USP inhibitors, methods of making and using the same

Abstract

This disclosure provides a compound that inhibits USP, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug, as shown in formula (I), wherein the definitions of each group are detailed in the specification. Furthermore, this disclosure also discloses methods for preparing the compound, pharmaceutical compositions comprising the compound, its use in the preparation of USP inhibitors, the preparation of drugs for treating cardiovascular diseases, neurological disorders, cancer, and immune diseases, or the preparation of kits for assessing the prognosis of cardiovascular diseases, neurological disorders, cancer, immune diseases, or patients, as well as methods for inhibiting USP activity in biological samples and methods for treating USP21-mediated diseases, cardiovascular diseases, neurological disorders, cancer, or immune diseases.

Description

Technical Field

[0001] This disclosure relates to the pharmaceutical field, and in particular to a compound with USP inhibitory activity, its uses and preparation method. Background Technology

[0002] The ubiquitin-specific proteasome system (USP) is a dynamic, bidirectional protein modification regulatory system within cells, involved in the degradation and modification of more than 80% of intracellular proteins. USP participates in various life activities, including cell cycle regulation, cell receptor function, gene transcription, immune responses, and tumor growth, through the polyubiquitination of substrate proteins followed by proteasome degradation. This pathway is mediated by an enzymatic conjugation cascade, involving the continuous activation of ubiquitin activator (E1), ubiquitin conjugator (E2), and ubiquitin ligase (E3) to complete the ubiquitination modification of the substrate protein (The ubiquitin-proteasome pathway: on protein death and cell life, Ciechanover, EMBO J. 1998 Dec 15; 17(24): 7151-60.), and the proteasome completes the degradation or modification of the target protein. On the other hand, the deubiquitinating enzyme family (DUBs) is responsible for hydrolyzing ubiquitin molecules specifically from ubiquitin-linked proteins or precursor proteins by hydrolyzing the ester bond, peptide bond, or isopeptide bond at the carboxyl terminus of ubiquitin, thereby playing a role in deubiquitination and reversing protein degradation, thus affecting protein function.

[0003] Currently, approximately 100 DUBs have been identified in the human genome. They play a monitor role in the regulation of the ubiquitination system and are crucial in regulating various intracellular activities such as cell cycle, DNA repair, immunity, and protein homeostasis (Regulation of proteolysis by human deubiquitinating enzymes, Ziad MEletr, 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.). Based on sequence and structural similarity, DUBs are divided into seven families: Ubiquitin C-terminal hydrolases (UCHs), Ubiquitin-specific proteases (USPs), Ovarian tumor domain proteases (OTUs), Machado-Josephin domain proteases (MJDs), Jab1 / MPN domain associated metalloproteases (JAMMs), UFM1-specific zinc finger peptidases (ZUFSPs), and a novel DUB family containing MIU (MINDY) (Jinhong et al., 2020).

[0004] USPs are the largest and most structurally diverse DUB family to date, containing approximately 60 members. This family belongs to the cysteine ​​proteases and contains two short, conserved sequences: the N-terminal Cys-box and the C-terminal His-box, composed of catalytically active cysteine ​​and histidine residues. The sequences include a catalytically active triplet of residues—cysteine, histidine, and aspartic acid / asparagine—that removes ubiquitin molecules from large proteins. Due to the protease activity of the USP family and its regulatory role in human life processes, USPs have become potential drug targets. For example, overexpression of USP2 is associated with prostate cancer (Priolo et al., 2006; Stevensone et al., 2007) and breast cancer (Qu et al., 2015); USP7 is aberrantly expressed in various 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.).

[0005] USP21, a member of the USP family, is involved in the regulation of many intracellular activities. It is involved in several key pathways of USP21 deubiquitination, including oncogenes and genes with oncogenic effects, such as HH / Gli, MEK2, MARK, Stem cell renewal / Nanog / GATA3, and WNT. USP21 plays a role in various types of tumors, such as pancreatic cancer, liver cancer, breast cancer (triple-negative breast cancer), kidney cancer, bladder cancer, and lung cancer. USP21 is also associated with the clinical prognosis of tumors. Furthermore, recent studies have shown that USP21 plays an important role in the negative regulation of the innate immune response against viruses, mainly through the deubiquitination of retinoic acid-induced gene protein I (RIG-I) and interferon-stimulated gene 15 (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.). Recent research has found that USP21 gene amplification is common in human pancreatic cancer (22% PDAC), and high USP21 expression is associated with PDAC progression. In a mouse pancreatic cancer model, exogenous high expression of USP21 accelerates tumor growth, while knockout of USP21 inhibits 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.

[0006] Inhibiting USP21 can suppress cell proliferation and tumor growth. Currently, numerous research institutions and pharmaceutical companies internationally are investigating inhibitors targeting DUBs, but no drugs targeting USP21 have yet been discovered. The clinical need for developing USP21 inhibitors is significant. Therefore, USP21 is a highly promising and marketable first-in-class cancer target. Developing specific inhibitors of USP21 for molecularly targeted therapy of related tumors and other diseases such as immune disorders associated with USP21 abnormalities is of great importance. Summary of the Invention

[0007] This disclosure provides a novel substituted fused-ring aromatic compound that exhibits high inhibitory activity as an enzyme inhibitor of USP. One aspect of this disclosure provides a compound of formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug:

[0008]

[0009] 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;

[0010] U1, U2, and U3 are each independently selected from CH, CR4, or N;

[0011] X1 and X2 are independently selected from hydrogen and -C, respectively. 1-6 Alkyl groups, -NR5R6, -OR5, -SR5, halogens, or X1 and X2 together form =O, =S, =NR5, or X1, X2 and the atoms attached to them together form a 4- to 6-membered cycloalkyl group, wherein the 4- to 6-membered cycloalkyl group is optionally substituted with a carbonyl group; provided that X1 and X2 are not simultaneously -NR5R6, -OR5 or -SR5.

[0012] R1, R2, and R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, and -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)2C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-C 2-4 alkynyl group, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-3 to 9-membered heterocyclic alkyl, -C 1-3 Alkyl-C 3-9 Cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -OC 1-3 Alkyl-3 to 9-membered heterocyclic 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 1-3 Alkyl-S(O)2C 1-3 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 5 or 6-membered heteroaryl, C5-7 Aryl, -S-R7, -C(O)OC 1-3 Alkyl, -S(O)2-NR a R b -NR a -S(O)2R b -S(O)NH, -CHO, or -NO2; 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 heterocyclic alkyl, -C 1-3 Alkyl-C 3-9 cycloalkyl, 5- or 6-membered heteroaryl, C 5-7 The aryl group is optionally substituted by one, two or three substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -N(CH3)2, hydroxyl, carboxyl or -CHO;

[0013] n is an integer between 1 and 3:

[0014] R4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy, amino, alkynyl, or adjacent R3 and R4 groups are linked together to form C 3-6 Cycloalkyl or 3- to 7-membered heterocycloalkyl, provided that at least one of U1 and U2 is CR4; the -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 The cycloalkyl or 3- to 7-membered heterocycloalkyl group is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and amino.

[0015] R5, R6, and R7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, -NR a R b -S(O)2C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-C 2-4 alkynyl group, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-3 to 9-membered heterocyclic alkyl, -C 1-3 Alkyl-C 3-9cycloalkyl, -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 group; 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 heterocyclic alkyl, -C 1-3 Alkyl-C 3-9 The cycloalkyl group is optionally substituted by one, two, or three independent substituents selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino, -N(CH3)2, hydroxyl, and carboxyl groups; or,

[0016] When X1 or X2 is -NR5R6, R5, R6, and the N atom attached to them together form a 5- or 6-membered heterocyclic alkyl group, wherein the 5- or 6-membered heterocyclic alkyl group is optionally selected from C. 1-6 Alkyl substituents;

[0017] R a R b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 3-9 cycloalkyl or -C(O)R7;

[0018] The heterocyclic alkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;

[0019] R1, R2, R3, and R4 are not all hydrogen at the same time.

[0020] As used in this article, adjacent R3 and R4 are connected together to form C. 3-6 Cycloalkyl or 3- to 7-membered heterocyclic groups refer to adjacent R3 and R4 groups that are connected to each other, forming a C1 ring with the atoms on the rings they are connected to. 3-6 Cycloalkyl or 3 to 7-membered heterocyclic groups.

[0021] Preferably, X1 and X2 are not both hydrogen.

[0022] In one embodiment, the compound does not include

[0023] In one embodiment, n is 1 in the compound represented by formula (I).

[0024] Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S;

[0025] U1, U2, and U3 are each independently selected from CH, CR4, or N;

[0026] X1 and X2 are independently selected from hydrogen, -NR5R6, -OR5, -SR5, halogen, or X1 and X2 together form =O, =S, =NR5, or X1, X2 and the atoms attached to them together form a 4- to 6-membered cycloalkyl group, wherein the 4- to 6-membered cycloalkyl group is optionally substituted with a carbonyl group; provided that X1 and X2 are not simultaneously NR5R6, OR5, or SR5.

[0027] R1, R2, and R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, and 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)2C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-C 2-4 alkynyl group, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-3 to 9-membered heterocyclic alkyl, -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)2C 1-3 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 5- or 6-membered heteroaryl or C 5-7 Aryl; and the -C1-6 Alkyl, -C 1-6 Alkoxy, -C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, -C 1-3 Alkyl-3 to 9-membered heterocyclic alkyl, -C 1-3 Alkyl-C 3-9 cycloalkyl, 5- or 6-membered heteroaryl, C 5-7 The aryl group is optionally substituted by one, two or three substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, N(CH3)2, hydroxyl or carboxyl;

[0028] R4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy, amino, alkynyl, or adjacent R3 and R4 groups are linked together to form C 3-6 Cycloalkyl or 3- to 7-membered heterocycloalkyl, provided that at least one of U1 and U2 is CR4; the -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 The cycloalkyl or 3- to 7-membered heterocycloalkyl group is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, and amino groups;

[0029] R5 and R6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, -NR a R b -S(O)2C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-C 2-4 alkynyl group, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-3 to 9-membered heterocyclic alkyl, -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 group; and the -C1-6 Alkyl, -C 1-6 Alkoxy, -C 3-9 Cycloalkyl, 3- to 9-membered heterocycloalkyl, -C 1-3 Alkyl-3 to 9-membered heterocyclic alkyl, -C 1-3 Alkyl-C 3-9 The cycloalkyl group is optionally substituted by one, two or three substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, amino, N(CH3)2, hydroxyl or carboxyl;

[0030] R a R b Each is independently selected from hydrogen and C. 1-3 Alkyl or C 3-9 cycloalkyl;

[0031] The heterocyclic alkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;

[0032] R1, R2 and R3, R4 are not all hydrogen at the same time.

[0033] 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 of formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof.

[0034]

[0035] In the formula,

[0036] U1, U2, U3, U4, and U5 are each independently selected from CH, CR4, or N;

[0037] X1 and X2 are independently selected from hydrogen and -C, respectively. 1-6 Alkyl groups, -NR5R6, -OR5, -SR5, halogens, or X1 and X2 together form =O, =S, =NR5, or X1, X2 and the atoms attached to them together form 4 to 6-membered heterocyclic alkyl groups, wherein the 4 to 6 heterocyclic alkyl groups are optionally substituted with carbonyl groups; provided that X1 and X2 are not simultaneously -NR5R6, -OR5, or -SR5.

[0038] In one embodiment, X1 and X2 are independently selected from hydrogen, -NR5R6, -OR5, -SR5, halogen, or X1 and X2 together form =O, =S, =NR5, or X1, X2 and the atoms attached to them together form a 4- to 6-membered heterocyclic alkyl group, wherein the 4- to 6-membered heterocyclic alkyl group is optionally substituted with a carbonyl group; provided that X1 and X2 are not simultaneously NR5R6, OR5, or SR5.

[0039] R1, R2, and R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, and -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)2C 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 heterocyclic alkyl, -C 1-3 Alkyl-C 3-9 Cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -OC 1-3 Alkyl-3 to 9-membered heterocyclic 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, -S-R7, -C(O)OC 1-3 Alkyl group, -S(O)2NR a R b -NR a -S(O)2R b -S(O)NH, -CHO, -NO2; 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 The aryl group is optionally substituted by one, two or three substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -N(CH3)2, hydroxyl or carboxyl;

[0040] In one embodiment, R1, R2, and R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, and -C. 1-6 Alkyl, -C 1-6Alkoxy, -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)2C 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 heterocyclic alkyl, -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 2-6 alkynyl, 5 or 6-membered heteroaryl, C 5-7 Aryl; 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 The aryl group may be optionally substituted by substituents of propyl, isopropyl, cyano, amino, N(CH3)2, hydroxyl, or carboxyl.

[0041] R4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 Alkyl groups, or adjacent R3 and R4 groups connected together to form C 3-6 Cycloalkyl or 3- to 7-membered heterocycloalkyl, provided that at least one of U1 and U2 is CR4; the -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 The cycloalkyl or 3- to 7-membered heterocycloalkyl group is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and amino.

[0042] In one embodiment, R4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 Alkyl groups, or adjacent R3 and R4 groups connected together to form C 3-6 Cycloalkyl or 3- to 7-membered heterocycloalkyl, provided that at least one of U1 and U2 is CR4; the -C1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 The cycloalkyl or 3- to 7-membered heterocycloalkyl group is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, etc.

[0043] R5, R6, and R7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, and -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 The cycloalkyl group and the 3 to 9-membered heterocycloalkyl group are optionally substituted by 1, 2 or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino, -N(CH3)2, hydroxyl or carboxyl;

[0044] In one embodiment, R5 and R6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, and -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 The cycloalkyl group or 3 to 9-membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, amino, N(CH3)2, hydroxyl or carboxyl.

[0045] R a R b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 3-9 cycloalkyl or -C(O)R7;

[0046] In one implementation scheme, R a R b Each is independently selected from hydrogen and C. 1-3 Alkane or C 3-9 Cycloalkyl.

[0047] The heterocyclic alkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;

[0048] R1, R2 and R3, R4 are not all hydrogen at the same time.

[0049] In one implementation scheme, U1, U2, U3, U4, and U5 are each independently selected from CR4.

[0050] In one implementation scheme, U1, U2, U3, and U5 are each independently selected from CR4, and U4 is N.

[0051] In one implementation scheme, U1, U2, U3, and U4 are each independently selected from CR4, and U5 is N.

[0052] In one implementation scheme, U1, U2, and U3 are each independently selected from CR4, and U4 and U5 are both N.

[0053] In one implementation scheme, U2 and U3 are each independently selected from CR4, and U1, U4, and U5 are all N.

[0054] In one implementation scheme, U3 is selected from CR4, and U1, U2, U4, and U5 are all N.

[0055] In one embodiment, the compound represented by formula (I) is a compound of formula (III), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof:

[0056]

[0057] In the formula,

[0058] 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 each a compound of formula (I) or formula (II), preferably n is 1.

[0059] In one embodiment, the compound represented by formula (I) is a compound of formula (VII), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof:

[0060]

[0061] In the formula,

[0062] 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 each defined as compounds of formula (I) or formula (II), preferably, n is 1.

[0063] In one embodiment, the compound represented by formula (I) is a (IIA) compound, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug:

[0064]

[0065] In the formula,

[0066] X1 and X2 are independently selected from hydrogen, -NR5R6, -OR5, -SR5, halogen, or X1 and X2 together form =O, =S, =NR5, or X1, X2 and the atoms attached to them together form a 4 to 6-membered heterocyclic alkyl group, wherein the 4 to 6-membered heterocyclic alkyl group is optionally substituted with a carbonyl group; provided that X1 and X2 are not simultaneously NR5R6, OR5, or SR5.

[0067] R1, R2, and R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, and -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 -SO2C 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 heterocyclic alkyl, -C 1-3 Alkyl-C 3-9 Cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -OC 1-3 Alkyl-3 to 9-membered heterocyclic 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 heteroaryl, C 5-7 Aryl, -S R7, -C(O)OC 1-3 Alkyl, -SO2NR a R b -NR a SO2R b -S(O)NH, -CHO, -NO2; and the -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-9Cycloalkyl, 3- to 9-membered heterocycloalkyl, 5- or 6-membered heteroaryl, C 5-7 The aryl group may be optionally substituted with deuterium, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -N(CH3)2, hydroxyl, or carboxyl substituents;

[0068] In one embodiment, R1, R2, and R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, and -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)2C 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 heterocyclic alkyl, -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 2-6 alkynyl, 5 or 6 heteroaryl, C 5-7 Aryl; 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 The aryl group may be optionally substituted by substituents of propyl, isopropyl, cyano, amino, N(CH3)2, hydroxyl, or carboxyl.

[0069] R5, R6, and R7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, and -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 -C1-6 Alkyl, -C 1-6 Alkoxy, -C 3-9 The cycloalkyl group and the 3 to 9-membered heterocycloalkyl group are optionally substituted by 1, 2 or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino, -N(CH3)2, hydroxyl or carboxyl;

[0070] In one embodiment, R5 and R6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, and -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 The cycloalkyl group or 3 to 9-membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, amino, N(CH3)2, hydroxyl or carboxyl;

[0071] R a R b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 3-9 cycloalkyl or -C(O)R7;

[0072] In one implementation scheme, R a R b Each is independently selected from hydrogen and C. 1-3 Alkane or C 3-9 cycloalkyl;

[0073] The heterocyclic alkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;

[0074] R1, R2 and R3, R4 are not all hydrogen at the same time.

[0075] In one embodiment, the compound represented by formula (I) is a (IIB) compound, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug:

[0076]

[0077] In the formula, X1, X2, R1, R2, and R3 are each defined as either a compound of formula (I) or a compound of formula (IIA).

[0078] In one embodiment, the compound represented by formula (I) is an (IIC) compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof:

[0079]

[0080] In the formula, X1, X2, R1, R2, and R3 are each defined as either a compound of formula (I) or a compound of formula (IIA).

[0081] In one embodiment, the compound represented by formula (I) is a (IID) compound, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug:

[0082]

[0083] In the formula, X1, X2, R1, R2, and R3 are each defined as either a compound of formula (I) or a compound of formula (IIA).

[0084] In one embodiment, the compound represented by formula (I) is a (IIE) compound, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug:

[0085]

[0086] In the formula, X, R1, R2, and R3 are each defined as either a compound of formula (I) or a compound of formula (IIA).

[0087] In one embodiment, the compound represented by formula (I) is an (IIF) compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof:

[0088]

[0089] In the formula, X1, X2, R1, R2, and R3 are each defined as either a compound of formula (I) or a compound of formula (IIA).

