USP inhibitor as well as preparation method and application thereof

Abstract

The invention relates to the field of medicine. The invention provides a USP inhibitor as well as a preparation method and application thereof. The invention specifically provides a compound having an inhibitory effect on USP, and pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, as shown in formula (I), and the definition of each group in the formula is detailed in the specification. In addition, the invention also discloses a pharmaceutical composition containing the compound, and an application of the pharmaceutical composition in treatment of cancers, immune diseases, cardiovascular diseases, neurological diseases and the like, or an application of the pharmaceutical composition in preparation of a kit for prognosis evaluation of cancers, immune diseases, cardiovascular diseases, neurological diseases or patients. # imgabs0 #

Description

[0001] This application claims the priority of Chinese patent application 202311251694.1 with an application date of September 26, 2023 and Chinese patent application 202410171830.4 with an application date of February 6, 2024, and this application cites the full text of the above-mentioned Chinese patent applications. Technical Field

[0002] The present disclosure relates to the field of medicine, and in particular to a compound having USP inhibitory effect, and its use and preparation method. Background Art

[0003] The ubiquitin-proteasome system (USP) is a dynamic protein bidirectional modification and regulation system in cells, which is involved in the degradation and modification of more than 80% of proteins in cells. USP participates in a variety of life activities including cell cycle regulation, cell receptor function, gene transcription, immune response and tumor growth by polyubiquitination of substrate proteins and degradation by proteasomes. This pathway is mediated by an enzymatic conjugation cascade, involving the continuous activation of ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3), completing the ubiquitination modification of substrate proteins (The ubiquitin-proteasome pathway: on protein death and cell life, Ciechanover, EMBO J. 1998 Dec 15; 17(24): 7151-60.), and the degradation or modification of target proteins is completed by the proteasome; on the other hand, the deubiquitinating enzyme family (DUBs) is responsible for hydrolyzing the ester bond, peptide bond or isopeptide bond at the carboxyl terminus of ubiquitin, specifically hydrolyzing ubiquitin molecules from proteins or precursor proteins linked to ubiquitin, playing a role in deubiquitination, reversely regulating protein degradation, and thus affecting the function of proteins.

[0004] At present, about 100 DUBs have been found in the human genome. They play the role of monitors in the regulation of the ubiquitination system and play an important role in regulating various intracellular activities such as cell cycle, DNA repair, immunity and protein homeostasis (Regulation of proteolysis by human deubiquitinating enzymes, Ziad M Eletr, Keith D Wilkinson, Biochim Biophys Acta. 2014 Jan; 1843 (1): 114-28.). Abnormal regulation of DUBs often causes various human diseases such as cardiovascular disease, neurological disorders and tumors (Development of inhibitors in the ubiquitination cascade, Wei Zhang, Sachdev S Sidhu, FEBSL et al. 2014 Jan 21; 588 (2): 356-67.). DUBs are divided into seven major families based on sequence and structural similarities, namely, ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs), ovarian tumordomain proteases (OTUs), Machado-Josephin domain proteases (MJDs), Jab1 / MPN domain associated metalloproteases (JAMMs), Zinc finger with UFM1-specific peptidases (ZUFSPs) and a new type of DUB family containing MIU (MINDY) (Jinhong et al., 2020).

[0005] USPs is the largest and most structurally diverse DUB family to date, containing about 60 members. This family belongs to cysteine ​​proteases and contains two short and conserved sequences, namely the N-terminal Cys-box and the C-terminal His-box composed of catalytic cysteine ​​and histidine residues. The sequence includes a catalytic tripartite residue, namely cysteine, histidine, and aspartic acid / asparagine, which can remove ubiquitin molecules from large proteins. Due to the protease activity of the USP family and its regulatory role in the human body's life processes, USPs have become potential drug targets. For example, prostate cancer (Priolo et al., 2006; Stevenson et al., 2007) and breast cancer (Qu et al., 2015) are related to the overexpression of USP2; USP7 is abnormally expressed in many cancers including prostate cancer, lung cancer, brain cancer, colon cancer, breast cancer, epithelial ovarian cancer, liver cancer and leukemia (Emerging insights into HAUSP (USP7) in physiology cancer and other diseases, Seemana Bhattacharya, Dipankar Chakraborty, Malini Basu, Mrinal KGhosh, Signal Transduct Target Ther. 2018 Jun 29; 3: 17.).

[0006] USP21 is a member of the USP family and is involved in the regulation of many intracellular activities. USP21 deubiquitinates several key pathway oncogenes and genes with carcinogenic effects, including HH / Gli, MEK2, MARK, Stem cell renewal / Nanog / GATA3, WNT, etc. USP21 plays a role in many types of tumors, such as pancreatic cancer, bile duct cancer, liver cancer, breast cancer (triple-negative breast cancer), kidney cancer, bladder cancer, lung cancer, esophageal squamous cell carcinoma (CN116676391A), etc. USP21 is also correlated with the clinical prognosis of tumors. In addition, recent studies have also shown that USP21 plays an important role in the negative regulation of antiviral innate immune responses, mainly through the deubiquitination of retinoic acid (retinoic acid)-induced gene protein I (RIG-I) and interferon-stimulated gene 15 protein (ISG15) (TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity, Michaela U Gack 1, Young C Shin, Chul-Hyun Joo, Tomohiko Urano et al. Nature. 2007Apr 19; 446(7138): 916-920). The latest study found that human pancreatic cancer often has USP21 gene amplification (22% PDAC), and high expression of USP21 is associated with PDAC progression. In a mouse pancreatic cancer model, exogenous high expression of USP21 accelerated tumor growth, while knocking out USP21 inhibited tumor growth. In vitro and in vivo studies have shown that USP21 plays a driving role in cancer. The study further revealed that USP21 plays a role in pancreatic cancer through the WNT pathway.

[0007] Inhibition of USP21 can inhibit cell proliferation and tumor growth. Currently, many research institutions and pharmaceutical companies around the world are studying inhibitors targeting DUBs, but no drugs targeting USP21 have been discovered. There is a significant clinical demand for the development of USP21 inhibitor drugs. Therefore, USP21 is a first-in-class cancer target with great potential and market value. It is of great significance to develop specific inhibitors for USP21 for molecular targeted therapy of related tumors and other diseases such as immunity associated with USP21 abnormalities. Summary of the invention

[0008] The invention provides a substituted condensed-ring aromatic compound with a novel structure, which has high inhibitory activity as a USP enzyme inhibitor.

[0009] In one aspect of the present invention, there is provided a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

[0010]

[0011] In formula (I), R 1 Selected from -R 4 -C(O)-C 2-6 Alkenyl, -C 2-6 Alkenyl, -N=NR a R b , -R 4 -C(O)-C 2-6 Alkynyl, -R 4 -SO 2 -C 2-6 Alkenyl, -R 4 -C(O)-C 1-3 Alkyl, -R 4 -C 2-6 Alkynyl, -R 4 -C(O)-C 3-9 Cycloalkyl, -R 4 -C(O)-3 to 9-membered heterocycloalkyl, -R 4 -C 1-3 Alkyl-C 3-9 Cycloalkyl, -R 4 -C 3-9 Cycloalkyl, -C(O)-NH-C 2-6 Alkynyl, -C(O)-NH-C 2-6 Alkenyl, -C(O)-NH-C 1-3 Alkyl or The C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1, 2 or 3 groups independently selected from hydrogen, halogen, cyano, -CF 3 , C 1-6 alkyl, 3- to 9-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 6-10 Aryl, -C 1-3 Alkyl-NR a R b , -C 1-3 Alkyl-hydroxy, -C(O)OR a 、-C(O)NR a R b 、-NR a R b Substituents are substituted, the C 1-3 Alkyl, C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, C 1-6The alkyl group is optionally substituted by 1, 2 or 3 groups independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF 3 , C 1-6 alkoxy, -O-3 to 9 membered heterocycloalkyl, -O-5 to 10 membered heteroaryl, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO 2 -C 1-3 Alkyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 alkoxy, 5- to 10-membered heteroaryl, 6- to 10-membered aryl, -NHC(O)-C 2-6 Alkenyl, -NHC(O)-C 2-6 Substitution of alkynyl groups by substituents;

[0012] In one embodiment, R 4 Selected from NH, NR a or CR a R b ;

[0013] In one embodiment, R a , R b are each independently selected from hydrogen, C 1-3 Alkyl, C 3-9 Cycloalkyl, the C 1-3 Alkyl, C 3-9 The cycloalkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, hydroxy, carboxyl, -CF 3 , C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO 2 C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Substitution of alkoxy groups;

[0014] In one embodiment, R 5 , R 6 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 9 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6Cycloalkyl, 3 to 9 membered heterocycloalkyl, optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, hydroxy, carboxyl, -CF 3 , C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO 2 -C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Substitution of alkoxy groups;

[0015] In one embodiment, R 2 , R 3 are independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b 、-C(O)-C 1-3 Alkyl, -C(O)NR a R b 、-SO 2 -C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-C 2-6 Alkynyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-NR a R b , -C 2-6 Alkenyl, -C 2-6 Alkynyl, 5- to 10-membered heteroaryl, C 6-10 Aryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl, C 2-6 Alkynyl, C 2-6 alkenyl, 5- to 10-membered heteroaryl, C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF 3 Substituents are substituted;

[0016] In one embodiment, the halogen is selected from fluorine, chlorine or bromine;

[0017] In one embodiment, U 1 , U 2 , U 3 Each independently selected from CR 7 or CH, or adjacent U 2 , U 3 Connected to each other to form a 6- to 10-membered aromatic group;

[0018] In one embodiment, the R 7 Selected from hydrogen, C 1-3 Alkyl, C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, -C 1-3 Alkyl-3 to 9 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-9 Cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF 3 , C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO 2 C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -NHC(O)-C 2-6 Alkenyl, -NHC(O)-C 2-6 Substitution of alkynyl groups by substituents;

[0019] In one embodiment, the heterocycloalkyl or heteroaryl has at least one heteroatom selected from N, O and S as ring atom.

[0020] In some embodiments, the R 1 Selected from -R 4 -C(O)-C(R 8 )=CR 9 R 10 ,-C(R 8 )=CR 9 R 10 ,-C(R 8 )=C(R 9 )-C(O)-NH 2 , -R 4 -C(O)-C(R 8 )=C(R 9 )-C(O)-NH2 , -R 4 -C(O)-C(R 8 )=C(R 9 )-C(O)-OR 10 , -R 4 -C(O)-C(R 8 )=C(R 9 )-CH 2 -NR a R b 、-N=NR a , -R 4 -C(O)-C≡C-CH 3 , -R 4 -C(O)-C≡CH, -R 4 -C(O)-CH 2 -C≡CH, -R 4 -SO 2 -C(R 8 )=CR 9 R 10 , -R 4 -C(O)-R 5 , -R 4 -CH 2 -C≡CH, -C(O)-NH-C 1-3 Alkyl, -R 4 -C(O)-C 1-3 Alkyl-R 4 -C(O)-C(R 8 )=CR 9 R 10 、-C(O)-R 4 -C 1-3 Alkyl-R 4 -C(O)-C(R 8 )=CR 9 R 10 , -R 4 -CH 2 -C 3-9 Cycloalkyl or The C 1-3 Alkyl, C 3-9 The cycloalkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF 3 , C 1-6 Substitution of alkoxy groups;

[0021] In one embodiment, R 4 Select from NH or NR a ;

[0022] In one embodiment, R 5 , R 6 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 9 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 9 membered heterocycloalkyl, optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, hydroxy, carboxyl, -CF 3 , C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO 2 -C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Substitution of alkoxy groups;

[0023] In one embodiment, R 8 , R 9 , R 10 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 9-membered heterocycloalkyl, -C 1-3 Alkyl-C 6-10 Aryl, -C 1-3 Alkyl-5 to 10 membered heteroaryl, -C 1-3 Alkyl-3 to 9 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-6 Alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 9-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF 3 , -C 1-6 Substitution of alkoxy groups;

[0024] In one embodiment, R a , R b are each independently selected from hydrogen, C 1-3 Alkyl, C 3-9 Cycloalkyl, the C 1-3 Alkyl, C 3-9The cycloalkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, hydroxy, carboxyl, -CF 3 , C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO 2 C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Substitution of alkoxy groups;

[0025] In one embodiment, R 2 , R 3 are independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b , the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 groups independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF 3 Substituents are substituted;

[0026] In one embodiment, the halogen is selected from fluorine or chlorine;

[0027] In one embodiment, U 1 , U 2 , U 3 Each independently selected from CR 7 or CH, or adjacent U 2 , U 3 Connected to each other to form a 6- to 10-membered aromatic group;

[0028] In one embodiment, the R 7 Selected from hydrogen, C 1-3 Alkyl, C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, -C 1-3 Alkyl-3 to 9 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-9 Cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -

[0029] NR a R b, hydroxyl, carboxyl, -CF 3 , C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO 2 C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -NHC(O)-C 2-6 Alkenyl, -NHC(O)-C 2-6 Substitution of alkynyl groups by substituents;

[0030] In one embodiment, the heterocycloalkyl or heteroaryl has at least one heteroatom selected from N, O and S as ring atom.

[0031] In some embodiments, R 1 Selected from

[0032]

[0033] In one embodiment, the R 2 , R 3 Each independently selected from H, CF 3 ;

[0034] In one embodiment, the U 1 , U 2 , U 3 All selected from CH, or adjacent U 2 , U 3 They are connected to each other to form a benzene ring;

[0035] In one embodiment, the R 7 Selected from -H, -CH 3 ,

[0036] In some embodiments, formula (I) is represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13), formula (II-14), formula (II-15), formula (II-16) or formula (II-17):

[0037]

[0038]

[0039] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a The definition of is as mentioned above.

[0040] In some embodiments, the compound described by Formula (I), Formula (II-1), Formula (II-2), Formula (II-3), Formula (II-4), Formula (II-5), Formula (II-6), Formula (II-7), Formula (II-8), Formula (II-9), Formula (II-10), Formula (II-11), Formula (II-12), Formula (II-13), Formula (II-14), Formula (II-15), Formula (II-16) or Formula (II-17), its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, is selected from the following group:

[0041]

[0042]

[0043]

[0044] Another aspect of the present invention provides a method for preparing some of the above compounds, their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, comprising the following steps:

[0045]

[0046] Compound (III-1) undergoes an amidation reaction with compound (Y) to generate compound (III-2);

[0047] The compound (Y) includes any one of acyl chloride, carboxylic acid or sulfonyl chloride;

[0048] The R 1 , R 2 , R 3 , R 7 The definition of is as mentioned above.

[0049] Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-mentioned method and at least one pharmaceutically acceptable excipient.

[0050] Another aspect of the present invention provides a use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-mentioned method, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating cardiovascular disease, neurological disorder, cancer or immune disease, or in the preparation of a kit for evaluating cardiovascular disease, neurological disorder, cancer, immune disease or patient prognosis;

[0051] In a preferred embodiment, the pharmaceutical composition further comprises another drug for treating cardiovascular disease, neurological disorder, cancer or immune disease;

[0052] In a preferred embodiment, use in the preparation of a method for treating a disease associated with USP21 activity;

[0053] In a preferred embodiment, the cancer includes prostate cancer, bile duct cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, esophageal squamous cell carcinoma, liver cancer and leukemia;

[0054] In a more preferred embodiment, the cancer includes pancreatic cancer, bile duct cancer, esophageal squamous cell carcinoma, liver cancer, breast cancer, kidney cancer, bladder cancer and lung cancer.

