CN116621778A - USP inhibitor, its preparation method and application - Google Patents

Abstract

The present disclosure provides a compound having an inhibitory effect on USP, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, as shown in formula (I), wherein each group is defined in the specification. In addition, the present disclosure also discloses a preparation method of the compound, a pharmaceutical composition containing the compound, an application of the compound in preparing a USP inhibitor, preparing a medicament for treating cardiovascular diseases, nerve disorders, cancers and immune diseases or preparing a kit for prognosis evaluation of cardiovascular diseases, nerve disorders, cancers, immune diseases or patients, and a method for inhibiting USP activity in biological samples and a method for treating USP 21-mediated diseases, cardiovascular diseases, nerve disorders, cancers or immune diseases.

Description

USP inhibitor, preparation method and application thereof

Technical Field

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

The ubiquitin-specific 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.

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 leads to various human diseases such as cardiovascular disease, neurological disorders and tumors (Development of inhibitors in the ubiquitination cascade, Wei Zhang, Sachdev S Sidhu, FEBS Lett. 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), MJD proteases (Machado-Josephin domain proteases, MJDs), Jab1/MPN domain associated metalloproteases (JAMMs), UFM1-specific zinc finger peptidases (ZUFSPs) and MIU-containing novel DUB family (MINDY) (Jinhong et al., 2020).

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 a variety of 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.).

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 oncogenic 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, liver cancer, breast cancer (triple-negative breast cancer), kidney cancer, bladder cancer, lung cancer, 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) (TRIM25RING-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. 2007 Apr 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.

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

The present disclosure provides a novel substituted fused ring aromatic compound, which has high inhibitory activity as a USP enzyme inhibitor. In one aspect of the present disclosure, a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof is provided:

The Cy1 ring is a 5-7 membered aromatic ring or a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S;

U ₁ , U ₂ , and U ₃ are each independently selected from CH, CR4 or N;

X ₁ and X ₂ are independently selected from hydrogen, -C _1-6 alkyl, -NR ₅ R ₆ , -OR ₅ , -SR ₅ , halogen, or X ₁ and X ₂ together form =O, =S, =NR ₅ , or X ₁ , X ₂ and the atoms to which they are attached together form a 4- to 6-membered cycloalkyl, and the 4- to 6-membered cycloalkyl is optionally substituted with a carbonyl group; provided that X ₁ and X ₂ are not simultaneously -NR ₅ R ₆ , -OR ₅ or -SR ₅ ;

R ₁ , R ₂ , and R ₃ are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -NR ^a R ^b , -C(O)-C _1-3 alkyl, -C(O)NR ^a R ^b , -S(O) ₂ C _1-3 alkyl, -C _1-3 alkyl-hydroxy, -C _1-3 alkyl-C _2-4 alkynyl, -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _1-6 alkoxy, -C _1-3 alkyl-3 to 9-membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -OC _1-3 alkyl-3 to 9-membered heterocycloalkyl, -C _1-3 alkyl-NR ^a R ^b , -C(NH)NR ^a R ^b , -C _1-3 alkyl-C(O)-C _1-3 alkyl, -C _1-3 alkyl-C(O)NR ^a R ^b , -C _1-3 alkyl-S(O) ₂ C _1-3 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 5- or 6-membered heteroaryl, C _5-7 aryl, -SR ₇ , -C(O)OC _1-3 alkyl, -S(O) ₂ -NR ^a R ^b , -NR ^a -S(O) ₂ R ^b , -S(O)NH, -CHO or -NO ₂ ; and the -C _1-3 alkyl, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -C _1-3 alkyl-3 to 9-membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl, 5 or 6-membered heteroaryl, C 5-7 aryl _5-7 aryl is optionally substituted with 1, 2 or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -N(CH ₃ ) ₂ , hydroxy, carboxyl or -CHO;

n is an integer from 1 to 3:

R ₄ is selected from hydrogen, halogen, cyano, hydroxyl, -C _1-3 alkyl, -C _1-3 alkoxy, amino, alkynyl, or adjacent R ₃ and R ₄ are connected to each other to form a C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl, provided that at least one of U ₁ and U ₂ is CR ₄ ; the -C _1-3 alkyl, -C _1-3 alkoxy, -C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, amino;

_R5 , _R6 , _R7 are each independently selected from hydrogen, halogen, cyano, hydroxy, _-C1-6 alkyl, _-C1-6 alkoxy, _-C3-9 cycloalkyl, ₃ to 9 membered heterocycloalkyl, ^-NRaRb , -S(O) _2C1-3alkyl , -C1-3alkyl-hydroxy, -C1-3alkyl-C2-4alkynyl, ^-C1-3alkyl -cyano, _-C1-3alkyl ^- _C1-6alkoxy , _-C1-3alkyl - ₃ to ₉ membered heterocycloalkyl, -C1-3alkyl-C3-9cycloalkyl, _-C1-3alkyl - ^RaRb , _-C1-3alkyl - _C (O) _{H , -C1-3alkyl} ^- _C (O) _-C1-3alkyl , _-C1-3alkyl -C(O) ^NRaRb , _-C2-6alkenyl or -C and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl is optionally substituted by 1, ₂ or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino, -N(CH ₃ ) ₂ , hydroxyl, carboxyl; or,

When _X1 or _{X2 is -NR5R6} , _R5 , _R6 and the N atom to which they are attached together form a 5- or 6-membered heterocycloalkyl group, and the 5- or 6-membered heterocycloalkyl group is optionally substituted by a substituent selected from _C1-6 alkyl groups;

R ^a and R ^b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-3 alkyl, deuterated C _1-3 alkyl, C _1-3 alkylhydroxyl, C _3-9 cycloalkyl or -C(O)R ₇ ;

The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;

R ₁ , R ₂ , R ₃ and R ₄ are not hydrogen at the same time.

As used herein, adjacent R ₃ and R ₄ are connected to each other to form a C _3-6 cycloalkyl or a 3-7 membered heterocyclyl means that adjacent R ₃ and R ₄ are connected to each other and, together with the atoms on the ring to which they are connected, form a C _3-6 cycloalkyl or a 3-7 membered heterocyclyl.

Preferably, X ₁ and X ₂ are not hydrogen atoms at the same time.

In one embodiment, the compound does not include

In one embodiment, in the compound represented by formula (I), n is 1.

The Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S;

U ₁ , U ₂ , and U ₃ are each independently selected from CH, CR ₄ or N;

X ₁ and X ₂ are independently selected from hydrogen, -NR ₅ R ₆ , -OR ₅ , -SR ₅ , halogen, or X ₁ and X ₂ together form ═O, ═S, ═NR ₅ , or X ₁ , X ₂ and the atoms to which they are attached together form a 4- to 6-membered cycloalkyl group, which is optionally substituted with a carbonyl group; provided that X ₁ and X ₂ are not NR ₅ R ₆ , OR ₅ , or SR ₅ at the same time;

_R1 , _R2 , and _R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, _C1-6 alkyl, _C1-6 alkoxy, _C3-9 cycloalkyl, 3 to ₉ membered heterocycloalkyl, ^-NRaRb , -C(O) _-C1-3 ^alkyl , -C(O ^{) NRaRb} , -S(O)2C1-3 alkyl, _-C1-3 alkyl-hydroxy, _-C1-3 alkyl- _C2-4 alkynyl, _-C1-3 alkyl- _cyano , _-C1-3 alkyl- _C1-6 alkoxy, _-C1-3 alkyl ^- 3 to 9 membered heterocycloalkyl, _-C1-3 alkyl- _C3-9 cycloalkyl, -O-3 to 9 membered heterocycloalkyl, _-C1-3 alkyl- ^NRaRb , -C(N) ^NRaRb , _-C1-3 alkyl- ^C (O)-C -C _1-3 alkyl, -C _1-3 alkyl-C(O)NR ^a R ^b , -C _1-3 alkyl-S(O) ₂ C _1-3 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 5- or 6-membered heteroaryl or C _5-7 aryl; and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -C _1-3 alkyl-3 to 9-membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl, 5 or 6-membered heteroaryl, C _5-7 aryl are optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, N(CH ₃ ) ₂ , hydroxyl, carboxyl;

R ₄ is selected from hydrogen, halogen, cyano, hydroxyl, -C _1-3 alkyl, -C _1-3 alkoxy, amino, alkynyl, or adjacent R ₃ and R ₄ are connected to each other to form a C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl, provided that at least one of U ₁ and U ₂ is CR ₄ ; the -C _1-3 alkyl, -C _1-3 alkoxy, -C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino;

R ₅ and R ₆ are each independently selected from hydrogen, halogen, cyano, hydroxy, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR ^a R ^b , -S(O) ₂ C _1-3 alkyl, -C _{1-3 alkyl-hydroxy, -C 1-3 alkyl} -C _2-4 alkynyl, -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _1-6 alkoxy, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl, -C _1-3 alkyl-R ^a R ^b , -C _1-3 alkyl-C(O)H, -C _1-3 alkyl-C(O)-C _1-3 alkyl, -C _1-3 alkyl-C(O)NR ^a R ^b , -C _2-6 alkenyl, -C and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl are optionally substituted by 1, ₂ or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, amino, N(CH ₃ ) ₂ , hydroxyl, carboxyl;

R ^a and R ^b are each independently selected from hydrogen, C _1-3 alkyl or C _3-9 cycloalkyl;

The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;

R ₁ , R ₂ and R ₃ , R ₄ are not hydrogen at the same time.

In one embodiment, the Cy1 ring is an imidazole ring, a benzene ring, a pyridine ring or a pyrimidine ring, preferably a benzene ring, a pyridine ring or a pyrimidine ring. In one embodiment, the compound represented by formula (I) is a compound represented by formula (II), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof:

In the formula,

U ₁ , U ₂ , U ₃ , U ₄ , U ₅ are each independently selected from CH, CR ₄ or N;

X ₁ and X ₂ are independently selected from hydrogen, -C _1-6 alkyl, -NR ₅ R ₆ , -OR ₅ , -SR ₅ , halogen, or X ₁ and X ₂ together form =O, =S, =NR ₅ , or X ₁ , X ₂ and the atoms to which they are attached together form a 4- to 6-membered heterocycloalkyl, which is optionally substituted with a carbonyl group; provided that X ₁ and X ₂ are not simultaneously -NR ₅ R ₆ , -OR ₅ or -SR ₅ ;

In one embodiment, X ₁ and X ₂ are independently selected from hydrogen, -NR ₅ R ₆ , -OR ₅ , -SR ₅ , halogen, or X ₁ and X ₂ together form ═O, ═S, ═NR ₅ , or X ₁ , X ₂ and the atoms to which they are attached together form a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with a carbonyl group; provided that X ₁ and X ₂ are not NR ₅ R ₆ , OR ₅ , or SR ₅ at the same time.

_R1 , _R2 , and _R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, _-C1-6 alkyl, _-C1-6 alkoxy, _-C3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, ^-NRaRb , _-C (O) _-C1-3 alkyl, -C ⁽ O ^{) NRaRb} , -S(O)2C1-3 alkyl, _-C1-3 alkyl-hydroxy, _-C1-3 alkyl- _cyano , _-C1-3 alkyl- _C1-6 alkoxy, _-C1-3 alkyl-3 to 9-membered heterocycloalkyl, _-C1-3 alkyl- _C3-9 cycloalkyl ^, -O-3 to 9-membered heterocycloalkyl, _-OC1-3 alkyl-3 to 9-membered heterocycloalkyl, _-C1-3 alkyl- ^NRaRb , -C(NH) ^{NRaRb ,} -C _-C1-3 alkyl-C(O) _-C1-3 alkyl, _-C1-3 alkyl-C(O) ^NRaRb , _-C2-6 alkynyl, 5 or 6 membered ^heteroaryl , _C5-7 aryl, _-SR7 , -C(O) _OC1-3 alkyl, -S(O ⁾ _2NRaRb , -NRa ^- S(O) ^2Rb , -S(O)NH, ^-CHO , _-NO2 ; and said _-C1-3 alkyl, _-C1-6 alkyl, _-C1-6 alkoxy, _-C3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, ₅ or 6 membered heteroaryl, _C5-7 aryl is optionally substituted with 1, 2 or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -N( _CH3 ) ₂ , hydroxyl, carboxyl;

In one embodiment, R ₁ , R ₂ , and R ₃ are each independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR ^a R ^b , -C(O)-C _1-3 alkyl, -C(O)NR ^a R ^b , -S(O) ₂ C _1-3 alkyl, -C _1-3 alkyl-hydroxy, -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _1-6 alkoxy, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl, -O-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-NR ^a R ^b , -C(N)NR ^a R ^b , -C _1-3 alkyl-C(O)-C _1-3 alkyl, -C wherein the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to ₉ membered heterocycloalkyl, 5 or 6 membered heteroaryl, C _{5-7 aryl} is ^optionally substituted with ^propyl , isopropyl, cyano, amino, N(CH ₃ ) ₂ , hydroxyl, or carboxyl _.

R ₄ is selected from hydrogen, halogen, cyano, hydroxyl, -C _1-3 alkyl, or adjacent R ₃ and R ₄ are connected to each other to form a C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl, provided that at least one of U ₁ and U ₂ is CR ₄ ; the -C _1-3 alkyl, -C _1-3 alkoxy, -C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, amino;

In one embodiment, R ₄ is selected from hydrogen, halogen, cyano, hydroxyl, -C _1-3 alkyl, or adjacent R ₃ and R ₄ are connected to each other to form a C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl, provided that at least one of U ₁ and U ₂ is CR ₄ ; the -C _1-3 alkyl, -C _1-3 alkoxy, -C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, amino, etc.

R ₅ , R ₆ , and R ₇ are each independently selected from hydrogen, halogen, cyano, hydroxy, -C _1-6 alkyl, -C _1-6 alkoxy, -C _1-3 alkyl-C(O)H, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-hydroxy; and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino, -N(CH ₃ ) ₂ , hydroxy, and carboxyl;

In one embodiment, R ₅ and R ₆ are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C _1-6 alkyl, -C _1-6 alkoxy, -C _1-3 alkyl-C(O)H, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-hydroxyl; and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, amino, N(CH ₃ ) ₂ , hydroxyl, and carboxyl.

R ^a and R ^b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-3 alkyl, C _1-3 alkoxy, C _3-9 cycloalkyl or -C(O)R ₇ ;

In one embodiment, ^Ra , ^Rb are each independently selected from hydrogen, _C1-3 alkane or _C3-9 cycloalkyl.

The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;

R ₁ , R ₂ and R ₃ , R ₄ are not hydrogen at the same time.

In one embodiment, U ₁ , U ₂ , U ₃ , U ₄ , U ₅ are each independently selected from CR ₄ .

In one embodiment, U ₁ , U ₂ , U ₃ , and U ₅ are each independently selected from CR ₄ , and U ₄ is N.

In one embodiment, U ₁ , U ₂ , U ₃ , and U ₄ are each independently selected from CR ₄ , and U ₅ is N.

In one embodiment, U ₁ , U ₂ , and U ₃ are each independently selected from CR ₄ , and U ₄ and U ₅ are both N.

In one embodiment, U ₂ and U ₃ are each independently selected from CR ₄ , and U ₁ , U ₄ and U ₅ are all N.

In one embodiment, U ₃ is selected from CR ₄ , and U ₁ , U ₂ , U ₄ , and U ₅ are all N.

In one embodiment, the compound represented by formula (I) is a compound represented by formula (III), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

In the formula,

The Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S; _R1 , _R2 , _R3 , _U1 , _U2 , _U3 and n are the same as those of the compound of formula (I) or (II); preferably, n is 1.

In one embodiment, the compound represented by formula (I) is a compound represented by formula (VII), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

In the formula,

Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S; _R1 , _R2 , _R3 , _R5 , _U1 , _U2 , _U3 and n are the same as those of the compound of formula (I) or (II); preferably, n is 1.

In one embodiment, the compound represented by formula (I) is compound (IIA), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

In the formula,

X ₁ and X ₂ are independently selected from hydrogen, -NR ₅ R ₆ , -OR ₅ , -SR ₅ , halogen, or X ₁ and X ₂ together form ═O, ═S, ═NR ₅ , or X ₁ , X ₂ and the atoms to which they are attached together form a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with a carbonyl group; provided that X ₁ and X ₂ are not NR ₅ R ₆ , OR ₅ , or SR ₅ at the same time;

_R1 , _R2 , and _R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, _-C1-6 alkyl, _-C1-6 alkoxy, _-C3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, ^-NRaRb , -C(O) _-C1-3 ^alkyl , -C(O ^{) NRaRb} , -SO2C1-3 alkyl, _-C1-3 alkyl _{- hydroxy} , -C1-3 alkyl-cyano, _-C1-3 alkyl- _{C1-6 alkoxy} , _-C1-3 alkyl-3 to 9-membered heterocycloalkyl, _-C1-3 alkyl- _C3-9 cycloalkyl, -O-3 to 9 ^- membered heterocycloalkyl, _-OC1-3 alkyl-3 to 9-membered heterocycloalkyl, _-C1-3 alkyl- ^NRaRb , -C(NH) ^NRaRb , _-C1-3 alkyl- ^C (O)-C -C _1-3 alkyl, -C _1-3 alkyl-C(O)NR ^a R ^b , -C _2-6 alkynyl, 5 or 6 membered heteroaryl, C _5-7 aryl, -SR ₇ , -C(O)OC _1-3 alkyl, -SO ₂ NR ^a R ^b , -NR ^a SO ₂ R ^b , -S(O)NH , -CHO , -NO ₂ ; and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, 5 or 6 membered heteroaryl, C _5-7 aryl is optionally substituted with deuterium, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -N(CH ₃ ) ₂ , hydroxyl, carboxyl substituents;

In one embodiment, R ₁ , R ₂ , and R ₃ are each independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR ^a R ^b , -C(O)-C _1-3 alkyl, -C(O)NR ^a R ^b , -S(O) ₂ C _1-3 alkyl, -C _1-3 alkyl-hydroxy, -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _1-6 alkoxy, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl, -O-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-NR ^a R ^b , -C(N)NR ^a R ^b , -C _1-3 alkyl-C(O)-C _1-3 alkyl, -C wherein the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to ₉ membered heterocycloalkyl, 5 or 6 membered heteroaryl, C _{5-7 aryl} is ^optionally substituted with ^propyl , isopropyl, cyano, amino, N(CH ₃ ) ₂ , hydroxyl, or carboxyl _.

R ₅ , R ₆ , and R ₇ are each independently selected from hydrogen, halogen, cyano, hydroxy, -C _1-6 alkyl, -C _1-6 alkoxy, -C _1-3 alkyl-C(O)H, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-hydroxy; and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino, -N(CH ₃ ) ₂ , hydroxy, and carboxyl;

In one embodiment, R ₅ and R ₆ are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C _1-6 alkyl, -C _1-6 alkoxy, -C _1-3 alkyl-C(O)H, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-hydroxyl; and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, amino, N(CH ₃ ) ₂ , hydroxyl, carboxyl;

R ^a and R ^b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-3 alkyl, C _1-3 alkoxy, C _3-9 cycloalkyl or -C(O)R ₇ ;

In one embodiment, ^Ra , ^Rb are each independently selected from hydrogen, _C1-3 alkane or _C3-9 cycloalkyl;

The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;

R ₁ , R ₂ and R ₃ , R ₄ are not hydrogen at the same time.

In one embodiment, the compound represented by formula (I) is compound (IIB), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

In the formula, X ₁ , X ₂ , R ₁ , R ₂ , and R ₃ are defined as the compound of formula (I) or the compound of formula (IIA).

In one embodiment, the compound represented by formula (I) is compound (IIC), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

In the formula, X ₁ , X ₂ , R ₁ , R ₂ , and R ₃ are defined as the compound of formula (I) or the compound of formula (IIA).

In one embodiment, the compound represented by formula (I) is compound (IID), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

In the formula, X ₁ , X ₂ , R ₁ , R ₂ , and R ₃ are defined as the compound of formula (I) or the compound of formula (IIA).

In one embodiment, the compound represented by formula (I) is compound (IIE), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

In the formula, X, R ₁ , R ₂ and R ₃ are defined as the compound of formula (I) or the compound of formula (IIA).

In one embodiment, the compound represented by formula (I) is compound (IIF), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof:

In the formula, X ₁ , X ₂ , R ₁ , R ₂ , and R ₃ are defined as the compound of formula (I) or the compound of formula (IIA).

In one embodiment, X ₁ and X ₂ are each independently selected from hydrogen, hydroxy, halogen, -C _1-6 alkyl, C _1-3 alkyl substituted or unsubstituted 5- or 6-membered heterocycloalkyl, preferably hydrogen, hydroxy, halogen, methyl, morpholinyl, methyl substituted piperazinyl; or,

X ₁ and X ₂ together form =O, =S or =NR ₅ , wherein R ₅ is selected from hydroxy, -C _1-6 alkoxy, -C _1-3 alkyl-hydroxy, -C _1-3 alkyl-carboxyl, preferably hydroxy, ethoxy, -(CH ₂ ) ₂ OH, -CH ₂ COOH; or,

X ₁ , X ₂ and the atoms to which they are attached together form a carbonyl-substituted C _3-6 cycloalkyl group, preferably a cyclobutyl group.

In one embodiment, X ₁ and X ₂ are each independently selected from hydrogen, hydroxyl, -C _1-6 alkyl, preferably hydrogen, hydroxyl, methyl; or,

X ₁ and X ₂ together form =O or =NR ₅ , wherein R ₅ is selected from hydroxy or -C _1-6 alkoxy, preferably hydroxy or ethoxy.

In one embodiment, R ₁ and R ₂ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyano, dimethylamino, methoxy, methyl, trifluoromethoxy, -CH ₂ CN, -O-CN,

In one embodiment, R ₁ and R ₂ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyano, dimethylamino, methoxy, methyl,

In one embodiment, R ₁ is selected from hydrogen, halogen, cyano, hydroxyl, thiocyano, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR ^a R ^b , -NH-C(O)-C _1-3 alkoxy, -C(O)-C _1-3 alkyl, -C(O)NR ^a R ^b , -S(O) ₂ C _1-3 alkyl, -OC _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C(NH)NR ^a R ^b , 5 or 6 membered heteroaryl; and the -C _1-6 alkyl, 3 to 9 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 halogens;

Wherein, ^Ra and ^Rb are each independently selected from hydrogen or _-C1-3 alkyl.

In one embodiment, R ₁ is selected from hydrogen, F, Cl, hydroxy, amino, cyano, trifluoromethyl, cyclopropyl, thiocyano, dimethylamino, methoxy, methyl,

In one embodiment, _R2 is selected from hydrogen, hydroxy, _-C1-6 alkyl or _-C1-6 alkoxy.

In one embodiment, _R2 is selected from hydrogen, hydroxy, methyl or methoxy.

In one embodiment, in Formula (I), (II), (III), (VII), (IIA), (IIB), (IIC), (IID), (IIE), or (IIF), _R is selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, trifluoromethyl, cyclopropyl, thiocyano, dimethylamino, methoxy, or the following group:

In one embodiment, in Formula (I), (II), (III), (IV), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF), _R2 is selected from hydroxy, methyl, methoxy or trifluoromethyl.

