WO2020192302A1 - Composé d'imidazole tri-substitué contenant de la pyrimidine et utilisation associée - Google Patents

Composé d'imidazole tri-substitué contenant de la pyrimidine et utilisation associée Download PDF

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WO2020192302A1
WO2020192302A1 PCT/CN2020/075475 CN2020075475W WO2020192302A1 WO 2020192302 A1 WO2020192302 A1 WO 2020192302A1 CN 2020075475 W CN2020075475 W CN 2020075475W WO 2020192302 A1 WO2020192302 A1 WO 2020192302A1
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substituted
alkyl
amino
methyl
ethyl
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蔡雄
翁运幄
卿远辉
林明生
刘斌
范福顺
封巧
刘怡婷
钱长庚
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广州必贝特医药技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a pyrimidine-containing tri-substituted imidazole compound and its application.
  • Lung cancer is the world’s largest malignant tumor in men and the third largest in women. In 2018, there were 2.09 million new cases and 1.761 million deaths worldwide (CA: Cancer J Clin. 2018; 68: 394-424), of which about 85% were non- Small cell lung cancer (NSCLC).
  • NSCLC non- Small cell lung cancer
  • EGFR is a member of the receptor tyrosine kinase (receptor tyrosine kinase, RTKs) family. It can specifically bind to the extracellular ligand epidermal growth factor (Epidermal Growth Factor) to cause conformational changes, trigger receptor dimerization and self Phosphorylation to activate and initiate a series of downstream cascade signal pathways, such as mitogen-activated protein kinase (mitogen-activated protein kinase, MAPK) signal transduction pathway and phosphatidylinositol-3 kinase (PI3K) signal transduction This pathway can ultimately promote the DNA synthesis and mitosis of target cells (J Clin Oncol 2008; 26:1742–1751).
  • MAPK mitogen-activated protein kinase
  • PI3K phosphatidylinositol-3 kinase
  • the mutation frequency of EGFR gene is very high, especially in Asian non-smokers. About 30%-40% of Asian NSCLC patients will have EGFR mutations, while only about 10% of white populations (Nat Rev Cancer 2010; 10: 760-774; Oncogene 2009; 28(Suppl 1): S24–S31).
  • the common mutation sites of EGFR gene occur in exons 18, 19, 20 and 21.
  • the non-frameshift deletion (ex19del) mutation of exon 19 accounts for about 45%, and the L858R point mutation of exon 21 accounts for about 45%. 40% (J Clin Oncol 2008; 26:1742–1751).
  • the first-generation targeted drugs developed for these two EGFR mutations include gefitinib (Iressa), erlotinib (Trocet), icotinib (Kemna), etc. These inhibitors It is a reversible competitive inhibitor that can competitively bind to the receptor adenosine triphosphate binding site in the tyrosine kinase domain. In these non-small cell lung cancer patients with EGFR activating mutations, the response rate of erlotinib and gefitinib is approximately 70% (Clin Cancer Res 2006; 12: 3908-3914).
  • Afatinib and Dacomitinib are second-generation EGFR inhibitors. Different from the first generation of reversible EGFR TKIs, afatinib and dacomitinib can irreversibly block EGFR and other related members of the ErbB family.
  • Dacomitinib significantly prolonged the progression-free survival of patients. The median progression-free survival in the Dacomitinib group was 14.7 months, while that in the gefitinib group was 9.2 months.
  • the duration of efficacy in the Dacomitinib group was longer at 14.8 months, while the gefitinib group had only 8.3 months.
  • T790M mutation The 790th amino acid position of exon 20 of wild-type EGFR gene is threonine (T), and the T790M mutation is that the 790th position of EGFR gene exon 20 has a large volume of methionine (M) instead of threonine (T).
  • the T790M mutation changes the affinity of ATP, causing the first and second generation EGFR TKIs (tyrosine kinase inhibitors) to not effectively block the signal, resulting in drug resistance (N Eng J Med 2005; 352:786-792; PLoS Med 2005; 2: e73; Oncogene 2009; 28(Suppl1): S24–S31.).
  • the FDA has successively approved ossitinib for use in patients with advanced NSCLC who have undergone TKI (first- and second-generation EGFR inhibitors) treatment, EGFR T790M mutation-positive advanced NSCLC, and as EGFR mutation (exon 19 deletion or exon) 21 L858R mutation) first-line treatment for patients with metastatic NSCLC.
  • TKI first- and second-generation EGFR inhibitors
  • EGFR T790M mutation-positive advanced NSCLC and as EGFR mutation (exon 19 deletion or exon) 21 L858R mutation) first-line treatment for patients with metastatic NSCLC.
  • the purpose of this study is to provide a class of compounds that can effectively inhibit the EGFR C797S mutation.
  • the present invention provides a pyrimidine-containing tri-substituted imidazole compound.
  • Such compounds can effectively inhibit the activity and cell proliferation of EGFR C797S mutants including EGFR ex19del/T790M/C797S and L858R/T790M/C797S, and can also inhibit enzymes including single point mutation ex19del and double point mutations such as L858R/T790M. Viability and cell proliferation.
  • X is selected from: CH or N;
  • Y is selected from: O, S, NH, or none;
  • R 1 is selected from: H, C1-C6 alkyl
  • R 2 is selected from: H, C1-C6 alkyl, C1-C6 alkoxy, halogen;
  • R 3 is selected from: H, C1-C6 alkyl
  • R 4 is selected from: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkyl;
  • Each R 9 is independently selected from: H, C1-C6 alkyl
  • Each R 10 is independently selected from: R 11 is a substituted C1-C10 alkyl, R 11 is a substituted C3-C8 cycloalkyl group, a substituted vinyl group R 11, R 11 substituted ethynyl; wherein each R 11 each Independently selected from: H, C1-C10 alkyl, C1-C10 alkyl substituted with C1-C6 alkoxy, C1-C10 alkyl substituted with amino, C1-C10 alkyl substituted with C1-C6 alkylamino , C1-C10 alkyl substituted with 3-8 membered heterocyclyl;
  • R 6 is selected from: H, or the following groups:
  • R 12 and R 13 are each independently selected from: H, C1-C6 alkyl
  • p is selected from: 1, 2, 3 or 4;
  • n is selected from: 0, 1 or 2;
  • n is selected from: 1, 2 or 3;
  • Z is selected from: C, N or O, and when Z is O, Q does not exist;
  • Q is selected from: H, C1-C12 alkyl, R 18 is a substituted C3-C8 cycloalkyl group, R 18 is a substituted 3-8 membered heterocyclyl, C3-C6 cycloalkyl substituted with methyl, C1-C12 alkyl Acyl group, C1-C12 alkyl substituted by hydroxy, -N(R 14 )(R 15 );
  • R 14 and R 15 are each independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted methyl, C1-C6 alkylsulfonyl, C1-C6 alkyl Acyl, or R 14 , R 15 and the N connected to it together form a 3-8 membered heterocyclic group substituted by R 18 ;
  • R 18 is selected from: H, C1-C12 alkyl, C1-C12 alkyl acyl, C1-C12 alkylsulfonyl, C1-C12 alkyl substituted by C1-C6 alkylsulfonyl, C1-C12 alkyl substituted by hydroxy Group, C1-C12 alkyl substituted with C1-C6 alkoxy, C1-C12 alkyl substituted with amino, C1-C12 alkyl substituted with C1-C6 alkylamino;
  • Ring A is a 5-12-membered substituted or unsubstituted monocyclic or bicyclic fused ring
  • the monocyclic or bicyclic fused ring is a saturated monocyclic or bicyclic fused ring, a partially unsaturated monocyclic or bicyclic fused ring or aromatic
  • a monocyclic or bicyclic fused ring, and the ring carbon atoms on the monocyclic or bicyclic fused ring are substituted with 0 to 5 heteroatoms, and the heteroatoms refer to O, N or S.
  • ring A is selected from:
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 are independently selected from: CR 16 or N;
  • Each R 16 is independently selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, C1-C6 alkyl substituted with hydroxy, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with amino, C1-C6 substituted with C1-C4 alkylamino Alkyl, C6-C10 aryl, C2-C10 heteroaryl, nitro, cyano, -OR, -N(R) 2 , -SR, -C(O)OR, -C(O)N(R ) 2 , -C(O)R, -S(O)R, -S(O) 2 R, -S(O) 2 N(R) 2
  • Each R 17 is independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1- C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C4 alkylamino substituted C1-C6 alkyl ;
  • Each R is independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 Alkyl, C1-C6 alkyl substituted with hydroxy, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with amino, C1-C6 alkyl substituted with C1-C4 alkylamino.
  • ring A is selected from:
  • ring A is selected from:
  • ring A is selected from:
  • Each R 17 is independently selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl , C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with amino, and C1-C6 alkyl substituted with C1-C4 alkylamino.
  • the pyrimidine-containing tri-substituted imidazole compounds have the structure shown in formula II:
  • W is selected from: R 7 is a substituted C1-C8 alkyl, R 7 is a substituted C3-C6 cycloalkyl group, R 7 is a substituted 3-7 membered heterocyclyl, R 7 is phenyl substituted with .
  • W is selected from: hydroxy-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, and hydroxyphenoxy-substituted C1-C6 alkyl.
  • W is selected from: n-propyl substituted with hydroxy, and n-butyl substituted with hydroxy.
  • R 1 is selected from: H, methyl, ethyl, and propyl.
  • R 2 is selected from: H, methyl, ethyl, propyl, methoxy, halogen.
  • R 3 is selected from: H, methyl, ethyl, and propyl.
  • R 4 is selected from: methoxy, ethoxy, propoxy, fluorine-substituted methoxy, fluorine-substituted ethoxy, and fluorine-substituted propoxy.
  • R 1 , R 2 and R 3 are all H, and R 4 is selected from methoxy or fluorine-substituted ethoxy.
  • each R 9 is independently selected from: H, C1-C3 alkyl
  • Each R 10 is independently selected from: R 11 is a substituted C1-C8 alkyl, R 11 is a substituted C3-C6 cycloalkyl group, a substituted vinyl group R 11, R 11 substituted ethynyl; wherein each R 11 each Independently selected from: H, C1-C6 alkyl, C1-C6 alkyl substituted with C1-C3 alkoxy, C1-C6 alkyl substituted with amino, C1-C6 alkyl substituted with C1-C3 alkylamino , C1-C6 alkyl substituted with 3-6 membered heterocyclyl.
  • each R 9 is independently selected from: H, methyl
  • Each R 10 is independently selected from: C1-C8 alkyl, C3-C6 cycloalkyl, vinyl, dimethylaminomethyl substituted vinyl, piperidine methyl substituted vinyl, methoxymethyl Substituted vinyl, C1-C6 alkyl substituted vinyl, ethynyl, C1-C6 alkyl substituted ethynyl.
  • R 5 is selected from: nitro, cyano, carboxamido, acetyl, formyl, methanesulfonamido, or the following groups:
  • R 9 is selected from: H;
  • R 10 is selected from: C1-C6 alkyl, C3-C6 cycloalkyl, vinyl, dimethylaminomethyl substituted vinyl, and C1-C3 alkyl substituted vinyl.
  • R 5 is selected from:
  • R 9 is selected from: H;
  • R 10 is selected from: C2-C4 alkyl, cyclopropyl, vinyl, propenyl.
  • R 6 is selected from: H, or the following groups:
  • R 9 is C1-C3 alkyl
  • R 12 and R 13 are both H
  • p is selected from: 1, 2, 3 or 4;
  • n is selected from: 0, 1 or 2;
  • n is selected from: 1, 2 or 3;
  • Z is selected from: C, N or O, and when Z is O, Q does not exist;
  • Q is selected from: H, C1-C6 alkyl group, R 18 is a substituted C3-C6 cycloalkyl group, R 18 is a substituted 3-6 membered heterocyclyl group, C1-C6 alkyl group, a hydroxy-substituted C1-C6 alkyl , -N(R 14 )(R 15 );
  • R 14 and R 15 are each independently selected from: H, C1-C3 alkyl, cyclopropyl, cyclopropyl substituted methyl, C1-C3 alkylsulfonyl, C1-C3 alkyl acyl, R 14 , R 15 and the N connected to it together form a 3-6 membered heterocyclic group substituted by R 18 ;
  • R 18 is selected from: H, C1-C6 alkyl, C1-C6 alkyl acyl, C1-C6 alkylsulfonyl, C1-C6 alkyl substituted with C1-C4 alkylsulfonyl, C1-C6 alkyl substituted with hydroxy Group, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with amino, C1-C6 alkyl substituted with C1-C4 alkylamino.
  • R 6 is selected from: H, or the following groups:
  • R 9 is C1-C3 alkyl
  • R 12 and R 13 are both H
  • p is 2
  • Both R 14 and R 15 are C1-C3 alkyl.
  • R 6 is selected from:
  • Q is selected from: H, C1-C4 alkyl group, R 18 is a substituted C3-C6 cycloalkyl group, R 18 is a substituted 5-6 membered heterocyclyl group, C1-C3 alkyl group, a hydroxy-substituted C1-C3 Alkyl group, -N(R 14 )(R 15 );
  • R 14 and R 15 are each independently selected from: H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted methyl, C1-C3 alkylsulfonyl, C1-C3 alkyl Acyl, or R 14 , R 15 and the N connected to it together form a 5-6 membered heterocyclic group substituted by R 18 ;
  • R 18 is selected from: H, C1-C4 alkyl, C1-C3 alkyl acyl, C1-C3 alkylsulfonyl, C1-C3 alkyl substituted by C1-C3 alkylsulfonyl, C1-C3 alkyl substituted by hydroxy Group, C1-C3 alkyl substituted with C1-C3 alkoxy, C1-C3 alkyl substituted with amino, C1-C3 alkyl substituted with C1-C3 alkylamino.
  • Q is selected from: H, -N(CH 3 ) 2 , -N(CH2CH 3 ) 2 , methyl, ethyl, propyl, methanesulfonamido, acetamido, cyclopropyl , Cyclopentyl, acetyl, hydroxy-substituted methyl, hydroxy-substituted ethyl,
  • Each R 18 is selected from: H, methyl, ethyl, isopropyl, butyl, acetyl, methyl substituted with methylsulfonyl, and ethyl substituted with methylsulfonyl.
  • the pyrimidine-containing tri-substituted imidazole compound is selected from the following compounds:
  • the tumor is a malignant tumor carrying EGFR gene mutations.
  • the EGFR gene mutation is selected from one or more of ex19del EGFR gene mutation, L858R EGFR gene mutation, T790M EGFR gene mutation, and C797S EGFR gene mutation.
  • the EGFR gene mutation is selected from: C797S EGFR gene mutation.
  • the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal cancer Hematoma, leukemia, histocytic lymphoma, nasopharyngeal carcinoma, head and neck tumor, colon cancer, rectal cancer or glioma.
  • the tumor is: non-small cell lung cancer.
  • the invention also provides a pharmaceutical composition for preventing and/or treating tumors.
  • a pharmaceutical composition for preventing and/or treating tumors comprising an active ingredient and a pharmaceutically acceptable carrier.
  • the active ingredient comprises the above-mentioned pyrimidine-containing tri-substituted imidazole compound or its pharmaceutically acceptable salt or its stereo Isomers or prodrug molecules.
  • the present invention prepares a series of new pyrimidine-containing tri-substituted imidazole compounds. These compounds can effectively inhibit EGFR C797S mutant enzyme activity and cell proliferation including EGFR ex19del/T790M/C797S and L858R/T790M/C797S, and simultaneously Single-point mutations such as L858R, ex19del and double-point mutations such as L858R/T790M, ex19del/T790M and other EGFR enzymes and cell proliferation also have high inhibitory activity, and most compounds have weak inhibitory effects on the proliferation of Ba/F3 mother cells that do not express EGFR Some compounds have weak inhibitory effects on the proliferation of cells expressing wild-type EGFR, suggesting that they have good selectivity. It has the potential to be used as a drug for the treatment of malignant tumors carrying EGFR C797S mutations, especially non-small cell lung cancer (NSCLC), and has great application value.
  • NSCLC non-small cell
  • Fig. 1 is a graph of drug concentration-time curves of compounds 3, 7, 15, 16, 19, 20, 26, 28, 34, 98, 104, 105 in Example 75.
  • the compound provided by the present invention is a pyrimidine-containing tri-substituted imidazole compound having the structure shown in formula I, or its pharmaceutically acceptable salt, or its stereoisomer or its prodrug molecule:
  • X is selected from: CH or N;
  • Y is selected from: O, S, NH, or none;
  • R 1 is selected from: H, C1-C6 alkyl
  • R 2 is selected from: H, C1-C6 alkyl, C1-C6 alkoxy, halogen;
  • R 3 is selected from: H, C1-C6 alkyl
  • R 4 is selected from: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkyl;
  • Each R 9 is independently selected from: H, C1-C6 alkyl
  • Each R 10 is independently selected from: R 11 is a substituted C1-C10 alkyl, R 11 is a substituted C3-C8 cycloalkyl group, a substituted vinyl group R 11, R 11 substituted ethynyl; wherein each R 11 each Independently selected from: H, C1-C10 alkyl, C1-C10 alkyl substituted with C1-C6 alkoxy, C1-C10 alkyl substituted with amino, C1-C10 alkyl substituted with C1-C6 alkylamino , C1-C10 alkyl substituted with 3-8 membered heterocyclyl;
  • R 6 is selected from: H, or the following groups:
  • R 12 and R 13 are each independently selected from: H, C1-C6 alkyl
  • p is selected from: 1, 2, 3 or 4;
  • n is selected from: 0, 1 or 2;
  • n is selected from: 1, 2 or 3;
  • Z is selected from: C, N or O, and when Z is O, Q does not exist;
  • Q is selected from: H, C1-C12 alkyl, R 18 is a substituted C3-C8 cycloalkyl group, R 18 is a substituted 3-8 membered heterocyclyl, C3-C6 cycloalkyl substituted with methyl, C1-C12 alkyl Acyl group, C1-C12 alkyl substituted by hydroxy, -N(R 14 )(R 15 );
  • R 14 and R 15 are each independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted methyl, C1-C6 alkylsulfonyl, C1-C6 alkyl Acyl, or R 14 , R 15 and the N connected to it together form a 3-8 membered heterocyclic group substituted by R 18 ;
  • R 18 is selected from: H, C1-C12 alkyl, C1-C12 alkyl acyl, C1-C12 alkylsulfonyl, C1-C12 alkyl substituted by C1-C6 alkylsulfonyl, C1-C12 alkyl substituted by hydroxy Group, C1-C12 alkyl substituted with C1-C6 alkoxy, C1-C12 alkyl substituted with amino, C1-C12 alkyl substituted with C1-C6 alkylamino;
  • Ring A is a 5-12-membered substituted or unsubstituted monocyclic or bicyclic fused ring
  • the monocyclic or bicyclic fused ring is a saturated monocyclic or bicyclic fused ring, a partially unsaturated monocyclic or bicyclic fused ring or aromatic
  • a monocyclic or bicyclic fused ring, and the ring carbon atoms on the monocyclic or bicyclic fused ring are substituted with 0 to 5 heteroatoms, and the heteroatoms refer to O, N or S.
