CN105294669A - Tenth factor inhibitor and preparation method and application thereof - Google Patents
Tenth factor inhibitor and preparation method and application thereof Download PDFInfo
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- CN105294669A CN105294669A CN201510697138.6A CN201510697138A CN105294669A CN 105294669 A CN105294669 A CN 105294669A CN 201510697138 A CN201510697138 A CN 201510697138A CN 105294669 A CN105294669 A CN 105294669A
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 15
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- 235000008206 alpha-amino acids Nutrition 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 144
- -1 heterocyclic amine Chemical class 0.000 claims description 61
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- 239000007821 HATU Substances 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 150000004982 aromatic amines Chemical class 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D409/02—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to a tenth factor inhibitor and a preparation method and application thereof. The tenth factor inhibitor is of a structure as the formula I. According to the inhibitor, alpha- amino acid is used as a template, a series of compounds of the novel structure are formed by using amide and carbamic acid ester or urea as branched chains, the compounds can be effectively combined with the tenth factor, and thrombus formation is prevented.
Description
Technical Field
The invention relates to the field of medicine invention, in particular to a tenth factor (FXa) inhibitor and a preparation method and application thereof.
Background
Thrombi are blood clots or deposits of blood components formed on the surface of blood vessels or the endocardium, which can occur anywhere in the blood vessel, causing blood flow to stop. The thromboembolic diseases are all manifested from head to foot, and cerebrovascular thrombosis can cause the patients to have one side of limb dysfunction, namely hemiplegia, aphasia, visual and sensory disorders, coma, and can cause disability and death. Thrombosis of the heart vessels, i.e. arteriosclerotic thrombosis, can lead to severe angina and even myocardial infarction. According to the statistics of the World Health Organization (WHO), about 1,200 million people die from cerebral thrombosis, cerebral infarction, myocardial infarction, coronary heart disease, arteriosclerosis and other diseases every year in the world, which is close to 1/4 of the total death number in the world.
Antithrombotic drugs mainly include anticoagulants, antiplatelet aggregation drugs and thrombolytic drugs, wherein the anticoagulant drugs and the antiplatelet aggregation drugs have wide clinical application. Among anticoagulant drugs, warfarin (walfrin), heparin (heprin) and low molecular weight heparin dominate for more than half a century and hold a place in antithrombotic drugs. The anti-platelet aggregation drugs include aspirin (aspirin) and clopidogrel (clopidogrel), and the biggest side effect of the most commonly used antithrombotic drugs is bleeding, wherein the aspirin and the clopidogrel can cause recurrent thrombosis due to insufficient dosage. Heparin-induced thrombocytopenia, and warfarin-induced skin necrosis, and more, warfarin has a narrow therapeutic window, slow onset, more frequent blood monitoring to adjust the dosage, and interaction with various foods or drugs, which limits its clinical application.
The novel drug target is mainly based on the search of inhibitors participating in various factors of the coagulation cascade reaction (coagulation cascade), the tenth factor is positioned at the junction of the internal pathway and the external pathway in the coagulation cascade reaction, and the inhibition of the tenth factor can effectively inhibit the massive formation of fresh thrombin factors to block the coagulation cascade reaction on one hand, and reduce the bleeding risk because the tenth factor does not interfere with the thrombin factors already existing in blood on the other hand.
In recent years, the focus of development has gradually focused on factor ten, and the inhibitor of factor ten has been developed as follows:
benzamidine derivative DX-9065a (NagaharaT, YokoyamaY, Inamura K, oral, Diasic (amidinoaryl) propanococcal having a specific activity of a. Jud. chem 1994; 37: 1200-7);
otamixaban from Sanofi-Aventis pharmaceuticals, Inc. (Guertin KR, Gardner CI, KleinSI, et. OptimizationofHebet-aminoestclassf FactorXiainhibitors. Part2: identifying efficiency of FXV673a starting and electrokinetic inhibitor with the cellulose activity. bioorg Chem Lett2002; 12: 1671-4);
razaxaban (QuanMI, LamPY, HanQ, ethyl. Discoveryof1- (3 ' -aminobenzezoxazol- ' -yl) -3-trifluoromethylphenyl-N- [2-fluoro-4- [ (2 ' -methylenediazanyl) imidazol-1-yl ] phenyl ] -1H-pyrazole-5-carboxamidohydrochloride (razaxban), ahighlypote, selective, andorarylbivailableFactorXaihibitor. MedChem 2005; 48:1729-44) from DuPont pharmaceuticals;
antithrombotic drugs approved for marketing in recent years are:
rivaroxaban (rivaroxaban, BAY59-7939) (Roerigs, Strauba, Pohlmann J, et al, Discoveyftohented anthropometical agent5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxomorphin-4-yl) phenyl ] -1, 3-oxolidin-5-yl } methyl) thiophene-2-carboxamide (BAY59-7939): anaral, directfacorxaihibitor. JMedChem 2005; 48: 5900-8);
apixaban (Apixaban, BMS-562247-1) (PintoDJ, OrwatMJ, Kochs, et. Discoveryof1- (4-methoxyphenyl) -7-oxo-6- (4- (2-oxoperidin-1-yl) phenyl) -4,5,6, 7-tetrahydroo-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (Apixaban, BMS-562247), ahighlypotent, selective, infectious, and anthropogenic biological available layer of arbo catalytic MedcorXa.JChem 2007; 50:5339-56), and the like.
The novel tenth factor inhibitor provided by the invention has the advantages of novel structure, high inhibitory activity and good selectivity.
Disclosure of Invention
The object of the present invention is to provide a novel factor tenth inhibitor.
The invention provides a compound or pharmaceutically acceptable salt with a structure shown in a general formula I:
wherein,
R1is aryl, heterocyclic group, alkyl, aryl ether, heterocyclic ether, alkyl ether, arylamine, heterocyclic amine or alkylamino;
R2is aryl, heterocyclic group or alkyl;
R3is a morpholinophenyl, aryl, heterocyclic group or alkyl group;
x is nitrogen.
The heterocyclic group includes pyridine, pyrimidine, thiazole, thiophene, oxazole, imidazole, pyrazole, pyrrole or indole groups and the like.
Preferably, the compound is a compound having the structure:
the invention also provides a preparation method of the compound, as shown in Scheme1, and the method comprises the following steps of reacting N-protected α -amino acid with corresponding R3-NH2The corresponding amide is obtained by reaction, the protective agent is removed under the acidic condition, and then the product is condensed with carboxylic acid or acyl chloride, or isocyanate, chloroformate and the like are reacted to obtain the corresponding tenth factor inhibitor compound.
Synthesis and preparation of Scheme1 compound with general formula I
The invention also provides a preparation containing the compound, and the preparation consists of the compound and a pharmaceutically acceptable carrier.
The preparation can be tablet, capsule and granule.
The pharmaceutically acceptable carrier is selected from the group consisting of fillers, disintegrants, binders, lubricants, including but not limited to any and all solvents, dispersion media, coatings, absorption delaying agents, and the like, such media and agents being well known in the art for pharmaceutically active substances.
The present invention also provides a method for preparing the above formulation, which is a conventional method well known to those skilled in the art.
The invention also provides the use of the compound or formulation in the manufacture of a medicament for the treatment and prophylaxis of thrombosis in patients with non-valvular Atrial Fibrillation (AF) who have suffered a stroke or Systemic Embolism (SE), and in the prophylaxis of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) in patients after hip and knee replacement.
The compound provided by the invention has the following advantages:
1. the inhibitor of the invention takes alpha-amino acid as a template, and forms a series of compounds with novel structures by taking amide, carbamate or urea as branched chains respectively, and the compounds can be effectively combined with the tenth factor to prevent the formation of thrombus.
2. The compound provided by the invention can selectively inhibit the tenth inhibition, the tenth factor is positioned at the junction of an internal pathway and an external pathway in a coagulation cascade reaction (figure 1), and the FXa is inhibited, so that on one hand, the compound can effectively inhibit the massive formation of fresh thrombin factor to block the coagulation cascade reaction, and on the other hand, the compound does not interfere with the existing thrombin factor in blood to reduce the bleeding risk, therefore, the tenth factor inhibitor can be used as a medicament for anticoagulation.
