WO2023208151A1 - Usp inhibitor, preparation method therefor, and application - Google Patents

Usp inhibitor, preparation method therefor, and application Download PDF

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WO2023208151A1
WO2023208151A1 PCT/CN2023/091368 CN2023091368W WO2023208151A1 WO 2023208151 A1 WO2023208151 A1 WO 2023208151A1 CN 2023091368 W CN2023091368 W CN 2023091368W WO 2023208151 A1 WO2023208151 A1 WO 2023208151A1
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alkyl
trifluoromethyl
mmol
pyrimidin
indeno
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PCT/CN2023/091368
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French (fr)
Chinese (zh)
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刘晓辉
王玉珣
张伟
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北京华森英诺生物科技有限公司
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Definitions

  • the present disclosure relates to the field of medicine, and in particular to a compound with USP inhibitory effect, its use and preparation method.
  • the ubiquitin-specific proteasome system is a dynamic bidirectional protein modification regulation system in cells, participating in the degradation and modification of more than 80% of proteins in cells. USP participates in a variety of life activities including cell cycle regulation, cell receptor function, gene transcription, immune response, and tumor growth through polyubiquitination of substrate proteins and degradation by the proteasome. This pathway is mediated by an enzymatic conjugation cascade, involving the continuous activation of ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) to complete ubiquitination of substrate proteins.
  • E1 ubiquitin activating enzyme
  • E2 ubiquitin conjugating enzyme
  • E3 ubiquitin ligase
  • the deubiquitinating enzyme family (DUBs) is responsible for specifically hydrolyzing ubiquitin molecules from proteins or precursor proteins linked to ubiquitin by hydrolyzing the ester bonds, peptide bonds or isopeptide bonds at the carboxyl terminus of ubiquitin. It plays the role of deubiquitination and reversely regulates protein degradation, thereby affecting protein function.
  • DUBs There are about 100 DUBs that have been discovered in the human genome. They play a supervisory role in the regulation of the ubiquitination system and regulate a variety of intracellular activities such as cell cycle, DNA repair, immunity, and protein homeostasis. Plays an important role (Regulation of proteolysis by human deubiquitinating enzymes, Ziad M Eletr, Keith D Wilkinson, Biochim Biophys Acta. 2014Jan; 1843(1):114-28.). Abnormal regulation of DUBs often leads to various human diseases such as cardiovascular diseases, neurological disorders, and tumors (Development of inhibitors in the ubiquitination cascade, Wei Zhang, Sachdev S Sidhu, FEBS Lett.
  • DUBs are divided into seven families based on sequence and structural similarities, namely the ubiquitin C-terminal hydrolase family (Ubiquitin C-terminal hydrolases, UCHs), the ubiquitin-specific protease family (Ubiquitin-specific proteases, USPs), the ovarian Ovarian tumor domain proteases (OTUs), MJD protease family (Machado-Josephin domain proteases, MJDs), Jab1/MPN domain associated metalloproteases (JAMMs), UFM1-specific zinc Refers to the peptidase family (Zinc finger with UFM1-specific peptidases, ZUFSPs) and the new MIU-containing DUB family (MINDY) (Jinhong et al., 2020).
  • Ubiquitin C-terminal hydrolases Ubiquitin C-terminal hydrolases, UCHs
  • Ubiquitin-specific protease family Ubiquitin-specific protea
  • USPs are by far the largest and most structurally diverse DUB family, containing approximately 60 members. This family belongs to cysteine proteases and contains two short and conserved sequences, namely the N-terminal Cys-box and C-terminal His-box composed of catalytically active cysteine and histidine residues. The sequence includes a catalytic triplet of residues, cysteine, histidine, and aspartate/asparagine, that remove ubiquitin molecules from larger proteins.
  • USPs Due to the protease activity of the USP family and its regulatory role in human life activities, USPs have become potential drug targets, for example, prostate cancer (Priolo et al., 2006; Stevenson et al., 2007) and breast cancer ( Qu et al., 2015) is related to the overexpression of USP2; USP7 is abnormally expressed in a variety of cancers including prostate cancer, lung cancer, brain cancer, colon cancer, breast cancer, epithelial ovarian cancer, liver cancer, and leukemia (Emerging insights into HAUSP (USP7) in physiology cancer and other diseases, Seemana Bhattacharya, Dipankar Chakraborty, Malini Basu, Mrinal K Ghosh, Signal Transduct Target Ther. 2018 Jun 29; 3:17.).
  • USP21 is a member of the USP family and is involved in the regulation of many intracellular activities.
  • Several key pathway oncogenes for USP21 deubiquitination and genes with oncogenic effects include HH/Gli, MEK2, MARK, Stem cell renewal/Nanog/GATA3, WNT, etc.
  • USP21 plays a role in many types of tumors, such as pancreatic cancer, liver cancer, breast cancer (triple negative breast cancer), kidney cancer, bladder cancer, lung cancer, etc. USP21 is also related to clinical prognosis of tumors.
  • USP21 Inhibiting USP21 inhibits cell proliferation and tumor growth.
  • USP21 inhibitor drugs There is significant clinical need for the development of USP21 inhibitor drugs. Therefore, USP21 is a First-in-Class cancer target with great potential and market value. It is of great significance to develop specific inhibitors for USP21 for molecular targeted therapy of related tumors and immune and other diseases related to abnormal USP21.
  • the present disclosure provides a substituted fused ring aromatic compound with a novel structure, which has high inhibitory activity as a USP enzyme inhibitor.
  • One aspect of the disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • the Cy1 ring is a 5-7 membered aromatic ring or a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S;
  • U 1 , U 2 , and U 3 are each independently selected from CH, CR 4 or N;
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 ring Alkyl group, 3 to 9-membered heterocycloalkyl group, -NR a R b , -C(O)-C 1-3 alkyl group, -C(O)NR a R b , -S(O) 2 C 1- 3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1 -6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl , -
  • n is an integer from 1 to 3;
  • R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, -C 1-3 alkoxy, amino, alkynyl, or adjacent R 3 and R 4 are connected to each other to form C 3 -6 cycloalkyl or 3 to 7-membered heterocycloalkyl, provided that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl, -C 1-3 alkoxy, - C 3-6 cycloalkyl or 3 to 7-membered heterocycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and amino;
  • R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl , -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 Alkyl-C 3-9 cycloalkyl, -C 1-3 alkyl-R a R b , -C 1-3 alkyl-C(O)H, -C 1-3 alkyl-C(O) -C 1-3 alkyl, -C
  • R a and R b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 alkylhydroxy, C 3-9 cycloalkyl or -C( O) R7 ;
  • the heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
  • R 1 , R 2 , R 3 and R 4 are not hydrogen at the same time.
  • adjacent R 3 and R 4 are connected to each other to form a C 3-6 cycloalkyl or 3 to 7-membered heterocyclyl group. It means that adjacent R 3 and R 4 are connected to each other and the ring to which they are respectively connected. The atoms on together form a C 3-6 cycloalkyl group or a 3 to 7 membered heterocyclyl group.
  • X 1 and X 2 are not hydrogen at the same time.
  • the compound does not include
  • n 1
  • the Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S;
  • U 1 , U 2 , and U 3 are each independently selected from CH, CR 4 or N;
  • X 1 and X 2 are independently selected from hydrogen , -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and X 2 and The atoms they are connected together form a 4- to 6-membered cycloalkyl group, and the 4- to 6-membered cycloalkyl group is optionally substituted by a carbonyl group; the condition is that X 1 and X 2 are not simultaneously NR 5 R 6 , OR 5 , SR 5 ;
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-9 cycloalkyl, 3 to 9
  • R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, -C 1-3 alkoxy, amino, alkynyl, or adjacent R 3 and R 4 are connected to each other to form C 3 -6 cycloalkyl or 3 to 7-membered heterocycloalkyl, provided that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl, -C 1-3 alkoxy, - C 3-6 cycloalkyl or 3 to 7-membered heterocycloalkyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, and amino;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered hetero Cycloalkyl, -NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl -C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl- C 3-9 cycloalkyl, -C 1-3 alkyl-R a R b , -C 1-3 alkyl-C(O)H, -C 1-3 alkyl-C(O)-C 1 -3 alkyl, -C 1-3 alkyl
  • R a and R b are each independently selected from hydrogen, C 1-3 alkyl or C 3-9 cycloalkyl;
  • the heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
  • R 1 , R 2 and R 3 , R 4 are not hydrogen at the same time.
  • 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.
  • the compound represented by formula (I) is a compound of formula (II), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof:
  • U 1 , U 2 , U 3 , U 4 and U 5 are each independently selected from CH, CR 4 or N;
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 ring Alkyl group, 3 to 9-membered heterocycloalkyl group, -NR a R b , -C(O)-C 1-3 alkyl group, -C(O)NR a R b , -S(O) 2 C 1- 3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -OC 1-3 alkyl-3 to 9-membered heterocycloalkyl,
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3 -9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR a R b , -C(O)-C 1-3 alkyl, -C(O)NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl Base-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-NR a R b , -C(N)
  • R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, or adjacent R 3 and R 4 are connected to each other to form a C 3-6 cycloalkyl or 3 to 7-membered heterocycloalkyl,
  • the condition is that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl group, -C 1-3 alkoxy group, -C 3-6 cycloalkyl group or 3 to 7-membered heterocycloalkyl group
  • the group is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and amino;
  • R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, or adjacent R 3 and R 4 are connected to each other to form a C 3-6 cycloalkyl group or 3 to 7-membered heterocycloalkyl, provided that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl group or 3- to 7-membered heterocycloalkyl group is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, etc.
  • R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl-C(O )H, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl-hydroxy; and the -C 1-6 alkyl, -C 1-6 alkoxy base, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino , -N(CH 3 ) 2 , hydroxyl, carboxyl substituent substitution;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl- C(O)H, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl-hydroxy; and the -C 1-6 alkyl, -C 1- 6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl optionally 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl, isopropyl, Substituted with substituents of amino group, N(CH 3 ) 2 , hydroxyl group, and carboxyl group.
  • R a and R b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-3 alkyl, C 1-3 alkyl hydroxyl, C 3-9 cycloalkyl or -C(O)R 7 ;
  • R a and R b are each independently selected from hydrogen, C 1-3 alkyl, or C 3-9 cycloalkyl.
  • the heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
  • R 1 , R 2 and R 3 , R 4 are not hydrogen at the same time.
  • U 1 , U 2 , U 3 , U 4 , and U 5 are each independently selected from CR 4 .
  • U 1 , U 2 , U 3 and U 5 are each independently selected from CR 4 , and U 4 is N.
  • U 1 , U 2 , U 3 and U 4 are each independently selected from CR 4 , and U 5 is N.
  • U 1 , U 2 , and U 3 are each independently selected from CR 4 , and U 4 and U 5 are both N.
  • U 2 and U 3 are each independently selected from CR 4 , and U 1 , U 4 and U 5 are all N.
  • U 3 is selected from CR 4 and U 1 , U 2 , U 4 and U 5 are all N.
  • the compound represented by formula (I) is a compound of formula (III), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof:
  • the Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S; R 1 , R 2 , R 3 , U 1 , U 2 , U 3 and n are each defined in the same formula (I ) compound or compound of formula (II), preferably, n is 1.
  • the compound represented by formula (I) is a compound of formula (VII), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof:
  • the Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S; R 1 , R 2 , R 3 , R 5 , U 1 , U 2 , U 3 and n are each defined With the compound of formula (I) or the compound of formula (II), preferably, n is 1.
  • the compound represented by formula (I) is compound (IIA), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
  • X 1 and X 2 are independently selected from hydrogen , -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and X 2 and the atoms connected to them together form a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by a carbonyl group; the condition is that X 1 and X 2 are not NR 5 R 6 at the same time , OR 5 , SR 5 ;
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR a R b , -C(O)-C 1-3 alkyl, -C(O)NR a R b , -SO 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkane base, -C 1-3 alkyl -C 3-9 cycloalkyl, -O-3 to 9 membered heterocycloalkyl, -OC 1-3 alkyl -3 to 9 membered heterocycloalkyl, -OC 1-3 alkyl
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3 -9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR a R b , -C(O)-C 1-3 alkyl, -C(O)NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl Base-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-NR a R b , -C(N)
  • R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl-C(O )H, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl-hydroxy; and the -C 1-6 alkyl, -C 1-6 alkoxy base, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino , -N(CH 3 ) 2 , hydroxyl, carboxyl substituent substitution;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl- C(O)H, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl-hydroxy; and the -C 1-6 alkyl, -C 1- 6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl optionally 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl, isopropyl, Substitution of amino, N(CH 3 ) 2 , hydroxyl, and carboxyl substituents;
  • R a and R b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-3 alkyl, C 1-3 alkyl hydroxyl, C 3-9 cycloalkyl or -C(O)R 7 ;
  • R a and R b are each independently selected from hydrogen, C 1-3 alkyl or C 3-9 cycloalkyl;
  • the heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
  • R 1 , R 2 and R 3 , R 4 are not hydrogen at the same time.
  • the compound represented by formula (I) is compound (IIB), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
  • X 1 , X 2 , R 1 , R 2 and R 3 are each defined the same as the compound of formula (I) or the compound of formula (IIA).
  • the compound represented by formula (I) is compound (IIC), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof:
  • X 1 , X 2 , R 1 , R 2 and R 3 are each defined the same as the compound of formula (I) or the compound of formula (IIA).
  • the compound represented by formula (I) is compound (IID), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
  • X 1 , X 2 , R 1 , R 2 and R 3 are each defined the same as the compound of formula (I) or the compound of formula (IIA).
  • the compound represented by formula (I) is compound (IIE), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
  • X, R 1 , R 2 and R 3 each have the same definition as the compound of formula (I) or the compound of formula (IIA).
  • the compound represented by formula (I) is compound (IIF), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
  • X 1 , X 2 , R 1 , R 2 and R 3 are each defined the same as the compound of formula (I) or the compound of formula (IIA).
  • X 1 and preferably piperazinyl substituted from hydrogen, hydroxyl, halogen, methyl, morpholinyl, methyl; or,
  • X 1 and _ _ _ _ _ Base - carboxyl preferably from hydroxyl, ethoxy, -(CH 2 ) 2 OH, -CH 2 COOH; or,
  • X 1 , X 2 and the atoms connected to them together form a carbonyl-substituted C 3-6 cycloalkyl group, preferably a cyclobutyl group.
  • X 1 and X 2 are each independently selected from hydrogen, hydroxyl, and -C 1-6 alkyl, preferably from hydrogen, hydroxyl, and methyl; or,
  • R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyanate, dimethylamino, methoxy , methyl, trifluoromethoxy, -CH 2 CN, -O-CN,
  • R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyanate, dimethylamino, methoxy ,methyl,
  • R 1 is selected from hydrogen, halogen, cyano, hydroxyl, thiocyanate, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -NR a R b , -NH-C(O)-C 1-3 alkoxy, -C(O)-C 1-3 alkyl, -C(O)NR a R b , -S(O) 2 C 1-3 alkyl, -OC 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C(NH)NR a R b , 5- or 6-membered heteroaryl ; And the -C 1-6 alkyl and 3 to 9-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 halogens;
  • R a and R b are each independently selected from hydrogen or -C 1-3 alkyl.
  • R1 is selected from hydrogen, F, Cl, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyanate, dimethylamino, methoxy, methyl,
  • R 2 is selected from hydrogen, hydroxyl, -C 1-6 alkyl or -C 1-6 alkoxy.
  • R2 is selected from hydrogen, hydroxyl, methyl or methoxy.
  • R 1 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyanate, dimethylamino, methoxy or the following group:
  • R 2 is selected from hydroxyl, methyl, methoxy or trifluoromethyl.
  • R 3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxyl, cyclopropyl, ethynyl, phenyl, nitro, amino, isopropyl, -C (O)OCH 3 , -C(O)H, -S-CF 3 , -S(O) 2 NH 2 , -S(O) 2 -CF 3 , -C(O)NH 2 , -C(O )N(CH 3 ) 2 , -C(O)NHOH, -C(O)NHCH 3 , -C(OH)(CH 3 ) 2 , -S(O) 2 CH 3 , -S(O)CH 2 CHO, -CH(CH 3 )OH, -CH 2 Br, -CH 2 OH, -CH 2 COOH,
  • R 3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxyl, cyclopropyl, phenyl, nitro, amino, isopropyl, -C(O) OCH 3 , -C(O)H, -S-CF 3 , -S(O) 2 NH 2 , -S(O) 2 -CF 3 , -C(O)NH 2 , -C(O)N( CH 3 ) 2 , -C(O)NHOH, -C(O)NHCH 3 , -C(OH)(CH 3 ) 2 , -S(O) 2 CH 3 , -CH(CH 3 )OH, -CH 2 Br, -CH 2 OH, -CH 2 COOH,
  • R 3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxylic acid or CONH 2 .
  • the halogen is selected from fluorine or chlorine.
  • R 4 is selected from halogen, cyano group, -C 1-3 alkyl; or, adjacent R 3 and R 4 are connected to each other to form a 5- or 6-membered oxygen-containing heterocyclic group.
  • R 4 is selected from halogen, cyano, -C 1-3 alkyl; or, adjacent R 3 and R 4 are connected to each other to form
  • formula (I), formula (II), formula (III), formula (IV), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) Or the compound described in formula (IIF)) is selected from the following group:
  • Another aspect of the present disclosure provides a method for preparing the above-mentioned compound.
  • the compound represented by formula (I) is a compound of formula (III) or a compound of formula (IV)
  • it is prepared by a method including the following steps:
  • Cy1 U 1 , U 2 , U 3 , R 1 , R 2 , R 3 , R 5 and n are each defined as above.
  • n is 1.
  • the oxidizing agent is selected from the group consisting of tert-butyl hydroperoxide, hydrogen peroxide, cumene hydroperoxide, dicumyl hydroperoxide, and 2,2,6,6-tetramethylpiperidine Oxide.
  • the catalyst is selected from the group consisting of tetrabutylammonium halide, potassium halide, sodium halide and elemental iodine.
  • the solvent is selected from methanol, ethanol, tert-butanol, isopropanol, n-butanol, sec-butanol, N,N-dimethylformamide, N,N-dimethylacetamide , N-methylpyrrolidone, dimethyl sulfoxide, methylene chloride, chloroform, carbon tetrachloride or 1,2-dichloroethane.
  • the oxidizing agent is tert-butyl hydroperoxide.
  • the catalyst is tetrabutylammonium iodide.
  • the solvent is 1,2-dichloroethane.
  • the compound of formula (III-1) is prepared by a method comprising the following steps:
  • U 1 , U 2 , U 3 , Cy1, R 1 , R 2 , R 3 and n are each defined as above.
  • n is 1;
  • R _ _ _ Borate ester group when R X' is selected from halogen atom, R X is selected from borate group or borate ester group.
  • R X is B(OH) 2 and R X' is Br.
  • Another aspect of the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug or a compound prepared by the above method and Pharmaceutically acceptable excipients.
  • the pharmaceutical composition further includes another drug for treating cardiovascular disease, neurological disorders, cancer, or immune disease.
  • Another aspect of the present disclosure provides the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-mentioned method for the treatment of cardiovascular diseases and neurological disorders. , drugs for cancer, immune diseases, or use in preparing kits for cardiovascular diseases, neurological disorders, cancer, immune diseases, or patient prognosis assessment.
  • Another aspect of the present disclosure provides a pharmaceutical composition for preparing drugs for treating cardiovascular diseases, neurological disorders, cancer, and immune diseases, or for preparing reagents for evaluating cardiovascular diseases, neurological disorders, cancer, immune diseases, or patient prognosis. Purpose in the box.
  • the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above method is provided for use in the preparation of treatments related to USP21 activity. uses in diseases.
  • the cancer includes prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, and leukemia.
  • the cancer includes pancreatic cancer, liver cancer, breast cancer, kidney cancer, bladder cancer and lung cancer.
  • the immune disease is an immune disease associated with USP activity.
  • the USP inhibitor is a USP21 inhibitor.
  • a method for inhibiting USP activity in a biological sample comprises mixing the biological sample with the above-mentioned compound, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, or a precursor thereof.
  • Another aspect of the present disclosure provides a method of treating a disease, cardiovascular disease, neurological disorder, cancer or immune disease related to USP21 activity, comprising administering the above compound, a pharmaceutically acceptable salt thereof, to a patient in need thereof , stereoisomers, solvates, prodrugs thereof, compounds prepared by the above methods, or steps of adding pharmaceutical compositions.
  • the cancer includes prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, and leukemia.
  • the disease associated with USP21 activity refers to a disease associated with abnormal USP21 activity.
  • Compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of this disclosure.
  • Compounds of the present disclosure also include tautomeric forms.
  • the tautomeric form results from the exchange of a single bond with an adjacent double bond and the accompanying migration of a proton.
  • C 1 -C 6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms;
  • C 3 - C6 means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur.
  • a heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present. This description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • substituted means that any one or more hydrogen atoms on a specific atom or group are replaced by a substituent, as long as the valence state of the specific atom or group is normal and the substituted compound is stable.
  • substituent O
  • the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable e.g., Rn
  • Rn variable
  • its definition in each instance is independent.
  • R for example, if a group is substituted by 1 to 5 R, then said group may optionally be substituted with up to 5 R, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably a lower alkyl group of 1 to 6 carbon atoms, non-limiting examples include methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl base, 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
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6 to 12 members, such as benzene base and naphthyl. More preferred is phenyl.
  • the aryl ring can be condensed on a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group containing a sulfur atom; or a three-membered nitrogen-containing fused ring containing a benzene ring.
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio group, carboxyl group or carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 12 yuan, more preferably 5 yuan or 6 yuan, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxalyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably pyridine, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidine Aldinyl or thiazolyl; more preferred are pyrazolyl, pyrrolyl and oxazolyl.
  • the heteroaryl ring may be fused to an ary
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio group, heterocycloalkylthio group, carboxyl group or carboxylate group.
  • Alkenyl refers to an alkenyl group, also known as an alkenyl group, wherein the alkenyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), wherein the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, cyano, nitro, phenol, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio group, carboxyl group or carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydrogen, nitro, chlorine, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkyl Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydrogen, nitro, chlorine, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkyl Thio group, heterocycloalkylthio group
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Carbonyl refers to -C(O)-.
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc refers to ethyl acetate
  • DMF N,N-dimethylformamide
  • TBAI refers to tetrabutylammonium iodide.
  • TFA trifluoroacetic acid
  • PdCl 2 (dppf) refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • DCE 1,2 dichloroethane
  • DIPEA diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • cbz-cr refers to benzyl chloroformate.
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone)dipalladium
  • Dppf refers to 1,1’-bisdiphenylphosphine ferrocene.
  • HATU refers to 2-(7-azabenzotriazole)-N,N,N’,N’-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilamide.
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi refers to lithium methyl
  • n-BuLi refers to n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • Boc refers to tert-butoxycarbonyl, and its structural formula is
  • ACN refers to acetonitrile
  • DCM dichloromethane
  • LDA lithium diisopropylamide
  • NMI 1-methyl-1H-imidazole
  • TCFH refers to N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.
  • DIBAL-H refers to diisobutylaluminum hydride.
  • m-CPBA refers to m-chloroperoxybenzoic acid.
  • Dioxane refers to 1,4-dioxane.
  • DMSO dimethyl sulfoxide
  • AIBN refers to azobisisobutyronitrile
  • TAA triethylamine
  • Oxone potassium peroxymonosulfonate
  • BINAP refers to 1,1'-binaphthyl-2,2'-bisdiphenylphosphine.
  • iPrOH refers to isopropyl alcohol.
  • Any hydrogen atom described in this disclosure may be replaced by its isotope deuterium.
  • R 1 is middle, The indicated position is connected to the Cy1 ring.
  • pharmaceutically acceptable means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissue without, commensurate with a reasonable benefit/risk ratio, undue toxicity, irritation, allergic reaction or other problems or complications of those compounds, materials, compositions and/or dosage forms.
  • pharmaceutically acceptable salt refers to a salt that retains the biological potency of the free acid and base of a particular compound without adverse biological effects.
  • acid including organic acids and inorganic acids
  • base addition salts including organic bases and inorganic bases.
  • salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the drugs or pharmaceutical compositions of the present disclosure may be administered orally, topically, parenterally, or mucosally (eg, bucally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers Apply. It is usually desirable to use the oral route.
  • the active agent may be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).
  • the active pharmaceutical ingredient may be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized cornstarch, polyvinylpyrrolidone, or hydroxypropylmethyl).
  • binders e.g., pregelatinized cornstarch, polyvinylpyrrolidone, or hydroxypropylmethyl.
  • cellulose cellulose
  • fillers for example, lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or calcium hydrogen phosphate
  • lubricants for example, , magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.
  • disintegrating agent for example, potato starch or hydroxyl sodium starch acetate
  • wetting agents for example, sodium lauryl sulfate
  • coloring and flavoring agents gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginate), Buffer salt, carboxymethyl cellulose, polyethylene glycol, wax, etc.
  • the pharmaceutical component may be derivatized with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), anti-sedimentation agent (e.g., sorbitol syrup, cellulose or hydrogenated edible fats), emulsifiers (e.g., lecithin or gum arabic), non-aqueous carriers (e.g., almond oil, oil esters, ethanol or fractionated vegetable oils), preservatives (e.g., p-hydroxybenzoic acid methyl ester or p-hydroxybenzoic acid propyl ester or sorbic acid) and other combinations.
  • Stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.
  • compositions of the present disclosure comprising a compound of formula I as active compound may also incorporate beads, microspheres or microcapsules, for example constructed from polyglycolic acid/lactic acid (PGLA).
  • PGLA polyglycolic acid/lactic acid
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions or they may be presented as a dry product for constitution with water or other suitable excipients before use.
  • Formulations for oral administration may be suitably formulated to provide controlled or delayed release of the active compound.
  • the drugs or pharmaceutical compositions of the present disclosure may be delivered parenterally, i.e., intravenously (i.v.), intracerebroventricularly (i.c.v.), subcutaneously (s.c.), intraperitoneally (i.p.), intramuscularly (i.m.), subcutaneously (s.d.) or intradermal (i.d.) administration, by direct injection, by, for example, bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, eg in ampoules or multi-dose containers with an added preservative.
  • compositions may take the form of excipients, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as anti-sedimentation agents, stabilizers and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.
  • the drugs or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as suppositories or retention enemas (eg, containing conventional suppository bases such as cocoa butter or other glycerides).
  • suppositories or retention enemas eg, containing conventional suppository bases such as cocoa butter or other glycerides.
  • treating includes inhibiting, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.
  • excipient is used herein to include any other compound that may be contained in or on the microparticles that is not a therapeutic or biologically active compound. Therefore, the excipients should be pharmaceutically or biologically acceptable or relevant, eg, the excipients are generally non-toxic to the subject. "Excipient” includes a single such compound and is also intended to include a plurality of compounds.
  • composition means a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the mode of administration and the nature of the dosage form, Including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, flavors, antibacterial agents , antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.
  • patient refers to any animal or cells thereof that is subject to the methods described herein, whether in vitro or in situ.
  • the patient, subject or individual is a human.
  • 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 body fluids, or extracts thereof things. 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, biological analysis, gene expression studies, and biological target identification.
  • USP21-mediated disorder, disease and/or condition refers to any disease or other deleterious condition in which USP21 or mutants thereof are known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or reducing the severity of one or more diseases in which USP21 or mutants thereof are known to play a role.
  • cancers of the present disclosure include, but are not limited to, leukemias (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyeloid leukemia, acute myelomonocytic leukemia , acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (such as Hodgkin's disease or non-Hodgkin's disease) , Waldenström's macroglobulinemia, multiple myeloma, heavy chain diseases, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, notochord Tumor, angiosarcoma, endot
  • the present disclosure provides combination therapies using compounds as described herein with other therapeutic agents.
  • the term "combination therapy" as used in this disclosure includes administration of these agents in a sequential manner, in which each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two agents, substantially simultaneously.
  • the sequence, or substantially simultaneous administration of each agent may be effected by any appropriate route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, and direct absorption through mucosal tissue.
  • the agents can be administered by the same route or by different routes. For example, a first agent may be administered orally and a second agent administered intravenously. Additionally, selected combination agents can be administered by intravenous injection, while other agents of the combination can be administered orally. Alternatively, for example, two or more agents may be administered by intravenous or subcutaneous injection.
  • NMR Agilent 400MR DD2 nuclear magnetic instrument.
  • the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ).
  • the internal standard is tetramethylsilane ( TMS).
  • Liquid mass spectrometry LC-MS: Agilent 1260 Infinity II–InfinityLab LC/MSD mass spectrometer.
  • HPLC Agilent 1260Infinity II high pressure liquid chromatograph (Sunfire C18 5 ⁇ m 150x 4.6mm column).
  • Thin layer chromatography silica gel plate HSGF254 silica gel plate (Yantai Jiangyou Silica Gel Development Co., Ltd.), specification 0.9mm-1mm.
  • TLC silica gel plate GF254 silica gel plate (Yucheng Chemical (Shanghai) Co., Ltd.), specifications 0.2mm ⁇ 0.25mm.
  • Reagents 4-bromo-3-formylbenzonitrile, (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid, (2-formyl-4-(trifluoromethyl)phenyl)boronic acid, Other reagents and starting materials such as 5-bromo-2-cyclopropylpyrimidine were purchased from Shanghai Bid or Leyan Reagent Company, or synthesized using methods known in the art.
  • Second step Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile (1) and 7-chloro-5-oxo-5H-indeno[ Preparation of 1,2-c]pyridine-3-carbonitrile (2)
  • Step 2 Preparation of 7-chloro-2-cyclopropyl-9H-indeno[2,1-d]pyrimidin-9-one (4)
  • Step 2 Preparation of tert-butyl (7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-2-yl) carbamate (5)
  • tert-butyl (5-(4-chloro-2-formylphenyl)pyrimidin-2-yl)carbamate 5a, 246 mg, 0.737 mmol
  • 1,2-dichloroethane 10 ml
  • tetrabutylammonium iodide 14 mg, 0.037 mmol
  • tert-butyl hydroperoxide 399 mg, 4.42 mmol
  • Step 2 Preparation of 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile (8)
  • Step 1 Preparation of 4′-chloro-2′-formyl-[1,1′-biphenyl 1-4-carbonitrile (17a)
  • Step 1 Preparation of 4'-chloro-6-formyl-[1,1'-biphenyl]-3-carbonitrile (30a)
  • Step 3 Preparation of 7-chloron-cyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidine-9-imine (40)
  • the target product 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one was finally purified by HPLC to obtain the target product compound 40: 7-chloro- n-Cyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidine-9-imine (3.18 mg, 13.97%).
  • Step 1 7-(trifluoromethyl)-9H-[1,3]dioxetane[4',5':5,6]indeno[2,1-d]pyrimidin-9-one 6
  • Step 1 7-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxetane-5-carbonaldehyde (43a)
  • the third step synthesis of 7-chloro-2-(trifluoromethyl)-9H-pyrido[3',2':3,4]cyclopentane[1,2-d]pyrimidin-9-one ( 46)
  • Step 1 Synthesis of methyl 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzoate (50-a)
  • Step 2 Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50)
  • Step 3 Synthesis of 7-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60)
  • 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, 2.10mg, yield 23.6%).
  • Step 1 Synthesis of 5-(1-methyl-1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (61-a)
  • Second step synthesis of 7-(1-methyl-1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one ( 61)
  • the crude product was purified by a preparation method to obtain the target product 7-bromo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-a, 260 mg, yield 31.7%).
  • Step 3 Synthesis of 7-(S-methylsulfonylimido)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67)
  • Step 1 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (68-a)
  • Step 4 Synthesis of 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile (73)
  • Step 1 Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (82-a)
  • 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.
  • Step 3 Preparation of 7-chloro-2-methoxy-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (83)
  • Step 1 Synthesis of 5-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d1[1,31dioxola-4-carbaldehyde (86-a)
  • Second step Synthesis of 8-(trifluoromethyl)-10H-[1,31dioxetane[4',5':4,51indeno[2,1-d]pyrimidin-10-one) ( 86)
  • N-(3-formylphenyl)methanesulfonamide 200mg, 1mmol
  • 4-chloro-2-(trifluoromethyl)aniline 39mg, 0.2mmol
  • N-bromosuccinimide 213.6 mg, 1.2 mmol
  • Step 2 Preparation of N-(3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)methanesulfonamide (91-b)
  • N-(4-Bromo-3-formylphenyl)methanesulfonamide (91-a, 130mg, 0.431mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (99.25mg, 0.517 mmol), palladium acetate (1.25mg, 0.022mmol), potassium fluoride (193.5mg, 0.862mmol) were dissolved in acetonitrile (2ml), reacted in nitrogen-protected microwave at 120°C for 1 hour, added water (10ml), ethyl acetate (10ml* 2) Extract, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure.
  • Step 3 Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)methanesulfonamide (91)
  • Step 1 Preparation of (E)-2-(Hydroxyimino)-5-isopropyl-2,3-dihydro-1H-inden-1-one (93-a)
  • the second step is the preparation of 5-isopropyl-1H-indene-1,2(3H)-dione (93-b)
  • Test Example 1 Bioluminescence test of compounds inhibiting USP21 enzyme activity
  • GST-USP21 protein Boston Biochem
  • Ub-AML aminofluorescein-labeled ubiquitin, Boston Biochem
  • DUB buffer 50mM HEPES, pH7.8, 100mM NaCl, 0.5mM EDTA, 0.01% (v/v) Tween-20 , 1mM DTT), luciferin detection reagent (Promega), DMSO.
  • Microplate reader TECAN
  • white 384-well plate microplate constant temperature shaker.
  • Bioluminescence assay was used to test the inhibitory activity of compounds on USP21 catalytic activity:
  • Ub-AML-LDR reagent Dilute Ub-AML to 3 ⁇ M with 50mM HEPES, pH 7.5, and prepare Ub-AML-LDR reagent by mixing the diluted Ub-AML solution and luciferin detection reagent at a ratio of 1:9.
  • GST-USP21 was diluted to 8 nM with DUB buffer and transferred to a 384-well plate, and incubated with the diluted compound on a microplate constant-temperature shaker for 30 minutes (30°C, 500 rpm). After adding the Ub-AML-LDR reagent to the test well (final concentration: 2nM GST-USP21, 150nM Ub-AML), immediately use the TECAN Spark multi-mode microplate reader to measure the bioluminescence signal.
  • Detection parameters kinetic mode detection of bioluminescence, The detection time is 40 minutes, and the test is performed every two minutes, with an integration time of 500ms. The initial reaction rate (slope of the first-order reaction) was calculated for each well and the data were analyzed using a 4-parameter logistic model to calculate IC50 values.
  • the USP21 enzyme inhibitory activity test results are as follows in Table 1:
  • IC 50 value For IC 50 value, "++++” means IC 50 ⁇ 10nM;"+++” means IC 50 is between 10nM and 100nM (inclusive); “++” means IC 50 is between 100nM and 1 ⁇ M between 100nM (inclusive); “+” means that the IC 50 is between 1 ⁇ M and 10 ⁇ M (inclusive of 1 ⁇ M).

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Abstract

The present disclosure provides a compound which has an inhibitory effect on USP, a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, as shown in formula (I), the definition of each group in the formula being detailed in the description. In addition, the present disclosure further provides a preparation method for the compound, a pharmaceutical composition including the compound, a use thereof in preparing a USP inhibitor, preparing a drug for treating cardiovascular diseases, neurological disorders, cancers or immune diseases, or preparing a kit for cardiovascular disease, neurological disorder, cancer, immune disease or patient prognosis evaluation, a method for inhibiting USP activity in a biological sample, and a method for treating USP21-mediated diseases, cardiovascular diseases, neurological disorders, cancers or immune diseases.