  • substitution in the present invention means that one or more replaceable hydrogen atoms in the given structure are replaced by specific substituents.
  • a substituted group may have a substituent at each substitutable position of the group. Substitution, when more than one position in the given structural formula can be substituted by one or more substituents of a specific group, then the substituents can be substituted at each position, the same or different.
  • Ca-Cb means containing a to b carbon atoms
  • Ca-Cb alkyl means a linear or branched saturated alkyl containing a to b carbon atoms, including methyl and ethyl , Propyl, isopropyl,..., such as "C1-C12 alkyl” means a linear or branched saturated alkyl containing 1 to 12 carbon atoms
  • Ca-Cb alkoxy means containing A group consisting of an alkyl group with a to b carbon atoms and an oxygen atom, including methoxy, ethoxy, propoxy, isopropoxy, etc.
  • Ca-Cb cycloalkyl means containing a Monocyclic saturated aliphatic hydrocarbon groups with up to b carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.
  • halogen means chlorine, fluorine, bromine and iodine.
  • the present invention includes the free form of the compound of formula I-II, as well as its pharmaceutically acceptable salts and stereoisomers.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form” refers to amine compounds in non-salt form.
  • the included pharmaceutically acceptable salts include not only the exemplary salts of the specific compounds described herein, but also the typical pharmaceutically acceptable salts of all compounds of formula I-II in free form.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous alkali solution such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, a dilute ammonia and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous alkali solution such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, a dilute ammonia and a dilute aqueous solution of sodium bicarbonate.
  • the free forms are somewhat different from their respective salt forms in certain physical properties such as solubility in polar solvents, but for the purpose of the invention, the acid and base salts are equivalent to their respective free forms in other pharmaceutical aspects.
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the compound of the present invention containing a basic part or an acidic part by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reacting a free base and a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in an appropriate solvent or a combination of solvents.
  • the salt of an acidic compound is formed by reacting with a suitable inorganic or organic base.
  • the pharmaceutically acceptable salt of the compound of the present invention includes the conventional non-toxic salt of the compound of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.
  • conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyruvic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl Salts prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanes
  • the appropriate "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganous salt, potassium salt, sodium salt, zinc salt, etc. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as refined Acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , Piperidine, quama, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • substituted amines include
  • the present invention includes the compound of formula I, and also includes its prodrug, that is, the prodrug that can be transformed into the structure of the compound of the present invention and its pharmaceutically acceptable salt in vivo, and is also included in the claims of the present application.
  • R is C1-C6 alkyl or C1-C6 alkyl substituted by halogen;
  • R 21 is H, C1-C6 alkyl or phenyl substituted by R 8 ;
  • R 6 , R 8 , R 10 , and R 16 are as defined As mentioned above;
  • y is an integer between 1-12;
  • q is 1 or 2.
  • R is C1-C6 alkyl or C1-C6 alkyl substituted by halogen;
  • R 21 is H, C1-C6 alkyl or phenyl substituted by R 8 ;
  • R 6 , R 8 , R 10 , and R 16 are as defined As mentioned above;
  • y is an integer between 1-12;
  • q is 1 or 2.
  • R is C1-C6 alkyl or C1-C6 alkyl substituted by halogen;
  • R 21 is H, C1-C6 alkyl or phenyl substituted by R 8 ;
  • R 6 , R 8 , R 10 , and R 16 are as defined As mentioned above;
  • y is an integer between 1-12;
  • q is 1 or 2;
  • A is O, S or NH.
  • R is C1-C6 alkyl or C1-C6 alkyl substituted by halogen;
  • R 21 is H, C1-C6 alkyl or phenyl substituted by R 8 ;
  • R 6 , R 8 , R 10 , and R 16 are as defined As mentioned above;
  • y is an integer between 1-12;
  • q is 1 or 2;
  • A is O, S or NH.
  • R is C1-C6 alkyl or C1-C6 alkyl substituted by halogen;
  • R 21 is H, C1-C6 alkyl or phenyl substituted by R 8 ;
  • R 6 , R 8 , R 10 , and R 16 are as defined As mentioned above;
  • y is an integer between 1-12;
  • q is 1 or 2;
  • A is O, S or NH.
  • R 6 , R 10 , and R 16 are as defined above; R is a C1-C6 alkyl group or a halogen-substituted C1-C6 alkyl group.
  • R is C1-C6 alkyl or C1-C6 alkyl substituted by halogen;
  • R 21 is H, C1-C6 alkyl or phenyl substituted by R 8 ;
  • R 6 , R 8 , R 10 , and R 16 are as defined As mentioned above;
  • y is an integer between 1-12;
  • q is 1 or 2.
  • the compounds with the structure of formula I-II and their pharmaceutically acceptable salts and their stereoisomers and prodrug molecules provided by the present invention can be used to inhibit the activity of mutant EGFR, especially one or more of the following EGFR activity of gene mutations: ex19del EGFR gene mutation, L858R EGFR gene mutation, T790M EGFR gene mutation and C797S EGFR gene mutation. Therefore, the compounds of the present invention can be used to treat or prevent hyperproliferative diseases or symptoms such as human or other mammalian tumors.
  • non-small cell lung cancer small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, Histocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma and other transitional proliferative diseases.
  • non-small cell lung cancer small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, Histocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma and other transitional proliferative diseases.
  • non-small cell lung cancer Especially for the treatment or control of non-small cell lung cancer.
  • the present invention also provides a pharmaceutical composition, which contains active ingredients in a safe and effective amount, and a pharmaceutically acceptable carrier.
  • the "active ingredient” described in the present invention includes the compound of formula I-II described in the present invention or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule.
  • the pharmaceutical composition of the present invention can be used as an EGFR protease inhibitor, and can be used to prepare drugs for preventing and/or treating tumors.
  • Safety and effective amount refers to: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity.
  • composition here means that the components in the composition can be blended with the active ingredients of the present invention and between them without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid). , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose
  • the compounds of formula I-II of the present invention can form complexes with macromolecular compounds or polymers through non-bonding interactions.
  • the compounds of formula I-II of the present invention as small molecules can also be connected to macromolecular compounds or macromolecules through chemical bonds.
  • the macromolecular compound may be a biological macromolecule such as high glycans, proteins, nucleic acids, polypeptides and the like.
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), etc.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients:
  • Fillers or compatibilizers for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;
  • Binders for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;
  • Humectants for example, glycerin
  • Disintegrants for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • a slow solvent such as paraffin
  • wetting agents such as cetyl alcohol and glyceryl monostearate
  • Sorbent for example, kaolin
  • Lubricants for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.
  • the dosage form may also contain buffering agents.
  • the solid dosage forms can also be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of active ingredients in such compositions may be released in a certain part of the digestive tract in a delayed manner.
  • coatings and shell materials such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of active ingredients in such compositions may be released in a certain part of the digestive tract in a delayed manner.
  • embedding components that can be used are polymeric substances and waxes.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compound of the present invention can be administered alone or in combination with other therapeutic drugs (such as hypoglycemic agents).
  • other therapeutic drugs such as hypoglycemic agents.
  • a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) in need of treatment, where the dosage is the pharmaceutically effective dosage considered to be administered.
  • a mammal such as a human
  • the daily The dosage is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • Combination drugs The compounds of formula I-II can be combined with other drugs known to treat or improve similar conditions. When combined administration, the original drug administration mode and dosage remain unchanged, while the compound of formula I-II is administered at the same time or subsequently. When the compound of formula I-II is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I-II.
  • the combination of drugs also includes taking the compound of formula I-II and one or more other known drugs in overlapping time periods. When the compound of formula I-II is used in combination with one or more other drugs, the dose of the compound of formula I-II or known drugs may be lower than the dose when they are used alone.
  • the drugs or active ingredients that can be used in combination with the compounds of formula I-II include but are not limited to:
  • the drugs or active ingredients that can be used in combination with the compound of formula I-II include but are not limited to: aldesleukin, alendronic acid, interferon, atranoin, allopurinol, allopurinol, Sodium purine, palonosetron hydrochloride, hexamethylmelamine, aminogluminide, amifostine, amrubicin, an acridine, anatozole, dolastron, aranesp, arglabin, Arsenic trioxide, arsenoxine, 5-azacytidine, azathioprine, BCG or tice BCG, betamethasone, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromuria Glycine, bortezomib, busulfan, calcitonin, alemtuzumab injection, capecitabine, carboplatin, constellation, ce
  • Such compounds can effectively inhibit EGFR protein kinase resistance mutants (including ex19del EGFR mutation, L858R EGFR mutation, T790M EGFR mutation and C797S EGFR mutation), and can be used to prepare anti-tumor drugs.
  • Such compounds can overcome drug resistance induced by existing drugs, are selective to wild-type EGFR, and have good pharmacokinetic properties.
  • Example 1 N-(3-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino) -4-Methoxyphenyl)acrylamide (N-(3-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2- yl)amino)-4-methoxyphenyl)acrylamide) (Compound 1) preparation (prepared according to the route of Scheme 1)
  • Step 1a Preparation of 3-(triisopropylsilyloxy)propan-1-ol (3-((triisopropylsilyl)oxy)propan-1-ol) (compound 0102-1): under nitrogen protection, in an ice water bath In the tetrahydrofuran (50 ml) solution of 1,3-propanediol (0101-1) (5.0 g, 65.8 mmol, 1.0 equiv) was added 60% sodium hydride (4.0 g, 98.7 mmol, 1.5 equiv) in batches ).
  • Step 1d 4-(4-fluorophenyl)-2-(2-(triisopropylsiloxy)ethyl)-1H-imidazole(4-(4-fluorophenyl)-2-(2-(( Preparation of triisopropylsilyl)oxy)ethyl)-1H-imidazole)
  • Compound 0106-1 2-(4-fluorophenyl)-2-oxoacetaldehyde (0105-1) (0.86 g, 5.65 mmol, 1.0 equivalent) in methanol (20 ml) was added dropwise to 3-(triisopropylsiloxy)propionaldehyde (0103-1) (1.3 g, 5.65 mmol, 1.0 equivalent) and ammonium acetate (2.2 g, 28.25) Millimoles, 5.0 equivalents) in a mixed solution of methanol (30 ml).
  • Step 1e 4-(4-Fluorophenyl)-1-(methoxymethyl)-2-(2-(triisopropylsiloxy)ethyl)-1H-imidazole (4-(4- Preparation of fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazol (compound 0107-1): under the protection of nitrogen, in an ice water bath, to 4-(4- Fluorophenyl)-2-(2-(triisopropylsiloxy)ethyl)-1H-imidazole (0106-1) (1.0 g, 2.75 mmol, 1.0 equivalent) of N,N-dimethyl Add 60% sodium hydride (220 mg, 5.50 mmol, 2.0 equivalents) to the solution of formamide (10 ml) in batches.
  • Step 1f 4-(4-Fluorophenyl)-5-iodo-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-
  • imidazole (4-(4-fluorophenyl)-5-iodo-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole)
  • Compound 0108-1 To 4- (4-Fluorophenyl)-1-(methoxymethyl)-2-(2-(triisopropylsiloxy)ethyl)-1H-imidazole (0107-1) (4.3 g, 10.59 milli N-iodosuccinimide (2.74 g, 12.18 mmol, 1.15 equiv) was added to a solution of acetonitrile (50 ml) in 1.0 equivalent), and the mixture was stirred at room temperature for
  • Step 1g 4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-5-(trimethyl Stannyl)-1H-imidazole (4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-5-(trimethylstannyl)-1H-imidazole) (Compound 0109 -1) Preparation: Under the protection of nitrogen, at a temperature lower than -65°C, to 4-(4-fluorophenyl)-5-iodo-1-(methoxymethyl)-2-(2-( (Triisopropylsilyl)oxy)ethyl)-1H-imidazole (0108-1) (1.5 g, 2.82 mmol, 1.0 equivalent) in tetrahydrofuran (25 ml) was added dropwise n-butyl lithium (
  • Step 1h 4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole -5-yl)-2-(methylthio)pyrimidine(4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazol- Preparation of 5-yl)-2-(methylthio)pyrimidine) (Compound 0111-1): Under nitrogen protection, 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl (195 A 1,4-dioxane (15 mL) solution of palladium acetate (30 mg, 0.14 mmol, 0.05 equivalent) and palladium acetate (30 mg, 0.14 mmol, 0.05 equivalent) was stirred at room temperature for 30 minutes
  • Step 1i 4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole -5-yl)-2-(methylsulfonyl)pyrimidine(4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazol -5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0112-1): To compound 4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-( 2-((Triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (0111-1) (478 mg, 0.9 mmol, 1.0 equivalent M-chloroperoxybenzoic
  • Step 1j 4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole -5-yl)pyrimidin-2-amine (4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl) pyrimidin-2-amine) (Compound 0113-1): To compound 4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropyl) (Silyl)oxy)ethyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (0112-1) (506 mg, 0.9 mmol, 1.0 equivalent) in tetrahydrofuran (5 mL ) Add ammonia (1
  • Step 1k 4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole -5-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidin-2-amine(4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2- ((triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidin-2-amine) (Compound 0115-1): Under the protection of nitrogen, the 4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole-5- Base) pyrimidin-2-amine (0113-1) (250 mg, 0.5 mmol
  • Step 11 N-(3-((4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy) Ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(3-((4-(4-(4-fluorophenyl)- 1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide)(Compound 0116-1) Preparation: 4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole -5-yl)-N-(2-
  • Step 1m N-(3-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)- 4-Methoxyphenyl)acrylamide (N-(3-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl )amino)-4-methoxyphenyl)acrylamide) (Compound 1): N-(3-((4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2- (2-((Triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (0116-1 ) (185 mg, 0.274 mmol, 1.0 equivalent) was
  • Example 2 N-(3-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino) -4-Methoxyphenyl)propionamide N-(3-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl )amino)-4-methoxyphenyl)propionamide (compound 2) preparation (prepared according to the route of scheme 1)
  • Step 2a N-(3-((4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy) Ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide (N-(3-((4-(4-(4-fluorophenyl)- 1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide)(Compound 0116-2) Preparation: 4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole -5-yl)-N
  • Step 2b N-(3-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)- 4-Methoxyphenyl)propionamide (N-(3-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl )amino)-4-methoxyphenyl)propionamide) (Compound 2): Add N-(3-((4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2- (2-((Triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide (0116-2 ) (110 mg, 0.16 mmol, 1.0
  • the reaction system was stirred at 50°C for 16 hours. Water was added, 2M sodium hydroxide aqueous solution was added dropwise to adjust the pH to 14, and after liquid separation, the aqueous phase was extracted twice with dichloromethane. The obtained organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 3 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(2 -Hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl )amino)-5-((4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 3) preparation (prepared according to scheme 1 route)
  • Step 3a N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2 -((Triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene- 1,4-Diamine (N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy )ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine) (Compound 0115-3) Preparation: under nitrogen protection Next, the
  • Step 3b N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-1-(methoxy Methyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl )Acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2- ((triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 0116-3) preparation: N 1 -(2-( ⁇ Meth
  • Step 3c N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(2- Hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl) amino)-5-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide)( Compound 3) Preparation: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-1 -(Methoxymethyl)-2-(2-
  • the reaction system was stirred at 85°C for 16 hours. Water was added, 2M sodium hydroxide aqueous solution was added dropwise to adjust the pH to 14, and after liquid separation, the aqueous phase was extracted twice with dichloromethane. The obtained organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 4a N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-1-(methoxy Methyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl )Propionamide (N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-1-(methoxymethyl)-2-(2- ((triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide) (Compound 0116-4) Preparation: N 1 -(2-( ⁇
  • Step 4b N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(2- Hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide (N-(2-((2-(dimethylamino)ethyl)(methyl) amino)-5-((4-(4-(4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide)( Compound 4) Preparation: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-1 -(Methoxymethyl)-2-
  • the reaction system was stirred at 50°C for 16 hours. Water was added, 2M sodium hydroxide aqueous solution was added dropwise to adjust the pH to 14, and after liquid separation, the aqueous phase was extracted twice with dichloromethane. The obtained organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 5 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(3 -Hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl )amino)-5-((4-(4-fluorophenyl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 7) preparation (prepared according to scheme one and two routes)
  • Step 5a Preparation of 4-(triisopropylsilyloxy)butan-1-ol (4-((triisopropylsilyl)oxy)butan-1-ol) (compound 0102-7): under nitrogen protection, in ice In a water bath, to 1,4-butanediol (0101-7) (7.46 g, 82.9 mmol, 1.0 equivalent) in tetrahydrofuran (60 ml) was added 60% sodium hydride (3.64 g, 91.1 mmol) in batches , 1.1 equivalent).
