CN110272436A - Deuterated imidazo thiadiazoles derivative and its medical usage - Google Patents
Deuterated imidazo thiadiazoles derivative and its medical usage Download PDFInfo
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- CN110272436A CN110272436A CN201810227661.6A CN201810227661A CN110272436A CN 110272436 A CN110272436 A CN 110272436A CN 201810227661 A CN201810227661 A CN 201810227661A CN 110272436 A CN110272436 A CN 110272436A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
The present invention relates to imidazo thiadiazoles derivative deuterated shown in formula (I) or its pharmaceutically acceptable salts or ester or solvate.The compound of the present invention can be used for preparing prevention or treat the drug of thromboembolic disorders.
Description
Technical field
The present invention relates to deuterated imidazo thiadiazoles derivative or its pharmaceutically acceptable salts or ester or solvate.
The compounds of this invention can be used for preparing prevention or treat the drug of thromboembolic disorders.
Background technique
The receptor 4 (PAR4) of blood platelet albumen enzyme activation is by thrombin activation in thrombus sprawling and pathologic vessels embolism
In play an important role.PAR4 antagonist has potential effectiveness in terms for the treatment of and preventing thrombotic disease.It is preclinical dynamic
Arteries and veins thrombotic model shows that effectiveness is more than existing antithrombotic reagent (such as aspirin, clopidogrel, vorapaxar)
By force, but bleeding risk is lower.BMS-986120 is that the one kind disclosed in 2013/163279 A of WO did a phase clinical evaluation
Imidazo thiadiazoles derivative, it is the antagonist of PAR4 a kind of, platelet aggregation can be inhibited, thus be expected to inhibit blood
The formation of bolt.The inventors discovered that, BMS-986120 is in aqueous solution and unstable in practical study, places under room temperature
6h or so, which is easy for going bad, leads to active reduction, this may be caused by the structure of methoxy-substituted imidazo thiadiazoles
's.This may also further influence its metabolic stability in vivo.
Therefore, there is still a need for the PAR4 antagonists that exploitation has more preferable physicochemical property and pharmacokinetics performance for this field.
On the other hand, by deuterate, this technology is possible to the physicochemical property that can change drug and its generation in organism
It thanks to behavior, and then improves the chemical stability and its drug concentration in vivo of drug, to improve curative effect of medication.
Summary of the invention
Novel there is PAR4 antagonistic activity and more preferable pharmacodynamics, pharmacokinetics performance it is an object of the invention to provide a kind of
Compound and application thereof.
In the first aspect of the present invention, provide a kind of imidazo thiadiazoles derivative deuterated shown in formula (I) or its
Pharmaceutically acceptable salt or ester or solvate:
In formula:
L is O or S
R1Independently selected from:
Halogen；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；
Not deuterated, one or many deuterated or complete deuterated C2-C3 alkenyl；
Not deuterated, one or many deuterated or complete deuterated C2-C3 alkynyl；
Not deuterated, one or many deuterated or complete deuterated C3-C4 naphthenic base；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkoxy；
Not deuterated, one or many deuterated or complete deuterated C1-C2 alkoxy -C 1-C2 alkyl；
Not deuterated, one or many deuterated or complete deuterated tetrahydrofuran -2- base；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl sulfenyl；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl NH-；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl ND-；
(not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl)2N-；
Halogenated-C1-C2 alkyl contains 1~5 halogen, wherein halogen be F or Cl, C1-C2 alkyl be it is not deuterated,
One or many deuterated C1-C2 alkyl；
Halogenated-C3-C4 naphthenic base, wherein C3-C4 naphthenic base is not deuterated, one or many deuterated C3-C4 cycloalkanes
Base；
Halogenated-C1-C2 alkoxy, wherein C1-C2 alkoxy is not deuterated, one or many deuterated C1-C2 alcoxyls
Base；
Halogenated-C1-C2 alkyl sulfenyl, wherein C1-C2 alkyl sulfenyl is not deuterated, one or many deuterated C1-C2
Alkyl sulfenyl；
R2It is selected from:
H；Deuterium；Halogen；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkoxy；
Cyano；
X1Selected from CH, CD, N or CR1；
X2、X3And X4Independently selected from CR3Or N；
R3It is selected from: H；Deuterium；Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；It is not deuterated, one
Secondary or multiple deuterated or complete deuterated C2-C4 alkenyl；Not deuterated, one or many deuterated or complete deuterated C2-C4 alkynes
Base；Not deuterated, one or many deuterated or complete deuterated C1-C4 alkoxy；It is not deuterated, one or many deuterated or
Complete deuterated C1-C4 alkyl sulfenyl；Halogen；OH；OD；CN；OCF3；OCHF2；OCDF2；OCH2F；OCHDF；OCD2F；It is not deuterated
, one or many deuterated or complete deuterated C1-C2- alkoxy -C 1-C2- alkoxy；Halogenated-C1-C3- alkyl, contains
1~5 halogen, C1-C3- alkyl are not deuterated, one or many deuterated C1-C3- alkyl；Benzyl oxygroup, by 0~
5 independently selected from deuterium or 0~3 independently selected from halogen, not deuterated, one or many deuterated or complete deuterated C1-
It is C4 alkoxy, not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl, not deuterated, one or many deuterated
Or complete deuterated cyclopropyl, CF3、OCF3, 5 or 6 yuan heteroaryl, OH, OD, OCHF2、OCDF2, it is two (not deuterated, primary
Or repeatedly deuterated or complete deuterated-C1-C4- alkyl) group of amino and cyano replaces；With-(CH2) n- phenyl, by 0
~5 independently selected from deuterium or 0~3 independently selected from halogen, it is not deuterated, one or many deuterated or complete deuterated
It is C1-C4 alkoxy, not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl, not deuterated, one or many
Deuterated or complete deuterated cyclopropyl, CF3、OCF3, 5 or 6 yuan heteroaryl, OH, OD, OCHF2、OCDF2, two (it is not deuterated,
One or many deuterated or complete deuterated C1-C4- alkyl) group of amino and cyano replaces；
R4And R5Independently selected from:
H；Deuterium；
Not deuterated, one or many deuterated or complete deuterated C1-C6 alkyl；
Or R4And R5It can be formed together with carbon connected to them not deuterated, one or many deuterated or complete deuterated
C3-C7 cycloalkyl ring；
A ring is selected from phenyl ring；It can be by single or multiple R6Substituted phenyl ring；Heteroaryl comprising at least one O, N or S atom
Ring；It can be by single or multiple R6The heteroaryl ring comprising at least one O, N, S atom replaced；
R6It is selected from: halogen；OCF3；OCHF2；OH；CN；NO2；COOH；C1-C4 alkoxy carbonyl；Substituted amino；Replace
Amide groups；C1-C4 alkyl sulphonyl；Substituted sulfoamido；C1-C5 alkyl, by 0~7 independently selected from halogen,
CF3、OCF3, OH, hydroxyl-C1-C4- alkyl, C1-C4 alkoxy, C1-C4 alkoxy -C 1-C4 alkoxy, two-C1-C4- alkyl
Aminophenyl-C1-C4- alkyl, (two-C1-C4- alkoxy -C 1-C4- alkyl)-C1-C4- alkyl, C3-C6- naphthenic base and
The group of C1-C4 alkyl sulfenyl replaces；It is unsubstituted or can substituted C6-C10 aryl, unsubstituted or can substituted 5
To 10 yuan of heteroaryls, it is unsubstituted or can be substituted 4 to 10 yuan heterocycle, unsubstituted or can substituted C3-C6
It is naphthenic base, unsubstituted or can substituted C5-C11 spiro cycloalkyl group；
Additional conditions are R1、R2、R3、R4、R5、R6In at least one be deuterated or deuterium.
