CN116283750A - Heterocyclic amide derivative and preparation method and application thereof - Google Patents

Heterocyclic amide derivative and preparation method and application thereof Download PDF

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CN116283750A
CN116283750A CN202211096418.8A CN202211096418A CN116283750A CN 116283750 A CN116283750 A CN 116283750A CN 202211096418 A CN202211096418 A CN 202211096418A CN 116283750 A CN116283750 A CN 116283750A
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alkyl
halogen
amino
nitro
carboxyl
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徐燕军
李清
蒙柳卫
张裔
邓小艳
祁伟
冯建
熊亮
谭康利
付熙
吴逢伟
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Chengdu Taihe Weiye Biotechnology Co ltd
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Abstract

The invention provides a heterocyclic amide derivative, a preparation method and application thereof, and belongs to the field of chemical medicines. The heterocyclic amide derivative is a compound shown in a formula I, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a mixture thereof. The heterocyclic amide derivative can be used as FXIa small molecule inhibitor, fluorine atoms are introduced into the compound, and compared with a compound without fluorine, the heterocyclic amide derivative has higher activity and can effectively improve the anticoagulation effect of the compound. In addition, the compounds of the present invention are useful for the effective treatment and/or prevention of cardiovascular and cerebrovascular diseases and thrombosis symptoms.

Description

Heterocyclic amide derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to a heterocyclic amide derivative, and a preparation method and application thereof.
Background
Thrombotic diseases are diseases caused by two pathological mechanisms, thrombosis and thromboembolism. Over 1000 ten thousand patients with global thrombotic diseases, about 3% of people in China can develop thrombotic diseases with different degrees each year. Thrombus exacerbates the risk of cardiovascular events in patients with hypertension, hyperlipidemia, and diabetes, increasing mortality. At present, medicines for clinically treating thrombotic diseases mainly comprise anticoagulant medicines and antiplatelet medicines, but the anticoagulant medicines and the antiplatelet medicines cannot distinguish pathological coagulation from physiological coagulation, and serious bleeding complications (bleeding) can be caused when the thrombus is treated, so that the clinical application of the medicines is limited. Thus, new anticoagulants are urgently needed.
Factor XI (FXI) is a key protease in the intrinsic coagulation pathway, and becomes factor XIa (FXIa) after activation of factor XI, which plays a major role in the amplification stage of the coagulation cascade. Studies have shown that FXI gene silenced mice have protective effects on thrombosis, but do not increase bleeding time. Patients with congenital FXI deficiency (hemophilia C) do not spontaneously bleed and show no symptoms in adulthood, only a fraction of which may have a mild or moderate bleeding tendency after surgery or trauma. Epidemiological studies have shown that too high a concentration of FXI in the blood is a risk factor for thrombosis, and that low concentrations of FXI have a protective effect on thrombosis, and patients with congenital FXI defects are not prone to ischemic stroke and venous thromboembolism. Animal experiments show that antibodies targeting FXI or FXIa and direct FXIa inhibitors have antithrombotic efficacy, but have less impact on normal hemostasis. Phase II clinical experiments indicate that FXI-targeted antisense oligonucleotide IONIS-416858 treatment reduces the chance of venous thromboembolism in patients undergoing selective total knee replacement, with comparable effect to enoxaparin, but with lower bleeding risk. Thus, both genetic, epidemiological, and preclinical and clinical studies have demonstrated that FXIa is a potential less bleeding risk anticoagulant drug target.
FXIa is a novel target of anticoagulants, and published patent applications with small molecule inhibitors of FXIa are CN105164112, WO2016015593, WO2017005725, WO2018041122, WO2019175043, WO2021057818. Among these, the main clinical studies entered are JNJ-70033093 (BMS-986177, possen pharmaceutical) and BAY-2433334 (Bayer), and ONO-5450598 (field pharmaceutical) and SHR2285 (Hengrui pharmaceutical) at clinical stage I. The data previously disclosed indicate that they have a certain clinical effect. However, poor selectivity and low oral bioavailability are major drawbacks of these FXIa inhibitors, and no small molecule FXIa inhibitors have been marketed to date. There is therefore still a need to investigate novel FXIa inhibitors.
Disclosure of Invention
The invention aims to provide a heterocyclic amide derivative, a preparation method and application thereof.
The present invention provides a compound of formula I, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof:
Figure BDA0003838975750000021
wherein,,
n is substituent R on benzene ring 1 Is an integer of 0 to 5;
each R 1 Are respectively independentSelected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
x is selected from CR 3 Or N;
R 3 selected from hydrogen, C 1 ～C 8 Alkyl, halogen, 3-8 membered cycloalkyl, -OR 4 ；
R 4 Selected from substituted or unsubstituted C 1 ～C 8 Alkyl and 3-8 membered cycloalkyl;
the ring A is selected from 5-10 membered aryl and 5-10 membered unsaturated heterocyclic group, the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atom is 1-2;
m is a substituent R on the A ring 2 Is an integer of 0 to 5;
each R 2 Independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, cyano, -C (O) R 5 、-S(O)(O)R 5 、-OR 5’ 、-NR 6 C(O)R 7 Aryl of 5-10 membered;
R 5 selected from hydrogen, C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, hydroxy, -N (H) R 8 、-NR 9 R 10 ；
R 5’ Selected from hydrogen, C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, hydroxy, -N (H) R 8 ；
R 6 Selected from hydrogen, C 1 ～C 8 An alkyl group;
R 7 selected from hydrogen, C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, -N (H) R 8 ；
R 8 Selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyAmino, carboxyl, nitro, mercapto, ester, cyano, 3-8 membered cycloalkyl;
R 9 、R 10 Are respectively and independently selected from C 1 ～C 8 An alkyl group;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
Further, the method comprises the steps of,
n is 0, 1 or 2;
each R 1 Are respectively and independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, and the number of the hetero atoms is 3-4;
x is selected from CR 3 Or N;
R 3 selected from hydrogen, C 1 ～C 4 Alkyl, halogen, 3-6 membered cycloalkyl, -OR 4 ；
R 4 Selected from substituted or unsubstituted C 1 ～C 4 Alkyl and 3-6 membered cycloalkyl;
the ring A is selected from phenyl and 5-10 membered unsaturated heterocyclic groups, the hetero atoms of the unsaturated heterocyclic groups are N, O or S, and the number of the hetero atoms is 1-2;
m is 0, 1 or 2;
each R 2 Independently selected from substituted or unsubstituted C 1 ～C 4 Alkyl, halogen, cyano, -C (O) R 5 、-S(O)(O)R 5 、-OR 5’ 、-NR 6 C(O)R 7 Phenyl;
R 5 Selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, hydroxy, -N (H) R 8 、-NR 9 R 10 ；
R 5’ Selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, hydroxy, -N (H) R 8 ；
R 6 Selected from hydrogen, C 1 ～C 4 An alkyl group;
R 7 selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, -N (H) R 8 ；
R 8 Selected from hydrogen, substituted or unsubstituted C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, mercapto, ester, cyano, 3-6 membered cycloalkyl;
R 9 、R 10 are respectively and independently selected from C 1 ～C 4 An alkyl group;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
Further, the method comprises the steps of,
n is 0, 1 or 2;
each R 1 Are respectively and independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-to 6-membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;
x is selected from CR 3 Or N;
R 3 selected from hydrogen, C 1 ～C 4 Alkyl, halogen, 3-6 membered cycloalkyl, -OR 4 ；
R 4 Selected from substituted or unsubstituted C 1 ～C 4 Alkyl and 3-6 membered cycloalkyl;
the A ring is selected from phenyl, indazolyl, indolyl, quinoxalinyl, thienyl, isoxazolyl, thiazolyl, pyrazolyl and dihydrobenzimidazolyl;
m is 0, 1 or 2;
each R 2 Independently selected from substituted or unsubstituted C 1 ～C 4 Alkyl, halogen, cyano, -C (O) R 5 、-S(O)(O)R 5 、-OR 5’ 、-NR 6 C(O)R 7 Phenyl;
R 5 selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, hydroxy, -N (H) R 8 、-NR 9 R 10 ；
R 5’ Selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, hydroxy, -N (H) R 8 ；
R 6 Selected from hydrogen, C 1 ～C 4 An alkyl group;
R 7 selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, -N (H) R 8 ；
R 8 Selected from hydrogen, substituted or unsubstituted C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, mercapto, ester, cyano, 3-6 membered cycloalkyl;
R 9 、R 10 are respectively and independently selected from C 1 ～C 4 An alkyl group;
the substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
Further, the compound is represented by formula II:
Figure BDA0003838975750000041
wherein,,
R 1a 、R 1b independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
x, A ring, m and R 2 As described previously;
preferably, the method comprises the steps of,
R 1a 、R 1b are respectively and independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, and the number of the hetero atoms is 3-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxyA group, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
more preferably, the process is carried out,
R 1a 、R 1b are respectively and independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-to 6-membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;
the substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
Further, the compound is represented by formula III:
Figure BDA0003838975750000051
wherein,,
R 1b independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
x, A ring, m and R 2 As described previously;
preferably, the method comprises the steps of,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, and the number of the hetero atoms is 3-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
more preferably, the process is carried out,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-to 6-membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;
the substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
The substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
Further, the compound is represented by formula IIIa:
Figure BDA0003838975750000061
wherein,,
R 1b independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
ring A, m and R 2 As described previously;
preferably, the method comprises the steps of,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, and the number of the hetero atoms is 3-4;
The substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
more preferably, the process is carried out,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano substituted or unsubstituted 3-to 6-membered cycloalkyl, substituted or unsubstituted triazolyl,Substituted or unsubstituted tetrazolyl;
the substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
Further, the compound is represented by formula IIIb:
Figure BDA0003838975750000071
wherein,,
R 1b independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
The substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
ring A, m and R 2 As described previously;
preferably, the method comprises the steps of,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclyl, said unsaturationAnd the hetero atom of the heterocyclic group is N, and the number of the hetero atom is 3-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
more preferably, the process is carried out,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-to 6-membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;
The substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
Further, the compound is one of the following compounds:
Figure BDA0003838975750000081
Figure BDA0003838975750000091
Figure BDA0003838975750000101
the invention also provides a preparation method of the compound, which comprises the following steps:
Figure BDA0003838975750000102
carrying out condensation reaction on the compound of the formula AI-A and the compound of the formula AI-B or hydrochloride thereof under alkaline conditions, and hydrolyzing to obtain the compound of the formula AI;
wherein,,
R 1 ring n, X, A, R 2 And m is as defined above.
The invention also provides the use of the aforementioned compounds, or salts, stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers, hydrates, solvates, prodrugs or mixtures thereof, for the preparation of inhibitors of coagulation factor FXIa and/or inhibitors of plasma bradykinin kinase PKA.
The invention also provides the use of the aforementioned compounds, or salts, stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers, hydrates, solvates, prodrugs or mixtures thereof, for the preparation of a medicament for the prevention and/or treatment of factor XIa mediated diseases, for the prevention and/or treatment of cardiovascular and cerebrovascular diseases;
Preferably, the disease is a thromboembolic disease;
more preferably, the disease is myocardial infarction, angina pectoris, reocclusion and restenosis following angioplasty or aortic coronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis.
The invention also provides a medicine which is a preparation prepared by taking the compound, or salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereoisomer, hydrate, solvate, prodrug or mixture thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The invention also provides a pharmaceutical composition comprising a compound of the foregoing, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, and a pharmaceutically acceptable carrier, diluent, and excipient.
Another aspect of the invention relates to a method for preventing and/or treating factor XIa mediated diseases, comprising administering to a patient a therapeutically effective dose of a compound of the foregoing, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or a mixture thereof, or a pharmaceutical composition comprising the same.
Another aspect of the present invention relates to a method of treatment for preventing and/or treating cardiovascular and cerebrovascular diseases, comprising administering to a patient a therapeutically effective amount of a compound of the foregoing, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a pharmaceutical composition comprising the same, wherein said cardiovascular and cerebrovascular diseases are selected from myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortic coronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis.
Another aspect of the invention relates to a medicament for inhibiting factor XIa, PKA, comprising a compound as described above, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, or a pharmaceutical composition comprising the same.
Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or melts. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.
The aqueous suspension contains the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.
The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
Dispersible powders and granules suitable for use in preparing an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.
The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.
The compounds of the present invention are administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.): in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the aforementioned compounds, or the type of pharmaceutically acceptable salts, can be verified according to conventional treatment protocols.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic radical which is a straight or branched chain radical containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentane Radical, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, etc. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more of the following groups independently selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituted group, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 5 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cycloalkyl groups being preferred; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (called a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a completely common electron-withdrawing system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl.
The term "aryl" refers to all-carbon monocyclic or fused-polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. Aryl groups may be substituted or unsubstituted, i.e., substituted with 0 to 4 substituents such as deuterium, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halogen, nitro, cyano, hydroxy, carboxyl, amino, and the like. Aryl groups include spiro, fused and bridged aryl groups.
The term "unsaturated heterocyclyl" is an unsaturated cycloalkyl group containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, including partially unsaturated heterocyclyl groups as well as aromatic heterocyclyl groups.
The invention designs a novel small molecule inhibitor, the introduction of fluorine atoms has remarkable anticoagulation effect and oral absorption effect on the whole compound, and compared with the compound without the introduction of fluorine atoms, the compound has higher activity. In particular, the compound of the invention has excellent anticoagulation activity and better drug generation property, and can be used for effectively treating and/or preventing cardiovascular and cerebrovascular diseases and thrombosis symptoms.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
Melting point was measured by using a RY-1 type melting point apparatus from Tianjin analytical instrument factory;
1 H-NMR 13 C-NMR was performed using a Bruker AM-600MHz/400MHz nuclear magnetic resonance apparatus, TMS as an internal standard;
MS was determined with a thermo LC/MS type mass spectrometer.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product used by the TLC is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea on a tobacco stage as carrier.
Average inhibition rate of enzyme and IC 50 The values were determined using a Varioskan LUX multifunctional microplate reader (thermoelectric company, USA).
The known starting materials of the present invention can be synthesized using or according to methods known in the art or can be purchased from the companies ABCR GmbH & Co.KG. Acros Organics, aldrich Chemical Company, shaogue chemical technology, an Naiji, pichia medicine, daruin chemicals, etc.
The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume. The hydrogen atmosphere means that the reactor flask is connected to a balloon of hydrogen gas of about L volume.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.
The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.
The monitoring of the reaction progress in the examples adopts Thin Layer Chromatography (TLC), the developing agent used in the reaction, the system of the eluent used in the column chromatography used for purifying the compound and the developing agent system of the thin layer chromatography comprise A methylene dichloride/methanol system, B normal hexane/ethyl acetate system, C petroleum riddle/ethyl acetate system, D acetone, E methylene dichloride/acetone system, F ethyl acetate/methylene dichloride system, G ethyl acetate/methylene dichloride/normal hexane, H ethyl acetate/methylene dichloride/acetone, I petroleum ether/ethyl acetate/methylene dichloride, and the volume ratio of the solvent can be adjusted according to the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like can also be added for adjustment.