In one embodiment, _R3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxyl, cyclopropyl, ethynyl, phenyl, nitro, amino, isopropyl, -C(O) _OCH3 , -C(O)H, -S- _CF3 , -S(O) _2NH2 , -S(O) _{2 - CF3} , -C(O) _NH2 , -C(O)N( _CH3 ) ₂ , -C(O) _NHOH , -C(O)NHCH3, -C(OH) _{( CH3} ) ₂ , -S(O) _2CH3 , -S(O) _CH2CHO , -CH( _CH3 )OH, _-CH2Br , _-CH2OH , _-CH2COOH ,

In one embodiment, _R3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxyl, cyclopropyl, phenyl, nitro, amino, isopropyl, -C(O) _OCH3 , -C(O)H, -S- _CF3 , -S(O) _2NH2 , -S(O) _{2- CF3 ,} -C(O) _NH2 , -C(O)N( _CH3 ) ₂ , -C(O)NHOH, -C(O) _NHCH3 , -C ₍ OH)(CH3) ₂ , -S(O) _2CH3 , -CH( _CH3 )OH, _{-CH2Br , -CH2OH} , _-CH2COOH ,

In one embodiment, in Formula (I), (II), (III), (IV), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF), R ₃ is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxylic acid or CONH ₂ .

The halogen is selected from fluorine or chlorine.

In one embodiment, R ₄ is selected from halogen, cyano, -C _1-3 alkyl; or, adjacent R ₃ and R ₄ are connected to each other to form a 5- or 6-membered oxygen-containing heterocyclic group.

In one embodiment, R ₄ is selected from halogen, cyano, -C _1-3 alkyl; or, adjacent R ₃ and R ₄ are connected to form

In one embodiment, the compound of Formula (I), (II), (III), (IV), (IIA), (IIB), (IIC), (IID), (IIE), or (IIF) is selected from the group consisting of:

Another aspect of the present disclosure provides a method for preparing the above-mentioned compound. When the compound represented by formula (I) is a compound represented by formula (III) or a compound represented by formula (IV), it is prepared by a method comprising the following steps:

Wherein, Cy1, U ₁ , U ₂ , U ₃ , R ₁ , R ₂ , R ₃ , R ₅ and n are respectively as defined above. Preferably, n is 1.

In one embodiment, the oxidizing agent is selected from the group consisting of tert-butyl hydroperoxide, hydrogen peroxide, cumene hydroperoxide, diisopropylbenzene hydroperoxide, and 2,2,6,6-tetramethylpiperidinoxide.

In one embodiment, the catalyst is selected from tetrabutylammonium halide, potassium halide, sodium halide and elemental iodine.

In one embodiment, the solvent is selected from methanol, ethanol, tert-butanol, isopropanol, n-butanol, sec-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane.

In a preferred embodiment, the oxidizing agent is tert-butyl hydroperoxide.

In a preferred embodiment, the catalyst is tetrabutylammonium iodide.

In a preferred embodiment, the solvent is 1,2-dichloroethane.

The compound of formula (III) is subjected to appropriate carbonylamine condensation reaction with R ₅ —NH ₂ to obtain the compound of formula (IV).

In one embodiment, the compound of formula (III-1) is prepared by a method comprising the following steps:

Wherein, U ₁ , U ₂ , U ₃ , Cy1, R ₁ , R ₂ , R ₃ and n are respectively as defined above, and preferably, n is 1;

_RX and _RX' are selected from halogen atoms, boronic acid groups or boronic ester groups, and the halogen atoms are selected from F, Cl, and Br; provided that when _RX is selected from halogen atoms, _RX' is selected from boronic acid groups or boronic ester groups, and when RX _' is selected from halogen atoms, _RX is selected from boronic acid groups or boronic ester groups.

Preferably, R _x is B(OH) ₂ and R _x' is Br.

Another aspect of the present disclosure 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 a pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutical composition further comprises another drug for treating cardiovascular disease, neurological disorder, cancer or immune disease.

Another aspect of the present disclosure 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 in the preparation of a drug for treating cardiovascular disease, neurological disorder, cancer, immune disease, or a kit for preparing cardiovascular disease, neurological disorder, cancer, immune disease or patient prognosis assessment.

Another aspect of the present disclosure provides a use of the above-mentioned pharmaceutical composition in preparing a drug for treating cardiovascular disease, neurological disorder, cancer, immune disease, or preparing a kit for evaluating cardiovascular disease, neurological disorder, cancer, immune disease or patient prognosis.

In a preferred embodiment, there is provided a use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-mentioned method in the preparation of a drug for treating a disease associated with USP activity, preferably a disease associated with USP21 activity.

In a preferred embodiment, a use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease associated with USP activity, preferably a disease associated with USP21 activity is provided.

In one embodiment, the cancer includes prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, and leukemia.

In a preferred embodiment, the cancer includes pancreatic cancer, liver cancer, breast cancer, kidney cancer, bladder cancer and lung cancer.

In one embodiment, the immune disease is an immune disease associated with USP activity.

Another aspect of the present disclosure provides a use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, the compound prepared by the above-mentioned method, or the above-mentioned pharmaceutical composition in the preparation of a USP inhibitor.

In one embodiment, the USP inhibitor is a USP21 inhibitor.

Another aspect of the present disclosure provides a method for inhibiting USP activity in a biological sample, comprising the step of contacting the biological sample with the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, the compound prepared by the above-mentioned method, and the above-mentioned pharmaceutical composition.

Another aspect of the present disclosure provides a method for treating diseases associated with USP21 activity, cardiovascular diseases, neurological disorders, cancers or immune diseases, comprising the step of administering the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, the compound prepared by the above-mentioned method, or the above-mentioned pharmaceutical composition to a patient in need thereof.

In one embodiment, the cancer includes prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, and leukemia.

In one embodiment, the disease associated with USP21 activity refers to a disease associated with abnormal USP21 activity.

DETAILED DESCRIPTION

I. Definitions

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.

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.

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.

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.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence of said event or circumstance and the non-occurrence of said event or circumstance.

Numeric ranges herein refer to each integer in the given range. For example, "C ₁ -C ₆ " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C ₃ -C ₆ " means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

"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.

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 =0, it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be any on the basis of chemically achievable.

When any variable (e.g., Rn) 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 Rs, the group may be optionally substituted with up to 5 Rs, 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.

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 a lower alkyl group of 1 to 6 carbon atoms, non-limiting examples 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 term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-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.

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is 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.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 12 yuan, more preferably 5 yuan or 6 yuan, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably pyridine, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

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.

"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.

"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.

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.

"-CHO" or "-C(O)H" means "Hydroxy" refers to an -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Carbonyl" refers to -C(O)-.

"Carboxy" refers to -C(O)OH.

"Carboxamidyl" refers to

"THF" refers to tetrahydrofuran.

"EtOAc" means ethyl acetate.

"MeOH" refers to methanol.

"EtOH" refers to ethanol.

"DMF" refers to N,N-dimethylformamide.

"TBAI" refers to tetrabutylammonium iodide.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetylene.

" _PdCl2 (dppf)" refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

"DCE" refers to 1,2-dichloroethane.

"DIPEA" refers to diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"CBZ-CR refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ " refers to tris(dibenzylideneacetone)dipalladium

"Dppf' refers to 1,1'-bis(diphenylphosphino)ferrocene.

"HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

"Boc" refers to tert-butyloxycarbonyl, whose structural formula is

“FA” stands for formic acid.

"ACN" refers to acetonitrile.

"DCM" refers to dichloromethane.

"LDA" refers to lithium diisopropylamide.

"NMI" refers to 1-methyl-1H-imidazole.

"TCFH" refers to N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.

"DIBAL-H" refers to diisobutylaluminum hydride.

"m-CPBA" refers to meta-chloroperbenzoic acid.

"Dioxane" refers to 1,4-dioxane.

"DMSO" refers to dimethyl sulfoxide.

"AIBN" refers to azobisisobutyronitrile.

"TEA" refers to triethylamine. "Oxone" refers to potassium peroxymonosulfonate.

"BINAP" refers to 1,1'-binaphthyl-2,2'-bisdiphenylphosphine.

"iPrOH" refers to isopropyl alcohol.

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

Substituents in Refers to the chemical bond connection. For example, R ₁ is middle, The indicated positions are connected to the Cy1 ring.

Compounds Indicates that stereoisomerism exists at the chemical bond, including the configurations represented by solid wedges and dashed wedges. For example, It means that there is stereoisomerism between the N atom connected to the central five-membered ring of indeno[2,1-d]pyrimidine and the hydroxyl group. The structure of the compound is or a mixture thereof.

Drug or drug composition

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.

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).

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.

The medicament or pharmaceutical composition of the present disclosure can be administered orally, topically, parenterally or mucosally (e.g., buccally, by inhalation or rectally) in a dosage unit formulation containing a conventional non-toxic pharmaceutically acceptable carrier. 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).

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, etc. 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.

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.

The medicine or pharmaceutical composition of the present disclosure can be delivered parenterally, i.e., administered intravenously (i.v.), intracerebroventricularly (i.c.v.), subcutaneously (s.c.), intraperitoneally (i.p.), intramuscularly (i.m.), subcutaneously (s.d.) or intradermally (i.d.), 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 form 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.

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).

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.

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.

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.

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.

Uses and treatments

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.

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.

As used herein, the term "USP21-mediated" disorder, disease and/or condition refers to 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.

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, g′stumor), leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct cancer, choriocarcinoma, seminoma, embryonal tumor, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma and retinoblastoma).

Combination therapy approach

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 through 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.

Example

The present disclosure is further explained below with reference to examples. The description of specific exemplary embodiments of the present disclosure is for the purpose of illustration and demonstration. 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 this application specification. The purpose of selecting and describing 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 various different exemplary embodiments of the present disclosure and various different selections and changes.

Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

Instruments and reagents:

NMR: Agilent 400MR DD2 NMR, the solvents used were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was tetramethylsilane (TMS). LC-MS: Agilent 1260 InfinityII-InfinityLabLC/MSD mass spectrometer. HPLC: Agilent 1260 Infinity II high pressure liquid chromatograph (Sunfire C18 5um 150x 4.6mm column).

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 Finomei ClaricepFlash amorphous silica gel purification column). Reagents: 4-bromo-3-formylbenzonitrile, (2-(trifluoromethyl)pyrimidin-5-yl)boric acid, (2-formyl-4-(trifluoromethyl)phenyl)boric acid, 5-bromo-2-cyclopropylpyrimidine and other reagents and starting materials were purchased from Shanghai Bid or Leyan Reagent Company, or synthesized using methods known in the art.

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.

The following are the intermediate numbers:

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

5-Bromo-2-trifluoromethylpyrimidine (5g, 22.03mmol) was dissolved in tetrahydrofuran (50ml), triisopropyl borate (7.62ml, 33.04mmol) was added, nitrogen was replaced, and the mixture was placed in -85℃ cold hydrazine to cool down. After the temperature dropped to -78℃, n-butyl lithium (11.5ml, 28.64mmol, 2.5M) was slowly added dropwise at a temperature below -70℃. After the addition was completed, the mixture was reacted at this temperature for another hour. Saturated ammonium chloride was added to quench the mixture below 0℃, the pH was adjusted to weak acidity with 1N hydrochloric acid, ethyl acetate was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target crude product 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 4.92g), which was directly used for subsequent reactions. ESI[MH] ⁺ =191.1

Examples 1 and 2: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile and 7-chloro-5-oxo-5H-indeno[1,2-c]pyridine-3-carbonitrile

Step 1: Preparation of 5-(4-chloro-2-formylphenyl)pyridinecarbonitrile (1a)

Dissolve (4-chloro-2-formylphenyl)boronic acid (302mg, 1.64mmol) in methanol (10ml), add 5-bromochloronitrile (200mg, 1.09mmol), potassium fluoride (127mg, 2.19mmol) and palladium acetate (12mg, 0.054mmol), and react at 120℃ for 0.5 hours under microwave. Filter and evaporate the solvent under reduced pressure to obtain the target product crude 5-(4-chloro-2-formylphenyl)pyridinecarbonitrile (1a, 240mg, yield 90.50%). MS (ESI) [M+H] ⁺ 243.0, 245.1.

Step 2: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile (1) and 7-chloro-5-oxo-5H-indeno[1,2-c]pyridine-3-carbonitrile (2)

5-(4-chloro-2-formylphenyl)pyridinecarbonitrile (1a, 240 mg, 0.99 mmol) was dissolved in 1,2-dichloroethane (10 ml), tetrabutylammonium iodide (18 mg, 0.049 mmol) and tert-butyl hydroperoxide (533 mg, 3.96 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube for 5 hours. The impurities were removed by recrystallization from (dichloromethane), and then purified, resolved and freeze-dried using preparative HPLC to obtain two target products, compound 1: 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile (3.2 mg, yield 0.88%), MS (ESI) [M+H] ⁺ 241.1, 243.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.32 (s, 1H), 8.24 (s, 1H), 8.06 (d, J=8, 0 Hz1H), 7.82 (dd, J=12.1, 4.0 Hz, 2H). and compound 2 (HSN003B004): 7-chloro-5-oxo-5H-indeno[1,2-c]pyridine-3-carbonitrile (2, 2.1 mg, yield 1.34%). MS (ESI) [M+H] ⁺ 241.0, 243.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.49 (d, J=7.9Hz, 1H), 8.21-8.16 (m, 1H), 8.02 (d, J=8.0Hz, 1H), 7.85-7.71 (m 2H).

Example 3: Preparation of 7-chloro-9-oxo-9H-fluorene-2,3-dicarbonitrile

Step 1: Preparation of 4′-chloro-2′-formyl-[1,1′-biphenyl]-3,4-dicarbonitrile (3a)

Dissolve (4-chloro-2-formylphenyl)boronic acid (134 mg, 0.725 mmol) in methanol (4 ml), add 4-bromophthalonitrile (100 mg, 0.483 mmol), potassium fluoride (56 mg, 0.966 mmol) and palladium acetate (5 mg, 0.024 mmol), and react at 120°C for 30 minutes under microwave. Filter and evaporate the solvent under reduced pressure to obtain the target product, crude 4′-chloro-2′-formyl-[1,1′-biphenyl]-3,4-dicarbonitrile (3a, 240 mg, yield 93.16%).

Step 2: Preparation of 7-chloro-9-oxo-9H-fluorene-2,3-dicarbonitrile (3)

4′-Chloro-2′-formyl-[1,1′-biphenyl]-3,4-dicarbonitrile (3a, 240 mg, 0.9 mmol) was dissolved in 1,2-dichloroethane (8 ml), tetrabutylammonium iodide (17 mg, 0.045 mmol) and tert-butyl hydroperoxide (324 mg, 3.6 mmol) were added, and the mixture was reacted at 100°C in a sealed tube for 16 hours. The solvent was evaporated under reduced pressure, and then purified and freeze-dried by preparative HPLC to obtain compound 3: 7-chloro-9-oxo-9H-fluorene-2,3-dicarbonitrile (1.6 mg, yield 0.67%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.36 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.86-7.77 (m, 2H).

Example 4: Preparation of 7-chloro-2-cyclopropyl-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2-cyclopropylpyrimidin-5-yl)benzaldehyde (4a)

Dissolve (4-chloro-2-formylphenyl)boronic acid (139 mg, 0.754 mmol) in ethanol (4 ml), add 5-bromo-2-cyclopropylpyrimidine (100 mg, 0.502 mmol), potassium carbonate (58 mg, 1 mmol) and palladium acetate (6 mg, 0.025 mmol), and react overnight at 120°C in a sealed tube. Filter and evaporate the solvent under reduced pressure to obtain the target product crude 5-chloro-2-(2-cyclopropylpyrimidin-5-yl)benzaldehyde (4a, 90 mg, yield 69.25%). MS (ESI) [M+H] ⁺ 259.2, 261.1.

Step 2: Preparation of 7-chloro-2-cyclopropyl-9H-indeno[2,1-d]pyrimidin-9-one (4)

5-Chloro-2-(2-cyclopropylpyrimidin-5-yl)benzaldehyde (4a, 90 mg, 0.348 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (6 mg, 0.017 mmol) and tert-butyl hydroperoxide (125 mg, 1.39 mmol) were added, and the mixture was reacted at 100°C in a sealed tube for 16 hours. The solvent was evaporated under reduced pressure, and the mixture was purified and freeze-dried by preparative HPLC to obtain the target product compound 4: 7-chloro-2-cyclopropyl-9H-indeno[2,1-d]pyrimidin-9-one (14.1 mg, yield 15.79%). MS (ESI) [M+H] ⁺ 257.1, 259.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 7.92-7.83 (m, 1H), 7.80-7.66 (m, 2H), 2.30 (ddd, J=12.7, 8.1, 4.7Hz, 1H), 1.17-0.98 (m,4H).

Example 5: Preparation of tert-butyl (7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-2-yl)carbamate

Step 1: Preparation of tert-butyl (5-(4-chloro-2-formylphenyl)pyrimidin-2-yl)carbamate (5a)

Dissolve 4-chloro-2-formylphenylboronic acid (505 mg, 2.74 mmol) in ethanol (20 ml), add tert-butyl (5-bromopyrimidin-2-yl) carbamate (500 mg, 1.82 mmol), potassium fluoride (210 mg, 3.64 mmol) and palladium acetate (20 mg, 0.091 mmol), and react at 120°C for 30 minutes under microwave. Evaporate the solvent under reduced pressure, and purify the residue by Flash column (ethyl acetate: petroleum ether = 10%-20%) to obtain the target product tert-butyl (5-(4-chloro-2-formylphenyl) pyrimidin-2-yl) carbamate (5a, 246 mg, yield 40.41%). MS (ESI) [M+H] ⁺ 334.2, 336.2. MS (ESI) [M-56+H] ⁺ 278.0, 280.0.

Step 2: Preparation of tert-butyl (7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-2-yl)carbamate (5)

Tert-butyl (5-(4-chloro-2-formylphenyl) pyrimidin-2-yl) carbamate (5a, 246 mg, 0.737 mmol) was dissolved in 1,2-dichloroethane (10 ml), tetrabutylammonium iodide (14 mg, 0.037 mmol) and tert-butyl hydroperoxide (399 mg, 4.42 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The crude product (120 mg, 49.08% yield) was obtained by recrystallization using (dichloromethane/methanol). 10 mg of the crude product was purified by preparative HPLC and lyophilized to obtain the target product, compound 6: tert-butyl (7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-2-yl) carbamate (0.7 mg, 0.29% yield). MS (ESI) [M + H] ⁺ 332.1, 334.1. MS (ESI) [M-56 + H] ⁺ 276.2, 278.1. ¹ H NMR (400MHz, CD3OD) δ 8.95 (s, 1H), 7.77-7.63 (m, 3H), 1.56 (d, J = 4.3Hz, 9H).

Example 6: Preparation of 2-amino-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one

Compound 5 obtained in the second step of Example 5 was added to 4N hydrochloric acid ethyl acetate (5 ml), and the reaction mixture was stirred at 25°C for 16 hours. The reaction was completed by LC-MS. The resulting mixture was concentrated under vacuum to obtain a crude product (45 mg, yield 71.61%). 10 mg of the crude product was purified by preparative HPLC and lyophilized to obtain the target product Compound 6: 2-amino-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one (2 mg, 3.18% yield). MS (ESI) [M+H] ⁺ 232.1, 234.1.

Example 7: Preparation of 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (7a)

Dissolve 4-chloro-2-formylphenylboronic acid (767 mg, 4.17 mmol) in methanol (15 ml), add 2-chloro-5-iodopyrimidine (500 mg, 2.08 mmol), potassium fluoride (242 mg, 4.17 mmol) and palladium acetate (24 mg, 0.11 mmol), and react at 120°C for 50 minutes under microwave. Evaporate the solvent under reduced pressure, and purify the residue with a Flash column (ethyl acetate: petroleum ether = 10%-25%) to obtain the target product 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (7a, 233 mg, yield 44.4%). MS (ESI) [M+H] ⁺ 253.1, 254.9.

Step 2: Preparation of 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7)

5-Chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (7a, 183 mg, 0.726 mmol) was dissolved in 1,2-dichloroethane (15 ml), tetrabutylammonium iodide (14 mg, 0.038 mmol) and tert-butyl hydroperoxide (420 μl, 4.356 mmol) were added, and the mixture was reacted at 100°C in a sealed tube for 8 hours. The solvent was evaporated under reduced pressure to obtain the target product compound 7: 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one crude product (145 mg, yield 79.7%), and a portion of the crude product was recrystallized using (methanol) to obtain 14.54 mg of the pure product. MS (ESI) [M+H] ⁺ 251.0, 253.0. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.00 (d, J = 8.0Hz, 1H), 7.88-7.79 (m, 2H).

Examples 8 and 9: Preparation of 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile and 7-chloro-4-fluoro-5-oxo-5H-indeno[1,2-c]pyridine-3-carbonitrile

Step 1: Preparation of 5-(4-chloro-2-formylphenyl)-3-fluoropyridinecarbonitrile (8a)

Dissolve 4-chloro-2-formylphenylboronic acid (688 mg, 3.73 mmol) in ethanol (25 ml), add 5-bromo-3-fluoropyridinecarbonitrile (500 mg, 2.49 mmol), potassium fluoride (290 mg, 4.98 mmol) and palladium acetate (30 mg, 0.125 mmol), and react at 120°C for 30 minutes under microwave. Filter and evaporate the solvent under reduced pressure, and purify the residue with a Flash column (ethyl acetate: petroleum ether = 10%-20%) to obtain the target product 5-(4-chloro-2-formylphenyl)-3-fluoropyridinecarbonitrile (8a, 450 mg, yield 69.40%). MS (ESI) [M+H] ⁺ 261.0, 263.0.

Step 2: Preparation of 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile (8)

5-(4-Chloro-2-formylphenyl)-3-fluoropyridine carbonitrile (8a, 400 mg, 1.53 mmol) was dissolved in 1,2-dichloroethane (20 ml), tetrabutylammonium iodide (28 mg, 0.076 mmol) and tert-butyl hydroperoxide (830 mg, 9.21 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube for 16 hours. The solvent was evaporated under reduced pressure, and the product was purified, resolved and freeze-dried using preparative HPLC to give the target product, Compound 8: 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile (5 mg, yield 1.26%). MS (ESI) [M+H] ⁺ 259.0, 261.0. ¹ H NMR (400 MHz, DMSO- _d6 ) δ8.62 (d, J=9.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.91-7.78 (m, 2H). And Compound 9: 7-chloro-4-fluoro-5-oxo-5H-indeno[1,2-c]pyridine-3-carbonitrile (933 mg, yield 8.31%). MS (ESI) [M+H] ⁺ 258.9, 261.0. ¹ H NMR (400MHz, DMSO-d6) δ 9.18 (d, J = 1.6Hz, 1H), 8.11 (d, J = 8.0Hz, 1H), 7.90-7.80 (m, 2H).

Example 10: Preparation of 7-chloro-2-morpholinyl-9H-indeno[2,1-d]pyrimidin-9-one

2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,30 mg, 0.119 mmol) was dissolved in N,N-dimethylformamide (2 ml), potassium carbonate (25 mg, 0.179 mmol) and morpholine (11 mg, 0.131 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The aqueous solution (10 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (6 ml × 3), and the combined organic layer was washed with brine (6 ml × 2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and freeze-dried to obtain the target product compound 10: 7-chloro-2-morpholinyl-9H-indeno[2,1-d]pyrimidin-9-one (6.9 mg, yield 19.14%). MS (ESI) [M+H] ⁺ 302.1, 304.1. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.54 (d, J = 15.1Hz, 1H), 7.62 (d, J = 1.3Hz, 1H), 7.52-7.41 (m, 1H), 7.34 (d, J = 8.0Hz, 1H), 3.91 (dd, J = 12 .1, 7.4Hz, 4H), 3.79-3.75 (m, 4H).