Drawings
FIG. 1: schematic representation of the coagulation mechanism.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1: preparation of (S) -N- (5-guanidino-1-oxo-1- (4- (3-oxomorphino) phenylamino) pentan-2-yl) -6-methoxynico-tinamide (FXa-01)
1. Preparation of intermediate (S) -tert-butyl-5- (3-nitroguindino) -1-oxo-1- (4- (3-oxomorphino) -phenylaminono) pentan-2-ylcarbamate
Starting material 4- (4-aminophenyl) morphin-3-one (250mg, 1.30mmol) was dissolved in N, N-dimethylformamide (1ml) and tetrahydrofuran (15ml), and N, N-diisopropylethylamine (0.7ml, 3.9mmol) and (S) -2- (tert-butoxycarbnyl) -5- (3-nitroguindino) pentanicacid (424mg, 1.33mmol) were added under ice bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (593mg, 1.56mmol) was added, and the reaction was stirred under ice bath for 15 minutes, followed by turning to room temperature for 2 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 80: 1-20: 1) to give a yellow solid, 350mg, purity: 95%, yield: 45 percent. LC-MS (ESI) M/z494(M + H)+。
2. Preparation of intermediate (S) -2-amino-5- (3-nitroguindino) -N- (4- (3-oxomorphino) phenyl) -pentanamide
The product obtained in step 1 (350mg, 0.71mmol) was dissolved in dichloromethane (2ml), and trifluoroacetic acid (1ml) was added dropwise under ice bath, followed by stirring for 15 minutes under ice bath, and then, warmed to room temperature for 4 hours. LCMS check reaction complete. The reaction solution was concentrated to dryness by rotary evaporation and then dried under vacuum to give a brown solid, 280mg, purity: 92%, yield: 100 percent. The residue was used directly in the next reaction. LC-MS (ESI) M/z394(M + H)+。
3. Preparation of intermediate (S) -6-methoxy-N- (5- (3-nitroguanidino) -1-oxo-1- (4- (3-oxomorphino) -phenylaminono) pentan-2-yl) nicotinamide
The product obtained in step 2 (280mg, 0.71mmol) was dissolved in N, N-dimethylformamide (1ml) and tetrahydrofuran (15ml), and N, N-diisopropylethylamine (0.37ml, 2.13mmol) and 6-methoxybiotinic acid (130mg, 0.85mmol) were added under ice bath, and the best was obtainedThen, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (323mg, 0.85mmol) was added thereto, and the mixture was stirred in an ice bath for reaction for 15 minutes, and then, the mixture was allowed to turn to room temperature for reaction for 2 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 80: 1-20: 1) to give a brown solid, 130mg, purity: 92%, yield: 35 percent. LC-MS (ESI) M/z529(M + H)+。
4. Preparation of (S) -N- (5-guanidino-1-oxo-1- (4- (3-oxomorphino) phenylamino) pentan-2-yl) -6-methoxynico-tinamide (FXa-1)
The product obtained in step 3 (110mg, 0.21mmol) was dissolved in a hydrogenation flask containing anhydrous ethanol, palladium on carbon (30mg) was added, replaced with hydrogen three times, pressurized to 50psi, and subjected to hydrogenation reaction for 6 hours at room temperature with rocking. LCMS detects that the reaction is complete, palladium carbon is filtered, the obtained filtrate is decompressed and concentrated to be dry, and the obtained residue is crystallized by methanol and petroleum ether (1:15) to obtain off-white solid, 80mg, purity: 99%, yield: 80 percent. LC-MS (ESI) M/z484(M + H)+；1HNMR(400MHz,MeOD)ppm1.6–1.9(m,2H),1.9–2.2(m,2H),3.1–3.4(m,3H),3.7–3.8(t,2H),3.9–4.0(s,3H),4.0–4.1(t,2H),4.2–4.3(s,2H),4.7–4.8(m,1H),6.8-6.9(d,1H，J＝8.8Hz),7.3–7.4(d,2H，J＝8.8Hz),7.7–7.8(d,2H，J＝8.8Hz),8.2-8.3(m,1H)；8.5-8.6(s；1H)；8.7-8.8(d，1H，J＝2.4Hz)。
Example 2: preparation of (2S,4R) -1- (2-chlorothiophene-5-carbonyl) -4-methoxy-N- (quinolin-2-yl) pyrolidine-2-carboxamide (FXa-03)
1. Preparation of intermediate (2S,4R) -tert-butyl4-methoxy-2- (quinolin-2-ylcarbamoyl) pyrolidine-1-carboxylate
Quinolin-2-amine (144mg,1.0mmol) was dissolved in N, N-dimethylformamide (0.5ml) and tetrahydrofuran (5ml), and N, N-diisopropylethylamine (0.53ml,3.0mmol) and (2S,4R) -1- (tert-butoxycarbonyl) -4-methoxypyrolidine-2-carboxylic acid (245mg,1.0mmol) were added under ice bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (456mg,1.2mmol) was added, followed by stirring for 15 minutes under ice bath, followed by turning to room temperature for 2 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (petroleum ether: ethyl acetate: 8:1 to 3:1) to give an off-white solid, 370mg, yield: 100 percent. LC-MS (ESI) M/z372(M + H)+。
2. Preparation of intermediate (2S,4R) -tert-butyl4-methoxy-2- (quinolin-2-ylcarbamoyl) pyrolidine-1-carboxylate
The product obtained in step 1 was dissolved in dichloromethane (2ml), tetrahydrofuran (1ml) was added dropwise under ice bath, and the reaction was stirred for 15 minutes under ice bath, followed by being turned to room temperature for 3 hours. LCMS check reaction complete. The reaction was concentrated to dryness by rotary evaporation and then dried in vacuo to give a yellow oily liquid, 70mg, purity: 92%, yield: 96 percent. The residue was used directly in the next reaction. LC-MS (ESI) M/z272(M + H)+。
3. Preparation of (2S,4R) -1- (2-chlorothiophene-5-carbonyl) -4-methoxy-N- (quinolin-2-yl) -pyrolidine-2-carboxamide (FXa-2)
The product obtained in step two (70mg,0.26mmol) was dissolved in N, N-dimethylformamide (0.5ml) and tetrahydrofuran (3ml), N, N-diisopropylethylamine (100mg,0.77mmol) and 5-chlorothiophene-2-carboxylic acid (46mg,0.28mmol) were added under ice bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (118mg,0.31mmol) was added, stirred for reaction for 15 minutes under ice bath, and then turned to room temperature for reaction for 2 hours. LCMS detects the reaction is complete, a small amount of water is added for quenching, extraction is carried out for three times by ethyl acetate, and the mixture is combined withThe organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate: 8:1 to 3:1) to give a yellow solid, 18mg, purity: 95%, yield: 17 percent. LC-MS (ESI) M/z416(M + H)+；1HNMR(400MHz,MeOD)ppm2.12–2.22(m,1H),2.52–2.62(m,1H),3.31–3.36(s,3H),3.9-4.2(m,2H),4.2-4.3(m,1H),4.4-4.6(m,2H),7.07–7.08(d,1H,J＝3.6Hz),7.48–7.50(m,1H),7.54–7.55(d,1H,J＝3.6Hz),7.68(t,1H)。7.83–7.86(d,2H,J＝8.4Hz),8.26(S,2H)。
Example 3: preparation of (S) -N- (3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxophosphorino) phenylaminoo) propan-2-yl) -5-chlorothiophene-2-carboxamide (FXa-04)
1. Preparation of the intermediate (S) -tert-butyl-3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxopholino) phenyl-amino) propan-2-ylcarbamate
4- (4-aminophenyl) morpholinon-3-one (600mg,3.12mmol) was dissolved in N, N-dimethylformamide (3ml) and tetrahydrofuran (30ml), N, N-diisopropylethylamine (0.81ml, 4.68mmol) and Boc-L-Histidine (798mg,3.12mmol) were added under ice-bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (1.425g,3.75mmol) was added, and the reaction was stirred under ice-bath for 15 minutes, after which it was turned to room temperature for 2 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 50:1 to 10: 1) to give a yellow solid, 480mg, purity: 98%, yield: 36 percent. LC-MS (ESI) M/z430(M + H)+。
2. Preparation of the intermediate (S) -2-amino-3- (1H-imidozol-5-yl) -N- (4- (3-oxomorphino) phenyl) -propanamide
The product obtained in step 1 (160mg,0.37mmol) was dissolved in dichloromethane (2ml), and trifluoroacetic acid (1ml) was added dropwise under ice bath, followed by stirring for 15 minutes under ice bath, and then, warmed to room temperature for 4 hours. LCMS check reaction complete. The reaction solution was concentrated to dryness by rotary evaporation and then dried under vacuum to give a yellow solid, 123mg, purity: 98%, yield: 99 percent. The residue was used directly in the next reaction. LC-MS (ESI) M/z330(M + H)+。
3. Preparation of (S) -N- (3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxomorpholino) phenyl-amino) propan-2-yl) -5-chlorothiophene-2-carboxamide
The product obtained in step two (123mg,0.37mmol) was dissolved in N, N-dimethylformamide (0.5ml) and tetrahydrofuran (10ml), N, N-diisopropylethylamine (0.16ml,0.94mmol) and 5-chlorothiophene-2-carboxylic acid (67mg,0.41mmol) were added under ice-bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (171mg,0.45mmol) was added, stirred under ice-bath for reaction for 15 minutes, and then turned to room temperature for reaction for 3 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 80:1 to 15:1) to give an off-white solid, 86mg, purity: 95%, yield: 49 percent. LC-MS (ESI) M/z474(M + H)+；1HNMR(400MHz,MeOD)ppm3.1–3.2(m,1H),3.2–3.3(m,1H),3.7-3.8(m,2H),4.0–4.1(m,2H),4.28(s,2H),6.92(s,1H),7.04–7.05(d,1H,J＝4Hz),7.31–7.33(d,2H,J＝8Hz),7.62–7.65(m,4H)。
Example 4: preparation of (S) -N- (3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) -4-chlorobenzamide (FXa-05)
(S) -2-amino-3- (1H-imidozol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide (100mg,0.304mmol) was dissolved in N, N-dimethylformamide (1ml) and tetrahydrofuran (5ml), N, N-diisopropylethylamine (0.16ml,0.94mmol) and p-chlorobenzoic acid (67mg,0.41mmol) were added under ice bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (171mg,0.45mmol) was added, and the reaction was stirred for 15 minutes under ice bath, after which it was turned to room temperature for 3 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 80: 1-15: 1) to give an off-white solid, 82mg, purity: 95%, yield: 58 percent. LC-MS (ESI) M/z468(M + H)+；1HNMR(400MHz,DMSO)ppm3.0–3.1(m,1H),3.1–3.2(m,1H),3.8-3.9(m,2H),4.1–4.2(m,2H),4.18(s,2H),6.97(S,1H),7.30–7.32(d,2H,J＝8Hz),7.55–7.57(d,2H,J＝8Hz),7.60–7.63(d,2H,J＝12Hz),7.82(S,1H),7.89–7.91(d,2H,J＝8.8Hz),8.85-8.87(d,1H,J＝8Hz),10.21(S,1H)。
Example 5: preparation of (S) -N- (3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) -4-chlorobenzamide (FXa-06)
1. Preparation of intermediate (S) -tert-butyl-3- (4-hydroxypentyl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-ylcarbamate
4- (4-aminophenyl) morphin-3-one (400mg,2.08mmol) was dissolved in N, N-dimethylformamide (2ml) and tetrahydrofuran (20ml), N, N-diisopropylethylamine (0.54ml,3.2mmol) and Boc-L-Tryptophan-OH (586mg,2.08mmol) were added under ice-bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (950mg,2.5mmol) was added under ice-bathThe reaction was stirred for 15 minutes, then turned to room temperature for 2 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-10: 1) to give an off-white solid, 375mg, purity: 98%, yield: 40 percent. LC-MS (ESI) M/z456(M + H)+。
2. Preparation of intermediate (S) -2-amino-3- (4-hydroxyphenylyl) -N- (4- (3-oxomorphino) phenyl) propanamide
The product obtained in step 1 (360mg,0.79mmol) was dissolved in dichloromethane (2ml), and trifluoroacetic acid (1ml) was added dropwise under ice bath, followed by stirring for 15 minutes under ice bath, and then, turning to room temperature for 4 hours. LCMS check reaction complete. The reaction solution was concentrated to dryness by rotary evaporation and then dried under vacuum to give a brown solid, 280mg, purity: 98%, yield: 99 percent. The residue was used directly in the next reaction. LC-MS (ESI) M/z356(M + H)+。