The preparation method of the compound comprises the following steps:
Figure BDA0003838975750000151
the first step of reaction is that a compound of formula AI-1 and a compound of formula AI-2 are subjected to nucleophilic substitution reaction in an organic solvent under alkaline conditions to obtain a compound of formula AI-3;
the second step of reaction is that the compound of the formula AI-3 is hydrolyzed under the acid condition to obtain the compound of the formula AI-A;
the third step of the reaction is that the compound of the formula AI-A and the compound of the formula AI-B or the hydrochloride thereof are subjected to condensation reaction under alkaline conditions, and are hydrolyzed under alkaline conditions to obtain the compound of the formula AI;
reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylaminide, potassium acetate, sodium t-butoxide, or potassium t-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and lithium hydroxide.
Conditions that provide acidity include, but are not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.
The condensing agent includes, but is not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N.N, N ', N' -tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, 2- (7-benzotriazol) -N, N, N ', N-tetramethylurea hexafluorophosphate, 2- (7-azobenzotriazol) -N, N, N', N-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphate or benzotriazol-1-yl-oxy-tripyrrolidinylphosphos-phate, preferably 2- (7-azobenzotriazol) -N, N ', N' -tetramethylurea hexafluorophosphate.
The above reaction is preferably carried out in a solvent, including but not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, water or NN-dimethylformamide.
Example 1 preparation of 4- (2- (4- (5-chloro-2-cyanobenzene) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) benzoic acid (Compound 1)
Figure BDA0003838975750000161
Figure BDA0003838975750000171
Step a: preparation of (2, 5-dimethoxypyridin-4-yl) boronic acid (1 b)
Figure BDA0003838975750000172
2, 5-Dimethoxypyridine (4.0 g,28.8 mmol) was added to 50mL of tetrahydrofuran, lithium diisopropylamide (16.2 mL,34.5 mmol) was slowly added dropwise at-78℃and reacted for 2-4 hours with stirring, triisopropyl borate (6.5 g,34.5 mmol) was slowly added dropwise and reacted for 2-3 hours with stirring again, and then slowly thawed to room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, stirred for 3 hours, tetrahydrofuran was removed in vacuo, the aqueous phase was acidified with hydrochloric acid (2N), usually yielding a precipitate, which was filtered and the filter cake was dried to give the title product 1b (3.9 g, yield: 74%).
Step b: preparation of 4-chloro-2- (2, 5-dimethoxypyridin-4-yl) benzonitrile (1 c)
Figure BDA0003838975750000173
1b (4.2 g,19.4 mmol) of (2, 5-dimethoxypyridin-4-yl) boronic acid was added to a mixed solvent of 1, 4-dioxane and water (100 mL, v/v, 4:1), followed by addition of 2-bromo-4-chlorobenzonitrile (3.9 g,21.3 mmol) and potassium carbonate (6.2 g,58.2 mmol), displacement of 3-4 times with nitrogen and finally addition of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.6 mg,1.9 mmol). The reaction solution was heated to 80℃under nitrogen and stirred for 10h. After TLC monitored complete reaction of the starting materials, the reaction solution was cooled to room temperature, the solvent was removed in vacuo, 50mL of water was added to the resulting residue, extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed 3-4 times with water (50 mL), saturated sodium chloride solution (50 mL) respectively, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE: ea=40:1, v/v) to give the title product 1c as an off-white solid (3.3 g, yield: 62%).
1 H NMR(400MHz,DMSO-d 6 )δ8.04(s,1H),7.98(d,J＝8.2Hz,1H),7.70(d,J＝8.5Hz,2H),6.86(s,1H),3.83(s,3H),3.78(s,3H).
Step c: preparation of 4-chloro-2- (5-methoxy-2-oxo-1, 2-dihydropyridin-4-yl) benzonitrile (1 d)
Figure BDA0003838975750000181
1c (3.1 g,11.3 mmol) was added to 10mL of acetonitrile, iodotrimethylsilane (3.4 g,16.9 mmol) was added, distilled water (101.7 mg,5.6 mmol) was added, and the mixture was heated to 60℃and stirred for 10 hours. The reaction solution was poured into 20mL of ice water, stirred for half an hour, filtered, and the cake was rinsed with distilled water and dried to give the title product 1d (2.6 g, yield: 87%). Directly put into the next step without purification.
1 H NMR(400MHz,DMSO-d 6 )δ7.96(dd,J＝8.3,1.8Hz,1H),7.73–7.66(m,2H),7.27(s,1H),6.41(d,J＝1.8Hz,1H),3.62(s,3H).
Step d: preparation of ethyl 2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetate (1 e)
Figure BDA0003838975750000182
1d (3.0 g,11.5 mmol) and cesium carbonate (5.6 g,17.3 mmol) were added to N, N-dimethylformamide (15 mL), and ethyl bromofluoroacetate (2.6 g,13.8 mmol) was slowly added thereto with cooling in an ice-water bath, followed by stirring and reaction for about 30 minutes. The reaction solution was poured into 40mL of water, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with water (50 mL), saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to give the title product 1e (0.86 g, yield: 20%) by purification.
1 H NMR(400MHz,DMSO-d 6 )δ7.99(d,J＝8.3Hz,1H),7.76(d,J＝12Hz,1H),7.60(s,1H),6.68(s,1H),6.62(s,1H),6.56(s,1H),4.22(q,J＝7.1Hz,2H),3.64(s,3H),1.21(t,J＝7.1Hz,3H).
Step e: preparation of 2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetic acid (1 f)
Figure BDA0003838975750000183
1e (1.1 g,3.4 mmol) was added to 5mL of methanol, and 1M lithium hydroxide (4.7 mL,4.7 mmol) was slowly added thereto with cooling in an ice-water bath, followed by stirring and reaction for about 2 hours. The methanol was removed in vacuo, the aqueous phase was acidified with hydrochloric acid (2M) and precipitate formed, which was filtered and the filter cake was dried to give the title product 1f (0.9 g, yield: 88%).
1 H NMR(400MHz,DMSO-d 6 )δ7.99(d,J＝8.3Hz,1H),7.77(s,1H),7.73(dd,J＝8.3,2.2Hz,1H),7.53(s,1H),6.61(s,1H),6.54(d,J＝47.2Hz,1H),3.63(s,3H).
Steps f and g: preparation of 4- (2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) benzoic acid (1)
Figure BDA0003838975750000191
1f (180 mg,0.54 mmol), tert-butyl 4-aminobenzoate (124 mg,0.64 mmol) and HATU (305 mg,0.80 mmol) were added to dichloromethane (2 mL), and DIPEA (103 mg,0.80 mmol) was added thereto and the reaction was stirred at room temperature for 16 hours. The dichloromethane was removed in vacuo, 30mL of ethyl acetate was added to the residue, washed 3-4 times with 0.5M HCl solution, and then 0.5M NaHCO was used 3 The solution was washed 3-4 times and finally washed with saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and filteredThe drying agent was removed and the filtrate was concentrated under reduced pressure to give the crude product which was purified by column chromatography (DCM: meoh=150:1 to 50:1, v/v) to give the intermediate (150 mg, yield: 55%). The intermediate (200 mg,0.39 mmol) was added to 5mL of ethyl acetate, and fresh HCl gas was introduced at-5 ℃. After the completion of the reaction of the starting materials, TLC showed that a solid was precipitated during slow rotary evaporation, and was filtered, and the excess HCl gas was removed by an oil pump to give the title product 1 as a white solid (47 mg, yield: 26%).
HPLC purity:98.5％； 1 H NMR(400MHz,DMSO-d 6 )δ12.77(s,1H),10.72(s,1H),7.99(d,J＝8.2Hz,1H),7.93–7.90(m,2H),7.87–7.83(m,2H),7.77(d,J＝1.9Hz,1H),7.75–7.72(m,1H),7.56(s,1H),6.82(d,J＝47.2Hz,1H),6.62(s,1H),3.64(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ167.34,163.35(d,J＝27.1Hz),158.97,145.11,142.44,140.39,139.90,138.75,135.08,130.69,130.47,130.23,126.64,122.43,120.19,118.39,117.30,110.76,92.95(d,J＝219.1Hz),57.06；HRMS(m/z):[M+H] + calcd for C 22 H 16 ClFN 3 O 5 + 456.0762,found 456.0765.
Example 2 preparation of 4- (2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluorobenzene (Compound 2)
Figure BDA0003838975750000201
The synthesis of example 1 was followed by the conversion of the starting compound, tert-butyl 4-aminobenzoate, to 4-amino-2-fluorobenzamide to give the title product 2 as a pale yellow solid (56 mg, yield: 40%).
HPLC purity:99.5％； 1 H NMR(400MHz,DMSO-d 6 )δ10.76(s,1H),7.99(d,J＝8.3Hz,1H),7.77–7.75(m,1H),7.75–7.66(m,3H),7.60–7.57(m,1H),7.56(s,1H),7.55(s,2H),6.80(d,J＝47.2Hz,1H),6.62(s,1H),3.65(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ165.05,163.58(d,J＝27.2Hz),159.04(d,J＝21.3Hz),145.17,142.12(d,J＝11.4Hz),140.40,139.91,138.74,135.08,131.41,131.39,130.48,130.23,122.46,119.05(d,J＝13.8Hz),118.63,117.30,116.14(d,J＝3.1Hz),110.78,107.61(d,J＝28.7Hz),93.18(d,J＝219.6Hz),57.07；HRMS(m/z):[M+H] + calcd for C 22 H 16 ClF 2 N 4 O 4 + 473.0828 found 473.0822.
Example 3 preparation of 4- (2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluoro-N-methylbenzamide (Compound 3)
Figure BDA0003838975750000202
The synthesis of example 1 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 4-amino-2-fluoro-N-methylbenzamide to give the title product 3.
HPLC purity:97.7％； 1 H NMR(400MHz,DMSO-d 6 )δ10.76(s,1H),8.10–8.08(m,1H),7.99(d,J＝8.2Hz,1H),7.76–7.72(m,3H),7.70–7.66(m,1H),7.63(d,J＝8.3Hz,1H),7.60–7.57(m,1H),7.56(s,1H),6.79(d,J＝47.2Hz,1H),6.61(s,1H),3.64(s,3H),2.75(d,J＝4.6Hz,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.99,163.59(d,J＝26.7Hz),160.49,158.92(d,J＝21.9Hz),145.21,141.89(d,J＝11.2Hz),140.42,139.91,138.77,135.11,131.17,130.48,130.26,122.45,119.31(d,J＝14.3Hz),118.67,117.31,116.23,110.77,107.63(d,J＝28.4Hz),93.18(d,J＝283.5Hz),57.07,26.78；HRMS(m/z):[M+H] + calcd for C 23 H 18 ClF 2 N 4 O 4 + 487.0984 found 487.0973.
Example 4 preparation of 4- (2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -N-ethyl-2-fluorobenzamide (Compound 4)
Figure BDA0003838975750000211
The synthesis of example 1 was followed by the conversion of the starting compound, tert-butyl 4-aminobenzoate, to 4-amino-N-ethyl-2-fluorobenzamide to give the title product 4.
HPLC purity:95.1％； 1 H NMR(400MHz,DMSO-d 6 )δ10.75(s,1H),8.17–8.12(m,1H),7.99(d,J＝8.3Hz,1H),7.77–7.71(m,3H),7.70–7.64(m,1H),7.63–7.58(m,2H),7.57–7.56(m,1H),6.80(d,J＝47.3Hz,1H),6.62(s,1H),3.65(s,3H),3.24(q,J＝7.2Hz,2H),1.09(t,J＝7.2Hz,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.40(d,J＝21.8Hz),163.29,160.43,158.88(d,J＝26.7Hz),145.17,141.83,140.39,139.93,138.75,135.10,131.08,130.49,130.24,122.47,119.65,118.65,117.30,116.17,110.79,107.61(d,J＝27.9Hz),94.34(d,J＝174.0Hz),57.06,34.51,15.15；HRMS(m/z):[M+H] + calcd for C 24 H 20 ClF 2 N 4 O 4 + 501.1141 found 501.1136.
Example 5 preparation of 5- (2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -1H-indole-2-carboxylic acid ethyl ester (Compound 5)
Figure BDA0003838975750000212
The synthesis of example 1 was followed by the exchange of the starting compound tert-butyl 4-aminobenzoate for ethyl 5-amino-1H-indole-2-carboxylate to give the title product 5.
HPLC purity:98.7％； 1 H NMR(400MHz,DMSO-d 6 )δ11.86(s,1H),10.45(s,1H),8.05–8.03(m,1H),7.99(d,J＝8.3Hz,1H),7.76(d,J＝2.1Hz,1H),7.75–7.72(m,1H),7.53–7.45(m,2H),7.41(d,J＝8.9Hz,1H),7.14–7.12(m,1H),6.89(d,J＝47.2Hz,1H),6.63(s,1H),4.32(q,J＝7.1Hz,2H),3.64(s,3H),1.32(t,J＝7.1Hz,3H).HRMS(m/z):[M+H] + calcd for C 26 H 21 ClFN 4 O 5 + 523.1184 found 523.1177.
Example 6 preparation of 2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoro-N- (2-methyl-2H-indazol-5-yl) acetamide (Compound 6)
Figure BDA0003838975750000213
The procedure of example 1 was used to give the title product 6 by substituting tert-butyl 4-aminobenzoate as starting material for 2-methyl-2H-indazol-5-amine.
HPLC purity:96.6％； 1 H NMR(400MHz,DMSO-d 6 )δ10.44(s,1H),8.28(s,1H),8.12(d,J＝2.0Hz,1H),7.99(d,J＝8.3Hz,1H),7.76–7.72(m,2H),7.60–7.53(m,1H),7.51(s,1H),7.42(dd,J＝9.2,2.0Hz,1H),6.88(d,J＝47.2Hz,1H),6.63(s,1H),4.13(s,3H),3.64(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ162.63(d,J＝27.0Hz),159.00,146.34,144.94,140.35,139.94,138.73,135.09,131.45,130.48,130.21,125.09,122.45,122.00,121.60,117.69,117.54,117.30,110.79,110.77,92.29(d,J＝217.3Hz),57.04,40.46；HRMS(m/z):[M+H] + calcd for C 23 H 18 ClFN 5 O 3 + 466.1082 found 466.1087.
Example 7 preparation of 2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoro-N- (1-methyl-1H-indazol-5-yl) acetamide (Compound 7)
Figure BDA0003838975750000221
The procedure of example 1 was used to give the title product 7 by substituting tert-butyl 4-aminobenzoate as starting material for 1-methyl-1H-indazol-5-amine.
HPLC purity:96.6％； 1 H NMR(400MHz,DMSO-d 6 )δ10.52(s,1H),8.13(s,1H),8.01(s,1H),7.99(d,J＝8.3Hz,1H),7.76–7.72(m,2H),7.61(s,2H),7.52(s,1H),6.88(d,J＝47.3Hz,1H),6.63(s,1H),4.01(s,3H),3.64(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ162.74(d,J＝27.0Hz),159.02,144.97,140.36,139.92,138.74,137.60,135.09,132.80,131.29,130.47,130.22,123.64,122.46,121.70,117.83,117.30,112.22,110.77,110.17,92.48(d,J＝218.1Hz),57.04,35.88.HRMS(m/z):[M+H] + calcd for C 23 H 18 ClFN 5 O 3 + 466.1082 found 466.1081
Example 8 preparation of 2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoro-N- (quinoxalin-6-yl) acetamide (Compound 8)
Figure BDA0003838975750000222
The synthesis of example 1 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to quinoxalin-6-amine to give the title product 8.