  • Step 5c 4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole 4-(4-fluorophenyl)-2-(3- Preparation of ((triisopropylsilyl)oxy)propyl)-1H-imidazole (Compound 0106-7): To 2-(4-fluorophenyl)-2-oxoacetaldehyde (0105-1) (2.0 g, 13.15 mmol) , 1.0 equivalent) and 3-(triisopropylsiloxy) butyraldehyde (0103-7) (3.2 g, 13.15 mmol, 1.0 equivalent) in methanol (60 mL) was added ammonium acetate (5 g, 65.79 mmol) Mol, 5.0 equivalents).
  • Step 5d 4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy Yl)methyl)-1H-imidazole(4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole) (Compound 0201-7): Under the protection of nitrogen, in an ice water bath, to 4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)- 1H-imidazole (0106-7) (4.96 g, 13.15 mmol, 1.0 equivalent) in N,N-dimethylformamide (50 ml) was added in batches with 60% sodium hydride (1.05 mg, 26.3 mg) Mol, 2.0 equivalents).
  • Step 5e 4-(4-Fluorophenyl)-5-iodo-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilane) (Yl)ethoxy)methyl)-1H-imidazole(4-(4-fluorophenyl)-5-iodo-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-imidazole) (Compound 0202-7): To 4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1 -((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole (0201-7) (1.5 g, 3.1 mmol, 1.0 equivalent) in acetonitrile (30 ml) N-iodosuccinimide
  • Step 5f Preparation of 2-methylthio-4-(trimethylstannyl)pyrimidine (2-(methylthio)-4-(trimethylstannyl)pyrimidine) (compound 0203-7): under the protection of nitrogen, to 4-chloro -2-Methylthiopyrimidine (5.0 g, 31.1 mmol, 1.0 equivalent) and sodium iodide (23.0 g, 155.5 mmol, 5.0 equivalent) in acetonitrile (80 mL) was added trimethylsilyl iodide (0.5 mL) ), the mixture was heated to reflux for 2 hours. After cooling to room temperature, the reaction solution was quenched with sodium bisulfite aqueous solution and stirred for 10 minutes.
  • 4-chloro -2-Methylthiopyrimidine 5.0 g, 31.1 mmol, 1.0 equivalent
  • sodium iodide 23.0 g, 155.5 mmol, 5.0 equivalent
  • Step 5g 4-(4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl) )Ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine(4-(4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine) (Compound 0204-7) Preparation: Under nitrogen protection, 4-(4- Fluorophenyl)-5-iodo-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-imidazole (0202-7) (1 g, 1.58
  • Step 5h 4-(4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl) )Ethoxy)Methyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine(4-(4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy) propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0205-7): To 4-(4-(4 -Fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Imidazol-5-yl)-2
  • Step 5i 4-(4-(4-Fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl) )Ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine(4-(4-(4-fluorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1- Preparation of ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine) (Compound 0206-7): In a stuffy pot, 4-(4-(4-fluorobenzene) Yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- A mixture of 5-yl)-2-(methyls
  • Step 5j N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(3-((triisopropylsilyl) (Oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy- N 1 -Methyl-2-nitrobenzene-1,4-diamine (N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(3 -((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2- nitrobenzen
  • Step 5k N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(3- ((Triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidine-2- (Amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl) -2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) acrylamide) (Compound 0208
  • Step 51 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(3- Hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl) amino)-5-((4-(4-(4-fluorophenyl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide)( The preparation of compound 7): To N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2 -(3-((Triisopropyl
  • Propionyl chloride (15.5 mg, 0.17 mmol, 2.5 equivalents) was added dropwise to the mixture. The mixture was stirred at room temperature for 15 minutes. The mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 7 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(2 -Methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl) (methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) acrylamide) (Compound 9) preparation (prepared according to the route of Scheme 1)
  • Step 7a 4-(4-fluorophenyl)-2-(2-methoxyethyl)-1H-imidazole (4-(4-fluorophenyl)-2-(2-methoxyethyl)-1H-imidazole) ( Preparation of compound 0106-9): To a solution of 3-methoxypropane-1-ol (500 mg, 5.55 mmol, 1.0 equivalent) in dimethyl sulfoxide (20 mL) was added 2-iodoyl benzoic acid (2.3 G, 8.33 mmol, 1.5 equivalents). The mixture was stirred at room temperature for 16 hours.
  • Step 7b 2. 4-(4-fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazole(4-(4-fluorophenyl)-2-( The preparation of 2-methoxyethyl)-1-(methoxymethyl)-1H-imidazole) (compound 0107-9): under nitrogen protection, in an ice water bath, to 4-(4-fluorophenyl)-2-(2-methyl (Oxyethyl)-1H-imidazole (0106-9) (400 mg, 1.818 mmol, 1.0 equivalent) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride in batches (145 mg, 3.636 mmol, 2.0 equivalents).
  • Step 7c 5-bromo-4-(4-fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazole
  • Compound 0108-9 To 4-(4-fluorophenyl)-2-(2-methoxy Ethyl)-1-(methoxymethyl)-1H-imidazole (0107-9) (252 mg, 0.89 mmol, 1.0 equivalent) in acetonitrile (10 mL) was added N-bromobutane Imide (183 mg, 1.027 mmol, 1.15 equivalents), and the mixture was stirred at room temperature for 3 hours.
  • Step 7d 4-(4-(4-Fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)-2-( Methylthio)pyrimidine
  • Step 7e 4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)-2-( Methylsulfinyl)pyrimidine(4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)-2-(methylsulfinyl)pyrimidine)( Compound 0112-9) preparation: to 4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazole-5- A solution of m-chloroperoxybenzoic acid (100 mg, 0.58 mmol , 1.5 equivalents).
  • Step 7f 4-(4-(4-Fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)pyrimidine-2-
  • amine 4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)pyrimidin-2-amine)
  • Compound 0113-9) In the stuffy pot, 4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)-2
  • a mixture of -(methylsulfinyl)pyrimidine (0112-9) (156 mg, 0.38 mmol, 1.0 equivalent) and ammonia (1 mL) in tetrahydrofuran (5 mL) was stirred at 85°C for 2 hours.
  • Step 7g N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1- (Methoxymethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine (N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)pyrimidin-2 -yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine) (Compound 0115-9) preparation: 4-(4-(4-fluorophenyl)-2 under nitrogen protection -(2-Methoxyethyl)-1
  • Step 7h N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1H- (Imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine (N 1 -(2-(dimethylamino)ethyl)- N 4 -(4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene -1,4-diamine) (Compound 0116-9): To N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)- 2-(2-Meth
  • Step 7i N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(2- (Methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)( methyl)amino)-5-((4-(4-fluorophenyl)-2-(2-methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ) Preparation of (Compound 9): N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(2-methoxyethyl)-4
  • Example 8 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-phenyl -1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5 -((4-(2-(3-hydroxypropyl)-4-phenyl-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 14) (according to the protocol One line preparation)
  • Step 8b 4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole 4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)- Preparation of 1H-imidazole (Compound 0106-14): Add 2-oxo-2-phenylacetaldehyde (0105-14) (1.11 g, 8.32 mmol, 1.0 equivalent) and 4-(triisopropylsiloxy A solution of butyl aldehyde (0103-7) (2.80 g, 11.6 mmol, 1.4 equivalents) in methanol (50 mL) was added with ammonium acetate (1.92 g, 24.9 mmol, 3.0 equivalents).
  • Step 8c 1-(Methoxymethyl)-4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (1-(methoxymethyl)-4 -Phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0107-14): Under nitrogen protection, in an ice water bath, to 4-phenyl-2-(3- ((Triisopropylsilyl)oxy)propyl)-1H-imidazole (0106-14) (1.00 g, 2.70 mmol, 1.0 equivalent) of N,N-dimethylformamide (30 mL) 60% sodium hydride (335 mg, 8.38 mmol, 3.0 equivalents) was added to the solution in batches.
  • Step 8d 5-bromo-1-(methoxymethyl)-4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole
  • Compound 0108-14 Preparation: To 1-(methoxymethyl)-4- Phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0107-14) (500 mg, 1.24 mmol, 1.0 equivalent) in acetonitrile (15 mL) N-Bromosuccinimide (233 mg, 1.3 mmol, 1.05 equivalent) was added to the solution, and the mixture was stirred at room temperature for 1 hour.
  • reaction solution was quenched with aqueous sodium bisulfite solution and stirred for 10 minutes.
  • Acetic acid was added Extract with ethyl acetate, wash the organic layer with brine, and concentrate under reduced pressure.
  • Step 8e 4-(1-(Methoxymethyl)-4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl) -2-(Methylthio)pyrimidine(4-(1-(methoxymethyl)-4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylthio )pyrimidine) (Compound 0111-14): under nitrogen protection, 5-bromo-1-(methoxymethyl)4-phenyl-2-(3-((triisopropylsilyl)oxy ) Propyl)-1H-imidazole (0108-14) (460 mg, 0.956 mmol, 1.0 equivalent), 2-(methylthio)-4-(trimethylstannyl)pyrimidine (0203-7) (388 A mixture of 1 mg, 1.34 mmol, 1.4 equivalent) and bis(
  • Step 8f 4-(1-(Methoxymethyl)-4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl) -2-(Methylsulfonyl)pyrimidine(4-(1-(methoxymethyl)-4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfonyl )pyrimidine) (Compound 0112-14): To 4-(1-(methoxymethyl)-4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl )-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (0111-14) (390 mg, 0.74 mmol, 1.0 equivalent) in dichloromethane (10 mL) was added to m-chloroperoxybenzene Formic
  • Step 8g 4-(1-(Methoxymethyl)-4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl) Pyrimidine-2-amine
  • Step 8h N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 --(4-(1-(methoxymethyl)-4-phenyl-2-( 3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 1 -methyl-2-nitrobenzene-1,4-di Amine (N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 -(4-(1-(methoxymethyl)-4-phenyl-2-(3-((triisopropylsilyl)oxy)propyl)-1H -imidazol-5-yl)pyrimidin-2-yl)-N 1 -methyl-2-nitrobenzene-1,4-diamine) (Compound 0115-14) preparation: under the protection of nitrogen, 4-(1-(methoxy Methyl)-4-phenyl
  • Step 8i N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-phenyl- 1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5- ((4-(2-(3-hydroxypropyl)-4-phenyl-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 14): To N 1 -(2-(Dimethylamino)ethyl)-5-methoxy-N 4 --(4-(1-(methoxymethyl)-4-phenyl-2-(3-(( ⁇ Isopropylsilyl)oxy)propyl)-1H-imida
  • N,N-Diisopropylethylamine (1 mL) and acetonitrile (15 mL) were added, and the mixture was refluxed overnight. After cooling to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was concentrated under reduced pressure.
  • Example 9 N-(5-((4-(4-(benzofuran-6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran -6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- Preparation of methoxyphenyl)acrylamide) (compound 15) (prepared according to the route of Scheme 3)
  • Step 9a Preparation of 3-hydroxy-4-iodophenyl acetophenone (1-(3-hydroxy-4-iodophenyl)ethan-1-one) (compound 0302-15): under the protection of nitrogen, To a solution of ketone (0301-15) (25.0 g, 185.0 mmol, 1.0 equivalent) in acetic acid (250 ml) was added N-iodosuccinimide (45.8 g, 203.7 mmol, 1.1 equivalent), and the mixture was Stir overnight at room temperature. The reaction solution was poured into water and stirred for 30 minutes.
  • Step 9b Preparation of 1-(benzofuran-6-)ethan-1-one (1-(benzofuran-6-yl)ethan-1-one) (compound 0303-15): under nitrogen protection, turn 3 -Hydroxy-4-iodoacetophenone (0302-15) (25.6 g, 97.9 mmol, 1.0 equivalent), triethylamine (30.0 g, 293.8 mmol, 3.0 equivalent), cuprous iodide (380 mg, 1.96 To a solution of bis(triphenylphosphine) palladium dichloride (2.00 g, 2.94 mmol, 0.03 equiv) in tetrahydrofuran (350 ml) was added trimethylethynylsilane (19.2 g, 195.8 Millimoles, 2.0 equivalents), and the mixture was stirred at 62°C overnight.
  • selenium dioxide A mixture of 11.4 g, 102.4 mmol, 1.3 equivalents
  • water 10:1 (165 ml) was heated to 60°C until a clear solution appeared.
  • 1-(benzofuran-6-yl)ethane-1-one (0303-15) (12.6 g, 78.8 mmol
  • Step 9d 4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole (4-(benzofuran-6-yl)- Preparation of 2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazole)
  • Compound 0305-15 To 2-(benzofuran-6-yl)-2-oxoacetaldehyde (0304-15 ) (2.0 g, 11.5 mmol, 1.0 equivalent) and 3-(triisopropylsiloxy) propanal (0103-1) (4.0 g, 17.2 mmol, 1.5 equivalent) in methanol (60 mL) were added Ammonium acetate (4.4 g, 57.5 mmol, 5.0 equivalents).
  • Step 9e 4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-(trimethylsilyl) Ethoxy)methyl)-1H-imidazole(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- Preparation of 1H-imidazole) (Compound 0306-15): Under the protection of nitrogen, in an ice water bath, to 4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl) oxygen (Base) ethyl) -1H-imidazole (0305-15) (2.0 g, 5.2 mmol, 1.0 equivalent) in N,N-dimethylformamide (50 mL) was added 60% sodium hydride in batches (416 mg, 10.4 mmol, 2.0 equivalents
  • Step 9f 4-(benzofuran-6-yl)-5-bromo-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-(trimethyl (Silyl)ethoxy)methyl)-1H-imidazole (4-(benzofuran-6-yl)-5-bromo-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole) (Compound 0307-15): To 4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy ) Ethyl)-1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole (0306-15) (1.0 g, 1.9 mmol, 1.0 equivalent) of acetonitrile (30 (Ml) was added N-bromosuccinimide (416 mg, 2.3 mmol
  • Step 9g 4-(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-(trimethylmethyl Silyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (4-(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl) )oxy)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine) (Compound 0308-15) Preparation: Under nitrogen protection, 4 -(Benzofuran-6-yl)-5-bromo-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-(trimethylsilyl) (Ethoxy)methyl)-1H-imidazole (0307-15) (504 mg, 0.
  • Step 9h 4-(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-(trimethylmethyl Silyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (4-(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl) )oxy)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0309-15) Preparation: To 4-(4 -(Benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-(trimethylsilyl)ethoxy) (Methyl)-1H-imidazol-5-yl)
  • Step 9i 4-(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-(trimethylmethyl Silyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine (4-(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine) (Compound 0310-15) Preparation: In a stuffy pot, 4-(4-( Benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine
  • Step 9j N 1 -(4-(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1-((2-( (Trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy -N 4 -Methyl-5-nitrobenzene-1,4-diamine (N 1 -(4-(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4- met hyl-5-nitrobenzen
  • Step 9k 3-(4-(benzofuran-6-yl)-5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl (Oxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)ethane-1-ol (3-(4-(benzofuran-6-yl)-5-( 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)ethan-1- ol) Preparation of (Compound 0312-15): To N 1 -(4-(4-(benzofuran-6-yl)-2-(2-((triisopropylsilyl)oxy)ethyl )-1-((2-(Trimethylsilyl)eth
  • Step 9l N-(5-((4-(4-(benzofuran-6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran- 6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl )acrylamide) (Compound 15) Preparation: 3-(4-(benzofuran-6-yl)-5-(2-((4–((2-(dimethylamino)ethyl)(methyl )Amino)-2-methoxy-5-nitro
  • Example 10 N-(5-((4-(4-(benzofuran-6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propionamide (N-(5-((4-(4-(benzofuran -6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- Preparation of methoxyphenyl)propionamide) (compound 16) (prepared according to the scheme 3 route)
  • Example 11 N-(3-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxyphenyl)-acrylamide (N-(3-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl )pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 17) preparation (prepared according to the route of Scheme 3)
  • Step 11a 4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (4-(benzofuran-6-yl)- Preparation of 2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole)
  • Compound 0305-17 To 2-(benzofuran-6-yl)-2-oxoacetaldehyde (0304-15 ) (1.3 g, 7.5 mmol, 1.0 equivalent) and 4-(triisopropylsiloxy) butyraldehyde (0103-7) (1.3 g, 5.65 mmol, 1.0 equivalent) in methanol (50 mL) were added Ammonium acetate (2.9 g, 37.5 mmol, 5.0 equivalents).
  • Step 11b 4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl) Ethoxy)methyl)-1H-imidazole(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazole) (Compound 0306-17): under the protection of nitrogen, in an ice water bath, to 4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl) oxygen (Yl) propyl) -1H-imidazole (0305-17) (4.5 g, 11.5 mmol, 1.0 equivalent) in N,N-dimethylformamide (50 mL) was added 60% sodium hydride in batches (1.38 g, 34.5 mmol, 3.0 equivalents).
  • Step 11c 4-(benzofuran-6-yl)-5-bromo-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethyl (Silyl)ethoxy)methyl)-1H-imidazole(4-(benzofuran-6-yl)-5-bromo-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole) (Compound 0307-17) Preparation: to 4-(benzofuran-6-yl)-2-(3–((triisopropylsilyl)oxy ) Propyl)-1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole (0306-17) (1.69 g, 3.2 mmol, 1.0 equivalent) of acetonitrile (40 (ML) was added N-bromosuccinimide (598 mg,
  • Step 11d 4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylmethyl Silyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl) )oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine) (Compound 0308-17) Preparation: Under nitrogen protection, 4 -(Benzofuran-6-yl)-5-bromo-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl) (Ethoxy)methyl)-1H-imidazole (0307-17) (980 mg, 1.