3. Preparation of (S) -5-chloro-N- (3- (4-hydroxyphenylyl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) thiophene-2-carboxamide
The product obtained in step 2 (260mg, 0.73mmol) was dissolved in N, N-dimethylformamide (1ml) and tetrahydrofuran (10ml), N, N-diisopropylethylamine (284mg, 2.20mmol) and 5-chlorothiophene-2-carboxylic acid (120mg, 0.73mmol) were added under ice bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (334mg, 0.88mmol) was added, stirred under ice bath for reaction for 15 minutes, and then transferred to room temperature for reaction for 2 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 50:1 to 10: 1) to give an off-white solid, 70mg, purity: 96%, yield: 19 percent. LC-MS (ESI) M/z500(M + H)+；1HNMR(400MHz,DMSO)ppm2.8–2.9(m,2H),3.0–3.1(m,1H),3.5–3.6(m,1H),3.6–3.7(m,2H),3.9–4.0(m,2H),4.18(S,2H),4.6–4.7(m,1H),6.63–6.65(d,4H,J＝8.4Hz),7.13–7.16(d,2H,J＝8.4Hz),7.18–7.20(d,1H,J＝4Hz),7.31–7.34(d,2H,J＝8.8Hz),7.60–7.63(d,2H,J＝8.8HZ),7.79–7.81(d,1H,J＝4Hz),8.86–8.89(d,1H,J＝8.4Hz),10.28(s,1H)。
Example 6: preparation of (R) -N- (3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxophosphorino) phenylaminoo) propan-2-yl) -5-chlorothiophene-2-carboxamide (FXa-14)
1. Preparation of the intermediate (R) -tert-butyl-3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxophosphorino) -phenylaminono) -propan-2-ylcarbamate
4- (4-aminophenyl) morpholinon-3-one (2.0g, 10.41mmol) was dissolved in N, N-dimethylformamide (10ml) and tetrahydrofuran (20ml), N, N-diisopropylethylamine (5.4g, 41.64mmol) and Boc-D-Histidine-OH (2.66g, 10.41mmol) were added under ice-bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (4.75g, 12.49mmol) was added, and the reaction was stirred under ice-bath for 15 minutes, followed by turning to room temperature for 3 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 50:1 to 15:1) to give an off-white solid, 1.21g, purity: 94%, yield: 27 percent. LC-MS (ESI) M/z430(M + H)+。
2. Preparation of the intermediate (R) -2-amino-3- (1H-imidozol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide
The product obtained in step 1 (1.20g, 2.79mmol) was dissolved in dichloromethane (10ml), and trifluoroacetic acid (5ml) was added dropwise under ice bath, followed by stirring for 15 minutes under ice bath, and then, the reaction was allowed to turn to room temperature for 3 hours. LCMS check reaction complete. Will be provided withThe reaction solution was concentrated to dryness by rotary evaporation and then dried under vacuum to give a tan solid, 920mg, purity: 94%, yield: 100 percent. The residue was used directly in the next reaction. LC-MS (ESI) M/z330(M + H)+。
3. Preparation of (R) -N- (3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) -5-chlorothiophene-2-carboxamide
The product obtained in step 2 (900mg, 2.73mmol) was dissolved in N, N-dimethylformamide (5ml) and tetrahydrofuran (10ml), N, N-diisopropylethylamine (1.4g, 10.92mmol) and 5-chlorothiophene-2-carboxylic acid (442mg, 2.73mmol) were added under ice-bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (1.25g, 3.28mmol) was added, and the reaction was stirred under ice-bath for 15 minutes, after which it was allowed to turn to room temperature for 3 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 595mg, purity: 96%, yield: 46 percent. LC-MS (ESI) M/z474(M + H)+；1HNMR(400MHz,DMSO)ppm3.0–3.2(m,2H),3.6–3.8(m,2H),3.9-4.0(m,2H),4.18(s,2H),4.7-4.8(m,1H),6.85(s,1H),7.20–7.21(d,1H,J＝4Hz),7.30–7.33(d,2H,J＝8.4Hz),7.56(s,1H),7.61–7.64(d,2H,J＝8.8Hz),7.79–7.81(d,1H,J＝4.4Hz),8.91–8.94(d,1H,J＝7.6Hz),10.29(s,1H)。
Example 7: preparation of (R) -5-chloro-N- (3- (1-methyl-1H-imidozol-4-yl) -1-oxo-1- (4- (3-oxophosphorino) phenylamino) propan-2-yl) thiophene-2-carboxamide (FXa-19)
FXa-14(400mg, 0.84mmol) was dissolved in dimethyl sulfoxide (2ml), and sodium hydroxide (102mg, 2) was added under ice bath.53mmol), dimethyl sulfate (106mg, 0.84mmol) was added dropwise, the reaction was stirred in an ice bath for half an hour, and then the reaction was allowed to warm to room temperature for half an hour. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give a pale yellow solid, 28mg, purity: 95%, yield: 7 percent. LC-MS (ESI) M/z488(M + H)+；1HNMR(400MHz,DMSO)ppm2.9–3.1(m,2H),3.56(s,3H),3.6–3.8(m,2H),3.9-4.0(m,2H),4.18(s,2H),4.7-4.8(m,1H),6.89(s,1H),7.20–7.21(d,1H,J＝4Hz),7.30–7.33(m,2H),7.49(s,1H),7.61–7.64(d,2H,J＝9.2Hz),7.76–7.78(d,1H,J＝4Hz),8.87–8.89(d,1H,J＝7.6Hz),10.26(s,1H)。
Example 8: preparation of (R) -N- (3- (1H-indol-2-yl) -1-oxo-1- (4- (3-oxophosphorino) phenylaminono) propan-2-yl) -5-chlorothiophene-2-carboxamide (FXa-20)
1. Preparation of intermediate (R) -tert-butyl-3- (1H-indol-2-yl) -1-oxo-1- (4- (3-oxomorphino) phenylaminono) -propan-2-ylcarbamate
4- (4-aminophenyl) morphin-3-one (500mg, 2.60mmol) was dissolved in N, N-dimethylformamide (2ml) and tetrahydrofuran (6ml), N, N-diisopropylethylamine (1.2g, 9.1mmol) and Boc-D-Tryptophan-OH (792mg, 2.60mmol) were added under ice-bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (1.2g, 3.12mmol) was added, and the reaction was stirred under ice-bath for 15 minutes, followed by transfer to room temperature for 3 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Purifying the obtained residue by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to obtain a white-like solid,820mg, purity: 95%, yield: 66 percent. LC-MS (ESI) M/z479(M + H)+。
2. Preparation of the intermediate (R) -2-amino-3- (1H-indol-2-yl) -N- (4- (3-oxomorphino) phenyl) propanamide
The product obtained in step 1 (300mg, 0.63mmol) was dissolved in dichloromethane (2ml), and trifluoroacetic acid (1ml) was added dropwise under ice bath, followed by stirring for 15 minutes under ice bath, and then, the reaction was allowed to turn to room temperature for 3 hours. LCMS check reaction complete. The reaction solution was concentrated to dryness by rotary evaporation and then dried under vacuum to give a tan solid, 237mg, purity: 92%, yield: 100 percent. The residue was used directly in the next reaction. LC-MS (ESI) M/z379(M + H)+。
3. Preparation of (R) -N- (3- (1H-indol-2-yl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) -5-chlorothiophene-2-carboxamide
The product (237mg, 0.63mmol) obtained in step 2 was dissolved in N, N-dimethylformamide (1ml) and tetrahydrofuran (5ml), N, N-diisopropylethylamine (285mg, 2.2mmol) and 5-chlorothiophene-2-carboxylic acid (123mg, 0.75mmol) were added under ice bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (286mg, 0.75mmol) was added, stirred under ice bath for reaction for 15 minutes, and then transferred to room temperature for reaction for 3 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 46mg, purity: 96%, yield: 18 percent. LC-MS (ESI) M/z524(M + H)+；1HNMR(400MHz,DMSO)ppm3.1-3.3(m,2H),3.6–3.7(m,2H),3.9–4.0(m,2H),4.19(s,2H),4.8–4.9(m,1H),6.9–7.1(m,2H),7.1–7.2(m,2H),7.3-7.4(m,3H),7.6-7.7(d,2H,J＝8.8Hz),7.73–7.76(d,1H,J＝7.6Hz),7.81–7.83(d,1H,J＝4.4Hz),8.0–8.3(m,1H),8.87–8.90(d,1H,J＝8Hz),10.33(s,1H),10.80(s,1H)。
Example 9: preparation of (R) -1- (4-chlorophenylyl) -3- (3- (1-methyl-1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxophosphorino) phenylamido) propan-2-yl) urea (FXa-23)
1. Preparation of the intermediate (R) -1- (3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) -3- (4-chlorophenylyl) urea
(R) -2-amino-3- (1H-imidozol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide (230mg, 0.70mmol) was dissolved in dichloromethane (10ml), triethylamine (142mg, 1.4mmol) was added, a solution of 1-chloro-4-isocyanatobzene in dichloromethane (10ml) was added dropwise under ice bath, and the reaction was stirred at room temperature for 1 hour. LCMS detects the reaction is complete, water is added for quenching, an organic phase is separated out, anhydrous sodium sulfate is dried, and concentration is carried out. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 232mg, purity: 95%, yield: 68 percent. LC-MS (ESI) M/z483(M + H)+；
2. Preparation of the intermediate (R) -1- (4-chlorophenylyl) -3- (1-oxo-1- (4- (3-oxomorphino) phenylamino) -3- (1-trityl-1H-imidozol-5-yl) propan-2-yl) urea
The product obtained in step 1 (180mg, 0.37mmol) was dissolved in methylene chloride (5ml), and triethylamine (94mg, 0.93mmol) and triphenylchloromethane (125mg, 0.45mmol) were added to stir at room temperature for 1 hour. LCMS detects the reaction is complete, water is added for quenching, an organic phase is separated out, anhydrous sodium sulfate is dried, and concentration is carried out. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 252mg, purity: 95%, yield: 93 percent. LC-MS (ESI) M/z725(M + H)+；
3. Preparation of (R) -1- (4-chlorophenylyl) -3- (3- (1-methyl-1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxophosphorino) phenylamido) propan-2-yl) urea
The product obtained in step 2 (240mg,0.32mmol) was dissolved in dichloromethane (2ml), and trifluoroacetic acid (1ml) was added dropwise under ice bath, followed by stirring at room temperature for 2 hours. LCMS to detect reaction completion, solvent and excess trifluoroacetic acid were evaporated under reduced pressure and the resulting residue was purified by column chromatography (DCM: MeOH ═ 50: 1-15: 1) to give an off-white solid, 42mg, purity: 96%, yield: 26 percent. LC-MS (ESI) M/z497(M + H)+；1HNMR(400MHz,DMSO)ppm3.0–3.2(m,2H),3.69(m,2H),3.83(s,3H),3.96(m,2H),4.1-4.3(m,3H),4.7-4.8(m,1H),6.87-6.89(d,1H,J＝8.4Hz),7.2-7.5(m,7H),7.6(m,2H),8.81(s,1H),9.06(s,1H),10.42(s,1H)。
Example 10: preparation of (R) -5-chloro-N- (3- (1-ethyl-1H-imidozol-4-yl) -1-oxo-1- (4- (3-oxophosphorino) phenylamino) propan-2-yl) thiophene-2-carboxamide (FXa-24)
FXa-14(200mg, 0.42mmol) was dissolved in N, N-dimethylformamide (1ml), and potassium carbonate (146mg, 1.06mmol) and bromoethane (55mg, 0.51mmol) were added under ice-bath to react at room temperature for 3 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 32mg, purity: 94%, yield: 15 percent. LC-MS (ESI) M/z502(M + H)+；1HNMR(400MHz,DMSO)ppm2.9(m,2H),3.6–3.9(t,2H),3.8–4.0(m,4H),4.18(s,2H),4.7-4.8(m,1H),6.96(s,1H),7.20–7.21(d,1H,J＝4Hz),7.29–7.32(m,2H),7.56(s,1H),7.59–7.60(d,2H,J＝2Hz),7.61–7.77(m,1H),8.86–8.88(d,1H,J＝8Hz),10.24(s,1H)。
Example 11: (R) -2- (3- (4-fluorophenyl) ureido) -3- (1H-imidazol-5-yl) -N- (4- (3-oxolanyl) phenyl) propanamide (FXa-43)
1. Preparation of intermediate (R) -3- (1- (tert-butoxycarbonyl) -1H-imidazol-5-yl) -2- ((tert-butoxycarbonyl) -amino) propanoic acid
In 50ml three-port baked good, 10g (64.52mmol) histidine was dissolved in 15ml methanol at RT., then 1ml water was added with stirring to disperse the system, 19.55g (193.55mmol, 3eq) triethylamine was added, the solution was cooled to 0 ℃, 35.16g (161.29mmol,2.5eq) (Boc) were slowly added dropwise2O in methanol, then stirred at 25 ℃ until no suspended histidine solid was present in the solution (about 1.5h), the reaction was stopped, methanol was removed under reduced pressure, then dissolved in 100ml dichloromethane, dried over anhydrous magnesium sulfate for 0.5h, filtered and the filtrate was concentrated to give a colorless oil which was used directly in the next step. LCMS (M/z):356(M + H)+]