In another embodiment, compound is characterized in that:
R1Independently selected from:
Halogen；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkoxy；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl sulfenyl；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl NH-；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl ND-；
(not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl)2N-；
Halogenated-C1-C2 alkoxy, wherein C1-C2 alkoxy is not deuterated, one or many deuterated C1-C2 alcoxyls
Base；
Halogenated-C1-C2 alkyl sulfenyl, wherein C1-C2 alkyl sulfenyl is not deuterated, one or many deuterated C1-C2
Alkyl sulfenyl；
R2It is selected from:
H；Deuterium；Halogen；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；
Cyano；
X1Selected from CH, CD, N；
X2Selected from CH or CD；
X3It is CR3；
R3It is selected from: H；Deuterium；Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；It is not deuterated, one
Secondary or multiple deuterated or complete deuterated C1-C4 alkoxy；Not deuterated, one or many deuterated or complete deuterated C1-C4
Alkyl sulfenyl；Halogen；OH；OD；CN；OCF3；OCHF2；OCDF2；OCH2F；OCHDF；OCD2F；Not deuterated, one or many deuteriums
Generation or complete deuterated C1-C2- alkoxy -C 1-C2- alkoxy；Halogenated-C1-C3- alkyl contains 1~5 halogen, C1-
C3- alkyl is not deuterated, one or many deuterated C1-C3- alkyl；
X4Selected from CH or CD；
R4And R5Independently selected from:
H；Deuterium；
Not deuterated, one or many deuterated or complete deuterated C1-C6 alkyl,
Or R4And R5It can be formed together with carbon connected to them not deuterated, one or many deuterated or complete deuterated
C3-C7 cycloalkyl ring；
A ring is selected from phenyl ring；It can be by single or multiple R6Substituted phenyl ring；It can be by single or multiple R6Substituted thiazole；
R6It is selected from: halogen；OCF3；OCHF2；OH；CN；COOH；C1-C4 alkoxy carbonyl；Substituted amino；Substituted acyl
Amido；C1-C4 alkyl sulphonyl；Substituted sulfoamido；C1-C5 alkyl, by 0~7 independently selected from halogen, CF3、
OCF3, OH, hydroxyl-C1-C4- alkyl, C1-C4 alkoxy, C1-C4 alkoxy -C 1-C4 alkoxy, two-C1-C4- alkyl aminos
Phenyl-C1-C4- alkyl, (two-C1-C4- alkoxy -C 1-C4- alkyl)-C1-C4- alkyl, C3-C6- naphthenic base and C1-C4
The group of alkyl sulfenyl replaces；It is unsubstituted or can be substituted 4 to 10 yuan heterocycle, unsubstituted or can be substituted
It is C3-C6 naphthenic base, unsubstituted or can substituted C5-C11 spiro cycloalkyl group；
Additional conditions are R1、R2、R3、R4、R5、R6In at least one be deuterated or deuterium.
In another preferred example, deuterium is at least greater than natural deuterium isotopic content in the deuterium isotopic content of deuterium the position of substitution
(0.015%), it is preferably greater than 30%, even more preferably greater than 50%, even more preferably greater than 80%, even more preferably greater than 95%, more preferably
Greater than 99%.
In another preferred example, formula (I) compound at least contains 1 D-atom, more preferably 3 D-atoms, more preferably 5
D-atom, more preferably 7 D-atoms, more preferably 8 D-atoms, more preferably 9 D-atoms, more preferably 11 D-atoms.
In another preferred example, R1It is independently selected from deuterated methoxyl group, deuterated methyl mercapto；More preferably, three are selected from
Deuterium methoxyl group, three deuterium methyl mercaptos.
In another preferred example, X3Independently selected from the deuterated methyl mercapto of C- deuterated methoxyl group, C-；More preferably, it is selected from
Tri- deuterium methoxyl group of C-, tri- deuterium methyl mercapto of C-.
In another preferred example, R4And R5The two independently is deuterium；More preferably, R4For deuterium, R5For deuterium, R4And R5It is deuterium.
In another embodiment, the preferred compound of the present invention is as shown in table 1.
The structure and name of table 1, preferred compound
In the second aspect of the present invention, the compounds of this invention or its pharmaceutically acceptable salt or ester or solvation are provided
Purposes of the object in the drug that preparation prevents and treats thromboembolic disorders.
The thromboembolic disorders include but is not limited to: acute coronary syndrome, unstable angina pectoris,
It is the raised myocardial infarction of stable angina cordis, ST-, non-ST- Elevation Myocardial Infarction, atrial fibrillation, myocardial infarction, of short duration
Property cerebral ischemia attack, apoplexy, atherosclerosis, peripheral arterial disease, venous thronbosis, Deep vain thrombosis, thrombus
Property phlebitis, arterial embolism, coronary artery thrombosis formation, cerebral artery thrombosis formation, cerebral embolism, renal embolism, pulmonary embolism, cancer phase
The thrombosis of pass and because of medical implant, device and wherein blood is exposed to artificial surface to promote the operation of thrombosis
Thrombosis caused by program.