  • Step 11e 4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylmethyl Silyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl) )oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0309-17) Preparation: To 4-(4 -(Benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy) (Methyl)-1H-imidazol-5-yl)
  • Step 11f 4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylform Silyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine(4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine) (Compound 0310-17) Preparation: In a stuffy pot, 4-(4-( Benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrim
  • Step 11g 4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylform Silyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidin-2-amine (4-(4-(benzofuran- 6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxy-5 -nitrophenyl)pyrimidin-2-amine) (compound 0311-17): under nitrogen protection, 4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl) )Oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)
  • Step 11h 3-(4-(benzofuran-6-yl)-5-(2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazole -2-yl)propane-1-ol (3-(4-(benzofuran-6-yl)-5-(2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H- imidazol-2-yl)propan-1-ol) (Compound 0312-17): To 4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl) )Oxy)propyl)-1--((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxy-5- A solution of nitrophenyl)pyrimidin-2-amine (0311-17) (412 mg, 0.53 mmol, 1.0 equivalent)
  • Step 11i N-(3-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-4-methoxyphenyl)-acrylamide (N-(3-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl) pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 17): Add 3-(4-(benzofuran-6-yl)-5-(2-((2-methoxy -5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (0312-17) (145 mg, 0.30 mmol, 1.0 equivalent), iron powder ( 96 mg, 1.80 mmol, 6.0 equivalent) and ammonium chloride (1
  • Example 12 N-(3-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxyphenyl)propionamide (N-(3-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl) Preparation of pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide) (compound 18) (prepared according to the route of Scheme 3)
  • Example 13 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran -6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- Preparation of methoxyphenyl)acrylamide) (Compound 19) (prepared according to the route of Scheme 4)
  • Step 13a 4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole ( Preparation of 4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (compound 0401-19): under nitrogen protection, in ice water bath To 4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0305-17) (3.0 g, 7.5 milli Mol, 1.0 eq) of N,N-dimethylformamide (50 mL) was added 60% sodium hydride (603 mg, 15.0 mmol, 2.0 eq) in portions.
  • Step 13b 4-(benzofuran-6-yl)-5-bromo-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)- 1H-imidazole
  • Step 13c 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H -Imidazol-5-yl)-2-(methylthio)pyrimidine(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)- Preparation of 1H-imidazol-5-yl)-2-(methylthio)pyrimidine) (Compound 0403-19): Under nitrogen protection, 4-(benzofuran-6-yl)-5-bromo-1-(methoxy Methyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0402-19) (3.0 g, 5.8 mmol, 1.0 equivalent), 2-methylsulfide 4-(trimethyltinyl)pyrimidine
  • Step 13d 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H -Imidazol-5-yl)-2-(methylsulfonyl)pyrimidine(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)- Preparation of 1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0404-19): To 4-(4-(benzofuran-6-yl)-1-(methoxymethyl) -2-(3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (0403-19) (2.1g, 3.71ml Mol, 1.0 eq) in dich
  • Step 13e 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H -Imidazol-5-yl)pyrimidin-2-amine (4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol- Preparation of 5-yl)pyrimidin-2-amine) (Compound 0405-19): In a stuffy pot, 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2 -(3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (0404-19) (2.1 g, 3.5 mmol, A mixture of 1.0 equivalent) and ammonia (10 mL)
  • Step 13f N 1 -(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propane Yl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -methyl-5-nitro Benzene-1,4-diamine (N 1 -(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol- Preparation of 5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine) (Compound 0406-19) : Under nitrogen
  • Step 13g 3-(4-(benzofuran-6-yl)-5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl (Oxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (3-(4-(benzofuran-6-yl)-5-(2 -((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol ) (Compound 0312-19): To N 1 -(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropyl) (Silyl)oxy)propyl)-1H-imidazol-5
  • Step 13h N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran- 6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl )acrylamide) (Compound 19) preparation: 3-(4-(benzofuran-6-yl)-5-(2-((4–((2-(dimethylamino)ethyl)(methyl )Amino)-2-methoxy-5-nitropheny
  • Example 14 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propionamide (N-(5-((4-(4-(benzofuran -6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- Preparation of methoxyphenyl)propionamide) (compound 20) (prepared according to the route of Scheme 4)
  • Step 14a N 1 -(4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-( (Trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy -N 4 -Methyl-5-nitrobenzene-1,4-diamine (N 1 -(4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4- Preparation of methyl-5-nitrobenz
  • Step 14b 3-(4-(benzofuran-6-yl)-5-(2-((4--((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl (Oxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (3-(4-(benzofuran-6-yl)-5-(2 -((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol ) Preparation of (Compound 0312-19): To N 1 -(4-(4-(benzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl) -1-((2-(Trimethylsilyl)
  • Step 14c N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propionamide (N-(5-((4-(4-(benzofuran- 6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl )propionamide) (Compound 20) preparation: 3-(4-(benzofuran-6-yl)-5-(2-((4-((2-(dimethylamino)ethyl)(formula (Yl)amino)-2-meth
  • the reaction system was cooled to room temperature, filtered through Celite, and the filtrate was diluted with 10 ml of water.
  • Add saturated sodium bicarbonate aqueous solution to adjust the pH to 10 cool in an ice water bath, dissolve propionyl chloride (133 mg, 1.44 mmol, 5.0 equivalents) in 1 ml of tetrahydrofuran, add dropwise to the above mixture, and stir for 30 minutes.
  • Example 15 N-(5-((4-(4-(benzofuran-5-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran -5-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- Preparation of methoxyphenyl)acrylamide) (Compound 34) (prepared according to the route of Scheme 5)
  • Step 15a Preparation of 1-(benzofuran-5-yl)ethan-1-one (1-(benzofuran-5-yl)ethan-1-one) (Compound 0502-34): under the protection of nitrogen, the 5-Bromobenzofuran (0501-34) (1.0 g, 5.0 mmol, 1.0 equivalent), tributyl-1-ethoxyethylene (2.7 g, 7.5 mmol, 1.5 equivalent) and tetrakis(triphenyl) A mixture of phosphine)palladium (289 mg, 0.25 mmol, 0.05 equivalent) in toluene (30 mL) was stirred at 110°C for 5 hours.
  • Step 15c 4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (4-(benzofuran-5-yl)- Preparation of 2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0504-34): To 2-(benzofuran-5-yl)-2-oxoacetaldehyde (0503-24 ) (500 mg, 3.5 mmol, 1.0 equivalent) and 4-(triisopropylsiloxy)butyraldehyde (0103-7) (849 mg, 3.5 mmol, 1.2 equivalent) in methanol (20 mL) were added Ammonium acetate (1.1 g, 14.5 mmol, 5.0 equivalents).
  • Step 15d 4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl) Ethoxy)methyl)-1H-imidazole(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- Preparation of 1H-imidazole) (Compound 0505-34): Under the protection of nitrogen, in an ice water bath, to 4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl) oxygen (Base) propyl) -1H-imidazole (0504-34) (1.0 g, 2.5 mmol, 1.0 equivalent) in N,N-dimethylformamide (20 mL) was added 60% sodium hydride in batches (201 mg, 5.0 mmol, 2.0 equivalents).
  • Step 15e 4-(benzofuran-5-yl)-5-bromo-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethyl (Silyl)ethoxy)methyl)-1H-imidazole(4-(benzofuran-5-yl)-5-bromo-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole) (Compound 0506-34): To 4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy ) Propyl)-1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole (0505-34) (780 mg, 1.5 mmol, 1.0 equivalent) of acetonitrile (20 (Ml) N-bromosuccinimide (294 mg, 1.65 mmol,
  • Step 15f 4-(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylform Silyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine 4-(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl) oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -imidazol-5-yl)-2-(methylthio)pyrimidine (Compound 0507-34) preparation: under nitrogen protection, 4-( Benzofuran-5-yl)-5-bromo-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy (Yl)methyl)-1H-imidazole (0506-34) (410 mg, 0.68 m
  • Step 15g 4-(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylform Silyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (4-(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl) )oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0508-34) Preparation: To 4-(4 -(Benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy) (Methyl)-1H-imidazol-5-yl
  • Step 15h 4-(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylmethyl Silyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine (4-(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine) (Compound 0509-34) Preparation: In a stuffy pot, 4-(4-( Benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrim
  • Step 15i N 1 -(4-(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1-((2-( (Trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy -N 4 -Methyl-5-nitrobenzene-1,4-diamine (N 1 -(4-(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4- Preparation of methyl-5-nitrobenz
  • Step 15j 3-(4-(benzofuran-5-yl)-5-(2-((4--((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl (Oxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (3-(4-(benzofuran-5-yl)-5-(2 -((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophe nyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1- ol) Preparation of (Compound 0511-34): To N 1 -(4-(4-(benzofuran-5-yl)-2-(3-((triisopropylsilyl)oxy)propyl )-1-((2-(Trimethyl
  • Step 15k N-(5-((4-(4-(benzofuran-5-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran- 5-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl )acrylamide) (Compound 34): 3-(4-(benzofuran-5-yl)-5-(2-((4–((2-(dimethylamino)ethyl)(methyl )Amino)-2-methoxy-5-nitrophenyl
  • Example 16 N-(5-((4-(4-(benzofuran-5-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propionamide (N-(5-((4-(4-(benzofuran -5-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- Preparation of methoxyphenyl)acrylamide) (compound 35) (prepared according to the route of Scheme 5)
  • Example 17 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(benzofuran-6-yl)-2- (2-Methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino) ethyl)(methyl)amino)-5-((4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)- Preparation of 4-methoxyphenyl)acrylamide) (Compound 57) (prepared according to Scheme 4)
  • Step 17a 4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1H-imidazole (4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1H -imidazole) (compound 0305-57): to 3-methoxypropane-1-ol (300 mg, 3.33 mmol, 1.0 equivalent) in dimethyl sulfoxide (10 mL) was added 2-iodoyl Benzoic acid (1.4 g, 4.99 mmol, 1.5 equivalents). The mixture was stirred at room temperature for 16 hours.
  • Step 17b 4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazole (4-(benzofuran-6-yl) Preparation of -2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazole) (Compound 0401-57): Under nitrogen protection, in an ice water bath, to 4-(benzofuran-6-yl)- 2-(2-Methoxyethyl)-1H-imidazole (0305-57) (297 mg, 1.227 mmol, 1.0 equivalent) in N,N-dimethylformamide (5 mL) in batches Add 60% sodium hydride (131 mg, 2.454 mmol, 2.0 equivalents).
  • Step 17c 5-bromo-4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazole
  • 5-bromo-4 Preparation of -(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazole)
  • Compound 0402-57 To 4-(benzofuran-6-yl)-2 -(2-Methoxyethyl)-1-(methoxymethyl)-1H-imidazole (0401-57) (260 mg, 0.909 mmol, 1.0 equivalent) in acetonitrile (10 mL) N-Bromosuccinimide (186 mg, 1.045 mmol, 1.15 equivalents), and the mixture was stirred at room temperature for 2 hours.
  • Step 17d 4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)-2 -(Methylthio)pyrimidine(4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine )
  • Step 17e 4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)-2 -(Methylsulfinyl)pyrimidine(4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)-2-(methylsulfinyl )pyrimidine) (Compound 0404-57): To 4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)- 1H-imidazol-5-yl)-2-(methylthio)pyrimidine (0403-57) (153 mg, 0.373 mmol, 1.0 equivalent) in dichloromethane (10 mL) was added to m-chloroperoxybenzoic acid ( 96 mg, 0.56 mmol, 1.5
  • Step 17f 4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)pyrimidine- 2-amine (4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)pyrimidin-2-amine) (Compound 0405-57 ) Preparation: In a stuffy pot, 4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazole- A mixture of 5-yl)-2-(methylsulfinyl)pyrimidine (0404-57) (172 mg, 0.403 mmol, 1.0 equivalent) and ammonia (1 mL) in tetrahydrofuran (5 mL) was stirred at 80°C for 2 hour.
  • Step 17g N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)- 1-(Methoxymethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine ( N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1-(methoxymethyl)-1H-imidazol-5-yl )pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine) (Compound 0406-57): under nitrogen protection, 4-(4-(benzofuran- 6-yl)-2-(2-methoxyethyl)-1
  • Step 17h N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl) Base)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine (N 1 -(2-( dimethylamino)ethyl)-N 4 -(4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine) (Compound 0312-57): To N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-( Benzofuran-6-yl)-2-
  • Step 17i N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(benzofuran-6-yl)-2-( 2-Methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl )(methyl)amino)-5-((4-(4-(benzofuran-6-yl)-2-(2-methoxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4 -methoxyphenyl)acrylamide) (Compound 57): N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(benzofuran-6-yl)-2-( 2-Methoxyethyl)-1H
  • Example 18 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(2 -(4-Hydroxyphenoxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-5-((4-(4-fluorophenyl)-2-(2-(4-hydroxyphenoxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2 -yl)amino)-4-methoxyphenyl)acrylamide) (Compound 58) (prepared according to the route of Scheme 1)
  • Step 18a Preparation of 3-(4-(methoxymethoxy)phenoxy)propan-1-ol (3-(4-(methoxymethoxy)phenoxy)propan-1-ol) (Compound 0102-58) : Dissolve hydroquinone (5.5 g, 50.0 mmol, 1.0 equivalent) and diisopropylethylamine (13 mL, 80.0 mmol, 1.6 equivalent) in a mixed solvent of 40 mL tetrahydrofuran and 80 mL dichloromethane, Bromomethyl methyl ether (6.25 g, 50.0 mmol, 1.0 equivalent) was added dropwise to the above mixture, and the reaction was stirred overnight at room temperature.
  • Step 18b 4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1H-imidazole(4-(4-fluorophenyl)-2 -(2-(4-(methoxymethoxy)phenoxy)ethyl)-1H-imidazole)
  • Compound 0106-58 at room temperature, to 3-(4-(methoxymethoxy)phenoxy)propane -1-ol (0102-58) (1.0 g, 4.7 mmol, 1.0 equivalent) in dimethyl sulfoxide (14 mL) was added 2-iodoyl benzoic acid (1.98 g, 7.1 mmol, 1.5 Equivalent), and the mixture was stirred overnight.
  • Step 18c 4-(4-Fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl)-1H-imidazole
  • 4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl)-1H-imidazole) (Compound 0107-58): Nitrogen protection, at 0°C Next, 60% sodium hydride (266 mg, 6.65 mmol, 2.5 equivalents) was added to 4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy ) Ethyl)-1H-imidazole (0106-58) (910 mg, 2.66 mmol, 1 equivalent) in DMF (10 mL).
  • Step 18d 5-bromo-4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl) -1H-imidazole
  • 5-bromo-4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl)-1H-imidazole) (Compound 0108-58)
  • Preparation To 4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl)-1H-imidazole (0107-58) (271 mg, 0.7 mmol, 1.0 equivalent) of acetonitrile (16 mL) was added N-bromosuccinimide (125 mg, 0.7 mmol, 1.0 equivalent), the mixture was at room temperature Stir for 3 hours.
  • Step 18e 4-(4-(4-Fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl)- 1H-imidazol-5-yl)-2-(methylthio)pyrimidine(4-(4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl)
  • -1H-imidazol-5-yl)-2-(methylthio)pyrimidine compound 011-58): 5-bromo-4-(4-fluorophenyl)-2-(2-( 4-(Methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl)-1H-imidazole (0108-58) (229 mg, 0.49 mmol, 1.0 equivalent), 2- (Methylthio)-4-(trimethylstannyl)pyrimidine (0203-
  • Step 18f 4-(4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl)- 1H-imidazol-5-yl)pyrimidin-2-amine (4-(4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy)ethyl)-1-(methoxymethyl)-1H-imidazol -5-yl)pyrimidin-2-amine) (Compound 0113-58): To 4-(4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy) (Phenoxy) ethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (0111-58) (200 mg, 0.39 mmol, 1.0 equivalent M-chloroperoxybenzoic acid (119 mg, 0.59 mmol, 1.5
  • reaction solution was quenched with potassium carbonate aqueous solution and stirred for 10 minutes. After liquid separation, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure to obtain a residue. The residue was dissolved in tetrahydrofuran (10 mL), and ammonia (10 mL) was added. The mixture was placed in a stuffy pot and stirred at 85°C for 2 hours. After cooling to room temperature, the mixture was separated, and the organic phase was concentrated under reduced pressure.
  • Step 18g N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy) (Yl)phenoxy)ethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitro Benzene-1,4-diamine (N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(2-(4-(methoxymethoxy)phenoxy) ethyl)-1-(methoxymethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine) (Compound 0115-58) Preparation: Under
  • Step 18h 4-(2-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl )Amino)pyrimidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)ethoxy)phenol (4-(2-(5-(2-((4-( (2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)ethoxy)phenol ) (Compound 0116-58): To N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(2-( 4-(Methoxymethoxy)phenoxy)ethyl
  • Step 18i N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(2- (4-Hydroxyphenoxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-( dimethylamino)ethyl)(methyl)amino)-5-((4-(4-fluorophenyl)-2-(2-(4-hydroxyphenoxy)ethyl)-1H-imidazol-5-yl)pyrimidin-2- yl)amino)-4-methoxyphenyl)acrylamide) (Compound 58): Add 4-(2-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl )Amino)-2-methoxy-5-nitro
  • Example 20 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5–((4-(4-(4-fluorophenyl)-2-(methyl Sulfuryl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl)amino )-5-((4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide)(Compound 125) Preparation (prepared according to the sixth route of scheme)
  • Step 20a 4-(4-fluorophenyl)-2-(methylthio)-1H-imidazole (4-(4-fluorophenyl)-2-(methylthio)-1H-imidazole) (Compound 0602-125)
  • Step 20b 4-(4-Fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (4-( Preparation of 4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole) (Compound 0603-125): under nitrogen protection, in an ice water bath, (4-Fluorophenyl)-2-(methylthio)-1H-imidazole (0602-125) (1.0 g, 4.8 mmol, 1.0 equivalent) in tetrahydrofuran (25 ml) was added in batches of 60% Sodium hydride (576 mg, 14.4 mmol, 3.0 equivalents).