[0055] Another aspect of the present invention provides a use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or the compound prepared by the above-mentioned method, or the above-mentioned pharmaceutical composition in the preparation of USP inhibitors; preferably, use in the preparation of USP21 inhibitors.

[0056] Another aspect of the present invention provides a method for treating a USP mutation or amplification-related disease in a patient in need thereof, comprising administering the above-mentioned compound, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the above-mentioned pharmaceutical composition to the patient;

[0057] The USP mutation or amplification includes USP21 mutation or amplification;

[0058] Preferably, the USP mutation or amplification-related diseases include cardiovascular diseases, neurological disorders, cancer, and immune diseases;

[0059] Preferably, the cancer includes prostate cancer, bile duct cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, esophageal squamous cell carcinoma and leukemia;

[0060] More preferably, the cancer includes pancreatic cancer, bile duct cancer, esophageal squamous cell carcinoma, liver cancer, breast cancer, kidney cancer, bladder cancer and lung cancer.

[0061] In another aspect of the present invention, a method for inhibiting USP mutations in a biological sample for non-disease diagnosis or treatment purposes is provided, which comprises contacting the biological sample with the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-mentioned method, or the above-mentioned pharmaceutical composition. DETAILED DESCRIPTION

[0062] I. Definitions

[0063] According to the above contents of the present disclosure, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present disclosure, other various forms of modifications, replacements or changes may be made.

[0064] definition

[0065] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0066] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.

[0067] The compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0068] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring of said event or circumstance.

[0069] The numerical ranges herein refer to the individual integers in the given range. For example, "C 1-6" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C 1-3 ” means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0070] The term "substituted" means that any one or more hydrogen atoms on a particular atom or group are replaced by a substituent, as long as the valence state of the particular atom or group is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemical achievable.

[0071] When any variable (such as R n ) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-5 R, the group may be optionally substituted with up to 5 R, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0072] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 2,2-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting embodiments of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present disclosure.

[0073] The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 1-3 nitrogen atoms, 3-8 membered heterocyclic groups, optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups or nitrogen-containing spiro heterocyclic groups.

[0074] The heterocycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, substituted amino, hydroxy, carboxyl, -CF 3 , C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO 2 -C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -NHC(O)-C 2-6 Alkenyl, -NHC(O)-C 2-6 Alkynyl.

[0075] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

[0076] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, substituted amino, hydroxy, carboxyl, -CF 3 .

[0077] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12-membered, more preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl.

[0078] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0079] "Alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0080] "Alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, cyano, nitro, phenol, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0081] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0082] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon substituent, the ring atoms are all carbon atoms, preferably a 3-6 membered cycloalkyl, and the heteroaryl may be optionally substituted or unsubstituted.

[0083] The term "adjacent U 2 , U3 "U" refers to 2 , U 3 The carbon atoms of the amines are connected to each other to form a 6- to 10-membered aromatic group, preferably a benzene ring. Non-limiting examples of the compounds formed include wait.

[0084] HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate

[0085] DIEA or DIPEA: N,N-diisopropylethylamine

[0086] Pd 2 (dba) 3 : Trisdibenzylideneacetone dipalladium

[0087] Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene

[0088] Dioxane: 1,4-dioxane

[0089] DMSO: dimethyl sulfoxide

[0090] TCFH:N,N,N',N'-Tetramethylchlorouronium hexafluorophosphate

[0091] NMI: N-methylimidazole

[0092] DBU:1,8-diazabicycloundec-7-ene

[0093] DCM: dichloromethane

[0094] DMF: N,N-dimethylformamide

[0095] Cinnamic Acid:

[0096] TEA: Methacryloyl chloride

[0097] THF: Tetrahydrofuran

[0098] Furan-2,5-dione:

[0099] The hydrogen atoms described in the present disclosure may all be replaced by their isotope deuterium.

[0100] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0101] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0102] Refers to the chemical bond connection.

[0103] Drug or drug composition

[0104] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0105] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without adverse biological effects, such as acid (including organic acids and inorganic acids) addition salts or base addition salts (including organic bases and inorganic bases).

[0106] The pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, via the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid to prepare.

[0107] The medicaments or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally or mucosally (e.g., buccally, by inhalation or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is generally desirable to use the oral route. The active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0108] For oral administration in the form of tablets or capsules, the active drug component can be mixed with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like. For oral administration in liquid form, the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0109] Tablets containing the active compound can be coated by methods well known in the art. The compositions of the present disclosure containing the compound of formula I as the active compound can also introduce beads, microspheres or microcapsules, such as those constructed from polyglycolic acid / lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions or they can be presented as dry products reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to release the active compound in a controlled or delayed manner.

[0110] The medicine or pharmaceutical composition of the present disclosure can be delivered parenterally, that is, administered intravenously (iv), intracerebroventricularly (icv), subcutaneously (sc), intraperitoneally (ip), intramuscularly (im), subcutaneously (sd) or intradermally (id), by direct injection, for example, by bolus injection or continuous infusion. The formulation for injection can be presented in unit dosage form, for example, in an ampoule or multi-dose container with an added preservative. The composition can be in the shape of an excipient, in the form of a suspension, solution or emulsion in an oil or aqueous vehicle, and can include formulation agents such as anti-settling agents, stabilizers and / or dispersants. Alternatively, the active ingredient can be reconstituted with a suitable carrier (e.g., sterile pyrogen-free water) before use in powder form.

[0111] The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as a suppository or retention enema (eg, containing a conventional suppository base such as cocoa butter or other glycerides).

[0112] The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

[0113] The terms "reduce," "inhibit," "mitigate," or "reduce" are used relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.

[0114] The term "excipient" is used herein to include any other compound that may be contained in or on the microparticles that is not a therapeutic or biologically active compound. Thus, an excipient should be pharmaceutically or biologically acceptable or relevant, e.g., an excipient is generally non-toxic to a subject. An "excipient" includes a single such compound, and is also intended to include a plurality of compounds.

[0115] The term "pharmaceutical composition" means a composition comprising the compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0116] Uses and treatments

[0117] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cell thereof amenable to the methods described herein, whether in vitro or in situ. In some non-limiting embodiments, the patient, subject, or individual is a human.

[0118] The term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof. Inhibition of enzymes in biological samples can be used to achieve a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioanalysis, gene expression studies, and identification of biological targets.

[0119] As used herein, the term "USP21-mediated" disorder, disease and / or condition as used herein means any disease or other deleterious condition in which USP21 or a mutant thereof is known to play a role. Therefore, another embodiment of the present disclosure is directed to treating or lessening the severity of one or more diseases in which USP21 or a mutant thereof is known to play a role.

[0120] The cancer treated by the compounds or compositions of the present disclosure is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma or colon cancer. In certain embodiments, the cancer is primary effusion lymphoma (PEL).

[0121] The compounds of the present disclosure can be used to treat a proliferative disease selected from the group consisting of a benign or malignant tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid; a sarcoma, a glioblastoma, a neuroblastoma, multiple myeloma or a gastrointestinal cancer (particularly a colon cancer or a colorectal adenoma) or a tumor of the neck and head, epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin's and non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, an undifferentiated tumor, papillary carcinoma, a seminoma, melanoma, a MYD88 driven disorder, DLBCL, ABC DLBCL, IL-1 driven disorders, rheumatic or indolent multiple myeloma or leukemia.

[0122] Cancers described in the present disclosure include, but are not limited to, leukemias (e.g., acute leukemias, acute lymphocytic leukemias, acute myeloid leukemias, acute myeloblastic leukemias, acute promyelocytic leukemias, acute myelomonocytic leukemias, acute monocytic leukemias, acute erythroleukemias, chronic leukemias, chronic myelocytic leukemias, chronic lymphocytic leukemias), polycythemia vera, lymphomas (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcomas, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphoendotheliosarcoma, synovioma, mesothelioma, Ewing's tumors, the ovarian, ovarian, prostate, squamous cell, basal cell, adenocarcinoma, sweat gland, sebaceous gland, papillary, papillary adenocarcinoma, cystadenocarcinoma, medullary, bronchogenic, renal cell, hepatoma, bile duct, choriocarcinoma, seminoma, embryonal, Wilms' tumor, cervical, uterine, testicular, lung, small cell lung cancer, bladder, epithelial, glioma, astrocytoma, glioblastoma multiforme (GBM), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0123] Combination therapy approach

[0124] The present disclosure provides a combination therapy using compounds as described in the present disclosure and other therapeutic drugs. The term "combination therapy" used in the present disclosure includes the administration of these agents in a sequential manner, i.e., each therapeutic agent is administered at different times, and the administration of these therapeutic agents, or at least two agents, is substantially performed simultaneously. The order of each agent, or substantially simultaneous administration, can be affected by any appropriate route, including but not limited to, oral routes, intravenous routes, intramuscular routes, subcutaneous routes, and direct absorption by mucosal tissue. The agents can be administered by the same route or different routes. For example, the first agent can be administered orally, and the second agent can be administered intravenously. In addition, the selected combination can be administered by intravenous injection, and the other agents of the combination can be administered orally. Alternatively, for example, two or more agents can be administered by intravenous or subcutaneous injection.

[0125] II. Embodiment

[0126] The present disclosure is further explained below with reference to the embodiments. The description of the specific exemplary embodiments of the present disclosure is for the purpose of illustration and example. These descriptions are not intended to limit the present disclosure to the precise form disclosed, and it is clear that many changes and variations can be made according to the teachings of the present application specification. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present disclosure and its practical application, so that those skilled in the art can realize and utilize the various exemplary embodiments of the present disclosure and various selections and changes.

[0127] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods.

[0128] Unless otherwise specified, the materials, reagents, etc. used in the following embodiments can be obtained from commercial sources.

[0129] Instruments and reagents: NMR: Agilent 400MR DD2 NMR spectrometer, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), with tetramethylsilane (TMS) as the internal standard. LC-MS: Agilent 1260 Infinity II–InfinityLab LC / MSD mass spectrometer. HPLC: Agilent 1260 Infinity II high pressure liquid chromatograph (Sunfire C18 5 μm 150 x 4.6 mm column).

[0130] Thin layer chromatography silica gel plate: HSGF254 silica gel plate (Yantai Jiangyou Silica Gel Development Co., Ltd.), specification 0.9mm-1mm. TLC silica gel plate: GF254 silica gel plate (Yucheng Chemical (Shanghai) Co., Ltd.), specification 0.2mm~0.25mm. Column chromatography: carrier 300-400 mesh silica gel (Qingdao Hailang Silica Gel Desiccant Co., Ltd.), Flash column (Aiger Fino Claricep Flash amorphous silica gel purification column). Reagents: cis-3-chloroacrylic acid (Bidec Pharmaceuticals), trans-3-chloroacrylic acid (Thermo Fisher Scientific), 2-chloroacrylic acid, vinylsulfonyl chloride (Shanghai Adamas Reagent Co., Ltd.), 5-bromo-2-trifluoromethylpyrimidine, tetrahydrofuran, triisopropyl borate, n-butyl lithium, 2-bromo-1,3-dimethyl-5-nitrobenzene, carbon tetrachloride, N-bromosuccinimide, benzoyl peroxide, acetonitrile, 1,2-dichloroethane, N-bromosuccinimide, benzoyl peroxide, 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride, acryloyl chloride, N,N-dimethylformamide, acrylonitrile, 1,4-dioxane, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, tridibenzylideneacetone dipalladium, dimethyl sulfoxide, sodium sulfite, but-2-ynoic acid, N-methylimidazole, N,N,N',N'-tetramethylchlorourea hexafluorophosphate, ethylenesulfonyl chloride, dichloromethane, 1,8-diazabicycloundec-7-ene, ethyl acetate, cinnamic acid, N,N-dimethylformamide, (Z)-4-amino-4-oxobut-2-enoic acid, methacryloyl chloride, lithium hydroxide, furan-2,5-dihydrofuran ketone, concentrated sulfuric acid, 2-phenylacrylic acid, 7-amino-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-9-one, NN-diisopropylethylamine, 2-(trifluoromethyl)acrylic acid, 2-chloroethanesulfonyl chloride, (E)-4-(dimethylamino)but-2-enoic acid hydrochloride, trifluoroacetic acid, 2-(hydroxymethyl)acrylic acid, pyridine, phosphorus oxychloride, propiolic acid, dichloromethane, triethylamine, 2-chloroacetyl chloride, 2-benzylacrylic acid, 1-methylimidazole, 3-bromoprop-1-yne, (E)-4-ethoxy-4-oxobut-2-enoic acid, hydroxy Lithium chloride monohydrate, (Z)-3-cyanoacrylic acid, isobutyl chloroformate, 2-fluoropropionic acid, 2-chloro-2,2-difluoroacetic acid, iodomethane, 2-fluoroacrylic acid, 1-fluorocyclopropane-1-carboxylic acid, reduced iron powder, oxalyl chloride, triethylamine, 1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-carboxylic acid, 2-fluoro-2-methylpropionic acid, 1-methylpiperazine, stannous chloride, N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate, morpholine, anhydrous magnesium sulfate, tert-butyl piperazine-1-carboxylate, or synthesized using a method known in the art.

[0131] Unless otherwise specified, all reactions disclosed herein are carried out under continuous magnetic stirring, in dry nitrogen or argon, with dry solvents and reaction temperatures in degrees Celsius.

[0132] Intermediate I-1: Synthesis of 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1)

[0133]

[0134] Dissolve 5-bromo-2-trifluoromethylpyrimidine (5g, 22.03mmol) in tetrahydrofuran (50ml), add triisopropyl borate (7.62ml, 33.04mmol), replace with nitrogen, place in -85℃ cold hydrazine to cool down, after the temperature drops to -78℃, slowly add n-butyl lithium (11.5ml, 28.64mmol, 2.5M) at -70℃, and react at this temperature for another 1 hour. Add saturated ammonium chloride to quench below 0℃, adjust the pH to weak acidity with 1N hydrochloric acid, add ethyl acetate to extract, wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product crude 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 4.92g), which is directly used in subsequent reactions. ESI[MH] + =191.1

[0135] Intermediate I-2: Synthesis of 5-(bromomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2)

[0136]

[0137] Step 1: Synthesis of 2-bromo-1-(bromomethyl)-3-methyl-5-nitrobenzene (I-2-a)

[0138] 2-Bromo-1,3-dimethyl-5-nitrobenzene (2g, 8.7mmol) was dissolved in carbon tetrachloride (70mL), N-bromosuccinimide (1549mg, 8.7mmol) and benzoyl peroxide (105mg, 0.44mmol) were added to replace nitrogen, and the reaction was carried out overnight at 80°C. After the reaction was completed, the reaction solution was cooled to room temperature, and the crude product was directly used in the next step after the reaction solution was concentrated under reduced pressure to obtain the target product 2-bromo-1-(bromomethyl)-3-methyl-5-nitrobenzene (I-2-a, 2.7g, crude product).

[0139] Step 2: Synthesis of 2-bromo-3-methyl-5-nitrobenzaldehyde (I-2-b)

[0140] 2-Bromo-1-(bromomethyl)-3-methyl-5-nitrobenzene (I-2-a, 2.7 g, 8.7 mmol) was dissolved in acetonitrile and stirred at 0°C for 10 minutes, and N-methylmorpholine oxide (3 g, 8.7 mmol) was added in batches and stirred at 0°C for 10 minutes, and then reacted at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by Flash column (petroleum ether: ethyl acetate = 0-15%) to obtain the target product 2-bromo-3-methyl-5-nitrobenzaldehyde (I-2-b, 890 mg, yield 42.3%).