[0090] In one embodiment, X1 and X2 are each independently selected from hydrogen, hydroxyl, halogen, and -C. 1-6 Alkyl, C 1-3 Alkyl groups, substituted or unsubstituted, are 5- or 6-membered heterocyclic alkyl groups, preferably derived from hydrogen, hydroxyl, halogen, methyl, morpholino, or methyl-substituted piperazine groups; or,

[0091] X1 and X2 together form =O, =S, or =NR5, where R5 is selected from hydroxyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-carboxyl groups, preferably hydroxyl, ethoxy, -(CH2)2OH, -CH2COOH; or,

[0092] X1, X2, and the atoms bonded to them together form carbonyl-substituted C atoms. 3-6 Cycloalkyl, preferably cyclobutyl.

[0093] In one embodiment, X1 and X2 are each independently selected from hydrogen, hydroxyl, and -C. 1-6 Alkyl groups, preferably derived from hydrogen, hydroxyl, or methyl groups; or,

[0094] X1 and X2 together form =O or =NR5, where R5 is selected from hydroxyl or -C. 1-6 Alkyl groups, preferably hydroxyl or ethoxy groups.

[0095] In one embodiment, R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyano, dimethylamino, methoxy, methyl, trifluoromethoxy, -CH2CN, -O-CN,

[0096] In one embodiment, R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyano, dimethylamino, methoxy, methyl,

[0097] In one embodiment, R1 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 group, -C(O)-C 1-3 Alkyl, -C(O)NR a R b -S(O)2C 1-3 Alkyl, -OC 1-3 Alkyl-3 to 9-membered heterocyclic alkyl groups, -C(NH)NR a R b 5 or 6-membered heteroaryl; and the -C 1-6 Alkyl groups and 3 to 9-membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 halogens;

[0098] Among them, R a R b Each is independently selected from hydrogen or -C. 1-3 alkyl.

[0099] In one embodiment, R1 is selected from hydrogen, F, Cl, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyano, dimethylamino, methoxy, methyl,

[0100] In one embodiment, R2 is selected from hydrogen, hydroxyl, -C 1-6 Alkyl or -C 1-6 Alkyl group.

[0101] In one embodiment, R2 is selected from hydrogen, hydroxyl, methyl, or methoxy.

[0102] In one embodiment, R1 is selected from formula (I), formula (II), formula (III), formula (VII), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), or formula (IIF), where R1 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyano, dimethylamino, methoxy, or the group following:

[0103]

[0104] In one embodiment, R2 is selected from hydroxyl, methyl, methoxy, or trifluoromethyl in formulas (I), (II), (III), (IV), (IIA), (IIB), (IIC), (IID), (IIE), or (IIF).

[0105] 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,

[0106] 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,

[0107] In one embodiment, R3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxylic acid or CONH2 in formulas (I), (II), (III), (IV), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF).

[0108] The halogen is selected from fluorine or chlorine.

[0109] In one embodiment, R4 is selected from halogens, cyano groups, and -C groups. 1-3 Alkyl group; or, adjacent R3 and R4 are interconnected to form a 5- or 6-membered oxygen-containing heterocyclic group.

[0110] In one embodiment, R4 is selected from halogens, cyano groups, and -C groups. 1-3 Alkyl groups; or, adjacent R3 and R4 linked together to form alkyl groups.

[0111] In one embodiment, the compound of formula (I), formula (II), formula (III), formula (IV), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), or formula (IIF) is selected from the group consisting of:

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118] In another aspect of this disclosure, a method for preparing the above-mentioned compound is provided, wherein when the compound represented by formula (I) is a compound of formula (III) or formula (IV), it is prepared by a method comprising the following steps:

[0119]

[0120] Among them, Cy1, U1, U2, U3, R1, R2, R3, R5, and n are each defined as before, and preferably, n is 1.

[0121] In one embodiment, the oxidant is selected from tert-butyl hydroperoxide, hydrogen peroxide, cumene hydroperoxide, dicumene hydroperoxide, and 2,2,6,6-tetramethylpiperidine oxide.

[0122] In one embodiment, the catalyst is selected from tetrabutylammonium halide, potassium halide, sodium halide, and elemental iodine.

[0123] 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.

[0124] In a preferred embodiment, the oxidant is tert-butyl hydroperoxide.

[0125] In a preferred embodiment, the catalyst is tetrabutylammonium iodide.

[0126] In a preferred embodiment, the solvent is 1,2-dichloroethane.

[0127] Compound (III) was subjected to an appropriate carbonylamine condensation reaction with R5-NH2 to obtain compound (IV).

[0128] In one embodiment, the compound of formula (III-1) is prepared by a method comprising the following steps:

[0129]

[0130] Among them, U1, U2, U3, Cy1, R1, R2, R3, and n are each defined as before, and preferably, n is 1;

[0131] R X and R X’ The halogen atom is selected from halogen atoms, borate groups, or borate ester groups, wherein the halogen atom is selected from F, Cl, or Br; the condition is: R X When selected from halogen atoms, R X’ Selected from borate group or borate ester group, R x’ When selected from halogen atoms, R X Selected from borate group or borate ester group.

[0132] Preferably, R X For B(OH)2, R x’ It is Br.

[0133] In another aspect of this disclosure, a pharmaceutical composition is provided, the composition comprising the above-described compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a compound prepared by the above-described method, and a pharmaceutically acceptable excipient.

[0134] In one embodiment, the pharmaceutical composition further comprises another drug for treating cardiovascular diseases, neurological disorders, cancer, or immune diseases.

[0135] Another aspect of this disclosure provides the use of the above-described compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above method in the preparation of a medicament for treating cardiovascular diseases, neurological disorders, cancer, or immune diseases, or in the preparation of a kit for assessing the prognosis of cardiovascular diseases, neurological disorders, cancer, immune diseases, or patients.

[0136] Another aspect of this disclosure provides the use of the above-described pharmaceutical composition in the preparation of medicaments for treating cardiovascular diseases, neurological disorders, cancer, and immune diseases, or in the preparation of kits for assessing the prognosis of cardiovascular diseases, neurological disorders, cancer, immune diseases, or patients.

[0137] In a preferred embodiment, the use of the above-described compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above method in the preparation of a treatment for diseases related to USP activity, preferably diseases related to USP21 activity.

[0138] In a preferred embodiment, the use of the above-described pharmaceutical composition in the preparation of a treatment for diseases associated with USP activity, preferably diseases associated with USP21 activity is provided.

[0139] In one embodiment, the cancers include prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, and leukemia.

[0140] In a preferred embodiment, the cancer includes pancreatic cancer, liver cancer, breast cancer, kidney cancer, bladder cancer, and lung cancer.

[0141] In one embodiment, the immune disease is an immune disease related to USP activity.

[0142] In another aspect of this disclosure, there is a use of the above-described compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, the compound prepared by the above method, or the above-described pharmaceutical composition in the preparation of a USP inhibitor.

[0143] In one embodiment, the USP inhibitor is a USP21 inhibitor.

[0144] In another aspect of this disclosure, a method for inhibiting USP activity in a biological sample is provided, comprising the step of contacting the biological sample with the aforementioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, the compound prepared by the aforementioned method, or the aforementioned pharmaceutical composition.

[0145] Another aspect of this disclosure provides a method for treating diseases, cardiovascular diseases, neurological disorders, cancer, or immune diseases related to USP21 activity, comprising the step of administering the above-described compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, the compound prepared by the above-described method, or the above pharmaceutical composition to a patient in need.

[0146] In one embodiment, the cancers include prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, and leukemia.

[0147] In one embodiment, the disease associated with USP21 activity refers to a disease associated with abnormal USP21 activity. Detailed Implementation

[0148] I. Definition

[0149] Based on the above content of this disclosure, and in accordance with common technical knowledge and practices in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas of this disclosure.

[0150] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0151] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemic, diastereomer, and enantiomers are all included within the scope of this disclosure.

[0152] The disclosed compounds also include tautomer forms. The tautomer forms arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0153] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0154] The numerical ranges mentioned in this article refer to the integers within a given range. For example, "C1-C6" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C3-C6" means that the group can have 3, 4, 5, or 6 carbon atoms.

[0155] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0156] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom or group by a substituent, provided that the valence state of the atom or group is normal and the resulting compound is stable. When the substituent is =O, it means that two hydrogen atoms are substituted. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0157] When any variable (e.g., Rn) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 1-5 Rs, the group can optionally be substituted by up to 5 Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0158] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably a lower alkyl group with 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

[0159] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0160] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0161] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably pyridine, triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0162]

[0163] The heteroaryl group can be optionally substituted or unsubstituted. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0164] "Alkenyl" refers to alkenyl groups, also known as olefin groups, which can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0165] "Alynyl" refers to (CH≡C-), wherein the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, cyano, nitro, phenolic, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0166] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally 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, sulfhydryl, hydrogen, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0167] "-CHO" or "-C(O)H" refers to "Hydroxy" refers to the -OH group.

[0168] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0169] "Amino" refers to -NH2.

[0170] “Cyano” refers to -CN.

[0171] "Nitro" refers to -NO2.

[0172] "Carbonyl" refers to -C(O)-.

[0173] "Carboxyl group" refers to -C(O)OH.

[0174] "Methylammonium" refers to

[0175] "THF" refers to tetrahydrofuran.

[0176] “EtOAc” refers to ethyl acetate.

[0177] “MeOH” refers to methanol.

[0178] “EtOH” refers to ethanol.

[0179] "DMF" refers to N,N-dimethylformamide.

[0180] “TBAI” refers to tetrabutylammonium iodide.

[0181] "TFA" refers to trifluoroacetic acid.

[0182] “MeCN” refers to Yi Qing.

[0183] “PdCl2(dppf)” refers to [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride.

[0184] “DCE” refers to 1,2-dichloroethane.

[0185] "DIPEA" refers to diisopropylethylamine.

[0186] “NBS” refers to N-bromosuccinimide.

[0187] “NIS” refers to N-iodosuccinimide.

[0188] "cbz-cr refers to benzyl chloroformate".

[0189] "Pd2(dba)3" refers to tris(dibenzylacetone)dipalladium.

[0190] “Dppf” refers to 1,1’-bis(diphenylphosphine)ferrocene.

[0191] “HATU” refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0192] "KHMDS" refers to potassium hexamethyldisilamide.

[0193] "LiHMDS" refers to lithium bis(trimethylsilyl)amine.

[0194] “MeLi” refers to methyl lithium.

[0195] “n-BuLi” refers to n-butyllithium.

[0196] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0197] "Boc" refers to tert-butyloxycarbonyl, and its structural formula is:

[0198] “FA” stands for nail acid.

[0199] “ACN” refers to acetonitrile.

[0200] "DCM" refers to dichloromethane.

[0201] "LDA" refers to lithium diisopropylamine.

[0202] “NMI” refers to 1-methyl-1H-imidazole.

[0203] “TCFH” refers to N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate.

[0204] "DIBAL-H" refers to diisobutylaluminum hydride.

[0205] “m-CPBA” refers to interchloroperoxybenzoic acid.

[0206] “Dioxane” refers to 1,4-dioxane.

[0207] "DMSO" refers to dimethyl sulfoxide.

[0208] "AIBN" refers to azobisisobutyronitrile.

[0209] "TEA" refers to triethylamine. "Oxone" refers to potassium peroxymonosulfonate.

[0210] “BINAP” refers to 1,1′-binaphthyl-2,2′-bisdiphenylphosphine.

[0211] "iPrOH" refers to isopropanol.

[0212] All hydrogen atoms described in this disclosure can be replaced by their isotope deuterium.

[0213] In substituents This refers to the point where chemical bonds are joined. For example, R1 is... middle, The indicated position is connected to the Cy1 ring.

[0214] In compounds This indicates the presence of stereoisomerism at the chemical bond, including configurations represented by both solid and imaginary wedges. For example, This indicates that there is a stereoisomerism between the N atom and the hydroxyl group connected to the central five-membered ring of indo[2,1-d]pyrimidine. The structure of this compound is as follows: Or a mixture thereof.

[0215] Drugs or drug compositions

[0216] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0217] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound as a free acid or base without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0218] The pharmaceutically acceptable salts disclosed herein can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0219] The pharmaceutical products or pharmaceutical compositions disclosed herein can be administered orally, topically, parenterally, or via mucosal routes (e.g., sublingually, by inhalation, or rectally) in dosage units comprising a conventional, non-toxic, pharmaceutically acceptable carrier. Oral administration is generally preferred. The active agent can be administered orally in capsule, tablet, or other similar forms (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0220] For oral administration in tablet or capsule form, the active pharmaceutical ingredient may be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl docosanoate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium hydroxyacetic acid starch); or wetting agents (e.g., sodium lauryl sulfate), colorants and flavorings, gelatin, sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth, or alginate), buffer salts, carboxymethyl cellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical component may 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, esters, ethanol, or fractionated vegetable oils), and a preservative (e.g., methylparaben, propylparaben, or sorbic acid). Stabilizers such as antioxidants (BHA, BHT, propyl iodide, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

[0221] Tablets containing the active compound can be coated using methods well known in the art. The compositions of this disclosure containing a compound of formula I as the active compound can also incorporate beads, microspheres, or microcapsules, for example, constructed from polyglycolic acid / lactic acid (PGLA). Liquid formulations 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 prior to use. Formulations for oral administration can be suitably formulated to allow for controlled or delayed release of the active compound.

[0222] The pharmaceutical products or pharmaceutical compositions disclosed herein can be delivered parenterally, i.e., administered intravenously (IV), intraventricularly (ICV), subcutaneously (SC), intraperitoneally (IP), intramuscularly (IM), subcutaneously (SD), or intradermally (ID), by direct injection, such as rapid concentration or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as in ampoules or multi-dose containers with added preservatives. The compositions may be in the form of excipients, suspensions, solutions, or emulsions in oil or aqueous carriers, and may contain formulation agents such as anti-settling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0223] The pharmaceutical or pharmaceutical composition disclosed herein can also be formulated for rectal administration, for example as a suppository or retention enema (e.g., containing a conventional suppository base such as cocoa butter or other glycerides).

[0224] The term "treatment" includes suppressing, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0225] The terms “reduction,” “inhibition,” “mitigation,” or “reduction” are used relative to a control. Those 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 the compound is compared to a response in a subject or cell not treated with the compound.

[0226] The term "excipient" is used herein to include any other compound that is not therapeutic or biologically active and may be contained in or on microparticles. Therefore, excipients should be pharmaceutically or biologically acceptable or relevant, for example, excipients that are generally non-toxic to the subject. "Excipient" includes a single such compound and is also intended to include multiple compounds.

[0227] The term "pharmaceutical composition" means a composition comprising the compounds described in this disclosure or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the manner of administration and the nature of the dosage form: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0228] Uses and treatments

[0229] The terms “patient,” “subject,” “individual,” etc., are used interchangeably herein and refer to any animal or its cells, whether in vitro or in situ, that conform to the methods described herein. In some non-limiting embodiments, the patient, subject, or individual is a person.

[0230] The term "biological sample" includes (but is not limited to) cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily 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.

[0231] As used herein, the term “USP21-mediated” refers to any disease, ailment, and / or symptom where USP21 or its mutants are known to be involved. Therefore, another embodiment of this disclosure relates to treating or reducing the severity of one or more diseases where USP21 or its mutants are known to be involved.

[0232] The cancers described in this disclosure include (but are not limited to) leukemias (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphomas (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphoendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor). (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, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver tumor, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, angioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0233] combination therapy

[0234] This disclosure provides combination therapies using compounds as described herein in combination with other therapeutic agents. As used herein, the term "combination therapy" includes the sequential administration of these agents, i.e., each therapeutic agent is administered at different times, and the administration of these agents, or at least two agents, substantially simultaneously. The order, or substantially simultaneous administration, of each agent may be influenced by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous routes, and direct absorption through mucosal tissues. Agents may be administered via the same or different routes. For example, a first agent may be administered orally, while a second agent may be administered intravenously. Furthermore, selected combinations may be administered intravenously, while other agents in the combination may be administered orally. Alternatively, for example, two or more agents may be administered intravenously or subcutaneously.

[0235] Example

[0236] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

[0237] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0238] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0239] Instruments and reagents:

[0240] NMR: Agilent 400MR DD2 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard. LC-MS: Agilent 1260 Infinity II-InfinityLabLC / MSD mass spectrometer. HPLC: Agilent 1260 Infinity II high-performance liquid chromatograph (Sunfire C18 5µm 150x 4.6mm column).

[0241] Thin-layer chromatography silica gel plates: HSGF254 silica gel plates (Yantai Jiangyou Silica Gel Development Co., Ltd.), 0.9mm-1mm. TLC silica gel plates: GF254 silica gel plates (Yucheng Chemical (Shanghai) Co., Ltd.), 0.2mm-0.25mm. Column chromatography: 300-400 mesh silica gel support (Qingdao Hailang Silica Gel Desiccant Co., Ltd.), Flash column (Agilent Fenomex ClaricepFlash amorphous silica gel purification column). Reagents: 4-bromo-3-carboxybenzonitrile, (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid, (2-formyl-4-(trifluoromethyl)phenyl)boronic acid, 5-bromo-2-cyclopropylpyrimidine, and other reagents and starting materials were purchased from Shanghai Bide or Leyan Reagent Co., Ltd., or synthesized using methods known in the art.

[0242] Unless otherwise specified, all reactions in this disclosure are carried out under continuous magnetic stirring, in dry nitrogen or argon atmosphere, in dry solvent, and at temperatures in degrees Celsius.