  • Step 20c 5-Bromo-4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole
  • 5-bromo-4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole) (Compound 0604-125): Under nitrogen protection, Add 4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0603-125) ( 1.1 g, 3.25 mmol, 1.0 equivalent) was dissolved in 20 ml of anhydrous acetonitrile, cooled in an ice salt bath, and N-bromosuccinimide (579 mg, 3.25 mmol, 1.0 equivalent) was dissolved in 5 One milliliter of acetonitrile was added dropwise to
  • Step 20d 4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(trimethyltin Yl)-1H-imidazole (4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(trimethylstannyl)-1H-imidazole) (Compound 0605-125 )
  • Preparation Under the protection of nitrogen, add 5-bromo-4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy) (Methyl)-1H-imidazole (0604-125) (1.0 g, 2.4 mmol, 1.0 equivalent) was dissolved in 15 ml of dry tetrahydrofuran, and the reaction system was cooled in a dry ice-ethanol bath.
  • Step 20e Preparation of 4-iodo-2-(methylsulfonyl)pyrimidine (Compound 0606-125): Add 4-iodo-2-methylsulfonyl pyrimidine (500 mg, 2.0 Millimole, 1.0 equivalent) was dissolved in 50 ml of dichloromethane, and m-chloroperoxybenzoic acid (1.0 g, 5.0 millimole, 2.5 equivalent) was added to the reaction system. The reaction mixture was stirred at room temperature for two hours, and the reaction was quenched with aqueous sodium bicarbonate solution. The layers were separated, the organic phase was washed with saturated brine, and concentrated under reduced pressure.
  • 4-iodo-2-(methylsulfonyl)pyrimidine 500 mg, 2.0 Millimole, 1.0 equivalent
  • m-chloroperoxybenzoic acid 1.0 g, 5.0 millimole, 2.5 equivalent
  • Step 20f 4-(4-(4-Fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- 5-yl)-2-(methylsulfonyl)pyrimidine(4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5 -yl)-2-(methylsulfonyl)pyrimidine) (Compound 0607-125): Under the protection of nitrogen, the 4-(4-fluorophenyl)-2-(methylthio)-1-((2- (Trimethylsilyl)ethoxy)methyl)-5-(trimethylstannyl)-1H-imidazole (0605-125) (1.3 g, 1.7 mmol, 1.6 equivalents), 4-iodo- 2-(methylsulfonyl)pyrimidine (0606-125) (300
  • Step 20g 4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- 5-yl)pyrimidin-2-amine (4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin -2-amine) (Compound 0608-125): In a sealed tank, add 4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethyl) (Methylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (0607-125) (1.5g, 1.7mmol, 1.0eq) was dissolved in 25ml Tetrahydrofuran, 15 ml of ammonia was added, and stirred at
  • Step 20h N 1 -(2-(dimethylamino)ethyl)-N 4 --(4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2- (Trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1 ,4-Diamine (N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy) Preparation of methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine) (compound 0609-125): under nitrogen protection , The 4-(4-(4-fluorophenyl
  • Step 20i N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5--((4-(4-(4-fluorophenyl)-2-(methylsulfide) Yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) Acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide)(Compound 0610-125) Preparation: the N 1 -(2-(dimethyl Amino)ethy
  • Step 20j N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5--((4-(4-(4-fluorophenyl)-2-(methylsulfide) (Yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl)amino) -5-((4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide)(Compound 125) Preparation: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5–((4-(4-(4-fluorophenyl)-2-(methylsulfide)
  • Example 21 N-(5-((4-(4-(4-chlorophenyl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino) -2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(4-chlorophenyl )-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide) (Compound 12) preparation (prepared according to scheme 1 route)
  • 1-(4-chlorophenyl)ethan-1-one (0104-12) (1.00 g, 6.47 mmol, 1.0 equivalent) was added, and the reaction solution was refluxed for 16 hours.
  • Step 21b 4-(4-Chlorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole(4-(4-chlorophenyl)-2-( Preparation of 3-((triisopropylsilyl)oxy)propyl)-1H-imidazole)
  • Compound 0106-12 To 2-(4-chlorophenyl)-2-oxoacetaldehyde (0105-12) (981 mg, A mixture of 5.82 mmol, 1.0 equivalent) and 4-(triisopropylsiloxy)butyraldehyde (0103-7) (1.85 g, 7.57 mmol, 1.3 equivalent) in methanol (40 mL) was added to ammonium acetate (1.35 g) , 17.5 mmoles, 3.0 equivalents).
  • Step 21c 4-(4-Chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (4 -(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0107-12): under nitrogen protection, in an ice water bath, 4-(4-chlorophenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0106-12) (1.00 g, 2.49 mmol, 1.0 equivalent ) In N,N-dimethylformamide (30 mL) was added 60% sodium hydride (300 mg, 7.46 mmol, 3.0 equivalents) in portions.
  • Step 21d 5-Bromo-4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H -Imidazole (5-bromo-4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0108-12) Preparation: To 4 -(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0107-12)( To a solution of 590 mg, 1.35 mmol, 1.0 equivalent) in acetonitrile (15 mL) was added N-bromosuccinimide (253 mg, 1.42 mmol, 1.05 equivalent), and the mixture was stirred at room temperature for 1 hour.
  • Step 21e 4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H- Imidazol-5-yl)-2-(methylthio)pyrimidine(4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol Preparation of -5-yl)-2-(methylthio)pyrimidine) (Compound 0111-12): Under nitrogen protection, 5-bromo-4-(4-chlorophenyl)-1-(methoxymethyl) -2-(3-((Triisopropylsilyl)oxy)propyl)-1H-imidazole (0108-12) (470 mg, 0.91 mmol, 1.0 equivalent), 2-(methylthio) -4-(Trimethylstannyl)pyrimidine (0203-7)
  • Step 21f 4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H- Imidazol-5-yl)-2-(methylsulfonyl)pyrimidine(4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H- imidazol-5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0112-12): To 4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-( 3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (0111-12) (325 mg, 0.58 mmol, 1.0 Add m-chloroperoxybenzoic acid (200
  • Step 21g 4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H- Imidazol-5-yl)pyrimidin-2-amine (4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl )pyrimidin-2-amine) (Compound 0113-12): In a stuffy pot, 4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-( (Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (0112-12) (320 mg, 0.54 mmol, 1.0 equivalent) A mixture of tetrahydrofuran (15 mL)
  • Step 21h N 1 -(4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl )-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -methyl-5-nitrobenzene -1,4-Diamine (N 1 -(4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl )pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine) (Compound 0115-12) preparation: nitrogen protection Below, 4-(4-
  • Step 21i 3-(4-(4-chlorophenyl)-5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy -5-Nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (3-(4-(4-chlorophenyl)-5-(2-((4 -((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol)(Compound 0117 -12) Preparation: To N 1 -(4-(4-(4-chlorophenyl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy (Yl)propyl)-1H-imi
  • Step 21j N-(5-((4-(4-(4-chlorophenyl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(4-chlorophenyl) -2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide)( Compound 12) Preparation: 3-(4-(4-chlorophenyl)-5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2 -Methoxy-5-nitrophen
  • Example 22 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-(4 -Methoxyphenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl) (methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-(4-methoxyphenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) acrylamide) (Compound 13) preparation (prepared according to the route of Scheme 1)
  • Step 22b 4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (4-(4-methoxyphenyl)-2 -(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0106-13)
  • 2-(4-methoxyphenyl)-2-oxoacetaldehyde (0105-13) 820 mg, 5.0 mmol, 1.0 equivalent
  • 4-(triisopropylsiloxy)butyraldehyde (0103-7) (1.83 g, 7.5 mmol, 1.5 equivalent) in methanol (40 mL) were added to acetic acid Ammonium (1.15 g, 15.0 mmol, 3.0 equivalents).
  • Step 22c 1-(Methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole
  • (1-(methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0107-13): Under nitrogen protection, in an ice water bath , To 4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0106-13) (770 mg, 1.97 mg Mol, 1.0 eq) of N,N-dimethylformamide (30 mL) was added 60% sodium hydride (240 mg, 5.92 mmol, 3.0 eq) in portions.
  • Step 22d 5-Bromo-1-(methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)
  • -1H-imidazole 5-bromo-1-(methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole)
  • Compound 0108-13 To 1-(methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0107 -13) (527 mg, 1.22 mmol, 1.0 equivalent) in acetonitrile (15 mL) was added N-bromosuccinimide (228 mg, 1.28 mmol, 1.05 equivalent), and the mixture was stirred at room temperature 1 hour.
  • Step 22e 4-(1-(Methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)- 1H-imidazol-5-yl)-2-(methylthio)pyrimidine(4-(1-(methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H -imidazol-5-yl)-2-(methylthio)pyrimidine) (Compound 0111-13): 5-bromo-1-(methoxymethyl)-4-(4-methoxy Phenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0108-13) (370 mg, 0.724 mmol, 1.0 equivalent), 2-(methyl Sulfuryl)-4-(trimethylstannyl)pyrimidine (0203-7) (296 mg,
  • Step 22f 4-(1-(Methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)- 1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine(4-(1-(methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)- Preparation of 1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0112-13): To 4-(1-(methoxymethyl)-4-(4-methoxyphenyl) -2-(3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (0111-13) (290 mg, 0.521 A solution of m-chloroperoxybenz
  • Step 22g 4-(1-(Methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)- 1H-imidazol-5-yl)pyrimidin-2-amine (4-(1-(methoxymethyl)-4-(4-methoxyphenyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5 -yl)pyrimidin-2-amine) (Compound 0113-13) preparation: in a stuffy pot, 4-(1-(methoxymethyl)-4-(4-methoxyphenyl)-2- (3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (0112-13) (300 mg, 0.51 mmol , 1.0 equivalent) and ammonia (10 mL) in tetrahydr
  • Step 22h N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 -(4-(1-(methoxymethyl)-4-(4-methoxybenzene) Yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 1 -methyl-2-nitro Benzene-1,4-bis(N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 -(4-(1-(methoxymethyl)-4-(4-methoxyphenyl)-2-(3- ((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 1 -methyl-2-nitrobenzene-1,4-diamine) (Compound 0115-13) Preparation: Nitrogen protection Below,
  • Step 22i 3-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino) Pyrimidine-4-yl)-4-(4-methoxyphenyl)-1H-imidazol-2-yl)propan-1-ol (3-(5-(2-((4-((2-( dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-4-(4-methoxyphenyl)-1H-imidazol-2-yl)propan-1-ol)( The preparation of compound 0117-13): to N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 -(4-(1-(methoxymethyl)-4-( 4-methoxyphenyl)-2-(3-((triisopropyl
  • Step 22j N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-(4- Methoxyphenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)( methyl)amino)-5-((4-(3-hydroxypropyl)-4-(4-methoxyphenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ) (Compound 13) preparation: 3-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitro Phenyl)amino)pyrimidin-4-yl)-4--(
  • Example 23 N-2-((2-(dimethylamino)ethyl)(methyl)amino)(5-((4-(4-(5-fluorobenzofuran-6-yl)- 2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino) ethyl)(methyl)amino)-5-((4-(4-(5-fluorobenzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-4-methoxyphenyl)acrylamide) (Compound 21) preparation (prepared according to scheme 3 and 4)
  • Step 23a Preparation of 1-(2-fluoro-5-hydroxyphenyl)ethan-1-one (1-(2-fluoro-5-hydroxyphenyl)ethan-1-one) (compound 0301-21): Methyl methyl ether (778 mg, 6.276 mmol, 1.2 equivalent) was added dropwise to 3-bromo-4-fluorophenol (1 g, 5.23 mmol, 1 equivalent) and N,N-diisopropylethylamine (1.01 G, 7.845 mmol, 1.5 equivalents) in 2 ml of dichloromethane. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with water. The mixture was extracted with dichloromethane.
  • Step 23b Preparation of 4-fluoro-5-(1-hydroxyethyl)-2-iodobenzene 4-fluoro-5-(1-hydroxyethyl)-2-iodophenol (compound 0302-21): add sodium borohydride (370 mg, 9.74 mmol, 1.5 equiv) to 10 ml of 1-(2-fluoro-5-hydroxyphenyl)ethan-1-one (0301-21) (1 g, 6.49 mmol, 1 equiv) Methanol solution. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water. The mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain a white solid.
  • Step 23c Preparation of 1-(5-fluorobenzofuran-6-yl)ethan-1-one
  • 1-(5-fluorobenzofuran-6-yl)ethan-1-one compound 0303-21: under nitrogen protection ,
  • 4-fluoro-5-(1-hydroxyethyl)-2-iodobenzene (0302-21) (2.1 g, 7.47 mmol, 1.0 equivalent), triethylamine (2.26 g, 22.41 mmol, 3.0 Equivalent), cuprous iodide (21 mg, 0.11 mmol, 0.015 equivalent) and bis(triphenylphosphine) palladium dichloride (154 mg, 0.22 mmol, 0.03 equivalent) in tetrahydrofuran (20 mL)
  • Trimethylethynylsilane (1.46 g, 14.94 mmol, 2.0 equivalents) was added, and the mixture was stirred at 62°C overnight.
  • Step 23e 4-(5-Fluorobenzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)- Preparation of 1H-imidazole (4-(5-fluorobenzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0401-21): Nitrogen Under protection, in an ice-water bath, add 4-(5-fluorobenzofuran-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole ( 0305-21) (1.16 g, 2.79 mmol, 1.0 equivalent) of N,N-dimethylformamide (10 mL) was added 60% sodium hydride (223 mg, 5.58 mmol, 2.0 equivalent) in batches ).
  • Step 23f 5-Bromo-4-(5-fluorobenzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy) Propyl)-1H-imidazole
  • Step 23g 4-(4-(5-Fluorobenzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propane Yl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine(4-(4-(5-fluorobenzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl) )oxy)propyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine) (Compound 0403-21) Preparation: 5-bromo-4-(5-fluorobenzofuran-6) under nitrogen protection -Yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0402-21) (0.678 g, 1.258 milli Mol, 1.0 equivalent), 2-methylthio
  • Step 23h 4-(4-(5-Fluorobenzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propane Yl)-1H-imidazol-5-yl)-2-(methylsulfinyl)pyrimidine(4-(4-(5-fluorobenzofuran-6-yl)-1-(methoxymethyl)-2-(3-( (triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfinyl)pyrimidine) (Compound 0404-21): To 4-(4-(5-fluorobenzofuran-6-yl) )-1-(Methoxymethyl)-2-(3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylthio) A solution of pyrimidine (0403-21) (250 mg
  • Step 23i 4-(4-(5-Fluorobenzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propane Yl)-1H-imidazol-5-yl)pyrimidin-2-amine (4-(4-(5-fluorobenzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl )-1H-imidazol-5-yl)pyrimidin-2-amine) (Compound 0405-21) Preparation: In a stuffy pot, 4-(4-(5-fluorobenzofuran-6-yl)-1- (Methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfinyl)pyrimidine( A mixture of 0404-21) (256 mg, 0.427
  • Step 23j N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(5-fluorobenzofuran-6-yl)-1-(methoxymethyl) -2-(3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl- 2-Nitrobenzene-1,4-diamine (N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(5-fluorobenzofuran-6-yl)-1-(methoxymethyl)- 2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine)(compound 0406-21) preparation
  • Step 23k 3-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino) Pyrimidine-4-yl)-4-(5-fluorobenzofuran-6-yl)-1H-imidazol-2-yl)propan-1-ol (3-(5-(2-((4-(( 2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-4-(5-fluorobenzofuran-6-yl)-1H-imidazol-2-yl) propan-1-ol) (Compound 0312-21): To N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(4-(5-fluorobenzofuran-6) -Yl)-1-(methoxymethyl)-2-(3
  • Step 23l N-2-((2-(dimethylamino)ethyl)(methyl)amino)(5-((4-(4-(5-fluorobenzofuran-6-yl)-2 -(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide N-(2-((2-(dimethylamino)ethyl) (methyl)amino)-5-((4-(4-(5-fluorobenzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)- Preparation of 4-methoxyphenyl)acrylamide (Compound 21): 3-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy- 5-nitrophenyl)amino)pyr
  • Example 24 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)cyclopropylcarboxamide (N-(5-((4-(4 -(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino) Preparation of -4-methoxyphenyl)cyclopropanecarboxamide) (compound 26) (prepared according to the route of Scheme 4)
  • Example 25 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-3-methylbutanamide (N-(5-((4- (4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl) Amino)-4-methoxyphenyl)-3-methylbutanamide) (Compound 28) preparation (prepared according to the route of Scheme 4)
  • the synthesis method is as in Example 24, except that the compound cyclopropyl formic acid is replaced with 3-methylbutanoic acid (14 mg, 0.13 mmol, 1.5 equivalents), and a yellow solid N-(5-((4-( 4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino) )Ethyl)(methyl)amino)-4-methoxyphenyl)-3-methylbutanamide (29 mg, yield: 50.9%).
  • Example 26 (E)-N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidine- 2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-4-(dimethylamino)butan-2- Enamide ((E)-N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide) (Compound 31) preparation (prepared according to scheme 4)
  • the synthesis method is as in Example 24, except that the compound cyclopropylcarboxylic acid is replaced with (E)-4-(dimethylamino)but-2-enoic acid (22 mg, 0.13 mmol, 1.5 equivalents), and the preparation is obtained Yellow solid (E)-N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidine-2- Yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide (25 mg, yield: 41.7%).
  • Example 27 N-(5-((4-(4-(Benzo[b]thiophen-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidine-2 -Yl)amino)-2-(((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-( 4-(benzo[b]thiophen-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) Preparation of (methyl)amino)-4-methoxyphenyl)acrylamide) (Compound 38) (prepared according to scheme 3 and 4)
  • Step 27a 1-(benzo[b]thiophen-6-yl)ethane-1-one (1-(benzo[b]thiophen-6-yl)ethan-1-one) (compound 0303-38) Preparation: Under nitrogen protection, mix 6-bromobenzo[b]thiophene (2.13 g, 10.0 mmol, 1.0 equivalent), tributyl-1-ethoxyethylene (4.33 g, 12 mmol, 1.2 equivalent) and A mixture of tetrakis(triphenylphosphine)palladium (213 mg, 0.18 mmol, 0.02 equivalent) in toluene (10 mL) was stirred at 125°C for 3 hours.
