CN113563320A - Compound containing thiophene structure and application thereof in medicine - Google Patents

Compound containing thiophene structure and application thereof in medicine Download PDF

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CN113563320A
CN113563320A CN202110428580.4A CN202110428580A CN113563320A CN 113563320 A CN113563320 A CN 113563320A CN 202110428580 A CN202110428580 A CN 202110428580A CN 113563320 A CN113563320 A CN 113563320A
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nhch
methyl
amino
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魏群超
王岩石
吴宝金
吴海翔
刘鹏
孔晓华
郑志超
张士俊
李玉荃
黄长江
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Tianjin Institute of Pharmaceutical Research Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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Abstract

The present invention provides a compound of formula (I) wherein all variables are as defined in the specification, and pharmaceutically acceptable salts thereof, and their use in medicaments for the prevention and/or treatment of thromboembolic disorders and/or thromboembolic complications.

Description

Compound containing thiophene structure and application thereof in medicine
Technical Field
The invention belongs to the technical field of medicines. Specifically, the invention relates to a compound containing a thiophene structure and a pharmaceutically acceptable salt thereof, a preparation method and application thereof, and a pharmaceutical composition containing the compound and the pharmaceutically acceptable salt thereof.
Background
The thromboembolic diseases not only have high morbidity, but also have high fatality rate and disability rate, such as myocardial infarction, cerebral infarction and pulmonary infarction caused by thromboembolism are the first causes of death. The medicines for preventing and treating thrombotic diseases mainly comprise anticoagulant, antiplatelet and thrombolytic medicines, and bleeding is the most main and most common complication of the current clinical antithrombotic medicines. Traditional anticoagulant drugs, such as warfarin, heparin, Low Molecular Weight Heparin (LMWH), and recently marketed new drugs, such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (dabigatran etexilate, hirudin, etc.), have good effects in reducing thrombosis, but all face a common deficiency that bleeding complications may be caused. Therefore, the research and development of new antithrombotic drugs with small hemorrhagic side effects has important value.
The blood coagulation factor XI (F XI) was first recognized as a member of blood coagulation contact activation pathways, and activated in vivo to form the blood coagulation factor XI a (F XI a). However, with the progress of research, the traditional waterfall coagulation theory is modified, and the modified theory is considered as follows: the F xi may be activated by thrombin to form F xi a and plays a role in the continuous generation of thrombin and inhibition of fibrinolysis. In recent years, clinical data about the defect of the F XI in human beings or the rising level of the F XI in the human beings and antithrombotic experimental studies on the defect or the inhibited F XI in animals show that the F XI and the F XI a are new antithrombotic prevention and treatment targets with small bleeding risk and antithrombotic drug bleeding side effects aiming at the F XI and the F XI a targets. Therefore, the development of F XI a inhibitor medicine is expected to overcome the common defects of the traditional anticoagulant medicine: bleeding complications, and has important clinical requirements and wide market prospects.
Ola
Figure BDA0003030534450000021
An article entitled "Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure air Drug Design" published on PLOS ONE | DOI: 10.1371/journal.0113705 at 28.1.2015 reports a series of active 2-oxo-1, 2-dihydroquinoline class F XI a Inhibitors. However, the known F XI a inhibitors have many disadvantages such as poor physical and chemical properties such as solubility, which is disadvantageous for drug development. Therefore, there is a need in the art for the development of novel F xia inhibitors having good solubility and favorable absorption.
Disclosure of Invention
An object of the present invention is to provide a thiophene structure-containing compound which has good solubility, is easily absorbed and has an inhibitory effect on F XI a, and a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a process for the preparation of the compounds of the present invention.
It is still another object of the present invention to provide a pharmaceutical composition, which comprises the compound of formula (i) and its pharmaceutically acceptable salts and pharmaceutically acceptable carriers or excipients.
It is a further object of the present invention to provide the use of the compounds of the present invention and their pharmaceutically acceptable salts.
The purpose of the invention is realized by the following technical scheme:
in one aspect, the present invention provides a compound having the structure of formula (I):
Figure BDA0003030534450000031
wherein:
R1is selected from-CHR4R5、-(CH2)qCH(NH2)CO2H、-CH2R8、
Figure BDA0003030534450000032
Figure BDA0003030534450000033
R2Selected from H, C1-6An alkyl group;
R3is selected from-OR11、-OCH2OC(O)OCH2CH3、-NHR12、
Figure BDA0003030534450000041
R4Is selected from-NH2、-NHCH3、-NHCH2CH3、-NHCH(CH3)2、-NHCH(CH3)CH2CH3、-NHC(CH3)3；
R5Selected from H, C1-6Alkyl, -CH2CO2H、-(CH2)2CO2H；
R6Is selected from-NH2、-NHCH3、-NHCH2CH3、-NHCH(CH3)2、-NHC(CH3)3、-NHCH(CH3)CH2CH3、-CH2NH2、-CH2NHCH3、-CH2NHCH2CH3、-CH2NHCH(CH3)2、-CH2NHC(CH3)3、-CH2NHCH(CH3)CH2CH3、-N(CH3)2、-CH2N(CH3)2；
R7Is selected from-NH2、-NHCH3、-NHCH2CH3、-NHCH(CH3)2、-NHC(CH3)3、-NHCH(CH3)CH2CH3、-N(CH3)2；
R8Is selected from
Figure BDA0003030534450000042
-NR9R10；
R9And R10Each independently selected from C1-6An alkyl group;
R11selected from H, C1-6Alkyl and C3-6A cycloalkyl group;
R12selected from H, -CH2CO2H、-CH(CH3)CO2H、-CH(CH(CH3)2)CO2H、-(CH2)4CH(NH2)CO2H、-CH(CO2H)(CH2)4NH2、-CH(CH2CH(CH3)2)CO2H、-CH(CH(CH3)CH2CH3)CO2H；
W is selected from-CH2-、-NH-、-N(CH3)-、-N(CH2CH3)-、-N(CH2CH(CH3)2)-、-N(CH(CH3)2)-、-N(C(CH3)3)-、-NH(CH(CH3)CH2CH3)-；
X is selected from O, S, N;
y is selected from C, N;
z is selected from C;
a is selected from-CH2-、O、-NH-、-N(CH3)-、-N(CH2CH3)-、-N(CH(CH3)2)-、-N(C(CH3)3)-、-N(CH2CH(CH3)2)-、-NH(CH(CH3)CH2CH3)-；
i is selected from 1,2, 3 and 4;
m, p and q are each independently selected from 1 and 2.
In certain preferred embodiments of the present invention, in the compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein:
R1is selected from-CHR4R5、-(CH2)qCH(NH2)CO2H、-CH2R8、
Figure BDA0003030534450000051
Figure BDA0003030534450000052
R2Selected from H, C1-3An alkyl group;
R3is selected from-OR11、-NHR12、
Figure BDA0003030534450000053
R4Is selected from-NH2、-NHCH3；
R5Selected from H, C1-4Alkyl, -CH2CO2H、-(CH2)2CO2H；
R6Is selected from-NH2、-NHCH3；
R7Is selected from-NH2、-NHCH3；
R8Is selected from
Figure BDA0003030534450000061
-NR9R10；
R9And R10Each independently selected from C1-3An alkyl group;
R11selected from H, C1-6Alkyl groups of (a);
R12selected from H, -CH2CO2H、-CH(CH3)CO2H、-CH(CH(CH3)2)CO2H、-(CH2)4CH(NH2)CO2H、-CH(CO2H)(CH2)4NH2、-CH(CH2CH(CH3)2)CO2H、-CH(CH(CH3)CH2CH3)CO2H；
W is selected from-CH2-、-NH-、-N(CH3)-；
X is selected from O, N;
y is selected from C, N;
z is selected from C;
a is selected from-CH2-、O、-NH-、-N(CH3)-；
i is selected from 1,2, 3 and 4;
m, p and q are each independently selected from 1 and 2.
In certain more preferred embodiments of the present invention, in the compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein:
R1is selected from-CHR4R5、-(CH2)qCH(NH2)CO2H、-CH2R8、
Figure BDA0003030534450000071
Figure BDA0003030534450000072
R2Selected from H, -CH3；
R3Is selected from-OR11、-NHR12、
Figure BDA0003030534450000073
R4Is selected from-NH2；
R5Selected from H, -CH3、-CH(CH3)2、-CH(CH3)CH2CH3、-CH2CO2H、-(CH2)2CO2H；
R6Is selected from-NH2；
R7Is selected from-NH2；
R8Is selected from
Figure BDA0003030534450000074
-NR9R10；
R9And R10Each independently selected from-CH3；
R11Selected from H, -CH3；
R12Selected from H, -CH2CO2H、-(CH2)4CH(NH2)CO2H、-CH(CO2H)(CH2)4NH2；
W is selected from-CH2-、-NH-、-N(CH3)-；
X is selected from O, N;
y is selected from C, N;
z is selected from C;
a is selected from-CH2-、O；
i is selected from 1,2, 3 and 4;
m, p and q are each independently selected from 1 and 2.