[0243] The following are the intermediate component numbers:

[0244]

[0245] Intermediate I-1: Synthesis of 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1)

[0246]

[0247] 5-Bromo-2-trifluoromethylpyrimidine (5 g, 22.03 mmol) was dissolved in tetrahydrofuran (50 ml), and triisopropyl borate (7.62 ml, 33.04 mmol) was added. The mixture was purged with nitrogen and cooled in a cold hydrazine solution at -85 °C. Once the temperature reached -78 °C, n-butyllithium (11.5 ml, 28.64 mmol, 2.5 M) was slowly added dropwise below -70 °C. After the addition was complete, the reaction was continued at this temperature for 1 hour. The reaction was quenched with saturated ammonium chloride below 0 °C, and the pH was adjusted to weakly acidic with 1 N hydrochloric acid. Ethyl acetate was added for extraction, and 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 crude product, 2-(trifluoromethyl)pyrimidine-5-ylboronic acid (I-1, 4.92 g), which was used directly in subsequent reactions. ESI [MH] + =191.1

[0248] Examples 1 and 2: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbamate and 7-chloro-5-oxo-5H-indeno[1,2-c]pyridine-3-carbamate

[0249]

[0250] Step 1: Preparation of 5-(4-chloro-2-formylphenyl)pyridine nitrile (1a)

[0251] (4-Chloro-2-formylphenyl)boronic acid (302 mg, 1.64 mmol) was dissolved in methanol (10 mL), and 5-bromochloronitrile (200 mg, 1.09 mmol), potassium fluoride (127 mg, 2.19 mmol), and palladium acetate (12 mg, 0.054 mmol) were added. The mixture was microwaved at 120 °C for 0.5 h. The solvent was evaporated under reduced pressure after filtration to obtain the crude product 5-(4-chloro-2-formylphenyl)pyridinium (1a, 240 mg, yield 90.50%). MS (ESI) [M+H] + 243.0, 245.1.

[0252] Step 2: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbamate (1) and 7-chloro-5-oxo-5H-indeno[1,2-c]pyridine-3-carbamate (2)

[0253] 5-(4-chloro-2-formylphenyl)pyridinium nitrile (1a, 240 mg, 0.99 mmol) was dissolved in 1,2-dichloroethane (10 mL), and tetrabutylammonium iodide (18 mg, 0.049 mmol) and tert-butylhydrogen peroxide (533 mg, 3.96 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 5 hours. Impurities were removed by recrystallization with dichloromethane, and the product was purified by preparative HPLC and lyophilized to obtain two target product compounds: 1: 7-chloro-9-oxo-9H-indeno[2,1-b]pyridin-2-carbamate (3.2 mg, yield 0.88%), MS (ESI) [M+H] + 241.1, 243.0. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 9.32 (s, 1H), 8.24 (s, 1H), 8.06 (d, J = 8, 0 Hz 1H), 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-carbamate (2, 2.1 mg, yield 1.34%). MS (ESI) [M+H] + 241.0, 243.1. 1 H NMR (400MHz, DMSO-d6) δ8.49 (d, J=7.9Hz, 1H), 8.21-8.16 (m, 1H), 8.02 (d, J=8.0Hz, 1H), 7.85-7.71 (m 2H).

[0254] Example 3: Preparation of 7-chloro-9-oxo-9H-fluorene-2,3-dicarboxynitrile

[0255]

[0256] Step 1: Preparation of 4′-chloro-2′-formyl-[1,1′-biphenyl]-3,4-dicarboxynitrile (3a)

[0257] (4-chloro-2-formylphenyl)boronic acid (134 mg, 0.725 mmol) was dissolved in methanol (4 mL), and 4-bromophthalonitrile (100 mg, 0.483 mmol), potassium fluoride (56 mg, 0.966 mmol), and palladium acetate (5 mg, 0.024 mmol) were added. The mixture was then microwaved at 120 °C for 30 minutes. The solvent was evaporated under reduced pressure after filtration to obtain the crude product 4′-chloro-2′-formyl-[1,1′-biphenyl]-3,4-dicarboxynitrile (3a, 240 mg, yield 93.16%).

[0258] Step 2: Preparation of 7-chloro-9-oxo-9H-fluorene-2,3-dicarboxynitrile (3)

[0259] 4′-chloro-2′-formyl-[1,1′-biphenyl]-3,4-dicarboxynitrile (3a, 240 mg, 0.9 mmol) was dissolved in 1,2-dichloroethane (8 mL), and tetrabutylammonium iodide (17 mg, 0.045 mmol) and tert-butylhydrogen peroxide (324 mg, 3.6 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 16 hours. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC and lyophilized to give compound 3: 7-chloro-9-oxo-9H-fluorene-2,3-dicarboxynitrile (1.6 mg, yield 0.67%). 1 H NMR (400MHz, DMSO-d6) δ8.69 (s, 1H), 8.36 (s, 1H), 8.01 (d, J=8.0Hz, 1H), 7.86-7.77 (m, 2H).

[0260] Example 4: Preparation of 7-chloro-2-cyclopropyl-9H-indeno[2,1-d]pyrimidin-9-one

[0261]

[0262] Step 1: Preparation of 5-chloro-2-(2-cyclopropylpyrimidin-5-yl)benzaldehyde (4a)

[0263] (4-Chloro-2-formylphenyl)boronic acid (139 mg, 0.754 mmol) was dissolved in ethanol (4 mL), and 5-bromo-2-cyclopropylpyrimidine (100 mg, 0.502 mmol), potassium carbonate (58 mg, 1 mmol), and palladium acetate (6 mg, 0.025 mmol) were added. The mixture was reacted overnight at 120 °C in a sealed tube. The solvent was evaporated under reduced pressure after filtration to obtain the crude product 5-chloro-2-(2-cyclopropylpyrimidin-5-yl)benzaldehyde (4a, 90 mg, yield 69.25%). MS (ESI) [M+H] + 259.2, 261.1.

[0264] Step 2: Preparation of 7-chloro-2-cyclopropyl-9H-indeno[2,1-d]pyrimidin-9-one (4)

[0265] 5-Chloro-2-(2-cyclopropylpyrimidin-5-yl)benzaldehyde (4a, 90 mg, 0.348 mmol) was dissolved in 1,2-dichloroethane (2 ml), and tetrabutylammonium iodide (6 mg, 0.017 mmol) and tert-butyl hydroperoxide (125 mg, 1.39 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 16 hours. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC and lyophilized to obtain the target product compound 4: 7-chloro-2-cyclopropyl-9H-indenzo[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-d6) δ9.16 (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).

[0266] Example 5: Preparation of tert-butyl (7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-2-yl)carbamate

[0267]

[0268] Step 1: Preparation of tert-butyl (5-(4-chloro-2-formylphenyl)pyrimidin-2-yl)carbamate (5a)

[0269] 4-Chloro-2-aldehyde phenylboronic acid (505 mg, 2.74 mmol) was dissolved in ethanol (20 mL), and 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) were added. The mixture was microwaved at 120 °C for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0270] Step 2: Preparation of tert-butyl (7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-2-yl)carbamate (5)

[0271] 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), and tetrabutylammonium iodide (14 mg, 0.037 mmol) and tert-butylhydrogen peroxide (399 mg, 4.42 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. Recrystallization from dichloromethane / methanol yielded a crude product (120 mg, 49.08% yield). 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) δ8.95 (s, 1H), 7.77-7.63 (m, 3H), 1.56 (d, J=4.3Hz, 9H).

[0272] Example 6: Preparation of 2-amino-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one

[0273]

[0274] Compound 5, obtained in step 2 of Example 5, was added to 4N ethyl acetate (5 ml), and the reaction mixture was stirred at 25°C for 16 hours. The reaction was monitored by LC-MS to confirm completion. The resulting mixture was concentrated under vacuum to give a crude product (45 mg, yield 71.61%). 10 mg of the crude product was purified by preparative-grade HPLC and lyophilized to obtain the target product compound 6: 2-amino-7-chloro-9H-indenzo[2,1-d]pyrimidin-9-one (2 mg, 3.18% yield). MS (ESI) [M+H] + 232.1, 234.1.

[0275] Example 7: Preparation of 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one

[0276]

[0277] Step 1: Preparation of 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (7a)

[0278] 4-Chloro-2-aldehyde phenylboronic acid (767 mg, 4.17 mmol) was dissolved in methanol (15 mL), and 2-chloro-5-iodopyrimidine (500 mg, 2.08 mmol), potassium fluoride (242 mg, 4.17 mmol), and palladium acetate (24 mg, 0.11 mmol) were added. The mixture was microwaved at 120 °C for 50 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0279] Step 2: Preparation of 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7)

[0280] 5-Chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (7a, 183 mg, 0.726 mmol) was dissolved in 1,2-dichloroethane (15 ml), and tetrabutylammonium iodide (14 mg, 0.038 mmol) and tert-butylhydrogen peroxide (420 μl, 4.356 mmol) were added. The mixture was reacted in a sealed tube at 100 °C 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%). A portion of the crude product was recrystallized from methanol to obtain 14.54 mg of pure product. MS (ESI) [M+H] + 251.0, 253.0. 1 H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 8.00 (d, J=8.0Hz, 1H), 7.88-7.79 (m, 2H).

[0281] Examples 8 and 9: Preparation of 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbamate and 7-chloro-4-fluoro-5-oxo-5H-indeno[1,2-c]pyridine-3-carbamate

[0282]

[0283] Step 1: Preparation of 5-(4-chloro-2-formylphenyl)-3-fluoropyridine nitrile (8a)

[0284] 4-Chloro-2-aldehyde phenylboronic acid (688 mg, 3.73 mmol) was dissolved in ethanol (25 mL), and 5-bromo-3-fluoropyridinium nitrile (500 mg, 2.49 mmol), potassium fluoride (290 mg, 4.98 mmol), and palladium acetate (30 mg, 0.125 mmol) were added. The mixture was microwaved at 120 °C for 30 min. The solvent was evaporated under reduced pressure after filtration, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 10%-20%) to obtain the target product 5-(4-chloro-2-formylphenyl)-3-fluoropyridinium nitrile (8a, 450 mg, yield 69.40%). MS (ESI) [M+H] + 261.0, 263.0.

[0285] Step 2: Preparation of 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbamate (8)

[0286] 5-(4-chloro-2-formylphenyl)-3-fluoropyridine nitrile (8a, 400 mg, 1.53 mmol) was dissolved in 1,2-dichloroethane (20 mL), and tetrabutylammonium iodide (28 mg, 0.076 mmol) and tert-butylhydrogen peroxide (830 mg, 9.21 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 16 hours. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC and lyophilized to obtain the target compound 8: 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbamate (5 mg, yield 1.26%) MS (ESI) [M+H + 259.0, 261.0. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.62 (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-carbamate (933 mg, yield 8.31%). MS (ESI) [M+H] + 258.9, 261.0. 1 H NMR (400MHz, DMSO-d6) δ9.18 (d, J=1.6Hz, 1H), 8.11 (d, J=8.0Hz, 1H), 7.90-7.80 (m, 2H).

[0287] Example 10: Preparation of 7-chloro-2-morpholino-9H-indeno[2,1-d]pyrimidin-9-one

[0288]

[0289] 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), and potassium carbonate (25 mg, 0.179 mmol) and morpholine (11 mg, 0.131 mmol) were added. The mixture was reacted at room temperature for 16 hours. An aqueous solution (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (6 mL × 3), and the combined organic layers were washed with brine (6 mL × 2), dried over anhydrous sodium sulfate, and filtered. The organic layers were concentrated under reduced pressure, purified by preparative HPLC, and lyophilized to give the target product compound 10: 7-chloro-2-morpholino-9H-indeno[2,1-d]pyrimidin-9-one (6.9 mg, yield 19.14%). MS (ESI) [M+H] + 302.1, 304.1. 1H NMR (400MHz, CDCl3) δ8.54 (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).

[0290] Example 11: Preparation of 7-chloro-2-(4,4-difluoropiperidin-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one

[0291]

[0292] 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), and potassium carbonate (25 mg, 0.179 mmol) and 4,4-difluoropiperidine (16 mg, 0.131 mmol) were added. The reaction mixture was reacted at room temperature for 16 hours. An aqueous solution (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (6 mL x 3), and the combined organic layers were washed with brine (6 mL x 2), dried over anhydrous sodium sulfate, and filtered. The organic layers were concentrated under reduced pressure, purified by preparative HPLC, and lyophilized to give the target product compound 11: 7-chloro-2-(4,4-difluoropiperidine-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, CDCl3) δ8.57 (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).

[0293] Example 12: Preparation of 7-chloro-2-(1H-imidazol-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one

[0294]

[0295] 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), and cesium carbonate (52 mg, 0.159 mmol), copper iodide (2 mg, 0.008 mmol), and imidazole (8 mg, 0.119 mmol) were added. The mixture was reacted at 50 °C for 16 hours. An aqueous solution (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (6 mL x 3), and the combined organic layers were washed with brine (6 mL x 2), dried over anhydrous sodium sulfate, and filtered. The organic layers were concentrated under reduced pressure, purified by preparative HPLC, and lyophilized to give 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.

[0296] Example 13: Preparation of 7-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0297]

[0298] Step 1: Preparation of 5-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (13a)

[0299] (4-fluoro-2-formylphenyl)boronic acid (222 mg, 1.32 mmol) was dissolved in ethanol (10 mL), and 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) were added. The mixture was microwaved at 120 °C for 30 minutes. The solvent was evaporated under reduced pressure after filtration to obtain the crude product 5-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (300 mg). MS (ESI) [M+H] + 271.2, 272.2.

[0300] Step 2: Preparation of 7-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (13)

[0301] 5-Fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (13a, 300 mg, 1.11 mmol) was dissolved in 1,2-dichloroethane (20 mL), and tetrabutylammonium iodide (20 mg, 0.056 mmol) and tert-butyl hydroperoxide (600 mg, 6.66 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 16 hours. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC and lyophilized 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-d6) δ9.57 (s, 1H), 8.13 (dd, J=8.2, 4.5Hz, 1H), 7.69 (q, J=8.7, 7.9Hz, 2H).

[0302] Example 14: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbamate

[0303]

[0304] Step 1: Preparation of 5-(4-chloro-2-formylphenyl)pyrimidine-2-carbamate (14a)

[0305] 4-Chloro-2-aldehyde phenylboronic acid (302 mg, 1.64 mmol) was dissolved in methanol (10 mL), and 5-bromo-2-cyanopyrimidine (200 mg, 1.09 mmol), potassium fluoride (127 mg, 2.19 mmol), and palladium acetate (13 mg, 0.058 mmol) were added. The mixture was microwaved at 120 °C for 0.5 h. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane) to give the target product 5-(4-chloro-2-formylphenyl)pyrimidine-2-carbamate (14a, 93 mg, yield 35.1%). MS (ESI) [M+H] + 244.0, 246.0.

[0306] Step 2: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbamate (14)

[0307] 5-(4-chloro-2-formylphenyl)pyrimidin-2-carbamate (14a, 40 mg, 0.16 mmol) was dissolved in 1,2-dichloroethane (3 mL), and tetrabutylammonium iodide (3 mg, 0.008 mmol) and tert-butyl hydroperoxide (95 μl, 0.96 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 5 hours. Impurities were removed by recrystallization from dichloromethane, and the filtrate was recrystallized from dichloromethane / methanol to give the target product compound 14: 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-2-carbamate (7.17 mg, yield 18.1%). MS (ESI) [M+H] + 242.0, 244.0. 1 H NMR (400MHz, DMSO-d6) δ9.58 (s, 1H), 8.11 (d, J=8.1Hz, 1H), 7.95-7.87 (m, 2H).

[0308] Example 15: Preparation of 7-chloro-2-(4-methylpiperazin-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one

[0309]

[0310] 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), and potassium carbonate (8 mg, 0.059 mmol) and 1-methylpiperazine (4 mg, 0.044 mmol) were added. The mixture was reacted at room temperature for 4 hours. An aqueous solution (5 ml) was added to the reaction mixture. The mixture was extracted with ethyl acetate (3 ml x 3), and the combined organic layers were washed with brine (3 ml x 2), dried over anhydrous sodium sulfate, and filtered. The organic layers were concentrated under reduced pressure, purified by preparative HPLC, and lyophilized to give the target product, 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).

[0311] Example 16: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2,3-dicarboxynitrile

[0312]

[0313] Step 1: Preparation of 2-chloro-5-(4-chloro-2-formylphenyl)nicotinonitrile (16a)

[0314] 4-Chloro-2-aldehyde phenylboronic acid (388 mg, 2.11 mmol) was dissolved in tetrahydrofuran / water (12 ml / 3 ml), and 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. The mixture was reacted overnight at 90 °C in a sealed tube. Insoluble matter was removed by filtration, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 15%-20%) to give 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.

[0315] Step 2: Preparation of 5-(4-chloro-2-formylphenyl)pyridine-2,3-dicarboxynitrile (16b)

[0316] 2-Chloro-5-(4-chloro-2-formylphenyl)nicotinonitrile (16a, 128 mg, 0.464 mmol) was dissolved in N-methylpyrrolidone (5 mL), and zinc cyanide (33 mg, 0.281 mmol) and tetrakis(triphenylphosphine)palladium (54 mg, 0.047 mmol) were added. The mixture was microwaved at 150 °C for 30 min. Insoluble matter was removed by filtration, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 20%-40%) to obtain the target product 5-(4-chloro-2-formylphenyl)pyridine-2,3-dicarboxynitrile (16b, 44 mg, yield 35.5%). MS (ESI) [M+H] + 268.1, 270.1.

[0317] Step 3: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2,3-dicarboxylonitrile (16)

[0318] 5-(4-chloro-2-formylphenyl)pyridine-2,3-dicarboxynitrile (16b, 44 mg, 0.165 mmol) was dissolved in 1,2-dichloroethane (3 mL), and tert-butyl hydroperoxide (127 μl, 1.32 mmol) was added. The mixture was reacted overnight at 100 °C in a sealed tube. Recrystallization from (dichloromethane / methanol) yielded the target product compound 16: 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2,3-dicarboxynitrile (4.18 mg, yield 9.7%). MS (ESI) [M+H] + 266.0, 268.1. 1H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 9.11 (s, 1H), 8.05 (d, J=7.7Hz, 2H).

[0319] Example 17: Preparation of 7-chloro-9-oxo-9H-fluorene-2-carbamate

[0320]

[0321] Step 1: Preparation of 4′-chloro-2′-formyl-[1,1′-biphenyl]-4-carbamate (17a)

[0322] 4-Chloro-2-aldehydephenylboronic acid (209 mg, 1.14 mmol) was dissolved in methanol (10 mL), and 4-iodocyanobenzene (200 mg, 0.873 mmol), potassium fluoride (101 mg, 1.74 mmol), and palladium acetate (10 mg, 0.045 mmol) were added. The mixture was microwaved at 120 °C for 40 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 10%-20%) to give the target product 4′-chloro-2′-formyl-[1,1′-biphenyl]-4-carbamate (17a, 162 mg, yield 61.6%). MS (ESI) [M+H] + 242.1, 244.1.