[0141] Step 3: Synthesis of 3-methyl-5-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (I-2-c)

[0142] 2-Bromo-3-methyl-5-nitrobenzaldehyde (I-2-b, 890 mg, 3.66 mmol) was dissolved in acetonitrile (20 mL), (2-(trifluoromethyl)pyrimidin-5-yl)boric acid (1 g, 5.86 mmol), potassium phosphate (2.3 g, 10.98 mmol) and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (134 mg, 0.18 mmol) were added, nitrogen was purged for 1 minute, and microwave reaction was carried out at 120 ° C for 1 hour. After the reaction, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by Flash column (petroleum ether: ethyl acetate = 0-20%) to obtain the target product 3-methyl-5-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (I-2-c, 770 mg, yield 67.6%). ESI[M+H] + =312.2

[0143] Step 4: Synthesis of 5-methyl-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2-d)

[0144] 3-Methyl-5-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (I-2-c, 770 mg, 2.47 mmol) was dissolved in 1,2-dichloroethane (20 mL), and tetrabutylammonium iodide (46 mg, 0.12 mmol) and 2-hydroperoxide-2-methylpropane (aqueous solution) (1426 μL, 14.89 mmol) were added, and nitrogen was replaced three times, and the mixture was sealed and reacted at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by Flash column (petroleum ether: ethyl acetate = 0-35%) to obtain the target product 5-methyl-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2-d, 250 mg, yield 32.7%). ESI[M+H] + =310.2

[0145] Step 5: Synthesis of 5-(bromomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2)

[0146] 5-Methyl-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2-d, 250 mg, 0.8 mmol) was dissolved in carbon tetrachloride (10 mL), N-bromosuccinimide (288 mg, 1.62 mmol) and benzoyl peroxide (195 mg, 0.81 mmol) were added, nitrogen was replaced, and the reaction was carried out at 100°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by Flash column (petroleum ether: ethyl acetate = 0-35%) to obtain the target product 5-(bromomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2, 160 mg, yield 51.1%)

[0147] Example 1: Synthesis of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (1)

[0148]

[0149] 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.0754 mmol.) was dissolved in acetonitrile and water (1 ml / 0.2 ml), and acryloyl chloride (5 mg, 0.0905 mmol.) and potassium carbonate (20 mg, 0.226 mmol.) were added at 0°C, and the reaction was continued at 0°C for 1 hour. After the reaction solution was filtered and concentrated under reduced pressure, the crude product was purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1) to obtain the target product N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (1, 9 mg, yield 37.38%). ESI[M+H] + =320.00 1 H NMR (400 MHz, DMSO-d 6 )δ10.61(s,1H),9.46(s,1H),8.20(s,1H),8.05–7.89(m,2H),6.45–6.31(m,2H),5.89–5.82(m,1H).

[0150] Example 2: Synthesis of 2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (2)

[0151]

[0152] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (28 mg, 0.106 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (14 mg, 0.106 mmol), N,N-diisopropylethylamine (15 mg, 0.318 mmol), and 2-fluoroacrylic acid (14.5 mg, 0.127 mmol) were added to the reaction solution in sequence and the reaction was allowed to react overnight at room temperature. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a preparative plate to obtain the target product 2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (2, 0.32 mg, yield 0.9%). ESI [M+H] + =338.10

[0153] Example 3: Synthesis of (E)-3-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylonitrile (3)

[0154]

[0155] 7-Bromo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (50 mg, 0.15 mmol) and acrylonitrile (16.1 mg, 0.30 mmol) were dissolved in 1,4-dioxane (3 ml), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg, 0.03 mmol), trisdibenzylideneacetone dipalladium (13.7 mg, 0.015 mmol) and potassium carbonate (63 mg, 0.46 mmol) were added and reacted in a microwave at 120°C for 0.5 hour. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product (E)-3-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylonitrile (3, 18.2 mg, yield 40.4%). ESI [M+H] + =302.2, 1 H NMR (400 MHz, DMSO-d 6 )δ9.61(s,1H),8.23–8.10(m,2H),8.05(d,J=7.8Hz,1H),7.78(d,J=16.7Hz,1H),6.74(d,J=16.7Hz,1H).

[0156] Example 4: Synthesis of (E)-3-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (4)

[0157]

[0158] (E)-3-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylonitrile (3, 17 mg, 0.05 mmol), potassium carbonate (2 mg, 0.02 mmol) were added to ethanol (3 ml) and dimethyl sulfoxide (0.2 ml) and then added to 35% hydrogen peroxide (12 mg, 0.3 mmol). The reaction was allowed to react at room temperature for 2 hours. The mixture was quenched with saturated sodium sulfite solution, monitored with starch potassium iodide test paper, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid phase to obtain the target product (E)-3-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (4, 0.8 mg, yield 4.2%). ESI[M+H] + =320.3, 1 H NMR (400 MHz, DMSO-d 6 )δ9.59(s,1H),8.46(s,1H),8.10(d,J=8.1Hz,1H),7.99(s,1H),7.53(d,J=16.0Hz,1H),7.22(s,1H),6.82(d,J=15.9Hz,1H).

[0159] Example 5: Synthesis of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)but-2-ynamide (5)

[0160]

[0161] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (10 mg, 0.038 mmol) and but-2-ynoic acid (6.4 mg, 0.075 mmol) were dissolved in N,N-dimethylformamide (1 ml), and N-methylimidazole (12 μl, 0.15 mmol) and N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (21 mg, 0.075 mmol) were added. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, sodium bicarbonate was added for dilution, and the mixture was extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase (Pack Column 20 ID*250 mm*10 μm; A:H 2O (0.1% FA), B: ACN, B%: 10%-90% over 22 min) to obtain the target product N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)but-2-ynamide (5, 0.53 mg, yield 4%). ESI [M+H] + =332.20 1 H NMR (400 MHz, DMSO-d 6 )δ11.10(s,1H),9.45(d,J=3.1Hz,1H),8.05(s,1H),7.98(d,J=8.1Hz,1H),7.89(d,J=8.4Hz,1H),2.08(s,3H).

[0162] Example 6: Synthesis of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)ethylenesulfonamide (6)

[0163]

[0164] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.076 mmol) and ethylenesulfonyl chloride (12.5 mg, 0.098 mmol) were dissolved in dichloromethane (2 ml) and 1,8-diazabicycloundec-7-ene (34 mg, 0.22 mmol) was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, sodium bicarbonate was added for dilution, and the mixture was extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase (Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-90% over 22 min) to obtain the target product N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)ethylenesulfonamide (6, 1.21 mg, yield 4.2%). ESI [M+H] + =356.20 1 H NMR (400 MHz, DMSO-d 6 )δ9.47(s,1H),8.05(d,J=8.1Hz,1H),7.28(d,J=8.0Hz,1H),7.25(s,1H),4.58(t,J=6.8Hz,2H),3.88(t,J=6.7Hz,2H).

[0165] Example 7: Synthesis of (E)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cinnamamide (7)

[0166]

[0167] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) and cinnamic acid (6.4 mg, 0.075 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N-methylimidazole (24 μl, 0.3 mmol) and N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (42 mg, 0.15 mmol) were added. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, sodium bicarbonate was added for dilution, and the mixture was extracted with ethyl acetate. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase (Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-90% over 22 min) to obtain the target product (E)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cinnamamide (7, 4.8 mg, yield 16.1%). ESI [M+H] + =396.20 1 H NMR (400 MHz, DMSO-d 6 )δ10.69(s,1H),9.45(s,1H),8.24(s,1H),8.05–7.89(m,2H),7.65(d,J=7.9Hz,3H),7.51–7.34(m,3H),6.82(d,J=15.7Hz,1H).

[0168] Example 8: Synthesis of (Z)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid ethyl ester (8)

[0169]

[0170] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (50 mg, 0.19 mmol) and (Z)-4-ethoxy-4-oxobut-2-enoic acid (55 mg, 0.38 mmol) were dissolved in N,N-dimethylformamide (4 ml), and N-methylimidazole (62 mg, 0.76 mmol) and N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (107 mg, 0.38 mmol) were added. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, sodium bicarbonate was added for dilution, and the mixture was extracted with ethyl acetate. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase (Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-90% over 22 min) to obtain the target product (Z)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid ethyl ester (8, 42 mg, yield 57.3%). ESI [M+H] + =392.10 1 H NMR (400 MHz, DMSO-d 6 )δ10.99(s,1H),9.48(s,1H),8.18(d,J=2.0Hz,1H),8.02(d,J=8.2Hz,1H),7.93(d,J=2.0Hz,1H ),7.20(d,J=15.5Hz,1H),6.76(d,J=15.4Hz,1H),4.23(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).

[0171] Example 9: N 1 Synthesis of -(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)maleamide (9)

[0172]

[0173] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) and (Z)-4-amino-4-oxobut-2-enoic acid (10 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N-methylimidazole (25 mg, 0.3 mmol) and N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (42 mg, 0.15 mmol) were added. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, sodium bicarbonate was added for dilution, and the mixture was extracted with ethyl acetate. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase (Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-90% over 22min) to obtain the target product N 1 -(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)maleamide (9, 0.68 mg, yield 2.5%). ESI [M+H] + =363.10 1 HNMR (400 MHz, DMSO-d 6 )δ11.04(s,1H),9.49(s,1H),8.18(d,J=2.0Hz,1H),8.04(d,J=8.1Hz,1H), 7.91(dd,J=8.2,2.1Hz,1H),7.16(d,J=16.1Hz,1H),6.75(d,J=16.1Hz,1H).

[0174] Example 10: Synthesis of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)methacrylamide (10)

[0175]

[0176] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) was dissolved in dichloromethane (2 ml) and methacryloyl chloride (10 mg, 0.09 mmol) was added at 0°C and reacted at room temperature for 2 hours. After the reaction was completed, sodium bicarbonate was added for dilution, and dichloromethane was used for extraction. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase (Pack Column 20ID*250mm*10μm; A:H 2O (0.1% FA), B: ACN, B%: 10%-90% over 22 min) to obtain the target product N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)methacrylamide (10, 7.2 mg, yield 28.8%). ESI [M+H] + =334.10 1 H NMR (400 MHz, DMSO-d 6 )δ10.23(s,1H),9.45(s,1H),8.18(s,1H),8.03(d,J=8.2Hz,1H),7.97(d,J=8.2Hz,1H),5.89(s,1H),5.61(s,1H),1.97(s,3H).

[0177] Example 11: Synthesis of 2-chloro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (11)

[0178]

[0179] 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) and 2-chloroacrylic acid (16 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N-methylimidazole (25 mg, 0.3 mmol) and N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (42 mg, 0.15 mmol) were added. After the reaction was completed, sodium bicarbonate was added for dilution, and ethyl acetate was used for extraction. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase (Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA, B: ACN, B%: 10%-90% over 22 min) to obtain the target product 2-chloro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (11, 7.2 mg, yield 2.1%). ESI [M+H] + =354.00,355.90 1 H NMR (400 MHz, DMSO-d 6 )δ10.66(s,1H),9.48(s,1H),8.46(s,1H),8.15(s,1H),8.03(s,1H),6.51(d,J=2.0Hz,1H),6.18(d,J=2.1Hz,1H).

[0180] Example 12: Synthesis of (Z)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid (12)

[0181]

[0182] (Z)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid ethyl ester (8, 33 mg, 0.084 mmol) was dissolved in tetrahydrofuran (2 ml) at 0°C, and lithium hydroxide (5.4 mg, 0.127 mmol) was dissolved in water (0.5 ml) and slowly added dropwise into the reaction system for 0.5 hours. After the reaction was completed, the pH was adjusted to 6, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase (Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA, B: ACN, B%: 10%-90% over 22 min) to obtain the target product (Z)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid (12, 1.00 mg, yield 3.3%). ESI [M+H] + =364.00 1 HNMR (400 MHz, DMSO-d 6 )δ10.94(s,1H),9.47(s,1H),8.18(s,1H),8.01(d,J=8.2Hz,1H),7.93(d,J=8.1Hz,1H),7.11(d,J=15.4Hz,1H),6.72(d,J=15.4Hz,1H).

[0183] Example 13: Synthesis of 1-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)-1H-pyrrole-2,5-dione (13)

[0184]

[0185] Dissolve 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (32 mg, 0.121 mmol) in acetic acid (1 ml), add furan-2,5-dione (13 mg, 0.133 mmol), react at 60°C for 6 minutes, add two drops of concentrated sulfuric acid, react at 60°C for 5 minutes, and purify by thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target product 1-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)-1H-pyrrole-2,5-dione (13, 1.93 mg, yield 4.63%). ESI[M+H] + =346.2 1 H NMR (600 MHz, DMSO-d 6 )δ9.60(s,1H),8.18(d,J=8.0Hz,1H),7.82(s,1H),7.78(d,J=8.0Hz,1H),7.26(s,2H).

[0186] Example 14: Synthesis of (E)-3-chloro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (14)

[0187]

[0188] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.0755 mmol) was dissolved in N,N-dimethylformamide (1 ml), and (E)-3-chloroacrylic acid (16.1 mg, 0.151 mmol), N-methylimidazole (24.8 mg, 0.302 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (42.4 mg, 0.151 mmol) were added. The mixture was reacted overnight at room temperature. After filtration, the filtrate was purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target product (E)-3-chloro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (14, 1.47 mg, yield 7.74%). ESI[M+H] + =354.2,356.2 1 H NMR (600 MHz, DMSO-d 6 )δ10.68(s,1H),9.47(s,1H),8.15(s,1H),8.00(d,J=8.2Hz,1H),7.87(d,J=8.2Hz,1H),7.52(d,J=13.2Hz,1H),6.64(d,J=13.2Hz,1H).

[0189] Example 15: Synthesis of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)-2-phenylacrylamide (15)

[0190]

[0191] 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.0755 mmol) was dissolved in N,N-dimethylformamide (1 ml), 2-phenylacrylic acid (22.4 mg, 0.151 mmol), N-methylimidazole (24.8 mg, 0.302 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (42.4 mg, 0.151 mmol) were added, and the mixture was reacted at room temperature for 4 hours. After filtration, the filtrate was purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target product N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)-2-phenylacrylamide (15, 1.54 mg, yield 5.16%). ESI[M+H] + =396.2 1 H NMR (600 MHz, DMSO-d 6 )δ10.72(s,1H),9.47(s,1H),8.22(s,1H),8.02(dd,J=22.5,8.2Hz,2H),7. 52(d,J=8.0Hz,2H),7.39(dt,J=14.0,7.2Hz,3H),6.03(s,1H),5.84(s,1H).

[0192] Example 16: Synthesis of (Z)-3-chloro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (16)

[0193]

[0194] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.0755 mmol) was dissolved in N,N-dimethylformamide (1 ml), and (Z)-3-chloroacrylic acid (16.1 mg, 0.151 mmol), N-methylimidazole (24.8 mg, 0.302 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (42.4 mg, 0.151 mmol) were added. The mixture was reacted overnight at room temperature, and the filtrate was filtered and purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target product (Z)-3-chloro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (16, 1.44 mg, yield 5.4%). ESI[M+H] + =354.2,356.2 1 H NMR (600 MHz, DMSO-d 6 )δ10.68(s,1H),9.46(s,1H),8.14(s,1H),8.00(d,J=8.2Hz,1H),7.92(d,J=1.5Hz,1H),7.01(d,J=8.0Hz,1H),6.58(d,J=8.0Hz,1H).