In the third aspect of the present invention, a kind of pharmaceutical composition is provided, wherein the present invention the containing therapeutically effective amount
Any compound or its pharmaceutically acceptable salt or ester or solvate are as active constituent and pharmacy in one side
Upper acceptable carrier.
The pharmaceutically acceptable salt refers to that the compounds of this invention and acid or alkali are formed by the salt for being suitable as drug.
Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the salt that the compounds of this invention and acid are formed.It is suitable
The acid for closing forming salt includes but is not limited to: galactosaccharic acid, D- glucuronic acid, phosphoglycerol, hippuric acid, isethionic acid, cream
Saccharic acid, maleic acid, 1,5- naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, neopentanoic acid, terephthalic acid (TPA), thiocyanic acid, cholic acid, dodecyl sulphur
Acid, benzene sulfonic acid, citric acid, D-Glucose, glycolic, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulphur
Acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, Loprazolam, niacin, nitric acid, orotic acid, oxalic acid, picric acid, L-
Pyroglutamic acid, saccharinic acid, salicylic acid, gentianic acid, p-methyl benzenesulfonic acid, valeric acid, palmitinic acid, sebacic acid, stearic acid, lauric acid, second
Acid, adipic acid, carbonic acid, 4- benzene sulfonic acid, ethane disulfonic acid, ethylsuccinic acid, fumaric acid, 3- hydroxyl naphthalene -2- formic acid, 1- hydroxyl
Naphthalene -2- formic acid, oleic acid, undecenoic acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, ethane sulfonic acid and asparagus fern
The acidic amino acids such as propylhomoserin, glutamic acid.
The pharmaceutical composition be capsule, powder, tablet, granule, pill, injection, syrup, oral solution,
Conventional dosage form on the galenic pharmacies such as inhalant, ointment, suppository or patch.
The compound of the present invention can also with the Drug combinations of other treatment thromboembolic disorders, they include but
It is not limited to: medicament for resisting platelet aggregation, such as Abciximab, eptifibatide, tirofiban, clopidogrel, prasugrel, thiophene chlorine
Pyridine, cangrelor, according to promise Gray, ticagrelor, beraprost sodium, prostacyclin, iloprost, treprostinil, Ah
Take charge of a woods, Aloxiprin, carbasalate calcium, Indobufen, Triflusal, Dipyridamole, picotamide, Terutroban, western Lip river
His azoles, cloricromen or ditazole；Anticoagulant, such as acenocoumarol, bicoumarin, tromexan, phenylpropyl alcohol
Hydroxycoumarin, clorindione, diphenadione, phenindione, Tioclomarol, bemiparin, certoparin, reaches warfarin
Heparin, nadroparin, parnaparin, reviparin, tinzaparin, Fondaparinux sodium, Ai Zhuo heparin, danaparoid, relaxes at Enoxaparin
Lip river Di Te, dermatan sulfate, Eliquis, betrixaban, Yi Dushaban, otamixaban, razaxaban, bivalirudin, next
Lu Ding, hirudin, argatroban, dabigatran, melagatran, ximelagatran, go fine glycosides, Leimaquban, antithrombase or
Drotrecogin alfa；Thrombolytic agent, as Alteplase, Reteplase, Tenecteplase, urokinase, Saruplase, chain swash
Enzyme, Anistreplase, Monteplase, ancrod, fibrinolysin or plasmase.
The preparation method of the compounds of this invention is referring to embodiment.
Detailed description of the invention:
The platelet aggregation activity of the anti-AYP induction of Fig. 1 Compound ira vitro；
The nuclear magnetic resonance spectroscopy of Fig. 2 compound 2；
The nuclear magnetic resonance spectroscopy of Fig. 3 compound 3；
The nuclear magnetic resonance spectroscopy of Fig. 4 compound 5；
The nuclear magnetic resonance spectroscopy of Fig. 5 compound 6；
The nuclear magnetic resonance spectroscopy of Fig. 6 compound 8；
The nuclear magnetic resonance spectroscopy of Fig. 7 compound 9；
The nuclear magnetic resonance spectroscopy of Fig. 8 compound 10.
Specific embodiment
The contents of the present invention are illustrated below by embodiment.In the present invention, embodiments discussed below be in order to
It preferably illustrates the present invention, is not for limiting the scope of the invention.Under the premise of without departing substantially from the spirit and scope of the present invention,
Various change and modification can be carried out to the present invention.
Embodiment 1
6- (4- (benzyloxy) -6- (three deuterium methoxyl groups) benzofuran -2- base) -2- methoxyl group imidazo [2,1-b] [1,3,
4] thiadiazoles (compound 1)
Under Ar atmosphere, phloroglucin (3g, 0.024mol) is dissolved in anhydrous DMF (30mL), is slowly added dropwise at 0 DEG C
Phosphorus oxychloride (2.2mL, 0.024mol) after finishing, is warmed to room temperature stirring 4 hours.After reaction, reaction solution is poured into ice
It is quenched, with mixed solvent, (methylene chloride: methanol=10: 1) extracting, after concentration, dissolved with ethyl acetate, then repeatedly with saturation
Saline solution and 20%LiCl solution wash remaining DMF, evaporated under reduced pressure solvent, through rapid column chromatography (petroleum ether: ethyl acetate
=2: 1), obtaining compound 1-1 (white solid, 2.9g), yield 80%.1H NMR (300MHz, DMSO) δ 11.46 (s, 2H),
10.65 (s, 1H), 9.93 (s, 1H), 5.79 (s, 2H)
Under Ar protection, it is anhydrous that 2,4,6- tri hydroxybenzaldehydes (compound 1-1) (0.30g, 1.95mmol) are dissolved in 6mL
Acetonitrile is slowly added dropwise at 0 DEG C into reaction solution triethylamine (0.57mL, 4.07mmol), keeps temperature-resistant, delays into system
The slow anhydrous acetonitrile that chloromethyl methyl ether (4.07mmol) is added dropwise after finishing, stirs 80mins at 0 DEG C, and TLC detects raw material
It is exhausted, 15mL ice water is added and is quenched, ethyl acetate (5mLx3) aqueous phase extracted merges organic phase, by organic phase saturation food
Salt water washing, anhydrous sodium sulfate are dry, are evaporated organic phase and obtain crude product, through rapid column chromatography (petroleum ether: ethyl acetate=10: 1),
Obtain compound 1-2 (white solid, 0.28g), yield 60%.1H NMR (300MHz, DMSO) δ 12.17 (s, 1H), 10.10
(s, 1H), 6.29 (d, J=1.8Hz, 1H), 6.20 (d, J=1.8Hz, 1H), 5.31 (s, 2H), 5.26 (s, 2H), 3.44 (s,
3H), 3.39 (s, 3H)
By bis- (methoxy methoxy base) benzaldehydes (compound 1-2) (0.12g, 0.50mmol) of 2- hydroxyl -4,6- and anhydrous carbon
Sour potassium (0.14g, 1.0mmol) is added in 3mL anhydrous DMF, under stirring at room temperature, cylite is added into reaction solution
(0.07mL, 0.55mmol), is stirred at room temperature 4h, and reaction system carries out under Ar gas shielded.TLC detection consumption of raw materials finishes, and adds
Entering 10mL ice water to be quenched, ethyl acetate (3mLx3) aqueous phase extracted, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry,
Be evaporated organic phase and obtain crude product, through rapid column chromatography (petroleum ether: ethyl acetate=4: 1), obtain compound 1-3 (white solid,
0.15g), yield 92%.