Example 11: Preparation of 7-chloro-2-(4,4-difluoropiperidin-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one

2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,30 mg, 0.119 mmol) was dissolved in N,N-dimethylformamide (2 ml), potassium carbonate (25 mg, 0.179 mmol) and 4,4-difluoropiperidine (16 mg, 0.131 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The aqueous solution (10 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (6 ml×3), and the combined organic layer was washed with brine (6 ml×2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and freeze-dried to obtain the target product Compound 11: 7-chloro-2-(4,4-difluoropiperidin-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one (11.1 mg, yield 27.67%). MS (ESI) [M+H] ⁺ 336.1, 338.1. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.57 (s, 1H), 7.64 (s, 1H), 7.47 (d, J = 7.9Hz, 1H), 7.36 (d, J = 7.9Hz, 1H), 4.15-4.05 (m, 4H), 2.03 (dt, J=12.9, 7.7Hz, 4H).

Example 12: Preparation of 7-chloro-2-(1H-imidazol-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one

2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,20 mg, 0.08 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium carbonate (52 mg, 0.159 mmol), copper iodide (2 mg, 0.008 mmol) and imidazole (8 mg, 0.119 mmol) were added, and the mixture was reacted at 50°C for 16 hours. The aqueous solution (10 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (6 ml×3), and the combined organic layer was washed with brine (6 ml×2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and freeze-dried to obtain the target product Compound 12: 7-chloro-2-(1H-imidazol-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one (2 mg, yield 8.88%). MS (ESI) [M+H] ⁺ 283.0, 285.1.

Example 13: Preparation of 7-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (13a)

Dissolve (4-fluoro-2-formylphenyl)boronic acid (222 mg, 1.32 mmol) in ethanol (10 ml), add 5-bromo-2-(trifluoromethyl)pyrimidine (200 mg, 0.881 mmol), potassium fluoride (102 mg, 1.76 mmol) and palladium acetate (10 mg, 0.044 mmol), and react at 120°C for 30 minutes under microwave. Filter and evaporate the solvent under reduced pressure to obtain the target product crude 5-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (300 mg). MS (ESI) [M+H] ⁺ 271.2, 272.2.

Step 2: Preparation of 7-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (13)

5-Fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (13a, 300 mg, 1.11 mmol) was dissolved in 1,2-dichloroethane (20 ml), tetrabutylammonium iodide (20 mg, 0.056 mmol) and tert-butyl hydroperoxide (600 mg, 6.66 mmol) were added, and the mixture was reacted at 100°C in a sealed tube for 16 hours. The solvent was evaporated under reduced pressure, and the mixture was purified and freeze-dried by preparative HPLC to obtain the target product Compound 13: 7-Fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (18.8 mg, yield 6.31%). MS (ESI) [M+H] ⁺ 269.1, 270.0. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.13 (dd, J=8.2, 4.5Hz, 1H), 7.69 (q, J=8.7, 7.9Hz, 2H).

Example 14: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbonitrile

Step 1: Preparation of 5-(4-chloro-2-formylphenyl)pyrimidine-2-carbonitrile (14a)

Dissolve 4-chloro-2-formylphenylboronic acid (302 mg, 1.64 mmol) in methanol (10 ml), add 5-bromo-2-cyanopyrimidine (200 mg, 1.09 mmol), potassium fluoride (127 mg, 2.19 mmol) and palladium acetate (13 mg, 0.058 mmol), and react at 120°C for 0.5 hours in a microwave oven. Evaporate the solvent under reduced pressure, and purify the residue with a Flash column (dichloromethane) to obtain the target product 5-(4-chloro-2-formylphenyl)pyrimidine-2-carbonitrile (14a, 93 mg, yield 35.1%). MS (ESI) [M+H] ⁺ 244.0, 246.0.

Step 2: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbonitrile (14)

5-(4-chloro-2-formylphenyl)pyrimidine-2-carbonitrile (14a, 40 mg, 0.16 mmol) was dissolved in 1,2-dichloroethane (3 ml), tetrabutylammonium iodide (3 mg, 0.008 mmol) and tert-butyl hydroperoxide (95 μl, 0.96 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube for 5 hours. Impurities were removed by recrystallization from (dichloromethane), and the filtrate was recrystallized from (dichloromethane/methanol) to obtain the target product compound 14: 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbonitrile (7.17 mg, yield 18.1%). MS (ESI) [M+H] ⁺ 242.0, 244.0. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 8.11 (d, J = 8.1Hz, 1H), 7.95-7.87 (m, 2H).

Example 15: Preparation of 7-chloro-2-(4-methylpiperazin-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one

2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,10 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (1 ml), potassium carbonate (8 mg, 0.059 mmol) and 1-methylpiperazine (4 mg, 0.044 mmol) were added, and the mixture was reacted at room temperature for 4 hours. The aqueous solution (5 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (3 ml×3), and the combined organic layer was washed with brine (3 ml×2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and freeze-dried to obtain the target product 7 Compound 15: -chloro-2-(4-methylpiperazin-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one (3.5 mg, yield 27.92%). MS(ESI)[M+H] ⁺ 315.2, 317.2. ¹ H NMR (400MHz, DMSO-d6) δ8.86 (s, 1H), 7.69-7.55 (m, 3H), 3.79 (s, 2H), 3.41 (d, J=3.8Hz, 2H), 2.39-2.35 (m, 2H), 2.20 (s, 2H ), 1.19(s, 3H).

Example 16: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2,3-dicarbonitrile

Step 1: Preparation of 2-chloro-5-(4-chloro-2-formylphenyl)nicotinonitrile (16a)

4-Chloro-2-formylphenylboronic acid (388 mg, 2.11 mmol) was dissolved in tetrahydrofuran/water (12 ml/3 ml), 5-bromo-2-chloronicotinonitrile (350 mg, 1.62 mmol), potassium carbonate (447 mg, 3.24 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (118 mg, 0.16 mmol) were added, and the mixture was reacted at 90°C overnight in a sealed tube. The insoluble matter was removed by filtration, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 15%-20%) to obtain the target product 2-chloro-5-(4-chloro-2-formylphenyl)nicotinonitrile (16a, 208 mg, yield 40.7%). MS (ESI) [M+H] ⁺ 277.1, 279.0.

Step 2: Preparation of 5-(4-chloro-2-formylphenyl)pyridine-2,3-dicarbonitrile (16b)

2-Chloro-5-(4-chloro-2-formylphenyl)nicotinonitrile (16a, 128 mg, 0.464 mmol) was dissolved in N-methylpyrrolidone (5 ml), zinc cyanide (33 mg, 0.281 mmol) and tetrakistriphenylphosphine palladium (54 mg, 0.047 mmol) were added, and the reaction was carried out at 150°C for 30 minutes in a microwave oven. The insoluble matter was removed by filtration, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 20%-40%) to obtain the target product 5-(4-chloro-2-formylphenyl)pyridine-2,3-dicarbonitrile (16b, 44 mg, yield 35.5%). MS (ESI) [M+H] ⁺ 268.1, 270.1.

Step 3: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2,3-dicarbonitrile (16)

5-(4-chloro-2-formylphenyl)pyridine-2,3-dicarbonitrile (16b, 44 mg, 0.165 mmol) was dissolved in 1,2-dichloroethane (3 ml), tert-butyl hydroperoxide (127 μl, 1.32 mmol) was added, and the mixture was reacted at 100°C in a sealed tube overnight. The target product, compound 16, was obtained by recrystallization from (dichloromethane/methanol): 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2,3-dicarbonitrile (4.18 mg, yield 9.7%). MS (ESI) [M+H] ⁺ 266.0, 268.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 9.11 (s, 1H), 8.05 (d, J=7.7 Hz, 2H).

Example 17: Preparation of 7-chloro-9-oxo-9H-fluorene-2-carbonitrile

Step 1: Preparation of 4′-chloro-2′-formyl-[1,1′-biphenyl]-4-carbonitrile (17a)

Dissolve 4-chloro-2-formylphenylboronic acid (209 mg, 1.14 mmol) in methanol (10 ml), add 4-iodocyanobenzene (200 mg, 0.873 mmol), potassium fluoride (101 mg, 1.74 mmol) and palladium acetate (10 mg, 0.045 mmol), and react at 120°C for 40 minutes under microwave. Evaporate the solvent under reduced pressure, and purify the residue with a Flash column (ethyl acetate: petroleum ether = 10%-20%) to obtain the target product 4′-chloro-2′-formyl-[1,1′-biphenyl]-4-carbonitrile (17a, 162 mg, yield 61.6%). MS (ESI) [M+H] ⁺ 242.1, 244.1.

Step 2: Preparation of 7-chloro-9-oxo-9H-fluorene-2-carbonitrile (17)

4′-Chloro-2′-formyl-[1,1′-biphenyl]-4-carbonitrile (30 mg, 0.124 mmol) was dissolved in 1,2-dichloroethane (3 ml), tert-butyl hydroperoxide (48 μl, 0.496 mmol) was added, and the mixture was reacted at 100°C in a sealed tube overnight. The target product, compound 17, was obtained by recrystallization from (dichloromethane/methanol): 7-chloro-9-oxo-9H-fluorene-2-carbonitrile (7.33 mg, yield 24.6%). ¹ HNMR (400 MHz, DMSO-d6) δ8.14 (d, J=8.6 Hz, 1H), 8.06 (dJ=8.2 Hz, 2H), 7.99 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.71 (s, 1H).

Example 18: Preparation of 7-chloro-2-methoxy-9H-indeno[2,1-d]pyrimidin-9-one

2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,4 mg, 0.016 mmol) was dissolved in methanol/tetrahydrofuran (1 m/1 ml), potassium carbonate (4 mg, 0.024 mmol) was added, and the mixture was reacted at room temperature for 3 hours. The insoluble matter was removed by filtration, and the residue was semi-preparatively purified to obtain the target product, compound 18: 7-chloro-2-methoxy-9H-indeno[2,1-d]pyrimidin-9-one (1.42 mg, yield 36.4%). MS (ESI) [M+H] ⁺ 247.1, 249.0.

Example 19: Preparation of 7-chloro-2-(dimethylamino)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2-(dimethylamino)pyrimidin-5-yl)benzaldehyde (19a)

4-Chloro-2-formylphenylboronic acid (118 mg, 0.641 mmol) was dissolved in ethanol (5 ml), and 5-bromo-2-(dimethylamino)pyrimidine (100 mg, 0.495 mmol), potassium fluoride (57 mg, 0.983 mmol) and palladium acetate (6 mg, 0.027 mmol) were added, and the mixture was reacted by microwave at 120°C for 40 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (dichloromethane: methanol = 0%-10%) to obtain the target product 5-chloro-2-(2-(dimethylamino)pyrimidin-5-yl)benzaldehyde (19a, 20 mg, yield 15.5%). MS (ESI) [M+H] ⁺ 262.1, 264.2.

Step 2: Preparation of 7-chloro-2-(dimethylamino)-9H-indeno[2,1-d]pyrimidin-9-one (19)

5-Chloro-2-(2-(dimethylamino)pyrimidin-5-yl)benzaldehyde (19a, 20 mg, 0.077 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (2 mg, 0.0054 mmol) and tert-butyl hydroperoxide (44 μl, 0.462 mmol) were added, and the mixture was reacted at 100° C. for 5 hours in a sealed tube. The target product, compound 19, was obtained by recrystallization using (dichloromethane/methanol): 7-chloro-2-(dimethylamino)-9H-indeno[2,1-d]pyrimidin-9-one (1.45 mg, yield 7.3%). MS (ESI) [M+H] ⁺ 260.1, 262.1. ¹ H NMR (400MHz, DMSO-d6) δ 8.88 (s, 1H), 7.67 (s, 2H), 7.59 (s, 1H), 3.20 (s, 6H).

Example 20: Preparation of 7-chloro-2-methyl-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2-methylpyrimidin-5-yl)benzaldehyde (20a)

Dissolve 4-chloro-2-formylphenylboronic acid (138 mg, 0.75 mmol) in ethanol (5 ml), add 2-methyl-5-bromopyrimidine (100 mg, 0.578 mmol), potassium fluoride (67 mg, 1.16 mmol) and palladium acetate (7 mg, 0.031 mmol), and react at 120°C for 1 hour in a microwave oven. Evaporate the solvent under reduced pressure, and purify the residue with a Flash column (dichloromethane: methanol = 0%-5%) to obtain the target product 5-chloro-2-(2-methylpyrimidin-5-yl)benzaldehyde (20a, 102 mg, yield 76.1%). MS (ESI) [M+H] ⁺ 233.1, 235.1.

Step 2: Preparation of 7-chloro-2-methyl-9H-indeno[2,1-d]pyrimidin-9-one (20)

5-Chloro-2-(2-methylpyrimidin-5-yl)benzaldehyde (20a, 50 mg, 0.216 mmol) was dissolved in 1,2-dichloroethane (3 ml), tetrabutylammonium iodide (4 mg, 0.011 mmol) and tert-butyl hydroperoxide (83 μl, 0.864 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The target product, compound 20, was obtained by recrystallization using (dichloromethane/methanol): 7-chloro-2-methyl-9H-indeno[2,1-d]pyrimidin-9-one (10.81 mg, yield 21.8%). MS(ESI)[M+H] ⁺ 231.0，233.0. ¹ H NMR(400MHz，DMSO-d ₆ )δ9.26(s，1H)，7.93(d，J＝8.0Hz，1H)，7.79(dd，J＝8.0，2.0Hz，1H)，7.73(d，J＝1.9Hz，1H)，2.71(s，3H).

Example 21: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (21a)

4-Chloro-2-formylphenylboronic acid (106 mg, 0.576 mmol) was dissolved in ethanol (5 ml), and 5-bromo-2-trifluoromethylpyrimidine (100 mg, 0.442 mmol), potassium fluoride (51 mg, 0.879 mmol) and palladium acetate (5 mg, 0.022 mmol) were added, and the mixture was reacted by microwave at 120°C for 40 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 5%-10%) to obtain the target product 5-chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (21a, 94 mg, yield 74.3%). MS (ESI) [M+H] ⁺ 287.0, 289.0.

Step 2: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (21)

5-Chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (21a, 50 mg, 0.175 mmol) was dissolved in 1,2-dichloroethane (3 ml), tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (67 μl, 0.7 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The target product, compound 21, was obtained by recrystallization using (dichloromethane/methanol): 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (2.03 mg, yield 4.0%). MS(ESI)[M+H] ⁺ 285.1, 287.1. ¹ HNMR (400MHz, DMSO-d6) δ9.60, 8.11, 8.09, 7.91, 7.90, 7.88, 3.38, 2.50.

Example 22: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carboxamide

Dissolve 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbonitrile (14, 15 mg, 0.062 mmol) in isopropanol/water (1 ml/1 ml), add manganese dioxide (54 mg, 0.62 mmol), and react at 100°C in a sealed tube for 10 minutes. Filter and semi-preparatively purify the filtrate to obtain the target product compound 22: 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carboxamide (1.55 mg, yield 9.7%). MS (ESI) [M+H] ⁺ 260.1, 262.1.

Examples 23 and 24: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one o-ethyl oxime

7-Chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (21,31 mg, 0.109 mmol) was dissolved in pyridine (6 ml), ethoxylated amine hydrochloride (32 mg, 0.328 mmol) and 5A molecular sieves were added, and the mixture was reacted at room temperature overnight. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether = 1:10) to obtain the target product, which was arbitrarily designated as compound 23: (E) 7-Chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one o-ethyl oxime (10.9 mg, yield 61.4%) MS (ESI) [M+H] ⁺ 328.1, 330.1. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.54 (s, 1H), 8.25-8.15 (m, 2H), 7.78 (dd, J=8.2, 1.8 Hz, 1H), 4.63 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H)., another one arbitrarily designated as compound 24 (HSN003B007-P2): (Z) 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one o-ethyl oxime (11.03 mg, yield 61.4%). MS (ESI) [M+H] ⁺ 328.1, 330.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.63 (s, 1H), 8.28-8.17 (m, 1H), 8.12 (d, J = 8.2Hz, 1H), 7.69 (d, J = 7.6Hz, 1H), 4.57 (dd, J = 13.9, 6.9 Hz, 2H), 1.43 (d, J=6.6Hz, 3H).

Example 25: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one oxime

7-Chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (21,40 mg, 0.141 mmol) was dissolved in pyridine (3 ml), ethoxyamine hydrochloride (29 mg, 0.417 mmol) and 5A molecular sieves were added, and the mixture was reacted at room temperature for 6 hours. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure and semi-preparatively purified to obtain the target product, compound 25: 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one oxime (2.69 mg, yield 6.4%). MS (ESI) [M+H] ⁺ 300.1, 302.1. ¹ H NMR (400MHz, DMSO-d6) δ 9.57 (s, 1H), 8.40 (d, J = 1.6Hz, 1H), 8.23 (d, J = 8.2Hz, 1H), 7.79 (dd, J = 8.2, 1.9Hz, 1H).

Example 26: Preparation of 2,7-dichloro-4-methyl-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2-chloro-4-methylpyrimidin-5-yl)benzaldehyde (26a)

Dissolve 4-chloro-2-formylphenylboronic acid (320 mg, 1.74 mmol) in ethanol (20 ml), add 5-bromo-2-chloro-4-methylpyrimidine (300 mg, 1.45 mmol), potassium fluoride (168 mg, 2.9 mmol) and palladium acetate (16 mg, 0.071 mmol), and react at 120°C for 30 minutes under microwave. Evaporate the solvent under reduced pressure, and purify the residue by Flash column (ethyl acetate: petroleum ether = 5%-20%) to obtain the target product 5-chloro-2-(2-chloro-4-methylpyrimidin-5-yl)benzaldehyde (26a, 45 mg, yield 10.0%). MS (ESI) [M+H] ⁺ 267.0, 268.9.

Step 2: Preparation of 2,7-dichloro-4-methyl-9H-indeno[2,1-d]pyrimidin-9-one (26)

5-Chloro-2-(2-chloro-4-methylpyrimidin-5-yl)benzaldehyde (26a, 45 mg, 0.169 mmol) was dissolved in 1,2-dichloroethane (4 ml), tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (97 μl, 1.015 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was evaporated to dryness under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether = 1:5) to obtain the target product compound 26: 2,7-dichloro-4-methyl-9H-indeno[2,1-d]pyrimidin-9-one (0.89 mg, yield 2.0%). MS (ESI) [M+H] ⁺ 265.0, 267.0.

Example 27: Preparation of 7-chloro-2-fluoro-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2-fluoropyrimidin-5-yl)benzaldehyde (27a)

4-Chloro-2-formylphenylboronic acid (375 mg, 2.04 mmol) was dissolved in sec-butyl alcohol (15 ml), and 5-bromo-2-fluoropyrimidine (300 mg, 1.69 mmol), potassium fluoride (198 mg, 3.41 mmol) and palladium acetate (18 mg, 0.08 mmol) were added, and the mixture was reacted by microwave at 120°C for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 5%-20%) to obtain the target product 5-chloro-2-(2-fluoropyrimidin-5-yl)benzaldehyde (27a, 75 mg, yield 18.8%). MS (ESI) [M+H] ⁺ 237.0, 239.0.

Step 2: Preparation of 7-chloro-2-fluoro-9H-indeno[2,1-d]pyrimidin-9-one (27)

5-Chloro-2-(2-fluoropyrimidin-5-yl)benzaldehyde (27a, 30 mg, 0.127 mmol) was dissolved in 1,2-dichloroethane (3 ml), tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (73 μl, 0.763 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was evaporated to dryness under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether = 1:5) to obtain the target product compound 27: 7-chloro-2-fluoro-9H-indeno[2,1-d]pyrimidin-9-one (23.52 mg, yield 11.9%). MS (ESI) [M+H] ⁺ 235.0, 237.0.

Example 28: Preparation of 2,7-bis(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (28a)

Dissolve 4-trifluoromethyl-2-formylphenylboronic acid (150 mg, 0.688 mmol) in ethanol (9 ml), add 5-bromo-2-trifluoromethylpyrimidine (141 mg, 0.621 mmol), potassium fluoride (72 mg, 1.24 mmol) and palladium acetate (9 mg, 0.04 mmol), and react at 120°C for 30 minutes under microwave. Evaporate the solvent under reduced pressure, and purify the residue with a Flash column (ethyl acetate: petroleum ether = 5%-20%) to obtain the target product 5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (28a, 70 mg, yield 31.8%). MS (ESI) [M+H] ⁺ 321.1.

Step 2: Preparation of 2,7-bis(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (28)

5-(Trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (28a, 35 mg, 0.109 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (2 mg, 0.0055 mmol) and tert-butyl hydroperoxide (63 μl, 0.654 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was evaporated to dryness under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether = 1:5) to obtain the target product compound 28: 2,7-bis(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (3.56 mg, yield 10.2%). MS (ESI) [M+H] ⁺ 319.0.

Example 29: Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile

Step 1: Preparation of 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (29a)

2-(Trifluoromethyl)pyrimidin-5-ylboronic acid (100 mg, 0.521 mmol) was dissolved in acetonitrile (10 ml), 4-bromo-3-formylbenzonitrile (109 mg, 0.521 mmol), potassium fluoride (61 mg, 1.05 mmol) and palladium acetate (6 mg, 0.027 mmol) were added, and microwave reaction was performed at 120°C for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-20%) to obtain the target product 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (29a, 35 mg, yield 24.3%). MS (ESI) [M+H] ⁺ 278.1.

Step 2: Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (29)

3-Formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (35 mg, 0.126 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (97 μl, 1.01 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was evaporated to dryness under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether=1:2) to obtain the target product, compound 29: 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (14.42 mg, yield 41.6%). MS(ESI)[M+H] ⁺ 276.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.73 (s, 1H), 8.37-8.26 (m, 3H).

Example 30: Preparation of 7-chloro-9-oxo-9H-fluorene-3-carbonitrile

Step 1: Preparation of 4′-chloro-6-formyl-[1,1′-biphenyl]-3-carbonitrile (30a)

Dissolve (4-chlorophenyl)boronic acid (112.3 mg, 0.714 mmol) in methanol (3 ml), add 3-bromo-4-formylbenzonitrile (100 mg, 0.114 mmol), palladium acetate (5.4 mg, 0.0057 mmol), potassium fluoride (55.6 mg, 0.228 mmol), and react at 120°C for 40 minutes under nitrogen protection. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1/5) to obtain the target product 4′-chloro-6-formyl-[1,1′-biphenyl]-3-carbon tricarbonitrile (30a, 94 mg, yield 81.5%). MS (ESI) [M+H] ⁺ 242.3.

Step 2: Preparation of 7-chloro-9-oxo-9H-fluorene-3-carbonitrile (30)

4′-Chloro-6-formyl-[1,1′-biphenyl]-3-carbonitrile (30a, 30 mg, 0.124 mmol) was dissolved in dichloroethane (2 ml), and 2-hydroperoxy-2-methylpropane (89.8 mg, 0.992 mmol) was added. The reaction was carried out in a sealed state at 100° C. for 6 hours. After concentration under reduced pressure, the crude product was purified by preparative high performance liquid chromatography (water: methanol = 1/50) to obtain the target product compound 30: 7-chloro-9-oxo-9H-fluorene-3-carbonitrile (2.9 mg, yield 9.8%). MS (ESI) [M+H] ⁺ 240.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.88 (d, J = 8.8Hz, 1H), 7.80-7.77 (m, 1H), 7.77-7.75 (m, 1H), 7.70 (d, J=1.9Hz, 1H).