[0195] Example 17: Synthesis of (E)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)-3-(pyridin-4-yl)acrylamide (17)

[0196]

[0197] (E)-3-(4-pyridyl)acrylic acid (11.3 mg, 0.076 mmol) was dissolved in N,N-dimethylformamide (2 ml), and then N-methylimidazole (12.4 mg, 0.151 mmol), 7-amino-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-9-one (10 mg, 0.038 mmol) were added to the reaction solution in sequence, and finally N,N,N',N'-tetramethyluronium chloride hexafluorophosphate (21 mg, 0.075 mmol) was added and the mixture was reacted at room temperature overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (E)-N-(9-oxo-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-7-yl)-3-(4-pyridyl)acrylamide (17, 1.09 mg, yield 7.3%) ESI [M+H] + =397.1 1H NMR (600 MHz, DMSO-d 6 )δ10.87(s,1H),9.47(s,1H),8.66(d,J=4.9Hz,2H),8.25(s,1H),8.02(d,J= 8.2Hz,1H),7.95(d,J=8.2Hz,1H),7.64–7.59(m,2H),7.04(d,J=15.8Hz,2H).

[0198] Example 18: Synthesis of (E)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)-3-(3-pyridyl)acrylamide (18)

[0199]

[0200] (E)-3-(3-pyridyl)acrylic acid (11.3 mg, 0.076 mmol) was dissolved in N,N-dimethylformamide (2 ml), and then N-methylimidazole (12.4 mg, 0.151 mmol), 7-amino-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-9-one (10 mg, 0.038 mmol) were added to the reaction solution in sequence, and finally N,N,N',N'-tetramethyluronium chloride hexafluorophosphate (21 mg, 0.075 mmol) was added and the mixture was reacted at room temperature overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (E)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)-3-(3-pyridyl)acrylamide (18, 2.78 mg, yield 19.3%) ESI [M+H] + =397.1 1 H NMR (600 MHz, DMSO-d 6 )δ10.79(s,1H),9.47(s,1H),8.86(s,1H),8.60(d,J=4.5Hz,1H),8.25(s,1H),8.13–7. 84(m,3H),7.70(d,J=15.8Hz,1H),7.50(dd,J=7.7,4.9Hz,1H),6.93(d,J=15.8Hz,1H).

[0201] Example 19: Synthesis of (E)-N-9-oxo-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-7-yl)-3-(2-pyridyl)acrylamide (19)

[0202]

[0203] (E)-3-(2-pyridyl)acrylic acid (11.3 mg, 0.079 mmol) was dissolved in N,N-dimethylformamide (2 ml), and then O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (28.7 mg, 0.075 mmol), NN-diisopropylethylamine (19.6 mg, 0.15 mmol) were added to the reaction solution in sequence, and finally 7-amino-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-9-one (10 mg, 0.038 mmol) was added and the reaction was allowed to react overnight at room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (E)-N-(9-oxo-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-7-yl)-3-(2-pyridyl)acrylamide (19, 1.04 mg, yield 6.98%). ESI [M+H] + =397.1 1 H NMR (600 MHz, DMSO-d 6 )δ10.86(s,1H),9.47(s,1H),8.66(d,J=4.4Hz,1H),8.25(s,1H),8.01(d,J=8.2Hz,1H),7.97(d,J=8.2 Hz,1H),7.89(t,J=7.6Hz,1H),7.73–7.61(m,2H),7.42(dd,J=7.3,4.8Hz,1H),7.35(d,J=15.3Hz,1H).

[0204] Example 20: Synthesis of N-(9-oxo-2-trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)-2-(trifluoromethyl)acrylamide (20)

[0205]

[0206] 7-Amino-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-9-one (10 mg, 0.038 mmol) and 2-(trifluoromethyl)acrylic acid (7.9 mg, 0.056 mmol) were dissolved in N,N-dimethylformamide (2 ml). Then pyridine (8.9 mg, 0.11 mmol) and phosphorus oxychloride (8.7 mg, 0.056 mmol) were slowly added dropwise to the reaction solution and the reaction was carried out at room temperature for 5 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative plate (petroleum ether: ethyl acetate = 2:1) to obtain the target product N-(9-oxo-2-trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)-2-(trifluoromethyl)acrylamide (20, 1.49 mg, yield 10.02%) ESI [M+H] + =388.1 1 H NMR (600 MHz, DMSO-d 6 )δ10.86(s,1H),9.49(s,1H),8.11(d,J=1.8Hz,1H),8.03(d,J=8.2Hz,1H),7.99(dd,J=8.2,1.9Hz,1H),6.67(s,1H),6.61(s,1H).

[0207] Example 21: Synthesis of (E)-N,N-dimethyl-N'-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)carboxamide (21)

[0208]

[0209] 7-Amino-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-9-one (10 mg, 0.0377 mmol) was dissolved in N,N-dimethylformamide (2 ml), 2-chloroethanesulfonyl chloride (5 μl, 0.0453 mmol) and potassium carbonate (16 mg, 0.116 mmol) were added, and the mixture was reacted at room temperature for 1 hour. Saturated ammonium chloride solution was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the target product (E)-N,N-dimethyl-N'-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)formamide (21, 2.32 mg, yield 19.2%). ESI[M+H] + =321.0 1 H NMR (600 MHz, DMSO-d 6)δ9.18(s,1H),7.96(s,1H),7.67(d,J=7.8Hz,1H),7.20(d,J=49.9Hz,2H),2.88(d,J=65.6Hz,3H),2.32(s,3H).

[0210] Example 22: Synthesis of (E)-4-(dimethylamino)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)but-2-enamide (22)

[0211]

[0212] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.75 mmol) and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (25 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N-methylimidazole (24 μL, 0.3 mmol) and N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (42 mg, 0.15 mmol) were added. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, sodium bicarbonate was added for dilution, and the mixture was extracted with ethyl acetate. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase (Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA, B: ACN, B%: 10%-90% over 22 min) to obtain the target product (E)-4-(dimethylamino)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)but-2-enamide (22, 2.82 mg, yield 7.14%). ESI [M+H] + =376.90 1 H NMR (400 MHz, DMSO-d 6 )δ10.82(s,1H),9.46(s,1H),8.21(d,J=2.0Hz,1H),8.00(d,J=8.1Hz,1H),7.91(dd,J=8.2,2.1H z,1H),6.81(dt,J=14.8,7.0Hz,1H),6.47(d,J=15.3Hz,1H),3.92(d,J=7.0Hz,2H),2.78(s,6H).

[0213] Example 23: Synthesis of 2,2,2-trifluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (23)

[0214]

[0215] 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) and trifluoroacetic acid (11 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N-methylimidazole (25 mg, 0.3 mmol) and N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (42 mg, 0.15 mmol) were added and reacted overnight. After the reaction was completed, sodium bicarbonate was added for dilution, and ethyl acetate was used for extraction. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product 2,2,2-trifluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (23, 2.54 mg, yield 9.4%). ESI [M+H] + =362.10 1 H NMR (400 MHz, DMSO-d 6 )δ9.52(s,1H),8.12–8.05(m,2H),8.00(dd,J=8.2,2.0Hz,1H).

[0216] Example 24: Synthesis of 2-(hydroxymethyl)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (24)

[0217]

[0218] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) and 2-(hydroxymethyl)acrylic acid (15.3 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 ml), and pyridine (19 μl, 0.225 mmol) was added. Phosphorus oxychloride (14 μl, 0.15 mmol) was added at 0°C. After the reaction was completed at room temperature, the reaction solution was added dropwise to a sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product 2-(hydroxymethyl)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (24, 0.89 mg, yield 3.4%). ESI [M+H] + =350.30 1 H NMR (400 MHz, DMSO-d 6 )δ10.33(s,1H),9.45(s,1H),8.19(s,1H),8.05–7.94(m,1H),5.96(s,1H),5.75(s,1H),5.18(s,1H),4.24(s,2H).

[0219] Example 25: Synthesis of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propynamide (25)

[0220]

[0221] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) and propiolic acid (10 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 ml), and pyridine (19 μl, 0.225 mmol) was added. Phosphorus oxychloride (14 μl, 0.15 mmol) was added at 0°C. After the reaction was completed at room temperature, the reaction solution was added dropwise to a sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propyneamide (25, 1.78 mg, yield 7.4%). ESI [M+H] + =318.20 1 H NMR (400 MHz, DMSO-d 6 )δ11.28(s,1H),9.47(s,1H),8.05(d,J=1.6Hz,1H),8.00(d,J=8.2Hz,1H),7.90(dd,J=8.2,1.8Hz,1H),4.56(s,1H).

[0222] Example 26: Synthesis of 2-chloro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (26)

[0223]

[0224] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.0755 mmol) was dissolved in dichloromethane (2 ml), triethylamine (16 μl, 0.113 mmol) was added, and 2-chloroacetyl chloride (12 μl, 0.151 mmol) was slowly added under ice bath. The reaction was allowed to react at room temperature for one hour. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with dichloromethane, and the organic phase was collected and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the target product 2-chloro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (26, 5.21 mg, yield 20.3%) was obtained. ESI[M+H] + =342.3 1 H NMR (400 MHz, DMSO-d 6 )δ10.85(s,1H),9.47(s,1H),8.10(dd,J=5.7,1.7Hz,1H),8.00(dd,J=8.1,2.9Hz,1H),7.87(dd,J=8.2,1.6Hz,1H),4.34(s,2H).

[0225] Example 27: Synthesis of 2-benzyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (27)

[0226]

[0227] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.0755 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2-benzyl acrylic acid (24.5 mg, 0.151 mmol), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (42 mg, 0.151 mmol) and 1-methylimidazole (25 μl, 0.3 mmol) were added. The reaction was allowed to react overnight at room temperature. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, and the liquid phase was prepared after concentration under reduced pressure [Pack Column 20ID*250mm*10μm; A:H 2O (0.1% FA), B: ACN, B%: 10%-95% over 40 min] was purified twice to obtain the target product 2-benzyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (27, 1.54 mg, yield 5.0%).

[0228] ESI[M+H] + =410.3 1 H NMR (400 MHz, DMSO-d 6 )δ10.37(s,1H),9.44(s,1H),8.15(s,1H),7.98(dt,J=19.4,5.0Hz,2H),7.25(qd,J=14.8,7.5Hz,5H),5.95(s,1H),5.58(s,1H),3.70(s,2H).

[0229] Example 28: Synthesis of 7-(prop-2-yn-1-ylamino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (28)

[0230]

[0231] 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.0755 mmol) was dissolved in N,N-dimethylformamide (2 ml), 3-bromoprop-1-yne (13.5 μl, 0.151 mmol) and potassium carbonate (16 mg, 0.113 mmol) were added and reacted at room temperature for 3 hours, and then the temperature was raised to 80°C and reacted overnight. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate, and the liquid phase was prepared after concentration under reduced pressure [Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-90% over 35 min] was purified twice to obtain the target product 7-(prop-2-yn-1-ylamino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (28, 1.38 mg, yield 6.04%). ESI [M+H] + =304.2 1 H NMR (600 MHz, DMSO-d 6)δ9.21(s,1H),7.72(d,J=8.3Hz,1H),7.03(t,J=4.5Hz,2H),6.92(dd,J=8.3,2.3Hz,1H),4.03(dd,J=5.2,1.8Hz,2H),3.17(t,J=2.3Hz,1H).

[0232] Example 29: Synthesis of (E)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid (29)

[0233]

[0234] Step 1: Synthesis of ethyl (E)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoate (29-a)

[0235] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.1132 mmol) was dissolved in N,N-dimethylformamide (2 ml), and (E)-4-ethoxy-4-oxobut-2-enoic acid (33 mg, 0.2264 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (64 mg, 0.2264 mmol) and 1-methylimidazole (38 μl, 0.4528 mmol) were added. The mixture was reacted at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared on a plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (E)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid ethyl ester (29-a, 20 mg, yield 45.2%). ESI [M+H] + =392.2.

[0236] Step 2: Synthesis of (E)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid (29)

[0237] (E)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid ethyl ester (29-a, 20 mg, 0.052 mmol) was dissolved in a mixed solution (2 ml) of tetrahydrofuran and water (5:1), and lithium hydroxide monohydrate (3.3 mg, 0.078 mmol) was added at low temperature to react at room temperature for one hour. After the reaction was completed, the reaction pH was adjusted to 6 with a 1M aqueous solution of hydrogen chloride, and then extracted with ethyl acetate, the organic phase was collected, washed with brine, and then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparing a plate (petroleum ether: ethyl acetate = 1:1), and then preparing a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-70% over 20 min] to obtain the target product (E)-4-oxo-4-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)but-2-enoic acid (29, 4.78 mg, yield 25.74%). ESI [M+H] + =363.4 1 H NMR (600 MHz, DMSO-d 6 )δ10.94(s,1H),9.47(s,1H),8.17(s,1H),8.01(d,J=8.2Hz,1H),7.92(d,J=8.1Hz,1H),7.11(d,J=15.4Hz,1H),6.71(d,J=15.4Hz,1H).

[0238] Example 30: Synthesis of (Z)-3-cyano-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (30)

[0239]

[0240] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.0755 mmol) was dissolved in N,N-dimethylformamide (2 ml), and (Z)-3-cyanoacrylic acid (22 mg, 0.226 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (63.5 mg, 0.226 mmol) and 1-methylimidazole (38 μl, 0.453 mmol) were added. The reaction was allowed to react overnight at room temperature. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified once by preparing a plate (petroleum ether: ethyl acetate = 1:1), and then the liquid phase [Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-95% over 40 min] was purified twice to obtain the target product (Z)-3-cyano-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (30, 2.89 mg, yield 7.42%). ESI [M+H] + =345.2 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),9.47(s,1H),8.16(s,1H),8.02(d,J=8.1Hz,1H),7.89(d,J=7.9Hz,1H),7.16(d,J=16.1Hz,1H),6.73(d,J=16.1Hz,1H).

[0241] Example 31 and Example 32: Synthesis of 2-(Morpholinomethyl)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (31), Synthesis of (E)-4-Morpholino-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)but-2-enamide (32)

[0242]

[0243] 2-(Morpholinemethyl)acrylic acid (96.9 mg, 0.5657 mmol) was dissolved in tetrahydrofuran (6 ml) and cooled to 0 ° C under a nitrogen atmosphere. N-methylmorpholine (75 μl, 0.679 mmol) and isobutyl chloroformate (58.5 μl, 0.226 mmol) were added and stirred at 0 ° C for 1 hour, and then a solution of 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60 mg, 0.226 mmol) in pyridine (2 ml) was added. The reaction was allowed to react overnight at room temperature. After the reaction was completed, the reaction was poured into an ice-cold saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and then washed with saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate, and the liquid phase was prepared after concentration under reduced pressure [Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA), B: CAN, B%: 10%-95% over 25 min] was purified three times to obtain the target product 2-(morpholinomethyl)-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (31, 1.68 mg, yield 3.55%). ESI [M+H] + =419.20 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(s,1H),7.68(d,J=8.2Hz,1H),7.12(t,J=5.7Hz,1H),6.98(s,1H),6.89(d,J=7.9Hz,1H),5.43(s,1H),5.19(s,1H),4.02(d,J=5.4Hz,2H),3.44(d,J=19.1Hz,8H). The target product (E)-4-morpholinyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)but-2-enamide (32, 2.14 mg, yield 4.52%). ESI[M+H] + =419.20 1 H NMR (400 MHz, DMSO-d 6 )δ11.23(s,1H),9.47(s,1H),8.19(s,1H),7.99(d,J=8.2Hz,1H),7.90(d,J=8.2Hz,1H),6.10(s,1H),5.69(s,1H),3.65(s,2H),2.50(s,8H).