[0323] Step 2: Preparation of 7-chloro-9-oxo-9H-fluorene-2-carbamate (17)

[0324] 4′-chloro-2′-formyl-[1,1′-biphenyl]-4-carbamate (30 mg, 0.124 mmol) was dissolved in 1,2-dichloroethane (3 mL), and tert-butyl hydroperoxide (48 μl, 0.496 mmol) was added. The mixture was reacted overnight at 100 °C in a sealed tube. Recrystallization from (dichloromethane / methanol) yielded the target product compound 17: 7-chloro-9-oxo-9H-fluorene-2-carbamate (7.33 mg, yield 24.6%). 1 HNMR (400MHz, DMSO-d6) δ8.14 (d, J=8.6Hz, 1H), 8.06 (dJ=8.2Hz, 2H), 7.99 (d, J=8.0Hz, 1H), 7.77 (d, J=8.0Hz, 1H), 7.71 (s, 1H).

[0325] Example 18: Preparation of 7-chloro-2-methoxy-9H-indeno[2,1-d]pyrimidin-9-one

[0326]

[0327] 2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7.4 mg, 0.016 mmol) was dissolved in methanol / tetrahydrofuran (1 mM / 1 mL), and potassium carbonate (4 mg, 0.024 mmol) was added. The reaction was carried out at room temperature for 3 hours. Insoluble matter was removed by filtration, and the residue was purified semi-preparatively 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.

[0328] Example 19: Preparation of 7-chloro-2-(dimethylamino)-9H-indeno[2,1-d]pyrimidin-9-one

[0329]

[0330] Step 1: Preparation of 5-chloro-2-(2-(dimethylamino)pyrimidin-5-yl)benzaldehyde (19a)

[0331] 4-Chloro-2-aldehyde phenylboronic 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. The mixture was microwaved at 120 °C for 40 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane:methanol = 0%-10%) to obtain the target product 5-chloro-2-(2-(dimethylamino)pyrimidine-5-yl)benzaldehyde (19a, 20 mg, yield 15.5%). MS (ESI) [M+H] + 262.1, 264.2.

[0332] Step 2: Preparation of 7-chloro-2-(dimethylamino)-9H-indeno[2,1-d]pyrimidin-9-one (19)

[0333] 5-Chloro-2-(2-(dimethylamino)pyrimidin-5-yl)benzaldehyde (19a, 20 mg, 0.077 mmol) was dissolved in 1,2-dichloroethane (2 mL), and tetrabutylammonium iodide (2 mg, 0.0054 mmol) and tert-butyl hydroperoxide (44 μl, 0.462 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 5 hours. Recrystallization from (dichloromethane / methanol) yielded the target product compound 19: 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. 1H NMR (400MHz, DMSO-d6) δ8.88 (s, 1H), 7.67 (s, 2H), 7.59 (s, 1H), 3.20 (s, 6H).

[0334] Example 20: Preparation of 7-chloro-2-methyl-9H-indeno[2,1-d]pyrimidin-9-one

[0335]

[0336] Step 1: Preparation of 5-chloro-2-(2-methylpyrimidin-5-yl)benzaldehyde (20a)

[0337] 4-Chloro-2-aldehyde phenylboronic acid (138 mg, 0.75 mmol) was dissolved in ethanol (5 mL), and 2-methyl-5-bromopyrimidine (100 mg, 0.578 mmol), potassium fluoride (67 mg, 1.16 mmol), and palladium acetate (7 mg, 0.031 mmol) were added. The mixture was microwaved at 120 °C for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0338] Step 2: Preparation of 7-chloro-2-methyl-9H-indeno[2,1-d]pyrimidin-9-one (20)

[0339] 5-Chloro-2-(2-methylpyrimidin-5-yl)benzaldehyde (20a, 50 mg, 0.216 mmol) was dissolved in 1,2-dichloroethane (3 mL), and tetrabutylammonium iodide (4 mg, 0.011 mmol) and tert-butyl hydroperoxide (83 μl, 0.864 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. Recrystallization from (dichloromethane / methanol) yielded the target product compound 20: 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-d6) 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).

[0340] Example 21: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0341]

[0342] Step 1: Preparation of 5-chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (21a)

[0343] 4-Chloro-2-aldehyde phenylboronic 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. The mixture was microwaved at 120 °C for 40 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0344] Step 2: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (21)

[0345] 5-Chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (21a, 50 mg, 0.175 mmol) was dissolved in 1,2-dichloroethane (3 mL), and tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (67 μl, 0.7 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. Recrystallization from (dichloromethane / methanol) yielded the target product compound 21: 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.

[0346] Example 22: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carboxamide

[0347]

[0348] 7-Chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbamate (14, 15 mg, 0.062 mmol) was dissolved in isopropanol / water (1 ml / 1 ml), and manganese dioxide (54 mg, 0.62 mmol) was added. The mixture was reacted in a sealed tube at 100 °C for 10 minutes. After filtration, the filtrate was partially purified 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.

[0349] Examples 23 and 24: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one o-ethyl oxime

[0350]

[0351] 7-Chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (21, 31 mg, 0.109 mmol) was dissolved in pyridine (6 mL), and ethoxyamine hydrochloride (32 mg, 0.328 mmol) and 5A molecular sieve were added. The mixture was reacted overnight at room temperature. After filtration, the filtrate was evaporated to dryness under reduced pressure and purified by a plate (tetrahydrofuran:petroleum ether = 1:10) to obtain the target product, one of 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 ¹H NMR (400 MHz, DMSO-d⁶) δ 9.54 (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 compound arbitrarily designated is 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-d6) δ9.63 (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, 6.9Hz, 2H), 1.43 (d, J=6.6Hz, 3H).

[0352] Example 25: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-9-one oxime

[0353]

[0354] 7-Chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (21, 40 mg, 0.141 mmol) was dissolved in pyridine (3 mL), and ethoxyamine hydrochloride (29 mg, 0.417 mmol) and 5A molecular sieve were added. The reaction was carried out at room temperature for 6 hours. After filtration, the filtrate was evaporated to dryness under reduced pressure and 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) δ9.57 (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).

[0355] Example 26: Preparation of 2,7-dichloro-4-methyl-9H-indeno[2,1-d]pyrimidin-9-one

[0356]

[0357] Step 1: Preparation of 5-chloro-2-(2-chloro-4-methylpyrimidin-5-yl)benzaldehyde (26a)

[0358] 4-Chloro-2-aldehyde phenylboronic acid (320 mg, 1.74 mmol) was dissolved in ethanol (20 mL), and 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) were added. The mixture was microwaved at 120 °C for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 5%-20%) to obtain the target product 5-chloro-2-(2-chloro-4-methylpyrimidine-5-yl)benzaldehyde (26a, 45 mg, yield 10.0%). MS (ESI) [M+H] + 267.0, 268.9.

[0359] Step 2: Preparation of 2,7-dichloro-4-methyl-9H-indeno[2,1-d]pyrimidin-9-one (26)

[0360] 5-Chloro-2-(2-chloro-4-methylpyrimidin-5-yl)benzaldehyde (26a, 45 mg, 0.169 mmol) was dissolved in 1,2-dichloroethane (4 ml), and tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (97 μl, 1.015 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. After evaporation under reduced pressure, the reaction solution was purified by a plate (tetrahydrofuran:petroleum ether = 1:5) to obtain the target product compound 26a: 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.

[0361] Example 27: Preparation of 7-chloro-2-fluoro-9H-indeno[2,1-d]pyrimidin-9-one

[0362]

[0363] Step 1: Preparation of 5-chloro-2-(2-fluoropyrimidin-5-yl)benzaldehyde (27a)

[0364] 4-Chloro-2-aldehyde phenylboronic acid (375 mg, 2.04 mmol) was dissolved in sec-butanol (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. The mixture was microwaved at 120 °C for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0365] Step 2: Preparation of 7-chloro-2-fluoro-9H-indeno[2,1-d]pyrimidin-9-one (27)

[0366] 5-Chloro-2-(2-fluoropyrimidin-5-yl)benzaldehyde (27a, 30 mg, 0.127 mmol) was dissolved in 1,2-dichloroethane (3 ml), and tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (73 μl, 0.763 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. After evaporation under reduced pressure, the reaction solution was purified by a 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.

[0367] Example 28: Preparation of 2,7-bis(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0368]

[0369] Step 1: Preparation of 5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (28a)

[0370] 4-Trifluoromethyl-2-aldehyde phenylboronic acid (150 mg, 0.688 mmol) was dissolved in ethanol (9 mL), and 5-bromo-2-trifluoromethylpyrimidine (141 mg, 0.621 mmol), potassium fluoride (72 mg, 1.24 mmol), and palladium acetate (9 mg, 0.04 mmol) were added. The mixture was microwaved at 120 °C for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0371] Step 2: Preparation of 2,7-bis(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (28)

[0372] 5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (28a, 35 mg, 0.109 mmol) was dissolved in 1,2-dichloroethane (2 ml), and tetrabutylammonium iodide (2 mg, 0.0055 mmol) and tert-butyl hydroperoxide (63 μl, 0.654 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. After evaporation under reduced pressure, the reaction solution was purified by stencil preparation (tetrahydrofuran:petroleum ether = 1:5) to obtain the target product compound 28a: 2,7-di(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (3.56 mg, yield 10.2%). MS (ESI) [M+H] + 319.0.

[0373] Example 29: Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbamate

[0374]

[0375] Step 1: Preparation of 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (29a)

[0376] 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (100 mg, 0.521 mmol) was dissolved in acetonitrile (10 mL), and 4-bromo-3-carboxybenzonitrile (109 mg, 0.521 mmol), potassium fluoride (61 mg, 1.05 mmol), and palladium acetate (6 mg, 0.027 mmol) were added. The mixture was microwaved at 120 °C for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0377] Step 2: Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbamate (29)

[0378] 3-Formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (35 mg, 0.126 mmol) was dissolved in 1,2-dichloroethane (2 ml), and tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (97 μl, 1.01 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. After evaporation under reduced pressure, the reaction solution was purified by a plate (tetrahydrofuran:petroleum ether = 1:2) to obtain the target product compound 29: 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-carbamate (14.42 mg, yield 41.6%). MS (ESI) [M+H] + 276.1. 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 8.37-8.26 (m, 3H).

[0379] Example 30: Preparation of 7-chloro-9-oxo-9H-fluorene-3-carbamate

[0380]

[0381] Step 1: Preparation of 4′-chloro-6-formyl-[1,1′-biphenyl]-3-carbamate (30a)

[0382] (4-Chlorophenyl)boronic acid (112.3 mg, 0.714 mmol) was dissolved in methanol (3 mL), and 3-bromo-4-carboxybenzonitrile (100 mg, 0.114 mmol), palladium acetate (5.4 mg, 0.0057 mmol), and potassium fluoride (55.6 mg, 0.228 mmol) were added. The mixture was reacted with microwave at 120 °C for 40 min under nitrogen protection. The crude product was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate:petroleum ether = 1 / 5) to give the target product 4′-chloro-6-carboxylic acid-[1,1′-biphenyl]-3-carbatrionitrile (30a, 94 mg, yield 81.5%). MS (ESI) [M+H] + 242.3.

[0383] Step 2: Preparation of 7-chloro-9-oxo-9H-fluorene-3-carbamate (30)

[0384] 4′-chloro-6-formyl-[1,1′-biphenyl]-3-carbamate (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 mixture was reacted under sealed conditions 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-carbamate (2.9 mg, yield 9.8%). MS (ESI) [M+H] + 240.1. 1 H NMR (400MHz, DMSO-d6) 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).

[0385] Example 31: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carboxamide

[0386]

[0387] 7-Chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbamate (14, 20 mg, 0.083 mmol) was dissolved in methanol (0.3 mL), and sodium methoxide (22.4 mg, 0.415 mmol) was added. 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, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by high-performance liquid chromatography (HPLC) (water:methanol = 1 / 10) to obtain the target product compound 31: 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-formamidin (1.37 mg, yield 6.4%). MS (ESI) [M+H] + 259.3. 1 H NMR (400MHz, DMSO-d6) δ9.73 (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).

[0388] Example 32: Preparation of 7-chloro-2-(1H-pyrazol-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one

[0389]

[0390] 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), and cesium carbonate (52 mg, 0.159 mmol), copper iodide (2 mg, 0.008 mmol), and pyrazole (8 mg, 0.119 mmol) were added. The mixture was reacted at 50 °C for 16 hours. An aqueous solution (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (6 mL x 3), and the combined organic layers were washed with brine (6 mL x 2), dried over anhydrous sodium sulfate, and filtered. The organic layers were concentrated under reduced pressure, purified by preparative HPLC, and lyophilized to give 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.

[0391] Example 33: Preparation of 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0392]

[0393] Step 1: Preparation of 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (33a)

[0394] (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (145 mg, 0.754 mmol) was dissolved in acetonitrile (5 mL), and 2-bromo-5-methylbenzaldehyde (100 mg, 0.502 mmol), potassium fluoride (58 mg, 1.004 mmol), and palladium acetate (6 mg, 0.025 mmol) were added. The mixture was microwaved at 120 °C for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0395] Step 2: Preparation of 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (33)

[0396] 5-Methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (33a, 90 mg, 0.338 mmol) was dissolved in 1,2-dichloroethane (5 ml), and tetrabutylammonium iodide (6 mg, 0.017 mmol) and tert-butyl hydroperoxide (244 mg, 2.7 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. After evaporation under reduced pressure, the reaction solution was purified by plate preparation (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) δ9.09 (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).

[0397] Example 34: 2-Acetyl-7-chloro-9H-indeno[2,1-d]pyrimidine - Preparation of 9-one

[0398]

[0399] Step 1: Preparation of 2-(2-acetylpyrimidin-5-yl)-5-fluorobenzaldehyde (34a)

[0400] (4-Chloro-2-formylphenyl)boronic acid (182 mg, 0.995 mmol) was dissolved in acetonitrile (5 mL), and 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) were added. The tube was sealed and reacted overnight at 120 °C. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 0%-50%) to give the target product 2-(2-acetylpyrimidin-5-yl)-5-chlorobenzaldehyde (34a, 110 mg, yield 42.41%). MS (ESI) [M+H] + 261.0, 263.0.

[0401] Step 2: Preparation of 2-acetyl-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one (34)

[0402] 2-(2-acetylpyrimidin-5-yl)-5-chlorobenzaldehyde (34a, 110 mg, 0.422 mmol) was dissolved in 1,2-dichloroethane (10 mL), and tetrabutylammonium iodide (8 mg, 0.021 mmol) and tert-butyl hydroperoxide (434 mg, 3.38 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was evaporated to dryness under reduced pressure and then purified by preparative HPLC and lyophilized 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 HNMR (400MHz, Chloroform-d) δ9.22 (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).

[0403] Example 35: Preparation of 2,7-dichloro-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0404]

[0405] Step 1: Preparation of 5-chloro-2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (35a)

[0406] 4-Chloro-2-aldehyde phenylboronic 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. The mixture was microwaved at 120 °C for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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

[0407] Step 2: Preparation of 2,7-dichloro-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (35)

[0408] 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), and tetrabutylammonium iodide (1 mg, 0.0027 mmol) and tert-butyl hydroperoxide (46 μl, 0.472 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. After evaporation under reduced pressure, the reaction solution was purified by plate preparation (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-d6) δ8.00 (d, J=2.0Hz, 1H), 7.93 (dd, J=8.3, 2.0Hz, 1H), 7.86-7.81 (m, 1H).

[0409] Example 36: Preparation of 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one

[0410]

[0411] 2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7.20 mg, 0.08 mmol) was dissolved in formic acid (2 mL), and potassium thiocyanate (10 mg, 0.096 mmol) was added. The mixture was reacted at 80 °C for 3 hours. The reaction solution was evaporated to dryness under reduced pressure and purified by liquid chromatography. Recrystallization (methanol / water) yielded 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 (400MHz, DMSO-d6) δ12.12 (s, 1H), 8.51 (s, 1H), 7.77 (d, J=1.0Hz, 2H), 7.70 (s, 1H).

[0412] Example 37: Preparation of 7-chloro-2-thiocyanate-9H-indeno[2,1-d]pyrimidin-9-one

[0413]

[0414] 2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7.32 mg, 0.128 mmol) was dissolved in formic acid (3 mL), and potassium thiocyanate (15 mg, 0.154 mmol) was added. The mixture was reacted overnight at 40 °C. The reaction solution was evaporated to dryness under reduced pressure and then purified by liquid chromatography 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 (400MHz, DMSO-d6) δ9.40 (s, 1H), 8.00 (d, J=7.9Hz, 1H), 7.91-7.79 (m, 2H).

[0415] Example 38: Preparation of 7-chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0416]

[0417] Step 1: Preparation of 2-bromo-5-chloro-4-fluorobenzaldehyde (38a)

[0418] 3-Chloro-4-fluorobenzaldehyde (500 mg, 3.15 mmol) was dissolved in 1,2-dichloroethane and trifluoroacetic acid (20 mL, 5 mL). N-bromosuccinimide (673 mg, 3.78 mmol), 2-amino-5-chlorotrifluorotoluene (90 μl, 0.63 mmol), and palladium acetate (71 mg, 0.315 mmol) were added. The mixture was purged with nitrogen and reacted overnight at 60 °C. Insoluble matter in the reaction solution was filtered off, and the filtrate was evaporated to dryness under reduced pressure and purified by Flash column chromatography to obtain the target product, 2-bromo-5-chloro-4-fluorobenzaldehyde (38a, 509 mg, yield 68.4%).

[0419] Step 2: Preparation of 5-chloro-4-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (38b)

[0420] 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (38a, 141 mg, 0.734 mmol) was dissolved in acetonitrile (13 mL), and 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. The mixture was microwaved at 120 °C for 60 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0421] Step 3: Preparation of 7-chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (38)

[0422] 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), and tetrabutylammonium iodide (2 mg, 0.0054 mmol) and tert-butyl hydroperoxide (84 μl, 0.864 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. After evaporation under reduced pressure, the reaction solution was purified by a 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. 1H NMR (400MHz, DMSO-d6) δ9.58 (s, 1H), 8.25 (d, J=8.8Hz, 1H), 8.14 (d, J=6.9Hz, 1H).

[0423] Example 39: Preparation of 7-chloro-4-hydroxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0424]

[0425] Step 1: Preparation of 5-bromo-2-(trifluoromethyl)pyrimidin-4-ol (39a)

[0426] 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 conditions. The reaction mixture was then placed at 80 °C for 1.5 h. After TLC, the solution was adjusted to neutral with saturated sodium bicarbonate solution, and 10 ml of aqueous solution was added to the reaction mixture. The mixture was extracted with ethyl acetate (6 ml × 3), and the combined organic layers were washed with brine (6 ml × 2). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain the crude product 5-bromo-2-(trifluoromethyl)pyrimidin-4-ol (39a, 60 mg, yield 81.04%).