Example 31: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carboxamide

7-Chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbonitrile (14,20 mg, 0.083 mmol) was dissolved in methanol (0.3 ml), sodium methoxide (22.4 mg, 0.415 mmol) was added, and after stirring at room temperature for 5 hours, ammonium chloride (44.4 mg, 0.832 mmol) was added, and the reaction was continued at room temperature for 24 hours. Water (5 ml) was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (water: methanol = 1/10) to obtain the target product compound 31: 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carboximidamide (1.37 mg, yield 6.4%). MS (ESI) [M+H] ⁺ 259.3. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.73 (s, 2H), 9.12 (s, 1H), 8.14 (d, J = 7.9Hz, 1H), 7.91 (dd, J = 10.5, 2.3Hz, 1H), 7.28 (d, J = 9.0Hz, 1H), 7.15 ( d, J=9.6Hz, 1H).

Example 32: Preparation of 7-chloro-2-(1H-pyrazol-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one

2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,20 mg, 0.08 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium carbonate (52 mg, 0.159 mmol), copper iodide (2 mg, 0.008 mmol) and pyrazole (8 mg, 0.119 mmol) were added, and the mixture was reacted at 50°C for 16 hours. The aqueous solution (10 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (6 ml×3), and the combined organic layer was washed with brine (6 ml×2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and freeze-dried to obtain the target product compound 32: 7-chloro-2-(1H-pyrazol-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one (0.5 mg, yield 2.22%). MS (ESI) [M+H] ⁺ 283.0, 285.1.

Example 33: Preparation of 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (33a)

Dissolve (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (145 mg, 0.754 mmol) in acetonitrile (5 ml), add 2-bromo-5-methylbenzaldehyde (100 mg, 0.502 mmol), potassium fluoride (58 mg, 1.004 mmol) and palladium acetate (6 mg, 0.025 mmol), and react at 120°C for 30 minutes under microwave. Evaporate the solvent under reduced pressure, and purify the residue with a Flash column (ethyl acetate: petroleum ether = 0%-20%) to obtain the target product 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (33a, 90 mg, yield 67.29%). MS (ESI) [M+H] ⁺ 267.1.

Step 2: Preparation of 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (33)

5-Methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (33a, 90 mg, 0.338 mmol) was dissolved in 1,2-dichloroethane (5 ml), tetrabutylammonium iodide (6 mg, 0.017 mmol) and tert-butyl hydroperoxide (244 mg, 2.7 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was evaporated to dryness under reduced pressure and purified on a preparative plate (ethyl acetate: petroleum ether = 1:4) to obtain the target product, compound 33: 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (3.35 mg, yield 3.75%). MS (ESI) [M+H] ⁺ 265.1. ¹ H NMR (400MHz, Chloroform-d) δ 9.09 (s, 1H), 7.69 (d, J = 1.0Hz, 1H), 7.62 (d, J = 7.7Hz, 1H), 7.50 (d, J = 7.7Hz, 1H), 2.47 (s, 3H).

Example 34: Preparation of 2-acetyl-7-chloro-9H-indeno[2,1-d]pyrimidin _- 9-one

Step 1: Preparation of 2-(2-acetylpyrimidin-5-yl)-5-fluorobenzaldehyde (34a)

Dissolve (4-chloro-2-formylphenyl)boronic acid (182 mg, 0.995 mmol) in acetonitrile (5 ml), add 1-(5-bromopyrimidin-2-yl)ethane-1-one (200 mg, 0.995 mmol), potassium fluoride (116 mg, 1.99 mmol) and palladium acetate (10 mg, 0.05 mmol), seal the tube and react at 120°C overnight. Evaporate the solvent under reduced pressure, and purify the residue with a Flash column (ethyl acetate: petroleum ether = 0%-50%) to obtain the target product 2-(2-acetylpyrimidin-5-yl)-5-chlorobenzaldehyde (34a, 110 mg, yield 42.41%). MS (ESI) [M+H] ⁺ 261.0, 263.0.

Step 2: Preparation of 2-acetyl-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one (34)

2-(2-acetylpyrimidin-5-yl)-5-chlorobenzaldehyde (34a, 110 mg, 0.422 mmol) was dissolved in 1,2-dichloroethane (10 ml), tetrabutylammonium iodide (8 mg, 0.021 mmol) and tert-butyl hydroperoxide (434 mg, 3.38 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was evaporated to dryness under reduced pressure and then purified by preparative HPLC and freeze-dried to obtain the target product compound 34: 2-acetyl-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one (1.18 mg, yield 1.08%). MS (ESI) [M+H] ⁺ 259.0, 261.1. ¹ H NMR (400MHz, Chloroform-d) δ 9.22 (s, 1H), 7.84 (d, J = 1.9Hz, 1H), 7.70 (d, J = 0.6Hz, 1H), 7.67 (d, J = 1.9Hz, 1H), 2.85 (s, 3H).

Example 35: Preparation of 2,7-dichloro-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (35a)

4-Chloro-2-formylphenylboronic acid (194 mg, 1.052 mmol) was dissolved in acetonitrile (21 ml), and 5-bromo-2-chloro-4-(trifluoromethyl)pyrimidine (250 mg, 0.956 mmol), potassium fluoride (111 mg, 1.91 mmol) and palladium acetate (11 mg, 0.048 mmol) were added, and the mixture was subjected to microwave reaction at 120°C for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-10%) to obtain the target product 5-chloro-2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (35a, 19 mg g, yield 6.2%). MS (ESI) [M+H] ⁺ 320.9, 323.0

Step 2: Preparation of 2,7-dichloro-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (35)

5-Chloro-2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (35a, 19 mg, 0.059 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (1 mg, 0.0027 mmol) and tert-butyl hydroperoxide (46 μl, 0.472 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was evaporated to dryness under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether = 1:8) to obtain the target product, compound 35: 2,7-dichloro-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (3.86 mg, yield 20.4%). MS (ESI) [M+H] ⁺ 318.9, 321.0. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.00 (d, J=2.0Hz, 1H), 7.93 (dd, J=8.3, 2.0Hz, 1H), 7.86-7.81 (m, 1H).

Example 36: Preparation of 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one

2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,20 mg, 0.08 mmol) was dissolved in formic acid (2 ml), potassium thiocyanate (10 mg, 0.096 mmol) was added, and the mixture was reacted at 80°C for 3 hours. The reaction solution was evaporated to dryness under reduced pressure and purified by preparative liquid phase, and then recrystallized (methanol/water) to obtain the target product compound 36: 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (2.05 mg, yield 11.0%). MS (ESI) [M+H] ⁺ 233.0, 235.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.12 (s, 1H), 8.51 (s, 1H), 7.77 (d, J=1.0 Hz, 2H), 7.70 (s, 1H).

Example 37: Preparation of 7-chloro-2-thiocyanato-9H-indeno[2,1-d]pyrimidin-9-one

2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,32 mg, 0.128 mmol) was dissolved in formic acid (3 ml), potassium thiocyanate (15 mg, 0.154 mmol) was added, and the mixture was reacted at 40°C overnight. The reaction solution was evaporated to dryness under reduced pressure and purified by preparative liquid phase to obtain the target product, compound 37: 7-chloro-2-thiocyanate-9H-indeno[2,1-d]pyrimidin-9-one (2.76 mg, yield 7.9%). MS (ESI) [M+H] ⁺ 273.9, 276.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.91-7.79 (m, 2H).

Example 38: Preparation of 7-chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 2-bromo-5-chloro-4-fluorobenzaldehyde (38a)

3-Chloro-4-fluorobenzaldehyde (500 mg, 3.15 mmol) was dissolved in 1,2-dichloroethane and trifluoroacetic acid (20 ml, 5 ml), and N-bromosuccinimide (673 mg, 3.78 mmol), 2-amino-5-chlorobenzotrifluoride (90 μl, 0.63 mmol) and palladium acetate (71 mg, 0.315 mmol) were added, and the atmosphere was replaced with nitrogen, and the reaction was carried out at 60°C overnight. The insoluble matter in the reaction solution was filtered off, and the filtrate was evaporated to dryness under reduced pressure and then purified by Flash column to obtain the target product 2-bromo-5-chloro-4-fluorobenzaldehyde (38a, 509 mg, yield 68.4%).

Step 2: Preparation of 5-chloro-4-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (38b)

2-(Trifluoromethyl)pyrimidin-5-ylboronic acid (38a, 141 mg, 0.734 mmol) was dissolved in acetonitrile (13 ml), 2-bromo-5-chloro-4-fluorobenzaldehyde (173 mg, 0.733 mmol), potassium fluoride (86 mg, 1.48 mmol) and palladium acetate (8 mg, 0.036 mmol) were added, and the mixture was reacted at 120°C for 60 minutes under microwave. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-10%) to obtain the target product 5-chloro-4-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (38b, 66 mg, yield 27.8%). MS (ESI) [M+H] ⁺ 305.0, 307.0.

Step 3: Preparation of 7-chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (38)

7-Chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (38b, 33 mg, 0.108 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (2 mg, 0.0054 mmol) and tert-butyl hydroperoxide (84 μl, 0.864 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was evaporated to dryness under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether=1:7) to obtain the target product, compound 38: 7-chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (10.39 mg, yield 31.5%). MS (ESI) [M+H] ⁺ 303.0, 305.0. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 8.25 (d, J = 8.8Hz, 1H), 8.14 (d, J = 6.9Hz, 1H).

Example 39: Preparation of 7-chloro-4-hydroxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-bromo-2-(trifluoromethyl)pyrimidin-4-ol (39a)

2-(Trifluoromethyl)pyrimidin-4-ol (50 mg, 0.304 mmol) was dissolved in acetic acid (4 ml), potassium acetate (90 mg, 0.914 mmol) was added, and liquid bromine (18 μl, 0.335 mmol) was added under ice bath and then reacted at 80°C for 1.5 hours. After spot reaction, saturated sodium bicarbonate solution was added to adjust to neutrality, and aqueous solution (10 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (6 ml × 3), and the combined organic layer was washed with brine (6 ml × 2), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain the target product crude 5-bromo-2-(trifluoromethyl)pyrimidin-4-ol (39a, 60 mg, yield 81.04%).

Step 2: Preparation of 5-chloro-2-(4-hydroxy-2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (39b)

Dissolve (4-chloro-2-formylphenyl)boronic acid (68 mg, 0.37 mmol) in acetonitrile (4 ml), add 5-bromo-2-(trifluoromethyl)pyrimidin-4-ol (39a, 60 mg, 0.247 mmol), potassium fluoride (29 mg, 0.494 mmol) and palladium acetate (3 mg, 0.012 mmol), and react at 120°C for 60 minutes in a microwave oven. Evaporate the solvent under reduced pressure, and purify the residue by preparative plate (ethyl acetate: petroleum ether = 0%-50%) to obtain the target product 5-chloro-2-(4-hydroxy-2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (39b, 10 mg, yield 13.38%). MS (ESI) [M+H] ⁺ 303.1, 305.1.

Step 3: Preparation of 7-chloro-4-hydroxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (39)

5-Chloro-2-(4-hydroxy-2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (10 mg, 0.033 mmol) was dissolved in 1,2-dichloroethane (1 ml), tetrabutylammonium iodide (1 mg, 0.0016 mmol) and tert-butyl hydroperoxide (24 mg, 0.264 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was evaporated to dryness under reduced pressure and then purified by preparative HPLC and freeze-dried to obtain the target product compound 39: 7-chloro-4-hydroxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (0.62 mg, yield 6.24%). MS (ESI) [M+H] ⁺ 301.0, 303.0.

Example 40: Preparation of 7-chloro-n-cyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidine-9-imine

Step 1: Preparation of 5-chloro-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (40a)

5-Bromo-2-trifluoromethylpyrimidine (2g, 8.85mmol) was dissolved in ethanol (40ml), 4-chloro-2-formylphenylboronic acid (2.12g, 11.51mmol), potassium fluoride (1.028g, 17.7mmol) and palladium acetate (99.36mg, 0.44mmol) were added, and the mixture was reacted in an oil bath at 120℃ for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-40%) to obtain the target product 5-chloro-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (40a, 1.3740g, yield 54.27%). MS (ESI) [M+H] ⁺ 287.0.

Step 2: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (40b)

5-Chloro-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (40a, 700 mg, 2.45 mmol) was dissolved in 1,2-dichloroethane (25 ml), tetrabutylammonium iodide (45.19 mg, 0.12 mmol) and tert-butyl hydroperoxide (1.80 g, 19.97 mmol) were added, and the mixture was reacted at 100°C in a sealed tube under nitrogen protection for 30 hours. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-40%) to obtain the target product 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (40b, 336.4 mg, yield 48.38%). MS (ESI) [M+H] ⁺ 285.0.

Step 3: Preparation of 7-chloro-n-cyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidine-9-imine (40)

7-Chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (40b, 20 mg, 0.07 mmol) was dissolved in ultra-dry toluene (4 ml), cyclopropylamine (8.04 mg, 0.14 mmol) and molecular sieves were added, and microwave reaction was performed at 150°C for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was purified on a preparative plate (ethyl acetate: petroleum ether = 1:2) to obtain the target product 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one, and finally purified by HPLC to obtain the target product compound 40: 7-chloro-n-cyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidin-9-imine (3.18 mg, 13.97%). MS (ESI) [M+H] ⁺ 324.0. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.27-1.22 (m, 3H), 1.51-1.47 (m, 2H), 7.74-7.67 (m, 2H), 8.09-8.14 (m, 1H), 9.68 (s, 1H).

Example 41: Preparation of 7-chloro-2-methylsulfonyl-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2-methylsulfonyl)pyrimidin-5-yl)benzaldehyde (41a)

5-Bromo-2-(methylsulfonyl)pyrimidine (200 mg, 0.8 mmol) was dissolved in acetonitrile (20 ml), 4-chloro-2-formylphenylboronic acid (160 mg, 0.8 mmol), potassium fluoride (100 mg, 1.6 mmol) and palladium acetate (6 mg, 0.04 mmol) were added, and the mixture was reacted at 120°C for 50 minutes under microwave. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-40%) to obtain the target product 5-chloro-2-(2-methylsulfonyl)pyrimidin-5-yl)benzaldehyde (41a, 65.4 mg, yield 26.19%). MS (ESI) [M+H] ⁺ 297.0.

Step 2: Preparation of 7-chloro-2-methylsulfonyl-9H-indeno[2,1-d]pyrimidin-9-one (41)

5-Chloro-2-(2-methylsulfonyl)pyrimidin-5-yl)benzaldehyde (41a, 40 mg, 0.14 mmol) was dissolved in 1,2-dichloroethane (10 ml), tetrabutylammonium iodide (2.50 mg, 0.007 mmol) and tert-butyl hydroperoxide (97.43 mg, 1.08 mmol) were added, and the mixture was reacted at 100°C in a sealed tube under nitrogen protection for 16 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative plate (tetrahydrofuran: petroleum ether = 1:1) to obtain the target product compound 41: 7-chloro-2-methylsulfonyl-9H-indeno[2,1-d]pyrimidin-9-one (0.62 mg, yield 1.56%). MS (ESI) [M+H] ⁺ 295.0.

Example 42: Preparation of 7-methoxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-methoxy-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (42a)

4-Methoxy-2-formylphenylboronic acid (200 mg, 1.11 mmol) was dissolved in acetonitrile (15 ml), 5-bromo-2-trifluoromethylpyrimidine (251 mg, 1.11 mmol), potassium fluoride (129 mg, 2.22 mmol) and palladium acetate (12 mg, 0.1 mmol) were added, and microwave reaction was performed at 120°C for 50 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-40%) to obtain the target product 5-methoxy-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (42a, 197.1 mg, yield 62.91%). MS (ESI) [M+H] ⁺ 283.0.

Step 2: Preparation of 7-methoxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (42)

5-Methoxy-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (42a, 50 mg, 0.18 mmol) was dissolved in 1,2-dichloroethane (10 ml), tetrabutylammonium iodide (3.27 mg, 0.009 mmol) and tert-butyl hydroperoxide (127.80 mg, 1.42 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube under nitrogen protection for 16 hours. The solvent was evaporated under reduced pressure, and the crude product was purified on a preparative plate (ethyl acetate: petroleum ether=1:2) to obtain the target product compound 42: 7-methoxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (4.18 mg, yield 8.42%). MS (ESI) [M+H] ⁺ 281.0.1H NMR (400MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 7.98-7.95 (m, 1H), 7.37-7.32 (m, 2H), 3.89 (s, 3H).

Example 43: Preparation of 7-(trifluoromethyl)-9H-[1,3]dioxacyclo[4′,5′:5,6]indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 7-(trifluoromethyl)-9H-[1,3]dioxetane[4′,5′:5,6]indeno[2,1-d]pyrimidin-9-one 6-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxetane-5-carbaldehyde (43a)

5-Bromo-2-(trifluoromethyl)pyrimidine (50 mg, 0.2203 mmol) was dissolved in acetonitrile (3 ml), (6-formylbenzo[d][1,3]dioxol-5-yl)boric acid (51.2 mg, 0.2644 mmol), palladium acetate (2.5 mg, 0.0110 mmol), potassium fluoride (25.6 mg, 0.4406 mmol) were added, and the mixture was reacted at 120°C for 30 minutes under nitrogen protection in a microwave oven. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1/5) to obtain the target product 6-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxol-5-carbaldehyde (43a, 30 mg, yield 46%). MS (ESI) [M+H] ⁺ 297.3.

Step 2: Preparation of 7-(trifluoromethyl)-9H-[1,3]dioxacyclo[4′,5′:5,6]indeno[2,1-d]pyrimidin-9-one (43)

6-(2-(Trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxadioxe-5-carboxaldehyde (43a, 30 mg, 0.1013 mmol) was dissolved in dichloroethane (2 ml), 2-hydroperoxy-2-methylpropane (73 mg, 0.8102 mmol) was added, and the mixture was reacted in a sealed manner at 100°C for 16 hours. After concentration under reduced pressure, the crude product was purified by preparative HPLC (water:methanol=1/50) to obtain the target product compound 43: 7-(trifluoromethyl)-9H-[1,3]dioxadioxe[4′,5′:5,6]indeno[2,1-d]pyrimidin-9-one (43, 1.48 mg, yield 5.0%). MS(ESI)[M+H] ⁺ 295.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.31 (s, 1H), 7.68 (s, 1H), 7.37 (s, 1H), 6.28 (s, 2H).

Example 44: Preparation of 7-chloro-2-(pyridin-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-bromo-2-(pyridin-2-yl)pyrimidine (44a)

5-Bromo-2-iodopyrimidine (300 mg, 0.8109 mmol) was dissolved in toluene (3 ml), 2-tri-n-butylstannylpyridine (231 mg, 0.8109 mmol), triphenylphosphine (28.5 mg, 0.0811 mmol), bis(triphenylphosphine)palladium(II) dichloride (21.3 mg, 0.0405 mmol) were added, and the mixture was reacted at 120°C overnight under nitrogen protection. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (dichloromethane: methanol = 1/20) to obtain the target product 5-bromo-2-(pyridin-2-yl)pyrimidine (44a, 110 mg, yield 37.6%). MS (ESI) [M+H] ⁺ 236.1.

Step 2: Preparation of 5-chloro-2-(2-(pyridin-2-yl)pyrimidin-5-yl)benzaldehyde (44b)

Dissolve (4-chloro-2-formylphenyl)boronic acid (86.3 mg, 0.466 mmol) in acetonitrile (3 ml), add 5-bromo-2-(pyridin-2-yl)pyrimidine (110 mg, 0.466 mmol), palladium acetate (5.3 mg, 0.0233 mmol), potassium fluoride (54.4 mg, 0.932 mmol), and react at 120°C for 30 minutes under nitrogen protection. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (dichloromethane: methanol = 1/15) to obtain the target product 5-chloro-2-(2-(pyridin-2-yl)pyrimidin-5-yl)benzaldehyde (44b, 13 mg, yield 9.4%). MS (ESI) [M+H] ⁺ 296.3.

Step 3: Preparation of 7-chloro-2-(pyridin-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one (44)

5-Chloro-2-(2-(pyridin-2-yl)pyrimidin-5-yl)benzaldehyde (44b, 13 mg, 0.0439 mmol) was dissolved in dichloroethane (2 ml), 2-hydroperoxy-2-methylpropane (31.7 mg, 0.3512 mmol) was added, and the reaction was carried out in a closed manner at 100°C for 16 hours. After concentration under reduced pressure, the crude product was purified by preparative HPLC (water: methanol = 1/50) to obtain the target product compound 44: 7-chloro-2-(pyridin-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one (1.18 mg, yield 9.1%). MS (ESI) [M+H] ⁺ 294.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.52 (s, 1H), 8.77 (d, J = 4.8Hz, 1H), 8.42 (d, J = 8.0Hz, 1H), 8.07-8.02 (m, 1H), 8.01-7.97 (m, 1H), 7.88- 7.83 (m, 1H), 7.81 (d, J=2.0Hz, 1H), 7.56 (t, J=6.3Hz, 1H).

Example 45: Synthesis of 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Synthesis of 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (45-a)

Place (4-chloro-2-formylphenyl)boric acid (3.45g, 18.72mmol), 2-chloro-5-iodopyrimidine (3g, 12.48mmol), potassium fluoride (1.44g, 24.96mmol) and palladium acetate (141mg, 0.624mmol) in a microwave reaction tube, add ethanol (80ml), seal after nitrogen purge, and react at 120℃ overnight. Filter the reaction solution to remove insoluble matter, concentrate the filtrate under reduced pressure, and purify the residue with a Flash column (ethyl acetate: petroleum ether = 0% to 20%) to obtain the target product 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (45-a, 2g, yield 63.33%). ESI [M+H] ⁺ = 253.0, 255.0

Step 2: Synthesis of 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (45-b)

Dissolve 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (45-a, 1 g, 3.95 mmol) in 1,2-dichloroethane (20 ml), add tetrabutylammonium iodide (70 mg, 0.198 mmol) and tert-butyl hydroperoxide (2.85 g, 31.6 mmol), and react overnight at 100°C in a sealed tube under nitrogen protection. After the reaction solution was filtered and concentrated under reduced pressure, the residue was purified by Flash column (ethyl acetate: petroleum ether = 0% to 20%) to obtain the target product 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (45-b, 300 mg, yield 30.24%). ESI [M+H] ⁺ = 251.0, 252.9

Step 3: Synthesis of 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (45)

2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (45-b, 20 mg, 0.08 mmol) was dissolved in formic acid (2 ml), potassium thiocyanate (10 mg, 0.103 mmol) was added, and the mixture was reacted at 80°C for 3 hours. After the reaction solution was concentrated under reduced pressure, the by-product 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (45, 2.05 mg, yield 11.0%) was directly prepared and purified. ESI[M+H] ⁺ =233.0, 235.0 ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.12(s, 1H), 8.51(s, 1H), 7.77(d, J=1.0 Hz, 2H), 7.70(s, 1H).