[0244] Example 33: Synthesis of 2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (33)

[0245]

[0246] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.113 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2-fluoropropionic acid (18 μl, 0.226 mmol), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (63.5 mg, 0.2264 mmol) and 1-methylimidazole (38 μl, 0.453 mmol) were added. The mixture was reacted at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (33, 5.91 mg, yield 15.4%). ESI [M+H] + =340.6 1 H NMR (400 MHz, DMSO-d 6 )δ10.75(s,1H),9.47(s,1H),8.19(s,1H),8.00(q,J=8.5Hz,2H),5.27(dq,J=48.5,6.7Hz,1H),1.55(dd,J=24.5,6.7Hz,3H).

[0247] Example 34: Synthesis of 2-(dimethylamino)methyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (34)

[0248]

[0249] Step 1: Synthesis of 2-(dimethylaminomethyl)acrylic acid (34-a)

[0250] 2-(Bromomethyl)acrylic acid (100 mg, 0.61 mmol), dimethylamine hydrochloride (49 mg, 0.6 mmol) and N,N-diisopropylethylamine (211 μl, 1.21 mmol) were dissolved in dichloromethane (5 ml) and reacted at room temperature for 1 hour. After filtration and concentration under reduced pressure, the target product 2-(dimethylaminomethyl)acrylic acid (34-a, 60 mg, yield 60.1%) was obtained. ESI [M+H] + =130.7

[0251] Step 2: Synthesis of 2-(dimethylamino)methyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (34)

[0252] 2-(Dimethylaminomethyl)acrylic acid (34-a, 49 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (2 ml), 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (50 mg, 0.19 mmol) and pyridine (76 μl, 0.94 mmol) were added, and phosphorus oxychloride (53 μl, 0.57 mmol) was added at 0°C under nitrogen protection and reacted for 1.5 hours. Sodium bicarbonate was added for dilution, and ethyl acetate was used for extraction. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product 2-(dimethylamino)methyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (34, 2.46 mg, yield 3.5%). ESI [M+H] + =377.2 1 HNMR (400 MHz, DMSO-d 6 )δ11.41(s,1H),9.47(s,1H),8.15(s,1H),8.00(d,J=8.2Hz,1H),7.92(d,J= 9.8Hz,1H),6.87(s,1H),6.66(s,1H),6.08(s,1H),5.68(s,1H),2.28(s,6H).

[0253] Example 35: Synthesis of 3-cyano-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (35)

[0254]

[0255] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.08 mmol), 3-cyanopropionic acid (15 mg, 0.15 mmol), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (42 mg, 0.15 mmol) and NMI (25 μl, 0.31 mmol) were dissolved in N,N-dimethylformamide (2 ml) and reacted at room temperature overnight. Sodium bicarbonate was added for dilution, ethyl acetate was used for extraction, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20 ID*250 mm*10 μm; A:H 2O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product 3-cyano-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (35, 2.34 mg, yield 9%). ESI [M+H] + =346.9 1 H NMR (400 MHz, DMSO-d 6 )δ10.61(s,1H),9.45(s,1H),8.09(s,1H),7.98(d,J=8.2Hz,1H),7.85(d,J=8.2Hz,1H),2.76(s,4H).

[0256] Example 36: Synthesis of 2,2-difluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (36)

[0257]

[0258] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.113 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2,2-difluoropropionic acid (25 mg, 0.226 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (64 mg, 0.226 mmol) and 1-methylimidazole (38 μl, 0.452 mmol) were added and reacted at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 2,2-difluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (36, 4.72 mg, yield 11.68%). ESI [M+H] + =358.00 1 HNMR (400 MHz, DMSO-d 6 )δ11.02(s,1H),9.50(s,1H),8.17(s,1H),8.10–7.97(m,2H),1.92(dd,J=35.4,15.7Hz,3H).

[0259] Example 37: Synthesis of (E)-4,4,4-trifluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)but-2-enamide (37)

[0260]

[0261] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.113 mmol) was dissolved in N,N-dimethylformamide (2 ml), and (E)-4,4,4-trifluorobut-2-enoic acid (31.7 mg, 0.226 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (64 mg, 0.226 mmol) and 1-methylimidazole (38 μl, 0.452 mmol) were added and reacted at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (E)-4,4,4-trifluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)but-2-enamide (37, 5.06 mg, yield 11.55%). ESI [M+H] + =388.00 1 H NMR (400 MHz, DMSO-d 6 )δ11.04(s,1H),9.47(s,1H),8.16(d,J=1.5Hz,1H),8.01(d,J=8.2Hz,1H),7.87(dd,J=8.2,1.7Hz,1H),7.07–6.91(m,2H).

[0262] Example 38: Synthesis of 2-chloro-2,2-difluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (38)

[0263]

[0264] 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) and 2-chloro-2,2-difluoroacetic acid (20 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N-methylimidazole (25 mg, 0.3 mmol) and N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (42 mg, 0.15 mmol) were added and reacted overnight. After the reaction was completed, sodium bicarbonate was added for dilution, and ethyl acetate was used for extraction. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product 2-chloro-2,2-difluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (38, 8.24 mg, yield 29.4%). ESI [M+H] + =378.10,380.10 1 H NMR (400 MHz, DMSO-d 6 )δ11.53(s,1H),9.52(s,1H),8.13–8.05(m,2H),8.01(dd,J=8.2,2.0Hz,1H).

[0265] Example 39: Synthesis of 9-oxo-N-(prop-2-yn-1-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (39)

[0266]

[0267] 9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (20 mg, 0.058 mmol), prop-2-yn-1-amine (5 mg, 0.08 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (2 ml) and then N,N-diisopropylethylamine (38 μl, 0.20 mmol) was added to react overnight. After the reaction was completed, sodium bicarbonate was added for dilution, ethyl acetate was used for extraction, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-80% over 23min] to obtain the target product 9-oxo-N-(prop-2-yn-1-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (39, 1.78 mg, yield 8.09%). ESI [M+H] + =332.10 1 H NMR (400 MHz, DMSO-d 6 )δ9.65(s,1H),9.26(t,J=5.3Hz,1H),8.28(d,J=9.8Hz,2H),8.18(d,J=7.7Hz,1H),4.10(dd,J=5.3,2.3Hz,2H),3.17(t,J=2.4Hz,1H)

[0268] Example 40: Synthesis of 2-cyano-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (40)

[0269]

[0270] 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) and 2-cyanopropionic acid (11 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N-methylimidazole (25 mg, 0.3 mmol) and N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (42 mg, 0.15 mmol) were added to react overnight. After the reaction was completed, sodium bicarbonate was added for dilution, and ethyl acetate was used for extraction. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product 2-cyano-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (40, 11.23 mg, yield 43.2%). ESI [M+H] + =347.20 1 H NMR (400 MHz, DMSO-d 6 )δ10.84(s,1H),9.47(s,1H),8.05(d,J=1.1Hz,1H),8.01(d,J=8.2Hz,1H) ,7.85(dd,J=8.2,1.5Hz,1H), 4.00(q,J=7.2Hz,1H), 1.54(d,J=7.2Hz,3H).

[0271] Example 41: Synthesis of 2,2-difluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (41)

[0272]

[0273] 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) and 2,2-difluoroacetic acid (11 μl, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N-methylimidazole (25 mg, 0.3 mmol) and N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (42 mg, 0.15 mmol) were added to react overnight. After the reaction was completed, sodium bicarbonate was added for dilution, and ethyl acetate was used for extraction. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product 2,2-difluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (41, 7.09 mg, yield 31.6%). ESI [M+H] + =344.20 1 H NMR (400 MHz, DMSO-d 6 )δ9.49(s,1H),8.13(d,J=1.1Hz,1H),8.03(d,J=8.2Hz,1H),7.97(dd,J=8.2,1.4Hz,1H),6.44(t,J=53.5Hz,1H).

[0274] Example 42: Synthesis of N-(cyanomethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (42)

[0275]

[0276] 9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (20 mg, 0.058 mmol), 2-aminoacetonitrile (3 mg, 0.08 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (2 ml) and then N,N-diisopropylethylamine (38 μl, 0.20 mmol) was added to react overnight. After the reaction was completed, sodium bicarbonate was added for dilution, ethyl acetate was used for extraction, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2O (0.1% FA), B: ACN, B%: 10%-80% over 23 min] to obtain the target product N-(cyanomethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (42, 2.21 mg, yield 9.3%). ESI [M+H] + =333.10 1 H NMR (400 MHz, DMSO-d 6 )δ9.66(s,1H),9.55(t,J=5.2Hz,1H),8.32–8.25(m,2H),8.21(d,J=7.8Hz,1H),4.37(d,J=5.3Hz,2H).

[0277] Example 43: Synthesis of 2-fluoro-N-(3-oxo-3-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)propyl)acrylamide (43)

[0278]

[0279] Step 1: Synthesis of tert-butyl (3-oxo-3-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)propyl)carbamate (43-a)

[0280] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (50 mg, 0.19 mmol) and 3-((tert-butoxycarbonyl)amino)propionic acid (71 mg, 0.377 mmol) were dissolved in N,N-dimethylformamide (3 ml), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (144 mg, 0.377 mmol) and N-methylimidazole (62 μl, 0.756 mmol) and reacted at room temperature overnight. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (tert-butyl 3-oxo-3-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)propyl)carbamate (43-a, 80 mg, yield 97.6%). ESI [M+H] + =437.1

[0281] Step 2: Synthesis of 3-amino-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propionamide (43-b)

[0282] Dissolve tert-butyl (3-oxo-3-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)propyl)carbamate (43-a, 30 mg, 0.069 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (2 ml) at 0°C and react for 1.5 hours. After the reaction is completed, concentrate under reduced pressure to obtain the target product 3-amino-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (43-b, 45 mg). ESI[M+H] + =337.2

[0283] Step 3: Synthesis of 2-fluoro-N-(3-oxo-3-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)propyl)acrylamide (43)

[0284] 3-amino-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propionamide (43-b, 20 mg, 0.059 mmol), 2-fluoroacrylic acid (8 mg, 0.089 mmol), dissolved in N,N-dimethylformamide (2 ml), added with N,N-diisopropylethylamine (33 μl, 0.18 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (34 mg, 0.089 mmol) and reacted at room temperature overnight. Diluted with sodium bicarbonate, extracted with ethyl acetate, collected the organic phase and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and prepared the liquid phase [Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product 2-fluoro-N-(3-oxo-3-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)amino)propyl)acrylamide (43, 3.56 mg, yield 14.7%). ESI [M+H] + =409.02 1 H NMR (400 MHz, DMSO-d 6)δ10.46(s,1H),9.44(s,1H),8.65(s,1H),8.11(d,J=1.2Hz,1H),7.96(d,J=8.2Hz,1H),7.84(dd,J=8.2,1.5Hz,1H),5 .52(dd,J=48.2,3.3Hz,1H),5.31(ddd,J=19.0,10.9,2.5Hz,1H),3.47(dd,J=12.6,6.5Hz,2H),2.62(t,J=6.8Hz,2H).

[0285] Example 44: Synthesis of (S)-2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (44)

[0286]

[0287] Dissolve 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) in N,N-dimethylformamide (2 ml), add (S)-2-fluoropropionic acid (10 mg, 0.11 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (42 mg, 0.226 mmol) and N-methylimidazole (25 μl, 0.315 mmol) and react at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (S)-2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (44, 7.96 mg, yield 31.1%). ESI [M+H] + =340.10 1 HNMR (400 MHz, DMSO-d 6 )δ10.54(s,1H),9.45(s,1H),8.16(s,1H),8.01–7.96(m,2H),5.24(dq,J=48.4,6.7Hz,1H),1.55(dd,J=24.5,6.7Hz,3H).

[0288] Example 45: Synthesis of N-(2-(2-fluoroacrylamide)ethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (45)

[0289]

[0290] Step 1: Synthesis of tert-butyl (2-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamido)ethyl)carbamate (45-a)

[0291] 9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (30 mg, 0.10 mmol) and tert-butyl (2-aminoethyl)carbamate (24 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (3 ml), N,N-diisopropylethylamine (55 μl, 0.3 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57 mg, 0.15 mmol) and reacted at room temperature overnight. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (tert-butyl 2-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamido)ethyl)carbamate (45-a, 40 mg, yield 90.9%). ESI [M+H] + =437.1

[0292] Step 2: Synthesis of N-(2-aminoethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (45-b)

[0293] Dissolve tert-butyl (2-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamido)ethyl)carbamate (45-a, 40 mg, 0.092 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (2 ml) at 0°C and react for 1.5 hours. After the reaction is completed, concentrate under reduced pressure to obtain the target product N-(2-aminoethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (45-b, 38 mg). ESI[M+H] + =337.2

[0294] Step 3: Synthesis of N-(2-(2-fluoroacrylamide)ethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (45)

[0295] N-(2-aminoethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (45-b, 20 mg, 0.0059 mmol), 2-fluoroacrylic acid (8 mg, 0.089 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (34 mg, 0.089 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N,N-diisopropylethylamine (33 μl, 0.18 mmol) was added, and the mixture was reacted at room temperature overnight. Sodium bicarbonate was added for dilution, and ethyl acetate was used for extraction. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain the target product N-(2-(2-fluoroacrylamide)ethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (45, 0.83 mg, yield 3.4%). ESI [M+H] + =409.02 1 H NMR (400 MHz, DMSO-d 6 )δ11.69(s,1H),9.64(s,1H),8.89–8.85(m,1H),8.64(s,1H),8.25(dd,J=4.0,2.4Hz,1H),8.17(d,J=8.2Hz,1H),5.39–5.34(m,1H ),5.25(dd,J=15.7,3.3Hz,1H),4.28–4.24(m,1H),4.16(dd,J=14.7,6.8Hz,1H),4.08(dd,J=13.2,6.9Hz,1H),4.05–4.01(m,1H).

[0296] Example 46: Synthesis of 2-fluoro-N-methyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (46)

[0297]

[0298] Step 1: Synthesis of 7-(methylamino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (46-a)

[0299] 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60 mg, 0.23 mmol) was dissolved in acetonitrile (3 ml), potassium carbonate (47 mg, 0.34 mmol) and iodomethane (48 mg, 0.34 mmol) were added, and the mixture was sealed at 90°C for overnight reaction. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 2:1) to obtain the target product 7-(methylamino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (46-a, 14 mg, yield 22.22%). ESI[M+H] + =280.3

[0300] Step 2: Synthesis of 2-fluoro-N-methyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (46)

[0301] 7-(Methylamino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (46-a, 14 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2-fluoroacrylic acid (9 mg, 0.10 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (28 mg, 0.10 mmol) and N-methylimidazole (17 μl, 0.20 mmol) were added to react at room temperature for 12 h. 2-Fluoroacrylic acid (9 mg, 0.10 mmol) and N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (28 mg, 0.10 mmol) were added to the mixture and the temperature was raised to 40°C for reaction for 12 h. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to prepare a liquid phase [Pack Column 20ID*250mm*10um; A:H 2 O (0.1% FA), B: CAN, B%: 10%-95% over 35 min] was purified twice to obtain the target product 2-fluoro-N-methyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (46, 1.18 mg, yield 6.7%). ESI [M+H] + =352.2 1 H NMR (600 MHz, DMSO-d 6 )δ9.58(s,1H),8.11(d,J=7.9Hz,1H),7.84(s,1H),7.76(d,J=7.9Hz,1H),5.35–5.21(m,2H),3.33(s,3H).