HPLC purity:98.7％； 1 H NMR(400MHz,DMSO-d 6 )δ10.93(s,1H),8.89(d,J＝1.9Hz,1H),8.84(d,J＝1.9Hz,1H),8.57(d,J＝2.3Hz,1H),8.16(dd,J＝9.1,2.4Hz,1H),8.08(d,J＝9.1Hz,1H),7.99(d,J＝8.3Hz,1H),7.76(d,J＝2.1Hz,1H),7.73(dd,J＝8.3,2.2Hz,1H),7.60(s,1H),6.87(d,J＝47.3Hz,1H),6.63(s,1H),3.66(s,3H).HRMS(m/z):[M+H] + calcd for C 23 H 16 ClFN 5 O 3 + 464.0925 found 464.0928.
EXAMPLE 9 preparation of N- (3- (tert-butyl) -1-phenyl-1H-pyrazol-5-yl) -2- (4- (5-chloro-2-cyanophenyl) 5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamide (Compound 9)
Figure BDA0003838975750000231
The synthesis of example 1 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 3- (tert-butyl) -1-phenyl-1H-pyrazol-5-amine to give the title product 9.
HPLC purity:98.7％； 1 H NMR(400MHz,DMSO-d 6 )δ10.53(s,1H),7.99(d,J＝8.9Hz,1H),7.75–7.72(m,2H),7.60–7.56(m,2H),7.48–7.44(m,2H),7.39(s,1H),7.36–7.31(m,1H),6.78(d,J＝47.2Hz,1H),6.65(s,1H),6.34(s,1H),3.57(s,3H),1.28(s,9H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.73(d,J＝27.9Hz),161.33,158.90,145.11,140.36,139.87,139.23,138.73,135.12,134.80,130.46,130.25,129.53,127.38,123.61,122.50,117.92,117.26,110.77,100.57,92.72(d,J＝217.9Hz),56.95,32.58,30.61；HRMS(m/z):[M+H] + calcd for C 28 H 26 ClFN 5 O 3 + 534.1708 found 534.1720.
Example 10 preparation of 2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoro-N- (4- (trifluoromethyl) phenyl) acetamide (Compound 10)
Figure BDA0003838975750000232
The synthesis of example 1 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 4- (trifluoromethyl) aniline to give the title product 10.
HPLC purity:98.9％； 1 H NMR(400MHz,DMSO-d 6 )δ10.76(s,1H),7.99(d,J＝8.3Hz,1H),7.95(d,J＝8.4Hz,2H),7.77–7.73(m,2H),7.71(d,J＝8.4Hz,2H),7.56(s,1H),6.82(d,J＝47.3Hz,1H),6.62(s,1H),3.65(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.54(d,J＝26.9Hz),158.98,145.14,142.66,140.39,139.91,138.73,135.08,130.48,130.22,126.44(q,J＝3.8Hz),124.76(q,J＝31.9Hz),124.75(q,J＝271.5Hz),122.46,120.82,118.51,117.29,110.79,93.04(d,J＝219.3Hz),57.06；HRMS(m/z):[M+H] + calcd for C 22 H 15 ClF 4 N 3 O 3 + 480.0738,found 480.0737.
Example 11 preparation of 2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -N- (3-cyano-4- (trifluoromethyl) phenyl) -2-fluoroacetamide (Compound 11)
Figure BDA0003838975750000241
The synthesis of example 1 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 5-amino-2- (trifluoromethyl) benzonitrile to give the title product 11.
HPLC purity:98.9％； 1 H NMR(400MHz,DMSO-d 6 )δ11.11(s,1H),8.43(d,J＝2.0Hz,1H),8.23(dd,J＝8.6,2.0Hz,1H),8.14(d,J＝8.5Hz,1H),7.99(d,J＝8.3Hz,1H),7.76–7.72(m,2H),7.63(s,1H),6.80(d,J＝47.5Hz,1H),6.62(s,1H),3.66(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ164.38(d,J＝27.7Hz),158.99,145.35,140.47,139.88,138.74,137.00,135.08,132.07(q,J＝32.1Hz),130.48,130.24,123.79,123.56,122.89(q,J＝271.5Hz),122.43,119.08,118.08(d,J＝5.3Hz),117.28,116.14,110.78,103.08,93.51(d,J＝220.3Hz),57.10；HRMS(m/z):[M+H] + calcd for C 23 H 14 ClF 4 N 4 O 3 + 505.0690 found 505.0694.
Example 12 preparation of N- (3- (tert-butyl) -1H-pyrazol-5-yl) -2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamide (Compound 12)
Figure BDA0003838975750000242
The synthesis of example 1 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 3- (tert-butyl) -1H-pyrazol-5-amine to give the title product 12.
HPLC purity:99.0％； 1 H NMR(400MHz,DMSO-d 6 )δ12.22(s,1H),10.88(s,1H),8.04–7.94(m,1H),7.73(d,J＝7.3Hz,2H),7.44(s,1H),6.90(d,J＝46.7Hz,1H),6.61(s,1H),6.29(s,1H),3.63(s,3H),1.24(s,9H)； 13 C NMR(151MHz,DMSO-d 6 )δ161.68(d,J＝28.4Hz),158.85,144.79,140.27,139.96,138.71,135.09,130.47,130.20,122.26,117.27,116.97,110.79,110.10,93.50,92.67(d,J＝247.5Hz),90.42,57.03,31.19,30.37；HRMS(m/z):[M+H] + calcd for C 22 H 22 ClFN 5 O 3 + 458.1395,found 458.1400.
EXAMPLE 13 preparation of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamide (Compound 13)
Figure BDA0003838975750000251
The synthesis of example 1 was followed by the replacement of the starting compound tert-butyl 4-aminobenzoate with 3- (tert-butyl) isoxazol-5-amine to give the title product 13.
HPLC purity:87.6％； 1 H NMR(400MHz,DMSO-d 6 )δ11.48(s,1H),7.99(d,J＝8.9Hz,1H),7.78–7.68(m,2H),7.52(s,1H),6.78(d,J＝47.0Hz,1H),6.60(s,1H),6.56(s,1H),3.64(s,3H),1.29(s,9H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.23(d,J＝28.4Hz),158.88,157.45,145.09,140.31,139.91,138.72,135.11,130.46,130.22,122.36,118.51,117.27,110.79,94.05,92.61(d,J＝217.5Hz),91.66,57.05,32.54,28.79；HRMS(m/z):[M+H] + calcd for C 22 H 21 ClFN 4 O 4 + 459.1235,found 459.1244.
EXAMPLE 14 preparation of N- (4- (tert-butyl) thiazol-2-yl) -2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamide (Compound 14)
Figure BDA0003838975750000252
The synthesis of example 1 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 4- (tert-butyl) thiazol-2-amine to give the title product 14.
HPLC purity:97.5％； 1 H NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),8.00–7.97(m,1H),7.76–7.71(m,2H),7.51(s,1H),6.85(d,J＝48.0Hz,1H),6.82(s,1H),6.60(s,1H),3.64(s,3H),1.26(s,9H)；HRMS(m/z):[M+H] + calcd for C 22 H 21 ClFN 4 O 3 S + 475.1007,found 475.1010.
Example 15 preparation of 2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) yl) -2-fluoro-N- (4- (methylsulfonyl) phenyl) acetamide (Compound 15)
Figure BDA0003838975750000253
The synthesis of example 1 was followed by the replacement of the starting compound tert-butyl 4-aminobenzoate with 3- (tert-butyl) -1-phenyl-1H-pyrazol-5-amine to give the title product 15.
HPLC purity:99.6％； 1 H NMR(400MHz,DMSO-d 6 )δ10.83(s,1H),8.01–7.96(m,3H),7.91–7.87(m,2H),7.76–7.76(m,1H),7.72–7.75(m,1H),7.57(s,1H),6.81(d,J＝47.3Hz,1H),6.62(s,1H),3.65(s,3H),3.17(s,3H)； 13 CNMR(101MHz,DMSO-d 6 )δ163.66(d,J＝27.0Hz),158.96,145.15,142.95,140.38,139.88,138.72,136.16,135.06,130.45,130.21,128.49,122.44,120.71,118.58,117.27,110.75,93.13(d,J＝219.1Hz),57.04,44.18；HRMS(m/z):[M+H] + calcd for C 22 H 18 ClFN 3 O 5 S + 490.0639 found 490.0631
Example 16 preparation of 2- (4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoro-N- (3-methoxyphenyl) acetamide (Compound 16)
Figure BDA0003838975750000261
The synthesis of example 1 was followed by the replacement of the starting compound tert-butyl 4-aminobenzoate with 3-methoxyaniline to give the title product 16.
HPLC purity:99.6％； 1 H NMR(400MHz,DMSO-d 6 )δ10.43(s,1H),7.99(d,J＝8.3Hz,1H),7.77–7.75(m,2H),7.51(s,1H),7.39(t,J＝2.2Hz,1H),7.32–7.29(m,1H),7.24(t,J＝8.1Hz,1H),6.82(d,J＝47.2Hz,1H),6.72–6.69(m,1H),6.62(s,1H),3.72(s,3H),3.64(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ162.90,162.72,159.88,158.95,144.99,140.34,139.94,139.52,138.73,135.08,130.48,130.21,129.98,122.46,117.97,117.29,113.01,110.79,110.29,106.56,57.05,55.50；HRMS(m/z):[M+H] + calcd for C 22 H 18 ClFN 3 O 4 + 442.0970,found 442.0970.
Example 17 preparation of 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) benzoic acid (Compound 17)
Figure BDA0003838975750000262
Figure BDA0003838975750000271
Step a: 1-azido-2-bromo-4-chlorobenzene (17 b)
Figure BDA0003838975750000272
To a solution of 2-bromo-4-chloroaniline (20 g,97 mmol) in acetonitrile (150 mL) at 0 ℃ was added isoamyl nitrite (17 g,145 mmol), followed by dropwise addition of azido trimethylsilane (16.7 g,145 mmol), after 10 minutes the ice bath was removed, the reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours, and the reaction was completed. Acetonitrile was removed in vacuo, water (80 mL) was added, extracted with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified to give the title product 17b (18 g, yield: 80%).
1 H NMR(600MHz,CDCl 3 )δ7.56(d,J＝2.3Hz,1H),7.32(dd,J＝8.6,2.3Hz,1H),7.10(d,J＝8.6Hz,1H).
Step b:1- (2-bromo-4-chlorophenyl) -4- (trimethylsilyl) -1H-1,2, 3-triazole (17 c)
Figure BDA0003838975750000273
17b (17 g,73 mmol) was added to 100mL of toluene, then trimethylethynyl silicon (21.5 g,219 mmol) was added dropwise, the reaction was carried out at 110℃for 12 hours, toluene was removed in vacuo after completion of the reaction, water (80 mL) was added, extraction was carried out with ethyl acetate (80 mL. Times.3), the organic phases were combined, each of which was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified to give the title product 17c (23 g, yield: 92%).
1 H NMR(600MHz,CDCl 3 )δ7.82(s,1H),7.69(d,J＝2.0Hz,1H),7.43–7.39(m,2H),0.32(s,9H).
Step c:1- (2-bromo-4-chlorophenyl) -4-chloro-1H-1, 2, 3-triazole (17 d)
Figure BDA0003838975750000281
17c (10 g,30 mmol) was added to 100mL of acetonitrile, NCS (48.5 g, 803 mmol) and KF (10.5 g,182 mmol) were added at 25℃and heated to 90℃for 40 hours, the reaction mixture was directly filtered, the filtrate was dried by spinning, water (80 mL) was added, extraction (80 mL. Times.3) was performed with ethyl acetate, the organic phases were combined, the organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified to give the title product 17d (6 g, yield: 67%).
1 H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.78(d,J＝1.3Hz,1H),7.50(d,J＝1.3Hz,2H).
Step d:4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (17 e)
Figure BDA0003838975750000282
17d (6.0 g,5.0 mmol), 2, 5-dimethoxy-4-pyridineboronic acid (4.5 g,24.6 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.84 g,1.0 mmol) and sodium carbonate (5.4 g,51.2 mmol) were added to a 1, 4-dioxane aqueous solution (60 mL, v/v, 4/1), and the reaction mixture was heated to 80℃under nitrogen protection and stirred for 10 hours. The reaction solution was cooled to room temperature naturally, the solvent was removed in vacuo, 50mL of water was added to the reaction solution, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phases were combined, each of which was washed with water (50 mL), a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified to give the title product 17e (5 g, yield: 69%).
1 H NMR(400MHz,DMSO-d 6 )δ8.55(s,1H),7.76(d,J＝1.3Hz,2H),7.75–7.74(m,1H),7.69–7.68(m,1H),6.78(s,1H),3.81(s,3H),3.44(s,3H).
Step e:4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (17 f)
Figure BDA0003838975750000291
17e (5 g,14.2 mmol) was added to 20mL of DMF, pyridine hydrobromide (22.8 g,142 mmol) was added, and the mixture was heated to 110℃and stirred for 4 hours. The reaction solution was poured into 20mL of ice water, stirred for half an hour, filtered, and the cake was rinsed with distilled water and dried to give the title product 17f (4.2 g, yield: 87%).
1 H NMR(400MHz,DMSO-d 6 )δ11.20(s,1H),8.60(s,1H),7.74(d,J＝2.3Hz,1H),7.72(s,1H),7.65(d,J＝2.2Hz,1H),6.96(s,1H),6.33(s,1H),3.27(s,3H).
Step f:2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetate (17 g)
Figure BDA0003838975750000292
17f (4.1 g,12 mmol) and cesium carbonate (5.9 mg,18 mmol) were added to 15mL of DMF, ethyl bromofluoroacetate (2.7 g,15 mmol) was slowly added under ice water bath cooling, and the reaction was stirred for about 30 minutes. The reaction mixture was poured into 20mL of water, extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with water, saturated brine, and dried Na 2 SO 4 Drying, concentration of the filtrate under reduced pressure and purification by column chromatography gave the title product 17g (1.6 g, yield: 30%).
1 H NMR(400MHz,DMSO-d 6 )δ8.73(s,1H),7.80(d,J＝2.2Hz,1H),7.78–7.76(m,2H),7.29(s,1H),6.54(d,J＝48Hz,1H),6.53(s,1H),4.21(q,J＝7.1Hz,2H),3.31(s,3H),1.21(t,J＝7.1Hz,3H).
Step g:2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetic acid (17H)
Figure BDA0003838975750000293
17g (1.5 g,3.4 mmol) of lithium hydroxide (1M) (0.5 mL,0.5 mmol) was added to 4mL of methanol, and the mixture was stirred for about 2 hours while cooling in an ice-water bath. The methanol was removed in vacuo and the aqueous phase was acidified with hydrochloric acid (2M) with precipitate formation, filtered and the filter cake was dried to give the title product for 17h (1.3 g, yield: 92%).
1 H NMR(400MHz,DMSO-d 6 )δ8.74(s,1H),7.79(d,J＝2.2Hz,1H),7.77–7.75(m,2H),7.20(s,1H),6.53(s,1H),6.45(d,J＝48Hz,1H),3.28(s,3H).
Step h: tert-butyl 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) benzoate (17 i)
Figure BDA0003838975750000301
17h (100 mg,0.24 mmol), tert-butyl 4-aminobenzoate (56 mg,0.29 mmol) and HATU (138 mg,0.36 mmol) were added to 2mL of dichloromethane, N-diisopropylethylamine (47 mg,0.36 mmol) was added thereto, and the reaction was stirred at room temperature for 16 hours. Dichloromethane was removed in vacuo, 10mL of water was added to the reaction, extracted with ethyl acetate (10 ml×3), the organic phases combined, washed with water, saturated NaCl solution, na-free 2 SO 4 Drying and column chromatography purification gave the title product 17i (105 mg, yield: 73%).