Example 46: Synthesis of 7-chloro-2-(trifluoromethyl)-9H-pyrido[3′,2′:3,4]cyclopenta[1,2-d]pyrimidin-9-one

Step 1: Synthesis of 3-bromo-6-chloropyridinecarboxaldehyde (46-a)

Dissolve (3-bromo-6-chloropyridin-2-yl)methanol (450 mg, 2.02 mmol) in dioxane (20 ml), add manganese dioxide (1.76 g, 20.23 mmol), and react at 100°C for 8 hours. Filter to remove manganese dioxide, and concentrate the filtrate under reduced pressure to obtain the target product, crude 3-bromo-6-chloropyridinecarboxaldehyde (46-a, 425 mg, yield 95.9%). ESI [M+H] ⁺ = 219.8, 221.8

Step 2: Synthesis of 6-chloro-3-(2-(trifluoromethyl)pyrimidin-5-yl)pyridinecarboxaldehyde (46-b)

3-Bromo-6-chloropyridinecarboxaldehyde (46-a, 250 mg, 1.14 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 285 mg, 1.48 mmol), potassium fluoride (132 mg, 2.28 mmol) and palladium acetate (13 mg, 0.058 mmol) were placed in a microwave reaction tube, acetonitrile (15 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was carried out at 120°C for 60 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product 6-chloro-3-(2-(trifluoromethyl)pyrimidin-5-yl)pyridinecarboxaldehyde (46-b, 23 mg, yield 5.8%). ESI [M+H] ⁺ = 288.0, 290.0

Step 3: Synthesis of 7-chloro-2-(trifluoromethyl)-9H-pyrido[3′,2′:3,4]cyclopenta[1,2-d]pyrimidin-9-one (46)

6-Chloro-3-(2-(trifluoromethyl)pyrimidin-5-yl)picolinaldehyde (46-b, 23 mg, 0.080 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (1.5 mg, 0.0041 mmol) and tert-butyl hydroperoxide (62 μl, 0.64 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether = 1:2) to obtain the target product 7-chloro-2-(trifluoromethyl)-9H-pyrido[3′,2′:3,4]cyclopenta[1,2-d]pyrimidin-9-one (46, 1.21 mg, yield 5.3%). ESI[M+H] ⁺ = 286.0, 288.0

Example 47: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

Step 1: Synthesis of 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (47-a)

2-(Trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 100 mg, 0.52 mmol), 4-bromo-3-formylbenzonitrile (109 mg, 0.52 mmol), potassium fluoride (61 mg, 1.05 mmol) and palladium acetate (6 mg, 0.027 mmol) were placed in a microwave reaction tube, acetonitrile (10 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was carried out at 120°C for 30 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0% to 20%) to obtain the target product 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (47-a, 35 mg, yield 24.3%). ESI [M+H] ⁺ = 278.1

Step 2: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (47-b)

3-Formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (47-a, 35 mg, 0.126 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (97 μl, 1.01 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether = 1:2) to obtain the target product 9-oxo-2-(trifluoromethyl)-9H indeno[2,1-d]pyrimidine-7-carbonitrile (47-b, 14.42 mg, yield 41.6%). ESI [M+H] ⁺ = 276.1

Step 3: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (47)

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (47-b, 5.6 mg, 0.020 mmol) was dissolved in water/isopropanol (0.5 ml/0.5 ml), and manganese dioxide (18 mg, 0.207 mmol) was added, and the mixture was reacted at 100° C. for 5 hours. Manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (47, 2.06 mg, yield 34.3%). ESI[M+H] ⁺ =294.1 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.64 (s, 1H), 8.29 (d, J = 7.8Hz, 3H), 8.16 (d, J = 7.9Hz, 1H), 7.68 (s, 1H).

Example 48: Synthesis of 2,7-dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Synthesis of 5-chloro-2-(2-chloro-4-methoxypyrimidin-5-yl)benzaldehyde (48-a)

4-Chloro-2-formylphenylboronic acid (375 mg, 2.04 mmol), 2-chloro-4-methoxy-5-bromopyrimidine (350 mg, 1.56 mmol), potassium fluoride (182 mg, 3.14 mmol) and palladium acetate (18 mg, 0.080 mmol) were placed in a microwave reaction tube, acetonitrile (25 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was carried out at 120°C for 60 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0% to 20%) to obtain the target product 5-chloro-2-(2-chloro-4-methoxypyrimidin-5-yl)benzaldehyde (48-a, 74 mg, yield 14.7%). ESI [M+H] ⁺ = 283.1, 285.1

Step 2: Synthesis of 2,7-dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidin-9-one (48)

5-Chloro-2-(2-chloro-4-methoxypyrimidin-5-yl)benzaldehyde (48-a, 37 mg, 0.131 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (2.4 mg, 0.0065 mmol) and tert-butyl hydroperoxide (101 μl, 1.05 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and purified by preparative plate (tetrahydrofuran: petroleum ether = 1:2) to obtain the target product 2,7-dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidin-9-one (48, 7.63 mg, yield 20.8%). ESI[M+H] ⁺ =281.2, 283.2 ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.76 (dd, J=5.2, 2.0Hz, 2H), 7.68-7.65 (m, 1H), 4.17 (s, 3H).

Example 49: Synthesis of 7-chloro-2,4-dihydroxy-9H-indeno[2,1-d]pyrimidin-9-one

2,7-Dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidin-9-one (48, 4 mg, 0.014 mmol) was dissolved in formic acid (1 ml) and reacted at 80°C overnight. The reaction solution was concentrated under reduced pressure and purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the target product 7-chloro-2,4-dihydroxy-9H-indeno[2,1-d]pyrimidin-9-one (49, 0.90 mg, yield 25.7%). ESI [M+H] ⁺ = 249.0, 251.0

Example 50: Synthesis of methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylate

Step 1: Synthesis of methyl 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzoate (50-a)

Place 4-bromo-3-formylbenzoic acid methyl ester (200 mg, 0.826 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 206 mg, 1.07 mmol), potassium fluoride (96 mg, 1.66 mmol) and palladium acetate (10 mg, 0.045 mmol) in a microwave reaction tube, add acetonitrile (20 ml), seal after nitrogen purge, and microwave reaction at 120°C for 60 minutes. Filter the reaction solution to remove insoluble matter, concentrate the filtrate under reduced pressure, and purify the residue with a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzoic acid methyl ester (50-a, 54 mg, yield 21.1%). ESI [M+H] ⁺ = 311.2

Step 2: Synthesis of methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylate (50)

Methyl 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzoate (50-a, 54 mg, 0.174 mmol) was dissolved in 1,2-dichloroethane (4 ml), tetrabutylammonium iodide (3.2 mg, 0.0087 mmol) and tert-butyl hydroperoxide (134 μl, 1.39 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether=1:3) to obtain the target product, methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylate (50, 28.4 mg, yield 52.9%). ESI[M+H] ⁺ =309.1 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.71 (s, 1H), 8.38 (d, J = 7.8Hz, 1H), 8.27-8.18 (m, 2H), 3.92 (s, 3H).

Example 51: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50, 20 mg, 0.065 mmol) was dissolved in tetrahydrofuran/water (1 ml/0.5 ml), lithium hydroxide monohydrate (6 mg, 0.143 mmol) was added, and the reaction was carried out at room temperature for 1 hour. 1N hydrochloric acid was used to adjust the pH to neutral, and the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 4.13 mg, yield 21.6%). ESI[M+H] ⁺ =295.1 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.65 (s, 1H), 8.33 (d, J = 7.7Hz, 1H), 8.21-8.10 (m, 2H), 6.87 (s, 1H).

Example 52: Synthesis of N-cyclopropyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 10 mg, 0.034 mmol) was dissolved in dichloromethane (1 ml), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (19 mg, 0.050 mmol), N,N-diisopropylethylamine (9 μl, 0.051 mmol) and cyclopropylamine (3 μl, 0.034 mmol) were added, and the reaction was carried out at room temperature for 2 hours. Saturated ammonium chloride solution was added to quench the reaction, and the reaction was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the target product N-cyclopropyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (52, 2.70 mg, yield 11.9%). ESI[M+H] ⁺ =334.1, ESI[2M+H] ⁺ =667.2 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.63 (s, 1H), 8.75 (d, J = 4.0Hz, 1H), 8.28-8.21 (m, 2H), 8.16 (d, J = 8.2Hz, 1H), 2.89 (ddd, J =11.3, 7.6, 4.0Hz, 1H), 1.35(s, 2H), 1.23(s, 2H).

Example 53: Synthesis of N-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 40 mg, 0.136 mmol) was dissolved in dichloromethane (5 ml), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (77 mg, 0.203 mmol), N,N-diisopropylethylamine (59 μl, 0.34 mmol) and methylamine hydrochloride (9 mg, 0.133 mmol) were added, and the reaction was carried out at room temperature for 2 hours. Saturated ammonium chloride solution was added to quench the reaction, and the reaction was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the target product N-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (53, 12.41 mg, yield 29.7%). ESI[M+H] ⁺ =308.1, ESI[2M+H] ⁺ =615.2 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.63 (s, 1H), 8.77 (d, J = 4.4Hz, 1H), 8.28-8.21 (m, 2H), 8.16 (d, J = 7.8Hz, 1H), 2.82 (d, J = 4.4Hz, 3H).

Example 54: Synthesis of 2-(trifluoromethyl)-7-(trifluoromethylthio)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Synthesis of 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (54-a)

3-((Trifluoromethyl)thio)benzaldehyde (400 mg, 1.94 mmol) was dissolved in dichloroethane (15 ml), and 4-chloro-2-(trifluoromethyl)aniline (54.8 μl, 0.391 mmol), N-bromosuccinimide (414 mg, 2.33 mmol), palladium acetate (44 mg, 0.192 mmol), and trifluoroacetic acid (4 ml) were added. After overnight reaction at 60°C under nitrogen atmosphere, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (99% petroleum ether) to obtain the target product 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (54-a, 320 mg, yield 58.8%). (ESI) [M+H] ⁺ = 285.1.

Step 2: 2-(2-(trifluoromethyl)pyrimidin-5-yl)-5-(trifluoromethylthio)benzaldehyde (54-b)

2-Bromo-5-((trifluoromethyl)thio)benzaldehyde (54-a, 120 mg, 0.423 mmol) was dissolved in acetonitrile (5 ml), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (122 mg, 0.634 mmol), potassium fluoride (49 mg, 0.846 mmol), palladium acetate (65.2 mg, 0.0212 mmol) were added, and microwave reaction was carried out at 120°C for 30 minutes under nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product 2-(2-(trifluoromethyl)pyrimidin-5-yl)-5-(trifluoromethylthio)benzaldehyde (54-b, 80 mg, yield 53.8%). (ESI) [M+H] ⁺ = 353.1.

Step 3: Synthesis of 2-(trifluoromethyl)-7-(trifluoromethylthio)-9H-indeno[2,1-d]pyrimidin-9-one (54)

2-(2-(trifluoromethyl)pyrimidin-5-yl)-5-(trifluoromethylthio)benzaldehyde (54-b, 40 mg, 0.114 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (2 mg, 0.0054 mmol) and tert-butyl hydroperoxide (109 μl, 1.14 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and then purified to obtain the target product 2-(trifluoromethyl)-7-(trifluoromethylthio)-9H-indeno[2,1-d]pyrimidin-9-one (54, 2.45 mg, yield 6.1%). ESI[M+H] ⁺ =351.2 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.69 (s, 1H), 8.25 (d, J = 7.8Hz, 1H), 8.21-8.15 (m, 1H), 8.08 (s, 1H).

Example 55: Synthesis of 6-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile

Step 1: Synthesis of 4-bromo-5-formyl-2-methylbenzonitrile (55-a)

5-Formyl-2-methylbenzonitrile (50 mg, 0.344 mmol), 4-chloro-2-(trifluoromethyl)aniline (13.45 mg, 0.0688 mmol), N-bromosuccinimide (73.47 mg, 0.4128 mmol), palladium acetate (7.7 mg, 0.0344 mmol) were dissolved in dichloroethane (2 ml), and then trifluoroacetic acid (0.5 ml) was added, and nitrogen was replaced three times. The mixture was reacted at 100° C. for 12 hours under nitrogen protection. The reaction solution was filtered, concentrated under reduced pressure, and purified by thin layer chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 4-bromo-5-formyl-2-methylbenzonitrile (55-a, 19 mg, yield 24.6%). ESI[M+H] ⁺ = 225.06

Step 2: Synthesis of 5-formyl-2-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (55-b)

4-Bromo-5-formyl-2-methylbenzonitrile (55-a, 30 mg, 0.134 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 34 mg, 0.177 mmol), potassium fluoride (16 mg, 0.276 mmol) and palladium acetate (2 mg, 0.0089 mmol) were placed in a microwave reaction tube, acetonitrile (3 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was carried out at 120°C for 30 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by preparation plate (ethyl acetate: petroleum ether = 1:5) to obtain the target product 5-formyl-2-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (55-b, 14 mg, yield 35.9%). ESI [M+H] ⁺ = 292.2

Step 3: Synthesis of 6-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (55)

5-Formyl-2-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (55-b, 14 mg, 0.0481 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (1 mg, 0.0027 mmol) and tert-butyl hydroperoxide (37 μl, 0.385 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether=1:5) to obtain the target product 6-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (55, 3.85 mg, yield 27.5%). ESI[M+H] ⁺ =290.1 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.65 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 2.65 (s, 3H).

Example 56: Synthesis of 8-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile

Step 1: Synthesis of 4-bromo-2-fluoro-3-formylbenzonitrile (56-a)

4-Bromo-2-fluorobenzonitrile (500 mg, 2.51 mmol) was dissolved in ultra-dry tetrahydrofuran (10 ml), and diisopropylamine lithium (2 M, 1.9 ml, 3.77 mmol) was added dropwise at -78°C under nitrogen protection, and the reaction was continued for 0.5 hours after the addition was completed, and then N,N-dimethylformamide (387 μl, 5.02 mmol) was added dropwise, and the reaction was continued for 15 minutes after the addition was completed. Saturated ammonium chloride solution was added to quench, 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 on a Flash column (ethyl acetate: petroleum ether = 0% to 20%) to obtain the target product 4-bromo-2-fluoro-3-formylbenzonitrile (56-a, 135 mg, yield 23.7%).

Step 2: Synthesis of 2-fluoro-3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (56-b)

4-Bromo-2-fluoro-3-formylbenzonitrile (56-a, 60 mg, 0.264 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 76 mg, 0.396 mmol), potassium fluoride (31 mg, 0.534 mmol) and palladium acetate (3 mg, 0.0134 mmol) were placed in a microwave reaction tube, acetonitrile (5 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was performed at 120°C for 45 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative plate (ethyl acetate: petroleum ether = 1:5) to obtain the target product 2-fluoro-3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (56-b, 65 mg, yield 45.4%). ESI [M+H] ⁺ = 296.4

Step 3: Synthesis of 8-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (56)

2-Fluoro-3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (56-b, 35 mg, 0.119 mmol) was dissolved in 1,2-dichloroethane (3 ml), tetrabutylammonium iodide (2 mg, 0.00541 mmol) and tert-butyl hydroperoxide (91 μl, 0.952 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and purified on a preparative plate (tetrahydrofuran: petroleum ether=1:3) to obtain the target product 8-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (56, 18.36 mg, yield 52.4%). ESI[M+H] ⁺ =294.3 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.77 (s, 1H), 8.43 (dd, J=7.5, 6.3Hz, 1H), 8.15 (d, J=7.8Hz, 1H).

Example 57: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-sulfonamide

Step 1: Synthesis of 2-chloro-5-sulfamoylbenzoic acid (57-a)

At 0°C, 2-chloro-5-(chlorosulfonyl)benzoic acid (2 g, 7.8 mmol) was dissolved in ammonia hydrate (30 ml) and stirred at room temperature for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the target product, crude 2-chloro-5-aminosulfonylbenzoic acid (57-a, 2.53 g, yield 130.4%). ESI [MH] ⁺ = 234.1, 236.2

Step 2: Synthesis of 2-chloro-N-methoxy-N-methyl-5-sulfamoylbenzamide (57-b)

2-Chloro-5-sulfamoylbenzoic acid (57-a, 1 g, 4.26 mmol), N, O-dimethylhydroxylamine hydrochloride (413 mg, 4.26 mmol) and 1-methyl-1H-imidazole (1.4 ml, 17.02 mmol) were dissolved in acetonitrile (20 ml), stirred at room temperature for 10 minutes, and then N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (1.19 g, 4.26 mmol) was added and reacted at room temperature for 2 hours. The reaction solution was filtered and concentrated under reduced pressure, and then purified by Flash column (ethyl acetate: petroleum ether = 0% to 50%) to obtain the target product 2-chloro-N-methoxy-N-methyl-5-sulfamoylbenzamide (57-b, 1.208 g, yield 102.15%). ESI [M+H] ⁺ = 278.2, 280.2

Step 3: Synthesis of 4-chloro-3-formylbenzenesulfonamide (57-c)

2-Chloro-N-methoxy-N-methyl-5-aminosulfonylbenzamide (57-b, 150 mg, 0.539 mmol) was dissolved in ultra-dry dichloromethane (10 ml), and diisobutylaluminum hydride (1 M, 1 ml, 1.078 mmol) was added at 0°C under nitrogen protection, and the mixture was reacted at 0°C for 2 hours. Saturated ammonium chloride solution was added to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 4-chloro-3-formylbenzenesulfonamide (57-c, 46 mg, yield 38.9%). ESI [M+H] ⁺ = 220.2, 222.2

Step 4: Synthesis of 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide (57-d)

4-Chloro-3-formylbenzenesulfonamide (57-c, 46 mg, 0.21 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 52 mg, 0.273 mmol), cesium carbonate (137 mg, 0.42 mmol) and tetrakistriphenylphosphine palladium (12 mg, 0.0104 mmol) were placed in a microwave reaction tube, dioxane/water (5 ml/0.5 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was carried out at 120°C for 30 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by preparation plate (dichloromethane: methanol = 15: 1) to obtain the target product 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide (57-d, 17 mg, yield 24.5%). ESI [M+H] ⁺ = 332.3

Step 5: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (57)

3-Formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide (57-d, 17 mg, 0.0514 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (1 mg, 0.0027 mmol) and tert-butyl hydroperoxide (42 μl, 0.411 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and purified on a preparative plate (dichloromethane: methanol = 15: 1) to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (57, 3.04 mg, yield 17.9%). ESI[M+H] ⁺ =330.3 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.28-8.19 (m, 2H), 8.15 (d, J = 0.9Hz, 1H), 7.67 (s, 2H).

Example 58: Synthesis of 5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile

Step 1: Synthesis of 4-bromo-3-formyl-5-methylbenzonitrile (58-a)

3-Cyano-5-methylbenzaldehyde (200 mg, 1.38 mmol) was dissolved in 1,2-dichloroethane/trifluoroacetic acid (8 ml/2 ml), and N-bromosuccinimide (295 mg, 1.66 mmol), 4-chloro-2-(trifluoromethyl)aniline (39 μl, 0.276 mmol) and palladium acetate (31 mg, 0.138 mmol) were added. The mixture was protected by nitrogen and reacted overnight at 100°C in a sealed tube. The insoluble matter in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by Flash column (ethyl acetate: petroleum ether = 0% to 5%) to obtain the target product 4-bromo-3-formyl-5-methylbenzonitrile (58-a, 15 mg, yield 4.9%). ESI [M+H] ⁺ = 224.0, 225.9

Step 2: Synthesis of 3-formyl-5-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (58-b)

4-Bromo-3-formyl-5-methylbenzonitrile (58-a, 12 mg, 0.0538 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 14 mg, 0.0729 mmol), potassium fluoride (7 mg, 0.121 mmol) and palladium acetate (1 mg, 0.00445 mmol) were placed in a microwave reaction tube, acetonitrile (2 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was carried out at 120°C for 30 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative plate (ethyl acetate: petroleum ether = 1: 6) to obtain the target product 3-formyl-5-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (58-b, 10 mg, yield 63.7%). ESI [M+H] ⁺ = 292.2

Step 3: Synthesis of 5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (58)

3-Formyl-5-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (58-b, 10 mg, 0.0344 mmol) was dissolved in 1,2-dichloroethane (1 ml), tetrabutylammonium iodide (0.63 mg, 0.00171 mmol) and tert-butyl hydroperoxide (27 μl, 0.275 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and then purified to obtain the target product 5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (58, 0.84 mg, yield 8.4%). ESI[M+H] ⁺ =290.4

Example 59: Synthesis of 2-(trifluoromethyl)-7-(trifluoromethanesulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

2-(Trifluoromethyl)-7-(trifluoromethylthio)-9H-indeno[2,1-d]pyrimidin-9-one (54, 13 mg, 0.0371 mmol) was dissolved in dichloromethane (2 ml), and m-chloroperbenzoic acid (19 mg, 0.11 mmol) was added at 0°C, and then reacted at room temperature for 36 hours. The reaction solution was concentrated under reduced pressure and then purified to obtain the target product 2-(trifluoromethyl)-7-(trifluoromethanesulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (59, 2.48 mg, yield 17.7%). ESI[M+H] ⁺ =383.1 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 8.66 (d, J = 8.0Hz, 1H), 8.57 (d, J = 8.0Hz, 1H), 8.33 (s, 1H).

Example 60: Synthesis of 7-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Synthesis of 5-bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a)

5-Bromo-2-iodobenzaldehyde (50 mg, 0.161 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 50 mg, 0.26 mmol), potassium fluoride (19 mg, 0.327 mmol) and palladium acetate (2 mg, 0.0089 mmol) were placed in a microwave reaction tube, ethanol (4 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was performed at 120°C for 30 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0% to 25%) to obtain the target product 5-bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a, 45 mg, yield 42.4%). ESI [M+H] ⁺ = 331.1, 333.0

Step 2: Synthesis of 5-(1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-b)

5-Bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a, 25 mg, 0.0757 mmol), 1H-pyrazole-3-boric acid (10 mg, 0.0893 mmol), potassium fluoride (9 mg, 0.155 mmol) and palladium acetate (1 mg, 0.00445 mmol) were placed in a microwave reaction tube, ethanol (3 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was performed at 120°C for 40 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by preparation plate (dichloromethane: methanol = 10: 1) to obtain the target product 5-(1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-b, 9 mg, yield 20.9%). ESI [M+H] ⁺ = 319.1

Step 3: Synthesis of 7-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60)

5-(1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-b, 9 mg, 0.0283 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (0.52 mg, 0.00141 mmol) and tert-butyl hydroperoxide (22 μl, 0.226 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and then purified to obtain the target product 7-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60, 2.10 mg, yield 23.6%). ESI[M+H] ⁺ =317.1, ESI[2M+H] ⁺ =633.2, ESI[2M+Na] ⁺ =655.2 ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.15 (s, 1H), 9.56 (s, 1H), 8.29-8.19 (m, 2H), 8.09 (d, J = 7.7Hz, 1H ), 7.86 (s, 1H), 6.97 (d, J=2.1Hz, 1H).