[0302] Example 47: Synthesis of 1-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (47)

[0303]

[0304] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.113 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 1-fluorocyclopropane-1-carboxylic acid (24 mg, 0.226 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (64 mg, 0.226 mmol) and 1-methylimidazole (38 μl, 0.452 mmol) were added and reacted at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 1-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (47, 4.45 mg, yield 10.07%). ESI [M+H] + =352.20 1 H NMR (600 MHz, DMSO-d 6 )δ10.69(s,1H),9.47(s,1H),8.21(d,J=1.3Hz,1H),8.08(dd,J=8.2,1.6Hz,1H ),8.00(d,J=8.2Hz,1H),1.48(ddd,J=18.1,8.5,5.6Hz,2H),1.40–1.31(m,2H).

[0305] Example 48: Synthesis of (R)-2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (48)

[0306]

[0307] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.113 mmol) was dissolved in N,N-dimethylformamide (2 ml), and (R)-2-fluoropropionic acid (20.8 mg, 0.226 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (64 mg, 0.226 mmol) and N-methylimidazole (38 μl, 0.452 mmol) were added and reacted at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (R)-2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (48, 4.42 mg, yield 11.50%). ESI [M+H] + =340.3 1 H NMR (600 MHz, DMSO-d 6 )δ10.76(s,1H),9.46(s,1H),8.19(s,1H),8.00(q,J=8.2Hz,2H),5.27(dq,J=48.5,6.7Hz,1H),1.55(dd,J=24.6,6.7Hz,3H).

[0308] Example 49: Synthesis of 2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-6-yl)acrylamide (49)

[0309]

[0310] Step 1: Synthesis of 4-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (49-a)

[0311] 2-Bromo-4-nitrobenzaldehyde (300 mg, 1.30 mmol) was dissolved in acetonitrile (10 ml), potassium phosphate (827 mg, 3.9 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boric acid (I-1, 345 mg, 1.82 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (47.6 mg, 0.065 mmol) were added and reacted at 100°C overnight. After the reaction was completed, the temperature was cooled to room temperature, the reaction mixture was filtered and concentrated under reduced pressure, and then purified by normal phase chromatography (petroleum ether: ethyl acetate = 2:1) to obtain the target product 4-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (49-a, 340 mg, yield 87.63%). ESI [M+H] + =298.1.

[0312] Step 2: Synthesis of 4-amino-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (49-b)

[0313] 4-Nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (49-a, 340 mg, 1.14 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 ml) and water (8 ml) and stirred at 15°C for 10 min, then sodium sulfide nonahydrate (907 mg, 3.76 mmol) was added and stirred at 15°C for 10 min, and then reacted at room temperature for 2 h. After the reaction was completed, it was extracted with ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 2:1) to obtain the target product 4-amino-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (49-b, 180 mg, yield 59.02%). ESI[M+H] + =268.1

[0314] Step 3: Synthesis of tert-butyl (4-formyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)carbamate (49-c)

[0315] 4-Amino-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (49-b, 180 mg, 0.674 mmol) was dissolved in tetrahydrofuran (6 ml), and 4-dimethylaminopyridine (4.2 mg, 0.0337 mmol) and di-tert-butyl dicarbonate (4.2 mg, 0.169 mmol) were added to react at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the target product (tert-butyl 4-formyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)carbamate (49-c, 320 mg, crude product). ESI[M+H] + =368.2

[0316] Step 4: Synthesis of tert-butyl (9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-6-yl)carbamate (49-d)

[0317] Dissolve tert-butyl (4-formyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)carbamate (49-c, 320 mg, 0.685 mmol) in 1,2-dichloroethane (10 ml), then add tetrabutylammonium iodide (12.6 mg, 0.034 mmol) and 2-hydroperoxide-2-methylpropane (aqueous solution) (394 μl, 4.11 mmol) to the reaction, replace with nitrogen three times, seal and react at 100°C overnight. Filter the reaction solution to remove insoluble matter, concentrate the filtrate under reduced pressure, and purify the target product (tert-butyl (9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-6-yl)carbamate (49-d, 50 mg, yield 15.72%). ESI[M+H] + =366.2

[0318] Step 5: Synthesis of 6-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (49-e)

[0319] Dissolve tert-butyl (9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-6-yl)carbamate (49-d, 50 mg, 0.674 mmol) in ethyl acetate (1 ml), add hydrogen chloride ethyl acetate solution (3 ml, 4 M) at 0°C, and react at room temperature overnight. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain the target product 6-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (49-e, 240 mg, crude product). ESI[M+H] + =266.1

[0320] Step 6: Synthesis of 2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-6-yl)acrylamide (49)

[0321] 6-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (49-e, 24 mg, 0.091 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2-fluoroacrylic acid (18 mg, 0.0109 mmol), pyridine (23 μl, 0.273 mmol) and phosphorus oxychloride (12.5 μl, 0.1365 mmol) were added to react at room temperature for 48 h. After the reaction was completed, the reaction was quenched with ice water, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified once by preparing a plate (petroleum ether: ethyl acetate = 1.5:1), and then the liquid phase [Pack Column 20ID*250mm*10um; A:H 2O (0.1% FA), B: ACN, B%: 10%-90% over 40 min] purification for the second time to obtain the target product 2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-6-yl)acrylamide (49, 0.77 mg, yield 2.50%). ESI [M+H] + =338.1 1 HNMR (600 MHz, DMSO-d 6 )δ9.51(s,1H),8.44(s,1H),8.41(s,1H),7.83(q,J=8.3Hz,2H),5.83(dd,J=47.4,2.8Hz,1H),5.55(dd,J=15.3,2.9Hz,1H).

[0322] Example 50: Synthesis of 1-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclobutane-1-carboxamide (50)

[0323]

[0324] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 1-fluorocyclobutane-1-carboxylic acid (13 mg, 0.11 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (42 mg, 0.226 mmol) and 1-methylimidazole (25 μl, 0.315 mmol) were added and reacted at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 1-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclobutane-1-carboxamide (50, 7.71 mg, yield 28.6%). ESI [M+H] + ,=366.10 1 H NMR (400 MHz, DMSO-d 6 )δ10.44(d,J=2.9Hz,1H),9.46(s,1H),8.21(d,J=2.0Hz,1H),8.06(dd,J=8.2,2.0Hz,1H),7.98(d, J=8.2Hz,1H),2.69–2.58(m,2H),2.49–2.37(m,2H),2.01–1.90(m,1H),1.79(q,J=11.1,9.9Hz,1H).

[0325] Example 51: Synthesis of 2-fluoro-2-methyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (51)

[0326]

[0327] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.113 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2-fluoro-2-methylpropionic acid (24 mg, 0.226 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (64 mg, 0.226 mmol) and 1-methylimidazole (38 μl,

[0328] 0.452mmol) was reacted at room temperature overnight. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified once on a plate (petroleum ether: ethyl acetate = 1:1), and then a liquid phase [Pack Column 20ID*250mm*10um; A:H 2 O (0.1% FA), B: ACN, B%: 10%-90% over 30 min] purification for the second time to obtain the target product 2-fluoro-2-methyl-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)propanamide (51, 2.06 mg, yield 40%). ESI [M+H] + =354.30 1 H NMR (400 MHz, DMSO-d 6 )δ10.43(d,J=2.6Hz,1H),9.45(s,1H),8.20(s,1H),8.12–7.89(m,2H),1.60(d,J=21.9Hz,6H).

[0329] Example 52: Synthesis of (1R, 2R)-2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (52)

[0330]

[0331] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (20 mg, 0.075 mmol) was dissolved in N,N-dimethylformamide (2 ml), and (1R,2R)-2-fluorocyclopropane-1-carboxylic acid (16 mg, 0.11 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (42 mg, 0.226 mmol) and 1-methylimidazole (25 μl, 0.315 mmol) were added and reacted at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (1R, 2R)-2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (52, 3.60 mg, yield 13.8%). ESI [M+H] + =352.20 1 H NMR (400 MHz, DMSO-d 6 )δ10.76(s,1H),9.44(s,1H),8.14–8.06(m,1H),7.96(d,J=8.2Hz,1H),7.91–7.82( m,1H),4.99(dtd,J=66.1,6.2,3.6Hz,1H),2.04(q,J=7.3Hz,1H),1.82–1.61(m,2H).

[0332] Example 53: Synthesis of 2-fluoro-N-(7-oxo-9-(trifluoromethyl)-7H-benzo[6,7]indeno[2,1-d]pyrimidin-5-yl)acrylamide (53)

[0333]

[0334] Step 1: Synthesis of N-(2-methylnaphthalen-1-yl)acetamide (53-a)

[0335] 2-Methylnaphthalene-1-amine (3g, 19.1mmol) was dissolved in dichloromethane (30ml), and acetyl chloride (2ml, 28.65mmol) and triethylamine (5.3ml, 38.2mmol) were added at 0℃ and reacted at room temperature for 3 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a Flash column (petroleum ether: ethyl acetate = 0-25%) to obtain the target product N-(2-methylnaphthalene-1-yl)acetamide (53-a, 3.7g, yield 97.4%). ESI[M+H] + =200.20

[0336] Step 2: Synthesis of N-(2-methyl-4-nitronaphthalene-1-yl)acetamide (53-b)

[0337] Dissolve N-(2-methylnaphthalene-1-yl)acetamide (53-a, 3g, 15mmol) in acetic anhydride (50ml), slowly add nitric acid (1.48ml, 16.5mmol) at 0℃, and react at room temperature for 3 hours. After the reaction, adjust pH to 8 with sodium hydroxide solution, quench the reaction with sodium sulfite, extract with ethyl acetate, collect the organic phase, dry it with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with Flash column (petroleum ether: ethyl acetate = 0-25%) to obtain the target product N-(2-methyl-4-nitronaphthalene-1-yl)acetamide (53-b, 1.78g, yield 48.6%). ESI[M+H] + =245.10

[0338] Step 3: Synthesis of 2-methyl-4-nitronaphthalene-1-amine (53-c)

[0339] N-(2-methyl-4-nitronaphthalene-1-yl)acetamide (53-b, 1.78 g, 7.3 mmol) was dissolved in ethanol (30 ml), and 6M hydrochloric acid solution (6 ml) was added, and the mixture was reacted at 100°C for 16 hours. After the reaction, the pH was adjusted to 8 with sodium hydroxide solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a Flash column (petroleum ether: ethyl acetate = 0-35%) to obtain the target product 2-methyl-4-nitronaphthalene-1-amine (53-c, 1.3 g, yield 91.5%). ESI[M+H] + =203.10

[0340] Step 4: Synthesis of 1-iodo-2-methyl-4-nitronaphthalene (53-d)

[0341] 2-Methyl-4-nitronaphthalene-1-amine (53-c, 1.3 g, 6.43 mmol) and cuprous iodide (3.66 g, 19.3 mmol) were dissolved in acetonitrile (30 ml), and isoamyl nitrite (2.58 ml, 19.3 mmol) was added dropwise at 0°C, and the mixture was reacted overnight at room temperature. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the target product 1-iodo-2-methyl-4-nitronaphthalene (53-d, 1 g, yield 50.1%) was obtained. ESI[M+H] + =314.10,316.10

[0342] Step 5: Synthesis of 5-(2-methyl-4-nitronaphthalene-1-yl)-2-(trifluoromethyl)pyrimidine (53-e)

[0343] 1-iodo-2-methyl-4-nitronaphthalene (53-d, 1 g, 3.19 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boric acid (920 mg, 4.79 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (117 mg, 0.16 mmol) and potassium phosphate (2 g, 9.58 mmol) were dissolved in acetonitrile (20 ml), and microwaved at 120°C for 60 minutes under nitrogen protection. The reaction solution was filtered, concentrated under reduced pressure, and flash column (petroleum ether: ethyl acetate = 0-35%) was used to obtain the target product 5-(2-methyl-4-nitronaphthalene-1-yl)-2-(trifluoromethyl)pyrimidine (53-e, 780 mg, yield 73.4%). ESI [M+H] + =334.20

[0344] Step 6: Synthesis of 5-nitro-9-(trifluoromethyl)-7H-benzo[6,7]indeno[2,1-d]pyrimidin-7-one (53-f)

[0345] 5-(2-methyl-4-nitronaphthalen-1-yl)-2-(trifluoromethyl)pyrimidine (53-e, 780 mg, 2.34 mmol) was dissolved in dichloroethane (40 ml), 2-hydroperoxide-2-methylpropane (1.8 ml, 18.7 mmol) and tetrabutylammonium iodide (43 mg, 0.12 mmol) were added, and the mixture was reacted at 120°C overnight under nitrogen protection. After concentration under reduced pressure, the target product 5-nitro-9-(trifluoromethyl)-7H-benzo[6,7]indeno[2,1-d]pyrimidin-7-one (53-f, 35 mg, yield 4.3%) was obtained by flash column (petroleum ether: ethyl acetate = 0-35%). ESI[M+H] + =346.20

[0346] Step 7: Synthesis of 5-amino-9-(trifluoromethyl)-7H-benzo[6,7]indeno[2,1-d]pyrimidin-7-one (53-g)

[0347] 5-Nitro-9-(trifluoromethyl)-7H-benzo[6,7]indeno[2,1-d]pyrimidin-7-one (53-f, 35 mg, 0.1 mmol) was dissolved in ethanol (5 ml) and water (6 ml), and reduced iron powder (28 mg, 0.5 mmol) and ammonium chloride (53 mg, 1 mmol) were added to react at 80°C for 1 hour under nitrogen protection. The reaction solution was filtered while hot, concentrated under reduced pressure, and flash column (petroleum ether: ethyl acetate = 0-35%) was used to obtain the target product 5-amino-9-(trifluoromethyl)-7H-benzo[6,7]indeno[2,1-d]pyrimidin-7-one (53-g, 20 mg, yield 62.5%). ESI[M+H] + =315.20

[0348] Step 8: Synthesis of 2-fluoro-N-(7-oxo-9-(trifluoromethyl)-7H-benzo[6,7]indeno[2,1-d]pyrimidin-5-yl)acrylamide (53)

[0349] 2-Fluoroacrylic acid (11 mg, 0.12 mmol) was dissolved in dichloromethane (5 ml), and oxalyl chloride (11 μl, 0.12 mmol) and a catalytic amount of NN-dimethylformamide were added dropwise at 0°C under a nitrogen atmosphere. The mixture was reacted at this temperature for 3 hours, and then triethylamine (42 μl, 0.17 mmol) and 5-amino-9-(trifluoromethyl)-7H-benzo[6,7]indeno[2,1-d]pyrimidin-7-one (2-h, 20 mg, 0.058 mmol) were added and reacted for one hour. After the reaction was completed, the dichloromethane was diluted with water for extraction. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 2-fluoro-N-(7-oxo-9-(trifluoromethyl)-7H-benzo[6,7]indeno[2,1-d]pyrimidin-5-yl)acrylamide (53, 4.53 mg, yield 20.6%). ESI [M+H] + =388.20 1 H NMR (400 MHz, DMSO-d 6 )δ10.84(s,1H),9.97(s,1H),8.77–8.68(m,1H),8.20–8.10(m,1H),7.92(s,1H) ,7.90–7.84(m,2H),5.82(dd,J=47.7,3.8Hz,1H),5.55(dd,J=15.6,3.8Hz,1H).

