHF2, OCF3, OCH 3、 Or cyclopropyl.

8. The compound according to claim 6, wherein, Y 2 For CR 6 Or N; R 6 H, deuterium, hydroxyl, F, Cl, Br, C 1-4 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-9 heteroaryl, C 1-9 Heterocyclic group or C 3-8 cycloalkyl; preferably, R 6 It can be H, deuterium, hydroxyl, F, Cl, Br or methyl.

9. The compound according to claim 1 or 5, wherein L is -(CR 16 R 17 ) t -, -O(CR 16 R 17 ) t -, -NH(CR 16 R 17 ) t -, -C(=O)-, -C(=O)(CR 16 R 17 ) t -, -C(=O)O(CR 16 R 17 ) t - or -OC(=O)(CR 16 R 17 ) t -; t can be 0, 1, 2, or 3; R 16 and R 17 Each is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl or C 1-9 Heterocyclic groups; Preferably, R 16 and R 17 Each of the following is independently represented as hydrogen, deuterium, F, Cl, Br, hydroxyl, cyano, amino, C 1-4 Alkyl, F-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl, C 1-9 heteroaryl, C 3-6 cycloalkyl or C 1-9 Heterocyclic group.

10. The compound according to claim 1 or 5, wherein, R 4 It is cyano, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, C 1-9 heteroaryl, R 7 -Q-、 R 10 C(=O)-、R 10 C(=S)-、R 10 C(=O)-C 1-4 Alkyl or R 11 S(=O)2-; Q is -CR 13 R 14 -, -S(=O)₂-, -(CR 13 R 14 ) m -, -(CR 13 R 14 ) n -NH- or -(CR 13 R 14 ) n -O-; m is 2 or 3; n is 1, 2, or 3; R 7 It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-4 Alkyl, C 6-10 Aryl, C 1-9 heteroaryl, R 9 C(=O)-、R 15 C(=O)-C 1-6 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, R 20 R 21 N-;R 7 The C mentioned in 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 1-4 Alkyl groups are substituted; R 12 For hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 cycloalkyl or C 1-4 Alkyl OC (=O)-; R 8 R 9 R 10 R 11 and R 15 Each can be independently composed of hydrogen, deuterium, amino, hydroxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatics; R 13 and R 14 Each is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, C 1-9 Heterocyclic group or C 1-4 Alkyl OC (=O)-; Or R 13 R 14 Together with the carbon atom attached to it, it forms double bonds, cyclopropyl groups, cyclobutyl groups, etc. R 20 and R 21 Each is independently hydrogen, deuterium, and C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

11. The compound according to claim 10, wherein, R 4 It is cyano, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, phenyl, C 1-9 heteroaryl, R 9 C(=O)-、R 10 C(=O)-C 1-4 Alkyl, R 11 S(=O)2-、 R 7 It consists of hydrogen, deuterium, cyano, hydroxyl, and C. 1-4 Alkyl, C 1-9 heteroaryl, R 9 C(=O)-、R 15 C(=O)-C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, R 20 R 21 N-;R 7 The C mentioned in 1-9 The heteroaryl group is optionally surrounded by 1, 2, 3 or 4 halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 1-4 Alkyl groups are substituted; R 12 It is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, or C 1-4 Alkyl OC (=O)-; R 9 and R 15 Each can be independently classified as amino, hydroxyl, or C. 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 cycloalkyl; R 10 For amino, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-8 cycloalkyl; R 11 Amino or C 1-4 alkyl; R 13 and R 14 Each of the following C groups is independently substituted with hydrogen, deuterium, F, Cl, Br, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, or F. 1-4 Alkyl, C 1-4 Hydroxyalkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, C 1-9 Heterocyclic group or C 1-4 Alkyl OC (=O)-; Or R 13 R 14 Together with the carbon atom attached to it, it forms double bonds, cyclopropyl groups, cyclobutyl groups, etc. R 20 and R 21 Each can be independently hydrogen, deuterium, methyl, ethyl, or C. 1-4 Halogenated alkyl groups.

12. The compound according to any one of claims 1-11, wherein, The compound has one of the following structures, or is a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug.

13. A pharmaceutical composition comprising the compound of any one of claims 1-12, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

14. Use of the compound of any one of claims 1-12 or the pharmaceutical composition of claim 13 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.

15. The use according to claim 14, 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.

16. A method of preventing and / or treating a disease associated with or caused, mediated and / or proliferated by an SRPK1 inhibitor, comprising administering to a patient an effective amount of the compound of any one of claims 1-12 or the pharmaceutical composition of claim 13.

17. The method of claim 16, 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.

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