Description

USP抑制剂、其制备方法及应用USP inhibitors, preparation methods and applications thereof 技术领域Technical field
本公开涉及医药领域，特别涉及一种具有USP抑制作用的化合物，其用途及制备方法。The present disclosure relates to the field of medicine, and in particular to a compound with USP inhibitory effect, its use and preparation method.
背景技术Background technique
泛素特异性蛋白酶体系统(USP)在细胞内是一种动态的蛋白质双向修饰调控系统，参与细胞内80％以上的蛋白的降解和修饰。USP通过对底物蛋白的多聚泛素化并经蛋白酶体降解，参与包括细胞周期调节、细胞受体功能、基因转录、免疫反应以及肿瘤生长等多种生命活动。该途径由酶促共轭级联介导，涉及到泛素活化酶(E1)、泛素结合酶(E2)、泛素连接酶(E3)的持续激活，完成对底物蛋白的泛素化修饰(The ubiquitin-proteasome pathway:on protein death and cell life，Ciechanover，EMBO J.1998 Dec 15；17(24):7151-60.)，并由蛋白酶体完成对目标蛋白的降解或修饰；另一方面，去泛素化酶家族(DUBs)负责通过水解泛素羧基末端的酯键、肽键或异肽键，将泛素分子特异性的从链接有泛素的蛋白质或者前体蛋白水解下来，起到去泛素化的作用，对蛋白降解进行反向调节，从而影响蛋白质的功能。The ubiquitin-specific proteasome system (USP) is a dynamic bidirectional protein modification regulation system in cells, participating in the degradation and modification of more than 80% of proteins in cells. USP participates in a variety of life activities including cell cycle regulation, cell receptor function, gene transcription, immune response, and tumor growth through polyubiquitination of substrate proteins and degradation by the proteasome. This pathway is mediated by an enzymatic conjugation cascade, involving the continuous activation of ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) to complete ubiquitination of substrate proteins. Modification (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; another On the other hand, the deubiquitinating enzyme family (DUBs) is responsible for specifically hydrolyzing ubiquitin molecules from proteins or precursor proteins linked to ubiquitin by hydrolyzing the ester bonds, peptide bonds or isopeptide bonds at the carboxyl terminus of ubiquitin. It plays the role of deubiquitination and reversely regulates protein degradation, thereby affecting protein function.
目前在人类基因组中已经发现的DUB约有100个，他们在泛素化系统调节过程中扮演着监控者的角色，在调节细胞周期、DNA修复、免疫和蛋白质稳态等多种胞内活动中发挥着重要作用(Regulation of proteolysis by human deubiquitinating enzymes，Ziad M Eletr,Keith D Wilkinson，Biochim Biophys Acta.2014Jan；1843(1):114-28.)。DUBs的调节异常往往会引发如心血管疾病、神经紊乱以及肿瘤等多种人类疾病(Development of inhibitors in the ubiquitination cascade，Wei Zhang,Sachdev S Sidhu，FEBS Lett.2014 Jan 21；588(2):356-67.)。根据序列和结构的相似性将DUBs分为七大家族，分别是泛素羧基末端水解酶家族(Ubiquitin C-terminal hydrolases，UCHs)，泛素特异性蛋白酶家族(Ubiquitin-specific proteases，USPs)，卵巢瘤蛋白酶家族(Ovarian tumor domain proteases，OTUs)，MJD蛋白酶家族(Machado-Josephin domain proteases，MJDs)，Jab1/MPN相关的金属肽酶家族(Jab1/MPN domain associated metalloproteases，JAMMs)，UFM1特异性的锌指肽酶家族(Zinc finger with UFM1-specific peptidases，ZUFSPs)和含MIU的新型DUB家族(MINDY)(Jinhong et al.,2020)。There are about 100 DUBs that have been discovered in the human genome. They play a supervisory role in the regulation of the ubiquitination system and regulate a variety of intracellular activities such as cell cycle, DNA repair, immunity, and protein homeostasis. Plays an important role (Regulation of proteolysis by human deubiquitinating enzymes, Ziad M Eletr, Keith D Wilkinson, Biochim Biophys Acta. 2014Jan; 1843(1):114-28.). Abnormal regulation of DUBs often leads to various human diseases such as cardiovascular diseases, neurological disorders, and tumors (Development of inhibitors in the ubiquitination cascade, Wei Zhang, Sachdev S Sidhu, FEBS Lett. 2014 Jan 21; 588(2):356 -67.). DUBs are divided into seven families based on sequence and structural similarities, namely the ubiquitin C-terminal hydrolase family (Ubiquitin C-terminal hydrolases, UCHs), the ubiquitin-specific protease family (Ubiquitin-specific proteases, USPs), the ovarian Ovarian tumor domain proteases (OTUs), MJD protease family (Machado-Josephin domain proteases, MJDs), Jab1/MPN domain associated metalloproteases (JAMMs), UFM1-specific zinc Refers to the peptidase family (Zinc finger with UFM1-specific peptidases, ZUFSPs) and the new MIU-containing DUB family (MINDY) (Jinhong et al., 2020).
USPs是迄今最大且结构最具多样性的DUB家族，包含约60个成员。该家族属于半胱氨酸蛋白酶，含有两个短而保守的序列即具有催化活性的半胱氨酸和组氨酸残基组成的N端Cys-box和C端His-box。序列包括起催化作用的三联残基，即半胱氨酸、组氨酸、天冬氨酸/天冬酰胺，能将泛素分子从大的蛋白上移除。由于USP家族的蛋白酶活性及其在人体生命活动进程中的调节作用，使得USPs成为潜在的药物靶点，例如，前列腺癌(Priolo et al.,2006；Stevenson et al.,2007)和乳腺癌(Qu et al.,2015)与USP2的过度表达有关；USP7在多种癌症包括前列腺癌、肺癌、脑癌、结肠癌、乳腺癌、上皮性卵巢癌、肝癌以及白血病中表达异常(Emerging insights into HAUSP(USP7)in physiology cancer and other diseases，Seemana Bhattacharya,Dipankar Chakraborty,Malini Basu，Mrinal K Ghosh，Signal Transduct Target Ther.2018 Jun 29；3:17.)。USPs are by far the largest and most structurally diverse DUB family, containing approximately 60 members. This family belongs to cysteine proteases and contains two short and conserved sequences, namely the N-terminal Cys-box and C-terminal His-box composed of catalytically active cysteine and histidine residues. The sequence includes a catalytic triplet of residues, cysteine, histidine, and aspartate/asparagine, that remove ubiquitin molecules from larger proteins. Due to the protease activity of the USP family and its regulatory role in human life activities, USPs have become potential drug targets, for example, prostate cancer (Priolo et al., 2006; Stevenson et al., 2007) and breast cancer ( Qu et al., 2015) is related to the overexpression of USP2; USP7 is abnormally expressed in a variety of cancers including prostate cancer, lung cancer, brain cancer, colon cancer, breast cancer, epithelial ovarian cancer, liver cancer, and leukemia (Emerging insights into HAUSP (USP7) in physiology cancer and other diseases, Seemana Bhattacharya, Dipankar Chakraborty, Malini Basu, Mrinal K Ghosh, Signal Transduct Target Ther. 2018 Jun 29; 3:17.).
USP21是USP家族的一员，参与很多胞内活动的调节。USP21去泛素化的几个关键通路癌基因以及具有致癌作用的基因，包括HH/Gli,MEK2,MARK,Stem cell renewal/Nanog/GATA3,WNT等。USP21在多种类型肿瘤中起作用，例如，胰腺癌，肝癌，乳腺癌(三阴性乳腺癌)，肾癌，膀胱癌，肺癌等。USP21还和肿瘤临床预后有相关性。另外，近来的研究还表明，USP21在对抗病毒先天免疫反应的负调节中发挥着重要作用，主要是通过对视黄酸(维甲酸)诱导基因蛋白I(RIG-I)和干扰素刺激基因15蛋白(ISG15)的去泛素化实现(TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity，Michaela U Gack 1,Young C Shin,Chul-Hyun Joo,Tomohiko Urano et al.Nature.2007 Apr 19；446(7138):916-920.)。最新研究发现人胰腺癌时常有USP21基因扩增(22％PDAC)，USP21高表达和PDAC进展相关。在小鼠胰腺癌模型中，外源高表达USP21加速肿瘤生长，而敲除USP21抑制肿瘤生长。体外及体内研究表明USP21在癌症中起驱动作用。研究进一步揭示USP21在胰腺癌中通过WNT通路介导起作用。USP21 is a member of the USP family and is involved in the regulation of many intracellular activities. Several key pathway oncogenes for USP21 deubiquitination and genes with oncogenic effects include HH/Gli, MEK2, MARK, Stem cell renewal/Nanog/GATA3, WNT, etc. USP21 plays a role in many types of tumors, such as pancreatic cancer, liver cancer, breast cancer (triple negative breast cancer), kidney cancer, bladder cancer, lung cancer, etc. USP21 is also related to clinical prognosis of tumors. In addition, recent studies have also shown that USP21 plays an important role in negative regulation of the innate immune response to antiviral viruses, mainly by regulating retinoic acid (retinoic acid)-inducible gene protein I (RIG-I) and interferon-stimulated gene 15 Deubiquitination of protein (ISG15) is achieved (TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity, Michaela U Gack 1, Young C Shin, Chul-Hyun Joo, Tomohiko Urano et al. Nature. 2007 Apr 19;446(7138):916-920.). The latest research found that human pancreatic cancer often has USP21 gene amplification (22% PDAC), and high USP21 expression is related to the progression of PDAC. In mouse pancreatic cancer models, exogenous high expression of USP21 accelerates tumor growth, while knocking out USP21 inhibits tumor growth. In vitro and in vivo studies indicate that USP21 plays a driving role in cancer. The study further revealed that USP21 plays a role in pancreatic cancer through the WNT pathway.
抑制USP21能够抑制细胞增殖和肿瘤生长。目前，国际上有多家研究机构和制药公司都在对靶向DUBs的抑制剂进行研究，但是还没有靶向USP21的药物发现。开发USP21抑制剂药物的临床需求显著。因此，USP21是极具潜力和市场价值的First-in-Class癌症靶标。开发针对USP21的特异性抑制剂用于相关肿瘤及与USP21异常相关的免疫等其他疾病的分子靶向治疗具有重要意义。Inhibiting USP21 inhibits cell proliferation and tumor growth. Currently, many international research institutions and pharmaceutical companies are studying inhibitors targeting DUBs, but no drugs targeting USP21 have yet been discovered. There is significant clinical need for the development of USP21 inhibitor drugs. Therefore, USP21 is a First-in-Class cancer target with great potential and market value. It is of great significance to develop specific inhibitors for USP21 for molecular targeted therapy of related tumors and immune and other diseases related to abnormal USP21.
发明内容Contents of the invention
本公开提供了一种结构新颖的取代的稠环芳香化合物，其作为USP的酶抑制剂，具有较高的抑制活性。本公开的一方面，提供一种式(I)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
The present disclosure provides a substituted fused ring aromatic compound with a novel structure, which has high inhibitory activity as a USP enzyme inhibitor. One aspect of the disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
Cy1环为5-7元芳环或包含至少一个选自N、O或S的杂原子的5或6元杂芳环；The Cy1 ring is a 5-7 membered aromatic ring or a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S;
U1、U2、U3各自独立地选自CH、CR4或N；U 1 , U 2 , and U 3 are each independently selected from CH, CR 4 or N;
X1、X2分别独立地选自氢、-C1-6烷基、-NR5R6、-OR5、-SR5、卤素，或X1、X2共同形成＝O、＝S、＝NR5，或X1、X2和与它们相连的原子共同形成4至6元环烷基，所述4至6元环烷基任选地被羰基取代；条件是，X1、X2不同时为-NR5R6、-OR5或-SR5；X 1 and X 2 are independently selected from hydrogen, -C 1-6 alkyl, -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and =NR 5 , or X 1 , Not simultaneously -NR 5 R 6 , -OR 5 or -SR 5 ;
R1、R2、R3各自独立地选自氢、卤素、氰基、羟基、羧基、硝基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-C(O)-C1-3烷基、-C(O)NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-C2-4炔基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-O-3至9元杂环烷基、-O-C1-3烷基-3至9元杂环烷基、-C1-3烷基-NRaRb、-C(NH)NRaRb、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C1-3烷基-S(O)2C1-3烷基、-C2-6烯基、-C2-6炔基、5或6元杂芳基、C5-7芳基、-S-R7、-C(O)O-C1-3烷基、-S(O)2-NRaRb、-NRa-S(O)2Rb、-S(O)NH、-CHO或-NO2；且所述的-C1-3烷基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、5或6元杂芳基、C5-7芳基任选地被1、2或3个独立地选自氘、卤素、甲基、乙基、丙基、异丙基、氰基、氨基、-N(CH3)2、羟基、羧基或-CHO的取代基取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 ring Alkyl group, 3 to 9-membered heterocycloalkyl group, -NR a R b , -C(O)-C 1-3 alkyl group, -C(O)NR a R b , -S(O) 2 C 1- 3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1 -6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl , -OC 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-NR a R b , -C (NH)NR a R b , -C 1-3 alkyl-C (O)-C 1-3 alkyl, -C 1-3 alkyl-C(O)NR a R b , -C 1-3 alkyl-S(O) 2 C 1-3 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 5 or 6-membered heteroaryl, C 5-7 aryl, -SR 7 , -C(O)OC 1-3 alkyl, -S(O) 2 -NR a R b , -NR a -S(O) 2 R b , -S(O)NH, -CHO or -NO 2 ; and the -C 1-3 alkyl group, -C 1-6 Alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl - 3 to 9 membered heterocycloalkyl, -C 1 -3 alkyl-C 3-9 cycloalkyl, 5 or 6 membered heteroaryl, C 5-7 aryl optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl , propyl, isopropyl, cyano, amino, -N(CH 3 ) 2 , hydroxyl, carboxyl or -CHO substituents;
n为1-3的整数；n is an integer from 1 to 3;
R4选自氢、卤素、氰基、羟基、-C1-3烷基、-C1-3烷氧基、氨基、炔基、或者相邻的R3与R4相互连接共同形成C3-6环烷基或3至7元杂环烷基，条件是，U1和U2至少有一个为CR4；所述-C1-3烷基、-C1-3烷氧基、-C3-6环烷基或3至7元杂环烷基任选地被一个或多个选自氘、卤素、氰基、羟基、氨基的取代基所取代；R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, -C 1-3 alkoxy, amino, alkynyl, or adjacent R 3 and R 4 are connected to each other to form C 3 -6 cycloalkyl or 3 to 7-membered heterocycloalkyl, provided that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl, -C 1-3 alkoxy, - C 3-6 cycloalkyl or 3 to 7-membered heterocycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and amino;
R5、R6、R7各自独立地选自氢、卤素、氰基、羟基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-C2-4炔基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-C1-3烷基-RaRb、-C1-3烷基-C(O)H、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C2-6烯基或-C2-6炔基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基任选地被1、2或3个独立地选自氘、卤素、甲基、乙基、丙基、异丙基、氨基、-N(CH3)2、羟基、羧基的取代基取代；或，R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl , -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 Alkyl-C 3-9 cycloalkyl, -C 1-3 alkyl-R a R b , -C 1-3 alkyl-C(O)H, -C 1-3 alkyl-C(O) -C 1-3 alkyl, -C 1-3 alkyl -C(O)NR a R b , -C 2-6 alkenyl or -C 2-6 alkynyl; and the -C 1-6 Alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl - 3 to 9 membered heterocycloalkyl, -C 1 -3 alkyl -C 3-9 cycloalkyl optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino, -N(CH 3 ) 2. Substitution of hydroxyl and carboxyl substituents; or,
X1或X2为-NR5R6时，R5、R6与其相连的N原子共同形成5或6元杂环烷基，所述5或6元杂环烷基任选地被选自C1-6烷基的取代基取代； When X 1 or _ _ C 1-6 alkyl substituent substitution;
Ra、Rb各自独立地选自氢、氘、羟基、C1-3烷基、氘代C1-3烷基、C1-3烷羟基、C3-9环烷基或-C(O)R7；R a and R b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 alkylhydroxy, C 3-9 cycloalkyl or -C( O) R7 ;
所述杂环烷基或杂芳基具有至少一个选自N、O和S的杂原子作为环原子；The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
R1、R2、R3和R4不同时为氢。R 1 , R 2 , R 3 and R 4 are not hydrogen at the same time.
如本文所用，相邻的R3与R4相互连接共同形成C3-6环烷基或3至7元杂环基指的是相邻的R3与R4相互连接，与其各自连接的环上的原子共同形成C3-6环烷基或3至7元杂环基。As used herein, adjacent R 3 and R 4 are connected to each other to form a C 3-6 cycloalkyl or 3 to 7-membered heterocyclyl group. It means that adjacent R 3 and R 4 are connected to each other and the ring to which they are respectively connected. The atoms on together form a C 3-6 cycloalkyl group or a 3 to 7 membered heterocyclyl group.
优选地，X1、X2不同时为氢。Preferably, X 1 and X 2 are not hydrogen at the same time.
在一实施方案中，所述化合物不包括 In one embodiment, the compound does not include
在一实施方案中，式(I)所示的化合物中，n为1。In one embodiment, in the compound represented by formula (I), n is 1.
Cy1环为包含至少一个选自N、O或S的杂原子的5或6元杂芳环；The Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S;
U1、U2、U3各自独立地选自CH、CR4或N；U 1 , U 2 , and U 3 are each independently selected from CH, CR 4 or N;
X1、X2分别独立地选自氢、-NR5R6、-OR5、-SR5、卤素，或X1、X2共同形成＝O、＝S、＝NR5，或X1、X2和与 它们相连的原子共同形成4至6元环烷基，所述4至6元环烷基任选地被羰基取代；条件是，X1、X2不同时为NR5R6、OR5、SR5；X 1 and X 2 are independently selected from hydrogen , -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and X 2 and The atoms they are connected together form a 4- to 6-membered cycloalkyl group, and the 4- to 6-membered cycloalkyl group is optionally substituted by a carbonyl group; the condition is that X 1 and X 2 are not simultaneously NR 5 R 6 , OR 5 , SR 5 ;
R1、R2、R3各自独立地选自氢、卤素、氰基、羟基、羧基、C1-6烷基、C1-6烷氧基、C3-9环烷基、3至9元杂环烷基、-NRaRb、-C(O)-C1-3烷基、-C(O)NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-C2-4炔基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-O-3至9元杂环烷基、-C1-3烷基-NRaRb、-C(N)NRaRb、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C1-3烷基-S(O)2C1-3烷基、-C2-6烯基、-C2-6炔基、5或6元杂芳基或C5-7芳基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、5或6元杂芳基、C5-7芳基任选地被1、2或3个独立地选自卤素、甲基、乙基、丙基、异丙基、氰基、氨基、N(CH3)2、羟基、羧基的取代基取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-9 cycloalkyl, 3 to 9 One-membered heterocycloalkyl, -NR a R b , -C(O)-C 1-3 alkyl, -C(O)NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -C 1-3 Alkyl-NR a R b , -C(N)NR a R b , -C 1-3 alkyl-C(O)-C 1-3 alkyl, -C 1-3 alkyl-C(O) NR a R b , -C 1-3 alkyl -S(O) 2 C 1-3 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 5- or 6-membered heteroaryl or C 5-7 aryl; and the -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -C 1-3 Alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, 5- or 6-membered heteroaryl, C 5-7 aryl optionally substituted by 1, 2 or Substituted with 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, N(CH 3 ) 2 , hydroxyl, and carboxyl;
R4选自氢、卤素、氰基、羟基、-C1-3烷基、-C1-3烷氧基、氨基、炔基、或者相邻的R3与R4相互连接共同形成C3-6环烷基或3至7元杂环烷基，条件是，U1和U2至少有一个为CR4；所述-C1-3烷基、-C1-3烷氧基、-C3-6环烷基或3至7元杂环烷基任选地被一个或多个选自卤素、氰基、羟基、氨基的取代基所取代；R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, -C 1-3 alkoxy, amino, alkynyl, or adjacent R 3 and R 4 are connected to each other to form C 3 -6 cycloalkyl or 3 to 7-membered heterocycloalkyl, provided that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl, -C 1-3 alkoxy, - C 3-6 cycloalkyl or 3 to 7-membered heterocycloalkyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, and amino;
R5、R6各自独立地选自氢、卤素、氰基、羟基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-C2-4炔基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-C1-3烷基-RaRb、-C1-3烷基-C(O)H、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C2-6烯基、-C2-6炔基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基、异丙基、氨基、N(CH3)2、羟基、羧基的取代基取代；R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered hetero Cycloalkyl, -NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl -C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl- C 3-9 cycloalkyl, -C 1-3 alkyl-R a R b , -C 1-3 alkyl-C(O)H, -C 1-3 alkyl-C(O)-C 1 -3 alkyl, -C 1-3 alkyl -C(O)NR a R b , -C 2-6 alkenyl, -C 2-6 alkynyl; and the -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl - 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl -C 3-9 cycloalkyl optionally substituted by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl, isopropyl, amino, N(CH 3 ) 2 , hydroxyl, carboxyl substituent substitution;
Ra、Rb各自独立地选自氢、C1-3烷基或C3-9环烷基；R a and R b are each independently selected from hydrogen, C 1-3 alkyl or C 3-9 cycloalkyl;
所述杂环烷基或杂芳基具有至少一个选自N、O和S的杂原子作为环原子；The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
R1、R2和R3、R4不同时为氢。R 1 , R 2 and R 3 , R 4 are not hydrogen at the same time.
在一实施方案中，Cy1环为咪唑环、苯环、吡啶环或嘧啶环，优选为苯环、吡啶环或嘧啶环。在一实施方案中，式(I)所示的化合物为式(II)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
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, a stereoisomer, a solvate or a prodrug thereof:
式中，In the formula,
U1、U2、U3、U4、U5各自独立地选自CH、CR4或N；U 1 , U 2 , U 3 , U 4 and U 5 are each independently selected from CH, CR 4 or N;
X1、X2分别独立地选自氢、-C1-6烷基、-NR5R6、-OR5、-SR5、卤素，或X1、X2共同形成＝O、＝S、＝NR5，或X1、X2和与它们相连的原子共同形成4至6元杂环烷基，所述4至6杂环烷基任选地被羰基取代；条件是，X1、X2不同时为-NR5R6、-OR5或-SR5；X 1 and X 2 are independently selected from hydrogen, -C 1-6 alkyl, -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and =NR 5 , or X 1 , 2 does not mean -NR 5 R 6 , -OR 5 or -SR 5 at the same time;
在一实施方案中，X1、X2分别独立地选自氢、-NR5R6、-OR5、-SR5、卤素，或X1、X2共同形成＝O、＝S、＝NR5，或X1、X2和与它们相连的原子共同形成4至6元杂环烷基，所述4至6杂环烷基任选地被羰基取代；条件是，X1、X2不同时为NR5R6、OR5、SR5。In one embodiment, X 1 and X 2 are each independently selected from hydrogen, -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and X 2 together form =O, =S, =NR 5 , or X 1 , It is NR 5 R 6 , OR 5 , SR 5 at the same time.
R1、R2、R3各自独立地选自氢、卤素、氰基、羟基、羧基、硝基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-C(O)-C1-3烷基、-C(O)NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-O-3至9元杂环烷基、-O-C1-3烷基-3至9元杂环烷基、-C1-3烷基-NRaRb、-C(NH)NRaRb、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C2-6炔基、5或6元杂芳基、C5-7芳基、-S-R7、-C(O)O-C1-3烷基、-S(O)2NRaRb、-NRa-S(O)2Rb、-S(O)NH、-CHO、-NO2；且所述的-C1-3烷基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、5或6元杂芳基、C5-7芳基任选地被1、2或3个独立地选自氘、卤素、甲基、乙基、丙基、异丙基、氰基、氨基、-N(CH3)2、羟基、羧基的取代基取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 ring Alkyl group, 3 to 9-membered heterocycloalkyl group, -NR a R b , -C(O)-C 1-3 alkyl group, -C(O)NR a R b , -S(O) 2 C 1- 3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -OC 1-3 alkyl-3 to 9-membered heterocycle Alkyl, -C 1-3 alkyl -NR a R b , -C(NH)NR a R b , -C 1-3 alkyl -C(O)-C 1-3 alkyl, -C 1- 3Alkyl -C(O)NR a R b , -C 2-6 alkynyl, 5- or 6-membered heteroaryl, C 5-7 aryl, -SR 7 , -C(O)OC 1-3 alkyl base, -S(O) 2 NR a R b , -NR a -S(O) 2 R b , -S(O)NH, -CHO, -NO 2 ; and the -C 1-3 alkyl group , -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, 5 or 6 membered heteroaryl, C 5-7 aryl Optionally substituted by 1, 2 or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -N(CH 3 ) 2 , hydroxyl, carboxyl replace;
在一实施方案中，R1、R2、R3各自独立地选自氢、卤素、氰基、羟基、羧基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-C(O)-C1-3烷基、-C(O)NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-O-3至9元杂环烷基、-C1-3烷基-NRaRb、-C(N)NRaRb、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C2-6炔基、5或6元杂芳基、C5-7芳基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、5或6元杂芳基、C5-7芳基任选地被、丙基、异丙基、氰基、氨基、N(CH3)2、羟基、羧基的取代基取代。In one embodiment, R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3 -9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR a R b , -C(O)-C 1-3 alkyl, -C(O)NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl Base-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-NR a R b , -C(N)NR a R b , -C 1-3 alkyl-C(O)-C 1-3 alkyl, -C 1-3 alkyl-C(O)NR a R b , - C 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 base, 3 to 9-membered heterocycloalkyl, 5- or 6-membered heteroaryl, C 5-7 aryl optionally, propyl, isopropyl, cyano, amino, N(CH 3 ) 2 , hydroxyl , substituent substitution of carboxyl group.
R4选自氢、卤素、氰基、羟基、-C1-3烷基、或相邻R3与R4相互连接共同形成C3-6环烷基或3至7元杂环烷基，条件是，U1和U2至少有一个为CR4；所述-C1-3烷基、-C1-3烷氧基、-C3-6环烷基或3至7元杂环烷基任选地被一个或多个选自氘、卤素、氰基、羟基、氨基的取代基所取代；R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, or adjacent R 3 and R 4 are connected to each other to form a C 3-6 cycloalkyl or 3 to 7-membered heterocycloalkyl, The condition is that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl group, -C 1-3 alkoxy group, -C 3-6 cycloalkyl group or 3 to 7-membered heterocycloalkyl group The group is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and amino;
在一实施方案中，R4选自氢、卤素、氰基、羟基、-C1-3烷基、或相邻R3与R4相互连接共同形成C3-6环烷基或 3至7元杂环烷基，条件是，U1和U2至少有一个为CR4；所述-C1-3烷基、-C1-3烷氧基、-C3-6环烷基或3至7元杂环烷基任选地被一个或多个选自卤素、氰基、羟基、氨基、的取代基所取代。In one embodiment, R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, or adjacent R 3 and R 4 are connected to each other to form a C 3-6 cycloalkyl group or 3 to 7-membered heterocycloalkyl, provided that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl group or 3- to 7-membered heterocycloalkyl group is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, etc.
R5、R6、R7各自独立地选自氢、卤素、氰基、羟基、-C1-6烷基、-C1-6烷氧基、-C1-3烷基-C(O)H、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-羟基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基任选地被1、2或3个独立选自氘、卤素、甲基、乙基、丙基、异丙基、氨基、-N(CH3)2、羟基、羧基的取代基取代；R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl-C(O )H, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl-hydroxy; and the -C 1-6 alkyl, -C 1-6 alkoxy base, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino , -N(CH 3 ) 2 , hydroxyl, carboxyl substituent substitution;
在一实施方案中，R5、R6各自独立地选自氢、卤素、氰基、羟基、-C1-6烷基、-C1-6烷氧基、-C1-3烷基-C(O)H、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-羟基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基、异丙基、氨基、N(CH3)2、羟基、羧基的取代基取代。In one embodiment, R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl- C(O)H, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl-hydroxy; and the -C 1-6 alkyl, -C 1- 6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl optionally 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl, isopropyl, Substituted with substituents of amino group, N(CH 3 ) 2 , hydroxyl group, and carboxyl group.
Ra、Rb各自独立地选自氢、氘、羟基、C1-3烷基、C1-3烷羟基、C3-9环烷基或-C(O)R7；R a and R b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-3 alkyl, C 1-3 alkyl hydroxyl, C 3-9 cycloalkyl or -C(O)R 7 ;
在一实施方案中，Ra、Rb各自独立地选自氢、C1-3烷或C3-9环烷基。In one embodiment, R a and R b are each independently selected from hydrogen, C 1-3 alkyl, or C 3-9 cycloalkyl.
所述杂环烷基或杂芳基具有至少一个选自N、O和S的杂原子作为环原子；The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
R1、R2和R3、R4不同时为氢。R 1 , R 2 and R 3 , R 4 are not hydrogen at the same time.
在一实施方案中，U1、U2、U3、U4、U5各自独立地选自CR4。In one embodiment, U 1 , U 2 , U 3 , U 4 , and U 5 are each independently selected from CR 4 .
在一实施方案中，U1、U2、U3、U5各自独立地选自CR4，U4为N。In one embodiment, U 1 , U 2 , U 3 and U 5 are each independently selected from CR 4 , and U 4 is N.
在一实施方案中，U1、U2、U3、U4各自独立地选自CR4，U5为N。In one embodiment, U 1 , U 2 , U 3 and U 4 are each independently selected from CR 4 , and U 5 is N.
在一实施方案中，U1、U2、U3各自独立地选自CR4，U4、U5均为N。In one embodiment, U 1 , U 2 , and U 3 are each independently selected from CR 4 , and U 4 and U 5 are both N.
在一实施方案中，U2、U3各自独立地选自CR4，U1、U4、U5均为N。In one embodiment, U 2 and U 3 are each independently selected from CR 4 , and U 1 , U 4 and U 5 are all N.
在一实施方案中，U3选自CR4，U1、U2、U4、U5均为N。In one embodiment, U 3 is selected from CR 4 and U 1 , U 2 , U 4 and U 5 are all N.
在一实施方案中，式(I)所示的化合物为式(III)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
In one embodiment, the compound represented by formula (I) is a compound of formula (III), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof:
式中，In the formula,
Cy1环为包含至少一个选自N、O或S的杂原子的5或6元杂芳环；R1、R2、R3、U1、U2、U3、n各自定义同式(I)化合物或式(II)化合物，优选地，n为1。The Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S; R 1 , R 2 , R 3 , U 1 , U 2 , U 3 and n are each defined in the same formula (I ) compound or compound of formula (II), preferably, n is 1.
在一实施方案中，式(I)所示的化合物为式(VII)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
In one embodiment, the compound represented by formula (I) is a compound of formula (VII), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof:
式中，In the formula,
Cy1环为包含至少一个选自N、O或S的杂原子的5或6元的杂芳环；R1、R2、R3、R5、U1、U2、U3、n各自定义同式(I)化合物或式(II)化合物，优选地，n为1。The Cy1 ring is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S; R 1 , R 2 , R 3 , R 5 , U 1 , U 2 , U 3 and n are each defined With the compound of formula (I) or the compound of formula (II), preferably, n is 1.
在一实施方案中，式(I)所示的化合物为(IIA)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
In one embodiment, the compound represented by formula (I) is compound (IIA), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
式中，In the formula,
X1、X2分别独立地选自氢、-NR5R6、-OR5、-SR5、卤素，或X1、X2共同形成＝O、＝S、＝NR5，或X1、X2和与它们相连的原子共同形成4至6元杂环烷基，所述4至6杂环烷基任选地被羰基取代；条件是，X1、X2不同时为NR5R6、OR5、SR5；X 1 and X 2 are independently selected from hydrogen , -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and X 2 and the atoms connected to them together form a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by a carbonyl group; the condition is that X 1 and X 2 are not NR 5 R 6 at the same time , OR 5 , SR 5 ;
R1、R2、R3各自独立地选自氢、卤素、氰基、羟基、羧基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-C(O)-C1-3烷基、-C(O)NRaRb、-SO2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-O-3至9元杂环烷基、-O-C1-3烷基-3至9元杂环烷基、-C1-3烷基-NRaRb、-C(NH)NRaRb、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C2-6炔基、5或6元杂芳基、C5- 7芳基、-SR7、-C(O)O-C1-3烷基、-SO2NRaRb、-NRaSO2Rb、-S(O)NH、-CHO、-NO2；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、5或6元杂芳基、C5-7芳基任选地被氘、卤素、甲基、乙基、丙基、 异丙基、氰基、氨基、-N(CH3)2、羟基、羧基的取代基取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR a R b , -C(O)-C 1-3 alkyl, -C(O)NR a R b , -SO 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkane base, -C 1-3 alkyl -C 3-9 cycloalkyl, -O-3 to 9 membered heterocycloalkyl, -OC 1-3 alkyl -3 to 9 membered heterocycloalkyl, -C 1 -3 alkyl-NR a R b , -C(NH)NR a R b , -C 1-3 alkyl-C(O)-C 1-3 alkyl, -C 1-3 alkyl-C( O )NR a R b , -C 2-6 alkynyl, 5- or 6-membered heteroaryl, C 5-7 aryl, -SR 7 , -C(O)OC 1-3 alkyl, -SO 2 NR a R b , -NR a SO 2 R b , -S(O)NH, -CHO, -NO 2 ; and the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 3 -9 cycloalkyl, 3 to 9 membered heterocycloalkyl, 5 or 6 membered heteroaryl, C 5-7 aryl optionally deuterated, halogen, methyl, ethyl, propyl, Substituted with isopropyl, cyano, amino, -N(CH 3 ) 2 , hydroxyl, and carboxyl substituents;
在一实施方案中，R1、R2、R3各自独立地选自氢、卤素、氰基、羟基、羧基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-C(O)-C1-3烷基、-C(O)NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-O-3至9元杂环烷基、-C1-3烷基-NRaRb、-C(N)NRaRb、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C2-6炔基、5或6元杂芳基、C5-7芳基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、5或6元杂芳基、C5-7芳基任选地被、丙基、异丙基、氰基、氨基、N(CH3)2、羟基、羧基的取代基取代。In one embodiment, R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3 -9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -NR a R b , -C(O)-C 1-3 alkyl, -C(O)NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl Base-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-NR a R b , -C(N)NR a R b , -C 1-3 alkyl-C(O)-C 1-3 alkyl, -C 1-3 alkyl-C(O)NR a R b , - C 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 base, 3 to 9-membered heterocycloalkyl, 5- or 6-membered heteroaryl, C 5-7 aryl optionally, propyl, isopropyl, cyano, amino, N(CH 3 ) 2 , hydroxyl , substituent substitution of carboxyl group.
R5、R6、R7各自独立地选自氢、卤素、氰基、羟基、-C1-6烷基、-C1-6烷氧基、-C1-3烷基-C(O)H、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-羟基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基任选地被1、2或3个独立选自氘、卤素、甲基、乙基、丙基、异丙基、氨基、-N(CH3)2、羟基、羧基的取代基取代；R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl-C(O )H, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl-hydroxy; and the -C 1-6 alkyl, -C 1-6 alkoxy base, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino , -N(CH 3 ) 2 , hydroxyl, carboxyl substituent substitution;
在一实施方案中，R5、R6各自独立地选自氢、卤素、氰基、羟基、-C1-6烷基、-C1-6烷氧基、-C1-3烷基-C(O)H、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-羟基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基、异丙基、氨基、N(CH3)2、羟基、羧基的取代基取代；In one embodiment, R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl- C(O)H, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl-hydroxy; and the -C 1-6 alkyl, -C 1- 6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl optionally 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl, isopropyl, Substitution of amino, N(CH 3 ) 2 , hydroxyl, and carboxyl substituents;
Ra、Rb各自独立地选自氢、氘、羟基、C1-3烷基、C1-3烷羟基、C3-9环烷基或-C(O)R7；R a and R b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-3 alkyl, C 1-3 alkyl hydroxyl, C 3-9 cycloalkyl or -C(O)R 7 ;
在一实施方案中，Ra、Rb各自独立地选自氢、C1-3烷基或C3-9环烷基；In one embodiment, R a and R b are each independently selected from hydrogen, C 1-3 alkyl or C 3-9 cycloalkyl;
所述杂环烷基或杂芳基具有至少一个选自N、O和S的杂原子作为环原子；The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
R1、R2和R3、R4不同时为氢。R 1 , R 2 and R 3 , R 4 are not hydrogen at the same time.
在一实施方案中，式(I)所示的化合物为(IIB)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
In one embodiment, the compound represented by formula (I) is compound (IIB), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
式中，X1、X2、R1、R2、R3各自定义同式(I)化合物或式(IIA)化合物。In the formula, X 1 , X 2 , R 1 , R 2 and R 3 are each defined the same as the compound of formula (I) or the compound of formula (IIA).
在一实施方案中，式(I)所示的化合物为(IIC)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
In one embodiment, the compound represented by formula (I) is compound (IIC), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof:
式中，X1、X2、R1、R2、R3各自定义同式(I)化合物或式(IIA)化合物。In the formula, X 1 , X 2 , R 1 , R 2 and R 3 are each defined the same as the compound of formula (I) or the compound of formula (IIA).
在一实施方案中，式(I)所示的化合物为(IID)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
In one embodiment, the compound represented by formula (I) is compound (IID), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
式中，X1、X2、R1、R2、R3各自定义同式(I)化合物或式(IIA)化合物。In the formula, X 1 , X 2 , R 1 , R 2 and R 3 are each defined the same as the compound of formula (I) or the compound of formula (IIA).
在一实施方案中，式(I)所示的化合物为(IIE)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
In one embodiment, the compound represented by formula (I) is compound (IIE), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
式中，X、R1、R2、R3各自定义同式(I)化合物或式(IIA)化合物。In the formula, X, R 1 , R 2 and R 3 each have the same definition as the compound of formula (I) or the compound of formula (IIA).
在一实施方案中，式(I)所示的化合物为(IIF)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
In one embodiment, the compound represented by formula (I) is compound (IIF), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof:
式中，X1、X2、R1、R2、R3各自定义同式(I)化合物或式(IIA)化合物。In the formula, X 1 , X 2 , R 1 , R 2 and R 3 are each defined the same as the compound of formula (I) or the compound of formula (IIA).
在一实施方式中，X1、X2各自独立地选自氢、羟基、卤素、-C1-6烷基、C1-3烷基的取代或未取代的5或6元杂环烷基，优选自氢、羟基、卤素、甲基、吗啉基、甲基取代的哌嗪基；或，In one embodiment , X 1 and , preferably piperazinyl substituted from hydrogen, hydroxyl, halogen, methyl, morpholinyl, methyl; or,
X1、X2共同形成＝O、＝S或＝NR5，其中，R5选自羟基、-C1-6烷氧基、-C1-3烷基-羟基、-C1-3烷基-羧基，优选自羟基、乙氧基、-(CH2)2OH、-CH2COOH；或， X 1 and _ _ _ _ Base - carboxyl, preferably from hydroxyl, ethoxy, -(CH 2 ) 2 OH, -CH 2 COOH; or,
X1、X2和与它们相连的原子共同形成羰基取代的C3-6环烷基，优选为环丁基。X 1 , X 2 and the atoms connected to them together form a carbonyl-substituted C 3-6 cycloalkyl group, preferably a cyclobutyl group.
在一实施方式中，X1、X2各自独立地选自氢、羟基、-C1-6烷基，优选自氢、羟基、甲基；或，In one embodiment, X 1 and X 2 are each independently selected from hydrogen, hydroxyl, and -C 1-6 alkyl, preferably from hydrogen, hydroxyl, and methyl; or,
X1、X2共同形成＝O或＝NR5，其中，R5选自羟基或-C1-6烷氧基，优选自羟基或乙氧基。X 1 and X 2 together form =O or =NR 5 , wherein R 5 is selected from hydroxyl or -C 1-6 alkoxy, preferably from hydroxyl or ethoxy.
在一实施方式中，R1、R2各自独立地选自氢、氘、卤素、羟基、氨基、氰基、三氟甲基、环丙基、硫氰基、二甲基氨基、甲氧基、甲基、三氟甲氧基、-CH2CN、-O-CN、 In one embodiment, R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyanate, dimethylamino, methoxy , methyl, trifluoromethoxy, -CH 2 CN, -O-CN,
在一实施方式中，R1、R2各自独立地选自氢、氘、卤素、羟基、氨基、氰基、三氟甲基、环丙基、硫氰基、二甲基氨基、甲氧基、甲基、 In one embodiment, R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyanate, dimethylamino, methoxy ,methyl,
在一实施方式中，R1选自氢、卤素、氰基、羟基、硫氰基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-NH-C(O)-C1-3烷氧基、-C(O)-C1-3烷基、-C(O)NRaRb、-S(O)2C1-3烷基、-O-C1-3烷基-3至9元杂环烷基、-C(NH)NRaRb、5或6元杂芳基；且所述的-C1-6烷基、3至9元杂环烷基任选地被1、2或3个卤素取代；In one embodiment, R 1 is selected from hydrogen, halogen, cyano, hydroxyl, thiocyanate, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -NR a R b , -NH-C(O)-C 1-3 alkoxy, -C(O)-C 1-3 alkyl, -C(O)NR a R b , -S(O) 2 C 1-3 alkyl, -OC 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C(NH)NR a R b , 5- or 6-membered heteroaryl ; And the -C 1-6 alkyl and 3 to 9-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 halogens;
其中，Ra、Rb各自独立地选自氢或-C1-3烷基。Wherein, R a and R b are each independently selected from hydrogen or -C 1-3 alkyl.
在一实施方式中，R1选自氢、F、Cl、羟基、氨基、氰基、三氟甲基、环丙基、硫氰基、二甲基氨基、甲氧基、甲基、 In one embodiment, R1 is selected from hydrogen, F, Cl, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyanate, dimethylamino, methoxy, methyl,
在一实施方案中，R2选自氢、羟基、-C1-6烷基或-C1-6烷氧基。In one embodiment, R 2 is selected from hydrogen, hydroxyl, -C 1-6 alkyl or -C 1-6 alkoxy.
在一实施方案中，R2选自氢、羟基、甲基或甲氧基。In one embodiment, R2 is selected from hydrogen, hydroxyl, methyl or methoxy.
在一实施方案中，式(I)、式(II)、式(III)、式(VII)、式(IIA)、式(IIB)、式(IIC)、式(IID)、式(IIE)或式(IIF)中，R1选自氢、氘、卤素、羟基、氨基、氰基、三氟甲基、环丙基、硫氰基、二甲基氨基、甲氧基或下组：
In one embodiment, formula (I), formula (II), formula (III), formula (VII), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) Or in formula (IIF), R 1 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyanate, dimethylamino, methoxy or the following group:
在一实施方案中，式(I)、式(II)、式(III)、式(IV)、式(IIA)、式(IIB)、式(IIC)、式(IID)、式(IIE)或式(IIF)中，R2选自羟基、甲基、甲氧基或三氟甲基。In one embodiment, formula (I), formula (II), formula (III), formula (IV), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) Or in formula (IIF), R 2 is selected from hydroxyl, methyl, methoxy or trifluoromethyl.
在一实施方案中，R3选自卤素、甲基、甲氧基、氰基、三氟甲基、羧基、环丙基、乙炔基、苯基、硝基、氨基、异丙基、-C(O)OCH3、-C(O)H、-S-CF3、-S(O)2NH2、-S(O)2-CF3、-C(O)NH2、-C(O)N(CH3)2、-C(O)NHOH、-C(O)NHCH3、-C(OH)(CH3)2、-S(O)2CH3、-S(O)CH2CHO、-CH(CH3)OH、-CH2Br、-CH2OH、-CH2COOH、 In one embodiment, R 3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxyl, cyclopropyl, ethynyl, phenyl, nitro, amino, isopropyl, -C (O)OCH 3 , -C(O)H, -S-CF 3 , -S(O) 2 NH 2 , -S(O) 2 -CF 3 , -C(O)NH 2 , -C(O )N(CH 3 ) 2 , -C(O)NHOH, -C(O)NHCH 3 , -C(OH)(CH 3 ) 2 , -S(O) 2 CH 3 , -S(O)CH 2 CHO, -CH(CH 3 )OH, -CH 2 Br, -CH 2 OH, -CH 2 COOH,
在一实施方案中，R3选自卤素、甲基、甲氧基、氰基、三氟甲基、羧基、环丙基、苯基、硝基、氨基、异丙基、-C(O)OCH3、-C(O)H、-S-CF3、-S(O)2NH2、-S(O)2-CF3、-C(O)NH2、-C(O)N(CH3)2、-C(O)NHOH、-C(O)NHCH3、-C(OH)(CH3)2、-S(O)2CH3、-CH(CH3)OH、-CH2Br、-CH2OH、-CH2COOH、 In one embodiment, R 3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxyl, cyclopropyl, phenyl, nitro, amino, isopropyl, -C(O) OCH 3 , -C(O)H, -S-CF 3 , -S(O) 2 NH 2 , -S(O) 2 -CF 3 , -C(O)NH 2 , -C(O)N( CH 3 ) 2 , -C(O)NHOH, -C(O)NHCH 3 , -C(OH)(CH 3 ) 2 , -S(O) 2 CH 3 , -CH(CH 3 )OH, -CH 2 Br, -CH 2 OH, -CH 2 COOH,
在一实施方案中，式(I)、式(II)、式(III)、式(IV)、式(IIA)、式(IIB)、式(IIC)、式(IID)、式(IIE)或式(IIF)中，R3选自卤素、甲基、甲氧基、氰基、三氟甲基、羧酸或CONH2。In one embodiment, formula (I), formula (II), formula (III), formula (IV), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) Or in formula (IIF), R 3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxylic acid or CONH 2 .
所述卤素选自氟或氯。The halogen is selected from fluorine or chlorine.
在一实施方案中，R4选自卤素、氰基、-C1-3烷基；或，相邻R3与R4相互连接共同形成5或6元含氧杂环基。In one embodiment, R 4 is selected from halogen, cyano group, -C 1-3 alkyl; or, adjacent R 3 and R 4 are connected to each other to form a 5- or 6-membered oxygen-containing heterocyclic group.
在一实施方案中，R4选自卤素、氰基、-C1-3烷基；或，相邻R3与R4相互连接共同形成 In one embodiment, R 4 is selected from halogen, cyano, -C 1-3 alkyl; or, adjacent R 3 and R 4 are connected to each other to form
在一实施方案中，式(I)、式(II)、式(III)、式(IV)、式(IIA)、式(IIB)、式(IIC)、式(IID)、式(IIE)或式(IIF))所述化合物选自下组：





In one embodiment, formula (I), formula (II), formula (III), formula (IV), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) Or the compound described in formula (IIF)) is selected from the following group:





本公开的另一方面，提供上述化合物的制备方法，当式(I)所示的化合物为式(III)化合物或式(IV)化合物时，其通过包括以下步骤的方法制备得到：
Another aspect of the present disclosure provides a method for preparing the above-mentioned compound. When the compound represented by formula (I) is a compound of formula (III) or a compound of formula (IV), it is prepared by a method including the following steps:
其中，Cy1、U1、U2、U3、R1、R2、R3、R5、n各自定义同前，优选地，n为1。Among them, Cy1, U 1 , U 2 , U 3 , R 1 , R 2 , R 3 , R 5 and n are each defined as above. Preferably, n is 1.
在一实施方案中，所述氧化剂选自叔丁基过氧化氢、过氧化氢、过氧化氢异丙苯、过氧化氢二异丙苯和2,2,6,6-四甲基哌啶氧化物。In one embodiment, the oxidizing agent is selected from the group consisting of tert-butyl hydroperoxide, hydrogen peroxide, cumene hydroperoxide, dicumyl hydroperoxide, and 2,2,6,6-tetramethylpiperidine Oxide.
在一实施方案中，所述催化剂选自四丁基卤化铵、卤化钾、卤化钠和单质碘。In one embodiment, the catalyst is selected from the group consisting of tetrabutylammonium halide, potassium halide, sodium halide and elemental iodine.
在一实施方案中，所述溶剂选自甲醇、乙醇、叔丁醇、异丙醇、正丁醇、仲丁醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、二氯甲烷、氯仿、四氯化碳或1,2-二氯乙烷。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, methylene chloride, chloroform, carbon tetrachloride or 1,2-dichloroethane.
在一优选的实施方案中，所述氧化剂为叔丁基过氧化氢。In a preferred embodiment, the oxidizing agent is tert-butyl hydroperoxide.
在一优选的实施方案中，所述催化剂为四丁基碘化铵。In a preferred embodiment, the catalyst is tetrabutylammonium iodide.
在一优选的实施方案中，所述溶剂为1,2-二氯乙烷。In a preferred embodiment, the solvent is 1,2-dichloroethane.
将上述式(III)化合物与R5-NH2进行适当的羰胺缩合反应，得到式(IV)化合物。The compound of formula (III) and R 5 -NH 2 are subjected to an appropriate carbonylamine condensation reaction to obtain the compound of formula (IV).
在一实施方案中，所述式(III-1)化合物通过包括以下步骤的方法制备得到：
In one embodiment, the compound of formula (III-1) is prepared by a method comprising the following steps:
其中，U1、U2、U3、Cy1、R1、R2、R3、n各自定义同前，优选地，n为1；Wherein, U 1 , U 2 , U 3 , Cy1, R 1 , R 2 , R 3 and n are each defined as above. Preferably, n is 1;
RX和RX’选自卤素原子、硼酸基或硼酸酯基，所述卤素原子选自F、Cl、Br；条件是：RX选自卤素原子时，RX’选自硼酸基或硼酸酯基，RX’选自卤素原子时，RX选自硼酸基或硼酸酯基。 R _ _ _ Borate ester group, when R X' is selected from halogen atom, R X is selected from borate group or borate ester group.
优选地，RX为B(OH)2，RX’为Br。Preferably, R X is B(OH) 2 and R X' is Br.
本公开的另一方面，提供一种药物组合物，所述组合物包含上述化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药或上述方法制备得到的化合物和药学上可接受的辅料。Another aspect of the present disclosure provides a pharmaceutical composition comprising the above compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug or a compound prepared by the above method and Pharmaceutically acceptable excipients.
在一实施方案中，所述药物组合物中还包含另一种治疗心血管疾病、神经紊乱、癌症或免疫疾病的药物。In one embodiment, the pharmaceutical composition further includes another drug for treating cardiovascular disease, neurological disorders, cancer, or immune disease.
本公开的另一方面，提供一种上述化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药、或上述方法制备得到的化合物在制备治疗心血管疾病、神经紊乱、癌症、免疫疾病的药物、或制备心血管疾病、神经紊乱、癌症、免疫疾病或患者预后评估的试剂盒中的用途。Another aspect of the present disclosure provides the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above-mentioned method for the treatment of cardiovascular diseases and neurological disorders. , drugs for cancer, immune diseases, or use in preparing kits for cardiovascular diseases, neurological disorders, cancer, immune diseases, or patient prognosis assessment.
本公开的另一方面，提供一种上述药物组合物在制备治疗心血管疾病、神经紊乱、癌症、免疫疾病的药物、或制备心血管疾病、神经紊乱、癌症、免疫疾病或患者预后评估的试剂盒中的用途。Another aspect of the present disclosure provides a pharmaceutical composition for preparing drugs for treating cardiovascular diseases, neurological disorders, cancer, and immune diseases, or for preparing reagents for evaluating cardiovascular diseases, neurological disorders, cancer, immune diseases, or patient prognosis. Purpose in the box.
在一优选的实施方案中，提供一种上述的化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药、或上述方法制备得到的化合物在制备治疗与USP21活性相关的疾病中的用途。In a preferred embodiment, the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the above method is provided for use in the preparation of treatments related to USP21 activity. uses in diseases.
在一优选的实施方案中，提供一种上述药物组合物在制备治疗与USP21活性相关的疾病中的用途。In a preferred embodiment, the use of the above pharmaceutical composition in the preparation and treatment of diseases related to USP21 activity is provided.
在一实施方案中，所述癌症包括前列腺癌、胰腺癌、乳腺癌、肺癌、脑癌、结肠癌、肾癌、膀胱癌、上皮性卵巢癌、肝癌以及白血病。In one embodiment, the cancer includes prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, and leukemia.
在一优选的实施方案中，所述癌症包括胰腺癌、肝癌、乳腺癌、肾癌、膀胱癌以及肺癌。 In a preferred embodiment, the cancer includes pancreatic cancer, liver cancer, breast cancer, kidney cancer, bladder cancer and lung cancer.
在一实施方案中，所述免疫疾病为与USP活性相关的免疫疾病。In one embodiment, the immune disease is an immune disease associated with USP activity.
本公开的另一方面，提供一种上述化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药、上述方法制备得到的化合物、或上述药物组合物在制备USP抑制剂中的用途。In another aspect of the present disclosure, there is provided a kind of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, the compound prepared by the above-mentioned method, or the above-mentioned pharmaceutical composition in the preparation of USP Inhibition uses in pharmaceuticals.
在一实施方案中，所述USP抑制剂为USP21抑制剂。In one embodiment, the USP inhibitor is a USP21 inhibitor.
本公开的另一方面，提供一种抑制生物样品中的USP活性的方法，其包含使所述生物样品与上述化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药、上述的方法制备得到的化合物、上述的药物组合物接触的步骤。In another aspect of the present disclosure, a method for inhibiting USP activity in a biological sample is provided, which comprises mixing the biological sample with the above-mentioned compound, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, or a precursor thereof. The step of contacting the medicine, the compound prepared by the above method, and the above pharmaceutical composition.
本公开的另一方面，提供一种治疗与USP21活性相关的疾病、心血管疾病、神经紊乱、癌症或免疫疾病的方法，其包含向有需要的患者施用上述化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药、上述方法制备得到的化合物、或上药物组合物的步骤。Another aspect of the present disclosure provides a method of treating a disease, cardiovascular disease, neurological disorder, cancer or immune disease related to USP21 activity, comprising administering the above compound, a pharmaceutically acceptable salt thereof, to a patient in need thereof , stereoisomers, solvates, prodrugs thereof, compounds prepared by the above methods, or steps of adding pharmaceutical compositions.
在一实施方案中，所述癌症包括前列腺癌、胰腺癌、乳腺癌、肺癌、脑癌、结肠癌、肾癌、膀胱癌、上皮性卵巢癌、肝癌以及白血病。In one embodiment, the cancer includes prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer, and leukemia.
在一实施方案中，所述与USP21活性相关的疾病指的是与USP21活性异常相关的疾病。In one embodiment, the disease associated with USP21 activity refers to a disease associated with abnormal USP21 activity.
具体实施方式Detailed ways
I.定义I.Definition
根据本公开的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本公开上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。According to the above content of the present disclosure, various other forms of modifications, replacements or changes can be made according to the common technical knowledge and common means in the field without departing from the above basic technical ideas of the present disclosure.
除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分。Unless expressly stated otherwise, throughout the specification and claims, the term "comprises" or its variations such as "comprises" or "comprising" will be understood to include the stated elements or components, and to Other elements or other components are not excluded.
本公开化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。外消旋体、非对映异构体、对映异构体都包括在本公开的范围之内。Compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of this disclosure.
本公开化合物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。Compounds of the present disclosure also include tautomeric forms. The tautomeric form results from the exchange of a single bond with an adjacent double bond and the accompanying migration of a proton.
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the absence of the stated event or circumstance.
本文中的数字范围，是指给定范围中的各个整数。例如，“C1-C6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子；“C3-C6”是指该基团可具有3个碳原子、4个碳原子、5个碳原子或6个碳原子。A numerical range in this article refers to each integer in a given range. For example, "C 1 -C 6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; "C 3 - C6 " means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present. This description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
术语“被取代的”是指特定原子或基团上的任意一个或多个氢原子被取代基取代，只要特定原子或基团的价态是正常的并且取代后的化合物是稳定的。当取代基为＝O时，意味着两个氢原子被取代。除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom or group are replaced by a substituent, as long as the valence state of the specific atom or group is normal and the substituted 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 may be arbitrary on the basis of chemical achievability.
当任何变量(例如Rn)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被1-5个R所取代，则所述基团可以任选地至多被5个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., Rn) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 1 to 5 R, then said group may optionally be substituted with up to 5 R, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably a lower alkyl group of 1 to 6 carbon atoms, non-limiting examples include methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl base, 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.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，包括苯并5-10元杂芳基、苯并3-8元环烷基和苯并3-8元杂烷基，优选苯并5-6元杂芳基、苯并3-6元环烷基和苯并3-6元杂烷基，其中杂环基为含1-3氮原子、氧原子、硫原子的杂环基；或者还包含含苯环的三元含氮稠环。The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6 to 12 members, such as benzene base and naphthyl. More preferred is phenyl. The aryl ring can be condensed on a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group containing a sulfur atom; or a three-membered nitrogen-containing fused ring containing a benzene ring.
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、琉基、氢基，硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio group, carboxyl group or carboxylate group.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至12元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁哇基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为吡啶、三唑基、噻吩基、咪唑基、吡唑基、噁唑基、嘧 啶基或噻唑基；更优选吡唑基、吡咯基和噁唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12 yuan, more preferably 5 yuan or 6 yuan, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxalyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably pyridine, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidine Aldinyl or thiazolyl; more preferred are pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、氢基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio group, heterocycloalkylthio group, carboxyl group or carboxylate group.
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、氢基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkenyl" refers to an alkenyl group, also known as an alkenyl group, wherein the alkenyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, carboxyl group or carboxylate group.
“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、氰基、硝基、酚基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkynyl" refers to (CH≡C-), wherein the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, cyano, nitro, phenol, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio group, carboxyl group or carboxylate group.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、氢基、硝基、氯基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydrogen, nitro, chlorine, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkyl Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.
“-CHO”或“-C(O)H”指“羟基”指-OH基团。“-CHO” or “-C(O)H” means "Hydroxy" refers to the -OH group.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“氨基”指-NH2。"Amino" refers to -NH2 .
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO2。"Nitro" refers to -NO 2 .
“羰基”指-C(O)-。"Carbonyl" refers to -C(O)-.
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“甲脒基”指 "Formamidinyl" means
“THF”指四氢呋喃。"THF" refers to tetrahydrofuran.
“EtOAc”指乙酸乙酯。"EtOAc" refers to ethyl acetate.
“MeOH”指甲醇。"MeOH" methanol.
“EtOH”指乙醇。"EtOH" refers to ethanol.
“DMF”指N,N-二甲基甲酰胺。"DMF" refers to N,N-dimethylformamide.
“TBAI”指四丁基碘化铵。"TBAI" refers to tetrabutylammonium iodide.
“TFA”指三氟乙酸。"TFA" refers to trifluoroacetic acid.
“MeCN”指乙晴。“MeCN” refers to Yiqing.
“PdCl2(dppf)”指[1,1'-双(二苯基膦基)二茂铁]二氯化钯。"PdCl 2 (dppf)" refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
“DCE”指1,2二氯乙烷。"DCE" refers to 1,2 dichloroethane.
“DIPEA”指二异丙基乙胺。"DIPEA" refers to diisopropylethylamine.
“NBS”指N-溴代琥珀酰亚胺。"NBS" refers to N-bromosuccinimide.
“NIS”指N-碘代丁二酰亚胺。"NIS" refers to N-iodosuccinimide.
“cbz-cr指氯甲酸苄酯。"cbz-cr refers to benzyl chloroformate.
“Pd2(dba)3”指三(二亚苄基丙酮)二钯"Pd 2 (dba) 3 " refers to tris(dibenzylideneacetone)dipalladium
“Dppf’指1,1’-双二苯基膦二茂铁。“Dppf’ refers to 1,1’-bisdiphenylphosphine ferrocene.
“HATU”指2-(7-氮杂苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。“HATU” refers to 2-(7-azabenzotriazole)-N,N,N’,N’-tetramethylurea hexafluorophosphate.
“KHMDS”指六甲基二硅基胺基钾。"KHMDS" refers to potassium hexamethyldisilamide.
“LiHMDS”指双三甲基硅基胺基锂。"LiHMDS" refers to lithium bistrimethylsilylamide.
“MeLi”指甲基锂。"MeLi" refers to lithium methyl.
“n-BuLi”指正丁基锂。"n-BuLi" refers to n-butyllithium.
“NaBH(OAc)3”指三乙酰氧基硼氢化钠。 "NaBH(OAc) 3 " refers to sodium triacetoxyborohydride.
“Boc”指叔丁氧羰基，其结构式为 "Boc" refers to tert-butoxycarbonyl, and its structural formula is
“FA”指甲酸。"FA" nail acid.
“ACN”指乙腈。"ACN" refers to acetonitrile.
“DCM”指二氯甲烷。"DCM" refers to dichloromethane.
“LDA”指二异丙基胺基锂。"LDA" refers to lithium diisopropylamide.
“NMI”指1-甲基-1H-咪唑。"NMI" refers to 1-methyl-1H-imidazole.
“TCFH”指N,N,N',N'-四甲基氯甲脒六氟磷酸盐。"TCFH" refers to N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.
“DIBAL-H”指二异丁基氢化铝。"DIBAL-H" refers to diisobutylaluminum hydride.
“m-CPBA”指间氯过氧苯甲酸。"m-CPBA" refers to m-chloroperoxybenzoic acid.
“Dioxane”指1,4-二氧六环。"Dioxane" refers to 1,4-dioxane.
“DMSO”指二甲基亚砜。"DMSO" refers to dimethyl sulfoxide.
“AIBN”指偶氮二异丁腈。"AIBN" refers to azobisisobutyronitrile.
“TEA”指三乙胺。“Oxone”指过氧单磺酸钾。"TEA" refers to triethylamine. "Oxone" refers to potassium peroxymonosulfonate.
“BINAP”指1,1'-联萘-2,2'-双二苯膦。"BINAP" refers to 1,1'-binaphthyl-2,2'-bisdiphenylphosphine.
“iPrOH”指异丙醇。"iPrOH" refers to isopropyl alcohol.
本公开所述的氢原子均可被其同位素氘所取代。Any hydrogen atom described in this disclosure may be replaced by its isotope deuterium.
取代基中的是指化学键连接处。例如，R1为中，表示的位置和Cy1环相连接。in substituents It refers to the connection point of chemical bond. For example, R 1 is middle, The indicated position is connected to the Cy1 ring.
化合物中的表示该化学键处存在立体异构，包括实楔线和虚楔线表示的构型。例如，表示茚并[2,1-d]嘧啶中心五元环连接的N原子与羟基之间存在立体异构，该化合物结构为 或其混合物。in compounds Indicates the existence of stereoisomerism at this chemical bond, including the configurations represented by solid wedge lines and dashed wedge lines. For example, It means that there is stereoisomerism between the N atom connected to the central five-membered ring of indeno[2,1-d]pyrimidine and the hydroxyl group. The structure of this compound is or mixtures thereof.
药物或药物组合物Drug or pharmaceutical composition
术语“药学上可接受的”是指在合理的医学判断的范围内适合用于与人类和动物的组织接触而没有，与合理利益/风险比相称的，过度毒性、刺激、过敏反应或其它问题或并发症的那些化合物、材料、组合物和/或剂型。The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissue without, commensurate with a reasonable benefit/risk ratio, undue toxicity, irritation, allergic reaction or other problems or complications of those compounds, materials, compositions and/or dosage forms.
术语“药学上可接受的盐”是指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。例如酸(包括有机酸和无机酸)加成盐或碱加成盐(包括有机碱和无机碱)。The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of the free acid and base of a particular compound without adverse biological effects. For example, acid (including organic acids and inorganic acids) addition salts or base addition salts (including organic bases and inorganic bases).
本公开的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。Pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
本公开的药物或药物组合物可以经口地、局部地、肠胃外地或粘膜地(例如，含服地、通过吸入或直肠地)以包含常规的非-毒性药学可接受的载体的剂量单位配制剂施用。通常希望使用口服途径。所述活性试剂可以经口地以胶囊、片剂等形式(参见Remington：The Science and Practice of Pharmacy，20th Edition)施用。The drugs or pharmaceutical compositions of the present disclosure may be administered orally, topically, parenterally, or mucosally (eg, bucally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers Apply. It is usually desirable to use the oral route. The active agent may be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).
对于以片剂或胶囊形式的口服给药，活性药物组分可以与非-毒性的、药学可接受的辅料如粘结剂(例如，预胶化的玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素)；填料(例如，乳糖、蔗糖、葡萄糖、甘露糖醇、山梨糖醇和其它还原性和非-还原性糖类、微晶纤维素、硫酸钙或磷酸氢钙)；润滑剂(例如，硬脂酸镁、滑石粉或硅土、硬脂酸、硬脂基富马酸酯钠、甘油二十二烷酸酯、硬脂酸钙等)；崩解剂(例如，马铃薯淀粉或羟乙酸淀粉钠)；或润湿剂(例如，月桂基硫酸钠)、着色剂和调味剂、明胶、甜味剂、天然和合成的胶(如阿拉伯胶、黄蓍胶或藻朊酸盐)、缓冲盐、羧甲纤维素、聚乙二醇、蜡、等。对于以液体形式的口服给药，所述药物组分可以与非-毒性、药学可接受的惰性载体(例如，乙醇、甘油、水)、防沉降剂(例如，山梨糖醇糖浆、纤维素衍生物或氢化的可食用脂肪)、乳化剂(例如，卵磷脂或阿拉伯胶)、非-水性载体(例如，扁桃油、油酯类、乙醇或经分馏的植物油)、保藏剂(例如， p-羟基苯甲酸甲酯或p-羟基苯甲酸丙酯或山梨酸)等组合。还可以加入稳定剂如抗氧化剂(BHA、BHT、桔酸丙酯、抗坏血酸钠、柠檬酸)以稳定所述剂型。For oral administration in the form of tablets or capsules, the active pharmaceutical ingredient may be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized cornstarch, polyvinylpyrrolidone, or hydroxypropylmethyl). cellulose); fillers (for example, lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or calcium hydrogen phosphate); lubricants (for example, , magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrating agent (for example, potato starch or hydroxyl sodium starch acetate); or wetting agents (for example, sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginate), Buffer salt, carboxymethyl cellulose, polyethylene glycol, wax, etc. For oral administration in liquid form, the pharmaceutical component may be derivatized with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), anti-sedimentation agent (e.g., sorbitol syrup, cellulose or hydrogenated edible fats), emulsifiers (e.g., lecithin or gum arabic), non-aqueous carriers (e.g., almond oil, oil esters, ethanol or fractionated vegetable oils), preservatives (e.g., p-hydroxybenzoic acid methyl ester or p-hydroxybenzoic acid propyl ester or sorbic acid) and other combinations. Stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.
包含作为活性化合物的片剂可以通过本领域熟知的方法包衣。包含作为活性化合物的式I化合物的本公开的所述组合物还可以引入小珠、微球或微胶囊，例如由聚乙醇酸/乳酸(PGLA)构建的。用于口服给药的液体的制剂可以采取例如溶液，糖浆剂，乳液或混悬液的形式或者它们可以呈现为在使用前用水或其它适宜的辅料重构的干产品。用于口服给药的制剂可以适宜地配制以使活性化合物受控或延迟地释放。Tablets containing the active compound may be coated by methods well known in the art. Said compositions of the present disclosure comprising a compound of formula I as active compound may also incorporate beads, microspheres or microcapsules, for example constructed from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions or they may be presented as a dry product for constitution with water or other suitable excipients before use. Formulations for oral administration may be suitably formulated to provide controlled or delayed release of the active compound.
本公开的药物或药物组合物可以经肠胃外递送，即，通过静脉内(i.v.)、脑室内(i.c.v.)、皮下(s.c.)、腹膜内(i.p.)、肌内(i.m.)、皮下(s.d.)或皮内(i.d.)施用，通过直接注射，经例如快速浓注或连续输液。用于注射的配制剂可以单位剂型呈现，例如在具有添加的保藏剂的安瓿瓶或多-剂量容器中。所述组合物可以采用赋形剂(excipient)的形状，在油或水性载体中的混悬液、溶液或乳液的形式，并可以包含配制试剂如防沉降剂、稳定剂和/或分散剂。备选地，所述活性成分可以以粉末形式在使用前用适宜的载体(例如无菌无热原水)重构。The drugs or pharmaceutical compositions of the present disclosure may be delivered parenterally, i.e., intravenously (i.v.), intracerebroventricularly (i.c.v.), subcutaneously (s.c.), intraperitoneally (i.p.), intramuscularly (i.m.), subcutaneously (s.d.) or intradermal (i.d.) administration, by direct injection, by, for example, bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg in ampoules or multi-dose containers with an added preservative. The compositions may take the form of excipients, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as anti-sedimentation agents, stabilizers and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.
本公开的药物或药物组合物还可以配制用于直肠给药，例如呈栓剂或保留灌肠(例如，包含常规栓剂基质如可可油或其它甘油酯)。The drugs or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as suppositories or retention enemas (eg, containing conventional suppository bases such as cocoa butter or other glycerides).
术语“治疗”包括抑制、缓解、预防或消除与所治疗的疾病、病症或失调相关的一种或多种症状或副作用。The term "treating" includes inhibiting, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.
术语“减少”、“抑制”、“减轻”或“减小”的使用是相对于对照的。本领域技术人员将容易地确定用于每个实验的适当对照。例如，将用化合物处理的受试者或细胞中的降低了的反应与未用化合物处理的受试者或细胞中的反应进行比较。The use of the terms "reduce," "inhibit," "mitigate," or "reduce" is relative to a control. One skilled in the art will readily determine the appropriate controls for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.
术语“赋形剂”在本文中用于包括可以包含在微粒中或其上的不是治疗或生物活性化合物的任何其它化合物。因此，赋形剂应当是药学上或生物学上可接受的或相关的，例如赋形剂通常对受试者无毒性。“赋形剂”包括单一的这种化合物，并且还旨在包括多种化合物。The term "excipient" is used herein to include any other compound that may be contained in or on the microparticles that is not a therapeutic or biologically active compound. Therefore, the excipients should be pharmaceutically or biologically acceptable or relevant, eg, the excipients are generally non-toxic to the subject. "Excipient" includes a single such compound and is also intended to include a plurality of compounds.
术语“药物组合物”意指包含本公开所述化合物或其药学上可接受的盐，以及依施用方式和剂型的性质而定的至少一种选自以下药学上可接受的成分的组合物，包括但不限于：载体、稀释剂、佐剂、赋形剂、防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、矫味剂、香味剂、抗菌剂、抗真菌剂、润滑剂、分散剂、温敏材料、温度调节剂、黏附剂、稳定剂、助悬剂等。The term "pharmaceutical composition" means a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the mode of administration and the nature of the dosage form, Including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, flavors, antibacterial agents , antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.
用途和治疗方法Uses and Treatments
术语“患者”、“对象”、“个体”等等在本文中可交换使用，并指的是服从本文描述方法的任何动物或其细胞，不论是体外或原位。在一些非限制性实施方式中，患者、对象或个体为人。The terms "patient," "subject," "individual" and the like are used interchangeably herein and refer to any animal or cells thereof that is subject to the methods described herein, whether in vitro or in situ. In some non-limiting embodiments, the patient, subject or individual is a human.
术语“生物样品”包括(但不限于)细胞培养物或其提取物；从哺乳动物获得的活检材料或其提取物；以及血液、唾液、尿液、粪便、精液、泪液或其它体液或其提取物。生物样品中的酶的抑制可用于达成本领域的技术人员已知的多种目的。此类目的的实例包括(但不限于)生物分析、基因表达研究和生物目标鉴别。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 body fluids, or extracts thereof things. 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, biological analysis, gene expression studies, and biological target identification.
如本文所用，术语“USP21介导”的病症、疾病和/或病状指已知USP21或其突变体起作用的任何疾病或其它有害病状。因此，本公开的另一实施例涉及治疗已知USP21或其突变体起作用的一种或多种疾病或减轻其严重程度。As used herein, the term "USP21-mediated" disorder, disease and/or condition refers to any disease or other deleterious condition in which USP21 or mutants thereof are known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or reducing the severity of one or more diseases in which USP21 or mutants thereof are known to play a role.
本公开所述的癌症包括(不限于)白血病(例如急性白血病、急性淋巴细胞性白血病、急性骨髓细胞性白血病、急性成髓细胞性白血病、急性前髓细胞性白血病、急性骨髓单核细胞性白血病、急性单核细胞性白血病、急性红白血病、慢性白血病、慢性骨髓细胞性白血病、慢性淋巴细胞性白血病)、真性红血球增多症、淋巴瘤(例如霍奇金氏病或非霍奇金氏病)、瓦尔登斯特伦氏巨球蛋白血症、多发性骨髓瘤、重链病和实体瘤，例如肉瘤和癌瘤(例如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴内皮肉瘤、滑膜瘤、间皮瘤、尤文氏肿瘤(Ewing′s tumor)、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓性癌、支气管癌、肾细胞癌、肝瘤、胆管癌、绒膜癌、精原细胞瘤、胚胎性瘤、威尔姆斯瘤、子宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、多形性成胶质细胞瘤(GBM，又称为成胶质细胞瘤)、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、神经鞘瘤、神经纤维肉瘤、脑膜瘤、黑素瘤、成神经细胞瘤和成视网膜细胞瘤)。Cancers of the present disclosure include, but are not limited to, leukemias (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyeloid leukemia, acute myelomonocytic leukemia , acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (such as Hodgkin's disease or non-Hodgkin's disease) , Waldenström's macroglobulinemia, multiple myeloma, heavy chain diseases, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, notochord Tumor, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovialoma, mesothelioma, Ewing's tumor (Ewing's tumor), leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovary Carcinoma, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver tumor, Cholangiocarcinoma, choriocarcinoma, seminoma, embryonal tumor, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astroma Glioblastoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma , acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).
联合治疗方法combination therapy
本公开提供了使用如本公开所述的化合物与其他治疗药物的联合疗法。本公开所用的“联合疗法”一词包括以顺序方式施用这些药剂，即其中每种治疗剂在不同时间施用，以及施用这些治疗剂，或至少二种药剂，基本上同时进行。每种试剂的顺序，或基本上同时给药，可受任何适当途径的影响，包括，但不限于，口服途径、静脉内途径、肌肉内、皮下途径，以及通过黏膜组织的直接吸收。药剂可以通过相同的途径或不同的途径来施用。例如，可以口服给予第一药剂，而以静脉内施用第二药剂。此外，选择的组合剂可通过静脉内注射施用，而组合的其它药剂可以口服给药。或者，例如，可以通过静脉内或皮下注射施用二种或更多种药剂。The present disclosure provides combination therapies using compounds as described herein with other therapeutic agents. The term "combination therapy" as used in this disclosure includes administration of these agents in a sequential manner, in which each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two agents, substantially simultaneously. The sequence, or substantially simultaneous administration of each agent may be effected by any appropriate route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, and direct absorption through mucosal tissue. The agents can be administered by the same route or by different routes. For example, a first agent may be administered orally and a second agent administered intravenously. Additionally, selected combination agents can be administered by intravenous injection, while other agents of the combination can be administered orally. Alternatively, for example, two or more agents may be administered by intravenous or subcutaneous injection.
实施例Example
下面参照实施例进一步阐释本公开。对本公开的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本公开限定为所公开的精确形式，并且很显然，根据本申请说明书的教导，可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本公开的特定原理及其实际应用，从而使得本领域的技术人员能够 实现并利用本公开的各种不同的示例性实施方案以及各种不同的选择和改变。The present disclosure is further explained below with reference to examples. Specific exemplary embodiments of the present disclosure have been described for purposes of illustration and illustration. These descriptions are not intended to limit the disclosure to the precise forms disclosed, and obviously many modifications and variations are possible in light of the teachings of this specification. The exemplary embodiments were chosen and described in order to explain certain principles of the disclosure and its practical applications to thereby enable others skilled in the art to Various exemplary embodiments of the present disclosure, as well as various alternatives and modifications, can be implemented and utilized.
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。The experimental methods used in the following examples are conventional methods unless otherwise specified.
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。Materials, reagents, etc. used in the following examples can all be obtained from commercial sources unless otherwise specified.
仪器和试剂：Instruments and reagents:
NMR：Agilent 400MR DD2核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代甲醇(CD3OD)和氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)。液质联用色谱LC-MS：Agilent 1260Infinity II–InfinityLab LC/MSD质谱仪。HPLC：Agilent 1260Infinity II高压液相色谱仪(Sunfire C18 5μm 150x 4.6mm色谱柱)。NMR: Agilent 400MR DD2 nuclear magnetic instrument. The measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). The internal standard is tetramethylsilane ( TMS). Liquid mass spectrometry LC-MS: Agilent 1260 Infinity II–InfinityLab LC/MSD mass spectrometer. HPLC: Agilent 1260Infinity II high pressure liquid chromatograph (Sunfire C18 5μm 150x 4.6mm column).
薄层层析硅胶板：HSGF254硅胶板(烟台江友硅胶开发有限公司)，规格0.9mm-1mm。TLC硅胶板：GF254硅胶板(于成化工(上海)有限公司)，规格0.2mm～0.25mm。柱层析：载体300-400目硅胶(青岛海浪硅胶干燥剂有限公司)，Flash柱(艾杰尔飞诺美Claricep Flash无定形硅胶纯化柱)。试剂：4-溴-3-甲酰苯甲腈，(2-(三氟甲基)嘧啶-5-基)硼酸，(2-甲酰基-4-(三氟甲基)苯基)硼酸，5-溴-2-环丙基嘧啶等其他试剂和起始原料均购自上海毕得或乐研试剂公司，或采用本领域已知的方法来合成。Thin layer chromatography silica gel plate: HSGF254 silica gel plate (Yantai Jiangyou Silica Gel Development Co., Ltd.), specification 0.9mm-1mm. TLC silica gel plate: GF254 silica gel plate (Yucheng Chemical (Shanghai) Co., Ltd.), specifications 0.2mm ~ 0.25mm. Column chromatography: carrier 300-400 mesh silica gel (Qingdao Hailang Silica Gel Desiccant Co., Ltd.), Flash column (Aijer Feinomei Claricep Flash amorphous silica gel purification column). Reagents: 4-bromo-3-formylbenzonitrile, (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid, (2-formyl-4-(trifluoromethyl)phenyl)boronic acid, Other reagents and starting materials such as 5-bromo-2-cyclopropylpyrimidine were purchased from Shanghai Bid or Leyan Reagent Company, or synthesized using methods known in the art.
在无特殊说明的情况下，本公开的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。Unless otherwise specified, all reactions of the present disclosure are carried out under continuous magnetic stirring, under dry nitrogen or argon, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.
以下为中间体编号：
The following are the intermediate numbers:
中间体I-1:2-(三氟甲基)嘧啶-5-基硼酸的合成(I-1)
Intermediate I-1: Synthesis of 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1)
将5-溴-2-三氟甲基嘧啶(5g，22.03mmol)溶于四氢呋喃(50ml)，加入硼酸三异丙酯(7.62ml，33.04mmol)，氮气置换，置于-85℃冷肼中降温，待温度降至-78℃后，控温-70℃以下缓慢滴加正丁基锂(11.5ml，28.64mmol，2.5M)，滴完后在此温度下再反应1小时。在0℃以下加入饱和氯化铵淬灭，用1N盐酸调节PH成弱酸性，加入乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤，滤液减压浓缩后得目标产物粗品2-(三氟甲基)嘧啶-5-基硼酸(I-1，4.92g)，直接用于后续反应。ESI[M-H]+＝191.1Dissolve 5-bromo-2-trifluoromethylpyrimidine (5g, 22.03mmol) in tetrahydrofuran (50ml), add triisopropyl borate (7.62ml, 33.04mmol), replace with nitrogen, and place in cold hydrazine at -85°C Cool down, wait until the temperature drops to -78°C, then control the temperature below -70°C and slowly add n-butyllithium (11.5ml, 28.64mmol, 2.5M) dropwise. After the dripping is completed, react at this temperature for another 1 hour. Add saturated ammonium chloride below 0°C to quench, adjust the pH to weak acidity with 1N hydrochloric acid, add ethyl acetate for extraction, wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target The crude product 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 4.92g) was directly used in subsequent reactions. ESI[MH] + =191.1
实施例1和2:7-氯-9-氧代-9H-茚并[2，1-b]吡啶-2-碳腈和7-氯-5-氧代-5H-茚并[1，2-c]吡啶-3-碳腈的制备
Examples 1 and 2: 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile and 7-chloro-5-oxo-5H-indeno[1,2 -C] Preparation of pyridine-3-carbonitrile
第一步:5-(4-氯-2-甲酰基苯基)吡啶腈的制备(1a)Step 1: Preparation of 5-(4-chloro-2-formylphenyl)pyridinenitrile (1a)
将(4-氯-2-甲酰基苯基)硼酸(302mg，1.64mmol)溶于甲醇(10ml)，加入5-溴代氯硝腈(200mg，1.09mmol)，氟化钾(127mg,2.19mmol)和醋酸钯(12mg,0.054mmol)，120℃微波反应0.5小时。过滤减压蒸干溶剂得目标产物粗品5-(4-氯-2-甲酰基苯基)吡啶腈(1a，240mg,产率90.50％)。MS(ESI)[M+H]+243.0，245.1.Dissolve (4-chloro-2-formylphenyl)boronic acid (302mg, 1.64mmol) in methanol (10ml), add 5-bromochloronitrile (200mg, 1.09mmol), potassium fluoride (127mg, 2.19mmol) ) and palladium acetate (12 mg, 0.054 mmol), microwave reaction at 120°C for 0.5 hours. The solvent was filtered and evaporated to dryness under reduced pressure to obtain the crude target product 5-(4-chloro-2-formylphenyl)pyridinenitrile (1a, 240 mg, yield 90.50%). MS(ESI)[M+H] + 243.0, 245.1.
第二步:7-氯-9-氧代-9H-茚并[2，1-b]吡啶-2-碳腈的制备(1)和7-氯-5-氧代-5H-茚并[1，2-c]吡啶-3-碳腈(2)的制备Second step: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile (1) and 7-chloro-5-oxo-5H-indeno[ Preparation of 1,2-c]pyridine-3-carbonitrile (2)
将5-(4-氯-2-甲酰基苯基)吡啶腈(1a,240mg,0.99mmol)溶于1,2-二氯乙烷(10ml)，加入四丁基碘化铵(18mg，0.049mmol)和叔丁基过氧化氢(533mg，3.96mmol)，于封管中100℃反应5小时。使用(二氯甲烷)重结晶去除杂质，再用制备级HPLC纯化拆分冻干得两个目标产物化合物1:7-氯-9-氧代-9H-茚并[2,1-b]吡啶-2-碳腈(3.2mg,产率0.88％)，MS(ESI)[M+H]+241.1，243.0.1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.24(s,1H),8.06(d,J＝8,0Hz1H),7.82(dd,J＝12.1,4.0Hz,2H).和化合物2(HSN003B004)：7-氯-5-氧代-5H-茚并[1,2-c]吡啶-3-碳腈(2，2.1mg,产率1.34％)。MS(ESI)[M+H]+241.0，243.1.1H 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). Dissolve 5-(4-chloro-2-formylphenyl)pyridinenitrile (1a, 240mg, 0.99mmol) in 1,2-dichloroethane (10ml), and add tetrabutylammonium iodide (18mg, 0.049 mmol) and tert-butyl hydroperoxide (533 mg, 3.96 mmol), react in a sealed tube at 100°C for 5 hours. Use (dichloromethane) to recrystallize to remove impurities, and then use preparative HPLC to purify, separate and freeze-dry to obtain two target product compounds 1: 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine -2-Carbonitrile (3.2 mg, yield 0.88%), MS (ESI) [M+H] + 241.1, 243.0. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.32 (s, 1H), 8.24 (s, 1H), 8.06 (d, J = 8, 0Hz1H), 7.82 (dd, J = 12.1, 4.0Hz, 2H). And compound 2 (HSN003B004): 7-chloro-5-oxo-5H-indene Para[1,2-c]pyridine-3-carbonitrile (2, 2.1 mg, yield 1.34%). MS (ESI) [M+H] + 241.0, 243.1. 1 H NMR (400MHz, DMSO-d 6 ) 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).
实施例3:7-氯-9-氧代-9H-芴-2，3-二甲腈的制备
Example 3: Preparation of 7-chloro-9-oxo-9H-fluorene-2,3-dicarbonitrile
第一步:4'-氯-2'-甲酰基-[1，1'-联苯]-3，4-二甲腈的制备(3a)Step 1: Preparation of 4'-chloro-2'-formyl-[1,1'-biphenyl]-3,4-dicarbonitrile (3a)
将(4-氯-2-甲酰基苯基)硼酸(134mg，0.725mmol)溶于甲醇(4ml)，加入4-溴邻苯二腈(100mg，0.483mmol)，氟化钾(56mg,0.966mmol)和醋酸钯(5mg,0.024mmol)，120℃微波反应30分钟。过滤减压蒸干溶剂得目标产物粗品4'-氯-2'-甲酰基-[1,1'-联苯]-3,4-二甲腈(3a,240mg,产率93.16％)。Dissolve (4-chloro-2-formylphenyl)boronic acid (134mg, 0.725mmol) in methanol (4ml), add 4-bromophthalonitrile (100mg, 0.483mmol), potassium fluoride (56mg, 0.966mmol) ) and palladium acetate (5 mg, 0.024 mmol), microwave reaction at 120°C for 30 minutes. The solvent was filtered and evaporated to dryness under reduced pressure to obtain the crude target product 4'-chloro-2'-formyl-[1,1'-biphenyl]-3,4-dicarbonitrile (3a, 240 mg, yield 93.16%).
第二步:7-氯-9-氧代-9H-芴-2，3-二甲腈的制备(3)Step 2: Preparation of 7-chloro-9-oxo-9H-fluorene-2,3-dicarbonitrile (3)
将4'-氯-2'-甲酰基-[1,1'-联苯]-3,4-二甲腈(3a,240mg,0.9mmol)溶于1,2-二氯乙烷(8ml)，加入四丁基碘化铵(17mg，0.045mmol)和叔丁基过氧化氢(324mg，3.6mmol)，于封管中100℃反应16小时。减压蒸干溶剂,再用制备级HPLC纯化冻干得化合物3：7-氯-9-氧代-9H-芴-2,3-二甲腈(1.6mg,产率0.67％)。1H 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).Dissolve 4'-chloro-2'-formyl-[1,1'-biphenyl]-3,4-dicarbonitrile (3a, 240 mg, 0.9 mmol) in 1,2-dichloroethane (8 ml) , add tetrabutylammonium iodide (17 mg, 0.045 mmol) and tert-butyl hydroperoxide (324 mg, 3.6 mmol), and react in a sealed tube at 100°C for 16 hours. The solvent was evaporated to dryness under reduced pressure, and then purified by preparative HPLC and lyophilized to obtain compound 3: 7-chloro-9-oxo-9H-fluorene-2,3-dicarbonitrile (1.6 mg, yield 0.67%). 1 H NMR (400MHz, DMSO-d 6 ) δ8.69 (s, 1H), 8.36 (s, 1H), 8.01 (d, J = 8.0Hz, 1H), 7.86–7.77 (m, 2H).
实施例4:7-氯-2-环丙基-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 4: Preparation of 7-chloro-2-cyclopropyl-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-环丙基嘧啶-5-基)苯甲醛的制备(4a)Step 1: Preparation of 5-chloro-2-(2-cyclopropylpyrimidin-5-yl)benzaldehyde (4a)
将(4-氯-2-甲酰基苯基)硼酸(139mg，0.754mmol)溶于乙醇(4ml)，加入5-溴-2-环丙基嘧啶(100mg，0.502mmol)，碳酸钾(58mg,1mmol)和醋酸钯(6mg,0.025mmol)，于封管中120℃反应过夜。过滤减压蒸干溶剂得目标产物粗品5-氯-2-(2-环丙基嘧啶-5-基)苯甲醛(4a,90mg,产率69.25％)。MS(ESI)[M+H]+259.2，261.1.Dissolve (4-chloro-2-formylphenyl)boronic acid (139mg, 0.754mmol) in ethanol (4ml), add 5-bromo-2-cyclopropylpyrimidine (100mg, 0.502mmol), potassium carbonate (58mg, 1 mmol) and palladium acetate (6 mg, 0.025 mmol), react overnight at 120°C in a sealed tube. The solvent was filtered and evaporated to dryness under reduced pressure to obtain the crude target product 5-chloro-2-(2-cyclopropylpyrimidin-5-yl)benzaldehyde (4a, 90 mg, yield 69.25%). MS(ESI)[M+H] + 259.2, 261.1.
第二步:7-氯-2-环丙基-9H-茚并[2，1-d]嘧啶-9-酮的制备(4)Step 2: Preparation of 7-chloro-2-cyclopropyl-9H-indeno[2,1-d]pyrimidin-9-one (4)
将5-氯-2-(2-环丙基嘧啶-5-基)苯甲醛(4a,90mg，0.348mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(6mg，0.017mmol)和叔丁基过氧化氢(125mg，1.39mmol)，于封管中100℃反应16小时。减压蒸干溶剂,再用制备级HPLC纯化冻干得目标产物化合物4：7-氯-2-环丙基-9H-茚并[2,1-d]嘧啶-9-酮(14.1mg,产率15.79％)。MS(ESI)[M+H]+257.1，259.1.1H 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).Dissolve 5-chloro-2-(2-cyclopropylpyrimidin-5-yl)benzaldehyde (4a, 90 mg, 0.348 mmol) in 1,2-dichloroethane (2 ml), and add tetrabutylammonium iodide (6 mg, 0.017 mmol) and tert-butyl hydroperoxide (125 mg, 1.39 mmol) were reacted in a sealed tube at 100°C for 16 hours. The solvent was evaporated to dryness under reduced pressure, and then purified by preparative HPLC and lyophilized to obtain the target product compound 4: 7-chloro-2-cyclopropyl-9H-indeno[2,1-d]pyrimidin-9-one (14.1 mg, Yield 15.79%). MS(ESI)[M+H] + 257.1, 259.1. 1 H NMR (400MHz, DMSO-d 6 ) 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).
实施例5:叔丁基(7-氯-9-氧-9H-茚并[2，1-d]嘧啶-2-基)氨基甲酸酯的制备
Example 5: Preparation of tert-butyl (7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-2-yl) carbamate
第一步：叔丁基(5-(4-氯-2-甲酰基苯基)嘧啶-2-基)氨基甲酸酯的制备(5a)Step 1: Preparation of tert-butyl (5-(4-chloro-2-formylphenyl)pyrimidin-2-yl)carbamate (5a)
将4-氯-2-醛基苯硼酸(505mg，2.74mmol)溶于乙醇(20ml)，加入叔丁基(5-溴嘧啶-2-基)氨基甲酸酯(500mg，1.82mmol)，氟化钾(210mg,3.64mmol)和醋酸钯(20mg,0.091mmol)，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝10％-20％)纯化得目标产物叔丁基(5-(4-氯-2-甲酰基苯基)嘧啶-2-基)氨基甲酸酯(5a，246mg,产率40.41％)。MS(ESI)[M+H]+334.2，336.2.MS(ESI)[M-56+H]+278.0，280.0.Dissolve 4-chloro-2-aldehyde phenylboronic acid (505 mg, 2.74 mmol) in ethanol (20 ml), add tert-butyl (5-bromopyrimidin-2-yl) carbamate (500 mg, 1.82 mmol), fluorine Potassium chloride (210 mg, 3.64 mmol) and palladium acetate (20 mg, 0.091 mmol) were reacted under microwave at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 10%-20%) to obtain the target product tert-butyl (5-(4-chloro-2-formylphenyl)pyrimidine-2- base) carbamate (5a, 246 mg, yield 40.41%). MS(ESI)[M+H] + 334.2, 336.2. MS(ESI)[M-56+H] + 278.0, 280.0.
第二步：叔丁基(7-氯-9-氧-9H-茚并[2，1-d]嘧啶-2-基)氨基甲酸酯的制备(5)Step 2: Preparation of tert-butyl (7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidin-2-yl) carbamate (5)
将叔丁基(5-(4-氯-2-甲酰基苯基)嘧啶-2-基)氨基甲酸酯(5a,246mg,0.737mmol)溶于1,2-二氯乙烷(10ml)，加入四丁基碘化铵(14mg，0.037mmol)和叔丁基过氧化氢(399mg，4.42mmol)，于封管中100℃反应过夜。使用(二氯甲烷/甲醇)重结晶得粗品(120mg,产率49.08％)。取10mg粗产物通过制备级HPLC纯化冻干得目标产物化合物6：叔丁基(7-氯-9-氧-9H-茚并[2,1-d]嘧啶-2-基)氨基甲酸酯(0.7mg，0.29％产率)。MS(ESI)[M+H]+332.1,334.1.MS(ESI)[M-56+H]+276.2,278.1.1H NMR(400MHz,CD3OD)δ8.95(s,1H),7.77–7.63(m,3H),1.56(d,J＝4.3 Hz,9H).Dissolve tert-butyl (5-(4-chloro-2-formylphenyl)pyrimidin-2-yl)carbamate (5a, 246 mg, 0.737 mmol) in 1,2-dichloroethane (10 ml) , add tetrabutylammonium iodide (14 mg, 0.037 mmol) and tert-butyl hydroperoxide (399 mg, 4.42 mmol), and react overnight at 100°C in a sealed tube. Recrystallization using (dichloromethane/methanol) gave crude product (120 mg, yield 49.08%). 10 mg of the crude product was purified and lyophilized by preparative HPLC 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, CD 3 OD)δ8.95(s,1H),7.77 –7.63(m,3H),1.56(d,J＝4.3 Hz,9H).
实施例6:2-氨基-7-氯-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 6: Preparation of 2-amino-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one
将实施例5第二步所得化合物5加入4N盐酸乙酸乙酯(5ml)中，反应混合物在25℃下搅拌16小时。通过LC-MS检测反应完成。所得混合物在真空下浓缩以得到粗产物(45mg,产率71.61％)。取10mg粗产物通过制备级HPLC纯化冻干得目标产物化合物6：2-氨基-7-氯-9H-茚并[2,1-d]嘧啶-9-酮(2mg，3.18％产率)。MS(ESI)[M+H]+232.1,234.1.Compound 5 obtained in the second step of Example 5 was added to 4N hydrochloric acid ethyl acetate (5 ml), and the reaction mixture was stirred at 25°C for 16 hours. Reaction completion was detected by LC-MS. The resulting mixture was concentrated in vacuo to give crude product (45 mg, 71.61% yield). 10 mg of the crude product was purified by preparative HPLC and lyophilized to obtain the target product compound 6: 2-amino-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one (2 mg, 3.18% yield). MS(ESI)[M+H] + 232.1,234.1.
实施例7:2，7-二氯-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 7: Preparation of 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-氯嘧啶-5-基)苯甲醛的制备(7a)Step 1: Preparation of 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (7a)
将4-氯-2-醛基苯硼酸(767mg，4.17mmol)溶于甲醇(15ml)，加入2-氯-5-碘嘧啶(500mg，2.08mmol)，氟化钾(242mg,4.17mmol)和醋酸钯(24mg,0.11mmol)，120℃微波反应50分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝10％-25％)纯化得目标产物5-氯-2-(2-氯嘧啶-5-基)苯甲醛(7a,233mg,产率44.4％)。MS(ESI)[M+H]+253.1,254.9.Dissolve 4-chloro-2-aldehyde phenylboronic acid (767mg, 4.17mmol) in methanol (15ml), add 2-chloro-5-iodopyrimidine (500mg, 2.08mmol), potassium fluoride (242mg, 4.17mmol) and Palladium acetate (24 mg, 0.11 mmol), microwave reaction at 120°C for 50 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate:petroleum ether=10%-25%) to obtain the target product 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (7a, 233 mg). , yield 44.4%). MS(ESI)[M+H] + 253.1,254.9.
第二步:2，7-二氯-9H-茚并[2，1-d]嘧啶-9-酮的制备(7)Step 2: Preparation of 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7)
将5-氯-2-(2-氯嘧啶-5-基)苯甲醛(7a,183mg,0.726mmol)溶于1,2-二氯乙烷(15ml)，加入四丁基碘化铵(14mg，0.038mmol)和叔丁基过氧化氢(420μl，4.356mmol)，于封管中100℃反应8小时。减压蒸干溶剂得目标产物化合物7：2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮粗品(145mg,产率79.7％)，取部分粗品使用(甲醇)重结晶得纯品14.54mg。MS(ESI)[M+H]+251.0,253.0.1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.00(d,J＝8.0Hz,1H),7.88–7.79(m,2H).Dissolve 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (7a, 183mg, 0.726mmol) in 1,2-dichloroethane (15ml), add tetrabutylammonium iodide (14mg , 0.038mmol) and tert-butyl hydroperoxide (420μl, 4.356mmol), react in a sealed tube at 100°C for 8 hours. The solvent was evaporated to dryness under reduced pressure to obtain the target product compound 7: 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one crude product (145 mg, yield 79.7%), and part of the crude product was used (methanol ) was recrystallized to obtain 14.54 mg of pure product. MS (ESI) [M+H] + 251.0, 253.0. 1 H NMR (400MHz, DMSO-d 6 ) δ9.33 (s, 1H), 8.00 (d, J = 8.0Hz, 1H), 7.88–7.79 ( m,2H).
实施例8和9:7-氯-3-氟-9-氧-9H-茚并[2，1-b]吡啶-2-碳腈和7-氯-4-氟-5-氧-5H-茚并[1，2-c]吡啶-3-碳腈的制备
Examples 8 and 9: 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile and 7-chloro-4-fluoro-5-oxo-5H- Preparation of indeno[1,2-c]pyridine-3-carbonitrile
第一步:5-(4-氯-2-甲酰基苯基)-3-氟吡啶腈的制备(8a)Step 1: Preparation of 5-(4-chloro-2-formylphenyl)-3-fluoropyridinenitrile (8a)
将4-氯-2-醛基苯硼酸(688mg，3.73mmol)溶于乙醇(25ml)，加入5-溴-3-氟吡啶腈(500mg，2.49mmol)，氟化钾(290mg,4.98mmol)和醋酸钯(30mg,0.125mmol)，120℃微波反应30分钟。过滤减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝10％-20％)纯化得目标产物5-(4-氯-2-甲酰基苯基)-3-氟吡啶腈(8a，450mg,产率69.40％)。MS(ESI)[M+H]+261.0,263.0.Dissolve 4-chloro-2-aldehyde phenylboronic acid (688mg, 3.73mmol) in ethanol (25ml), add 5-bromo-3-fluoropyridinenitrile (500mg, 2.49mmol) and potassium fluoride (290mg, 4.98mmol) And palladium acetate (30 mg, 0.125 mmol), microwave reaction at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure by filtration, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 10%-20%) to obtain the target product 5-(4-chloro-2-formylphenyl)-3-fluoropyridinenitrile ( 8a, 450 mg, yield 69.40%). MS(ESI)[M+H] + 261.0,263.0.
第二步:7-氯-3-氟-9-氧-9H-茚并[2，1-b]吡啶-2-碳腈(8)的制备Step 2: Preparation of 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbonitrile (8)
将5-(4-氯-2-甲酰基苯基)-3-氟吡啶腈(8a，400mg,1.53mmol)溶于1,2-二氯乙烷(20ml)，加入四丁基碘化铵(28mg，0.076mmol)和叔丁基过氧化氢(830mg，9.21mmol)，于封管中100℃反应16小时。减压蒸干溶剂，再用制备级HPLC纯化拆分冻干得目标产物化合物8：7-氯-3-氟-9-氧-9H-茚并[2,1-b]吡啶-2-碳腈(5mg,产率1.26％)MS(ESI)[M+H]+259.0,261.0.1H NMR(400MHz,DMSO-d6)δ8.62(d,J＝9.0Hz,1H),8.01(d,J＝8.0Hz,1H),7.91–7.78(m,2H).和化合物9：7-氯-4-氟-5-氧-5H-茚并[1,2-c]吡啶-3-碳腈(933mg,产率8.31％)。MS(ESI)[M+H]+258.9,261.0.1H NMR(400MHz,DMSO-d6)δ9.18(d,J＝1.6Hz,1H),8.11(d,J＝8.0Hz,1H),7.90–7.80(m,2H).Dissolve 5-(4-chloro-2-formylphenyl)-3-fluoropyridinenitrile (8a, 400 mg, 1.53 mmol) in 1,2-dichloroethane (20 ml), and add tetrabutylammonium iodide (28 mg, 0.076 mmol) and tert-butyl hydroperoxide (830 mg, 9.21 mmol) were reacted in a sealed tube at 100°C for 16 hours. The solvent was evaporated to dryness under reduced pressure, and then purified and separated by preparative HPLC and lyophilized to obtain the target product compound 8: 7-chloro-3-fluoro-9-oxo-9H-indeno[2,1-b]pyridine-2-carbon. Nitrile (5mg, yield 1.26%) MS (ESI) [M+H] + 259.0, 261.0. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.62 (d, J = 9.0Hz, 1H), 8.01 ( d, J = 8.0Hz, 1H), 7.91–7.78 (m, 2H). and compound 9: 7-chloro-4-fluoro-5-oxo-5H-indeno[1,2-c]pyridine-3- Carbonitrile (933 mg, yield 8.31%). MS(ESI)[M+H]+258.9,261.0. 1 H NMR(400MHz, DMSO-d 6 )δ9.18(d,J＝1.6Hz,1H),8.11(d,J＝8.0Hz,1H) ,7.90–7.80(m,2H).