[0350] Example 54: Synthesis of 3-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)azetidine-3-carboxamide (54)

[0351]

[0352] Step 1: Synthesis of tert-butyl 3-fluoro-3-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)carbamoyl)azetidine-1-carboxylate (54-a)

[0353] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (80 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (5 ml), and 1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-carboxylic acid (99 mg, 0.45 mmol), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (168 mg, 0.60 mmol) and 1-methylimidazole (99 μl, 1.2 mmol) were added and reacted at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 3-fluoro-3-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester (54-a, 140 mg, yield 99%). ESI [M+H] + =467.20

[0354] Step 2: Synthesis of 3-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)azetidine-3-carboxamide (54)

[0355] 3-Fluoro-3-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester (54-a, 30 mg, 0.064 mmol) was dissolved in ethyl acetate (3 ml) and 4 M hydrochloric acid ethyl acetate solution (3 ml) was added at room temperature. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the liquid phase was prepared by concentrating under reduced pressure [Pack Column 20 ID*250 mm*10 μm; A:H 2 O (0.1% FA), B: ACN, B%: 10%-70% over 22 min] to obtain 3-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)azetidine-3-carboxamide (54, 1.89 mg, yield 8.2%). ESI [M+H] + =367.20 1 H NMR (400 MHz, DMSO-d 6 )δ10.73(d,J=2.3Hz,1H),9.49(s,1H),8.24(s,1H),8.04(s,2H),4.54(d,J=18.2Hz,4H).

[0356] Example 55 and Example 56: Synthesis of 3-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclobutane-1-carboxamide (55) and Synthesis of 7-((1-(3-fluorocyclobutyl)ethyl)amino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (56)

[0357]

[0358] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.113 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2-fluoro-2-methylpropionic acid (24 mg, 0.226 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (64 mg, 0.226 mmol) and 1-methylimidazole (38 μl, 0.452 mmol) were added at room temperature for 4 hours. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain 7-((1-(3-fluorocyclobutyl)ethyl)amino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (55, 2.60 mg, yield 5.8%). ESI [M+H] + =366.30 1 H NMR (400 MHz, DMSO-d 6 )δ10.46(s,1H),9.44(s,1H),8.11(d,J=1.4Hz,1H),7.95(d,J=8.2Hz,1H),7.86(dd,J=8.2,1.7Hz,1H),5.11(dt,J=14.1,7.1Hz,1H),4.97(dt,J=14.2,7.1Hz,1H),4.13(q,J=5.2Hz,1H),3.16(d,J=5.2Hz,3H),2.78–2.66(m,1H),2.64–2.53(m,2H),2.42–2.26(m,2H). Then prepare the liquid phase [Pack Column20ID*250mm*10um; A:H 2 O (0.1% FA), B: ACN, B%: 10%-90% over 25 min] purification for the second time to obtain the target product 3-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclobutane-1-carboxamide (56, 0.77 mg, yield 1.7%). ESI [M+H] + =366.20 1HNMR (600 MHz, DMSO-d 6 )δ10.44(s,1H),9.42(s,1H),8.10(s,1H),7.94(d,J=8.2Hz,1H),7.85(d,J=7.6Hz,1H),5.31–5.25(m,1H ),5.21–5.16(m,1H),3.25(dd,J=12.9,9.7Hz,1H),2.57(ddd,J=13.0,9.4,3.0Hz,2H),2.49–2.40(m,2H).

[0359] Example 57: Synthesis of 3,3-difluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclobutane-1-carboxamide (57)

[0360]

[0361] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.113 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2-fluoro-2-methylpropionic acid (24 mg, 0.226 mmol), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (64 mg, 0.226 mmol) and 1-methylimidazole (38 μl, 0.452 mmol) were added to react at room temperature overnight. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified once by preparing a plate (petroleum ether: ethyl acetate = 1:1), and then preparing a liquid phase [Pack Column 20 ID*250mm*10um; A:H 2 O (0.1% FA), B: ACN, B%: 10%-90% over 30 min] purification for the second time to obtain the target product 3,3-difluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclobutane-1-carboxamide (57, 1.13 mg, yield 2.5%). ESI [M+H] + =384.30 1 H NMR (400 MHz, DMSO-d 6 )δ10.56(s,1H),9.42(s,1H),8.07(d,J=1.2Hz,1H),7.93(d,J=8.2Hz,1H),7 .82(dd,J=8.2,1.5Hz,1H),3.18–3.06(m,1H),2.83(dt,J=17.0,8.5Hz,4H).

[0362] Example 58: Synthesis of (1R,2S)-2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (58)

[0363]

[0364] 7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (30 mg, 0.113 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2-fluoro-2-methylpropionic acid (24 mg, 0.226 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (64 mg, 0.226 mmol) and 1-methylimidazole (38 μl, 0.452 mmol) were added and reacted at room temperature for 2 hours. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product (1R, 2S)-2-fluoro-N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (58, 4.69 mg, yield 11.8%). ESI [M+H] + =352.30 1 H NMR (400 MHz, DMSO-d 6 )δ10.92(s,1H),9.41(s,1H),8.03(s,1H),7.92(d,J=8.2Hz,1H),7.83–7.73(m,1H),4.91(d,J=65.1 Hz,1H),2.34(ddd,J=17.4,10.0,7.1Hz,1H),1.63–1.49(m,1H),1.26(ddd,J=21.3,13.8,7.3Hz,1H).

[0365] Example 59: Synthesis of 2-fluoro-N-(5-((4-methylpiperazin-1-yl)methyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (59)

[0366]

[0367] Step 1: Synthesis of 5-((4-methylpiperazin-1-yl)methyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (59-a)

[0368] 5-(Bromomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2, 140 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 1-methylpiperazine (48 μL, 0.43 mmol) and diisopropylethylamine (94 μL, 0.54 mmol) were added. The mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate three times, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by Flash column (dichloromethane: methanol = 0-15%) to obtain the target product 5-((4-methylpiperazin-1-yl)methyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (59-a, 74 mg, yield 50.5%). ESI[M+H] + =408.3

[0369] Step 2: Synthesis of 7-amino-5-((4-methylpiperazin-1-yl)methyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (59-b)

[0370] 5-((4-methylpiperazin-1-yl)methyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (59-a, 74 mg 0.201 mmol) was dissolved in ethanol (5 mL), 1M hydrochloric acid aqueous solution (5 mL) and stannous chloride (85 mg, 0.602 mmol) were added, nitrogen was replaced 3 times, and the reaction was carried out at 50°C for 2 hours. After the reaction was completed, the pH was adjusted to about 8 with saturated sodium bicarbonate aqueous solution, extracted three times with ethyl acetate, and the organic phase was washed three times with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product, which was purified by preparative plate to obtain the target product 7-amino-5-((4-methylpiperazin-1-yl)methyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (59-b, 58 mg, yield 76.5%). ESI[M+H] + =378.2

[0371] Step 3: Synthesis of 2-fluoro-N-(5-((4-methylpiperazin-1-yl)methyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (59)

[0372] 7-amino-5-((4-methylpiperazin-1-yl)methyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (59-b, 35 mg, 0.093 mmol) was dissolved in acetonitrile (2 mL), 2-fluoroacrylic acid (17 mg, 0.186 mmol), N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (52 mg, 0.186 mmol) and 1-methylimidazole (46 μL, 0.37 mmol) were added, and the mixture was reacted at room temperature overnight. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then the liquid phase was prepared [Pack Column 30ID*250mm*10μm; A:H 2 O (0.01% TFA), B: ACN, B%: 10%-80% over 33 min] to obtain the target product 2-fluoro-N-(5-((4-methylpiperazin-1-yl)methyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (59, 2.69 mg, yield 6.4%). ESI [M+H] + =450.2 1 H NMR (400 MHz, DMSO-d 6 )δ9.26(s,1H),8.61(s,1H),8.17(d,J=1.9Hz,1H),8.05(d,J=1.7Hz,1H),5.79(dd,J=47.5,3.9Hz,1H),5 .53(dd,J=15.5,3.9Hz,1H),3.87(s,2H),3.07(s,3H),2.69(s,3H),2.53–2.51(m,2H),2.50–2.48(m,3H).

[0373] Example 60: Synthesis of 2-fluoro-N-(5-(morpholinomethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (60)

[0374]

[0375] Step 1: Synthesis of 5-(morpholinomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60-a)

[0376] 5-(Bromomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2, 240 mg, 0.62 mmol) was dissolved in N,N-dimethylformamide (5 mL), and morpholine (59 μL, 0.68 mmol) and diisopropylethylamine (108 μL, 0.93 mmol) were added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate three times, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by Flash column (petroleum ether: ethyl acetate = 0-40%) to obtain the target product 5-(morpholinomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60-a, 110 mg, yield 45%). ESI[M+H] + =394.3

[0377] Step 2: Synthesis of 7-amino-5-(morpholinomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60-b)

[0378] 5-(Morpholinomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60-a, 110 mg, 0.28 mmol) was dissolved in ethanol (5 mL), 1M hydrochloric acid aqueous solution (5 mL) and stannous chloride (117 mg, 0.84 mmol) were added, nitrogen was replaced 3 times, and the reaction was carried out at 50°C for 2 hours. After the reaction was completed, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate three times, the organic phase was washed with saturated brine three times, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product, which was purified by preparative thin layer chromatography to obtain the target product 7-amino-5-(morpholinomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60-b, 60 mg, yield 58.8%). ESI[M+H] + =365.2

[0379] Step 3: Synthesis of 2-fluoro-N-(5-(morpholinomethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (60)

[0380] 7-amino-5-(morpholinomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60-b, 20 mg, 0.066 mmol) was dissolved in acetonitrile (2 mL), 2-fluoroacrylic acid (12 mg, 0.132 mmol), N,N,N',N'-tetramethylchlorouronium hexafluorophosphate (37 mg, 0.132 mmol) and 1-methylimidazole (22 μL, 0.264 mmol) were added, and the mixture was reacted at room temperature overnight. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then the liquid phase was prepared [Pack Column 30 ID*250 mm*10 μm; A:H 2 O (0.01% TFA), B: ACN, B%: 10%-80% over 33 min] to obtain the target product 2-fluoro-N-(5-(morpholinomethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (60, 2.46 mg, yield 8.5%). ESI [M+H] + =437.2 1 H NMR (400 MHz, DMSO-d 6 )δ10.78(s,1H),9.38(s,1H),8.18(s,1H),8.09(s,1H),5.80(dd,J=47.5,3.9 Hz,1H),5.53(dd,J=15.5,3.9Hz,1H),3.61(s,4H),2.51(s,2H),2.50(s,4H).

[0381] Example 61: Synthesis of 2-fluoro-N-(5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (61)

[0382]

[0383] Step 1: Synthesis of 7-amino-5-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (61-a)

[0384] 5-Methyl-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2-d, 30 mg, 0.097 mmol) was dissolved in dioxane (2 mL) and water (2 mL), and sodium sulfide nonahydrate (77 mg, 0.32 mmol) was added at 15°C, and nitrogen was replaced 3 times. The reaction was allowed to react at room temperature for 3 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate three times, and the organic phase was washed with saturated brine three times, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product, which was purified by thin layer chromatography on silica gel plates (ethyl acetate: petroleum ether = 1:1) to obtain the target product 7-amino-5-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (61-a, 17 mg, yield 62.5%). ESI[M+H] + =280.2

[0385] Step 2: Synthesis of 2-fluoro-N-(5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (61)

[0386] 7-Amino-5-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (61-a, 17 mg, 0.061 mmol) was dissolved in acetonitrile (2 mL), 2-fluoroacrylic acid (10 mg, 0.12 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (34 mg, 0.12 mmol) and 1-methylimidazole (20 μL, 0.24 mmol) were added, and the mixture was reacted at room temperature overnight. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared by liquid phase preparation [Pack Column 30 ID*250mm*10μm; A:H 2 O (0.01% TFA), B: ACN, B%: 10%-80% over 27 min] to obtain the target product 2-fluoro-N-(5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (61, 1.7 mg, yield 7.9%). ESI [M+H] + =352.2 1 H NMR (400 MHz, DMSO-d 6 )δ10.66(s,1H),9.39(s,1H),8.06(s,1H),7.90(s,1H),5.78(dd,J=47.4,3.5Hz,1H),5.51(dd,J=15.5,3.7Hz,1H),2.62(s,3H).

[0387] Example 62: Synthesis of 1-fluoro-N-(5-(morpholinomethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (62)

[0388]

[0389] 7-amino-5-(morpholinomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60-b, 40 mg, 0.11 mmol) was dissolved in acetonitrile (3 mL), 1-fluorocyclopropane-1-carboxylic acid (23 mg, 0.22 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (62 mg, 0.22 mmol) and 1-methylimidazole (36 μL, 0.44 mmol) were added, and the mixture was reacted at room temperature overnight. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared by liquid phase preparation [Pack Column 30 ID*250 mm*10 μm; A:H 2 O (0.01% TFA), B: ACN, B%: 10%-80% over 33 min] to obtain the target product 1-fluoro-N-(5-(morpholinomethyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (62, 8.11 mg, yield 16.5%). ESI [M+H] + =451.2 1 H NMR (400 MHz, DMSO-d 6 )δ10.71(s,1H),9.26(s,1H),8.16(d,J=2.0Hz,1H),8.02(d,J=2.2Hz,1H),3.75(s,2H),3.55(t,J =4.6Hz,4H),2.54–2.48(m,2H),2.48–2.46(m,2H),1.50–1.44(m,2H),1.36(tt,J=9.2,5.0Hz,2H).

[0390] Example 63: Synthesis of 1-fluoro-N-(5-((4-methylpiperazin-1-yl)methyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (63)

[0391]

[0392] 7-amino-5-((4-methylpiperazin-1-yl)methyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (59-b, 20 mg, 0.053 mmol) was dissolved in acetonitrile (2 mL), 2-fluoroacrylic acid (11 mg, 0.11 mmol), N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (31 mg, 0.11 mmol) and 1-methylimidazole (26 μL, 0.22 mmol) were added, and the mixture was reacted at room temperature overnight. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared by liquid phase preparation [Pack Column 30ID*250mm*10μm; A:H 2 O (0.01% TFA), B: ACN, B%: 10%-80% over 33min] to obtain the target product 1-fluoro-N-(5-((4-methylpiperazin-1-yl)methyl)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)cyclopropane-1-carboxamide (63, 2.69 mg, yield 6.4%). ESI [M+H] + =464.2 1 H NMR (400 MHz, DMSO-d 6 )δ9.46(s,1H),9.25(s,1H),8.15(d,J=1.9Hz,1H),8.05(d,J=1.9Hz,1H),3.85(s,2H),3.39(d,J=11.9Hz,2H),3.06(d,J=12.8Hz, 2H),2.97(d,J=10.9Hz,2H),2.77(s,3H),2.40(t,J=11.7Hz,2H),1.49(ddd,J=18.1,8.6,5.5Hz,2H),1.36(dt,J=14.7,7.3Hz,2H).

[0393] Example 64: Synthesis of 2-fluoro-N-(9-oxo-5-(piperazin-1-ylmethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (64)

[0394]

[0395] Step 1: Synthesis of 5-(bromomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (64-a)

[0396] 5-(Bromomethyl)-7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (I-2, 150 mg, 0.39 mmol) was dissolved in ethanol (5 mL), 1M hydrochloric acid aqueous solution (5 mL) and stannous chloride (163 mg, 1.16 mmol) were added, nitrogen was replaced 3 times, and the reaction was carried out at 50°C for 2 hours. After the reaction was completed, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate three times, the organic phase was washed with saturated brine three times, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product, which was purified by a preparative plate to obtain the target product 7-amino-5-(morpholinomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (64-a, 80 mg, yield 57.6%).