  • Step 27b 2-(benzo[b]thiophen-6-yl)-2-oxoacetaldehyde (2-(benzo[b]thiophen-6-yl)-2-oxoacetaldehyde) (compound 0304-38)
  • a mixture of selenium dioxide (470 mg, 4.24 mmol, 1.5 equivalents) of dioxane: water 10:1 (11 ml) was heated to 60°C until a clear solution appeared.
  • 1-(Benzo[b]thiophen-6-yl)ethane-1-one (0303-38) 500 mg, 2.82 mmol, 1.0 equivalent
  • was added 500 mg, 2.82 mmol, 1.0 equivalent
  • the reaction solution was refluxed for 16 hours.
  • the solid was filtered, and the solvent of the filtrate was removed under reduced pressure to obtain the crude product 2-(benzo[b]thiophen-6-yl)-2-oxoacetaldehyde. step.
  • Step 27c 4-(benzo(b)thiophen-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (4-(benzo(b) ]thiophen-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole)
  • Compound 0305-38 To 2-(benzo(b)thiophen-6-yl) -2-oxoacetaldehyde (0304-38) (550 mg, 2.82 mmol, 1.0 equivalent) and 4-(triisopropylsiloxy)butyraldehyde (0103-7) (1034 mg, 4.24 mmol, A solution of 1.5 equivalents) in methanol (10 mL) was added with ammonium acetate (1.08 g, 14.1 mmol, 5.0 equivalents).
  • Step 27d 4-(benzo[b]thiophen-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-
  • 1H-imidazole (4-(benzo[b]thiophen-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0401-38) : Under the protection of nitrogen, in an ice water bath, add 4-(benzo[b]thiophen-6-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H- To a solution of imidazole (0305-38) (1.167 g, 2.82 mmol, 1.0 equivalent) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (170 mg, 4.23 mmol, 1.5 equivalents).
  • Step 27e 4-(Benzo(b)thiophen-6-yl)-5-bromo-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy) Propyl)-1H-imidazole (4-(benzo[b]thiophen-6-yl)-5-bromo-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0402-38): To 4-(benzo(b)thiophen-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl) (Oxy) propyl)-1H-imidazole (0401-38) (678 mg, 1.48 mmol, 1.0 equivalent) in acetonitrile (10 mL) was added N-bromosuccinimide (303 mg, 1.7 mmol Mol, 1.15 equivalents), and the mixture was stirred at room temperature for 3
  • Step 27f 4-(4-(Benzo(b)thiophen-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propane Yl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine 4-(4-(benzo[b]thiophen-6-yl)-1-(methoxymethyl)-2-(3-(( triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (compound 0403-38): under nitrogen protection, 4-(benzo[b]thiophen-6-yl)- 5-bromo-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0402-38) (461 mg, 0.86 mg Mol, 1.0 equivalent), 2-methylthio-4-(trimethylstannyl)pyrim
  • Step 27g 4-(4-(Benzo(b)thiophen-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propane Yl)-1H-imidazol-5-yl)-2-(methylsulfinyl)pyrimidine(4-(4-(benzo[b]thiophen-6-yl)-1-(methoxymethyl)-2-(3 -((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfinyl)pyrimidine) (Compound 0404-38) Preparation: To 4-(4-(benzo(b)thiophene-6 -Yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfide A solution of pyrimidine (0403
  • Step 27h 4-(4-(Benzo(b)thiophen-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propane Yl)-1H-imidazol-5-yl)pyrimidin-2-amine(4-(4-(benzo[b]thiophen-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy )propyl)-1H-imidazol-5-yl)pyrimidin-2-amine) (Compound 0405-38): In a stuffy pot, 4-(4-(benzo[b]thiophen-6-yl)- 1-(Methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfinyl) A mixture of pyrimidine (0404-38) (362 mg, 0.605 mmol
  • Step 27i N 1 -(4-(4-(benzo[b]thiophen-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl) (Oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -methyl- 5-Nitrobenzene-1,4-diamine (N 1 -(4-(4-(benzo[b]thiophen-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy )propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine) (Compound 0406
  • Step 27j 3-(4-(benzo(b)thiophen-6-yl)-5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)- 2-Methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (3-(4-(benzo(b)thiophen-6- yl)-5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2- yl)propan-1-ol) (Compound 0312-38)): To N 1 -(4-(4-(benzo(b)thiophen-6-yl)-1-(methoxymethyl) -2-(3-((Triisopropylsilyl)oxy)propy
  • Step 27k N-(5-((4-(4-(benzo(b)thiophen-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidine-2- Yl)amino)-2-(((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4 -(benzo[b]thiophen-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)( Preparation of methyl)amino)-4-methoxyphenyl)acrylamide) (Compound 38): 3-(4-(benzo(b)thiophen-6-yl)-5-(2-((4-((2-( (Dimethylamino)ethyl)
  • Example 28 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)methanesulfonamide (N-(5-((4-(4-( benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4 -methoxyphenyl)methanesulfonamide) (Compound 69)
  • Example 29 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-(2,2,2-trifluoroethoxy)phenyl)acrylamide (N-(5 -((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino) Preparation of ethyl)(methyl)amino)-4-(2,2,2-trifluoroethoxy)phenyl)acrylamide) (Compound 88) (prepared according to the route of Scheme 4)
  • Step 29a N 1 -(4-bromo-2-nitro-5-(2,2,2-trifluoroethoxy)phenyl)-N 2 ,N 2 -dimethylethane-1,2 -Diamine (N 1 -(4-bromo-2-nitro-5-(2,2,2-trifluoroethoxy)phenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine) (Compound 0114-88) Preparation:
  • Step 29b N 1 -(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propane Yl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-N 4 -methyl-5-nitro-2-(2 ,2,2-Trifluoroethoxy)benzene-1,4-diamine (N 1 -(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-(( triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-N 4 -methyl-5-nitro-2-(2,2, Preparation of 2-trifluoroethoxy)benzene
  • Step 29c 3-(4-(benzofuran-6-yl)-5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitro 2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (3-(4-( benzofuran-6-yl)-5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitro-2-(2,2,2-trifluoroethoxy)phenyl)amino) pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol) (compound 0312-88) preparation: the compound N 1 -(4-(4-(benzofuran-6-yl) -1-(Methoxymethyl)-2-(3-((Triisopropylsilyl
  • Step 29d N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-(2,2,2-trifluoroethoxy)phenyl)acrylamide (N-(5- ((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl )(methyl)amino)-4-(2,2,2-trifluoroethoxy)phenyl)acrylamide) (Compound 88): Add 3-(4-(benzofuran-6-yl)-5-(2- ((4-((2-(Dimethylamino)ethyl
  • the synthesis method is as in Example 24, except that the compound cyclopropyl formic acid is replaced with (E)-but-2-enoic acid (12 mg, 0.13 mmol, 1.5 equivalents) to prepare a yellow solid (E)-N- (5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-( (2—(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)but-2-enamide (35 mg, yield: 62.5%).
  • Example 31 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-3-methylbut-2-enamide (N-(5- ((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl )(methyl)amino)-4-methoxyphenyl)-3-methylbut-2-enamide) (Compound 91) (prepared according to the route of Scheme 4)
  • the synthesis method is as in Example 24, except that the compound cyclopropyl formic acid is replaced with 3-methylbut-2-enoic acid (13 mg, 0.13 mmol, 1.5 equivalents), and a yellow solid N-(5-( (4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2--( Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-3-methylbut-2-enamide (38 mg, yield: 67.9%).
  • Example 32 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (N-(5-((4-(4 -(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1- yl)piperidin-1-yl)phenyl)acrylamide) (Compound 98) (prepared according to the route of Scheme 4)
  • Step 32a 1-(1-(4-Bromo-5-methoxy-2-nitrophenyll)piperidin-4-yl)-4-methylpiperazine (1-(1-(4- Preparation of bromo-5-methoxy-2-nitrophenyl)piperidin-4-yl)-4-methylpiperazine) (Compound 0114-98):
  • Step 32b 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H -Imidazol-5-yl)-N-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)pyrimidine -2-Amine (4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-N-( Preparation of 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)pyrimidin-2-amine) (Compound 0406-98): Under the protection of nitrogen, the 4-(4-(benzofuran-6-yl)-1-(methoxy
  • Step 32c 3-(4-(benzofuran-6-yl)-5-(2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine -1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (3-(4-(benzofuran-6-yl)- 5-(2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2 -yl)propan-1-ol) (Compound 0312-98): The compound 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3- ((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-N-(2-meth
  • Step 32d 3-(5-(2-((5-amino-2-methoxy-4-(4-(4-methoxypiperazine-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)-4-(benzofuran-6-yl)-1H-imidazol-2-yl)propan-1-ol (compound 0313-98): Preparation of 3-(4 -(Benzofuran-6-yl)-5-(2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5 -Nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (100 mg, 0.15 mmol, 1.0 equivalent), iron powder (59 mg, 1.05 mmol , 7.0 equivalents), ammonium chloride (64.2 mg, 1.2 mmol, 8.0 equivalents), a mixture of
  • Step 32e N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (N-(5-((4-(4- (benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl )piperidin-1-yl)phenyl)acrylamide) (Compound 98): Add 3-chloropropionyl chloride (57.0 mg, 0.45 mmol, 3.0 equivalents) in tetrahydrofuran (1 ml) solution dropwise at 0°C to the previous step In the reaction solution
  • Step 33a (S)-1-(4-bromo-5-methoxy-2-nitrophenyl)-3-dimethylaminopyrrole ((S)-1-(4-bromo-5-methoxy -2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine) (Compound 0114-100):
  • Step 33b (S)-N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidine-2 -Yl)amino)-2-(3-(dimethylamino)pyrrol-1-yl)-4-methoxyphenyl)acrylamide ((S)-N-(5-((4-(4 -(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4 -Methoxyphenyl)acrylamide) (Compound 100): The synthesis method is as in Example 32, steps 32b to 32e, except that 0114-98 in step 32b is replaced with (S)-1-(4-bromo-5- Methoxy-2-nitrophenyl)-3-d
  • Step 34a (R)-1-(4-Bromo-5-methoxy-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine ((R)-1-(4 -bromo-5-methoxy-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine) (Compound 0114-101):
  • Step 34b (R)-N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidine-2 -Yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide ((R)-N-(5-((4-(4 -(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4 -methoxyphenyl)acrylamide) (Compound 101): The synthesis method is the same as in Example 32, steps 32b to 32e, except that 0114-98 in step 32b is replaced with (R)-1-(4-bromo-5- Methoxy-2-nitrophenyl
  • Example 35 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(3-(dimethylamino)azetidin-1-yl)-4-methoxyphenyl)acrylamide N-(5-((4-(4-(benzofuran- 6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)azetidin-1-yl)-4-methoxyphenyl)acrylamide Preparation of (Compound 102) (prepared according to the route of Scheme 4)
  • Step 35a 1-(4-bromo-5-methoxy-2-nitrophenyl)-3-dimethylaminoazetidine (1-(4-bromo-5-methoxy-2-nitrophenyl )-N,N-dimethylazetidin-3-amine) (Compound 0114-102) Preparation:
  • Step 35b N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-(3-(Dimethylamino)azetidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran- 6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)azetidin-1-yl)-4-methoxyphenyl)acrylamide ) Preparation of (Compound 102): The synthesis method is as in Example 32, Step 32b to Step 32e, except that 0114-98 in Step 32b is replaced with 1-(4-bromo-5-methoxy-2-nitro Phenyl)-3-dimethyla
  • Example 36 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-(methoxy)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (N-(5-((4-(4-(benzofuran-6-yl) -2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide)(Compound 103) Preparation (prepared according to the route of Scheme 4)
  • Step 36a 1-(4-bromo-5-methoxy-2-nitrophenyl)-4-methylpiperazine (1-(4-bromo-5-methoxy-2-nitrophenyl)-4-methylpiperazine ) Preparation of (Compound 0114-103):
  • Step 36b N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-4-(methoxy)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (N-(5-((4-(4-(benzofuran-6-yl)- Preparation of 2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (Compound 103) : The synthesis method is as in Example 32, Step 32b to Step 32e, except that 0114-98 in Step 32b is replaced with 1-(4-bromo-5-methoxy-2-nitrophenyl)-4-methyl Piperazine (0114-103) to prepare a yellow solid N-(5-((4
  • Example 37 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran-6- yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide)( Compound 104) Preparation (prepared according to the route of Scheme 4)
  • Step 37a 1-(4-Bromo-5-methoxy-2-nitrophenyl)-N,N-dimethylpiperidin-4-amine (1-(4-bromo-5-methoxy-2 -nitrophenyl)-N,N-dimethylpiperidin-4-amine) (Compound 0114-104):
  • the 1-(5-methoxy-2-nitrophenyl)-N,N-dimethylpiperidin-4-amine obtained above The crude product was dissolved in a mixed solution of acetic acid (10 mL) and water (10 mL), and then a 0.5 mL acetic acid solution of bromine (336 mg, 2.1 mmol, 1.05 equivalent) was added dropwise. The mixture was stirred at room temperature for 30 minutes. A 2M aqueous sodium hydroxide solution was added to adjust the pH to 12, then dichloromethane was added for extraction, and the organic phase was concentrated under reduced pressure.
  • Step 37b N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-(4-(Dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran-6-yl )-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide)(Compound 104) Preparation: The synthesis method is as in Example 32, step 32b to step 32e, except that 0114-98 in step 32b is replaced with 1-(4-bromo-5-methoxy-2-nitrophenyl) -N,N-Dimethylpiperidin
  • Example 38 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide N-(5-((4-(4-(benzofuran- 6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)-4 -Methoxyphenyl)acrylamide (compound 105) preparation (prepared according to the route of scheme 4)
  • Step 38a 1-(4-bromo-5-methoxy-2-nitrophenyl)-4-(pyrrolidin-1-yl)piperidine (1-(4-bromo-5-methoxy-2- Preparation of nitrophenyl)-4-(pyrrolidine-1-yl)piperidine) (Compound 7-277-2):
  • Step 38b N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran- 6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)-4 -methoxyphenyl)acrylamide) (Compound 105): The synthesis method is as in Example 32, steps 32b to 32e, except that 0114-98 in step 32b is replaced with 1-(4-bromo-5-methoxy 2-Nitrophenyl)-4-(pyrrolidin-1-yl
  • Example 39 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalene -2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl )amino)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) acrylamide) (Compound 111) (prepared according to the route of Scheme 7)
  • Step 39b 4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (4-(naphthalen-2-yl)-2 -(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (Compound 0703-111)
  • Preparation To 2-(naphthalene-2-yl)-2-oxoacetaldehyde (0702-111) (1.29 G, 7.05 mmol, 1.0 equivalent) and 4-(triisopropylsiloxy)butyraldehyde (0103-7) (2.4 g, 9.87 mmol, 1.3 equivalent) in methanol (80 mL) was added to ammonium acetate ( 1.63 g, 21.1 mmol, 3.0 equivalents).
  • Step 39c 1-(Methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole
  • 1 Preparation of -(methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole) (compound 0704-11): under nitrogen protection, in ice water bath , To 4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0703-111) (2.88 g, 7.05 mmol, To a solution of 1.0 equivalent) of N,N-dimethylformamide (50 mL) was added 60% sodium hydride (846 mg, 21.1 mmol, 3.0 equivalents) in portions.
  • Step 39d 5-Bromo-1-(methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H
  • -imidazole 5-bromo-1-(methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole)
  • Compound 0705-111 To 1-(methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazole (0704-111 ) (890 mg, 1.846 mmol, 1.0 equivalent) in acetonitrile (15 mL) was added N-bromosuccinimide (345 mg, 1.938 mmol, 1.05 equivalent), and the mixture was stirred at room temperature for 1 hour .
  • Step 39e 4-(1-(Methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H- Imidazol-5-yl)-2-(methylthio)pyrimidine(4-(1-(methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H -imidazol-5-yl)-2-(methylthio)pyrimidine) (Compound 0706-111): Under nitrogen protection, 5-bromo-1-(methoxymethyl)-4-(naphthalene-2-yl) )-2-(3-((Triisopropylsilyl)oxy)propyl)-1H-imidazole (0705-111) (440 mg, 0.843 mmol, 1.0 equivalent), 2-(methylthio )-4-(trimethylstannyl)pyrimidine (0203-7)
  • Step 39f 4-(1-(Methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H- Imidazol-5-yl)-2-(methylsulfonyl)pyrimidine(4-(1-(methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)- Preparation of 1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0707-11): To 4-(1-(methoxymethyl)-4-(naphthalene-2-yl)-2 -(3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (0706-111) (360 mg, 0.625 mmol , 1.0 equivalent) in dich
  • Step 39g 4-(1-(Methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H- Imidazol-5-yl)pyrimidin-2-amine (4-(1-(methoxymethyl)-4-(naphthalen-2-yl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5 -yl)pyrimidin-2-amine) (Compound 0708-111): In a stuffy pot, 4-(1-(methoxymethyl)-4-(naphthalene-2-yl)-2-(3 -((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (0707-111) (320 mg, 0.52 mmol, 1.0 A mixture of tetrahydrofuran (15 mL)
  • Step 39h N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 -(4-(1-(methoxymethyl)-4-(naphthalen-2-yl) -2-(3-((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 1 -methyl-2-nitrobenzene- 1,4-Diamine (N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 -(4-(1-(methoxymethyl)-4-(naphthalen-2-yl)-2-(3 -((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 1 -methyl-2-nitrobenzene-1,4-diamine) (Compound 0709-111) Preparation: Nitrogen Under protection, 4-(
  • Step 39i 3-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino) Pyrimidine-4-yl)-4-(naphthalen-2-yl)-1H-imidazol-2-yl)propan-1-ol (3-(5-(2-((4-((2-(dimethylamino) ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-4-(naphthalen-2-yl)-1H-imidazol-2-yl)propan-1-ol)( The preparation of compound 0710-11): to N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 -(4-(1-(methoxymethyl)-4-( Naphth-2-yl)-2-(3-((triiso
  • Step 39j N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalene- 2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-((2-(dimethylamino)ethyl)(methyl) amino)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ) (Compound 111): Put 3-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitro (Phenyl)amino)pyrimidin-4-yl)-4-(
  • Example 40 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalene -2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)cyclopropylcarboxamide (N-(2-((2-(dimethylamino)ethyl )(methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4 Preparation of -methoxyphenyl)cyclopropanecarboxamide) (Compound 119) (prepared according to the route of Scheme 7)
  • Step 40a 3-(5-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidine -4-yl)-4-(naphthalen-2-yl)-1H-imidazol-2-yl)propan-1-ol (3-(5-(2-((5-amino-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-4-(naphthalen-2-yl)-1H-imidazol-2-yl)propan-1-ol)(Compound 0711-111): Add 3-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitro Phenyl)amino)pyrimidin-4-yl)-4-(
  • Step 40b N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalene- 2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)cyclopropylcarboxamide (N-(2-((2-(dimethylamino)ethyl) (methyl)amino)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4- methoxyphenyl)cyclopropanecarboxamide) (Compound 119): Add 3-(5-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- Methoxyphenyl)a
  • reaction mixture was quenched with aqueous sodium bicarbonate solution and stirred for 10 minutes. Water was added and ethyl acetate was added for extraction, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo.