Example 61: Synthesis of 7-(1-methyl-1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Synthesis of 5-(1-methyl-1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (61-a)

5-Bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a, 60 mg, 0.182 mmol), 1-methyl-1H-pyrazole-5-boric acid (28 mg, 0.222 mmol), potassium fluoride (21 mg, 0.362 mmol) and palladium acetate (2 mg, 0.0089 mmol) were placed in a microwave reaction tube, ethanol (4 ml) was added, the tube was sealed after nitrogen purge, and microwave reaction was carried out at 120°C for 30 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by preparation plate (dichloromethane: methanol = 15: 1) to obtain the target product 5-(1-methyl-1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (61-a, 22 mg, yield 36.7%). ESI [M+H] ⁺ = 333.2

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

5-(1-methyl-1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (61-a, 22 mg, 0.0663 mmol) was dissolved in 1,2-dichloroethane (3 ml), tetrabutylammonium iodide (1.22 mg, 0.0033 mmol) and tert-butyl hydroperoxide (51 μl, 0.53 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the target product 7-(1-methyl-1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (61, 7.54 mg, yield 34.3%). ESI[M+H] ⁺ =331.1, ESI[2M+Na] ⁺ =683.2 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.64 (s, 1H), 8.19 (d, J = 7.8Hz, 1H), 8.00 (dd, J = 7.8, 1.5Hz, 1H), 7.95 (d, J = 0.8Hz, 1H), 7.5 3(d, J=1.8Hz, 1H), 6.62 (d, J=1.8Hz, 1H), 3.93 (s, 3H).

Example 62: Synthesis of N-hydroxy-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50, 15 mg, 0.0487 mmol) was dissolved in tetrahydrofuran/water (2 ml/0.2 ml), sodium hydroxide (4 mg, 0.1 mmol) and hydroxylamine hydrochloride (3.7 mg, 0.0528 mmol) were added, and lithium hydroxide monohydrate (4 mg, 0.1 mmol) was added, and the mixture was reacted at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure and then purified to obtain the target product N-hydroxy-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (18, 1.11 mg, yield 7.4%). ESI[M+H] ⁺ =310.1 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 8.97 (s, 1H), 8.28 (d, J = 7.9Hz, 1H), 8.22 (d, J = 7.9Hz, 1H).

Example 63: Synthesis of 7-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50, 15 mg, 0.0487 mmol) was dissolved in ultra-dry tetrahydrofuran (3 ml), and methylmagnesium bromide (1 M, 122 μl, 0.123 mmol) was added dropwise at 0°C under nitrogen protection, and then reacted at room temperature for 4 hours. Saturated ammonium chloride solution was added to quench, extracted with ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain the target product 7-(2-hydroxypropane-2-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (63, 1.20 mg, yield 8.0%). ESI[M+H] ⁺ =309.1 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.71 (s, 1H), 8.39 (d, J = 5.6Hz, 1H), 8.29-8.17 (m, 2H), 1.23 (s, 6H).

Example 64: Synthesis of 2-methoxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Synthesis of 2-chloro-5-(methylsulfonyl)benzoic acid (64-a)

Dissolve 2-chloro-5-(methylthio)benzoic acid (2 g, 9.87 mmol) in methanol (60 ml), add potassium peroxymonosulfonate (12.1 g, 19.66 mmol), and react at room temperature overnight. Filter to remove insoluble matter, concentrate the filtrate under reduced pressure, dissolve the residue in dichloromethane, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product 2-chloro-5-(methylsulfonyl)benzoic acid (64-a, 2.2 g, yield 95.7%). ESI [MH] ⁺ = 233.0, 235.0

Step 2: Synthesis of (2-chloro-5-(methylsulfonyl)phenyl)methanol (64-b)

2-Chloro-5-(methylsulfonyl)benzoic acid (64-a, 800 mg, 3.42 mmol) was dissolved in ultra-dry tetrahydrofuran (30 ml), and lithium aluminum tetrahydride (260 mg, 6.84 mmol) was added at 0°C under nitrogen protection, and then reacted at room temperature for 1 hour. Saturated ammonium chloride solution was added to quench, extracted with ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (2-chloro-5-(methylsulfonyl)phenyl)methanol (64-b, 415 mg, yield 55.2%).

Step 3: 2-Chloro-5-(methylsulfonyl)benzaldehyde (64-c)

Dissolve (2-chloro-5-(methylsulfonyl)phenyl)methanol (64-b, 315 mg, 1.43 mmol) in 1,4-dioxane (30 ml), add manganese dioxide (1.25 g, 14.37 mmol), and react at 100°C overnight. Remove manganese dioxide by filtration, and concentrate the filtrate under reduced pressure to obtain the target product 2-chloro-5-(methylsulfonyl)benzaldehyde (64-c, 250 mg, yield 60.8%). ESI [M+H] ⁺ = 219.0, 221.0

Step 4: Synthesis of 2-(2-methoxypyrimidin-5-yl)-5-(methylsulfonyl)benzaldehyde (64-d)

2-Chloro-5-(methylsulfonyl)benzaldehyde (64-c, 230 mg, 1.055 mmol), 2-methoxy-5-pyrimidineboronic acid (211 mg, 1.37 mmol), cesium carbonate (688 mg, 2.11 mmol) and tetrakistriphenylphosphine palladium (61 mg, 0.0528 mmol) were placed in a microwave reaction tube, 1,4-dioxane/water (25 ml/2.5 ml) was added, the tube was sealed after nitrogen purging, and microwave reaction was performed at 120°C for 50 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 10% to 100%) to obtain the target product 2-(2-methoxypyrimidin-5-yl)-5-(methylsulfonyl)benzaldehyde (64-d, 280 mg, yield 83.6%). ESI [M+H] ⁺ = 293.1

Step 5: Synthesis of 2-methoxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (64)

2-(2-methoxypyrimidin-5-yl)-5-(methylsulfonyl)benzaldehyde (64-d, 230 mg, 0.788 mmol) was dissolved in 1,2-dichloroethane (10 ml), tetrabutylammonium iodide (14.5 mg, 0.0392 mmol) and tert-butyl hydroperoxide (455 μl, 4.73 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and then recrystallized from tetrahydrofuran to obtain the target product 2-methoxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (64, 44 mg, yield 19.3%). ESI[M+H] ⁺ =291.1 ¹ H NMR (600MHz, DMSO-d ₆ ) δ9.29 (s, 1H), 8.25 (dd, J=7.8, 1.6Hz, 1H), 8.10 (d, J=7.9Hz, 2H), 4.03 (s, 3H), 3.32 (s, 3H).

Example 65: Synthesis of 2-hydroxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

2-Methoxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (64, 10 mg, 0.0345 mmol) was dissolved in formic acid (2 ml), and concentrated hydrochloric acid (0.3 ml) was added, and the mixture was reacted at 80°C for 5 hours. The reaction solution was concentrated under reduced pressure and then purified to obtain the target product 2-hydroxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (65, 0.90 mg, yield 9.5%). ESI[M+H] ⁺ =277.1, ESI[2M+H] ⁺ =553.1 ¹ H NMR (600MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.22 (dd, J = 8.0, 1.1Hz, 1H), 8.09 (s, 1H), 7.98 (d, J = 8.0Hz, 1H), 3.30 (s, 3H) .

Example 66: Synthesis of N-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)sulfonyl)acetamide

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (57, 18 mg, 0.0547 mmol) was dissolved in acetonitrile (3 ml), acetic anhydride (8 μl, 0.0821 mmol) and concentrated sulfuric acid (30 μl) were added, and the mixture was reacted at 80°C for 8 hours. Saturated brine was added to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain the target product N-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)sulfonyl)acetamide (66, 1.75 mg, yield 8.6%). ESI[M+H] ⁺ =372.1 ¹ H NMR (600MHz, DMSO-d ₆ ) δ9.74 (s, 1H), 8.34-8.32 (m, 2H), 8.15 (s, 1H), 1.96 (s, 3H).

Example 67: Synthesis of 7-(s-methylsulfonylimino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: 7-bromo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one was synthesized (67-a)

5-Bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a, 520 mg, 1.58 mmol) was dissolved in dichloroethane (25 ml), 2-hydroperoxide-2-methylpropane (908 μl, 7.88 mmol) and tetrabutylammonium iodide (19 mg, 0.05 mmol) were added, and the mixture was reacted at 100°C overnight under nitrogen protection. After concentration under reduced pressure, the crude product was purified by the preparative method to obtain the target product 7-bromo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-a, 260 mg, yield 31.7%).

Step 2: Synthesis of 7-(methylthio)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-b)

7-Bromo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-a, 135 mg, 0.412 mmol) was dissolved in dimethyl sulfoxide (8 ml), triethylenediamine (92 mg, 0.821 mmol) and cuprous iodide (78 mg, 0.409 mmol) were added, and the mixture was reacted at 130°C overnight under nitrogen protection. Saturated brine 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 on a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product 7-(methylthio)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-b, 45 mg, yield 36.9%). ESI[M+H] ⁺ = 297.1

Step 3: Synthesis of 7-(S-methylsulfonylimino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67)

7-(Methylthio)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-b, 45 mg, 0.152 mmol) was dissolved in ethanol (4 ml), iodophenyl diacetic acid (59 mg, 0.456 mmol) and ammonium acetate (47 mg, 0.61 mmol) were added, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was concentrated under reduced pressure and then purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the target product 7-(S-methylsulfonylimino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67, 2.25 mg, yield 4.5%). ESI[M+H] ⁺ =328.2 ¹ H NMR (600MHz, DMSO-d ₆ ) δ 11.94 (s, 1H), 9.71 (s, 1H), 8.36 (d, J = 7.8Hz, 1H), 8.30 (d, J = 7.8Hz, 1H), 8.24 (s, 1H), 3.19 (s, 3H).

Example 68: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbaldehyde

Step 1: 7-(Hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (68-a)

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50, 350 mg, 1.14 mmol) was dissolved in ultra-dry dichloromethane (10 ml), and diisobutylaluminum hydride (1 M, 3.4 ml, 3.42 mmol) was added at 0°C under nitrogen protection, and the mixture was reacted at 0°C for 1 hour. Saturated ammonium chloride solution was added to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (68-a, 75 mgg, yield 21.7%). ESI[M+H] ⁺ =281.1

Step 2: 9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbaldehyde (68)

7-(Hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (68-a, 75 mg, 0.268 mmol) was dissolved in 1,4-dioxane (5 ml), and manganese dioxide (233 mg, 2.68 mmol) was added, and the mixture was reacted at 100° C. overnight. Manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbaldehyde (68, 34 mg, yield 45.9%). ESI[M+H] ⁺ =278.9 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.72 (s, 1H), 8.37-8.33 (m, 1H), 8.30 (d, J = 7.7Hz, 1H), 8.27 (s, 1H).

Example 69: Synthesis of 7-(1-hydroxyethyl)-9-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-ol

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbaldehyde (68, 34 mg, 0.122 mmol) was dissolved in ultra-dry tetrahydrofuran (4 ml), and methylmagnesium bromide (1 M, 98 μl, 0.0978 mmol) was added at 0°C under nitrogen protection, and the mixture was reacted at 0°C for 2 hours. 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 then purified to obtain the target product 7-(1-hydroxyethyl)-9-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-9-ol (69, 0.74 mg, yield 1.9%). ESI[M+H] ⁺ =311.1, ESI[M+Na] ⁺ =333.1, ESI[2M+Na] ⁺ =643.3 ¹ H NMR (600MHz, DMSO-d ₆ ) δ9.38 (s, 1H), 7.96 (d, J = 7.8Hz, 1H), 7.67 (d, J = 4.3Hz, 1H), 7.47 (t, J = 9.0Hz, 1H), 6.09 (d, J=1.8Hz, 1H), 5.34 (d, J=4.1Hz, 1H), 4.82 (dd, J=10.6, 5.3Hz, 1H), 1.61 (s, 3H), 1.37 (d, J=6.4Hz, 3H).

Example 70: Synthesis of N-(methyl-d3)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 55 mg, 0.187 mmol) was dissolved in dichloromethane (5 ml), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (107 mg, 0.282 mmol), N,N-diisopropylethylamine (81 μl, 0.468 mmol) and deuterated methylamine hydrochloride (13 mg, 0.187 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 concentrated under reduced pressure and purified to obtain the target product N-(methyl-d3)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (70, 3.74 mg, yield 6.4%). ESI[M+H] ⁺ =311.2 ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.64 (s, 1H), 8.75 (s, 1H), 8.29-8.22 (m, 2H), 8.16 (d, J = 7.9Hz, 1H).

Example 71: Synthesis of 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Synthesis of 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (71-a)

2-Bromo-5-methylbenzaldehyde (1 g, 5.02 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 1.16 g, 6.03 mmol), potassium carbonate (0.83 g, 6.03 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (200 mg, 0.242 mmol) were placed in a reaction bottle, N,N-dimethylformamide (100 ml) was added, nitrogen was replaced, and the reaction was carried out at 100°C overnight. Water was added to quench, ethyl acetate was extracted, the organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column to obtain the target product 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (71-a, 0.58 g, yield 40.0%). ESI[M+H] ⁺ =267.0

Step 2: Synthesis of 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71-b)

5-Methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (71-a, 0.5 g, 1.88 mmol) was dissolved in 1,2-dichloroethane (10 ml), tetrabutylammonium iodide (35 mg, 0.095 mmol) and tert-butyl hydroperoxide (543 mg, 6.03 mmol) were added, and the mixture was reacted at 100°C in a sealed tube overnight. The reaction solution was concentrated under reduced pressure and purified on a preparative plate to obtain the target product 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71-b, 120 mg, yield 24.0%). ESI[M+H] ⁺ =265.0

Step 3: Synthesis of 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71)

7-(Methyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71-b, 120 mg, 0.45 mmol) was dissolved in carbon tetrachloride (10 mL), N-bromosuccinimide (105.2 mg, 0.59 mmol) and azobisisobutyronitrile (20 mg, 0.09 mmol) were added, and the mixture was reacted at 85°C overnight. The reaction solution was concentrated under reduced pressure and directly purified by silica gel column chromatography to obtain the target product 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71, 60 mg, yield 39.0%). ESI[M+H] ⁺ =343.0 ¹ H NMR (400MHz, CCl ₃ D) δ 9.21 (s, 1H), 8.55 (s, 1H), 8.47 (d, J = 7.8Hz, 1H), 7.82 (d, J = 1.1Hz, 1H), 5.49 (s, 2H).

Example 72: Synthesis of 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

7-(Bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71, 60 mg, 0.175 mmol) was dissolved in acetonitrile (4 ml), and cuprous cyanide (10.24 mg, 0.0875 mmol) was added, and the mixture was reacted at 75° C. for 0.5 hours. The by-product 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (72, 1.16 mg, yield 2.4%) was obtained by purification on a preparative plate. ESI[M+H] ⁺ =281.0 ¹ H NMR (400MHz, CCl ₃ D) δ 9.21 (s, 1H), 8.55 (s, 1H), 8.47 (d, J = 7.8Hz, 1H), 7.82 (d, J = 1.1Hz, 1H), 5.59 (s, 2H), 5.29 (s, 2H).

Example 73: Synthesis of 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile

Step 1: Synthesis of 4-bromo-5-(dibromomethyl)-2-fluorobenzonitrile (73-a)

Dissolve 4-bromo-2-fluoro-5-methylbenzonitrile (2.12 g, 9.91 mmol) in carbon tetrachloride (40 mL), add N-bromosuccinimide (4.52 g, 25.39 mmol) and azobisisobutyronitrile (555 mg, 3.38 mmol), and react at 85°C overnight. The reaction solution was concentrated under reduced pressure and directly purified by silica gel column chromatography to obtain the target product 4-bromo-5-(dibromomethyl)-2-fluorobenzonitrile (73-a, 1.2 g, yield 32.0%). ESI[M+H] ⁺ =370.0

Step 2: Synthesis of 4-bromo-2-fluoro-5-formylbenzonitrile (73-b)

Dissolve 4-bromo-5-(dibromomethyl)-2-fluorobenzonitrile (73-a, 600 mg, 1.63 mmol) in ethanol/water (10 ml/10 ml), add silver nitrate (0.55 g, 3.26 mmol), and react at room temperature for 2 hours. Filter to remove the solid, concentrate the filtrate under reduced pressure, and purify it by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 20%) to obtain the target product 4-bromo-2-fluoro-5-formylbenzonitrile (73-b, 300 mg, yield 81.0%). ESI[M+H] ⁺ = 228.0

Step 3: Synthesis of 2-fluoro-5-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (73-c)

4-Bromo-2-fluoro-5-formylbenzonitrile (73-b, 100 mg, 0.44 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 101 mg, 0.53 mmol), potassium phosphate (280 mg, 1.32 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.022 mmol) were placed in a reaction bottle, acetonitrile (5 ml) was added, nitrogen was replaced, and the reaction was carried out at 95° C. for 18 hours. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product 2-fluoro-5-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (73-c, 70 mg, yield 54.0%). ESI[M+H] ⁺ =296.0

Step 4: Synthesis of 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (73)

2-Fluoro-5-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (73-c, 70 mg, 0.24 mmol) was dissolved in 1,2-dichloroethane (6 ml), tetrabutylammonium iodide (4.4 mg, 0.012 mmol) and tert-butyl hydroperoxide (123 mg, 0.96 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube for 2 hours. The reaction solution was concentrated under reduced pressure and purified on a preparative plate to obtain the target product 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (73, 10 mg, yield 14.0%). ESI[M+H] ⁺ =294.0 ¹ H NMR (400MHz, CDCl ₃ ) δ9.30 (s, 1H), 8.18 (d, J = 5.8Hz, 1H), 7.68 (d, J = 7.6Hz, 1H).

Example 74: Synthesis of 2-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetic acid

7-(Bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71, 60 mg, 0.175 mmol) was dissolved in acetonitrile (4 ml), and cuprous cyanide (10.24 mg, 0.0875 mmol) was added, and the mixture was reacted at 75° C. for 0.5 hours. The product 2-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetic acid (74, 1.40 mg, yield 2.6%) was obtained by purification on a preparative plate. ESI[M+H] ⁺ =309.0 ¹ H NMR (400MHz, CDCl ₃ ) δ12.16 (s, 1H), 9.21 (s, 1H), 9.21 (s, 1H), 8.55 (s, 1H), 8.47 (d, J = 7.8Hz, 1H), 7.82 (d, J = 1.1Hz, 1H), 4.69 (s, 2H) .

Example 75: Synthesis of 9-oxo-7-phenyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile

Step 1: Synthesis of 7-chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (75-a)

7-Chloro-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (2.8 g, 11.08 mmol) was added to acetic acid (30 ml), and then a solution of potassium dichromate (5.87 g, 19.95 mmol) dissolved in acetic acid (50 ml) and water (15 ml) was added, and the temperature was slowly raised to 100°C for reaction for 1 hour, and then quenched with sodium bicarbonate solution, and then extracted with ethyl acetate. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:4) to obtain the target product 7-chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (75-a, 700 mg, yield 23.69%).

Step 2: Synthesis of 9-oxo-7-phenyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (75)

7-Chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (75-a, 30 mg, 0.113 mmol), phenylboronic acid (21 mg, 0.159 mmol), palladium acetate (1 mg, 0.006 mmol) and potassium fluoride (13 mg, 0.226 mmol) were dissolved in methanol (2 ml) and reacted in a microwave sealed container at 120°C for 30 minutes. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by liquid phase preparation to obtain the target product 9-oxo-7-phenyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (75, 0.8 mg, yield 2.31%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.86 (d, J=2.2Hz, 1H), 7.78 (dd, J=8.3, 2.3Hz, 1H), 7.65-7.47 (m, 6H)

Example 76: Preparation of 7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Synthesis of 5-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (76-a)

2-Bromo-5-nitrobenzaldehyde (200 mg, 0.869 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boric acid (250 mg, 1.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (31.8 mg, 0.043 mmol) and potassium phosphate (553 mg, 2.6 mmol) were dissolved in acetonitrile (15 ml) and reacted in a microwave oven under nitrogen protection for 40 minutes. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:3) to obtain the target product 5-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (76-a, 185 mg, yield 71.59%). (ESI) [M+H] ⁺ = 298.0

Step 2: Preparation of 7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (76)

5-Nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (76-a, 60 mg, 0.2 mmol) was dissolved in dichloroethane (3 ml), 70% 2-hydroperoxide-2-methylpropane (156 mg, 1.21 mmol) and tetrabutylammonium iodide (4 mg, 0.01 mmol) were added, and the mixture was reacted at 100°C overnight under nitrogen protection. After concentration under reduced pressure, the crude product was purified by preparative silica gel plate (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (76, 21.52 mg, yield 36.11%). ESI[M+H] ⁺ =296, ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 8.69 (d, J = 7.8Hz, 1H), 8.45 (s, 1H), 8.37 (d, J = 8.3Hz, 1H).

Example 77: Preparation of 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

7-Nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (76, 30 mg, 0.1 mmol) was dissolved in acetic acid (2 ml), and iron powder (22.7 mg, 0.4 mmol) was added. The mixture was reacted at 75°C overnight under nitrogen protection. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by preparative silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (77, 18.5 mg, yield 51.48%). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 6.16 (d, J = 8.5 Hz, 2H)

Example 78: Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide

7-Amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (77, 16 mg, 0.06 mmol) was dissolved in dichloroethane (1 ml), and triethylamine (12 mg, 0.12 mmol) and acetyl chloride (5.7 mg, 0.072 mmol) were added to react at room temperature for 4 hours under nitrogen protection. The reaction solution was quenched with water at 0°C, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. After concentration under reduced pressure, the crude product was purified by preparative method to obtain the target product N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (78, 8 mg, yield 43.16%). ESI[M+H] ⁺ =308.2, ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 9.42 (s, 1H), 8.09 (d, J = 2.0Hz, 1H), 7.93 (d, J = 8.2Hz, 1H), 7.81 (dd, J = 8.2, 2.1Hz, 1H), 1.35 (s, 3H).

Example 79: Preparation of 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (79-a)

3-(Trifluoromethyl)thio)benzaldehyde (400 mg, 1.94 mmol) was dissolved in dichloroethane (15 ml), and 4-chloro-2-(trifluoromethyl)aniline (54.8 μl, 0.391 mmol), N-bromosuccinimide (414 mg, 2.33 mmol), palladium acetate (44 mg, 0.192 mmol), and trifluoroacetic acid (4 ml) were added. After overnight reaction at 60°C under nitrogen atmosphere, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (99% petroleum ether) to obtain the target product 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (79-a, 320 mg, yield 58.8%). ESI[M+H] ⁺ = 285.1.

Step 2: Preparation of 2-(2-methoxypyrimidin-5-yl)-5-((trifluoromethyl)thio)benzaldehyde (79-b)

2-Bromo-5-((trifluoromethyl)thio)benzaldehyde (79-a, 320 mg, 1.12 mmol) was dissolved in 1,4-dioxane (10 ml), and a drop of water was added. (2-methoxypyrimidin-5-yl)boric acid (206 mg, 1.34 mmol), cesium carbonate (776 mg, 2.68 mmol), and tetrakis(triphenylphosphine)palladium (65.2 mg, 0.056 mmol) were added. The mixture was subjected to microwave reaction at 120°C for 30 minutes under nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain the target product 2-(2-methoxypyrimidin-5-yl)-5-((trifluoromethyl)thio)benzaldehyde (79-b, 193 mg, yield 54.5%). ESI[M+H] ⁺ = 315.1.