2. Preparation of intermediate (R) -tert-butyl5- (2- ((tert-butyl) amino) -3-oxo-3- ((4- (3-oxomorpholino) phenyl) amino) propyl) -1H-imidazole-1-carboxylate
In a 50ml dry three-necked flask, (R) -3- (1- (tert-butoxycarbonyl) -1H-imidozol-5-yl) -2- ((tert-butoxycarbonyl) amino) propanoic acid obtained in the first step was dissolved in 20ml of DMF at room temperature, followed by addition of 33.29g (4.0eq) of DIEA and 13.39g (1.0eq) of 4- (4-aminophenyl) -3-morpholinone with stirring, and then the system was cooled to 0 ℃ and 29.42g (1.2eq) of HATU was added in portions, followed by stirring at 25 ℃ for 1 hour. The reaction was stopped, quenched with 50ml of water, extracted with ethyl acetate several times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH: DCM ═ 1:150) to give 18.6g of an off-white solid product (two-step yield: 54.5%). LCMS (M/z) 530(M + H)+]；1HNMR(DMSO,400MHz):ppm8.1(1H),7.2～7.6(5H),7.0(2H),4.4(1H),4.2(2H),4.0(2H),3.7(2H),2.7(2H),1.5(9H),1.3(9H)。
3. Preparation of the intermediate (R) -2-amino-3- (1H-imidozol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide
(R) -tert-butyl5- (2- ((tert-butyl-butyryl) amino) -3-oxo-3- ((4- (3-oxozolino) phenyl) amino) propyl) -1H-imidozole-1-carboxylate (150mg) obtained in the above step was dissolved in 1ml of dry dichloromethane in a 5ml dry flask at room temperature, 1ml of trifluoroacetic acid was added at about 10 ℃ and RT. was stirred under a closed condition for 1 hour. Cooling to below 10 ℃, slowly adding 4ml of DIEA dropwise, stirring for 2h, and directly using in the next step. LCMS (M/z):330(M + H)+]。
4. Preparation of (R) -2- (3- (4-fluorophenyl) ureido) -3- (1H-imidazol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide
Cooling the FXa-43-A3 reaction system to 0-5 ℃, controlling the temperature, slowly adding the FXa-43-A4 system, RT. stirring overnight, adding water for the next day to quench the reaction, removing the organic solvent by spinning, washing the water phase with diethyl ether for 3 times, extracting with DCM for multiple times, washing the organic phase with saturated saline solution, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, recrystallizing with EA, filtering, and drying to obtain 13.2mg of the product. LCMS (M/z):467(M + H)+]；1HNMR(DMSO,400MHz):ppm10.2(1H),8.9(1H),7.0～7.5(9H),6.9(1H),6.5(1H),4.6(1H),4.2(2H),3.9(4H),2.9(2H)。
Example 12: (R) -2- (3- (4-chlorophenylyl) ureido) -3- (1H-imidazol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide (FXa-46)
1. Preparation of intermediate (R) -3- (1- (tert-butoxycarbonyl) -1H-imidazol-5-yl) -2- ((tert-butoxycarbonyl) amino) propanoic acid
In 50ml of a three-necked-flask, 10g (64.52mmol) of histidine were dissolved in 15ml of methanol at RT., followed by stirringUnder these conditions, 1ml of water was added to disperse the system, 19.55g (193.55mmol, 3eq) of triethylamine was added, the solution was cooled to 0 ℃ and 35.16g (161.29mmol,2.5eq) (Boc) were slowly added dropwise2O in methanol, then stirred at 25 ℃ until no suspended histidine solid was present in the solution (about 1.5h), the reaction was stopped, methanol was removed under reduced pressure, then dissolved in 100ml dichloromethane, dried over anhydrous magnesium sulfate for 0.5h, filtered and the filtrate was concentrated to give a colorless oil which was used directly in the next step. LCMS (M/z):356(M + H)+]
2. Preparation of the intermediate (R) -tert-butyl5- (2- ((tert-butyl) amino) -3-oxo-3- ((4- (3-oxomorpholino) phenyl) amino) propyl) -1H-imidazole-1-carboxylate
In a 50ml dry three-necked flask, (R) -3- (1- (tert-butoxycarbonyl) -1H-imidozol-5-yl) -2- ((tert-butoxycarbonyl) amino) propanoic acid obtained in the first step was dissolved in 20ml of DMF at room temperature, followed by addition of 33.29g (4.0eq) of DIEA and 13.39g (1.0eq) of 4- (4-aminophenyl) -3-morpholinone with stirring, and then the system was cooled to 0 ℃ and 29.42g (1.2eq) of HATU was added in portions, followed by stirring at 25 ℃ for 1 hour. The reaction was stopped, quenched with 50ml of water, extracted with ethyl acetate several times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH: DCM ═ 1:150 to 1:60) to give the product as an off-white solid (two-step yield: 54.5%). LCMS (M/z) 530(M + H)+]；1HNMR(DMSO,400MHz):ppm8.1(1H),7.2～7.6(5H),7.0(2H),4.4(1H),4.2(2H),4.0(2H),3.7(2H),2.7(2H),1.5(9H),1.3(9H).
3. Preparation of the intermediate (R) -2-amino-3- (1H-imidozol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide
150mg of (R) -tert-butyl5- (2- ((tert-butyl) amino) -3-oxo-3- ((4- (3-oxomorpholino) phenyl) amino) propyl) -1H-imidozole-1-carboxylate obtained in the second step was dissolved in 1ml of dry dichloromethane at room temperature in a 5ml dry flask, 1ml of trifluoroacetic acid was added at about 10 ℃ and RT. was stirred under sealed conditions for 1 hour. Cooling to below 10 ℃, slowly dripping 4ml of DIEA, and stirring2h, used directly in the next step. LCMS (M/z):330(M + H)+]。
4. Preparation of (R) -2- (3- (4-chlorophenylyl) ureido) -3- (1H-imidazol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide
Cooling the FXa-46-A3 reaction system to 0-5 ℃, slowly adding the FXa-46-A4 system, stirring at room temperature overnight, adding water for quenching reaction, removing an organic solvent by spinning, washing a water phase with diethyl ether for 3 times, extracting with DCM for multiple times, washing an organic phase with saturated saline solution, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, recrystallizing with EA, filtering, and drying a filter cake to obtain a product of 36.6 mg. LCMS (M/z):483(M + H)+]；1HNMR(DMSO,400MHz):ppm:12.1(1H),10.2(1H),8.9(1H),7.2～7.6(9H),6.9(1H),6.6(1H),4.8(1H),4.2(2H),3.9(2H),3.5(2H)；2.9(2H)。
Example 13: preparation of (R) -1- (3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxophosphorino) phenylaminoo) propan-2-yl) -3- (4-bromophenyl) urea (FXa-49)
1. Preparation of the intermediate (R) -tert-butyl-3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxopholino) phenyl-amino) propan-2-ylcarbamate
4- (4-aminophenyl) morpholinon-3-one (2.0g, 10.41mmol) was dissolved in N, N-dimethylformamide (10ml) and tetrahydrofuran (20ml), N, N-diisopropylethylamine (5.4g, 41.64mmol) and Boc-D-Histidine-OH (2.66g, 10.41mmol) were added under ice-bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (4.75g, 12.49mmol) was added, and the reaction was stirred under ice-bath for 15 minutes, followed by turning to room temperature for 3 hours. LCMS to check reaction completion, quench with small amount of water, extract three times with ethyl acetate, wash combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue obtained is purified by column chromatography (dichloromethane)Alkane: methanol 50:1 to 15:1) to give an off-white solid, 1.21g, purity: 94%, yield: 27 percent. LC-MS (ESI) M/z430(M + H)+。
2. Preparation of the intermediate (R) -2-amino-3- (1H-imidozol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide
The product obtained in step 1 (1.20g, 2.79mmol) was dissolved in dichloromethane (10ml), and trifluoroacetic acid (5ml) was added dropwise under ice bath, followed by stirring for 15 minutes under ice bath, and then, the reaction was allowed to turn to room temperature for 3 hours. LCMS check reaction complete. Placing the reaction solution on a rotary evaporator, concentrating to dryness, and then drying in vacuum to obtain a tan solid, 920mg, purity: 94%, yield: 100 percent. The residue was used directly in the next reaction. LC-MS (ESI) M/z330(M + H)+。
3. Preparation of the intermediate (R) -1- (3- (1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) -3- (4-bromophenyl) urea
The product (230mg, 0.70mmol) obtained in step 2 was dissolved in dichloromethane (10ml), triethylamine (142mg, 1.4mmol) was added, and the dichloromethane solution (10ml) obtained in step three was added dropwise under ice bath, and the reaction was stirred at room temperature for 1 hour. LCMS detects the reaction is complete, water is added for quenching, an organic phase is separated out, anhydrous sodium sulfate is dried, and concentration is carried out. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 240mg, purity: 95%, yield: 65 percent. LC-MS (ESI) M/z527(M + H)+；1HNMR(400MHz,DMSO)ppm2.94(m,2H),3.68(m,2H),4.17(m,2H),4.33(m,2H),4.60(m,1H),6.55(m,1H),6.86(m,1H),7.2–7.6(m,10H),8.96(s,1H),10.18(s,1H),11.80(s,1H)。
Example 14: preparation of (R) -1- (4-bromophenyl) -3- (3- (1-methyl-1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxolanyl) phenylamino) propan-2-yl) urea (FXa-56)
1. Preparation of the intermediate (R) -1- (4-bromophenyl) -3- (1-oxo-1- (4- (3-oxomorphino) phenylamino) -3- (1-trityl-1H-imidozol-5-yl) propan-2-yl) urea
(R) -1- (3- (1H-Imidazol-5-yl) -1-oxo-1- (4- (3-oxomorphino) phenylaminono) -propan-2-yl) -3- (4-bromopenyl) urea (200mg, 0.40mmol) was dissolved in dichloromethane (5ml), triethylamine (101mg, 1mmol) and triphenylchloromethane (127mg, 0.46mmol) were added, and the reaction was stirred at room temperature for 1 hour. LCMS detects the reaction is complete, water is added for quenching, an organic phase is separated out, anhydrous sodium sulfate is dried, and concentration is carried out. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 257mg, purity: 92%, yield: 88 percent. LC-MS (ESI) M/z769(M + H)+；
2. Preparation of the intermediate (R) -1- (4-bromophenyl) -3- (1-oxo-1- (4- (3-oxomorphino) phenylamino) -3- (1-methyl-1H-imidozol-5-yl) propan-2-yl) urea
The product obtained in step 1 (250mg, 0.32mmol) was dissolved in N, N-dimethylformamide (2ml), sodium hydrogencarbonate (67mg, 0.80mmol) was added, and iodomethane (55mg, 0.39mmol) was added dropwise under ice bath, after which the reaction was stirred at room temperature for 2 hours. LCMS detects that the reaction is complete, water quenching is added, a large amount of solid is separated out, suction filtration is carried out, a filter cake is washed by water and dried, and a white-like solid is obtained, wherein the purity of the solid is 209 mg: 94%, yield: 82 percent. LC-MS (ESI) M/z784(M + H)+；
3. Preparation of (R) -1- (4-bromophenyl) -3- (3- (1-methyl-1H-imidozol-5-yl) -1-oxo-1- (4- (3-oxolanyl) phenylamino) propan-2-yl) urea
The product obtained in step 2 (180mg, 0.23mmol) was dissolved in dichloromethane (2ml), and trifluoroacetic acid (1ml) was added dropwise under ice bath, followed by stirring at room temperature for 2 hours. LCMS to detect reaction completion, solvent and excess trifluoroacetic acid were evaporated under reduced pressure and the resulting residue was purified by column chromatography (DCM: MeOH ═ 50: 1-15: 1) to give an off-white solid, 46mg, purity: 96%, yield: 37 percent. LC-MS (ESI) M/z541(M + H)+；1HNMR(400MHz,DMSO)ppm3.0–3.2(m,2H),3.6(m,2H),3.8(s,3H),3.96(m,2H),4.18(m,2H),4.71-4.73(m,1H),6.94-6.96(d,1H,J＝8.4Hz),7.3-7.5(m,8H),7.6(m,2H),8.81(s,1H),9.14(s,1H),10.44(s,1H).