1 H NMR(400MHz,DMSO-d 6 )δ10.68(s,1H),8.74(s,1H),7.89–7.81(m,4H),7.80(dd,J＝8.7,2.2Hz,1H),7.77–7.73(m,2H),7.24(s,1H),6.72(d,J＝47.3Hz,1H),6.55(s,1H),3.27(s,3H),1.52(s,9H).
Step i:4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H-yl) -2-fluoroacetamido) benzoic acid (17)
Figure BDA0003838975750000302
17i (70 mg,0.12 mmol) was added to 5mL of ethyl acetate, and the resultant HCl gas was saturated and stirred for 5 hours. Typically, a precipitate formed in the reaction mixture, and the solid was filtered and dried to give the title product 17 (20 mg, yield: 31%).
HPLC purity:99.1％； 1 H NMR(400MHz,DMSO-d 6 )δ12.77(s,1H),10.66(s,1H),8.72(s,1H),7.91(d,J＝8.8Hz,2H),7.82(d,J＝8.8Hz,2H),7.78(d,J＝2.2Hz,1H),7.75(dd,J＝5.4,3.1Hz,2H),7.23(s,1H),6.74(d,J＝47.4Hz,1H),6.54(s,1H),3.27(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ167.34,163.34(d,J＝27.2Hz),159.08,145.14,142.42,140.39,135.15,134.09,134.02,132.02,131.36,130.81,130.68,127.52,126.61,124.16,122.27,120.17,116.98,92.66(d,J＝215.0Hz),56.47；HRMS(m/z):[M+H] + calcd for C 23 H 17 Cl 2 FN 5 O 5 ,532.0591；found,532.0582.
Example 18 preparation of 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluorobenzene (Compound 18)
Figure BDA0003838975750000311
The procedure of example 17 was used to give the title product 18 by substituting tert-butyl 4-aminobenzoate as starting material for 4-amino-2-fluorobenzamide.
HPLC purity:99.1％； 1 H NMR(400MHz,DMSO-d 6 )δ10.71(s,1H),8.73(s,1H),7.81–7.78(m,1H),7.76–7.74(m,2H),7.72–7.69(m,1H),7.68–7.64(m,1H),7.57(dd,J＝8.6,2.0Hz,1H),7.54(s,2H),7.24(s,1H),6.71(d,J＝47.4Hz,1H),6.54(s,1H),3.27(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ165.06(d,J＝1.5Hz),163.55(d,J＝27.2Hz),159.92(d,J＝247.5Hz),159.07,145.20,142.10(d,J＝11.3Hz),140.40,135.14,134.07,134.03,132.03,131.40,131.37,130.80,127.52,124.18,122.29,119.02(d,J＝13.9Hz),117.21,116.12(d,J＝2.8Hz),107.58(d,J＝28.4Hz),92.92(d,J＝220.6Hz),56.49；HRMS(ESI)m/z:[M+H] + calcd for C 23 H 17 Cl 2 F 2 N 6 O 4 ,548.0578；found,548.0651.
Example 19, 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluoro-N-methylbenzamide (19)
Figure BDA0003838975750000312
The synthesis of example 17 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 4-amino-2-fluoro-N-methylbenzamide to afford the title product 19.
HPLC purity:99.3％； 1 H NMR(400MHz,DMSO-d 6 )δ10.70(s,1H),8.73(s,1H),8.09(t,J＝4.2Hz,1H),7.81–7.78(m,1H),7.76–7.74(m,2H),7.69(dd,J＝13.2,1.9Hz,1H),7.63(t,J＝8.4Hz,1H),7.58–7.55(m,1H),7.24(s,1H),6.71(d,J＝47.4Hz,1H),6.54(s,1H),3.27(s,3H),2.75(d,J＝4.6Hz,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.97(d,J＝2.1Hz),163.54(d,J＝27.2Hz),159.65(d,J＝247.2Hz),159.08,145.22,141.86(d,J＝11.5Hz),140.41,135.15,134.09,134.02,132.02,131.36,131.13(d,J＝4.0Hz),130.81,127.51,124.16,122.27,119.27(d,J＝14.1Hz),117.19,116.20(d,J＝3.0Hz),107.60(d,J＝28.3Hz),92.92(d,J＝218.8Hz),56.49,26.77；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 19 Cl 2 F 2 N 6 O 4 ,563.0813；found,563.0804.
Example 20, 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -N-ethyl-2-fluorobenzamide (20)
Figure BDA0003838975750000321
The title product 20 was obtained by the synthetic method of example 17 by substituting tert-butyl 4-aminobenzoate as the starting compound into 4-amino-N-ethyl-2-fluorobenzamide.
HPLC purity:98.6％； 1 H NMR(400MHz,DMSO-d 6 )δ10.72(s,1H),8.73(s,1H),8.16(s,1H),7.81–7.78(m,1H),7.77–7.73(m,2H),7.69(dd,J＝13.3,1.8Hz,1H),7.61(t,J＝8.2Hz,1H),7.59–7.55(m,1H),7.26(s,1H),6.73(d,J＝47.4Hz,1H),6.54(s,1H),3.27(s,3H),3.24(q,J＝7.2Hz,2H),1.09(t,J＝7.2Hz,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.53(d,J＝27.8Hz),163.42,159.60(d,J＝247.3Hz),159.09,145.24,141.75(d,J＝11.4Hz),140.41,135.15,134.11,133.99,131.99,131.33,131.02(d,J＝4.2Hz),130.84,127.52,124.14,122.20,119.60(d,J＝14.2Hz),117.29,116.18,107.63(d,J＝28.1Hz),92.92(d,J＝218.0Hz),56.51,34.54,15.11；HRMS(ESI)m/z:[M+H] + calcd for C 25 H 21 Cl 2 F 2 N 6 O 4 ,577.0969；found,577.0962.
Example 21, 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -N, N-dimethyl-2-fluorobenzamide (21)
Figure BDA0003838975750000322
The synthesis of example 17 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 4-amino-N, N-dimethyl-2-fluorobenzamide to give the title product 21.
HPLC purity:98.7％； 1 H NMR(400MHz,DMSO-d 6 )δ10.69(s,1H),8.73(s,1H),7.81–7.78(m,1H),7.76–7.72(m,2H),7.70(dd,J＝12.2,1.9Hz,1H),7.59(dd,J＝8.5,1.9Hz,1H),7.35(t,J＝8.1Hz,1H),7.24(s,1H),6.71(d,J＝47.5Hz,1H),6.54(s,1H),3.28(s,3H),2.97(s,3H),2.84(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ165.61,163.48(d,J＝27.4Hz),159.06,157.86(d,J＝243.4Hz),145.17,140.89(d,J＝11.0Hz),140.39,135.13,134.05,132.05,131.38,130.79,129.63,129.59,127.53,124.19,122.31,120.43(d,J＝18.0Hz),117.17,116.62,107.40(d,J＝27.0Hz),92.85(d,J＝220.2Hz),56.49,38.32,34.81；HRMS(ESI)m/z:[M+H] + calcd for C 25 H 21 Cl 2 F 2 N 6 O 4 ,577.0969；found,577.0961.
Example 22, 5- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -1-methyl-1H-indole-2-carboxylic acid (22)
Figure BDA0003838975750000331
The synthesis of example 17 was followed by the replacement of the starting compound tert-butyl 4-aminobenzoate with tert-butyl 5-amino-1-methyl-1H-indole-2-carboxylate to give the title product 22.
HPLC purity:96.0％； 1 H NMR(400MHz,DMSO-d 6 )δ12.89(s,1H),10.42(s,1H),8.72(s,1H),8.04(s,1H),7.81–7.78(m,1H),7.76–7.72(m,2H),7.54(s,2H),7.19(s,2H),6.82(d,J＝47.4Hz,1H),6.56(s,1H),3.99(s,3H),3.27(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.33,162.49(d,J＝27.2Hz),159.11,144.94,140.35,137.11,135.14,134.08,134.05,132.07,131.39,131.33,130.79,129.61,127.54,125.43,124.19,122.32,120.05,116.24,113.92,111.37,109.90,93.42(d,J＝210.4Hz),56.46,32.07；HRMS(ESI)m/z:[M+H] + calcd for C 26 H 20 Cl 2 FN 6 O 5 ,585.0856；found,585.0842.
Example 23, 2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoro-N- (2-methyl-2H-indazol-5-yl) acetamide (23)
Figure BDA0003838975750000332
The procedure of example 17 was used to give the title product 23 by substituting tert-butyl 4-aminobenzoate as starting material for 2-methyl-2H-indazol-5-amine.
HPLC purity:99.3％； 1 H NMR(400MHz,DMSO-d 6 )δ10.39(s,1H),8.72(s,1H),8.28(s,1H),8.10–8.09(m,1H),7.81–7.78(m,1H),7.76–7.72(m,2H),7.55(d,J＝9.0Hz,1H),7.40(dd,J＝9.2,2.0Hz,1H),7.19(s,1H),6.81(d,J＝47.3Hz,1H),6.55(s,1H),4.12(s,3H),3.27(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ162.60(d,J＝27.2Hz),159.09,146.33,144.93,140.34,135.12,134.06,134.05,132.07,131.43,131.38,130.78,127.54,125.07,124.19,122.31,121.97,121.59,117.53,116.19,110.71,91.62(d,J＝218.5Hz),56.46,39.83；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 19 Cl 2 FN 7 O 3 ,542.0910；found,542.0913.
Example 24, 2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoro-N- (1-methyl-1H-indazol-5-yl) acetamide (24)
Figure BDA0003838975750000341
The procedure of example 17 was used to give the title product 24 by substituting tert-butyl 4-aminobenzoate as starting material for 1-methyl-1H-indazol-5-amine.
HPLC purity:99.8％； 1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),8.73(s,1H),8.11(s,1H),8.01(s,1H),7.81–7.78(m,1H),7.76–7.72(m,2H),7.60(s,2H),7.20(s,1H),6.80(d,J＝47.4Hz,1H),6.56(s,1H),4.01(s,3H),3.27(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ162.71(d,J＝27.2Hz),159.12,144.97,140.36,137.59,135.13,134.08,134.05,132.79,132.06,131.37,131.28,130.78,127.53,124.18,123.63,122.33,121.66,116.36,112.17,110.15,92.09(d,J＝220.6Hz),56.46,35.89；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 19 Cl 2 FN 7 O 3 ,542.0910；found,542.0899.
Example 25, 2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoro-N- (quinoxalin-6-yl) acetamide (25)
Figure BDA0003838975750000342
The synthesis of example 17 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to quinoxalin-6-amine to give the title product 25.
HPLC purity:97.5％； 1 H NMR(400MHz,DMSO-d 6 )δ10.88(s,1H),8.89(d,J＝1.9Hz,1H),8.84(d,J＝1.9Hz,1H),8.73(s,1H),8.56(d,J＝2.3Hz,1H),8.14(dd,J＝9.2,2.3Hz,1H),8.07(d,J＝9.1Hz,1H),7.82–7.77(m,1H),7.76–7.74(m,2H),7.28(s,1H),6.87–6.71(m,1H),6.56(s,1H),3.29(s,3H)； 13 CNMR(151MHz,DMSO-d 6 )δ163.71(d,J＝27.6Hz),159.13,146.56,145.21,144.99,143.15,140.44,139.97,139.67,135.15,134.10,134.03,132.03,131.37,130.81,129.95,127.52,124.98,124.17,122.31,117.71,117.20,92.92(d,J＝222.2Hz),56.51；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 17 Cl 2 FN 7 O 3 ,540.0754；found,540.0755.
Example 26, 2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoro-N- (4- (methylsulfonyl) phenyl) acetamide (26)
Figure BDA0003838975750000351
The procedure of example 17 was used to prepare the title product 26 by substituting tert-butyl 4-aminobenzoate as the starting material for 4- (methylsulfonyl) aniline.
HPLC purity:99.3％； 1 H NMR(400MHz,DMSO-d 6 )δ10.78(s,1H),8.73(s,1H),7.98–7.93(m,2H),7.91–7.86(m,2H),7.82–7.77(m,1H),7.76–7.74(m,2H),7.25(s,1H),6.73(d,J＝47.4Hz,1H),6.54(s,1H),3.28(s,3H),3.16(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.66(d,J＝27.5Hz),159.07,145.19,142.97,140.40,136.17,135.14,134.07,134.04,132.04,131.37,130.80,128.50,127.53,124.19,122.30,120.70,117.17,92.86(d,J＝222.3Hz),56.49,44.21；HRMS(ESI)m/z:[M+H] + calcd for C 23 H 19 Cl 2 FN 5 O 5 S,566.0468；found,566.0456.
Example 27 preparation of 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluorobenzoic acid (Compound 27)
Figure BDA0003838975750000352
The synthesis of example 17 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 4- (methylsulfonyl) aniline to give the intermediate and the hydrolysis of tert-butyl ester with HCl gas to give the title product 27.
HPLC purity:97.6％； 1 H NMR(400MHz,DMSO-d 6 )δ13.01(s,1H),10.78(s,1H),8.73(s,1H),7.85(t,J＝8.6Hz,1H),7.79(dd,J＝8.6,2.2Hz,1H),7.76–7.69(m,3H),7.62(dd,J＝8.7,2.0Hz,1H),7.25(s,1H),6.71(d,J＝47.4Hz,1H),6.54(s,1H),3.28(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ164.99(d,J＝3.3Hz),163.75(d,J＝27.3Hz),161.92(d,J＝255.5Hz),159.06,145.23,143.95(d,J＝11.5Hz),140.41,135.14,134.07,134.03,133.14,132.03,131.38,130.80,127.52,124.18,122.29,117.31,115.92(d,J＝3.3Hz),114.60(d,J＝10.2Hz),108.03(d,J＝27.6Hz),92.98(d,J＝217.3Hz),56.50；HRMS(ESI)m/z:[M+H] + calcd for C 23 H 16 Cl 2 F 2 N 5 O 5 ,550.0496；found,550.0487.
Example 28, 2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -N- (1- (difluoromethyl) -1H-indazol-5-yl) -2-fluoroacetamide (28)
Figure BDA0003838975750000361
The procedure of example 17 was used to give the title product 28 by substituting tert-butyl 4-aminobenzoate as starting material for 1- (difluoromethyl) -1H-indazol-5-amine.
HPLC purity:98.5％； 1 H NMR(400MHz,DMSO-d 6 )δ10.70–10.56(m,1H),8.73(s,1H),8.40(d,J＝0.6Hz,1H),8.30–8.26(m,1H),8.06(d,J＝58.4Hz,1H),7.80(q,J＝1.8Hz,2H),7.78(d,J＝2.2Hz,1H),7.75(dd,J＝5.3,3.0Hz,2H),7.22(s,1H),6.79(d,J＝47.4Hz,1H),6.56(s,1H),3.28(s,3H)； 13 CNMR(101MHz,DMSO-d 6 )δ163.04(d,J＝27.1Hz),159.09,145.03,140.35,138.68,135.39,135.11,134.05,134.02,133.77,132.03,131.35,130.76,127.51,125.57,124.16,123.50,122.31,116.66,112.88,111.95(t,J＝245.3Hz),92.59(d,J＝219.6Hz),111.00,56.45；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 17 Cl 2 F 3 N 7 O 3 ,578.0722；found,578.0713.