Step 3: Preparation of 2-methoxy-7-((trifluoromethyl)thio)-9H-indeno[2,1-d]pyrimidin-9-one (79-c)

2-(2-methoxypyrimidin-5-yl)-5-((trifluoromethyl)thio)benzaldehyde (79-b, 193 mg, 0.615 mmol) was dissolved in dichloroethane (10 ml), tert-butyl hydroperoxide (346 mg, 3.69 mmol) and tetrabutylammonium iodide (11.8 mg, 0.308 mmol) were added, and the mixture was reacted in a sealed manner at 100°C overnight. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 2-methoxy-7-((trifluoromethyl)thio)-9H-indeno[2,1-d]pyrimidin-9-one (79-c, 140 mg, yield 73.1%). ESI[M+H] ⁺ = 313.1.

Step 4: Preparation of 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (79)

2-Methoxy-7-((trifluoromethyl)thio)-9H-indeno[2,1-d]pyrimidin-9-one (79-c, 10 mg, 0.320 mmol) was dissolved in dichloroethane (2 ml), and m-chloroperbenzoic acid (11 mg, 0.640 mmol) was added. After reacting at room temperature overnight, the mixture was concentrated under reduced pressure. The crude product was purified by high-efficiency preparative liquid phase (methanol: 0.1% formic acid aqueous solution = 9:1) to obtain the target product 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (79, 1.2 mg, yield 10.9%). ESI[M+H] ⁺ =345.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 8.66 (d, J = 8.0Hz, 1H), 8.57 (d, J = 8.0Hz, 1H), 8.33 (s, 1H), 3.84 (s, 1H).

Example 80: Preparation of 2,7-dichloro-4-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-chloro-2-(2,4-dichloropyrimidin-5-yl)benzaldehyde (80-a)

2,4-dichloro-5-iodopyrimidine (500 mg, 1.82 mmol) was dissolved in sec-butyl alcohol (10 ml), 4-chloro-2-formylphenylboronic acid (436 mg, 2.36 mmol), potassium fluoride (211.4 mg, 3.64 mmol) and palladium acetate (20.4 mg, 0.091 mmol) were added, and the mixture was reacted at 120°C for 30 minutes under nitrogen protection. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (methanol: dichloromethane = 0% to 50%) to obtain the target product 5-chloro-2-(2,4-dichloropyrimidin-5-yl)benzaldehyde (80-a, 194.8 mg, yield 37.45%). ESI [M+H] ⁺ = 287.0, 289.0.

Step 2: Preparation of 2,7-dichloro-4-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (80)

5-Chloro-2-(2,4-dichloropyrimidin-5-yl)benzaldehyde (80-a, 100 mg, 0.34 mmol) was dissolved in 1,2-dichloroethane (10 ml), tetrabutylammonium iodide (6.46 mg, 0.02 mmol) and tert-butyl hydroperoxide (270 μl, 2.72 mmol) were added, and the mixture was reacted at 100°C in a sealed tube under nitrogen protection for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0% to 20%) and then subjected to liquid phase preparative purification to obtain the target product 2,7-dichloro-4-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (80, 3.95 mg, yield 4.24%). ESI[M+H] ⁺ =267.0, 269.0. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.15-8.08 (m, 1H), 8.24 (d, J = 2.3Hz, 1H), 8.59 (d, J = 8.6Hz, 1H), 9.76 (s, 1H).

Example 81: Preparation of 2-hydroxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

To 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (79, 15 mg, 0.436 mmol) was added formic acid (2 ml) and hydrochloric acid (50 μl). After reacting at 80°C for 5 hours, the mixture was concentrated under reduced pressure. The crude product was purified by high-efficiency preparative liquid phase (methanol: 0.1% formic acid aqueous solution = 9:1) to obtain the target product 2-hydroxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (81, 1.08 mg, yield 7.5%). ESI[M+H] ⁺ = 331.1.

Example 82: Preparation of N,N-dimethyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

Step 1: Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (82-a)

Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (40 mg, 0.130 mmol) in tetrahydrofuran (5 ml), add water (1 ml), slowly add lithium hydroxide monohydrate (10.9 mg, 0.260 mmol) at 0°C, react at room temperature for 4 hours, adjust the pH to neutral with 1M hydrochloric acid solution, add water (5 ml), extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (82-a, 24 mg, yield 63.2%). ESI[M+H] ⁺ =295.2.

Step 2: Preparation of N,N-dimethyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (82)

At 0°C, 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (82-a, 12 mg, 0.0408 mmol) was dissolved in dichloroethane (3 ml), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (14.7 mg, 0.0490 mmol) was added, and after stirring for 10 minutes, dimethylamine hydrochloride (3.4 mg, 0 .0408mmol), N, N-diisopropylethylamine (24.4μl, 0.122mmol), reacted at room temperature for 4 hours and then concentrated under reduced pressure. The crude product was purified by high-efficiency preparative liquid phase (acetonitrile: 0.1% formic acid aqueous solution = 9:1) to obtain the target product N, N-dimethyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (82, 1.49mg, yield 11.4%). ESI[M+H] ⁺ =322.2.

Example 83: Preparation of 7-chloro-2-methoxy-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-bromo-2-methoxy-4-(trifluoromethyl)pyrimidine (83-a)

Dissolve 5-bromo-4-(trifluoromethyl)pyrimidin-2-ol (470 mg, 1.943 mmol) in tetrahydrofuran (10 ml), add benzotriazole-1-tris(trimethylamino)-hexafluorophosphate (1.7 g, 3.89 mmol), stir for 10 minutes, add methanol (1.6 ml, 38.9 mmol), cesium carbonate (2.5 g, 7.77 mmol), react at room temperature for 2 hours, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product 5-bromo-2-methoxy-4-(trifluoromethyl)pyrimidine (83-a, 195 mg, yield 44.4%). ESI[M+H] ⁺ = 257.2.

Step 2: Preparation of 5-chloro-2-(2-methoxy-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (83-b)

5-Bromo-2-methoxy-4-(trifluoromethyl)pyrimidine (83-a, 195 mg, 0.863 mmol) was dissolved in 1,4-dioxane (5 ml), and a drop of water, (4-chloro-2-formylphenyl)boric acid (159 mg, 0.863 mmol), cesium carbonate (562 mg, 1.73 mmol), tetrakistriphenylphosphine palladium (50 mg, 0.432 mmol) were added. The mixture was subjected to microwave reaction at 120°C for 30 minutes under nitrogen atmosphere, and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain the target product 5-chloro-2-(2-methoxy-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (83-b, 250 mg, yield 91.5%). ESI [M+H] ⁺ = 317.2.

Step 3: Preparation of 7-chloro-2-methoxy-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (83)

Dissolve 5-chloro-2-(2-methoxy-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (83-b, 104 mg, 3.29 mmol) in dichloroethane (5 ml), add tert-butyl hydroperoxide (237 mg, 26.3 mmol), tetrabutylammonium iodide (6 mg, 0.165 mmol), react overnight at 100°C in a sealed container, concentrate under reduced pressure, and purify the crude product by silica gel chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 7-chloro-2-methoxy-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (83, 14 mg, yield 63.6%). ESI[M+H] ⁺ = 315.3.

Example 84: Preparation of 7-chloro-2-(thiazol-5-yl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 5-(5-bromopyrimidin-2-yl)thiazole (84-a)

5-Bromo-2-iodopyrimidine (300 mg, 1.05 mmol) was dissolved in toluene (5 ml), 5-(tributyltinyl)thiazole (394 mg, 1.05 mmol), triphenylphosphine (27.6 mg, 0.105 mmol), bistriphenylphosphine palladium dichloride (37 mg, 0.0527 mmol) were added, and the mixture was reacted overnight at 120°C under nitrogen atmosphere. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 5-(5-bromopyrimidin-2-yl)thiazole (84-a, 115 mg, yield 45.3%). ESI [M+H] ⁺ = 242.2.

Step 2: Preparation of 5-chloro-2-(2-(thiazol-5-yl)pyrimidin-5-yl)benzaldehyde (84-b)

5-(5-bromopyrimidin-2-yl)thiazole (84-a, 115 mg, 0.477 mmol) was dissolved in acetonitrile (5 ml), (4-chloro-2-formylphenyl)boric acid (131 mg, 0.716 mmol), potassium fluoride (55.5 mg, 0.954 mmol), palladium acetate (5.4 mg, 0.0224 mmol) were added, and microwave reaction was carried out at 120°C for 45 minutes under nitrogen atmosphere. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 5-chloro-2-(2-(thiazol-5-yl)pyrimidin-5-yl)benzaldehyde (84-b, 10 mg, yield 7.1%). (ESI) [M+H] ⁺ = 302.2.

Step 3: Preparation of 7-chloro-2-(thiazol-5-yl)-9H-indeno[2,1-d]pyrimidin-9-one (84)

5-Chloro-2-(2-(thiazol-5-yl)pyrimidin-5-yl)benzaldehyde (84-b, 10 mg, 0.0332 mmol) was dissolved in dichloroethane (5 ml), tert-butyl hydroperoxide (23 mg, 0.266 mmol) and tetrabutylammonium iodide (0.6 mg, 0.00166 mmol) were added, and the mixture was reacted in a sealed manner at 100°C overnight. After concentration under reduced pressure, the crude product was purified by high-efficiency preparative liquid phase method (acetonitrile: 0.1% formic acid aqueous solution = 9:1) to obtain the target product 7-chloro-2-(thiazol-5-yl)-9H-indeno[2,1-d]pyrimidin-9-one (84, 0.73 mg, yield 6.5%). ESI[M+H] ⁺ = 300.0.

Example 85: Preparation of 7-chloro-2-(thiazol-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Preparation of 2-(5-bromopyrimidin-2-yl)thiazole (85-a)

5-Bromo-2-iodopyrimidine (114 mg, 0.400 mmol) was dissolved in toluene (5 ml), 2-(tributyltinyl)thiazole (150 mg, 0.400 mmol), triphenylphosphine (10.5 mg, 0.040 mmol), bistriphenylphosphine palladium dichloride (14.1 mg, 0.02 mmol) were added, and the mixture was reacted overnight at 120°C under nitrogen atmosphere. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 2-(5-bromopyrimidin-2-yl)thiazole (85-a, 75 mg, yield 77.8%). ESI [M+H] ⁺ = 242.2.

Step 2: Preparation of 5-chloro-2-(2-(thiazol-2-yl)pyrimidin-5-yl)benzaldehyde (85-b)

2-(5-bromopyrimidin-2-yl)thiazole (85-a, 75 mg, 0.311 mmol) was dissolved in acetonitrile (5 ml), (4-chloro-2-formylphenyl)boric acid (85.9 mg, 0.467 mmol), potassium fluoride (36.2 mg, 0.622 mmol), palladium acetate (3.5 mg, 0.0156 mmol) were added, and microwave reaction was carried out at 120°C for 45 minutes under nitrogen atmosphere. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 5-chloro-2-(2-(thiazol-2-yl)pyrimidin-5-yl)benzaldehyde (85-b, 28 mg, yield 30.1%). ESI [M+H] ⁺ = 302.2.

Step 3: Preparation of 7-chloro-2-(thiazol-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one (85)

5-Chloro-2-(2-(thiazol-2-yl)pyrimidin-5-yl)benzaldehyde (85-b, 28 mg, 0.0930 mmol) was dissolved in dichloroethane (5 ml), tert-butyl hydroperoxide (67 mg, 0.744 mmol) and tetrabutylammonium iodide (1.7 mg, 0.00465 mmol) were added, and the mixture was reacted in a sealed manner at 100°C overnight. After concentration under reduced pressure, the crude product was purified by high-efficiency preparative liquid phase method (acetonitrile: 0.1% formic acid aqueous solution = 9:1) to obtain the target product 7-chloro-2-(thiazol-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one (85, 0.65 mg, yield 2.6%). ESI[M+H] ⁺ = 300.0.

Example 86: Synthesis of 8-(trifluoromethyl)-10H-[1,3]dioxacyclo[4',5':4,5]indeno[2,1-d]pyrimidin-10-one

Step 1: Synthesis of 5-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxolane-4-carbaldehyde (86-a)

5-Bromobenzo[d][1,3]dioxine-4-carboxaldehyde (200 mg, 0.87 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boric acid (2180 mg, 1.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.04 mmol) and potassium phosphate (370 mg, 1.74 mmol) were dissolved in acetonitrile (12 ml), and microwaved at 120°C for 50 minutes under nitrogen protection. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:2) to obtain the target product 5-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxolane-4-carboxaldehyde (86-a, 80 mg, yield 31.2%). ESI[M+H] ⁺ = 297

Step 2: Synthesis of 8-(trifluoromethyl)-10H-[1,3]dioxacyclo[4',5':4,5]indeno[2,1-d]pyrimidin-10-one (86)

5-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxol-4-carboxaldehyde (86-a, 80 mg, 0.27 mmol) was dissolved in dichloroethane (5 ml), 2-hydroperoxide-2-methylpropane (156 μl, 1.62 mmol) and tetrabutylammonium iodide (5 mg, 0.05 mmol) were added, and the mixture was reacted at 100° C. overnight under nitrogen protection. After concentration under reduced pressure, the crude product was purified by the preparative method to obtain the target product 8-(trifluoromethyl)-10H-[1,3]dioxacyclo[4',5':4,5]indeno[2,1-d]pyrimidin-10-one (86, 5.15 mg, yield 6.4%). ESI[M+H] ⁺ =295. ¹ H NMR 400MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 7.53 (d, J = 7.7Hz, 1H), 7.23 (d, J = 7.7Hz, 1H), 6.33 (s, 2H).

Example 87: Synthesis of 7-(methylsulfonyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

Step 1: Synthesis of 2-chloro-5-(methylsulfonyl)benzoic acid (87-a)

Dissolve 2-chloro-5-(methylthio)benzoic acid (6 g, 29.56 mmol) in methanol (100 ml), add potassium peroxymonosulfonate (36.38 g, 59.12 mmol). After reacting at room temperature overnight, concentrate under reduced pressure and purify the crude product by silica gel chromatography (methanol: dichloromethane -20:1) to obtain the target product 2-chloro-5-(methylsulfonyl)benzoic acid (87-a, 5.42 g, yield 96.6%). ESI [M+H] ⁺ = 235.

Step 2: Synthesis of (2-chloro-5-(methylsulfonyl)phenyl)methanol (87-b)

Dissolve 2-chloro-5-(methylsulfonyl)benzoic acid (87-a, 2g, 8.54mmol) in tetrahydrofuran (50ml), slowly add lithium aluminum hydride (640mg, 16.84mmol) at 0℃. After reacting at room temperature for 2 hours, add saturated ammonium chloride solution to quench, extract with ethyl acetate, concentrate under reduced pressure, and purify the crude product by silica gel chromatography (methanol: dichloromethane = 15:1) to obtain the target product (2-chloro-5-(methylsulfonyl)phenyl)methanol (87-b, 1.1g, yield 58.5%). ESI[M+H] ⁺ = 221.

Step 3: Synthesis of 2-chloro-5-(methylsulfonyl)benzaldehyde (87-c)

Dissolve (2-chloro-5-(methylsulfonyl)phenyl)methanol (87-b, 1.1 g, 5 mmol) in dioxane (50 ml), add manganese dioxide (2.17 g, 24.9 mmol). Reaction was carried out at 100°C overnight, and after vacuum concentration, the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 2:1) to obtain the target product 2-chloro-5-(methylsulfonyl)benzaldehyde (87-c, 370 mg, yield 34.6%). ESI [M+H] ⁺ = 219.

Step 4: Synthesis of 5-(methylsulfonyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (87-d)

2-Chloro-5-(methylsulfonyl)benzaldehyde (87-c, 280 mg, 1.28 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boric acid (400 mg, 2.09 mmol), tetrakis(triphenylphosphine)palladium (74 mg, 0.06 mmol) and cesium carbonate (837 mg, 2.57 mmol) were dissolved in dioxane (10 ml) and water (2 ml), and microwaved at 120°C for 1 hour under nitrogen protection. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:2) to obtain the target product 5-(methylsulfonyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (87-d, 200 mg, yield 47.7%). ESI [M+H] ⁺ = 331.

Step 5: Preparation of 7-(methylsulfonyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (87)

5-(Methylsulfonyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (87-d, 200 mg, 0.60 mmol) was dissolved in dichloroethane (8 ml), 2-hydroperoxide-2-methylpropane (291 μl, 3.03 mmol) and tetrabutylammonium iodide (11 mg, 0.03 mmol) were added, and the mixture was reacted at 100°C overnight under nitrogen protection. After concentration under reduced pressure, the crude product was purified by the preparative method to obtain the target product 7-(methylsulfonyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (87, 19.88 mg, yield 16.5%). ESI[M+H] ⁺ =329. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.36 (s, 2H), 8.26 (s, 1H), 3.29 (s, 3H).

Example 88: Preparation of 2-methoxy-9-oxy-9H-indeno[2,1d]pyrimidine-7-sulfonamide

Step 1: 2-Chloro-5-sulfonylbenzoic acid (88-a)

2-Chloro-5-(chlorosulfonyl)benzoic acid (1 g, 3.92 mmol) was slowly added to 15 ml of ammonia water at 0°C and reacted for half an hour. The reaction was then monitored by a plate with dichloromethane/methanol = 10:1. After the reaction was complete, the crude product 2-chloro-5-sulfonylbenzoic acid (88-a, 1.15 g) was obtained by concentration under reduced pressure.

Step 2: Preparation of 2-chloro-N-methoxy-N-methyl-5-sulfamoylbenzamide (88-b)

2-Chloro-5-sulfamoylbenzoic acid (88-a, 1.15 g, 4.89 mmol), N,O-dimethylhydroxylamine hydrochloride (475 mg, 4.89 mmol), N-methylimidazole (1.4 g, 17.1 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (1.5 g, 5.38 mmol) were dissolved in acetonitrile and reacted at room temperature for 2 hours. After monitoring the reaction completion, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane/methanol = 20/1) to obtain 2-chloro-N-methoxy-N-methyl-5-sulfamoylbenzamide (88-b, 0.87 g, yield 64%). ESI [M+H] ⁺ = 279.2

Step 3: Preparation of 4-chloro-3-formylbenzenesulfonamide (88-c)

2-Chloro-N-methoxy-N-methyl-5-aminosulfonylbenzamide (88-b, 500 mg, 1.8 mmol) was dissolved in anhydrous dichloromethane. Under nitrogen protection, diisobutylaluminum hydride (3.6 ml, 3.6 mmol) was slowly added at 0°C to react for half an hour. After the reaction was completed, the reaction was quenched, extracted, concentrated under reduced pressure, and the organic phase was dried to obtain a crude product of 4-chloro-3-formylbenzenesulfonamide (88-c, 450 mg).

Step 4: Preparation of 3-formyl-4-(2-methoxypyrimidin-5-yl)benzenesulfonamide (88-d)

Dissolve (2-methoxypyrimidin-5-yl)boric acid (93 mg, 0.6 mmol), cesium carbonate (295 mg, 0.9 mmol), 4-chloro-3-formylbenzenesulfonamide (88-c, 100 mg, 0.45 mmol) in 4 ml of dioxane, add tetrakistriphenylphosphine palladium, and react at 120°C for 1 hour under nitrogen protection. After reduced pressure concentration, the crude product was purified by silica gel chromatography (dichloromethane: methanol = 15/1) to obtain the target product 3-formyl-4-(2-methoxypyrimidin-5-yl)benzenesulfonamide (88-d, 83 mg, yield 73%). ESI [M+H] ⁺ = 294.

Step 5: Preparation of 2-methoxy-9-oxy-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (88)

3-Formyl-4-(2-methoxypyrimidin-5-yl)benzenesulfonamide (88-d, 50 mg, 0.17 mmol) was dissolved in dichloroethane (4 ml), 2-hydroperoxide-2-methylpropane (92.2 mg, 1.02 mmol), tetrabutylammonium iodide (3.3 mg, 0.08 mmol) were added, and the mixture was reacted at 100°C for 16 hours under nitrogen protection. After concentration under reduced pressure, the crude product was purified by preparative TLC plate (ethyl acetate: petroleum ether = 2/1) to obtain the target product 2-methoxy-9-oxy-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (88, 3.68 mg, yield 4.3%). ESI[M+H] ⁺ =292.2. ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.10 (d, J = 8.9Hz, 1H), 8.04-8.00 (m, 2H), 7.55 (s, 2H), 4.03 (s, 3H).

Example 89: Preparation of (R)-7-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)-9H-indeno[2,1d]pyrimidin-9-one

Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (40 mg, 0.16 mmol) in ultra-dry toluene (4 ml), add N-methyl-L-prolinol (18.74 mg, 0.16 mmol), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (BINAP) (19.93 mg, 0.032 mmol), cesium carbonate (104.27 mg, 3.2 mmol) and palladium acetate (7.19 mg, 0.032 mmol), protect with nitrogen, and react in microwave at 110°C for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (methanol: dichloromethane = 0% to 50%) and then subjected to liquid phase preparative purification to obtain the target product (R)-7-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)-9H-indeno[2,1-d]pyrimidin-9-one (89, 6.22 mg, yield 11.81%). ESI[M+H] ⁺ =330.10. ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.00-1.81 (m, 3H), 2.12-2.02 (m, 1H), 2.33-2.19 (m, 2H), 2.95 (s, 3H), 3.14 (d, J = 9.6Hz, 1H), 4.65-4.5 1 (m, 1H), 4.75-4.65 (m, 1H), 7.73 (d, J=2.0Hz, 1H), 7.81-7.76 (m, 1H), 7.89 (d, J=8.0Hz, 1H), 9.19 (s, 1H).

Example 90: Preparation of 2-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-7-carbonitrile

Step 1: Preparation of 4-(2-chloropyrimidin-5-yl)-3-formylbenzonitrile (90-a)

4-Bromo-3-formylbenzonitrile (300 mg, 1.43 mmol) was dissolved in sec-butyl alcohol (20 ml), and 2-chloropyrimidine-5-boric acid (293.41 mg, 1.86 mmol), potassium fluoride (165.98 mg, 2.86 mmol) and palladium acetate (16.03 mg, 0.07 mmol) were added. Nitrogen was protected and microwave reaction was carried out at 120°C for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (methanol: dichloromethane = 0% to 50%) to obtain the target product 4-(2-chloropyrimidin-5-yl)-3-formylbenzonitrile (90-a, 154.2 mg, yield 44.42%). ESI [M+H] ⁺ = 244.0, 245.0.

Step 2: Preparation of 2-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (90)

4-(2-chloropyrimidin-5-yl)-3-formylbenzonitrile (90-a, 100 mg, 0.41 mmol) was dissolved in 1,2-dichloroethane (10 ml), tetrabutylammonium iodide (7.60 mg, 0.02 mmol) and tert-butyl hydroperoxide (317 μl, 3.29 mmol) were added, and the mixture was reacted at 100° C. in a sealed tube under nitrogen protection for 16 hours. The solvent was evaporated under reduced pressure, and the residue was beaten with tetrahydrofuran to obtain a crude product, which was then subjected to liquid phase preparation and purification to obtain the target product 2-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (90, 1.29 mg, yield 1.30%). ESI[M+H] ⁺ =242.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.16 (d, J = 7.8Hz, 1H), 8.24 (d, J = 6.8Hz, 2H), 9.43 (s, 1H).

Example 91: Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1d]pyrimidin-7-yl)methanesulfonamide

Step 1: Preparation of N-(4-bromo-3-formylphenyl)methanesulfonamide (91-a)

N-(3-Formylphenyl)methanesulfonamide (200 mg, 1 mmol), 4-chloro-2-(trifluoromethyl)aniline (39 mg, 0.2 mmol), N-bromosuccinimide (213.6 mg, 1.2 mmol) were added to 5 ml of dichloroethane and 2 ml of trifluoroacetic acid, and the mixture was reacted in a sealed manner under nitrogen protection at 100° C. overnight. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether=1/5) to obtain the target product N-(4-bromo-3-formylphenyl)methanesulfonamide (91-a, 150 mg, yield 53.96%).