  • Example 41 N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4 -Methoxyphenyl)acrylamide (N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino) Preparation of -4-methoxyphenyl)acrylamide) (Compound 123) (prepared according to the route of Scheme 6)
  • Step 41a 4-(4-(4-Fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- 5-yl)-N-(2-methoxy-5-nitrophenylpyrimidin-2-amine (4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-( trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidin-2-amine) (Compound 0609-123): Under the protection of nitrogen, the 4- (4-(4-Fluorophenyl)-2-(methylthio)-1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidine -2-amine (0608-125) (310 mg, 0.72 mmol, 1.0 equivalent), 2-bromo-1-methoxy-4-
  • Step 41b N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl Yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(3-((4-(4-(4-fluorophenyl)-2 -(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 0610-123) : 4-(4-(4-Fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5- Base) pyrimidin-2-amine (0609-123) (128 mg, 0.22 m
  • Step 41c N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4- Methoxyphenyl)acrylamide (N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)- Preparation of 4-methoxyphenyl)acrylamide) (compound 123): N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-( ⁇ (Methylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (0610-123) (110 mg, 0.18 mmol, 1.0 equivalent) was dissolved in 5 m
  • Example 42 N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4 -Methoxyphenyl)propionamide (N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino) Preparation of -4-methoxyphenyl)propionamide) (Compound 124) (prepared according to the route of Scheme 6)
  • Step 42a N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl Yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide (N-(3-((4-(4-(4-fluorophenyl)-2 -(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide) (Compound 0610-124) : 4-(4-(4-Fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5- Base) pyrimidin-2-amine (0610-124) (164 mg, 0.28 (
  • Step 42b N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4- Methoxyphenyl) propionamide (N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)- Preparation of 4-methoxyphenyl)propionamide) (compound 124): N-(3-((4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-( ⁇ (Methylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)propionamide (0610-124) (174 mg, 0.28 mmol, 1.0 equivalent) was dissolved in
  • Example 43 N-(5-((4-(4-(benzofuran-6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran -6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- Preparation of methoxyphenyl)acrylamide) (compound 136) (prepared according to scheme 1, 3 and 4)
  • Step 43a Preparation of 5-((triisopropylsilyl)oxy)pentyl-1-ol (5-((triisopropylsilyl)oxy)pentan-1-ol) (compound 0102-136): nitrogen protection In an ice-water bath, to a solution of pentane-1,5-diol (1.0 g, 9.615 mmol, 1.0 equivalent) in tetrahydrofuran (25 ml) was added 60% sodium hydride (423 mg, 10.57 ml) in batches Mol, 1.1 equivalents).
  • Step 43b Preparation of 5-((triisopropylsilyl)oxy)pentanal (5-((triisopropylsilyl)oxy)pentanal) (compound 0103-136): At room temperature, the preparation of 5-((triisopropyl) (Propylsilyl)oxy)pentyl-1-ol (0102-136) (2.48 g, 9.538 mmol, 1.0 equivalent) in dimethyl sulfoxide (60 ml) was added in batches with 2-iodoyl Benzoic acid (3.47 g, 12.4 mmol, 1.3 equivalents), and the mixture was stirred overnight.
  • Step 43c Preparation of 2-(benzofuran-6-yl)-2-oxoacetaldehyde
  • 1-(benzofuran-6-yl)ethan-1-one (0103-136) (2.75 g, 17.1 mmol, 1.0 equivalent) was added, and the reaction solution was refluxed for 16 hours.
  • Step 43d 4-(benzofuran-6-yl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazole (4-(benzofuran-6-yl) -2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazole) (Compound 0305-136): To 2-(benzofuran-6-yl)-2-oxoacetaldehyde (0304- 15) (600 mg, 3.448 mmol, 1.0 equivalent) and 5-((triisopropylsilyl)oxy) valeraldehyde (980 mg, 3.793 mmol, 1.1 equivalent) in methanol (40 mL) were added Ammonium acetate (797 mg, 10.34 mmol, 3.0 equivalents).
  • Step 43e 4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazole
  • 4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazole) (Compound 0401-136): Under nitrogen protection, in ice In a water bath, add 4-(benzofuran-6-yl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazole (0305-136) (900 gm , 2.184 mmol, 1.0 equivalent) of N,N-dimethylformamide (40 mL) was added 60% sodium hydride (262 mg, 6.552 mmol, 3.0 equivalent) in portions.
  • Step 43f 4-(benzofuran-6-yl)-5-bromo-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl) -1H-imidazole (4-(benzofuran-6-yl)-5-bromo-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazole) (Compound 0402-136)
  • Preparation To 4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazole (0401-136) (730 mg, 1.61 mmol, 1.0 equivalent) in acetonitrile (20 mL) was added N-bromosuccinimide (302 mg, 1.69 mmol, 1.05 equivalent), and the mixture was at room temperature Stir for 1 hour.
  • Step 43g 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)- 1H-imidazol-5-yl)-2-(methylthio)pyrimidine (4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl) -1H-imidazol-5-yl)-2-(methylthio)pyrimidine) (Compound 0403-136): Under nitrogen protection, 4-(benzofuran-6-yl)-5-bromo-1-(methyl Oxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazole (0402-136) (605 mg, 1.133 mmol, 1.0 equivalent), 2- (Methylthio)-4-(trimethylstannyl)pyrimidine (0203-7) (493
  • Step 43h 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)- 1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl )-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine) (Compound 0404-136): To 4-(4-(benzofuran-6-yl)-1-(methoxymethyl Yl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (0403-136) (487 mg , 0.839 mmol, 1.0 equivalent) in dichlorome
  • Step 43i 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)- 1H-imidazol-5-yl)pyrimidin-2-amine (4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazol -5-yl)pyrimidin-2-amine) (Compound 0405-136): In a stuffy pot, 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)- 2-(4-((Triisopropylsilyl)oxy)butyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (0404-136) (500 mg, 0.816 A mixture of tetrahydrofuran (15 mL) (mmol, 1.0 equivalent)
  • Step 43j N 1 -(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy) (Butyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -methyl-5-nitro Benzene-1,4-diamine (N 1 -(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazol -5-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine) (Compound 0406-136) Preparation: Under nitrogen protection, 4-
  • Step 43k 4-(4-(benzofuran-6-yl)-5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl (Oxy-5-nitrophenyl)amino)pyrimidin-4yl)-1H-imidazol-2-yl)butan-1-ol (4-(4-(benzofuran-6-yl)-5-(2- ((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)butan-1-ol) (Compound 0312-136): To N 1 -(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropyl) (Silyl)oxy)butyl)-1H-imidazol-5-yl)
  • Step 43l N-(5-((4-(4-(benzofuran-6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran- 6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl )acrylamide) (Compound 136): The 4-(4-(benzofuran-6-yl)-5-(2-((4-((2-(dimethylamino)ethyl)(formula (Yl)amino)-2-methoxy-5
  • Example 44 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)cyclopropylcarboxamide (N-(5-((4 -(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin -1-yl)piperidin-1-yl)phenyl)acrylamide) (Compound 143) (prepared according to the route of Scheme 3)
  • Example 45 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(4-(4-isopropylpiperazin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-( 4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(4-isopropylpiperazin-1-yl)piperidin -1-yl)-4-methoxyphenyl)acrylamide) (Compound 144) (prepared according to the route of Scheme 4)
  • Step 45a 1-(1-(4-Bromo-5-methoxy-2-nitrophenyl)piperidin-4-yl)-4-isopropylpiperazine (1-(1-(4- Preparation of bromo-5-methoxy-2-nitrophenyl)piperidin-4-yl)-4-isopropylpiperazine) (Compound 0114-144): To 1-(4-bromo-5-methoxy-2-nitrophenyl) ) Piperidin-4-one (200 mg, 0.61 mmol, 1.0 equivalent) in 10 ml methanol and 4 ml tetrahydrofuran mixed solvent solution was added 0.04 ml acetic acid and 1-isopropylpiperazine (118 mg, 0.91 mmol, 1.5 equivalents).
  • Step 45b N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-(4-(4-isopropylpiperazin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4 -(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4- (4-isopropylpiperazin-1-yl)piperidin- Preparation of 1-yl)-4-methoxyphenyl)acrylamide) (Compound 144): The synthesis method is as in Example 32, steps 32b to 32e, except that 0114-98 in step 32b is replaced with 1-(1-(4 -Bromo-5-methoxy
  • Example 46 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4 -(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(4-ethylpiperazin-1-yl)piperidin- Preparation of 1-yl)-4-methoxyphenyl)acrylamide) (Compound 145) (prepared according to the route of Scheme 4)
  • Step 46a 1-(1-(4-Bromo-5-methoxy-2-nitrophenyl)piperidin-4-yl)-4-ethylpiperazine (1-(1-(4-bromo -5-methoxy-2-nitrophenyl)piperidin-4-yl)-4-ethylpiperazine) (Compound 0114-145): To 1-(4-bromo-5-methoxy-2-nitrophenyl) A solution of piperidin-4-one (200 mg, 0.61 mmol, 1.0 equiv) in 15 ml methanol and 3 ml tetrahydrofuran mixed solvent was added 0.08 ml acetic acid and 1-ethylpiperazine (208 mg, 1.82 mmol, 3.0 equiv) ).
  • Step 46b N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-(4-(4-Ethylpiperazin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4- (benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(4-ethylpiperazin-1-yl)piperidin-1 -yl)-4-methoxyphenyl)acrylamide) (Compound 145): The synthesis method is the same as in Example 32, steps 32b to 32e, except that 0114-98 in step 32b is replaced with 1-(1-(4- Bromo-5-methoxy-2-nitrophen
  • Example 47 N-(2-(4-(4-Acetylpiperazin-1-yl)piperidin-1-yl)-5-((4-(4-(benzofuran-6-yl) -2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-(4-(4- acetylpiperazin-1-yl)piperidin-1-yl)-5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2- yl)amino)-4-methoxyphenyl)acrylamide) (Compound 146) (prepared according to the route of Scheme 4)
  • Step 47a 1-(4-(1-(4-Bromo-5-methoxy-2-nitrophenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one (1 -(4-(1-(4-bromo-5-methoxy-2-nitrophenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one) (Compound 0114-146) Preparation:
  • Step 47b N-(2-(4-(4-Acetylpiperazin-1-yl)piperidin-1-yl)-5-((4-(4-(benzofuran-6-yl)- 2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-(4-(4-acetylpiperazin -1-yl)piperidin-1-yl)-5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl )amino)-4-methoxyphenyl)acrylamide) (Compound 146): The synthesis method is as in Example 32, steps 32b to 32e, except that 0114-98 in step 32b is replaced with 1-(4-(1- (4-Bromo-5-methoxy-2-nitrophenyl
  • Example 48 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxy-2-(4-dimethylaminopiperidin-1-yl)phenyl)cyclopropylcarboxamide (N-(5-((4-(4-(benzofuran-6 -yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)cyclopropanecarboxamide) Preparation of (Compound 147) (prepared according to scheme 3 route)
  • Example 49 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)-3-methylbutanamide (N-(5-((4-(4- (benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4- Preparation of methoxyphenyl)-3-methylbutanamide) (compound 148) (prepared according to the route of Scheme 3)
  • the synthesis method is as in Example 48, except that the cyclopropyl formic acid is replaced with 3-methylbutanoic acid (18 mg, 0.18 mmol, 1.5 equivalents), and a yellow solid N-(5-((4-( 4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(dimethylamino) Piperidin-1-yl)-4-methoxyphenyl)-3-methylbutanamide (50 mg, yield: 62.5%).
  • Example 50 N-(5-((4-(4-(benzofuran-6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran-6- yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide)( Compound 149) Preparation (prepared according to the route of Scheme 4)
  • Step 50a 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)- 1H-imidazol-5-yl)-N-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (4 -(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazol-5-yl)-N-(4-(4-( dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)pyrimidin-2-amine) (Compound 0406-149): Under the protection of nitrogen, the 4-(4-(benzofuran-6- Base)-1-(Methoxymethyl)-2-(4-((Triisopropy
  • Step 50b 4-(4-(benzofuran-6-yl)-5-(2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy- 5-Nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)butan-1-ol (4-(4-(benzofuran-6-yl)-5-(2-(( 4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)butan-1-ol) (Compound 0312- 149) preparation: the compound 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy) Butyl)-1H-imidazol-5-yl)-N-(4-(4-(dimethyl
  • Step 50c N-(5-((4-(4-(benzofuran-6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-(4-(Dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran-6-yl )-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide)(Compound 149) preparation: 4-(4-(benzofuran-6-yl)-5-(2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methyl (Oxy-5-nitrophenyl)amino)pyrimidin-4-
  • Example 51 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(4-(diethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran-6-yl )-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(diethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide)(Compound 150) Preparation (prepared according to the route of Scheme 4)
  • Step 51a 1-(4-bromo-5-methoxy-2-nitrophenyl)-N,N-diethylpiperidin-4-amine (1-(4-bromo-5-methoxy-2 -nitrophenyl)-N,N-diethylpiperidin-4-amine) (Compound 0114-150):
  • Step 51b N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-(4-(Diethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran-6-yl) -2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(diethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide) (Compound 150 ) Preparation: The synthesis method is as in Example 32, step 32b to step 32e, except that 0114-98 in step 32b is replaced with 1-(4-bromo-5-methoxy-2-nitrophenyl)- N,N-Diethylpiperid
  • the synthesis method is as in Example 48, except that the cyclopropyl formic acid is replaced with crotonic acid (15.5 mg, 0.18 mmol, 1.5 equivalents) to prepare a yellow solid (E)-N-(5-((4-( 4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4- Dimethylaminopiperidin-1-yl)phenyl)but-2-enamine (17 mg, yield: 21.8%).
  • Step 53a N-(1-(4-Bromo-5-methoxy-2-nitrophenyl)piperidin-4-yl)methanesulfonamide (N-(1-(4-bromo-5-methoxy -2-nitrophenyl)piperidin-4-yl)methanesulfonamide) (Compound 0114-153):
  • N-(piperidin-4-yl)methanesulfonamide 2.0 g, crude product
  • dimethyl 2-fluoro-4-methoxy-1-nitrobenzene 684 mg, 4.0 mmol, 1.0 equivalent
  • the formamide solution was added with the N-(piperidin-4-yl)methanesulfonamide (2.0 g, 4.44 mmol, 1.1 equivalent) obtained above and potassium carbonate (1.1 g, 8.0 mmol, 2.0 equivalent).
  • N-(1-(5-(5-methoxy-2-nitrophenyl)piperidin-4-yl)methanesulfonamide (1.0 g, 3.0 mmol, 1.0 equivalent) was added to 10 ml of acetic acid In a mixed solvent of 5ml water and 5ml water. The mixture was stirred at room temperature to dissolve the solid. Bromine (510mg, 3.2mmol, 1.05eq) was dissolved in 1.0ml acetic acid and added dropwise to the above mixture. The mixture was stirred at room temperature One hour. The reaction was quenched with a saturated aqueous sodium sulfite solution, and the pH was adjusted to 10 with a 2M aqueous sodium hydroxide solution.