Bis- (methoxy methoxy base) benzaldehydes (compound 1-3) (0.18g, 0.53mmol) of 2- (benzyloxy) -4,6- are dissolved in
In 3mL tetrahydrofuran solution, 0.25mL 6M HCl solution is added.Counterflow condition stirs 3h, and TLC detection consumption of raw materials finishes, adds
Enter 10mL saturation NaHCO3Solution is quenched, ethyl acetate (3mLx3) aqueous phase extracted, merges organic phase, organic phase saturated common salt
Water washing, anhydrous sodium sulfate are dry, are evaporated organic phase and obtain crude product, (petroleum ether: ethyl acetate=4: 1), obtain through rapid column chromatography
To compound 1-4 (white solid, 0.077g), yield 60%.1H NMR (300MHz, DMSO) δ 12.31 (s, 1H), 10.92
(s, 1H), 10.02 (s, 1H), 7.53-7.30 (m, 6H), 6.08 (d, J=1.8Hz, 1H), 5.88 (d, J=1.6Hz, 1H),
5.18 (s, 2H)
Under Ar protection, by 2- (benzyloxy) -4,6- 4-dihydroxy benzaldehyde (compound 1-4) (0.50g, 2.0mmol) and
Triphenylphosphine (0.52g, 2.0mmol) is dissolved in the anhydrous THF of 10mL, and CD is added3OD (0.073mL, 1.80mmol), at 0 DEG C,
Into reaction solution, diisopropyl azodiformate (0.40mL, 2.10mmol) is slowly added dropwise, is slowly increased to be stirred at room temperature after finishing
4h, evaporated under reduced pressure solvent, through rapid column chromatography (petroleum ether: ethyl acetate=40: 1) obtain compound 1-5 (white solid,
0.31g), yield 60%.1H NMR (300MHz, DMSO) δ 12.34 (s, 1H), 10.08 (s, 1H), 7.50-7.32 (m, 5H),
6.26 (d, J=1.6Hz, 1H), 6.11 (d, J=1.5Hz, 1H), 5.23 (s, 2H).
By 2- (benzyloxy) -6- hydroxyl -4- (three deuterium methoxyl groups) benzaldehyde (compound 1-5) (5.11g, 19.79mmol)
It is added in 50mL acetone with Anhydrous potassium carbonate (3.5g, 25.73mmol), is stirred at room temperature down, chlorine third is slowly dropped into reaction solution
Reaction after finishing, is heated at reflux 7h, TLC detects raw material and disappears, and the reaction is cooled to rooms by ketone (1.88mL, 23.75mmol)
Temperature, is removed by filtration potassium carbonate, evaporated under reduced pressure filtrate, (petroleum ether: methylene chloride=1: 2), obtains compound through rapid column chromatography
1-6 (light yellow solid, 5.05g), yield 86%.1H NMR (300MHz, CDCl3) δ 7.57 (s, 1H), 7.50-7.31 (m,
5H), 6.65 (s, 1H), 6.39 (d, J=1.4Hz, 1H), 5.15 (s, 2H), 2.52 (s, 3H).
At room temperature, by 1- (4- (benzyl oxygroup) -6- (three deuterium methoxyl groups) benzofuran -2- base) ethyl ketone (compound 1-6)
(3.3g, 11mmol) is dissolved in 50mL ethyl acetate, and copper bromide (2.953g, 13.24mmol) is added in above-mentioned system later,
6h is maintained the reflux at 80 DEG C.It is cooled to room temperature, filters and filter off solid content, filtrate is concentrated, through rapid column chromatography (petroleum ether: two
Chloromethanes=1: 1) compound 1-7 (buff dope, 1.8g), yield 43% are obtained,.
By 1- (4- (benzyl oxygroup) -6- (three deuterium methoxyl groups) benzofuran -2- base) -2- bromine ethyl ketone (compound 1-7)
Pressure resistance is added in (1.8g, 4.76mmol), 2- amino -5- bromo- 1,3,4- thiadiazoles (1.03g, 5.71mmol) and 20mL isopropanol
In reaction tube, 80 DEG C of stirrings 6h, TLC detect that largely non-cyclised intermediates generate, and reaction temperature is continued to rise to 130 DEG C, is stirred
3h is mixed, is cooled to room temperature after reaction, crude Compound 1-8 is obtained after being directly evaporated, direct plunges into and reacts in next step.