Step 2: Preparation of N-(3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)methanesulfonamide (91-b)

N-(4-bromo-3-formylphenyl)methanesulfonamide (91-a, 130 mg, 0.431 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boric acid (99.25 mg, 0.517 mmol), palladium acetate (1.25 mg, 0.022 mmol) and potassium fluoride (193.5 mg, 0.862 mmol) were dissolved in acetonitrile (2 ml), and the mixture was reacted at 120° C. in a nitrogen-protected microwave for 1 hour. Water (10 ml) was added, and the mixture was extracted with ethyl acetate (10 ml*2). The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether=1/1) to obtain the target product N-(3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)methanesulfonamide (91-b, 13 mg, yield 8.74%).

Step 3: Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1d]pyrimidin-7-yl)methanesulfonamide (91)

N-(3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)methanesulfonamide (91-b, 13 mg, 0.038 mmol) was dissolved in dichloroethane (2 ml), 2-hydroperoxide-2-methylpropane (27.4 mg, 0.3 mmol) and tetra-n-butylammonium iodide (0.7 mg, 0.002 mmol) were added and reacted at 100°C for 16 hours under nitrogen protection. Water (10 ml) was added, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by liquid phase preparation (trifluoroacetic acid 0.1%) to obtain the target product N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)methanesulfonamide (91, 1.51 mg, yield 11.62%). ESI[M+H] ⁺ =344.3

Example 92: Preparation of 9-oxo-9H-indeno[2,1-d]pyrimidine-2,7-dicarbonitrile

Step 1: Preparation of 5-(4-cyano-2-formylphenyl)pyrimidine-2-carbonitrile (92-a)

4-Bromo-3-formylbenzonitrile (250 mg, 1.19 mmol) was dissolved in acetonitrile (4 ml), and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-5-carbonitrile (354.3 mg, 1.547 mmol), potassium fluoride (138 mg, 2.38 mmol) and palladium acetate (13.3 mg, 0.0595 mmol) were added. The mixture was protected by nitrogen and microwaved at 120°C for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column (methanol: dichloromethane = 0% to 50%) to obtain the target product 5-(4-cyano-2-formylphenyl)pyrimidine-2-carbonitrile (92-a, 250 mg, yield 89.67%).

Step 2: Preparation of 9-oxo-9H-indeno[2,1-d]pyrimidine-2,7-dicarbonitrile (92)

5-(4-cyano-2-formylphenyl)pyrimidine-2-carbonitrile (92-a, 5 mg, 0.213 mmol) was dissolved in 1,2-dichloroethane (2 ml), tetrabutylammonium iodide (3.93 mg, 0.0106 mmol) and tert-butyl hydroperoxide (153.6 mg, 1.704 mmol) were added, and the mixture was reacted at 100°C in a sealed tube under nitrogen protection for 16 hours. The solvent was evaporated under reduced pressure, and the crude product was subjected to liquid phase preparation and purification to obtain the target product 9-oxo-9H-indeno[2,1-d]pyrimidine-2,7-dicarbonitrile (92-a, 1.26 mg, yield 2.55%). ESI[M+H] ⁺ =233.1

Example 93: Preparation of 7-isopropyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile

Step 1: Preparation of (E)-2-(hydroxyimino)-5-isopropyl-2,3-dihydro-1H-indene-1-one (93-a)

Dissolve 5-isopropyl-2,3-dihydro-1H-indene-1-one (400 mg, 2.72 mmol) in methanol (10 ml), add isoamyl nitrite (296 mg, 2.99 mmol), 36% hydrochloric acid (2 ml), react at 40°C for 1 hour, and then concentrate under reduced pressure. The crude product is purified by silica gel chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the target product (E)-2-(hydroxyimino)-5-isopropyl-2,3-dihydro-1H-indene-1-one (93-a, 337 mg, yield 72.3%). ESI[2M+H] ⁺ = 407.2.

Step 2 Preparation of 5-isopropyl-1H-indene-1,2(3H)-dione (93-b)

(E)-2-(Hydroxyimino)-5-isopropyl-2,3-dihydro-1H-indene-1-one (93-a, 337 mg, 1.66 mmol) was dissolved in 36% formaldehyde solution (7 ml), 36% hydrochloric acid (14 ml) was added, and the reaction was allowed to react overnight at room temperature, then quenched with water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product 5-isopropyl-1H-indene-1,2(3H)-dione (93-b, 165 mg, yield 52.9%).

Step 3: Preparation of 7-isopropyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (93-c)

5-isopropyl-1H-indene-1,2(3H)-dione (93-b, 165 mg, 0.877 mmol) was dissolved in isopropanol (7 ml), 2,3-diaminomaleonitrile (94.8 mg, 0.877 mmol) was added, and the mixture was reacted at room temperature for 24 hours, and then concentrated under reduced pressure. The crude product was purified by thin layer preparation method (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 7-isopropyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (93-c, 31 mg, yield 10.8%). ESI[M+H] ⁺ = 261.2

Step 4: Preparation of 7-isopropyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (93)

Potassium dichromate (61 mg, 0.207 mmol) was dissolved in water (0.4 ml), and 7-isopropyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (93-c, 30 mg, 0.115 mmol) and acetic acid (1.6 ml) were added. After reacting at 100°C for 1 hour, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by high-efficiency preparative liquid chromatography (acetonitrile: 0.1% formic acid aqueous solution = 5:1) to obtain the target product 7-isopropyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (93, 1.6 mg, yield 5.06%). ESI[M+H] ⁺ = 275.2.

Example 94: Synthesis of ethyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1d]pyrimidine-7-carboxylate

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 10 mg, 0.034 mmol) was dissolved in anhydrous ethanol (2 ml), concentrated sulfuric acid (50 μl) was added, and the mixture was reacted at 50° C. for 12 hours. The reaction solution was concentrated under reduced pressure and purified by preparative chromatography to obtain the target product, 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid ethyl ester (94, 1.25 mg, yield 11.4%). ESI[M+H] ⁺ ＝323.1， ¹ H NMR(400MHz，DMSO)δ9.71(s，1H)，8.38(dd，J＝7.8，1.4Hz，1H)，8.22(dd，J＝14.4，4.3Hz，2H)，4.38(q，J＝7.1Hz，2H)，1.36(t，J＝7.1Hz，3H).

Example 95: Synthesis of methyl-d ₃ -9-oxo-2-(trifluoromethyl)-9H-indeno[2,1d]pyrimidine-7-carboxylate

9-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 40 mg, 0.136 mmol) was dissolved in deuterated methanol (1 ml), concentrated sulfuric acid (50 μl) was added, and the mixture was reacted at 50° C. for 12 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC preparative chromatography to obtain the target product methyl-d ₃ -9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylate (95, 2.1 mg, yield 4.6%). ESI [M+H] ⁺ =312.2, ¹ H NMR (400MHz, Chloroform-d) δ9.27 (s, 1H), 8.53 (s, 1H), 8.42 (dd, J=7.8, 1.6Hz, 1H), 7.87 (d, J=7.8Hz, 1H), 1.43 (s, 3H).

Test Example 1: Bioluminescence test of compounds inhibiting UsP21 enzyme activity

Experimental reagents and instruments:

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.

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

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 prepared in a ratio of 1:9 to prepare Ub-AML-LDR reagent. 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 value. The results of USP21 enzyme inhibition activity test are shown in Table 1:

For _IC50 values, "++++" indicates _IC50 <10 nM; "+++" indicates _IC50 between 10 nM and 100 nM (including 10 nM); "++" indicates _IC50 between 100 nM and 1 μM (including 100 nM); and "+" indicates _IC50 between 1 μM and 10 μM (including 1 μM).

Table 1

The foregoing description of specific exemplary embodiments of the present disclosure is for the purpose of illustration and demonstration. 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 based on the above teachings. 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 various different exemplary embodiments of the present disclosure and various different options and changes. The scope of the present disclosure is intended to be defined by the claims and their equivalents.

Claims (10)

1. Formula (I) compound, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug: In the formula, The Cy1 ring is a 5-7 membered aromatic ring or a 5 or 6 membered heteroaromatic ring containing at least one heteroatom selected from N, O or S; U ₁ , U ₂ , U ₃ are each independently selected from CH, CR ₄ or N; X ₁ and X ₂ are independently selected from hydrogen, -C _1-6 alkyl, -NR ₅ R ₆ , -OR ₅ , -SR ₅ , halogen, or X ₁ and X ₂ together form =O, =S, =NR ₅ , or X ₁ , X ₂ and the atoms connected to them together form a 4 to 6 membered cycloalkyl group optionally substituted by a carbonyl group; with the proviso that X ₁ , X ₂ Not simultaneously -NR ₅ R ₆ , -OR ₅ or -SR ₅ ; R ₁ , R ₂ , and R ₃ are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 ring Alkyl, 3 to 9 membered heterocycloalkyl, -NR ^a R ^b , -C(O)-C _1-3 alkyl, -C(O)NR ^a R ^b , -S(O) ₂ C _{1- 3} alkyl, -C _1-3 alkyl-hydroxyl, -C _1-3 alkyl-C _2-4 alkynyl, -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _{1 -6} alkoxy, -C _1-3 alkyl -3 to 9 membered heterocycloalkyl, -C _1-3 alkyl -C _3-9 cycloalkyl, -O-3 to 9 membered heterocycloalkyl , -OC _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-NR ^a R ^b , -C(NH)NR ^a R ^b , -C _1-3 alkyl-C (O)-C _1-3 Alkyl, -C _1-3 Alkyl-C(O)NR ^a R ^b , -C _1-3 Alkyl-S(O) ₂ C _1-3 Alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 5 or 6 membered heteroaryl, C _5-7 aryl, -SR ₇ , -C(O)OC _1-3 alkyl, -S(O) ₂ -NR ^a R ^b , -NR ^a -S(O) ₂ R ^b , -S(O)NH, -CHO or -NO ₂ ; and the -C _1-3 alkyl, -C _1-6 Alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _{1 -3} alkyl-C _3-9 cycloalkyl, 5 or 6 membered heteroaryl, C _5-7 aryl are optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl , propyl, isopropyl, cyano, amino, -N(CH ₃ ) ₂ , hydroxyl, carboxyl or -CHO substituents; n is an integer of 1-3; R ₄ is selected from hydrogen, halogen, cyano, hydroxyl, -C _1-3 alkyl, -C _1-3 alkoxy, amino, alkynyl, or adjacent R ₃ and R ₄ are connected together to form C _{3 -6} cycloalkyl or 3 to 7-membered heterocycloalkyl, provided that at least one of U ₁ and U ₂ is CR ₄ ; the -C _1-3 alkyl, -C _1-3 alkoxy, - C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl are optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, amino; R ₅ , R ₆ , and R ₇ are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -NR ^a R ^b , -S(O) ₂ C _1-3 alkyl, -C _1-3 alkyl-hydroxyl, -C _1-3 alkyl-C _2-4 alkynyl , -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _1-6 alkoxy, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 Alkyl-C _3-9 cycloalkyl, -C _1-3 alkyl-R ^a R ^b , -C _1-3 alkyl-C(O)H, -C _1-3 alkyl-C(O) -C _1-3 alkyl, -C _1-3 alkyl-C(O)NR ^a R ^b , -C _2-6 alkenyl or -C _2-6 alkynyl; and the -C _1-6 Alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _{1 -3} alkyl-C _3-9 cycloalkyl is optionally selected from 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino, -N(CH ₃ ) ₂ , substituted by substituents of hydroxyl and carboxyl; or, When X ₁ or X ₂ is -NR ₅ R ₆ , R ₅ and R ₆ together form a 5 or 6-membered heterocycloalkyl group with the N atom connected to it, and the 5 or 6-membered heterocycloalkyl group is optionally selected from Substituent substitution of C _1-6 alkyl; R ^a , R ^b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-3 alkyl, deuterated C _1-3 alkyl, C _1-3 alkoxyl, C _3-9 cycloalkyl or -C( O) R ₇ ; The heterocycloalkyl or heteroaryl has at least one heteroatom selected from N, O and S as a ring atom; R ₁ , R ₂ , R ₃ and R ₄ are not simultaneously hydrogen. 2. The compound as claimed in claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, wherein the Cy1 ring comprises at least one heteroatom selected from N, O or S A 5- or 6-membered heteroaryl ring; U ₁ , U ₂ , U ₃ are each independently selected from CH, CR ₄ or N; X ₁ and X ₂ are independently selected from hydrogen, -NR ₅ R ₆ , -OR ₅ , -SR ₅ , halogen, or X ₁ and X ₂ jointly form =O, =S, =NR ₅ , or X ₁ , X ₂ and the atoms connected to them together form a 4 to 6-membered cycloalkyl group optionally substituted by a carbonyl group; provided that X ₁ and X ₂ are not simultaneously NR ₅ R ₆ , OR ₅ , SR ₅ ; R ₁ , R ₂ , and R ₃ are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-9 cycloalkyl, 3 to 9 Membered heterocycloalkyl, -NR ^a R ^b , -C(O)-C _1-3 alkyl, -C(O)NR ^a R ^b , -S(O) ₂ C _1-3 alkyl, -C _1-3 alkyl-hydroxyl, -C _1-3 alkyl-C _2-4 alkynyl, -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _1-6 alkoxy, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl, -O-3 to 9 membered heterocycloalkyl, -C _1-3 Alkyl-NR ^a R ^b , -C(N)NR ^a R ^b , -C _1-3 alkyl-C(O)-C _1-3 alkyl, -C _1-3 alkyl-C(O) NR ^a R ^b , -C _1-3 alkyl-S(O) ₂ C _1-3 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 5 or 6 membered heteroaryl or C _5-7 aryl; and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 Alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl, 5 or 6 membered heteroaryl, C _5-7 aryl are optionally replaced by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, N(CH ₃ ) ₂ , hydroxyl, carboxyl; R ₄ is selected from hydrogen, halogen, cyano, hydroxyl, -C _1-3 alkyl, -C _1-3 alkoxy, amino, alkynyl, or adjacent R ₃ and R ₄ are connected together to form C _{3 -6} cycloalkyl or 3 to 7-membered heterocycloalkyl, provided that at least one of U ₁ and U ₂ is CR ₄ ; the -C _1-3 alkyl, -C _1-3 alkoxy, - C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino; R ₅ and R ₆ are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered hetero Cycloalkyl, -NR ^a R ^b , -S(O) ₂ C _1-3 alkyl, -C _1-3 alkyl-hydroxyl, -C _1-3 alkyl-C _2-4 alkynyl, -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _1-6 alkoxy, -C _1-3 alkyl-3 to 9-membered heterocycloalkyl, -C _1-3 alkyl- C _3-9 cycloalkyl, -C _1-3 alkyl-R ^a R ^b , -C _1-3 alkyl-C(O)H, -C _1-3 alkyl-C(O)-C _{1 -3} alkyl, -C _1-3 alkyl-C(O)NR ^a R ^b , -C _2-6 alkenyl, -C _2-6 alkynyl; and the -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-3 to 9 membered heterocycloalkyl, -C _1-3 alkane Group-C _3-9 cycloalkyl is optionally represented by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl, isopropyl, amino, N(CH ₃ ) ₂ , hydroxyl, carboxyl substituent substitution; R ^a and R ^b are each independently selected from hydrogen, C _1-3 alkyl or C _3-9 cycloalkyl; The heterocycloalkyl or heteroaryl has at least one heteroatom selected from N, O and S as a ring atom; R ₁ , R ₂ and R ₃ , R ₄ are not hydrogen at the same time. 3. The compound as claimed in claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, wherein, said compound is as shown in formula (II): In the formula, U ₁ , U ₂ , U ₃ , U ₄ , U ₅ are each independently selected from CH, CR ₄ or N; X ₁ and X ₂ are independently selected from hydrogen, -C _1-6 alkyl, -NR ₅ R ₆ , -OR ₅ , -SR ₅ , halogen, or X ₁ and X ₂ together form =O, =S, =NR ₅ , or X ₁ , X ₂ and the atoms attached to them together form a 4 to 6 membered heterocycloalkyl optionally substituted by carbonyl; with the proviso that X ₁ , X ₂ is not -NR ₅ R ₆ , -OR ₅ or -SR ₅ at the same time; R ₁ , R ₂ , and R ₃ are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 ring Alkyl, 3 to 9 membered heterocycloalkyl, -NR ^a R ^b , -C(O)-C _1-3 alkyl, -C(O)NR ^a R ^b , -S(O) ₂ C _{1- 3} alkyl, -C _1-3 alkyl-hydroxyl, -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _1-6 alkoxy, -C _1-3 alkyl-3 to 9-membered heterocycloalkyl, -C _1-3 alkyl-C _3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -OC _1-3 alkyl-3 to 9-membered heterocycle Alkyl, -C _1-3 alkyl-NR ^a R ^b , -C(NH)NR ^a R ^b , -C _1-3 alkyl-C(O)-C _1-3 alkyl, -C _{1- 3} alkyl-C(O)NR ^a R ^b , -C _2-6 alkynyl, 5 or 6 membered heteroaryl, C _5-7 aryl, -SR ₇ , -C(O)OC _1-3 alkane -S(O) ₂ NR ^a R ^b , -NR ^a -S(O) ₂ R ^b , -S(O)NH, -CHO, -NO ₂ ; and the -C _1-3 alkyl , -C _1-6 alkyl, -C _1-6 alkoxy, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, 5 or 6 membered heteroaryl, C _5-7 aryl Optionally substituted by 1, 2 or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -N(CH ₃ ) ₂ , hydroxyl, carboxyl replace; R ₄ is selected from hydrogen, halogen, cyano, hydroxyl, -C _1-3 alkyl, or adjacent R ₃ and R ₄ are connected to each other to form C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkyl, The condition is that at least one of U ₁ and U ₂ is CR ₄ ; the -C _1-3 alkyl, -C _1-3 alkoxy, -C _3-6 cycloalkyl or 3 to 7 membered heterocycloalkane The group is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, amino; R ₅ , R ₆ , and R ₇ are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C _1-6 alkyl, -C _1-6 alkoxy, -C _1-3 alkyl-C(O )H, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C _1-3 alkyl-hydroxyl; and the -C _1-6 alkyl, -C _1-6 alkoxy Base, -C _3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl are optionally selected from 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino , -N(CH ₃ ) ₂ , hydroxyl, and carboxyl substituents; R ^a and R ^b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-3 alkyl, C _1-3 alkoxyl, C _3-9 cycloalkyl or -C(O)R ₇ ; The heterocycloalkyl or heteroaryl has at least one heteroatom selected from N, O and S as a ring atom; R ₁ , R ₂ , R ₃ and R ₄ are not simultaneously hydrogen. 4. The compound according to any one of claims 1-3, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, wherein, said compound is such as formula (IIA), formula ( IIB), formula (IIC), formula (IID), formula (IIE), formula (IIF), formula (III) or formula (IV): In each formula, U ₁ , U ₂ , U ₃ , X ₁ , X ₂ , R ₁ , R ₂ , R ₃ , R ₅ , and n are each defined as the compound of formula (I). 5. The compound according to any one of claims 1-4, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, wherein: _R is selected from hydrogen, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyano, dimethylamino, methoxy, methyl, trifluoromethoxy, -CH _CN , _R is selected from hydrogen, hydroxy, methyl, methoxy, cyano or trifluoromethyl; R ₃ is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxyl, cyclopropyl, ethynyl, phenyl, nitro, amino, isopropyl, -C(O)OCH ₃ , -S-CF ₃ , -S(O) ₂ NH ₂ , -S(O) ₂ -CF ₃ , -C(O)NH ₂ , -C(O)N(CH ₃ ) ₂ , -C(O) NHOH, -C(O)NHCH ₃ , -C(OH)(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , -S(O) ₂ CH ₂ CHO, -CH(CH ₃ )OH, -CH ₂ Br, -CH ₂ OH, -CH ₂ C(O)OH, The halogen is selected from fluorine or chlorine. 6. The compound according to any one of claims 1-5, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof, wherein the compound is selected from the group consisting of: 7. The compound according to any one of claims 1-6, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, wherein, said compound is as formula (III) or formula (IV ), it is prepared by a method comprising the following steps: Wherein, Cy1, U ₁ , U ₂ , U ₃ , R _{1 , R 2 ,} R ₃ , R ₅ , and n each define the same compound as formula (III) or formula (IV); The oxidizing agent is selected from tert-butyl hydroperoxide, hydrogen peroxide, cumene hydroperoxide, dicumyl hydroperoxide or 2,2,6,6-tetramethylpiperidine oxide; the catalyst selected from tetrabutylammonium halide, potassium halide, sodium halide or elemental iodine; the solvent is selected from methanol, ethanol, tert-butanol, isopropanol, n-butanol, sec-butanol, N,N-dimethylformaldehyde Amide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, methylene chloride, chloroform, carbon tetrachloride or 1,2-dichloroethane; Preferably, the oxidizing agent is tert-butyl hydroperoxide; Preferably, the catalyst is tetrabutylammonium iodide; Preferably, the solvent is 1,2-dichloroethane; Carrying out the appropriate carbonylamine condensation reaction between the above compound of formula (III) and R ₅ -NH ₂ to obtain the compound of formula (IV); Optionally, the compound of formula (III-1) is prepared by a method comprising the following steps: Wherein, U ₁ , U ₂ , U ₃ , Cy1, R ₁ , R ₂ , R ₃ , and n are each defined as the compound of formula (Ⅲ); R _X and R _X' are selected from a halogen atom, a boronic acid group or a borate ester group, and the halogen atom is selected from F, Cl, Br; the condition is: when R _X is selected from a halogen atom, R _X' is selected from a boronic acid group or A borate group, when R _X' is selected from a halogen atom, R _X is selected from a borate group or a borate group; Preferably, R _X is B(OH) ₂ and R _X' is Br. 8. A pharmaceutical composition, characterized in that the composition comprises the compound according to any one of claims 1-6, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug or The compound prepared by the method of claim 7 and pharmaceutically acceptable auxiliary materials. 9. The compound described in any one of claims 1-6, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the method described in claim 7, right The pharmaceutical composition described in claim 8 is used in the preparation of USP inhibitors or drugs for the treatment of diseases related to USP activity, cardiovascular diseases, nervous disorders, cancer or immune diseases, or for the preparation of diseases related to USP activity, cardiology Use in a kit for assessment of vascular disease, neurological disorder, cancer, immune disease or patient prognosis; Preferably, the pharmaceutical composition also contains another drug for treating cardiovascular disease, nervous disorder, cancer or immune disease; Preferably, the use in the preparation of USP21 inhibitors or in the treatment of diseases related to USP21 activity; Preferably, said cancer comprises prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer and leukemia; More preferably, the cancer includes pancreatic cancer, liver cancer, breast cancer, kidney cancer, bladder cancer and lung cancer. 10. A method for inhibiting USP activity in a biological sample, comprising making the biological sample and a compound according to any one of claims 1-6, its pharmaceutically acceptable salt, stereoisomer, solvent compound, its prodrug, or the compound prepared by the method of claim 7, or the pharmaceutical composition of claim 8.