In certain preferred embodiments of the present invention, the compound of formula (i) and pharmaceutically acceptable salts thereof are selected from the following compounds:
Figure BDA0003030534450000081
Figure BDA0003030534450000091
Figure BDA0003030534450000101
in another aspect, the present invention provides a process for preparing a compound having the structure of formula (I), comprising the steps of:
the method comprises the following steps:
Figure BDA0003030534450000111
(1) reacting the compound A with the compound B, and then removing a protecting group to obtain a compound C;
(2) reacting the compound C with the compound D to obtain a compound E;
(3) reducing the compound E to obtain a compound F;
(4) reacting the compound F with a corresponding reagent, and removing a protecting group to obtain a partial compound shown in the formula (I), or directly reacting the compound F with the corresponding reagent to obtain the partial compound shown in the formula (I);
wherein R is1、R2、R3X, Y, Z are as defined above.
The second method comprises the following steps:
Figure BDA0003030534450000121
(1) reacting the compound A with the compound B, and then removing a protecting group to obtain a compound C;
(2) reacting the compound C with a compound G to obtain a compound H;
(3) reducing the compound H to obtain a compound I;
(4) reacting the compound I with a corresponding reagent to obtain a compound J;
(5) removing a protecting group of the compound J to obtain a compound K;
(6) reacting the compound K with a corresponding reagent, and then removing a corresponding protecting group to obtain a partial compound shown in the formula (I), or directly reacting the compound K with the corresponding reagent to obtain the partial compound shown in the formula (I);
wherein R is1、R2、R3X, Y, Z are as defined above.
In still another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (i) of the present invention and pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
In the present invention, the pharmaceutically acceptable auxiliary material refers to conventional carriers and/or excipients and the like which do not affect the efficacy of the compound of formula (i) of the present invention and the pharmaceutically acceptable salts thereof.
In a further aspect, the present invention provides the use of a compound of formula (i) of the present invention and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention and/or treatment of thromboembolic disorders and/or thromboembolic complications.
In a further aspect, the present invention provides a method for the prophylaxis and/or treatment of thromboembolic disorders and/or thromboembolic complications, which comprises administering to a patient a compound of formula (I) as described herein and pharmaceutically acceptable salts thereof, or administering to a patient a pharmaceutical composition comprising a compound of formula (I) as described herein and pharmaceutically acceptable salts thereof.
Within the scope of the present invention, "thromboembolic disorders" include, inter alia, disorders such as myocardial infarction with and without ST elevation (STEMI), stable/unstable angina, reocclusion and restenosis after coronary interventions such as angioplasty or aortic coronary bypass surgery, peripheral vascular occlusive disorders, pulmonary embolism, deep vein thrombosis and renal vein thrombosis, transient ischemic attacks and thrombo-and thromboembolic strokes.
The thromboembolic disorders also include cardiac thromboembolisms, such as stroke, cerebral ischemia, systemic thromboembolism and ischemia, as well as acute, intermittent or persistent cardiac arrhythmias, cardioversion, valvular heart disease, and the like.
The thromboembolic diseases also include atherosclerotic vascular diseases and inflammatory diseases (such as motor system rheumatic diseases), as well as thromboembolism caused by other diseases (such as diabetes, neoplastic diseases, especially in patients undergoing major surgical interventions or radiotherapy/chemotherapy).
The thromboembolic disorder also includes Disseminated Intravascular Coagulation (DIC).
The thromboembolic complications include microvascular hemolytic anemia, complications that occur in the case of extracorporeal blood circulation such as hemodialysis and heart valve repair.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
When the present invention relates to a compound substituted with a plurality of substituents, each substituent may be the same or different.
The elemental carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include their isotopes, and the elemental carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include12C、13C、14C, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F19Isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Preferably an alkyl group having 1 to 10 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-nonyl, and various branched isomers thereof, and the like; more preferred are lower alkyl groups having 1 to 4 carbon atoms, and non-limiting examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably 1 to 5, independently selected from F, Cl, Br, I, ═ O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, mercapto, hydroxyl, nitro, cyano, amino, alkylacylamino, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylmercapto, hydroxyalkyl, carboxyl, carboxylate, heterocycloalkylthio.
"optional," "optional," or "optionally" means that the subsequently described event or circumstance may, but need not, occur, including instances where the event or circumstance occurs or does not. For example, "aryl is optionally substituted with alkyl" means that alkyl may, but need not, be present, and that the description includes instances where aryl is substituted with alkyl and instances where aryl is not substituted with alkyl.
Detailed Description
The present invention is further illustrated by the following examples, which are illustrative and explanatory only and are not meant to limit the scope of the invention in any way.
The structure of the compound is shown by nuclear magnetic resonance hydrogen spectrum (1H NMR) and/or Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker model AV400 NMR spectrometer.
MS measurements were performed using a Thermo scientific (ESI) mass spectrometer.
The thin layer chromatography silica gel plate adopts a cigarette platform yellow sea GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials for the present invention may be synthesized by methods known in the art or may be purchased from companies such as the welfare technology, the alading technology, and the like.
The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
In the examples, the reaction was carried out under a nitrogen atmosphere unless otherwise specified.
In the examples, unless otherwise specified, the solution means an aqueous solution.
In the examples, the reaction temperature was room temperature unless otherwise specified.
The room temperature is the most suitable reaction temperature and is 20-30 ℃.
Intermediate 1: synthesis of (S) -2- ((tert-butoxycarbonyl) amino) -3- (6-nitropyridin-3-yl) propionic acid
Figure BDA0003030534450000171
The first step is as follows: synthesis of (R) - (2- ((tert-butoxycarbonyl) amino) -3-methoxy-3-oxopropyl) zinc iodide (1b)
Iodine (400mg, 1.08mmol) was added to a suspension of zinc powder in DMF and stirred at room temperature under nitrogen for 10min, compound 1a (3.45g, 10.5mmol) and iodine (400mg, 1.08mmol) were added to the suspension and stirred at room temperature for 30min and the next reaction was carried out without purification.
The second step is that: synthesis of methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (6-nitropyridin-3-yl) propionate (1c)
Anhydrous DMF (5mL) was added to a solution containing 2-nitro-5-bromopyridine (2.6g, 12.8mmol), Pd2(dba)3(292mg, 0.318mmol) and SPhos ligand (0.52g, 1.27mmol) in a reaction flask protected with nitrogen, stirring at room temperature for 5min, adding the prepared zinc reagent 1b to the reaction solution under nitrogen atmosphere, heating at 60 ℃ for 6h, cooling to room temperature, filtering with diatomaceous earth, and performing column chromatography to obtain compound 1 c.
The third step: synthesis of (S) -2- ((tert-butoxycarbonyl) amino) -3- (6-nitropyridin-3-yl) propionic acid (intermediate 1)
LiOH (800mg, 19mmol) in water (10mL) was added to a methanol (10mL) solution of Compound 1c, stirred at room temperature for 2h, the solvent was evaporated under reduced pressure, and column chromatography was performed to give intermediate 1(1.4g, 43% yield in two steps)
1H NMR(400MHz,DMSO-d6):δ8.59(s,1H),8.00(d,1H),8.24(d,1H),7.33(d,1H),4.56(t,1H),3.54(m,1H),3.17(m,1H),1.39(s,9H)。
MS m/z＝312.24[M+H]+。
Intermediate 2: synthesis of 6-chloro-4- ((methylamino) methyl) quinolin-2 (1H) -one
Figure BDA0003030534450000191
The first step is as follows: synthesis of N- (4-chlorophenyl) -3-oxobutanamide (2b)
4-chloroaniline (2a) (12.0g, 94.1mmol), DMAP (11.5g, 94.1) and pyridine (48mL) were added to xylene (240mL) and the reaction was heated to reflux. After 8h, the reaction was complete. The reaction mixture was cooled to room temperature, poured into a mixed solution of 2N hydrochloric acid (240mL) and ethyl acetate (240mL), and stirred for 20 min. The layers were separated and the aqueous layer was washed with ethyl acetate (120 mL. times.2). The organic layers were combined, concentrated to dryness under reduced pressure, and column chromatographed to give the title compound 2b (10.7g, 53.7% yield).