Example 29, 2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -N- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) acetamide (29)
Figure BDA0003838975750000362
The procedure of example 17 was used to prepare the title product 29 by substituting tert-butyl 4-aminobenzoate as the starting material for 4- (methylsulfonyl) aniline.
HPLC purity:99.1％； 1 H NMR(400MHz,DMSO-d 6 )δ10.60(s,1H),10.54(s,1H),10.32(s,1H),8.72(s,1H),7.81–7.78(m,1H),7.76–7.74(m,2H),7.43(d,J＝1.8Hz,1H),7.19–7.12(m,2H),6.85(d,J＝8.4Hz,1H),6.76(d,J＝44.0Hz,1H),6.54(s,1H),3.26(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ162.27(d,J＝27.2Hz),159.08,155.98,144.92,140.33,135.13,134.07,134.04,132.05,131.67,131.37,130.78,130.02,127.53,126.98,124.18,122.30,116.21,113.77,108.63,102.39,91.98(d,J＝207.8Hz),56.45；HRMS(ESI)m/z:[M+H] + calcd for C 23 H 17 Cl 2 FN 7 O 4 ,544.0703；found,544.0707.
Example 30 preparation of 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) benzoic acid (Compound 30)
Figure BDA0003838975750000371
Step a:1- (2-bromo-4-chlorophenyl) -1H-tetrazole (30 b)
Figure BDA0003838975750000372
Sodium azide (0.94 g,14.53 mmol) was added to the reaction flask, 10ml acetic acid was added, then 2-bromo-4-chloroaniline (1.00 g,4.84 mmol) was added, and finally triethyl orthoformate (2.42 ml,14.53 mmol) was added and reacted at 80℃for 10 hours. Acetic acid was removed in vacuo, 30mL of water was added, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spun-dried to give the title product 30b (1.1 g, yield: 87%).
1 H NMR(600MHz,CDCl 3 )δ9.00(s,1H),7.84(d,J＝2.1Hz,1H),7.55(dd,J＝8.5,2.1Hz,1H),7.51(d,J＝8.5Hz,1H).
Step b:4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 5-dimethoxypyridine (30 c)
Figure BDA0003838975750000381
30b (3.8 g,14.6 mmol), 2, 5-dimethoxypyridin-4-yl (2.7 g,14.6 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.60 g,0.73 mmol) and sodium carbonate (4.66 g,43.9 mmol) were added to an aqueous 1, 4-dioxane solution (60 mL)V/v, 4/1), the reaction solution is heated to 80 ℃ under the protection of nitrogen after the addition is finished, and the reaction is stirred for 10 hours. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo, 50mL of water was added to the reaction mixture, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, and the organic phases were washed with water, saturated NaCl solution, and anhydrous Na, respectively 2 SO 4 Drying and column chromatography purification gave the title product 30c (2.6 g, yield: 56%).
1 H NMR(400MHz,DMSO-d 6 )δ9.60(s,1H),7.82(d,J＝1.4Hz,2H),7.73(d,J＝2.5Hz,2H),6.84(s,1H),3.81(s,3H),3.40(s,3H).
Step c:4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (30 d)
Figure BDA0003838975750000382
30c (0.50 g,1.57 mmol) was added to 5mL of acetonitrile, iodotrimethylsilane (0.47 g,2.36 mmol) was added, distilled water (14.2 mg,0.78 mmol) was added, and the mixture was heated to 60℃and stirred for 10 hours. The reaction solution was poured into 6mL of ice water, stirred for half an hour, filtered, and the cake was rinsed with distilled water and dried to give the title product 30d (430 mg, yield: 89%).
1 H NMR(400MHz,DMSO-d 6 )δ9.64(s,1H),7.80(d,J＝1.1Hz,2H),7.72(t,J＝1.4Hz,1H),6.95(s,1H),6.40(s,1H),3.24(s,3H).
Step d:2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetic acid ethyl ester (30 e)
Figure BDA0003838975750000383
30d (320 mg,1.05 mmol) and cesium carbonate (858 mg,2.63 mmol) were added to 5mL of N, N-dimethylformamide, and ethyl bromofluoroacetate (389 mg,2.11 mmol) was slowly added thereto with cooling in an ice-water bath, followed by stirring and reaction for about 30 minutes. The reaction mixture was poured into 10mL of water, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combinedWashing with water, saturated NaCl solution, anhydrous Na 2 SO 4 Drying and column chromatography purification gave the title product 30e (120 mg, yield: 28%).
1 H NMR(600MHz,DMSO-d 6 )δ9.76(s,1H),7.85(d,J＝2.3Hz,2H),7.82(d,J＝1.8Hz,1H),7.28(s,1H),6.60(s,1H),6.53(d,J＝47.2Hz,1H),4.23–4.18(m,2H),3.26(s,3H),1.21(t,J＝7.2Hz,3H).
Step e:2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetic acid (30 f)
Figure BDA0003838975750000391
30e (100 mg,0.24 mmol) was added to 2mL of methanol, and 1M lithium hydroxide (0.37 mL,0.37 mmol) was slowly added thereto with cooling in an ice-water bath, followed by stirring and reaction for about 2 hours. The methanol was removed in vacuo and the aqueous phase was acidified with hydrochloric acid (2M) and precipitated, filtered and dried to give the title product 30f (83 mg, 88%).
1 H NMR(600MHz,DMSO-d 6 )δ9.77(s,1H),7.85(d,J＝2.2Hz,2H),7.82(d,J＝1.8Hz,1H),7.24(s,1H),6.60(s,1H),6.45(d,J＝47.2Hz,1H),3.17(s,3H).
Step f: tert-butyl 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamide) benzoate (30 g)
Figure BDA0003838975750000392
30f (50 mg,0.132 mmol), tert-butyl 4-aminobenzoate (30.5 mg,0.158 mmol) and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (75 mg, 0.197mmol) were added to 2mL of methylene chloride, and N, N-diisopropylethylamine (17.5 mg, 0.197mmol) was added thereto, and the reaction was stirred at room temperature for 16 hours. Dichloromethane was removed in vacuo, 10mL of water was added to the reaction, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined, and then water, saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturatedWashing with saline solution, anhydrous Na 2 SO 4 Drying and column chromatography purification gave the title product 30g (64 mg, yield: 87%).
1 H NMR(600MHz,DMSO-d 6 )δ10.70(s,1H),9.77(s,1H),7.89(d,J＝8.8Hz,2H),7.85(t,J＝4.4Hz,4H),7.83–7.82(m,1H),7.17(s,1H),6.78–6.67(m,1H),6.62(s,1H),3.17(s,3H),1.54(s,9H).
Step g:4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) benzoic acid (30)
Figure BDA0003838975750000401
30g (200 mg,0.36 mmol) was added to 5mL of ethyl acetate, fresh HCl gas was introduced, and after the reaction was completed, during slow rotary evaporation, a solid was precipitated, filtered off with suction and the solid was dried to give the title product 30 (27 mg, yield: 15%).
HPLC purity:98.6％； 1 H NMR(400MHz,DMSO-d 6 )δ12.76(s,1H),10.66(s,1H),9.73(s,1H),7.92–7.89(m,2H),7.84–7.82(m,4H),7.80–7.79(m,1H),7.22(s,1H),6.72(d,J＝47.3Hz,1H),6.59(s,1H),3.24(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ167.34,163.29(d,J＝27.5Hz),158.99,144.85,144.41,142.42,139.95,135.71,132.43,131.36,131.25,130.93,130.68,127.97,126.61,122.70,120.16,117.26,92.77(d,J＝228.0Hz),56.46；HRMS(ESI)m/z:[M+H] + calcd for C 22 H 17 ClFN 6 O 5 ,499.0933；found,499.0921.
Example 31 preparation of 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluorobenzamide (Compound 31)
Figure BDA0003838975750000402
The procedure of example 30 was used to give the title product 31 by substituting tert-butyl 4-aminobenzoate as starting material for 4-amino-2-fluorobenzamide.
HPLC purity:98.6％； 1 H NMR(400MHz,DMSO-d 6 )δ10.71(s,1H),9.74(s,1H),7.83–7.79(m,3H),7.72–7.63(m,2H),7.58–7.55(m,3H),7.23(s,1H),6.69(d,J＝47.4Hz,1H),6.59(s,1H),3.24(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ165.05,163.51(d,J＝27.6Hz),159.92(d,J＝247.6Hz),158.98,144.87,144.48,142.10(d,J＝11.4Hz),139.96,135.70,132.44,131.40,131.37,131.27,130.92,127.98,122.73,119.03(d,J＝13.7Hz),117.52,116.12,107.58(d,J＝28.5Hz),92.97(d,J＝220.8Hz),56.47；HRMS(ESI)m/z:[M+H] + calcd for C 22 H 17 ClF 2 N 7 O 4 ,516.0998；found,516.0991.
Example 32 preparation of 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluoro-N-methylbenzamide (Compound 32)
Figure BDA0003838975750000411
The title product 32 was obtained by the synthetic method of example 30 by substituting tert-butyl 4-aminobenzoate as the starting compound into 4-amino-2-fluoro-N-methylbenzamide.
HPLC purity:93.8％； 1 H NMR(400MHz,DMSO-d 6 )δ10.71(s,1H),9.74(s,1H),8.14–8.05(m,1H),7.83–7.79(m,3H),7.71–7.61(m,2H),7.58–7.55(m,1H),7.23(s,1H),6.69(d,J＝47.4Hz,1H),6.59(s,1H),3.24(s,3H),2.75(d,J＝4.5Hz,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.94,163.59,159.65(d,J＝247.0Hz),158.98,144.87,144.48,141.86(d,J＝11.6Hz),139.96,135.70,132.44,131.37,131.27,131.12,130.92,127.98,122.72,119.30(d,J＝14.3Hz),117.42,116.18,107.58(d,J＝28.3Hz),92.67(d,J＝106.6Hz),56.47,26.77；HRMS(ESI)m/z:[M+H] + calcd for C 23 H 19 ClF 2 N 7 O 4 ,530.1155；found,530.1152.
Example 33 preparation of 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluoro-N-ethylbenzamide (Compound 33)
Figure BDA0003838975750000412
The title product 33 was obtained by the synthetic method of example 30 by substituting tert-butyl 4-aminobenzoate as the starting compound into 4-amino-N-ethyl-2-fluorobenzamide.
HPLC purity:97.9％； 1 H NMR(400MHz,DMSO-d 6 )δ10.70(s,1H),9.74(s,1H),8.19–8.13(m,1H),7.85–7.81(m,3H),7.73–7.61(m,2H),7.59–7.57(m,1H),7.23(s,1H),6.69(d,J＝47.4Hz,1H),6.59(s,1H),3.30–3.23(m,5H),1.09(t,J＝7.2Hz,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.48(d,J＝27.2Hz),163.31,159.60(d,J＝247.0Hz),158.97,144.87,144.47,141.76(d,J＝11.4Hz),139.96,135.70,132.44,131.37,131.28,131.06(d,J＝4.3Hz),130.92,127.97,122.73,119.66(d,J＝14.2Hz),117.46,116.14(d,J＝2.8Hz),107.59(d,J＝28.3Hz),92.95(d,J＝229.1Hz),56.47,34.53,15.14；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 21 ClF 2 N 7 O 4 ,544.1311；found,544.1306.
Example 34 preparation of 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluoro-N, N-dimethylbenzamide (Compound 34)
Figure BDA0003838975750000421
The synthesis of example 30 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 4-amino-2-fluoro-N, N-dimethylbenzamide to give the title product 34.
HPLC purity:99.5％； 1 H NMR(400MHz,DMSO-d 6 )δ10.71(s,1H),9.76(s,1H),7.85–7.81(m,3H),7.74–7.70(m,1H),7.62–7.59(m,1H),7.37(t,J＝8.2Hz,1H),7.25(s,1H),6.79–6.63(m,1H),6.61(s,1H),3.26(s,3H),2.99(s,3H),2.85(d,J＝1.3Hz,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ165.62,163.44(d,J＝27.2Hz),158.98,157.86(d,J＝243.5Hz),144.87,144.47,140.88(d,J＝10.8Hz),139.96,135.69,132.44,131.38,131.27,130.92,129.61(d,J＝5.3Hz),127.98,122.72,120.43(d,J＝18.1Hz),117.43,116.62(d,J＝2.8Hz),107.40(d,J＝27.1Hz),92.97(d,J＝211.0Hz),56.48,38.32,34.82；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 21 ClF 2 N 7 O 4 ,544.1311；found,544.1316.
Example 35 preparation of 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluorobenzoic acid (Compound 35)
Figure BDA0003838975750000422
The synthesis of example 30 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to tert-butyl 4-amino-2-fluorobenzoate to give the title product 35.
HPLC purity:97.3％； 1 H NMR(400MHz,DMSO-d 6 )δ10.79(s,1H),9.74(s,1H),7.88–7.79(m,4H),7.74–7.70(m,1H),7.63–7.61(m,1H),7.25(s,1H),6.68(d,J＝47.4Hz,1H),6.59(s,1H),3.24(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ164.99(d,J＝3.7Hz),163.70(d,J＝27.4Hz),161.92(d,J＝255.3Hz),158.98,144.86,144.52,143.93(d,J＝11.5Hz),139.98,135.70,133.14,132.42,131.36,131.26,130.93,127.97,122.70,117.62,115.92(d,J＝3.0Hz),114.61(d,J＝10.2Hz),108.03(d,J＝27.8Hz),93.15(d,J＝221.0Hz),60.25；HRMS(ESI)m/z:[M+H] + calcd for C 22 H 15 ClF 2 N 6 O 5 ,517.0839；found,517.0832.
Example 36 preparation of 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -N- (2, 2-difluoroethyl) -2-fluorobenzamide (Compound 36)
Figure BDA0003838975750000431
35 (30 mg,0.058 mmol) was added to the reaction flask, 1mL of acetonitrile was added, and then 2, 2-difluoroethylamine hydrochloride (4.5 uL,0.063 mmol), N-methylimidazole (16 uL,0.203 mmol), N, N, N ', N' -tetramethyl chloroformamidine hexafluorophosphate (24 mg,0.087 mmol) were added sequentially, followed by stirring at room temperature for 16 hours. Acetonitrile was removed in vacuo, 60mL of water was added to the reaction, extracted with ethyl acetate (15 mL. Times.3), the organic phases combined, water, saturated NaCl solution, saturated NaHCO 3 Solution (10 mL. Times.3), diluted hydrochloric acid solution (10 mL. Times.3), washing, anhydrous Na 2 SO 4 Drying and column chromatography purification gave the title product 36 (15 mg, yield: 45%).
HPLC purity:98.8％； 1 H NMR(400MHz,DMSO-d 6 )δ10.76(s,1H),9.76(s,1H),8.56–8.54(m,1H),7.85–7.81(m,2H),7.74(d,J＝13.2Hz,1H),7.68(t,J＝8.3Hz,1H),7.62–7.57(m,1H),7.26(s,1H),6.70(d,J＝47.3Hz,1H),6.61(s,1H),6.30–5.95(m,1H),3.71–3.61(m,2H),3.25(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ164.25,163.58(d,J＝27.8Hz),160.62,158.98,144.86,144.51,142.37(d,J＝11.5Hz),139.97,135.71,132.43,131.36,131.26,131.24,130.93,127.98,122.70,118.42(d,J＝13.8Hz),117.52,116.22,114.91(t,J＝241Hz),107.62(d,J＝27.8Hz),93.02(d,J＝225.3Hz),56.47,41.95(t,J＝26.2Hz)；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 18 ClF 4 N 7 O 4 ,580.1123；found,580.1120.