By 6- (4- (benzyl oxygroup) -6- (three deuterium methoxyl groups) benzofuran -2- base) -2- bromine imidazo [2,1- of crude product
B] [1,3,4] thiadiazoles (compound 1-8) be dissolved in methylene chloride (120mL) and methanol (40mL) composition in the mixed solvent, add
1h is stirred at room temperature in the methanol solution for entering 1.8mL 25wt.% sodium methoxide, and TLC detects raw material and disappears, and saturated ammonium chloride solution is added
Quenching reaction, ethyl acetate aqueous phase extracted (30mLx3) merge organic phase, organic phase saturated common salt water washing, anhydrous slufuric acid
Sodium is dry, is evaporated organic phase and obtains crude product, and through rapid column chromatography, (petroleum ether: ethyl acetate=8: 1), obtaining light yellow solid, warp
Petrol ether/ethyl acetate/recrystallize with dichloromethane obtains compound 1 (light yellow solid, 630mg), the last two steps yield 32%.1H
NMR (300MHz, CDCl3) δ 7.81 (s, 1H), 7.50-7.28 (m, 5H), 7.07 (s, 1H), 6.67 (s, 1H), 6.37 (s,
1H), 5.16 (s, 2H), 4.18 (s, 3H) .MS (ESI): m/z 411.1 [M+H]+.
Embodiment 2
4- (4- (((6- (three deuterium methoxyl groups) -2- (2- methoxyl group imidazo [2,1-b] [1,3,4] thiadiazoles -6- base) benzene
And furans -4- base) oxygroup) methyl) -5- methylthiazol -2- base) morpholine (compound 2)
The synthetic method of compound 2-1 is referring to 2013/163279 A1 of patent WO.
(5- methyl -2- morpholinyl thiazole-4-yl) methanol (compound 2-1) (0.25g, 1.16mmol) is dissolved in 5ml
In anhydrous methylene chloride, phosphorus tribromide (60 μ L, 0.58mmol) is dissolved in 1ml methylene chloride at 0 DEG C, is instilled dropwise above-mentioned
It in system, is added dropwise, reacts at room temperature 4h, 10ml saturated sodium bicarbonate solution quenching reaction is added, with methylene chloride extraction water
Phase (5mLx3) merges organic phase, and organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, is evaporated organic phase and obtains crude product,
(petroleum ether: ethyl acetate=8: compound 2-2 (white crystal, 0.145g), yield 45% 1) are obtained through rapid column chromatography.
Under Ar atmosphere, by 6- (4- (benzyl oxygroup) -6- (three deuterium methoxyl groups) benzofuran -2- base) -2- methoxyl group miaow
Simultaneously [2,1-b] [1,3,4] thiadiazoles (compound 1) (0.6g, 1.46mmol) and pentamethylbenzene (1.52g, 10.24mmol) are molten for azoles
In 10mL anhydrous methylene chloride, the CH of (4mL, 3.95mmol) boron chloride is added dropwise under the conditions of -78 DEG C2Cl2Solution,
System stirs 1h under the conditions of being placed in -78 DEG C.Then water (25mL) solution that sodium bicarbonate (1.5g) is added stops reaction.It removes cold
But it bathes, gained mixture is stirred at room temperature 1 hour.It will be formed by solid filtering, successively washed with water and methylene chloride, done
Dry filter cake obtains crude product, then obtains compound 2-3 (light yellow solid, 0.48g), yield with the grinding of 5mL toluene, washing
99%.1H NMR (300MHz, DMSO) δ 9.96 (s, 1H), 8.29 (s, 1H), 6.96 (s, 1H), 6.62 (s, 1H), 6.23 (s,
1H), 4.17 (s, 3H).
By 6- (three deuterium methoxyl groups) -2- (2- methoxyl group imidazo [2,1-b] [1,3,4] thiadiazoles -6- base) benzofuran -
4- alcohol (compound 2-3) (0.08g, 0.25mmol) is dissolved in 5ml anhydrous DMF, is vacuumized and is changed argon gas, and sodium tert-butoxide is added
(0.026g, 0.28mmol), by 4- (4- (bromomethyl) -5- methylthiazol -2- base) morpholine (compound 2-2) (0.076g,
It 0.28mmol) is dissolved in 1ml anhydrous DMF, is added dropwise in above-mentioned system, react 2.5 hours under room temperature.TLC monitoring is anti-
20ml ethyl acetate diluted system should be added completely, successively use water (5mLx2), saturated common salt water washing organic phase, anhydrous slufuric acid
Sodium is dry, through rapid column chromatography (petroleum ether/dichloromethane/ethyl acetate=6: 4: 1), obtain compound 2 (gray solid,
0.049g), yield: 38%.1H NMR (300MHz, CDCl3) δ 7.83 (s, 1H), 7.06 (s, 1H), 6.69 (s, 1H), 6.51
(s, 1H), 5.06 (s, 2H), 4.20 (s, 3H), 3.84-3.78 (m, 4H), 3.47-3.38 (m, 4H), 2.37 (s, 3H) .MS
(ESI): m/z 517.0 [M+H]+.
Embodiment 3
4- (4- (((6- (three deuterium methoxyl groups) -2- (2- methoxyl group imidazo [2,1-b] [1,3,4] thiadiazoles -6- base) benzene
And furans -4- base) oxygroup) methyl-deuterium) -5- methylthiazol -2- base) morpholine (compound 3)
(5- methyl -2- morpholinyl thiazole-4-yl) methanol (compound 2-1) (0.05g, 0.23mmol) is dissolved in 5ml bis-
In chloromethanes solution, pyridine (45 μ L, 0.56mmol) is added, wears this Martin reagent (0.12g, 0.28mmol), reacts at room temperature 2h,
TLC monitoring reaction is basically completed, and is filtered, and methylene chloride washs filter cake, collects filtrate, concentration, rapid column chromatography (petroleum ether: second
Acetoacetic ester=4: 1) compound 3-1 (light cyan solid, 0.032g), yield: 65% are obtained,.
5- methyl -2- morpholinyl thiazole-4-formaldehyde (compound 3-1) (0.187g, 0.88mmol) is dissolved in the deuterated first of 8ml
In alcohol, boron deuterate sodium (0.037g, 0.88mmol) is added at 0 DEG C, room temperature reaction 5h, TLC is kept to monitor after completion of the reaction, add
5ml water quenching reaction, ethyl acetate extract (5mLx3), and saturated common salt water washing organic phase, anhydrous sodium sulfate is dry, depressurize dense
Contracting, rapid column chromatography (petroleum ether: ethyl acetate=1: 3), obtain compound 3-2 (white solid, 0.14g), yield: 74%.
Synthetic method of the synthesis of compound 3-3 referring to compound 2-2 in embodiment 2.