实施例10:7-氯-2-吗啉基-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 10: Preparation of 7-chloro-2-morpholinyl-9H-indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(7，30mg，0.119mmol)溶于N,N-二甲基甲酰胺(2ml)，加入碳酸钾(25mg，0.179mmol)和吗啉(11mg，0.131mmol)，室温反应16小时。将水溶液(10ml)加到反应混合物中。混合溶液用乙酸乙酯(6ml×3)萃取，再用盐水(6m×2)洗涤合并的有机层，用无水硫酸钠干燥并过滤。有机层在减压下浓缩再通过制备级HPLC纯化冻干得目标产物化合物10：7-氯-2-吗啉基-9H-茚并[2,1-d]嘧啶-9-酮(6.9mg，产率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).Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7, 30 mg, 0.119 mmol) in N, N-dimethylformamide (2 ml), and add potassium carbonate (25 mg, 0.179 mmol) and morpholine (11 mg, 0.131 mmol), react at room temperature for 16 hours. The aqueous solution (10 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (6ml×3), and the combined organic layer was washed with brine (6m×2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and lyophilized to obtain 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. 1 H NMR (400MHz, CDCl 3 ) δ8.54 (d, J = 15.1 Hz, 1H), 7.62 (d, J = 1.3 Hz, 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).
实施例11:7-氯-2-(4，4-二氟哌啶-1-基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 11: Preparation of 7-chloro-2-(4,4-difluoropiperidin-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(7，30mg，0.119mmol)溶于N,N-二甲基甲酰胺(2ml)，加入碳酸钾(25mg，0.179mmol)和4,4-二氟哌啶(16mg，0.131mmol)，室温反应16小时。将水溶液(10ml)加到反应混合物中。混合溶液用乙酸乙酯(6ml×3)萃取，再用盐水(6mlx2)洗涤合并的有机层，用无水硫酸钠干燥并过滤。有机层在减压下浓缩再通过制备级HPLC纯化冻干得目标产物化合物11：7-氯-2-(4,4-二氟哌啶-1-基)-9H-茚并[2,1-d]嘧啶-9-酮(11.1mg,产率27.67％)。MS(ESI)[M+H]+336.1,338.1.1H 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).Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7, 30 mg, 0.119 mmol) in N, N-dimethylformamide (2 ml), and add potassium carbonate (25 mg, 0.179 mmol) and 4,4-difluoropiperidine (16 mg, 0.131 mmol), react at room temperature for 16 hours. The aqueous solution (10 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (6ml×3), and the combined organic layers were washed with brine (6ml×2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and lyophilized to obtain the target product compound 11: 7-chloro-2-(4,4-difluoropiperidin-1-yl)-9H-indeno[2,1 -d]pyrimidin-9-one (11.1 mg, yield 27.67%). MS(ESI)[M+H] + 336.1,338.1. 1 H NMR (400MHz, CDCl 3 ) 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).
实施例12:7-氯-2-(1H-咪唑-1-基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 12: Preparation of 7-chloro-2-(1H-imidazol-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(7，20mg，0.08mmol)溶于N,N-二甲基甲酰胺(2ml)，加入碳酸铯(52mg，0.159mmol)，碘化铜(2mg，0.008mmol)和咪唑(8mg，0.119mmol)，在50℃反应16小时。将水溶液(10ml)加到反应混合物中。混合溶液用乙酸乙酯(6ml×3)萃取，再用盐水(6mlx2)洗涤合并的有机层，用无水硫酸钠干燥并过滤。有机层在减压下浓缩再通过制备级HPLC纯化冻干得目标产物化合物12：7-氯-2-(1H-咪唑-1-基)-9H-茚并[2,1-d]嘧啶-9-酮(2mg,产率8.88％)。MS(ESI)[M+H]+283.0,285.1.Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7, 20 mg, 0.08 mmol) in N, N-dimethylformamide (2 ml), and add cesium carbonate (52 mg, 0.159 mmol), copper iodide (2 mg, 0.008 mmol) and imidazole (8 mg, 0.119 mmol), reacted at 50°C for 16 hours. The aqueous solution (10 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (6ml×3), and the combined organic layers were washed with brine (6ml×2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and lyophilized to obtain the target product compound 12: 7-chloro-2-(1H-imidazol-1-yl)-9H-indeno[2,1-d]pyrimidine- 9-one (2 mg, yield 8.88%). MS(ESI)[M+H] + 283.0,285.1.
实施例13:7-氟-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 13: Preparation of 7-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氟-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的制备(13a)Step 1: Preparation of 5-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (13a)
将(4-氟-2-甲酰基苯基)硼酸(222mg，1.32mmol)溶于乙醇(10ml)，加入5-溴-2-(三氟甲基)嘧啶(200mg，0.881mmol)，氟化钾(102mg,1.76mmol)和醋酸钯(10mg,0.044mmol)，120℃微波反应30分钟。过滤减压蒸干溶剂得目标产物粗品5-氟-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(300mg)。MS(ESI)[M+H]+271.2,272.2.Dissolve (4-fluoro-2-formylphenyl)boronic acid (222mg, 1.32mmol) in ethanol (10ml), add 5-bromo-2-(trifluoromethyl)pyrimidine (200mg, 0.881mmol), and fluoride Potassium (102 mg, 1.76 mmol) and palladium acetate (10 mg, 0.044 mmol) were reacted under microwave at 120°C for 30 minutes. The solvent was filtered and evaporated to dryness under reduced pressure to obtain the crude target product 5-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (300 mg). MS(ESI)[M+H] + 271.2,272.2.
第二步:7-氟-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(13)Step 2: Preparation of 7-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (13)
将5-氟-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(13a,300mg,1.11mmol)溶于1,2-二氯乙烷(20ml)，加入四丁基碘化铵(20mg，0.056mmol)和叔丁基过氧化氢(600mg，6.66mmol)，于封管中100℃反应16小时。减压蒸干溶剂，再用制备级HPLC纯化冻干得目标产物化合物13：7-氟-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(18.8mg,产率6.31％)。MS(ESI)[M+H]+269.1,270.0.1H 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). Dissolve 5-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (13a, 300mg, 1.11mmol) in 1,2-dichloroethane (20ml), add tetrabutyl Ammonium iodide (20 mg, 0.056 mmol) and tert-butyl hydroperoxide (600 mg, 6.66 mmol) were reacted in a sealed tube at 100°C for 16 hours. The solvent was evaporated to dryness under reduced pressure, and then 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-d 6 ) δ9.57 (s, 1H), 8.13 (dd, J = 8.2, 4.5Hz, 1H), 7.69 ( q,J＝8.7,7.9Hz,2H).
实施例14:7-氯-9-氧代-9H-茚并[2，l-d]嘧啶-2-碳腈的制备
Example 14: Preparation of 7-chloro-9-oxo-9H-indeno[2,ld]pyrimidine-2-carbonitrile
第一步:5-(4-氯-2-甲酰基苯基)嘧啶-2-碳腈的制备(14a)Step 1: Preparation of 5-(4-chloro-2-formylphenyl)pyrimidine-2-carbonitrile (14a)
将4-氯-2-醛基苯硼酸(302mg，1.64mmol)溶于甲醇(10ml)，加入5-溴-2-氰基嘧啶(200mg，1.09mmol)，氟化钾(127mg,2.19mmol)和醋酸钯(13mg,0.058mmol)，120℃微波反应0.5小时。减压蒸干溶剂，剩余物Flash柱(二氯甲烷)纯化得目标产物5-(4-氯-2-甲酰基苯基)嘧啶-2-碳腈(14a,93mg,产率35.1％)。MS(ESI)[M+H]+244.0,246.0.Dissolve 4-chloro-2-aldehyde phenylboronic acid (302mg, 1.64mmol) in methanol (10ml), add 5-bromo-2-cyanopyrimidine (200mg, 1.09mmol) and potassium fluoride (127mg, 2.19mmol) And palladium acetate (13mg, 0.058mmol), microwave reaction at 120°C for 0.5 hours. The solvent was evaporated to dryness under reduced pressure, and the residue was purified with Flash column (dichloromethane) to obtain the target product 5-(4-chloro-2-formylphenyl)pyrimidine-2-carbonitrile (14a, 93 mg, yield 35.1%). MS(ESI)[M+H] + 244.0,246.0.
第二步:7-氯-9-氧代-9H-茚并[2，1-d]嘧啶-2-碳腈的制备(14)Step 2: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbonitrile (14)
将5-(4-氯-2-甲酰基苯基)嘧啶-2-碳腈(14a,40mg,0.16mmol)溶于1,2-二氯乙烷(3ml)，加入四丁基碘化铵(3mg，0.008mmol)和叔丁基过氧化氢(95μl，0.96mmol)，于封管中100℃反应5小时。使用(二氯甲烷)重结晶去除杂质，滤液再用(二氯甲烷/甲醇)重结晶得目标产物化合物14：7-氯-9-氧代-9H-茚并[2,1-d]嘧啶-2-碳腈(7.17mg,产率18.1％)。MS(ESI)[M+H]+242.0,244.0.1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.11(d,J＝8.1Hz,1H),7.95–7.87(m,2H).Dissolve 5-(4-chloro-2-formylphenyl)pyrimidine-2-carbonitrile (14a, 40 mg, 0.16 mmol) in 1,2-dichloroethane (3 ml), and add tetrabutylammonium iodide (3 mg, 0.008 mmol) and tert-butyl hydroperoxide (95 μl, 0.96 mmol) were reacted in a sealed tube at 100°C for 5 hours. Recrystallize with (dichloromethane) to remove impurities, and the filtrate is recrystallized with (dichloromethane/methanol) to obtain the target product compound 14: 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine -2-Carbonitrile (7.17 mg, yield 18.1%). MS (ESI) [M+H] + 242.0, 244.0. 1 H NMR (400MHz, DMSO-d 6 ) δ9.58 (s, 1H), 8.11 (d, J = 8.1Hz, 1H), 7.95–7.87 ( m,2H).
实施例15:7-氯-2-(4-甲基哌嗪-1-基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 15: Preparation of 7-chloro-2-(4-methylpiperazin-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(7,10mg，0.04mmol)溶于N,N-二甲基甲酰胺(1ml)，加入碳酸钾(8mg，0.059mmol)和1-甲基哌嗪(4mg，0.044mmol)，室温反应4小时。将水溶液(5ml)加到反应混合物中。混合溶液用乙酸乙酯(3ml×3)萃取，再用盐水(3mlx2)洗涤合并的有机层，用无水硫酸钠干燥并过滤。有机层在减压下浓缩再通过制备级HPLC纯化冻干得目标产物15：-氯-2-(4-甲基哌嗪-1-基)-9H茚并[2,1-d]嘧啶-9-酮(3.5mg,产率27.92％)。MS(ESI)[M+H]+315.2,317.2.1H 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).Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,10mg, 0.04mmol) in N,N-dimethylformamide (1ml), and add potassium carbonate (8 mg, 0.059 mmol) and 1-methylpiperazine (4 mg, 0.044 mmol), react at room temperature for 4 hours. The aqueous solution (5 ml) was added to the reaction mixture. The mixed solution was extracted with ethyl acetate (3ml×3), and the combined organic layers were washed with brine (3ml×2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and lyophilized to obtain the target product 15: -Chloro-2-(4-methylpiperazin-1-yl)-9H indeno[2,1-d]pyrimidine- 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).
实施例16:7-氯-9-氧代-9H-茚并[2，1-b]吡啶-2，3-二甲腈的制备
Example 16: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2,3-dicarbonitrile
第一步:2-氯-5-(4-氯-2-甲酰基苯基)烟腈的制备(16a)Step 1: Preparation of 2-chloro-5-(4-chloro-2-formylphenyl)nicotinonitrile (16a)
将4-氯-2-醛基苯硼酸(388mg，2.11mmol)溶于四氢呋喃/水(12ml/3ml)，加入5-溴-2-氯烟腈(350mg，1.62mmol)，碳酸钾(447mg,3.24mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(118mg,0.16mmol)，于封管中90℃反应过夜。过滤除去不溶物，剩余物Flash柱(乙酸乙酯：石油醚＝15％-20％)纯化得目标产物2-氯-5-(4-氯-2-甲酰基苯基)烟腈(16a,208mg,产率40.7％)。MS(ESI)[M+H]+277.1,279.0.Dissolve 4-chloro-2-aldehyde phenylboronic acid (388mg, 2.11mmol) in tetrahydrofuran/water (12ml/3ml), add 5-bromo-2-chloronicotinonitrile (350mg, 1.62mmol), potassium carbonate (447mg, 3.24 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (118 mg, 0.16 mmol) were reacted overnight at 90°C in a sealed tube. The insoluble matter was removed by filtration, and the remaining residue was purified by Flash column (ethyl acetate:petroleum ether=15%-20%) to obtain the target product 2-chloro-5-(4-chloro-2-formylphenyl)nicotinonitrile (16a, 208 mg, yield 40.7%). MS(ESI)[M+H] + 277.1,279.0.
第二步:5-(4-氯-2-甲酰基苯基)吡啶-2，3-二甲腈的制备(16b)Step 2: Preparation of 5-(4-chloro-2-formylphenyl)pyridine-2,3-dicarbonitrile (16b)
将2-氯-5-(4-氯-2-甲酰基苯基)烟腈(16a,128mg，0.464mmol)溶于N-甲基吡咯烷酮(5ml)，加入氰化锌(33mg，0.281mmol)和四三苯基膦钯(54mg,0.047mmol)，微波150℃反应30分钟。过滤除去不溶物，剩余物Flash柱(乙酸乙酯：石油醚＝20％-40％)纯化得目标产物5-(4-氯-2-甲酰基苯基)吡啶-2,3-二甲腈(16b,44mg,产率35.5％)。MS(ESI)[M+H]+268.1,270.1.Dissolve 2-chloro-5-(4-chloro-2-formylphenyl)nicotinonitrile (16a, 128mg, 0.464mmol) in N-methylpyrrolidone (5ml), and add zinc cyanide (33mg, 0.281mmol) And tetrakis triphenylphosphine palladium (54 mg, 0.047 mmol), microwave reaction at 150°C for 30 minutes. Insoluble matter was removed by filtration, and the remaining residue was purified with Flash column (ethyl acetate: petroleum ether = 20%-40%) to obtain the target product 5-(4-chloro-2-formylphenyl)pyridine-2,3-dicarbonitrile. (16b, 44 mg, yield 35.5%). MS(ESI)[M+H] + 268.1,270.1.
第三步:7-氯-9-氧代-9H-茚并[2，1-b]吡啶-2，3-二甲腈的制备(16)Step 3: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2,3-dicarbonitrile (16)
将5-(4-氯-2-甲酰基苯基)吡啶-2,3-二甲腈(16b,44mg,0.165mmol)溶于1,2-二氯乙烷(3ml)，加入叔丁基过氧化氢(127μl，1.32mmol)，于封管中100℃反应过夜。使用(二氯甲烷/甲醇)重结晶得目标产物化合物16：7-氯-9-氧代-9H-茚并[2,1-b]吡啶-2,3-二甲腈(4.18mg,产率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).Dissolve 5-(4-chloro-2-formylphenyl)pyridine-2,3-dicarbonitrile (16b, 44mg, 0.165mmol) in 1,2-dichloroethane (3ml), add tert-butyl Hydrogen peroxide (127 μl, 1.32 mmol) was reacted in a sealed tube at 100°C overnight. Recrystallization using (dichloromethane/methanol) gave the target product compound 16: 7-chloro-9-oxo-9H-indeno[2,1-b]pyridine-2,3-dicarbonitrile (4.18 mg, product rate 9.7%). MS(ESI)[M+H] + 266.0,268.1. 1 H NMR(400MHz,DMSO-d6)δ9.56(s,1H),9.11(s,1H),8.05(d,J＝7.7Hz,2H ).
实施例17:7-氯-9-氧代-9H-芴-2-碳腈的制备
Example 17: Preparation of 7-chloro-9-oxo-9H-fluorene-2-carbonitrile
第一步:4′-氯-2′-甲酰基-[1，1′-联苯1-4-碳腈的制备(17a)Step 1: Preparation of 4′-chloro-2′-formyl-[1,1′-biphenyl 1-4-carbonitrile (17a)
将4-氯-2-醛基苯硼酸(209mg，1.14mmol)溶于甲醇(10ml)，加入4-碘氰基苯(200mg，0.873mmol)，氟化钾(101mg,1.74mmol)和醋酸钯(10mg,0.045mmol)，120℃微波反应40分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝10％-20％)纯化得目标产物4'-氯-2'-甲酰基-[1,1'-联苯]-4-碳腈(17a,162mg,产率61.6％)。MS(ESI)[M+H]+242.1,244.1.Dissolve 4-chloro-2-aldehyde phenylboronic acid (209mg, 1.14mmol) in methanol (10ml), add 4-iodocyanobenzene (200mg, 0.873mmol), potassium fluoride (101mg, 1.74mmol) and palladium acetate (10 mg, 0.045 mmol), microwave reaction at 120°C for 40 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 10%-20%) to obtain the target product 4'-chloro-2'-formyl-[1,1'-biphenyl]-4. -Carbonitrile (17a, 162 mg, yield 61.6%). MS(ESI)[M+H] + 242.1,244.1.
第二步:7-氯-9-氧代-9H-芴-2-碳腈的制备(17)Step 2: Preparation of 7-chloro-9-oxo-9H-fluorene-2-carbonitrile (17)
将4'-氯-2'-甲酰基-[1,1'-联苯]-4-碳腈(30mg,0.124mmol)溶于1,2-二氯乙烷(3ml)，加入叔丁基过氧化氢(48μl，0.496mmol)，于封管中100℃反应过夜。使用(二氯甲烷/甲醇)重结晶得目标产物化合物17：7-氯-9-氧代-9H-芴-2-碳腈(7.33mg,产率24.6％)。1H NMR(400MHz,DMSO-d6)δ8.14(d,J＝8.6Hz,1H),8.06(d,J＝8.2Hz,2H),7.99(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.71(s,1H).Dissolve 4'-chloro-2'-formyl-[1,1'-biphenyl]-4-carbonitrile (30mg, 0.124mmol) in 1,2-dichloroethane (3ml), add tert-butyl Hydrogen peroxide (48 μl, 0.496 mmol) was reacted in a sealed tube at 100°C overnight. Recrystallization using (dichloromethane/methanol) gave the target product compound 17: 7-chloro-9-oxo-9H-fluorene-2-carbonitrile (7.33 mg, yield 24.6%). 1 H NMR (400MHz, DMSO-d6) δ8.14(d,J＝8.6Hz,1H),8.06(d,J＝8.2Hz,2H),7.99(d,J＝8.0Hz,1H),7.77( d,J＝8.0Hz,1H),7.71(s,1H).
实施例18:7-氯-2-甲氧基-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 18: Preparation of 7-chloro-2-methoxy-9H-indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(7,4mg，0.016mmol)溶于甲醇/四氢呋喃(1m/1ml)，加入碳酸钾(4mg，0.024mmol)，室温反应3小时。过滤去除不溶物，剩余物半制备纯化得目标产物化合物18：7-氯-2-甲氧基-9H-茚并[2,1-d]嘧啶-9-酮(1.42mg,产率36.4％)。MS(ESI)[M+H]+247.1,249.0.Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,4mg, 0.016mmol) in methanol/tetrahydrofuran (1m/1ml), add potassium carbonate (4mg, 0.024 mmol), react at room temperature for 3 hours. Insoluble matter was removed by filtration, and the residue was semi-preparatively purified to obtain the target product compound 18: 7-chloro-2-methoxy-9H-indeno[2,1-d]pyrimidin-9-one (1.42 mg, yield 36.4% ). MS(ESI)[M+H] + 247.1,249.0.
实施例19:7-氯-2-(二甲氨基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 19: Preparation of 7-chloro-2-(dimethylamino)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-(二甲氨基)嘧啶-5-基)苯甲醛的制备(19a)Step 1: Preparation of 5-chloro-2-(2-(dimethylamino)pyrimidin-5-yl)benzaldehyde (19a)
将4-氯-2-醛基苯硼酸(118mg，0.641mmol)溶于乙醇(5ml)，加入5-溴-2-(二甲基氨基)嘧啶(100mg，0.495mmol)，氟化钾(57mg,0.983mmol)和醋酸钯(6mg,0.027mmol)，120℃微波反应40分钟。减压蒸干溶剂，剩余物Flash柱(二氯甲烷：甲醇＝0％-10％)纯化得目标产物5-氯-2-(2-(二甲氨基)嘧啶-5-基)苯甲醛(19a,20mg,产率15.5％)。MS(ESI)[M+H]+262.1,264.2.Dissolve 4-chloro-2-aldehyde phenylboronic acid (118mg, 0.641mmol) in ethanol (5ml), add 5-bromo-2-(dimethylamino)pyrimidine (100mg, 0.495mmol), potassium fluoride (57mg ,0.983mmol) and palladium acetate (6mg, 0.027mmol), microwave reaction at 120°C for 40 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (dichloromethane: methanol=0%-10%) to obtain the target product 5-chloro-2-(2-(dimethylamino)pyrimidin-5-yl)benzaldehyde ( 19a, 20 mg, yield 15.5%). MS(ESI)[M+H] + 262.1,264.2.
第二步:7-氯-2-(二甲氨基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(19)Step 2: Preparation of 7-chloro-2-(dimethylamino)-9H-indeno[2,1-d]pyrimidin-9-one (19)
将5-氯-2-(2-(二甲氨基)嘧啶-5-基)苯甲醛(19a,20mg,0.077mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(2mg，0.0054mmol)和叔丁基过氧化氢(44μl，0.462mmol)，于封管中100℃反应5小时。使用(二氯甲烷/甲醇)重结晶得得目标产物化合物19：7-氯-2-(二甲氨基)-9H-茚并[2,1-d]嘧啶-9-酮(1.45mg,产率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).Dissolve 5-chloro-2-(2-(dimethylamino)pyrimidin-5-yl)benzaldehyde (19a, 20mg, 0.077mmol) in 1,2-dichloroethane (2ml), add tetrabutyl iodide Ammonium chloride (2 mg, 0.0054 mmol) and tert-butyl hydroperoxide (44 μl, 0.462 mmol) were reacted in a sealed tube at 100°C for 5 hours. Recrystallization using (dichloromethane/methanol) gave the target product compound 19: 7-chloro-2-(dimethylamino)-9H-indeno[2,1-d]pyrimidin-9-one (1.45 mg, product rate 7.3%). MS(ESI)[M+H] + 260.1,262.1. 1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),7.67(s,2H),7.59(s,1H),3.20(s ,6H).
实施例20:7-氯-2-甲基-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 20: Preparation of 7-chloro-2-methyl-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-甲基嘧啶-5-基)苯甲醛的制备(20a)Step 1: Preparation of 5-chloro-2-(2-methylpyrimidin-5-yl)benzaldehyde (20a)
将4-氯-2-醛基苯硼酸(138mg，0.75mmol)溶于乙醇(5ml)，加入2-甲基-5-溴嘧啶(100mg，0.578mmol)，氟化钾(67mg,1.16mmol)和醋酸钯(7mg,0.031mmol)，120℃微波反应1小时。减压蒸干溶剂，剩余物Flash柱(二氯甲烷：甲醇＝0％-5％)纯化得目标产物5-氯-2-(2-甲基嘧啶-5-基)苯甲醛(20a,102mg,产率76.1％)。MS(ESI)[M+H]+233.1,235.1.Dissolve 4-chloro-2-aldehyde phenylboronic acid (138mg, 0.75mmol) in ethanol (5ml), add 2-methyl-5-bromopyrimidine (100mg, 0.578mmol) and potassium fluoride (67mg, 1.16mmol) And palladium acetate (7mg, 0.031mmol), microwave reaction at 120°C for 1 hour. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (dichloromethane: methanol = 0%-5%) to obtain the target product 5-chloro-2-(2-methylpyrimidin-5-yl)benzaldehyde (20a, 102 mg , yield 76.1%). MS(ESI)[M+H] + 233.1,235.1.
第二步:7-氯-2-甲基-9H-茚并[2，1-d]嘧啶-9-酮的制备(20)Step 2: Preparation of 7-chloro-2-methyl-9H-indeno[2,1-d]pyrimidin-9-one (20)
将5-氯-2-(2-甲基嘧啶-5-基)苯甲醛(20a,50mg,0.216mmol)溶于1,2-二氯乙烷(3ml)，加入四丁基碘化铵 (4mg，0.011mmol)和叔丁基过氧化氢(83μl，0.864mmol)，于封管中100℃反应过夜。使用(二氯甲烷/甲醇)重结晶得目标产物化合物20：7-氯-2-甲基-9H-茚并[2,1-d]嘧啶-9-酮(10.81mg,产率21.8％)。MS(ESI)[M+H]+231.0,233.0.1H 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).Dissolve 5-chloro-2-(2-methylpyrimidin-5-yl)benzaldehyde (20a, 50mg, 0.216mmol) in 1,2-dichloroethane (3ml), and add tetrabutylammonium iodide (4 mg, 0.011 mmol) and tert-butyl hydroperoxide (83 μl, 0.864 mmol) were reacted overnight at 100°C in a sealed tube. Recrystallization using (dichloromethane/methanol) gave 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-d 6 ) δ9.26 (s, 1H), 7.93 (d, J = 8.0Hz, 1H), 7.79 (dd, J＝8.0,2.0Hz,1H),7.73(d,J＝1.9Hz,1H),2.71(s,3H).
实施例21:7-氯-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 21: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的制备(21a)Step 1: Preparation of 5-chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (21a)
将4-氯-2-醛基苯硼酸(106mg，0.576mmol)溶于乙醇(5ml)，加入5-溴-2-三氟甲基嘧啶(100mg，0.442mmol)，氟化钾(51mg,0.879mmol)和醋酸钯(5mg,0.022mmol)，120℃微波反应40分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝5％-10％)纯化得目标产物5-氯-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(21a,94mg,产率74.3％)。MS(ESI)[M+H]+287.0,289.0.Dissolve 4-chloro-2-aldehyde phenylboronic acid (106mg, 0.576mmol) in ethanol (5ml), add 5-bromo-2-trifluoromethylpyrimidine (100mg, 0.442mmol), potassium fluoride (51mg, 0.879 mmol) and palladium acetate (5 mg, 0.022 mmol), microwave reaction at 120°C for 40 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 5%-10%) to obtain the target product 5-chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzene. Formaldehyde (21a, 94 mg, yield 74.3%). MS(ESI)[M+H] + 287.0,289.0.
第二步:7-氯-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(21)Step 2: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (21)
将5-氯-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(21a,50mg,0.175mmol)溶于1,2-二氯乙烷(3ml)，加入四丁基碘化铵(3mg，0.0081mmol)和叔丁基过氧化氢(67μl，0.7mmol)，于封管中100℃反应过夜。使用(二氯甲烷/甲醇)重结晶得目标产物化合物21：7-氯-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(2.03mg,产率4.0％)。MS(ESI)[M+H]+285.1,287.1.1H NMR(400MHz,DMSO-d6)δ9.60,8.11,8.09,7.91,7.90,7.88,3.38,2.50.Dissolve 5-chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (21a, 50mg, 0.175mmol) in 1,2-dichloroethane (3ml), add tetrabutyl Ammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (67 μl, 0.7 mmol) were reacted in a sealed tube at 100°C overnight. Recrystallization using (dichloromethane/methanol) gave the target product compound 21: 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (2.03 mg, product rate 4.0%). MS(ESI)[M+H] + 285.1,287.1. 1 H NMR(400MHz, DMSO-d6)δ9.60,8.11,8.09,7.91,7.90,7.88,3.38,2.50.
实施例22:7-氯-9-氧代-9H-茚并[2，1-d]嘧啶-2-甲酰胺的制备
Example 22: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carboxamide
将7-氯-9-氧代-9H-茚并[2,1-d]嘧啶-2-碳腈(14,15mg，0.062mmol)溶于异丙醇/水(1ml/1ml)，加入二氧化锰(54mg，0.62mmol)，于封管中100℃反应10分钟。过滤，滤液半制备纯化得目标产物化合物22：7-氯-9-氧代-9H-茚并[2,1-d]嘧啶-2-甲酰胺(1.55mg,产率9.7％)。MS(ESI)[M+H]+260.1,262.1.Dissolve 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbonitrile (14,15mg, 0.062mmol) in isopropanol/water (1ml/1ml), add Manganese oxide (54 mg, 0.62 mmol) was reacted in a sealed tube at 100°C for 10 minutes. After filtration, the filtrate was semi-preparatively 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.
实施例23和24:7-氯-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮邻乙基肟的制备
Examples 23 and 24: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one o-ethyl oxime
将7-氯-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(21,31mg，0.109mmol)溶于吡啶(6ml)，加入乙氧基胺盐酸盐(32mg，0.328mmol)和5A分子筛，室温反应过夜。过滤，滤液减压蒸干后制备板(四氢呋喃：石油醚＝1:10)纯化分离得目标产物，一个任意指定为化合物23：(E)7-氯-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮邻乙基肟(10.9mg,产率61.4％)MS(ESI)[M+H]+328.1,330.1.1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.25–8.15(m,2H),7.78(dd,J＝8.2,1.8Hz,1H),4.63(q,J＝7.1Hz,2H),1.46(t,J＝7.1Hz,3H).，另一个任意指定为化合物24(HSN003B007-P2)：(Z)7-氯-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮邻乙基肟(11.03mg,产率61.4％)。MS(ESI)[M+H]+328.1,330.1.1H 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).Dissolve 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (21,31 mg, 0.109 mmol) in pyridine (6 ml), and add ethoxyamine Hydrochloride (32 mg, 0.328 mmol) and 5A molecular sieve were reacted at room temperature overnight. Filter, evaporate the filtrate to dryness under reduced pressure and then purify and isolate the target product using a preparation plate (tetrahydrofuran: petroleum ether = 1:10), which is arbitrarily designated as compound 23: (E) 7-chloro-2-(trifluoromethyl)-9H -Indeno[2,1-d]pyrimidin-9-one o-ethyl oxime (10.9 mg, yield 61.4%) MS (ESI) [M+H] + 328.1,330.1. 1 H NMR (400MHz, DMSO- d 6 )δ9.54(s,1H),8.25–8.15(m,2H),7.78(dd,J＝8.2,1.8Hz,1H),4.63(q,J＝7.1Hz,2H),1.46(t ,J=7.1Hz,3H)., and the other one is arbitrarily designated as compound 24 (HSN003B007-P2): (Z)7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d] Pyrimidin-9-one o-ethyl oxime (11.03 mg, yield 61.4%). MS(ESI)[M+H] + 328.1,330.1. 1 H NMR(400MHz, DMSO-d 6 )δ9.63(s,1H),8.28–8.17(m,1H),8.12(d,J＝8.2 Hz,1H),7.69(d,J＝7.6Hz,1H),4.57(dd,J＝13.9,6.9Hz,2H),1.43(d,J＝6.6Hz,3H).
实施例25:7-氯-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮肟的制备
Example 25: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one oxime
将7-氯-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(21,40mg，0.141mmol)溶于吡啶(3ml)，加入乙氧基胺盐酸盐(29mg，0.417mmol)和5A分子筛，室温反应6小时。过滤，滤液减压蒸干后半制备纯化得目标产物化合物25：7-氯-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮肟(2.69mg,产率6.4％)。MS(ESI)[M+H]+300.1,302.1.1H 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).Dissolve 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (21,40 mg, 0.141 mmol) in pyridine (3 ml), and add ethoxyamine Hydrochloride (29 mg, 0.417 mmol) and 5A molecular sieve were reacted at room temperature for 6 hours. Filter, and the filtrate is evaporated to dryness under reduced pressure and then semi-prepared 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).
实施例26:2，7-二氯-4-甲基-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 26: Preparation of 2,7-dichloro-4-methyl-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-氯-4-甲基嘧啶-5-基)苯甲醛的制备(26a)Step 1: Preparation of 5-chloro-2-(2-chloro-4-methylpyrimidin-5-yl)benzaldehyde (26a)
将4-氯-2-醛基苯硼酸(320mg，1.74mmol)溶于乙醇(20ml)，加入5-溴-2-氯-4-甲基嘧啶(300mg，1.45mmol)，氟化钾(168mg,2.9mmol)和醋酸钯(16mg,0.071mmol)，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝5％-20％)纯化得目标产物5-氯-2-(2-氯-4-甲基嘧啶-5-基)苯甲醛(26a,45mg,产率10.0％)。MS(ESI)[M+H]+267.0,268.9.Dissolve 4-chloro-2-aldehyde phenylboronic acid (320mg, 1.74mmol) in ethanol (20ml), add 5-bromo-2-chloro-4-methylpyrimidine (300mg, 1.45mmol), potassium fluoride (168mg , 2.9mmol) and palladium acetate (16mg, 0.071mmol), microwave reaction at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 5%-20%) to obtain the target product 5-chloro-2-(2-chloro-4-methylpyrimidin-5-yl)benzene. Formaldehyde (26a, 45 mg, yield 10.0%). MS(ESI)[M+H] + 267.0,268.9.
第二步:2，7-二氯-4-甲基-9H-茚并[2，1-d]嘧啶-9-酮的制备(26)Step 2: Preparation of 2,7-dichloro-4-methyl-9H-indeno[2,1-d]pyrimidin-9-one (26)
将5-氯-2-(2-氯-4-甲基嘧啶-5-基)苯甲醛(26a,45mg,0.169mmol)溶于1,2-二氯乙烷(4ml)，加入四丁基碘化铵(3mg，0.0081mmol)和叔丁基过氧化氢(97μl，1.015mmol)，于封管中100℃反应过夜。反应液减压蒸干后制备板(四氢呋喃：石油醚＝1:5)纯化得目标产物化合物26：2,7-二氯-4-甲基-9H-茚并[2,1-d]嘧啶-9-酮(0.89mg,产率2.0％)。MS(ESI)[M+H]+265.0,267.0.Dissolve 5-chloro-2-(2-chloro-4-methylpyrimidin-5-yl)benzaldehyde (26a, 45mg, 0.169mmol) in 1,2-dichloroethane (4ml), add tetrabutyl Ammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (97 μl, 1.015 mmol) were reacted in a sealed tube at 100°C overnight. The reaction solution was evaporated to dryness under reduced pressure and purified using a preparation plate (tetrahydrofuran: petroleum ether = 1:5) to obtain the target product compound 26: 2,7-dichloro-4-methyl-9H-indeno[2,1-d]pyrimidine. -9-one (0.89 mg, yield 2.0%). MS(ESI)[M+H] + 265.0,267.0.
实施例27:7-氯-2-氟-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 27: Preparation of 7-chloro-2-fluoro-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-氟嘧啶-5-基)苯甲醛的制备(27a)Step 1: Preparation of 5-chloro-2-(2-fluoropyrimidin-5-yl)benzaldehyde (27a)
将4-氯-2-醛基苯硼酸(375mg，2.04mmol)溶于仲丁醇(15ml)，加入5-溴-2-氟嘧啶(300mg，1.69mmol)，氟化钾(198mg,3.41mmol)和醋酸钯(18mg,0.08mmol)，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝5％-20％)纯化得目标产物5-氯-2-(2-氟嘧啶-5-基)苯甲醛(27a,75mg,产率18.8％)。MS(ESI)[M+H]+237.0,239.0.Dissolve 4-chloro-2-aldehyde phenylboronic acid (375mg, 2.04mmol) in sec-butanol (15ml), add 5-bromo-2-fluoropyrimidine (300mg, 1.69mmol), potassium fluoride (198mg, 3.41mmol) ) and palladium acetate (18 mg, 0.08 mmol), microwave reaction at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate:petroleum ether=5%-20%) to obtain the target product 5-chloro-2-(2-fluoropyrimidin-5-yl)benzaldehyde (27a, 75 mg). , yield 18.8%). MS(ESI)[M+H] + 237.0,239.0.
第二步:7-氯-2-氟-9H-茚并[2，1-d]嘧啶-9-酮的制备(27)Step 2: Preparation of 7-chloro-2-fluoro-9H-indeno[2,1-d]pyrimidin-9-one (27)
将5-氯-2-(2-氟嘧啶-5-基)苯甲醛(27a,30mg,0.127mmol)溶于1,2-二氯乙烷(3ml)，加入四丁基碘化铵(3mg，0.0081mmol)和叔丁基过氧化氢(73μl，0.763mmol)，于封管中100℃反应过夜。反应液减压蒸干后制备板(四氢呋喃：石油醚＝1:5)纯化得目标产物化合物27：7-氯-2-氟-9H-茚并[2,1-d]嘧啶-9-酮(23.52mg,产率11.9％)。MS(ESI)[M+H]+235.0,237.0.Dissolve 5-chloro-2-(2-fluoropyrimidin-5-yl)benzaldehyde (27a, 30mg, 0.127mmol) in 1,2-dichloroethane (3ml), add tetrabutylammonium iodide (3mg , 0.0081 mmol) and tert-butyl hydroperoxide (73 μl, 0.763 mmol), react overnight at 100°C in a sealed tube. The reaction solution was evaporated to dryness under reduced pressure and purified using a preparation 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.
实施例28:2，7-二(三、氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 28: Preparation of 2,7-bis(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-(三氟甲基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的制备(28a)Step 1: Preparation of 5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (28a)
将4-三氟甲基-2-醛基苯硼酸(150mg，0.688mmol)溶于乙醇(9ml)，加入5-溴-2-三氟甲基嘧啶(141mg，0.621mmol)，氟化钾(72mg,1.24mmol)和醋酸钯(9mg,0.04mmol)，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝5％-20％)纯化得目标产物5-(三氟甲基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(28a,70mg,产率31.8％)。MS(ESI)[M+H]+321.1.Dissolve 4-trifluoromethyl-2-aldehyde phenylboronic acid (150 mg, 0.688 mmol) in ethanol (9 ml), add 5-bromo-2-trifluoromethylpyrimidine (141 mg, 0.621 mmol), potassium fluoride ( 72mg, 1.24mmol) and palladium acetate (9mg, 0.04mmol), microwave reaction at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 5%-20%) to obtain the target product 5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidine- 5-yl)benzaldehyde (28a, 70 mg, yield 31.8%). MS(ESI)[M+H] + 321.1.
第二步:2，7-二(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(28)Step 2: Preparation of 2,7-bis(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (28)
将5-(三氟甲基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(28a,35mg,0.109mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(2mg，0.0055mmol)和叔丁基过氧化氢(63μl，0.654mmol)，于封管中100℃反应过夜。反应液减压蒸干后制备板(四氢呋喃：石油醚＝1:5)纯化得目标产物化合物28：2,7-二(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(3.56mg,产率10.2％)。MS(ESI)[M+H]+319.0.Dissolve 5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (28a, 35mg, 0.109mmol) in 1,2-dichloroethane (2ml) , add tetrabutylammonium iodide (2 mg, 0.0055 mmol) and tert-butyl hydroperoxide (63 μl, 0.654 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was evaporated to dryness under reduced pressure and purified using a preparation plate (tetrahydrofuran:petroleum ether=1:5) to obtain the target product compound 28: 2,7-bis(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine. -9-one (3.56 mg, yield 10.2%). MS(ESI)[M+H] + 319.0.
实施例29:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-碳腈的制备
Example 29: Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile
第一步:3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈的制备(29a)Step 1: Preparation of 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (29a)
将2-(三氟甲基)嘧啶-5-基硼酸(100mg，0.521mmol)溶于乙腈(10ml)，加入4-溴-3-甲酰苯甲腈(109mg，0.521mmol)，氟化钾(61mg,1.05mmol)和醋酸钯(6mg,0.027mmol)，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％-20％)纯化得目标产物3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(29a,35mg,产率24.3％)。MS(ESI)[M+H]+278.1.Dissolve 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (100 mg, 0.521 mmol) in acetonitrile (10 ml), add 4-bromo-3-formylbenzonitrile (109 mg, 0.521 mmol), potassium fluoride (61 mg, 1.05 mmol) and palladium acetate (6 mg, 0.027 mmol), microwave reaction at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-20%) to obtain the target product 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl). Benzonitrile (29a, 35 mg, yield 24.3%). MS(ESI)[M+H] + 278.1.
第二步:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-碳腈的制备(29)Step 2: Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (29)
将3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(35mg,0.126mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(3mg，0.0081mmol)和叔丁基过氧化氢(97μl，1.01mmol)，于封管中100℃反应过夜。反应液减压蒸干后制备板(四氢呋喃：石油醚＝1:2)纯化得目标产物化合物29：9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-碳腈(14.42mg,产率41.6％)。MS(ESI)[M+H]+276.1.1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.37–8.26(m,3H).Dissolve 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (35mg, 0.126mmol) in 1,2-dichloroethane (2ml), add tetrabutyl Ammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (97 μl, 1.01 mmol) were reacted in a sealed tube at 100°C overnight. The reaction solution was evaporated to dryness under reduced pressure and purified using a preparation plate (tetrahydrofuran: petroleum ether = 1:2) to obtain the target product compound 29: 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d ]pyrimidine-7-carbonitrile (14.42 mg, yield 41.6%). MS(ESI)[M+H] + 276.1. 1 H NMR(400MHz, DMSO-d 6 )δ9.73(s,1H),8.37–8.26(m,3H).
实施例30:7-氯-9-氧代-9H-芴-3-碳腈的制备
Example 30: Preparation of 7-chloro-9-oxo-9H-fluorene-3-carbonitrile
第一步:4'-氯-6-甲酰基-[1，1'-联苯]-3-碳腈的制备(30a)Step 1: Preparation of 4'-chloro-6-formyl-[1,1'-biphenyl]-3-carbonitrile (30a)
将(4-氯苯基)硼酸(112.3mg，0.714mmol)溶于甲醇(3ml)，加入3-溴-4-甲酰苯甲腈(100mg，0.114mmol)，醋酸钯(5.4mg，0.0057mmol)，氟化钾(55.6mg,0.228mmol)，在氮气保护下120℃微波反应40分钟。减压浓缩后粗品经硅胶色谱法纯化(乙酸乙酯：石油醚＝1/5)得目标产物4'-氯-6-甲酰基-[1,1'-联苯]-3-碳三腈(30a,94mg,产率81.5％)。MS(ESI)[M+H]+242.3.Dissolve (4-chlorophenyl)boronic acid (112.3mg, 0.714mmol) in methanol (3ml), add 3-bromo-4-formylbenzonitrile (100mg, 0.114mmol) and palladium acetate (5.4mg, 0.0057mmol) ), potassium fluoride (55.6 mg, 0.228 mmol), react in microwave at 120°C for 40 minutes under nitrogen protection. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1/5) to obtain the target product 4'-chloro-6-formyl-[1,1'-biphenyl]-3-carbonitrile. (30a, 94 mg, yield 81.5%). MS(ESI)[M+H] + 242.3.
第二步:7-氯-9-氧代-9H-芴-3-碳腈的制备(30)Step 2: Preparation of 7-chloro-9-oxo-9H-fluorene-3-carbonitrile (30)
将4'-氯-6-甲酰基-[1,1'-联苯]-3-碳腈(30a,30mg,0.124mmol)溶于二氯乙烷(2ml)，加入2-氢过氧基-2-甲基丙烷(89.8mg，0.992mmol)，100℃下密闭反应6小时，减压浓缩后粗品经制备高效液相纯化(水：甲醇＝1/50)得目标产物化合物30：7-氯-9-氧代-9H-芴-3-碳腈(2.9mg,产率9.8％)。MS(ESI)[M+H]+240.1.1H NMR(400MHz,DMSO-d6)δ8.40(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).Dissolve 4'-chloro-6-formyl-[1,1'-biphenyl]-3-carbonitrile (30a, 30 mg, 0.124 mmol) in dichloroethane (2 ml), and add 2-hydroperoxy -2-Methylpropane (89.8 mg, 0.992 mmol), sealed reaction at 100°C for 6 hours, concentrated under reduced pressure, and the crude product was purified by preparative high-performance liquid phase (water: methanol = 1/50) to obtain the target product compound 30:7- Chloro-9-oxo-9H-fluorene-3-carbonitrile (2.9 mg, yield 9.8%). MS(ESI)[M+H] + 240.1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.40 (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).
实施例31：7-氯-9-氧代-9H-茚并[2,1-d]嘧啶-2-羧酰胺的制备
Example 31: Preparation of 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carboxamide
将7-氯-9-氧代-9H-茚并[2,1-d]嘧啶-2-碳腈(14,20mg，0.083mmol)溶于甲醇(0.3ml)，加入甲醇钠(22.4mg，0.415mmol)，室温下搅拌5小时后，加入氯化铵(44.4mg,0.832mmol)，室温下继续反应24小时。加入水(5ml)，乙酸乙酯萃取，无水硫酸镁干燥，过滤，滤液减压浓缩后制备高效液相纯化(水：甲醇＝1/10)得目标产物化合物31：7-氯-9-氧代-9H-茚并[2,1-d]嘧啶-2-甲脒(1.37mg,产率6.4％)。MS(ESI)[M+H]+259.3.1H 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).Dissolve 7-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-2-carbonitrile (14,20 mg, 0.083 mmol) in methanol (0.3 ml), and add sodium methoxide (22.4 mg, 0.415mmol), stirred at room temperature for 5 hours, then added ammonium chloride (44.4mg, 0.832mmol), and continued the reaction at room temperature for 24 hours. Add water (5ml), extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to prepare high-performance liquid phase purification (water: methanol = 1/10) to obtain the target product compound 31: 7-chloro-9- Oxo-9H-indeno[2,1-d]pyrimidine-2-carboxamidine (1.37 mg, yield 6.4%). MS(ESI)[M+H] + 259.3. 1 H NMR (400MHz, DMSO-d 6 ) 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).
实施例32:7-氯-2-(1H-吡唑-1-基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 32: Preparation of 7-chloro-2-(1H-pyrazol-1-yl)-9H-indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(7,20mg，0.08mmol)溶于N,N-二甲基甲酰胺(2ml)，加入碳酸铯(52mg，0.159mmol)，碘化铜(2mg，0.008mmol)和吡唑(8mg，0.119mmol)，在50℃反应16小时。将水溶液(10ml)加 到反应混合物中。混合溶液用乙酸乙酯(6ml×3)萃取，再用盐水(6mlx2)洗涤合并的有机层，用无水硫酸钠干燥并过滤。有机层在减压下浓缩再通过制备级HPLC纯化冻干得目标产物化合物32：7-氯-2-(1H-吡唑-1-基)-9H-茚并[2,1-d]嘧啶-9-酮(0.5mg,产率2.22％)。MS(ESI)[M+H]+283.0,285.1.Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,20 mg, 0.08 mmol) in N,N-dimethylformamide (2 ml), and add cesium carbonate (52 mg, 0.159 mmol), copper iodide (2 mg, 0.008 mmol) and pyrazole (8 mg, 0.119 mmol), reacted at 50°C for 16 hours. Add aqueous solution (10ml) into the reaction mixture. The mixed solution was extracted with ethyl acetate (6ml×3), and the combined organic layers were washed with brine (6ml×2), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC and lyophilized to obtain the target product compound 32: 7-chloro-2-(1H-pyrazol-1-yl)-9H-indeno[2,1-d]pyrimidine. -9-one (0.5 mg, yield 2.22%). MS(ESI)[M+H] + 283.0,285.1.
实施例33:7-甲基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 33: Preparation of 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-甲基-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的制备(33a)Step 1: Preparation of 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (33a)
将(2-(三氟甲基)嘧啶-5-基)硼酸(145mg，0.754mmol)溶于乙腈(5ml)，加入2-溴-5-甲基苯甲醛(100mg，0.502mmol)，氟化钾(58mg,1.004mmol)和醋酸钯(6mg,0.025mmol)，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％-20％)纯化得目标产物5-甲基-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(33a,90mg,产率67.29％)。MS(ESI)[M+H]+267.1.Dissolve (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (145 mg, 0.754 mmol) in acetonitrile (5 ml), add 2-bromo-5-methylbenzaldehyde (100 mg, 0.502 mmol), and fluoride Potassium (58 mg, 1.004 mmol) and palladium acetate (6 mg, 0.025 mmol) were reacted in microwave at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-20%) to obtain the target product 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl). Benzaldehyde (33a, 90 mg, yield 67.29%). MS(ESI)[M+H] + 267.1.
第二步:7-甲基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(33)Step 2: Preparation of 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (33)
将5-甲基-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(33a,90mg,0.338mmol)溶于1,2-二氯乙烷(5ml)，加入四丁基碘化铵(6mg，0.017mmol)和叔丁基过氧化氢(244mg，2.7mmol)，于封管中100℃反应过夜。反应液减压蒸干后制备板(乙酸乙酯：石油醚＝1:4)纯化得目标产物化合物33：7-甲基-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(3.35mg,产率3.75％)。MS(ESI)[M+H]+265.1.1H 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).Dissolve 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (33a, 90mg, 0.338mmol) in 1,2-dichloroethane (5ml), add tetrabutylene Ammonium iodide (6 mg, 0.017 mmol) and tert-butyl hydroperoxide (244 mg, 2.7 mmol) were reacted in a sealed tube at 100°C overnight. The reaction solution was evaporated to dryness under reduced pressure and purified using a preparation plate (ethyl acetate: petroleum ether = 1:4) to obtain the target product compound 33: 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1 -d]pyrimidin-9-one (3.35 mg, yield 3.75%). MS (ESI) [M+H] + 265.1. 1 H NMR (400MHz, Chloroform-d) δ9.09 (s, 1H), 7.69 (d, J = 1.0 Hz, 1H), 7.62 (d, J = 7.7 Hz,1H),7.50(d,J＝7.7Hz,1H),2.47(s,3H).
实施例34:2-乙酰-7-氯-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 34: Preparation of 2-acetyl-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one
第一步:2-(2-乙酰嘧啶-5-基)-5-氯苯甲醛的制备(34a)Step 1: Preparation of 2-(2-acetypyrimidin-5-yl)-5-chlorobenzaldehyde (34a)
将(4-氯-2-甲酰基苯基)硼酸(182mg，0.995mmol)溶于乙腈(5ml)，加入1-(5-溴嘧啶-2-基)乙烷-1-酮(200mg，0.995mmol)，氟化钾(116mg,1.99mmol)和醋酸钯(10mg,0.05mmol)，封管120℃反应过夜。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％-50％)纯化得目标产物2-(2-乙酰嘧啶-5-基)-5-氯苯甲醛(34a,110mg,产率42。41％)。MS(ESI)[M+H]+261.0,263.0.(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), seal the tube and react at 120°C overnight. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-50%) to obtain the target product 2-(2-acetypyrimidin-5-yl)-5-chlorobenzaldehyde (34a, 110 mg , yield 42.41%). MS(ESI)[M+H] + 261.0,263.0.
第二步:2-乙酰-7-氯-9H-茚并[2，1-d]嘧啶-9-酮的制备(34)Step 2: Preparation of 2-acetyl-7-chloro-9H-indeno[2,1-d]pyrimidin-9-one (34)
将2-(2-乙酰嘧啶-5-基)-5-氯苯甲醛(34a,110mg,0.422mmol)溶于1,2-二氯乙烷(10ml)，加入四丁基碘化铵(8mg，0.021mmol)和叔丁基过氧化氢(434mg，3.38mmol)，于封管中100℃反应过夜。反应液减压蒸干后再用制备级HPLC纯化冻干得目标产物化合物34：2-乙酰-7-氯-9H-茚并[2,1-d]嘧啶-9-酮(1.18mg,产率1.08％)。MS(ESI)[M+H]+259.0,261.1.1H NMR(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).Dissolve 2-(2-acetypyrimidin-5-yl)-5-chlorobenzaldehyde (34a, 110mg, 0.422mmol) in 1,2-dichloroethane (10ml), add tetrabutylammonium iodide (8mg , 0.021mmol) and tert-butyl hydroperoxide (434mg, 3.38mmol) were 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, product rate 1.08%). MS(ESI)[M+H] + 259.0,261.1. 1 H NMR(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).
实施例35:2，7-二氯-4-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 35: Preparation of 2,7-dichloro-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-氯-4-(三氟甲基)嘧啶-5-基)苯甲醛的制备(35a)Step 1: Preparation of 5-chloro-2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (35a)
将4-氯-2-醛基苯硼酸(194mg，1.052mmol)溶于乙腈(21ml)，加入5-溴-2-氯-4-(三氟甲基)嘧啶(250mg，0.956mmol)，氟化钾(111mg,1.91mmol)和醋酸钯(11mg,0.048mmol)，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％-10％)纯化得目标产物5-氯-2-(2-氯-4-(三氟甲基)嘧啶-5-基)苯甲醛(35a,19mg,产率6.2％)。MS(ESI)[M+H]+320.9,323.0 Dissolve 4-chloro-2-aldehyde phenylboronic acid (194mg, 1.052mmol) in acetonitrile (21ml), add 5-bromo-2-chloro-4-(trifluoromethyl)pyrimidine (250mg, 0.956mmol), fluorine Potassium chloride (111 mg, 1.91 mmol) and palladium acetate (11 mg, 0.048 mmol) were reacted under microwave at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-10%) to obtain the target product 5-chloro-2-(2-chloro-4-(trifluoromethyl)pyrimidine-5). -Benzaldehyde (35a, 19 mg, yield 6.2%). MS(ESI)[M+H] + 320.9,323.0
第二步:2，7-二氯-4-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备的制备(35)Step 2: Preparation of 2,7-dichloro-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (35)
将5-氯-2-(2-氯-4-(三氟甲基)嘧啶-5-基)苯甲醛(35a,19mg,0.059mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(1mg，0.0027mmol)和叔丁基过氧化氢(46μl，0.472mmol)，于封管中100℃反应过夜。反应液减压蒸干后制备板(四氢呋喃：石油醚＝1:8)纯化得目标产物化合物35：2,7-二氯-4-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(3.86mg,产率20.4％)。MS(ESI)[M+H]+318.9,321.0.1H 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).Dissolve 5-chloro-2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (35a, 19mg, 0.059mmol) in 1,2-dichloroethane (2ml), Add tetrabutylammonium iodide (1 mg, 0.0027 mmol) and tert-butyl hydroperoxide (46 μl, 0.472 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was evaporated to dryness under reduced pressure and purified using a preparation plate (tetrahydrofuran: petroleum ether = 1:8) to obtain the target product compound 35: 2,7-dichloro-4-(trifluoromethyl)-9H-indeno[2,1 -d]pyrimidin-9-one (3.86 mg, yield 20.4%). MS(ESI)[M+H] + 318.9,321.0. 1 H NMR(400MHz, DMSO-d 6 )δ8.00(d,J＝2.0Hz,1H),7.93(dd,J＝8.3,2.0Hz, 1H),7.86–7.81(m,1H).
实施例36:7-氯-2-羟基-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 36: Preparation of 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(7,20mg,0.08mmol)溶于甲酸(2ml)，加入硫氰酸钾(10mg，0.096mmol)，于80℃反应3小时。反应液减压蒸干后制备液相纯化，再经重结晶(甲醇/水)得目标产物化合物36：7-氯-2-羟基-9H-茚并[2,1-d]嘧啶-9-酮(2.05mg,产率11.0％)。MS(ESI)[M+H]+233.0,235.0.1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.51(s,1H),7.77(d,J＝1.0Hz,2H),7.70(s,1H).Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,20 mg, 0.08 mmol) in formic acid (2 ml), and add potassium thiocyanate (10 mg, 0.096 mmol) , react at 80°C for 3 hours. The reaction solution was evaporated to dryness under reduced pressure, then liquid phase purified, and then recrystallized (methanol/water) to obtain the target product compound 36: 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidine-9- Ketone (2.05 mg, yield 11.0%). MS(ESI)[M+H] + 233.0,235.0. 1 H NMR(400MHz, DMSO-d 6 )δ12.12(s,1H),8.51(s,1H),7.77(d,J＝1.0Hz, 2H),7.70(s,1H).
实施例37:7-氯-2-硫氰酸-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 37: Preparation of 7-chloro-2-thiocyanate-9H-indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(7,32mg,0.128mmol)溶于甲酸(3ml)，加入硫氰酸钾(15mg，0.154mmol)，于40℃反应过夜。反应液减压蒸干后制备液相纯化得目标产物化合物37：7-氯-2-硫氰酸-9H-茚并[2,1-d]嘧啶-9-酮(2.76mg,产率7.9％)。MS(ESI)[M+H]+273.9,276.0.1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.00(d,J＝7.9Hz,1H),7.91–7.79(m,2H).Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (7,32mg, 0.128mmol) in formic acid (3ml), and add potassium thiocyanate (15mg, 0.154mmol) , react overnight at 40°C. The reaction solution was evaporated to dryness under reduced pressure and then liquid-phase purified 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-d 6 ) δ9.40 (s, 1H), 8.00 (d, J = 7.9Hz, 1H), 7.91–7.79 ( m,2H).
实施例38:7-氯-6-氟-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 38: Preparation of 7-chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:2-溴-5-氯-4-氟苯甲醛的制备(38a)Step 1: Preparation of 2-bromo-5-chloro-4-fluorobenzaldehyde (38a)
将3-氯-4-氟苯甲醛(500mg,3.15mmol)溶于1,2-二氯乙烷和三氟乙酸(20ml，5ml)，加入N-溴代丁二酰亚胺(673mg，3.78mmol)，2-氨基-5-氯三氟甲苯(90μl，0.63mmol)和醋酸钯(71mg，0.315mmol)，氮气置换，于60℃反应过夜。滤除反应液不溶物，滤液减压蒸干后Flash柱纯化得目标产物2-溴-5-氯-4-氟苯甲醛(38a,509mg,产率68.4％)。Dissolve 3-chloro-4-fluorobenzaldehyde (500mg, 3.15mmol) in 1,2-dichloroethane and trifluoroacetic acid (20ml, 5ml), add N-bromosuccinimide (673mg, 3.78 mmol), 2-amino-5-chlorotrifluorotoluene (90 μl, 0.63 mmol) and palladium acetate (71 mg, 0.315 mmol), replaced with nitrogen, and reacted overnight at 60°C. The insoluble matter in the reaction solution was filtered off, and the filtrate was evaporated to dryness under reduced pressure and purified by Flash column to obtain the target product 2-bromo-5-chloro-4-fluorobenzaldehyde (38a, 509 mg, yield 68.4%).
第二步:5-氯-4-氟-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的制备(38b)Step 2: Preparation of 5-chloro-4-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (38b)
将2-(三氟甲基)嘧啶-5-基硼酸(38a,141mg，0.734mmol)溶于乙腈(13ml)，加入2-溴-5-氯-4-氟苯甲醛(173mg，0.733mmol)，氟化钾(86mg,1.48mmol)和醋酸钯(8mg,0.036mmol)，120℃微波反应60分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％-10％)纯化得目标产物5-氯-4-氟-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(38b,66mg,产率27.8％)。MS(ESI)[M+H]+305.0,307.0.Dissolve 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (38a, 141 mg, 0.734 mmol) in acetonitrile (13 ml), and add 2-bromo-5-chloro-4-fluorobenzaldehyde (173 mg, 0.733 mmol) , potassium fluoride (86mg, 1.48mmol) and palladium acetate (8mg, 0.036mmol), microwave reaction at 120°C for 60 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-10%) to obtain the target product 5-chloro-4-fluoro-2-(2-(trifluoromethyl)pyrimidine-5). -Benzaldehyde (38b, 66 mg, yield 27.8%). MS(ESI)[M+H] + 305.0,307.0.
第三步:7-氯-6-氟-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(38) Step 3: Preparation of 7-chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (38)