Example 15: preparation of (R) -5-chloro-N- (3- (4-hydroxyphenylyl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) thiophene-2-carboxamide (FXa-60)
1. Preparation of intermediate (R) -tert-butyl-3- (4-hydroxypentyl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl-carbamate
4- (4-aminophenyl) morpholinon-3-one (1.37g, 7.11mmol) and Boc-D-Tryptophan-OH (2.0g, 7.11mmol) were dissolved in N, N-dimethylformamide (6ml) and tetrahydrofuran (20ml), and N, N-diisopropylethylamine (3.22g, 24.89mmol) was added under ice-bath, and finally 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (3.24g, 8.53mmol) was added, and the reaction was stirred under ice-bath for 15 minutes, followed by turning to room temperature for 3 hours. LCMS detects that the reaction is complete, decompression concentration is carried out on the reaction liquid, most tetrahydrofuran is removed, the reaction liquid is slowly added into about 100ml of water to be stirred, a large amount of off-white solid is separated out, suction filtration is carried out, decompression concentration and drying are carried out, and the off-white solid, 1.5g, purity: 92%, yield: and 47 percent. LC-MS (ESI) M/z456(M + H)+。
2. Preparation of intermediate (R) -2-amino-3- (4-hydroxyphenylyl) -N- (4- (3-oxomorphino) phenyl) -propanamide
The product obtained in step 1 (300mg, 0.66mmol) was dissolved in dichloromethane (2.0ml), and trifluoroacetic acid (1.0ml) was added dropwise under ice bath, followed by stirring for 15 minutes under ice bath, and then, the reaction was allowed to turn to room temperature for 3 hours. LCMS check reaction complete. The reaction solution was concentrated to dryness by rotary evaporation and then dried under vacuum to give a brown solid, 230mg, purity:97%, yield: 98 percent. The residue was used directly in the next reaction. LC-MS (ESI) M/z356(M + H)+。
3. Preparation of (R) -5-chloro-N- (3- (4-hydroxyphenylyl) -1-oxo-1- (4- (3-oxomorpholino) -phenylaminono) propan-2-yl) thiophene-2-carboxamide
The product (312mg, 0.88mmol) obtained in step 2 was dissolved in a mixed solution of N, N-dimethylformamide (1ml) and tetrahydrofuran (5ml), 5-chlorothiophene-2-carboxylic acid (143mg, 0.88mmol) was added thereto, N, N-diisopropylethylamine (0.77ml, 4.4mmol) was added thereto with stirring under ice bath, and after stirring for 6min, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (403mg, 1.06mmol) was added thereto, and the reaction was stirred at room temperature for 2 hours. LCMS detects that the reaction is complete, a certain amount of water is added to precipitate off-white solid, the filtration and the vacuum drying are carried out, and the obtained product is purified by a reverse phase column to obtain the off-white solid, 90mg, the purity: 98%, yield: 28 percent. LC-MS (ESI) M/z500(M + H)+；1HNMR(400MHz,DMSO)ppm2.9–3.01(m,2H),3.59–3.69(m,4H),3.95(m,2H),4.17(s,2H),4.71(s,1H),6.65(m,2H),7.14(m,3H),7.33(m,2H,),7.61(m,2H),7.8(s,1H),8.81(s,1H),9.20(s,1H).
Example 16: preparation of (R) -1- (4-bromophenyl) -3- (3- (4-hydroxypentynyl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) urea (FXa-61)
Synthesis of intermediate (R) -2-amino-3- (4-hydroxyphenylyl) -N- (4- (3-oxomorphino) phenyl) -propanamide As compound example 15.
1. Preparation of 1-bromo-4-isocyanatobenzene
Para-bromoaniline (170mg, 0.99mmol) was dissolved in dichloromethane (4.0ml), triethylamine (200mg, 1.98mmol) was added, a solution of triphosgene (293mg, 0.99mmol) in dichloromethane (2.0ml) was added dropwise under ice bath, and the reaction was stirred at room temperature for 15 minutes, followed by heating to reflux for 1 hour. LCMS check reaction complete. The resulting solution was used directly in the next reaction.
2. Preparation of (R) -1- (4-bromophenyl) -3- (3- (4-hydroxyphenylphenyl) -1-oxo-1- (4- (3-oxophosphorino) phenylamino) propan-2-yl) urea
(R) -2-amino-3- (4-hydroxyphenyl) -N- (4- (3-oxomorphino) phenyl) -propanamide (230mg, 0.65mmol) was dissolved in dichloromethane (10ml), triethylamine (130mg, 1.3mmol) was added, a dichloromethane solution (10ml) of the product obtained in step one was added dropwise under ice bath, and the reaction was stirred at room temperature for 1 hour. LCMS detects the reaction is complete, water is added for quenching, an organic phase is separated out, anhydrous sodium sulfate is dried, and concentration is carried out. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 100mg, purity: 98%, yield: 28 percent. . LC-MS (ESI) M/z554(M + H)+；1HNMR(400MHz,DMSO)ppm2.8-3.0(m,2H),3.69(m,2H),3.95(m,2H),4.18(m,2H),4.55(m,1H),6.45-6.47(d,1H,J＝8Hz),6.64-6.66(d,2H,J＝8.2Hz),7.0(m,2H),7.3-7.4(m,6H,),7.5(m,2H),8.87(s,1H),9.20(s,1H),10.20(s,1H)。
Example 17: preparation of (R) -5-chloro-N- (3- (4-methoxyphenylyl) -1-oxo-1- (4- (3-oxophosphorino) phenylaminoo) propan-2-yl) thiophene-2-carboxamide (FXa-62)
1. Preparation of intermediate (R) -methyl2- (tert-butoxycarbonyl) -3- (4-methoxyphenyl) propanoate
Boc-D-Tryptophan-OH (500mg, 1.78mmol) was dissolved in N, N-dimethylformamide (4.0ml), stirred under ice bath until completely dissolved, after which potassium carbonate (700mg, 3.0mmol) and iodomethane (550mg, 2.20mmol) were added in one portion, followed by turning to room temperature for reaction for 3 hours. TLC detection of the completion of the reaction of the raw materials, the reactionThe reaction solution is extracted, and the organic phase is concentrated and dried under reduced pressure to obtain brown oily liquid with the purity of 500 mg: 95%, yield: 90 percent.1HNMR(400MHz,CDCl3)ppm1.31(s,9H),2.78–2.85(m,2H),3.65(s,3H),4.03-4.23(s,3H),5.37(s,1H),6.62-7.03(m,4H).
2. Preparation of intermediate (R) -2- (tert-butoxycarbnyl) -3- (4-methoxyphenyl) propanoic acid
The product obtained in step 1 (500mg, 1.61mmol) was dissolved in anhydrous methanol (3.0ml), and 10% aqueous sodium hydroxide solution (1.5ml) was slowly added under ice bath, followed by stirring and reacting for 1.5 hours. TLC detects that the raw materials react completely, adjusts the PH of the reaction solution to about 6 with 1N hydrochloric acid aqueous solution, extracts, and then performs pressure concentration and drying on the organic phase to obtain a brown solid, 350mg, purity: 95%, yield: 75 percent.1HNMR(400MHz,DMSO)ppm1.33(s,9H),2.79–2.88(m,2H),3.60-3.71(s,3H),6.84-7.21(m,4H).
3. Preparation of intermediate (R) -tert-butyl-3- (4-methoxyphenyl) -1-oxo-1- (4- (3-oxomorphino) -phenylaminono) propan-2-ylcarbamate
The product obtained in step 2 (350mg, 1.185mmol) and 4- (4-aminophenyl) morpholin-3-one (230mg, 1.185mmol) were dissolved in N, N-dimethylformamide (1ml) and tetrahydrofuran (5ml), and N, N-diisopropylethylamine (536mg, 4.147mmol) was added under ice-bath, and finally (540mg, 1.422mmol) was added, and the reaction was stirred under ice-bath for 15 minutes, after which it was allowed to turn to room temperature for 3 hours. LCMS detects that the reaction is complete, decompression concentration is carried out on the reaction liquid, most tetrahydrofuran is removed, the reaction liquid is slowly added into about 80ml of water to be stirred, a large amount of off-white solid is separated out, suction filtration is carried out, decompression concentration and drying are carried out, and the off-white solid is obtained, 390mg, purity: 99%, yield: 71 percent. LC-MS (ESI) M/z470(M + H)+。
4. Preparation of intermediate (R) -2-amino-3- (4-methoxyphenyl) -N- (4- (3-oxomorphino) phenyl) -propanamide
The product obtained in step 3 (200mg, 0.427mmol) was dissolved in dichloromethane (2.0ml), trifluoroacetic acid (1.0ml) was added dropwise in ice bath, and the reaction was stirred for 15 minutes in ice bath,then, the reaction mixture was cooled to room temperature for 3 hours. LCMS check reaction complete. The reaction solution was concentrated to dryness by rotary evaporation and then dried under vacuum, and the residue was used directly in the next reaction. LC-MS (ESI) M/z370(M + H)+。
5. Preparation of (R) -5-chloro-N- (3- (4-methoxyphenyl) -1-oxo-1- (4- (3-oxophosphorino) -phenylaminono) propan-2-yl) thiophene-2-carboxamide
The product obtained in step 4 (312mg, 0.362mmol) and 7(58.9mg, 0.362mmol) were dissolved in a mixed solution of N, N-dimethylformamide and tetrahydrofuran, N, N-diisopropylethylamine (0.32ml, 1.81mmol) was added with stirring in an ice bath, and after stirring for 6min, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (165mg, 0.434mmol) was added, and the reaction was stirred at room temperature for 2 hours. LCMS detects that the reaction is complete, a certain amount of water is added to precipitate off-white solid, the filtration and the vacuum drying are carried out, and the obtained product is purified by a reverse phase column to obtain the off-white solid, 40mg, the purity: 98%, yield: 22 percent. LC-MS (ESI) M/z514(M + H)+；1HNMR(400MHz,DMSO)ppm2.97–3.33(m,4H),3.69(s,5H),3.95(m,2H),4.17(s,2H),6.83(m,2H),7.19-7.34(m,5H),7.62(d,2H,J＝6Hz),7.81(d,1H,J＝4Hz),8.92(d,1H,J＝6Hz)
Example 18: preparation of (R) -1- (3- (1H-indol-2-yl) -1-oxo-1- (4- (3-oxophosphorino) phenylamino) propan-2-yl) -3- (3-bromophenyl) urea (FXa-63)
1. Preparation of 1-bromo-3-isocyanatobenzene
M-bromoaniline (110mg, 0.64mmol) was dissolved in dichloromethane (3.0ml), triethylamine (130mg, 1.28mmol) was added, and a solution of triphosgene (190mg, 0.64mmol) in dichloromethane (5.0ml) was added dropwise under ice bath, stirred at room temperature for reaction for 15 minutes, and then heated to reflux for 1 hour. LCMS check reaction complete. The resulting solution was used directly in the next reaction.