Compound 3 is made referring to the synthetic method of compound 2 in embodiment 2:1H NMR (300MHz, CDCl3) δ 7.83 (s,
1H), 7.06 (s, 1H), 6.69 (s, 1H), 6.51 (s, 1H), 5.06 (s, 1H), 4.20 (s, 3H), 3.84-3.78 (m, 4H),
3.47-3.38 (m, 4H), 2.37 (s, 3H) .MS (ESI): m/z 518.0 [M+H]+.
Embodiment 4
6- (4- (benzyloxy) -6- Methoxvbenzofuran -2- base) -2- (three deuterium methoxyl groups) imidazo [2,1-b] [1,3,
4] thiadiazoles (compound 4)
The synthesis of compound 4 makees deuterium the difference is that change methanol herein referring to the synthetic method of compound 1 in embodiment 1
For methanol as solvent, and the methanol solution of 25wt.% sodium methoxide is changed to the deuterated methanol solution for making 25wt.% deuterated methanol sodium,
Compound 4 is made:1H NMR (300MHz, CDCl3) δ 7.81 (s, 1H), 7.50-7.28 (m, 5H), 7.07 (s, 1H), 6.67 (s,
1H), 6.37 (s, 1H), 5.16 (s, 2H), 3.81 (s, 3H) .MS (ESI): m/z 411.1 [M+H]+.
Embodiment 5
4- (4- (((6- methoxyl group -2- (2- tri- deuterium methoxyl group imidazo [2,1-b] [1,3,4] thiadiazoles -6- base) benzo
Furans -4- base) oxygroup) methyl) -5- methylthiazol -2- base) morpholine (compound 5)
Compound 5 is made referring to the method for embodiment 1,2 and 4:1H NMR (300MHz, CDCl3) δ 7.83 (s, 1H), 7.06
(s, 1H), 6.69 (s, 1H), 6.51 (s, 1H), 5.06 (s, 2H), 3.85 (s, 3H), 3.84-3.78 (m, 4H), 3.47-3.38
(m, 4H), 2.37 (s, 3H) .MS (ESI): m/z 517.1 [M+H]+.
Embodiment 6
4- (4- (((6- methoxyl group -2- (2- tri- deuterium methoxyl group imidazo [2,1-b] [1,3,4] thiadiazoles -6- base) benzo
Furans -4- base) oxygroup) methyl-deuterium) -5- methylthiazol -2- base) morpholine (compound 6)
Compound 6 is made referring to the method for embodiment 1,3 and 4:1H NMR (300MHz, CDCl3) δ 7.83 (s, 1H), 7.06
(s, 1H), 6.69 (s, 1H), 6.51 (s, 1H), 5.06 (s, 1H), 3.85 (s, 3H), 3.84-3.78 (m, 4H), 3.47-3.38
(m, 4H), 2.37 (s, 3H) .MS (ESI): m/z 518.1 [M+H]+.
Embodiment 7
6- (4- (benzyloxy) -6- (three deuterium methoxyl groups) benzofuran -2- base) -2- (three deuterium methoxyl groups) imidazo [2,1-
B] [1,3,4] thiadiazoles (compound 7)
Compound 7 is made referring to the method for embodiment 1 and 4:1H NMR (300MHz, CDCl3) δ 7.81 (s, 1H), 7.50-
7.28 (m, 5H), 7.07 (s, 1H), 6.67 (s, 1H), 6.37 (s, 1H), 5.16 (s, 2H) .MS (ESI): m/z 415.1 [M+H
]+.
Embodiment 8
4- (4- (((6- (three deuterium methoxyl groups) -2- (2- (three deuterium methoxyl groups) imidazo [2,1-b] [1,3,4] thiadiazoles -6-
Base) benzofuran -4- base) oxygroup) methyl) -5- methylthiazol -2- base) morpholine (compound 8)
Compound 8 is made referring to the method for embodiment 1,2 and 4:1H NMR (300MHz, CDCl3) δ 7.83 (s, 1H), 7.06
(s, 1H), 6.69 (s, 1H), 6.51 (s, 1H), 5.06 (s, 2H), 3.84-3.78 (m, 4H), 3.47-3.38 (m, 4H), 2.37
(s, 3H) .MS (ESI): m/z 520.1 [M+H]+.
Embodiment 9
4- (4- (((6- (three deuterium methoxyl groups) -2- (2- (three deuterium methoxyl groups) imidazo [2,1-b] [1,3,4] thiadiazoles -6-
Base) benzofuran -4- base) oxygroup) methyl-deuterium) -5- methylthiazol -2- base) morpholine (compound 9)
Compound 9 is made referring to the method for embodiment 1,3 and 4:1H NMR (300MHz, CDCl3) δ 7.83 (s, 1H), 7.06
(s, 1H), 6.69 (s, 1H), 6.51 (s, 1H), 5.06 (s, 1H), 3.84-3.78 (m, 4H), 3.47-3.38 (m, 4H), 2.37
(s, 3H) .MS (ESI): m/z 521.1 [M+H]+.
Embodiment 10
4- (4- (((6- methoxyl group -2- (2- methoxyl group imidazo [2,1-b] [1,3,4] thiadiazoles -6- base) benzofuran -
4- yl) oxygroup) methyl-deuterium) -5- methylthiazol -2- base) morpholine (compound 10)
Compound 10 is made referring to the method for embodiment 1,3 and 4:1H NMR (300MHz, CDCl3) δ 7.83 (s, 1H),
7.06 (s, 1H), 6.69 (s, 1H), 6.51 (s, 1H), 5.06 (s, 1H), 4.20 (s, 3H), 3.85 (s, 3H), 3.84-3.78
(m, 4H), 3.47-3.38 (m, 4H), 2.37 (s, 3H) .MS (ESI): m/z 515.1 [M+H]+.
Embodiment 11
The platelet aggregation activity test of external anti-AYP induction:
Test philosophy: AYP is the specificity excitement peptide of PAR4, sequence AYPGKF-NH2, activate to the property of can choose
PAR4, causes platelet aggregation, and the compounds of this invention can be with antagonism blood platelet PAR4, to inhibit platelet aggregation.Blood platelet
Aggregation inhibiting rate can reflect the activity of compound.Test uses the filtering blood platelet for being derived from rat aorta blood plasma.