将7-氯-6-氟-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(38b,33mg,0.108mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(2mg，0.0054mmol)和叔丁基过氧化氢(84μl，0.864mmol)，于封管中100℃反应过夜。反应液减压蒸干后制备板(四氢呋喃：石油醚＝1:7)纯化得目标产物化合物38：7-氯-6-氟-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(10.39mg,产率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).Dissolve 7-chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (38b, 33 mg, 0.108 mmol) in 1,2-dichloro Ethane (2 ml), add tetrabutylammonium iodide (2 mg, 0.0054 mmol) and tert-butyl hydroperoxide (84 μl, 0.864 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was evaporated to dryness under reduced pressure and purified using a preparation plate (tetrahydrofuran: petroleum ether = 1:7) to obtain the target product compound 38: 7-chloro-6-fluoro-2-(trifluoromethyl)-9H-indeno[2, 1-d]pyrimidin-9-one (10.39 mg, yield 31.5%). MS (ESI) [M+H] + 303.0, 305.0. 1 H NMR (400MHz, DMSO-d 6 ) δ9.58 (s, 1H), 8.25 (d, J = 8.8Hz, 1H), 8.14 (d, J＝6.9Hz,1H).
实施例39:7-氯-4-羟基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 39: Preparation of 7-chloro-4-hydroxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-溴-2-(三氟甲基)嘧啶-4-醇的制备(39a)Step 1: Preparation of 5-bromo-2-(trifluoromethyl)pyrimidin-4-ol (39a)
将2-(三氟甲基)嘧啶-4-醇(50mg,0.304mmol)溶于乙酸(4ml)，加入醋酸钾(90mg，0.914mmol)，冰浴下加入液溴(18μl，0.335mmol)后置于80℃反应1.5小时。点板反应后加入饱和碳酸氢钠溶液调至中性，将水溶液(10ml)加到反应混合物中。混合溶液用乙酸乙酯(6ml×3)萃取，再用盐水(6ml×2)洗涤合并的有机层，用无水硫酸钠干燥并过滤。滤液减压蒸干后得目标产物粗品5-溴-2-(三氟甲基)嘧啶-4-醇(39a,60mg,产率81.04％)。Dissolve 2-(trifluoromethyl)pyrimidin-4-ol (50 mg, 0.304 mmol) in acetic acid (4 ml), add potassium acetate (90 mg, 0.914 mmol), and add liquid bromine (18 μl, 0.335 mmol) under ice bath. Place at 80°C to react for 1.5 hours. After spotting reaction, add saturated sodium bicarbonate solution to make it neutral, and add aqueous solution (10 ml) to the reaction mixture. The mixed solution 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 filtrate was evaporated to dryness under reduced pressure to obtain the crude target product 5-bromo-2-(trifluoromethyl)pyrimidin-4-ol (39a, 60 mg, yield 81.04%).
第二步:5-氯-2-(4-羟基-2-(三氟甲基)嘧啶-5-基)苯甲醛的制备(39b)Step 2: Preparation of 5-chloro-2-(4-hydroxy-2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (39b)
将(4-氯-2-甲酰基苯基)硼酸(68mg，0.37mmol)溶于乙腈(4ml)，加入5-溴-2-(三氟甲基)嘧啶-4-醇(39a,60mg，0.247mmol)，氟化钾(29mg,0.494mmol)和醋酸钯(3mg,0.012mmol)，120℃微波反应60分钟。减压蒸干溶剂，剩余物制备板(乙酸乙酯：石油醚＝0％-50％)纯化得目标产物5-氯-2-(4-羟基-2-(三氟甲基)嘧啶-5-基)苯甲醛(39b,10mg,产率13.38％)。MS(ESI)[M+H]+303.1,305.1.Dissolve (4-chloro-2-formylphenyl)boronic acid (68mg, 0.37mmol) in acetonitrile (4ml), and add 5-bromo-2-(trifluoromethyl)pyrimidin-4-ol (39a, 60mg, 0.247mmol), potassium fluoride (29mg, 0.494mmol) and palladium acetate (3mg, 0.012mmol), microwave reaction at 120°C for 60 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified using a preparation plate (ethyl acetate: petroleum ether = 0%-50%) to obtain the target product 5-chloro-2-(4-hydroxy-2-(trifluoromethyl)pyrimidine-5). -Benzaldehyde (39b, 10 mg, yield 13.38%). MS(ESI)[M+H] + 303.1,305.1.
第三步:7-氯-4-羟基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(39)Step 3: Preparation of 7-chloro-4-hydroxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (39)
将5-氯-2-(4-羟基-2-(三氟甲基)嘧啶-5-基)苯甲醛(10mg,0.033mmol)溶于1,2-二氯乙烷(1ml)，加入四丁基碘化铵(1mg，0.0016mmol)和叔丁基过氧化氢(24mg，0.264mmol)，于封管中100℃反应过夜。反应液减压蒸干后再用制备级HPLC纯化冻干得目标产物化合物39：7-氯-4-羟基-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(0.62mg,产率6.24％)。MS(ESI)[M+H]+301.0,303.0.Dissolve 5-chloro-2-(4-hydroxy-2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (10 mg, 0.033 mmol) in 1,2-dichloroethane (1 ml), add tetrafluoroethane Butylammonium iodide (1 mg, 0.0016 mmol) and tert-butyl hydroperoxide (24 mg, 0.264 mmol) were reacted in a sealed tube at 100°C overnight. The reaction solution was evaporated to dryness under reduced pressure and then purified by preparative HPLC and freeze-dried to obtain the target product compound 39: 7-chloro-4-hydroxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine. -9-one (0.62 mg, yield 6.24%). MS(ESI)[M+H] + 301.0,303.0.
实施例40:7-氯正环丙基-2-三氟甲基-9H-茚并[2，1-d]嘧啶-9-亚胺的制备
Example 40: Preparation of 7-chloron-cyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidine-9-imine
第一步:5-氯-2-(2-三氟甲基)嘧啶-5-基)苯甲醛的制备(40a)Step 1: Preparation of 5-chloro-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (40a)
将5-溴-2-三氟甲基嘧啶(2g，8.85mmol)溶于乙醇(40ml)，加入4-氯-2-醛基苯硼酸(2.12g，11.51mmol)，氟化钾(1.028g,17.7mmol)和醋酸钯(99.36mg,0.44mmol)，120℃油浴反应2小时。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％-40％)纯化得目标产物5-氯-2-(2-三氟甲基)嘧啶-5-基)苯甲醛(40a,1.3740g,产率54.27％)。MS(ESI)[M+H]+287.0.Dissolve 5-bromo-2-trifluoromethylpyrimidine (2g, 8.85mmol) in ethanol (40ml), add 4-chloro-2-aldehyde phenylboronic acid (2.12g, 11.51mmol), potassium fluoride (1.028g ,17.7mmol) and palladium acetate (99.36mg, 0.44mmol), reacted in an oil bath at 120°C for 2 hours. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate:petroleum ether=0%-40%) to obtain the target product 5-chloro-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde. (40a, 1.3740g, yield 54.27%). MS(ESI)[M+H] + 287.0.
第二步:7-氯-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(40b)Step 2: Preparation of 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (40b)
将5-氯-2-(2-三氟甲基)嘧啶-5-基)苯甲醛(40a,700mg,2.45mmol)溶于1,2-二氯乙烷(25ml)，加入四丁基碘化铵(45.19mg，0.12mmol)和叔丁基过氧化氢(1.80g，19.97mmol)，在氮气保护下于封管中100℃反应30小时。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％-40％)纯化得目标产物7-氯-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(40b,336.4mg,产率48.38％)。MS(ESI)[M+H]+285.0.Dissolve 5-chloro-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (40a, 700mg, 2.45mmol) in 1,2-dichloroethane (25ml), add tetrabutyl iodide Ammonium chloride (45.19 mg, 0.12 mmol) and tert-butyl hydroperoxide (1.80 g, 19.97 mmol) were reacted in a sealed tube at 100°C for 30 hours under nitrogen protection. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-40%) to obtain the target product 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1- d]pyrimidin-9-one (40b, 336.4 mg, yield 48.38%). MS(ESI)[M+H] + 285.0.
第三步:7-氯正环丙基-2-三氟甲基-9H-茚并[2，1-d]嘧啶-9-亚胺的制备(40)Step 3: Preparation of 7-chloron-cyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidine-9-imine (40)
将7-氯-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(40b,20mg,0.07mmol)溶于超干甲苯(4ml)，加入环丙胺(8.04mg,0.14mmol)和分子筛，150℃微波反应1小时。减压蒸干溶剂，粗品制备板(乙酸乙酯：石油醚＝1:2)纯 化得目标产物7-氯-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮，最后再进行一次HPLC纯化得目标产物化合物40：7-氯-正环丙基-2-三氟甲基-9H-茚并[2,1-d]嘧啶-9-亚胺(3.18mg,13.97％)。MS(ESI)[M+H]+324.0.1H 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).Dissolve 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (40b, 20mg, 0.07mmol) in ultradry toluene (4ml), and add cyclopropylamine (8.04 mg, 0.14 mmol) and molecular sieves, reacted in microwave at 150°C for 1 hour. The solvent was evaporated to dryness under reduced pressure, and the crude product was pure (ethyl acetate: petroleum ether = 1:2). The target product 7-chloro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one was finally purified by HPLC to obtain the target product compound 40: 7-chloro- n-Cyclopropyl-2-trifluoromethyl-9H-indeno[2,1-d]pyrimidine-9-imine (3.18 mg, 13.97%). MS(ESI)[M+H] + 324.0. 1 H NMR(400MHz, DMSO-d 6 )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).
实施例41:7-氯-2-甲磺酰基-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 41: Preparation of 7-chloro-2-methanesulfonyl-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-甲磺酰基)嘧啶-5-基)苯甲醛的制备(41a)Step 1: Preparation of 5-chloro-2-(2-methanesulfonyl)pyrimidin-5-yl)benzaldehyde (41a)
将5-溴-2-(甲磺酰基)嘧啶(200mg，0.8mmol)溶于乙腈(20ml)，加入4-氯-2-醛基苯硼酸(160mg，0.8mmol)，氟化钾(100mg,1.6mmol)和醋酸钯(6mg,0.04mmol)，120℃微波反应50分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％-40％)纯化得目标产物5-氯-2-(2-甲磺酰基)嘧啶-5-基)苯甲醛(41a,65.4mg,产率26.19％)。MS(ESI)[M+H]+297.0.Dissolve 5-bromo-2-(methanesulfonyl)pyrimidine (200mg, 0.8mmol) in acetonitrile (20ml), add 4-chloro-2-aldehyde phenylboronic acid (160mg, 0.8mmol), potassium fluoride (100mg, 1.6mmol) and palladium acetate (6mg, 0.04mmol), microwave reaction at 120°C for 50 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate:petroleum ether=0%-40%) to obtain the target product 5-chloro-2-(2-methanesulfonyl)pyrimidin-5-yl)benzaldehyde ( 41a, 65.4mg, yield 26.19%). MS(ESI)[M+H] + 297.0.
第二步:7-氯-2-甲磺酰基-9H-茚并[2，1-d]嘧啶-9-酮的制备(41)Step 2: Preparation of 7-chloro-2-methanesulfonyl-9H-indeno[2,1-d]pyrimidin-9-one (41)
将5-氯-2-(2-甲磺酰基)嘧啶-5-基)苯甲醛(41a,40mg,0.14mmol)溶于1,2-二氯乙烷(10ml)，加入四丁基碘化铵(2.50mg，0.007mmol)和叔丁基过氧化氢(97.43mg，1.08mmol)，在氮气保护下于封管中100℃反应16小时。减压蒸干溶剂，粗品制备板(四氢呋喃：石油醚＝1:1)纯化得目标产物化合物41：7-氯-2-甲磺酰基-9H-茚并[2,1-d]嘧啶-9-酮(0.62mg,产率1.56％)。MS(ESI)[M+H]+295.0.Dissolve 5-chloro-2-(2-methanesulfonyl)pyrimidin-5-yl)benzaldehyde (41a, 40mg, 0.14mmol) in 1,2-dichloroethane (10ml), add tetrabutyl iodide Ammonium (2.50 mg, 0.007 mmol) and tert-butyl hydroperoxide (97.43 mg, 1.08 mmol) were reacted at 100°C for 16 hours under nitrogen protection in a sealed tube. The solvent was evaporated to dryness under reduced pressure, and the crude product was purified using a preparation plate (tetrahydrofuran: petroleum ether = 1:1) to obtain the target product compound 41: 7-chloro-2-methanesulfonyl-9H-indeno[2,1-d]pyrimidine-9 -Ketone (0.62 mg, yield 1.56%). MS(ESI)[M+H] + 295.0.
实施例42:7-甲氧基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 42: Preparation of 7-methoxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-甲氧基-2-(2-三氟甲基)嘧啶-5-基)苯甲醛的制备(42a)Step 1: Preparation of 5-methoxy-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (42a)
将4-甲氧基-2-甲酰基苯硼酸(200mg，1.11mmol)溶于乙腈(15ml)，加入5-溴-2-三氟甲基嘧啶(251mg，1.11mmol)，氟化钾(129mg,2.22mmol)和醋酸钯(12mg,0.1mmol)，120℃微波反应50分钟。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％-40％)纯化得目标产物5-甲氧基-2-(2-三氟甲基)嘧啶-5-基)苯甲醛(42a,197.1mg,产率62.91％)。MS(ESI)[M+H]+283.0.Dissolve 4-methoxy-2-formylphenylboronic acid (200mg, 1.11mmol) in acetonitrile (15ml), add 5-bromo-2-trifluoromethylpyrimidine (251mg, 1.11mmol), potassium fluoride (129mg ,2.22mmol) and palladium acetate (12mg, 0.1mmol), microwave reaction at 120°C for 50 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0%-40%) to obtain the target product 5-methoxy-2-(2-trifluoromethyl)pyrimidin-5-yl) Benzaldehyde (42a, 197.1 mg, yield 62.91%). MS(ESI)[M+H] + 283.0.
第二步:7-甲氧基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(42)Step 2: Preparation of 7-methoxy-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (42)
将5-甲氧基-2-(2-三氟甲基)嘧啶-5-基)苯甲醛(42a,50mg,0.18mmol)溶于1,2-二氯乙烷(10ml)，加入四丁基碘化铵(3.27mg，0.009mmol)和叔丁基过氧化氢(127.80mg，1.42mmol)，在氮气保护下于封管中100℃反应16小时。减压蒸干溶剂，粗品制备板(乙酸乙酯：石油醚＝1:2)纯化得目标产物化合物42：7-甲氧基-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(4.18mg,产率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).Dissolve 5-methoxy-2-(2-trifluoromethyl)pyrimidin-5-yl)benzaldehyde (42a, 50mg, 0.18mmol) in 1,2-dichloroethane (10ml), add tetrabutylene Ammonium iodide (3.27 mg, 0.009 mmol) and tert-butyl hydroperoxide (127.80 mg, 1.42 mmol) were reacted at 100°C for 16 hours under nitrogen protection in a sealed tube. The solvent was evaporated to dryness under reduced pressure, and the crude product was purified using a preparation plate (ethyl acetate: petroleum ether = 1:2) to obtain the target product compound 42: 7-methoxy-2-(trifluoromethyl)-9H-indeno[2, 1-d]pyrimidin-9-one (4.18 mg, yield 8.42%). MS(ESI)[M+H] + 281.0.1H NMR(400MHz, DMSO-d 6 )δ9.43(s,1H),7.98–7.95(m,1H),7.37–7.32(m,2H),3.89 (s,3H).
实施例43:7-(三氟甲基)-9H-[1，3]二氧杂环[4'，5':5，6]茚并[2，1-d]嘧啶-9-酮的制备
Example 43: 7-(trifluoromethyl)-9H-[1,3]dioxetane[4',5':5,6]indeno[2,1-d]pyrimidin-9-one preparation
第一步:7-(三氟甲基)-9H-[1，3]二氧杂环[4'，5':5，6]茚并[2，1-d]嘧啶-9-酮6-(2-(三氟甲基)嘧啶-5-基)苯并[d][1，3]二氧杂环-5-碳醛的制备(43a)Step 1: 7-(trifluoromethyl)-9H-[1,3]dioxetane[4',5':5,6]indeno[2,1-d]pyrimidin-9-one 6 Preparation of -(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxetane-5-carbonaldehyde (43a)
将5-溴-2-(三氟甲基)嘧啶(50mg，0.2203mmol)溶于乙腈(3ml)，加入(6-甲酰基苯并[d][1,3]二氧醇-5-基)硼酸(51.2mg，0.2644mmol)，醋酸钯(2.5mg，0.0110mmol)，氟化钾(25.6mg,0.4406mmol)，在氮气保护下120℃微波反应30分钟。减压浓缩后粗品经硅胶色谱法纯化(乙酸乙酯：石油醚＝1/5)得目标产物6-(2-(三氟甲基)嘧啶-5-基)苯并[d][1,3]间二氧杂环-5-碳醛(43a,30mg,产率46％)。MS(ESI)[M+H]+297.3.Dissolve 5-bromo-2-(trifluoromethyl)pyrimidine (50mg, 0.2203mmol) in acetonitrile (3ml), add (6-formylbenzo[d][1,3]dioxol-5-yl ) Boric acid (51.2mg, 0.2644mmol), palladium acetate (2.5mg, 0.0110mmol), potassium fluoride (25.6mg, 0.4406mmol), react in microwave at 120°C for 30 minutes under nitrogen protection. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1/5) to obtain the target product 6-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1, 3] Dioxetane-5-carbon aldehyde (43a, 30 mg, yield 46%). MS(ESI)[M+H] + 297.3.
第二步:7-(三氟甲基)-9H-[1，3]二氧杂环[4'，5':5，6]茚并[2，1-d]嘧啶-9-酮的制备(43)Step 2: 7-(trifluoromethyl)-9H-[1,3]dioxetane[4',5':5,6]indeno[2,1-d]pyrimidin-9-one Preparation(43)
将6-(2-(三氟甲基)嘧啶-5-基)苯并[d][1,3]二间二氧杂环-5-碳醛(43a,30mg,0.1013mmol)溶于二氯乙烷 (2ml)，加入2-氢过氧基-2-甲基丙烷(73mg，0.8102mmol)，100℃下密闭反应16小时，减压浓缩后粗品经制备高效液相纯化(水：甲醇＝1/50)得目标产物化合物43：7-(三氟甲基)-9H-[1,3]二氧杂环[4'，5'：5,6]茚并[2,1-d]嘧啶-9-酮(43,1.48mg,产率5.0％)。MS(ESI)[M+H]+295.1.1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),7.68(s,1H),7.37(s,1H),6.28(s,2H).Dissolve 6-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxetane-5-carbonaldehyde (43a, 30 mg, 0.1013 mmol) in di Ethyl chloride (2ml), add 2-hydroperoxy-2-methylpropane (73mg, 0.8102mmol), conduct a sealed reaction at 100°C for 16 hours, concentrate under reduced pressure and the crude product is purified by preparative high-performance liquid phase (water: methanol = 1/ 50) Obtain the target product compound 43: 7-(trifluoromethyl)-9H-[1,3]dioxetane[4',5':5,6]indeno[2,1-d]pyrimidine- 9-one (43, 1.48 mg, yield 5.0%). MS(ESI)[M+H] + 295.1. 1 H NMR(400MHz, DMSO-d 6 )δ9.31(s,1H),7.68(s,1H),7.37(s,1H),6.28(s, 2H).
实施例44:7-氯-2-(吡啶-2-基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 44: Preparation of 7-chloro-2-(pyridin-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-溴-2-(吡啶-2-基)嘧啶的制备(44a)Step 1: Preparation of 5-bromo-2-(pyridin-2-yl)pyrimidine (44a)
将5-溴-2-碘嘧啶(300mg，0.8109mmol)溶于甲苯(3ml)，加入2-三正丁基甲锡烷基吡啶(231mg，0.8109mmol)，三苯基磷(28.5mg，0.0811mmol)，双(三苯基膦)二氯化钯(II)(21.3mg,0.0405mmol)，在氮气保护下120℃反应过夜。减压浓缩后粗品经硅胶色谱法纯化(二氯甲烷：甲醇＝1/20)得目标产物5-溴-2-(吡啶-2-基)嘧啶(44a,110mg,产率37.6％)。MS(ESI)[M+H]+236.1.Dissolve 5-bromo-2-iodopyrimidine (300mg, 0.8109mmol) in toluene (3ml), add 2-tri-n-butylstannylpyridine (231mg, 0.8109mmol) and triphenylphosphine (28.5mg, 0.0811mmol) , bis(triphenylphosphine)palladium(II) dichloride (21.3 mg, 0.0405 mmol), reacted overnight at 120°C under nitrogen protection. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (dichloromethane: methanol = 1/20) to obtain the target product 5-bromo-2-(pyridin-2-yl)pyrimidine (44a, 110 mg, yield 37.6%). MS(ESI)[M+H] + 236.1.
第二步:5-氯-2-(2-(吡啶-2-基)嘧啶-5-基)苯甲醛的制备(44b)Step 2: Preparation of 5-chloro-2-(2-(pyridin-2-yl)pyrimidin-5-yl)benzaldehyde (44b)
将(4-氯-2-甲酰基苯基)硼酸(86.3mg，0.466mmol)溶于乙腈(3ml)，加入5-溴-2-(吡啶-2-基)嘧啶(110mg，0.466mmol)，醋酸钯(5.3mg，0.0233mmol)，氟化钾(54.4mg,0.932mmol)，在氮气保护下120℃微波反应30分钟。减压浓缩后粗品经硅胶色谱法纯化(二氯甲烷：甲醇＝1/15)得目标产物5-氯-2-(2-(吡啶-2-基)嘧啶-5-基)苯甲醛(44b,13mg,产率9.4％)。MS(ESI)[M+H]+296.3.Dissolve (4-chloro-2-formylphenyl)boronic acid (86.3mg, 0.466mmol) in acetonitrile (3ml), add 5-bromo-2-(pyridin-2-yl)pyrimidine (110mg, 0.466mmol), Palladium acetate (5.3 mg, 0.0233 mmol), potassium fluoride (54.4 mg, 0.932 mmol) were reacted in a microwave at 120°C for 30 minutes under nitrogen protection. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (dichloromethane: methanol = 1/15) to obtain the target product 5-chloro-2-(2-(pyridin-2-yl)pyrimidin-5-yl)benzaldehyde (44b , 13 mg, yield 9.4%). MS(ESI)[M+H] + 296.3.
第三步:7-氯-2-(吡啶-2-基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(44)Step 3: Preparation of 7-chloro-2-(pyridin-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one (44)
将5-氯-2-(2-(吡啶-2-基)嘧啶-5-基)苯甲醛(44b,13mg,0.0439mmol)溶于二氯乙烷(2ml)，加入2-氢过氧基-2-甲基丙烷(31.7mg，0.3512mmol)，100℃下密闭反应16小时，减压浓缩后粗品经制备高效液相纯化(水：甲醇＝1/50)得目标产物化合物44：7-氯-2-(吡啶-2-基)-9H-茚并[2,1-d]嘧啶-9-酮(1.18mg,产率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),8.07–8.02(m,1H),8.01–7.97(m,1H),7.88–7.83(m,1H),7.81(d,J＝2.0Hz,1H),7.56(t,J＝6.3Hz,1H).Dissolve 5-chloro-2-(2-(pyridin-2-yl)pyrimidin-5-yl)benzaldehyde (44b, 13mg, 0.0439mmol) in dichloroethane (2ml), and add 2-hydroperoxy -2-Methylpropane (31.7 mg, 0.3512 mmol), sealed reaction at 100°C for 16 hours, concentrated under reduced pressure, and the crude product was purified by preparative high-performance liquid phase (water: methanol = 1/50) to obtain the target product compound 44:7- Chloro-2-(pyridin-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one (1.18 mg, yield 9.1%). MS(ESI)[M+H] + 294.1. 1 H NMR (400MHz, DMSO-d 6 ) δ9.52 (s, 1H), 8.77 (d, J＝4.8Hz, 1H), 8.42 (d, J＝ 8.0Hz,1H),8.07–8.02(m,1H),8.01–7.97(m,1H),7.88–7.83(m,1H),7.81(d,J＝2.0Hz,1H),7.56(t,J =6.3Hz,1H).
实施例45:7-氯-2-羟基-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 45: Synthesis of 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-氯嘧啶-5-基)苯甲醛的合成(45-a)Step 1: Synthesis of 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (45-a)
将(4-氯-2-甲酰基苯基)硼酸(3.45g，18.72mmol)，2-氯-5-碘嘧啶(3g，12.48mmol)，氟化钾(1.44g，24.96mmol)和醋酸钯(141mg，0.624mmol)置于微波反应管中，加入乙醇(80ml)，氮气吹扫后密封，120℃反应过夜。将反应液过滤去除不溶物，滤液减压浓缩，剩余物Flash柱(乙酸乙酯：石油醚＝0％～20％)纯化得目标产物5-氯-2-(2-氯嘧啶-5-基)苯甲醛(45-a，2g,收率63.33％)。ESI[M+H]+＝253.0,255.0(4-Chloro-2-formylphenyl)boronic acid (3.45g, 18.72mmol), 2-chloro-5-iodopyrimidine (3g, 12.48mmol), potassium fluoride (1.44g, 24.96mmol) and palladium acetate were combined (141 mg, 0.624 mmol) was placed in a microwave reaction tube, added ethanol (80 ml), purged with nitrogen, sealed, and reacted at 120°C overnight. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0% ~ 20%) to obtain the target product 5-chloro-2-(2-chloropyrimidin-5-yl) ) Benzaldehyde (45-a, 2g, yield 63.33%). ESI[M+H] + =253.0,255.0
第二步:2，7-二氯-9H-茚并[2，1-d]嘧啶-9-酮的合成(45-b)Step 2: Synthesis of 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (45-b)
将5-氯-2-(2-氯嘧啶-5-基)苯甲醛(45-a，1g，3.95mmol)溶于1,2-二氯乙烷(20ml)，加入四丁基碘化铵(70mg，0.198mmol)和叔丁基过氧化氢(2.85g，31.6mmol)，氮气保护下于封管中100℃反应过夜。反应液过滤减压浓缩后，剩余物Flash柱(乙酸乙酯：石油醚＝0％～20％)纯化得目标产物2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(45-b，300mg， 收率30.24％)。ESI[M+H]+＝251.0,252.9Dissolve 5-chloro-2-(2-chloropyrimidin-5-yl)benzaldehyde (45-a, 1g, 3.95mmol) in 1,2-dichloroethane (20ml), and add tetrabutylammonium iodide (70 mg, 0.198 mmol) and tert-butyl hydroperoxide (2.85 g, 31.6 mmol) were reacted overnight at 100°C in a sealed tube under nitrogen protection. After the reaction solution was filtered and concentrated under reduced pressure, the residue was purified using a Flash column (ethyl acetate: petroleum ether = 0% to 20%) to obtain the target product 2,7-dichloro-9H-indeno[2,1-d]pyrimidine- 9-keto(45-b, 300mg, Yield 30.24%). ESI[M+H] + =251.0,252.9
第三步:7-氯-2-羟基-9H-茚并[2，1-d]嘧啶-9-酮的合成(45)Step 3: Synthesis of 7-chloro-2-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (45)
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(45-b，20mg，0.08mmol)溶于甲酸(2ml)，加入硫氰酸钾(10mg，0.103mmol)，80℃反应3小时。反应液减压浓缩后直接制备纯化得副产物7-氯-2-羟基-9H-茚并[2,1-d]嘧啶-9-酮(45，2.05mg，收率11.0％)。ESI[M+H]+＝233.0,235.01H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.51(s,1H),7.77(d,J＝1.0Hz,2H),7.70(s,1H).Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (45-b, 20mg, 0.08mmol) in formic acid (2ml), and add potassium thiocyanate (10mg, 0.103 mmol), react at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure and directly purified to obtain the by-product 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-d 6 ) δ12.12 (s, 1H), 8.51 (s, 1H), 7.77 (d, J = 1.0Hz, 2H), 7.70(s,1H).
实施例46:7-氯-2-(三氟甲基)-9H-吡啶并[3'，2':3，4]环戊烷[1，2-d]嘧啶-9-酮的合成
Example 46: Synthesis of 7-chloro-2-(trifluoromethyl)-9H-pyrido[3',2':3,4]cyclopentane[1,2-d]pyrimidin-9-one
第一步:3-溴-6-氯吡啶甲醛的合成(46-a)Step 1: Synthesis of 3-bromo-6-chloropyridinecarboxaldehyde (46-a)
将(3-溴-6-氯吡啶-2-基)甲醇(450mg，2.02mmol)溶于二氧六环(20ml)，加入二氧化锰(1.76g，20.23mmol)，100℃反应8小时。过滤除去二氧化锰，滤液减压浓缩后得目标产物粗品3-溴-6-氯吡啶甲醛(46-a，425mg，收率95.9％)。ESI[M+H]+＝219.8,221.8Dissolve (3-bromo-6-chloropyridin-2-yl)methanol (450 mg, 2.02 mmol) in dioxane (20 ml), add manganese dioxide (1.76 g, 20.23 mmol), and react at 100°C for 8 hours. Manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude target product 3-bromo-6-chloropyridinecarbaldehyde (46-a, 425 mg, yield 95.9%). ESI[M+H] + =219.8,221.8
第二步:6-氯-3-(2-(三氟甲基)嘧啶-5-基)吡啶甲醛的合成(46-b)Step 2: Synthesis of 6-chloro-3-(2-(trifluoromethyl)pyrimidin-5-yl)pyridinecarbaldehyde (46-b)
将3-溴-6-氯吡啶甲醛(46-a，250mg，1.14mmol)，2-(三氟甲基)嘧啶-5-基硼酸(I-1，285mg，1.48mmol)，氟化钾(132mg，2.28mmol)和醋酸钯(13mg，0.058mmol)置于微波反应管中，加入乙腈(15ml)，氮气吹扫后密封，120℃微波反应60分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物Flash柱(乙酸乙酯：石油醚＝0％～30％)纯化得目标产物6-氯-3-(2-(三氟甲基)嘧啶-5-基)吡啶甲醛(46-b，23mg，收率5.8％)。ESI[M+H]+＝288.0,290.03-Bromo-6-chloropyridinecarboxaldehyde (46-a, 250mg, 1.14mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 285mg, 1.48mmol), potassium fluoride ( 132 mg, 2.28 mmol) and palladium acetate (13 mg, 0.058 mmol) were placed in a microwave reaction tube, added acetonitrile (15 ml), 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 (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
第三步:7-氯-2-(三氟甲基)-9H-吡啶并[3'，2':3，4]环戊烷[1，2-d]嘧啶-9-酮的合成(46)The third step: synthesis of 7-chloro-2-(trifluoromethyl)-9H-pyrido[3',2':3,4]cyclopentane[1,2-d]pyrimidin-9-one ( 46)
将6-氯-3-(2-(三氟甲基)嘧啶-5-基)吡啶甲醛(46-b，23mg，0.080mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(1.5mg，0.0041mmol)和叔丁基过氧化氢(62μl，0.64mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备板(四氢呋喃：石油醚＝1:2)纯化得目标产物7-氯-2-(三氟甲基)-9H-吡啶并[3',2':3,4]环戊烷[1,2-d]嘧啶-9-酮(46，1.21mg，收率5.3％)。ESI[M+H]+＝286.0,288.0Dissolve 6-chloro-3-(2-(trifluoromethyl)pyrimidin-5-yl)pyridinecarboxaldehyde (46-b, 23 mg, 0.080 mmol) in 1,2-dichloroethane (2 ml), add tetrafluoroethylene Butylammonium iodide (1.5 mg, 0.0041 mmol) and tert-butyl hydroperoxide (62 μl, 0.64 mmol) were reacted overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified using a preparatory plate (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
实施例47:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲酰胺的合成
Example 47: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide
第一步:3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈的合成(47-a)Step 1: Synthesis of 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (47-a)
将2-(三氟甲基)嘧啶-5-基硼酸(I-1，100mg，0.52mmol)，4-溴-3-甲酰苯甲腈(109mg，0.52mmol)，氟化钾(61mg，1.05mmol)和醋酸钯(6mg，0.027mmol)置于微波反应管中，加入乙腈(10ml)，氮气吹扫后密封，120℃微波反应30分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物Flash柱(乙酸乙酯：石油醚＝0％～20％)纯化得目标产物3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(47-a，35mg,收率24.3％)。ESI[M+H]+＝278.12-(Trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 100 mg, 0.52 mmol), 4-bromo-3-formylbenzonitrile (109 mg, 0.52 mmol), potassium fluoride (61 mg, 1.05mmol) and palladium acetate (6mg, 0.027mmol) were placed in a microwave reaction tube, acetonitrile (10ml) 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 with a Flash column (ethyl acetate: petroleum ether = 0% to 20%) to obtain the target product 3-formyl-4-(2-(trifluoromethyl) )pyrimidin-5-yl)benzonitrile (47-a, 35 mg, yield 24.3%). ESI[M+H] + =278.1
第二步:9-氧代-2-(三氟甲基)-9H茚并[2，1-d]嘧啶-7-碳腈的合成(47-b)Step 2: Synthesis of 9-oxo-2-(trifluoromethyl)-9H indeno[2,1-d]pyrimidine-7-carbonitrile (47-b)
将3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(47-a，35mg,0.126mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(3mg，0.0081mmol)和叔丁基过氧化氢(97μl，1.01mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备板(四氢呋喃：石油醚＝1:2)纯化得目标产物9-氧代-2-(三氟甲基)-9H茚并[2,1-d]嘧啶-7-碳腈(47-b， 14.42mg,收率41.6％)。ESI[M+H]+＝276.1Dissolve 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (47-a, 35 mg, 0.126 mmol) in 1,2-dichloroethane (2 ml), Add tetrabutylammonium iodide (3 mg, 0.0081 mmol) and tert-butyl hydroperoxide (97 μl, 1.01 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified using a preparatory plate (tetrahydrofuran: petroleum ether = 1:2) to obtain the target product 9-oxo-2-(trifluoromethyl)-9H indeno[2,1-d]pyrimidine-7- Carbonitrile (47-b, 14.42mg, yield 41.6%). ESI[M+H] + =276.1
第三步:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲酰胺的合成(47)Step 3: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (47)
将9-氧代-2-(三氟甲基)-9H茚并[2,1-d]嘧啶-7-碳腈(47-b，5.6mg，0.020mmol)溶于水/异丙醇(0.5ml/0.5ml)，加入二氧化锰(18mg，0.207mmol)，100℃反应5小时。过滤除去二氧化锰，滤液减压浓缩后制备板(二氯甲烷：甲醇＝15:1)纯化得目标产物9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-甲酰胺(47，2.06mg，收率34.3％)。ESI[M+H]+＝294.11H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H indeno[2,1-d]pyrimidine-7-carbonitrile (47-b, 5.6 mg, 0.020 mmol) in water/isopropanol ( 0.5ml/0.5ml), add manganese dioxide (18mg, 0.207mmol), and react at 100°C for 5 hours. Manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure and purified using a preparation plate (dichloromethane: methanol = 15:1) to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1 -d]pyrimidine-7-carboxamide (47, 2.06 mg, yield 34.3%). ESI[M+H] + =294.1 1 H NMR (400MHz, DMSO-d 6 ) δ9.64 (s, 1H), 8.29 (d, J = 7.8Hz, 3H), 8.16 (d, J = 7.9Hz, 1H),7.68(s,1H).
实施例48:2，7-二氯-4-甲氧基-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 48: Synthesis of 2,7-dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2-氯-4-甲氧基嘧啶-5-基)苯甲醛的合成(48-a)Step 1: Synthesis of 5-chloro-2-(2-chloro-4-methoxypyrimidin-5-yl)benzaldehyde (48-a)
将4-氯-2-醛基苯硼酸(375mg，2.04mmol)，2-氯-4-甲氧基-5-溴嘧啶(350mg，1.56mmol)，氟化钾(182mg，3.14mmol)和醋酸钯(18mg，0.080mmol)置于微波反应管中，加入乙腈(25ml)，氮气吹扫后密封，120℃微波反应60分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物Flash柱(乙酸乙酯：石油醚＝0％～20％)纯化得目标产物5-氯-2-(2-氯-4-甲氧基嘧啶-5-基)苯甲醛(48-a，74mg,收率14.7％)。ESI[M+H]+＝283.1,285.14-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 acetic acid were combined Palladium (18 mg, 0.080 mmol) was placed in a microwave reaction tube, acetonitrile (25 ml) was added, 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 (ethyl acetate: petroleum ether = 0% ~ 20%) to obtain the target product 5-chloro-2-(2-chloro-4-methoxy) pyrimidin-5-yl)benzaldehyde (48-a, 74 mg, yield 14.7%). ESI[M+H] + =283.1,285.1
第二步:2，7-二氯-4-甲氧基-9H-茚并[2，1-d]嘧啶-9-酮的合成(48)Step 2: Synthesis of 2,7-dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidin-9-one (48)
将5-氯-2-(2-氯-4-甲氧基嘧啶-5-基)苯甲醛(48-a，37mg，0.131mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(2.4mg，0.0065mmol)和叔丁基过氧化氢(101μl，1.05mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备板(四氢呋喃：石油醚＝1:2)纯化得目标产物2,7-二氯-4-甲氧基-9H-茚并[2,1-d]嘧啶-9-酮(48，7.63mg,收率20.8％)。ESI[M+H]+＝281.2,283.21H NMR(400MHz,DMSO-d6)δ7.76(dd,J＝5.2,2.0Hz,2H),7.68–7.65(m,1H),4.17(s,3H).Dissolve 5-chloro-2-(2-chloro-4-methoxypyrimidin-5-yl)benzaldehyde (48-a, 37 mg, 0.131 mmol) in 1,2-dichloroethane (2 ml), and add Tetrabutylammonium iodide (2.4 mg, 0.0065 mmol) and tert-butyl hydroperoxide (101 μl, 1.05 mmol) were reacted overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified using a preparative plate (tetrahydrofuran: petroleum ether = 1:2) to obtain the target product 2,7-dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidine-9- Ketone (48, 7.63 mg, yield 20.8%). ESI[M+H] + =281.2,283.2 1 H NMR (400MHz, DMSO-d 6 ) δ7.76 (dd, J = 5.2, 2.0Hz, 2H), 7.68–7.65 (m, 1H), 4.17 (s ,3H).
实施例49：7-氯-2,4-二羟基-9H-茚并[2,1-d]嘧啶-9-酮的合成
Example 49: Synthesis of 7-chloro-2,4-dihydroxy-9H-indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-4-甲氧基-9H-茚并[2,1-d]嘧啶-9-酮(48，4mg，0.014mmol)溶于甲酸(1ml)，80℃反应过夜。反应液减压浓缩后制备板(二氯甲烷：甲醇＝15:1)纯化得目标产物7-氯-2,4-二羟基-9H-茚并[2,1-d]嘧啶-9-酮(49，0.90mg,收率25.7％)。ESI[M+H]+＝249.0,251.0Dissolve 2,7-dichloro-4-methoxy-9H-indeno[2,1-d]pyrimidin-9-one (48, 4 mg, 0.014 mmol) in formic acid (1 ml), and react at 80°C overnight. The reaction solution was concentrated under reduced pressure and purified using a preparation plate (dichloromethane: methanol = 15:1) to obtain the target product 7-chloro-2,4-dihydroxy-9H-indeno[2,1-d]pyrimidin-9-one. (49, 0.90 mg, yield 25.7%). ESI[M+H] + =249.0,251.0
实施例50:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-羧酸甲酯的合成
Example 50: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester
第一步:3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲酸甲酯的合成(50-a)Step 1: Synthesis of methyl 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzoate (50-a)
将4-溴-3-甲酰基苯甲酸甲酯(200mg，0.826mmol)，2-(三氟甲基)嘧啶-5-基硼酸(I-1，206mg，1.07mmol)，氟化钾(96mg，1.66mmol)和醋酸钯(10mg，0.045mmol)置于微波反应管中，加入乙腈(20ml)，氮气吹扫后密封，120℃微波反应60分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物Flash柱(乙酸乙酯：石油醚＝0％～30％)纯化得目标产物3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲酸甲酯(50-a，54mg,收率21.1％)。ESI[M+H]+＝311.24-Bromo-3-formylbenzoic acid methyl ester (200mg, 0.826mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 206mg, 1.07mmol), potassium fluoride (96mg , 1.66mmol) and palladium acetate (10mg, 0.045mmol) were placed in a microwave reaction tube, added acetonitrile (20ml), 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 (ethyl acetate: petroleum ether = 0% ~ 30%) to obtain the target product 3-formyl-4-(2-(trifluoromethyl) )pyrimidin-5-yl)benzoic acid methyl ester (50-a, 54 mg, yield 21.1%). ESI[M+H] + =311.2
第二步:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-羧酸甲酯的合成(50)Step 2: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50)
将3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲酸甲酯(50-a，54mg，0.174mmol)溶于1,2-二氯乙烷(4ml)，加入四丁基碘化铵(3.2mg，0.0087mmol)和叔丁基过氧化氢(134μl，1.39mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备板(四氢呋喃：石油醚＝1:3)纯化得目标产物9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸甲酯(50，28.4mg,收率52.9％)。ESI[M+H]+＝309.11H 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). Dissolve 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzoic acid methyl ester (50-a, 54 mg, 0.174 mmol) in 1,2-dichloroethane (4 ml) , add tetrabutylammonium iodide (3.2 mg, 0.0087 mmol) and tert-butyl hydroperoxide (134 μl, 1.39 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified using a preparation plate (tetrahydrofuran: petroleum ether = 1:3) to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7. - Methyl carboxylate (50, 28.4 mg, yield 52.9%). ESI[M+H] + =309.1 1 H NMR (400MHz, DMSO-d 6 ) δ9.71 (s, 1H), 8.38 (d, J = 7.8Hz, 1H), 8.27–8.18 (m, 2H), 3.92(s,3H).
实施例51:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-羧酸的合成
Example 51: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸甲酯(50，20mg，0.065mmol)溶于四氢呋喃/水(1ml/0.5ml)，加入氢氧化锂一水合物(6mg，0.143mmol)，室温反应1小时。使用1N盐酸调节PH呈中性，反应液减压浓缩后HPLC制备纯化得目标产物9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸(51，4.13mg,收率21.6％)。ESI[M+H]+＝295.11H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50, 20 mg, 0.065 mmol) in tetrahydrofuran/water (1 ml/ 0.5 ml), add lithium hydroxide monohydrate (6 mg, 0.143 mmol), and react at room temperature for 1 hour. Use 1N hydrochloric acid to adjust the pH to neutral. The reaction solution is concentrated under reduced pressure and purified by HPLC to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7- Carboxylic acid (51, 4.13 mg, yield 21.6%). ESI[M+H] + =295.1 1 H NMR (400MHz, DMSO-d 6 ) δ9.65 (s, 1H), 8.33 (d, J = 7.7Hz, 1H), 8.21–8.10 (m, 2H), 6.87(s,1H).
实施例52:N-环丙基-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲酰胺的合成
Example 52: Synthesis of N-cyclopropyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸(51，10mg，0.034mmol)溶于二氯甲烷(1ml)，加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(19mg，0.050mmol)，N,N-二异丙基乙胺(9μl，0.051mmol)和环丙胺(3μl，0.034mmol)，室温反应2小时。加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相减压浓缩后制备板(二氯甲烷：甲醇＝15:1)纯化得目标产物N-环丙基-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-甲酰胺(52，2.70mg，收率11.9％)。ESI[M+H]+＝334.1,ESI[2M+H]+＝667.21H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 10 mg, 0.034 mmol) in dichloromethane (1 ml), and add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (19 mg, 0.050 mmol), N,N-diisopropyl Ethylamine (9 μl, 0.051 mmol) and cyclopropylamine (3 μl, 0.034 mmol) were reacted at room temperature for 2 hours. Add saturated ammonium chloride solution to quench, extract with ethyl acetate, concentrate the organic phase under reduced pressure and purify using a preparative plate (dichloromethane: methanol = 15:1) to obtain the target product N-cyclopropyl-9-oxo-2- (Trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (52, 2.70 mg, yield 11.9%). ESI[M+H] + =334.1, ESI[2M+H] + =667.2 1 H NMR (400MHz, DMSO-d 6 ) δ9.63 (s, 1H), 8.75 (d, J = 4.0Hz, 1H) ,8.28–8.21(m,2H),8.16(d,J＝8.2Hz,1H),2.89(ddd,J＝11.3,7.6,4.0Hz,1H),1.35(s,2H),1.23(s,2H ).
实施例53:N-甲基-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲酰胺的合成
Example 53: Synthesis of N-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸(51，40mg，0.136mmol)溶于二氯甲烷(5ml)，加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(77mg，0.203mmol)，N,N-二异丙基乙胺(59μl，0.34mmol)和盐酸甲胺(9mg，0.133mmol)，室温反应2小时。加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相减压浓缩后制备板(二氯甲烷：甲醇＝15:1)纯化得目标产物N-甲基-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-甲酰胺(53，12.41mg，收率29.7％)。ESI[M+H]+＝308.1,ESI[2M+H]+＝615.21H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 40 mg, 0.136 mmol) in dichloromethane (5 ml), and add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (77mg, 0.203mmol), N,N-diisopropyl Ethylamine (59 μl, 0.34 mmol) and methylamine hydrochloride (9 mg, 0.133 mmol) were reacted at room temperature for 2 hours. Add saturated ammonium chloride solution to quench, extract with ethyl acetate, concentrate the organic phase under reduced pressure and purify using a plate (dichloromethane: methanol = 15:1) to obtain the target product N-methyl-9-oxo-2-( Trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (53, 12.41 mg, yield 29.7%). ESI[M+H] + =308.1, ESI[2M+H] + =615.2 1 H NMR (400MHz, DMSO-d 6 ) δ9.63 (s, 1H), 8.77 (d, J = 4.4Hz, 1H) ,8.28–8.21(m,2H),8.16(d,J＝7.8Hz,1H),2.82(d,J＝4.4Hz,3H).
实施例54:2-(三氟甲基)-7-(三氟甲硫基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 54: Synthesis of 2-(trifluoromethyl)-7-(trifluoromethylthio)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:2-溴-5-((三氟甲基)硫代)苯甲醛的合成(54-a)Step 1: Synthesis of 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (54-a)
将3-((三氟甲基)硫代)苯甲醛(400mg,1.94mmol)溶于二氯乙烷(15ml)，加入4-氯-2-(三氟甲基)苯胺(54.8μl，0.391mmol)，N-溴代琥珀酰亚胺(414mg,2.33mmol),醋酸钯(44mg,0.192mmol),三氟乙酸(4ml),在氮气氛围下60℃过夜反应后，减压浓缩，粗品经硅胶色谱法纯化(99％石油醚)得到目标产物2-溴-5-((三氟甲基)硫代)苯甲醛(54-a，320mg,收率58.8％)。(ESI)[M+H]+＝285.1.Dissolve 3-((trifluoromethyl)thio)benzaldehyde (400mg, 1.94mmol) in dichloroethane (15ml), add 4-chloro-2-(trifluoromethyl)aniline (54.8μl, 0.391 mmol), N-bromosuccinimide (414mg, 2.33mmol), palladium acetate (44mg, 0.192mmol), trifluoroacetic acid (4ml), reacted at 60°C overnight under a nitrogen atmosphere, then concentrated under reduced pressure, and the crude product was Purification by silica gel chromatography (99% petroleum ether) gave the target product 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (54-a, 320 mg, yield 58.8%). (ESI)[M+H] + =285.1.
第二步:2-(2-(三氟甲基)嘧啶-5-基)-5-(三氟甲硫基)苯甲醛(54-b) Step 2: 2-(2-(trifluoromethyl)pyrimidin-5-yl)-5-(trifluoromethylthio)benzaldehyde (54-b)
将2-溴-5-((三氟甲基)硫代)苯甲醛(54-a，120mg,0.423mmol)溶于乙腈(5ml)，加入2-(三氟甲基)嘧啶-5-基硼酸(122mg，0.634mmol)，氟化钾(49mg,0.846mmol),醋酸钯(65.2mg,0.0212mmol),在氮气氛围下120℃微波反应30分钟，过滤后滤液减压浓缩，粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝10:1)得到目标产物2-(2-(三氟甲基)嘧啶-5-基)-5-(三氟甲硫基)苯甲醛(54-b，80mg,收率53.8％)。(ESI)[M+H]+＝353.1.Dissolve 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (54-a, 120mg, 0.423mmol) in acetonitrile (5ml), and add 2-(trifluoromethyl)pyrimidin-5-yl Boric acid (122mg, 0.634mmol), potassium fluoride (49mg, 0.846mmol), and palladium acetate (65.2mg, 0.0212mmol) were reacted with microwave at 120°C for 30 minutes in a nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel chromatography. Purification method (petroleum ether: ethyl acetate = 10:1) to obtain the target product 2-(2-(trifluoromethyl)pyrimidin-5-yl)-5-(trifluoromethylthio)benzaldehyde (54-b , 80mg, yield 53.8%). (ESI)[M+H] + =353.1.
第三步:2-(三氟甲基)-7-(三氟甲硫基)-9H-茚并[2，1-d]嘧啶-9-酮的合成(54)Step 3: Synthesis of 2-(trifluoromethyl)-7-(trifluoromethylthio)-9H-indeno[2,1-d]pyrimidin-9-one (54)
将2-(2-(三氟甲基)嘧啶-5-基)-5-(三氟甲硫基)苯甲醛(54-b，40mg，0.114mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(2mg，0.0054mmol)和叔丁基过氧化氢(109μl，1.14mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备纯化得目标产物2-(三氟甲基)-7-(三氟甲硫基)-9H-茚并[2,1-d]嘧啶-9-酮(54，2.45mg,收率6.1％)。ESI[M+H]+＝351.21H 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).Dissolve 2-(2-(trifluoromethyl)pyrimidin-5-yl)-5-(trifluoromethylthio)benzaldehyde (54-b, 40 mg, 0.114 mmol) in 1,2-dichloroethane (2 ml), add tetrabutylammonium iodide (2 mg, 0.0054 mmol) and tert-butyl hydroperoxide (109 μl, 1.14 mmol), and react 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-d 6 ) δ9.69 (s, 1H), 8.25 (d, J = 7.8Hz, 1H), 8.21–8.15 (m, 1H), 8.08(s,1H).
实施例55:6-甲基-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-腈的合成
Example 55: Synthesis of 6-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile
第一步:4-溴-5-甲酰基-2-甲基苯甲腈的合成(55-a)Step 1: Synthesis of 4-bromo-5-formyl-2-methylbenzonitrile (55-a)
将5-甲酰基-2-甲基苯甲腈(50mg，0.344mmol)，4-氯-2-(三氟甲基)苯胺(13.45mg，0.0688mmol)，N-溴代丁二酰亚胺(73.47mg，0.4128mmol)，醋酸钯(7.7mg，0.0344mmol)溶于二氯乙烷(2ml)，然后加入三氟乙酸(0.5ml)，置换氮气三次，在氮气保护下100℃反应12小时。反应液过滤，减压浓缩后薄层层析(石油醚：乙酸乙酯＝3:1)纯化得目标产物4-溴-5-甲酰基-2-甲基苯甲腈(55-a，19mg，收率24.6％)。ESI[M+H]+＝225.065-Formyl-2-methylbenzonitrile (50mg, 0.344mmol), 4-chloro-2-(trifluoromethyl)aniline (13.45mg, 0.0688mmol), N-bromosuccinimide (73.47mg, 0.4128mmol), palladium acetate (7.7mg, 0.0344mmol) was dissolved in dichloroethane (2ml), then trifluoroacetic acid (0.5ml) was added, nitrogen was replaced 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
第二步:5-甲酰基-2-甲基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈的合成(55-b)Step 2: Synthesis of 5-formyl-2-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (55-b)
将4-溴-5-甲酰基-2-甲基苯甲腈(55-a，30mg，0.134mmol)，2-(三氟甲基)嘧啶-5-基硼酸(I-1，34mg，0.177mmol)，氟化钾(16mg，0.276mmol)和醋酸钯(2mg，0.0089mmol)置于微波反应管中，加入乙腈(3ml)，氮气吹扫后密封，120℃微波反应30分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物制备板(乙酸乙酯：石油醚＝1:5)纯化得目标产物5-甲酰基-2-甲基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(55-b，14mg,收率35.9％)。ESI[M+H]+＝292.24-Bromo-5-formyl-2-methylbenzonitrile (55-a, 30 mg, 0.134 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 34 mg, 0.177 mmol), potassium fluoride (16 mg, 0.276 mmol) and palladium acetate (2 mg, 0.0089 mmol) were placed in a microwave reaction tube, added acetonitrile (3 ml), 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 with a preparation plate (ethyl acetate: petroleum ether = 1:5) to obtain the target product 5-formyl-2-methyl-4-(2-(tri Fluoromethyl)pyrimidin-5-yl)benzonitrile (55-b, 14 mg, yield 35.9%). ESI[M+H] + =292.2
第三步:6-甲基-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-腈的合成(55)Step 3: Synthesis of 6-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile (55)
将5-甲酰基-2-甲基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(55-b，14mg，0.0481mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(1mg，0.0027mmol)和叔丁基过氧化氢(37μl，0.385mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备板(四氢呋喃：石油醚＝1:5)纯化得目标产物6-甲基-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-腈(55，3.85mg,收率27.5％)。ESI[M+H]+＝290.11H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.28(s,1H),8.22(s,1H),2.65(s,3H).Dissolve 5-formyl-2-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (55-b, 14 mg, 0.0481 mmol) in 1,2-dichloroethyl alkane (2 ml), add tetrabutylammonium iodide (1 mg, 0.0027 mmol) and tert-butyl hydroperoxide (37 μl, 0.385 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified using a preparatory plate (tetrahydrofuran: petroleum ether = 1:5) to obtain the target product 6-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1- d] Pyrimidine-7-nitrile (55, 3.85 mg, yield 27.5%). ESI[M+H] + =290.1 1 H NMR (400MHz, DMSO-d 6 ) δ9.65(s,1H),8.28(s,1H),8.22(s,1H),2.65(s,3H).
实施例56:8-氟-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-腈的合成
Example 56: Synthesis of 8-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile
第一步:4-溴-2-氟-3-甲酰基苯甲腈的合成(56-a)Step 1: Synthesis of 4-bromo-2-fluoro-3-formylbenzonitrile (56-a)
将4-溴-2-氟苯腈(500mg，2.51mmol)溶于超干四氢呋喃(10ml)，氮气保护下于-78℃滴加二异丙基胺基锂(2M，1.9ml，3.77mmol)，滴完后反应0.5小时，然后再滴加N,N-二甲基甲酰胺(387μl，5.02mmol)，滴完后反应15分钟。加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相无水硫酸镁干燥，过滤，滤液减压浓缩后Flash柱(乙酸乙 酯：石油醚＝0％～20％)纯化得目标产物4-溴-2-氟-3-甲酰基苯甲腈(56-a，135mg，收率23.7％)。Dissolve 4-bromo-2-fluorobenzonitrile (500mg, 2.51mmol) in ultra-dry tetrahydrofuran (10ml), and add lithium diisopropylamine (2M, 1.9ml, 3.77mmol) dropwise at -78°C under nitrogen protection. , react for 0.5 hours after the dropping is completed, and then add N,N-dimethylformamide (387 μl, 5.02 mmol) dropwise, and react for 15 minutes after the dropping is completed. Add saturated ammonium chloride solution to quench, extract with ethyl acetate, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure on a Flash column (ethyl acetate). Esters: petroleum ether = 0% ~ 20%), the target product 4-bromo-2-fluoro-3-formylbenzonitrile (56-a, 135 mg, yield 23.7%) was purified.
第二步:2-氟-3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈的合成(56-b)Step 2: Synthesis of 2-fluoro-3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (56-b)
将4-溴-2-氟-3-甲酰基苯甲腈(56-a，60mg，0.264mmol)，2-(三氟甲基)嘧啶-5-基硼酸(I-1，76mg，0.396mmol)，氟化钾(31mg，0.534mmol)和醋酸钯(3mg，0.0134mmol)置于微波反应管中，加入乙腈(5ml)，氮气吹扫后密封，120℃微波反应45分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物制备板(乙酸乙酯：石油醚＝1:5)纯化得目标产物2-氟-3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(56-b，65mg,收率45.4％)。ESI[M+H]+＝296.44-Bromo-2-fluoro-3-formylbenzonitrile (56-a, 60mg, 0.264mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 76mg, 0.396mmol) ), potassium fluoride (31 mg, 0.534 mmol) and palladium acetate (3 mg, 0.0134 mmol) were placed in a microwave reaction tube, added acetonitrile (5 ml), 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 with a preparation plate (ethyl acetate: petroleum ether = 1:5) to obtain the target product 2-fluoro-3-formyl-4-(2-(trifluoro Methyl)pyrimidin-5-yl)benzonitrile (56-b, 65 mg, yield 45.4%). ESI[M+H] + =296.4
第三步:8-氟-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-腈的合成(56)Step 3: Synthesis of 8-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile (56)
将2-氟-3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(56-b，35mg，0.119mmol)溶于1,2-二氯乙烷(3ml)，加入四丁基碘化铵(2mg，0.00541mmol)和叔丁基过氧化氢(91μl，0.952mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备板(四氢呋喃：石油醚＝1:3)纯化得目标产物8-氟-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-腈(56，18.36mg,收率52.4％)。ESI[M+H]+＝294.31H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.43(dd,J＝7.5,6.3Hz,1H),8.15(d,J＝7.8Hz,1H).Dissolve 2-fluoro-3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (56-b, 35 mg, 0.119 mmol) in 1,2-dichloroethane (3 ml), add tetrabutylammonium iodide (2 mg, 0.00541 mmol) and tert-butyl hydroperoxide (91 μl, 0.952 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified using a preparatory plate (tetrahydrofuran: petroleum ether = 1:3) to obtain the target product 8-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d ]pyrimidine-7-nitrile (56, 18.36 mg, yield 52.4%). ESI[M+H] + =294.3 1 H NMR (400MHz, DMSO-d 6 ) δ9.77 (s, 1H), 8.43 (dd, J = 7.5, 6.3Hz, 1H), 8.15 (d, J = 7.8 Hz,1H).
实施例57:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-磺酰胺的合成
Example 57: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-sulfonamide
第一步:2-氯-5-氨磺酰基苯甲酸的合成(57-a)Step 1: Synthesis of 2-chloro-5-sulfamoylbenzoic acid (57-a)
在0℃下，将2-氯-5-(氯磺酰基)苯甲酸(2g，7.8mmol)溶于氨水合物(30ml)中，在室温搅拌反应1小时。反应液过滤减压浓缩后得目标产物粗品2-氯-5-氨磺酰基苯甲酸(57-a，2.53g，收率130.4％)。ESI[M-H]+＝234.1,236.2Dissolve 2-chloro-5-(chlorosulfonyl)benzoic acid (2g, 7.8mmol) in ammonia hydrate (30ml) at 0°C, and stir for 1 hour at room temperature. The reaction solution was filtered and concentrated under reduced pressure to obtain the crude target product 2-chloro-5-sulfamoylbenzoic acid (57-a, 2.53g, yield 130.4%). ESI[MH] + =234.1,236.2
第二步:2-氯-N-甲氧基-N-甲基-5-氨磺酰基苯甲酰胺的合成(57-b)Step 2: Synthesis of 2-chloro-N-methoxy-N-methyl-5-sulfamoylbenzamide (57-b)
将2-氯-5-氨磺酰基苯甲酸(57-a，1g，4.26mmol)，N、O-二甲基羟胺盐酸盐(413mg，4.26mmol)和1-甲基-1H-咪唑(1.4ml，17.02mmol)溶于乙腈(20ml)中，室温搅拌10分钟后加入N,N,N',N'-四甲基氯甲脒六氟磷酸盐(1.19g，4.26mmol)，室温下反应2小时。反应液过滤减压浓缩后Flash柱(乙酸乙酯：石油醚＝0％～50％)纯化得目标产物2-氯-N-甲氧基-N-甲基-5-氨磺酰基苯甲酰胺(57-b，1.208g，收率102.15％)。ESI[M+H]+＝278.2,280.22-Chloro-5-sulfamoylbenzoic acid (57-a, 1g, 4.26mmol), N,O-dimethylhydroxylamine hydrochloride (413mg, 4.26mmol) and 1-methyl-1H-imidazole ( 1.4ml, 17.02mmol) was dissolved in acetonitrile (20ml), stirred at room temperature for 10 minutes, then added N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.19g, 4.26mmol), at room temperature Reaction takes 2 hours. The reaction solution was filtered and concentrated under reduced pressure, and purified by Flash column (ethyl acetate: petroleum ether = 0% ~ 50%) to obtain the target product 2-chloro-N-methoxy-N-methyl-5-sulfamoylbenzamide. (57-b, 1.208g, yield 102.15%). ESI[M+H] + =278.2,280.2