Example 37 preparation of 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -N- (2, 2-trifluoroethyl) -2-fluorobenzamide (Compound 37)
Figure BDA0003838975750000432
The procedure of example 36 was used to prepare the title product 37 by substituting 2, 2-trifluoroethylamine for the starting compound 2, 2-difluoroethylamine hydrochloride.
HPLC purity:98.6％； 1 H NMR(400MHz,DMSO-d 6 )δ10.78(s,1H),9.77(s,1H),8.84(s,1H),7.85–7.82(m,3H),7.75(d,J＝13.2Hz,1H),7.69–7.64(m,2H),7.27(s,1H),6.71(d,J＝47.3Hz,1H),6.62(d,J＝3.1Hz,1H),4.10–4.05(m,2H),3.26(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ164.37,163.60(d,J＝27.1Hz),160.61,158.97,144.87,144.49,142.53(d,J＝11.4Hz),139.96,135.70,132.44,131.37,131.27,131.17(d,J＝3.6Hz),130.92,127.98,125.18(q,J＝321.63Hz),122.72,118.27(d,J＝13.8Hz),117.57,116.24,107.65(d,J＝27.8Hz),93.03(d,J＝223.8Hz),56.47,40.50；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 18 ClF 5 N 7 O 4 ,598.1029；found,598.1022.
Example 38 preparation of 4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) -N-cyclopropyl-2-fluorobenzamide (Compound 38)
Figure BDA0003838975750000441
The procedure of example 36 was used to prepare the title product 38 by substituting cyclopropylamine for the starting compound 2, 2-difluoroethylamine hydrochloride.
HPLC purity:93.9％； 1 H NMR(400MHz,DMSO-d 6 )δ10.72(s,1H),9.76(s,1H),8.25(s,1H),7.85–7.81(m,3H),7.69(d,J＝13.6Hz,1H),7.62–7.56(m,2H),7.25(s,1H),6.70(d,J＝47.4Hz,1H),6.61(s,1H),3.25(s,3H),2.81(d,J＝7.6Hz,1H),0.68(d,J＝6.9Hz,2H),0.54(s,2H)； 13 C NMR(151MHz,DMSO-d 6 )δ164.97,163.56,159.50(d,J＝247.5Hz),158.98,144.87,144.48,141.70(d,J＝11.0Hz),139.96,135.70,132.43,131.37,131.26,130.93,130.86,127.98,122.71,119.85(d,J＝14.7Hz),117.56,116.09,107.60(d,J＝28.3Hz),92.99(d,J＝212.4Hz),56.47,23.42,6.27；HRMS(ESI)m/z:[M+H] + calcd for C 25 H 20 ClF 2 N 7 O 4 ,556.1311；found,556.1315.
Example 39 preparation of 4- (2- (4- (5-chloro-2- (4-trifluoromethyl-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) benzoic acid (Compound 39)
Figure BDA0003838975750000451
Step a: n- (2-bromo-4-chlorophenyl) carboxamide (39 b)
Figure BDA0003838975750000452
2-bromo-4-chloroaniline (50 g,242 mmol), formic acid (45 g,968 mmol) and sodium formate (8 g,121 mmol) were added to a reaction flask, and reacted at room temperature for 16 hours under argon atmosphere. The reaction mixture was diluted with ethyl acetate (200 mL), washed successively with water (200 mL. Times.3), saturated sodium bicarbonate solution (200 mL. Times.3), and anhydrous Na 2 SO 4 Drying, concentration under reduced pressure, precipitation of a solid, and suction filtration gave the title product 39b (49.8 g, yield: 88%).
Step b: 2-bromo-4-chloro-1-isocyanatobenzene (39 c)
Figure BDA0003838975750000453
39b (50 g,212 mmol) was added to a reaction flask, 500mL of anhydrous tetrahydrofuran was added, and then triethylamine (65 g, 428 mmol) was added, the reaction system was cooled to 0℃under Ar protection, the system temperature was maintained, and POCl dissolved in 250mL of anhydrous tetrahydrofuran was added 3 (39 g,255 mmol) was slowly added dropwise to the reaction mixture, and after the addition was completed, the reaction was carried out at 0℃for 12 hours. After the reaction was completed, the reaction mixture was poured into ice water at 0℃to quench, extracted with petroleum ether (150 mL. Times.3), and the organic phases were combined, anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave the title product 39c (40.4 g, yield: 87%).
Step c:1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole (39 d)
Figure BDA0003838975750000461
39c (10 g,46 mmol), 2-diazo-1, 1-trifluoroethane (182 mL,0.3-0.4M in toluene), silver carbonate (3.8 g,13.9 mmol) and 4A molecular sieve (5.5 g) were added to a reaction flask, DMF (60 mL) was added, heated to 40℃for 16 hours, the reaction solution was filtered, the filtrate was dried by spin, water (50 mL) was added, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (80 mL), anhydrous Na 2 SO 4 Drying and column chromatography purification gave the title product 39d (7.2 g, yield: 47%).
Step d:4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (39 e)
Figure BDA0003838975750000462
39d (32.7 g,100 mmol), 2, 5-dimethoxypyridin-4-yl (22.0 g,120 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (8 mg,10 mmol) and sodium carbonate (26.5 g,250 mmol) were added to an aqueous solution of 1, 4-dioxane (v/v, 4/1,300 mL), and the reaction mixture was heated to 80℃under nitrogen protection and stirred for 16 hours. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo, 200mL of water was added to the reaction mixture, extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, the organic phases were washed with saturated NaCl solution (200 mL), and anhydrous Na 2 SO 4 Drying and column chromatography purification gave the title product 39e (26.2 g, yield: 68%).
Step e:4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-pyridone (39 f)
Figure BDA0003838975750000463
39e (21 g,54.6 mmol) was added to 200mL of DMF, pyridine hydrobromide (87.4 g,546 mmol) was added, and the mixture was heated to 110℃under argon and stirred for 4 hours. After the completion of the reaction, the reaction solution was poured into 200mL of ice water, stirred for half an hour, filtered, and the cake was washed with distilled water and dried to give the title product 39f (16 g, yield: 79%).
Step f:2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetic acid ethyl ester (39 g)
Figure BDA0003838975750000471
39f (10 g,27 mmol) and cesium carbonate (13.2 g,40.5 mmol) were added to 60mL of N, N-dimethylformamide, the reaction system was cooled to 0℃and ethyl bromofluoroacetate (7.5 g,40.5 mmol) was slowly added dropwise thereto at 0℃and reacted at 0℃with stirring for about 30 minutes. The reaction mixture was poured into 300mL of water, extracted with ethyl acetate (60 mL. Times.3), the organic phases were combined, washed with saturated NaCl solution (300 mL), and dried Na 2 SO 4 Drying and column chromatography purification gave the title product 39g (3.3 g, yield: 26%).
1 H NMR(400MHz,DMSO-d 6 )δ9.27(s,1H),7.86–7.84(m,2H),7.81(t,J＝1.4Hz,1H),7.27(s,1H),6.62–6.45(m,2H),4.20(q,J＝7.2Hz,2H),3.24(s,3H),1.19(m,3H).
Step g:2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetic acid (39H)
Figure BDA0003838975750000472
39g (1.8 g,3.8 mmol) was added to 10mL of methanol, cooled to 0℃and 1M lithium hydroxide (5.7 mL,5.7 mmol) was slowly added dropwise and the reaction stirred for 2 hours. The methanol was removed in vacuo and the aqueous phase was acidified with hydrochloric acid (2M) to give a precipitate, which was filtered and dried to give the title product for 39h (0.53 g, yield: 30%).
Step h:4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-fluoroacetamido) benzoic acid tert-butyl ester (39 i)
Figure BDA0003838975750000473
39h (150 mg,0.34 mmol) and tert-butyl 4-aminobenzoate (78 mg,0.40 mmol) were added to the flask, 1.5mL of acetonitrile was added thereto, and N-methylimidazole (96 uL,1.18 mmol), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (141 mg,0.50 mmol) was then added thereto, and the reaction was stirred at room temperature for 16 hours. Acetonitrile was removed in vacuo, 60mL of water was added to the reaction, extracted with ethyl acetate (20 mL. Times.3), the organic phases combined, washed with saturated NaCl solution (50 mL), anhydrous Na 2 SO 4 Drying and column chromatography purification gave the title product 4a-8 (173 mg, yield: 73%).
1 H NMR(400MHz,DMSO-d 6 )δ10.69(s,1H),9.29(s,1H),7.89(d,J＝8.9Hz,2H),7.86–7.80(m,5H),7.23(s,1H),6.72(d,J＝47.3Hz,1H),6.62(s,1H),3.23(s,3H),1.54(s,9H).
Step i:4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxo-pyridin-1 (2H) -yl) -2-fluoroacetamido) benzoic acid (39)
Figure BDA0003838975750000481
39i (170 mg,0.27 mmol) was added to 5mL of ethyl acetate, and then the reaction was completed with the addition of fresh HCl gas, whereupon a solid was precipitated, filtered and dried to give the title product 39 (85 mg, yield: 55%).
HPLC purity:98.4％； 1 H NMR(400MHz,DMSO-d 6 )δ12.81(s,1H),10.68(s,1H),9.29(s,1H),7.94–7.90(m,2H),7.87–7.85(m,3H),7.84–7.81(m,2H),7.23(s,1H),6.73(d,J＝47.5Hz,1H),6.62(s,1H),3.23(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ167.32,163.31(d,J＝27.2Hz),159.02,144.81,142.44,140.15,137.18(q,J＝38.6Hz),135.54,133.59,132.39,131.42,130.88,130.66,127.82,127.66,126.60,122.67,121.11(q,J＝267.3Hz),120.13,116.84,92.71(d,J＝214.5Hz),56.26；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 17 ClF 4 N 5 O 5 ,566.0854；found,566.0850.
Example 40, 4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxo-pyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluorobenzoic acid (40)
Figure BDA0003838975750000482
The synthesis of example 39 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to tert-butyl 4-amino-2-fluorobenzoate to give the title product 40.
HPLC purity:99.1％； 1 H NMR(400MHz,DMSO-d 6 )δ13.08(s,1H),10.81(s,1H),9.29(s,1H),7.94–7.85(m,3H),7.82–7.81(m,1H),7.74(dd,J＝13.4,2.0Hz,1H),7.64(dd,J＝8.7,2.0Hz,1H),7.26(s,1H),6.70(d,J＝47.4Hz,1H),6.62(s,1H),3.23(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ164.99(d,J＝3.4Hz),163.73(d,J＝27.2Hz),161.92(d,J＝255.4Hz),159.02,144.93,143.94(d,J＝11.6Hz),140.19,137.19(q,J＝38.6Hz),135.55,133.58,133.12,132.37,131.42,130.90,127.81,127.66,122.65,121.10(q,J＝266.7Hz),117.26,115.91,114.59(d,J＝10.1Hz),108.01(d,J＝27.5Hz),93.14(d,J＝178.2Hz),56.28；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 16 ClF 5 N 5 O 5 ,584.076；found,584.072.
Example 40a, 4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxo-pyridin 1 (2H) -yl) -2-fluoroacetamido) -2-fluorobenzoic acid (enantiomer 1)
Splitting by adopting a Nexera UC SFC-UV system, wherein the splitting conditions are as follows: column temperature 40 ℃, chromatographic column: DAICEL OD-H4.6 mm I.D.×150mm L.5 μm, detection wavelength: 242nm, backpressure: 20MPa; mobile phase: scCO (scCO) 2 Methanol=80/20, flow rate: 3mL/min.
HPLC purity：99.7％； 1 H NMR(400MHz,DMSO-d 6 )δ13.07(s,1H),10.80(s,1H),9.29(s,1H),7.94–7.85(m,3H),7.82–7.81(m,1H),7.73(dd,J＝13.4,2.0Hz,1H),7.64(dd,J＝8.7,2.0Hz,1H),7.25(s,1H),6.70(d,J＝47.4Hz,1H),6.62(s,1H),3.22(s,3H)
Example 40b, 4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxo-pyridin 1 (2H) -yl) -2-fluoroacetamido) -2-fluorobenzoic acid (enantiomer 2)
Splitting by adopting a Nexera UC SFC-UV system, wherein the splitting conditions are as follows: column temperature 40 ℃, chromatographic column: DAICEL OD-H4.6 mm I.D.×150mm L.5 μm, detection wavelength: 242nm, backpressure: 20MPa; mobile phase: scCO (scCO) 2 Methanol=80/20, flow rate: 3mL/min.
HPLC purity：99.9％； 1 H NMR(400MHz,DMSO-d 6 )δ13.08(s,1H),10.80(s,1H),9.29(s,1H),7.94–7.85(m,3H),7.82–7.80(m,1H),7.74(dd,J＝13.4,2.0Hz,1H),7.64(dd,J＝8.7,2.1Hz,1H),7.26(s,1H),6.70(d,J＝47.4Hz,1H),6.61(s,1H),3.23(s,3H)
Example 41, 4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxo-pyridin-1 (2H) -yl) -2-fluoroacetamido) -2-fluorobenzamide (41)
Figure BDA0003838975750000491
The synthesis of example 39 was followed by the conversion of the starting compound tert-butyl 4-aminobenzoate to 4-amino-2-fluorobenzamide to give the title product 41.
HPLC purity:96.5％； 1 H NMR(400MHz,DMSO-d 6 )δ10.74(s,1H),9.30(s,1H),7.86–7.81(m,3H),7.74–7.66(m,2H),7.63–7.58(m,3H),7.25(s,1H),6.70(d,J＝47.4Hz,1H),6.63(s,1H),3.23(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ165.06,163.54(d,J＝27.2Hz),159.93(d,J＝247.7Hz),159.03,144.90,142.11(d,J＝11.4Hz),140.17,137.19(q,J＝38.7Hz),135.55,133.59,132.37,131.40(d,J＝4.5Hz),131.36,130.89,127.81,127.65(d,J＝2.9Hz),122.66,121.11(q,J＝267.3Hz),118.99(d,J＝13.8Hz),117.11,116.11(d,J＝2.9Hz),107.57(d,J＝28.4Hz),92.99(d,J＝230.7Hz),56.27；HRMS(ESI)m/z:[M+H] + calcd for C 24 H 17 ClF 5 N 6 O 4 ,583.092；found,583.090.
Example 42, 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoroacetamido) benzoic acid (42)
Figure BDA0003838975750000501
Step a: 2-amino-5-chlorophenylboronic acid pinacol ester (42 b)
Figure BDA0003838975750000502
The compound 2-bromo-4-chloroaniline (30.0 g,140.3 mmol) was dissolved in toluene (200 mL), and pinacol ester of bisboronic acid (40.6 g,159.8 mmol) and potassium acetate (37.1 g,377.8 mmol) were added sequentially and replaced with nitrogen 3-4 times. Under the protection of nitrogen, add PdCl rapidly 2 (dppf)·CH 2 Cl 2 (3.57 g,4.36 mmol), warmed to 90℃and stirred for 12h. After the reaction solution was cooled to room temperature, the reaction solution was dried by spin-drying. The crude product was purified by silica gel column chromatography to give compound 42b (24.68 g, yield: 67.1%).
1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝2.6Hz,1H),7.13(dd,J＝8.6,2.6Hz,1H),6.53(d,J＝8.6Hz,1H),4.75(s,2H),1.33(s,12H).