  • Step 53b N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-4-methoxy-2-(4-(methylsulfonamido)piperidin-1-yl)phenyl)acrylamide (N-(5-((4-(4-(benzofuran-6- yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(methylsulfonamido)piperidin-1-yl)phenyl)acrylamide) Preparation of (Compound 153): The synthetic method is as in Example 32, Step 32b to Step 32e, except that 0114-98 in Step 32b is replaced with N-(1-(4-bromo-5-methoxy-2- Nitrophenyl) piperidin-4
  • Example 54 N-(2-(4-Acetylaminopiperidin-1-yl)-5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl) -1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-(4-acetamidopiperidin-1-yl)-5-((4- Preparation of (4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 154) (according to Scheme 4 line preparation)
  • Step 54a N-(1-(4-bromo-5-methoxy-2-nitrophenyl))piperidin-4-yl)acetamide N-(1-(4-bromo-5-methoxy- Preparation of 2-nitrophenyl)piperidin-4-yl)acetamide (Compound 0114-154):
  • Step 54b N-(2-(4-Acetylaminopiperidin-1-yl)-5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)- 1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-(4-acetamidopiperidin-1-yl)-5-((4-( Preparation of 4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 154): synthetic method As in Example 32, step 32b to step 32e, only replace 0114-98 in step 32b with N-(1-(4-bromo-5-methoxy-2-nitrophenyl))piperidine- 4-yl)acetamide (Compound 0114-154), a yellow solid
  • Example 55 N-(5-((4-(4-(benzofuran-6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide (N-(5-((4-(4-(benzofuran -6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1 -yl)phenyl)acrylamide) (Compound 155) (prepared according to the route of Scheme 3)
  • Step 55a 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)- 1H-imidazol-5-yl)-N-(2-methoxy-5-nitro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2 -Amine(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazol-5-yl)-N-(2- Preparation of methoxy-5-nitro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)pyrimidin-2-amine) (compound 0311-155): Under nitrogen protection, the 4-(4 -(Benzofuran-6-yl)-1-(methoxymethyl)-2-(
  • Step 55b 2-(4-(benzofuran-6-yl)-5-(2-((2-methoxy-5-nitro-4-(4-(pyrrolidin-1-yl)piper (Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-ylethoxy-1-ol (2-(4-(benzofuran-6-yl)-5-(2 -((2-methoxy-5-nitro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)ethan- 1-ol) (Compound 0312-155): To 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(2-((triisopropyl) (Silyl)oxy)ethyl)-1H-imidazol-5-yl)-N-(4-(4
  • Step 55c N-(5-((4-(4-(benzofuran-6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide (N-(5-((4-(4-(benzofuran- 6-yl)-2-(2-hydroxyethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1- yl)phenyl)acrylamide) (Compound 155): Add 2-(4-(benzofuran-6-yl)-5-(2-((2-methoxy-5-nitro-4-( 4-(Pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)pyr
  • Example 56 (E)-N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidine- 2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)but-2-enamide ((E)-N- (5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( Preparation of 4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)but-2-enamide) (Compound 156)
  • Step 56a 3-(5-(2-((5-amino-2-methoxy-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine -4-yl)-4-(benzofuran-6-yl)-1H-imidazol-2-yl)propan-1-ol (3-(5-(2-((5-amino-2-methoxy- 4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-4-(benzofuran-6-yl)-1H-imidazol-2-yl)propan-1 -ol) (Compound 0313-105)
  • Step 56b (E)-N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidine-2 -Yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)but-2-enamide
  • Compound 156 To 3-(5-(2-((5-amino-2-methoxy-4- (4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)
  • Example 57 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)cyclopropylcarboxamide (N-(5-((4-(4 -(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl) Preparation of piperidin-1-yl)phenyl)cyclopropanecarboxamide) (Compound 157) (prepared according to the route of Scheme 3)
  • Example 58 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-3-methylbutanamide (N-(5-((4- (4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1- yl)piperidin-1-yl)phenyl)-3-methylbutanamide) (Compound 158) Preparation (prepared according to the route of Scheme 3)
  • the synthesis method is as in Example 57, except that the cyclopropanecarboxylic acid is replaced with 3-methylbutanoic acid (17 mg, 0.172 mmol, 1.5 equivalents), and N-(5-((4-(4-( Benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidine) 1-yl)piperidin-1-yl)phenyl)-3-methylbutanamide was a yellow solid (42 mg, yield: 52.71%).
  • Example 59 N-(5-((4-(4-(benzofuran-6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide (N-(5-((4-(4-(benzofuran -6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1 -yl)phenyl)acrylamide) (Compound 159) (prepared according to the route of Scheme 4)
  • Step 59a 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)- 1H-imidazol-5-yl)-N-(2-methoxy-5-nitro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2 -Amine(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropylsilyl)oxy)butyl)-1H-imidazol-5-yl)-N-(2- Preparation of methoxy-5-nitro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)pyrimidin-2-amine) (Compound 0406-159): Under the protection of nitrogen, the 4-( 4-(benzofuran-6-yl)-1-(methoxymethyl)-2-
  • Step 59b 4-(4-(benzofuran-6-yl)-5-(2-((2-methoxy-5-nitro-4-(4-(pyrrolidin-1-yl)piper (Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)butan-1-ol (4-(4-(benzofuran-6-yl)-5-(2- ((2-methoxy-5-nitro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)butan-1 -ol) (Compound 0312-159): The compound 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(4-((triisopropyl) (Silyl)oxy)butyl)-1H-imidazol-5-yl)-N-(2-me
  • Step 59c N-(5-((4-(4-(benzofuran-6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide (N-(5-((4-(4-(benzofuran- 6-yl)-2-(4-hydroxybutyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1- yl)phenyl)acrylamide) (Compound 159): Add 4-(4-(benzofuran-6-yl)-5-(2-((2-methoxy-5-nitro-4-( 4-(Pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)
  • Example 60 N-(2-([1,4'-Bipiperidine]-1'-yl)-5-((4-(4-(benzofuran-6-yl)-2-(3 -Hydroxypropyl)-1H-imidazol 5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-([1,4'-bipiperidin]-1' -yl)-5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) Preparation of acrylamide) (compound 160) (prepared according to the route of Scheme 4)
  • Step 60a 1'-(4-bromo-5-methoxy-2-nitrophenyl)-1,4'-bipiperidine (1'-(4-bromo-5-methoxy-2-nitrophenyl) -1,4'-bipiperidine) (Compound 0114-160): To a solution of piperidine hydrochloride (222 mg, 1.82 mmol, 3.0 equiv) in 10 ml tetrahydrofuran was added potassium carbonate (754 mg, 5.46 mmol) , 9.0 equivalent). The mixture was stirred at room temperature for 40 minutes.
  • Step 60b N-(2--([1,4'-Bipiperidine]-1'-yl)-5-((4-(4-(benzofuran-6-yl)-2-(3- Hydroxypropyl)-1H-imidazol 5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide N-(2-([1,4'-bipiperidin]-1'-yl )-5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide( The preparation of compound 160): The synthesis method is as in Example 32, step 32b to step 32e, except that 0114-98 in step 32b is replaced with 1'-(4-bromo-5-methoxy-2-nitrobenzene Yl)-1,4'-bipiperidine (0114-160
  • Example 61 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxy-2-(4-morpholinylpiperidin-1-yl)phenyl)acrylamide (N-(5-((4-(4-(benzofuran-6-yl)- Preparation of 2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-morpholinopiperidin-1-yl)phenyl)acrylamide (Compound 161) (Prepared according to the route of Scheme 4)
  • Step 61a 4-(1-(4-bromo-5-methoxy-2-nitrophenyl)piperidin-4-yl)morpholine (4-(1-(4-bromo-5-methoxy- 2-nitrophenyl)piperidin-4-yl)morpholine)
  • Compound 0114-161 To 1-(4-bromo-5-methoxy-2-nitrophenyl)piperidin-4-one (200 Add 0.04 ml of acetic acid and morpholine (212 mg, 2.43 mmol, 4.0 equiv) to a solution of 15 ml methanol and 3 ml tetrahydrofuran mixed solvent.
  • Step 61b N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-4-methoxy-2-(4-morpholinylpiperidin-1-yl)phenyl)acrylamide (N-(5-((4-(4-(benzofuran-6-yl)-2 -(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-morpholinopiperidin-1-yl)phenyl)acrylamide) (Compound 161): The synthesis method is as in Example 32, steps 32b to 32e, except that 0114-98 in step 32b is replaced with 4-(1-(4-bromo-5-methoxy-2-nitrophenyl)piperidine -4-yl)morpholine (0114-161), a yellow solid N
  • Example 62 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(4-cyclopentyl-1,4-diazepan-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4 -(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-cyclopentyl-1,4-diazepan-1-yl )-4-methoxyphenyl)acrylamide) (Compound 162) (prepared according to the route of Scheme 4)
  • Step 62a 1-(4-bromo-5-methoxy-2-nitrophenyl)-4-cyclopentyl-1,4-diazepane
  • 1-(4-bromo-5-methoxy -2-nitrophenyl)-4-cyclopentyl-1,4-diazepane (Compound 0114-162): To 2-fluoro-4-methoxy-1-nitrobenzene (855 mg, 5.0 mmol, 1.0 equivalent Add 1,4-diazepane (1.0 g, 10.0 mmol, 2.0 equiv) and potassium carbonate (2.76 g, 20.0 mmol, 2.0 equiv) to 20 ml of dimethylformamide solution. The mixture was stirred overnight at room temperature.
  • Step 62b 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)- 1H-imidazol-5-yl)-N-(4-(4-cyclopentyl-1,4-diazepan-1-yl)-2-methoxy-5-nitrophenyl)pyrimidine -2-Amine (4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)-N-( Preparation of 4-(4-cyclopentyl-1,4-diazepan-1-yl)-2-methoxy-5-nitrophenyl)pyrimidin-2-amine) (Compound 0406-162): Under the protection of nitrogen, the 4-( 4-(benzofuran-6-yl)-1-(methoxymethyl)
  • Step 62c 3-(4-(benzofuran-6-yl)-5-(2-((4-(4-cyclopentyl-1,4-diazepan-1-yl)-2 -Methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)-1-propanol (3-(4-(benzofuran-6-yl)-5- (2-((4-(4-cyclopentyl-1,4-diazepan-1-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan- 1-ol) (Compound 0312-162) preparation: add 4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropyl) (Silyl)oxy)propyl)-1H-imidazol-5-yl)-N-(4-
  • Step 62d N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-(4-Cyclopentyl-1,4-diazepan-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4- (benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-cyclopentyl-1,4-diazepan-1-yl) -4-methoxyphenyl)acrylamide) (Compound 162): Add 3-(4-(benzofuran-6-yl)-5-(2--((4-(4-cyclopentyl-1,4- Diazeppan-1-yl)-2-methoxy-5-nitrophenyl
  • Example 63 N-(2-(4-(dimethylamino)piperidin-1-yl)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalene-2- Yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-(4-(dimethylamino)piperidin-1-yl)-5 -((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide)(Compound 164 ) Preparation (prepared according to the route of Scheme 7)
  • Step 63a N-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(1-(methoxymethyl )-4-(naphthalen-2-yl)-2-(3-(((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-amine (N -(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(1-(methoxymethyl)-4-(naphthalen-2-yl)-2-(3- ((triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-amine)(Compound 0709-164): Under the protection of nitrogen, the 4-(1-(methoxymethyl) -4-(Naphthalene-2-yl)-2-(3-(
  • Step 63b 3-(5-(2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidine-4 -Yl)-4-(naphthalen-2-yl)-1H-imidazol-2-yl)propan-1-ol (3-(5-(2-((4-(4-(dimethylamino)piperidin-1- yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-4-(naphthalen-2-yl)-1H-imidazol-2-yl)propan-1-ol) (Compound 0710-164) Preparation: The compound N-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(1-(methoxy Methyl)-4-(naphthalen-2-yl)-2-(3-
  • Step 63c N-(2-(4-(dimethylamino)piperidin-1-yl)-5-((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl )-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-(4-(dimethylamino)piperidin-1-yl)-5- ((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide)(Compound 164) Preparation: 3-(5-(2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidine- 4-yl)-4-(naphthalen-2-yl)-1
  • Example 64 N-(5-((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino) -4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (N-(5-((4-(2-( 3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl) Preparation of piperidin-1-yl)phenyl)acrylamide) (Compound 165) (prepared according to the route of Scheme 7)
  • the synthesis method is as in Example 63, except that the compound 0114-104 is replaced with 1-(1-(4-bromo-5-methoxy-2-nitrophenyl)piperidin-4-yl)-4 -Methylpiperazine (0114-98) (333 mg, 0.807 mmol, 1.05 equivalent), to prepare a yellow solid N-(5-((4-(2-(3-hydroxypropyl)-4-(naphthalene -2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidine-1 -Yl)phenyl)acrylamide (93 mg, yield: 40.9%).
  • Example 65 N-(5-((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino) -4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)cyclopropylcarboxamide (N-(5-((4-( 2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1 -yl)piperidin-1-yl)phenyl)cyclopropanecarboxamide) (Compound 166) (prepared according to the route of Scheme 7)
  • Step 65a 3-(5-(2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)pyrimidin-4-yl)-4-(naphthalene-2-yl)-1H-imidazol-2-yl)propan-1-ol (3-(5-(2-((5-amino-2-methoxy -4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-4-(naphthalen-2-yl)-1H-imidazol-2-yl) propan-1-ol) (Compound 0711-166): The 3-(5-(2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piper (Pyridin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)
  • Step 65b N-(5-((4-(2-(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)- 4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)cyclopropylcarboxamide (N-(5-((4-(2 -(3-hydroxypropyl)-4-(naphthalen-2-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1- yl)piperidin-1-yl)phenyl)cyclopropanecarboxamide) (Compound 166): Add 3-(5-(2-((5-amino-2-methoxy-4-(4-(4-methyl (Piperazin-1-yl)piperidin-1-yl
  • reaction mixture was quenched with aqueous sodium bicarbonate solution and stirred for 10 minutes. Water was added and ethyl acetate was added for extraction, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure.
  • Example 66 N-(2-(4-Acetylpiperazin-1-yl)-5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl) -1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-(4-acetylpiperazin-1-yl)-5-((4- Preparation of (4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide) (Compound 167) (according to Scheme 4 line preparation)
  • Step 66a 1-(4-(4-bromo-5-methoxy-2-nitrophenyl)piperazin-1-yl)ethan-1-one (1-(4-(4-bromo-5 -methoxy-2-nitrophenyl)piperazin-1-yl)ethan-1-one) (Compound 0114-167):
  • Step 66b N-(2-(4-Acetylpiperazin-1-yl)-5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)- 1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (N-(2-(4-acetylpiperazin-1-yl)-5-((4-( Preparation of 4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 167): synthetic method As in Example 32, step 32b to step 32e, only replace 0114-98 in step 32b with 1-(4-(4-bromo-5-methoxy-2-nitrophenyl)piperazine-1 -Yl)-1-ketone (0114-167), a yellow solid N-(
  • Example 67 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran-6 -yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)-4-methoxyphenyl) acrylamide) (Compound 168) (prepared according to the route of Scheme 4)
  • Step 67a 2-(4-(4-((4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylmethyl) Silyl)oxy)propyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)piperazin-1-yl)ethyl-1 -Alcohol (2-(4-(4-((4-(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3-((triisopropylsilyl)oxy)propyl)-1H-imidazol- Preparation of 5-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)piperazin-1-yl)ethan-1-ol) (Compound 0406-168): Under the protection of nitrogen, the 4- (4-(benzofuran-6
  • Step 67b 3-(4-(benzofuran-6-yl)-5-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxy -5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol (3-(4-(benzofuran-6-yl)-5-(2-( (4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-1-ol)( Compound 0312-168)): The compound 2-(4-(4-((4-(4-(4-(benzofuran-6-yl)-1-(methoxymethyl)-2-(3 -((Triisopropylsilyl)oxy)propyl)-1H-imidazol-5-yl)
  • Step 67c N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino )-2-(4-(2-hydroxyethyl)piperazin-1-yl)-4-methoxyphenyl)acrylamide (N-(5-((4-(4-(benzofuran-6- yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)-4-methoxyphenyl)acrylamide ) (Compound 168): Add 3-(4-(benzofuran-6-yl)-5-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl) -2-Methoxy-5-nitrophenyl)amino)pyrimidin-4
  • Example 68 N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl)pyrimidin-2-yl) Amino)-4-methoxy-2-morpholinophenyl)acrylamide (N-(5-((4-(4-(benzofuran-6-yl)-2-(3-hydroxypropyl)-1H- Preparation of imidazol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide) (compound 169) (prepared according to the route of Scheme 4)
  • Step 68a Preparation of 4-(4-bromo-5-methoxy-2-nitrophenyl)morpholine 4-(4-bromo-5-methoxy-2-nitrophenyl)morpholine (Compound 0114-169):
  • the 4-(5-methoxy-2-nitrophenyl)morpholine obtained above (500 mg, 2.1 mmol, 1.0 equivalent) It was added to a mixed solvent of 15 ml of acetic acid and 10 ml of water, the mixture was stirred at room temperature, and the solid was dissolved. Bromine (352 mg, 2.2 mmol, 1.05 equivalent) was dissolved in 1.0 ml of acetic acid and added dropwise to the above mixture. The mixture was stirred at room temperature for one hour. The reaction was quenched with saturated aqueous sodium sulfite solution, and the pH was adjusted to 10 with 2M aqueous sodium hydroxide solution.

Abstract

L'invention concerne un composé d'imidazole tri-substitué contenant de la pyrimidine ayant la structure représentée dans la formule (I) et une utilisation associée. Le composé peut inhiber de manière efficace des mutations EGFR C797S comprenant l'EGFR ex19del/T790M/C797S et L858R/T790M/C797S, en même temps, ledit composé a également une activité inhibitrice supérieure vis-à-vis de mutations ponctuelles uniques L858R, ex19del et des mutations à point double telles que L858R/T790M et ex19del/T790M, en outre, le composé a un effet inhibiteur faible sur EGFR de type sauvage, présentant ainsi une bonne sélectivité. Le composé a le potentiel d'être utilisé en tant que médicament pour traiter une tumeur maligne portant des mutations EGFR C797S, en particulier le cancer du poumon non à petites cellules (NSCLC), et présente une grande valeur d'application.
PCT/CN2020/075475 2019-03-27 2020-02-17 Composé d'imidazole tri-substitué contenant de la pyrimidine et utilisation associée WO2020192302A1 (fr)

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WO2000026209A1 (fr) * 1998-11-03 2000-05-11 Novartis Ag 4-phenyl-5-pyrimidinyl-imidazoles anti-inflammatoires
WO2007051065A2 (fr) * 2005-10-28 2007-05-03 Numerate, Inc. Compositions et traitements destines a inhiber kinase et/ou hmg-coa reductase
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CN103702990A (zh) * 2011-07-27 2014-04-02 阿斯利康(瑞典)有限公司 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症

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WO2000026209A1 (fr) * 1998-11-03 2000-05-11 Novartis Ag 4-phenyl-5-pyrimidinyl-imidazoles anti-inflammatoires
WO2007051065A2 (fr) * 2005-10-28 2007-05-03 Numerate, Inc. Compositions et traitements destines a inhiber kinase et/ou hmg-coa reductase
CN102015686A (zh) * 2008-03-21 2011-04-13 诺瓦提斯公司 新的杂环化合物及其用途
CN103702990A (zh) * 2011-07-27 2014-04-02 阿斯利康(瑞典)有限公司 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症

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