1H NMR(400MHz,DMSO-d6):δ10.2(s,1H),7.57-7.60(m,2H),7.33-7.36(m,2H),3.54(s,2H),2.19(s,3H)。
MS m/z＝211.99[M+H]+。
The second step is that: synthesis of 4-bromo-N- (4-chlorophenyl) -3-oxobutanamide (2c)
To a solution of N- (4-chlorophenyl) -3-oxobutanamide (2b) (1.0g, 4.72mmol) in glacial acetic acid (10mL) at room temperature was added iodine (1mg), and a solution of bromine (0.8g, 4.96mmol) in glacial acetic acid (15mL) was slowly added dropwise. After the addition, the reaction was carried out at room temperature for 18 hours. The reaction mixture was poured into 250mL of ice water, stirred to precipitate a white solid, which was filtered, washed with water, and dried at room temperature to give the title compound, 4-bromo-N- (4-chlorophenyl) -3-oxobutanamide (2c) (1.1g, 80.3% yield).
1H NMR(400MHz,DMSO-d6):δ10.2(s,1H),7.56-7.63(m,2H),7.35-7.40(m,2H),4.47(s,2H),3.73(s,2H)。
MS m/z＝289.96[M+H]+。
The third step: synthesis of 4- (bromomethyl) 6-chloroquinolin-2 (1H) -one (2d)
4-bromo-N- (4-chlorophenyl) -3-oxobutanamide (2c) (100mg, 0.38mmol) was added to concentrated sulfuric acid (0.5mL) at room temperature. After the addition, the reaction was carried out at 80 ℃ for 3 hours. The reaction mixture was poured into ice water (15mL), stirred to precipitate a white solid, filtered with suction, washed with water, and dried at room temperature for 12H to give the title compound 4- (bromomethyl) 6-chloroquinolin-2 (1H) -one (2d) (70mg, 67.8% yield).
MS m/z＝272.06[M+H]+。
The fourth step: synthesis of 6-chloro-4- ((methylamino) methyl) quinolin-2 (1H) -one (intermediate 2)
To a suspension of 4- (bromomethyl) 6-chloroquinolin-2 (1H) -one (2d) (110mg, 0.40mmol) in tetrahydrofuran (1mL) and dioxane (1mL) was added dropwise a 40% aqueous methylamine solution (1 mL). After the addition, the reaction was carried out at 30 ℃ for 12 hours. Water (10mL) was added to precipitate a white solid, which was filtered off with suction and dried at 50 ℃ for 3h to give the title compound, intermediate 2(35mg, 38.9% yield).
1H NMR(400MHz,DMSO-d6):δ11.7(s,1H),7.83(d,1H),7.70(d,1H),7.37(d,1H),6.54(s,1H),3.82(s,2H),2.33(s,3H)。
MS m/z＝223.00[M+H]+。
Intermediate 3: synthesis of 5-carbamoylthiophene-2-carboxylic acid
Figure BDA0003030534450000211
The first step is as follows: synthesis of methyl 5-carbamoylthiophene-2-carboxylate (3b)
Dissolving 3a (2.18g, 11.7mmol) in anhydrous tetrahydrofuran (16mL), adding triethylamine (2.1mL, 15.2mmol) at-25 ℃, dropwise adding methyl chloroformate (1.52g, 14.0mmol), stirring for 2h, dropwise adding 25% ammonia water (4.7g, 69.1mmol), stirring for 3h after 5min, extracting with ethyl acetate, washing the organic phase with water, washing the organic phase with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, and directly carrying out the next reaction on the obtained crude product.
The second step is that: synthesis of 5-carbamoylthiophene-2-carboxylic acid (intermediate 3)
Dissolving the crude product 3b obtained in the previous step in methanol (10mL), adding an aqueous solution (2mL) of LiOH (440mg, 10.5mmol), stirring at room temperature for 5h, evaporating part of the solvent, adjusting to acidity with 1N hydrochloric acid to precipitate a large amount of white solid, performing suction filtration, washing a filter cake with water, and drying to obtain an intermediate 3.
1H NMR(400MHz,DMSO)δ13.36(s,1H),8.14(s,1H),7.74–7.66(m,2H),7.61(s,1H).
MS m/z＝171.93[M+H]+。
Intermediate 4: synthesis of methyl (S) -5- ((3- (6-aminopyridin-3-yl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylate
Figure BDA0003030534450000221
The first step is as follows: synthesis of tert-butyl (S) - (1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (6-nitropyridin-3-yl) -1-oxopropan-2-yl) carbamate (4a)
Intermediate 1(1.00g, 3.21mmol) and 6-chloro-4- ((methylamino) methyl) quinolin-2 (1H) -one (intermediate 2) (0.72g, 3.22mmol) were dissolved in DMF (15mL) and HOBT (0.87g, 6.44mmol), DIEA (1.25g, 9.66mmol) and EDCI (1.23g, 6.44mmol) were added and the reaction was stirred at room temperature. After 30 hours, water (30mL) was added to the reaction solution to precipitate a solid. Suction filtered, washed with water (10mL) and dried at 45 ℃ for 3h to give title compound 4a (1.25g, 75.4% yield).
The second step is that: synthesis of (S) -2-amino-N- ((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) -N-methyl-3- (6-nitropyridin-3-yl) propanamide (4b)
To compound 5a (1.20g, 2.33mmol) was added ethyl acetate (12 mL). A1M solution of hydrogen chloride in ethyl acetate (50mL) was added slowly with stirring and the reaction was carried out at room temperature for 20 h. And after the reaction is finished, carrying out suction filtration. Washed with ethyl acetate and dried at 45 ℃ for 3h to give the title compound 4b (1.00g, 94.9% yield).
The third step: synthesis of methyl (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (6-nitropyridin-3-yl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylate (4c)
4b (1.00g, 2.21mmol), 5- (methoxycarbonyl) thiophene-2-carboxylic acid (420mg, 2.22mmol), HOBT (600mg, 4.44mmol), EDCI (850mg, 4.44mmol) and DIEA (860mg, 6.66mmol) were dissolved in DMF (30mL) and the reaction was stirred at room temperature for 6 h. After TLC indicated the reaction was complete, water (300mL) was added and a solid precipitated. Slurried, washed and filtered to afford title compound 4c (1.11g, 86.0% yield).
The fourth step: synthesis of methyl (S) -5- ((3- (6-aminopyridin-3-yl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylate (intermediate 4)
To 4c (500mg, 0.86mmol) was added methanol (25mL) and THF (5 mL). Zinc powder (562mg, 8.60mmol) and ammonium chloride (460mg, 8.60mmol) were added with stirring. After the addition, the reaction was stirred at room temperature for 24 hours. Filtration was carried out, and the filtrate was concentrated to precipitate a solid. Filtration with suction gave intermediate 4(450mg, 94.2% yield).
1H NMR(400MHz,DMSO-d6)δ11.69(d,1H),8.50(dd,1H),7.91(d,1H),7.89–7.57(m,3H),7.36(d,1H),7.00–6.77(m,2H),6.44–6.41(m,1H),6.36–6.32(m,1H),5.05(dt,1H),4.62(d,2H),4.34(d,1H),3.77(d,3H),3.04(s,1H),2.87(d,3H),2.76(q,2H).
MS m/z＝553.87[M+H]+
Intermediate 5: synthesis of methyl (S) -5- ((3- (4-aminophenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropyl-2-yl) carbamoyl) thiophene-2-carboxylate
Figure BDA0003030534450000251
In the first step of this intermediate synthesis, Boc-4-nitro-L-phenylalanine (5a) was used instead of (S) -2- ((tert-butoxycarbonyl) amino) -3- (6-nitropyridin-3-yl) propionic acid (intermediate 1) in the first step of the intermediate 4 synthesis to give intermediate 5 in a similar manner to the synthesis of intermediate 4.
1H NMR(400MHz,DMSO-d6)δ11.73(d,1H),9.10(dd,1H),7.95(d,1H),7.89–7.57(m,3H),7.53(dt,1H),7.32(d,1H),7.00–6.77(m,2H),6.44–6.41(m,1H),6.36–6.32(m,1H),4.95(dt,1H),4.82(d,J＝32.4Hz,2H),4.70(d,1H),3.82(d,3H),3.29(s,1H),2.95(d,3H),2.87(q,2H).
MS m/z＝552.77[M+H]+。
Intermediate 6: synthesis of (S) -N- (3- (4-aminophenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropyl-2-yl) thiophene-2, 5-dicarboximide
Figure BDA0003030534450000261
In the third step of the synthesis of intermediate 6, 5-carbamoylthiophene-2-carboxylic acid (intermediate 3) was used instead of intermediate 4 to synthesize 5- (methoxycarbonyl) thiophene-2-carboxylic acid in the third step, and intermediate 6 was obtained by a method similar to that for the synthesis of intermediate 4.