[0427] Step 2: Preparation of 5-chloro-2-(4-hydroxy-2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (39b)

[0428] (4-Chloro-2-formylphenyl)boronic acid (68 mg, 0.37 mmol) was dissolved in acetonitrile (4 mL), and 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) were added. The mixture was microwaved at 120 °C for 60 min. The solvent was evaporated under reduced pressure, and the residue was purified by agar plate preparation (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.

[0429] Step 3: Preparation of 7-chloro-4-hydroxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (39)

[0430] 5-Chloro-2-(4-hydroxy-2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (10 mg, 0.033 mmol) was dissolved in 1,2-dichloroethane (1 ml), and tetrabutylammonium iodide (1 mg, 0.0016 mmol) and tert-butyl hydroperoxide (24 mg, 0.264 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was evaporated to dryness under reduced pressure and then purified by preparative HPLC and lyophilized 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.

[0431] Example 40: Preparation of 7-chloro-n-cyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidine-9-imine

[0432]

[0433] Step 1: Preparation of 5-chloro-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (40a)

[0434] 5-Bromo-2-trifluoromethylpyrimidine (2 g, 8.85 mmol) was dissolved in ethanol (40 mL), and 4-chloro-2-aldehydephenylboronic acid (2.12 g, 11.51 mmol), potassium fluoride (1.028 g, 17.7 mmol), and palladium acetate (99.36 mg, 0.44 mmol) were added. The mixture was reacted in an oil bath at 120 °C for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 0%-40%) to give the target product 5-chloro-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (40a, 1.3740 g, yield 54.27%). MS (ESI) [M+H] + 287.0.

[0435] Step 2: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (40b)

[0436] 5-Chloro-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (40a, 700 mg, 2.45 mmol) was dissolved in 1,2-dichloroethane (25 mL), and tetrabutylammonium iodide (45.19 mg, 0.12 mmol) and tert-butyl hydroperoxide (1.80 g, 19.97 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 30 hours under nitrogen protection. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate: petroleum ether = 0%-40%) to give 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.

[0437] Step 3: Preparation of 7-chlorocyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidine-9-imine (40)

[0438] 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), and cyclopropylamine (8.04 mg, 0.14 mmol) and molecular sieves were added. The mixture was microwaved at 150 °C for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was purified by HPLC (ethyl acetate:petroleum ether = 1:2) to obtain the target product 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one. Finally, a second HPLC purification was performed 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-d6) δ1.27-1.22(m, 3H), 1.51-1.47(m, 2H), 7.74-7.67(m, 2H), 8.09-8.14(m, 1H), 9.68(s, 1H).

[0439] Example 41: Preparation of 7-chloro-2-methanesulfonyl-9H-indeno[2,1-d]pyrimidin-9-one

[0440]

[0441] Step 1: Preparation of 5-chloro-2-(2-methanesulfonyl)pyrimidin-5-yl)benzaldehyde (41a)

[0442] 5-Bromo-2-(methanesulfonyl)pyrimidine (200 mg, 0.8 mmol) was dissolved in acetonitrile (20 mL), and 4-chloro-2-aldehydephenylboronic acid (160 mg, 0.8 mmol), potassium fluoride (100 mg, 1.6 mmol), and palladium acetate (6 mg, 0.04 mmol) were added. The mixture was microwaved at 120 °C for 50 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 0%-40%) to obtain the target product 5-chloro-2-(2-methanesulfonyl)pyrimidin-5-yl)benzaldehyde (41a, 65.4 mg, yield 26.19%). MS (ESI) [M+H] + 297.0.

[0443] Step 2: Preparation of 7-chloro-2-methanesulfonyl-9H-indeno[2,1-d]pyrimidin-9-one (41)

[0444] 5-Chloro-2-(2-methanesulfonyl)pyrimidin-5-yl)benzaldehyde (41a, 40 mg, 0.14 mmol) was dissolved in 1,2-dichloroethane (10 mL), and tetrabutylammonium iodide (2.50 mg, 0.007 mmol) and tert-butylhydrogen peroxide (97.43 mg, 1.08 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 16 hours under nitrogen protection. The solvent was evaporated under reduced pressure, and the crude product was purified by a 1:1 petroleum ether preparation plate to obtain the target product compound 41: 7-chloro-2-methanesulfonyl-9H-indeno[2,1-d]pyrimidin-9-one (0.62 mg, yield 1.56%). MS (ESI) [M+H] + 295.0.

[0445] Example 42: Preparation of 7-methoxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0446]

[0447] Step 1: Preparation of 5-methoxy-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (42a)

[0448] 4-Methoxy-2-formylphenylboronic acid (200 mg, 1.11 mmol) was dissolved in acetonitrile (15 mL), and 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. The mixture was microwaved at 120 °C for 50 min. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (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.

[0449] Step 2: Preparation of 7-methoxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (42)

[0450] 5-Methoxy-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (42a, 50 mg, 0.18 mmol) was dissolved in 1,2-dichloroethane (10 mL), and tetrabutylammonium iodide (3.27 mg, 0.009 mmol) and tert-butyl hydroperoxide (127.80 mg, 1.42 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 16 hours under nitrogen protection. The solvent was evaporated under reduced pressure, and the crude product was purified by ELISA (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-d6) δ9.43 (s, 1H), 7.98-7.95 (m, 1H), 7.37-7.32 (m, 2H), 3.89 (s, 3H).

[0451] Example 43: Preparation of 7-(trifluoromethyl)-9H-[1,3]dioxane[4′,5′:5,6]indeno[2,1-d]pyrimidin-9-one

[0452]

[0453] Step 1: Preparation of 7-(trifluoromethyl)-9H-[1,3]dioxane[4′,5′:5,6]indeno[2,1-d]pyrimidin-9-one 6-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxane-5-carbon aldehyde (43a)

[0454] 5-Bromo-2-(trifluoromethyl)pyrimidine (50 mg, 0.2203 mmol) was dissolved in acetonitrile (3 mL), and (6-formylbenzo[d][1,3]dioxol-5-yl)boronic acid (51.2 mg, 0.2644 mmol), palladium acetate (2.5 mg, 0.0110 mmol), and potassium fluoride (25.6 mg, 0.4406 mmol) were added. The mixture was reacted in a microwave oven at 120 °C for 30 minutes under nitrogen protection. The crude product was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate:petroleum ether = 1 / 5) to obtain the target product 6-(2-(trifluoromethyl)pyrimidine-5-yl)benzo[d][1,3]m-dioxane-5-carbonal (43a, 30 mg, yield 46%). MS (ESI) [M+H] + 297.3.

[0455] Step 2: Preparation of 7-(trifluoromethyl)-9H-[1,3]dioxane[4′,5′:5,6]indeno[2,1-d]pyrimidin-9-one (43)

[0456] 6-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]di-m-dioxane-5-carbonal (43a, 30 mg, 0.1013 mmol) was dissolved in dichloroethane (2 ml), and 2-hydroperoxy-2-methylpropane (73 mg, 0.8102 mmol) was added. The mixture was reacted under sealed conditions at 100 °C for 16 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 43: 7-(trifluoromethyl)-9H-[1,3]dioxane[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-d6) δ9.31 (s, 1H), 7.68 (s, 1H), 7.37 (s, 1H), 6.28 (s, 2H).

[0457] Example 44: Preparation of 7-chloro-2-(pyridin-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one

[0458]

[0459] Step 1: Preparation of 5-bromo-2-(pyridin-2-yl)pyrimidine (44a)

[0460] 5-Bromo-2-iodopyrimidine (300 mg, 0.8109 mmol) was dissolved in toluene (3 mL), and 2-tri-n-butyltinylpyridine (231 mg, 0.8109 mmol), triphenylphosphine (28.5 mg, 0.0811 mmol), and bis(triphenylphosphine)palladium(II) dichloride (21.3 mg, 0.0405 mmol) were added. The mixture was reacted overnight at 120 °C under nitrogen protection. The crude product was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane:methanol = 1 / 20) to give the target product 5-bromo-2-(pyridin-2-yl)pyrimidine (44a, 110 mg, yield 37.6%). MS (ESI) [M+H] + 236.1.

[0461] Step 2: Preparation of 5-chloro-2-(2-(pyridin-2-yl)pyrimidin-5-yl)benzaldehyde (44b)

[0462] (4-Chloro-2-formylphenyl)boronic acid (86.3 mg, 0.466 mmol) was dissolved in acetonitrile (3 mL), and 5-bromo-2-(pyridin-2-yl)pyrimidine (110 mg, 0.466 mmol), palladium acetate (5.3 mg, 0.0233 mmol), and potassium fluoride (54.4 mg, 0.932 mmol) were added. The mixture was reacted in a microwave oven at 120 °C for 30 minutes under nitrogen protection. The crude product was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane:methanol = 1 / 15) to give 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.

[0463] Step 3: Preparation of 7-chloro-2-(pyridin-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one (44)

[0464] 5-Chloro-2-(2-(pyridin-2-yl)pyrimidin-5-yl)benzaldehyde (44b, 13 mg, 0.0439 mmol) was dissolved in dichloroethane (2 ml), and 2-hydroperoxy-2-methylpropane (31.7 mg, 0.3512 mmol) was added. The mixture was reacted at 100 °C under sealed conditions for 16 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 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. 1H NMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 8.77 (d, J = 4.8Hz, 1H), 8.42 (d, J = 8.0Hz, 1H), 8.07-8.0 2 (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).

[0465] Example 45: Synthesis of 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one

[0466]

[0467] Step 1: Synthesis of 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (45-a)

[0468] (4-chloro-2-formylphenyl)boronic acid (3.45 g, 18.72 mmol), 2-chloro-5-iodopyrimidine (3 g, 12.48 mmol), potassium fluoride (1.44 g, 24.96 mmol), and palladium acetate (141 mg, 0.624 mmol) were placed in a microwave-safe reaction tube, ethanol (80 ml) was added, the tube was purged with nitrogen, sealed, and reacted overnight at 120 °C. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 0%–20%) to obtain the target product 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (45-a, 2 g, yield 63.33%). ESI [M+H] + =253.0, 255.0

[0469] Step 2: Synthesis of 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (45-b)

[0470] 5-Chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (45-a, 1 g, 3.95 mmol) was dissolved in 1,2-dichloroethane (20 ml), and tetrabutylammonium iodide (70 mg, 0.198 mmol) and tert-butylhydrogen peroxide (2.85 g, 31.6 mmol) were added. The reaction mixture was reacted overnight at 100 °C in a sealed tube under nitrogen protection. After filtration and concentration under reduced pressure, the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 0%–20%) to give 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

[0471] Step 3: Synthesis of 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (45)

[0472] 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), and potassium thiocyanate (10 mg, 0.103 mmol) was added. The reaction mixture was reacted at 80 °C for 3 hours. The reaction solution was concentrated under reduced pressure and then directly purified to obtain the byproduct 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (45, 2.05 mg, yield 11.0%). ESI[M+H] + =233.0, 235.0 1 H NMR (400MHz, DMSO-d6) δ12.12 (s, 1H), 8.51 (s, 1H), 7.77 (d, J=1.0Hz, 2H), 7.70 (s, 1H).

[0473] Example 46: Synthesis of 7-chloro-2-(trifluoromethyl)-9H-pyrido[3′,2′:3,4]cyclopentane[1,2-d]pyrimidin-9-one

[0474]

[0475] Step 1: Synthesis of 3-bromo-6-chloropyridinecarboxaldehyde (46-a)

[0476] (3-Bromo-6-chloropyridin-2-yl)methanol (450 mg, 2.02 mmol) was dissolved in dioxane (20 mL), and manganese dioxide (1.76 g, 20.23 mmol) was added. The mixture was reacted at 100 °C for 8 hours. The manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product 3-bromo-6-chloropyridinaldehyde (46-a, 425 mg, yield 95.9%). (ESI [M+H]) + =219.8, 221.8

[0477] Step 2: Synthesis of 6-chloro-3-(2-(trifluoromethyl)pyrimidin-5-yl)pyridinecarboxaldehyde (46-b)

[0478] 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-safe reaction tube, acetonitrile (15 ml) was added, the tube was purged with nitrogen, sealed, and microwaved 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 chromatography (ethyl acetate:petroleum ether = 0%–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

[0479] Step 3: Synthesis of 7-chloro-2-(trifluoromethyl)-9H-pyrido[3′,2′:3,4]cyclopentane[1,2-d]pyrimidin-9-one (46)

[0480] 6-Chloro-3-(2-(trifluoromethyl)pyrimidin-5-yl)pyridinecarboxaldehyde (46-b, 23 mg, 0.080 mmol) was dissolved in 1,2-dichloroethane (2 ml), and tetrabutylammonium iodide (1.5 mg, 0.0041 mmol) and tert-butyl hydroperoxide (62 μl, 0.64 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by stencil preparation (tetrahydrofuran:petroleum ether = 1:2) to obtain the target product 7-chloro-2-(trifluoromethyl)-9H-pyrido[3′,2′:3,4]cyclopentane[1,2-d]pyrimidin-9-one (46, 1.21 mg, yield 5.3%). ESI[M+H] + =286.0, 288.0

[0481] Example 47: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

[0482]

[0483] Step 1: Synthesis of 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (47-a)

[0484] 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 100 mg, 0.52 mmol), 4-bromo-3-carboxybenzonitrile (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-safe reaction tube, acetonitrile (10 mL) was added, the tube was purged with nitrogen, sealed, and microwaved 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 chromatography (ethyl acetate:petroleum ether = 0%–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

[0485] Step 2: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbamate (47-b)

[0486] 3-Formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (47-a, 35 mg, 0.126 mmol) was dissolved in 1,2-dichloroethane (2 ml), and tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (97 μl, 1.01 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by stencil preparation (tetrahydrofuran:petroleum ether = 1:2) to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-carbamate (47-b, 14.42 mg, yield 41.6%). ESI[M+H] + =276.1

[0487] Step 3: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (47)

[0488] 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbamate (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. The mixture was reacted at 100 °C for 5 hours. The manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure and purified 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 1H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.29 (d, J=7.8Hz, 3H), 8.16 (d, J=7.9Hz, 1H), 7.68 (s, 1H).

[0489] Example 48: Synthesis of 2,7-dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidin-9-one

[0490]

[0491] Step 1: Synthesis of 5-chloro-2-(2-chloro-4-methoxypyrimidin-5-yl)benzaldehyde (48-a)

[0492] 4-Chloro-2-aldehyde phenylboronic 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-safe reaction tube, acetonitrile (25 mL) was added, the tube was purged with nitrogen, sealed, and microwaved 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 chromatography (ethyl acetate:petroleum ether = 0%–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

[0493] Step 2: Synthesis of 2,7-dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidin-9-one (48)

[0494] 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), and tetrabutylammonium iodide (2.4 mg, 0.0065 mmol) and tert-butyl hydroperoxide (101 μl, 1.05 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by stencil preparation (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-d6) δ7.76 (dd, J=5.2, 2.0Hz, 2H), 7.68-7.65 (m, 1H), 4.17 (s, 3H).

[0495] Example 49: Synthesis of 7-chloro-2,4-dihydroxy-9H-indeno[2,1-d]pyrimidin-9-one

[0496]

[0497] 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 overnight at 80 °C. The reaction solution was concentrated under reduced pressure and purified by a plate preparation (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

[0498] Example 50: Synthesis of methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid

[0499]

[0500] Step 1: Synthesis of methyl 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzoate (50-a)

[0501] Methyl 4-bromo-3-carboxymethyl benzoate (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) were placed in a microwave-safe reaction tube, acetonitrile (20 mL) was added, the tube was purged with nitrogen, sealed, and microwaved 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 chromatography (ethyl acetate:petroleum ether = 0%–30%) to obtain the target product, methyl 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzoate (50-a, 54 mg, yield 21.1%). ESI [M+H] + =311.2

[0502] Step 2: Synthesis of methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (50)

[0503] 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), and tetrabutylammonium iodide (3.2 mg, 0.0087 mmol) and tert-butyl hydroperoxide (134 μl, 1.39 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by platting (tetrahydrofuran:petroleum ether = 1:3) to obtain the target product methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-carboxylic acid (50, 28.4 mg, yield 52.9%). ESI[M+H] + =309.1 1 H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 8.38 (d, J=7.8Hz, 1H), 8.27-8.18 (m, 2H), 3.92 (s, 3H).

[0504] Example 51: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid

[0505]

[0506] Methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (50, 20 mg, 0.065 mmol) was dissolved in tetrahydrofuran / water (1 ml / 0.5 ml), and lithium hydroxide monohydrate (6 mg, 0.143 mmol) was added. The reaction was carried out at room temperature for 1 hour. The pH was adjusted to neutral using 1N hydrochloric acid. 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-d6) δ9.65 (s, 1H), 8.33 (d, J=7.7Hz, 1H), 8.21-8.10 (m, 2H), 6.87 (s, 1H).

[0507] Example 52: Synthesis of N-cyclopropyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

[0508]

[0509] 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′-tetramethylurea hexafluorophosphate (19 mg, 0.050 mmol), N,N-diisopropylethylamine (9 μl, 0.051 mmol), and cyclopropylamine (3 μl, 0.034 mmol) were added. The reaction was carried out at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to prepare a plate (dichloromethane:methanol = 15:1) for purification 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-d6) 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).

[0510] Example 53: Synthesis of N-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

[0511]

[0512] 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′-tetramethylurea hexafluorophosphate (77 mg, 0.203 mmol), N,N-diisopropylethylamine (59 μl, 0.34 mmol), and methylamine hydrochloride (9 mg, 0.133 mmol) were added. The reaction was carried out at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to prepare a plate (dichloromethane:methanol = 15:1) for purification 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 1H NMR (400MHz, DMSO-d6) 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).

[0513] Example 54: Synthesis of 2-(trifluoromethyl)-7-(trifluoromethylthio)-9H-indeno[2,1-d]pyrimidin-9-one

[0514]

[0515] Step 1: Synthesis of 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (54-a)

[0516] 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. The mixture was reacted overnight at 60 °C under nitrogen atmosphere. The solution was then concentrated under reduced pressure, and 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.