Platelet aggregation measurement: drawing 300 μ L Tyrode ' s buffer and be placed in the zeroing of platelet aggregation instrument test section, then
It draws 270 μ L filtering blood platelet to be placed in pre- heat channel, is separately added into each given the test agent (compound concentration 10nM) of 20 μ L, 37 DEG C
Preheating 5min is placed on test section, and test pearl and 10 μ L AYP are added, and measures the maximum aggregation rate of blood platelet in 5min.It is wherein negative
Property control group be physiological saline.It is calculated by the following formula the aggregation inhibiting rate of blood platelet.Calculation formula: Platelet aggregation inhibitor
Rate=[(X-Y)/X] * 100%, wherein X is physiological saline group maximum platelet aggregation rate, and Y is the aggregation of compound blood platelet maximum
Rate.The experimental result of part of compounds is as shown in Figure 1.
Experimental result (Fig. 1) shows that deuterated imidazo thiadiazoles derivative of the invention has as PAR4 antagonist
The extracorporeal platelet aggregation inhibiting rate of significant platelet aggregation inhibitory activity, especially compound 1,2,3,6,8 and 10 is superior to
Clinic is grinding antiplatelet new drug BMS986120.Therefore, it is poly- to be expected to be developed into more potent antiplatelet for the compounds of this invention
Collect drug.
Embodiment 12
Compound is to people's hepatomicrosome metabolic stability Journal of Sex Research
The evaluation of people's hepatomicrosome metabolic stability is pre-clinical assessment candidate compound pharmacokinetics in medicament research and development
The important means of matter.
Experiment temperature incubates system (volume is 250 μ L, n=3) by hepatomicrosome, tested material working solution and phosphate-buffered
Temperature is incubated system and is incubated for a hour altogether in 37 DEG C by liquid, and timing starts after NADPH solution is added, and each time point is to be added end
Only liquid terminates reaction, and point is 0,5,15,30,60min between sampling, totally 5 points.NADPH is not added in negative control, and sampling time point is
0,60min.It is analyzed with LC-MS/MS, is measured tiltedly by the natural logrithm of the percentage of tested material surplus and time mapping
The absolute value k of rate, is calculated: T as follows1/2(half-life period)=ln2/k=0.693/k；Clint(μL/min/mg
Protein) (clearance rate)=Ln (2) * 1000/T1/2/Protein Conc.Experimental result is as shown in Table 1 and Table 2.
People's hepatomicrosome metabolic half life (T of table 1, compound1/2):
People's hepatomicrosome metabolic clearance rate (Clint) of table 2, compound:
The experimental results showed that the hepatomicrosome metabolic stability of the compounds of this invention is compared with not deuterated BMS-986120
It is improved, T1/2 is increased, and clearance rate Clint decreases.This shows the compounds of this invention using this deuterated strategy
Really its metabolic stability in organism is improved, this is likely to decrease the liver first-pass effect of drug, the display present invention
Compound has be more good pharmacokinetic property.
Embodiment 14
Tablet
By compound 9 (50g) obtained in embodiment 9, hypromellose E (150g), starch (200g), povidone
K30 is appropriate and magnesium stearate (1g) mixes, granulation, tabletting.
Claims (6)
1. deuterated imidazo thiadiazoles derivative or its pharmaceutically acceptable salt or ester or solvent shown in a kind of formula (I)
Compound:
In formula:
L is O or S；
R1Independently selected from:
Halogen；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；
Not deuterated, one or many deuterated or complete deuterated C2-C3 alkenyl；
Not deuterated, one or many deuterated or complete deuterated C2-C3 alkynyl；
Not deuterated, one or many deuterated or complete deuterated C3-C4 naphthenic base；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkoxy；
Not deuterated, one or many deuterated or complete deuterated C1-C2 alkoxy -C 1-C2 alkyl；
Not deuterated, one or many deuterated or complete deuterated tetrahydrofuran -2- base；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl sulfenyl；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl NH-；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl ND-；
(not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl)2N-；
Halogenated-C1-C2 alkyl contains 1~5 halogen, and wherein halogen is F or Cl, and C1-C2 alkyl is not deuterated, primary
Or multiple deuterated C1-C2 alkyl；
Halogenated-C3-C4 naphthenic base, wherein C3-C4 naphthenic base is not deuterated, one or many deuterated C3-C4 naphthenic base；
Halogenated-C1-C2 alkoxy, wherein C1-C2 alkoxy is not deuterated, one or many deuterated C1-C2 alkoxies；
Halogenated-C1-C2 alkyl sulfenyl, wherein C1-C2 alkyl sulfenyl is not deuterated, one or many deuterated C1-C2 alkyl
Sulfenyl；
R2It is selected from:
H；Deuterium；Halogen；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkoxy；
Cyano；
X1Selected from CH, CD, N or CR1；
X2、X3And X4Independently selected from CR3Or N；
R3It is selected from: H；Deuterium；Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；It is not deuterated, primary or more
Secondary deuterated or complete deuterated C2-C4 alkenyl；Not deuterated, one or many deuterated or complete deuterated C2-C4 alkynyl；Non- deuterium
Generation, one or many deuterated or complete deuterated C1-C4 alkoxy；It is not deuterated, one or many deuterated or complete deuterated
C1-C4 alkyl sulfenyl；Halogen；OH；OD；CN；OCF3；OCHF2；OCDF2；OCH2F；OCHDF；OCD2F；It is not deuterated, primary
Or multiple deuterated or complete deuterated C1-C2- alkoxy -C 1-C2- alkoxy；Halogenated-C1-C3- alkyl, contains 1~5
Halogen, C1-C3- alkyl are not deuterated, one or many deuterated C1-C3- alkyl；Benzyl oxygroup, solely by 0~5
On the spot selected from deuterium or 0~3 independently selected from halogen, not deuterated, one or many deuterated or complete deuterated C1-C4 alcoxyl
It is base, not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl, not deuterated, one or many deuterated or complete
Deuterated cyclopropyl, CF3、OCF3, 5 or 6 yuan heteroaryl, OH, OD, OCHF2、OCDF2, it is two (not deuterated, one or many