第三步:4-氯-3-甲酰基苯磺酰胺的合成(57-c)Step 3: Synthesis of 4-chloro-3-formylbenzenesulfonamide (57-c)
将2-氯-N-甲氧基-N-甲基-5-氨磺酰基苯甲酰胺(57-b，150mg，0.539mmol)溶于超干二氯甲烷(10ml)，氮气保护下于0℃加入二异丁基氢化铝(1M，1ml，1.078mmol)，0℃反应2小时。加入饱和氯化铵溶液淬灭，二氯甲烷萃取，有机相无水硫酸镁干燥，过滤，滤液减压浓缩后得目标产物4-氯-3-甲酰基苯磺酰胺(57-c，46mg，收率38.9％)。ESI[M+H]+＝220.2,222.2Dissolve 2-chloro-N-methoxy-N-methyl-5-sulfamoylbenzamide (57-b, 150 mg, 0.539 mmol) in ultra-dry dichloromethane (10 ml), and store it at 0 under nitrogen protection. Add diisobutylaluminum hydride (1M, 1 ml, 1.078 mmol) at 0°C and react at 0°C for 2 hours. Add saturated ammonium chloride solution to quench, extract with dichloromethane, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate the filtrate 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
第四步:3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯磺酰胺的合成(57-d)Step 4: Synthesis of 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide (57-d)
将4-氯-3-甲酰基苯磺酰胺(57-c，46mg，0.21mmol)，2-(三氟甲基)嘧啶-5-基硼酸(I-1，52mg，0.273mmol)，碳酸铯(137mg，0.42mmol)和四三苯基膦钯(12mg，0.0104mmol)置于微波反应管中，加入二氧六环/水(5ml/0.5ml)，氮气吹扫后密封，120℃微波反应30分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物制备板(二氯甲烷：甲醇＝15:1)纯化得目标产物3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯磺酰胺(57-d，17mg,收率24.5％)。ESI[M+H]+＝332.34-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 reaction tube, dioxane/water (5 ml/0.5 ml) was added, purged with nitrogen and sealed, followed by microwave reaction at 120°C 30 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified using a preparation plate (dichloromethane: methanol = 15:1) to obtain the target product 3-formyl-4-(2-(trifluoromethyl)pyrimidine- 5-yl)benzenesulfonamide (57-d, 17 mg, yield 24.5%). ESI[M+H] + =332.3
第五步:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-磺酰胺的合成(57)Step 5: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (57)
将3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯磺酰胺(57-d，17mg，0.0514mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(1mg，0.0027mmol)和叔丁基过氧化氢(42μl，0.411mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备板(二氯甲烷：甲醇＝15:1)纯化得目标产物9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-磺酰胺(57，3.04mg,收率17.9％)。ESI[M+H]+＝330.31H 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).Dissolve 3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide (57-d, 17mg, 0.0514mmol) in 1,2-dichloroethane (2ml), Add tetrabutylammonium iodide (1 mg, 0.0027 mmol) and tert-butyl hydroperoxide (42 μl, 0.411 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified using a preparation plate (dichloromethane: methanol = 15:1) to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine- 7-Sulfonamide (57, 3.04 mg, yield 17.9%). ESI[M+H] + =330.3 1 H NMR (400MHz, DMSO-d 6 ) δ9.69 (s, 1H), 8.28–8.19 (m, 2H), 8.15 (d, J = 0.9Hz, 1H), 7.67(s,2H).
实施例58:5-甲基-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-腈的合成
Example 58: Synthesis of 5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile
第一步:4-溴-3-甲酰基-5-甲基苄腈的合成(58-a)Step 1: Synthesis of 4-bromo-3-formyl-5-methylbenzonitrile (58-a)
将3-氰基-5-甲基苯甲醛(200mg，1.38mmol)溶于1,2-二氯乙烷/三氟乙酸(8ml/2ml)，加入N-溴代丁二酰亚胺(295mg，1.66mmol)，4-氯-2-(三氟甲基)苯胺(39μl，0.276mmol)和醋酸钯(31mg，0.138mmol)，氮气保护，于封管中100℃反应过夜。过滤除去反应液中不容物，滤液减压浓缩后Flash柱(乙酸乙酯：石油醚＝0％～5％)纯化得目标产物4-溴-3-甲酰基-5-甲基苄腈(58-a，15mg，收率4.9％)。ESI[M+H]+＝224.0,225.9Dissolve 3-cyano-5-methylbenzaldehyde (200mg, 1.38mmol) in 1,2-dichloroethane/trifluoroacetic acid (8ml/2ml), add N-bromosuccinimide (295mg , 1.66mmol), 4-chloro-2-(trifluoromethyl)aniline (39μl, 0.276mmol) and palladium acetate (31mg, 0.138mmol), under nitrogen protection, react overnight at 100°C in a sealed tube. The reaction solution was filtered to remove incompatible materials, and the filtrate was concentrated under reduced pressure and purified by Flash column (ethyl acetate: petroleum ether = 0% ~ 5%) to obtain the target product 4-bromo-3-formyl-5-methylbenzonitrile (58 -a, 15mg, yield 4.9%). ESI[M+H] + =224.0,225.9
第二步:3-甲酰基-5-甲基-4-(2-(三氟甲基)嘧啶-5-基)苄腈的合成(58-b)Step 2: Synthesis of 3-formyl-5-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (58-b)
将4-溴-3-甲酰基-5-甲基苄腈(58-a，12mg，0.0538mmol)，2-(三氟甲基)嘧啶-5-基硼酸(I-1，14mg，0.0729mmol)，氟化钾(7mg，0.121mmol)和醋酸钯(1mg，0.00445mmol)置于微波反应管中，加入乙腈(2ml)，氮气吹扫后密封，120℃微波反应30分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物制备板(乙酸乙酯：石油醚＝1:6)纯化得目标产物3-甲酰基-5-甲基-4-(2-(三氟甲基)嘧啶-5-基)苄腈(58-b，10mg,收率63.7％)。ESI[M+H]+＝292.2第三步:5-甲基-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-腈的合成(58)4-Bromo-3-formyl-5-methylbenzonitrile (58-a, 12 mg, 0.0538mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 14mg, 0.0729mmol) ), potassium fluoride (7 mg, 0.121 mmol) and palladium acetate (1 mg, 0.00445 mmol) were placed in a microwave reaction tube, added acetonitrile (2 ml), 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 using a preparation plate (ethyl acetate:petroleum ether=1:6) to obtain the target product 3-formyl-5-methyl-4-(2-(tri Fluoromethyl)pyrimidin-5-yl)benzonitrile (58-b, 10 mg, yield 63.7%). ESI[M+H] + =292.2 Step 3: Synthesis of 5-methyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile (58)
将3-甲酰基-5-甲基-4-(2-(三氟甲基)嘧啶-5-基)苄腈(58-b，10mg，0.0344mmol)溶于1,2-二氯乙烷(1ml)，加入四丁基碘化铵(0.63mg，0.00171mmol)和叔丁基过氧化氢(27μl，0.275mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备纯化得目标产物5-甲基-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-腈(58，0.84mg,收率8.4％)。ESI[M+H]+＝290.4Dissolve 3-formyl-5-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (58-b, 10 mg, 0.0344mmol) in 1,2-dichloroethane (1 ml), add tetrabutylammonium iodide (0.63 mg, 0.00171 mmol) and tert-butyl hydroperoxide (27 μl, 0.275 mmol), and react 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]pyrimidine-7-carbonitrile (58,0.84 mg, yield 8.4%). ESI[M+H] + =290.4
实施例59:2-(三氟甲基)-7-(三氟甲磺酰基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 59: Synthesis of 2-(trifluoromethyl)-7-(trifluoromethanesulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one
将2-(三氟甲基)-7-(三氟甲硫基)-9H-茚并[2,1-d]嘧啶-9-酮(54，13mg，0.0371mmol)溶于二氯甲烷(2ml)，0℃下加入间氯过氧苯甲酸(19mg，0.11mmol)，然后室温反应36小时。反应液减压浓缩后制备纯化得目标产物2-(三氟甲基)-7-(三氟甲磺酰基)-9H-茚并[2,1-d]嘧啶-9-酮(59，2.48mg,收率17.7％)。ESI[M+H]+＝383.11H 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).Dissolve 2-(trifluoromethyl)-7-(trifluoromethylthio)-9H-indeno[2,1-d]pyrimidin-9-one (54, 13 mg, 0.0371 mmol) in dichloromethane ( 2ml), add m-chloroperoxybenzoic acid (19mg, 0.11mmol) at 0°C, and then react at room temperature for 36 hours. The reaction solution was concentrated under reduced pressure and purified to obtain the target product 2-(trifluoromethyl)-7-(trifluoromethanesulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (59, 2.48 mg, yield 17.7%). ESI[M+H] + =383.1 1 H NMR (400MHz, DMSO-d 6 ) δ9.87 (s, 1H), 8.66 (d, J = 8.0Hz, 1H), 8.57 (d, J = 8.0Hz, 1H),8.33(s,1H).
实施例60:7-(1H-吡唑-5-基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 60: Synthesis of 7-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-溴-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的合成(60-a)Step 1: Synthesis of 5-bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a)
将5-溴-2-碘苯甲醛(50mg，0.161mmol)，2-(三氟甲基)嘧啶-5-基硼酸(I-1，50mg，0.26mmol)，氟化钾(19mg，0.327mmol)和醋酸钯(2mg，0.0089mmol)置于微波反应管中，加入乙醇(4ml)，氮气吹扫后密封，120℃微波反 应30分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物Flash柱(乙酸乙酯：石油醚＝0％～25％)纯化得目标产物5-溴-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(60-a，45mg,收率42.4％)。ESI[M+H]+＝331.1,333.05-Bromo-2-iodobenzaldehyde (50mg, 0.161mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 50mg, 0.26mmol), potassium fluoride (19mg, 0.327mmol) ) and palladium acetate (2 mg, 0.0089 mmol) were placed in a microwave reaction tube, added ethanol (4 ml), purged with nitrogen, sealed, and microwaved at 120°C. Should take 30 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 0% ~ 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
第二步:5-(1H-吡唑-5-基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的合成(60-b)Step 2: Synthesis of 5-(1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-b)
将5-溴-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(60-a，25mg，0.0757mmol)，1H-吡唑-3-硼酸(10mg，0.0893mmol)，氟化钾(9mg，0.155mmol)和醋酸钯(1mg，0.00445mmol)置于微波反应管中，加入乙醇(3ml)，氮气吹扫后密封，120℃微波反应40分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物制备板(二氯甲烷：甲醇＝10:1)纯化得目标产物5-(1H-吡唑-5-基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(60-b，9mg,收率20.9％)。ESI[M+H]+＝319.15-bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a, 25mg, 0.0757mmol), 1H-pyrazole-3-boronic acid (10mg, 0.0893mmol), Potassium fluoride (9 mg, 0.155 mmol) and palladium acetate (1 mg, 0.00445 mmol) were placed in a microwave reaction tube, ethanol (3 ml) was added, 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 using a preparation plate (dichloromethane: methanol = 10:1) to obtain the target product 5-(1H-pyrazol-5-yl)-2-(2- (Trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-b, 9 mg, yield 20.9%). ESI[M+H] + =319.1
第三步:7-(1H-吡唑-5-基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成(60)Step 3: Synthesis of 7-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (60)
将5-(1H-吡唑-5-基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(60-b，9mg，0.0283mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(0.52mg，0.00141mmol)和叔丁基过氧化氢(22μl，0.226mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备纯化得目标产物7-(1H-吡唑-5-基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(60，2.10mg,收率23.6％)。ESI[M+H]+＝317.1,ESI[2M+H]+＝633.2,ESI[2M+Na]+＝655.21H 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).Dissolve 5-(1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-b, 9 mg, 0.0283 mmol) in 1,2-bis To ethyl chloride (2 ml), add tetrabutylammonium iodide (0.52 mg, 0.00141 mmol) and tert-butyl hydroperoxide (22 μl, 0.226 mmol), and react 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, 2.10mg, yield 23.6%). ESI[M+H] + =317.1, ESI[2M+H] + =633.2, ESI[2M+Na] + =655.2 1 H NMR (400MHz, DMSO-d 6 ) δ13.15 (s, 1H), 9.56 (s,1H),8.29–8.19(m,2H),8.09(d,J＝7.7Hz,1H),7.86(s,1H),6.97(d,J＝2.1Hz,1H).
实施例61:7-(1-甲基-1H-吡唑-5-基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 61: Synthesis of 7-(1-methyl-1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-(1-甲基-1H-吡唑-5-基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的合成(61-a)Step 1: Synthesis of 5-(1-methyl-1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (61-a)
将5-溴-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(60-a，60mg，0.182mmol)，1-甲基-1H-吡唑-5-硼酸(28mg，0.222mmol)，氟化钾(21mg，0.362mmol)和醋酸钯(2mg，0.0089mmol)置于微波反应管中，加入乙醇(4ml)，氮气吹扫后密封，120℃微波反应30分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物制备板(二氯甲烷：甲醇＝15:1)纯化得目标产物5-(1-甲基-1H-吡唑-5-基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(61-a，22mg,收率36.7％)。ESI[M+H]+＝333.25-Bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a, 60 mg, 0.182 mmol), 1-methyl-1H-pyrazole-5-boronic acid (28 mg , 0.222mmol), potassium fluoride (21mg, 0.362mmol) and palladium acetate (2mg, 0.0089mmol) were placed in a microwave reaction tube, ethanol (4ml) was added, 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 using a preparation plate (dichloromethane: methanol = 15:1) to obtain the target product 5-(1-methyl-1H-pyrazol-5-yl)- 2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (61-a, 22 mg, yield 36.7%). ESI[M+H] + =333.2
第二步:7-(1-甲基-1H-吡唑-5-基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成(61)Second step: synthesis of 7-(1-methyl-1H-pyrazol-5-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one ( 61)
将5-(1-甲基-1H-吡唑-5-基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(61-a，22mg，0.0663mmol)溶于1,2-二氯乙烷(3ml)，加入四丁基碘化铵(1.22mg，0.0033mmol)和叔丁基过氧化氢(51μl，0.53mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备板(二氯甲烷：甲醇＝15:1)纯化得目标产物7-(1-甲基-1H-吡唑-5-基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(61，7.54mg,收率34.3％)。ESI[M+H]+＝331.1,ESI[2M+Na]+＝683.21H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.19(d,J＝7.8Hz,1H),8.00(dd,J＝7.8,1.5Hz,1H),7.95(d,J＝0.8Hz,1H),7.53(d,J＝1.8Hz,1H),6.62(d,J＝1.8Hz,1H),3.93(s,3H).Dissolve 5-(1-methyl-1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (61-a, 22 mg, 0.0663 mmol) in To 1,2-dichloroethane (3 ml), add tetrabutylammonium iodide (1.22 mg, 0.0033 mmol) and tert-butyl hydroperoxide (51 μl, 0.53 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified using a preparation plate (dichloromethane: methanol = 15:1) to obtain the target product 7-(1-methyl-1H-pyrazol-5-yl)-2-(trifluoromethyl)- 9H-Indeno[2,1-d]pyrimidin-9-one (61, 7.54 mg, yield 34.3%). ESI[M+H] + =331.1, ESI[2M+Na] + =683.2 1 H NMR (400MHz, DMSO-d 6 ) δ9.64 (s, 1H), 8.19 (d, J = 7.8Hz, 1H) ,8.00(dd,J＝7.8,1.5Hz,1H),7.95(d,J＝0.8Hz,1H),7.53(d,J＝1.8Hz,1H),6.62(d,J＝1.8Hz,1H) ,3.93(s,3H).
实施例62:N-羟基-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲酰胺的合成
Example 62: Synthesis of N-hydroxy-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸甲酯(50，15mg，0.0487mmol)溶于四氢呋喃/水(2ml/0.2ml)，加入氢氧化钠(4mg，0.1mmol)和盐酸羟胺(3.7mg，0.0528mmol)，加入氢氧化锂一水合物(4mg，0.1mmol)，室温反应1.5小时。反应液减压浓缩后制备纯化得目标产物N-羟基-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-甲酰胺(18，1.11mg，收率7.4％)。ESI[M+H]+＝310.11H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50, 15 mg, 0.0487 mmol) in tetrahydrofuran/water (2 ml/ 0.2 ml), add sodium hydroxide (4 mg, 0.1 mmol) and hydroxylamine hydrochloride (3.7 mg, 0.0528 mmol), add lithium hydroxide monohydrate (4 mg, 0.1 mmol), and react at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure and purified to obtain the target product N-hydroxy-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (18,1.11 mg, yield 7.4%). ESI[M+H] + =310.1 1 H NMR (400MHz, DMSO-d 6 ) δ9.62 (s, 1H), 8.97 (s, 1H), 8.28 (d, J = 7.9Hz, 1H), 8.22 ( d,J＝7.9Hz,1H).
实施例63:7-(2-羟基丙烷-2-基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 63: Synthesis of 7-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸甲酯(50，15mg，0.0487mmol)溶于超干四氢呋喃(3ml)，氮气保护下于0℃滴加甲基溴化镁(1M，122μl，0.123mmol)，然后室温反应4小时。加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相无水硫酸镁干燥，过滤，滤液减压浓缩后制备纯化得目标产物7-(2-羟基丙烷-2-基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(63，1.20mg，收率8.0％)。ESI[M+H]+＝309.11H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50, 15 mg, 0.0487 mmol) in ultradry tetrahydrofuran (3 ml) , add methylmagnesium bromide (1M, 122 μl, 0.123 mmol) dropwise at 0°C under nitrogen protection, and then react at room temperature for 4 hours. Add saturated ammonium chloride solution to quench, extract with ethyl acetate, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to prepare and purify the target product 7-(2-hydroxypropan-2-yl)-2-( Trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (63, 1.20 mg, yield 8.0%). ESI[M+H] + =309.1 1 H NMR (400MHz, DMSO-d 6 ) δ9.71 (s, 1H), 8.39 (d, J = 5.6Hz, 1H), 8.29–8.17 (m, 2H), 1.23(s,6H).
实施例64:2-甲氧基-7-(甲基磺酰基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 64: Synthesis of 2-methoxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:2-氯-5-(甲基磺酰基)苯甲酸的合成(64-a)Step 1: Synthesis of 2-chloro-5-(methylsulfonyl)benzoic acid (64-a)
将2-氯-5-(甲硫基)苯甲酸(2g，9.87mmol)溶于甲醇(60ml)，加入过氧单磺酸钾(12.1g，19.66mmol)，室温反应过夜。过滤除去不溶物，滤液减压浓缩后剩余物用二氯甲烷溶解，饱和食盐水洗涤，无水硫酸镁干燥，过滤，滤液减压浓缩后得目标产物2-氯-5-(甲基磺酰基)苯甲酸(64-a，2.2g，收率95.7％)。ESI[M-H]+＝233.0,235.0Dissolve 2-chloro-5-(methylthio)benzoic acid (2g, 9.87mmol) in methanol (60ml), add potassium peroxymonosulfonate (12.1g, 19.66mmol), and react at room temperature overnight. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. 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 obtain the target product 2-chloro-5-(methylsulfonyl). ) Benzoic acid (64-a, 2.2g, yield 95.7%). ESI[MH] + =233.0,235.0
第二步:(2-氯-5-(甲基磺酰基)苯基)甲醇的合成(64-b)Step 2: Synthesis of (2-chloro-5-(methylsulfonyl)phenyl)methanol (64-b)
将2-氯-5-(甲基磺酰基)苯甲酸(64-a，800mg，3.42mmol)溶于超干四氢呋喃(30ml)，氮气保护下于0℃加入四氢锂铝(260mg，6.84mmol)，然后室温反应1小时。加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相无水硫酸镁干燥，过滤，滤液减压浓缩后得目标产物(2-氯-5-(甲基磺酰基)苯基)甲醇(64-b，415mg，收率55.2％)。第三步:2-氯-5-(甲基磺酰基)苯甲醛(64-c)Dissolve 2-chloro-5-(methylsulfonyl)benzoic acid (64-a, 800 mg, 3.42 mmol) in ultra-dry tetrahydrofuran (30 ml), and add lithium aluminum tetrahydrofuran (260 mg, 6.84 mmol) at 0°C under nitrogen protection. ), and then react at room temperature for 1 hour. Add saturated ammonium chloride solution to quench, extract with ethyl acetate, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product (2-chloro-5-(methylsulfonyl)phenyl)methanol ( 64-b, 415 mg, yield 55.2%). Step 3: 2-chloro-5-(methylsulfonyl)benzaldehyde (64-c)
将(2-氯-5-(甲基磺酰基)苯基)甲醇(64-b，315mg，1.43mmol)溶于1,4-二氧六环(30ml)，加入二氧化锰(1.25g，14.37mmol)，100℃反应过夜。过滤除去二氧化锰，滤液减压浓缩后得目标产物2-氯-5-(甲基磺酰基)苯甲醛(64-c，250mg，收率60.8％)。ESI[M+H]+＝219.0,221.0Dissolve (2-chloro-5-(methylsulfonyl)phenyl)methanol (64-b, 315mg, 1.43mmol) in 1,4-dioxane (30ml), and add manganese dioxide (1.25g, 14.37mmol), react at 100°C overnight. Manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the target product 2-chloro-5-(methylsulfonyl)benzaldehyde (64-c, 250 mg, yield 60.8%). ESI[M+H] + =219.0,221.0
第四步:2-(2-甲氧基嘧啶-5-基)-5-(甲基磺酰基)苯甲醛的合成(64-d)Step 4: Synthesis of 2-(2-methoxypyrimidin-5-yl)-5-(methylsulfonyl)benzaldehyde (64-d)
将2-氯-5-(甲基磺酰基)苯甲醛(64-c，230mg，1.055mmol)，2-甲氧基-5-嘧啶硼酸(211mg，1.37mmol)，碳酸铯(688mg，2.11mmol)和四三苯基膦钯(61mg，0.0528mmol)置于微波反应管中，加入1,4-二氧六环/水(25ml/2.5ml)，氮气吹扫后密封，120℃微波反应50分钟。将反应液过滤去除不溶物，滤液减压浓缩，剩余物Flash柱(乙酸乙酯：石油醚＝10％～100％)纯化得目标产物2-(2-甲氧基嘧啶-5-基)-5-(甲基磺酰基)苯甲醛(64-d，280mg,收率83.6％)。ESI[M+H]+＝293.12-Chloro-5-(methylsulfonyl)benzaldehyde (64-c, 230mg, 1.055mmol), 2-methoxy-5-pyrimidineboronic acid (211mg, 1.37mmol), cesium carbonate (688mg, 2.11mmol) ) and tetrakis triphenylphosphine palladium (61 mg, 0.0528 mmol) were placed in a microwave reaction tube, add 1,4-dioxane/water (25 ml/2.5 ml), purge with nitrogen and seal, microwave reaction at 120°C for 50 minute. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column (ethyl acetate: petroleum ether = 10% ~ 100%) to obtain the target product 2-(2-methoxypyrimidin-5-yl)- 5-(methylsulfonyl)benzaldehyde (64-d, 280 mg, yield 83.6%). ESI[M+H] + =293.1
第五步:2-甲氧基-7-(甲基磺酰基)-9H-茚并[2，1-d]嘧啶-9-酮的合成(64)Step 5: Synthesis of 2-methoxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (64)
将2-(2-甲氧基嘧啶-5-基)-5-(甲基磺酰基)苯甲醛(64-d，230mg，0.788mmol)溶于1,2-二氯乙烷(10ml)，加入四丁基碘化铵(14.5mg，0.0392mmol)和叔丁基过氧化氢(455μl，4.73mmol)，于封管中100℃反应过夜。反应液减压浓缩后四氢呋喃重结晶得目标产物2-甲氧基-7-(甲基磺酰基)-9H-茚并[2,1-d]嘧啶-9-酮(64，44mg,收率19.3％)。ESI[M+H]+＝291.11H 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).Dissolve 2-(2-methoxypyrimidin-5-yl)-5-(methylsulfonyl)benzaldehyde (64-d, 230 mg, 0.788 mmol) in 1,2-dichloroethane (10 ml), Add tetrabutylammonium iodide (14.5 mg, 0.0392 mmol) and tert-butyl hydroperoxide (455 μl, 4.73 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and recrystallized from tetrahydrofuran to obtain the target product 2-methoxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (64, 44 mg, yield 19.3%). ESI[M+H] + =291.1 1 H NMR (600MHz, DMSO-d 6 ) δ9.29 (s, 1H), 8.25 (dd, J = 7.8, 1.6Hz, 1H), 8.10 (d, J = 7.9 Hz,2H),4.03(s,3H),3.32(s,3H).
实施例65:2-羟基-7-(甲基磺酰基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 65: Synthesis of 2-hydroxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one
将2-甲氧基-7-(甲基磺酰基)-9H-茚并[2,1-d]嘧啶-9-酮(64，10mg，0.0345mmol)溶于甲酸(2ml)，加入浓盐酸(0.3ml)，80℃反应5小时。反应液减压浓缩后制备纯化得目标产物2-羟基-7-(甲基磺酰基)-9H-茚并[2,1-d]嘧 啶-9-酮(65，0.90mg，收率9.5％)。ESI[M+H]+＝277.1,ESI[2M+H]+＝553.11H NMR(600MHz,DMSO-d6)δ8.68(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).Dissolve 2-methoxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (64, 10 mg, 0.0345 mmol) in formic acid (2 ml), and add concentrated hydrochloric acid (0.3ml), react at 80°C for 5 hours. The reaction solution was concentrated under reduced pressure and purified to obtain the target product 2-hydroxy-7-(methylsulfonyl)-9H-indeno[2,1-d]pyrimidine. Tridin-9-one (65, 0.90 mg, yield 9.5%). ESI[M+H] + =277.1, ESI[2M+H] + =553.1 1 H NMR (600MHz, DMSO-d 6 ) δ8.68 (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).
实施例66:N-((9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-基)磺酰基)乙酰胺的合成
Example 66: Synthesis of N-((9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)sulfonyl)acetamide
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-磺酰胺(57，18mg，0.0547mmol)溶于乙腈(3ml)，加入乙酸酐(8μl，0.0821mmol)和浓硫酸(30μl)，80℃反应8小时。加入饱和食盐水淬灭，二氯甲烷萃取，有机相饱和食盐水洗涤，无水硫酸镁干燥，过滤，滤液减压浓缩后制备纯化得目标产物N-((9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-基)磺酰基)乙酰胺(66，1.75mg，收率8.6％)。ESI[M+H]+＝372.11H NMR(600MHz,DMSO-d6)δ9.74(s,1H),8.34–8.32(m,2H),8.15(s,1H),1.96(s,3H).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (57, 18 mg, 0.0547 mmol) in acetonitrile (3 ml), and add acetic anhydride (8 μl, 0.0821 mmol) and concentrated sulfuric acid (30 μl), react at 80°C for 8 hours. Add saturated brine to quench, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to prepare and purify the target product N-((9-oxo-2-(tri Fluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)sulfonyl)acetamide (66, 1.75 mg, yield 8.6%). ESI[M+H] + =372.1 1 H NMR(600MHz, DMSO-d 6 )δ9.74(s,1H),8.34–8.32(m,2H),8.15(s,1H),1.96(s,3H ).
实施例67:7-(S-甲基磺酰亚胺基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 67: Synthesis of 7-(S-methylsulfonylimido)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:7-溴-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮得合成(67-a)Step 1: Synthesis of 7-bromo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-a)
将5-溴-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(60-a，520mg，1.58mmol)溶于二氯乙烷(25ml)，加入2-过氧化氢-2-甲基丙烷(908μl，7.88mmol)，四丁基碘化铵(19mg，0.05mmol)在氮气保护下100℃反应过夜。减压浓缩后粗品经制备法纯化得目标产物7-溴-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(67-a，260mg,收率31.7％)。Dissolve 5-bromo-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (60-a, 520 mg, 1.58 mmol) in dichloroethane (25 ml), and add 2-hydrogen peroxide -2-Methylpropane (908 μl, 7.88 mmol) and tetrabutylammonium iodide (19 mg, 0.05 mmol) were reacted overnight at 100°C under nitrogen protection. After concentration under reduced pressure, the crude product was purified by a preparation 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%).
第二步:7-(甲硫基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成(67-b)Step 2: Synthesis of 7-(methylthio)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-b)
将7-溴-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(67-a，135mg，0.412mmol)溶于二甲基亚砜(8ml)，加入三乙烯二胺(92mg，0.821mmol)和碘化亚铜(78mg，0.409mmol)，氮气保护下于130℃反应过夜。加入饱和食盐水淬灭，乙酸乙酯萃取，有机相无水硫酸镁干燥，过滤，滤液减压浓缩后Flash柱(乙酸乙酯：石油醚＝0％～30％)纯化得目标产物7-(甲硫基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(67-b，45mg，收率36.9％)。ESI[M+H]+＝297.1Dissolve 7-bromo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-a, 135 mg, 0.412 mmol) in dimethyl sulfoxide (8 ml) , add triethylenediamine (92mg, 0.821mmol) and copper iodide (78mg, 0.409mmol), and react overnight at 130°C under nitrogen protection. Add saturated brine to quench, extract with ethyl acetate, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure and purify 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
第三步:7-(S-甲基磺酰亚胺基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成(67)Step 3: Synthesis of 7-(S-methylsulfonylimido)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67)
将7-(甲硫基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(67-b，45mg，0.152mmol)溶于乙醇(4ml)，加入碘苯二乙酸(59mg，0.456mmol)和醋酸铵(47mg，0.61mmol)，室温反应过夜。反应液减压浓缩后制备板(二氯甲烷：甲醇＝15:1)纯化得目标产物7-(S-甲基磺酰亚胺基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(67，2.25mg，收率4.5％)。ESI[M+H]+＝328.21H 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).Dissolve 7-(methylthio)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (67-b, 45 mg, 0.152 mmol) in ethanol (4 ml) , add iodophenylacetic acid (59 mg, 0.456 mmol) and ammonium acetate (47 mg, 0.61 mmol), and react at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified using a preparation plate (dichloromethane: methanol = 15:1) to obtain the target product 7-(S-methylsulfonylimide)-2-(trifluoromethyl)-9H-indeno. [2,1-d]pyrimidin-9-one (67, 2.25 mg, yield 4.5%). ESI[M+H] + =328.2 1 H NMR (600MHz, DMSO-d 6 ) 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).
实施例68:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲醛的合成
Example 68: Synthesis of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbaldehyde
第一步:7-(羟甲基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮(68-a)Step 1: 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (68-a)
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸甲酯(50，350mg，1.14mmol)溶于超干二氯甲烷(10ml)，氮气保护下于0℃加入二异丁基氢化铝(1M，3.4ml，3.42mmol)，0℃反应1小时。加入饱和氯化铵溶液淬灭，二氯甲烷萃取，有机相无水硫酸镁干燥，过滤，滤液减压浓缩后得目标产物7-(羟甲基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(68-a，75mg，收率21.7％)。ESI[M+H]+＝281.19-Oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (50, 350 mg, 1.14 mmol) was dissolved in ultradry dichloromethane ( 10 ml), add diisobutylaluminum hydride (1M, 3.4 ml, 3.42 mmol) at 0°C under nitrogen protection, and react at 0°C for 1 hour. Add saturated ammonium chloride solution to quench, extract with dichloromethane, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product 7-(hydroxymethyl)-2-(trifluoromethyl)-9H. -Indeno[2,1-d]pyrimidin-9-one (68-a, 75 mg, yield 21.7%). ESI[M+H] + =281.1
第二步:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲醛(68) Step 2: 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbaldehyde (68)
将7-(羟甲基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(68-a，75mg，0.268mmol)溶于1,4-二氧六环(5ml)，加入二氧化锰(233mg，2.68mmol)，100℃反应过夜。过滤除去二氧化锰，滤液减压浓缩后得目标产物9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-甲醛(68，34mg，收率45.9％)。ESI[M+H]+＝278.91H 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).Dissolve 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (68-a, 75 mg, 0.268 mmol) in 1,4- dioxane (5 ml), add manganese dioxide (233 mg, 2.68 mmol), and react at 100°C overnight. Manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbaldehyde (68, 34 mg, collected rate 45.9%). ESI[M+H] + =278.9 1 H NMR (400MHz, DMSO-d 6 )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).
实施例69:7-(1-羟乙基)-9-甲基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-醇的合成
Example 69: Synthesis of 7-(1-hydroxyethyl)-9-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-ol
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-甲醛(68，34mg，0.122mmol)溶于超干四氢呋喃(4ml)，氮气保护下于0℃加入甲基溴化镁(1M，98μl，0.0978mmol)，0℃反应2小时。加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相无水硫酸镁干燥，过滤，滤液减压浓缩后制备纯化得目标产物7-(1-羟乙基)-9-甲基-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-醇(69，0.74mg，收率1.9％)。ESI[M+H]+＝311.1,ESI[M+Na]+＝333.1,ESI[2M+Na]+＝643.31H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbaldehyde (68, 34 mg, 0.122 mmol) in ultra-dry tetrahydrofuran (4 ml) under nitrogen protection Add methylmagnesium bromide (1M, 98 μl, 0.0978 mmol) at 0°C and react at 0°C for 2 hours. Add saturated ammonium chloride solution to quench, extract with ethyl acetate, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to prepare and purify the target product 7-(1-hydroxyethyl)-9-methyl-2. -(Trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-ol (69, 0.74 mg, yield 1.9%). ESI[M+H] + =311.1, ESI[M+Na] + =333.1, ESI[2M+Na] + =643.3 1 H NMR (600MHz, DMSO-d 6 ) δ9.38 (s, 1H), 7.96 (d,J＝7.8Hz,1H),7.67(d,J＝4.3Hz,1H),7.47(t,J＝9.0Hz,1H),6.09(d,J＝1.8Hz,1H),5.34(d ,J＝4.1Hz,1H),4.82(dd,J＝10.6,5.3Hz,1H),1.61(s,3H),1.37(d,J＝6.4Hz,3H).
实施例70:N-(甲基-d3)-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲酰胺的合成
Example 70: Synthesis of N-(methyl-d 3 )-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸(51，55mg，0.187mmol)溶于二氯甲烷(5ml)，加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(107mg，0.282mmol)，N,N-二异丙基乙胺(81μl，0.468mmol)和氘代甲胺盐酸盐(13mg，0.187mmol)，室温反应1小时。加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相减压浓缩后制备纯化得目标产物N-(甲基-d3)-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-甲酰胺(70，3.74mg，收率6.4％)。ESI[M+H]+＝311.21H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 55 mg, 0.187 mmol) in dichloromethane (5 ml), and add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (107mg, 0.282mmol), N,N-diisopropyl Ethylamine (81 μl, 0.468 mmol) and deuterated methylamine hydrochloride (13 mg, 0.187 mmol) were reacted at room temperature for 1 hour. Add saturated ammonium chloride solution to quench, extract with ethyl acetate, and concentrate the organic phase under reduced pressure to prepare and purify the target product N-(methyl-d 3 )-9-oxo-2-(trifluoromethyl)-9H. -Indeno[2,1-d]pyrimidine-7-carboxamide (70, 3.74 mg, yield 6.4%). ESI[M+H] + =311.2 1 H NMR(400MHz, DMSO-d 6 )δ9.64(s,1H),8.75(s,1H),8.29–8.22(m,2H),8.16(d,J =7.9Hz,1H).
实施例71:7-(溴甲基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 71: Synthesis of 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-甲基-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的合成(71-a)Step 1: Synthesis of 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (71-a)
将2-溴-5-甲基苯甲醛(1g，5.02mmol)，2-(三氟甲基)嘧啶-5-基硼酸(I-1，1.16g，6.03mmol)，碳酸钾(0.83g，6.03mmol)和1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(200mg，0.242mmol)置于反应瓶中，加入N,N-二甲基甲酰胺(100ml)，氮气置换，100℃反应过夜。加水淬灭，乙酸乙酯萃取，有机相无水硫酸镁干燥，过滤，滤液减压浓缩，剩余物硅胶柱纯化得目标产物5-甲基-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(71-a，0.58g,收率40.0％)。ESI[M+H]+＝267.02-Bromo-5-methylbenzaldehyde (1g, 5.02mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 1.16g, 6.03mmol), potassium carbonate (0.83g, 6.03mmol) and 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (200mg, 0.242mmol) were placed in the reaction bottle, and N,N-dimethyl was added formamide (100 ml), nitrogen replacement, and reaction at 100°C overnight. Add water to quench, extract with ethyl acetate, dry the organic phase over anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue on a silica gel column to obtain the target product 5-methyl-2-(2-(trifluoromethyl)pyrimidine- 5-yl)benzaldehyde (71-a, 0.58g, yield 40.0%). ESI[M+H] + =267.0
第二步:7-甲基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成(71-b)Step 2: Synthesis of 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71-b)
将5-甲基-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(71-a，0.5g，1.88mmol)溶于1,2-二氯乙烷(10ml)，加入四丁基碘化铵(35mg，0.095mmol)和叔丁基过氧化氢(543mg，6.03mmol)，于封管中100℃反应过夜。反应液减压浓缩后制备板纯化得目标产物7-甲基-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(71-b，120mg,收率24.0％)。ESI[M+H]+ ＝265.0Dissolve 5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (71-a, 0.5g, 1.88mmol) in 1,2-dichloroethane (10ml), Add tetrabutylammonium iodide (35 mg, 0.095 mmol) and tert-butyl hydroperoxide (543 mg, 6.03 mmol), and react overnight at 100°C in a sealed tube. The reaction solution was concentrated under reduced pressure and purified using a preparatory plate to obtain the target product 7-methyl-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71-b, 120 mg, collected rate 24.0%). ESI[M+H] + =265.0
第三步:7-(溴甲基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成(71)Step 3: Synthesis of 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71)
将7-(甲基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(71-b，120mg，0.45mmol)溶于四氯化碳(10mL)，加入N-溴代丁二酰亚胺(105.2mg，0.59mmol)和偶氮二异丁腈(20mg，0.09mmol)，85℃反应过夜。反应液减压浓缩后直接硅胶柱层析纯化得目标产物7-(溴甲基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(71，60mg，收率39.0％)。ESI[M+H]+＝343.01H 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).Dissolve 7-(methyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71-b, 120 mg, 0.45 mmol) in carbon tetrachloride ( 10 mL), add N-bromosuccinimide (105.2 mg, 0.59 mmol) and azobisisobutyronitrile (20 mg, 0.09 mmol), and react at 85°C overnight. The reaction solution was concentrated under reduced pressure and directly purified by silica gel column chromatography to obtain the target product 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71 , 60mg, yield 39.0%). ESI[M+H] + =343.0 1 H NMR (400MHz, CCl 3 D) 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).
实施例72:7-(羟甲基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 72: Synthesis of 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
将7-(溴甲基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(71，60mg，0.175mmol)溶于乙腈(4ml)，加入氰化亚铜(10.24mg，0.0875mmol)，75℃反应0.5小时。经制备板纯化得到副产物7-(羟甲基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(72，1.16mg，收率2.4％)。ESI[M+H]+＝281.01H 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).Dissolve 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71, 60 mg, 0.175 mmol) in acetonitrile (4 ml), and add Cuprous cyanide (10.24 mg, 0.0875 mmol), react at 75°C for 0.5 hours. The by-product 7-(hydroxymethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (72, 1.16 mg, yield 2.4%) was obtained after purification using the preparation plate. ). ESI[M+H] + =281.0 1 H NMR (400MHz, CCl 3 D) 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).
实施例73:6-氟-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-腈的合成
Example 73: Synthesis of 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile
第一步:4-溴-5-(二溴甲基)-2-氟苯甲腈的合成(73-a)Step 1: Synthesis of 4-bromo-5-(dibromomethyl)-2-fluorobenzonitrile (73-a)
将4-溴-2-氟-5-甲基苯甲腈(2.12g，9.91mmol)溶于四氯化碳(40mL)，加入N-溴代丁二酰亚胺(4.52g，25.39mmol)和偶氮二异丁腈(555mg，3.38mmol)，85℃反应过夜。反应液减压浓缩后直接硅胶柱层析纯化得目标产物4-溴-5-(二溴甲基)-2-氟苯甲腈(73-a，1.2g，收率32.0％)。ESI[M+H]+＝370.0Dissolve 4-bromo-2-fluoro-5-methylbenzonitrile (2.12g, 9.91mmol) in carbon tetrachloride (40mL), and add N-bromosuccinimide (4.52g, 25.39mmol) and azobisisobutyronitrile (555 mg, 3.38 mmol), and reacted at 85°C overnight. The reaction solution was concentrated under reduced pressure and directly purified by silica gel column chromatography to obtain the target product 4-bromo-5-(dibromomethyl)-2-fluorobenzonitrile (73-a, 1.2 g, yield 32.0%). ESI[M+H] + =370.0
第二步:4-溴-2-氟-5-甲酰基苯甲腈的合成(73-b)Step 2: Synthesis of 4-bromo-2-fluoro-5-formylbenzonitrile (73-b)
将4-溴-5-(二溴甲基)-2-氟苯甲腈(73-a，600mg,1.63mmol)溶于乙醇/水(10ml/10ml)，加入硝酸银(0.55g，3.26mmol)，室温反应2小时。过滤除去固体，滤液减压浓缩后经硅胶柱层析(乙酸乙酯：石油醚＝0％～20％)纯化得目标产物4-溴-2-氟-5-甲酰基苯甲腈(73-b，300mg，收率81.0％)。ESI[M+H]+＝228.0Dissolve 4-bromo-5-(dibromomethyl)-2-fluorobenzonitrile (73-a, 600mg, 1.63mmol) in ethanol/water (10ml/10ml), add silver nitrate (0.55g, 3.26mmol) ), react 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-formylbenzonitrile (73- b, 300 mg, yield 81.0%). ESI[M+H] + =228.0
第三步:2-氟-5-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈的合成(73-c)Step 3: Synthesis of 2-fluoro-5-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (73-c)
将4-溴-2-氟-5-甲酰基苯甲腈(73-b，100mg，0.44mmol)，2-(三氟甲基)嘧啶-5-基硼酸(I-1，101mg，0.53mmol)，磷酸钾(280mg，1.32mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(16mg，0.022mmol)置于反应瓶中，加入乙腈(5ml)，氮气置换，95℃反应18小时。将反应液过滤去除不溶物，滤液减压浓缩，剩余物硅胶柱层析纯化得目标产物2-氟-5-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(73-c，70mg,收率54.0％)。ESI[M+H]+＝296.04-Bromo-2-fluoro-5-formylbenzonitrile (73-b, 100mg, 0.44mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (I-1, 101mg, 0.53mmol) ), potassium phosphate (280mg, 1.32mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16mg, 0.022mmol) were placed in the reaction flask, and acetonitrile (5ml) was added , nitrogen replacement, reaction at 95°C for 18 hours. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product 2-fluoro-5-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzene. Carbonitrile (73-c, 70 mg, yield 54.0%). ESI[M+H] + =296.0
第四步:6-氟-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-腈的合成(73)Step 4: Synthesis of 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-nitrile (73)
将2-氟-5-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯甲腈(73-c，70mg，0.24mmol)溶于1,2-二氯乙烷(6ml)，加入四丁基碘化铵(4.4mg，0.012mmol)和叔丁基过氧化氢(123mg，0.96mmol)，于封管中100℃反应2小时。反应液减压浓缩后制备板纯化得目标产物6-氟-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-腈(73，10mg,收率14.0％)。ESI[M+H]+＝294.01H NMR(400MHz,CDCl3)δ9.30(s,1H),8.18(d,J＝5.8Hz,1H),7.68(d,J＝7.6Hz,1H).Dissolve 2-fluoro-5-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)benzonitrile (73-c, 70 mg, 0.24 mmol) in 1,2-dichloroethane (6 ml), add tetrabutylammonium iodide (4.4 mg, 0.012 mmol) and tert-butyl hydroperoxide (123 mg, 0.96 mmol), and react in a sealed tube at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified using a preparative plate to obtain the target product 6-fluoro-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (73, 10 mg , yield 14.0%). ESI[M+H] + =294.0 1 H NMR (400MHz, CDCl 3 ) δ9.30 (s, 1H), 8.18 (d, J = 5.8Hz, 1H), 7.68 (d, J = 7.6Hz, 1H) .
实施例74:2-(9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-基)乙酸的合成
Example 74: Synthesis of 2-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetic acid
将7-(溴甲基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(71，60mg，0.175mmol)溶于乙腈(4ml)，加入氰化亚铜(10.24mg，0.0875mmol)，75℃反应0.5小时。经制备板纯化得到产物2-(9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-基)乙酸(74，1.40mg，收率2.6％)。ESI[M+H]+＝309.01H 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).Dissolve 7-(bromomethyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (71, 60 mg, 0.175 mmol) in acetonitrile (4 ml), and add Cuprous cyanide (10.24 mg, 0.0875 mmol), react at 75°C for 0.5 hours. The product 2-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetic acid (74, 1.40 mg, yield 2.6 %). ESI[M+H] + =309.0 1 H NMR (400MHz, CDCl 3 ) δ12.16(s,1H),9.21(s,1H),9.21(s,1H),8.55(s,1H),8.47( d,J＝7.8Hz,1H),7.82(d,J＝1.1Hz,1H),4.69(s,2H).
实施例75:9-氧代-7-苯基-9H-茚并[1，2-b]吡嗪-2，3-二腈的合成
Example 75: Synthesis of 9-oxo-7-phenyl-9H-indeno[1,2-b]pyrazine-2,3-diconitrile
第一步:7-氯-9-氧-9H-茚并[1，2-b]吡嗪-2，3-二腈的合成(75-a)Step 1: Synthesis of 7-chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-diconitrile (75-a)
将7-氯-9H-茚并[1，2-b]吡嗪-2,3-二腈(2.8g，11.08mmol)加入乙酸(30ml)中，再加入重铬酸钾(5.87g，19.95mmol)溶于乙酸(50ml)和水(15ml)的溶液缓慢升温至100℃下反应1小时，后用碳酸氢钠溶液淬灭，后用乙酸乙酯萃取，减压浓缩后粗品经硅胶色谱法纯化(乙酸乙酯：石油醚＝1：4)得目标产物7-氯-9-氧-9H-茚并[1，2-b]吡嗪-2,3-二腈(75-a，700mg,收率23.69％)。Add 7-chloro-9H-indeno[1,2-b]pyrazine-2,3-diconitrile (2.8g, 11.08mmol) to acetic acid (30ml), and then add potassium dichromate (5.87g, 19.95 mmol) dissolved in acetic acid (50ml) and water (15ml) slowly heated to 100°C and reacted for 1 hour, then quenched with sodium bicarbonate solution, extracted with ethyl acetate, concentrated under reduced pressure, and the crude product was subjected to silica gel chromatography Purification (ethyl acetate: petroleum ether = 1:4) gave the target product 7-chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-diconitrile (75-a, 700 mg , yield 23.69%).
第二步:9-氧代-7-苯基-9H-茚并[1，2-d]吡嗪-2，3-二腈的合成(75)Step 2: Synthesis of 9-oxo-7-phenyl-9H-indeno[1,2-d]pyrazine-2,3-diconitrile (75)
将7-氯-9-氧-9H-茚并[1，2-b]吡嗪-2,3-二腈(75-a，30mg,0.113mmol)，苯基硼酸(21mg，0.159mmol)，醋酸钯(1mg,0.006mmol)和氟化钾(13mg，0.226mmol)溶于甲醇(2ml)，120℃下微波密闭反应30分钟。反应液过滤，减压浓缩后粗品经液相制备法纯化得目标产物9-氧代-7-苯基-9H-茚并[1，2-b]吡嗪-2,3-二腈(75，0.8mg,收率2.31％)。1H 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)7-Chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-diconitrile (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 the reaction was sealed under microwave at 120°C for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by a liquid phase preparation method to obtain the target product 9-oxo-7-phenyl-9H-indeno[1,2-b]pyrazine-2,3-diconitrile (75 , 0.8mg, yield 2.31%). 1 H NMR (400MHz, DMSO-d 6 ) δ7.86 (d, J＝2.2Hz, 1H), 7.78 (dd, J＝8.3, 2.3Hz, 1H), 7.65–7.47 (m, 6H)
实施例76:7-硝基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 76: Preparation of 7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-硝基-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的合成(76-a)Step 1: Synthesis of 5-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (76-a)
将2-溴-5-硝基苯甲醛(200mg，0.869mmol)，(2-(三氟甲基)嘧啶-5-基)硼酸(250mg，1.3mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(31.8mg，0.043mmol)和磷酸钾(553mg，2.6mmol)溶于乙腈(15ml)，氮气保护微波反应40分钟。反应液过滤，减压浓缩后粗品经硅胶色谱法纯化(乙酸乙酯：石油醚＝1：3)得目标产物5-硝基-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(76-a，185mg,收率71.59％)。(ESI)[M+H]+＝298.02-Bromo-5-nitrobenzaldehyde (200mg, 0.869mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (250mg, 1.3mmol), [1,1'-bis(di Phenylphosphino)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 reaction was carried out under nitrogen protection microwave for 40 minutes. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:3) to obtain the target product 5-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl). ) Benzaldehyde (76-a, 185 mg, yield 71.59%). (ESI)[M+H] + =298.0
第二步:7-硝基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(76)Step 2: Preparation of 7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (76)
将5-硝基-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(76-a，60mg，0.2mmol)溶于二氯乙烷(3ml)，加入70％含量的2-过氧化氢-2-甲基丙烷(156mg，1.21mmol)，四丁基碘化铵(4mg，0.01mmol)在氮气保护下100℃反应过夜。减压浓缩后粗品经制备硅胶板(石油醚：乙酸乙酯＝3:1)纯化得目标产物7-硝基-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(76，21.52mg,收率36.11％)。ESI[M+H]+＝296，1H 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).Dissolve 5-nitro-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (76-a, 60 mg, 0.2 mmol) in dichloroethane (3 ml), and add 70% of 2-Hydrogen peroxide-2-methylpropane (156 mg, 1.21 mmol) and tetrabutylammonium iodide (4 mg, 0.01 mmol) were reacted at 100°C overnight under nitrogen protection. After concentration under reduced pressure, the crude product was purified through a silica gel plate (petroleum ether: ethyl acetate = 3:1) to obtain the target product 7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d] Pyrimidin-9-one (76, 21.52 mg, yield 36.11%). ESI[M+H] + =296, 1 H NMR (600MHz, DMSO-d 6 ) δ9.80 (s, 1H), 8.69 (d, J = 7.8Hz, 1H), 8.45 (s, 1H), 8.37 (d,J＝8.3Hz,1H).
实施例77:7-氨基-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 77: Preparation of 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
将7-硝基-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(76，30mg，0.1mmol)溶于乙酸(2ml)，加入铁粉(22.7mg，0.4mmol)。在氮气保护下75℃反应过夜。反应液过滤，减压浓缩后粗品经制备硅胶板(石油醚：乙酸乙酯＝1:1)纯化得目标产物7-氨基-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(77，18.5mg,收率51.48％)。1H 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)Dissolve 7-nitro-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (76, 30 mg, 0.1 mmol) in acetic acid (2 ml), and add iron powder ( 22.7 mg, 0.4 mmol). React overnight at 75°C under nitrogen protection. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified through a silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 7-amino-2-(trifluoromethyl)-9H-indeno[2,1 -d]pyrimidin-9-one (77, 18.5 mg, yield 51.48%). 1 H NMR (600MHz, DMSO-d 6 ) δ9.15 (s, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 6.16 (d, J = 8.5Hz, 2H)
实施例78:N-(9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-基)乙酰胺的制备
Example 78: Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide
将7-氨基-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(77，16mg，0.06mmol)溶于二氯乙烷(1ml)，加入三乙胺(12mg，0.12mmol)，乙酰氯(5.7mg，0.072mmol)在氮气保护下室温反应4小时。反应液在0℃下用水淬灭反应，用二氯甲烷萃取，有机相经无水硫酸钠干燥后过滤，减压浓缩后粗品经制备法纯化得目标产物N-(9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-基)乙酰胺(78，8mg,收率43.16％)。ESI[M+H]+＝308.2，1H NMR(400MHz,DMSO-d6)δ10.42(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).Dissolve 7-amino-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (77, 16 mg, 0.06 mmol) in dichloroethane (1 ml), add tris Ethylamine (12 mg, 0.12 mmol) and acetyl chloride (5.7 mg, 0.072 mmol) were reacted at room temperature under nitrogen protection for 4 hours. The reaction solution was quenched with water at 0°C and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. After concentration under reduced pressure, the crude product was purified by the preparation method to obtain the target product N-(9-oxo-2- (Trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)acetamide (78, 8 mg, yield 43.16%). ESI[M+H] + =308.2, 1 H NMR (400MHz, DMSO-d 6 ) δ10.42 (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).
实施例79:2-甲氧基-7-((三氟甲基)磺酰基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 79: Preparation of 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:2-溴-5-((三氟甲基)硫代)苯甲醛的制备(79-a)Step 1: Preparation of 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (79-a)
将3-(三氟甲基)硫代)苯甲醛(400mg，1.94mmol)溶于二氯乙烷(15ml)，加入4-氯-2-(三氟甲基)苯胺(54.8μl，0.391mmol)，N-溴代琥珀酰亚胺(414mg，233mmol)，醋酸钯(44mg，0.192mmol)，三氟乙酸(4ml)，在氮气氛围下60℃过夜反应后，减压浓缩，粗品经硅胶色谱法纯化(99％石油醚)得到目标产物2-溴-5-((三氟甲基)硫代)苯甲醛(79-a，320mg，收率58.8％)。E5I[M+H]+＝285.1.Dissolve 3-(trifluoromethyl)thio)benzaldehyde (400mg, 1.94mmol) in dichloroethane (15ml), and add 4-chloro-2-(trifluoromethyl)aniline (54.8μl, 0.391mmol) ), N-bromosuccinimide (414 mg, 233 mmol), palladium acetate (44 mg, 0.192 mmol), trifluoroacetic acid (4 ml), react at 60°C overnight under nitrogen atmosphere, then concentrated under reduced pressure, and the crude product was subjected to silica gel chromatography Purification method (99% petroleum ether) gave the target product 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (79-a, 320 mg, yield 58.8%). E5I[M+H] + =285.1.