2. Preparation of (R) -1- (3- (1H-indol-2-yl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) -propan-2-yl) -3- (3-bromophenyl) urea
(R) -2-amino-3- (1H-indol-2-yl) -N- (4- (3-oxomorphino) phenyl) propanamide (156mg, 0.42mmol) was dissolved in dichloromethane (10ml), triethylamine (0.12ml, 0.84mmol) was added, and the dichloromethane solution (8ml) obtained in step one was added dropwise under ice bath, and the reaction was stirred at room temperature for 1 hour. LCMS detects the reaction is complete, water is added for quenching, an organic phase is separated out, anhydrous sodium sulfate is dried, and concentration is carried out. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 90mg, purity: 98%, yield: 38 percent. LC-MS (ESI) M/z568(M + H)+；1HNMR(400MHz,DMSO)ppm3.17(m,2H),3.95(m,2H),4.08(m,2H),4.8-5.0(m,1H),6.5(m,1H),6.85(m,2H),7.13(m,2H),7.3-7.4(m,6H),7.4(m,1H),7.57(m,2H),8.87(s,1H),10.24(s,1H)。
Example 19: preparation of (R) -1- (4-chlorophenylyl) -3- (3- (4-hydroxyphenylyl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) urea (FXa-65)
Synthesis of intermediate (R) -2-amino-3- (4-hydroxyphenylyl) -N- (4- (3-oxomorphino) phenyl) -propanamide As compound example 15.
1. Preparation of 1-chloro-4-isocyanatobenzene
P-chloroaniline (85mg, 0.66mmol) was dissolved in dichloromethane (3.0ml), triethylamine (135mg, 1.3mmol) was added, a solution of triphosgene (196mg, 0.66mmol) in dichloromethane (2.0ml) was added dropwise under ice bath, the reaction was stirred at room temperature for 15 minutes, and then heated to reflux for 1 hour. LCMS check reaction complete. The resulting solution was used directly in the next reaction.
2. Preparation of (R) -1- (4-chlorophenylyl) -3- (3- (4-hydroxyphenylyl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) urea
(R) -2-amino-3- (4-hydroxyphenyl) -N- (4- (3-oxomorphino) phenyl) -propanamide (150mg, 0.42mmol) was dissolved in dichloromethane (10ml), triethylamine (0.12ml, 0.84mmol) was added, and the dichloromethane solution (5ml) obtained in step one was added dropwise under ice bath, and the reaction was stirred at room temperature for 1 hour. LCMS detects the reaction is complete, water is added for quenching, an organic phase is separated out, anhydrous sodium sulfate is dried, and concentration is carried out. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 72mg, purity: 98%, yield: 34 percent. LC-MS (ESI) M/z509(M + H)+；1HNMR(400MHz,DMSO)ppm2.82(m,1H),2.94(m,1H),3.69(m,2H),3.96(m,2H),4.18(s,2H),4.556-4.570(m,1H,J＝1.6Hz),6.45(m,1H),6.646-6.668(m,2H,J＝8.8Hz),7.25-7.37(m,6H),7.57(m,2H),8.87(s,1H),9.20(s,1H),10.24(s,1H).
Example 20: preparation of (R) -1- (3- (1H-indol-2-yl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) propan-2-yl) -3- (4-chlorophenylyl) urea (FXa-66)
1. Preparation of 1-chloro-4-isocyanatobenzene
P-chloroaniline (650mg, 5.1mmol) was dissolved in dichloromethane (15ml), triethylamine (1.03g, 10.2mmol) was added, a solution of triphosgene (1.51g, 5.1mmol) in dichloromethane (5.0ml) was added dropwise under ice bath, and the reaction was stirred at room temperature for 15 minutes, followed by heating to reflux for 1 hour. LCMS check reaction complete. The resulting solution was used directly in the next reaction.
2. Preparation of (R) -1- (3- (1H-indol-2-yl) -1-oxo-1- (4- (3-oxomorphino) phenylamino) -propan-2-yl) -3- (4-chlorophenylyl) urea
(R) -2-amino-3- (1H-indol-2-yl) -N- (4- (3-oxomorphino) phenyl) propanamide (1.0g, 2.64mmol) was dissolved in methylene chloride (20ml), triethylamine (270mg, 2.64mmol) was added, and the methylene chloride solution (20ml) obtained in step one was added dropwise under ice bath, and the reaction was stirred at room temperature for 1 hour. LCMS detects the reaction is complete, water is added for quenching, an organic phase is separated out, anhydrous sodium sulfate is dried, and concentration is carried out. The residue was purified by column chromatography (dichloromethane: methanol: 50: 1-15: 1) to give an off-white solid, 560mg, purity: 96%, yield: 40 percent. LC-MS (ESI) M/z532(M + H)+；1HNMR(400MHz,DMSO)ppm2.5(s，1H)，3.2–3.3(m,2H),3.7(d,2H),3.9(s,2H),4.2(s,2H),4.6-4.7(m,1H),6.4(s,1H),6.9(m,1H),7.04(m,1H),7.12-7.13(m,1H),7.26-7.32(m,7H),7.6(m,3H),8.86(s,1H),10.2(s,1H),10.85(s,1H)。
Example 21: preparation of (S) -2- (3- (4-bromophenyl) ureido) -3- (1H-imidazol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide (FXa-80)
1. Preparation of the intermediate (S) -tert-butyl (3- (1H-imidozol-5-yl) -1-oxo-1- ((4- (3-oxopholino) phenyl) amino) propan-2-yl) carbamate
In a 50ml dry three-necked flask, 2g of N-Boc-L-histidine was dissolved in 15ml of DMF, followed by addition of 4.03g (4.0eq) of DIEA and 1.51g (1.0eq) of 4- (4-aminophenyl) -3-morpholinone with stirring, followed by cooling the system to 0 ℃ and addition of 3.58g (1.2eq) of HATU in portions, followed by stirring at 25 ℃ for 70 hours. The reaction was stopped, quenched with 60ml of water, extracted several times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH: DCM ═ 1:100 to 1:10) to give 2.2g of product as an off-white solid, [ LCMS (M/z):430(M + H)+]；1HNMR(DMSO,400MHz):ppm8.1(1H),7.2～7.6(5H),7.0(2H),4.4(1H),4.2(2H),4.0(2H),3.7(2H),2.7(2H),1.3(9H).
2. Preparation of the intermediate (S) -2-amino-3- (1H-imidozol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide
245mg of (S) -tert-butyl (3- (1H-imidozol-5-yl) -1-oxo-1- ((4- (3-oxolinolino) amino) propan-2-yl) carbamate obtained in step 1 was dissolved in 2ml of dry dichloromethane in a 5ml dry flask at room temperature, 1ml of trifluoroacetic acid was added thereto at about 10 ℃ and RT. was stirred under a closed condition for 2 hours. The reaction was spin-dried to give the trifluoroacetate salt of FXa-80-A2, which was used directly in the next step. LCMS (M/z):330(M + H)+].
3. Preparation of (S) -2- (3- (4-bromophenyl) ureido) -3- (1H-imidazol-5-yl) -N- (4- (3-oxomorphino) phenyl) propanamide
Dissolving FXa-80-A2 trifluoroacetate in DCM, cooling to 0-5 ℃, controlling the temperature, slowly adding 2.5g DIEA dropwise, reacting for 1h under stirring at RT, cooling to about 0 ℃, slowly adding an FXa-80-A3 system, stirring for 2h at RT., adding water for quenching reaction, removing an organic solvent by rotation, washing a water phase with diethyl ether for 3 times, extracting with DCM for multiple times, washing the organic phase with saturated saline solution, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, recrystallizing and filtering with EA, and drying a filter cake to obtain 18.7mg of a product. LCMS (M/z):527(M + H)+]；1HNMR(DMSO,400MHz):ppm10.2(1H),9.0(1H),7.7(1H),7.6(2H)7.3(6H),6.9(1H),6.6(1H),4.6(1H),4.2(2H),3.9(4H),3.1(2H).
Example 22: preparation of (S) -2- (5-chlorothiophene-2-carboxamido) -N1- (4- (3-oxomorphino) phenyl) succinamide (FXa-84)
1. Preparation of intermediate (S) -2-amino-4-methoxy-4-oxobutanoicacidyldichlororide
In 50ml three-portIn a bottle, 5g (39.59mmol,1.0eq) of D-aspartic acid was dissolved in 30ml of methanol at RT. deg.C, cooled to 0 deg.C, and 4.43g (39.6mmol,1.0eq) of SOCl was slowly added dropwise2Naturally raising the temperature to room temperature and stirring for reaction for 2 hours. 60ml of diethyl ether was added to the reaction system, suction filtration was carried out under reduced pressure, the filter cake was washed with diethyl ether, and the filter cake was dried to give 4.73g of a product, [ LCMS (M/z):148(M + H)+]；1HNMR(DMSO,400MHz):ppm8.5(2H),4.2(1H),3.6(3H),2.9(2H。
2. Preparation of intermediate (S) -2- ((tert-butoxycarbnyl) amino) -4-methoxy-4-oxobutanoicacid
In a 100ml dry three-necked flask, 4.73g (25.7mmol, 1.0eq) (S) -2-amino-4-methoxy-4-oxobutanoicidhydoxychloride was dissolved in 50ml1:1 THF/H at room temperature2O system, 5.45gNa is added2CO3(51mmol, 2.0eq), stirring at room temperature for 0.5h, cooling to about 5 deg.C, and slowly adding dropwise 6.17g (51.2mmol, 2.0eq) (Boc)2O in THF, RT stirred overnight. The THF was removed by spinning, the aqueous phase was extracted three times with EA, the PH of the aqueous phase was adjusted to around 4, the aqueous phase was dried to give a white solid, and the solid was washed several times with EA until no product signal was present. The EA was removed by rotary evaporation to give 2.54g of product. LCMS (M/z):248(M + H)+]；1HNMR(DMSO,400MHz):ppm6.5(1H),4.2(1H),3.6(3H),2.7(1H),2.6(1H),1.4(9H)。
3. Preparation of intermediate (S) -methyl-3- ((tert-butoxycarbnyl) amino) -4-oxo-4- ((4- (3-oxomorpholino) phenyl) amino) butanoate
In a 50ml dry three-necked flask, 1.94g (7.8mmol,1.0eq) of (S) -2- ((tert-butoxycarbonyl) amino) -4-methoxy-4-oxobutanoicic acid was dissolved in 12ml DMF at room temperature, followed by addition of 3.04g (23.56mmol,3.0eq) of DIEA and 1.5g (7.8mmol,1.0eq) of 4- (4-aminophenyl) -3-morpholinone with stirring, then the system was cooled to 0 ℃ and 3.58g (9.43mmol,1.2eq) of HATU were added in portions, followed by stirring at 25 ℃ overnight. Stopping the reaction, adding 50ml of water for quenching, extracting the mixture for multiple times by using ethyl acetate, washing an organic phase by using saturated saline solution, drying the organic phase by using anhydrous sodium sulfate, concentrating the dried organic phase under reduced pressure, and purifying a crude product by column chromatography (MeOH: DCM ═ 1: 150-1: 60) to obtain a light yellow solid product2.6g。[LCMS(m/z):422(M+H)+]；1HNMR(CDCl3,400MHz):ppm8.7(1H)7.6(2H),7.3(2H),5.9(1H),4.7(1H),4.4(2H),4.1(2H),3.7(5H),3.0(1H),2.8(1H)1.5(9H).