1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.98(t,1H),7.87(d,1H),7.80(d,1H),7.70(d,1H),7.58–7.53(m,2H),7.33(d,1H),7.01–6.95(m,2H),6.48–6.40(m,2H),6.36(d,2H),4.88(s,2H),4.71(s,2H),2.98(s,3H),2.94(d,1H),2.88(d,2H).
MS m/z＝538.64[M+H]+
Example 1: synthesis of (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (6- (cyclopropylcarboxamide) pyridin-3-yl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 1)
Figure BDA0003030534450000262
The first step is as follows: synthesis of methyl (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (6- (cyclopropylcarboxamide) pyridin-3-yl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylate (7a)
Intermediate 4(200mg, 0.36mmol), cyclopropanecarboxylic acid (31mg, 0.36mmol), HOBT (97mg, 0.72mmol), EDCI (138mg, 0.72mmol) and DIEA (140mg, 1.08mmol) were dissolved in DMF (10mL), reacted at room temperature with stirring for 24h, water and ethyl acetate were added, extracted, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and a solid precipitated. Suction filtration and drying at 45 ℃ for 3h gave compound 7a (193mg, 86.1% yield).
The second step is that: synthesis of (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (6- (cyclopropylcarboxamide) pyridin-3-yl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 1)
Compound 7a (174mg, 0.28mmol) was dissolved in a mixed solution of methanol (2mL) and tetrahydrofuran (2 mL). A solution of lithium hydroxide monohydrate (59mg, 1.4mmol) in water (6mL) was added and the reaction stirred at room temperature for 3 h. 1M hydrochloric acid was added dropwise to the system to a pH of 3-5, and extraction with ethyl acetate, drying and spin-drying were performed to give title compound 1(112mg, 64.3% yield).
1H NMR(400MHz,DMSO)δ11.83(s,1H),10.67(s,1H),9.22(d,1H),8.28(d,1H),7.92(dd,2H),7.79–7.68(m,3H),7.59–7.46(m,3H),7.32(d,1H),6.33(s,1H),5.12(d,2H),4.74(s,2H),3.09(s,3H),1.94(d,2H),0.87–0.70(m,8H).
MS m/z＝607.89[M+H]+。
Example 2: synthesis of (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (6- (cyclopenta-carboxamide) pyridin-3-yl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 2)
Figure BDA0003030534450000281
In this example, the title compound 2 was obtained in the same manner as in example 1 using cyclopentecarboxylic acid instead of cyclopropanecarboxylic acid in example 1.
1H NMR(400MHz,DMSO)δ11.83(s,1H),10.30(s,1H),9.21(d,1H),8.27(d,1H),7.93(dd,2H),7.79–7.67(m,3H),7.63–7.46(m,4H),7.32(d,1H),6.33(s,1H),5.17–4.95(m,2H),4.74(d,2H),3.08(d,4H),1.85–1.73(m,3H),1.65(dd,6H),1.55–1.43(m,4H).
MS m/z＝635.92[M+H]+。
Example 3: synthesis of (S) -5- ((1- (((((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (cyclopropanecarboxamido) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 3)
Figure BDA0003030534450000291
In this example, the title compound 3 was obtained in the same manner as in example 1 using intermediate 5 instead of intermediate 4 in example 1.
1H-NMR(400MHz,DMSO-d6):δ13.27(s,1H),11.83(s,1H),10.10(s,1H),9.18(d,1H),7.91(d,1H),7.79(d,1H),7.69(d,1H),7.54(ddd,2H),7.47(d,2H),7.35(dd,22H),7.26(d,2H),7.08(d,1H),6.34(s,1H),5.06(dt,1H),4.72(s,2H),2.95(s,2H),1.83–1.65(m,1H),0.75(d,4H).
MS m/z＝607.05[M+1]
Example 4: synthesis of (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (cyclopropanecarboximidoyl) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 4)
Figure BDA0003030534450000301
The first step is as follows: synthesis of methyl (S) -5- ((1- (((((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (cyclopropanecarboximido) phenyl) -1-oxopropan-2-ylcarbamoyl) thiophene-2-carboxylate (10a)
Intermediate 5(150mg, 0.27mmol) was dissolved in DMF (2mL), ethyl cyclopropanecarboximidoate (46mg, 0.41mmol) and glacial acetic acid (25mg, 0.41mmol) were added, and the reaction was stirred at room temperature for 40 h. The reaction was quenched with 5% aqueous NaHCO3 (5mL), extracted with ethyl acetate, the organic phase washed with saturated sodium chloride, dried over anhydrous NaSO4, filtered, concentrated, and isolated by column chromatography to give compound 10a (109mg, 65.3% yield).
The second step of this example was carried out in the same manner as in example 1 to obtain the title compound 4.
1H-NMR(400MHz,DMSO-d6):δ11.82(d,1H),8.99(d,1H),8.43(s,1H),7.78(s,1H),7.71–6.65(m,8H),6.45–6.15(m,1H),5.12(d,1H),4.93–4.53(m,2H),3.20–2.99(m,4H),2.94(s,2H),1.97(s,1H),1.34–0.55(m,5H).
MS m/z＝606.39[M+1]
Example 5: synthesis of methyl (S) -5- ((1- (((6-chloro-2-oxo-1, 2, dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (1-methylazetidin-3-carboxamido) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylate (Compound 5)
Figure BDA0003030534450000311
In this example, using 1-methylazetidine-3-carboxylic acid instead of cyclopropanecarboxylic acid in example 1 and intermediate 5 instead of intermediate 4, the title compound 5 was obtained in the same manner as in the first step of example 1.
1H-NMR(400MHz,DMSO-d6):δ11.76(d,1H),10.39–9.96(m,1H),9.20(dd,1H),7.98(d,1H),7.84–7.59(m,2H),7.57–7.10(m,5H),6.30(s,1H),5.13–4.95(m,1H),4.70(s,2H),3.81(d,5H),3.06–2.66(m,7H),1.23(d,4H),0.90(dt,1H).
MS m/z＝650.14[M+1]
Example 6: synthesis of (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (1-methylazetidin-3-carboxamido) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 6)
Figure BDA0003030534450000312
In this example, the title compound 6 was obtained in the same manner as in the second step of example 1.
1H-NMR(400MHz,DMSO-d6):δ11.81(d,1H),10.04(d,1H),8.89(dd,1H),8.04–7.63(m,2H),7.65–7.44(m,3H),7.43–7.32(m,2H),7.28(dd,2H),6.22(d,1H),5.07(q,1H),4.91(dt,1H),4.84–4.56(m,2H),3.91(t,2H),3.68(t,2H),3.56(p,2H),2.95(s,1H),2.54(d,3H),1.38–1.14(m,3H).
MS m/z＝635.09[M+1]
Example 7: synthesis of (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (1-methylpiperidine-4-carboxamido) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 7)
Figure BDA0003030534450000321
In the first step of this example, 1-methylpiperidine-4-carboxylic acid was used instead of cyclopropanecarboxylic acid in the first step of example 3, and the same procedure as in example 3 was used to obtain intermediate 11 a.
In the second step of this example, the title compound 7 was obtained in the same manner as in the second step of example 1.
1H-NMR(400MHz,DMSO-d6):δ11.85(s,1H),9.92(s,1H),8.99(d,1H),7.95(s,1H),7.87–7.64(m,2H),7.58–7.53(m,1H),7.50–7.43(m,2H),7.36(dd,8.5Hz,2H),7.26(t,Hz,2H),6.33(s,1H),5.05(d,1H),4.83–4.63(m,2H),3.76(s,1H),3.17(s,2H),3.03–2.96(m,2H),2.95(s,1H),2.89(s,3H),2.73(s,3H),1.93–1.70(m,3H),1.29–1.17(m,2H).
MS m/z＝664.23[M+1]
Example 8: synthesis of (S) -5- ((3- (4- (2-aminoacetamido) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 8)
Figure BDA0003030534450000331
In the first step of this example, N-Boc-glycine was used instead of cyclopropanecarboxylic acid in the first step of example 3, and the same procedure as in example 3 was used to obtain intermediate 12 a.