Step b: 4-chloro-2- (6-methoxypyrimidin-4-yl) aniline (42 c)
Figure BDA0003838975750000511
Compound 42b (24.7 g,97.3 mmol) was dissolved in a mixed solution of degassed 1, 4-dioxane (200 mL) and water (50 mL), then 4-chloro-6-methoxypyrimidine (14.1 g,97.3 mmol) and potassium acetate (23.9 g,243.4 mmol) were added and replaced 3-4 times with nitrogen. Rapidly adding PdCl under the protection of nitrogen 2 (dppf)·CH 2 Cl 2 (2.4 g,2.9 mmol) was heated to 80℃and stirred for 12h, TLC monitored complete consumption of compound 42b, the reaction solution was cooled to room temperature, dried by spinning, then extracted with ethyl acetate and the organic phases combined. The organic phase was washed 3 times with a saturated saline solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to give compound 42c as a white solid (14.7 g, yield: 64.3%).
1 H NMR(400MHz,CDCl 3 )δ8.78(d,J＝1.1Hz,1H),7.49(d,J＝2.5Hz,1H),7.15(dd,J＝8.7,2.4Hz,1H),6.99(d,J＝1.1Hz,1H),6.67(d,J＝8.6Hz,1H),5.35(s,2H),4.02(s,3H).
Step c:4- (2-azido-5-chlorophenyl) -6-methoxypyrimidine (42 d)
Figure BDA0003838975750000512
Compound 42c (10 g,42.4 mmol) was dissolved in 100mL of acetonitrile, cooled to 0deg.C, isoamyl nitrite (7.5 g,63.6 mmol) and azido trimethylsilane (8.3 g,63.6 mmol) were slowly added dropwise in sequence, stirred at 0deg.C for 5min, then warmed to room temperature and stirred for about 10h. The solid was precipitated, and the reaction solution was filtered to give a pale yellow solid, which was dried to give compound 42d (10.33 g, yield: 88.3%). Directly put into the next step without column chromatography purification.
Step d:4- (5-chloro-2- (4- (trimethylsilyl) -1H-1,2, 3-triazol-1-yl) phenyl) -6-methoxypyrimidine (42 e)
Figure BDA0003838975750000513
Compound 42d (10.3 g,39.5 mmol) was dissolved in toluene, ethynyl trimethylsilane (7.0 g,71.1 mmol) was added dropwise, the oil bath was heated to 110℃and stirred for 12h under reflux, TLC monitored complete reaction of starting materials, and then the reaction solution was cooled to room temperature. The reaction mixture was dried, water was added, extracted with ethyl acetate, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography to give compound 42e as a pale yellow solid (12 g, yield: 84.4%).
1 H NMR(600MHz,DMSO-d 6 )δ8.65(s,1H),8.36(s,1H),7.94(d,J＝2.4Hz,1H),7.82(dd,J＝8.5,2.4Hz,1H),7.75(d,J＝8.4Hz,1H),6.54(s,1H),3.89(s,3H),0.26(s,9H).
Step e:4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-methoxypyrimidine (42 f)
Figure BDA0003838975750000521
Compound 42e (10.7 g,29.6 mmol) was dissolved in 100mL of acetonitrile, NCS (29.1 g,217.7 mmol) and silica gel (29.7 g) were added sequentially, and the oil bath was warmed to 80℃and stirred under reflux for 6h. After the raw materials were completely consumed, the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the reaction solution was spin-dried. Water was added, extracted with ethyl acetate and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography to give compound 42f as a pale yellow solid (4.98 g, yield: 52.3%) for the next step.
1 H NMR(400MHz,DMSO-d 6 )δ8.75–8.71(m,1H),8.66–8.62(m,1H),7.98–7.93(m,1H),7.89–7.83(m,1H),7.81–7.76(m,1H),7.00–6.94(m,1H),3.96–3.90(m,3H).
Step f:6- (5-chloro-2-4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) pyrimidin-4 (3H) -one (42 g)
Figure BDA0003838975750000522
To a solution of compound 42f (5.0 g,15.4 mmol) in 4mL of acetic acid was slowly added dropwise 48% aqueous hydrobromic acid (16.6 mL,146.3 mmol). The temperature of the oil bath reaction is raised to 80 ℃, and the mixture is stirred for about 2.5 hours under the reflux state, so that the raw materials are completely reacted. After the reaction solution was cooled, the reaction solution was rotary evaporated to dryness, then ethyl acetate was added, diluted with saturated sodium bicarbonate solution, and the organic phase was collected by layering, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give 42g (4.6 g, yield: 96.8%) of a brown solid, which was used in the next step without purification.
1 H NMR(400MHz,DMSO-d 6 )δ8.69(s,1H),8.02(s,1H),7.84(d,J＝2.5Hz,1H),7.77(dd,J＝8.5,2.4Hz,1H),7.71–7.68(m,1H),6.17(s,1H).
Step g:2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoroethyl ester (42H)
Figure BDA0003838975750000531
42g (2.0 g,6.5 mmol) of the compound was dissolved in DMF, cesium carbonate (2.5 g,7.8 mmol) was added, and ethyl bromofluoroacetate (924. Mu.L, 7.79 mmol) was slowly added under ice-bath conditions and reacted at room temperature for 3h. After the completion of the reaction of the starting materials, the reaction mixture was poured into ice water, the pH was adjusted to 3 to 4 with 1M HCl solution, and a solid was precipitated, suction filtration was performed to dry the solid to give a crude product, which was purified by column chromatography to give the compound 42h as a white solid (854 mg, yield: 31.9%).
1 H NMR(400MHz,DMSO-d 6 )δ8.81(s,1H),8.48(s,1H),7.96(d,J＝2.4Hz,1H),7.84(dd,J＝8.5,2.4Hz,1H),7.76(d,J＝8.5Hz,1H),6.65(s,2H),4.22(q,J＝7.1Hz,2H),1.19(t,J＝7.1Hz,3H).
Step h:2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoroacetic acid (42 i)
Figure BDA0003838975750000532
Compound 42h (300 mg,0.73 mmol) was dissolved in 3mL of anhydrous methanol, and 1M aqueous lithium hydroxide (1.09 mL) was slowly added dropwise under ice-bath conditions, and the reaction was carried out at room temperature for about 1h. The reaction solution was dried by spinning, water was added to the residue, the pH was adjusted to 3-4 with 1M HCl solution, and a solid was precipitated, filtered off with suction and dried to give a crude product 42i as a white solid (252 mg, yield: 90%).
1 H NMR(400MHz,DMSO-d 6 )δ8.81(s,1H),8.43(s,1H),7.96(d,J＝2.4Hz,1H),7.83(dd,J＝8.5,2.3Hz,1H),7.75(d,J＝8.5Hz,1H),6.63(s,2H).
Step i:4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoroacetamido) benzoic acid tert-butyl ester (42 j)
Figure BDA0003838975750000533
Compound 42i (252 mg,0.66 mmol) was dissolved in dichloromethane and tert-butyl p-aminobenzoate (152 mg,0.79 mmol), HATU (264 mg,0.39 mmol) and finally DIPEA (163. Mu.L) were added. The reaction was carried out at room temperature for about 12h, and TLC was used to monitor the completion of the starting material reaction, and the reaction solution was dried by spinning. To the residue was added saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with 0.5M HCl and saturated saline solution respectively 3-4 times, and the organic phase was washed with anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure to obtain a crude product. Purification by column chromatography gave compound 42j as a white solid (200 mg, yield: 54.4%).
1 H NMR(400MHz,DMSO-d 6 )δ10.74(s,1H),8.82(s,1H),8.47(s,1H),7.97(d,J＝2.4Hz,1H),7.87(d,J＝8.8Hz,2H),7.83(d,J＝2.3Hz,1H),7.81(d,J＝8.7Hz,2H),7.76(d,J＝8.5Hz,1H),6.80(d,J＝46.4Hz,1H),6.64(s,1H),1.52(s,9H).
Step j:4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoroacetamido) benzoic acid (42)
Figure BDA0003838975750000541
Compound 42j (100 mg) was weighed out and dissolved in about 5mL of EA solution, and then fresh HCl gas was introduced under ice bath conditions. TLC monitoring the completion of the reaction starting material gave compound 42 as a white solid (54 mg, yield: 60.2%).
HPLC purity:95.1％； 1 H NMR(400MHz,DMSO-d 6 )δ10.73(s,1H),8.80(s,1H),8.47(s,1H),7.96(d,J＝2.3Hz,1H),7.91(d,J＝8.6Hz,2H),7.83(dd,J＝8.5,2.4Hz,1H),7.80(d,J＝8.7Hz,2H),7.75(d,J＝8.5Hz,1H),6.80(d,J＝46.4Hz,1H),6.63(s,1H)； 13 C NMR(151MHz,DMSO-d 6 )δ167.34,162.65(d,J＝25.8Hz),159.60,159.40,151.77,142.25,135.63,134.64,134.29,133.49,131.59,131.01,130.72,129.00,126.78,124.84,120.24,115.26,91.37(d,J＝221.1Hz)；HRMS(m/z):[M+H] + calcd for C 21 H 14 Cl 2 FN 6 O 4 + 503.0437,found 503.0433.
Example 43, 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoroacetamide) -2-fluorobenzamide (43)
Figure BDA0003838975750000542
Compound 42i (100 mg,0.260 mmol) was dissolved in dichloromethane and 4-amino-2-fluoroaniline (48 mg,0.31 mmol), HATU (148 mg,0.39 mmol) and finally DIPEA (64. Mu.L) were added. The reaction was carried out at room temperature for about 12 hours, and TLC was used to monitor the completion of the reaction, and the reaction solution was washed with 0.5M HCl, saturated sodium bicarbonate solution and saturated sodium chloride solution, and then with anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave the crude product, which was purified by column chromatography (DCM: meoh=100:1 to 40:1) to give 43 as a white solid (17 mg, yield: 12.6%).
HPLC purity:95.2％；mp:214.6～215.2℃； 1 H NMR(400MHz,DMSO-d 6 )δ10.80(s,1H),8.80(s,1H),8.47(s,1H),7.96(d,J＝2.4Hz,1H),7.84(dd,J＝8.6,2.4Hz,1H),7.75(d,J＝8.5Hz,1H),7.70–7.64(m,2H),7.55–7.53(m,3H),6.79(d,J＝46.4Hz,1H),6.64(s,1H)； 13 C NMR(151MHz,DMSO-d 6 )δ165.09,162.87(d,J＝25.9Hz),159.90(d,J＝248.0Hz),159.66,159.40,151.80,141.88(d,J＝11.3Hz),135.63,134.63,134.29,133.50,131.60,131.43(d,J＝3.9Hz),131.02,129.00,124.84,119.23(d,J＝14.0Hz),116.20(d,J＝2.9Hz),115.27,107.70(d,J＝28.3Hz),91.41(d,J＝221.6Hz)；HRMS(m/z):[M+H] + calcd for C 21 H 14 Cl 2 F 2 N 7 O 3 + 520.0503,found 520.0499.
Example 44, 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoroacetamido) -2-fluoro-N-methylbenzamide (44)
Figure BDA0003838975750000551
The preparation method is similar to that of the target compound 43. The starting material 4-amino-2-fluoroaniline was replaced by N-methyl-2-fluoro-4-aminobenzamide, which was prepared and purified to give the title compound 44 as a white solid (22 mg, yield: 15.8%).
HPLC purity:95.5％； 1 H NMR(400MHz,DMSO-d 6 )δ10.80(s,1H),8.81(s,1H),8.47(s,1H),8.12–8.08(m,1H),7.96(d,J＝2.3Hz,1H),7.84(dd,J＝8.5,2.4Hz,1H),7.76(d,J＝8.5Hz,1H),7.69–7.64(m,1H),7.63(d,J＝8.4Hz,1H),7.54(dd,J＝8.6,2.0Hz,1H),6.80(d,J＝46.4Hz,1H),6.64(s,1H),2.75(d,J＝4.6Hz,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.96,162.86(d,J＝26.1Hz),159.66,159.64(d,J＝247.3Hz),159.40,151.80,141.66(d,J＝11.3Hz),135.62,134.64,134.28,133.51,131.59,131.19(d,J＝4.2Hz),131.02,129.00,124.85,119.51(d,J＝14.2Hz),116.26(d,J＝2.8Hz),115.28,107.70(d,J＝28.3Hz),91.40(d,J＝221.3Hz),26.77；HRMS(m/z):[M+H] + calcd for C 22 H 16 Cl 2 F 2 N 7 O 3 + 534.0659,found 534.0652.
Example 45, 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoroacetamido) -N-ethyl-2-fluorobenzamide (45)
Figure BDA0003838975750000561
Preparation method in analogy to the preparation of target compound 43, starting material 4-amino-2-fluoroaniline was replaced by N-ethyl-2-fluoro-4-aminobenzamide and the target compound 45 was prepared and purified as a white solid (25 mg, yield: 17.5%).
HPLC purity:95.1％； 1 H NMR(400MHz,DMSO-d 6 )δ10.79(s,1H),8.82(s,1H),8.47(d,J＝1.0Hz,1H),8.15(q,J＝5.4Hz,1H),7.97(d,J＝2.3Hz,1H),7.84(dd,J＝8.5,2.4Hz,1H),7.76(d,J＝8.5Hz,1H),7.70–7.61(m,1H),7.61(d,J＝8.3Hz,1H),7.54(dd,J＝8.5,1.9Hz,1H),6.80(d,J＝46.4Hz,1H),6.65(s,1H),3.30–3.19(m,2H),1.09(t,J＝7.2Hz,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.28,162.83(d,J＝25.9Hz),159.64,159.56(d,J＝247.0Hz),159.38,151.79,141.54(d,J＝12Hz),135.59,134.64,134.23,133.51,131.57,131.10,131.02,129.00,124.85,119.88(d,J＝14.1Hz),116.20,115.28,107.67(d,J＝28.3Hz),91.40(d,J＝221.1Hz),34.51,15.13；HRMS(m/z):[M+H] + calcd for C 23 H 18 C l2 F 2 N 7 O 3 + 548.0816,found 548.0808.
Example 46, 2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoro-N- (4- (methylsulfonyl) phenyl) acetamide (46)
Figure BDA0003838975750000562
Using a similar synthetic route to the target compound 43, the starting material 4-amino-2-fluoroaniline was replaced with 4- (methylsulfonyl) aniline, which was prepared and purified to give the target compound 46 as a white solid (31 mg, yield: 22.2%).
HPLC purity:93.7％； 1 H NMR(400MHz,DMSO-d 6 )δ10.86(s,1H),8.80(s,1H),8.48(s,1H),7.96(d,J＝2.4Hz,1H),7.94–7.91(m,2H),7.90–7.87(m,2H),7.84(dd,J＝8.5,2.3Hz,1H),7.75(d,J＝8.5Hz,1H),6.81(d,J＝46.4Hz,1H),6.64(s,1H),3.16(s,3H)； 13 C NMR(151MHz,DMSO-d 6 )δ162.97(d,J＝26.0Hz),159.65,159.40,151.83,142.77,136.36,135.63,134.64,134.29,133.50,131.60,131.02,129.00,128.56,124.84,120.80,115.27,91.40(d,J＝221.3Hz),44.19；HRMS(m/z):[M+H] + calcd for C 21 H 16 Cl 2 FN 6 O 4 S + 537.0315,found 537.0305.