4. Preparation of intermediate (S) -methyl-3-amino-4-oxo-4- ((4- (3-oxomorphino) phenyl) amino) butanoate
In a 50ml dry flask, 1g (2.37mmol,1.0eq) (S) -methyl3- ((tert-butoxycarbonyl) amino) -4-oxo-4- ((4- (3-oxophosphorino) phenyl) amino) butanoate was dissolved in 5ml dry dichloromethane at room temperature, 1.8ml trifluoroacetic acid was added at about 10 ℃ and RT. was stirred under sealed conditions overnight. The obtained product is stored under sealed condition and directly used in the next step. LCMS (M/z):322(M + H)+]。
5. Preparation of intermediate (S) -methyl-3- (5-chlorothiophene-2-carboxamido) -4-oxo-4- ((4- (3-oxomorpholino) phenyl) amino) butanoate
Cooling the FXa-84-A4 reaction system to 0-5 ℃, slowly dropwise adding 5.07g of DIEA, stirring and reacting at room temperature for 0.5h, adding 385mg of 5-chloro-2-thiophenecarboxylic acid, adding 1.08g of HATU in batches at about 10 ℃, stirring and reacting at RT for 3h, adding water for quenching, extracting for multiple times by using EA, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating a crude product, and purifying by column chromatography to obtain 972mg of a product.
[LCMS(m/z):466(M+H)+]；1HNMR(DMSO,400MHz):ppm10.3(1H),9.0(1H),7.8(1H),7.6(2H),7.3(2H),7.1(1H),4.9(1H),4.2(2H),3.9(2H),3.6(5H),2.9(1H),2.8(1H)。
6. Preparation of intermediate (S) -3- (5-chlorothiophene-2-carboxamido) -4-oxo-4- ((4- (3-oxomorphino) phenyl) amino) butanoicacid
900mg (1.93mmol,1.0eq) of (S) -methyl-3- (5-chlorothiophene-2-carboxamido) -4-oxo-4- ((4- (3-oxophosphorino) phenyl) amino) butanoate are dissolved in 10ml of THF/MeOH/H2O (3:1:1), 243mg (243mg,3.0eq) of LiOH.H are added portionwise at 0 ℃2Stirring and reacting O, RT. for 1.5h, removing solvent, dissolving in water, extracting aqueous phase with EA three times, adjusting pH of aqueous phase to about 3, and extracting with EA for multiple timesWashing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain 120mg pure product.
[LCMS(m/z):452(M+H)+]；1HNMR(DMSO,400MHz):ppm10.1(1H),9.0(1H),7.7(1H),7.6(2H)7.3(2H),7.2(1H),4.7(1H),4.2(2H),3.9(2H),3.6(2H),3.0(1H),2.8(1H)。
7. Preparation of (S) -2- (5-chlorothiophene-2-carboxamido) -N1- (4- (3-oxomorphino) phenyl) succinylamide
In a 10ml dry flask, 89mg (0.2mmol,1.0eq) of (S) -3- (5-chlorothiophene-2-carboxamido) -4-oxo-4- ((4- (3-oxophosphorino) phenyl) amino) butanoicacid was dissolved in 2ml DMF at room temperature, followed by addition of 99mg (0.8mmol,4.0eq) DIEA, 41mg (0.8mmol,4.0eq) NH4Cl, 73.4mg (0.4mmol,2.0eq) EDCI and 52mg (0.4mmol,2.0eq) after which the reaction was stirred at 25 ℃ overnight. The reaction was stopped, 20ml of water was added and quenched, extracted several times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the crude EA recrystallized to yield 50mg of product.
[LCMS(m/z):451(M+H)+]；1HNMR(DMSO,400MHz):ppm10.1(1H),9.0(1H),7.7(1H),7.6(2H),7.5(1H),7.3(2H),7.2(2),4.7(1H),4.2(2H),3.9(2H),3.6(2H),3.0(1H),2.8(1H)。
Example 23: preparation of (R) -5-chloro-N- (1-oxo-1- ((4- (3-oxomorpholino) phenyl) amino) -3-phenylpropan-2-yl) thiophene-2-carboxamide (FXa-93)
1. Preparation of intermediate (R) -2- ((tert-butoxycarbnyl) amino) -3-phenylpropanoic acid
In a 50ml dry single-neck flask, 0.5g of (R) -2-amino-3-phenylpropanoic acid was dissolved in 4ml of THF and 1ml of water, and 0.127g was added under RT.(1.05eq) sodium hydroxide as alkali, stirring for 30min, cooling to about 0 deg.C, and slowly adding dropwise 0.727g (1.1eq) (Boc)2The THF solution of O naturally rises to RT for 3 h. The reaction was stopped, the PH was adjusted to 3 to 4 at low temperature, extracted with EA for about 5 times, washed with saturated brine, dried and concentrated to give 412mg of a light brown oil.
[LCMS(m/z):266(M+H)+]。
2. Preparation of intermediate (R) -tert-butyl (1-oxo-1- ((4- (3-oxomorphino) phenyl) amino) -3-phenylpropan-2-yl) carbamate
In a 50ml dry single-neck flask, 200mg of (R) -2- ((tert-butoxycarbonyl) amino) -3-phenylpropanoic acid was dissolved in 4ml DCM, 389mg (4.0eq) DIEA and 145mg (1.0eq)4- (4-aminophenyl) morpholinolin-3-one were added in succession under RT., 344mg (1.2eq) HATU was added in portions at about 10 ℃, and the reaction was stirred at room temperature for about 3 hours. The reaction was stopped, water was added to quench the reaction, and extraction was repeated with DCN, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 357mg of pure product.
[LCMS(m/z):440(M+H)+]。
3. Preparation of intermediate (R) -2-amino-N- (4- (3-oxomorphino) phenyl) -3-phenylpropanamide
In a 50ml dry flask, 300mg of ((R) -tert-butyl (1-oxo-1- ((4- (3-oxomorphino) phenyl) amino) -3-phenylpropan-2-yl) carbamate was dissolved in 4ml of dry dichloromethane under RT., 0.5ml of trifluoroacetic acid was added, the reaction was stirred for 1h in a closed system, and the solvent was spin-dried for use.
[LCMS(m/z):340(M+H)+]。
4. Preparation of the intermediate (R) -5-chloro-N- (1-oxo-1- ((4- (3-oxomorpholino) phenyl) amino) -3-phenylpropan-2-yl) thiophene-2-carboxa
Adding 3g DIEA into the product system obtained in the third step at 0 ℃, stirring and reacting for 0.5h at RT, adding 111mg5-chlorothiophene-2-carboxylic acid at RT. ℃, adding 312mg HATU at 10 ℃ below, and stirring and reacting at RTAfter the reaction was terminated for 1 hour, the reaction mixture was quenched with water, extracted with EA several times, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a purified product of 174 mg. LCMS (M/z):484(M + H)+)]。
1HNMR(MeOD,400MHz):ppm7.6(3H),7.3(7H),7.0(1H),4.9(1H),4.3(2H),4.0(2H),3.8(2H),3.2(1H),3.1(1H)。
Example 24: preparation of (R) -4- (5-chlorothiophene-2-carboxamido) -5-oxo-5- ((4- (3-oxomorphino) phenyl) amino) pentanicacid (FXa-98)
1. Preparation of intermediate (R) -2-amino-4-methoxy-4-oxobutanoicacidyldichlororide
In a 50ml three-necked flask, 5g (39.59mmol,1.0eq) of L-aspartic acid was dissolved in 30ml of methanol at RT. deg.C, and 4.43g (39.6mmol,1.0eq) of SOCl was slowly added dropwise thereto at 0 deg.C2Naturally raising the temperature to room temperature and stirring for reaction for 2 hours. Adding 60ml of diethyl ether into the reaction system, carrying out vacuum filtration, washing the filter cake with diethyl ether, and airing the filter cake to obtain 4.73g of the product.
[LCMS(m/z):148(M+H)+]；1HNMR(DMSO,400MHz):ppm8.5(2H),4.2(1H),3.6(3H),2.9(2H)。
2. Preparation of intermediate (R) -2- ((tert-butoxycarbnyl) amino) -4-methoxy-4-oxobutanoicacid
In a 100ml dry three-necked flask, 4.73g (25.7mmol, 1.0eq) (R) -2-amino-4-methoxy-4-oxobutanoicidhydoxychloride was dissolved in 50ml1:1 THF/H at room temperature2O system, 5.45gNa is added2CO3(51mmol, 2.0eq), stirring at room temperature for 0.5h, cooling to about 5 deg.C, and slowly adding dropwise 6.17g (51.2mmol, 2.0eq) (Boc)2O in THF, RT stirred overnight. THF was removed by spinning, the aqueous phase was extracted three times with EA, the pH of the aqueous phase was adjusted to about 4,the aqueous phase was spin dried to give a white solid, and the solid was washed several times with EA until no product signal was present. The EA was removed by rotary evaporation to give 2.54g of product.
[LCMS(m/z):248(M+H)+]；1HNMR(DMSO,400MHz):ppm6.5(1H),4.2(1H),3.6(3H),2.7(1H),2.6(1H),1.4(9H)。
3. Preparation of intermediate (R) -methyl3- ((tert-butoxycarbnyl) amino) -4-oxo-4- ((4- (3-oxomorpholino) phenyl) amino) butanoate
In a 50ml dry three-necked flask, (R) -2- ((tert-butoxycarbonyl) amino) -4-methoxy-4-oxobutanoicacid (1.94g, 7.8mmol,1.0eq) was added dissolved in 12ml DMF at room temperature, followed by addition of 3.04g (2356mmol,3.0eq) DIEA and 1.5g (7.8mmol,1.0eq)4- (4-aminophenyl) -3-morpholinone with stirring, and then the system was cooled to 0 ℃ and 3.58g (9.43mmol,1.2eq) HATU was added in portions, followed by stirring at 25 ℃ overnight. The reaction was stopped, quenched with 50ml of water, extracted with ethyl acetate several times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH: DCM ═ 1:150 to 1:60) to give 2.6g of a pale yellow solid product [ LCMS (M/z):422(M + H)+]。
1HNMR(CDCl3,400MHz):ppm8.7(1H)7.6(2H),7.3(2H),5.9(1H),4.7(1H),4.4(2H),4.1(2H),3.7(5H),3.0(1H),2.8(1H)，1.5(9H)。
4. Preparation of intermediate (R) -methyl3-amino-4-oxo-4- ((4- (3-oxomorphino) phenyl) amino) butanoate
In a 50ml dry flask, (R) -methyl3- ((tert-butoxycarbonyl) amino) -4-oxo-4- ((4- (3-oxophosphorino) phenyl) amino) butanoate (1.00g, 2.37mmol,1.0eq) was added at room temperature dissolved in 5ml dry dichloromethane, 1.8ml trifluoroacetic acid was added at about 10 ℃ and stirred under RT. closed conditions overnight. The obtained product is stored under sealed condition and directly used in the next step.