The second step is that: synthesis of (S) -5- ((3- (4- (2-aminoacetamido) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 8)
(S) -methyl-5- ((3- (4- (2- ((tert-butoxycarbonyl) amino) acetylamino) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylate (12a) (200mg, 0.28mmol) was dissolved in a mixed solution of methanol (2mL) and tetrahydrofuran (2 mL). 6M aqueous hydrochloric acid (5mL) was added, and the reaction was stirred at room temperature for 3 h. After concentration to dryness under reduced pressure, a solution of lithium hydroxide monohydrate (59mg, 1.4mmol) in water (6mL) was added to the system, and the reaction was stirred at room temperature for 3 hours. 1M aqueous hydrochloric acid was added dropwise to the system to a pH of 3-5, extracted with ethyl acetate, dried and spin-dried to give title compound 8(110mg, 65.9% yield).
1H-NMR(400MHz,DMSO-d6):δ11.82(d,1H),10.86(d,1H),9.19(dd,1H),8.55–8.16(m,3H),7.97(d,1H),7.78(d,1H),7.68(dd,1H),7.58–7.43(m,3H),7.42(s,1H),7.31(d,1H),7.20(dd,1H),6.19(d,1H),5.14–4.99(m,1H),4.99–4.77(m,1H),4.71(s,1H),3.74(dd,3H),3.04(d,1H),3.02(s,2H),2.94(s,1H).
MS m/z＝596.05[M+1]
Example 9: synthesis of 5- (((S) -3- (4- ((S) -2-aminopropionylamino) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 9)
Figure BDA0003030534450000341
In the first step of this example, Boc-L-alanine was used in place of N-Boc-glycine in the first step of example 8 to obtain the title compound 9 in the same manner as in example 8.
1H-NMR(400MHz,DMSO-d6):δ11.90(s,1H),10.48(d,1H),9.03(dd,2H),7.96–7.69(m,4H),7.62–7.52(m,5H),7.38(d,3H),6.88–6.61(m,1H),6.39(d,1H),5.14(q,1H),4.89–4.66(m,3H),4.03(s,1H),1.44(d,5H).
MS m/z＝610.14[M+1]
Example 10: synthesis of 5- (((S) -3- (4- ((S) -2-amino-3-methylbutanamido) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4- (yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 10)
Figure BDA0003030534450000351
In the first step of this example, Boc-L-valine was used instead of N-Boc-glycine in the first step of example 8, and the same procedure as in example 8 was used to obtain the title compound 10.
1H-NMR(400MHz,DMSO-d6):δ11.74(d,1H),10.38(d,1H),9.11(dd,1H),7.90(d,1H),7.80(d,1H),7.68–7.47(m,3H),7.37(dd,2H),7.18(dd,1H),6.21(d,1H),5.13–4.96(m,1H),4.86–4.67(m,1H),3.67(dd,1H),3.05(d,3H),2.96(s,1H),2.57–2.52(m,1H),2.15(dt,1H),2.00(q,1H),1.61–1.33(m,1H),1.24(d,3H),1.18–0.69(m,6H).
MS m/z＝638.20[M+1]
Example 11: synthesis of 5- (((S) -3- (4- ((2S, 3S) -2-amino-3-methylpentylamino) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 11)
Figure BDA0003030534450000361
In the first step of this example, N-Boc-L-isoleucine was used in place of N-Boc-glycine in the first step of example 8, and the same procedure as in example 8 was used to obtain the title compound 11.
1H-NMR(400MHz,DMSO-d6):δ11.74(d,1H),10.43(d,1H),9.14(dd,1H),7.92(d,1H),7.80(d,1H),7.67(dd,1H),7.60–7.48(m,2H),7.37(dd,2H),7.18(dd,1H),6.49–6.23(m,1H),5.23–4.58(m,3H),3.74(dd,1H),3.48(d,1H),3.05(d,3H),3.01–2.78(m,2H),2.54(s,1H),2.23–1.64(m,2H),1.56(ddd,1H),1.43–0.40(m,8H).
MS m/z＝652.24[M+1]
Example 12: synthesis of 5- (((S) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxo-3- (4- ((S) -pyrrolidine-2-carboxamido) phenyl) propan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 12)
Figure BDA0003030534450000362
In the first step of this example, Boc-L-proline was used in place of N-Boc-glycine in the first step of example 8, and the same procedure as in example 8 was used to obtain the title compound 12.
1H-NMR(400MHz,DMSO-d6):δ11.77(d,1H),10.45(d,1H),9.29–8.70(m,1H),7.91–7.66(m,2H),7.61–7.44(m,3H),7.40–7.28(m,2H),7.25–7.07(m,1H),6.33(d,1H),5.21–4.64(m,3H),4.24(d,1H),3.36(d,3H),3.25–2.85(m,7H),2.27(s,1H),1.87(s,2H),1.50–1.08(m,1H).
MS m/z＝636.10[M+1]
Example 13: synthesis of (S) -5- ((3- (4- (1-aminocyclohexanecarboxamido) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 13)
Figure BDA0003030534450000371
In the first step of this example, 1- (Boc-amino) cyclohexanecarboxylic acid was used in place of N-Boc-glycine in the first step of example 8, and the same procedure as in example 8 was used to obtain the title compound 13.
1H-NMR(400MHz,DMSO-d6):δ11.84(s,1H),9.99(d,1H),9.18(dd,1H),7.93(t,1H),7.79(t,1H),7.73–7.65(m,1H),7.59–7.49(m,2H),7.44(q,1H),7.38–7.23(m,2H),7.18(dd,1H),6.44–6.26(m,1H),5.14–4.96(m,1H),4.88–4.53(m,2H),3.07–2.97(m,4H),2.15(d,1H),2.03–1.89(m,1H),1.80–1.55(m,6H),1.52–1.07(m,6H).
MS m/z＝664.14[M+1]
Example 14: synthesis of (S) -5- ((3- (4- (1-aminocyclopropanecarboxamido) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 14)
Figure BDA0003030534450000381
In the first step of this example, Boc-1-aminocyclopropylformic acid was used in place of N-Boc-glycine in the first step of example 8, and the same procedure as in example 8 was used to obtain the title compound 14.
1H-NMR(400MHz,DMSO-d6):δ11.73(d,1H),9.74(d,1H),9.12(dd,1H),7.91(d,1H),7.78(d,1H),7.73–7.53(m,2H),7.54–7.46(m,2H),7.30(dd,2H),7.15(dd,1H),6.45–6.23(m,1H),5.30–4.84(m,2H),4.85–4.59(m,2H),2.98(d,6H),2.80(d,1H),1.28(dq,2H),0.99(dt,2H).
MS m/z＝622.11[M+1]
Example 15: synthesis of (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxo-3- (4- (2- (piperidin-1-yl) acetylamino) phenyl) propan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 15)
Figure BDA0003030534450000382
In the first step of this example, piperidin-1-yl-acetic acid hydrochloride was used in place of 1-methylpiperidine-4-carboxylic acid in the first step of example 7 to obtain the title compound 15 in the same manner as in example 7.
1H-NMR(400MHz,DMSO-d6):δ11.83(s,1H),9.79(d,1H),9.19(d,1H),7.92(d,1H),7.79(d,1H),7.69(t,1H),7.63(dd,3.2Hz,1H),7.59–7.47(m,3H),7.40(d,1H),7.32(dd,2H),7.17(dd,1H),6.32(s,1H),5.09(q,1H),4.73(d,1H),3.05(d,4H),2.96(s,1H),2.65(s,4H),1.61(p,4H),1.43(d,2H),1.24(d,2H).
MS m/z＝664.15[M+1]
Example 16: synthesis of ((S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (2-morpholinoacetamido) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 16)
Figure BDA0003030534450000391
In the first step of this example, morpholin-4-ylacetic acid was used in place of 1-methylpiperidine-4-carboxylic acid in the first step of example 7 to obtain the title compound 16 in the same manner as in example 7.
1H-NMR(400MHz,DMSO-d6):δ11.82(s,1H),9.67(d,1H),9.20(d,1H),7.92(d,1H),7.78(d,1H),7.70(d,1H),7.63(dd,3.1Hz,1H),7.56–7.48(m,3H),7.30(dd,3H),7.15(dd,1H),6.29(s,1H),5.14–5.02(m,1H),4.72(d,1H),3.62(dt,4H),3.16(s,2H),3.03(d,3H),2.94(s,1H),2.55(d,4H),1.22(s,1H).
MS m/z＝666.06[M+1]
Example 17: synthesis of (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (2- (dimethylamino) acetylamino) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 17)
Figure BDA0003030534450000401
In the first step of this example, N-dimethylglycine was used instead of 1-methylpiperidine-4-carboxylic acid in the first step of example 7 to obtain the title compound 17 in the same manner as in example 7.
1H-NMR(400MHz,DMSO-d6):δ11.87(s,1H),10.62(d,1H),9.28–9.11(m,1H),7.94(d,1H),7.80(d,1H),7.71(d,1H),7.64(dd,1H),7.60–7.31(m,7H),7.19(dd,1H),6.33(s,1H),5.10(q,1H),4.74(d,1H),3.97(d,2H),2.98(d,3H),2.77(d,6H),1.23(s,1H).