[0517] Step 2: 2-(2-(trifluoromethyl)pyrimidin-5-yl)-5-(trifluoromethylthio)benzaldehyde (54-b)

[0518] 2-Bromo-5-((trifluoromethyl)thio)benzaldehyde (54-a, 120 mg, 0.423 mmol) was dissolved in acetonitrile (5 mL), and 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (122 mg, 0.634 mmol), potassium fluoride (49 mg, 0.846 mmol), and palladium acetate (65.2 mg, 0.0212 mmol) were added. The mixture was microwaved at 120 °C for 30 minutes under a nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. 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.

[0519] Step 3: Synthesis of 2-(trifluoromethyl)-7-(trifluoromethylthio)-9H-indeno[2,1-d]pyrimidin-9-one (54)

[0520] 2-(2-(trifluoromethyl)pyrimidin-5-yl)-5-(trifluoromethylthio)benzaldehyde (54-b, 40 mg, 0.114 mmol) was dissolved in 1,2-dichloroethane (2 ml), and tetrabutylammonium iodide (2 mg, 0.0054 mmol) and tert-butyl hydroperoxide (109 μl, 1.14 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and 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-d6) δ9.69 (s, 1H), 8.25 (d, J=7.8Hz, 1H), 8.21-8.15 (m, 1H), 8.08 (s, 1H).

[0521] Example 55: Synthesis of 6-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile

[0522]

[0523] Step 1: Synthesis of 4-bromo-5-formyl-2-methylbenzonitrile (55-a)

[0524] 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), and palladium acetate (7.7 mg, 0.0344 mmol) were dissolved in dichloroethane (2 mL), followed by the addition of trifluoroacetic acid (0.5 mL). The mixture was purged with nitrogen three times, and the reaction was carried out 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

[0525] Step 2: Synthesis of 5-formyl-2-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (55-b)

[0526] 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-safe reaction tube, acetonitrile (3 ml) was added, the tube was purged with nitrogen, sealed, and microwaved 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 plate preparation (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

[0527] Step 3: Synthesis of 6-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile (55)

[0528] 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), and tetrabutylammonium iodide (1 mg, 0.0027 mmol) and tert-butyl hydroperoxide (37 μl, 0.385 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by platting (tetrahydrofuran:petroleum ether = 1:5) to obtain the target product 6-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-nitrile (55, 3.85 mg, yield 27.5%). ESI [M+H] + =290.1 1 H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 2.65 (s, 3H).

[0529] Example 56: Synthesis of 8-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile

[0530]

[0531] Step 1: Synthesis of 4-bromo-2-fluoro-3-carboxybenzonitrile (56-a)

[0532] 4-Bromo-2-fluorobenzonitrile (500 mg, 2.51 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL). Under nitrogen protection, diisopropylaminolithium (2 M, 1.9 mL, 3.77 mmol) was added dropwise at -78 °C. After the addition was complete, the reaction was allowed to proceed for 0.5 h. Then, N,N-dimethylformamide (387 μl, 5.02 mmol) was added dropwise, and the reaction was allowed to proceed for 15 min after the addition was complete. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate: petroleum ether = 0%–20%) to obtain the target product 4-bromo-2-fluoro-3-carboxybenzonitrile (56-a, 135 mg, yield 23.7%).

[0533] Step 2: Synthesis of 2-fluoro-3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (56-b)

[0534] 4-Bromo-2-fluoro-3-carboxybenzonitrile (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-safe reaction tube, acetonitrile (5 ml) was added, the tube was purged with nitrogen, sealed, and microwaved 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 plate preparation (ethyl acetate:petroleum ether = 1:5) to obtain the target product 2-fluoro-3-carboxy-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (56-b, 65 mg, yield 45.4%). ESI [M+H] + =296.4

[0535] Step 3: Synthesis of 8-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile (56)

[0536] 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), and tetrabutylammonium iodide (2 mg, 0.00541 mmol) and tert-butyl hydroperoxide (91 μl, 0.952 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by stencil preparation (tetrahydrofuran:petroleum ether = 1:3) to obtain the target product 8-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-nitrile (56, 18.36 mg, yield 52.4%). ESI[M+H] + =294.3 1H NMR (400MHz, DMSO-d6) δ9.77 (s, 1H), 8.43 (dd, J=7.5, 6.3Hz, 1H), 8.15 (d, J=7.8Hz, 1H).

[0537] Example 57: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-sulfonamide

[0538]

[0539] Step 1: Synthesis of 2-chloro-5-aminosulfonylbenzoic acid (57-a)

[0540] 2-Chloro-5-(chlorosulfonyl)benzoic acid (2 g, 7.8 mmol) was dissolved in ammonia hydrate (30 ml) at 0 °C, and the reaction was stirred at room temperature for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the crude product 2-chloro-5-aminosulfonylbenzoic acid (57-a, 2.53 g, yield 130.4%). ESI [MH] + =234.1, 236.2

[0541] Step 2: Synthesis of 2-chloro-N-methoxy-N-methyl-5-aminosulfonylbenzamide (57-b)

[0542] 2-Chloro-5-aminosulfonylbenzoic acid (57-a, 1 g, 4.26 mmol), N,O-dimethylhydroxylamine hydrochloride (413 mg, 4.26 mmol), and 1-methyl-1H-imidazolium (1.4 mL, 17.02 mmol) were dissolved in acetonitrile (20 mL). After stirring at room temperature for 10 minutes, N,N,N′,N′-tetramethylchloroformamidin hexafluorophosphate (1.19 g, 4.26 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by Flash column chromatography (ethyl acetate:petroleum ether = 0%–50%) to obtain the target product 2-chloro-N-methoxy-N-methyl-5-aminosulfonylbenzoamide (57-b, 1.208 g, yield 102.15%). ESI [M+H] + =278.2, 280.2

[0543] Step 3: Synthesis of 4-chloro-3-formylbenzenesulfonamide (57-c)

[0544] 2-Chloro-N-methoxy-N-methyl-5-aminosulfonylbenzamide (57-b, 150 mg, 0.539 mmol) was dissolved in ultradry dichloromethane (10 mL). Under nitrogen protection, diisobutylaluminum hydride (1 M, 1 mL, 1.078 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, 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

[0545] Step 4: Synthesis of 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide (57-d)

[0546] 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 tetrakis(triphenylphosphine)palladium (12 mg, 0.0104 mmol) were placed in a microwave-safe reaction tube. Dioxane / water (5 ml / 0.5 ml) was added, the tube was purged with nitrogen, sealed, and microwaved 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 a plate test (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

[0547] Step 5: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (57)

[0548] 3-Formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide (57-d, 17 mg, 0.0514 mmol) was dissolved in 1,2-dichloroethane (2 ml), and tetrabutylammonium iodide (1 mg, 0.0027 mmol) and tert-butyl hydroperoxide (42 μl, 0.411 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and then purified by plate preparation (dichloromethane:methanol = 15:1) to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-sulfonamide (57, 3.04 mg, yield 17.9%). ESI[M+H] + =330.3 1H NMR (400MHz, DMSO-d6) δ9.69 (s, 1H), 8.28-8.19 (m, 2H), 8.15 (d, J=0.9Hz, 1H), 7.67 (s, 2H).

[0549] Example 58: Synthesis of 5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile

[0550]

[0551] Step 1: Synthesis of 4-bromo-3-formyl-5-methylbenzylnitrile (58-a)

[0552] 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 reacted overnight at 100 °C under nitrogen protection in a sealed tube. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate:petroleum ether = 0%–5%) to obtain the target product, 4-bromo-3-formyl-5-methylbenzylnitrile (58-a, 15 mg, yield 4.9%). ESI [M+H] + =224.0, 225.9

[0553] Step 2: Synthesis of 3-formyl-5-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzylnitrile (58-b)

[0554] 4-Bromo-3-formyl-5-methylbenzylnitrile (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-safe reaction tube, acetonitrile (2 ml) was added, the tube was purged with nitrogen, sealed, and microwaved 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 plate preparation (ethyl acetate:petroleum ether = 1:6) to obtain the target product 3-formyl-5-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzylnitrile (58-b, 10 mg, yield 63.7%). ESI [M+H] + =292.2

[0555] Step 3: Synthesis of 5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile (58)

[0556] 3-Formyl-5-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl nitrile (58-b, 10 mg, 0.0344 mmol) was dissolved in 1,2-dichloroethane (1 ml), and tetrabutylammonium iodide (0.63 mg, 0.00171 mmol) and tert-butyl hydroperoxide (27 μl, 0.275 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified to obtain the target product 5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-nitrile (58, 0.84 mg, yield 8.4%). ESI[M+H] + =290.4

[0557] Example 59: Synthesis of 2-(trifluoromethyl)-7-(trifluoromethanesulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0558]

[0559] 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-chloroperoxybenzoic acid (19 mg, 0.11 mmol) was added at 0 °C. The reaction mixture was then reacted at room temperature for 36 hours. The reaction solution was concentrated under reduced pressure to prepare and purified 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-d6) δ9.87 (s, 1H), 8.66 (d, J=8.0Hz, 1H), 8.57 (d, J=8.0Hz, 1H), 8.33 (s, 1H).

[0560] Example 60: Synthesis of 7-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0561]

[0562] Step 1: Synthesis of 5-bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a)

[0563] 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-safe reaction tube, ethanol (4 ml) was added, the tube was purged with nitrogen, sealed, and microwaved 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 chromatography (ethyl acetate:petroleum ether = 0%–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

[0564] Step 2: Synthesis of 5-(1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-b)

[0565] 5-Bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a, 25 mg, 0.0757 mmol), 1H-pyrazole-3-boronic 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-safe reaction tube, ethanol (3 ml) was added, the tube was purged with nitrogen, sealed, and microwaved 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 plate preparation (dichloromethane:methanol = 10:1) to obtain the target product 5-(1H-pyrazole-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-b, 9 mg, yield 20.9%). ESI[M+H] + =319.1

[0566] Step 3: Synthesis of 7-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60)

[0567] 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), and tetrabutylammonium iodide (0.52 mg, 0.00141 mmol) and tert-butyl hydroperoxide (22 μl, 0.226 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and 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-d6) 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).

[0568] Example 61: Synthesis of 7-(1-methyl-1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0569]

[0570] Step 1: Synthesis of 5-(1-methyl-1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (61-a)

[0571] 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-safe reaction tube, ethanol (4 ml) was added, the tube was purged with nitrogen, sealed, and microwaved 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 plate preparation (dichloromethane:methanol = 15:1) to obtain the target product 5-(1-methyl-1H-pyrazole-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (61-a, 22 mg, yield 36.7%). ESI[M+H] + =333.2

[0572] Step 2: Synthesis of 7-(1-methyl-1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (61)

[0573] 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), and tetrabutylammonium iodide (1.22 mg, 0.0033 mmol) and tert-butyl hydroperoxide (51 μl, 0.53 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and then purified by plate preparation (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-d6) δ9.64 (s, 1H), 8.19 (d, J=7.8Hz, 1H), 8.00 (dd, J=7.8, 1.5Hz, 1 H), 7.95 (d, J=0.8Hz, 1H), 7.53 (d, J=1.8Hz, 1H), 6.62 (d, J=1.8Hz, 1H), 3.93 (s, 3H).

[0574] Example 62: Synthesis of N-hydroxy-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

[0575]

[0576] Methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (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, followed by lithium hydroxide monohydrate (4 mg, 0.1 mmol). The reaction was carried out at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to prepare the purified 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-d6) δ9.62 (s, 1H), 8.97 (s, 1H), 8.28 (d, J = 7.9Hz, 1H), 8.22 (d, J = 7.9Hz, 1H).

[0577] Example 63: Synthesis of 7-(2-hydroxypropane-2-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0578]

[0579] Methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-carboxylic acid (50, 15 mg, 0.0487 mmol) was dissolved in ultra-dry tetrahydrofuran (3 mL). Methyl magnesium bromide (1 M, 122 μl, 0.123 mmol) was added dropwise at 0 °C under nitrogen protection, and the reaction was carried out at room temperature for 4 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare the purified 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-d6) δ9.71 (s, 1H), 8.39 (d, J=5.6Hz, 1H), 8.29-8.17 (m, 2H), 1.23 (s, 6H).

[0580] Example 64: Synthesis of 2-methoxy-7-(methanesulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0581]

[0582] Step 1: Synthesis of 2-chloro-5-(methanesulfonyl)benzoic acid (64-a)

[0583] 2-Chloro-5-(methylthio)benzoic acid (2 g, 9.87 mmol) was dissolved in methanol (60 mL), and potassium peroxymonosulfonate (12.1 g, 19.66 mmol) was added. The mixture was reacted overnight at room temperature. Insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the target product, 2-chloro-5-(methylsulfonyl)benzoic acid (64-a, 2.2 g, yield 95.7%). ESI [MH] + =233.0, 235.0

[0584] Step 2: Synthesis of (2-chloro-5-(methylsulfonyl)phenyl)methanol (64-b)

[0585] 2-Chloro-5-(methanesulfonyl)benzoic acid (64-a, 800 mg, 3.42 mmol) was dissolved in ultra-dry tetrahydrofuran (30 mL). Under nitrogen protection, lithium aluminum hydride (260 mg, 6.84 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the target product (2-chloro-5-(methanesulfonyl)phenyl)methanol (64-b, 415 mg, yield 55.2%).

[0586] Step 3: 2-Chloro-5-(methylsulfonyl)benzaldehyde (64-c)

[0587] (2-Chloro-5-(methanesulfonyl)phenyl)methanol (64-b, 315 mg, 1.43 mmol) was dissolved in 1,4-dioxane (30 mL), and manganese dioxide (1.25 g, 14.37 mmol) was added. The mixture was reacted overnight at 100 °C. The manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure to give the target product, 2-chloro-5-(methanesulfonyl)benzaldehyde (64-c, 250 mg, yield 60.8%). ESI [M+H] + =219.0, 221.0

[0588] Step 4: Synthesis of 2-(2-methoxypyrimidin-5-yl)-5-(methanesulfonyl)benzaldehyde (64-d)

[0589] 2-Chloro-5-(methanesulfonyl)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 tetrakis(triphenylphosphine)palladium (61 mg, 0.0528 mmol) were placed in a microwave-safe reaction tube. 1,4-dioxane / water (25 ml / 2.5 ml) was added, the tube was purged with nitrogen, sealed, and microwaved 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 chromatography (ethyl acetate:petroleum ether = 10%–100%) to obtain the target product 2-(2-methoxypyrimidine-5-yl)-5-(methanesulfonyl)benzaldehyde (64-d, 280 mg, yield 83.6%). ESI [M+H] + =293.1

[0590] Step 5: Synthesis of 2-methoxy-7-(methanesulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (64)

[0591] 2-(2-methoxypyrimidin-5-yl)-5-(methanesulfonyl)benzaldehyde (64-d, 230 mg, 0.788 mmol) was dissolved in 1,2-dichloroethane (10 mL), and tetrabutylammonium iodide (14.5 mg, 0.0392 mmol) and tert-butylhydrogen peroxide (455 μl, 4.73 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and recrystallized from tetrahydrofuran to give the target product 2-methoxy-7-(methanesulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (64, 44 mg, yield 19.3%). ESI[M+H] + =291.1 1 H NMR (600MHz, DMSO-d6) 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).

[0592] Example 65: Synthesis of 2-hydroxy-7-(methanesulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0593]

[0594] 2-Methoxy-7-(methanesulfonyl)-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. The reaction mixture was reacted at 80 °C for 5 hours. The reaction solution was concentrated under reduced pressure to prepare and purified the target product 2-hydroxy-7-(methanesulfonyl)-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-d6) 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).

[0595] Example 66: Synthesis of N-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)sulfonyl)acetamide

[0596]

[0597] 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-sulfonamide (57, 18 mg, 0.0547 mmol) was dissolved in acetonitrile (3 mL), and acetic anhydride (8 μl, 0.0821 mmol) and concentrated sulfuric acid (30 μl) were added. The reaction was carried out at 80 °C for 8 hours. The mixture was quenched with saturated brine, extracted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure 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-d6) δ9.74 (s, 1H), 8.34-8.32 (m, 2H), 8.15 (s, 1H), 1.96 (s, 3H).

[0598] Example 67: Synthesis of 7-(s-methanesulfonylimino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0599]

[0600] Step 1: Synthesis of (67-a) from 7-bromo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0601] 5-Bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a, 520 mg, 1.58 mmol) was dissolved in dichloroethane (25 ml), and 2-hydroperoxide-2-methylpropane (908 μl, 7.88 mmol) and tetrabutylammonium iodide (19 mg, 0.05 mmol) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. After concentration under reduced pressure, the crude product was purified by 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%).

[0602] Step 2: Synthesis of 7-(methylthio)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-b)

[0603] 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), and triethylenediamine (92 mg, 0.821 mmol) and cuprous iodide (78 mg, 0.409 mmol) were added. The reaction was carried out overnight at 130 °C under nitrogen protection. The mixture was quenched with saturated brine, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate:petroleum ether = 0%–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

[0604] Step 3: Synthesis of 7-(S-methylsulfonylimino)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67)

[0605] 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), and iodophenyldiacetic acid (59 mg, 0.456 mmol) and ammonium acetate (47 mg, 0.61 mmol) were added. The mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by a plate preparation (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-d6) δ11.94 (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).

[0606] Example 68: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxaldehyde

[0607]

[0608] Step 1: 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (68-a)

[0609] Methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-carboxylic acid (50, 350 mg, 1.14 mmol) was dissolved in ultradry dichloromethane (10 mL). Under nitrogen protection, diisobutylaluminum hydride (1 M, 3.4 mL, 3.42 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 hour. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, 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 mg g, yield 21.7%). (ESI [M+H]) + =281.1

[0610] Step 2: 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxaldehyde (68)

[0611] 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. The mixture was reacted overnight at 100 °C. The 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]pyrimidin-7-carboxaldehyde (68, 34 mg, yield 45.9%). ESI[M+H] + =278.9 1 H NMR (400MHz, DMSO-d6) δ10.11 (s, 1H), 9.72 (s, 1H), 8.37-8.33 (m, 1H), 8.30 (d, J=7.7Hz, 1H), 8.27 (s, 1H).

[0612] Example 69: Synthesis of 7-(1-hydroxyethyl)-9-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyridin-9-ol

[0613]

[0614] 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxaldehyde (68, 34 mg, 0.122 mmol) was dissolved in ultra-dry tetrahydrofuran (4 mL). Methyl magnesium bromide (1 M, 98 μl, 0.0978 mmol) was added at 0 °C under nitrogen protection, and the reaction was carried out at 0 °C for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare the purified 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-d6) 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).