第二步：2-(2-甲氧基嘧啶-5-基)-5-((三氟甲基)硫代)苯甲醛的制备79-b)Step 2: Preparation of 2-(2-methoxypyrimidin-5-yl)-5-((trifluoromethyl)thio)benzaldehyde 79-b)
将2-溴-5-((三氟甲基)硫代)苯甲醛(79-a，320mg,1.12mmol)溶于1,4-二氧六环(10ml)，加入一滴水，加入(2-甲氧基嘧啶-5-基)硼酸(206mg，1.34mmol)，碳酸铯(776mg,2.68mmol),四(三苯基膦)钯(65.2mg,0.056mmol),在氮气氛围下120℃微波反应30分钟，过滤后滤液减压浓缩，粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝5:1)得到目标产物2-(2-甲氧基嘧啶-5-基)-5-((三氟甲基)硫代)苯甲醛(79-b，193mg,收率54.5％)。ESI[M+H]+＝315.1.Dissolve 2-bromo-5-((trifluoromethyl)thio)benzaldehyde (79-a, 320mg, 1.12mmol) in 1,4-dioxane (10ml), add a drop of water, and add (2 -Methoxypyrimidin-5-yl)boronic acid (206mg, 1.34mmol), cesium carbonate (776mg, 2.68mmol), tetrakis(triphenylphosphine)palladium (65.2mg, 0.056mmol), microwave at 120°C under nitrogen atmosphere React for 30 minutes. After filtration, the filtrate is concentrated under reduced pressure. The crude product is 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.
第三步:2-甲氧基-7-((三氟甲基)硫代)-9H-茚并[2，1-d]嘧啶-9-酮的制备(79-c)Step 3: Preparation of 2-methoxy-7-((trifluoromethyl)thio)-9H-indeno[2,1-d]pyrimidin-9-one (79-c)
将2-(2-甲氧基嘧啶-5-基)-5-((三氟甲基)硫代)苯甲醛(79-b，193mg,0.615mmol)溶于二氯乙烷(10ml)，加入叔丁基过氧化氢(346mg，3.69mmol)，四丁基碘化铵(11.8mg,0.308mmol),100℃下密闭反应过夜，减压浓缩后粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝3:1)得到目标产物2-甲氧基-7-((三氟甲基)硫代)-9H-茚并[2,1-d]嘧啶-9-酮(79-c,140mg,收率73.1％)。ESI[M+H]+＝313.1.Dissolve 2-(2-methoxypyrimidin-5-yl)-5-((trifluoromethyl)thio)benzaldehyde (79-b, 193 mg, 0.615 mmol) in dichloroethane (10 ml), Add tert-butyl hydroperoxide (346 mg, 3.69 mmol) and tetrabutylammonium iodide (11.8 mg, 0.308 mmol), and perform a sealed reaction at 100°C overnight. After concentration under reduced pressure, the crude product is purified by silica gel chromatography (petroleum ether: acetic acid). Ethyl ester = 3:1) to obtain the target product 2-methoxy-7-((trifluoromethyl)thio)-9H-indeno[2,1-d]pyrimidin-9-one (79-c, 140mg, yield 73.1%). ESI[M+H] + =313.1.
第四步:2-甲氧基-7-((三氟甲基)磺酰基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(79)Step 4: Preparation of 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (79)
将2-甲氧基-7-((三氟甲基)硫代)-9H-茚并[2,1-d]嘧啶-9-酮(79-c，10mg,0.320mmol)溶于二氯乙烷(2ml)， 加入间氯过氧苯甲酸(11mg，0.640mmol)，室温下过夜反应后，减压浓缩，粗品经高效制备液相纯化(甲醇：0.1％甲酸水溶液＝9：1)得到目标产物2-甲氧基-7-((三氟甲基)磺酰基)-9H-茚并[2,1-d]嘧啶-9-酮(79，1.2mg，收率10.9％)。ESI[M+H]+＝345.1.1H 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).Dissolve 2-methoxy-7-((trifluoromethyl)thio)-9H-indeno[2,1-d]pyrimidin-9-one (79-c, 10 mg, 0.320 mmol) in dichloro Ethane (2ml), Add m-chloroperoxybenzoic acid (11 mg, 0.640 mmol), react at room temperature overnight, and then concentrate under reduced pressure. The crude product is purified by high-efficiency preparative liquid phase (methanol: 0.1% formic acid aqueous solution = 9:1) to obtain the target product 2-methoxy. Base-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (79, 1.2 mg, yield 10.9%). ESI[M+H] + =345.1. 1 H NMR (400MHz, DMSO-d 6 ) 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).
实施例80:2，7-二氯-4-羟基-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 80: Preparation of 2,7-dichloro-4-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-氯-2-(2，4-二氯嘧啶-5-基)苯甲醛的制备(80-a)Step 1: Preparation of 5-chloro-2-(2,4-dichloropyrimidin-5-yl)benzaldehyde (80-a)
将2,4-二氯-5-碘嘧啶(500mg，1.82mmol)溶于仲丁醇(10ml)，加入4-氯-2-醛基苯硼酸(436mg，2.36mmol)，氟化钾(211.4mg,3.64mmol)和醋酸钯(20.4mg,0.091mmol)，氮气保护，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(甲醇：二氯甲烷＝0％～50％)纯化得目标产物5-氯-2-(2,4-二氯嘧啶-5-基)苯甲醛(80-a，194.8mg，收率37.45％).ESI[M+H]+＝287.0，289.0.Dissolve 2,4-dichloro-5-iodopyrimidine (500mg, 1.82mmol) in sec-butanol (10ml), add 4-chloro-2-aldehyde phenylboronic acid (436mg, 2.36mmol), potassium fluoride (211.4 mg, 3.64mmol) and palladium acetate (20.4mg, 0.091mmol), nitrogen protection, microwave reaction at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified using a Flash column (methanol: dichloromethane = 0% to 50%) to obtain the target product 5-chloro-2-(2,4-dichloropyrimidin-5-yl)benzaldehyde (80 -a, 194.8mg, yield 37.45%).ESI[M+H] + =287.0, 289.0.
第二步:2，7-二氯-4-羟基-9H-茚并[2，1-d]嘧啶-9-酮的制备(80)Step 2: Preparation of 2,7-dichloro-4-hydroxy-9H-indeno[2,1-d]pyrimidin-9-one (80)
将5-氯-2-(2,4-二氯嘧啶-5-基)苯甲醛(80-a，100mg，0.34mmol)溶于1,2-二氯乙烷(10ml)，加入四丁基碘化铵(6.46mg，0.02mmol)和叔丁基过氧化氢(270μl，2.72mmol)，在氮气保护下于封管中100℃反应16小时。减压蒸干溶剂，剩余物Flash柱(乙酸乙酯：石油醚＝0％～20％)纯化后再进行液相制备纯化得目标产物2,7-二氯-4-羟基-9H-茚并[2,1-d]嘧啶-9-酮(80，3.95mg，收率4.24％)。ESI[M+H]+＝267.0，269.0.1H 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).Dissolve 5-chloro-2-(2,4-dichloropyrimidin-5-yl)benzaldehyde (80-a, 100mg, 0.34mmol) in 1,2-dichloroethane (10ml), add tetrabutyl Ammonium iodide (6.46 mg, 0.02 mmol) and tert-butyl hydroperoxide (270 μl, 2.72 mmol) were reacted in a sealed tube at 100°C for 16 hours under nitrogen protection. The solvent was evaporated to dryness under reduced pressure, and the residue was purified using a Flash column (ethyl acetate: petroleum ether = 0% to 20%) and then subjected to liquid phase preparation and purification to obtain the target product 2,7-dichloro-4-hydroxy-9H-indeno. [2,1-d]pyrimidin-9-one (80, 3.95 mg, yield 4.24%). ESI[M+H] + =267.0, 269.0. 1 H NMR (400MHz, DMSO-d 6 ) δ8.15–8.08 (m, 1H), 8.24 (d, J = 2.3Hz, 1H), 8.59 (d, J＝8.6Hz,1H),9.76(s,1H).
实施例81:2-羟基-7-((三氟甲基)磺酰基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 81: Preparation of 2-hydroxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one
向2-甲氧基-7-((三氟甲基)磺酰基)-9H-茚并[2,1-d]嘧啶-9-酮(79，15mg,0.436mmol)中加入甲酸(2ml)，盐酸(50μl)，80℃下反应5小时后，减压浓缩，粗品经高效制备液相纯化(甲醇：0.1％甲酸水溶液＝9：1)得到目标产物2-羟基-7-((三氟甲基)磺酰基)-9H-茚并[2,1-d]嘧啶-9-酮(81，1.08mg，收率7.5％)。ESI[M+H]+＝331.1.To 2-methoxy-7-((trifluoromethyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (79, 15 mg, 0.436 mmol) was added formic acid (2 ml) , hydrochloric acid (50 μl), reacted at 80°C for 5 hours, concentrated under reduced pressure, and the crude product was purified by high-efficiency preparative liquid phase (methanol: 0.1% formic acid aqueous solution = 9:1) to obtain the target product 2-hydroxy-7-(trifluoro Methyl)sulfonyl)-9H-indeno[2,1-d]pyrimidin-9-one (81, 1.08 mg, yield 7.5%). ESI[M+H] + =331.1.
实施例82:N、N-二甲基-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲酰胺的制备
Example 82: Preparation of N, N-dimethyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide
第一步:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-羧酸的制备(82-a)Step 1: Preparation of 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (82-a)
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸甲酯(40mg,0.130mmol)溶于四氢呋喃(5ml)，加入水(1ml),0℃下，缓慢加入一水合氢氧化锂(10.9mg，0.260mmol)，室温反应4小时后，用1M盐酸溶液调节PH至中性，加入水(5ml),用乙酸乙酯萃取，有机相经无水硫酸钠干燥后，过滤后减压浓缩得到目标产物9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸(82-a，24mg，收率63.2％)。ESI[M+H]+＝295.2.Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid methyl ester (40 mg, 0.130 mmol) in tetrahydrofuran (5 ml), and add water ( 1ml), slowly add lithium hydroxide monohydrate (10.9mg, 0.260mmol) at 0°C, react at room temperature for 4 hours, adjust the pH to neutral with 1M hydrochloric acid solution, add water (5ml), and extract with ethyl acetate. After the organic phase was 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%). ESI[M+H] + =295.2.
第二步:N、N-二甲基-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-甲酰胺的制备(82)Step 2: Preparation of N, N-dimethyl-9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxamide (82)
0℃下，将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸(82-a，12mg,0.0408mmol)溶于二氯乙烷(3ml)，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(14.7mg,0.0490mmol),搅拌10分钟后，加入盐酸二甲胺(3.4mg，0.0408mmo),N,N-二异丙基乙胺(24.4μl，0.122mmol)，室温下反应4小时后减压浓缩，粗品经高效制备液相纯化(乙腈：0.1％甲酸水溶液＝9：1)得到目标产物N、N-二甲基-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-甲酰胺(82，1.49mg，收率11.4％)。ESI[M+H]+＝322.2.Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (82-a, 12 mg, 0.0408 mmol) in dichloro Ethane (3ml), add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (14.7mg, 0.0490mmol), stir for 10 minutes Afterwards, add dimethylamine hydrochloride (3.4mg, 0.0408mmo) and N,N-diisopropylethylamine (24.4μl, 0.122mmol), react at room temperature for 4 hours and then concentrate under reduced pressure. The crude product is purified by high-efficiency preparative liquid phase. (Acetonitrile: 0.1% formic acid aqueous solution = 9:1) 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.
实施例83:7-氯-2-甲氧基-4-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 83: Preparation of 7-chloro-2-methoxy-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-溴-2-甲氧基-4-(三氟甲基)嘧啶的制备(83-a)Step 1: Preparation of 5-bromo-2-methoxy-4-(trifluoromethyl)pyrimidine (83-a)
将5-溴-4-(三氟甲基)嘧啶-2-醇(470mg,1.943mmol)溶于四氢呋喃(10ml)，加入苯并三唑-1-三(三甲氨基)-六氟磷酸酯(1.7g,3.89mmol),搅拌10分钟后加入甲醇(1.6ml，38.9mmol),碳酸铯(2.5g,7.77mmol)，室温下反应2小时后过滤，滤液减压浓缩，粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝10:1)得到目标产物5-溴-2-甲氧基-4-(三氟甲基)嘧啶(83-a，195mg，收率44.4％)。ESI[M+H]+＝257.2.Dissolve 5-bromo-4-(trifluoromethyl)pyrimidin-2-ol (470 mg, 1.943 mmol) in tetrahydrofuran (10 ml), and add benzotriazole-1-tris(trimethylamino)-hexafluorophosphate ( 1.7g, 3.89mmol), stir for 10 minutes, add methanol (1.6ml, 38.9mmol) and cesium carbonate (2.5g, 7.77mmol), react at room temperature for 2 hours and then filter, the filtrate is concentrated under reduced pressure, and the crude product is purified by silica gel chromatography. (Petroleum ether: ethyl acetate = 10:1) to obtain the target product 5-bromo-2-methoxy-4-(trifluoromethyl)pyrimidine (83-a, 195 mg, yield 44.4%). ESI[M+H] + =257.2.
第二步:5-氯-2-(2-甲氧基-4-(三氟甲基)嘧啶-5-基)苯甲醛的制备(83-b)Step 2: Preparation of 5-chloro-2-(2-methoxy-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (83-b)
将5-溴-2-甲氧基-4-(三氟甲基)嘧啶(83-a，195mg,0.863mmol)溶于1,4-二氧六环(5ml)，加入一滴水，(4-氯-2-甲酰基苯基)硼酸(159mg,0.863mmol),碳酸铯(562mg，1.73mmol),四三苯基磷钯(50mg,0.432mmol)，在氮气氛围下120℃微波反应30分钟后，减压浓缩，粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝4:1)得到目标产物5-氯-2-(2-甲氧基-4-(三氟甲基)嘧啶-5-基)苯甲醛(83-b，250mg，收率91.5％)。ESI[M+H]+＝317.2.Dissolve 5-bromo-2-methoxy-4-(trifluoromethyl)pyrimidine (83-a, 195mg, 0.863mmol) in 1,4-dioxane (5ml), add a drop of water, (4 -Chloro-2-formylphenyl)boronic acid (159mg, 0.863mmol), cesium carbonate (562mg, 1.73mmol), tetrakis triphenylphosphorus palladium (50mg, 0.432mmol), microwave reaction at 120°C for 30 minutes under nitrogen atmosphere Afterwards, it was concentrated under reduced pressure, and 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)pyrimidine- 5-yl)benzaldehyde (83-b, 250 mg, yield 91.5%). ESI[M+H] + =317.2.
第三步:7-氯-2-甲氧基-4-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(83)Step 3: Preparation of 7-chloro-2-methoxy-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (83)
将5-氯-2-(2-甲氧基-4-(三氟甲基)嘧啶-5-基)苯甲醛(83-b，104mg,3.29mmol)溶于二氯乙烷(5ml)，加入叔丁基过氧化氢(237mg，26.3mmol)，四丁基碘化铵(6mg,0.165mmol),100℃下密闭反应过夜，减压浓缩后粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝3:1)得到目标产物7-氯-2-甲氧基-4-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(83,14mg,收率63.6％)。ESI[M+H]+＝315.3.Dissolve 5-chloro-2-(2-methoxy-4-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (83-b, 104 mg, 3.29 mmol) in dichloroethane (5 ml), Add tert-butyl hydroperoxide (237 mg, 26.3 mmol) and tetrabutylammonium iodide (6 mg, 0.165 mmol), conduct a sealed reaction at 100°C overnight, and concentrate under reduced pressure. The crude product is purified by silica gel chromatography (petroleum ether: ethyl acetate). Ester=3:1) to obtain the target product 7-chloro-2-methoxy-4-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (83,14 mg, collected rate 63.6%). ESI[M+H] + =315.3.
实施例84：7-氯-2-(噻唑-5-基)-9H-茚并[2,1-d]嘧啶-9-酮的制备
Example 84: Preparation of 7-chloro-2-(thiazol-5-yl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:5-(5-溴嘧啶-2-基)噻唑的制备(84-a)Step 1: Preparation of 5-(5-bromopyrimidin-2-yl)thiazole (84-a)
将5-溴-2-碘嘧啶(300mg,1.05mmol)溶于甲苯(5ml)，加入5-(三丁基锡基)噻唑(394mg，1.05mmol)，三苯基膦(27.6mg,0.105mmol),双三苯基膦二氯化钯(37mg,0.0527mmol)，在氮气氛围120℃下反应过夜，减压浓缩后粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝3:1)得到目标产物5-(5-溴嘧啶-2-基)噻唑(84-a,115mg,收率45.3％)。ESI[M+H]+＝242.2.Dissolve 5-bromo-2-iodopyrimidine (300mg, 1.05mmol) in toluene (5ml), add 5-(tributyltinyl)thiazole (394mg, 1.05mmol), triphenylphosphine (27.6mg, 0.105mmol), Bistriphenylphosphine palladium dichloride (37 mg, 0.0527 mmol) was reacted overnight at 120°C in 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.
第二步:5-氯-2-(2-(噻唑-5-基)嘧啶-5-基)苯甲醛的制备(84-b)Step 2: Preparation of 5-chloro-2-(2-(thiazol-5-yl)pyrimidin-5-yl)benzaldehyde (84-b)
将5-(5-溴嘧啶-2-基)噻唑(84-a，115mg,0.477mmol)溶于乙腈(5ml)，加入(4-氯-2-甲酰基苯基)硼酸(131mg，0.716mmol)，氟化钾(55.5mg,0.954mmol),醋酸钯(5.4mg,0.0224mmol)，在氮气氛围下120℃下微波反应45分钟，减压浓缩后粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝3:1)得到目标产物5-氯-2-(2-(噻唑-5-基)嘧啶-5-基)苯甲醛(84-b,10mg,收率7.1％)。(ESI)[M+H]+＝302.2. Dissolve 5-(5-bromopyrimidin-2-yl)thiazole (84-a, 115mg, 0.477mmol) in acetonitrile (5ml), and add (4-chloro-2-formylphenyl)boronic acid (131mg, 0.716mmol) ), potassium fluoride (55.5mg, 0.954mmol), palladium acetate (5.4mg, 0.0224mmol), microwave reaction at 120°C for 45 minutes under nitrogen atmosphere, concentrate under reduced pressure and the crude product is purified by silica gel chromatography (petroleum ether: acetic acid Ethyl ester = 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.
第三步:7-氯-2-(噻唑-5-基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(84)Step 3: Preparation of 7-chloro-2-(thiazol-5-yl)-9H-indeno[2,1-d]pyrimidin-9-one (84)
将5-氯-2-(2-(噻唑-5-基)嘧啶-5-基)苯甲醛(84-b，10mg,0.0332mmol)溶于二氯乙烷(5ml)，加入叔丁基过氧化氢(23mg，0.266mmol)，四丁基碘化铵(0.6mg,0.00166mmol),100℃下密闭反应过夜，减压浓缩后粗品经高效制备液相法纯化(乙腈：0.1％甲酸水溶液＝9：1)得到目标产物7-氯-2-(噻唑-5-基)-9H-茚并[2,1-d]嘧啶-9-酮(84,0.73mg,收率6.5％)。ESI[M+H]+＝300.0.Dissolve 5-chloro-2-(2-(thiazol-5-yl)pyrimidin-5-yl)benzaldehyde (84-b, 10 mg, 0.0332 mmol) in dichloroethane (5 ml), add tert-butyl alcohol Hydrogen oxide (23 mg, 0.266 mmol), tetrabutylammonium iodide (0.6 mg, 0.00166 mmol), sealed reaction at 100°C overnight, concentrated under reduced pressure, the crude product was purified by high-efficiency preparative liquid phase method (acetonitrile: 0.1% formic acid aqueous solution = 9:1) The target product 7-chloro-2-(thiazol-5-yl)-9H-indeno[2,1-d]pyrimidin-9-one (84, 0.73 mg, yield 6.5%) was obtained. ESI[M+H] + =300.0.
实施例85:7-氯-2-(噻唑-2-基)-9H-茚并[2，1-d]嘧啶-9-酮的制备
Example 85: Preparation of 7-chloro-2-(thiazol-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步：2-(5-溴嘧啶-2-基)噻唑的制备85-a)Step 1: Preparation of 2-(5-bromopyrimidin-2-yl)thiazole 85-a)
将5-溴-2-碘嘧啶(114mg,0.400mmol)溶于甲苯(5ml)，加入2-(三丁基锡基)噻唑(150mg，0.400mmol)，三苯基膦(10.5mg,0.040mmol),双三苯基膦二氯化钯(14.1mg,0.02mmol)，在氮气氛围120℃下反应过夜，减压浓缩后粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝3:1)得到目标产物2-(5-溴嘧啶-2-基)噻唑(85-a,75mg,收率77.8％)。ESI[M+H]+＝242.2.Dissolve 5-bromo-2-iodopyrimidine (114mg, 0.400mmol) in toluene (5ml), add 2-(tributyltinyl)thiazole (150mg, 0.400mmol), triphenylphosphine (10.5mg, 0.040mmol), Bistriphenylphosphine palladium dichloride (14.1 mg, 0.02 mmol) was reacted overnight at 120°C in 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 2-(5-bromopyrimidin-2-yl)thiazole (85-a, 75 mg, yield 77.8%). ESI[M+H] + =242.2.
第二步:5-氯-2-(2-(噻唑-2-基)嘧啶-5-基)苯甲醛的制备(85-b)Step 2: Preparation of 5-chloro-2-(2-(thiazol-2-yl)pyrimidin-5-yl)benzaldehyde (85-b)
将2-(5-溴嘧啶-2-基)噻唑(85-a，75mg,0.311mmol)溶于乙腈(5ml)，加入(4-氯-2-甲酰基苯基)硼酸(85.9mg，0.467mmol)，氟化钾(36.2mg,0.622mmol),醋酸钯(3.5mg,0.0156mmol)，在氮气氛围下120℃下微波反应45分钟，减压浓缩后粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝3:1)得到目标产物5-氯-2-(2-(噻唑-2-基)嘧啶-5-基)苯甲醛(85-b,28mg,收率30.1％)。ESI[M+H]+＝302.2.Dissolve 2-(5-bromopyrimidin-2-yl)thiazole (85-a, 75mg, 0.311mmol) in acetonitrile (5ml), and add (4-chloro-2-formylphenyl)boronic acid (85.9mg, 0.467 mmol), potassium fluoride (36.2mg, 0.622mmol), palladium acetate (3.5mg, 0.0156mmol), react with microwave at 120°C for 45 minutes in a nitrogen atmosphere, concentrate under reduced pressure and the crude product is 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.
第三步:7-氯-2-(噻唑-2-基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(85)Step 3: Preparation of 7-chloro-2-(thiazol-2-yl)-9H-indeno[2,1-d]pyrimidin-9-one (85)
5-氯-2-(2-(噻唑-2-基)嘧啶-5-基)苯甲醛(85-b，28mg,0.0930mmol)溶于二氯乙烷(5ml)，加入叔丁基过氧化氢(67mg，0.744mmol)，四丁基碘化铵(1.7mg,0.00465mmol),100℃下密闭反应过夜，减压浓缩后粗品经高效制备液相法纯化(乙腈：0.1％甲酸水溶液＝9：1)得到目标产物7-氯-2-(噻唑-2-基)-9H-茚并[2,1-d]嘧啶-9-酮(85,0.65mg,收率2.6％)。ESI[M+H]+＝300.0.5-Chloro-2-(2-(thiazol-2-yl)pyrimidin-5-yl)benzaldehyde (85-b, 28mg, 0.0930mmol) was dissolved in dichloroethane (5ml), and tert-butyl peroxide was added Hydrogen (67 mg, 0.744 mmol), tetrabutylammonium iodide (1.7 mg, 0.00465 mmol), sealed reaction at 100°C overnight, and concentrated under reduced pressure, the crude product was purified by high-efficiency preparative liquid phase method (acetonitrile: 0.1% formic acid aqueous solution = 9 : 1) 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.
实施例86:8-(三氟甲基)-10H-[1，31二氧杂环[4'，5':4，51茚并[2，1-d]嘧啶-10-酮的合成
Example 86: Synthesis of 8-(trifluoromethyl)-10H-[1,31dioxetane[4',5':4,51indeno[2,1-d]pyrimidin-10-one)
第一步:5-(2-(三氟甲基)嘧啶-5-基)苯并[d1[1，31二氧杂环戊-4-甲醛的合成(86-a)Step 1: Synthesis of 5-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d1[1,31dioxola-4-carbaldehyde (86-a)
将5-溴苯并[d][1,3]二氧杂环己烯-4-甲醛(200mg，0.87mmol)，(2-(三氟甲基)嘧啶-5-基)硼酸(2180mg，1.14mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(32mg，0.04mmol)和磷酸钾(370mg，1.74mmol)溶于乙腈(12ml)，氮气保护下120℃微波反应50分钟，反应液过滤，减压浓缩后粗品经硅胶色谱法纯化(乙酸乙酯：石油醚＝1：2)得目标产物5-(2-(三氟甲基)嘧啶-5-基)苯并[d][1,3]二氧杂环戊-4-甲醛(86-a，80mg,收率31.2％)。ESI[M+H]+＝2975-bromobenzo[d][1,3]dioxene-4-carbaldehyde (200 mg, 0.87 mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (2180 mg, 1.14mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32mg, 0.04mmol) and potassium phosphate (370mg, 1.74mmol) were dissolved in acetonitrile (12ml) under nitrogen protection Microwave reaction at 120°C for 50 minutes, the reaction solution was filtered, and after 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-(2-(trifluoromethyl)pyrimidine- 5-yl)benzo[d][1,3]dioxola-4-carbaldehyde (86-a, 80 mg, yield 31.2%). ESI[M+H] + =297
第二步:8-(三氟甲基)-10H-[1，31二氧杂环[4'，5':4，51茚并[2，1-d]嘧啶-10-酮的合成(86)Second step: Synthesis of 8-(trifluoromethyl)-10H-[1,31dioxetane[4',5':4,51indeno[2,1-d]pyrimidin-10-one) ( 86)
将5-(2-(三氟甲基)嘧啶-5-基)苯并[d][1,3]二氧杂环戊唑-4-甲醛(86-a,80mg，0.27mmol)溶于二氯乙烷(5ml)，加入2-过氧化氢-2-甲基丙烷(156μl，1.62mmol)，四丁基碘化铵(5mg，0.05mmol)在氮气保护下100℃反应过夜。减压浓缩后粗品经制备法纯化得目标产物8-(三氟甲基)-10H-[1,3]二氧杂环[4’，5’:4,5]茚并[2,1-d]嘧啶-10-酮(86，5.15mg,收率6.4％)。ESI[M+H]+＝295.1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),7.53(d,J＝7.7Hz,1H),7.23(d,J＝7.7Hz,1H),6.33(s,2H). Dissolve 5-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,3]dioxol-4-carbaldehyde (86-a, 80 mg, 0.27 mmol) in Dichloroethane (5 ml), add 2-hydroperoxide-2-methylpropane (156 μl, 1.62 mmol), and tetrabutylammonium iodide (5 mg, 0.05 mmol) react overnight at 100°C under nitrogen protection. After concentration under reduced pressure, the crude product was purified by a preparation method to obtain the target product 8-(trifluoromethyl)-10H-[1,3]dioxetane[4',5':4,5]indeno[2,1- d] Pyrimidin-10-one (86, 5.15 mg, yield 6.4%). ESI[M+H] + =295. 1 H NMR (400MHz, DMSO-d 6 ) δ9.51 (s, 1H), 7.53 (d, J = 7.7Hz, 1H), 7.23 (d, J = 7.7Hz ,1H),6.33(s,2H).
实施例87:7-(甲基磺酰基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的合成
Example 87: Synthesis of 7-(methylsulfonyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one
第一步:2-氯-5-(甲磺酰基)苯甲酸的合成(87-a)Step 1: Synthesis of 2-chloro-5-(methanesulfonyl)benzoic acid (87-a)
将2-氯-5-(甲硫基)苯甲酸(6g，29.56mmol)溶于甲醇(100ml)，加入过氧单磺酸钾(36.38g，59.12mmol)。在室温反应过夜后减压浓缩后粗品经硅胶色谱法纯化(甲醇：二氯甲烷＝20：1)得目标产物2-氯-5-(甲磺酰基)苯甲酸(87-a，5.42g,收率96.6％)。ESI[M+H]+＝235.2-Chloro-5-(methylthio)benzoic acid (6g, 29.56mmol) was dissolved in methanol (100ml), and potassium peroxymonosulfonate (36.38g, 59.12mmol) was added. After reacting at room temperature overnight, the crude product was concentrated under reduced pressure and purified by silica gel chromatography (methanol: dichloromethane = 20:1) to obtain the target product 2-chloro-5-(methanesulfonyl)benzoic acid (87-a, 5.42g, Yield 96.6%). ESI[M+H] + =235.
第二步:(2-氯-5-(甲基磺酰基)苯基)甲醇合成(87-b)Step 2: Synthesis of (2-chloro-5-(methylsulfonyl)phenyl)methanol (87-b)
将2-氯-5-(甲磺酰基)苯甲酸(87-a,2g，8.54mmol)溶于四氢呋喃(50ml)，在0℃下缓慢加入氢化铝锂(640mg，16.84mmol)。在室温下反应2小时后加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取，减压浓缩后粗品经硅胶色谱法纯化(甲醇：二氯甲烷＝15：1)得目标产物(2-氯-5-(甲基磺酰基)苯基)甲醇(87-b，1.1g，收率58.5％)。ESI[M+H]+＝221.2-Chloro-5-(methanesulfonyl)benzoic acid (87-a, 2g, 8.54mmol) was dissolved in tetrahydrofuran (50ml), and lithium aluminum hydride (640mg, 16.84mmol) was slowly added at 0°C. After reacting at room temperature for 2 hours, saturated ammonium chloride solution was added to quench, extracted with ethyl acetate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (methanol: dichloromethane = 15:1) to obtain the target product (2-chloromethane). -5-(methylsulfonyl)phenyl)methanol (87-b, 1.1 g, yield 58.5%). ESI[M+H] + =221.
第三步:2-氯-5-(甲磺酰基)苯甲醛的合成(87-c)Step 3: Synthesis of 2-chloro-5-(methanesulfonyl)benzaldehyde (87-c)
将(2-氯-5-(甲基磺酰基)苯基)甲醇(87-b,1.1g，5mmol)溶于二氧六环(50ml)，加入二氧化锰(2.17g，24.9mmol)。在100℃反应过夜，经减压浓缩后粗品经硅胶色谱法纯化(乙酸乙酯：石油醚＝2：1)得目标产物2-氯-5-(甲磺酰基)苯甲醛(87-c，370mg,收率34.6％)。ESI[M+H]+＝219.Dissolve (2-chloro-5-(methylsulfonyl)phenyl)methanol (87-b, 1.1g, 5mmol) in dioxane (50ml), and add manganese dioxide (2.17g, 24.9mmol). React overnight at 100°C. After concentration under reduced pressure, the crude product is purified by silica gel chromatography (ethyl acetate: petroleum ether = 2:1) to obtain the target product 2-chloro-5-(methanesulfonyl)benzaldehyde (87-c, 370mg, yield 34.6%). ESI[M+H] + =219.
第四步:5-(甲基磺酰基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛的合成(87-d)Step 4: Synthesis of 5-(methylsulfonyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (87-d)
将2-氯-5-(甲磺酰基)苯甲醛(87-c，280mg，1.28mmol)，(2-(三氟甲基)嘧啶-5-基)硼酸(400mg，2.09mmol)，四(三苯基膦)钯(74mg，0.06mmol和碳酸铯(837mg，2.57mmol)溶于二氧六环(10ml)和水(2ml)，氮气保护下120℃微波反应1小时，过滤，减压浓缩后粗品经硅胶色谱法纯化(乙酸乙酯：石油醚＝1：2)得目标产物5-(甲基磺酰基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(87-d，200mg,收率47.7％)。ESI[M+H]+＝331.2-Chloro-5-(methanesulfonyl)benzaldehyde (87-c, 280mg, 1.28mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (400mg, 2.09mmol), tetrakis( Triphenylphosphine) palladium (74 mg, 0.06 mmol) and cesium carbonate (837 mg, 2.57 mmol) were dissolved in dioxane (10 ml) and water (2 ml), reacted with microwave at 120°C for 1 hour under nitrogen protection, filtered, and concentrated under reduced pressure The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:2) to obtain the target product 5-(methylsulfonyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (87-d, 200mg, yield 47.7%). ESI[M+H] + =331.
第五步:7-(甲基磺酰基)-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-9-酮的制备(87)Step 5: Preparation of 7-(methylsulfonyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (87)
将5-(甲基磺酰基)-2-(2-(三氟甲基)嘧啶-5-基)苯甲醛(87-d，200mg，0.60mmol)溶于二氯乙烷(8ml)，加入2-过氧化氢-2-甲基丙烷(291μl，3.03mmol)，四丁基碘化铵(11mg，0.03mmol)在氮气保护下100℃反应过夜。减压浓缩后粗品经制备法纯化得目标产物7-(甲基磺酰基)-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-9-酮(87，19.88mg,收率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).Dissolve 5-(methylsulfonyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)benzaldehyde (87-d, 200 mg, 0.60 mmol) in dichloroethane (8 ml), and add 2-Hydrogen peroxide-2-methylpropane (291 μl, 3.03 mmol) and tetrabutylammonium iodide (11 mg, 0.03 mmol) were reacted overnight at 100°C under nitrogen protection. After concentration under reduced pressure, the crude product was purified by a preparation method to obtain the target product 7-(methylsulfonyl)-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-9-one (87,19.88 mg, yield 16.5%). ESI[M+H] + =329. 1 H NMR (400MHz, DMSO-d 6 ) δ9.75 (s, 1H), 8.36 (s, 2H), 8.26 (s, 1H), 3.29 (s, 3H) .
实施例88:2-甲氧基-9-氧基-9H-茚并[2，1-d]嘧啶-7-磺酰胺的制备
Example 88: Preparation of 2-methoxy-9-oxy-9H-indeno[2,1-d]pyrimidine-7-sulfonamide
第一步:2-氯-5-磺胺基苯甲酸(88-a)Step 1: 2-Chloro-5-sulfonamidobenzoic acid (88-a)
将2-氯-5-(氯磺酰基)苯甲酸(1g，3.92mmol)在0℃下缓慢加入15ml氨水中，反应半小时。后用二氯甲烷/甲醇＝10：1点板监测，反应完全后减压浓缩得粗品2-氯-5-磺胺基苯甲酸(88-a，1.15g)。2-Chloro-5-(chlorosulfonyl)benzoic acid (1g, 3.92mmol) was slowly added to 15 ml of ammonia water at 0°C, and the reaction was carried out for half an hour. Then use dichloromethane/methanol = 10:1 dot plate to monitor. After the reaction is complete, concentrate under reduced pressure to obtain crude 2-chloro-5-sulfonamidobenzoic acid (88-a, 1.15g).
第二步:2-氯-N-甲氧基-7N-甲基-5-氨磺酰基苯甲酰胺制备(88-b)Step 2: Preparation of 2-chloro-N-methoxy-7N-methyl-5-sulfamoylbenzamide (88-b)
将2-氯-5-磺胺基苯甲酸(88-a，1.15g，4.89mmol)，盐酸N、O-二甲基羟胺(475mg，4.89mmol)，N-甲基咪唑(1.4g，17.1mmol)，N,N,N',N'-四甲基氯甲脒六氟磷酸盐(1.5g，5.38mmol)溶于乙腈中室温反应2小时，后监测反应完全后，加入水和乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩。粗品经硅胶色谱法纯化(二氯甲烷/甲醇＝20/1)，得2-氯-N-甲氧基-N-甲基-5-氨磺酰基苯甲酰胺(88-b，0.87g，收率64％)。ESI[M+H]+＝279.22-Chloro-5-sulfonamidobenzoic acid (88-a, 1.15g, 4.89mmol), N,O-dimethylhydroxylamine hydrochloride (475mg, 4.89mmol), N-methylimidazole (1.4g, 17.1mmol) ), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.5g, 5.38mmol) was dissolved in acetonitrile and reacted at room temperature for 2 hours. After the reaction was completed, water and ethyl acetate were added. Extract, dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane/methanol=20/1) to obtain 2-chloro-N-methoxy-N-methyl-5-sulfamoylbenzamide (88-b, 0.87g, Yield 64%). ESI[M+H] + =279.2
第三步:4-氯-3-甲酰基苯磺酰胺的制备(88-c)Step 3: Preparation of 4-chloro-3-formylbenzenesulfonamide (88-c)
将2-氯-N-甲氧基-N-甲基-5-氨磺酰基苯甲酰胺(88-b，500mg，1.8mmol)，溶于无水二氯甲烷中，氮气保护下，0℃缓慢加入二异丁基氢化铝(3.6ml，3.6mmol)反应半个小时，点板监测反应完全后，淬灭，萃取，减压浓缩，有机相干燥，得粗品4-氯-3-甲酰基苯磺酰胺(88-c，450mg)。Dissolve 2-chloro-N-methoxy-N-methyl-5-sulfamoylbenzamide (88-b, 500 mg, 1.8 mmol) in anhydrous dichloromethane, under nitrogen protection, 0°C Slowly add diisobutylaluminum hydride (3.6 ml, 3.6 mmol) and react for half an hour. After the reaction is completed by spot plate monitoring, quench, extract, concentrate under reduced pressure, and dry the organic phase to obtain crude 4-chloro-3-formyl. Benzenesulfonamide (88-c, 450 mg).
第四步:3-甲酰基-4-(2-甲氧基嘧啶-5-基)苯磺酰胺制备(88-d)Step 4: Preparation of 3-formyl-4-(2-methoxypyrimidin-5-yl)benzenesulfonamide (88-d)
将(2-甲氧基嘧啶-5-基)硼酸(93mg，0.6mmol)，碳酸铯(295mg，0.9mmol)，4-氯-3-甲酰基苯磺酰胺(88-c，100mg，0.45mmol)溶于4ml二氧六环中加入四三苯基膦钯，在氮气保护下120℃反应1小时。减压浓缩后粗品经硅胶色谱法纯化(二氯甲烷：甲醇＝15/1)得目标产物3-甲酰基-4-(2-甲氧基嘧啶-5-基)苯磺酰胺(88-d，83mg,收率73％)。ESI[M+H]+＝294.(2-Methoxypyrimidin-5-yl)boronic acid (93mg, 0.6mmol), cesium carbonate (295mg, 0.9mmol), 4-chloro-3-formylbenzenesulfonamide (88-c, 100mg, 0.45mmol) ) was dissolved in 4 ml of dioxane, and tetraphenylphosphine palladium was added, and the reaction was carried out at 120°C for 1 hour under nitrogen protection. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (dichloromethane: methanol = 15/1) to obtain the target product 3-formyl-4-(2-methoxypyrimidin-5-yl)benzenesulfonamide (88-d , 83mg, yield 73%). ESI[M+H] + =294.
第五步:2-甲氧基-9-氧基-9H-茚并[2，1-d]嘧啶-7-磺酰胺的制备(88)Step 5: Preparation of 2-methoxy-9-oxy-9H-indeno[2,1-d]pyrimidine-7-sulfonamide (88)
将3-甲酰基-4-(2-甲氧基嘧啶-5-基)苯磺酰胺(88-d，50mg，0.17mmol)溶于二氯乙烷(4ml)，加入2-过氧化氢-2-甲基丙烷(92.2mg，1.02mmol)，四丁基碘化铵(3.3mg，0.08mmol)在氮气保护下100℃反应16小时。减压浓缩后粗品经制备TLC板纯化(乙酸乙酯：石油醚＝2/1)得目标产物2-甲氧基-9-氧基-9H-茚并[2,1-d]嘧啶-7-磺酰胺(88，3.68mg,收率4.3％)。ESI[M+H]+＝292.2.1H 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).Dissolve 3-formyl-4-(2-methoxypyrimidin-5-yl)benzenesulfonamide (88-d, 50 mg, 0.17 mmol) in dichloroethane (4 ml), and add 2-hydroperoxide- 2-Methylpropane (92.2 mg, 1.02 mmol) and tetrabutylammonium iodide (3.3 mg, 0.08 mmol) were reacted at 100°C for 16 hours under nitrogen protection. After concentration under reduced pressure, the crude product was purified by preparative TLC plate (ethyl acetate: petroleum ether = 2/1) to obtain the target product 2-methoxy-9-oxy-9H-indeno[2,1-d]pyrimidine-7 -Sulfonamide (88, 3.68 mg, yield 4.3%). ESI[M+H] + =292.2. 1 H NMR (600MHz, DMSO-d 6 ) 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).
实施例89:(R)-7-氯-2-((1-甲基吡咯烷-2-基)甲氧基)-9H茚并[2，1-d]嘧啶-9-酮的制备
Example 89: Preparation of (R)-7-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)-9H indeno[2,1-d]pyrimidin-9-one
将2,7-二氯-9H-茚并[2,1-d]嘧啶-9-酮(40mg，0.16mmol)溶于超干甲苯(4ml)，加入N-甲基-L-脯氨醇(18.74mg，0.16mmol)，1,1'-联萘-2,2'-双二苯膦(BINAP)(19.93mg，0.032mmol)，碳酸铯(104.27mg，3.2mmol)和醋酸钯(7.19mg，0.032mmol)，氮气保护，110℃微波反应1小时。减压蒸干溶剂，剩余物Flash柱(甲醇：二氯甲烷＝0％～50％)纯化后再进行液相制备纯化得目标产物(R)-7-氯-2-((1-甲基吡咯烷-2-基)甲氧基)-9H茚并[2,1-d]嘧啶-9-酮(89，6.22mg，收率11.81％)。ESI[M+H]+＝330.10.1H 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).Dissolve 2,7-dichloro-9H-indeno[2,1-d]pyrimidin-9-one (40 mg, 0.16 mmol) in ultradry toluene (4 ml), and add N-methyl-L-prolinol (18.74mg, 0.16mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP) (19.93mg, 0.032mmol), cesium carbonate (104.27mg, 3.2mmol) and palladium acetate (7.19 mg, 0.032mmol), nitrogen protection, microwave reaction at 110°C for 1 hour. The solvent was evaporated to dryness under reduced pressure, and the residue was purified using a Flash column (methanol: dichloromethane = 0% to 50%) and then subjected to liquid phase preparation and purification to obtain the target product (R)-7-chloro-2-((1-methyl) Pyrrolidin-2-yl)methoxy)-9H indeno[2,1-d]pyrimidin-9-one (89, 6.22 mg, yield 11.81%). ESI[M+H] + =330.10. 1 H NMR (400MHz, DMSO-d 6 ) δ2.00–1.81(m,3H),2.12–2.02(m,1H),2.33–2.19(m,2H), 2.95(s,3H),3.14(d,J＝9.6Hz,1H),4.65–4.51(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).
实施例90:2-氯-9-氧-9H-茚并[2，1-d]嘧啶-7-碳腈的制备
Example 90: Preparation of 2-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-7-carbonitrile
第一步:4-(2-氯嘧啶-5-基)-3-甲酰基苯甲腈的制备(90-a)Step 1: Preparation of 4-(2-chloropyrimidin-5-yl)-3-formylbenzonitrile (90-a)
将4-溴-3-甲酰苯甲腈(300mg，1.43mmol)溶于仲丁醇(20ml)，加入2-氯嘧啶-5-硼酸(293.41mg，1.86mmol)，氟化钾(165.98mg,2.86mmol)和醋酸钯(16.03mg,0.07mmol)，氮气保护，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(甲醇：二氯甲烷＝0％～50％)纯化得目标产物4-(2-氯嘧啶-5-基)-3-甲酰基苯甲腈(90-a，154.2mg，收率44.42％).ESI[M+H]+＝244.0,245.0.Dissolve 4-bromo-3-formylbenzonitrile (300mg, 1.43mmol) in sec-butanol (20ml), add 2-chloropyrimidine-5-boronic acid (293.41mg, 1.86mmol), potassium fluoride (165.98mg , 2.86mmol) and palladium acetate (16.03mg, 0.07mmol), nitrogen protection, microwave reaction at 120°C for 30 minutes. The solvent was evaporated to dryness under reduced pressure, and the residue was purified with a Flash column (methanol: dichloromethane = 0% to 50%) to obtain the target product 4-(2-chloropyrimidin-5-yl)-3-formylbenzonitrile (90- a, 154.2mg, yield 44.42%).ESI[M+H] + =244.0,245.0.
第二步:2-氯-9-氧-9H-茚并[2，1-d]嘧啶-7-碳腈的制备(90)Step 2: Preparation of 2-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-7-carbonitrile (90)
将4-(2-氯嘧啶-5-基)-3-甲酰基苯甲腈(90-a，100mg，0.41mmol)溶于1,2-二氯乙烷(10ml)，加入四丁基碘化铵(7.60mg，0.02mmol)和叔丁基过氧化氢(317μl，3.29mmol)，在氮气保护下于封管中100℃反应16小时。减压蒸干溶剂，剩余物用四氢呋喃进行打浆操作得粗产物再进行液相制备纯化得目标产物2-氯-9-氧-9H-茚并[2,1-d]嘧啶-7-碳腈(90，1.29mg，收率1.30％)。ESI[M+H]+＝242.1.1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝7.8Hz,1H),8.24(d,J＝6.8Hz,2H),9.43(s,1H).Dissolve 4-(2-chloropyrimidin-5-yl)-3-formylbenzonitrile (90-a, 100 mg, 0.41 mmol) in 1,2-dichloroethane (10 ml), and add tetrabutyl iodide Ammonium chloride (7.60 mg, 0.02 mmol) and tert-butyl hydroperoxide (317 μl, 3.29 mmol) were reacted at 100°C for 16 hours under nitrogen protection in a sealed tube. The solvent was evaporated to dryness under reduced pressure, and the residue was beaten with tetrahydrofuran to obtain a crude product, which was then prepared and purified by liquid phase to obtain the target product 2-chloro-9-oxo-9H-indeno[2,1-d]pyrimidine-7-carbonitrile. (90, 1.29 mg, yield 1.30%). ESI[M+H] + =242.1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.16 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 6.8 Hz, 2H), 9.43 (s ,1H).
实施例91:N-(9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-基)甲磺酰胺的制备
Example 91: Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)methanesulfonamide
第一步:N-(4-溴-3-甲酰基苯基)甲磺酰胺的制备(91-a)Step 1: Preparation of N-(4-bromo-3-formylphenyl)methanesulfonamide (91-a)
将N-(3-甲酰基苯基)甲磺酰胺(200mg，1mmol)，4-氯-2-(三氟甲基)苯胺(39mg,0.2mmol)，N-溴代琥珀酰亚胺(213.6mg，1.2mmol)加入5ml二氯乙烷，2ml三氟乙酸中，在100℃下氮气保护下密闭反应过夜。减压浓缩后粗品经硅胶色谱法纯化(乙酸乙酯：石油醚＝1/5)得目标产物N-(4-溴-3-甲酰基苯基)甲磺酰胺(91-a,150mg,收率53.96％)。N-(3-formylphenyl)methanesulfonamide (200mg, 1mmol), 4-chloro-2-(trifluoromethyl)aniline (39mg, 0.2mmol), N-bromosuccinimide (213.6 mg, 1.2 mmol) was added to 5 ml of dichloroethane and 2 ml of trifluoroacetic acid, and the reaction was carried out overnight under nitrogen protection at 100°C. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1/5) to obtain the target product N-(4-bromo-3-formylphenyl) methanesulfonamide (91-a, 150 mg, collected rate 53.96%).
第二步：N-(3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯基)甲磺酰胺的制备(91-b)Step 2: Preparation of N-(3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)methanesulfonamide (91-b)
将N-(4-溴-3-甲酰基苯基)甲磺酰胺(91-a,130mg，0.431mmol)，(2-(三氟甲基)嘧啶-5-基)硼酸(99.25mg，0.517mmol)，醋酸钯(1.25mg，0.022mmol)氟化钾(193.5mg，0.862mmol)溶于乙腈(2ml)，氮气保护微波120℃反应1小时，加入水(10ml)，乙酸乙酯(10ml*2)萃取，无水硫酸镁干燥，过滤，减压浓缩后粗品经硅胶色谱法纯化(乙酸乙酯：石油醚＝1/1)得目标产物N-(3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯基)甲磺酰胺(91-b,13mg,收率8.74％)。N-(4-Bromo-3-formylphenyl)methanesulfonamide (91-a, 130mg, 0.431mmol), (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (99.25mg, 0.517 mmol), palladium acetate (1.25mg, 0.022mmol), potassium fluoride (193.5mg, 0.862mmol) were dissolved in acetonitrile (2ml), reacted in nitrogen-protected microwave at 120°C for 1 hour, added water (10ml), ethyl acetate (10ml* 2) Extract, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. The crude product is 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%).
第三步:N-(9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-基)甲磺酰胺的制备(91)Step 3: Preparation of N-(9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)methanesulfonamide (91)
将N-(3-甲酰基-4-(2-(三氟甲基)嘧啶-5-基)苯基)甲磺酰胺(91-b,13mg，0.038mmol)溶于二氯乙烷(2ml)，加入2-过氧化氢-2-甲基丙烷(27.4mg，0.3mmol)，四正丁基碘化铵(0.7mg，0.002mmol)在氮气保护下100℃反应16小时。加入水(10ml)，二氯甲烷萃取，无水硫酸镁干燥，过滤，减压浓缩后粗品经液相制备纯化(三氟乙酸0.1％)得目标产物N-(9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-基)甲磺酰胺(91，1.51mg,收率11.62％)。ESI[M+H]+＝344.3Dissolve N-(3-formyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)methanesulfonamide (91-b, 13 mg, 0.038 mmol) in dichloroethane (2 ml ), add 2-hydroperoxide-2-methylpropane (27.4 mg, 0.3 mmol), and react with tetra-n-butylammonium iodide (0.7 mg, 0.002 mmol) at 100°C for 16 hours under nitrogen protection. Add water (10 ml), extract with dichloromethane, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. The crude product is purified through liquid phase preparation (trifluoroacetic acid 0.1%) to obtain the target product N-(9-oxo-2-( Trifluoromethyl)-9H-indeno[2,1-d]pyrimidin-7-yl)methanesulfonamide (91, 1.51 mg, yield 11.62%). ESI[M+H] + =344.3
实施例92:9-氧代-9H-茚并[2，1-d]嘧啶-2，7-二腈的制备
Example 92: Preparation of 9-oxo-9H-indeno[2,1-d]pyrimidine-2,7-dicarbonitrile
第一步:5-(4-氰基-2-甲酰基苯基)嘧啶-2-碳腈的制备(92-a)Step 1: Preparation of 5-(4-cyano-2-formylphenyl)pyrimidine-2-carbonitrile (92-a)
将4-溴-3-甲酰基苯甲腈(250mg，1.19mmol)溶于乙腈(4ml)，加入2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)嘧啶-5-腈(354.3mg，1.547mmol)，氟化钾(138mg,2.38mmol)和醋酸钯(13.3mg,0.0595mmol)，氮气保护，120℃微波反应30分钟。减压蒸干溶剂，剩余物Flash柱(甲醇：二氯甲烷＝0％～50％)纯化得目标产物5-(4-氰基-2-甲酰基苯基)嘧啶-2-碳腈(92-a，250mg，收率89.67％).Dissolve 4-bromo-3-formylbenzonitrile (250 mg, 1.19 mmol) in acetonitrile (4 ml), and add 2-(4,4,5,5-tetramethyl-1,3,2-dioxa Borane-2-yl)pyrimidine-5-nitrile (354.3 mg, 1.547 mmol), potassium fluoride (138 mg, 2.38 mmol) and palladium acetate (13.3 mg, 0.0595 mmol) were used for microwave reaction at 120°C for 30 minutes under nitrogen protection. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by Flash column (methanol: dichloromethane = 0% ~ 50%) to obtain the target product 5-(4-cyano-2-formylphenyl)pyrimidine-2-carbonitrile (92 -a, 250mg, yield 89.67%).
第二步:9-氧代-9H-茚并[2，1-d]嘧啶-2，7-二腈的制备(92)Step 2: Preparation of 9-oxo-9H-indeno[2,1-d]pyrimidine-2,7-diconitrile (92)
将5-(4-氰基-2-甲酰基苯基)嘧啶-2-碳腈(92-a，5mg，0.213mmol)溶于1,2-二氯乙烷(2ml)，加入四丁基碘化铵(3.93mg，0.0106mmol)和叔丁基过氧化氢(153.6mg，1.704mmol)，在氮气保护下于封管中100℃反应16小时。减压蒸干溶剂，粗产物进行液相制备纯化得目标产9-氧代-9H-茚并[2,1-d]嘧啶-2,7-二腈(92-a，1.26mg，收率2.55％)。ESI[M+H]+＝233.1Dissolve 5-(4-cyano-2-formylphenyl)pyrimidine-2-carbonitrile (92-a, 5 mg, 0.213 mmol) in 1,2-dichloroethane (2 ml), and add tetrabutyl Ammonium iodide (3.93 mg, 0.0106 mmol) and tert-butyl hydroperoxide (153.6 mg, 1.704 mmol) were reacted at 100°C for 16 hours under nitrogen protection in a sealed tube. The solvent was evaporated to dryness under reduced pressure, and the crude product was prepared and purified by liquid phase to obtain the target product 9-oxo-9H-indeno[2,1-d]pyrimidine-2,7-dinitrile (92-a, 1.26 mg, yield 2.55%). ESI[M+H] + =233.1
实施例93:7-异丙基-9-氧代-9H-茚并[1，2-b]吡嗪-2，3-二腈制备
Example 93: Preparation of 7-isopropyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-diconitrile
第一步:(E)-2-(羟基亚氨基)-5-异丙基-2，3-二氢-1H-茚-1-酮的制备(93-a)Step 1: Preparation of (E)-2-(Hydroxyimino)-5-isopropyl-2,3-dihydro-1H-inden-1-one (93-a)
将5-异丙基-2,3-二氢-1H-茚-1-酮(400mg,2.72mmol)溶于甲醇(10ml)，加亚硝酸异戊酯(296mg,2.99mmol),36％盐酸(2ml),在40℃下反应1小时后减压浓缩，粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝3:1)得到目标产物(E)-2-(羟基亚氨基)-5-异丙基-2,3-二氢-1H-茚-1-酮(93-a,337mg,收率72.3％)。ESI[2M+H]+＝407.2.Dissolve 5-isopropyl-2,3-dihydro-1H-inden-1-one (400mg, 2.72mmol) in methanol (10ml), add isoamyl nitrite (296mg, 2.99mmol) and 36% hydrochloric acid (2ml), reacted at 40°C for 1 hour and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product (E)-2-(hydroxyimino)-5 -Isopropyl-2,3-dihydro-1H-inden-1-one (93-a, 337 mg, yield 72.3%). ESI[2M+H] + =407.2.
第二步5-异丙基-1H-茚-1，2(3H)-二酮的制备(93-b)The second step is the preparation of 5-isopropyl-1H-indene-1,2(3H)-dione (93-b)
将(E)-2-(羟基亚氨基)-5-异丙基-2,3-二氢-1H-茚-1-酮(93-a，337mg,1.66mmol)溶于36％甲醛溶液(7ml)，加入36％盐酸(14ml),室温下反应过夜后，加水淬灭，用二氯甲烷萃取，有机相经无水硫酸钠干燥后过滤，滤液减压浓缩后得到目标产物5-异丙基-1H-茚-1,2(3H)-二酮(93-b,165mg,收率52.9％)。Dissolve (E)-2-(hydroxyimino)-5-isopropyl-2,3-dihydro-1H-inden-1-one (93-a, 337 mg, 1.66 mmol) in 36% formaldehyde solution ( 7ml), add 36% hydrochloric acid (14ml), react at room temperature overnight, add water to quench, extract with dichloromethane, dry the organic phase over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain the target product 5-isopropyl Base-1H-indene-1,2(3H)-dione (93-b, 165 mg, yield 52.9%).
第三步:7-异丙基-9H-茚并[1，2-b]吡嗪-2，3-二腈的制备(93-c)Step 3: Preparation of 7-isopropyl-9H-indeno[1,2-b]pyrazine-2,3-diconitrile (93-c)
将5-异丙基-1H-茚-1,2(3H)-二酮(93-b，165mg,0.877mmol)溶于异丙醇(7ml)，加入2,3-二氨基马来腈(94.8mg,0.877mmol),室温下反应24小时后，减压浓缩，粗品经薄层制备法纯化(石油醚：乙酸乙酯＝3:1)得到目标产物7-异丙基-9H-茚并[1，2-b]吡嗪-2,3-二腈(93-c,31mg,收率10.8％)。ESI[M+H]+＝261.2Dissolve 5-isopropyl-1H-indene-1,2(3H)-dione (93-b, 165mg, 0.877mmol) in isopropyl alcohol (7ml), and add 2,3-diaminomaleonitrile ( 94.8 mg, 0.877 mmol), reacted at room temperature for 24 hours, concentrated under reduced pressure, and the crude product was purified by thin layer preparation (petroleum ether: ethyl acetate = 3:1) to obtain the target product 7-isopropyl-9H-indeno. [1,2-b]pyrazine-2,3-diconitrile (93-c, 31 mg, yield 10.8%). ESI[M+H] + =261.2
第四步:7-异丙基-9-氧代-9H-茚并[1，2-b]吡嗪-23-二腈制备(93)Step 4: Preparation of 7-isopropyl-9-oxo-9H-indeno[1,2-b]pyrazine-23-dinitrile (93)
将重铬酸钾(61mg,0.207mmol)溶于水(0.4ml)，加入7-异丙基-9H-茚并[1，2-b]吡嗪-2,3-二腈(93-c，30mg,0.115mmol),醋酸(1.6ml),在100℃下反应1小时后，加水淬灭，用二氯甲烷萃取，有机相经无水硫酸钠干燥后过滤，滤液减压浓缩后粗品经高效制备液相法纯化(乙腈：0.1％甲酸水溶液＝5：1)得到目标产物7-异丙基-9-氧代-9H-茚并[1，2-b]吡嗪-2,3-二腈(93,1.6mg,收率5.06％)。ESI[M+H]+＝275.2.Dissolve potassium dichromate (61mg, 0.207mmol) in water (0.4ml), add 7-isopropyl-9H-indeno[1,2-b]pyrazine-2,3-diconitrile (93-c , 30 mg, 0.115 mmol), acetic acid (1.6 ml), react at 100°C for 1 hour, add water to quench, extract with dichloromethane, dry the organic phase over anhydrous sodium sulfate and filter, the filtrate is concentrated under reduced pressure and the crude product is The target product 7-isopropyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3- was obtained by efficient preparative liquid phase purification (acetonitrile: 0.1% formic acid aqueous solution = 5:1). Dinitrile (93, 1.6 mg, yield 5.06%). ESI[M+H] + =275.2.
实施例94:9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-羧酸乙酯的合成
Example 94: Synthesis of ethyl 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylate
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸(51，10mg，0.034mmol)溶于无水乙醇(2ml)，加入浓硫酸(50μl)，50℃反应12小时。将反应液减压浓缩后制备色谱纯化得目标产物9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸乙酯(94，1.25mg，收率11.4％)。ESI[M+H]+＝323.1，1H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 10 mg, 0.034 mmol) in absolute ethanol (2 ml), and add Concentrated sulfuric acid (50 μl), react at 50°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by preparative chromatography to obtain the target product 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid ethyl ester (94,1.25 mg, yield 11.4%). ESI[M+H] + =323.1, 1 H NMR (400MHz, DMSO) δ9.71 (s, 1H), 8.38 (dd, J = 7.8, 1.4Hz, 1H), 8.22 (dd, J = 14.4, 4.3 Hz, 2H), 4.38 (q, J = 7.1Hz, 2H), 1.36 (t, J = 7.1Hz, 3H).
实施例95:甲基-d3-9-氧代-2-(三氟甲基)-9H-茚并[2，1-d]嘧啶-7-羧酸盐的合成
Example 95: Synthesis of methyl-d 3 -9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylate
将9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸(51，40mg，0.136mmol)溶于氘代甲醇(1ml)，加入浓硫酸(50μl)，50℃反应12小时。将反应液减压浓缩后高效液相制备色谱纯化得目标产物甲基-d3-9-氧代-2-(三氟甲基)-9H-茚并[2,1-d]嘧啶-7-羧酸盐(95，2.1mg，收率4.6％)。ESI[M+H]+＝312.2，1H 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).Dissolve 9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7-carboxylic acid (51, 40 mg, 0.136 mmol) in deuterated methanol (1 ml), and add Concentrated sulfuric acid (50 μl), react at 50°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography to obtain the target product methyl-d 3 -9-oxo-2-(trifluoromethyl)-9H-indeno[2,1-d]pyrimidine-7 - Carboxylate (95, 2.1 mg, yield 4.6%). ESI[M+H] + =312.2, 1 H NMR (400MHz, Chloroform-d) δ9.27 (s, 1H), 8.53 (s, 1H), 8.42 (dd, J = 7.8, 1.6Hz, 1H), 7.87(d,J＝7.8Hz,1H),1.43(s,3H).
测试例1:化合物抑制USP21酶活性的生物发光测试Test Example 1: Bioluminescence test of compounds inhibiting USP21 enzyme activity
实验试剂和仪器：Experimental reagents and instruments:
GST-USP21蛋白(BostonBiochem)，Ub-AML(氨基荧光素标记泛素，BostonBiochem)，DUB缓冲液(50mM HEPES，pH7.8，100mM NaCl，0.5mM EDTA，0.01％(v/v)Tween-20，1mM DTT)，萤光素检测试剂(Promega)，DMSO。酶标仪(TECAN)，白色384孔板，微孔板恒温振荡器。GST-USP21 protein (Boston Biochem), Ub-AML (aminofluorescein-labeled ubiquitin, Boston Biochem), DUB buffer (50mM HEPES, pH7.8, 100mM NaCl, 0.5mM EDTA, 0.01% (v/v) Tween-20 , 1mM DTT), luciferin detection reagent (Promega), DMSO. Microplate reader (TECAN), white 384-well plate, microplate constant temperature shaker.
生物发光法测试化合物对USP21催化活性的抑制活性：Bioluminescence assay was used to test the inhibitory activity of compounds on USP21 catalytic activity:
用50mM HEPES，pH7.5条件下将Ub-AML稀释至3μM，将稀释后的Ub-AML溶液和萤光素检测试剂按照1:9的比例制备Ub-AML-LDR试剂。将GST-USP21用DUB缓冲液稀释至8nM并转移至384孔板，与稀释好的化合物在微孔板恒温振荡器孵育30分钟(30℃，500rpm)。将Ub-AML-LDR试剂加入测试孔(最终浓度：2nM GST-USP21，150nM Ub-AML)后，立即使用TECAN Spark多模式酶标仪测定生物发光信号，检测参数：动力学模式检测生物发光，检测时长40分钟，每间隔两分钟测试一次，整合时间500ms。计算每个孔的初始反应速率(一级反应的斜率)，使用4参数对数模型(4-parameter logistic model)分析数据以计算IC50值。USP21酶抑制活性测试结果如下表1：Dilute Ub-AML to 3 μM with 50mM HEPES, pH 7.5, and prepare Ub-AML-LDR reagent by mixing the diluted Ub-AML solution and luciferin detection reagent at a ratio of 1:9. GST-USP21 was diluted to 8 nM with DUB buffer and transferred to a 384-well plate, and incubated with the diluted compound on a microplate constant-temperature shaker for 30 minutes (30°C, 500 rpm). After adding the Ub-AML-LDR reagent to the test well (final concentration: 2nM GST-USP21, 150nM Ub-AML), immediately use the TECAN Spark multi-mode microplate reader to measure the bioluminescence signal. Detection parameters: kinetic mode detection of bioluminescence, The detection time is 40 minutes, and the test is performed every two minutes, with an integration time of 500ms. The initial reaction rate (slope of the first-order reaction) was calculated for each well and the data were analyzed using a 4-parameter logistic model to calculate IC50 values. The USP21 enzyme inhibitory activity test results are as follows in Table 1:
对于IC50值，其中“++++”表示IC50＜10nM；“+++”表示IC50介于10nM与100nM之间(含10nM)；“++”表示IC50介于100nM与1μM之间(含100nM)；“+”表示IC50介于1μM与10μM之间(含1μM)。For IC 50 value, "++++" means IC 50 <10nM;"+++" means IC 50 is between 10nM and 100nM (inclusive); "++" means IC 50 is between 100nM and 1μM between 100nM (inclusive); "+" means that the IC 50 is between 1μM and 10μM (inclusive of 1μM).
表1