MS m/z＝624.16[M+1]
Example 18: synthesis of (S) -5- ((3- (4- (4-aminotetrahydro-2H-pyran-4-carboxamido) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 18)
Figure BDA0003030534450000402
In the first step of this example, 4- (Boc-amino) tetrahydropyran-4-carboxylic acid was used in place of N-Boc-glycine in the first step of example 8 to obtain the title compound 18 in the same manner as in example 8.
1H-NMR(400MHz,DMSO-d6):δ11.85(s,1H),10.23(d,1H),9.24(d,1H),7.93(d,1H),7.80(d,1H),7.72(d,1H),7.62–7.54(m,3H),7.51–7.45(m,1H),7.38–7.25(m,3H),7.21–7.15(m,1H),6.30(s,1H),5.11(td,1H),4.79(d,1H),3.06(d,5H),2.96(d,2H),2.41(td,2H),1.99(dt,1H),1.87–1.70(m,4H),1.26–1.21(m,1H).
MS m/z＝666.04[M+1]
Example 19: synthesis of (S) -5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxo-3- (4- (2- (pyrrolidinyl-1-yl) acetamido) phenyl) propan-2-yl) carbamoyl) thiophene-2-carboxylic acid (Compound 19)
Figure BDA0003030534450000411
In the first step of this example, 2- (1-pyrrolidinyl) acetic acid was used instead of 1-methylpiperidine-4-carboxylic acid in the first step of example 7, and the same procedure as in example 7 was used to obtain the title compound 19.
1H-NMR(400MHz,DMSO-d6):δ11.85(s,1H),9.90(d,1H),7.64–7.47(m,5H),7.32(dd,3H),7.12(d,1H),6.32(s,1H),5.08(q,1H),4.81–4.68(m,2H),3.05(d,4H),2.95(d,2H),2.82(d,4H),1.80(dq,4H).
MS m/z＝650.17[M+1]
Example 20: synthesis of (S) -3-amino-4- ((4- ((S) -2- (5-carbamoylthiophene-2-carboxamido) -3- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3-propionyl) phenyl) amino) -4-oxobutanoic acid (Compound 20)
Figure BDA0003030534450000421
The first step is as follows: synthesis of methyl (S) -3- ((tert-butoxycarbonyl) amino) -4- ((4- ((S) -2- (5-carbamoylthiophene-2-carboxamido) -3- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3-propionyl) phenyl) amino) -4-oxobutanoate (24a)
Intermediate 6(54mg, 0.10mmol), tert-butoxycarbonyl-L-aspartic acid-4-tert-butyl ester (29mg, 0.10mmol), PyBop (78mg, 0.15mmol), DIPEA (129mg, 0.30mmol) were dissolved in DMF (10mL), the reaction was stirred at room temperature for 12 hours, water and ethyl acetate were added, extraction was performed, the organic phase was dried over anhydrous sodium sulfate, and concentration was performed to precipitate a solid. Suction filtration and drying at 45 ℃ for 3h gave compound 24a (62mg, 76% yield).
The second step is that: synthesis of (S) -3-amino-4- ((4- ((S) -2- (5-carbamoylthiophene-2-carboxamido) -3- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3-propionyl) phenyl) amino) -4-oxobutanoic acid (Compound 20)
Compound 24a (55mg, 0.067mmol) was dissolved in a solution of trifluoroacetic acid (3 mL). The reaction was stirred at room temperature for 12 h. The solvent was evaporated, slurried with methyl tert-butyl ether, filtered under suction, and the resulting solid dried in a vacuum oven at 45 ℃ to give title compound 20(30mg, 69% yield).
1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),10.40(s,1H),9.08(d,1H),8.07(s,1H),7.85(d,1H),7.78(s,1H),7.68(d,1H),7.61–7.51(m,2H),7.50–7.43(m,2H),7.34(dd,8.0Hz,4H),7.17(dd,1H),6.29(s,1H),5.08(q,1H),4.72(d,2H),4.01(q,1H),3.18–2.85(m,7H).
MS m/z＝653.34[M+1]
Example 21: synthesis of (S) -4-amino-5- ((4- ((S) -2- (5-carbamoylthiophene-2-carboxamido) -3- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3-propionyl) phenyl) amino) -5-oxopentanoic acid (Compound 21)
Figure BDA0003030534450000431
In the first step of this example, N-Boc-L-glutamic acid-5-tert-butyl ester was used in place of tert-butoxycarbonyl-L-aspartic acid-4-tert-butyl ester in the first step of example 20 to obtain the title compound 21 in a similar manner to example 20.
1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),10.43(s,1H),9.09(d,1H),8.26(s,3H),7.86(d,1H),7.78(d,1H),7.69(d,1H),7.55(td,2H),7.51–7.44(m,2H),7.42–7.29(m,3H),7.18(dd,8.6Hz,1H),6.31(s,1H),5.09(q,1H),4.82–4.62(m,2H),4.01(q,1H),3.24–2.76(m,7H).
MS m/z＝667.13[M+1]
Example 22: synthesis of (S) -2-amino-4- ((4- ((S) -2- (5-carbamoylthiophene-2-carboxamido) -3- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3-propionyl) phenyl) amino) -4-oxobutanoic acid (Compound 22)
Figure BDA0003030534450000441
In the first step of this example, N-tert-butoxycarbonyl-L-aspartic acid 1-tert-butyl ester was used in place of tert-butoxycarbonyl-L-aspartic acid 4-tert-butyl ester in the first step of example 20 to obtain the title compound 22 in a similar manner to example 20.
1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),10.15(s,1H),9.07(d,1H),8.20(s,3H),7.85(d,1H),7.78(d,1H),7.68(d,1H),7.60–7.53(m,2H),7.48–7.41(m,2H),7.31(dt,4H),6.31(s,1H),5.15–5.03(m,1H),4.72(s,2H),4.31–4.17(m,1H),3.13–2.85(m,7H).
MS m/z＝653.23[M+1]
Example 23: synthesis of (S) -2-amino-5- ((4- ((S) -2- (5-carbamoylthiophene-2-carboxamido) -3- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3-propionyl) phenyl) amino) -5-oxopentanoic acid (Compound 23)
Figure BDA0003030534450000442
In the first step of this example, Boc-L-glutamic acid-1-tert-butyl ester was used in place of tert-butoxycarbonyl-L-aspartic acid-4-tert-butyl ester in the first step of example 20 to obtain the title compound 23 by a similar manner to example 20.
1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),9.94(s,1H),9.06(d,1H),8.24(s,3H),7.85(d,1H),7.78(d,1H),7.68(d,1H),7.56(td,2H),7.49–7.43(m,2H),7.34(dd,2H),7.29–7.23(m,2H),6.31(s,1H),5.06(q,1H),4.72(s,2H),4.07–3.98(m,1H),3.22–2.88(m,7H).
MS m/z＝667.53[M+1]
Example 24: synthesis of N- ((2S) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxo-3- (4- (pyrrolidine-2-carboxamide) phenyl) propan-2-yl) thiophene-2, 5-dicarboxamide (Compound 24)
Figure BDA0003030534450000451
In the first step of this example, N-Boc-proline was used instead of t-butoxycarbonyl-L-aspartic acid-4-t-butyl ester in the first step of example 20 to obtain the title compound 24 in a similar manner to example 20.
1H NMR(400MHz,DMSO-d6):δ11.82(s,1H),10.45(s,1H),9.08(d,1H),8.07(s,1H),7.85(d,1H),7.78(d,1H),7.69(d,1H),7.59–7.51(m,3H),7.51–7.43(m,3H),7.35(dd,4H),7.15(d,1H),6.29(s,1H),5.09(d,1H),4.73(dd,2H),4.27(d,2H),3.04(s,4H),1.92(dt,4H).。
MS m/z＝634.93[M+H]+。
Example 25: (S) -N- (3- (4- (1-aminocyclohexane-1-carboxamide) phenyl) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -1-oxopropan-2-yl) thiophene-2, 5-dicarboxamide (Compound 25)
Figure BDA0003030534450000461
In this example, the title compound 25 was obtained in the same manner as in example 20 using 1- ((tert-butoxycarbonyl) amino) cyclohexane-1-carboxylic acid instead of tert-butoxycarbonyl-L-aspartic acid-4-tert-butyl ester in the first step in example 20.