[0615] Example 70: Synthesis of N-(methyl-d3)-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

[0616]

[0617] 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), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea 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. The reaction was carried out at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to prepare the purified 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 1H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.75 (s, 1H), 8.29-8.22 (m, 2H), 8.16 (d, J=7.9Hz, 1H).

[0618] Example 71: Synthesis of 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0619]

[0620] Step 1: Synthesis of 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (71-a)

[0621] 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(diphenylphosphine)ferrocene[200 mg, 0.242 mmol]palladium dichloromethane complex were placed in a reaction flask, and N,N-dimethylformamide (100 mL) was added. The mixture was purged with nitrogen and reacted overnight at 100 °C. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography 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

[0622] Step 2: Synthesis of 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71-b)

[0623] 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), and tetrabutylammonium iodide (35 mg, 0.095 mmol) and tert-butylhydrogen peroxide (543 mg, 6.03 mmol) were added. The mixture was reacted overnight at 100 °C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by plate preparation 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

[0624] Step 3: Synthesis of 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71)

[0625] 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), and N-bromosuccinimide (105.2 mg, 0.59 mmol) and azobisisobutyronitrile (20 mg, 0.09 mmol) were added. The reaction mixture was reacted overnight at 85 °C. The reaction solution was concentrated under reduced pressure and then purified by direct 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, CCl3D) δ9.21 (s, 1H), 8.55 (s, 1H), 8.47 (d, J=7.8Hz, 1H), 7.82 (d, J=1.1Hz, 1H), 5.49 (s, 2H).

[0626] Example 72: Synthesis of 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0627]

[0628] 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. The reaction was carried out at 75 °C for 0.5 h. The byproduct 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (72, 1.16 mg, yield 2.4%) was obtained by preparative ablation. ESI[M+H] + =281.0 1 H NMR (400MHz, CCl3D) δ9.21 (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).

[0629] Example 73: Synthesis of 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile

[0630]

[0631] Step 1: Synthesis of 4-bromo-5-(dibromomethyl)-2-fluorobenzonitrile (73-a)

[0632] 4-Bromo-2-fluoro-5-methylbenzonitrile (2.12 g, 9.91 mmol) was dissolved in carbon tetrachloride (40 mL), and N-bromosuccinimide (4.52 g, 25.39 mmol) and azobisisobutyronitrile (555 mg, 3.38 mmol) were added. The mixture was reacted overnight at 85 °C. The reaction solution was concentrated under reduced pressure and then purified by direct 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

[0633] Step 2: Synthesis of 4-bromo-2-fluoro-5-carboxybenzonitrile (73-b)

[0634] 4-Bromo-5-(dibromomethyl)-2-fluorobenzonitrile (73-a, 600 mg, 1.63 mmol) was dissolved in ethanol / water (10 ml / 10 ml), and silver nitrate (0.55 g, 3.26 mmol) was added. The mixture was reacted at room temperature for 2 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0%–20%) to obtain the target product, 4-bromo-2-fluoro-5-carboxybenzonitrile (73-b, 300 mg, yield 81.0%). ESI [M+H] + =228.0

[0635] Step 3: Synthesis of 2-fluoro-5-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (73-c)

[0636] 4-Bromo-2-fluoro-5-carboxybenzonitrile (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(diphenylphosphine)ferrocene]palladium dichloride (16 mg, 0.022 mmol) were placed in a reaction flask, acetonitrile (5 mL) was added, the mixture was purged with nitrogen, 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-carboxy-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (73-c, 70 mg, yield 54.0%). ESI [M+H] + =296.0

[0637] Step 4: Synthesis of 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile (73)

[0638] 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), and tetrabutylammonium iodide (4.4 mg, 0.012 mmol) and tert-butyl hydroperoxide (123 mg, 0.96 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by plate preparation to obtain the target product 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-nitrile (73, 10 mg, yield 14.0%). ESI[M+H] + =294.0 1 H NMR (400MHz, CDCl3) δ9.30 (s, 1H), 8.18 (d, J=5.8Hz, 1H), 7.68 (d, J=7.6Hz, 1H).

[0639] Example 74: Synthesis of 2-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetic acid

[0640]

[0641] 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. The reaction was carried out at 75 °C for 0.5 h. 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 purified by preparative ablation. ESI[M+H] + =309.0 1 H NMR (400MHz, CDCl3) 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).

[0642] Example 75: Synthesis of 9-oxo-7-phenyl-9H-indeno[1,2-b]pyrazine-2,3-dionitrile

[0643]

[0644] Step 1: Synthesis of 7-chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dionitrile (75-a)

[0645] 7-Chloro-9H-indeno[1,2-b]pyrazine-2,3-dionitrile (2.8 g, 11.08 mmol) was added to acetic acid (30 ml), followed by the addition of potassium dichromate (5.87 g, 19.95 mmol) dissolved in acetic acid (50 ml) and water (15 ml). The mixture was slowly heated to 100 °C and reacted for 1 hour. The reaction was then quenched with sodium bicarbonate solution, extracted with ethyl acetate, concentrated under reduced pressure, and 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-dionitrile (75-a, 700 mg, yield 23.69%).

[0646] Step 2: Synthesis of 9-oxo-7-phenyl-9H-indeno[1,2-b]pyrazine-2,3-dionitrile (75)

[0647] 7-chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dionitrile (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-controlled environment at 120 °C for 30 minutes. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by liquid chromatography to obtain the target product 9-oxo-7-phenyl-9H-indeno[1,2-b]pyrazine-2,3-dionitrile (75, 0.8 mg, yield 2.31%). 1 H NMR (400MHz, DMSO-d6) δ7.86 (d, J=2.2Hz, 1H), 7.78 (dd, J=8.3, 2.3Hz, 1H), 7.65-7.47 (m, 6H)

[0648] Example 76: Preparation of 7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0649]

[0650] Step 1: Synthesis of 5-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (76-a)

[0651] 2-Bromo-5-nitrobenzaldehyde (200 mg, 0.869 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (250 mg, 1.3 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (31.8 mg, 0.043 mmol), and potassium phosphate (553 mg, 2.6 mmol) were dissolved in acetonitrile (15 mL), and the mixture was reacted under nitrogen protection using microwave for 40 minutes. The reaction solution was filtered, concentrated under reduced pressure, and 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

[0652] Step 2: Preparation of 7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (76)

[0653] 5-Nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (76-a, 60 mg, 0.2 mmol) was dissolved in dichloroethane (3 ml), and 70% 2-hydroperoxide-2-methylpropane (156 mg, 1.21 mmol) and tetrabutylammonium iodide (4 mg, 0.01 mmol) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. After concentration under reduced pressure, the crude product was purified by silica gel plate preparation (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-d6) δ9.80 (s, 1H), 8.69 (d, J = 7.8Hz, 1H), 8.45 (s, 1H), 8.37 (d, J = 8.3Hz, 1H).

[0654] Example 77: Preparation of 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0655]

[0656] 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 reaction was carried out overnight at 75 °C under nitrogen protection. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel plate preparation (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 (600MHz, DMSO-d6) δ9.15 (s, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 6.16 (d, J = 8.5Hz, 2H)

[0657] Example 78: Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide

[0658]

[0659] 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. The reaction was carried out at room temperature for 4 hours under nitrogen protection. The reaction solution was quenched with water at 0 °C, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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-d6) 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).

[0660] Example 79: Preparation of 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0661]

[0662] Step 1: Preparation of 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (79-a)

[0663] 3-(trifluoromethyl)thiobenzaldehyde (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. The mixture was reacted overnight at 60 °C under nitrogen atmosphere. The solution was then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (99% petroleum ether) to give the target product 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (79-a, 320 mg, yield 58.8%). ESI [M+H] + =285.1.

[0664] Step 2: Preparation of 2-(2-methoxypyrimidin-5-yl)-5-((trifluoromethyl)thio)benzaldehyde (79-b)

[0665] 2-Bromo-5-((trifluoromethyl)thio)benzaldehyde (79-a, 320 mg, 1.12 mmol) was dissolved in 1,4-dioxane (10 ml), one drop of water was added, and then (2-methoxypyrimidin-5-yl)boric acid (206 mg, 1.34 mmol), cesium carbonate (776 mg, 2.68 mmol), and tetra(triphenylphosphine)palladium (65.2 mg, 0.056 mmol) were added. The mixture was microwaved at 120 °C for 30 minutes under a 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.

[0666] Step 3: Preparation of 2-methoxy-7-((trifluoromethyl)thio)-9H-indeno[2,1-d]pyrimidin-9-one (79-c)

[0667] 2-(2-methoxypyrimidin-5-yl)-5-((trifluoromethyl)thio)benzaldehyde (79-b, 193 mg, 0.615 mmol) was dissolved in dichloroethane (10 ml), and tert-butyl hydroperoxide (346 mg, 3.69 mmol) and tetrabutylammonium iodide (11.8 mg, 0.308 mmol) were added. The mixture was reacted overnight at 100 °C under sealed conditions. 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.

[0668] Step 4: Preparation of 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (79)

[0669] 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-chloroperoxybenzoic acid (11 mg, 0.640 mmol) was added. The mixture was reacted overnight at room temperature, concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography (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-d6) δ9.87 (s, 1H), 8.66 (d, J=8.0Hz, 1H), 8.57 (d, J=8.0Hz, 1H), 8.33 (s, 1H), 3.84 (s, 1H).

[0670] Example 80: Preparation of 2,7-dichloro-4-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one

[0671]

[0672] Step 1: Preparation of 5-chloro-2-(2,4-dichloropyrimidin-5-yl)benzaldehyde (80-a)

[0673] 2,4-Dichloro-5-iodopyrimidine (500 mg, 1.82 mmol) was dissolved in sec-butanol (10 mL), and 4-chloro-2-aldehydephenylboronic 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. The mixture was reacted under nitrogen protection at 120 °C with microwave for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (methanol:dichloromethane = 0%–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.

[0674] Step 2: Preparation of 2,7-dichloro-4-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (80)

[0675] 5-Chloro-2-(2,4-dichloropyrimidin-5-yl)benzaldehyde (80-a, 100 mg, 0.34 mmol) was dissolved in 1,2-dichloroethane (10 mL), and tetrabutylammonium iodide (6.46 mg, 0.02 mmol) and tert-butyl hydroperoxide (270 μl, 2.72 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 16 hours under nitrogen protection. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate:petroleum ether = 0%–20%) followed by preparative HPLC 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-d6) δ8.15-8.08 (m, 1H), 8.24 (d, J=2.3Hz, 1H), 8.59 (d, J=8.6Hz, 1H), 9.76 (s, 1H).

[0676] Example 81: Preparation of 2-hydroxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0677]

[0678] Formic acid (2 ml) and hydrochloric acid (50 μl) were added to 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (79, 15 mg, 0.436 mmol). The mixture was reacted at 80 °C for 5 hours, then concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (HPLC) (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.

[0679] Example 82: Preparation of N,N-dimethyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide

[0680]

[0681] Step 1: Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (82-a)

[0682] Methyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (40 mg, 0.130 mmol) was dissolved in tetrahydrofuran (5 ml), and water (1 ml) was added. Lithium hydroxide monohydrate (10.9 mg, 0.260 mmol) was slowly added at 0 °C. After reacting at room temperature for 4 hours, the pH was adjusted to neutral with 1 M hydrochloric acid solution, and water (5 ml) was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated 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%). + =295.2.

[0683] Step 2: Preparation of N,N-dimethyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (82)

[0684] 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), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (14.7 mg, 0.0490 mmol) was added. After stirring for 10 minutes, dimethylamine hydrochloride (3.4 mg, 0.0490 mmol) was added. 0.0408 mmol), N,N-diisopropylethylamine (24.4 μl, 0.122 mmol), reacted at room temperature for 4 hours, then concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (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, 1.49 mg, yield 11.4%). ESI[M+H] + =322.2.

[0685] Example 83: Preparation of 7-chloro-2-methoxy-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0686]

[0687] Step 1: Preparation of 5-bromo-2-methoxy-4-(trifluoromethyl)pyrimidine (83-a)

[0688] 5-Bromo-4-(trifluoromethyl)pyrimidin-2-ol (470 mg, 1.943 mmol) was dissolved in tetrahydrofuran (10 mL), and benzotriazole-1-tris(trimethylamino)-hexafluorophosphate (1.7 g, 3.89 mmol) was added. After stirring for 10 minutes, methanol (1.6 mL, 38.9 mmol) and cesium carbonate (2.5 g, 7.77 mmol) were added. The mixture was reacted at room temperature for 2 hours, then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give the target product 5-bromo-2-methoxy-4-(trifluoromethyl)pyrimidin (83-a, 195 mg, yield 44.4%). ESI [M+H] + =257.2.

[0689] Step 2: Preparation of 5-chloro-2-(2-methoxy-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (83-b)

[0690] 5-Bromo-2-methoxy-4-(trifluoromethyl)pyrimidine (83-a, 195 mg, 0.863 mmol) was dissolved in 1,4-dioxane (5 ml), and one drop of water, (4-chloro-2-formylphenyl)boronic acid (159 mg, 0.863 mmol), cesium carbonate (562 mg, 1.73 mmol), and tetratetraphenylphosphine palladium (50 mg, 0.432 mmol) were added. The mixture was reacted under nitrogen atmosphere at 120 °C with microwave for 30 minutes, followed by concentration 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.

[0691] Step 3: Preparation of 7-chloro-2-methoxy-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (83)

[0692] 5-Chloro-2-(2-methoxy-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (83-b, 104 mg, 3.29 mmol) was dissolved in dichloroethane (5 ml), and tert-butyl hydroperoxide (237 mg, 26.3 mmol) and tetrabutylammonium iodide (6 mg, 0.165 mmol) were added. The mixture was reacted overnight at 100 °C under sealed conditions. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to give 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.

[0693] Example 84: Preparation of 7-chloro-2-(thiazolyl-5-yl)-9H-indeno[2,1-d]pyrimidin-9-one

[0694]

[0695] Step 1: Preparation of 5-(5-bromopyrimidin-2-yl)thiazole (84-a)

[0696] 5-Bromo-2-iodopyrimidine (300 mg, 1.05 mmol) was dissolved in toluene (5 mL), and 5-(tributyltinyl)thiazole (394 mg, 1.05 mmol), triphenylphosphine (27.6 mg, 0.105 mmol), and bis(triphenylphosphine)palladium dichloride (37 mg, 0.0527 mmol) were added. The mixture was reacted overnight at 120 °C under a 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.

[0697] Step 2: Preparation of 5-chloro-2-(2-(thiazol-5-yl)pyrimidin-5-yl)benzaldehyde (84-b)

[0698] 5-(5-bromopyrimidin-2-yl)thiazole (84-a, 115 mg, 0.477 mmol) was dissolved in acetonitrile (5 mL), and (4-chloro-2-formylphenyl)boronic acid (131 mg, 0.716 mmol), potassium fluoride (55.5 mg, 0.954 mmol), and palladium acetate (5.4 mg, 0.0224 mmol) were added. The mixture was microwaved at 120 °C for 45 minutes under a 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.

[0699] Step 3: Preparation of 7-chloro-2-(thiazolyl-5-yl)-9H-indeno[2,1-d]pyrimidin-9-one (84)

[0700] 5-Chloro-2-(2-(thiazol-5-yl)pyrimidin-5-yl)benzaldehyde (84-b, 10 mg, 0.0332 mmol) was dissolved in dichloroethane (5 ml), and tert-butyl hydroperoxide (23 mg, 0.266 mmol) and tetrabutylammonium iodide (0.6 mg, 0.00166 mmol) were added. The mixture was reacted overnight at 100 °C under sealed conditions. After concentration under reduced pressure, the crude product was purified by high-performance liquid chromatography (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.

[0701] Example 85: Preparation of 7-chloro-2-(thiazolyl-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one

[0702]

[0703] Step 1: Preparation of 2-(5-bromopyrimidin-2-yl)thiazole (85-a)

[0704] 5-Bromo-2-iodopyrimidine (114 mg, 0.400 mmol) was dissolved in toluene (5 mL), and 2-(tributyltinyl)thiazole (150 mg, 0.400 mmol), triphenylphosphine (10.5 mg, 0.040 mmol), and bis(triphenylphosphine)palladium dichloride (14.1 mg, 0.02 mmol) were added. The mixture was reacted overnight at 120 °C under a nitrogen atmosphere. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to give the target product 2-(5-bromopyrimidin-2-yl)thiazole (85-a, 75 mg, yield 77.8%). ESI [M+H] + =242.2.

[0705] Step 2: Preparation of 5-chloro-2-(2-(thiazol-2-yl)pyrimidin-5-yl)benzaldehyde (85-b)

[0706] 2-(5-bromopyrimidin-2-yl)thiazole (85-a, 75 mg, 0.311 mmol) was dissolved in acetonitrile (5 mL), and (4-chloro-2-formylphenyl)boronic acid (85.9 mg, 0.467 mmol), potassium fluoride (36.2 mg, 0.622 mmol), and palladium acetate (3.5 mg, 0.0156 mmol) were added. The mixture was microwaved at 120 °C for 45 minutes under a 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.

[0707] Step 3: Preparation of 7-chloro-2-(thiazolyl-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one (85)

[0708] 5-Chloro-2-(2-(thiazol-2-yl)pyrimidin-5-yl)benzaldehyde (85-b, 28 mg, 0.0930 mmol) was dissolved in dichloroethane (5 ml), and tert-butyl hydroperoxide (67 mg, 0.744 mmol) and tetrabutylammonium iodide (1.7 mg, 0.00465 mmol) were added. The mixture was reacted overnight at 100 °C under sealed conditions. After concentration under reduced pressure, the crude product was purified by high-performance liquid chromatography (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.