Deuterated or complete deuterated-C1-C4- alkyl) group of amino and cyano replaces；With-(CH2) n- phenyl, solely by 0~5
On the spot selected from deuterium or 0~3 independently selected from halogen, not deuterated, one or many deuterated or complete deuterated C1-C4 alcoxyl
It is base, not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl, not deuterated, one or many deuterated or complete
Deuterated cyclopropyl, CF3、OCF3, 5 or 6 yuan heteroaryl, OH, OD, OCHF2、OCDF2, it is two (not deuterated, one or many
Deuterated or complete deuterated C1-C4- alkyl) group of amino and cyano replaces；
R4And R5Independently selected from:
H；Deuterium；
Not deuterated, one or many deuterated or complete deuterated C1-C6 alkyl；
Or R4And R5Not deuterated, one or many deuterated or complete deuterated C3- can be formed together with carbon connected to them
C7 cycloalkyl ring；
A ring is selected from phenyl ring；It can be by single or multiple R6Substituted phenyl ring；Heteroaryl ring comprising at least one O, N or S atom；It can
By single or multiple R6The heteroaryl ring comprising at least one O, N, S atom replaced；
R6It is selected from: halogen (such as F, Cl, Br)；OCF3；OCHF2；OH；CN；NO2；COOH；C1-C4 alkoxy carbonyl；Substituted ammonia
Base；Substituted amide groups；C1-C4 alkyl sulphonyl；Substituted sulfoamido；C1-C5 alkyl, by 0~7 independently selected from
Halogen, CF3、OCF3, OH, hydroxyl-C1-C4- alkyl, C1-C4 alkoxy, C1-C4 alkoxy -C 1-C4 alkoxy, two-C1-C4-
Alkylamino phenyl-C1-C4- alkyl, (two-C1-C4- alkoxy -C 1-C4- alkyl)-C1-C4- alkyl, C3-C6- naphthenic base,
Replace with the group of C1-C4 alkyl sulfenyl；It is unsubstituted or can substituted C6-C10 aryl, unsubstituted or can be substituted
5 to 10 yuan of heteroaryl, it is unsubstituted or can be substituted 4 to 10 yuan heterocycle, unsubstituted or can substituted C3-C6
It is naphthenic base, unsubstituted or can substituted C5-C11 spiro cycloalkyl group；
Additional conditions are R1、R2、R3、R4、R5、R6In at least one be deuterated or deuterium.
2. compound as described in claim 1, it is characterised in that:
R1Independently selected from:
Halogen；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkoxy；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl sulfenyl；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl NH-；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl ND-；
(not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl)2N-；
Halogenated-C1-C2 alkoxy, wherein C1-C2 alkoxy is not deuterated, one or many deuterated C1-C2 alkoxies；
Halogenated-C1-C2 alkyl sulfenyl, wherein C1-C2 alkyl sulfenyl is not deuterated, one or many deuterated C1-C2 alkyl
Sulfenyl；
R2It is selected from:
H；Deuterium；Halogen；
Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；
Cyano；
X1Selected from CH, CD, N；
X2Selected from CH or CD；
X3It is CR3；
R3It is selected from: H；Deuterium；Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl；It is not deuterated, primary or more
Secondary deuterated or complete deuterated C1-C4 alkoxy；Not deuterated, one or many deuterated or complete deuterated C1-C4 alkyl sulfide
Base；Halogen；OH；OD；CN；OCF3；OCHF2；OCDF2；OCH2F；OCHDF；OCD2F；It is not deuterated, one or many deuterated or
Complete deuterated C1-C2- alkoxy -C 1-C2- alkoxy；Halogenated-C1-C3- alkyl contains 1~5 halogen, C1-C3- alkyl
It is not deuterated, one or many deuterated C1-C3- alkyl；
X4Selected from CH or CD；
R4And R5Independently selected from:
H；Deuterium；
Not deuterated, one or many deuterated or complete deuterated C1-C6 alkyl；
Or R4And R5Not deuterated, one or many deuterated or complete deuterated C3- can be formed together with carbon connected to them
C7 cycloalkyl ring；
A ring is selected from phenyl ring；It can be by single or multiple R6Substituted phenyl ring；It can be by single or multiple R6Substituted thiazole；
R6It is selected from: halogen；OCF3；OCHF2；OH；CN；COOH；C1-C4 alkoxy carbonyl；Substituted amino；Substituted amide groups；
C1-C4 alkyl sulphonyl；Substituted sulfoamido；C1-C5 alkyl, by 0~7 independently selected from halogen, CF3、OCF3、OH、
Hydroxyl-C1-C4- alkyl, C1-C4 alkoxy, C1-C4 alkoxy -C 1-C4 alkoxy, two-C1-C4- alkylamino phenyl-C1-
C4- alkyl, (two-C1-C4- alkoxy -C 1-C4- alkyl)-C1-C4- alkyl, C3-C6- naphthenic base and C1-C4 alkyl sulfenyl
Group replace；It is unsubstituted or can be substituted 4 to 10 yuan heterocycle, unsubstituted or can substituted C3-C6 cycloalkanes
It is base, unsubstituted or can substituted C5-C11 spiro cycloalkyl group；
Additional conditions are R1、R2、R3、R4、R5、R6In at least one be deuterated or deuterium.
3. compound as described in claim 1, which is characterized in that the compound is following compounds or it can pharmaceutically connect
The salt or ester or solvate received:
4. the compound or its pharmaceutically acceptable salt or ester or solvate as described in claims 1 to 3 prevent in preparation
With the purposes in the drug for the treatment of thromboembolic disorders.
5. purposes as claimed in claim 4, wherein thromboembolic disorders include: acute coronary syndrome, the instability mode heart
The raised myocardial infarction of colic pain, stable angina cordis, ST-, non-ST- Elevation Myocardial Infarction, atrial fibrillation, cardiac muscle stalk
Extremely, transient ischemic attack, apoplexy, atherosclerosis, peripheral arterial disease, venous thronbosis, deep vein thrombosis shape
At, the formation of thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis formation, cerebral embolism, renal embolism, lung bolt
Plug, the relevant thrombosis of cancer or because of medical implant, device and wherein blood is exposed to artificial surface to promote thrombus shape
At operation sequence caused by thrombosis.
6. it is a kind of prevent and treat thromboembolic disorders pharmaceutical composition, wherein containing therapeutically effective amount such as claim
Compound described in 1~3 or its pharmaceutically acceptable salt or ester or solvate are as active constituent and pharmaceutically acceptable
Carrier.
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| 江文峰等: "氘代作用在药物研究中的应用", 《齐鲁药事》 * |
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Application publication date: 20190924 |