1H NMR(400MHz,DMSO)δ11.83(s,1H),9.88(d,1H),9.09(d,1H),8.25–8.04(m,3H),7.82(dd,2H),7.73–7.65(m,1H),7.54(ddd,4H),7.37(dd,3H),7.18(dd,1H),6.17(d,1H),5.10(d,1H),4.73(dd,2H),3.15–2.88(m,5H),2.14(d,2H),1.82–1.44(m,7H),0.88–0.76(m,2H).
MS m/z＝663.11[M+H]+。
Example 26: synthesis of N-6- (5- (((S) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (cyclopropylcarboxamido) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carbonyl) -L-lysine (Compound 26)
Figure BDA0003030534450000471
The first step is as follows: n is a radical of2- (tert-butyloxycarbonyl) -N6Synthesis of methyl (5- (((S) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (cyclopropylcarboxamide) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carbonyl) -L-lysine ester (30a)
Mixing Compound 3(219mg, 0.36mmol) with N2- (tert-Butoxycarbonyl) -L-lysine methyl ester (94mg, 0.36mmol), HOBT (97mg, 0.72mmol), EDCI (138mg, 0.72mmol) and DIEA (140mg, 1.08mmol) were dissolved in DMF (10mL), reacted at room temperature for 12h with stirring, water and ethyl acetate were added, extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated to precipitate a solid. Filtering, drying at 45 ℃ for 3h to obtain a compound 30 a.
In the second step of this example, a similar procedure to the second step of example 8 was conducted to give the title compound 26.
1H-NMR(400MHz,DMSO-d6):δ11.83(s,1H),10.10(s,1H),9.06(d,1H),8.60(t,1H),8.17(s,2H)7.86(d,1H),7.78(d,1H),7.68(d,1H),7.54(d,2H),7.46(d,2H),7.34(dd,1H),7.25(d,2H),6.32(s,1H),4.02(q,2H),1.97(s,2H),1.73(d,5H),1.59–1.33(m,6H),1.16(t,2H),0.74(d,5H).
MS m/z＝735.18[M+1]
Example 27: synthesis of (5- (((S) -1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (cyclopropylcarboxamido) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carbonyl) -L-lysine (Compound 27)
Figure BDA0003030534450000481
In the first step of this example, N is used6- (tert-Butoxycarbonyl) -L-lysine methyl ester instead of N in the first step of example 262- (tert-Butoxycarbonyl) -L-lysine methyl ester, the title compound 27 was obtained in a similar manner to example 26.
1H-NMR(400MHz,DMSO-d6):δ12.75(s,1H),11.76(d,1H),10.06(d,1H),9.09(d,1H),8.84–8.65(m,1H),7.95–7.76(m,2H),7.67(t,2H),7.54(d,1H),7.46(d,2H),7.37–7.30(m,2H),7.25(d,J＝7.8Hz,2H),6.32(s,1H),5.23–4.50(m,4H),2.77(t,3H),2.17–1.66(m,4H),1.47(dq,6H),0.74(dt,5H).
MS m/z＝735.26[M+1]
Example 28: synthesis of (S) - (5- ((1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino) -3- (4- (cyclopropylcarboxamide) phenyl) -1-oxopropan-2-yl) carbamoyl) thiophene-2-carbonyl) glycine (Compound 28)
Figure BDA0003030534450000491
In the first step of this example, methyl glycinate was used instead of N in the first step of example 262- (tert-butyloxycarbonyl) -L-lysine methyl ester, intermediate 32a was obtained in a similar manner to example 26.
In the second step of this example, compound 28 was obtained in the same manner as in the second step of example 3.
1H-NMR(400MHz,DMSO-d6):δ11.84(s,1H),10.07(d,1H),9.10(d,1H),8.94–8.66(m,1H),7.89(d,1H),7.79(d,1H),7.74(d,1H),7.55(dd,1H),7.47(d,2H),7.35(dd,2H),7.25(dd,2H),6.34(s,1H),5.24–4.79(m,3H),4.72(s,2H),3.83(dd,3H),1.41–1.16(m,2H),0.92–0.60(m,5H).
MS m/z＝664.10[M+1]
Example 29: synthesis of (S) -N- (1- (((6-chloro-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) (methyl) amino-3- (4- (cyclopropylcarboxamide) phenyl) -1-oxopropan-2-yl) -5- (4-methylpiperazine-1-carbonyl) thiophene-2-carboxamide (Compound 29)
Figure BDA0003030534450000501
In the first step of this example, 1-methylpiperazine was used instead of N in the first step of example 262- (tert-Butoxycarbonyl) -L-lysine methyl ester, the title compound 29 was obtained in a similar manner to example 26.
1H-NMR(400MHz,DMSO-d6):δ11.84(s,1H),10.07(d,1H),9.11(d,1H),7.88(d,1H),7.79(d,1H),7.60–7.51(m,2H),7.47(d,2H),7.40–7.32(m,2H),7.26(d,1H),6.33(s,1H),5.08(q,J＝7.7Hz,1H),4.72(s,2H),3.60(t,5H),2.33(t,5H),2.20(s,4H),1.24(s,2H),0.77(s,5H).
MS m/z＝689.24[M+1]
Comparative example 1: synthesis of control Compound 1 (Compound 13 in the PLOS ONE | DOI:10.1371/journal. bone.0113705 literature)
Figure BDA0003030534450000511
Control compound 1 was synthesized according to the procedure of this document.
Test example:
test example 1 inhibition of in vitro enzyme Activity of F XI a by Compounds
The following method was used to determine the inhibitory effect of the compounds on the activity of human F XI a in vitro.
The F xia enzyme was purchased from: haematologic Technologies.
BIOPHEN CS-21(66) activated protein C substrates were purchased from: HYPHEN BioMed.
Solution preparation: reaction buffer: 0.05M Tris, 0.3M NaCl, pH 7.4, Tris606mg, NaCl 1753mg, plus ddH2O80 mL, pH 7.4 adjusted with HCl, to 100 mL.
BIOPHEN CS-21(66) ACTIVATED PROTEIN C SUBSTRATE stock (10mM) A BIOPHEN CS-21(66) ACTIVATED PROTEIN C substrate (25mg) was dissolved in 5mL of sterile deionized water, stored at 4 ℃ and protected from light.
BIOPHEN CS-21(66) activated protein C substrate working solution: the reaction buffer was diluted 4-fold before use.
F XI a working solution: the stock solution was stored at-20 ℃ in a frozen state at a concentration of 50. mu.g/ml and diluted 1000-fold immediately before use.
The method comprises the following steps: adding 15 mu L of test sample solution (15 mu L of LDMSO is added in a control group), 15 mu L of FXIa working solution and 100 mu L of buffer solution into a 96-well plate, uniformly mixing, incubating for 5 minutes at 37 ℃, adding 20 mu L of CS-21(66) substrate working solution, starting reaction, measuring an absorbance value at 405nm, measuring once every 5 minutes, carrying out linear regression analysis on a signal value-time in a linear reaction period, and calculating the slope as the reaction rate. The enzyme activity inhibition rate was calculated according to the following formula.
Inhibition ratio%0-Vi)/V0 x100％
In the formula: v0As the reaction rate of a control well (no test compound added, same volume of DMSO was used instead), ViIs the reaction rate of the test compound.
The results are shown in Table 1.
TABLE 1 in vitro assay of F XI a enzyme Activity
Figure BDA0003030534450000531
Figure BDA0003030534450000541
Note that: a.937nM, F XI a inhibition 47.7%; b.937nM, F XI a inhibiting rate 14.7%
As can be seen from Table 1, the compounds of the present invention have a significant FXIa inhibitory effect.
Test example 2 Effect of Compounds on in vitro coagulation
Reagent: the aPTT reagent was purchased from mad pacific (tianjin) biotechnology limited.
The coagulation pathway includes the extrinsic coagulation pathway and the intrinsic coagulation pathway. The parameter associated with the extrinsic coagulation pathway is prothrombin time, expressed as pt (prothrombin time); the parameter associated with the intrinsic coagulation pathway is the activated partial thromboplastin time, expressed as aPTT (activated partial thromboplastin time).
aPTT (activated partial thromboplastin time) detection method:
after anticoagulation of rabbit blood, plasma is centrifugally separated and equally divided into a plurality of parts, a compound to be detected is added to ensure that the final concentration of the compound to be detected is 0.83-13.32 mu M, the mixture is evenly mixed and incubated at 37 ℃, and then a sample is put into a coagulation analyzer for aPTT detection. Equal volume of solvent DMSO was added to the blank plasma and the aPTT values of the samples and the blank plasma were recorded. The aPTT value is used for carrying out linear regression on the corresponding concentration of the sample, and the regression equation is used for calculating the time for prolonging the aPTT of the tested sample by one time relative to the blank sample, and the result is shown in Table 2.