[LCMS(m/z):322(M+H)+]；
5. Preparation of intermediate (R) -methyl-3- (5-chlorothiophene-2-carboxamido) -4-oxo-4- ((4- (3-oxomorpholino) phenyl) amino) butanoate
Cooling the FXa-94-A4 reaction system to 0-5 ℃, slowly dropwise adding 5.07g of DIEA, stirring and reacting at room temperature for 0.5h, adding 385mg of 5-chloro-2-thiophenecarboxylic acid, adding 1.08g of HATU in batches at about 10 ℃, stirring and reacting at RT for 3h, adding water for quenching, extracting for multiple times by using EA, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating a crude product, and purifying by column chromatography to obtain 972mg of a product. LCMS (M/z):466(M + H)+]。
1HNMR(DMSO,400MHz):ppm10.3(1H),9.0(1H),7.8(1H),7.6(2H),7.3(2H),7.1(1H),4.9(1H),4.2(2H),3.9(2H),3.6(5H),2.9(1H),2.8(1H)。
6. Preparation of (R) -3- (5-chlorothiophene-2-carboxamido) -4-oxo-4- ((4- (3-oxomorpholino) phenyl) amino) butanoicacid
(R) -methyl-3- (5-chlorothiophene-2-carboxamido) -4-oxo-4- ((4- (3-oxophosphorino) phenyl) amino) butanoate (900mg, 1.93mmol,1.0eq) was dissolved in 10ml THF/MeOH/H2O (3:1:1), 243mg (243mg,3.0eq) of LiOH.H are added portionwise at 0 ℃2Stirring and reacting O, RT. for 1.5h, removing the solvent, dissolving in water, extracting the water phase with EA three times, adjusting the pH of the water phase to about 3, extracting with EA for multiple times, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating the crude product, and purifying by column chromatography to obtain 120mg of pure product.
[LCMS(m/z):452(M+H)+]；1HNMR(DMSO,400MHz):ppm10.1(1H),9.0(1H),7.7(1H),7.6(2H)7.3(2H),7.2(1H),4.7(1H),4.2(2H),3.9(2H),3.6(2H),3.0(1H),2.8(1H)。
Example 25: preparation of (R) -2- (5-chlorothiophene-2-carboxamido) -N1- (4- (3-oxomorphino) phenyl) pentanediamide (FXa-99)
In a 10ml dry flask, 89mg of FXa-98 obtained in example 24 was dissolved in 2ml of DMF at room temperature, and 99mg (0.8mmol,4.0eq) of DIEA, 41mg (0.8mmol,4.0eq) of NH, was added under stirring4Cl, 73.4mg (0.4mmol,2.0eq) EDCI and 52mg (0.4mmol,2.0eq) after which the reaction was stirred at 25 ℃ overnight. The reaction was stopped, 20ml of water was added and quenched, extracted several times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the crude EA recrystallized to yield 50mg of product. LCMS (M/z):451(M + H)+].1HNMR(DMSO,400MHz):ppm10.1(1H),9.0(1H),7.7(1H),7.6(2H),7.5(1H),7.3(2H),7.2(2),4.7(1H),4.2(2H),3.9(2H),3.6(2H),3.0(1H),2.8(1H)。
Experimental example 1: biological activity test experiment:
1. compound inhibition of factor ten activity test experiment:
compounds were 3-fold serially diluted in dimethyl sulfoxide. The diluted compound was then re-used with reaction buffer (50mM Tris, pH 8.3; 150mM NaCl; 2mM CaCl)2(ii) a 0.005% tween 20) was further diluted 100-fold. After preincubation of the compound with the tenth factor (final concentration of 0.8 nm) in reaction buffer for 15 minutes, 1/2 volumes of fluorogenic substrate (Anaspec, USA) were added. The samples were read on a microplate reader in kinetic mode at 30 ℃ for 30 minutes (485nm excitation wavelength, and 530nm emission wavelength). The rate of signal increase is plotted against compound concentration and the data is fitted to a 4-parameter Hill equation to give a 50% Inhibitory Concentration (IC)50) The specific results are shown in Table 1.
TABLE 1 inhibitory Activity of the tenth factor (IC)50)
| Compound numbering | Inhibitory Activity of factor tenth (IC)50，μM) | Compound numbering | Inhibitory Activity of factor tenth (IC)50，μM) |
| Example 1 | 10 | Example 33 | 0.0008 |
| Example 2 | 10 | Example 34 | 3.06 |
| Example 3 | 2.20 | Example 35 | 0.0028 |
| Example 4 | 7.60 | Example 36 | 1.23 |
| Example 5 | 5.10 | Example 37 | 0.0048 |
| Example 6 | 10 | Example 38 | 0.016 |
| Example 7 | 10 | Example 39 | 0.0006 |
| Example 8 | 10 | Example 40 | 0.006 |
| Example 9 | 10 | EXAMPLE 41 | 0.006 |
| Example 10 | 2.50 | Example 42 | 0.0007 |
| Example 11 | 0.24 | Example 43 | 0.0019 |
| Example 12 | 10 | Example 44 | 2.35 |
| Example 13 | 10 | Example 45 | 1.9 |
| Example 14 | 0.32 | Example 46 | 3.66 |
| Example 15 | 0.002 | Example 47 | 10 |
| Example 16 | 0.020 | Example 48 | 10 |
| Example 17 | 0.0040 | Example 49 | 2.44 |
| Example 18 | 0.014 | Example 50 | 2.98 |
| Example 19 | 0.022 | Example 51 | 0.0036 |
| Example 20 | 10 | Example 52 | 0.043 |
| Example 21 | 10 | Example 53 | 0.01 |
| Example 22 | 10 | Example 54 | 0.005 |
| Example 23 | 10 | Example 55 | 10 |
| Example 24 | 10 | Example 56 | 0.009 |
| Example 25 | 10 | Example 57 | 0.09 |
| Example 26 | 0.13 | Example 58 | 0.035 |
| Example 27 | 0.0030 | Example 59 | 0.223 |
| Example 28 | 0.67 | Example 60 | 0.065 |
| Example 29 | 0.34 | Example 61 | 0.012 |
| Example 30 | 0.0002 | Example 62 | 0.009 |
| Example 31 | 0.70 | Example 63 | 1.3 |
| Example 32 | 5.81 |
2. Pharmacokinetic testing:
accurately weighing 1.33mg of compound, adding 0.333mL of DMSO, vortexing for 1 minute, sonicating for 2 minutes, then adding 2.66mL of PEG400, vortexing for 1 minute, sonicating for 2 minutes, finally adding 3.658mL of physiological saline, vortexing for 1 minute, sonicating for 2 minutes to obtain a clear solution, and preparing the clear solution with the concentration of 0.2mg/mL to be a colorless clear solution (pH value is 8) for intravenous administration of the group 1.
Accurately weighing 5.46mg of compound, adding 0.546mL of DMSO, vortexing for 1 minute, sonicating for 2 minutes, then adding 4.368mL of PEG400, vortexing for 1 minute, sonicating for 2 minutes, finally adding 6.006mL of physiological saline, vortexing for 1 minute, sonicating for 2 minutes to obtain a clear solution, preparing the clear solution with the concentration of 0.5mg/mL (pH-9) as a colorless clear solution, and using the clear solution for group 2 oral administration.
200 μ L of each test solution was retained and the concentration of the dosing solution was measured by HPLC.
6 rats were administered intravenously and orally in two groups. Fasting was for 12-16 hours before oral administration. Food intake was resumed 4 hours after dosing. Detailed clinical observations were made before and after dosing and no abnormalities were found.
Blood is respectively collected from each animal, and the blood collection time points of the animals are as follows: intravenous and oral: before administration, 5min, 15min, 30min, 1h, 2h, 3h, 5h, 8h and 24h after administration; approximately 0.25mL of blood was collected via the jugular vein and anticoagulated with heparin sodium. Blood samples were collected, placed on ice and plasma was centrifuged within 30 minutes (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ℃). The collected plasma was stored at-80 ℃ before analysis.
The sample was taken out of the refrigerator (-80 ℃), allowed to thaw spontaneously at room temperature, and vortexed for 30 seconds, and 50. mu.L of the sample was taken into a 1.5mL centrifuge tube. Add 250. mu.L of internal standard solution (200ng/mL of tolbutamide in methanol), vortex for 60 seconds and centrifuge for 5 minutes (15000 rpm), apply 200. mu.L of supernatant to a 96-well plate, and sample in an ultra high performance liquid chromatography system (Waters, ACQUITYUPLC) -Mass spectrometer (API4000, applied biosystems, USA, electrospray ionization (ESI), tandem quadrupole mass analyzer) for analysis.
The data are processed by an Analyst software data processing system to obtain pharmacokinetic results.
The results are shown in Table 2
Table 2 partial compound pharmacokinetic data
| Compound numbering | Tmax | t1/2 | ClzL/hr/kg | VzL/kg | F |
| FXa-14 | 2.00±0.00 | 1.46～1.70 | 0.88±0.17 | 1.37±0.10 | 2.19±0.24％ |
| FXa-84 | 2.33±0.58 | 2.96～3.78 | 0.38±0.08 | 0.71±0.11 | 14.75±4.52％ |
| FXa-49 | 2.86±4.46 | 1.58～2.99 | 1.27±0.59 | 2.83±1.08 | 0.78±0.16％ |
| FXa-86 | 1.50±0.87 | 0.77～0.92 | 1.29±0.24 | 1.54±0.31 | 0.31±0.11％ |
| FXa-93 | 0.25±0.00 | 0.87～1.39 | 2.40±0.27 | 1.30±0.13 | 6.78±1.63％ |
| FXa-61 | 2.00±0.0 | 2.12～2.85 | 1.69±0.63 | 2.71±1.05 | 1.82±0.37％。 |
| FXa-20 | 0.25±0.00 | 1.53～3.45 | 3.61±0.48 | 2.19±0.08 | 5.39±1.06％ |
The results in Table 2 show the absorption, drug distribution, metabolic rate, excretion and bioavailability of the compounds in rat animals.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A compound or pharmaceutically acceptable salt having the structure of formula I:
wherein,
R1is aryl, heterocyclic group, alkyl, aryl ether, heterocyclic ether, alkyl ether, arylamine, heterocyclic amine or alkylamino;
R2is aryl, heterocyclic group orAn alkyl group;
R3is a morpholinophenyl, aryl, heterocyclic group or alkyl group;
x is nitrogen.
2. The compound or pharmaceutically acceptable salt according to claim 1, wherein R is1Is one of the following structures:
R4，R5，R6each independently is H, F, Cl, Br, carboxyl or alkyl.
3. A process for the preparation of a compound according to claim 1 or 2, comprising the step of reacting an N-protected α -amino acid with the corresponding R3-NH2The corresponding amide is obtained by reaction, the protective agent is removed under the acidic condition, and then the product is condensed with carboxylic acid or acyl chloride, or isocyanate, chloroformate and the like are reacted to obtain the corresponding tenth factor inhibitor compound.
4. A method according to claim 3, characterized in that the method comprises the steps of:
protecting and deprotecting amino acid, condensing amino-protected amino acid and arylamine into amide under the action of a condensing agent, and reacting the deprotected amino group of the obtained compound with carboxylic acid, acyl chloride, isocyanate and chloroformate to obtain a compound shown in a general formula I; the condensing agent is HATU, EDCI or DCC.
5. A method according to claim 3, characterized in that the method comprises the steps of: protecting and deprotecting amino acid, condensing amino protected amino acid and arylamine into amide under the action of condensing agent, and reacting the deprotected amino with carboxylic acid, acyl chloride, isocyanate and chloroformate to obtain the compound of general formula I.
6. A pharmaceutical composition comprising a compound of claim 1 or 2, wherein said formulation consists of the compound and a pharmaceutically acceptable carrier.
7. The formulation of claim 6, wherein the formulation is a tablet, capsule, granule, injection.
8. The formulation according to claim 6, wherein the pharmaceutically acceptable carrier is selected from the group consisting of fillers, disintegrants, binders, lubricants.
9. Use of a compound according to claim 1 or 2 or a formulation according to any one of claims 5 to 8 in the manufacture of a medicament for the treatment or prophylaxis of thrombosis.
10. The use according to claim 9, wherein the thrombosis is stroke or systemic embolism in patients with non-valvular atrial fibrillation, deep vein thrombosis and pulmonary embolism in patients after hip and knee replacement.
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