Example 47, 2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) -2-fluoro-N- (quinoxalin-6-yl) acetamide (47)
Figure BDA0003838975750000571
Using the synthetic route of the target compound 43, the starting material 4-amino-2-fluoroaniline was replaced with 6-aminoquinoxaline, which was prepared and purified to give the target compound 47 as a white solid (34 mg, yield: 25.5%).
HPLC purity:95.6％； 1 H NMR(400MHz,DMSO-d 6 )δ10.96(s,1H),8.90(d,J＝1.9Hz,1H),8.85(d,J＝1.9Hz,1H),8.83(s,1H),8.53(d,J＝2.2Hz,1H),8.52(s,1H),8.13(dd,J＝9.1,2.3Hz,1H),8.08(d,J＝8.9Hz,1H),7.98(d,J＝2.3Hz,1H),7.85(dd,J＝8.5,2.4Hz,1H),7.77(d,J＝8.5Hz,1H),6.88(d,J＝46.4Hz,1H),6.67(d,J＝0.9Hz,1H)； 13 C NMR(151MHz,DMSO-d 6 )δ163.03(d,J＝26.1Hz),159.66,159.45,151.85,146.64,145.12,143.14,140.05,139.52,135.61,134.67,134.25,133.54,131.59,131.06,130.06,129.03,124.93,124.89,117.86,115.33,91.48(d,J＝222.6Hz)；HRMS(m/z):[M+H] + calcd for C 22 H 14 Cl 2 FN 8 O 2 + 510.0523,found 510.0518.
Example 48, 4- (2- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-oxopyrimidin-1 (6H) -yl) acetamide) benzoic acid (48)
Figure BDA0003838975750000572
The target compound is prepared by adopting a similar synthetic route of the compound 43 and changing the raw material in the step g into tert-butyl bromoacetate48, off-white solid (33 mg, yield: 36.8%). HPLC purity 98.0%; 1 H NMR(400MHz,DMSO-d6)δ12.72(s,1H),10.73(s,1H),8.78(s,1H),8.31(s,1H),7.94(d,J＝2.4Hz,1H),7.95–7.86(m,2H),7.84–7.79(m,1H),7.74(d,J＝8.5Hz,1H),7.71–7.63(m,2H),6.49(s,1H),4.76(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ167.34,165.73,160.52,159.21,153.14,142.94,135.67,135.40,134.20,133.49,131.22,131.02,130.83,129.19,126.02,124.89,118.88,113.98,49.29.HRMS(m/z):[M+H] + calcd for C 21 H 15 Cl 2 N 6 O 4 + 485.0532,found 485.0519.
the beneficial effects of the present invention are demonstrated by specific test examples below.
Test example 1 measurement of Factor XIa protease Activity by the Compounds of the invention
Human FXIa (Enzyme Research Laboratories) was used to test the FXIa inhibitory activity of the compounds of the invention in vitro. The chromogenic substrate used in the invention is Boc-Glu (OBzl) -Ala-Arg-AMC (Jier Biochemical), and the substrate is hydrolyzed by FXIa to release Aminomethylcoumarin (AMC), and the inhibition strength of the compound on FXIa is obtained by measuring the change of fluorescence intensity.
The experimental procedure is briefly described as follows: test compounds were prepared in 10mM stock solution in DMSO and then diluted to a series of concentrations in buffer (50 mM Tris/HCl pH 7.4, 100mM sodium chloride, 5mM calcium chloride, 0.1% bovine serum albumin). After adding 20. Mu.L of buffer solution, 20. Mu.L of FXIa enzyme solution (0.6 nM) and then 20. Mu.L of test compound solution to a microplate, incubating at a constant temperature of 37℃for 30min, adding 40. Mu.L of fluorogenic substrate solution (10. Mu.M), immediately measuring on a microplate reader, excitation wavelength of 360nM and emission wavelength of 460nM, continuously reading data, and fitting the data with GraphPad Prism 7 to obtain compound IC 50 Values, data are presented in Table 1.
TABLE 1 IC for the inhibitory Activity of the compounds of the invention against FXIa 50 Data
Example Compounds FXIa(IC 50 ，nM) Example Compounds FXIa(IC 50 ，nM)
17 7.3 33 27.6
18 9.3 34 221.3
19 30.1 35 20.5
20 24.3 36 55.7
21 396.1 37 114.0
22 5.5 38 133.5
23 34.2 39 5.7
24 18.2 40 12
25 17.3 40a 8.2
27 6.6 40b 8.9
30 3.8 41 65.9
31 34.1 48 201.5
32 40.1
As can be seen from Table 1, the compound of the present invention has a certain inhibitory effect on Fxla protease activity, and the inhibition effect of fluorine atom-introduced compounds on Fxla protease activity is much better than that of fluorine atom-not-introduced compounds. Of these, compounds 17, 18, 22, 27, 30, 39, 40a and 40b are excellent in inhibitory effect.
Test example 2 Activated Partial Thromboplastin Time (APTT) determination of the Compounds of the invention
The following methods were used to determine the in vitro anticoagulation of the compounds of the invention in human plasma. The method uses an APTT kit (product number: Y115) of Sunbio company to test, and human blood plasma is quality control freeze-dried blood plasma (Sunbio company).
The experimental method comprises the following steps: and adding 1mL of high-purity water into the freeze-dried plasma with quality control for dissolution, and mixing the mixture with light shaking. Test compounds were dissolved in DMSO and double-diluted in gradient with DMSO to prepare a series of solutions. The calcium chloride solution and APTT reagent are preheated at 37 ℃. Then, 20. Mu.L of the plasma to be measured is taken in a measuring cup, diluted test compound is added, 20. Mu.L of preheated APTT reagent is added, and the mixture is incubated for 5min at 37 ℃. The measuring cup was placed in the measuring channel of a semi-automatic coagulometer, then 20 μl of preheated calcium chloride solution was added, immediately measurement was performed, and the clotting time was recorded. Curve fitting was performed on the recorded clotting times with GraphPad Prism 7 software to calculate EC 1.5x I.e., 1.5 times the concentration of the compound corresponding to the APTT of the blank. The test results are shown in Table 2.
TABLE 2 EC of the compounds of the invention on the in vitro anticoagulation of human plasma 1.5x Data
Example Compounds EC 1.5x (μM) Example Compounds EC 1.5x (μM)
17 2.57 40 1.26
22 1.69 40a 1.20
27 2.93 40b 1.23
30 0.78 48 7.23
39 2.70
As can be seen from Table 2, the compounds of the present invention have a better in vitro anticoagulation in human plasma. Compared with the compound without fluorine atoms, the compound with fluorine atoms introduced by the invention has better anticoagulation effect.
In summary, the invention provides a novel compound which can be used as FXIa small molecule inhibitor, fluorine atoms are introduced into the compound, and compared with a compound without fluorine, the novel compound has higher activity and can effectively improve the anticoagulation effect of the compound. In addition, the compounds of the present invention are useful for the effective treatment and/or prevention of cardiovascular and cerebrovascular diseases and thrombosis symptoms.

Claims (13)

1. A compound of formula I, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof:
Figure FDA0003838975740000011
wherein,,
n is substituent R on benzene ring 1 Is an integer of 0 to 5;
each R 1 Independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
x is selected from CR 3 Or N;
R 3 selected from hydrogen, C 1 ～C 8 Alkyl, halogen, 3-8 membered cycloalkyl, -OR 4 ；
R 4 Selected from substituted or unsubstituted C 1 ～C 8 Alkyl and 3-8 membered cycloalkyl;
the ring A is selected from 5-10 membered aryl and 5-10 membered unsaturated heterocyclic group, the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atom is 1-2;
m is a substituent R on the A ring 2 Is an integer of 0 to 5;
each R 2 Independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, cyano, -C (O) R 5 、-S(O)(O)R 5 、-OR 5’ 、-NR 6 C(O)R 7 Aryl of 5-10 membered;
R 5 selected from hydrogen, C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, hydroxy, -N (H) R 8 、-NR 9 R 10 ；
R 5’ Selected from hydrogen, C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, hydroxy, -N (H) R 8 ；
R 6 Selected from hydrogen, C 1 ～C 8 An alkyl group;
R 7 selected from hydrogen, C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, -N (H) R 8 ；
R 8 Selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, mercapto, ester, cyano, 3-8 membered cycloalkyl;
R 9 、R 10 are respectively and independently selected from C 1 ～C 8 An alkyl group;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
2. The compound, or salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, according to claim 1, wherein:
n is 0, 1 or 2;
each R 1 Are respectively and independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, and the number of the hetero atoms is 3-4;
X is selected from CR 3 Or N;
R 3 selected from hydrogen, C 1 ～C 4 Alkyl, halogen, 3-6 membered cycloalkyl, -OR 4 ；
R 4 Selected from substituted or unsubstituted C 1 ～C 4 Alkyl and 3-6 membered cycloalkyl;
the ring A is selected from phenyl and 5-10 membered unsaturated heterocyclic groups, the hetero atoms of the unsaturated heterocyclic groups are N, O or S, and the number of the hetero atoms is 1-2;
m is 0, 1 or 2;
each R 2 Independently selected from substituted or unsubstituted C 1 ～C 4 Alkyl, halogen, cyano, -C (O) R 5 、-S(O)(O)R 5 、-OR 5’ 、-NR 6 C(O)R 7 Phenyl;
R 5 selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, hydroxy, -N (H) R 8 、-NR 9 R 10 ；
R 5’ Selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, hydroxy, -N (H) R 8 ；
R 6 Selected from hydrogen, C 1 ～C 4 An alkyl group;
R 7 selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, -N (H) R 8 ；
R 8 Selected from hydrogen, substituted or unsubstituted C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, mercapto, ester, cyano, 3-6 membered cycloalkyl;
R 9 、R 10 are respectively and independently selected from C 1 ～C 4 An alkyl group;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
3. The compound, or salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, according to claim 2, wherein:
n is 0, 1 or 2;
each R 1 Are respectively and independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-to 6-membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;
x is selected from CR 3 Or N;
R 3 selected from hydrogen, C 1 ～C 4 Alkyl, halogen, 3-6 membered cycloalkyl, -OR 4 ；
R 4 Selected from substituted or unsubstituted C 1 ～C 4 Alkyl and 3-6 membered cycloalkyl;
the A ring is selected from phenyl, indazolyl, indolyl, quinoxalinyl, thienyl, isoxazolyl, thiazolyl, pyrazolyl and dihydrobenzimidazolyl;
m is 0, 1 or 2;
each R 2 Independently selected from substituted or unsubstituted C 1 ～C 4 Alkyl, halogen, cyano, -C (O) R 5 、-S(O)(O)R 5 、-OR 5’ 、-NR 6 C(O)R 7 Phenyl;
R 5 selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, hydroxy, -N (H) R 8 、-NR 9 R 10 ；
R 5’ Selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, hydroxy, -N (H) R 8 ；
R 6 Selected from hydrogen, C 1 ～C 4 An alkyl group;
R 7 selected from hydrogen, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, -N (H) R 8 ；
R 8 Selected from hydrogen, substituted or unsubstituted C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, mercapto, ester, cyano, 3-6 membered cycloalkyl;
R 9 、R 10 are respectively and independently selected from C 1 ～C 4 An alkyl group;
the substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
4. The compound, or salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, according to claim 1, wherein: the compound is shown in a formula II:
Figure FDA0003838975740000031
wherein,,
R 1a 、R 1b independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
The substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
x, A ring, m and R 2 A method according to any one of claims 1 to 3;
preferably, the method comprises the steps of,
R 1a 、R 1b are respectively and independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, and the number of the hetero atoms is 3-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
more preferably, the process is carried out,
R 1a 、R 1b are respectively and independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxylA group, a nitro group, a cyano group, a substituted or unsubstituted 3-to 6-membered cycloalkyl group, a substituted or unsubstituted triazolyl group, a substituted or unsubstituted tetrazolyl group;
The substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
5. The compound, or salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, according to claim 1, wherein: the compound is shown in a formula III:
Figure FDA0003838975740000041
wherein,,
R 1b independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
The substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
x, A ring,m and R 2 A method according to any one of claims 1 to 3;
preferably, the method comprises the steps of,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, and the number of the hetero atoms is 3-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
more preferably, the process is carried out,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-to 6-membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;
the substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
6. The compound, or salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, according to claim 5, wherein: the compound is represented by formula IIIa:
Figure FDA0003838975740000051
wherein,,
R 1b independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
ring A, m and R 2 A method according to any one of claims 1 to 3;
Preferably, the method comprises the steps of,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, and the number of the hetero atoms is 3-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
more preferably, the process is carried out,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, aminoA carboxyl group, a nitro group, a cyano group, a substituted or unsubstituted 3-to 6-membered cycloalkyl group, a substituted or unsubstituted triazolyl group, a substituted or unsubstituted tetrazolyl group;
the substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
7. The compound, or salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, according to claim 5, wherein: the compound is represented by formula IIIb:
Figure FDA0003838975740000061
Wherein,,
R 1b independently selected from substituted or unsubstituted C 1 ～C 8 Alkyl, C 1 ～C 8 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, sulfhydryl, ester group, cyano, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, O or S, and the number of the hetero atoms is 1-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituent of the alkyl group is selected from C 1 ～C 8 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro;
the substituents of the cycloalkyl group are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
ring AM and R 2 A method according to any one of claims 1 to 3;
preferably, the method comprises the steps of,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the hetero atom of the unsaturated heterocyclic group is N, and the number of the hetero atoms is 3-4;
the substituents of the unsaturated heterocyclic groups are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
The substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
more preferably, the process is carried out,
R 1b independently selected from C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-to 6-membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;
the substituent of the triazolyl and tetrazolyl is selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano;
the substituents of the cycloalkyl group are selected from C 1 ～C 4 Alkyl, halogen, trifluoromethyl, hydroxy, amino, carboxyl, nitro, cyano.
8. The compound, or salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, according to claim 1, wherein: the compound is one of the following compounds:
Figure FDA0003838975740000071
Figure FDA0003838975740000081
Figure FDA0003838975740000091
9. a process for the preparation of a compound as claimed in any one of claims 1 to 8, characterized in that: it comprises the following steps:
Figure FDA0003838975740000101
carrying out condensation reaction on the compound of the formula AI-A and the compound of the formula AI-B or hydrochloride thereof under alkaline conditions, and hydrolyzing to obtain the compound of the formula AI;
Wherein,,
R 1 ring n, X, A, R 2 And m is as defined in any one of claims 1 to 8.
10. Use of a compound according to any one of claims 1 to 8, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or mixture thereof, for the preparation of a coagulation factor FXIa inhibitor and/or a plasma bradykinin kinase PKA inhibitor.
11. Use of a compound according to any one of claims 1 to 8, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or mixture thereof, for the preparation of a medicament for the prophylaxis and/or treatment of a factor XIa mediated disease, for the prophylaxis and/or treatment of cardiovascular and cerebrovascular diseases;
preferably, the disease is a thromboembolic disease;
more preferably, the disease is myocardial infarction, angina pectoris, reocclusion and restenosis following angioplasty or aortic coronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis.
12. A medicament, characterized in that: a formulation prepared by taking a compound according to any one of claims 1 to 8, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a mixture thereof as an active ingredient, and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
13. A pharmaceutical composition characterized by: a compound according to any one of claims 1 to 8, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or mixture thereof, and pharmaceutically acceptable carriers, diluents and excipients.
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