Table 1

前述对本公开的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本公开限定为所公开的精确形式，并且很显然，根据上述教导，可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本公开的特定原理及其实际应用，从而使得本领域的技术人员能够实现并利用本公开的各种不同的示例性实施方案以及各种不同的选择和改变。本公开的范围意在由权利要求书及其等同形式所限定。 The foregoing descriptions of specific exemplary embodiments of the present disclosure have been presented for purposes of illustration and illustration. These descriptions are not intended to limit the disclosure to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teachings. The exemplary embodiments were chosen and described in order to explain certain principles of the disclosure and its practical application, thereby enabling others skilled in the art to make and utilize various exemplary embodiments of the disclosure and various different applications. Choice and change. The scope of the disclosure is intended to be defined by the claims and their equivalents.

Claims (13)

  1. 式(I)化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药：
    Compounds of formula (I), their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof:
    式中，In the formula,
    Cy1环为5-7元芳环或包含至少一个选自N、O或S的杂原子的5或6元杂芳环；The Cy1 ring is a 5-7 membered aromatic ring or a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O or S;
    U1、U2、U3各自独立地选自CH、CR4或N；U 1 , U 2 , and U 3 are each independently selected from CH, CR 4 or N;
    X1、X2分别独立地选自氢、-C1-6烷基、-NR5R6、-OR5、-SR5、卤素，或X1、X2共同形成＝O、＝S、＝NR5，或X1、X2和与它们相连的原子共同形成4至6元环烷基，所述4至6元环烷基任选地被羰基取代；条件是，X1、X2不同时为-NR5R6、-OR5或-SR5；X 1 and X 2 are independently selected from hydrogen, -C 1-6 alkyl, -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and =NR 5 , or X 1 , Not simultaneously -NR 5 R 6 , -OR 5 or -SR 5 ;
    R1、R2、R3各自独立地选自氢、卤素、氰基、羟基、羧基、硝基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-C(O)-C1-3烷基、-C(O)NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-C2-4炔基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-O-3至9元杂环烷基、-O-C1-3烷基-3至9元杂环烷基、-C1-3烷基-NRaRb、-C(NH)NRaRb、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C1-3烷基-S(O)2C1-3烷基、-C2-6烯基、-C2-6炔基、5或6元杂芳基、C5-7芳基、-S-R7、-C(O)O-C1-3烷基、-S(O)2-NRaRb、-NRa-S(O)2Rb、-S(O)NH、-CHO或-NO2；且所述的-C1-3烷基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、5或6元杂芳基、C5-7芳基任选地被1、2或3个独立地选自氘、卤素、甲基、乙基、丙基、异丙基、氰基、氨基、-N(CH3)2、羟基、羧基或-CHO的取代基取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 ring Alkyl group, 3 to 9-membered heterocycloalkyl group, -NR a R b , -C(O)-C 1-3 alkyl group, -C(O)NR a R b , -S(O) 2 C 1- 3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1 -6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl , -OC 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-NR a R b , -C (NH)NR a R b , -C 1-3 alkyl-C (O)-C 1-3 alkyl, -C 1-3 alkyl-C(O)NR a R b , -C 1-3 alkyl-S(O) 2 C 1-3 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 5 or 6-membered heteroaryl, C 5-7 aryl, -SR 7 , -C(O)OC 1-3 alkyl, -S(O) 2 -NR a R b , -NR a -S(O) 2 R b , -S(O)NH, -CHO or -NO 2 ; and the -C 1-3 alkyl group, -C 1-6 Alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl - 3 to 9 membered heterocycloalkyl, -C 1 -3 alkyl-C 3-9 cycloalkyl, 5 or 6 membered heteroaryl, C 5-7 aryl optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl , propyl, isopropyl, cyano, amino, -N(CH 3 ) 2 , hydroxyl, carboxyl or -CHO substituents;
    n为1-3的整数；n is an integer from 1 to 3;
    R4选自氢、卤素、氰基、羟基、-C1-3烷基、-C1-3烷氧基、氨基、炔基、或者相邻的R3与R4相互连接共同形成C3-6环烷基或3至7元杂环烷基，条件是，U1和U2至少有一个为CR4；所述-C1-3烷基、-C1-3烷氧基、-C3-6环烷基或3至7元杂环烷基任选地被一个或多个选自氘、卤素、氰基、羟基、氨基的取代基所取代；R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, -C 1-3 alkoxy, amino, alkynyl, or adjacent R 3 and R 4 are connected to each other to form C 3 -6 cycloalkyl or 3 to 7-membered heterocycloalkyl, provided that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl, -C 1-3 alkoxy, - C 3-6 cycloalkyl or 3 to 7-membered heterocycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and amino;
    R5、R6、R7各自独立地选自氢、卤素、氰基、羟基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-C2-4炔基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-C1-3烷基-RaRb、-C1-3烷基-C(O)H、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C2-6烯基或-C2-6炔基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基任选地被1、2或3个独立地选自氘、卤素、甲基、乙基、丙基、异丙基、氨基、-N(CH3)2、羟基、羧基的取代基取代；或，R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl , -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 Alkyl-C 3-9 cycloalkyl, -C 1-3 alkyl-R a R b , -C 1-3 alkyl-C(O)H, -C 1-3 alkyl-C(O) -C 1-3 alkyl, -C 1-3 alkyl -C(O)NR a R b , -C 2-6 alkenyl or -C 2-6 alkynyl; and the -C 1-6 Alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl - 3 to 9 membered heterocycloalkyl, -C 1 -3 alkyl -C 3-9 cycloalkyl optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino, -N(CH 3 ) 2. Substitution of hydroxyl and carboxyl substituents; or,
    X1或X2为-NR5R6时，R5、R6与其相连的N原子共同形成5或6元杂环烷基，所述5或6元杂环烷基任选地被选自C1-6烷基的取代基取代； When X 1 or _ _ C 1-6 alkyl substituent substitution;
    Ra、Rb各自独立地选自氢、氘、羟基、C1-3烷基、氘代C1-3烷基、C1-3烷羟基、C3-9环烷基或-C(O)R7；R a and R b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 alkylhydroxy, C 3-9 cycloalkyl or -C( O) R7 ;
    所述杂环烷基或杂芳基具有至少一个选自N、O和S的杂原子作为环原子；The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
    R1、R2、R3和R4不同时为氢。R 1 , R 2 , R 3 and R 4 are not hydrogen at the same time.
  2. 如权利要求1所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药，其中，Cy1环为包含至少一个选自N、O或S的杂原子的5或6元杂芳环；The compound of claim 1, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, wherein the Cy1 ring is 5 containing at least one heteroatom selected from N, O or S. or 6-membered heteroaromatic ring;
    U1、U2、U3各自独立地选自CH、CR4或N；U 1 , U 2 , and U 3 are each independently selected from CH, CR 4 or N;
    X1、X2分别独立地选自氢、-NR5R6、-OR5、-SR5、卤素，或X1、X2共同形成＝O、＝S、＝NR5，或X1、X2和与它们相连的原子共同形成4至6元环烷基，所述4至6元环烷基任选地被羰基取代；条件是，X1、X2不同时为NR5R6、OR5、SR5；X 1 and X 2 are independently selected from hydrogen , -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and X 2 and the atoms connected to them together form a 4- to 6-membered cycloalkyl group, and the 4- to 6-membered cycloalkyl group is optionally substituted by a carbonyl group; the condition is that X 1 and X 2 are not simultaneously NR 5 R 6 , OR 5 , SR 5 ;
    R1、R2、R3各自独立地选自氢、卤素、氰基、羟基、羧基、C1-6烷基、C1-6烷氧基、C3-9环烷基、3至9元杂环烷基、-NRaRb、-C(O)-C1-3烷基、-C(O)NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-C2-4炔基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-O-3至9元杂环烷基、-C1-3烷基-NRaRb、-C(N)NRaRb、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C1-3烷基-S(O)2C1-3烷基、-C2-6烯基、-C2-6炔基、5或6元杂芳基或C5-7芳基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、5或6元杂芳基、C5-7芳基任选地被1、2或3个独立地选自卤素、甲基、乙基、丙基、异丙基、氰基、氨基、N(CH3)2、羟基、羧基的取代基取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-9 cycloalkyl, 3 to 9 One-membered heterocycloalkyl, -NR a R b , -C(O)-C 1-3 alkyl, -C(O)NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -C 1-3 Alkyl-NR a R b , -C(N)NR a R b , -C 1-3 alkyl-C(O)-C 1-3 alkyl, -C 1-3 alkyl-C(O) NR a R b , -C 1-3 alkyl -S(O) 2 C 1-3 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 5- or 6-membered heteroaryl or C 5-7 aryl; and the -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered heterocycloalkyl, -C 1-3 Alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, 5- or 6-membered heteroaryl, C 5-7 aryl optionally substituted by 1, 2 or Substituted with 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, N(CH 3 ) 2 , hydroxyl, and carboxyl;
    R4选自氢、卤素、氰基、羟基、-C1-3烷基、-C1-3烷氧基、氨基、炔基、或者相邻的R3与R4相互连接共同形成C3-6环烷基或3至7元杂环烷基，条件是，U1和U2至少有一个为CR4；所述-C1-3烷基、-C1-3烷氧基、-C3-6环烷基 或3至7元杂环烷基任选地被一个或多个选自卤素、氰基、羟基、氨基的取代基所取代；R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, -C 1-3 alkoxy, amino, alkynyl, or adjacent R 3 and R 4 are connected to each other to form C 3 -6 cycloalkyl or 3 to 7-membered heterocycloalkyl, provided that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl, -C 1-3 alkoxy, - C 3-6 cycloalkyl Or 3 to 7-membered heterocycloalkyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, and amino;
    R5、R6各自独立地选自氢、卤素、氰基、羟基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-C2-4炔基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-C1-3烷基-RaRb、-C1-3烷基-C(O)H、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C2-6烯基、-C2-6炔基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基、异丙基、氨基、N(CH3)2、羟基、羧基的取代基取代；R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9-membered hetero Cycloalkyl, -NR a R b , -S(O) 2 C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl -C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl- C 3-9 cycloalkyl, -C 1-3 alkyl-R a R b , -C 1-3 alkyl-C(O)H, -C 1-3 alkyl-C(O)-C 1 -3 alkyl, -C 1-3 alkyl -C(O)NR a R b , -C 2-6 alkenyl, -C 2-6 alkynyl; and the -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl - 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl -C 3-9 cycloalkyl optionally substituted by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl, isopropyl, amino, N(CH 3 ) 2 , hydroxyl, carboxyl substituent substitution;
    Ra、Rb各自独立地选自氢、C1-3烷基或C3-9环烷基；R a and R b are each independently selected from hydrogen, C 1-3 alkyl or C 3-9 cycloalkyl;
    所述杂环烷基或杂芳基具有至少一个选自N、O和S的杂原子作为环原子；The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
    R1、R2和R3、R4不同时为氢。R 1 , R 2 and R 3 , R 4 are not hydrogen at the same time.
  3. 如权利要求1所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药，其中，所述化合物如式(II)所示：
    The compound of claim 1, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, wherein the compound is represented by formula (II):
    式中，In the formula,
    U1、U2、U3、U4、U5各自独立地选自CH、CR4或N；U 1 , U 2 , U 3 , U 4 and U 5 are each independently selected from CH, CR 4 or N;
    X1、X2分别独立地选自氢、-C1-6烷基、-NR5R6、-OR5、-SR5、卤素，或X1、X2共同形成＝O、＝S、＝NR5，或X1、X2和与它们相连的原子共同形成4至6元杂环烷基，所述4至6杂环烷基任选地被羰基取代；条件是，X1、X2不同时为-NR5R6、-OR5或-SR5；X 1 and X 2 are independently selected from hydrogen, -C 1-6 alkyl, -NR 5 R 6 , -OR 5 , -SR 5 , halogen, or X 1 and =NR 5 , or X 1 , 2 does not mean -NR 5 R 6 , -OR 5 or -SR 5 at the same time;
    R1、R2、R3各自独立地选自氢、卤素、氰基、羟基、羧基、硝基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、-NRaRb、-C(O)-C1-3烷基、-C(O)NRaRb、-S(O)2C1-3烷基、-C1-3烷基-羟基、-C1-3烷基-氰基、-C1-3烷基-C1-6烷氧基、-C1-3烷基-3至9元杂环烷基、-C1-3烷基-C3-9环烷基、-O-3至9元杂环烷基、-O-C1-3烷基-3至9元杂环烷基、-C1-3烷基-NRaRb、-C(NH)NRaRb、-C1-3烷基-C(O)-C1-3烷基、-C1-3烷基-C(O)NRaRb、-C2-6炔基、5或6元杂芳基、C5-7芳基、-S-R7、-C(O)O-C1-3烷基、-S(O)2NRaRb、-NRa-S(O)2Rb、-S(O)NH、-CHO、-NO2；且所述的-C1-3烷基、-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基、5或6元杂芳基、C5-7芳基任选地被1、2或3个独立地选自氘、卤素、甲基、乙基、丙基、异丙基、氰基、氨基、-N(CH3)2、羟基、羧基的取代基取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, nitro, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 ring Alkyl group, 3 to 9-membered heterocycloalkyl group, -NR a R b , -C(O)-C 1-3 alkyl group, -C(O)NR a R b , -S(O) 2 C 1- 3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-3 to 9-membered heterocycloalkyl, -C 1-3 alkyl-C 3-9 cycloalkyl, -O-3 to 9-membered heterocycloalkyl, -OC 1-3 alkyl-3 to 9-membered heterocycle Alkyl, -C 1-3 alkyl -NR a R b , -C(NH)NR a R b , -C 1-3 alkyl -C(O)-C 1-3 alkyl, -C 1- 3Alkyl -C(O)NR a R b , -C 2-6 alkynyl, 5- or 6-membered heteroaryl, C 5-7 aryl, -SR 7 , -C(O)OC 1-3 alkyl base, -S(O) 2 NR a R b , -NR a -S(O) 2 R b , -S(O)NH, -CHO, -NO 2 ; and the -C 1-3 alkyl group , -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, 5 or 6 membered heteroaryl, C 5-7 aryl Optionally substituted by 1, 2 or 3 substituents independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, cyano, amino, -N(CH 3 ) 2 , hydroxyl, carboxyl replace;
    R4选自氢、卤素、氰基、羟基、-C1-3烷基、或相邻R3与R4相互连接共同形成C3-6环烷基或3至7元杂环烷基，条件是，U1和U2至少有一个为CR4；所述-C1-3烷基、-C1-3烷氧基、-C3-6环烷基或3至7元杂环烷基任选地被一个或多个选自氘、卤素、氰基、羟基、氨基的取代基所取代；R 4 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-3 alkyl, or adjacent R 3 and R 4 are connected to each other to form a C 3-6 cycloalkyl or 3 to 7-membered heterocycloalkyl, The condition is that at least one of U 1 and U 2 is CR 4 ; the -C 1-3 alkyl group, -C 1-3 alkoxy group, -C 3-6 cycloalkyl group or 3 to 7-membered heterocycloalkyl group The group is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and amino;
    R5、R6、R7各自独立地选自氢、卤素、氰基、羟基、-C1-6烷基、-C1-6烷氧基、-C1-3烷基-C(O)H、-C3-9环烷基、3至9元杂环烷基、-C1-3烷基-羟基；且所述的-C1-6烷基、-C1-6烷氧基、-C3-9环烷基、3至9元杂环烷基任选地被1、2或3个独立选自氘、卤素、甲基、乙基、丙基、异丙基、氨基、-N(CH3)2、羟基、羧基的取代基取代；R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl-C(O )H, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl, -C 1-3 alkyl-hydroxy; and the -C 1-6 alkyl, -C 1-6 alkoxy base, -C 3-9 cycloalkyl, 3 to 9 membered heterocycloalkyl optionally 1, 2 or 3 independently selected from deuterium, halogen, methyl, ethyl, propyl, isopropyl, amino , -N(CH 3 ) 2 , hydroxyl, carboxyl substituent substitution;
    Ra、Rb各自独立地选自氢、氘、羟基、C1-3烷基、C1-3烷羟基、C3-9环烷基或-C(O)R7；R a and R b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-3 alkyl, C 1-3 alkyl hydroxyl, C 3-9 cycloalkyl or -C(O)R 7 ;
    所述杂环烷基或杂芳基具有至少一个选自N、O和S的杂原子作为环原子；The heterocycloalkyl or heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom;
    R1、R2、R3和R4不同时为氢。R 1 , R 2 , R 3 and R 4 are not hydrogen at the same time.
  4. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药，其中，所述化合物如式(ⅡA)、式(ⅡB)、式(ⅡC)、式(ⅡD)、式(ⅡE)或式(ⅡF)所示：
    The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, wherein the compound is such as formula (IIA), formula (IIB) , formula (ⅡC), formula (ⅡD), formula (ⅡE) or formula (ⅡF):
    各式中，X1、X2、R1、R2、R3各自定义同式(I)化合物。 In each formula, X 1 , X 2 , R 1 , R 2 and R 3 are each defined the same as the compound of formula (I).
  5. 如权利要求1-4任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药，其中：The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein:
    R1选自氢、卤素、羟基、氨基、氰基、三氟甲基、环丙基、硫氰基、二甲基氨基、甲氧基、甲基、三氟甲氧基、-CH2CN、 R 1 is selected from hydrogen, halogen, hydroxyl, amino, cyano, trifluoromethyl, cyclopropyl, thiocyanate, dimethylamino, methoxy, methyl, trifluoromethoxy, -CH 2 CN ,
    R2选自氢、羟基、甲基、甲氧基、氰基或三氟甲基；R 2 is selected from hydrogen, hydroxyl, methyl, methoxy, cyano or trifluoromethyl;
    R3选自卤素、甲基、甲氧基、氰基、三氟甲基、羧基、环丙基、乙炔基、苯基、硝基、氨基、异丙基、-C(O)OCH3、-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)2CH2CHO、-CH(CH3)OH、-CH2Br、-CH2OH、-CH2C(O)OH、 R 3 is selected from halogen, methyl, methoxy, cyano, trifluoromethyl, carboxyl, cyclopropyl, ethynyl, phenyl, nitro, amino, isopropyl, -C(O)OCH 3 , -S-CF 3 , -S(O) 2 NH 2 , -S(O) 2 -CF 3 , -C(O)NH 2 , -C(O)N(CH 3 ) 2 , -C(O) NHOH, -C(O)NHCH 3 , -C(OH)(CH 3 ) 2 , -S(O) 2 CH 3 , -S(O) 2 CH 2 CHO, -CH(CH 3 )OH, -CH 2 Br, -CH 2 OH, -CH 2 C(O)OH,
    所述卤素选自氟或氯。The halogen is selected from fluorine or chlorine.
  6. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药，其中，所述化合物如式(ⅡI)或式(IV)所示：
    The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, wherein the compound is such as formula (III) or formula (IV) Shown:
    其中，R1、R2、R3、R5、U1、U2、U3、n定义各自定义同式(I)化合物。Among them, the definitions of R 1 , R 2 , R 3 , R 5 , U 1 , U 2 , U 3 and n are the same as those of the compound of formula (I).
  7. 如权利要求1-6任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药，其中，所述化合物选自下组：





    The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is selected from the following group:





  8. 权利要求1-7任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物或其前药，其中，所述化合物如式(Ⅲ)或式(IV)所示，其通过包括以下步骤的方法制备得到：
    The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, wherein the compound is as represented by formula (III) or formula (IV) As shown, it is prepared by a method including the following steps:
    其中，Cy1、U1、U2、U3、R1、R2、R3、R5、n各自定义同式(Ⅲ)或式(IV)化合物；Among them, Cy1, U 1 , U 2 , U 3 , R 1 , R 2 , R 3 , R 5 and n are each defined as the compound of formula (III) or formula (IV);
    所述氧化剂选自叔丁基过氧化氢、过氧化氢、过氧化氢异丙苯、过氧化氢二异丙苯或2,2,6,6-四甲基哌啶氧化物；所述催化剂选自四丁基卤化铵、卤化钾、卤化钠或单质碘；所述溶剂选自甲醇、乙醇、叔丁醇、异丙醇、正丁醇、仲丁醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、二氯甲烷、氯仿、四氯化碳或1,2-二氯乙烷；The oxidizing agent is selected from tert-butyl hydroperoxide, hydrogen peroxide, cumene hydroperoxide, dicumyl hydroperoxide or 2,2,6,6-tetramethylpiperidine oxide; the catalyst Selected from tetrabutylammonium halide, potassium halide, sodium halide or elemental iodine; the solvent is selected from methanol, ethanol, tert-butanol, isopropanol, n-butanol, sec-butanol, N,N-dimethylmethane Amide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane;
    优选地，所述氧化剂为叔丁基过氧化氢；Preferably, the oxidizing agent is tert-butyl hydroperoxide;
    优选地，所述催化剂为四丁基碘化铵；Preferably, the catalyst is tetrabutylammonium iodide;
    优选地，所述溶剂为1,2-二氯乙烷；Preferably, the solvent is 1,2-dichloroethane;
    将上述式(Ⅲ)化合物与R5-NH2进行适当的羰胺缩合反应，得到式(IV)化合物；Carry out appropriate carbonylamine condensation reaction between the above-mentioned compound of formula (III) and R 5 -NH 2 to obtain the compound of formula (IV);
    任选地，所述式(Ⅲ-1)化合物通过包括以下步骤的方法制备得到：
    Optionally, the compound of formula (III-1) is prepared by a method including the following steps:
    其中，U1、U2、U3、Cy1、R1、R2、R3、n各自定义同式(Ⅲ)化合物；Among them, U 1 , U 2 , U 3 , Cy1, R 1 , R 2 , R 3 and n each define the same compound of formula (III);
    RX和RX’选自卤素原子、硼酸基或硼酸酯基，所述卤素原子选自F、Cl、Br；条件是：RX选自卤素原子时，RX’选自硼酸基或硼酸酯基，RX’选自卤素原子时，RX选自硼酸基或硼酸酯基； R _ _ _ Borate ester group, when R X' is selected from a halogen atom, R
    优选地，RX为B(OH)2，RX’为Br。Preferably, R X is B(OH) 2 and R X' is Br.
  9. 药物组合物，其特征在于，所述组合物包含根据权利要求1-7任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药或权利要求8所述的方法制备得到的化合物和药学上可接受的辅料。Pharmaceutical composition, characterized in that the composition contains a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a prodrug thereof, or a claim thereof. The compound prepared by the method described in 8 and pharmaceutically acceptable excipients.
  10. 权利要求1-7任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药、或权利要求8所述的方法制备得到的化合物、权利要求9所述的药物组合物在制备治疗与USP活性相关的疾病、心血管疾病、神经紊乱、癌症或免疫疾病的药物、或制备与USP活性相关的疾病、心血管疾病、神经紊乱、癌症、免疫疾病或患者预后评估的试剂盒中的用途；The compound of any one of claims 1-7, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the method of claim 8, claim 9 The pharmaceutical composition is useful in preparing drugs for treating diseases, cardiovascular diseases, neurological disorders, cancer, or immune diseases related to USP activity, or for preparing drugs for treating diseases, cardiovascular diseases, neurological disorders, cancer, and immune diseases related to USP activity. or use in kits for patient prognosis assessment;
    优选地，所述药物组合物中还包含另一种治疗心血管疾病、神经紊乱、癌症或免疫疾病的药物；Preferably, the pharmaceutical composition also contains another drug for treating cardiovascular diseases, neurological disorders, cancer or immune diseases;
    优选地，在制备治疗与USP21活性相关的疾病中的用途；Preferably, use in the preparation of treatments for diseases associated with USP21 activity;
    优选地，所述癌症包括前列腺癌、胰腺癌、乳腺癌、肺癌、脑癌、结肠癌、肾癌、膀胱癌、上皮性卵巢癌、肝癌以及白血病；Preferably, the cancer includes prostate cancer, pancreatic cancer, breast cancer, lung cancer, brain cancer, colon cancer, kidney cancer, bladder cancer, epithelial ovarian cancer, liver cancer and leukemia;
    更优选地，所述癌症包括胰腺癌、肝癌、乳腺癌、肾癌、膀胱癌以及肺癌。More preferably, the cancer includes pancreatic cancer, liver cancer, breast cancer, kidney cancer, bladder cancer and lung cancer.
  11. 权利要求1-7任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药、或权利要求8所述的方法制备得到的化合物、权利要求9所述的药物组合物在制备USP抑制剂中的用途；优选地，在制备USP21抑制剂中的用途。The compound of any one of claims 1-7, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the compound prepared by the method of claim 8, claim 9 The use of the pharmaceutical composition in the preparation of USP inhibitors; preferably, the use in the preparation of USP21 inhibitors.
  12. 一种抑制生物样品中的USP活性的方法，其包含使所述生物样品与根据权利要求1-7任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药、或权利要求8所述的方法制备得到的化合物、权利要求9所述的药物组合物接触。A method for inhibiting USP activity in a biological sample, which comprises making the biological sample and a compound according to any one of claims 1-7, its pharmaceutically acceptable salts, stereoisomers, and solvates , its prodrug, or the compound prepared by the method of claim 8, or the pharmaceutical composition of claim 9.
  13. 一种治疗与USP活性相关的疾病、心血管疾病、神经紊乱、癌症或免疫疾病的方法，其包含向有需要的患者施用权利要求1-7任一项所述的化合物、其药学上可接受的盐、立体异构体、溶剂合物、其前药、或权利要求8所述的方法制备得到的化合物或权利要求9所述的药物组合物的步骤。 A method of treating a disease, cardiovascular disease, neurological disorder, cancer or immune disease associated with USP activity, comprising administering to a patient in need thereof a compound of any one of claims 1-7, which is pharmaceutically acceptable The salt, stereoisomer, solvate, prodrug thereof, or the compound prepared by the method of claim 8 or the step of the pharmaceutical composition of claim 9.
PCT/CN2023/091368 2022-04-29 2023-04-27 Usp inhibitor, preparation method therefor, and application WO2023208151A1 (en)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3491145A (en) * 1966-03-19 1970-01-20 Merck Ag E Halomethylmercapto-fluorenimines
GB1314899A (en) * 1970-07-28 1973-04-26 Sterling Winthrop Group Ltd Thiosemicarbazones processes for their preparations and compositions incorporating them
JPS6071635A (en) * 1983-09-29 1985-04-23 Toshiba Corp Aromatic polyether and its manufacture
CN104471022A (en) * 2012-07-26 2015-03-25 东进世美肯株式会社 Organic light-emitting compound comprising acridine derivatives, and organic light-emitting device comprising same
CN104513147A (en) * 2014-11-20 2015-04-15 上海众强药业有限公司 Preparation method of fluorene ethyl ketone derivative
KR20160017241A (en) * 2014-08-01 2016-02-16 엘지디스플레이 주식회사 Heterocyclic compounds and organic light emitting diode device comprising the same
US20170088520A1 (en) * 2014-06-02 2017-03-30 Pharmakea, Inc. Deubiquitinase inhibitors
CN109320426A (en) * 2018-11-16 2019-02-12 长春海谱润斯科技有限公司 Material for organic electroluminescent device and organic electroluminescence device comprising it

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3491145A (en) * 1966-03-19 1970-01-20 Merck Ag E Halomethylmercapto-fluorenimines
GB1314899A (en) * 1970-07-28 1973-04-26 Sterling Winthrop Group Ltd Thiosemicarbazones processes for their preparations and compositions incorporating them
JPS6071635A (en) * 1983-09-29 1985-04-23 Toshiba Corp Aromatic polyether and its manufacture
CN104471022A (en) * 2012-07-26 2015-03-25 东进世美肯株式会社 Organic light-emitting compound comprising acridine derivatives, and organic light-emitting device comprising same
US20170088520A1 (en) * 2014-06-02 2017-03-30 Pharmakea, Inc. Deubiquitinase inhibitors
KR20160017241A (en) * 2014-08-01 2016-02-16 엘지디스플레이 주식회사 Heterocyclic compounds and organic light emitting diode device comprising the same
CN104513147A (en) * 2014-11-20 2015-04-15 上海众强药业有限公司 Preparation method of fluorene ethyl ketone derivative
CN109320426A (en) * 2018-11-16 2019-02-12 长春海谱润斯科技有限公司 Material for organic electroluminescent device and organic electroluminescence device comprising it

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WEI, ZHANG; SACHDEV S. SIDHU: "Development of Inhibitors in the Ubiquitination Cascade", FEBS LETTERS, vol. 588, no. 2, 12 November 2013 (2013-11-12), XP028669977, ISSN: 0014-5793, DOI: 10.1016/j.febslet.2013.11.003 *

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