TABLE 2 Effect of Compound 1 on Rabbit aPTT
Figure BDA0003030534450000551
Figure BDA0003030534450000561
Note: aPTT ED2x: concentration doubling of aPTT relative to blank sample
As can be seen from Table 2, the compounds of the present invention have a significant aPTT protracting effect, indicating that the compounds of the present invention achieve an anti-intrinsic coagulation effect by inhibiting FXIa.
Test example 3 solubility test
Weighing a certain amount of the compound ground into fine powder, adding the compound into a conical flask with a plug, adding a buffer solution with a certain volume and a pH value of 8.0 at 25 +/-2 ℃, and strongly shaking for 30 seconds every 5 minutes; observing the dissolution within 30 minutes, i.e. no visible solute particles or droplets are present, i.e. complete dissolution is considered; if the dissolution can not be completed, a certain volume of buffer solution with pH value of 8.0 is added, and the above operations are repeated until the dissolution is completed. The test results are shown in Table 3.
TABLE 3 solubility of Compounds in pH 8.0 buffer
Figure BDA0003030534450000562
Figure BDA0003030534450000571
As can be seen from Table 3, the solubility of the compound of the present invention in the buffer solution at pH 8.0 was good, exceeding the solubility of the control compound 1 by 500 times or more. The invention has higher solubility, is beneficial to the development of pharmaceutical preparations and better administration, and is very beneficial to the absorption of medicaments.

Claims (9)

1. A compound having the structure of formula (I):
Figure FDA0003030534440000011
wherein R is1Is selected from-CHR4R5、-(CH2)qCH(NH2)CO2H、-CH2R8、
Figure FDA0003030534440000012
Figure FDA0003030534440000013
R2Selected from H, C1-6An alkyl group;
R3is selected from-OR11、-OCH2OC(O)OCH2CH3、-NHR12、
Figure FDA0003030534440000014
R4Is selected from-NH2、-NHCH3、-NHCH2CH3、-NHCH(CH3)2、-NHCH(CH3)CH2CH3、-NHC(CH3)3；
R5Selected from H, C1-6Alkyl, -CH2CO2H、-(CH2)2CO2H；
R6Is selected from-NH2、-NHCH3、-NHCH2CH3、-NHCH(CH3)2、-NHC(CH3)3、-NHCH(CH3)CH2CH3、-CH2NH2、-CH2NHCH3、-CH2NHCH2CH3、-CH2NHCH(CH3)2、-CH2NHC(CH3)3、-CH2NHCH(CH3)CH2CH3、-N(CH3)2、-CH2N(CH3)2；
R7Is selected from-NH2、-NHCH3、-NHCH2CH3、-NHCH(CH3)2、-NHC(CH3)3、-NHCH(CH3)CH2CH3、-N(CH3)2；
R8Is selected from
Figure FDA0003030534440000021
-NR9R10；
R9And R10Each independently selected from C1-6An alkyl group;
R11selected from H, C1-6Alkyl and C3-6A cycloalkyl group;
R12selected from H, -CH2CO2H、-CH(CH3)CO2H、-CH(CH(CH3)2)CO2H、-(CH2)4CH(NH2)CO2H、-CH(CO2H)(CH2)4NH2、-CH(CH2CH(CH3)2)CO2H、-CH(CH(CH3)CH2CH3)CO2H；
W is selected from-CH2-、-NH-、-N(CH3)-、-N(CH2CH3)-、-N(CH2CH(CH3)2)-、-N(CH(CH3)2)-、-N(C(CH3)3)-、-NH(CH(CH3)CH2CH3)-；
X is selected from O, S, N;
y is selected from C, N;
z is selected from C;
a is selected from-CH2-、O、-NH-、-N(CH3)-、-N(CH2CH3)-、-N(CH(CH3)2)-、-N(C(CH3)3)-、-N(CH2CH(CH3)2)-、-NH(CH(CH3)CH2CH3)-；
i is selected from 1,2, 3 and 4;
m, p and q are each independently selected from 1 and 2.
2. The compound according to claim 1, wherein:
R1is selected from-CHR4R5、-(CH2)qCH(NH2)CO2H、-CH2R8、
Figure FDA0003030534440000022
Figure FDA0003030534440000023
R2Selected from H, C1-3An alkyl group;
R3is selected from-OR11、-NHR12、
Figure FDA0003030534440000031
R4Is selected from-NH2、-NHCH3；
R5Selected from H, C1-4Alkyl, -CH2CO2H、-(CH2)2CO2H；
R6Is selected from-NH2、-NHCH3；
R7Is selected from-NH2、-NHCH3；
R8Is selected from
Figure FDA0003030534440000032
-NR9R10；
R9And R10Each independently selected from C1-3An alkyl group;
R11selected from H, C1-6Alkyl groups of (a);
R12selected from H, -CH2CO2H、-CH(CH3)CO2H、-CH(CH(CH3)2)CO2H、-(CH2)4CH(NH2)CO2H、-CH(CO2H)(CH2)4NH2、-CH(CH2CH(CH3)2)CO2H、-CH(CH(CH3)CH2CH3)CO2H；
W is selected from-CH2-、-NH-、-N(CH3)-；
X is selected from O, N;
y is selected from C, N;
z is selected from C;
a is selected from-CH2-、O、-NH-、-N(CH3)-；
i is selected from 1,2, 3 and 4;
m, p and q are each independently selected from 1 and 2.
3. The compound according to any one of claims 1-2, wherein:
R1is selected from-CHR4R5、-(CH2)qCH(NH2)CO2H、-CH2R8、
Figure FDA0003030534440000033
Figure FDA0003030534440000041
R2Selected from H, -CH3；
R3Is selected from-OR11、-NHR12、
Figure FDA0003030534440000042
R4Is selected from-NH2；
R5Selected from H, -CH3、-CH(CH3)2、-CH(CH3)CH2CH3、-CH2CO2H、-(CH2)2CO2H；
R6Is selected from-NH2；
R7Is selected from-NH2；
R8Is selected from
Figure FDA0003030534440000043
-NR9R10；
R9And R10Each independently selected from-CH3；
R11Selected from H, -CH3；
R12Selected from H, -CH2CO2H、-(CH2)4CH(NH2)CO2H、-CH(CO2H)(CH2)4NH2；
W is selected from-CH2-、-NH-、-N(CH3)-；
X is selected from O, N;
y is selected from C, N;
z is selected from C;
a is selected from-CH2-、O；
i is selected from 1,2, 3 and 4;
m, p and q are each independently selected from 1 and 2.
4. A compound according to any one of claims 1 to 3, selected from the following compounds:
Figure FDA0003030534440000051
Figure FDA0003030534440000061
Figure FDA0003030534440000071
5. a process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 4, comprising the steps of:
Figure FDA0003030534440000072
(1) reacting the compound A with the compound B, and then removing a protecting group to obtain a compound C;
(2) reacting the compound C with the compound D to obtain a compound E;
(3) reducing the compound E to obtain a compound F;
(4) reacting the compound F with a corresponding reagent, and removing a protecting group to obtain a partial compound shown in the formula (I), or directly reacting the compound F with the corresponding reagent to obtain the partial compound shown in the formula (I);
wherein R is1、R2、R3X, Y, Z ofAs defined in any one of claims 1 to 4.
6. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 4, comprising the steps of:
Figure FDA0003030534440000081
(1) reacting the compound A with the compound B, and then removing a protecting group to obtain a compound C;
(2) reacting the compound C with a compound G to obtain a compound H;
(3) reducing the compound H to obtain a compound I;
(4) reacting the compound I with a corresponding reagent to obtain a compound J;
(5) removing a protecting group of the compound J to obtain a compound K;
(6) reacting the compound K with a corresponding reagent, and then removing a corresponding protecting group to obtain a partial compound shown in the formula (I), or directly reacting the compound K with the corresponding reagent to obtain the partial compound shown in the formula (I);
wherein R is1、R2、R3X, Y, Z are as defined in any one of claims 1 to 4.
7. The use of a compound of formula (i) as claimed in any one of claims 1 to 4 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prophylaxis and/or treatment of thromboembolic disorders and/or thromboembolic complications.
8. A pharmaceutical composition comprising a compound of formula (i) as claimed in any one of claims 1 to 4 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or excipient.
9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is a solid oral formulation, a liquid oral formulation or an injection; preferably, the solid oral formulation is a tablet, capsule or granule; the liquid oral preparation is syrup or oral solution; and/or the injection is water injection for injection, powder injection for injection or small infusion.
CN202110428580.4A 2020-04-29 2021-04-21 Compound containing thiophene structure and application thereof in medicine Withdrawn CN113563320A (en)

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