[0397] Step 2: Synthesis of tert-butyl 4-((7-amino-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-5-yl)methyl)piperazine-1-carboxylate (64-b)

[0398] 7-amino-5-(morpholinomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (64-a, 80 mg, 0.224 mmol) was dissolved in N,N-dimethylformamide (4 mL), and tert-butyl piperazine-1-carboxylate (49 mg, 0.27 mmol) and diisopropylethylamine (57 μL, 0.33 mmol) were added. The mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate three times, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by Flash column (petroleum ether: ethyl acetate = 0-40%) to obtain the target product 4-((7-amino-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-5-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (64-b, 50 mg, yield 49.1%). ESI [M+H] + =464.2

[0399] Step 3: Synthesis of tert-butyl 4-((7-(2-fluoroacrylamide)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-5-yl)methyl)piperazine-1-carboxylate (64-c)

[0400] Dissolve tert-butyl 4-((7-amino-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-5-yl)methyl)piperazine-1-carboxylate (64-b, 50 mg, 0.11 mmol) in acetonitrile (3 mL), add 1-fluorocyclopropane-1-carboxylic acid (23 mg, 0.22 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (62 mg, 0.22 mmol) and 1-methylimidazole (36 μL, 0.44 mmol), and react at room temperature overnight. After the reaction, the reaction was quenched with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate to obtain a crude product, which was purified by Flash column (petroleum ether: ethyl acetate = 0-40%) to obtain the target product 4-((7-(2-fluoroacrylamide)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-5-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (64-c, 25 mg, yield 42.1%). ESI[M+H] + =536.2

[0401] Step 4: Synthesis of 2-fluoro-N-(9-oxo-5-(piperazin-1-ylmethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (64)

[0402] Dissolve tert-butyl 4-((7-(2-fluoroacrylamide)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-5-yl)methyl)piperazine-1-carboxylate (64-c, 25 mg, 0.047 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (0.6 mL), and react at room temperature for 2 hours. After the reaction is completed, concentrate under reduced pressure to prepare a liquid phase [Pack Column 30ID*250mm*10μm; A:H 2 O (0.01% TFA), B: ACN, B%: 10%-80% over 33min] purification to obtain the target product 2-fluoro-N-(9-oxo-5-(piperazin-1-ylmethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acrylamide (64, 0.98 mg, yield 4.78%). ESI [M+H] + =436.2 1 HNMR (400 MHz, DMSO-d 6)δ10.76(s,1H),9.26(s,1H),8.61(s,1H),8.17(d,J=1.9Hz,1H),8.05(d,J=1.7Hz,1H),5.79(dd,J=47 .5,3.9Hz,1H),5.53(dd,J=15.5,3.9Hz,1H),3.87(s,2H),3.07(s,3H),2.69(s,3H),2.53–2.51(m,2H).

[0403] Test Example 1: Bioluminescence test of compounds inhibiting USP21 enzyme activity

[0404] Experimental reagents and instruments:

[0405] GST-USP21 protein (Boston Biochem), Ub-AML (aminofluorescein labeled ubiquitin, Boston Biochem), DUB buffer (50 mM HEPES, pH 7.8, 100 mM NaCl, 0.5 mM EDTA, 0.01% (v / v) Tween-20, 1 mM DTT), luciferin detection reagent (Promega), DMSO. Microplate reader (TECAN), white 384-well plate, microplate constant temperature oscillator.

[0406] Bioluminescence assay to test the inhibitory activity of compounds on USP21 catalytic activity:

[0407] Ub-AML was diluted to 3 μM with 50 mM HEPES, pH 7.5, and the diluted Ub-AML solution and luciferin detection reagent were used to prepare Ub-AML-LDR reagent in a ratio of 1:9. GST-USP21 was diluted to 8 nM with DUB buffer and transferred to a 384-well plate, and incubated with the diluted compound in a microplate constant temperature oscillator for 30 minutes (30°C, 500 rpm). After adding the Ub-AML-LDR reagent to the test well (final concentration: 2 nM GST-USP21, 150 nM Ub-AML), the bioluminescent signal was immediately measured using a TECANSpark multi-mode microplate reader. The detection parameters were: kinetic mode detection of bioluminescence, detection time of 40 minutes, test every two minutes, and integration time of 500 ms. The initial reaction rate (slope of the first-order reaction) of each well was calculated, and the data were analyzed using a 4-parameter logistic model to calculate the IC 50 The results of USP21 enzyme inhibition activity test are as follows:

[0408] For IC 50 Value, where "+++" indicates IC 50Between 0nM and 100nM; "++" indicates IC 50 Between 100nM and 1μM (including 100nM); "+" indicates IC 50 Between 1 μM and 10 μM (including 1 μM).

[0409] Table 1

[0410] Example <![CDATA[Enzymatic activity (IC 50 )]]> Example <![CDATA[Enzymatic activity (IC 50 )]]> 1 ++ 33 +++ 2 +++ 34 ++ 3 +++ 35 ++ 4 ++ 36 +++ 5 + 37 ++ 6 + 38 +++ 7 + 39 +++ 8 ++ 40 ++ 9 ++ 41 +++ 10 ++ 42 +++ 11 ++ 43 ++ 12 ++ 44 +++ 13 +++ 45 +++ 14 ++ 46 +++ 15 ++ 47 +++ 16 ++ 48 +++ 17 ++ 49 ++ 18 ++ 50 ++ 19 + 51 ++ 20 ++ 52 ++ 21 ++ 53 ++ 22 ++ 54 +++ 23 +++ 55 ++ 24 ++ 56 +++ 25 ++ 57 ++ 26 ++ 58 ++ 27 ++ 59 +++ 28 ++ 60 ++ 29 ++ 61 ++ 30 +++ 62 ++ 31 ++ 63 +++ 32 ++ 64 +++

[0411] Test Example 2 Cell Proliferation Inhibition Activity Test

[0412] PANC-1 human pancreatic cancer cells and JIMT-1 human breast cancer cells were cultured in complete culture medium at 37°C and 5% CO. 2 After the cells in the logarithmic growth phase were digested and counted, the density was adjusted to 1.11 x 10 4 cells / mL, and 45 μL per well was inoculated in a 384-well cell culture plate (Greiner, 781098) and placed at 37°C with 5% CO 2 Incubate overnight in an incubator. The next day, prepare the test compound into a 10mM stock solution with DMSO, and dilute it 3-fold with DMSO starting from the highest dose of 10μM, setting a total of 8 concentration points, and then dilute it into working solutions of different concentrations with complete culture medium, add them to the corresponding wells, set 2 parallel wells for each well, set DMSO wells as negative controls, and finally all test wells have the same DMSO content of 0.1%. Incubate at 37°C, 5% CO 2 After 72 hours of continuous culture in an incubator, (Promega, G7571) reagent was used for detection, luminescence signal was detected by TECAN microplate reader Luminescence module, and the curve was fitted by GraphPad Prism software 4 parameter method to calculate IC 50 value.

[0413] The results of the cell proliferation inhibition activity test are shown in Table 2 below:

[0414] For IC 50 Value, where "+++" indicates IC 50 Between 0nM and 100nM; "++" indicates IC 50 Between 100nM and 1μM (including 100nM); "+" indicates IC 50 Between 1 μM and 10 μM (including 1 μM).

[0415] The results show that the compounds of the present invention exhibit strong cell proliferation inhibition activity on both PANC-1 pancreatic cancer cells and JIMT-1 human breast cancer cells.

[0416] Table 2

[0417]

[0418] The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made in accordance with the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. The scope of the present invention is intended to be limited by the claims and their equivalents.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof: In formula (I), R 1 Selected from -R 4 -C(O)-C 2-6 Alkenyl, -C 2-6 Alkenyl, -N=NR a R b , -R 4 -C(O)-C 2-6 Alkynyl, -R 4 -SO2-C 2-6 Alkenyl, -R 4 -C(O)-C 1-3 Alkyl, -R 4 -C 2-6 Alkynyl, -R 4 -C(O)-C 3-9 Cycloalkyl, -R 4 -C(O)-3 to 9-membered heterocycloalkyl, -R 4 -C 1-3 Alkyl-C 3-9 Cycloalkyl, -R 4 -C 3-9 Cycloalkyl, -C(O)-NH-C 2-6 Alkynyl, -C(O)-NH-C 2-6 Alkenyl, -C(O)-NH-C 1-3 Alkyl or The C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1, 2 or 3 groups independently selected from hydrogen, halogen, cyano, -CF3, C 1-6 alkyl, 3- to 9-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 6-10 Aryl, -C 1-3 Alkyl-NR a R b , -C 1-3 Alkyl-hydroxy, -C(O)OR a 、-C(O)NR a R b 、-NR a R b Substituents are substituted, the C 1-3 Alkyl, C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, C 1-6 The alkyl group is optionally substituted by 1, 2 or 3 groups independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF3, C 1-6 alkoxy, -O-3 to 9 membered heterocycloalkyl, -O-5 to 10 membered heteroaryl, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO2-C 1-3 Alkyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 alkoxy, 5- to 10-membered heteroaryl, 6- to 10-membered aryl, -NHC(O)-C 2-6 Alkenyl, -NHC(O)-C 2-6 Substitution of alkynyl groups by substituents; R 4 Selected from NH, NR a or CR a R b ; R a , R b are each independently selected from hydrogen, C 1-3 Alkyl, C 3-9 Cycloalkyl, the C 1-3 Alkyl, C 3-9 The cycloalkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, hydroxy, carboxyl, -CF3, C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO2C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Substitution of alkoxy groups; R 5 , R 6 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 9 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, hydroxyl, carboxyl, -CF3, C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO2-C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Substitution of alkoxy groups; R 2 , R 3 are independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b 、-C(O)-C 1-3 Alkyl, -C(O)NR a R b 、-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-C 2-6 Alkynyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-NR a R b , -C 2-6 Alkenyl, -C 2-6 Alkynyl, 5- to 10-membered heteroaryl, C 6-10 Aryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl, C 2-6 Alkynyl, C 2-6 alkenyl, 5- to 10-membered heteroaryl, C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF3 substituents; The halogen is selected from fluorine, chlorine or bromine; U 1 , U 2 , U 3 Each independently selected from CR 7 or CH, or adjacent U 2 , U 3 Connected to each other to form a 6- to 10-membered aromatic group; The R 7 Selected from hydrogen, C 1-3 Alkyl, C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, -C 1-3 Alkyl-3 to 9 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-9 Cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF3, C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO2C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -NHC(O)-C 2-6 Alkenyl, -NHC(O)-C 2-6 Substitution of alkynyl groups by substituents; The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom.

2. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein: R 1 Selected from -R 4 -C(O)-C(R 8 )=CR 9 R 10 ,-C(R 8 )=CR 9 R 10 ,-C(R 8 )=C(R 9 )-C(O)-NH2、-R 4 -C(O)-C(R 8 )=C(R 9 )-C(O)-NH2、-R 4 -C(O)-C(R 8 )=C(R 9 )-C(O)-OR 10 , -R 4 -C(O)-C(R 8 )=C(R 9 )-CH2-NR a R b 、-N=NR a , -R 4 -SO2-C(R 8 )=CR 9 R 10 , -R 4 -C(O)-R 5 , -C(O)-NH-C 1-3 Alkyl, -R 4 -C(O)-C 1-3 Alkyl-R 4 -C(O)-C(R 8 )=CR 9 R 10 、-C(O)-R 4 -C 1-3 Alkyl-R 4 -C(O)-C(R 8 )=CR 9 R 10 , -R 4 -CH2-C 3-9 Cycloalkyl or The C 1-3 Alkyl, C 3-9 The cycloalkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF3, C 1-6 Substitution of alkoxy groups; R 4 Select from NH or NR a ; R 5 , R 6 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 9 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, hydroxyl, carboxyl, -CF3, C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO2-C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Substitution of alkoxy groups; R 8 , R 9 , R 10 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 9-membered heterocycloalkyl, -C 1-3 Alkyl-C 6-10 Aryl, -C 1-3 Alkyl-5 to 10 membered heteroaryl, -C 1-3 Alkyl-3 to 9 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-6 Alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 9-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF3, -C 1-6 Substitution of alkoxy groups; R a , R b are each independently selected from hydrogen, C 1-3 Alkyl, C 3-9 Cycloalkyl, the C 1-3 Alkyl, C 3-9 The cycloalkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, hydroxy, carboxyl, -CF3, C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO2C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Substitution of alkoxy groups; R 2 , R 3 are independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b , the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 groups independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF3 substituents; The halogen is selected from fluorine or chlorine; U 1 , U 2 , U 3 Each independently selected from CR 7 or CH, or adjacent U 2 , U 3 Connected to each other to form a 6- to 10-membered aromatic group; The R 7 Selected from hydrogen, C 1-3 Alkyl, C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, -C 1-3 Alkyl-3 to 9 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-9 Cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 independently selected from -H, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -NR a R b , hydroxyl, carboxyl, -CF3, C 1-6 Alkoxy, -C(O)OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -SO2C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -NHC(O)-C 2-6 Alkenyl, -NHC(O)-C 2-6 Substitution of alkynyl groups by substituents; The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom.

3. The compound according to claim 1-2, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein: The R 1 Selected from The R 2 , R 3 Each independently selected from H, CF3; The U 1 , U 2 , U 3 All selected from CH, or adjacent U 2 , U 3 They are connected to each other to form a benzene ring; The R 7 Selected from -H, -CH3, 4. The compound according to claim 1-3, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein formula (I) is represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13), formula (II-14), formula (II-15), formula (II-16) or formula (II-17): R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a The definition as described in any one of claims 1 to 3.

5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein: The compound is selected from the group consisting of:

6. A method for preparing a partial compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, comprising the following steps: Compound (III-1) undergoes an amidation reaction with compound (Y) to generate compound (III-2); The compound (Y) includes any one of acyl chloride, carboxylic acid or sulfonyl chloride; The R 1 , R 2 , R 3 , R 7 The definition as described in any one of claims 1-5.

7. A pharmaceutical composition, characterized in that The composition comprises the compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or the compound prepared by the method according to claim 6 and at least one pharmaceutically acceptable excipient.

8. Use of the compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or the compound prepared by the method according to claim 6, or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating cardiovascular disease, neurological disorder, cancer or immune disease, or in the preparation of a kit for evaluating cardiovascular disease, neurological disorder, cancer, immune disease or patient prognosis; Preferably, the pharmaceutical composition further comprises another drug for treating cardiovascular disease, neurological disorder, cancer or immune disease; Preferably, use in the preparation of a method for treating a disease associated with USP21 activity; Preferably, the cancer includes prostate cancer, bile duct cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, esophageal squamous cell carcinoma and leukemia; More preferably, the cancer includes pancreatic cancer, bile duct cancer, esophageal squamous cell carcinoma, liver cancer, breast cancer, kidney cancer, bladder cancer and lung cancer.

9. Use of the compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or the compound prepared by the method according to claim 6, or the pharmaceutical composition according to claim 7 in the preparation of a USP inhibitor; Preferably, the invention relates to a method for preparing a USP21 inhibitor.

10. A method for treating a USP mutation or amplification-related disease in a patient in need thereof, comprising administering to the patient a compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to claim 7; The USP mutation or amplification includes USP21 mutation or amplification; Preferably, the USP mutation or amplification-related diseases include cardiovascular diseases, neurological disorders, cancer, and immune diseases; Preferably, the cancer includes prostate cancer, bile duct cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, esophageal squamous cell carcinoma and leukemia; More preferably, the cancer includes pancreatic cancer, bile duct cancer, esophageal squamous cell carcinoma, liver cancer, breast cancer, kidney cancer, bladder cancer and lung cancer.

11. A method for inhibiting USP mutations in a biological sample for non-disease diagnosis or treatment purposes, comprising contacting the biological sample with a compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, or a compound prepared by the method according to claim 6, or a pharmaceutical composition according to claim 7.

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