[0709] Example 86: Synthesis of 8-(trifluoromethyl)-10H-[1,3]dioxane[4',5':4,5]indeno[2,1-d]pyrimidin-10-one

[0710]

[0711] Step 1: Synthesis of 5-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxane-4-carboxaldehyde (86-a)

[0712] 5-Bromobenzo[d][1,3]dioxane-4-carboxaldehyde (200 mg, 0.87 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (2180 mg, 1.14 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (32 mg, 0.04 mmol), and potassium phosphate (370 mg, 1.74 mmol) were dissolved in acetonitrile (12 mL). The mixture was microwaved at 120 °C for 50 min 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]dioxane-4-carboxaldehyde (86-a, 80 mg, yield 31.2%). ESI[M+H] + =297

[0713] Step 2: Synthesis of 8-(trifluoromethyl)-10H-[1,3]dioxane[4',5':4,5]indeno[2,1-d]pyrimidin-10-one (86)

[0714] 5-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxane-4-carboxaldehyde (86-a, 80 mg, 0.27 mmol) was dissolved in dichloroethane (5 ml), and 2-hydroperoxide-2-methylpropane (156 μl, 1.62 mmol) and tetrabutylammonium iodide (5 mg, 0.05 mmol) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. After concentration under reduced pressure, the crude product was purified by preparative method to obtain the target product 8-(trifluoromethyl)-10H-[1,3]dioxane[4',5':4,5]indeno[2,1-d]pyrimidin-10-one (86, 5.15 mg, yield 6.4%). ESI[M+H] + =295. 1 H NMR400MHz, DMSO-d6) δ9.51 (s, 1H), 7.53 (d, J=7.7Hz, 1H), 7.23 (d, J=7.7Hz, 1H), 6.33 (s, 2H).

[0715] Example 87: Synthesis of 7-(methanesulfonyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one

[0716]

[0717] Step 1: Synthesis of 2-chloro-5-(methanesulfonyl)benzoic acid (87-a)

[0718] 2-Chloro-5-(methylthio)benzoic acid (6 g, 29.56 mmol) was dissolved in methanol (100 mL), and potassium peroxide monosulfonate (36.38 g, 59.12 mmol) was added. After reacting overnight at room temperature, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (methanol:dichloromethane-20:1) to obtain the target product 2-chloro-5-(methanesulfonyl)benzoic acid (87-a, 5.42 g, yield 96.6%). ESI [M+H] + =235.

[0719] Step 2: Synthesis of (87-b)methanol from (2-chloro-5-(methylsulfonyl)phenyl)

[0720] 2-Chloro-5-(methanesulfonyl)benzoic acid (87-a, 2 g, 8.54 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium aluminum hydride (640 mg, 16.84 mmol) was slowly added at 0 °C. After reacting for 2 hours at room temperature, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, concentrated under reduced pressure, and purified by silica gel chromatography (methanol:dichloromethane = 15:1) to give the target product (2-chloro-5-(methanesulfonyl)phenyl)methanol (87-b, 1.1 g, yield 58.5%). ESI [M+H] + =221.

[0721] Step 3: Synthesis of 2-chloro-5-(methanesulfonyl)benzaldehyde (87-c)

[0722] (2-Chloro-5-(methanesulfonyl)phenyl)methanol (87-b, 1.1 g, 5 mmol) was dissolved in dioxane (50 mL), and manganese dioxide (2.17 g, 24.9 mmol) was added. The reaction was carried out overnight at 100 °C. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 2:1) to give the target product 2-chloro-5-(methanesulfonyl)benzaldehyde (87-c, 370 mg, yield 34.6%). ESI [M+H] + =219.

[0723] Step 4: Synthesis of 5-(methanesulfonyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (87-d)

[0724] 2-Chloro-5-(methanesulfonyl)benzaldehyde (87-c, 280 mg, 1.28 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (400 mg, 2.09 mmol), tetra(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). The mixture was microwaved at 120 °C for 1 hour under nitrogen protection. After filtration and concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:2) to obtain the target product 5-(methanesulfonyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (87-d, 200 mg, yield 47.7%). ESI[M+H] + =331.

[0725] Step 5: Preparation of 7-(methanesulfonyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (87)

[0726] 5-(methanesulfonyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (87-d, 200 mg, 0.60 mmol) was dissolved in dichloroethane (8 mL), and 2-hydroperoxide-2-methylpropane (291 μl, 3.03 mmol) and tetrabutylammonium iodide (11 mg, 0.03 mmol) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. After concentration under reduced pressure, the crude product was purified by preparative method to obtain the target product 7-(methanesulfonyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (87, 19.88 mg, yield 16.5%). ESI[M+H] + =329. 1H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 8.36 (s, 2H), 8.26 (s, 1H), 3.29 (s, 3H).

[0727] Example 88: Preparation of 2-methoxy-9-oxy-9H-indeno[2,1d]pyrimidine-7-sulfonamide

[0728]

[0729] Step 1: 2-Chloro-5-sulfanilamide benzoic acid (88-a)

[0730] 2-Chloro-5-(chlorosulfonyl)benzoic acid (1 g, 3.92 mmol) was slowly added to 15 ml of ammonia water at 0 °C, and the reaction was allowed to proceed for half an hour. The reaction was then monitored by TLC using a dichloromethane / methanol ratio of 10:1. After the reaction was complete, the solution was concentrated under reduced pressure to obtain crude 2-chloro-5-sulfonamide benzoic acid (88-a, 1.15 g).

[0731] Step 2: Preparation of 2-chloro-N-methoxy-N-methyl-5-aminosulfonylbenzamide (88-b)

[0732] 2-Chloro-5-sulfanilamide benzoic 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), and N,N,N′,N′-tetramethylchloroformamidin hexafluorophosphate (1.5 g, 5.38 mmol) were dissolved in acetonitrile and reacted at room temperature for 2 hours. After monitoring the reaction to 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 give 2-chloro-N-methoxy-N-methyl-5-aminosulfonylbenzamide (88-b, 0.87 g, yield 64%). ESI [M+H] + =279.2

[0733] Step 3: Preparation of 4-chloro-3-formylbenzenesulfonamide (88-c)

[0734] 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 and the reaction was carried out for half an hour. After the reaction was completed by TLC monitoring, the reaction was quenched, extracted, concentrated under reduced pressure, and the organic phase was dried to obtain crude 4-chloro-3-carboxybenzenesulfonamide (88-c, 450 mg).

[0735] Step 4: Preparation of 3-formyl-4-(2-methoxypyrimidin-5-yl)benzenesulfonamide (88-d)

[0736] (2-Methoxypyrimidin-5-yl)boronic acid (93 mg, 0.6 mmol), cesium carbonate (295 mg, 0.9 mmol), and 4-chloro-3-formylbenzenesulfonamide (88-c, 100 mg, 0.45 mmol) were dissolved in 4 mL of dioxane and tetrakis(triphenylphosphine)palladium were added. The mixture was reacted at 120 °C for 1 hour under nitrogen protection. The crude product was concentrated under reduced pressure and 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.

[0737] Step 5: Preparation of 2-methoxy-9-oxy-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (88)

[0738] 3-Formyl-4-(2-methoxypyrimidin-5-yl)benzenesulfonamide (88-d, 50 mg, 0.17 mmol) was dissolved in dichloroethane (4 ml), and 2-hydroperoxide-2-methylpropane (92.2 mg, 1.02 mmol) and tetrabutylammonium iodide (3.3 mg, 0.08 mmol) were added. 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 (ethyl acetate:petroleum ether = 2 / 1) to obtain the target product 2-methoxy-9-oxy-9H-indeno[2,1-d]pyrimidin-7-sulfonamide (88, 3.68 mg, yield 4.3%). ESI[M+H] + =292.2. 1 H NMR (600MHz, DMSO-d6) δ9.23 (s, 1H), 8.10 (d, J=8.9Hz, 1H), 8.04-8.00 (m, 2H), 7.55 (s, 2H), 4.03 (s, 3H).

[0739] Example 89: Preparation of (R)-7-chloro-2-((1-methylpyrrolidone-2-yl)methoxy)-9H inden[2,1d]pyrimidin-9-one

[0740]

[0741] 2,7-Dichloro-9H-indeno[2,1-d]pyrimidin-9-one (40 mg, 0.16 mmol) was dissolved in ultra-dry toluene (4 ml), and N-methyl-L-prolyl (18.74 mg, 0.16 mmol), 1,1′-binaphthyl-2,2′-bis(diphenylphosphine) (BINAP) (19.93 mg, 0.032 mmol), cesium carbonate (104.27 mg, 3.2 mmol) and palladium acetate (7.19 mg, 0.032 mmol) were added. The mixture was then microwaved at 110 °C for 1 hour under nitrogen protection. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (methanol:dichloromethane = 0%–50%) followed by preparative liquid chromatography to obtain the target product (R)-7-chloro-2-((1-methylpyrrolidone-2-yl)methoxy)-9H inden[2,1-d]pyrimidin-9-one (89 mg, 6.22 mg, yield 11.81%). ESI [M+H] + =330.10. 1 H NMR (400MHz, DMSO-d6) 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) , 4.65-4.51 (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).

[0742] Example 90: Preparation of 2-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-7-carbamate

[0743]

[0744] Step 1: Preparation of 4-(2-chloropyrimidin-5-yl)-3-carboxybenzonitrile (90-a)

[0745] 4-Bromo-3-carboxybenzonitrile (300 mg, 1.43 mmol) was dissolved in sec-butanol (20 mL), and 2-chloropyrimidin-5-boronic 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. The mixture was reacted under nitrogen protection at 120 °C with microwave for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (methanol:dichloromethane = 0%–50%) to obtain the target product 4-(2-chloropyrimidin-5-yl)-3-carboxybenzonitrile (90-a, 154.2 mg, yield 44.42%). ESI [M+H] + =244.0, 245.0.

[0746] Step 2: Preparation of 2-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-7-carbamate (90)

[0747] 4-(2-chloropyrimidin-5-yl)-3-carboxybenzonitrile (90-a, 100 mg, 0.41 mmol) was dissolved in 1,2-dichloroethane (10 mL), and tetrabutylammonium iodide (7.60 mg, 0.02 mmol) and tert-butylhydrogen peroxide (317 μl, 3.29 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 16 hours under nitrogen protection. The solvent was evaporated under reduced pressure, and the residue was pulped with tetrahydrofuran to obtain a crude product. This crude product was then purified by liquid chromatography to obtain the target product, 2-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-7-carbamate (90, 1.29 mg, yield 1.30%). ESI[M+H] + =242.1. 1 H NMR (400MHz, DMSO-d6) δ8.16 (d, J=7.8Hz, 1H), 8.24 (d, J=6.8Hz, 2H), 9.43 (s, 1H).

[0748] Example 91: Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1d]pyrimidin-7-yl)methanesulfonamide

[0749]

[0750] Step 1: Preparation of N-(4-bromo-3-formylphenyl)methanesulfonamide (91-a)

[0751] N-(3-formylphenyl)methanesulfonamide (200 mg, 1 mmol), 4-chloro-2-(trifluoromethyl)aniline (39 mg, 0.2 mmol), and N-bromosuccinimide (213.6 mg, 1.2 mmol) were added to 5 mL of dichloroethane and 2 mL of trifluoroacetic acid, and reacted overnight under nitrogen protection at 100 °C. The crude product was concentrated under reduced pressure and 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%).

[0752] Step 2: Preparation of N-(3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)methanesulfonamide (91-b)

[0753] N-(4-bromo-3-formylphenyl)methanesulfonamide (91-a, 130 mg, 0.431 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boronic 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). The mixture was reacted in a microwave at 120 °C for 1 hour under nitrogen protection. Water (10 ml) and ethyl acetate (10 ml * 2) were added for extraction. The mixture was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and 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%).

[0754] Step 3: Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1d]pyrimidin-7-yl)methanesulfonamide (91)

[0755] N-(3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)methanesulfonamide (91-b, 13 mg, 0.038 mmol) was dissolved in dichloroethane (2 ml), and 2-hydroperoxide-2-methylpropane (27.4 mg, 0.3 mmol) and tetra-n-butylammonium iodide (0.7 mg, 0.002 mmol) were added. The mixture was reacted at 100 °C for 16 hours under nitrogen protection. Water (10 ml) was added, and the mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by liquid chromatography (0.1% trifluoroacetic acid) 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

[0756] Example 92: Preparation of 9-oxo-9H-indeno[2,1-d]pyrimidine-2,7-dionitrile

[0757]

[0758] Step 1: Preparation of 5-(4-cyano-2-formylphenyl)pyrimidine-2-carbamate (92-a)

[0759] 4-Bromo-3-carboxybenzonitrile (250 mg, 1.19 mmol) was dissolved in acetonitrile (4 mL), and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrimidin-5-onitrile (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 reacted under nitrogen protection in a microwave oven at 120 °C for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by Flash column chromatography (methanol:dichloromethane = 0%–50%) to obtain the target product 5-(4-cyano-2-carboxyphenyl)pyrimidin-2-carboxynitrile (92-a, 250 mg, yield 89.67%).

[0760] Step 2: Preparation of 9-oxo-9H-indeno[2,1-d]pyrimidine-2,7-dionitrile (92)

[0761] 5-(4-cyano-2-formylphenyl)pyrimidin-2-carbamate (92-a, 5 mg, 0.213 mmol) was dissolved in 1,2-dichloroethane (2 mL), and tetrabutylammonium iodide (3.93 mg, 0.0106 mmol) and tert-butylhydrogen peroxide (153.6 mg, 1.704 mmol) were added. The mixture was reacted in a sealed tube at 100 °C for 16 hours under nitrogen protection. The solvent was evaporated under reduced pressure, and the crude product was purified by liquid chromatography to obtain the target product 9-oxo-9H-indeno[2,1-d]pyrimidin-2,7-dionitrile (92-a, 1.26 mg, yield 2.55%). ESI[M+H] + =233.1

[0762] Example 93: Preparation of 7-isopropyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dionitrile

[0763]

[0764] Step 1: Preparation of (E)-2-(hydroxyimino)-5-isopropyl-2,3-dihydro-1H-inden-1-one (93-a)

[0765] 5-Isopropyl-2,3-dihydro-1H-indene-1-one (400 mg, 2.72 mmol) was dissolved in methanol (10 ml), and isoamyl nitrite (296 mg, 2.99 mmol) and 36% hydrochloric acid (2 ml) were added. The mixture was reacted at 40 °C for 1 hour, then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to give 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.

[0766] Step 2: Preparation of 5-isopropyl-1H-inden-1,2(3H)-dione (93-b)

[0767] (E)-2-(hydroxyimino)-5-isopropyl-2,3-dihydro-1H-indone (93-a, 337 mg, 1.66 mmol) was dissolved in 36% formaldehyde solution (7 ml), and 36% hydrochloric acid (14 ml) was added. The reaction was carried out overnight at room temperature, quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 5-isopropyl-1H-indone-1,2(3H)-dione (93-b, 165 mg, yield 52.9%).

[0768] Step 3: Preparation of 7-isopropyl-9H-indeno[1,2-b]pyrazine-2,3-dionitrile (93-c)

[0769] 5-Isopropyl-1H-inden-1,2(3H)-dione (93-b, 165 mg, 0.877 mmol) was dissolved in isopropanol (7 mL), and 2,3-diaminomaleonitrile (94.8 mg, 0.877 mmol) was added. The mixture was reacted at room temperature for 24 hours, then concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to give the target product 7-isopropyl-9H-inden[1,2-b]pyrazine-2,3-dionitrile (93-c, 31 mg, yield 10.8%). ESI[M+H] + =261.2

[0770] Step 4: Preparation of 7-isopropyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dionitrile (93)

[0771] 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-dianitron (93-c, 30 mg, 0.115 mmol) and acetic acid (1.6 mL) were added. The mixture was reacted at 100 °C for 1 hour, quenched with water, and 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-performance 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-dianitron (93, 1.6 mg, yield 5.06%). + =275.2.

[0772] Example 94: Synthesis of ethyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1d]pyrimidine-7-carboxylate

[0773]

[0774] 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), and concentrated sulfuric acid (50 μl) was added. The reaction mixture was reacted at 50 °C for 12 hours. The reaction solution was concentrated under reduced pressure and then purified by chromatography to obtain the target product, ethyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (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).

[0775] Example 95: Synthesis of methyl-d3-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1d]pyrimidine-7-carboxylate

[0776]

[0777] 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), and concentrated sulfuric acid (50 μl) was added. The reaction mixture was reacted at 50 °C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (HPLC) to obtain the target product, methyl-d3-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid salt (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).

[0778] Test Example 1: Bioluminescent Assay for Inhibition of USP21 Enzyme Activity by Compounds

[0779] Experimental reagents and instruments:

[0780] GST-USP21 protein (Boston Biochem), Ub-AML (aminofluorescein-labeled ubiquitin, Boston Biochem), DUB buffer (50mM HEPES, pH 7.8, 100mM NaCl, 0.5mM EDTA, 0.01% (v / v) Tween-20, 1mM DTT), fluorescein assay kit (Promega), DMSO. Microplate reader (TECAN), white 384-well plate, microplate shaker.

[0781] Bioluminescence assay for the inhibitory activity of compounds on the catalytic activity of USP21:

[0782] Ub-AML was diluted to 3 μM with 50 mM HEPES at pH 7.5. The diluted Ub-AML solution and luciferin detection reagent were then mixed at a 1:9 ratio to prepare the Ub-AML-LDR reagent. GST-USP21 was diluted to 8 nM with DUB buffer and transferred to a 384-well plate. The plate was incubated with the diluted compound in a microplate shaker for 30 minutes (30°C, 500 rpm). The Ub-AML-LDR reagent was added to the test wells (final concentration: 2 nM GST-USP21, 150 nM Ub-AML). Immediately afterward, the bioluminescence signal was measured using a TECANSpark multimode microplate reader. Detection parameters: kinetic mode bioluminescence detection, detection time 40 minutes, tests every two minutes, integration time 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 IC50. 50 Values. The results of the USP21 enzyme inhibitory activity test are shown in Table 1 below:

[0783] For IC 50 The value, where "++++" represents IC. 50 <10nM; "+++" indicates IC 50 Between 10nM and 100nM (inclusive); "++" indicates IC 50 Between 100 nM and 1 μM (inclusive); "+" indicates IC 50 Between 1 μM and 10 μM (inclusive).

[0784] Table 1

[0785]

[0786]

[0787] The foregoing description of specific exemplary embodiments of this disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit this disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of this disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of this disclosure, as well as various different choices and variations. The scope of this disclosure is intended to be defined by the claims and their equivalents.

Claims

1. The following compounds or their pharmaceutically acceptable salts: 、 、 。 2. A pharmaceutical composition, characterized in that, The composition comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a USP inhibitor or a medicament for treating diseases associated with USP activity, or in the preparation of a kit for treating diseases associated with USP activity.

4. In the use according to claim 3, the diseases associated with the USP activity are selected from cardiovascular diseases, neurological disorders, cancer, or immune diseases.

5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a USP21 inhibitor or in a medicament for treating diseases associated with USP21 activity.

6. The use as described in claim 4, wherein the cancer is selected from prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, or leukemia.

7. The use as described in claim 6, wherein the cancer is selected from pancreatic cancer, liver cancer, breast cancer, kidney cancer, bladder cancer, or lung cancer.

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